PHARMACEUTICAL
INDUSTRY

Hazardous Waste Generation,
Treatment, and Disposal

 

1 {my 1 " 1376

Q

 

This report has been reviewed by the U.S. Environmentai Protection Agency
and approved for publication. Approva] does not signify that the contents
necessariiy refiect the views and poiicies of the U.S. Environmenta]
Protection Agency, nor does mention of commercia] products constitute
endorsement by the U.S. Government.

An environmental protection pubiication (SW-508) in the soiid waste
management series.

PHARMACEUTICAL INDUSTRY
\‘\\

Hazardous Waste Generation, Treatment, and Disposa1

This final report (SW-508) describes work performed
for the Federal solid waste management program
under contract no. 68-01a2684
and is reproduced as received from the contractor

LU'S' ENVIRONMENTAL PROTECTION AGENC/YJ
1976

 

 

 

«(90 Warm

List of Tables

List of Figures

1.0

2.0

3.0

(w- -

TABLE OF CONTENTS

EXECUTIVE SUMMARY

1.1
1.2
1.3
1.4
1.5
1.6
1.7

INTRODUCTION

PURPOSE OF THE STUDY

STUDY APPROACH

CHARACTERIZATION OF THE PHARMACEUTICAL INDUSTRY
WASTE CHARACTERIZATION

TREATMENT AND DISPOSAL TECHNOLOGY

TREATMENT AND DISPOSAL COSTS

CHARACTERIZATION OF THE U.S. PHARMACEUTICAL INDUSTRY

2.1
2.2

2.3
2.4

2.5
2.6

2.7
2.8

CHARACTERIZATION OF THE INDUSTRY BY FUNCTION
BREAKDOWN OF THE PHARMACEUTICAL INDUSTRY BY

SIC CODES

DOMESTIC SALES OF THE U.S. PHARMACEUTICAL INDUSTRY
HISTORICAL GROWTH OF THE U.S. PHARMACEUTICAL
INDUSTRY

ROLE OF RESEARCH AND DEVELOPMENT IN GROWTH OF
THE U.S. PHARMACEUTICAL INDUSTRY

PHARMACEUTICAL CONSUMPTION — RECENT TRENDS
PHARMACEUTICAL INDUSTRY OUTLOOK FOR 1975-1980
NUMBER OF PHARMACEUTICAL PLANTS AND EMPLOYMENT
IN THE INDUSTRY

WASTE CHARACTERIZATION IN THE PHARMACEUTICAL INDUSTRY

3.1

SELECTION AND APPLICATION OF HAZARDOUS WASTE
CRITERIA

3.1.1 Background Information for the Selection of
Hazardous Wastes
3.1.2 Selection of Criteria for Classification of Potentially
Hazardous Substances from the Pharmaceutical Industry
3.1.3 Application of the Classification Scheme to Categorize
Wastes from the Pharmaceutical Industry as Priority
1 or Priority l| Potentially Hazardous Wastes

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11

11

12
13

16
19
22
23
25

31

31

31

32

36

3.0

4.0

TABLE OF CONTENTS (Continued)

WASTE CHARACTERIZATION IN THE PHARMACEUTICAL INDUSTRY
(Continued)

3.2

WASTE GENERATION DATA DEVELOPMENT

3.2.1 Approach to the Problem of Obtaining Valid Industry
Hazardous Waste Data

3.2.1.1 Wastes from Research and Development
Installations

3.2.1.2

3.2.1.3

3.2.1.4

Wastes from the Production of Active
Ingredients

3.2.1.2.1
3.2.1.2.2
3.2.1.2.3
3.2.1.2.4
3.2.1.2.5
3.2.1.2.6

Synthetic Organic Medicinal Chemicals
Inorganic Medicinal Chemicals
Fermentation Products (Antibiotics)
Botanicals

Medicinals from Animal Glands
Biologicals

Pharmaceutical Preparations

U.S. Pharmaceutical Industry Process Wastes and
Projections to 1977 and 1983

3.2.1.4.1

3.2.1.4.2

3.2.1.4.3

Annual Waste of Pharmaceutical
Industry

Typical Types of Pharmaceutical
Hazardous Wastes and Their
Properties

Projections of Pharmaceutical Process
Wastes to 1977 and 1983

DATA SOURCES FOR SECTION 3.1
DATA SOURCES FOR SECTION 3.2

TREATMENT AND DISPOSAL TECHNOLOGIES

4.1
4.2

BACKGROUND

DESCRIPTION OF PRESENT TREATMENT AND DISPOSAL

TECHNOLOGIES

iv

Page

38

38

42

43

44
48
49
53

60

63

66

66

74

74

80
85

87
87

87

TABLE OF CONTENTS (Continued)

Page
4.0 TREATMENT AND DISPOSAL TECHNOLOGIES (Continued)
4.2.1 Present Treatment/Disposal Technologies for General
Process Wastes (Hazardous and Non-hazardous) 87
4.2.2 Present Treatment/Disposal Technologies for Waste
Solvents 96
4.2.3 Present Treatment/ Disposal Technologies for Organic
Chemical Residues 101
4.2.4 Present Treatment/Disposal Technologies for Potentially
Hazardous High Inert Content Wastes (Such as Filter Cakes) 103
4.2.5 Present Treatment/ Disposal Technologies for Heavy
Metal Wastes 104
4.2.6 Present Treatment/ Disposal Technologies for Returned
Goods and Reject Material from Formulation 104
4.2.7 General Description of Treatment and Disposal Tech-
nologies 106
4.3 ANALYSIS OF ON-SITE/OFF-SITE DISPOSAL METHODS 114
4.4 SAFEGUARDS USED IN DISPOSAL 115
4.5 TREATMENT AND DISPOSAL TECHNOLOGY LEVELS AS
APPLIED TO LAND-DESTINED HAZARDOUS WASTE STREAMS
FROM THE PHARMACEUTICAL INDUSTRY 115
4.5.1 Treatment and Disposal Levels for Halogenated and
Non-Halogenated Waste Solvents 118
4.5.2 Treatment and Disposal Levels for Organic Chemical
Residues 120
4.5.3 Treatment and Disposal Levels for Potentially Hazardous
High Inert Content Wastes, Such as Filter Cakes 122
4.5.4 Treatment and Disposal Levels for Heavy Metal Wastes 126
4.5.5 Treatment and Disposal Levels for Returned Goods and
Reject Materials from Formulation 127
GENERAL BIBLIOGRAPHY—SECTION 4.0 130
5.0 COST ANALYSIS 133
5.1 BACKGROUND 133

5.2 SUMMARY OF COSTS FOR CONTROLLED TREATMENT

AND DISPOSAL OF LAND-DESTINED HAZARDOUS WASTES 133
5.3 RATIONALE AND REFERENCES USED IN COST ESTIMATING 133
5.4 COSTS FOR TREATMENT AND DISPOSAL OF HAZARDOUS

WASTES 138

TABLE OF CONTENTS (Continued)

5.0 COST ANALYSIS (Continued)
5.4.1 Research and Development
5.4.2 Production of Active Ingredients (SIC 2831 and 2833)
5.4.3 Formulation and Packaging (SIC 2834)

APPENDIX A — DESCRIPTION OF HAZARD GRADES

APPENDIX B — PROPERTIES OF HAZARDOUS CONSTITUENTS —
EXPLANATION OF SPECIAL TERMS

GLOSSARY OF TERMS

vi

Page

138
138
142

155

161

175

Table No.
1.5
1.6
1.7A
1.7B
2.3A
2.3B
2.30
2.5
2.6
2.8A

2.8B
3.1.2A
3.1.23
3.1.3A
3.1.3B
3.1.3C
3.2.1.2.1

3.2.1.2.3
3.2.1.2.4.1

3.2.1.2.4.2
3.2.1.2.5

3.2.1.4.1A
3.2.1.4.1B
3.2.1.4.1C

3.2.1.4.2

LIST OF TABLES

Estimates of Pharmaceutical Industry Generated Wastes for
1973, 1977 and 1983

Technology Levels for Disposal and Treatment of Pharmaceutical
Industry Process Wastes

Perspectives on the Pharmaceutical Industry: Hazardous Waste
Treatment and Disposal Costs

Perspectives on the Pharmaceutical Industry: Cost Impact of
Hazardous Waste Treatment and Disposal

Shipments of Ethical and Proprietary Products

Estimated Domestic Sales of Ethical Pharmaceutical Products
Facilities by Sales and Geographic Location

Ranking of Research Categories by Number of Compounds
Under Study

Number of Prescriptions Filled at Retail Pharmacies

Estimated Number of Pharmaceutical Plants (SIC 2831, 2833,
and 2834) Total Number of Plants and Those with More

Than 100 Employees

Number of Employees

Summary of Hazard Evaluation Criteria

Biological Functions and Toxicities of Selected Elements
Priority I Hazardous Wastes

Characterization of Typical Waste Solvents or Still Bottoms
Containing the Listed Chemicals

Typical Toxicities of Pharmaceutical Active Ingredients

as Measured by Oral LD500n Mice and Rats

Estimated Average of Chemical Wastes Generated in Organic
Medicinal Chemical Production

Typical Antibiotic Production Plant (Procaine Penicillin G)
Typical Plant for Producing Botanical Medicinals (Plant
Alkaloids)

Typical Plant for Producing Botanical Medicinals

(Stigmasterol for Hormone Synthesis)

Typical Plant for Producing Medicinals from Animal Glands
(Insulin)

Pharmaceutical Industry Waste Generation Estimate for 1973
Distribution of Pharmaceutical Industry Waste Generation (1973)
Estimated Distribution of Waste Generated by the Pharmaceutical
Industry in 1973

Summary of Typical Types of Pharmaceutical Hazardous Waste
Materials

vii

Page

10
13
15
17
22
24

26
27
34
35
37
37

39

50
55
56
60
68
70
73

75

Table No.
3.2.1.4.3A
3.2.1.4.3B
3.2.1.4.3C
4.2.2
4.2.3
4.2.4
4.2.5
4.2.6
4.2.7A
4.2.7B
4.3
4.4
4.5.1A
4.5.1B
4.5.2
4.5.3A
4.5.3B
4.5.4
4.5.5
5.2A
5.2B
5.2C
5.3A

5. 3B
5. 3C

LIST OF TABLES (Continued)

Estimates of Pharmaceutical Industry Generated Wastes for 1973,
1977 and 1983

Projected Distribution by State of Wastes Generated by the
Pharmaceutical Industry in 1977

Projected Distribution by State of Wastes Generated by the
Pharmaceutical Industry in 1983

Waste Solvent Disposal Methods

Organic Chemical Residue Disposal Methods

High Inert Content Wastes Disposal Methods

Heavy Metal Waste Disposal Methods

Disposal Methods for Returned Goods and Reject Material
Functions and Waste Types of Currently Used Hazardous
Waste Treatment and Disposal Processes

Waste Treatment Processes Used to Separate a Waste Destined
for Land Disposal

Analysis of On-Site/Off-Site Disposal Methods

Use of Safeguards in Disposal Operations

Treatment and Disposal Technology Levels for Non-Halogenated
Waste Solvents

Treatment and Disposal Technology Levels for Halogentated
Waste Solvents

Treatment and Disposal Technology Levels for Organic
Chemical Residues

Treatment and Disposal Technology Levels for Potentially
Hazardous High Inert Content Wastes

Treatment and Disposal Technology Levels for Potentially
Hazardous High Inert Content Wastes

Treatment and Disposal Technology Levels for Heavy Metal
Wastes

Treatment and Disposal Technology Levels for Potentially
Hazardous Returned Goods and Reject Material from Formulation
Perspective on the Pharmaceutical Industry: Treatment and
Disposal Costs Per Unit of Hazardous Waste

Perspective on the Pharmaceutical Industry: Hazardous
Waste Treatment and Disposal Costs

Perspectives on the Pharmaceutical Industry: Cost Impact

of Hazardous Waste Treatment and Disposal

Cost of Transporting Wastes

Contract Disposal Charges for Hazardous Wastes

Capital Investment for Industrial Solid Waste Incineration

viii

Page

76

78

79

98
101
103
104
105
107
108
116
117
119
121
123
124
125
128
129
134
135
136
137

137
140

Table No.

5.4.2.1A

5.4.2.13

5.4.2.1C

5.4.2.1D

5.4.2.3A

5.4.2.33

5.4.2.4A

5.4.2.43

5.4.2.4C

5.4.2.5

5.4.2.6

5.4.3

LIST OF TABLES (Continued)

Treatment and Disposal Costs: Active Ingredient Production;
Organic Medicinal Chemicals Waste Stream — Non-Halogenated
Waste Solvent

Treatment and Disposal Costs: Active Ingredient Production;
Organic Medicinal Chemicals Waste Stream — Halogenated Waste
Solvent

Treatment and Disposal Costs: Active Ingredient Production;
Organic Medicinal Chemicals Waste Stream: Potentially Hazardous
High Inert Content Wastes

Treatment and Disposal Costs: Active Ingredient Production;
Organic Medicinal Chemicals Waste Stream — Organic Chemical
Residues

Active Ingredient Production; Fermentation Products; Penicillin
Waste Stream — Waste Solvent Concentrate (50% Solids)
Treatment and Disposal Costs: Active Ingredient Production;
Fermentation Products; Penicillin Waste Stream - Waste
Solvent Concentrate (50% Solids)

Treatment and Disposal Costs: Active Ingredient Production;
Botanicals; Alkaloids Waste Stream — Aqueous Solvent with
Solids (30% Solvent, 20% Water, 50% Solids)

Treatment and Disposal Costs — Active Ingredient Production;
Botanicals; Alkaloids Waste Tream — Halogenated Waste
Solvent

Treatment and Disposal Costs: Active Ingredient Production;
Botanicals; Alkaloids Waste Stream — Non-Halogenated Waste
Solvent

Treatment and Disposal Costs: Active Ingredient Production;
Drugs from Animal Sources; Insulin Waste Stream - Aqueous
Alcohol with Organic Solids (25% Alcohol, 25% Solids, 50%
Water)

Treatment and Disposal Costs: Active Ingredient Production;
Biological Products; Plasma Protein Fractions

Waste Stream — Aqueous Solvent

Treatment and Disposal Costs: Formulation and Packaging
(Finished Pharmaceutical Preparations) Waste Stream —
Returned Goods and Reject Material

Page

143

144

145

146

147

148

149

150

151

152

153

154

 

Figure No.
2.3A

2.33

2.5

2.8A
2.88
2.8C
3.2.1.2.1
3.2.1.2.3

3.2.1.2.4.1
3.2.1.2.4.2
3.2.1.2.5

3.2.1.2.6
3.2.1.3A
3.2.1.3B
3.2.1.3C
4.2.1.5
5.3A
5.3B

5.3C

LIST OF FIGURES

Estimated Domestic Sales at Manufacturers' Level of Ethical
Products

Industry Concentration of Domestic Ethical Sales

Research and Development Expenditures for Ethical Products
Number of Plants

Number of Plants (> 100 Employees)

Pharmaceutical Employment Trends by SIC Codes

Typical Synthetic Organic Medicinal Chemical Process
Representative Process for Antibiotic Production (Procaine
Penicillin G)

Representative Process for Botanical Medicinals (Plant
Alkaloids)

Representative Process for Botanical Medicinals (Stigmasterol
for Hormone Synthesis)

Representative Process for Medicinals from Animal Glands
(Insulin)

Diagrammatic Representation of Method 6 Blood Fractionation
Pharmaceutical Tablet Production

Pharmaceutical Capsule Production

Pharmaceutical Ointment Production

Solid Waste Disposal Facilities in Puerto Rico

In-Plant Storage and Landfill Charges

General Industrial Solid Waste Incineration — Capacity Ranges
and Investment Costs

General Industrial Solid Waste Incineration Operating Costs

xi

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14
18
20
28
29.
30
45

51
54
57

59
62
64
65
67
95
1 39

139
139

 

1.0 EXECUTIVE SUMMARY
1.1 INTRODUCTION

This report is the result of a study commissioned by the US. Environmental Protection
Agency (EPA) to assess “Hazardous Waste Generation, Treatment and Disposal in the
Pharmaceutical Industry.” This industry study is one of a series sponsored by the Office of
Solid Waste Management Programs, Hazardous Waste Management Division. The studies
were conducted for information purposes only and not in response to a Congressional
regulatory mandate. As such, the studies serve to provide EPA with: (I) an initial data base
concerning current and projected types and quantities of industrial wastes and applicable
disposal methods and costs; (2) a data base for technical assistance activities; and (3) a
background for guidelines development work pursuant to Sec. 209, Solid Waste Disposal
Act, as amended.

The definition of “potentially hazardous waste” in this study was developed based
upon contractor investigations and professional judgment. This definition does net neces-
sarily reflect EPA thinking since such a definition, especially in a regulatory context, must
be broadly applicable to widely differing types of waste streams. Obviously, the presence of
a toxic substance should not be the major determinant of hazardousness if there were
mechanisms to represent or illustrate actual effects of wastes in specified environments.
Thus, the reader is cautioned that the data presented in this report constitute only the
contractor’s assessment of the hazardous waste management problem in this industry. EPA
reserves its judgments pending a specific legislative mandate.

1.2 PURPOSE OF THE STUDY
The study had four basic objectives:

1. to determine the nature and quantities of hazardous wastes originating from
the pharmaceutical industry (1973) and to project these wastes to 1977 and
1983;

2. to determine the current treatment and disposal practices within the indus-
try;

3. to examine improved control technologies which could be applied to reduce
hazards presented by the wastes; and

4. to calculate the cost of implementing three levels of control technology in a
typical hypothetical or existing plant. The three levels of technology are:
Level I — Technology currently applied by typical facilities;
Level II — Best technology currently employed; and

Level III - Technology necessary to provide adequate health and environ-
mental protection.

1.3 STUDY APPROACH
Our study consisted of four interrelated tasks:
1. Industry characterization (Section 2.0);
2. Waste characterization (Section 3.0);
3. Treatment and Disposal Technology (Section 4.0); and
4. Cost Analysis (Section 5.0).

Since no Federal law (except the Federal Insecticide, Fungicide and Rodenticide Act, Public
Law 92-516) has yet been passed requiring industry to obtain and report data on non-radio-
active hazardous wastes destined for land disposal, we had to obtain the voluntary coopera-
tion of companies that represented a significant portion of the pharmaceutical industry.
Fortunately, the Pharmaceutical Manufacturers Association (PMA) supported the planned
attempt to obtain useful information on which EPA’s Office of Solid Waste Management
Programs could base part of its future planning‘ and programs. The PMA Environmental
Control Committee lent us its support and assisted in obtaining the cooperation of several
major pharmaceutical producers.

Because the industry had never had to report detailed composition of waste streams,
we realized that mailing of questionnaires would not produce usable information. We there-
fore chose to conduct in-depth interviews and plant inspections at the plants of the cooper—
ating companies. We visited the principal production facilities of companies which repre-
sented an estimated 27 percent of the total US. sales of ethical pharmaceuticals and an even
higher percentage of active ingredient production of the industry. All 14 facilities we visited
had multiple plants and multiple operations, so that in all we surveyed more than 35 com-
ponent plants. Good representative information was obtained on research and development
(R&D), fermentation, biological products, organic synthesis, extraction of animal glands,
and formulation and'packaging operations in the United States, including Puerto Rico. We
checked the information we received in the interviews and by letter and confirmed it with
the companies. We then extrapolated the collected data to obtain information applicable to
the entire industry.

During the course of the study we also visited eight landfills and four contractors that
were treating wastes, principally by incineration. We also interviewed 11 contractors by tele-
phone to confirm information obtained frém plant visits.

1.4 CHARACTERIZATION OF THE PHARMACEUTICAL INDUSTRY

For this report we found it advantageous to characterize the industry by function as well
as by SIC codes. The main function of the pharmaceutical industry is to provide delivery of
active therapeutic substances in stable, useful dosage forms, such as tablets, injectables,
capsules, and the like. However, the overall pharmaceutical industry can be considered to have
four functional sections:

2

1. Research and Development (R&D) — The function of R&D is to discover new
drugs and to develop and improve formulations of these and older drugs.

2. Production of Active Ingredients — This stage involves the production of the
basic active drugs in bulk form.

3. Formulation and Packaging — Bulk drugs are formulated into dosage forms,
such as tablets, ointments, syrups, injectable solutions, and the like, that can be
taken or used by patients easily and in accurate amounts.

4. Marketing and Distribution — To get pharmaceuticals to doctors, hospitals,
pharmacies, and ultimately to the patient or consumer, pharmaceuticals are
promoted by pharmaceutical companies and distributed either directly or
through wholesalers. Pharmaceuticals promoted by advertising directly to the
consumer are called “proprietary pharmaceuticals” and those advertised to the
medical, dental and veterinary professions are called ‘ethical pharmaceuticals.”

The US. Department of Commerce has divided the pharmaceutical industry into three
SIC codes: 2831, 2833, and 2834. SIC 2834 (Pharmaceutical Preparations) is essentially the
same as the Formulation and Packaging function described above. SIC 2833 covers the major
portion of bulk active ingredient manufacture. SIC 2831 covers a group of products which
were formerly regulated by the Division of Biologics Standards in the National Institute of
Health and not by the Food and Drug Administration. Because the manufacturing and isola-
tion procedures are similar to those in SIC 2833 (Medicinals and Botanicals), the SIC 2831
(Biological Products) operations are combined with SIC 2833 for the purposes of this'study.

While the Department of Commerce indicated a 1972 total of 1058 plants in the United
States manufactured pharmaceutical products, only 416 of those plants had 20 or more
employees. These 416 plants were distributed as follows: SIC 2834 — 302 plants, SIC 2831 —
60 plants, and SIC 2833 — 54 plants. Employment in these three SIC categories in 1972*
totaled approximately 130,000. Estimated U.S. domestic sales of ethical pharmaceuticals in
1973* were approximately $5.5 billion and sales of proprietary pharmaceuticals were about
$1.9 billion.

1.5 WASTE CHARACTERIZATION

The largest tonnage of process wastes currently being landfilled comes from the produc-
tion of antibiotics by fermentation. In the fermentation industry the antibiotics are produced

* Employment figures are based on Census of Manufactures data which are published every five years (the last
being 1972), whereas sales figures have been estimated by ADL utilizing US. Department of Commerce data
for 1973 and other sources.

as by-products of the growth of microorganisms (molds and bacteria). During operations to
recover the antibiotics, the microorganisms are filtered off , usually with the addition of an
inorganic filter aid, such as diatomaceous earth. This discarded product is usually called
“mycelium.”

Because mycelium wastes consist only of cells of organisms, filter aid and residual
nutrients, the product is not considered hazardous. However, due to the large quantities pro-
duced by a typical fermentation plant and the tendency of the mycelium to emit odors on
decomposition, the waste can be a nuisance if not properly handled. The fermentation industry
likewise produces a high BOD effluent stream, similar to that produced in the brewing
industry, that must be treated in an activated sludge system. Neither the mycelium waste nor
the biological sludge from treatment of the effluent streams contains significant quantities of
hazardous materials.

Hazardous wastes are produced during the recovery of antibiotics in the form of waste
solvents and still bottoms. These solvents are usually nonhalogenated and are relatively non-
toxic, but they are hazardous due to their flammability.

The production of organic medicinal ingredients represent the major source of hazard-
ous wastes and a significant source of nonhazardous wastes. Of the roughly 90,700 metric
tons of organic medicinals (excluding antibiotics) produced in the United States in 1973,
only about 34,000 metric tons were produced by the pharmaceutical industry itself. The
remainder was produced by closely allied suppliers to the industry. Production of organic
medicinals resulted in wastes consisting of filter cakes, carbon, filter paper, sewage process
sludge, unrecoverable halogenated and nonhalogenated solvents, and still bottoms.

Wastes produced by the packaging and shipping sections of the industry are mostly glass,
paper, wood, rubber, aluminum, and the like, that are discarded. We estimate only a small
fraction of 1 percent of this material to be active pharmaceutical ingredient. We further
estimate that 75,000 metric tons of this rubbish is disposed of in regular municipal landfills,
along with cafeteria wastes, office wastes, and the like.

Goods returned to the pharmaceutical producer are received by the formulation and
packaging section of the industry. We estimate that the approximately 10,000 metric tons of
returned goods consist of approximately 85% glass, paper, water, and the like. Of the remaining
15% solids, the active ingredient may range from 100% down to approximately 1%. Because of
the low concentration of active ingredient in many products and the low toxicity of the active
ingredients, the resulting mix of materials disposed of on land is considered nonhazardous.
However, a small number of compounds, such as mercurials, controlled drugs, and the like, are
segregated and treated by environmentally acceptable methods.

The only hazardous waste of major concern produced in sufficient quantity from R&D
installations is waste solvents (1500 metric tons). Because of the generally flammable nature
and the wide variety of solvents in the mixed solvents disposed of, all of these materials are
considered hazardous. Many of the R&D personnel are scattered in small groups throughout
the industry, but some companies may employ from 200 to over 2000 researchers at a single
location. 4

We classified waste streams from the various industry segments as hazardous or
nonhazardous according to criteria explained in Section 3.1.2. Estimates of waste quantities
are summarized in Table 1.5. ‘

We expect quantities of both nonhazardous and hazardous wastes to increase in propor-
tion to production in the future with no significant effect of air and water guidelines for 1977
and 1983. We estimate production will increase only at a 3% compounded annual rate from
1973 to 1977 due to the present energy shortages and economic recession. We anticipate
economic recovery and the passage of national health insurance will take place in 1976. There-
fore, we expect production and concomitant wastes to increase at an annual compounded rate
of 7% from 1977 to 1983. Waste projections for 1977 and 1983 are also included in Table 1.5.

Approximately 244,000 metric tons of land-destined process wastes (on a dry basis)
were produced by the pharmaceutical industry in 1973. The amount of hazardous wastes is
about 25 percent of the total waste, or 61,000 metric tons in 1973. The total wastes are
expected to grow to nearly 400,000 metric tons per year and hazardous wastes to 100,000
metric tons per year by 1983.

1.6 TREATMENT AND DISPOSAL TECHNOLOGY

Approximately 85 percent of total wastes and 60 percent of hazardous wastes are esti-
mated to be treated and disposed of by contractors. Of the total wastes, ADL estimates that 60
percent, or 150,000 metric tons, are finally disposed of on land. About 9 percent, or 5,600
metric tons of the hazardous wastes, are finally disposed of on land. These percentages reflect
the extensive use of incineration, both on-site and by contractors off-site, by the pharma—
ceutical industry. Where possible, materials are recovered for reuse. Also secure chemical land-
fills and encapsulation are being used now — and will most probably be used in the future — for
the disposal of heavy metal wastes and the like, which are too dilute or contaminated for re-
covery, and general process wastes of a nonhazardous nature.

In the disposal of a major portion of hazardous wastes generated in the pharmaceutical
industry, Level I technology will be adequate for Level II and Level III also. This is true for
those wastes such as solvents and organic chemical residues that-are presently disposed of
by incineration. Some other pharmaceutical wastes that are presently landfilled, such as
returned goods and rejected product and high inert content wastes, such as filter cakes, may
require incineration to meet Level II and III criteria.

The heavy metal wastes or high inert content wastes, such as filter cakes, that contain
heavy metals and are presently landfilled, may require further treatment to meet Level II and
Level III criteria.

Table 1.6 presents a summary of the treatment and disposal technology levels for pharma-
ceutical industry process wastes determined to be hazardous.

1.7 TREATMENT AND DISPOSAL COSTS
We have calculated costs for “end-of-pipe” treatment and disposal of each hazardous

pharmaceutical waste. These costs do not include charges for in-process changes made to
5

TABLE 1.5

ESTIMATES OF PHARMACEUTICAL INDUSTRY GENERATED WASTES FOR 1973, 1977 AND 1983*
(All Figures in Metric Tons Per Year)

 

 

 

 

 

1973 1977 1983
Non-Hazardous Hazardous NonHazardous Hazardous Non-Hazardous Hazardous
mam” 5.9...." Dry Basis w“ 3355’ Dry Basia Wat Basist Dry Basis Wat Buis' Dry Basis We! easis' Dry Basis Wet Buis' Dry Buis Wet Basisf
RaiD
Solvent — - 1,500 1,500 -— — 1,900 1,900 — — 2,700 2,700

 

 

Total R&D - - 1,500 1,500 — — 1,900 1,900 —- — 2,700 2,700

SIC Code 2833: Production of Active Ingredients
Organic Medicinal Chalniuls (34,000 Metric Tons/Yr)

 

 

Biological Sludge (from wastewater treatment) 47.500 476.000 — - 53,500 536,000 — — 80.400 304,000 - —

High Inert Content (filter aid, carbon) 3.400 6,800 - — 3,800 7,6m — - 5,700 1 1.400 - —
Contaminated High Inert Content (i.e., filter aid and solvent) — — 1.700 3.400 — — 1.900 3,800 — — 2,900 5,800
0‘ Organic Chemical Residues (tars, mud, still bottoms) — - 13,600 13,600 — — 15.300 15,300 -— — 23,000 23,000
Halogenated Solvent — — 3,400 3,400 - —- 3,800 3,81!) — — 5,700 5,700
Non-Halogenated Solvent — — 23,800 23,800 - — 26,800 26,800 —— — 40.000 40,000

Heavy Metal Wastes

Zinc Compounds —- — 2,200 2,200 — — 2,500 2,500 - — 3,700 3,700
Arsenic Compounds — - 450 450 — — 500 500 — — 750 750
Chromium Compounds — - 20 2O - - 22 22 -— — 35 35
Copper Compounds — — 4 4 — — 4 4 — —— 6 6
Mercury Compounds — — 1 1 — -— 1 1 — — 1 1
Total for Organic Medicinal Chemicais 51,000 482,800 45,175 46,875 57,400 543,600 50,827 52,727 86,100 - 815,400 76,092 78,992
Rounded to: 51,000 480,000 45,000 47,000 57,000 540,000 51,000 53,000 86,000 815,000 76,000 79,000

Inorganic Medicinal
Heavy Metals (i.e., selenium waste) - - 200 200 - — 225 225 — — 350 350

Antibiotics (by Fermentation, 10,01” Metric Tons/Yr)

 

 

 

 

 

Mycelium (plus filter aid and sawdust) 75.000 300.000 — — 84,400 338,000 — — 127.000 508.000 — —
Biological Sludge 35,000 350,000 — — 39,400 394,000 — — 60,000 600,000 — -
Waste Solvent Concentrate — — 12.000 12.000 - - 13.500 13.500 — — 20.000 20.000
Total for Antibiotics 110,000 650,000 12,000 1 2,000 123,800 732,000 13,500 13,500 187,000 1,108,000 20,000 20,000
Rounded to: 110,000 650,000 12,000 12,000 124,000 730,000 14,000 14,000 190,000 1,100,000 20,000 20,000
Botanicals (Plant Alkaloids, 2,000 Metric Tons/Yr Plant Material)
Wet Plant Material 2.000 4.000 - — 2.250 4.500 -— — 3,400 6,800 — -—
Aqueous Solvent Concentrate - — 720 850 — — 810 960 - — 1,200 1,400
Halogenated Solvent 5- — 60 60 — —- 70 70 — — 100 100
Non—Halogenated Solvent - — 120 120 — — 140 140 - — 200 200
Total for Plant Alkaloids 2.000 4,011) 900 1,030 2,250 4,500 1,020 1,170 3,400 6,800 1,400 1,700

Botanical: (Plant Steroids, 150 Metric Tons/Yr Stigmaterol)
Fused Plant Steroid Ingots 750 750 — - 840 840 — — 1,000 1,000 - ~

TABLE 1.5 (Continued)

 

 

 

 

 

 

 

 

 

 

 

1973 1977 1983
Non—Hazardous Hazardous Non-Hazardous Hazardous Non-Houdini: Hazardous
lndunry Segment Dry Basis Wet auas' Dry Basis Wet Bais' Dry m w« Basis' Dry Basis w" anis‘ Dry Basis Wet Basis' Dry am Wet auis'
Medicinals from Animal Glands (8,01!) Metric Tons Glands/Yr)
Extracted Animal Tissue 7,500 7,500 - — 8,400 8,40) — — 12,500 12,500 - -
Fats or Oils 350 350 — — 400 400 — — 600 600 - -
Filter Cake (Containing protein) 250 500 - — 280 560 — — 420 840 — —
Aqueous Solvent Concentrate — — 800 1,600 — — 900 1,800 — — 1.350 2.700
Total Medicinals from Animal Glands 8,100 8,350 800 1.600 9,0w 9,360 900 1,800 13,520 13,940 1,350 2,7“)
Total for Production of Active Ingredients (SIC Code 2833) 172,000 1,143,000 59,000 62,000 193,000 1,285,000 67,000 70,011) 294,000 1,937,000 99,000 103,000
SIC Code 2831: Biological Products
Aqueous Ethanol Waste from Blood Fractionation — — 250 600 - - 280 680 — — 400 1.000
Antiviral Vaccine — — 300 300 — — 350 350 — — 500 500
Other Biologicals — — 200 200 — — 225 225 - — 350 350
Total lor Biological Products - — 750 1,100 —- — 855 1,255 — — 1.250 1.850
SIC Code 2334: Phrmaoeutiul Preparations
Returned Goods 10.0“) 10,000 — - 11,300 11,300 — — 17,000 17,0“) - —
Contaminated or Deoomposed Active Ingredient — — 500 5!!) — — 600 600 -— — 900 900
10,000 10,000 500 500 1 1,300 1 1,3“) 603 600 17,1130 17,000 900 900
Totals for All Industry Segments 181,850 1,153,011) 61,650 65,100 204,300 1,836.31” 70,445 73,755 311,0“) 1,954,000 103,850 1w,450
Rounded to: 182,000 1 ,153,000 62,000 65,011) 204,000 1 336,0“) 70,000 74,000 310.0“) 1,954,000 104,000 1w.000

”Source: Arthur D. Little, Incl. estimates.

tWet weight estimates are given for all wastes. The two wastes that typically have the highest moisture content are biological sludge and
myoelium from fermentations. Where the wet waste estimates are the some as on the dry basis, the waste is usually disposed of with only
a minor amount of moisture. However, disposal practices vary from plant to plant, depending on the form in which the waste is produced.

TABLE 1.6

TECHNOLOGY LEVELS FOR DISPOSAL AND TREATMENT OF PHARMACEUTICAL INDUSTRY PROCESS WASTES‘r

Industry Segment

0 R&D
Solvent
Animals
Heavy metals

0 Active Ingredient Production
-— Organic Medicinal Chemicals
Non-halogenated waste solvent
Halogenated waste solvent
High inert content wastes
— containing flammables only
— containing heavy metals or corrosives
Heavy metal wastes
Organic chemical residues
— Inorganic Medicinal Chemicals
Heavy metal wastes
Fermentation Products
Waste solvent concentrate
Botanicals
Aqueous solvent
Halogenated waste solvent
Non-halogenated waste solvent
— Drugs from Animal Sources
Aqueous alcohol
—— Biologicals
Aqueous alcohol
Antiviral vaccines
Other biologicals (toxoids, serum)
0 Pharmaceutiml Preparations
Returned goods and reject material

Level I

Treatment and Disposal Technology

Level II

Level III

 

Incineration
Incineration

l

 

Recovery

 

Incineration
Incineration

Landfill or incineration

 

Incineration

*

 

 

 

 

 

 

 

 

 

 

 

 

Landfill Secure chemical landfill 7
Secure chemical landfill” Level I and recovery Recovery and engineered storage
Incineration '7
Chemical |andfi|l*** Secure chemical landfill*** r
Incineration » :
Incineration 7
Incineration r
Incineration *
Incineration 4
Incineration *
Incineration fl.
Incineration ’
Landfill Incineration ;

*Neutralize waste or precipitate heavy metal prior to placing in landfill.
MConvert heavy metal to most insoluble form and place in drum prior to placing in landfill.
*“Waste is dilute; therefore, Level II technology will involve a more secure landfill rather than a recovery operation.

tSource: Arthur D. Little, Inc.

minimize or to change the hazardous nature of the wastes. More detailed analyses are given
in Section 5.0. Table 1.7A and 1.7B summarize generalized costs of treatment and disposal
systems either currently in use or recommended for future use in pharmaceutical production
facilities. Because typical plants were used to develop an estimate of the total industry cost
of treatment and disposal of hazardous wastes, the total industry costs should be taken only
as an indication of the order of magnitude of such costs rather than as the outcome of a
detailed industry survey of the costs. Issues such as site specific costs, different products or
product mixes, local disposal rates, and available disposal methods were not included in this
estimate.

TABLE 1.7A

PERSPECTIVES ON THE PHARMACEUTICAL INDUSTRY:
HAZARDOUS WASTE TREATMENT AND DISPOSAL COSTST

Total Annual Costs, $000“

 

1973 1977 1983
Product Category
0 Bulk Active Ingredient
Organic Medicinal Chemicals 3,800 4,295 6,140
Inorganic Medicinal Chemicals* — — ——
Fermentation Products 1,440 1,620 2,300
Botanicals 165 180 260
Drugs from Animal Sources 115 130 180
Biologicals 50 60 85
0 Pharmaceutical Preparations 15 40 50
Partial Tota|+ 5585 6325 9015

*One hazardous waste cost is included in organic medicinal chemicals.
”December 1973 dollars.
+Excludes R&D costs.

1Source: Arthur D. Little, Inc.

TABLE 1.7B

PERSPECTIVES ON THE PHARMACEUTICAL INDUSTRY:

COST IMPACT OF HAZARDOUS WASTE TREATMENT AND DISPOSAL?

Estimated Hazardous Waste
Control Cost as Percent of Price“

 

 

Price
Product Category Level Level I Level II Level III
$/k9
0 Bulk Active Ingredient
Organic Medicinal Chemicals 22 0.2% 0.22% as Level II
Inorganic Medicinal Chemicals “V — — — -—‘
Fermentation Products 44 0.34% as Level I as Level I
Botanicals ***
Drugs from Animal Sources *** < 0.1 as Level I as Level |
Biologicals ' ***

* Manufacturers selling price in the case of pharmaceutical preparations; value of sales,
that is, the net selling value FOB plant or warehouse, or delivered value, whichever

represents the normal practice for bulk activity ingredient.

** Representative data not available because most inorganic medicinal ingredients that

might produce a hazardous waste are purchased from the chemical industry.

*** Data not available; the selling price of many of these products is stated in terms of

biological activity.

TSource: Arthur D. Little, Inc.

10

2.0 CHARACTERIZATION OF THE US. PHARMACEUTICAL INDUSTRY
2.1 CHARACTERIZATION OF THE INDUSTRY BY FUNCTION

The pharmaceutical industry can be described or characterized in several ways, depend-
ing on the needs of the particular study. For purposes of this report, we found it
advantageous to break down the industry-along functional lines in addition to classifying it
by SIC codes.

The main function of the pharmaceutical industry is to provide delivery of active
therapeutic substances in stable, useful dosage forms. Thus it may be distinguished from the
chemical industry, the function of which is to synthesize various chemicals which may be
useful in a variety of applications. It is true that the pharmaceutical industry may integrate
vertically and become involved in the synthesis of active ingredients, but its major function
is to prepare the tablets, injectables, ointments, capsules, and the like, to provide what is
needed, where it is needed, and when it is needed.

The production and sale of pharmaceuticals may be outlined in a four-step series:

1'. Research and Development: New drugs are discovered and developed by
research laboratories (principally those of the pharmaceutical industry itself,
but also those of government and educational institutions). After clinical
trials and government approval, the drugs are ready for general production
and sale.

2. Production of Active Ingredients: At this stage, the basic active drugs used in
medicine are produced in bulk. These drugs can be categorized according to
their principal ingredients as follows:

3. organic medicinal chemicals (such as aspirin), inorganic medicinal chem-
icals (such as magnesium sulfate), fermentation products (such as peni-
cillin and tetracycline), botanicals (such as quinine), and drugs from
animal sources (such as insulin); and

b. biological products, including vaccines (such as smallpox vaccine),
toxoids (such as tetanus toxoid), serums (such as tetanus antitoxin),
and products from human blood (such as plasma).

3. Formulation and Packaging: The basic drugs, which are manufactured in
bulk, are formulated into various dosage forms such as tablets, ointments,
syrups, lotions, injectable solutions, and the like, that can be taken by
patients easily and in accurate amounts. The formulated products are pack-
aged in appropriate containers.

11

4. Pharmaceutical Marketing and Distribution: To get the pharmaceuticals to
doctors, hospitals, pharmacies, and ultimately to the patient or consumer,
they are promoted by the pharmaceutical Companies and distributed either
directly by the companies or through wholesalers. Pharmaceuticals promoted
by advertising directly to the consumer are called “proprietary pharmaceu-
ticals” and those advertised to the medical, dental, and veterinary profes-
sions are called “ethical pharmaceuticals.”

The larger, established pharmaceutical companies engage in all four functions - re-
search, production, formulation, and marketing — although these may be carried out by
separate divisions, often located many miles apart. Other companies, however, specialize in
only one phase, such as producing medicinal chemicals in bulk or in formulating pharmaceu-
tical products from purchased raw materials.

2.2 BREAKDOWN OF THE PHARMACEUTICAL INDUSTRY BY SIC CODES

The drug industry as defined by the U.S. Department of Commerce actually consists of
three industries, consisting of producers of biological products, medicinal chemicals and
botanical products, and pharmaceutical preparations. Under the 1972 SIC system, the three
industry codes are assigned as follows:

0 SIC 2831—Biological Products: Establishments primarily engaged in the
production of bacterial and virus vaccines, toxoids and analogous prod-
ucts (such as allergenic extracts), serums, plasmas, and other blood
derivatives for human and veterinary use.

0 SIC 2833—Medicz'nals and Botanicals: Establishments primarily engaged in
(1) manufacturing bulk organic and inorganic medicinal chemicals and
their derivatives; and (2) processing (grading, grinding, and milling) bulk
botanical drugs and herbs. Also included in the industry are establish-
ments primarily engaged in manufacturing agar-agar and similar prod-
ucts of natural origin, endocrine products, manufacturing or isolating
basic vitamins, and isolating active medicinal principals, such as alka-
loids, from botanical drugs and herbs.

0 SIC 2834—Pharmaceutical Preparations: Establishments primarily engaged in
manufacturing, fabricating, or processing drugs in pharmaceutical prep-
arations for human and veterinary use. Most of the products of these
establishments are finished in the form intended for final consumption,
such as ampuls, tablets, capsules, vials, ointments, medicinal powders,
solutions, and suspensions. Products of this industry consist of two
important lines, namely (1) pharmaceutical preparations promoted pri-
marily to the dental, medical, or veterinary professions; and (2) phar-
maceutical preparations promoted primarily to the public.

12

While there is no SIC code for Research and Development, the other SIC codes —
2831, 2833, and 2834 — can be fitted into the functional classification of the industry.

SIC 2834 (Pharmaceutical Preparations) is essentially the same as the Formulation and
Packaging function described in Section 2.1.

SIC 2831 (Biological Products) has many manufacturing and isolation procedures
similar to those in SIC 2833 (Medicinals and Botanicals). Therefore, for purposes of this
study, "we combined plant operations of both SIC 2831 and 2833 under Production of
Active Ingredients.

2.3 DOMESTIC SALES OF THE US. PHARMACEUTICAL INDUSTRY

Total dollar volume of shipments for ethical products and proprietary products by the
three sectors, according to Census Bureau figures, rose nearly 8% per year between 1954 and
1972, increasing from $2.05 to $7.54 billion, as shown in Table 2.3A.

TABLE 2.3A

SHIPMENTS OF ETHICAL AND PROPRIETARY PRODUCTS-r

 

 

 

($ Millions)
1954 1958 1963 1967 1972
Biological Products (SIC 2831) 66.6 63.8 167.3 220.6 481.1
Medicinals and Botanicals (SIC 2833) 281.0 322.3 434.0 593.8 782.6
Pharmaceutical Preparations (SIC 2834) 1,700.5 2,591.8 3,000.2 4,139.7 6,276.0
Total 2,048.1 2,977.9 3,601.5 4,954.1 7,539.7

fSource: US. Department of Commerce

During the comparable period, U.S. domestic sales for ethical products grew at a 9%
annual rate to $5.45 billion in 1973 from $1.00 billion in 1953, as shown in Figure 2.3A.
Proprietary pharmaceutical sales are estimated at $1.9 billion for 1973 compared to
approximately $0.4 billion in 1953. Prior to World War II, proprietaries outsold ethicals but
the tremendous increase in new active ingredients has led to a remarkably accelerated
growth of pharmaceuticals under prescription and other pharmaceuticals only promoted as
ethicals. We expect ethical pharmaceuticals to continue to be the dominant factor in the
expanded markets of the future.

Table 2.3B shows the estimated domestic sales of ethical pharmaceutical products and
their growth rates by major therapeutic classes for selected years during the past decade.
Within these major categories, the growth rates have varied substantially — from a slight
decline in sulfonamides to a 19% growth for anti-arthritics. The most important factors
stimulating demand during the period were:

13

Sales ($ Millions)

 

6, 000

5,000

4,000

3,000

2, 000

1,000

 

 

JJIIIIIIJIIIIIIIIIIJ

 

 

1955 1960 1965 1970
Year

1’Source: Arthur D. Little, Inc., estimates.

FIGURE 2.3A ESTIMATED DOMESTIC SALES AT MANUFACTURERS'
LEVEL OF ETHICAL PRODUCTS?

14

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15

0 The introduction of several important new drugs (e.g., Indocin [anti-
arthritic], Lasix [diuretic], oral' contraceptives, Valium and Librium
[ataraxics] );

O Routine consumption of more drug products to control chronic illnesses and
geriatric deterioration;

0 New medical techniques and other health care products; and
0 Continued growth in private and public health insurance.

At the present time, more than 1000 companies are considered as pharmaceutical
firms because they sell drug products. Many are relatively small with annual sales less than
$1 million and they frequently service a limited geographic area. Many do not manufacture
their own products, but sell products to various drug outlets on a contract basis. They
represent a small part of total drug sales. The distribution of pharmaceutical facilities by
sales volume and geographical location is shown in Table 2.3C. Although sales data are not
available for some firms (those in columns headed “G”), these firms usually are small and
the numbers of facilities listed in columns headed “F” can be taken as indicative of the
numbers of facilities with more than $10 million worth of annual sales. An inspection of the
table indicates that only approximately 5 percent of the facilities in SIC codes 2831 and
2833 have sales greater than $10 million per year and only about 10 percent of the facilities
in SIC code 2834 are of that size.

The Pharmaceutical Manufacturers Association (PMA) estimates that perhaps 600 to
700 U.S. firms actually produce ethical products. Many of these firms are quite small. In
fact, the l 10 members of the Pharmaceutical Manufacturers Association account for 95% of
industry sales of ethical pharmaceuticals in this country. As shown in Figure 2.3B, this
figure can be broken down with the top 15 companies accounting for greater than 50% of
ethical sales and the top 40 companies accounting for 80% of domestic ethical sales.
Moreover, since many drug companies function as a division of a larger corporation, the top
40 companies actually represent 33 corporations.

The evolving environment for pharmaceuticals suggests further concentration, with
balanced resources in manufacturing, marketing, and research/development essential for
successful participation in the expected growth. The industry leaders today possess the
balanced resources necessary for success in the future. Because the barriers are substantial,
probably few new pharmaceutical firms will be established.

2.4 HISTORICAL GROWTH OF THE U.S. PHARMACEUTICAL INDUSTRY
Historically, drug companies started as drugstores established to provide drugs to the

public, but gradually they became more involved in preparing formulations for local
physicians. The druggist ran a one-man show and acted as purchasing agent, production

16

TABLE 2.3C
FACILITIES BY SALES AND GEOGRAPHIC LOCATIONT

SIC 2831 SIC 2833 SIC 2834
Biggggt Medicinal: Ed Botanigs Phat aoeuti lPra ration State Total
A££££i£A1£2£Lfiiiifiiifiiliiiii
IV Alabama 2 3 5 2 2 7 2 5
X Alaska
IX Arizona I 2 2 1 1 I 1 1 4 1 4 1 1 1 6
VI Arkamas 1 1 2 1 3 3 1 4
IX Calitornia 3 5 1 4 1 I 12 9 11 7 4 2 1 24 18 23 17 18 2 8 57 30 39 25 26 5 10 9
VIII Colorado 1 1 1 4 1 1 1 1 3 1 6 1 2 5 2 11
I Connecticut 1 1 4 1 3 1 2 4 5 6 4 2 5 7 10 1 7 1 4
III Delaware 2 1 2 2 3 2 2 6
I II District of Columbia I 2 1
IV Florida 3 1 1 3 3 3 1 1 11 12 9 1 6 14 18 2 9 1 1 10
IV Georgia 1 4 3 2 1 1 4 7 5 1 3 1 7 8 9 5 4 1 13
IX Hawaii
X Idaho
V Illinois 2 2 1 10 4 7 4 1 26 15 20 8 17 2 7 34 21 29 8 21 4 7 70
V Indiana 4 1 1 5 5 4 1 4 3 9 6 5 1 4 3 18
VII Iowa 1 1 1 1 1 1 3 2 1 3 7 4 2 2 4 1 9
VII Kansas 1 3 1 5 1 1 1 4 4 3 4 5 9
IV Kentucky 1 1 3 l 1 3 1 4 1 3
VI Louisiana 1 1 2 1 3 2 1 4 2 3 2 7
I Maine 1 2 1 1 2 1 2
III Maryland 1 2 I 2 3 1 1 1 1 3 6 2 2 1 1 3 5 9 3 3 3 1 7
| Massachusetts 1 1 1 1 1 1 1 14 8 3 2 1 2 8 16 9 3 4 1 2 10
V Michigan 1 1 2 2 4 1 1 4 11 6 3 3 3 4 10 13 11 3 4 3 6 16
V Minnesota 1 1 1 2 1 5 6 1 2 1 5 6 9 1 3 1 6
IV Mississippi 1 1 2 2 3 7 2 6 8
VII Missouri 1 2 2 1 2 2 11 9 10 4 5 3 24 11 11 6 5 6 37
VIII Montana 1 1
VII Nebraska 1 1 2 1 1 1 1 2 1 2 6 2 3 1 5 I 7
IX Nevada 1 1
I New Hampshire 1 1 2
II New Jersey 3 2 2 1 1 2 9 4 2 1 2 22 7 13 8 25 8 15 68 9 25 I4 29 10 17 91
VI New Mexico
II New York 1 5 1 5 6 4 7 6 5 2 1 23 37 42 12 29 3 16 71 42 54 19 39 5 17 100
IV North Carolina 1 I 1 2 3 4 4 1 2 1 10 4 7 1 2 1 1 14
VIII North Dakota
V Ohio 1 1 4 1 3 13 5 3 1 I 2 14 18 6 3 2 1 2 17
VI Oklahoma 1 1 3 1 1 2 ‘I 2 2 5 1 4
X Oregon 1 1 3 1 1 2 2 1 2 1 3 3 4 3
III Pennsylvania 1 1 3 4 1 6 11 14 14 6 10 5 7 24 16 21 9 10 5 7 39
ll Puerto Rico
I Rhode Island 1 3 2 I 1 1 2 I I I 4
IV South Carolina 1 3 1 1 4 I 2 7
VIII South Dakota 1 I 1 1 1 1
IV Tennessee 1 3 1 2 1 3 2 15 2 1 3 1 2 19
VI Texas 5 4 2 8 5 7 1 1 6 11 10 5 7 1 1 20 21 21 6 9 1 2 34
VIII Utah 2 1 2 1 1 4 I 2
I Vermont 2 2
III Virginia 1 1 2 6 4 1 3 6 6 5 2 3 8
X Washington 1 1 2 5 3 1 3 6 3 1 1 5
III West Virginia 2 2
V Wisconsin 2 4 3 4 2 1 3 4 2 I 4 8 7 8 1 6 1 15
VIII Wyoming
National Totals 25 46 14 24 9 5 91 52 80 26 27 8 11 171 231 232 88 170 32 80 469 308 358 128 221 49 96 731
Region Totals
I 2 0 0 1 1 0 2 3 7 1 4 1 3 9 20 18 4 7 1 4 14 26 25 5 12 3 7 25
II 1 8 3 7 1 0 7 6 16 10 7 3 3 45 44 55 20 54 11 31 139 51 79 33 68 15 34 191
III 2 4 3 I 2 0 9 2 7 2 0 0 0 15 25 24 9 15 6 13 38 29 35 14 16 8 13 62
IV 3 II 4 0 2 1 13 3 7 2 1 0 0 12 33 31 3 17 3 3 54 39 49 9 18 5 4 79
V 3 6 0 2 1 1 20 15 19 0 7 2 1 42 53 43 17 31 7 16 80 71 68 17 40 10 18 142
VI 6 4 0 2 0 0 11 7 10 1 0 0 1 9 15 15 5 11 2 1 29 28 29 6 13 2 2 49
VII 2 4 1 4 1 2 9 4 2 2 1 0 2 12 14 14 6 14 0 3 41 20 20 9 19 1 7 62
VIII 1 1 1 2 O O 4 3 0 1 0 0 0 2 3 3 3 1 0 0 7 7 4 5 3 0 13
IX 4 7 1 4 1 1 14 9 12 7 4 2 1 24 18 24 18 19 2 9 62 31 43 26 27 5 11 100
X 1 1 1 1 0 0 2 0 0 0 3 0 0 1 6 5 3 1 0 0 5 7 6 4 5 0 0 8
(31.000) ($1,000,000)
Key: A S O — S 99.9 D $ 1 — 34.9
6 $100 — $499.9 E S 5 — 39.9
C 3500 - $999.9 F 810 :— over
G Not Available

1Source: Arthur D. Little, Inc., estimates based on data from Dun 8i Bradstreet.

l7

Number of Firms/ Cumulative Percent of

 

Percent Sales Domestic Ethical Sales
$399,399?“ 100%

1090 Firms— 5%
<<<<<<<<<<<<<<<<’<<<<<
<<<<<<<<<<<<<<<<<<<<<
<<<<<<<70Firms—15%<<<<<<
<<<<<<<<\\\\\\\<<<<<<
<<<<<<<<<<<<<<<<<<<<<
<<<<<<<<<<<<<<<<<<<<<

\\ V

25 Firms —— 28%

 

95%

 

 

52%

.15f'rrna 13.2%

 

 

 

 

tSource: Arthur D. Little, lnc., estimates.

FIGURE 2.33 INDUSTRY CONCENTRATION OF DOMESTIC ETHICAL SALES?

18

superintendent, salesman, and treasurer. Traditionally, the drug operation was a family
business, with the children taking an active role in the growing company. Because of this
structure of strong family ties, most drug manufacturers were quite secretive about their
businesses, and a strong relationship developed between the various companies. Several of
the families developed significant businesses and began to employ professional managers to
run their businesses profitably.

The drug industry was relatively small prior to World War 11. Two distinct categories of
drugs were available in 1939 — proprietary and ethical products, with proprietary outselling
ethicals. Proprietaries were sold directly to the consumer, while ethicals were specified or
prescribed by doctors. Most products were designated by a house label; for example, Lilly
aspirin or Parke-Davis throat discs, and not by brand or trade names. The company name
was an important part of the product description. Most products were relatively unsophisti-
cated compared to those of today. Most of today’s drugs were unknown, with rather simple
preparations used to treat conditions now treated with a variety of complex, highly selective
agents.

The principal activities of the larger drug companies did not vary considerably from
those of the one—man shop, with the essential duties being sales and manufacturing. The size
of the operation increased as the firms began selling nationally, and, quality control
laboratories were installed primarily to ensure standardized production and a high-quality
image “house name” for the physician. The drug industry, as we now know it, came into
existence after World War II.

2.5 ROLE OF RESEARCH AND DEVELOPMENT IN GROWTH OF THE
U.S. PHARMACEUTICAL INDUSTRY

Much of the growth in ethical sales has resulted from new classes of compounds. The
ethical pharmaceutical field is characterized by a heavy commitment to the research and
development of significant new agents. Before 1950, traditional products like vitamins,
barbiturates, and laxatives accounted for most of the industry’s grthh. After 1950, the
heavy research investment begun during the war and continuing afterwards resulted in the
new product explosion of antibiotics, steroids, and tranquilizers. The industry’s emphasis on
development of new products since then has produced an impressive array of effective
products.

Figure 2.5 shows that the research and development (R&D) budget for the ethical drug
industry has grown from $50 million in 1951 to $850 million in 1974. Traditionally, the
ethical drug industry spends about 9-10% of its worldwide sales dollars on research effort —
a higher percentage than in most other industries. Moreover, the R&D budget for specific
companies may be substantially higher. For example, Lilly had worldwide pharmaceutical
sales of $633.6 million in 1974, while its R&D spending was $93.3 million — nearly 15% of
sales. Industry sources indicate the following partial analysis of expenditures:

19

Research and Development Expenditures ($ Millions)

900

 

800

700

600

500

400

300

200

 

 

 

 

100
0 I I I I I l I I I I I I I I I I I I I I I I
1951 1955 1960 1965 1970 1974

TSource: Pharmaceutical Manufacturers Association.

FIGURE 2.5 RESEARCH AND DEVELOPMENT EXPENDITURES FOR ETHICAL‘PRODUCTS“?

*Government contract funds are not included nor is R&D funding for veterinary ethical
products.

20

Modifying and/or improving existing products 29%

Biological screening and testing 18
Clinical testing 1 7
Synthesis and extraction 16
Process development, manufacturing work-up,
and quality control 10
Toxicology and safety evaluation __9_
99%

In general, we believe that about one-sixth of the current industry-wide R&D budget is
devoted to basic research and close to one-third to help existing products meet the FDA’s
more stringent requirements on bioavailability, efficacy, safety, and so forth. Thus, slightly
more than one-half of the stated budget is devoted to new products.

In the past 30 years, almost 900 new active medicinal ingredients have been introduced
to the US. market, two-thirds originating in the United States. (These active medicinal
ingredients are unique compounds in terms of molecular structure. However, they may be
used as an active ingredient in varying concentrations or in conjunction with other active
ingredients in a number of different pharmaceutical products.) For the past decade, the
number of new entities introduced annually into the US. market has tended to decline. In
part, this decrease may be due to a trend in research to seek major breakthroughs for
treatment of the more intractable diseases. However, the increased time needed for testing
and meeting the FDA’s regulatory requirements is an important factor. We estimate that the
time factor can run five to eight years and cost from $9 to $18 million. Only the leading
pharmaceutical companies have the money and research capacity needed to meet these
demands.

Table 2.5 ranks published research activities on compounds by therapeutic categories
to determine which research areas are currently of greatest interest. As future commercial
production will depend in part on the areas now being researched, these data should give
some indication of the future importance of various therapeutic classes. The 19 categories
listed represent nearly 75% of all the compounds currently being investigated. The types of
compounds under study suggest that there will be no drastic shift in the general types of
active medicinal ingredients in the next 10 years, nor in the general processes (such as
organic syntheses and fermentations) required to produce them.

R&D will be valued even more highly in the future, but it will also be more difficult to
develop significant new agents. Much of the work which could lead quickly to drug
discoveries has already been completed, and now investigators are concentrating on more
difficult subjects, such as developing a basic understanding of heart disease, cancer, con-
genital disease, and stroke —— all difficult areas in which to achieve quick developments.
However, new breakthroughs in pharmacology will be forthcoming, involving not only new
classes of therapeutic drugs but also advances brought about by molecular biology, that is,
supplying missing or substitute chemicals in minute doses or in elaborate delivery systems in
order to correct aberrant metabolism.

21

TABLE 2.5

RANKING OF RESEARCH CATEGORIES BY NUMBER OF
COMPOUNDS UNDER STUDY?

Percent of Total Number of
Category Compounds Under Study

Cardiovasculars 14

Psychotropic Drugs

Cancer Chemotherapy Agents

Antibiotics

Hormones

Antivirals

Analgesics

Antagonists/Antidotes

Muscle Relaxants

Anti-inflammatory Agents

Fungicides

Cholesterol Reducers

Enzyme Inhibitors

Diuretics

Bronchodilators

Antibacterials

Immunosuppressants

Anticoagulants

Antispasmodics

Others, each comprising less than
2% of the total compounds 27

nnnnnnnnwwwwwwhmmco

TSources: Paul de Haen, lnc., and Arthur D. Little, lnc., estimates.

2.6 PHARMACEUTICAL CONSUMPTION — RECENT TRENDS

There is no simple unit of measure, such as millions of tablets or tons of chemicals,
which shows overall unit consumption. of pharmaceuticals. However, the trend of unit
consumption can be inferred from the number of prescriptions filled at retail pharmacies.*

 

* Retail pharmacies account for approximately 75% of all prescriptions, with hospitals and other institu-
tions accounting for the balance.

22

Table 2.6 presents data on the number of prescriptions filled at retail pharmacies and shows
that from 1968 to 1973, the number of prescriptions filled at retail pharmacies rose at a 6%
compound annual rate to a total of 1.5 billion. New prescriptions rose at a somewhat higher
rate of 6.4% and refill prescriptions grew at a 5.6% rate. The higher rate of growth in new
prescriptions is primarily due to government restrictions on prescription refills for drugs that
are subject to abuse, and above average growth in prescriptions for antibiotics. These data
give a general indication of unit growth in drug consumption, but not a complete picture,
because various drugs are taken with different frequencies and in different quantities. If
anything, however, the growth rate is probably understated, since studies indicate that there
has been an increase in the size of the average prescription in terms of numbers of tablets,
capsules, and the like, per prescription.

2.7 PHARMACEUTICAL INDUSTRY OUTLOOK FOR 1975-1980

We expect the pharmaceutical industry to maintain a domestic dollar growth rate on
the order of 7-9% over the next five years, and that international growth will probably be
stronger in the near future. However, we believe that the production requirements of the
industry will become more important as unit consumption increases. The following factors
will be affecting the drug industry during this period:

0 Enactment of an expanded program of National Health Insurance will be of
prime importance during this period. We expect National Health Insurance
to increase pharmaceutical sales and to boost drug consumption, particularly
over the long-term, when coverage is extended to outpatient drugs. However,
we do not anticipate legislation to be passed before 1976, with additional
time required before the program can be implemented smoothly.

0 Price pressures are being, and will continue to be, exerted by the Govern-
ment. For example, HEW is currently assessing the maximum allowable cost
regulations which would have an adverse impact on the profitability of the
industry, particularly since the regulatory environment will encourage the
use of price-competitive, multi—source drugs.

0 Several Congressional hearings are being held which are investigating various
practices of the pharmaceutical industry. For example, the Kennedy Health
Subcommittee investigated many of the established marketing techniques of
the industry, and we expect enforcement of related changes, particularly in
the use of sampling and in the regulation of the activities of the medical
representatives (detailmen). Such proposed curbs on promotional practices
of drug companies could have a slightly adverse effect for a limited period of
time.

0 The availability of new drugs has slowed significantly from the flood of
products introduced in the late 1950’s and 1960’s and is encouraging use of
older, established drugs.

23

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24

2.8 NUMBER OF PHARMACEUTICAL PLANTS AND EMPLOYMENT
IN THE INDUSTRY

The latest available Census of Manufactures lists a total of 1058 establishments in 1972
for the SIC codes under evaluation. In addition, there were 42 plants in operation in Puerto
Rico in 1974. Overall, a total of approximately 1100 plants are currently producing drug
products in the United States and its territories. Most of these plants are small. Of the 1058
plants listed in the 1972 Census of Manufactures, in fact, only 416 had 20 or more
employees each. For this study it is noteworthy that in the important function of producing
organic chemical-active ingredients (SIC 2833), only 54 plants in the United States had 20
or more employees. Only 60 plants in the production of biologicals (SIC 2831) were in the
comparable category and 302 were of this size in the formulation and packaging sector (SIC
2834).

Because Government data on a state-by-state basis were not complete at the time of
this study, we have estimated the number of pharmaceutical plants in some of the States
and Puerto Rico as shown in Table 2.8A. Totals of plants by EPA regions and for the
individual states are presented on the map in Figure 2.8A. The corresponding map for plants
with more than 100 employees is presented in Figure 2.8B. As may be observed in these
tables and figures, drug industry production is concentrated primarily in the northeastern
and north central regions, with relatively heavy involvement also in California. As designated
by EPA regions, these include Regions II (282 plants— 26% of total), Region V (215
plants —— 20% of total), and Region IX (143 plants — 13% of total). It should be noted that
the new Puerto Rican facilities are incorporated into the total number of plants for
Region II. For the continental United States, Region 11 contains 240 plants (22% of total).

A further indication of the geographic concentration of the US. pharmaceutical
industry is the fact that five states have nearly 50% of all plants — New York (12%),
California (12%), New Jersey (10%), Illinois (7%), and Pennsylvania (6%). Not only is the
total number greater in these states, but the plants are also the largest in the industry. As
shown in Figure 2.8B, these five states and Puerto Rico contain nearly two-thirds of the
plants which have more then 100 employees.-

An interesting observation from the Census data is that the total number of establish-
ments in the continental United States dropped from 1359 facilities in 1958 to 1058 in
1972 (a decrease of 22%), but establishments with more than 20 employees increased from
403 to 416 during the same period (an increase of 3%). This shift is a further indication of
the smaller producer disappearing from the industry with the larger manufacturers becoming
even more dominant factors.

The number of employees in the various sections of the pharmaceutical industry from
1947 to 1972 are listed in Table 2.8B and presented graphically in Figure 2.8C. The
industry employed a total of 129,300 workers in 1972, 67,400 of which were production
workers. During the period 1958 to 1972, total employment increased by 26%, while
production workers increased by 19%. This substantial increase in employment took place
during the period noted above in which total plants decreased — again an indication of the
concentration occurring within the industry.

25

TABLE 2.8A

ESTIMATED NUMBER OF PHARMACEUTICAL PLANTS (SIC 2831, 2833, AND 2834)
TOTAL NUMBER OF PLANTS AND THOSE WITH MORE THAN 100 EMPLOYEESI

EPA Region

IV
X
IX
VI
IX
VIII
I
III
III
IV
IV
IX
X
V
V
VII
VII
IV
VI

IV
VII
VIII
VII
IX

II
VI
II
IV
VIII

VI

IV
VIII

State

 

Alabama
Alaska
Arizona
Arkansas
California
Colorado
Connecticut
Delaware
District of Columbia
Florida
Georgia
Hawaii

Idaho

Illinois
Indiana

Iowa

Kansas
Kentucky
Louisiana
Maine
Maryland
Massachusetts
Michigan
Minnesota
Mississippi
Missouri
Montana
Nebraska
Nevada

New Hampshire
New Jersey
New Mexico
New York
North Carolina
North Dakota
Ohio
Oklahoma
Oregon
Pennsylvania
Puerto Rico
Rhode Island
South Carolina
South Dakota

Total Plants1

% of Total2

Plants @
>100
Employees

% of Plants2
>100
Employees

 

 

I 7)

0
I 8)
I 2)
134
I 15)

16

28
18

78
26
16
12

I 11)
23
31
39

I 21)

44

112

128
I 18)

69
42
I 4)

26

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TABLE 2.8A (Continued) -

Plants @ % of Plants2

 

>100 >100
EPA Region State Total Plantsl % of Total2 Employees Employees
IV Tennessee 16 1 7 3
VI Texas 50 5 4 2
VIII Utah I 3) * 1 *
I Vermont 0 0 0 0
III Virginia I 16) 1 3 1
X Washington I 7) * 0 *
|I| West Virginia ( 3) * 0 *
V Wisconsin 17 2 1 *
VIII Wyoming 0 0 0 *
National Totals 1100 219
Regional Totals

I 54 5 8 4

II 282 26 87 40

III 115 10 24 11

IV 106 10 19 9

V 215 20 40 18

VI 68 6 4 2

VII 81 7 16 7

VIII 20 2 2 *

IX 143 13 18 8

X 16 - 1 1 *

1. Figures in parentheses are Arthur D. Little, Inc., estimates, based on 1967 Census of Manufactures and
Dun and Bradstreet 1974 data; all others from 1972 Census of Manufactures (Preliminary).

2. *designates less than 1%.

1Sources: Arthur D. Little, Inc., estimates and Census of Manufactures.

 

 

 

 

TABLE 2.83
Number of Employeesf
SIC 2831 SIC 2833 SIC 2834 Total Industry
Production Production Production Production

Total Workers Total Workers Total Workers Total Workers
1947 2,987 NA 13,097 NA 65,143 NA 81.227 NA
1954 3,965 NA 1 1,541 NA 76,555 NA 92,061 NA
1958 3,692 2,567 10,246 6,640 82,000 45.708 95.938 54.915
1963 5.800 3.600 8,100 5,300 85,100 45,900 99,000 54,800
1967 7,400 4,800 8,400 5,600 102,000 55,200 117,800 65,600
1972 9, 800 5,500 8,700 5,300 1 10,800 56,600 129,300 67,400

fSource: Census of Manufactures

27

83

 

 

 

 

 

we”
Alaska Wm. I — 54 Me
(7) f N. Oak, Minn. r"\\ H _ 282 (3)
()reg. ~ ~ \ ,
’E
X‘ 16 Idaho 0 Wis ‘\? o
w o S. Oak ‘ ’ I N
yo, Mich. s I 33-
I 128 M
Cam. (9) VIII 20 (2) (21) ‘ I w- 1 a. . (4)
NeV. 0 Iowa 17 39 I I ’ 00““
Utah New, ’ P3
0 ”L Ind. 01110 69 NJ.
Com. ‘6 — 21 oeI- (4)
1x 143 9 Mo. 34 wme 115
Kans. 26
(3) VII — 81 73 W" ‘3’ (16)
l (15 (5)
(1) Aug. N“ max 12 44 N.C.
x ”fex, Okla» Ark. Tenn- 16 (18)
5.0.
Hawaii 3 Mi 5’ Am Ga.
0 134 (5) S (6’ Puerto Rico (II)
(2) IV 106 42
0 La. )
(8) v| _ 68 (8) (7) 18
Fla.
50 (11)
28

N.B.: Numbers in parentheses are Arthur D. Little, Inc., estimates; Roman numerals designate EPA regions.

fSouroes: Arthur D. Little, Inc., estimates and Census of Manufactures, 1972 (preliminary).

FIGURE 2.8A NUMBER OF PLANTS?

62

Wash.

 

 

 

 

 

 

 

Mont.
N. Oak. Minn.
0
0’89.
Alaska X _
0 Metro 0 Wis
0 s. Dak.
WYO,
Cam. ‘ vm — 2 2
Week 0 10wa
Utah Nebr.
C0|o_ 3
IX 18 2 Mo
Kans.
1 VII — 16
0 flail. 1 1
N“ MBX‘ Okla

Tex, I Ark

0

18
L V
o 0 a
VI — 4
Hawaii
0 4

N.B.: Roman numerals designate EPA regions.
fSource: Arthur D. Little, Inc., estimates.

I”.

10

1 _ 8 Me.
-‘x ”—87 0
~\ V‘
\ ’1 N-
Mi h. \ ’ . a.
C x ' 26 W
’/ N-V RA. 0
1 10 z” Pa con“
ma. Ohio 19 45
V—40 Md 061
5 W-Va' Va 0
9 M m 24
13 3
0
N.C
Term. 5
s.c.
M155. 9‘3- ea“
2
IV 19
0
1 Ma.
Puerto Rico (ll)
16
1.

FIGURE 283 NUMBER OF PLANTS(>100 EMPLOYEES)?

Number of Employees

140,000

 

     

 

 

  
 

 

 

 

SIC 2834 Pharmaceutical
130,000 _. SIC 2833 Medicinal Chemicals and Botanical Products
SIC 2831 Biological
120,000 _
110,000 ,-
100,000 _
2834
90,000 _ 2833
2831 Total Employees
80,000 I/
70,000 — 2834 __
/ /__, __ _—
/
60,000 _ I,/
2834, 2833, 2831 ______ /’ ’,-""'""'"‘
50,000 _ [z
2834 ______ x,
40,000 _ Production Employees
30,000 _
20,000 — 2833
Total Employees {2831 } Production Employees
10,000 =— 2833 ._——-——-
Total Employees _ _ __ __________
,—— 2831 ________________,____
Iliiilliiil—‘I—Iliiiiliill
1947 1954 1958 1963 1967 1972

TSource: Census of Manufactures

FIGURE 2.8C PHARMACEUTICAL EMPLOYMENT TRENDS BY SIC CODES?

30

3.0 WASTE CHARACTERIZATION IN THE PHARMACEUTICAL INDUSTRY

3.1 SELECTION AND APPLICATION OF HAZARDOUS WASTE CRITERIA

3.1.1 Background Information for the Selection of Hazardous Wastes

In the studies covering various industries, the individual contractors were asked to:
. . identify and describe the wastes generated by each industry which pose a
potential health or environmental hazard upon final disposal. In performing his
analysis, the contractor should pay particular attention to wastes which contain
any of the following specific substances, or types of substances: asbestos, arsenic,
beryllium, cadmium, chromium, copper, cyanides, lead, mercury, halogenated
hydrocarbons, pesticides, selenium, and zinc. EPA believes these substances, on
the basis of initial analysis, to have the potential for producing serious public
health and environmental problems when contained in wastes for disposal. Other
wastes, believed by the contractor to be of a hazardous nature, such as car-
cinogens, should also be identified. ”

To identify the wastes that pose a potential health or environmental hazard upon final
disposal, we had to develop a set of criteria to select the hazardous wastes generated by the
pharmaceutical industry. Whereas some industries have only a few well defined inorganic
substances to classify, the pharmaceutical industry manufactures or purchases an estimated
15,000 inorganic and organic chemicals to make its formulated pharmaceutical products.
Potential hazards of these chemicals range from essentially nonhazardous to highly hazard-
ous due to such characteristics as flammability or toxicity.

We studied other hazard classification schemes to assist in developing criteria for
selecting potentially hazardous and highly hazardous wastes generated in the pharmaceutical
industry, but found no universally applicable scheme for classifying the types of hazards and
the degree to which they are hazardous. Each classification scheme was selected to meet
specific needs. Industrial toxicologists selected criteria to assist them in handling the toxic
materials produced in industry, and public health toxicologists assembled criteria to assist
the physician in treating acute poisoning by various chemicals and commercial products.
Classification schemes designed to aid the physician in treating acute poisonings were
usually developed on the basis of LD5 0 values alone, while the industrial hygienist was often
more concerned with the toxicity of inhaled vapors, irritation to the skin, allergic reactions,
and flammability of products.

While none of the other systems have addressed the same problems that the Office of

Solid Waste Management Programs will face, the Coast Guard addressed a related problem in
the safe handling of materials in bulk water transportation. During 1965-66 the National

31

Academy of Sciences (NAS) developed an initial evaluation system for the Coast Guard.* In
this system the substances were rated on a simple numerical scale of 0, l, 2, 3 or 4,
indicating an increasing degree of hazard in each of 10 categories describing different types
of hazards (flammability, human toxicity, etc.). The publication was revised from time to
time;the current edition is dated 1970rwith additions to September 22, 1972. Comments
were received from overseas sources including the Intergovernmental Maritime Consultative
Organization (IMCO), the Netherlands, and the United Kingdom, suggesting the need for
further extension and amplification of the guidelines to define the ratings more precisely.
Thus in 1974 the NAS submitted a revised publication, “System for Evaluation of the
Hazards of Bulk Water Transportation of Industrial Chemicals,” which brought the grade
classifications for human toxicity and aquatic toxicity into agreement with grade classifica-
tions developed by IMCO and one hazard category (effect on amenities) was dropped. The
suggested classification scheme now has nine hazard categories as follows: (1) fire, (2) skin
and eyes, (3) vapor inhalation, (4) gas inhalation, (5) repeated inhalation, (6) human
toxicity, (7) aquatic toxicity, (8) water reaction, and (9) self reaction. The same rating scale
of O, 1, 2, 3 and 4 was retained and used for all hazard categories.

We also examined the IMCO system which was developed by the Joint Group of
Experts on the Scientific Aspects of Marine Pollution to review the environmental hazards
of transporting substances besides oil. In contrast to the NAS system which has nine
categories of hazards, the IMCO system has only five categories: (1) bio-accumulation, (2)
damage to living resources, (3) oral intake hazard to human health, (4) skin contact and
inhalation hazard to human health, and (5) reduction of amenities.

3.1.2 Selection of Criteria for Classification of Potentially Hazardous Substances from
the Pharmaceutical Industry

Classification of materials as hazardous or nonhazardous is an arbitrary process.
Whether or not a substance is hazardous depends on its quantity, concentration, location,
and the species affected. Even air and water can be hazardous in certain situations. For
example, air injected into a vein may cause a fatal air embolism. Likewise water can be fatal
if too much water gets into the lungs by blocking access of air to the lungs and seriously
disrupting the ionic balance of the blood. On the other hand, a substance such as
hydrochloric acid, which can be fatal if ingested in concentrated form, can also be beneficial
in dilute solutions for patients who have a deficiency of normal hydrochloric acid secretions
in the stomach.

Despite the difficulties of developing a universally applicable scheme for grading
hazardous materials, materials with the highest potential for environmental damage and
human hazard can be identified for various handling or disposal techniques. Theoretically,
such a classification scheme should take in all possible hazards. In observing the pragmatic

 

”Described in NAS publication No. 1465, "Evaluation of the Hazard of Bulk Water Transportation of
Industrial Chemicals —— A Tentative Guide."

32

approaches taken by IMCO, NAS-Coast Guard, and the Hazardous Substances Branch of
EPA’s Office of Water Planning and Standards, it is apparent that firm decisions had to be
made to eliminate or exclude certain hazard categories. For example, effects on amenities
was eliminated in the 1974 NAS proposed system and bio-accumulation was not included as
a hazard category. Likewise, the IMCO scheme did not include consideration of flamma-
bility in its hazard ratings, presumably because it is concerned with dumping of materials
from ships on the high seas where toxicity is a more important consideration than
flammability.

Because of the wide range of hazards considered in the NAS scheme, and because of
the extensive data that had been collected for the scheme, we proposed that the 1974
modification suggested to the Coast Guard by NAS be used as a basis for evaluating the
hazards of materials for disposal on land. Initially, we suggested classifying substances which
fell into hazard grades 3 and 4 in any category of the NAS scheme as highly hazardous and
those in grades 1 and 2 as moderately hazardous as shown in Table 3.1.2A. Another
contractor (TRW, Inc.) suggested expansion of the NAS-Coast Guard classification to
include bio-accumulation to toxic levels and addition of substances that are carcinogenic,
foncogenic, teratogenic, or mutagenic. Since the classification scheme developed for this
preliminary study of hazardous wastes would not bind EPA to the same criteria, the Office?
of Solid Waste Management Programs, ADL, and TRW agreed that both contractors would
luse the expanded classification scheme for the pharmaceutical and organic chemical indusv
ltries, but with a modification involving the water pollution hazards. The criteria for highly
hazardous wastes were retained and, therefore, included any substances falling into hazard
l grades 3 or 4 in any category of the NAS classification scheme. Criteria for moderately
hazardous wastes included any substance falling in grades 1 or 2 in any category, except that
under the “water pollution” heading substances falling in grade 1 were considered non-
hazardous unless they presented a hazard upon collection. We thus have nine graded criteria
to use in making preliminary judgments in evaluating the hazard of a given material. In
addition, bio-concentratable materials are raised to the next higher hazard classification and
suspected carcinogens* are rated as Grade 4, highly hazardous. A summary of the classifica-
tion criteria is presented in Table 3.1.2A with the boundaries between the three hazard
classifications (highly hazardous, moderately hazardous, and essentially nonhazardous)
delineated by heavy lines. A more detailed explanation of the criteria for hazard grades in
each of the nine categories is given in Appendix A.

When one attempts to apply the classification scheme developed above to a specific
industrial situation, other precautions must be observed. The problems of quantity and
concentration arise immediately when we consider the inorganic chemicals (heavy metals
and fluorides, for example) that are usually considered to be toxic. The assumption that any
exposure to a toxic chemical is harmful at any dose is erroneous; for many chemical
substances a deficiency is known to be every bit as injurious as an excess.

Several examples illustrate that substances can be nutritional at one level and toxic at
another. For example, fluorine is essential for life (Table 3.1.2B) and is a demonstrated
growth factor in rats. A fluorine deficiency leads to tooth decay, but in slight excess this

.*Does not include list of "suspected carcinogens” published by NIOSH in the Federal Register, 48,
No. 121, pp 26,390-26,496, June 23, 1975. NIOSH is asking for information on the carcinogenicity of
compounds on this list. 33

17$

TAB LE 3.1.2A

SUMMARY OF HAZARD EVALUATION CRITERIA

 

 

 

 

 

 

 

 

“Priorities are discussed in Subsection 3.1.3

Note: Bio-concentratable materials are raised to next higher hazard classification. Suspected carcinogens are rated as Grade 4.

Hazard Categories
G I II III IV V VI VII VIII IX
R
3 A E Health Water Pollution Reaction
.. D
> i E [ Skin and Vapor Gas Repeated I Woman Aquatic I i Water I
=. 3 Eyes Inhalation Inhdation Inhalation Toxicity Toxicity Reaction Self-Reaction
‘3 '§ — __ ——
a 3 Not lnsignif.
I" g Applicable Hazard
5 0 All not All not
Non-combust- described described OSHA 2 LB“ > TL"I > 1WD mg/IZ No appreciable
ible below below 1000 ppm 5000 mg/kg self-reaction
1
. FPcc > 140° F Corrosive Depressants, All not OSHA LO; 0 TLm 8.9., CI, May polymerize
3 (60°C) to eyes asphyxiants described 1001000 ppm 5005000 mg/kg 1001000 mg/IZ with low heat
_ g below evolution
g: 8 Contamination
E g 3 may cause
g 2 FPcc e.g., NH; polymerization;
2 100°F-140°F Corrosive Lcso Lcso OSHA L050 TLm no inhibitor
(37.8°-60°C) to skin 2002000 ppm 200-2000 ppm 10100 ppm 50500 mg/kg 10100 mg/Q required
3 (373°C) LDso
_ FPcc < 100°F 20200 mg/kg May polymerize;
13: BP > 100°F 24-hr. skin L050 50200 ppm LCso OSHA LD50 requires
‘_ E _ (318°C) contact or 0.5-2 mg/ll 50200 ppm 1.10 ppm 550 mg/kg TLm 1-10 mg/Il 8.9., Oleum stabilizer
E i: a .
.g 2‘ 3 4 (37.8 C) Self-reaction
‘- i. FPcc < 100° F L050 < 20 mg may cause
1 BP < 100°F 24-nr. skin Lcso < 50 ppm explosion or
(373°C) contact or < 0.5 mg/IZ LCso < 50 ppm OSHA < 1 ppm LDso < 5 mg/kg TLm < 1 mg/Il e.g., $03 detonation

TABLE 3.1.23

BIOLOGICAL FUNCTIONS AND TOXICITIES OF SELECTED ELEMENTS

Element

Hydrogen
Boron

Carbon
Nitrogen

Oxygen

Fluorine

Sodium

Magnesium

Silicon

Phosphorus

Sulfur

Chlorine
Potassium

Calcium
Vanadium

Chromium

Manganese

lron

Cobalt

Copper

Zinc

Selenium

Molybdenum
Tin

Iodine

Biological Function'
Constituent of water and organic
compounds

Essential in some plants; function
unknown

Constituent of organic compounds

Constituent of many organic
compounds

Constituent of water and organic
compounds

Growth factor in rats; possible
constituent of teeth and bones

Principal extracellular cation

Required for activity of many
enzymes

Shown essential in chicks; pos-
sible structural unit in
diatoms

Essential for biochemical synthesis
and energy transfer

Required for proteins and other
biological compounds

Principal extracellular anion

Principal cellular cation

Major component of bone; required
by some enzymes

Essential in lower plants: certain
marine animals and rats

Essential in higher animals; related
to action of insulin

Required for activity of several
enzymes

Most important transition metal ion
essential for hemoglobin and
many enzymes

Required for activity of several
enzymes; in vitamin B. 1

Essential in oxidative and other
enzymes and hemocyanin

Required for activity of many
enzymes; deficiency causes
anemia

Essential for liver function

Required for activity of several
enzymes

Essential in rats; function
unknown

Essential constituent of thyroid
hormones

Toxlu'ty"

Used in insecticides and rat poisons;
fluorides are protoplasmic poisons,
removing essential body calcium inter-
fering with enzyme reactions causing
death from respiratory or cardiac failure

High plasma levels can result in respira-
tory depression and death

Quite toxic, especially as V105 dust

Carcinogenic in rats and mice; industrial
exposure has resulted in dermatitis, skin
ulcers, liver injury, and lung cancer.

industrial exposure to dust has resulted in
a neurological syndrome and a pneumonitis

Excessive doses have caused severe symptoms
and a high proportion of deaths, especially

in children; acidosis, cardiovascular

collapse and tissue damage to the gastro-
intestinal tract, liver and kidneys

Produces polycythemia, nephritis, etc.

Excessive doses damage liver, kidneys,
capillaries, and central nervous systems

Relatively nontoxic to mammals; yet causes
illness due to inhalation of Zn compounds

High toxicity, similar to Te and As; Even
natural levels cause serious disease (blind
staggers) in cattle: inhibits enzyme
function

lodism in some persons: irritation of
mucous membranes and mum-intestinal tract

“from E. Frieden, Scienfific Americm, V01227, No. 1, p 52 (July 1972).

“ “from J.R. DiPalma (ed.l. Drill's Pharmacology in Medicine, l3rd ed.l, McGraw~Hill
Book Co., New York (1965).

same element produces an unsightly mottling of tooth enamel. In large excess it is a very
dangerous poison — the active ingredient, in fact, in some insecticides and rat poisons.

Another example is zinc.» Many enzymes require this element yet it can be an industrial
health hazard and has been responsible for fish kills. The list of chemical elements essential
to life is growing fast. It includes eight other “toxic heavy metals” — vanadium, chromium,
manganese, iron, cobalt, copper, molybdenum, and tin — which were listed by Frieden in
1972 (cf. Table 3.1.2B).

3.1.3 Application of the Classification Scheme to Categorize Wastes from
the Pharmaceutical Industry as Priority | or Priority ll
Potentially Hazardous Wastes

As was discussed in Section 3.1.2, the toxicity or degree of hazard presented by a given
waste depends on many factors. In this preliminary survey of hazardous wastes from the
pharmaceutical industry potentially destined for land disposal, we were unable to make
final judgments on the degree of “hazard” for wastes from the industry. We recognize that
more information will be required on a plant by plant basis before the hazards at an
individual plant can be evaluated. In this report, we have focused on the “potential hazard”
in a given waste, choosing to label the potentially highly hazardous materials as Priority I
Hazardous Wastes, and the potentially moderately hazardous materials as Priority II Hazard-
ous Wastes.

Priority I hazardous wastes include all “elementary” toxic materials, viz., materials
whichare potentially harmful, regardless of their state of chemical combination. Priority I
hazardous wastes also include materials which owe their hazardous properties to their mole-
cular arrangement and which fall in hazard grades 3 or 4 in Table 3.1.2A.

Priority II hazardous wastes owe their hazardous properties to their molecular arrange-
ment and fall in hazard grades 1 or 2 in Table 3.1.2A.

All other process wastes are considered essentially nonhazardous in this study if they
fall in the essentially nonhazardous section of Table 3.1.2A.

A list of Priority I inorganic chemicals was made up and used during interviews as a
checklist to see whether the plant had any of these materials in its waste (see Table 3.1.3A).
As the study proceeded, we found that we had to make some judgments as to whether cer-
tain wastes had significant concentrations of “hazardous” metals, as trace quantities of
metals can be found in almost any waste. Because of the approximately 15,000 active ingre-
dients used in the pharmaceutical industry, a similar list for organic compounds was im-
practical. The industry also uses some quantity of practically every organic solvent com-
mercially available, either in its R&D groups or production plants. As will be described later,
wastes from these solvents are incinerated. In this preliminary study-we were not attempting
to catalog all possible components of waste streams, but were merely trying to identify
major hazardous wastes. In general, we were looking for information on waste solvents, still
bottoms, and solid wastes such as process “muds” or presscakes that were discharged from
the plants manufacturing active medicinal ingredients. Representative solvents and still
bottoms containing these solvents are characterized in Table 3.1.3B.

36

TABLE 3.1 .3A

PRIORITY I HAZARDOUS WASTES

Inorganic Elements and Compounds

 

Mercury Molybdenum (molybdates)
Cadmium on first proposed toxic pollutant list* Nickel

Cyanide Nitrites

Antimony Osmium

Arsenic Selenium

Azides Silver

Barium Thallium

Beryllium Tin

Chromium (chromates) Uranium

Cobalt Vanadium

Copper Zinc

Fluorides Radioactive elements
Lead

*Published in the Federal Register, 38FR 35388, December 27, 1973.

TABLE 3.1.3B

CHARACTERIZATION OF TYPICAL WASTE SOLVENTS
OR STILL BOTTOMS CONTAINING THE LISTED CHEMICALS

Priority l Priority ll
(Highly Hazardous) (Moderately Hazardous)
Acetone Ethylene Glycol
Acetonitrile Monomethyl Ether
Amyl Acetate Heptane
Benzene Methylene Chloride
Butanol Naphtha

Butyl Acetate
Chloroform*

Ethanol

Ethylene Dichloride
lsopropyl Alcohol
Methanol

Methyl Isobutyl Ketone
Toluene

Xylene

*Chloroform would normally be in the Priority ll classification, but possible carcinogenic action causes
its shift to Priority l.

37

Anyone considering landfilling of returned pharmaceuticals or disposal of active
ingredients is concerned with the possible hazardous properties of the ingredients. Formu-
lated pharmaceuticals and most active medicinal ingredients are not hazardous because of
flammability, reactivity with water, self-reactivity, or corrosiveness to skin or eyes. Likewise
these products do not usually produce vapors that are toxic on inhalation. The principal
hazard categories that would place these pharmaceuticals or ingredients in the hazardous
classification are aquatic toxicity (TLm ), oral toxicity (LDSO), bio-concentration or car-
cinogenicity. It is unlikely that the Food and Drug Administration would leave a pharma-
ceutical on the market for general use that is a known carcinogen. There are essentially no
data on the TLm values of these compounds and on their bio-concentration in natural
flora and fauna. However, there are extensive data on the oral toxicity of these compounds
in test animals.

We therefore decided to evaluate the toxicity of the most common products in five of
the largest selling pharmaceutical categories: analgesics, antibiotics, ataractics, cardio-
vasculars, and hormones. The oral LDSO values of typical compounds under each pharma-
ceutical category are listed in Table 3.1.3C. As indicated in the summary at the end of
Table 3.1.3C, 48 out of 66 compounds were in toxicity grade 1 (LDso of 500 to 5000
mg/kg — essentially nonhazardous), 17 of the 66 were in grade 2 (50-500 mg/kg — moder—
ately hazardous) and only one compound was in grade 3 (5 to 50 mg/kg — highly
hazardous). While the pharmaceutical ingredients sometimes may have a high activity for
man when they are injected or ingested, the most active ones are usually dispensed in highly
diluted forms so that only a small percentage of active ingredient is present in the dosage
form. Although some of the active ingredients can qualify as moderately hazardous, we do
not consider the typical mix of returned goods that would actually ‘be disposed of on land
to be hazardous. It is highly unlikely that the diluted ingredients would be ingested. Never-
theless, some companies have a few products (such as mercurial ointments) that they screen
out of their returned goods to ensure that the discarded material is environmentally accept-
able. If a company takes the conservative position that all returned goods and discarded
products are considered as moderately hazardous until they are examined, the handling and
disposal of these compounds can be done without hazard to personnel or the environment.

3.2 WASTE GENERATION DATA DEVELOPMENT
3.2.1 Approach to the Problem of Obtaining Valid Industry Hazardous Waste Data

No Federal law has yet been passed requiring industry to obtain and report data on
hazardous materials produced as wastes destined for land disposal. To conduct this study it
was therefore imperative to obtain the voluntary cooperation of companies that represented
a significant portion of the US. production of pharmaceutical products. Fortunately, the
Pharmaceutical Manufacturers Association (PMA) supported the planned attempt to obtain
useful information on which EPA’s Office of Solid Wastes Programs could base its future
planning and programs. The PMA Environmental Control Committee lent us its support and
assisted in obtaining the cooperation of several major pharmaceutical producers.

38

TABLE 3.1.3C

TYPICAL TOXICITIES OF PHARMACEUTICAL ACTIVE INGREDIENTS
AS MEASURED BY ORAL LDso ON MICE AND RATS*

Oral LD50 (mg/kg)

 

Drug Class Compound Mouse E Reference

Analgesics A 2404 1
B 815 1500 2,3
C 4025 4
D 748 4
E 542 5
F 18 1
G 170 6
H 95 7
I 887 8
J 693 9
K 1650 10
L 84 5
M 1890 1
N 1600 11

Antibiotics A > 3750 12
3 1188 1
C 2500 13
D 3400 1
E 3000 12
F 2618 14
G 2372 1
H 2000 15
I 4600 16
J 1447 1
K > 4000 17
L > 2880 12
M 4800 18
N 300 1
O 808 807 1
P 3579 1
0 3550 1
R 702 1

*Table references follows table.

39

Drug Class

Ata ractics

Cardiovasculars

Hormones

Toxicity Grade

Analgesics
Antibiotics
Ataractics
Cardiovasculars
Hormones

Total

TABLE 3.1.3C (Continued)

Compound

Zgr‘KL—Im'nmUOmp

OZ§P7<‘—‘Immm00co>

DOW>

Oral LDso (mg/kg)

Mouse

126
148-176
>515
980

150
1250

1350
330

213

292

300
680

890

> 2500

1737
950

Rat

433
548
710

346-460

840

710
1552
318

1800
995
740

56
2600
1 000

2221
1 100
1750

>80
440
300
2500

1 000
3200

>300

2952

Reference

19
20,1
1
21
. 1
22
23
24,1
19
25
4,26
1
27,26
28

33,34

Oral LD50 Summary of Typical Classes of Pharmaceuticals

(Classified by lower of rat or mouse toxicity values)

 

4 (05) 3 (550) 2 (50500) 1 (5005000) 0 (> 5000)
0 1 3 10 o
o o 1 18 o
o o 6 8 0
o o 6 9 0
_°_ _0 _1 _3 1
o 1 17 48 0

4o

PWNP‘WPPNT‘

Add
19??

13.
14.
15.
16.
17.
18.
19.
20.

21.
22.
23.
24.

25.
26.

27.

28.
29.
30.
31.
32.
33.
34.
35.
36.
37.

REFERENCES TO TABLE 3.1.30

Toxicol. Appl. Pharmacol., 18, 185, 1971. (TXAPA9 —- Toxic Substance List, 1973)

Toxicol. Appl. Pharmacol., 23, 537, 1972. (TXAPA9 — Toxic Substance List, 1973)

J. Pharmacol. Exp. Ther., 99, 450, 1950. (JPETAB —- Toxic Substance List, 1973)

Merck Index. (12VXA4 — Toxic Substance List, 1973)

J. Pharmacol. Exp. Ther., 134, 332, 1961. (JPETAB — Toxic Substance List, 1973)

J. Pharmacol. Exp. Ther., 103, 147, 1951. (JPETAB — Toxic Substance List, 1973)

J. Pharmacol. Exp. Ther., 92, 269, 1948. (JPETAB — Toxic Substance List, 1973)

Food Cosmet. Toxicol., 2, 327, 1964. (FCTXAV — Toxic Substance List, 1973)

Arch. Int. Pharmacodyn. Ther., 190, 124, 1971. (AIPTAK — Toxic Substance List, 1973)
Toxicol. Appl. Pharmacol., 1, 240, 1959. (TXAPA9 — Toxic Substance List, 1973)

J. Pharmacol. Exp. Ther., 89, 205, 1947. (JPETAB —— Toxic Substance List, 1973)

Spector, W.S., ed. Handbook of Toxicology, Volume I: Acute Toxicities. W.B. Saunders Co.
(Philadelphia), 1956.

Toxicol. Appl. Pharmacol., 8, 398, 1966. (TXAPA9 — Toxic Substance List, 1973)

Toxicol. Appl. Pharmacol., 21, 516, 1972. (TXAPA9 — Toxic Substance List, 1973)

Toxicol. Appl. Pharmacol., 10, 402, 1967. (TXAPA9 — Toxic Substance List, 1973)

J. Antibiot., 19, 30, 1966. (JANTAJ — Toxic Substance List, 1973)

Toxicol. Appl. Pharmacol., 6, 746, 1964. (TAP — Journal)

Acta Pol. Pharm., 24, 451, 1967. (APPHAX — Toxic Substance List, 1973)

Toxicol. Appl. Pharmacol., 21, 315, 1972. (TXAPA9 — Toxic Substance List, 1973)

Mouse — Physicians Desk Reference (PDR), 1974 and Proc. Eur. Soc. Study Drug Toxicity, 8,
177, 1967. Rat — Toxicol. Appl. Pharmacol., 181, 185, 1971 (PSDTAP and TXAPA9 —- Toxic
Substance List, 1973)

Physicians Desk Reference (PDR), 1974

J. Pharmacol. Exp. Ther., 127, 318, 1959. (JPETAB — Toxic Substance List, 1973)

Am. lnd. Hyg. Assoc. J., 30, 470, 1969. (AIHAAP — Toxic Substance List, 1973)

Mouse — J. Pharmacol. Exp. Ther., 129, 75, 1960. Rat — Toxicol. Appl. Pharmacol., 18, 185,
1971. (JPETAB and TXAPA9 -— Toxic Substance List, 1973)

Toxicol. Appl. Pharmacol., 21, 302, 1972. (TXAPA9 — Toxic Substance List, 1973)

Barnes, C.C., Eltherington, L.G., Drug Dosage in Laboratory Animals — A Handbook, Univ. of
California Press, Berkeley, 1965. (DDLA — Toxic Substance List, 1973)

Smith, Kline and French Laboratories (Philadelphia ) — Mouse. Barnes, C.C., Eltherington,
L.G., Drug Dosage in Laboratory Animals —— A Handbook. Univ. of California Press, Berkeley,
1965) (SKFL and DD LA — Toxic Substance List, 1973)

J. Pharmacol. Exp. Ther., 127, 318, 1959. (JPETAB — Toxic Substance List, 1973)

J. Pharmacol. Exp. Ther., 128, 22, 1960. (JPETAB — Toxic Substance List, 1973)

Toxicol. Appl. Pharmacol., 7, 598, 1965. (TXAPA9 — Toxic Substance List, 1973)

J. Pharmacol. Exp. Ther., 179, 580, 1971. (JPETAB — Toxic Substance List, 1973)

Arch. ltal. Sci. Farmacol., 6, 153, 1937. (AISFAR — Toxic Substance List, 1973)

J. Pharm. Pharmacol., 121, 179, 1960. (JPPMAB — Toxic Substance List, 1973)

Arch. Int. Pharmacodyn. Ther., 180, 155, 1969. (AIPTAK — Toxic Substance List, 1973)
Ann. N.Y. Acad. Sci., 107, 1,068, 1963. (ANYAA9 —- Toxic Substance List, 1973)

Toxicol. App. Pharmacol., 21, 253, 1972. (TXAPA9 — Toxic Substance List, 1973)

Klin. Wochenschr., 18, 156, 1939. (KLWOAZ — Toxic Substance List, 1973)

41

Because the industry had never had to report detailed composition of waste streams,
we realized that mailing of questionnaires would not produce usable information. We
therefore chose to conduct in-depth interviews and plant inspections at the plants of the
cooperating companies. We visited the principal production plants of companies repre-
senting 27 percent of total US. sales of ethical pharmaceuticals. These plants represented an
even higher percentage of the active ingredient production of the industry. All facilities
visited had multiple operations so that good representative information was available on
R&D, fermentation, biological products, organic synthesis, extraction of animal glands and
formulation and packaging operations in the United States, including Puerto Rico. Infor-
mation given to us in the interviews and by letter was checked and confirmed with the
companies. From the collected data we extrapolated to obtain information applicable to the
entire industry.

During the course of the study we also visited eight landfills and four contractors that
were treating wastes, principally by incineration. We also interviewed 11 contractors by
telephone to confirm information obtained from plant Visits.

As explained in Section 2.0 of this report, the SIC codes of the US. Department of
Commerce do not exactly follow functional divisions of the pharmaceutical industry. For
example, we were interested in obtaining information on R&D wastes and the R&D
category does not have a SIC code. Another complication in data collection from the plants
was that many of the pharmaceutical plants producing active ingredients were diversified,
i.e., some parts of the manufacturing complex produced materials for animal feeds, cos—
metics, pesticides, fine organic chemicals, etc., as well as medicinal ingredients. For this
study we have attempted to isolate those wastes that are associated only with the phar-
maceutical production.

The information that we collected on plant visits was categorized under three of the
four functional divisions of the pharmaceutical industry: (1) Research and Development,
(2) Production of Active Ingredients, and (3) Formulation and Packaging. The fourth
functional division, Marketing and Distribution, did not dispose of significant quantities of
process wastes or hazardous wastes, as damaged or outdated goods were normally returned
to the formulation plants for disposition.

As indicated in Section 2, we considered plants listed as 2831 and 2833 under the
production of active ingredients category and plants listed as 2834 under the formulation
and packaging category.
3.2.1.1 Wastes from Research and Development Installations

Based on surveys conducted by the Pharmaceutical Manufacturers Association that

show a total of approximately 23,000 personnel employed in research and development
(R&D) activities in its member firms, we estimate that total pharmaceutical R&D personnel

42

amount to about 25,000. About one-half of the R&D staff is made up of scientific and
professional people and the other half is about equally divided between technical and .
supporting staff.

R&D activities are often concentrated in research centers run by the industry that
employ from 200 to over 2000 R&D personnel so that sizable quantities of wastes may be
generated in these centers. On the other hand, some R&D activities are dispersed throughout
the individual companies so only a few R&D personnel may be in a given plant, and the
R&D wastes may not be segregated.

Depending on the type of research being done the wastes from these activities may
involve a heavy use of solvents in one installation while at another installation most of the
work may involve tests on animals. Thus in one case there will be waste solvents to be
disposed of and in the other there will be test animals to be incinerated. We found that the
average mixed solvent waste at the installations we visited was about 66 liters per
man-year or a yearly total of approximately 1500 metric tons in the United States.

Other hazardous wastes occurred in much smaller amounts than the solvents and were
usually handled as specified by the “Laboratory Waste Disposal Manual” issued by the
Manufacturing Chemists’ Association. Heavy metal wastes, such as mercury or mercury salts,
were often stored until a sufficient quantity was on hand to sell to a reprocessor.

3.2.1.2 Wastes from the Production of Active Ingredients

In addition to the active ingredients that it produces itself, the pharmaceutical industry
purchases many of its active ingredients from chemical companies that are not really in the
pharmaceutical industry. Most of the plants listed under SIC 2831 (Biological Products) are
a part of the pharmaceutical industry and manufacture active ingredients consumed by the
industry. On the other hand, many of the products listed under “Medicinal Chemicals” by
the US Tariff Commission are manufactured by chemical companies that are not in the
pharmaceutical business. A good example of the latter is choline chloride in the “Medicinal
Chemicals” category, which is made almost entirely by chemical companies, but which is
used almost entirely in animal feed production. We have subtracted substances such as
choline and other materials that are made mostly by the chemical companies to arrive at
the active ingredient production that could be assigned to SIC code 2833. We estimate that
the pharmaceutical industry’s 1973 production of organic medicinal ingredients, excluding
antibiotic production, was no more than 34,000 metric tons (75 million pounds).

In the subsections that follow, we discuss methods of active ingredient production and
the generation of process and hazardous wastes. We have selected the processes shown from
the open literature, and they are typical of industry practice, but do not refer to a specific
company’s installation.

43

3.2.1 .2.1 Synthetic Organic Medicinal Chemicals

The production of organic medicinal chemicals may involve the chemical (or biologi-
cal) modification of an antibiotic, botanical, or drug from animal sources, or it might be the
complete chemical synthesis of a complex chemical, such as vitamin A, whose synthesis
starts with acetone, acetic acid, acetylene, and methyl vinyl ketone. Unlike the “heavy
chemicals,” those chemicals which are. produced by the chemical industry in thousands of
tons annually, the total annual production of any given organic chemical medicinal might
only be 1 or 2 tons. Heavy chemicals are produced in continuous processes and generate a
uniform waste stream, but many different medicinals are produced in single batches which
causes a wide variation in their waste streams.

The amount of process waste generated per ton of product will vary greatly, depending
on the number of synthesis steps, the yield in each step, and the solvents used. The chemical
synthesis may only require a two-step synthesis with recovery of unreacted raw materials,
such as in aspirin production, or as many as 13 steps as in the production of vitamin A.
With an overall yield of over 80%, less than 0.2 kg of organic residue waste would be
generated per kg of aspirin, whereas the overall yield in the production of vitamin A might
be as low as 15-20%, thus generating as much as 7 kg of organic waste per kg of product.
The by-product organic residue waste material is separated from the main product by any of
a number of methods such as extraction, distillation, precipitation, crystallization, or
filtration, and may be recovered as hard still bottoms, chemical muds, or in a solvent
solution. This residue may still contain residual hazardous organics such as hydroquinone,
pyridine, or oxalic acid.

Wastewater from the production of organic medicinal chemicals (containing up to
several thousand ppm of biodegradable organics such as isopropanol, acetone, ethanol, or
acetic acid) must be treated to meet effluent requirements.* This wastewater is usually
treated biologically, such as an activated sludge treatment, either on-site or in local
municipal treatment systems. This biological treatment, in turn, generates from 0.3 to 0.7
kg of biological sludge solids per kg of organic solids removed, the remainder being
converted to carbon dioxide and water by the biological sludge organisms.

The volume of solvent waste generated depends on the degree to which the solvent is
contaminated, to what extent solvent recovery is practiced, and the type of reaction and
solvent required. Some reactions, such as hydrogenation, may require no solvent at all; some
may use ethanol or acetic acid which is diluted and discharged to biological treatment, while
still others may use toluene or benzene which must be recovered or incinerated. A “typical”
synthetic organic medicinal chemical production process might be summarized as shown in
Figure 3.2.1.2.1.

*State or Federal.

44

Finished Medicinal Products
Raw Materials (500,000 kg)
(5,000,000 kg)

 

 

Recycle

 

 

 

  
 

Solvents Aqeous Wastes

8,000,000 kg) (1,400,000 kg)
(solids)

    

 

 

 

 

 

 

 

 
  
 

 
  
 

Waste Solvents Biological Wastewater Solid Wastes (dry)
(400.000 k9) Treatment (300,000 kg)
1 I ‘\
Biological
[sludge‘ \
0n Ite (700,000 kg) (solids) \
By Con ractor l ‘/ On Site
' Onb‘te \
fig." / ractor \

   

 

 

 

Landfill

Incineration

FIGURE 3.2.1.2.1 TYPICAL SYNTHETIC ORGANIC MEDICINAL CHEMICAL PROCESS

45

Based on interviews and waste figures provided us by the industry, we have estimated
the average quantities of waste generated per ton of product as shown in Table 3.2.1.2.].
The production of aspirin will generate less waste than the averages given in this table while
the production of certain tranquilizers and vitamins will generate more waste per ton of
product. We believe that the averages we present in Table 3.2.1.2.1 represent the waste
generated for a typical or “average” mixture of synthetic organic medicinal products.

The wastes as shown in this table are segregated into solvents, organic residues,
biological sludge, solid inorganic wastes containing materials such as filter aid and carbon
and heavy metal wastes.

Most of the hazardous waste generated in the synthesis of organic medicinal chemicals
is organic in nature (composed of hydrogen, oxygen, carbon, and nitrogen) and is generally
disposed of by incineration. A limited amount of heavy-metal wastes, such as those
containing mercury, chromium, copper, arsenic, and zinc, is also generated, however.

Zinc waste generally occurs in pharmaceutical chemical production as metallic zinc,
zinc oxide, or zinc chloride. Metallic zinc is used as a reducing agent and its salts as a
catalyst. It is usually recovered (for disposal or recycle) from the reaction mixture by
filtration. The waste zinc salts are recovered by precipitation or solvent evaporation.

TABLE 3.2.1.2.1

ESTIMATED AVERAGE OF CHEMICAL WASTES GENE RATED IN
ORGANIC MEDICINAL CHEMICAL PRODUCTION‘r

Kilogram of Waste per

 

Non-Hazardous Waste Metric Ton Product (dry basis)
— Biological Sludge 1400* (14,000 wet)
(from Organic Chemical Wastewater Treatment) »
— High Inert Content Wastes (Filter and, Activated Carbon) 100
Kilogram of Waste per Heavy Metal Content
Metric Ton Product (kg Per Metric Ton Product
Hazardous Wastes“ (dry basis) of Waste)
— Halogenated Solvent 100
— Non Halogenated Solvent 700
— Organic Chemical Residues
(Tars, Muds, Still Bottoms) 400
— Contaminated High Inert Content Wastes
(Filter and, Activated Carbon) 50
— Solid Heavy-Metal Wastes
Zinc 70 30
Arsenic 15 0.3
Chromium 0.7 0.3
Copper 0.1 0.04
Mercury 0.02 0.01

‘From 2800 kg of solids in organic chemical wastewater.

”Contains some heavy metal, corrosive chemical, or flammable solvent

fSource: Interviews and A.D. Little, lnc., estimates.

46

To put the 2,200 metric tons/yr of zinc waste landfilled by the pharmaceutical in-
dustry in perspective, an estimated 36,000 metric tons of zinc oxide annually finds its way
into landfills throughout the United States as photocopy paper.

Arsenic wastes are generated in the pharmaceutical industry as a by-product of
arsenical production and where arsenic compounds are used as catalysts or oxidizing agents.

We do not believe there is widespread use of chromium or chromium salts in the
pharmaceutical industry. The oxide is used in the heavy chemical industry as one of many
catalysts for hydrogenation and oxidation, and as an oxidizing agent in some organic
chemical syntheses. However, many of these oxidation (dehydration) reactions can be
conducted, using other oxidizing agents, such as chlorates, peroxides or permanganates. In
the one case where we know that chromium is being used in the pharmaceutical industry,
the chromium waste is reCovered by precipitation and filtration and then sold.

We know of only one pharmaceutical company which produces a copper waste, and it
is presently disposed of by deep-well injection.

We estimate that organic mercury wastes containing about 270 kg of elemental
mercury are produced by the pharmaceutical industry annually. A limited number of
pharmaceutical companies produce the mercurial products which include nitromersol and
thimerosal. These companies take considerable care to ensure that mercury is removed from
the plant wastewater effluents.

There are a number of processes available for the removal of mercury from wastewater.
Ion exchange, solvent extraction, carbon adsorption, sulfide precipitation, cementation, and
reduction/precipitation have all been used with varying degrees of success. The type of
mercury-removal process that should be used for a specific application depends on the
following:

0 Concentration of mercury in the wastewater;

0 Maximum allowable concentration of mercury in effluent;

0 Chemical form of the mercury to be removed;

0 Type and quantity of other chemical constituents in the wastewater; and

O Desirability of recovering metallic mercury.

According to our investigations, reduction/precipitation processes are being used in-

creasingly where the wastewater flow rate is relatively small and intermittent. Mercury is
recovered either as pure metallic mercury or as an amalgam.

47

In the most common reduction/precipitation process, which is currently being com-
mercialized, a caustic solution of sodium borohydride (NaBH4) is mixed with the mercury-
containing wastewater where the ionic mercury is directly reduced to metallic mercury
which rapidly precipitates out of solution. The following reaction occurs:

4Hg2++BH4—+ 8 OH” =4Hg+ B(OH)4‘+4H20

If the mercury solution is in the form of an‘organic complex, the driving force of the
reduction reaction may not be sufficient to break the complex. In that case, the wastewater
must be chlorinated prior to the reduction step to break down the metal-organic bond.

When elemental mercury recovery is not desired, the reduction process can be used to
form mercury amalgams to produce a less hazardous solid waste for ultimate disposal by
encapsulation and landfill.

3.2.1 .2.2 Inorganic Medicinal Chemicals

Antacids make up a major share of inorganic medicinal chemical production. Generally
antacids have magnesium hydroxide or aluminum hydroxide as their primary active ingredi-
ent. These antacids are produced by precipitating a water—insoluble compound from a
solution of a soluble aluminum or magnesium salt by a sodium salt. Some formulations also
include magnesium trisilicate, calcium carbonate, sodium bicarbonate, alumina gel, and
bismuth aluminate. The waste stream generated contains no toxic metals or salts and is
usually a solution of sodium chloride or sodium sulfate. Bad batches of antacid active
ingredient may occasionally be produced, and these are either reprocessed or disposed of by
landfilling, but they would also be considered nonhazardous.

We did find one toxic metal-containing waste generated in the production of inorganic
medicinal chemicals. This waste contains about 0.2% selenium and amounts to about
160,000 kg annually.

The pharmaceutical industry produces several laxatives of botanical origin such as
senna, cascara, and a synthetic organic medicinal, phenolphthalein. However, milk of
magnesia (magnesium hydroxide suspension) is the principal inorganic laxative. The produc-
tion of magnesium hydroxide for this use would also generate aqueous sodium sulfate or
sodium chloride.

Active ingredients for many other inorganic medicinals are purchased for products such
as mouthwashes, throat lozenges, and topical medicinals, such as the mercurials, zinc oxide
ointments, and foot powders. Since these purchased active ingredients are produced by the
chemical industry (rather than the pharmaceutical industry), the only waste containing
these purchased ingredients is that generated in the compounding and packaging of pharma-
ceutical preparations.

48

3.2.1 .2.3 Fermentation Products (Antibiotics)

Most commercial antibiotics are the products of living microorganisms, such as fungi
(molds) or bacteria. The crude antibiotic produced by the microorganism is recovered from
the fermentor broth (a water solution containing nutrients) by extraction, precipitation, or
adsorption, depending on the type of antibiotic. Bacitracin, the penicillins, cephalosporins,
and erythromycins are usually recovered from the filtered broth by solvent extraction.
Chlortetracycline is recovered by solvent extraction of the whole broth (containing
mycelium) or filtered broth. Streptomycin is recovered from the filtered broth by ion ex-
change. Oxytetracycline is recovered from the filtered broth by precipitation with a
quaternary ammonium compound.

Following recovery from the fermentor broth, the antibiotic is purified, in most cases,
by several stages of recrystallization. Other antibiotics, such as the semi-synthetic penicillins
and cephalosporin derivatives, are produced by chemically modifying antibiotics produced
by fermentation.

The production of antibiotics results in the generation of several large waste streams:
the filtered micro-organism (mycelium*); the filtered, extracted, fermentor broth; and
contaminated solvent generated in the solvent recovery operation.

The fermentor broth is sometimes concentrated and sold as an animal feed supplement, but
in most cases the fermentor broth and other wastewater streams are treated biologically to
meet effluent requirements. The 0.3 to 0.7 kg of biological sludge generated per kg of dis-
solved organics removed in wastewater treatment is either landfilled or incinerated.

A good example of antibiotic production (and a large volume product) is penicillin as
shown in Table 3.2.1.2.3 and Figure 3.2.1.2.3.

Commercial penicillin is produced by the submerged-culture fermentation process in
which a strain of Penicillium mold is grown in an aerated, stirred tank, the fermentor, in a
water medium. This medium contains carbohydrates (starches, sugars) as an energy source,
nitrogen in the form of ammonium salts or corn-steep liquor solids for mycelium cell wall
protein, and trace minerals, such as magnesium, which are necessary for growth; Rapid
growth of the mycelium takes place during the first 24 to 48 hours and the production of
penicillin takes place from 24 to 120 hours.

 

_*The term mycelium should be reserved for describing the thread-like growth of molds, such as Penicillium,
or the analagous growth in Actinomyces. However, the term is commonly used in the industry to designate
the mixture of cells, filter aid, undigested grain solids, etc., that is filtered off and discarded from all types
of fermentations, including bacterial fermentations that do not produce true mycelia.

49

TABLE 3.2.1.2.3
TYPICAL ANTIBIOTIC PRODUCTION PLANT (PROCAINE PENICILLIN G)
A. Annual Production 950,000 kg
B. Waste Characterization

Weight per 1000 kg Product

Non-Hazardous Waste Stream No. Dry Wet
Mycelium G) 2,300 kg 10,000 kg
Biological sludge (9 3,500 kg 35,000 kg

Non-Hazardous Waste to Biological Treatment
Liters per 1000 kg Product

Waste fermentation broth © 56,000
Crystallization water @ 100
Phosphate buffer solution @ 3,000
Crystallization water (3 100
Potassium chloride solution 4,000
Hazardous Waste
Liters per 1000 kg Product

Solvent Waste Concentrate ® . 1,200

Solvent (butyl acetate) 600

Dissolved organics (fats, protein) 600

Source: Arthur D. Little, Inc., estimates.

Carbohydrate is fed to the fermentor over the course of the fermentation as an energy
source for the mycelium. After the initial mycelium growth phase, a precursor, such as
phenylacetic acid or its salts, is added to increase production of a specific type of penicillin.
The mold uses this precursor directly in producing the penicillin. With phenylacetic acid, the
yield of penicillin G is greatly increased.

The strain of penicillium, the exact composition of the growth medium, the yield of
penicillin, and some details of the purification of the penicillin are trade secrets of the
manufacturers. The penicillin produced and recovered from the fermentation may also be
chemically modified to produce one of many commercial penicillins, but the fermentation
process for initially producing the basic penicillin is generally the same.

A typical penicillin production process (Figure 3.2.1 .23) consists of the initial fermen-
tation in which the antibiotic is produced by the micro-organism, the recovery of the crude
antibiotic from the fermentation broth by several stages of solvent and aqueous buffer
extraction, crystallization of the crude antibiotic, and finally the sterilization of the
antibiotic. The same process steps are used by many producers, but the exact conditions of
pH and temperature and extraction procedures (type of extractor, type of solvent, etc.) will
vary from producer to producer. Likewise there was some variation in quantity of mycelium
waste reported by our industrial contacts. Nonetheless we believe that the system for
penicillin production, as shown in Figure 3.2.1.23, is representative of industry practice and
is representative of the types and quantities of waste generated in penicillin production and
antibiotic production in general. 50

Sodium Phenylecetete

CO
(loogkg)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(300 kg)
Nutrients _ Ferrnentors Cleril‘ier Broéh
(6700 kg) M'd" (280,000 lam") R°""V pH 7.0 end 25 C
Sterilization (7‘ 000 l) Vecuum
Corn Steep Liquor Solids . ' 9' , pm"
Hydrolyzed Sterch Worklng c'm'w
Glucose
Ammonium Nitrate
Magnesium Sullete (10,000 kg) Wet
Seed Culture 5 'I A' Mvcglium Weste
F "" ’ " (2,300 kg dry solids)
Air Sterile Broth
Compressor Filter Chiller
_
Makeup Butyl Acetate
(700 litersl _ Butyl Acetate
l (4200 liters) Sulfuric Acid
(9 Butyl " ' ' (400 kg)
Solvent Waste Butyl Acetate .
(1200 liters) Bu’tavl A"‘"° 3900 liters 7000 liter: Podblelnlek 5
ecoverv ..
600 kg autyl Acetate ‘ ,1 ex‘mm" pH 2.0 Broth at pH 7.0 ‘3‘
. U
600 kg Sollds l Extracted Broth end 4 C E.
3
L® Penincillin in E
Butyl Acetate E
5% Phosphate Butter :3.
Solution at pH 7.5 or ‘
S | P db‘ | . k Potassium Acetate Solution E
o vent 0 le ma .
(3000 I t 5
N30” —"—'. Stripping f Extractor I or i i
(300 kg) Butyl Acetate .- O
N
i I
a“
O _ ‘ ~
6) w s l ‘ r E Q 3 % E
Waste Fermentation Broth "I". .0 “"°" ° - “ 8 3 _.
(56‘000 liters) n-Butenol Penmlllln at pH 6.5—6.8 E E g g
(6700 kg solids) (300° "‘9'” Sulmic Acid g m 3 "
r * { Alternate A Alternate B r (20 kg) "a
pH 2.0 «C
C "r ( Butyl Acetate ‘5
. Butanol 'Yflfl '18 '00 Podbielniek (3000 liters) :5
Water Pheserto Disposal *— Recovery (precipitation) ‘————- Extractor
“00 "‘3'” Water Phfll to
Procaine Penicillin Product Solvent 5“"
(1000 kg) and Disposal
(3 liters) E a 7
Butvl Acetate g E: %
Solution of ‘ a,
VSCW'“ Penicillin E g -“
. Egg
Fm" Potmium Acetate _—.l § L‘.
| (200 kg) S
a
3
Potauiurn Chloride Procaine a
Centrifuge .___. Water Waite HCI ISolvent and Water Condeneer
(4000 More) ‘— 2 .- . V and o
(180 kg KCI) Solvent Waste to end efflulunfion mam"
Butyl Acetate 0
Recovery
5‘3”" Diesolving (1 20 men) 0
Filter *— ka ®
Water Phat. to CD
Filter Solvent Stripplng
end Dupes-l
(100 liters)
. Sterile , . J
Mix Tank ‘ Filter Dlmlzlng ‘
T." Crude Foteuium Penicillin
(700 kg)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Sources: Brunner. Elder, Prescott, Rehm, Standen, Underkofler; Webb and Arthur D. Little, Inc., estlrnates
(see Blbllography at end of Section).

FIGURE 3.2.1.2.3 REPRESENTATIVE PROCESS FOR ANTIBIOTIC PRODUCTION
(PROCAINE PENICILLIN G)

51

(9

Biological Sludge

(3500 kg dry wt.)

Nutrients necessary for mycelia growth and penicillin production are dissolved in water
to form the fermentation medium which is then sterilized by heat, either before or after
being added to the fermentor. Then the medium is cooled to near room temperature
(20—24°C) and inoculated with a concentrated culture of the Penicillium organism, about 5%
by volume. The inoculated medium is agitated by a turbine-type impeller and compressed,
sterile air necessary for the growth of the mycelium is sparged into the fermentor. After
24 hours the mycelium has grown to near its maximum concentration in the fermentor and
penicillin production by the mycelium increases rapidly. Penicillin production continues
with supplemental additions of carbohydrates and a precursor to the end of the fermenta-
tion cycle, about 5 days, when the penicillin reaches near maximum concentration. At this
point the fermentor is harvested and the mycelium is filtered from the spent growth
medium (broth). The filtered broth is chilled to prevent penicillin deterioration and
acidified to liberate penicillic acid which is extracted by a water-immiscible solvent such as
butyl or amyl acetate. The waste broth from this extraction may be neutralized and
discharged to a biological treatment system or concentrated for sale as an animal feed
supplement. The solvent containing the penicillin is extracted with an alkaline buffer to
form the sodium or potassium salt and remove it from the solvent into a water solution. At
this point the crude sodium or potassium salt may be precipitated out directly with a
solvent, or acidified and re-extracted by a water-immiscible solvent followed by neutraliza-
tion and crystallization. Finally, the crude salt is redissolved in water passed through a
sterile filter to a mix tank where it is combined with a sterile precipitating agent, and the
insoluble sterile salt is recovered by centrifuging and then dried in a vacuum drier. As an
alternative to recovery as the potassium or procaine salt, the penicillin may be chemically
modified to other penicillin derivatives before sterilization. In this report, the chemical
modification of antibiotics is considered to be part of the organic medicinal chemical
segment of the industry.

Since the medium in which this living organism, the mycelium, is grown is not toxic
to the organism, the spent medium would also be expected to have low toxicity. This is
generally true. The mycelium from the spent medium (fermentor broth) is incinerated,
landfilled, or used as a soil builder. Some states require that mycelium have a solid content
of 30% or more before it is landfilled, since higher concentrations of water might cause
leaching of hazardous materials from other substances in the landfill. To increase the solids
content of the mycelium from penicillin production, a filler such as sawdust may be added.
Mycelia from other antibiotic fermentations contains filter aid which is necessary for the
filtration of the more gelatinous mycelia produced in these fermentations, and this increases
the solids concentration to an acceptable level.

The extracted, acidified fermentation broth must be neutralized before it can be
disposed of by one of several methods such as incineration, biological treatment, or
concentration and sale as an animal feed supplement. In the case of biological treatment, the
resulting sludge must also be disposed of by incineration or landfill. In figure 3.2.1.2.3 we
have assumed biological treatment of the spent broth and other wastewater streams.

52

The only hazardous wastes resulting from antibiotic production are the waste solvents
which contain organic material from the extracted broth and which are generated in the
recovery of the major portion of the solvent used in the process. In this report, any chemical
wastes from antibiotic modification are considered to be part of synthetic organic medicinal
chemical production.

3.2.1.2.4 Botanicals

The pharmaceuticals produced from plant material — leaves, bark, and roots - include
the alkaloids such as quinine and reserpine, plant steroids for chemical synthesis of
cortisones and oral contraceptives, and laxatives such as emodin from cascara bark.

3. 2.1.2.4.] Alkaloid Production from Botanicals Alkaloids are usually defined as basic
(alkaline), nitrogenous botanical products which produce a marked physiological action
when administered to animals. Commercial alkaloids include quinine, emodin (a cascara
alkaloid), reserpine, and vincristine (a new anticancer drug). The alkaloid content of the
plant material can vary greatly. For example, quinine is present in amounts of up to 10% in
cinchona bark, while vinscristine is present in Vinca rosea (periwinkle) leaf in a concentration
of only about 0.02%.

A process flow sheet for the production of a (alkaloid) botanical medicinal from plant
material is presented as Figure 3.2.1.2.4.l, and Table 3.2.1.2.4.1 summarizes the waste-
streams. The dried, ground plant material (roots, bark, seeds, or leaf) is generally extracted
with an acidified water-miscible solvent such as alcohol and this leachate, in turn, is ex-
tracted with a water-immiscible solvent such as ethylene dichloride. Variations in this pro-
cedure include: (1) using an aqueous solvent mixture of water and alcohol for the initial
extractions, and (2) concentration of the initial alcohol extract before the second (liquid-
liquid) extraction, transferring the alkaloid into the water-immiscible solvent.

The equipment used for the initial extraction may be a series of stirred tanks, each
followed by a filter to remove the plant material, or a series of vessels with wire screen
supports to hold the plant material while the leaching solvent is changed after each
extraction. ‘

The crude alkaloid is recovered from the second (water-immiscible) solvent by vacuum
evaporation and further purified by crystallization, precipitation, ion exchange, or chrom-
atography.

Waste solvent containing plant extract is the hazardous waste generated in the extrac—
tion of the crude alkaloids from plant materials. (The subsequent conversion of these
alkaloids to other derivatives may create additional hazardous wastes, but these wastes
would be included in organic medicinal chemical production.) The extracted plant material
waste must be steamed, however, to remove residual solvent that would otherwise pose a
fire hazard.

53

®

Dried Leaves, Root, Seeds or Bark

 

 

 

 

 

 

 

 

 

 

  
 
   
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(330 kg)
Solvent 60% wt Methanol
Extraction 40% Wt Water 0 . A 'd
. rgamc ca
(leaching) (3500 IIteI'S) (40 kg)
*—
Makeup
Recovered Methanol/Water Methanol/Water
(130 liters) (300 liters)
4.
Wet Plant
Material
To Land III Plant <—‘ and e
Material Concentrate
Concentrated Methanol/Water
Extract
(1100 liters)
Steam (200 kg)
Chlorinated Solvent l . ‘b Methanol/Water
(700 liters) mm'sc' '9 (1100 liters)
Solvent
Makeup Exchange
Chlorinated
Solvent Sodium Hydroxide A
‘7 ”‘9'5’ (10 kg) Alkaloid in Methanoll
Chlorinated Water
Solvent (3200 liters)
V
Chlorinated Crude Alkaloid
Solvent ‘— Recovery Methanol/Water
Recovery (vacuum evaporation) Recovery
Crude Alkaloid G) l
Solvent Waste (130 liters)
40 kg Methanol
Waste Precipitation 20 kg Water
Chlorinated Chromatography 70 kg Plant Extract and
Solvent or lon Exchange Solvent E 5 Organic Acid Salt
(7 liters) Waste

 

 

 

 

 

 

 

 

 

 

 

 

l

Active Alkaloid
(1 kg)

(30 liters)

Source: Forbath, Manske, Nobler and Arthur D. Little, lnc., estimates. (See Bibliography)

FIGURE 3.2.1.2.4.1 REPRESENTATIVE PROCESS FOR BOTANICAL MEDICINALS
(PLANT AL KALOIDS)

54

TABLE 3.2.1.2.4.1

TYPICAL PLANT FOR PRODUCING BOTANICAL MEDICINALS (PLANT ALKALOIDSI

Annual Production 680 kg

Waste Characterization

 

 

Stream No. Weight per kg Product
Non-Hazardous Waste m VB:
Wet botanical material (D 330 kg 660 kg
kg per kg
Botaniwl Material Quantity per kg Product
Liters lg
Hazardous Waste
Halogenated solvent (E 0.03 7 9
Methanol — water concentrate @ 0.36 130 120
Non-halogenated solvent ® 0.06 30 20

Source: Arthur D. Little, Inc., estimates.

55

The solvent waste generated in the initial extraction will contain alcohol, water, and
dissolved plant extract (resins, fats, etc.). In the second step of alkaloid isolation, extraction
of the alkaloid from the aqueous leaching solvent into a water-immiscible solvent, much of
the water-soluble organic material is left behind in the aqueous solvent. Consequently, not
as much of this second solvent (e.g., chlorinated solvent) becomes waste in this process.

In the final purification steps (e.g., crystallization, precipitation) of the alkaloid,
additional waste solvent is generated.

3.2.1.242 Steroid Production from Botanicals Most of the steroid products now
produced commercially were originally extracted from animal organs, requiring tons of
animal organs to produce a few grams of hormone. When the structures of the various hor-
mones and other steroids were determined and synthesis routes were developed, it became
possible to produce many of these hormones commercially on a large scale from steroids
present in plant materials. Soybeans and Mexican yams now supply the steroids stigmas-
terol and diosgenin, respectively, used in the commercial production of cortisone derivatives
and oral contraceptives.

In 1964, over 70% of the cortical hormones were produced from diosgenin from
Mexican yams. Since a high export tax must be paid in Mexico on shipments of crude
product, the diosgenin is extracted from the yams and purified or converted to other steroid
derivatives before export to the United States. Stigmasterol is produced in the United States
by the solvent extraction of soybean oil distillation residue. Table 3.2.1.2.4.2 summarizes the
wastestreams and Figure 3.2.1.2.4.2 shows a representative flow diagram for the latter
process.

TABLE 3.2.1.2.4.2

TYPICAL PLANT FOR PRODUCING BOTANICAL MEDICINALS
(STIGMASTEROL FOR HORMONE SYNTHESIS)

A. Annual Production of Stigmasterol 130 Metric Tons
B. Waste Characterization Weight per MT Product
Non-Hazardous Waste
Fused Soybean Steroid lngots 5000 kg

Still bottoms from soybean oil refining, which contain around 20% stigmasterol and
about 45% B-sitosterol, are dissolved in a hot solvent mixture of hexane and ethylene
dichloride. About 1000 kg of 97% stigmasterol product and 5000 kg of residue are
generated from 6000 kg of feed steriods through a series of crystallizations from a solvent
mixture of 63% ethylene dichloride and 37% hexane by volume. In each crystallization step,

56

 

lngot Casting of Fused Soybean Waste

Molten Sterdids —__'+ Steggctgolflgots

 

 

 

10,000 kg Heptane
35,000 kg Ethylene Dichloride

 

 

 

Solvent Recovery
Steroid Melting

 

 

 

Steroid
4 Solution

 

 

 

 

Solvent Crystallization
Drying Filtration

 

 

 

 

 

Steroid
Solution

l

Feed Dissolving Residue from Soybean
and Filtering ‘———— Oil Refining
(6000 kg)

Filter Cake
Recycled Solvent

 

 

 

 

Steroid
Solution Filter Cake

 

Dissolving
4’ Crystallization
Filtration

l

1000 kg Stigmasterol
Raw Material for Hormone Production
Sources: Poulos et al and Arthur D. Little, lnc., estimates. (See Bibliography)

FIGURE 3.2.1.2.4.2 REPRESENTATIVE PROCESS FOR BOTANICAL MEDICINALS
(STIGMASTEROL FOR HORMONE SYNTHESIS)

57

 

Recycled Solvent

 

 

 

 

 

successively purer stigmasterol is crystallized out by cooling the hot (60°C) solvent solution
to 30°C. The crystals of stigmasterol are recovered by filtration and then redissolved in the
solvent mixture for the next crystallization. At the end of the process, the 97% pure
stigmasterol containing 45-50% solvent is dried in a vacuum oven to less than 0.06% solvent.

Unlike many other’of the extraction processes, the production of the steroid raw
material, stigmasterol, does not generate a hazardous waste stream, but instead generates a
solid waste of fused plant material steroids. The waste residue of soybean steroids from this
extraction process is fused at 160°C which, after cooling to a solid mass, is stored or
landfilled. As an alternative, this mixture of steroid residues (containing about 50%
B—sitosterol) can be processed for recovery of the fi-sitosterol which also can be used as a
steroid raw material. The other major steroid raw material source, diosgenin from Mexican
yams, is imported from Mexico.

In January 1975, GD. Searle & Company announced plans to produce raw material for
steroid synthesis by fermentation of the steroid, {i-sitosterol. Some of the B-sitosterol which
was formerly a waste product may thus be recycled to produce other products.

The conversion of these steroids to cortisone and oral contraceptives is done by a
combination of fermentation and chemical synthesis steps. The wastes generated in these
conversion steps is included as part of the production of synthetic organic medicinal
chemicals (Section 3.2.1 .2.] ).

3.2.1.2.5 Medicinals from Animal Glands

The major medicinal products obtained from animal glands are insulin from beef and
hog pancreas and heparin from lung tissues. Since the extraction processes are similar, we
will use insulin production as an example. On a small scale in the laboratory, insulin can be
extracted from the pancreas by acidic water alone, but on a commercial scale this is
impractical, so acidic 90% denatured alcohol is used. A process for commercial production
of medicinals from animal glands (insulin) is presented in Figure 3.2.1.2.5, and Table
3.2.1 .2.5 summarizes the wastestreams. The ground glands are extracted with acidic ethanol
or methanol and the extract recovered from the ground glands by centrifugation or
filtration. Neutralization of the extract with concentrated ammonium hydroxide to pH 8.0
precipitates extraneous protein. A stronger alkali, such as sodium hydroxide, or too high a
pH will decompose the insulin. The precipitated extraneous protein is filtered, and the
extract is acidified and then concentrated to about a seventh of its original volume by
vacuum evaporation at 20°C. The concentrated extract is raised quickly to 50°C to release
solubilized fats, then cooled to 20°C. The fats are skimmed and recovered for soap
manufacture and the extract filtered to remove additional precipitated protein. Crude insulin
is precipitated by dissolving sodium chloride in the concentrated clarified extract.

The crude insulin is further purified by redissolving the insulin in acidic water and
iso—electric precipitation at pH 5.2 and 4°C. In a final step, zinc insulin is prepared by

58

Ground Glandular Material

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(3200 kg)
(7000 liters Extraction
I Ethanol pH 2.5
Methanol
Water
Hydrochloric
Acid
Extracted Pancreas (3000 kg)
Centrifugation Rendered for Fat Recovery
(clarification) Sold as Feed Protein
36% Hydrochloric Acid _—————p
(80 kg) l
Neutralization Conc. (30%)
pH 8.0 <——-'Ammonium Hydroxide
(1 10 kg)
Precipitated Protein anéilter
“who, Makeup Finer Aid to Landfill
(200 liters) “60 k9 wet)
(80 kg solids)
Acidification Sulfuri; 1 kg Purified Bulk Zinc Insulin
A 'd
P” 3-0 ‘— °' 9 9‘ eo Liters Acidified
(65 kg)
Water
Recycled
Ethanol
Methanol _ Dissolving
Water Evaporgtlon and ‘_.__.._ Zinc Acetate
3‘ 2° C Precipitation (0 2 kg)
55 H o '
Recovered Solvent ( 00 I are) Haat t° 5° C
E (70° "m" 1000 liters @ 50°C A
thanol pH 2_2_5
Methanol
Water ®
Skim Tank Fat: to
Cool to 20°C '——-> Recoverv Wm w n
( 140 kg) r a a
(80 liters)
Precipitated
@ Waste Solvent Solvent Protein and
. F' . .
£33m ‘— Recovery 4:124) lam-ms»
Al h I Landfill Acidified Water
F co 3.] (40 kg wet) 0.04 kg Sulfuric Acid
ats, l s l (20 kg solids)
Dissolving and
. . Crude lsoeIectric Sodium Hydroxide
Sigrglkcrlorlde Insulin —-—. Precipitation I (0.04 k9)
g Precipitation Crude at pH 5.2, 4°C
Insulin
(1.2 kg)

 

Solvent
Strip

 

 

I

Ammonium Sulfate
Sodium Chloride Waste
(400 kg) @

70 liter: @

Water Waste

Sources: Standen, Webb, and Arthur 0. Little, Inc., estimates. (See Bibliography)

FIGURE 3.2.1.2.5 REPRESENTATIVE P

(INSULIN — 1 KG OF PRODUCT)

59

ROCESS FOR MEDICINALS FROM ANIMAL GLANDS

TABLE 3.2.1.2.5

TYPICAL PLANT FOR PRODUCING MEDICINALS FROM ANIMAL GLANDS (INSULIN)

A. Annual Production 284 kg
kg per
kg Animal k
g per k Product
Stream Glands 4—
8. Waste Characterization No. (Dry Wt.) D_rv VE'
Non-Hazardous Waste
Rendered pancreas ® 0.94 3000 -
Protein and filter aid (2) 0.025 80 160
Recovered fats © 0.04 140 —
Protein and filter aid @ 0.006 20 4O
Ammonium sulfate/sodium ® 0.125 400
chloride
Insulin precipitation wastewater (3 0.022 - 70
Quantity per kg Product
Liters I2
Hazardous Waste
Waste solvent concentrate © 0.10 350 320
(Ethanol, methanol, water,
fats, oils)
Precipitation wastewater 0.025 80 80
(May contain traces of zinc) (1~5 gm Zn per kg product)

Source: Arthur D. Little, Inc., estimates.

redissolving the insulin in acidified water and then adding zinc acetate to precipitate zinc
insulin, or plain insulin may be precipitated by using acetone. The solution of sodium
chloride in water and alcohol is solvent-stripped to recover solvent and is then discarded.

The extracted glands are rendered to recover fat (and remove alcohol) and then are
sold as animal feed protein. The precipitated protein containing filter aid is landfilled.

The hazardous wastes generated in this process are the solvent concentrate (containing
fats and oils) left behind when the aqueous alcohol is recovered in the solvent recovery
system and the wastewater from insulin precipitation which may contain traces of zinc salts.
(Treatment of this wastewater with alkali would precipitate any zinc as the hydroxide which
can then be removed by filtration.)

3.2.1 .2.6 Biologicals

The biological products listed in SIC code 2831 include vaccines, toxoids, serum, and
human blood fractions. The vaccines (such as influenza vaccine) are produced by growing
virus mutants in chicken egg embryos, extracting the eg with a salt solution, and precipitat-
ing the active antigen with ammonium sulfate for use in vaccine production. Most toxoid
production today is effected by tissue cell culture of the virus, followed by formaldehyde
treatment of the culture medium to give the toxoid. Salk-type poliomyelitis toxoid is
produced by this method. 60

Tetanus antiserum is produced from the blood of a horse that has been infected with .
the tetanus organism. While the horse itself remains healthy and active, tetanus antibodies
are produced in its bloodstream.

Human blood plasma contains a series of protein fractions that have commercial
medicinal use. Included in these protein fractions are antihemophilic globuhn (to arrest
severe hemorrhaging), gamma-globulins (for prevention of hepatitis, measles, chicken pox,
and tetanus), thrombin (for blood coagulation), and albumin (for treating shock).

The two major classes of biologicals produced in the United States today are virus
vaccines from chicken egg embryos and human blood fractions. A typical process for human
blood fraction production is described below. Whole blood is received from donors (or
obtained from placentas following childbirth) and the cells are removed (by centrifugation)
to yield plasma. The sterile plasma may be used as is, or processed further to produce blood
protein fractions. These protein fractions are precipitated from the plasma at -5°C by adding
ethanol containing sodium acetate-acetic acid buffer in steps to increase the ethanol
concentration and lower the pH. The number of steps and pH at each stage are dependent
on the “method” of fractionation used and the protein fractions desired. The final step of
Method 6 (outlined in Figure 3.2.1.2.6) is precipitation of albumin at pH 5.2 and _40%
ethanol. Following this final precipitation, there is generally less than 2% of the original
plasma protein left in solution.

The cells from the whole blood can be removed and discarded; they are removed for
recovery of erythrocytes (red cells) for therapeutic treatment or, as in more recent practice,
returned to the donor.

The production of commercial quantities of plasma protein fractions does not require
very large equipment. A typical fractionation facility may handle a batch size of 500 liters
of plasma (from over 1500 donors) with a maximum in-process volume of 2000 liters. From
1943-1963, an average of 50,000 liters per year of plasma were fractionated.

After the final precipitation, the diluted plasma contains about 40% ethanol by
volume, less than 1% salts (sodium acetate, chloride, phosphate, carbonate) and about
0.03% protein. This would generate a total waste stream of about 240,000 liters (60,000
gal.) per year of watery waste containing 40% ethanol.

This waste can be (1) diluted and treated biologically, (2) the ethanol can be recovered
and the residual liquor treated biologically, or (3) concentrated and incinerated. About 12
kg of diatomaceous earth per 500 liters of plasma are also used in this process as filter aid.
If placentas are used, when discarded, they are incinerated. The other unwanted solids or
solutions are usually discharged to the sanitary sewer and are handled by the liquid waste
treatment system.

61

1

ethanol
temp.
protein
pH

 

Supernatant |

 

 

 

ethanol 25% J

temp. —5°C
protein 3.0%
pH 6.9

8%
—3°c
5.1%
7.2

PLASMA

7

 

 

Precipitate |

 

 

Fibrinogen

(for treatment of hemophilia)

 

 

 

Supernatant I|+lll

 

 

 

ethanol 18% l
o

temp. —-5 C
protein 1.6%
pH 5.1

7

 

 

Precipitate ll+lll

 

 

Immune Globulins

(for prevention of hepatitis, measles)

 

 

 

Supernatant iV—1

 

 

 

ethanol 40% 1

temp. —5°C
protein 1.0%
pH 5.8

1

 

 

Precipitate IV—1

 

 

Oz—Globulin

 

 

Supernatant lV—4

 

 

 

 

ethanol 40%

temp. —5°C
protein 0.8%
pH 4.8

1

 

 

Precipitate IV—4

 

 

01— and B—Globulins

 

 

Supernatant V

 

 

 

 

Aqueous Ethanol Waste

l

7

 

 

Precipitate V

 

 

10% 1 Albumin

 

l

 

Supernatant

 

 

 

ethanol 40% ;

 

 

 

 

 

 

 

temp. —5°C
protein 2.5%
pH 5.2
L
l
Supernatant

 

 

 

l

Aqueous Ethanol Waste

 

ethanol
temp. —3°C (for treatment of
protein 3% traumatic shock)
pH 4.5
Impurities
7
Albumin

 

 

 

Source: A. Standen, Kirk-Othmer Encyclopedia of Chemical Technology. (See Bibliography)
FIGURE 3.2.1.2.6 DIAGRAMMATICREPRESENTATION 0F METHOD 6 BLOOD FRACTIONATION

62

3.2.1.3 Pharmaceutical Preparations (SIC 2834)

Pharmaceuticals are prepared in dosage forms such as tablets, capsules, liquids, or
ointments from the bulk pharmaceuticals and biologicals of SIC codes 2833 and 2831 and
from other purchased raw materials. The methods used to manufacture these dose forms of
pharmaceuticals are described below:

0 Tablets — The flowsheet for production of coated and uncoated tablets is
shown in Figure 3.2.1.3A. The active ingredient, filler, and binder are
weighed, blended, and granulated. Additional binder, or filler, is added, if
required, and the tablets are produced in a tablet press machine. Some
tablets are coated by tumbling with a coating material and drying. The filler,
(usually starch, sugar, etc.) is required to dilute the active medicinal to the
proper concentration, and binder (such as corn syrup or starch) is necessary
to bind the tablet particles together. A lubricant, such as magnesium
stearate, may be added for proper tablet machine operation. The dust
generated during the mixing and tabletting operation is collected and is
usually recycled directly in the same batch. Broken tablets are generally
collected and recycled to the granulation operation in a subsequent lot.

After the tablets have been coated and dried, they are bottled and packaged.
A small amount of breakage does occur during this operation, and this
does generate some nonhazardous solid waste.

0 Capsules — Empty hard gelatine capsules are produced by machines that dip
rows of rounded metal dowels into a molten gelatine solution and then strip
the capsules from the dowels after the capsules have cooled and solidified.
Imperfect empty capsules are remelted and reused, if possible, or sold for
glue manufacture. Most pharmaceutical companies purchase empty capsules
from a few specialist producers.

Capsule filling and packaging operations are shown in Figure 3.2.1.33. The
active ingredient and any filler are mixed and sometimes granulated before
being poured into the empty gelatine capsules by machine. The filled capsules
are then bottled and packaged. As in the case of tablet production, some dust is
generated. This is recycled and small amounts disposed of. Some glass and
packaging waste from broken bottles and cartons results from this operation.

0 Liquid Preparations — The first step in liquid preparation is weighing the
ingredients and then dissolving“ them in water. Injectable solutions are
packaged in bottles and heat- or bulk-sterilized by sterile filtration and then
poured into sterile bottles. Oral liquid preparations are bottled directly
without subsequent sterilization. There are small amounts of liquid wastes
generated in this process that go to the sewer. Solid wastes are non—
hazardous and consist of broken bottles and some packaging waste.

63

179

 

 

 

 

 

 

 

 

 

Dust to

 

 

Broken Tablets

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

0 Indicates Start of Alternate Process.

Source: Arthur D. Little, Inc.

 

 

 

 

 

 

 

 

FIGURE 3.2.1.3-A PHARMACEUTICAL TABLET PRODUCTION

Recycle or to Recycle
Waste or Waste
Raw Materials Raw Materials GBlemllen-g, Tablet F ‘I‘
Receiving —~—> Storage ranu ating, Compression —.—>‘ 0' "‘9
and Drying
Blending Slugging —__>. Granulating
Pan Coating Tablet Bottle .
and Polishing ————>. Counter __>.. Labeling ——_>. Packing
(
Finished . . Broken Glass
Goods ——>— Shipping to Waste
Storage

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Foiling

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dust to
Recycle or
Waste
Raw Materials Raw Materials
Receiving —"—>‘ Storage Blending Capsule Filling Capsule Printing
Granulating
y and
Drying
4
0\
Ln
Capsule Bottle _
Counter —_"'>' Labeling ——-> PaCk'"9
Finished Broken Glass
Goods ———->- Shipping to Waste
Storage

 

 

 

 

 

 

. Indicates Start of Alternate Process.

Source: Arthur D. Little, Inc.

 

 

 

FIGURE 3.2.1.2-8 PHARMACEUTICAL CAPSULE PRODUCTION

 

O Ointments and Salves — Ointment production is outlined in Figure 3.2.1 .3C.
The active ingredients (zinc oxide, antibiotic, cortisone, or other) are mixed
and then blended with thickening agents such as petroleum jelly or lanolin.
The ointment or salve is then injected into tubes or jars and packaged.

FDA regulations require that all formulations be tested to assure that they contain the
proper concentration of active ingredient, and that all active ingredient have been accounted
for. For this reason, and because of the value of the product, a concerted effort is made by
the pharmaceutical companies to convert as much active ingredient into final product as
possible. This requires as much reprocessing of product as possible and the complete
“running out” of active ingredient during production of the pharmaceutical preparations.
Some formulated material is sent to the sewer in cleanup operations, but typically only a
few kilograms per day of material may be disposed of as solid waste from a large
formulation and packaging operation.

The largest source of waste material that has to be handled at any given time is from
recalled lots of pharmaceuticals. The recall may be due to company action in discontinuing
a product, or due to some product deficiency, such as a loss of potency. In the latter case,
the FDA may enter the picture and require a recall of the questionable lot. Products may
also be recalled due to mislabeling or product mixups. Some of the recalls are readily
correctable and the product can then be reshipped. In other cases it is necessary to destroy
the entire lot. The waste generated in these operations is about 85% broken glass and waste
packaging materials and only about 15% product waste. The product waste, in turn, is
estimated to contain only about 20% active ingredient on the average.

We estimate that the US. pharmaceutical industry disposes of approximately 10,000
metric tons of returned goods annually, primarily consisting of packaging materials and
dilute active ingredient. There are also occasional batches of material that must be rejected
due to cross-contamination, decomposition, and so forth, that must be disposed of. Certain of
the active ingredients and some formulations in bulk form may be hazardous enough to
warrant special disposal. We estimate that approximately 500 metric tons per year fall into this
hazardous category for disposal from plants in SIC 2834.

In addition, we estimated that 75,000 metric tons of general rubbish are produced by the
packaging and shipping sections of the industry. These rubbish wastes consist mostly of glass,
paper, wood, rubber, aluminum and the like. We estimate that only a small fraction of 1 per-
cent of this material consists of active ingredient. The material is disposed of in regular
municipal landfills, together with cafeteria wastes, office wastes, and so forth. For purposes of
this study we do not consider that this waste should be categorized as a “process waste.”

3.2.1.4 U.S. Pharmaceutical Industry Process Wastes and Projections to 1977 and 1983

3.2.1.4.1 Annual Waste of Pharmaceutical Industry

Tables 3.2.1.4.1A and B present our estimates of hazardous and non-hazardous
wastes generated by the pharmaceutical industry in 1973 and their distribution in
the EPA regions. The quantities of each type of waste for the various products were

66

L9

 

 

Raw Materials

Receiving —_'>'

 

 

 

Finished
Goods
Storage

 

 

 

 

 

Raw MateriaIs
Storage

 

 

 

 

Blending or
Homogenizing

 

 

 

 

Tube or Jar
Filler

 

 

L 4

 

 

——> Shipping

 

 

 

Damaged Tubes
or Jars
to Waste

 

 

 

. Indicates Start of Alternate Process.

Source: Arthur D. Little, Inc.

FIGURE 3.2.1.3—C PHARMACEUTICAL OINTMENT PRODUCTION

 

 

 

 

Labeling

 

 

Packing

 

 

 

 

 

TABLE 3.2.1 .4.1.A

1973I
PHARMACEUTICAL INDUSTRY WASTE GENERATION ESTIMATE FOR

Metric Tons Waste (1973)

 

 

 

89

 

 

 

 

Non-Hazardous Hazardous
Industry Segment Dry Basis Wet Basis Dry Basis Wet Basis '
R&D Solvent 66 liters/researcher — — 1,500 1,500
Animals (Incinerated) — — — ~
Heavy Metals (Contract Disposal) — ‘ <1 <1
Total for R&D — — 1,500 1.500
SIC Code 2833: Production at Active Ingredients
Organic Medicinal Chemicals (34,000 Metric Tons/Yr) Tons/Ton Product
‘.
Biological Sludge (trom Wastewater Treatment) 14 47,600 476,000
High Inert Content Waste — NonAHaZardous (Filter aid, activated carbon) 0.1 3,400 6,800
High Inert Content Waste — Hazardous (Contaminated filter aid, activated carbon) 0.05 1,700 3,400
Organic Chemical Residue (Tars, muds, still bottoms) 0.4 13,600 13,600
Halogenated Solvent 0.1 3,400 3.400
Non-Halogenated Solvent 0.7 23,800 23,800
Heavy Metal Wastes
Zinc 0.070 2,200 2.2“)
Arsenic 0.015 450 450
Chromium 0.001 20 20
Copper (0.001 4 4
Mercury (0.001 1 ‘|
Total for Organic Medicinal Chemicals 51 ,000 482,800 45,175 46,875
Rounded to 51 .000 480,000 45,000 47,000
Inorgnic Medicinal Chemicals
Heavy Metals (i.e., selenium) 200 200
Total (or Inorganic Medicinal Chemicals 200 200
Antibiotics (by Fermentation, 10,000 Metric Tons/Vr)
Mvcelium (plus filter aid and sawdust) 7.5 tons (drv wt)/ton antibiotic 75,000 300,000 — —
Biological Sludge (from wastewater treatment) 3.5 tons/ton antibiotic 35,000 350,000 — —
Waste Solvent Concentrate 1.2 tons/ton antibiotic — — 12,000 12,000
Total for Fermentation (Antibiotics) 110,000 650,000 12,000 12,000
Botanicals (Plant Alkaloids, 2,000 Metric Tom/Yr Plant Material)
Wet Plant Material 1 ton (dry basis) per ton plant material 2,000 4,000 - —
Aqueous Solvent Concentrate 0.36 ton/ton plant material — — 720 850
Halogenated Solvent 0.03 ton/ton plant material — — 60 60
Non-Halogenated Solvent 0.06 ton/ton plant material — - 120 120
Total for Plant Alkaloids (Botanical) 2,000 4,000 900 1,030

69

TABLE 3.2.1 .4.1 .A (Continued)

Metric Tons Waste (1973)

 

 

 

 

 

 

 

 

Non-Hazardous Hazardous
Industry Segment Dry Basis Wet Basis Dry Basis Wot Buis'
Botanicals (Plant Steroids, 150 Metric Tons/VI Stigmastarol)
Fused Plant Steroid Ingots 5 tons/ton stigmasterol 750 750 - —
Total for Plant Stermds 750 750 — —.
Modicinals from Animal Glands (8000 Metric Tons Clams/Yr)
Tons/Ton Animal Glands
Extracted Animal Tissue 0.940 7,500 7.500 — —
Fats or Oils 0.044 350 350 - —
Filter Cake (contains prxipitated protein) 0.031 250 500 — —
Aqueous Solvent Concentrate 0.100 — — 800 1 .600
Total lor Medicinals lrorn Animal Glands 8,100 8.350 300 1,600
Total for Production 01 Active lngredients (SIC Code 2833) 172,000 \ 1,143,000 59,000 62,000
SIC Code 2831: Biological Products
Aqueous Ethanol Waste lrorn Blood Fractionation 5 liters/liter plasma — — 250 600
Antiviral Vaccine — — 300 300
Other Biologicals (Toxoids, serum) — - 200 200
Total for Biological Products SIC Code 2831 - - 750 1,1(1)
SIC Code 2834: 'r‘r—r ‘ ' 17‘: i (For ' 'r‘ ' and Returns)
Total Returned Goods (Primarily packaging material and dilute active ingredient) 10,000 10,000 — -—
Contaminated or Decomposed Active Ingredient — — 500 500
Total for Pharmaceutical Preparations 10,000 10.000 500 500
Totals for all lndustrv Segments 181 .850 1,153,000 61,650 65,100
Rounded to: 182,000 1 ,153.000 62,000 65,000

'Wet weight estimates are given for all wastes. The two wastes that typically have the highest moisture content are biological sludge and mvcelium from lermentations. Where the wet waste estimates are the same as
on the dry basis, the waste is usually disposed of with only a minor amount at moisture. However, disposal practices vary lrom plant to plant, depending on the form in which the waste is produced.

fSource: Arthur D. Little, lnc., estimates.

0L

Industryfigmmt

R&D

Synthetic Organic
Medicinal:

 

Fermentation
IAntibiotisl

Botanicals

Fused Plant Steroids
Animal Source

W5

Formulation, Packaging.
Returned Goods

Heavy Metal Wastes from
Orpnic and lnorgar-‘c
WM Prochction

TABLE 3.2.1.4.13

DISTRIBUTION OF PHARMACEUTICAL INDUSTRY WASTE GENERATION (1973)?

Waste Type

Solvent

Biological Sludge

Inert Wastes

Contain. lnerts
Halogenated Solvents
Non-Halogenated Sovent
Org-tic Residues

Mycelia (Dry Basis)
Biological Sludge
Waste Solvent Carmen.

Plant Material

Aqueous Solvent
Halogenated Solvent
Non-Halopnated Solvent

Animal Tissue
Fats or Oils
Filter Cake
Aqueous Solvent

Waste Solvent
Other

Returned Goods
Active Ingredient

 

 

La’nd: Non-Hug = Nonllazardotas

 

 

 

 

 

 

 

 

Metric TonsWaste
Mom I a II a..." lll Reg-o" IV Reg‘on v Rajon VI Region VII fiejon VIII Rfl‘ IX Total
Nonflu. “a Marlin. H“ Non-Hal Hal. Non-flu. Haz. Non-Mu. Ila: Non-Hal. Hal. Non-Hal. Hal. Non-Hal. "ll. Non-flu. Non—Nu. H:
_ 73° _ _ — - — 420 — 60 - 60 — — — ran — LSOD
28,600 A — 4,800 - 4,800 — 7.100 — 400 — 700 — — — L200 — 41m _
2,000 — 300 -— 300 — 500 — 50 — 100 — — - 150 — 3.400 —
— 1,000 — ‘50 — 150 — 200 — _ _ too — — — roo — 1,700
- 2,000 ill) — 300 — 500 — 50 — 1w — - — 150 - 3,400
— 14,3)0 — 2,4“) 2.4!!) — 3,600 _ 150 _ 350 _ _ _ an _ 233w
— 8.2m — LIN — IAN — 2,1“) _ 50 ._ 150 _ _ - m _ 13.6“)
34,000 — 7.9m — — — 13.000 — _ _ 1,000 _ _ _ 2,500 _ 75 M _
15,0“) — 3.500 - — — 14,000 — _ _ 7m _ _ _ 1_7m _ 3m _
— 5,000 — l.200 - — — 4.800 _ _ _ 200 _ .. _ mo _ ‘2!!!)
1,2!” — zoo — 200 — 300 —- _ _ __ _ _ _ 1m _ 2m _
- 420 — III) — 50 — 1w _ _ _ - .. _ _ 5o _ 72°
— 30 — 10 — 5 — 10 _ _ _ - - _ _ 5 _ m
— 60 - 20 - I0 — 20 _ _ - _ _ _ _ 10 _ 12°
———————————————————————————————— DistributionNotDam-mined——————————————————-———»———————— 750 -
4,400 — 740 — 740 - 1,200 — _ _ 2m _ _ _ 220 _ 7 m -
200 — 5 - 35 — 50 - — — 15 — — — 15 - £0 —
140 — II) — 30 — 40 — — - 5 — — — 5 — 250 _
- 500 - w — 00 - I20 — — _ m _ _ _ 7o _ m
— 25 — 25 - 2s — so - — — 50 — — — 65 - 250
— 50 — so — 50 - 120 - — - too — — — 130 - 500
4,400 — LII!) 1.000 — 1.800 — 300 — 500 — — — 9w —— 10M —
— 220 — 60 — 50 - 90 — 15 - 25 — — — 40 - son
———————————————————————————————— DistributionNotDetermimd———————-——————~———-—-———————— 2.9“)
r
Totalsfor All lnt‘hstry 52mm; 18150 61,860
Handed to: 132m 82.!!!)

Mu. = Hazardous

'm mm: o. Lam, Inn, «tin-mes

extrapolated to an annual (1973) basis from data gathered at the plants visited using
the following three methods:

1. Production of a given pharmaceutical product at the plants visited compared
to total industry production in the United States;

2. Value of production of a pharmaceutical product at the plants visited as a
percentage of annual total value of that product in the United States; and

3. Generation of a given waste as related to total value of production or
number of production employees.

We estimated the total annual quantity of solvent waste originating from R&D
Operations on the basis of quantities generated per researcher at the facilities we visited.
Since test animals are routinely incinerated on-site and the amount of heavy metal waste is
very small and disposed of by waste disposal contractors, we did not include figures for
these wastes in this table.

The production of organic medicinal chemicals creates waste solvents, chemical tars
and residues, wet filter aid or carbon, some heavy metal waste, and biological sludge from
on-site or off-site biological treatment of water-soluble organic compounds, such as acetic
acid or alcohol. The wet filter aid or carbon may be non-hazardous or may contain
contaminating materials such as solvent, corrosives or heavy metals that render it hazardous.
(The heavy metal contents of the heavy metal wastes listed in Table 3.2.1.4.1A were
presented earlier in Table 3.2.1.2.1.) Many pharmaceutical companies also produce crude
antibiotics and growth stimulants such as arsanilic acid for the animal feed industry, but
these products are not listed as part of SIC code 2833. Several companies are also producers
of some heavy chemical fermentation products, such as citric and itaconic acid, but these
again are not part of SIC code 2833.

Inorganic, medicinal, chemical, active-ingredient production usually generates non-
hazardous aqueous waste salt solution and little or no solid hazardous waste. In addition, a
large portion of the active ingredients for manufacture of inorganic medicinals is purchased
from the heavy chemicals industry.

Fermentation is used for the production of most crude antibiotics, for chemical
conversion of some steroids, and for the production of some industrial heavy chemicals. The
fermentation, product recovery, and purification processes result in considerable quantities
of non-hazardous wastes, such as mycelia and spent nutrient broth. The main hazardous
waste generated is a solvent concentrate. This waste contains organics from recovery of
solvent used in the product recovery and purification sections of the process. The weight of
dry mycelia waste per ton of product is considerably higher for other antibiotics than it is
for penicillin, since it is necessary to use a significant amount of filter aid to remove the
mycelia from the broth and the yields of some of the other antibiotics per ton of mycelia is

71

. lower. Some State regulations also require a minimum solids content of the mycelia waste
for landfill disposal, so an additional filter such as sawdust must be added to increase the
solids content.

The extraction of botanicals, such as roots and leaves, and animal organs, such as
pancreas glands or lung tissue for alkaloid, steroid, and hormone products, respectively, is
usually accomplished using acidic aqueous alcohol and often requires a second halogenated
solvent in the purification process. These solvents are recovered for reuse, thus generating a
waste solvent concentrate. The wet botanicals are disposed of by landfill,but the animal
organ by-products (extracted glands and fats) are sold when possible.

The quantities of returned goods and active ingredients disposed of were projected as
being proportional to the total value of production.

The major wastes generated in the production of biologicals include aqueous alcohol
‘ and dissolved salts from human blood plasma fractions and formaldehyde-egg waste from
antiviral production. There is a limited amount of production of other biologicals, such as
horse serum products and toxoids, but the total production of biologicals is quite small
compared to the production of other pharmaceuticals.

Heavy metal wastes occur mostly in the production of organic medicinal chemicals. In
some cases, such as the selenium waste, the waste stream is unique to one process and one
manufacturer. In other cases, there are several producers that have a similar waste heavy
metal (mercurials), and yet other heavy metal wastes, such as zinc compounds, are found
throughout the industry. This factor was taken into consideration in estimating the annual
generation of each of these heavy metal wastes.

In Table 3.2.1.4.lB we have apportioned the waste generation figures for the whole
United States, as listed in Table 3.2.1.4.1A, among the various EPA regions. Our estimates
of waste generation distribution are based on production figures for antibiotics, synthetic
organic medicinals, and biologicals of the pharmaceutical companies in these regions. Waste
generation from R&D facilities was estimated from PMA data showing locations of R&D
personnel. Location of , major formulation and packaging facilities was used to estimate
distribution of returned goods. Regions I and II were combined in Table 3.2.1.4.1B to avoid
disclosure of confidential information on production or waste stream data on plants in
Region I which has only one large plant in SIC 2833.

Waste generation on a state-by-state basis is presented in Table 3.2.1.4.1C. Regional
and national totals are also given. State totals for heavy metals are not estimated because of
the difficulty in estimating the specialized use of these materials in individual plants. State
estimates for mycelium waste generation have also been omitted, because only 16 major
fermentation installations produce antibiotics in the continental United States. Seven states
have only one. plant each, one state has two, one state has. three, and only one state has four
major plants. Again, state-by-state figures on mycelium production would divulge confiden-
tial information on several companies. Many states have so few people employed in the
pharmaceutical industry that the waste is considered insignificant, and blanks therefore
appear in the table. The reason for the spotty distribution is apparent when one considers
that SIC code 2833 (which contributes almost all the hazardous and nonhazardous waste
from the industry) contains only 54 installations that have more than 20 employees each.

72

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I I I I I I I I I I I I I 39.8 552 _._>
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03.5 I 8" . can So . 83. 8. o I 8 8m 8n." 8.. a 8m 45> 5: ._
I I | I I I I I I I. I | | 0915: {NZ —>
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I I I I I I I I I I I I I lie: x.
mm . I 8.. on H I 9. I I o. 8 8 E 5.35.2 ._>
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I I I I I I I I I I I I I 332:3. >_
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ink 15...... 39!. :2... .153: .i... .3529... .53 it: 5.3 "Earns. Isle-6. 35:81:..az . 3.3.1.2.:
.3515: . I 585.:

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may 2. >xhw3oz_ ._<u_._.3mo<sE<:n_ wzh >m nmh<¢wzw0 w._.m<.s no zo_._.Dm_m._.m.o nwk<s=hmw

Up.v.F.N.M w..m<._.

73

3.2.1 .42 Typical Types of Pharmaceutical Hazardous Wastes and Their Properties

Table 3.2.1.4.2 lists the typical types of hazardous waste materials discharged from
pharmaceutical operations. The physical, chemical, and biological properties of the hazard-
ous constituents of these wastes are listed in Appendix B.

3.2.1.4.3 Projections of Pharmaceutical Process Wastes to 1977 and 1983.

Medicinal ingredient production in the United States has increased at an annual
compounded rate of 6.3% for the past 20 years. Also, prescription numbers have been
increasing at approximately the same rate. However, we note that production has sometimes
slackened during recessions, and thus we anticipate that the present energy shortages and
disruptions of the economy may have an adverse effect on medicinal ingredient production
in the immediate future. We are therefore projecting waste increases on the basis of a 3
percent compounded rate until 1977. We expect passage of a National Health Care Act in
1976 and believe that growth will then be slightly above historical trends. We have therefore
projected waste growth from 1977 to 1983 on the basis of a 7 percent compounded rate.
Final effluent guidelines have not been set for the pharmaceutical industry. We examined
the preliminary recommendations for the industry and concluded that the guidelines will
not add to the tonnage of wastes to be landfilled from air and wastewater treatment pro-
cesses. Projections of hazardous and non-hazardous wastes by industry segments for 1977
and 1983 are shown in Table 3.2.1.4.3A. The totals of hazardous and non-hazardous waste
generated in 1973 and the waste generation factors for each waste (metric tons of waste per
metric ton of product or raw material) were developed earlier in Table 3.2.1.4.1A and
Section 3.2.1.2.]. The projected distribution of wastes by state was calculated from Ta-
ble 3.2.1.4.1C by using the same 3 percent and 7 percent compounded rate referred to above.
Estimates of state data for 1977 are presented in Table 3.2.1.4.3B and for 1983 in
Table 3.2.1 .4.3C. Due to rounding, totals of the various tables may not agree exactly.

74

TABLE 3.2.1.4.2

SUMMARY OF TYPICAL TYPES OF
PHARMACEUTICAL HAZARDOUS WASTE MATERIALS?

Antibiotics (Penicillin, Tetracyclines, Cephalosporins)

Recovery Solvents
Amyl acetate
Butanol
Butyl acetate
Methylisobutyl ketone

Purification Solvents
Butanol
Acetone
Ethylene Glycol Monomethyl Ether

Alkaloids (Ouinine, Reserpine, Vincristine) from Plant Material

Extraction Solvents
Methanol
Acetone
Ethanol
Chloroform
Heptane
Ethylene Dichloride

Crude Steroids from Plant Material
Still bottoms (Soybean Oil Residue)

Medicinals from Animal Organs (Insulin, Heparin)
Ethanol
Methanol
Acetone

Synthetic Organic Medicinals

Typical Solvents
‘Acetone
Toluene
Xylene
Benzene
lsopropyl alcohol
Methanol
Ethylene Dichloride
Acetonitrile
Organic Residues (Still Bottoms, Sludges,
Polymers, Tars)
Terpenes
Steroids
Vitamins
Tranquilizers

Blood Plasma Fractions

Solvent
Ethanol

fSource: Arthur D. Little, lnc., estimates.

75

Purification Solvents
Ethylene Dichloride
Naphtha
Methylene Chloride
Benzene

lnert Solids (Generally Non-Hazardous)
Activated Carbon
Filter Aid
Filter Cloths
Heavy Metals
Copper
Mercury
Arsenic
Selenium
Zinc
Chromium

Salts
Sodium Acetate
Sodium Chloride
Sodium Phosphate

TABLE 3.2.1.4.3A

ESTIMATES OF PHARMACEUTICAL INDUSTRY GENERATED WASTES FOR 1973, 1977 AND 1983*
(All Figures in Metric Tons Per Year)

1973 1977 1983
Non-Hazardous Halardous Non—Hanrdous Hazardous Non-Hazardous Hazardous
Industry sogmonl Dry Basis Wat stasist Dry Basis Wet Basis'r Dry Basis Wet Basist Dry Basis win Basisf Dry Basis Wet Basis' Dry Basis Wu Basis
RBrD ‘
Solvent ’ — 1.500 1.500 — — 1.900 1.900 — - 2,700 2,700
Total REID ‘ — 1.500 1.500 — ‘— 1.900 1,900 — — 2,700 2,700
SIC Code 2833: Production of Active Ingredients
Organic Medicinal Chemicals (34,000 Metric Tons/Yr)
Biological Sludge (from wastewater treatment) 47,600 476.000 — — 53,600 536,000 — — 80,400 804,000 — —
High inert Content (filter aid, carbon) 3,400 6,800 — — 3,800 7,600 W 2 5,700 11,400 — —
Contaminated High Inert Content (i.e., filter aid and solvent) — - 1,700 3,400 - — 1,900 3,800 -— — 2,900 5,800
Organic Chemioel Residues (tars, mud, still bottoms) — — 13,600 13,600 — -— 15,300 15,300 — — 23,000 23,000
Halogenated Solvent " — 3.400 3.400 - - 3.800 3.300 — 7 5.700 5.700
Non-Halogenated Solvent - — 23,800 23,800 — — 26,800 26,800 — — 40,000 40,000
Heavy Metal Wastes
Zinc Compounds — — 2,200 2,200 — — 2,500 2,500 — - 3,700 3,700
Arsenic Compounds - — 450 450 — — 500 500 — - 750 750
a Chromium Compounds — — 20 20 — — 22 22 — ~ 35 35
Copper Compounds -— — 4 4 — — ’ 4 4 — — 6 6
Mercury Compounds - — 1 1 — — 1 1 — —— 1 1
Total for Organic Medicinal Chemicals 51,000 482,800 45,175 46,875 57,400 543,600 50,827 52,727 86,100 815,400 76,092 78,992
Rounded to: 51,000 480,000 45,000 47,0“) 57,000 540,000 51,000 53,000 86,000 815,000 76,000 79,000
Inorganic Medicinal
Heavy Metals (i.e., selenium waste) - — 200 200 — - 225 225 — — 350 350
Antibiotics (by Fermentation, 10,01!) Metric Tons/Yr)
Mvcelium (plus filter aid and sawdust) 75.000 300.000 — — 34.400 338.000 '- ~ 127.000 508.000 — -—
Biological Sludge 35,000 350,000 - - 39,400 394,000 — — 60,000 1 600,000 — —
Waste Solvent Concentrate — - 12.000 12.000 — — 13.500 13.500 - - 20.000 20.000
Total for Antibiotics 110,000 650,000 12,000 12,000 123,800 732,000 13,500 13,500 187,000 1,108,000 20,000 20,000
Rounded to: 110,000 650,000 12,000 12,000 124,000 730,0“) 14,000 14,000 190,000 1,100,000 20,000 20,000
Botanical: (Plant Alkaloids, 2,000 Metric Tons/Yr Plant Material)
Wet Plant Material 2.000 4.00.0 — - 2.250 4,500 — — 3,400 6.800 - —
Aqueous Solvent Concentrate — — 720 850 — — 810 960 — — 1,200 1,400
Halogenated Solvent - - 60 60 — -— 70 70 — — 100 100
Non-Halogenated Solvent — — 120 120 — - 140 140 — — 200 200
Total for Plant Alkaloids 2,000 4,000 900 1,030 2,250 4.500 1,020 1,170 3,400 6,800 1,400 1,700
Botanicals (Plant Steroids, 150 Metric Tons/Yr Stigmastarol)
Fused Plant Steroid lngots 750 750 - — 840 840 — — 1,000 1.000 - —

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ll.

TABLE 3.2.1.4.3A (Continued)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1973 1977 1983
Non-Hazardous Halardous Non-Hazardous Hazardous Non-Hazerdous Hazardous
Industry Segment Dry Basis Wet Basist Dry Basis Wet Basist Dry Basis Wat Basis? Dry Basis Wet BasisT Dry Basis Wet Basist Dry Basis We! Basist
Madicinals from Animal Glands (8,000 Metric Tons Glands/VI)
E xtracted Animal Tissue 7,500 7,500 — — 8.400 8,400 —— — 12,500 12,500 —— —
Fats or Oils 350 350 — — 400 ‘ 400 — — 600 600 — —
Filter Cake (Containing protein) . 250 500 — v 280 560 - — 420 840 — —
Aqueous Solvent Concentrate — - 800 1,600 — — 900 . 1,800 — — 1,350 2,700
Total Medicinals Irom Animal Glands 8,100 8,350 800 1.600 9,080 9,360 900 1,800 13,520 13,940 1,350 2.700
Total for Production 01 Active lngredients (SIC Code 2833) 172,000 1,143,000 59,000 62,000 193,000 1,285,000 67.000 70.000 294,000 1,937,000 99,000 103.000
SIC Code 2831 : Biological Products
Aqueous Ethanol Waste lrom Blood Fractionation — - 250 600 — — 280 680 — ~ 400 1.000
Antiviral Vaccine — — 300 300 A — 350 350 — — 500 500
Other Biologicals — — 200 200 — ~— 225 225 — - ' 350 350
Total for Biological Products — — 750 1,100 r — 855 1,255 — r 1,250 1.850
SIC Code 2834: Pharmaceutical Preparations
Returned Goods 10,000 10,000 — — 1 1,300 11,300 — — 17,000 17,000 — —
Contaminated or Decomposed Active Ingredient — — 500 500 A — 600 600 — - 900 900
10,000 10,000 500 500 1 1,300 1 1,300 600 600 17.000 17,000 900 900
Totals for All Industry Segments 181,850 1,153,000 61,650 65,100 204,300 1,836,300 70,445 73,755 311,000 1,954,000 103,850 108,450
Rounded to: 182,000 1,153,000 62.000 65.000 204,000 1,836,000 70,000 74,000 310,000 1,954,000 104,000 108,000

‘Source: Arthur D. Little, Ino, estimates.

tWet weight estimates are given for all wastes. The two wastes that typically have the highest moisture content are biological sludge and
rnycelium from lermentations. Where the wet waste estimates are the same as on the dry basis, the waste is usually disposed of with only
a minor amount of moisture, However, disposal practices vary from plant to plant. depending on the form in which the waste is produced.

8L

TABLE 3.2.1.4.38

PROJECTED DISTRIBUTION BY STATE OF WASTES GENERATED BY THE PHARMACEUTICAL INDUSTRY IN 1977
(annual metric tons — dry basis)

 

 

 

 

 

Hazardous Non-Hazardous
1 Organlc" Conlammated ‘ Plant Mateml‘ High Inerts3'6
Halogenated Non Halogenated (Chemlcall High Inerts Act-we HI-vy Total 3.0109153” Antmzl “sue, Waste Returned Total
State Solvent Waste Solvent Waste Res-dues Waste Ingredtent Metals Hazardous‘ Sludge Fats, Oil INon-HalJ' Goods Myanum7 Nomi-humans”
IV Alabama 7 7 7 7 _ _ - —
X Alaska 7 7 77 _ 7 7 7- *-
IX Arizona 77 7 7 7 7 7 _ _ 7 —
VI Arkansas 77 - 7 7 7 100 7 10 80 7 ‘90
IX Calllornia 370 1,800 430 110 .45 7 2,005 3,300 370 I 70 1,010 7 4.850
VIII Colorado 7 7 7 7 7 7 7 7 _ _ 7 -—
I Connecllcul 220 1,600 560 110 20 7 2,510 3,400 450 110 340 - 4300
III Delaware 7 77 7 7 7 7 7 7 7 7 7 —
IV Honda 45 450 280 30 6 7 811 560 110 35 110 — 815
IV Georgta 70 560 220 30 5 7 886 560 110 35 110 — 815
[X HawaII 7 7 7 7 7 7 7 _ _ 7 7 —
x Idaho 7 77 7 7 7 7 7 _ _ _ 7 —
V Illlnois 340 3,300 860 80 35 7 4,615 7,900 560 200 680 — 9.340
V Indlana 370 3,500 910 80 35 — 4,895 3,500 630 210 730 — 1ONO
VI I Iowa 35 150 55 20 6 7 266 790 120 55 I10 7 1 .075
Vll Kansas 7 7 7 7 7 7 _ 7 7 _ — -
IV Kentucky 7 77 7 77 7 7 7 _ 7 _ — - —
VI Louismna IO 10 6 7 7 — 26 45 7 10 35 — 90
I Mame 7 7 7 7 7 7 7— .7 7 7 7 - '—
IIl Maryland 7 7 7 7 7 7 7 530 80 20 go 7 870
I Massachusetts 7 77 7 7 _ 7 7 680 110 ”0 HO - 1,010
V Mlchigan 220 2,100 510 45 20 - 2.895 5,200 330 130 450 - 5-1 5°
V Mlnnesola 77 — 7 7 7 - — 7 _ 7 7 — -
Iv Mississlppi 7 7 7 7 . 7 7 990 220 55 220 — 17395
VII MIssourI 120 490 190 80 20 7 900 790 so 40 340 ~ 1550
VIII Montana 7 7 7 7 7 7 7 7 7 7 — — —
VII Nebraska 20 90 35 10 7 7 155 7 40 20 I10 - ‘70
Ix Nevada 7 7 7 7 7 _ 7 _ _ _ 7 7 7
I New Hampshtre 7 7 7 7 7 _ 7 _ _ _ 7 — —
II New Jarsey 1,800 12,400 5,300 550 130 7 20,190 27,200 3,600 1,300 2,700 — 34300
VI New Mextco 7 7 7 7 7 _ 7 _ _ _ 7 — —
II New York 900 6,760 2,000 340 70 7 10,670 13,500 1,800 680 1,350 — 17.330
IV North Carollna 110 1,000 620 55 20 7 1,805 1,700 340 130 340 — 2510
VIII North Dakota 7 7 7 _ 7 7 _ _ 7 _ 7 _ 7
v 01110 80 680 170 10 10 7 950 1,700 120 45 130 7 1.996
VI Oklahoma 77 7 7 7 _ 7 _ 7 _ _ _ 7 7
X Oregon 7 7 7 7 _ 7 _ _ _ __ _ _ _
III Pennsylvama 300 3, 700 1,400 150 55 7 5,605 7,300 900 230 960 — 9.440
II Puerto Rico 220 2,200 340 110 20 _ 3,390 4,300 550 220 450 7 5.530
| Rhode Island 7 7 7 7 7 _ 7 7 _ 7 _ 7 7
IV South Carolina 7 7 7 7 7 7. 7 560 I 10 20 110 — m
VIII South Dakota 7 7 7 .7 7 7 7 7 7 7 7 —
lV Tennessee 110 900 510 55 20 7 1.595 1,100 220 90 220 — LSJD
VI Texas 1 10 160 50 77 15 7 335 300 — 35 220 — 565
VIII Utah 7 7 7 7 7 _, _ 7 7 _ 7 7 7
| Vermont 7 — 7 77 _ 7 _ 7 _ _ _ 7 7
III VIrginia 45 620 220 20 1o 7 915 1,200 110 55 160 - 1,525
X Washington 7 7 7 7 7 7 _ _ _ _ 7 — 7
III West Virgtma 7 7 7 7 7 7 220 35 10 35 — 3w
v WISconsin 35 220 55 10 7 . 320 450 55 10 35 - 550
VIII Wyoming 7 -- 7 7 7 7 _ 7 7 _ 7 — -
National Totals 5,530 42,690 15,871 1,905 543 3,250 56,539 93,035 11,110 4,085 11,235 84,000 119,465
Region Totals
1 220 1,600 560 I10 20 -- ' 2.510 4,080 560 220 450 - 5.310
II 2,920 21,360 8,740 1,010 220 7 34.250 45,000 5,900 2,200 4.500 - 57.660
III 345 4,320 1,620 170 65 ,7 6.520 9,400 1,125 365 1.245 — 12.135
IV 335 2,910 l,630 170 52 —~ 5.097 5,380 1,110 365 1.110 - 7.965
v 1,045 9,800 2,505 225 100 — 13,675 23.850 1,745 595 2,025 - 23.215
v1 120 170 56 7- 15 ~ 361 445 7 55 335 - 835
VII 175 730 280 110 26 - 1.321 1,530 240 115 560 - 2,495
VIII 77 7 7 _ 7. 7 7 7 7 — — 7
Ix 370 1,800 480 110 45 7 2.805 3,300 370 ‘70 1.010 — 0,50
x 7 7 7 _ 7 7 - — 7
Notes: 1. Includes REID solvent waste 5, Wet weight dry welght x-l72,
2. Includes biological product alganlc wastes 6. Includes liltet cake from animal source pharmaceuticals. 'lexcludes "(excludes
3. Wet weight '7' dry weight x 2. 7, Wet walght ’ dry welght x 435 "Ht-'9 myoattum)
4. Wet weight 1 dry weight x 10.

6L

TABLE 3.2.1.4.30

PROJECTED DISTRIBUTION BY STATE OF WASTES GENERATED BY THE PHARMACEUTICAL INDUSTRY IN 1983
’ (annual metric tons — dry basis)

 

 

 

 

 

H-urdou: NmHu-rdous
Organic 3 Cumin-10113 PIant MatariaIs Hig- 1mm“
Halomm‘ Non-Halogenmd (Chaniiull High 1m Amin Hoary Total aiolooieaI‘ Animal Til-II, w-to Returnod 7 You
State Solvent Waste Solvom Wane n-iouaa Waste thdiom Metals Hazardous - sundae Fun Oil (Non-Hal.) Good medium Nwfln-fllws "
IV Alabama _ _ _ _ _ _ _ _ _ - _ _ _
x Alaska _ , - _ - _ _ _ _ _ _ _ _
Ix Arizona - _ _ - - _ _ - _ _ _ — —
VI Arkanras — — — — _ - — 150 — 15 I 20 — 285
Ix CaliIornia 560 2,700 730 170 70 — 4,230 4,900 560 250 l .500 — 7,210
VI ll Colorado - _ _ _ _ _ _ _ _ 2 _ _ -
l Connecticut 340 2,400 640 170 30 — 3,730 5,100 600 I 70 510 64460
III Del-var: _ - _ _ _ _ _ _ _ — _ — —
IV FInrioo 70 680 420 40 10 — 1,220 840 I70 50 170 — 1.230
IV Georgia loo 840 340 40 10 — 1,330 040 170 50 I 70 — 1.230
Ix Hawaii _ _ _ _ _ _ _ _ _ _ - — —
x Idaho - _ _ - _ _ _ _ _ _ _ - _
v Illinois 510 4,900 1,300 120 50 — 6,880 11300 640 300 1.000 — ”.940
v 560 5,200 1,400 120 50 — 7,330 12,900 950 320 1.100 — 15.170
VII 50 220 35 30 10 - 395 1,200 190 05 I70 _ 1,645
VII Kansas 9 _ _ _ _ _ _ _ _ _ _ - —
IV Kontueky _ — - _ _ _ _ _ _ - _ _ —
VI Louisiana 15 15 lo — — _ 4o 70 - 15 50 — 135
I Maine _ _ _ _ , _ _ _ _ _ A _ _
Ill Maryland _ A — — _ _ _ 1,000 120 30 130 _ 1.290
I Massachusens — — — — - _ _ I ,000 I 70 I70 170 — 1,510
V Miohigan 340 3,200 760 70 30 _ 4,400 7 900 570 200 680 — 9,250
V Minnotota _ — - - _ _ _ _ _ _ _ _ _
IV Mississippi — — — — — _ a 1,300 340 85 340 — 2,065
VII Missouri 190 740 290 120 30 _ 1,370 1,200 120 60 510 _ 1,890
VIII Montana _ _ - _ _ _ _ _ _ _ - _ _
VII Nebraska 30 1 30 50 15 — _ 225 — 60 30 I 70 - 260
Ix Nevada _ - _ _ _ _ _ - _ _ — _ _
| New Hampshire — — v _ _ _ _ _ _ _ _ _ _
II New Jersey 2,700 18,600 7,900 840 200 .. 30,240 40,900 5,400 1,900 4,000 — 52,200
VI New Maxioo - _ _ _ - - _ _ _. — _ _ _
II New Vork 1,300 10,100 3,900 510 100 _ 15,910 20,300 2,700 1,000 2,000 _ 26,000
IV North Carolina 170 1,500 930 65 30 _ 2,715 2,500 510 200 510 - 3,720
VIII North Dakota _ _ - _ _ a _ - _ — — — —
v Ohio 120 l ,000 250 15 15 ~ 1,400 2,500 190 70 200 — 2,960
VI Oklahoma _ — _ — _ a _ _ — — — — —
x Oregon _ -— _ _ _ - _ _ — — — — —
111 Pennsylvania 460 5,600 2,100 220 30 - 9,450 11000 1,300 420 1,400 — 14,120
II Pma Rico 340 3,400 1,300 170 30 _ 5,240 6.400 1340 340 680 — 9.260
I Rhode Island _ _ _ — - _ _ _ — . - — — -
Iv South Carolina — — — — - _ - 340 170 30 170 _ 1,210
VIII South Dakota _ _ _ _ .. _ _ _ — _ — — —
IV Tennessee 170 1,300 760 85 30 _ 2,345 1,700 340 130 340 _ 2510
VI Texas 170 240 00 — 25 — 515 460 — 50 340 _ 350
VIII Unh _ ._ _ _ _ _ _ _ _ _ _ _ _
I Vermont _ - _ _ - _ _ _ - - _ _ _
III Virginia 70 930 340 30 15 _ 1,385 1900 170 as 240 _ 2,395
x washington - _ _ _ - _ _ _ _ _ — _ _
III Wlst Virginia _ _ — — — _ _ 340 50 15 50 _ 455
v WIlconain 50 340 85 15 — - 490 $0 as 15 50 - 8:10
VIII Wyoming _ _ - _ _ _ , _ _ _ _ _ _
National Touls 9,315 64,035 23,070 2,965 615 4,900 99,900 139,620 16,695 6,065 16,770 127,000 I 79,070
Rogioml Tot-II
1 340 2,400 040 I70 30 — 3,780 6,100 850 340 600 — 7,970
ll 4,340 32,100 13,100 1,520 330 — 61,390 67500 3,940 3,240 6,600 — 66,490
II I 530 6,530 2.940 250 95 — 9,045 14,240 1,640 550 1,020 — 18,250
IV 510 4,320 2,450 250 00 — 7,6I0 0,020 1,700 545 1,700 - 11,965
V 1,590 14,640 3,795 340 145 — 20,500 35,500 2,635 905 3,030 — 42.150
VI 195 255 90 — 25 — 655 680 — 90 510 — 1.270
VI I 270 1,090 425 165 40 — 1.090 2,400 370 175 850 - 3,795
VIII — — - _ _ .. ._ _ _ ._ _ _ _
Ix 560 2,700 730 I 70 7o — 4,230 4,900 560 250 1,500 — 7,210
x _ _ _ _ _ _ _ _ _ __ _ - _
Moms: 1. lncludls nu) rolvont mm. 5. Wet weight = dry weight )1 1.2. 'lmluhs mm
2. lrlcludn biologic-l producl organic min. 6. Includu (ilur elk! from animal source phnrmaumiclla. "(cxcludu myoelium)
3. Wet weight - dry might x 2. 7. Wet weight - dry weight 71 4.35.

4. We: "3’“ - dry miflu x ‘0.

DATA SOURCES FOR SECTION 3.1
A. GENERAL SOURCES

Manufacturers’ Technical Bulletins — This is usually the best single source of
general information about the compound.

Material Safety. Data Sheets — Provided by the manufacturer using the US
Department of Labor Form OSHA-20 or an approved modification.

Code of Federal Regulations — Office of the Federal Register, Archives and
Record Service, Washington, DO, 1972. Titles 46 (Shipping) and 49 (Transportation) in the

most recent revision available.

Chemical Safety Data Sheets — Manufacturing Chemists Association, Washington,
DC.

Industrial Safety Data Sheets — National Safety Council, Chicago, Illinois.

International Maritime Dangerous Goods Code — Inter-Governmental Maritime
Consultative Organization (IMCO), London, 1972.

Petroleum Products Handbook — V.B. Guthrie (ed.), McGraw—Hill, New York,
1960.

Glossary of Terms Used in Petroleum Refining — 2nd edition, American Petroleum
Institute, New York, 1962.

The Handling and Storage of Liquid Propellants — Office of Defense Research and
Engineering, U.S. Government Printing Office, Washington, DC, 1963.

Industrial Chemicals — W.L. Faith, D.B. Keyes, and R.L. Clark, 3rd edition, Wiley,
New'York, 1965.

Chemical Technology of Petroleum — W.A. Gruse and DR. Stevens, 3rd edition,
McGraw—Hill, New York, 1960.

Chemical Rocket/Propellant Hazards — CPIA Publication No. 194, Vol. III, 1970.

Organic Solvents — J.A. Riddick and W.B. Bunger, 3rd edition, Wiley-Interscience,
New York, 1970.

Transport of Dangerous Goods — (4 vols) United Nations, New York, 1970.

80

Kirk-Othmer Encyclopedia of Chemical Technology — lst edition (1947-1960)
and 2nd edition (1963-1970), Interscience-Wiley, New York.

Evaluation of the Hazard of Bulk Water Transportation of Industrial Chemicals, A
Tentative Guide — National Academy of Sciences, Washington, DC, 1970; includes supple-
ment with additions to September 1972.

System for Evaluation of the Hazards of Bulk Water Transportation of Industrial
Chemicals — National Academy of Sciences, Washington, DC, 1974.

B. HEALTH HAZARDS

Industrial Hygiene and Toxicology — F.A. Patty, 2nd edition, "Vol. II, Inter-
science, New York, 1963.

Toxicity and Metabolism of Industrial Solvents — E. Browning, Elsevier, New
York, 1965.

Practical Toxicology of Plastics — R. Lefaux, CRC Press, Cleveland, Ohio, 1968.

Industrial Toxicology — L.T. Fairhill, Williams and Wilkins, 2nd edition, Balti-
more, Maryland, 1957.

Toxicology of Drugs and Chemicals— W.B. Deichmann and H.W. Girarde,
Academic Press, New York, 1969.

Clinical Toxicology of Commercial Products — M.N. Gleason, et a1., 3rd edition,
Williams and Wilkins, Baltimore, Maryland, 1969.

Handbook of Toxicology: Acute Toxicities of Solids, Liquids and Gases to
Laboratory Animals — W.S. Spector, Saunders, Philadelphia, Pa., 1956.

Occupational Diseases: A Guide to Their Recognition — US Department of
Health, Education, and Welfare, Public Health Service Publication No. 1097. Superintendent
of Documents, Washington, DC, 1964.

First Aid Textbook — American National Red Cross, Washington, DC, 1972.

Electrical Safety Practice: Odor Warning for Safety — Monograph 1 13 Instrument
Society of America (ISA), Pittsburgh, Pa., 1972.

Toxic Substances — Annual List 1973 — H.E. Christensen, US. Department of
Health, Education, and Welfare, Superintendent of Documents, Washington, DC, 1973.

81

Encyclopedia of Occupational Health and Safety, Two Volumes, International
Labour Organization, Geneva, 1972.

Fawcett, H.H., Toxicity vs. Hazard, pages 279-289, and Foulger, J .H., Effect of
Toxic Agents, pages 250-278, in Fawcett and Wood, Safety and Accident Prevention in
Chemical Operations, Interscience, Wiley, New York, 1965 .

Murphy, Sheldon C., The Toxicity of Pesticides and Their Metabolites, pages
313-335, in Degradation of Synthetic Organic Molecules in the Biosphere— Natural,
Pesticidal, and Various Other Man-Made Compounds, Proceedings of a Conference, San
Francisco, California, June 12-13, 1971, Committee on Agriculture and the Environment,
ISBN 0-309-02046-8, National Academy of Sciences, 2101 Constitution AVenue, N.W.,
Washington, DC. 20418, 1972.

C. FIRE HAZARDS

The Fire and Explosion Hazards of Commercial Oils— W. Vlachos and CA.
Vlachos, Vlachos and Co., Philadelphia, Pa., 1921.

1972 Annual Book of ASTM Standards— American Society for Testing and
Materials, Philadelphia, Pa., 1972.

Fire Protection Guide on Hazardous Materials — 5th edition, Nos. 325A, 325M, 49,
491M, and 704M, National Fire Protection Association (NFPA), Boston, Mass., 1972.

Fire Protection Handbook — G.H. Tryon (ed.), 13th edition, National Fire Protec-
tion Association (NFPA), Boston, Mass., 1969.

Handbook of Industrial Loss Prevention — 2nd edition, Factory Mutual Engineering
Corp., McGraw-Hill, New York, 1967.

D. WATER POLLUTION

Water Quality Criteria Data Book — Vol. 1 — Organic Chemicals (1970) and Vol.
2 — Inorganic Chemicals (1971), Vol. 5 —— Effect of Chemicals on Aquatic Life (1974),
United States Environmental Protection Agency, Superintendent of Documents, Washing-
ton, D.C.

Engineering Management of Water Quality — P.H. McGauhey, McGraw-Hill, New
York, 1968.

The BOD of Textile Chemicals — Proceedings of the American Association of
Textile Chemists and Colorists, American Dyestuff Reporter, August 29, 1966, p. 39.

Biodegradable Surfactants for the Textile Industry — American Dyestuff Reporter,
January 30, 1967.

82

Water Quality Criteria — J .E. McKee and MW. Wolf, 2nd edition, California State
Water Quality Control Board, Sacramento, California, 1963.

Water Quality Criteria — National Technical Advisory Committee, Federal Water
Pollution Control Administration, Washington, DC, 1968.

OHM-TADS (EPA) — The Oil and Hazardous Materials Technical Assistance Data
System (OHM-TADS) has been developed by the Environmental Protection Agency (EPA)
to provide information on physical and chemical properties, hazards, pollution character-
istics, and shipping information for over 800 hazardous materials. OHM-TADS consists of a
computerized data base which can be accessed from terminals at the 10 EPA Regional
Offices and from EPA Headquarters in Washington, DC. The system can provide either
information on specifically requested properties for a material, or it can print all the
information in its files for that material.

Water Quality Characteristics of Hazardous Materials, ,4 Volumes, f R.W. Hann,

Jr. and Paul A. Jensen, Environmental Engineering Division, Civil Engineering Department,
Texas A&M University, College Station, Texas, 1974.

83

BIBLIOGRAPHY FOR ANIMAL ORGAN EXTRACTS AND BIOLOGICALS
ANIMAL ORGAN EXTRACTS

Standen, A. (editor), Kirk—OIhmer Encyclopedia of Chemical Technology, 2nd Edit.,
V01. 11 (1966) pp. 838-845.

Webb, F.C., Biochemical Engineering, D. Van Nostrand Co., London (1964), pp.
539-540.

BIOLOGICALS

Standen, A. (editor), Kirk-0thmer Encyclopedia of Chemical Technology, 2nd Edit.,
Vol. 111 (1966) pp. 576-601.

Webb, F.C., Biochemical Engineering, D. Van Nostrand Co., London (1964) pp.
449-450.

84

DATA SOURCES FOR SECTION 3.2
BIBLIOGRAPHY FOR ANTIBIOTIC MANUFACTURE
PENICILLIN

Brunner, R., G. Machek, E. Brandl and A. Schmid, Die Antibiotica Band I Die
Grossen Antibiotica Verlag Hans Carl, Nurnberg (1962) pp. 285-37 6.

Elder, Albert L. (editor), “Centrifugal Solvent Extraction” in The History of Penicillin
Production, Chemical Engineering Progress Symposium Series, No. 100, Vol. 66 (1970),
American Institute of Chemical Engineers, Chap. VI.

Prescott, 8.0, and CG. Dunn, Industrial Microbiology, 3rd Edit., McGraw—Hill
(1959), pp. 77-784.

Rehm, Hans—Jurgen, Industrielle Mikrobiologie, Verlag Springer, Berlin (1967) pp.
159—180.

Standen, A. (editor), Kirk-Othmer Encyclopedia of Chemical Technology, 2nd Edit.,
Vol. 14 (1967) pp. 688-707.

Underkofler, L.A., and Richard Hickey, Industrial Fermentations, Vol. 11, Chemical
Publishing Co., New York (1954) pp. 226-384.

Webb, F.C., Biochemical Engineering, D. Van Nostrand Co., London (1964) pp.
549-550, 645-661.

TETRACYCLINE

Rehm, Hans—Jiirgen, Industrielle Mikrobiologie, Verlag Springer, Berlin (1967) pp
215-219.

Forbath, T.P., “Tetracycline: Engineered to Market,” Chemical Engineering, (March,
1957) pp. 228-231.

BACITRACIN AND ERYTHROMYCIN

Underkofler, LA. and Richard Hickey, Industrial Fermentations, Vol. 11, Chemical
Publishing Co., New York (1954) pp. 304-308,316-3l8.

85

BIBLIOGRAPHY FOR BOTANICAL MEDICINALS
ALKALOIDS

Forbath, T.O., “Liquid Extraction Commerciallizes Reserpine” Chemical Engineering
(April, 1957) pp. 230-233.

Manske, R.H.F., The Alkaloids, Vol.1, Chap. I “Sources of Alkaloids and their
Isolation.”

Nobler, Carl L., Chemistry of Organic Compounds, 2nd Edit., W.B. Saunders, Co.
(1957) pp. 648-655.

STEROIDS

Nobler, Carl L., Chemistry of Organic Compounds, 2nd Edit, W.B. Saunders, Co.
(1957) pp. 868-872.

Krieg, Margaret B., Green Medicine, Rand McNally (1964) pp. 269-291.
Poulos, Arthur; J .W. Greiner and GA. Fevig. “Separation of Sterols by Countercurrent
Crystallization,” Industrial and Engineering Chemistry, Vol.53, No. 12 (December 1961)

pp. 949-962.

Underkofler, L.A., and Richard Hickey, Industrial Fermentations, Vol.11, Chemical
Publishing Co., New York (1954) pp. 398-410.

86

4.0 TREATMENT AND DISPOSAL TECHNOLOGIES
4.1 BACKGROUND

Approximately 244,000 metric tons of land-destined process wastes (dry weight basis)
are generated annually by the pharmaceutical industry.* The amount of hazardous wastes
generated is about 25 percent of the total waste, or 61,000 metric tons per year. The waste
generation rate is expected to grow to nearly 400,000 metric tons of total wastes per year
and to 100,000 metric tons of hazardous wastes per year by 1983.

4.2 DESCRIPTION OF PRESENT TREATMENT AND DISPOSAL TECHNOLOGIES

Approximately 85 percent of current total wastes generated and 60 percent of current
hazardous wastes generated are estimated to be both treated and then disposed of by
contractors. Of the current total wastes generated, ADL estimates that 60 percent, or
150,000 metric tons, are disposed of on land. About 9 percent, or 5600 metric tons, of
current hazardous wastes generated are disposed of on land. These percentages reflect the
extensive use of incineration by the pharmaceutical industry both on-site and by contractors
off-site. Where possible, materials are recovered for reuse. Secure chemical landfills and
encapsulation techniques are now being used — and will most probably be in the future —
for the disposal of heavy metal wastes which are too dilute or contaminated for recovery,
and general process wastes of a non-hazardous nature.

The current process waste treatment and disposal methods are briefly described in
Section 4.2.1; for each hazardous waste identified in Chapter 3, current treatment and
disposal practices are discussed in Sections 4.2.2 to 4.2.6. Section 4.2.7 describes the
treatment and disposal methods discussed in the sections on hazardous waste treatment and
disposal.

4.2.1 Present Treatment/ Disposal Technologies for General Process Wastes
(Hazardous and Non-hazardous)

4. 2. 1. 1 Research and Development

Numerous large pharmaceutical companies have research and development operations.
In fact, there are currently 25,000 researchers within the industry.

The wastes from this industry section include:

0 waste solvents and still bottoms, and
0 test animals.

 

*See Table 3.2.1.4 for summary of total process wastes and potentially hazardous wastes for the
pharmaceutical industry in 1973.

87

Waste solvents and still bottoms (1500 metric tons annually) are either disposed of by
contract incineration, or are company-incinerated, if the research facility is located near
pharmaceutical manufacturing operations with liquid incineration capability.

Test animals are either rendered or incinerated. Large animals are rendered with the
bones converted to bonemeal. Small animals are usually incinerated and the inert ash is sent
to a landfill. Often these small animals are either autoclaved or frozen, if the animals are not
to be incinerated immediately.

4.2.1.2 Production of Active Ingredients (SIC 2831 and 2833)
4.2.1 .21 Organic Medicinal Chemicals

Pharmaceutical companies manufactured about 75 million pounds of organic medicinal
chemicals in 1973.* The wastes from these operations include:

0 waste solvents, halogenated and non-halogenated;

0 organic chemical residues;

0 biological sludge (from organic chemical wastewater treatment);
0 heavy metals, and

0 high inert content wastes such as filter cakes.

With the exception of the biological sludge and part of the high inert content wastes,
they are all hazardous wastes. The present methods of hazardous waste treatment and
disposal are discussed in more detail in Sections 4.2.2 through 4.2.6.

The pharmaceutical industry recovers a large amount (95 percent or more) of its
process solvents for reuse. Those solvents that are considered wastes come from solvent-
recovery operations. Essentially all of these waste solvents are incinerated, either on-site or
by contractors off-site. Organic chemical residues are usually incinerated, although some
operations are sending them to landfills off-site.

ADL surveyed about 25 to 30 percent of the pharmaceutical companies’ production
capacity of organic chemicals for this study. Of those visited, half had on—site biological
treatment of waste water; 90 percent disposed of the resulting sludge in off-site landfills.

Heavy metals are used as catalysts, oxidants, and product ingredients in the production
of organic medicinal chemicals. A limited amount is used within the pharmaceutical
industry (see Section 3.2.1.21). The locations using heavy metals are also limited. The heavy
metal wastes are handled in various ways, including recovery off—site and encapsulation and

 

*See Section 3.2.1.2.
88

landfill in a separate section of a landfill. These methods are discussed further in Section
4.2.5.

The properties of the high inert content wastes vary greatly. ADL estimates that as
much as 30 percent of those materials are potentially hazardous because of flammability,
corrosiveness, or toxicity. The remaining 70 percent are innocuous materials, such as filter
aid and water or charcoal and water, which are usually landfilled. Of the 30 percent that are
potentially hazardous some are considered potentially hazardous from the standpoint of
flammability because of the presence of solvent. These can be rendered non-hazardous by
incineration. About 25 companies incinerate this material. The remainder of the potentially
hazardous waste must be landfilled with special precautions because they contain material
such as heavy metals. These cannot be incinerated.

4.2.1.2.2 Inorganic Medicinal Chemicals

Since most inorganic medicinal-chemical active ingredients are purchased from
sources outside the pharmaceutical industry, there is little waste produced in this industry
section. Preparations such as stomach antacids are, however, generally produced within the
pharmaceutical industry. While the majority of the process waste leaves with the water
effluent, there may infrequently be reject materials, such as aluminum hydroxide or
magnesium hydroxide. These wastes may be landfilled.

The only hazardous waste stream we found in this industry segment was a waste which
contained about 0.2 percent selenium. The waste, about 160,000 kg per year, is in its most
insoluble form, the sulfide, when it is disposed of by a contractor in a state-approved secure
chemical landfill.

4.2.1.2.3 Fermentation Products

When active ingredients such as antibiotics are produced by fermentation, three types
of wastes that are destined for land disposal are also produced.* They are:

0 Mycelia;
0 Biological sludge from spent broth treatment;
0 Solvent concentrate (hazardous waste, see section 3.2.1 23).

Because there are few companies involved in fermentation and most of the operations
are large scale, ADL was able to study about 65 percent of the US. fermentation
production capacity. The volumes of waste from such operations represent a significant
problem to the industry.

 

* Figure 3.2.1 .2.3 shows the waste generation from a typical fermentation product — penicillin.

89

Of the estimated 75,000 metric tons of mycelia (on a dry basis) produced by
fermentation operations each year, ADL estimates that 85 to 90 percent of the waste is
land-disposed at some off-site location. Of the remainder, some portions are incinerated or
used as soil builders. In the past, ocean dumping was used for mycelia disposal, until 1972
EPA regulations on ocean dumping halted this practice temporarily by invoking stricter
requirements on analysis of wastes prior to permit renewals. A typical large operation has on
the order of 25,000 to 45,000 metric tons of mycelia to 'dispose of each year. Since this
material is wet (generally 25 to 35 percent solids after dewatering), it must be disposed of
immediately to eliminate odor problems.

Many disposal methods have been investigated. When mixed with 1 percent lime, for
example, mycelia can be used as a soil builder. It can also be incinerated, but the water
content is too high for the operation to be cost-effective. Although this waste is not
considered hazardous, it is indeed a problem for the industry.

Waste broth solids are high-volume materials which can either be disposed of as a waste
or can be changed to a useful by-product. About 72,000 metric tons are produced annually
by fermentation operations. Until stricter effluent restrictions were placed on fermentation
operations, the spent broth was usually treated biologically, producing a sludge that was
landfilled. Approximately 0.5 kg of biological sludge is produced for each kg of waste broth
solids. Since the spent broth contains a significant amount of food value, it can be
concentrated by evaporation and sold as a molasses substitute in animal feeds. Still some
operations handle the broth as a waste either because the capital investment for the
equipment is too great, or because there is no market for the concentrate. None of those
operations producing the broth concentrate are making a profit, just breaking even at best.
On the other hand, they do not have the significant cost of biologically treating the high
BOD waste. Occasionally the waste broth is incinerated, even though incineration is
expensive because of the relatively low-Btu content of the waste broth.

The third type of waste, the solvent concentrate, which is a waste product of solvent
recovery operations, contains as much as 50 percent by weight of organic solids. About 50
million pounds of the concentrate is produced annually by fermentation operations within
the United States. Sixty-five percent of the pharmaceutical industry fermentation produc-
tion capacity was surveyed. The waste solvent concentrate at all these locations was
incinerated either on-site or by contractors off-site. Because of the similar nature of the other
plants in this industry, we estimate that all of this waste is currently being incinerated,
either on-site or by contractors off—site. Because this waste is flammable, it is considered
hazardous. Disposal is discussed further in Section 4.2.2.2.3.

4.2.1.2.4 Botanicals
Medicinal active ingredients, such as alkaloids and steroids, are obtained from plant

material. The wastes potentially destined for land disposal are listed below, the last two
being hazardous:

90

O Moisture-laden plant material,
0 Waste solvent (50 percent solids and 30 percent water), and
0 Waste chlorinated hydrocarbons.

A typical alkaloid operation* produces 1820 kg per day of wet waste plant material
and operates 250 days per year. This totals to 454 metric tons per year of waste plant

material. The waste is steamed to remove residual solvent and is then sent to sanitary landfill
off-site.

Three types of solvents are used in the extraction process to produce alkaloids. The one
used in the initial extract ends up with water, plant extract, and organic acid salts
after solvent-recovery operations. This waste solvent is either incinerated on-site or by
contractors off-site. A second water-immiscible, chlorinated solvent, is used to extract the
alkaloid from the first solvent. More of the chlorinated solvent can be recovered than the
first solvent which contains most of the water-soluble organic material after extraction. But,
since this second solvent is chlorinated, problems can develop if it is incinerated without the
proper precautions. The amount of chlorinated solvent is only 5 cubic meters (1,250
gallons) per year for the typical plant, five percent of the total solvent. This amount is small
enough to drum for contractor incineration. We estimate that 60 percent of each of the two
waste solvents are incinerated on-site and the remainder off-site by contractors. A third waste
solvent is non-halogenated.

4.2.1 .25 Drugs from Animal Sources

Medicinal products such as insulin or heparin are obtained from animal sources. The
wastes from these operations that are destined for land disposal include:

rendered organs or animal tissue;

fats and oils;

filter cake, containing precipitated protein; and

aqueous solvent (hazardous waste, see Section 3.2.1.2.5).

The typical extraction operation** will dispose of 839 metric tons of organs or animal tissue
annually in the production of 284 kg of active ingredient. Two methods of disposal are used
interchangeably in most operations. When a market exists, the waste product is sold as a
protein-source feed for animals; otherwise it is disposed of in a sanitary landfill. The fats (40
metric tons per year) are recovered for sale to soap manufacturers. The filter cake (25.5
metric tons per year), which contains precipitated protein, is landfilled or incinerated if the
operation is near other pharmaceutical operations with incineration capability.

 

* Figure 3.2.1 .2.4.1 presents the flow scheme of waste generation for a typical alkaloid operation.
* *Figure 3.2.1.2.5 describes the waste generation in a typical operation extracting glandular materials.

91

The hazardous waste from the operation in which medicinals are obtained from animal
glands is a waste solvent emanating from the solvent-recovery system. A typical operation
produces 91 metric tons (25,000 gallons) of waste solvent annually, a generation rate of 350
liters per kilogram of product. These solvents, which contain 50 percent water and 25
percent organic solids, are incinerated either on-site or by a contractor off-site.

4.2.1 .2.6 Biological Products

Some pharmaceutical companies manufacture biological products such as blood prod—
ucts, vaccines, serums and toxoids. The wastes from these operations include:

0 Aqueous solvent waste;
0 Miscellaneous incineratable wastes; and
0 Filter material.

ADL estimates that SIC 2831 has 500 metric tons of hazardous waste. Most of this amount
is considered hazardous because of its flammability. All hazardous wastes are incinerated
either on-site or by contractor off-site. The filter material contains only traces of protein
and can be landfilled.

4.2.1.3 Formulation and Packaging (SIC 2834)

The wastes from the formulation and packaging segment of the pharmaceutical
industry are returned goods and reject material.* The total returned goods and reject
material from this segment annually are indicated below:

0 Glass, paper, water, etc. 10,000 metric tons
0 Active ingredient 500 metric tons

Normal trash waste from the formulation and packaging segment of the industry is handled
in much the same way as in other industries. Paper, cartons, and the like, not identifiable as
the company’s own can be recycled through salvage dealers, while materials bearing the
company’s name are either shredded or incinerated on-site. -

Returned goods are handled specifically by the formulating and packaging operations
of a company. “Controlled drugs,” such as narcotics, must be destroyed in the presence of
Drug Enforcement Agency (DEA) personnel, according to the regulation which is presented
on the next page. Other pharmaceuticals are handled in a method detailed by the specific
company and pharmaceuticals recalled by the FDA may be required to be destroyed under
FDA observation. Generally, non-salvageable goods are crushed on-site and then sent to
landfill. Smaller percentages are either incinerated or are slurried with water which is sent to
an activated sludge treatment facility.

 

*Section 3.2.1.3 discusses waste generation in this industry segment.

92

T Source:

Federal Regulations: . Disposal of Controlled

§ 1307.15 Incidental manufacture of
controlled substances.

Any registered manufacturer who, in.
cidentally but necessarily. manufacture;
a controlled substance as a result of the
manufacture of a controlled substance
or basic class of controlled substance for
which he is registered and has been is.
sued an individual manufacturing quota
pursuant to Part 1303 of this chapter (ii
such substance or class is listed in sched-
ule I or 11) shall be exempt from the
requirement of registration pursuant to
Part 1301 of this chapter and. if such
incidentally manufactured substance is
listed in schedule I or 11. shall be exempt
from the requirement of an individual
manufacturing quota pursuant to Part
1303 of this chapter. if such substances
are disposed of in accordance with
§ 1307.21.

Drsrosn. or Commoner: Sussnncss

§ 1307.21 Procedure for disposing of
controlled substances.

. (a) Any person in possession of any
controlled substance and desiring or re-
quired to dispose of such substance may
request the Regional Administrator of
the Administration in the region in
which the person is located for author-
ity and instructions to dispose of such
substance. The request should be made
as follows:

(1) If the person is a registrant re-
quired to make reports pursuant to Part
1304 of this chapter. he shall list the con-
trolled substance or substances which
he desires to dispose of on the “b” subpart
of the report normally filed by him, and
submit three copies of that subpart to
the Regional Administrator of the Ad-
ministration in his region;

(2) If the person is a registrant not
required to make reports pursuant to
Part 1304 of this chapter, he shall list the
controlled substance or substances which
he desires to dispose of on DEA Form
41. and submit three copies of that form
to the Regional Administrator in his reg-
ion; and

(3) If the person is not a registrant.
he shall submit to the Regional Admin-
istrator a letter stating:

(l) The name and address of the
person:

(ii) The name and quantity of each
controlled substance to be disposed of ;

(iii) How the applicant obtained the
substance. if known; and

(iv) The name, address, and registra-
tion number. if known. of the person
who possessed the controlled substances
prior to the applicant. if known.

(b) The Regional Administrator shall
authorize and instruct the applicant to
dispose of the controlled substance in
one of the following manners:

 

93

PharmaceuticalslL

(1) By transfer to person registered
under the Act and authorized to possess
the substance:

(2) By delivery to an agent of the
Administration or to the nearest oflice
of the Administration;

(3) By destruction in the presence of
an agent of the Administration or other
authorized person; or

(4) By such other means as the Re-
gional Administrator may determine to
assure that the substance does not be-
come available to unauthorized persons.

(c) In the event that a registrant
is required regularly to dispose of con-
trolled substances, the Regional Admin-
istrator may authorize the registrant to
dispose of such substances. in accord-
ance with paragraph (b) of this section,
without prior approval of the Adminis-
tration in each instance, on the condi-
tion that the registrant keep records of
such disposals and file periodic reports
with the Regional Administrator sum-
marizing the disposals made by the regis-
trant. In granting such authority, the
Regional Administrator may place such
conditions as he deems proper on the
disposal of controlled substances, includ-
ing the method of disposal and the fre-
quency and detail of reports.

(d) This section shall not be construed
as aflecting or altering in any way the
disposal of controlled substances through
procedures provided in laws and regula-
tions adopted by any State.

[36 RR. 7801. Apr. 24. 1971. as amended at
37 FR. 15922. Aug. 8, 1972]

§ 1307.22 Disposal of controlled sub-
stances by the Administration.

Any controlled substance delivered to
the Administration under § 1307.21 or
forfeited pursuant to section 511 of the
Act (21 U.S.C. 881) may be delivered to
any department, bureau. or other agency
of the United States or of any State upon
proper application addressed to the Ad-
ministrator, Drug Enforcement Adminis-
tration. Department of Justice, Washing-
ton, DC. 28083. The application shall
show the name. address, and official title
of the person or agency to whom the con-
trolled drugs are to be delivered, includ-
ing the name and quantity of the sub-
stances desired and the purpose for
which intended. The delivery of such
controlled drugs shall be ordered by the
Administrator, if, in his opinion, there
exists a medical or scientific need there-
or.

Code of Federal Regulations, No. 21, Food and Drugs, Part 1300 to end.

Reject material from formulation is very limited. Because of the value of the raw
materials involved, potentially faulty batches of pharmaceuticals are reformulated to meet
specifications. When a material cannot be upgraded, the “bad batches” are either in-
activated, by neutralization, for example, and sent through biological treatment, or are
landfilled or incinerated, depending upon the nature of the material.

(For the purpose of this study, a portion of the returned goods and reject material have
been segregated as potentially hazardous wastes.) Section 4.2.4 provides a more detailed
discussion on present treatment and disposal technologies of the potentially hazardous
wastes resulting from the returned goods and reject material. Section 4.5.5 describes Level I,
II, and III technologies for treating and disposing of returned goods and reject material from
formulation. ‘

4.2.1.4 Marketing and Distribution

Wastes from marketing and distribution merely represent large volumes of paper, wood,
and cardboard. Since there are no process wastes from this segment of the industry and
returned goods are normally sent back to the formulation and packaging facilities, this
segment of the industry has not been studied further.

4.2.1.5 Pharmaceutical Operations in Puerto Rico I,

An organization called Fomento was set up by the Puerto Rican government to
encourage industry to settle in Puerto Rico and to provide assistance to those companies in
the areas of siting, employment, and services, such as electricity, water, and regional
wastewater treatment. Industries investigating the attractive tax-break offers in the mid-’60’s
were also told that, should they settle in an area like Barceloneta (about 40 miles west of
San Juan) adequate regional wastewater treatment facilities would be provided. The planned
completion date has slipped a little. It was planned to be on stream in 1974, but it will
probably not be in operation until mid-1975. Therefore, pharmaceutical companies involved
have had to ocean-dump their process wastewater, because they are not permitted to send it
to the nearby Manati River.

Numerous US. and European pharmaceutical firms were encouraged to construct
operations in Puerto Rico. Since the early ’60’s, the number of these installations has been
growing rapidly. At present, we estimate that as many as 42 plants have been constructed
and are now in operation. These operations have severe impacts on the pollution control
problems of the area.

Solid waste disposal sites are provided by the local municipal governments in Puerto
Rico (see Figure 4.2.1.5 for outline of current facilities). In the past these disposal sites have
simply been dumps with open burning of trash. The Puerto Rican Environmental Quality
Board (EQB) is pressuring the municipalities to upgrade the disposal sites and to provide
sanitary landfills. The EQB does not consider two of the sites — the Manati dump and the

94

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Barceloneta landfill— to be satisfactory for disposal of chemical wastes. But the EQB
considers a third site — the landfill at Mayagiiez — suitable for chemical wastes. In addition
a new site has been recommended between Barceloneta and Arecibo in the Cana Tiburones
area which the EQB feels will be satisfactory for chemical waste disposal. We visited the
Manati, Barceloneta, and Mayagiiez disposal sites. The Manati dump clearly is not satis-
factory for chemical disposal and is currently no longer being so used. The Barceloneta
landfill is currently being used for chemical waste disposal and, on casual examination, it
appears that the site could be upgraded to serve as a satisfactory site for chemical waste
disposal. However, studies by the EQB indicate that subsurface drainage to the nearby
_ Manati River would be excessive, and hence the EQB is attempting to stop the municipality
from accepting chemical wastes. There may be a problem for several months as the
pharmaceutical companies were assured of municipally operated solid waste and liquid
waste facilities. The Mayagiiez landfill appears to be well located, well run, and should be
satisfactory for chemical waste disposal. There is at least one company available to recover
and incinerate solvents on a contract basis in the Barceloneta area.

The Commonwealth of Puerto Rico appears presently to be making good progress in
improving the handling of solid wastes, but regulations and facilities have lagged behind U.S.
mainland practices. An excerpt from a development plan for a proposed Solid Waste
Management Authority is presented on the following page.

4.2.2 Present Treatment/ Disposal Technologies for Waste Solvents

Small companies and R&D installations in isolated areas are currently disposing of
some solvents by landfill, but the trend is to incinerate waste solvents. Depending upon local
conditions, outside contractors may be used for waste incineration by both large and small
companies, or large companies may choose to install their own incinerators. Table 4.2.2
summarizes the disposal methods used for waste solvents in the pharmaceutical industry.

Incineration is an environmentally adequate means of waste solvent disposal.* Where
quantities of halogenated solvent are incinerated the use of scrubbing to minimize the air
pollution risk should be investigated.

4.2. 2. 1 Research and Development

Since there is no measurable unit of production for the research and development
operations, the amount of wastes has been estimated on the basis of the number of
researchers. Although the degree of recovery is not well known for this segment of the
industry, solvents are commonly distilled for reuse. The 25,000 members of the R&D
section of the industry produce approximately 1500 metric tons of mixed waste solvents
each year. This number is based upon an extrapolation using data supplied to ADL by a
number of companies.

 

*Tables 4.5.1-A and 4.5.1-B describe the various levels of treatment and disposal technologies used for
waste-solvent disposal in the pharmaceutical industry.

96

A Plan for Hazardous Waste Disposal in Puerto Rico}r

The proposed Authority should have the sole responsi-
bility in Puerto Rico for processing, recovery, disposing,
and storing of hazardous and toxic wastes, in order to pro
vide uniform and reliable control. The proposed Authority
should serve as a servicing agent for all producers of
hazardous and toxic wastes. Sites and handling techniques
conforming to Puerto Rico Environmental Quality Board
‘and Federal standards should be established. Special user
fees should be charged producers of these wastes, based
upon difficulty and expense of providing this service. The
service should not only be self-liquidating financially, but
produce a replacement fund for facilities and equipment.

Program Recommendations

Currently, Federal standards governing hazardous and
toxic wastes are still pending, and patterning a program for
Puerto Rico according to these standards appears specu-
lative. Nevertheless, enough is now known about types
and classes of these wastes to begin forming directions for
Puerto Rico. Therefore, the following steps should be
taken to initiate an operating capability for handling
hazardous and toxic wastes by the proposed Authority.

1. Conduct an island-wide survey to determine the
types, amounts, and locations of hazardous and toxic
waste production. Identification of present storage
sites should be made as well.

2. Investigate and evaluate existing Commonwealth
of Puerto Rico and Federal regulations applicable to
hazardous and toxic wastes.

3. Develop a plan which can be implemented by the
Authority for handling hazardous and toxic wastes in
Puerto Rico. The plan should consider such aspects as:

(a) Land disposal methods

(b) Disposal facility locations

(c) Topographical and geological conditions
(d) Drainage control

(6) Protection of water supplies

(f) Handling hazards and protection

(9) Transportation and unloading

(h) Security

(i) Personnel training and safety

(i) Records and monitoring

(k) Technologies of processing and storing
(l) Prevention of accidental catalytic reactions
(m) Abandonment of sites

4. An adjunct to this plan should be a locational
plan showing desirable locations for new industries
which may have hazardous and toxic substances as a
manufacturing by-product. These locations should be
amenable to the environment. Industries producing
hazardous and toxic wastes should be prohibited from
any location not specified for this purpose. The indus-
trial location plan should be developed and implement-
ed in conjunction with the Environmental Quality
Board, Fomento, Department of Natural Resources,
the Planning Board, and the Department of Health.

5. All plans developed for hazardous and toxic
wastes must comply with regulations of the Environ-
mental Ouality Board, the Environmental Protection
Agency and other applicable Commonwealth of Puerto
Rico standards.

J'Source: Proposed Solid Waste Management.Environmence1 Quality Board, Puerto Rico.

97

Industry Segment

R&D
Active Ingredient Production

Organic Medicinal Chemicals
Halogenated solvent
Non-halogenated solvent

Inorganic Medicinal Chemicals
Fermentation products
Botanicals
Aqueous solvent
Halogenated solvent
Non-halogenated solvent
Drugs from Animal Sources
Biologicals

Formulation 8: Packaging

Total

TABLE 4.2.2

WASTE SOLVENT DISPOSAL METHODS.r

Current Disposal Methods

 

 

 

 

 

 

On-Site Off-Site
Total Incineration
Hazardous At Nearby
Waste Company-
(metric tons Owned Incineration by
per year) Incineration Facility 0ther* Contractor
1,500 — 450 — 1,050
3,400 800 — — 2,600
23,800 9,300 14,500
0 _ _ _ _
12,000 5,000 — -— 7,000
1,000 400 —— ~ 600
50 5 — — 45
120 50 — —- 70
800 260 — 40 500
250 100 - —— 150
0 _ ._ __ _
42,920 15,915 450 40 26,515

*Treatment in on-site biological wastewater treatment facility or in municipal system.

TSource: Interviews and Arthur D. Little, lnc., estimates.

R&D installations surveyed were either sending waste solvents to contractors for
incineration off—site (about 70 percent is estimated to be disposed of in this manner), or were
incinerating them in nearby company-owned facilities. The Laboratory Waste Disposal
Manual published by the Manufacturing Chemists’ Association, lnc., suggests incineration

for even very small amounts of solvents. Incineration of these waste solvents is an environ-

mentally adequate disposal technique.

4.2.2.2 Production of Active Ingredients (SIC 2831 and 2833)

When the pharmaceutical industry was much smaller, most pharmaceutical companies

discarded waste solvents and still bottoms in dumps or landfills. With the increased

production of active ingredients, greater difficulty in finding suitable landfills, and more

98

stringent state and local government controls, incineration is being increasingly employed
for disposal of waste solvents.

4.2.2.2.1 Organic Medicinal Chemicals

We estimate that all waste solvents from solvent-recovery operations used in the
production of organic medicinal chemicals are disposed of by incineration. Approximately
half of the larger pharmaceutical companies have some on-site incineration capacity, even
though they may send more troublesome wastes, such as halogenated solvents, to off-site
contractors. Others continue to utilize outside contractors; however, some additional
pharmaceutical companies are currently planning on-site incineration. For this study, ADL
surveyed about 25 to 30 percent of the production capacity of organic medicinal chemicals
of the pharmaceutical companies. Since the production of active ingredients is centered in
the larger pharmaceutical companies, such disposal methods as found would also extend to
the part of the industry not interviewed.

There are about 10,100 metric tons per year of on-site incineration capacity. This
figure is predicated on the basis of 27,200 metric tons of solvent for the pharmaceutical
companies involved in organic medicinal chemical production. Not all of the in-place
incinerator capacity can adequately handle air and water pollution control for all waste
solvents. Often, because of stack emissions or potential equipment corrosion, halogenated
solvents are not handled in on-site incinerators. Since liquid incinerators are relatively new
to the pharmaceutical industry, potential problem wastes are often sent to outside contrac-
tors for incineration.

Off-site incineration techniques range from excellent to poor. There are numerous
contract disposal and recycling operations across the country that are well designed and
operated.

4.2.2.2.2 Inorganic Medicinal Chemicals

There are no known significant amounts of waste solvents or organics from this industry
section.*

4.2.2.2.3 Fermentation Products
The disposal of solvents used in fermentation operations is in the form of a solvent

concentrate from the solvent-recovery operations. This material, which may contain as
much as 50 percent of organic solids, is hazardous, mainly because of its flammability.

 

*Section 3.2.1 .2.2 discusses wastes from this industry segment.

99

Approximately 12,000 metric tons of waste solvent concentrate from fermentation
operations is disposed of annually. We estimate that all of the concentrate is incinerated
either on-site or by contractors off-site. The trend is toward on-site incineration. Some
plants which are currently sending these materials out to contractors for disposal have
incineration units being designed, on order, or under construction. This incineration is very
straightforward, as is evidenced by the number of on-site units.

The study encompassed approximately 65 percent of the U.S. fermentation capacity.
On the basis of the estimated 12,000 metric tons per year of waste solvent concentrate,
there is approximately 5000 metric tons per year of on-site incineration capacity. Most of
the in-place incinerators have adequate air and water pollution control equipment. This
essentially means particulate control only. However, since most fermentation operations are
also associated with other active ingredient manufacturing operations, there is generally
co-incineration of the wastes which may dictate additional pollution control requirements.
Approximately 7000 metric tons (1.5 million gallons) per year is sent to outside contractors
for incineration. A typical charge for this material would be $0.30 per gallon.

4.2.2.2.4 Botanicals

Nearly 1200 metric tons (310,000 gallons) of waste solvent are estimated to be
disposed of annually by operations producing botanicals. Three types of solvent wastes are
produced in extracting alkaloids from plant material. The first solvent waste isanon-
halogenated solvent concentrate containing water plant extract and organic acid salts. The
second solvent waste is a concentrate of the water-immiscible chlorinated solvent used to
extract the alkaloid from the first solvent. The third, a non-halogenated‘usolvent waste, is
generated in the purification of the crude alkaloid. The first ends up both with water, plant
extract, and organic acid salts and as a more concentrated non-halogenated solvent stream.
The second is used to extract the alkaloid from the first solvent. Water-immiscible chlori-
nated solvents are used for the second solvent. The chlorinated solvent is five percent of the
total. These waste solvents are either incinerated on-site or by contractors off-site. We
estimate that 60 percent are incinerated by contractors off-site.

4.2.2.2.5 Drugs from Animal Sources

The waste solvent from the operation of obtaining medicinals from animal glands is an
aqueous solvent containing as much as 50 percent water and 25 percent organic solids. The
800 metric tons (220,000 gallons) of waste solvent are generally incinerated or, when the
amount is small, treatment in a biological wastewater treatment facility provides environ-
mentally adequate disposal.

4.2.2.2.6 Biologicals

Much of the solvent from biological operations is recoverable. An industry total of 250
metric tons (60,000 gallons) must be disposed of from biological operations. It is in-
cinerated on-site or by contractors off—site. We estimate that 60 percent is handled by
contractors off-site.

100

4.2.3 Present Treatment/ Disposal Technologies for Organic Chemical Residues

In many instances, little is known about the constituents in organic chemical residues.
The recovery operations which produce many of them are used for many various solvents
and products. The residues may contain contaminants that have been removed from the
product, non-reclaimable product, and other materials. Since these residues are so varied,
the trend in the pharmaceutical industry has been to incinerate them. Extensive testing will
be needed if these materials are to continue to be landfilled. Table 4.2.3 shows the total
organic chemical residues and indicates the various methods by which they are disposed.

TABLE 4.2.3
ORGANIC CHEMICAL RESIDUE DISPOSAL METHODST

Current Disposal Methods

 

Total Hazardous

 

 

 

 

 

On-Site Off-Site
Waste
(metric tons per Incineration by Landfill
Industry Segment year) Incineration 0ther* Contractor by Contractor

R&D Nil —— — — —
Active Ingredient Production

Organic medicinal chemicals 13,500' 5,440 1,360 3400 min. 3400 max.

6800 max.

Inorganic medicinal chemicals Nil — — _. _

Fermentation products Nil — — _. _

Botanicals Nil .— ._ _ _

Drugs from animal sources Nil —— — -— —

Biologicals Nil — — ._ _
Formulation 8: Packaging 0 — — _ -
Total 13,600 5,440 1,360 3400-6800 < 3,400

*About 10 percent of the residues are disposed of on-site by other methods, such as mixing with plant waste-
water prior to its treatment

1lsouroe: Interviews and Arthur D. Little, Inc. estimates.
4.2. 3.1 Research and Development

Organic chemical residues from research and development are disposed of with the
waste solvents. This means that they are either sent for incineration by a contractor, or are
incinerated in company-owned facilities that are associated with the manufacturing opera-
tions.

101

4. 2. 3.2 Production of Active Ingredients
4.2.3.2.] Organic Medicinal Chemicals

Organic chemical residues from organic medicinal chemical production are generally
incinerated. Approximately 40 percent of the active ingredient producers have on-site
incineration for their residues. This is becoming increasingly true since these residues are
seen as potential problems. Consequently, plant personnel are removing less solvent than the
common previous practice to maintain pumpability for liquid type incineration. Another 25
to 50 percent utilize off-site incineration contractors. Tracing the ultimate disposal of these
materials is difficult. Some are incinerated by the contractor, while others are landfilled in
containers by the contractor. In addition, about another 10 percent utilize other methods of
disposal, such as mixing with plant wastewater prior to its treatment.

4.2.3.2.2 Inorganic Medicinal Chemicals
There are no organic chemical residues from these operations.
4.2.3.2.3 Fermentation Products

The solvent concentrate from fermentation operations is discussed as a waste solvent in
this report (see Section 4.2.2.2.3).

4.2.3.2.4 Botanicals

There are no significant amounts of organic chemical residues from this industry
segment. They are either handled with waste solvents or are sent to biological treatment or
landfill.

4.2.3.2.5 Drugs from Animal Sources

There are no significant amounts of organic chemical residues from this industry
segment. They are either' handled with waste solvents or are sent to biological treatment or
landfill.

4.2.3.2.6 Biologicals

There are no significant amounts of organic chemical residues from this industry

segment. They are either handled with waste solvents or are sent to biological treatment or
landfill.

102

4.2.4 Present Treatment/Disposal Technologies for Potentially Hazardous High
Inert Content Wastes (Such as Filter Cakes)

While high inert content wastes may show up in small amounts in the R&D segment of
the industry, by far the bulk occurs in the production of organic medicinal active ingre-
dients. Generally, they are handled in the same manner no matter which type of active
ingredient is being produced. Most are landfilled, but a growing percent is being incinerated
to remove the organic portion. The ash is then landfilled. Table 4.2.4 shows the total high
inert content wastes and indicates the various methods by which they are disposed.

Approximately 75 percent of the solid materials, such as filter cake and filter paper
from organic medicinal chemical production, are disposed of in landfills. Most of these
landfills are either municipal or private commercial facilities located off-site, and they are
generally operated as sanitary landfills. The industry has been careful to avoid bad publicity
that might accompany poor disposal techniques. Another 25 percent of the solids of this
type are incinerated either on-site or off-site.

TABLE 4.2.4

HIGH INERT CONTENT WASTES DISPOSAL METHODST

 

 

 

 

 

 

Total
Hazardous Current Disposal Methods
was“ On-Site Off-Site
(metric tons . .
Industry Segment per year) Incineration* Incineration* Landfill
______———
R&D Nil — — —
Active Ingredient Production
Organic medicinal chemicals 425
-— Waste containing flammables only 850 225 200 850”
—- Waste containing heavy metals or 850 — —
corrosives
1,700 225 200 1,275

Total

*Inert ash is landfilled.
“About 20 percent of the waste is neutral '
secure chemical landfill. Nearly 40 percent is placed untreated In a sec
capsulated in drums. The remainder goes to general landfill locations.

ized, or the heavy metal is precipitated and then placed in a
ure chemical landfill, often en-

TSource: Interviews and Arthur D. Little, lnc., estimates.

103

4.2.5 Present Treatment/Disposal Technologies for Heavy Metal Wastes

ADL has surveyed pharmaceutical active ingredient manufacturers producing an esti-
mated 20 to 40 percent of the heavy metal wastes. Table 4.2.5 shows the total heavy metal
wastes and indicates the various methods by which they are disposed.

TABLE 4.2.5

HEAVY METAL WASTE DISPOSAL METHODS,r

 

 

 

Total Hazardous Current Disposal Methods
Wis“ On-Site Off-Site
(metric tons _._________
Industry Segment per year) Recovery Landfill“
R&D Nil — x —-
Active Ingredient Production
Organic medicinal chemicals 2,675 — 575 2,100
Inorganic medicinal chemicals 200 — —- 200
Total 2,875 — 575 2,300

*Heavy metal is converted to its most insoluble form,and is generally drummed and placed in a secure
chemical landfill.

TSource: Interviews and Arthur D. Little, lnc., estimates.

With the exception of recovered R&D wastes and some large amounts of zinc and
chromium wastes that are sent off-site for recovery, the heavy metal wastes are usually too
dilute or contaminated for recovery. The number of facilities using heavy metals within the
pharmaceutical industry is limited. Production appears to be exclusively with the larger
companies. Most non-recovered heavy metal wastes are landfilled. Zinc oxide is a relatively
stable and insoluble form of zinc, and much of the landfilled zinc takes this form.

Arsenic is landfilled in drums with the surrounding soil conditioned with lime to
inhibit its change to a soluble form in case a drum develops a leak. The landfilled selenium
wastes are dilute (an estimated 0.2 percent selenium sulfide). Mercurial wastes, generally as
amalgams, are landfilled. A number of heavy metal wastes are deep-well disposed in
Michigan where state approval can be obtained.

4.2.6 Present Treatment/Disposal Technologies for Returned Goods and Reject Material
from Formulation

Returned goods (as described in Section 3.2.1.3) are handled specifically by the

formulating and packaging operations of a company. Table 4.2.6 shows the total returned
goods and reject material and indicates the various methods by which they are disposed.

104

 

 

TABLE 4.2.6

DISPOSAL METHODS FOR RETURNED GOODS AND REJECT MATERIALT

 

 

 

Total Hazardous Current Disposal Methods
Waste On-Site Off-Site
(metric tons —-—-—
Industry Segment per year) Incineration Other* Landfill**
Formulation and Packaging 500 50 100 350

* Material is crushed and slurried with water, and the resulting slurry is sent to a biological wastewater
treatment facility.
** The waste is crushed on-site to form a sludge or cake before it is sent to off-site landfill.

TSource: Interviews and Arthur D. Little, lnc., estimates.

Handling the amounts of pharmaceuticals that have been returned — for instance because
they have reached their expiration date — requires care. Some returned goods can be
salvaged, but of the returned goods that are non-salvageable, somewhere in the range of
60-80 percent are crushed in special equipment on-site to form a sludge or cake, which is
then sent to a landfill off-site. The remainder is either incinerated on site, or crushed and
slurried with water which is sent to an activated sludge treatment facility on-site, while the
glass, metal, rubber, and cardboard are sent to a landfill off-site. Numerous types of crushers
are used. Some of the names include Somat, Wascon, Rodeva, and Cumberland.

The disposal of pharmaceuticals in landfills raises many questions. Dosage levels in
medicines are generally measured in milligrams; nevertheless, because many of the products
may have biological or physiological effects on the environment and on man, disposal of
these wastes must be carefully controlled. Because of the Drug Enforcement Agency’s strict
regulation on the disposal of controlled substances, there is little chance that controlled
materials would be scavengable from any landfilled wastes.

Fearing the possibility of bad publicity from the scavenging of a returned good, each
pharmaceutical firm has extended the care in handling controlled substances (such as
narcotics) to the disposal of non-controlled substances as well. Representatives of the
company witness the destruction of returned goods, whether on-site or off-site, to ensure
that no tablet, Vial, capsule, or the like is scavengable. To this extent, the disposal practices
of the industry are excellent. Yet, little is known of the effect of such items on the landfill
and the potential for hazardous quantities to leach into groundwater or streams. In this
study, in an attempt to provide some basis from which to work, we used the toxicity of the
active ingredients to assess the hazard.* However, additional work in this area is advisable.

*Section 3.1.3 discusses the properties of these materials.

105

4.2.7 General Description of Treatment and Disposal Technologies

Treatment processes should reduce the volume, separate components, detoxify, and
recover as much as possible for reuse. In general, no single process can adequately perform
these functions. Table 4.2.7-A presents those treatment and disposal technologies found
within the pharmaceutical industry, and each is discussed in the subsections which follow.

In order to fully utilize the information obtained in the study,* those processes which
treat liquid effluent streams have been viewed as Waste-producing steps rather than as
waste-treatment steps. Table 4.2.7-B presents the processes, their functions, and the types of
wastes treated.

4.2. 7.1 Segregation of Wastes

There is great need to segregate wastes to obtain optimum waste treatment and
disposal. Not only is segregation necessary for recovery, treatment, and disposal, it is also
necessary for safe handling, transport, and treatment. Use of a system of chemical compati-
bility which was developed by the National Academy of Sciences has been proposed for use
as a guide for the compatibility of waste materials.** Usually the same handling techniques
are required for wastes as for the raw materials.

4. 2. 7. 2 Incineration of Halogenated and Non-halogenated Solvents

When high—energy content solvents with small amounts of water and solids persist
through normal process-recovery operations, they are often destroyed by thermal oxidation
at high temperatures in liquid injection incinerators. These units typically operate at or
above 1800°F and with sufficient turbulence and time to destroy solvents effectively. If
combustion is controlled, by means of excess air, for example, no air pollution control
devices are needed for solvents containing only carbon, hydrogen, and oxygen. However,
these liquid injection incinerators are being increasingly equipped with air pollution control
systems, because solvents often contain either suspended and dissolved solids or substances
which could react to form noxious gases, such as hydrogen chloride, sulfur oxides, and
nitrogen oxides.

 

*We had difficulty in tracing all disposal steps, and considerable overlap with the work on the water
effluent guidelines’ study being prepared by Roy F. Weston, |nc., occurred.
”Witt, Philip A., Jr. "Disposal of Solid Wastes,” Chemical Engineering, October 4, 1971 , p. 61.

106

TABLE 4.2.7-A

FUNCTIONS AND WASTE TYPES OF CURRENTLY USED
HAZARDOUS WASTE TREATMENT AND DISPOSAL PROCESSES

Process Functions Performed Types of Waste

 

0 Chemical Treatment:
—— Oxidation of sludges Detoxification Inorganic chemical with/without
' heavy metal
Organic chemical with/without
heavy metal

0 Thermal Treatment:

-— Incineration of solvents Volume reduction, Organic chemical without heavy
— Incineration of solids detoxification, metal
disposal Biological
Flammable
Explosive

° Biological Treatment:

— Activated sludge or Detoxification Organic chemical
other biological without heavy metal
treatment

0 Disposal/Storage:
— Land burial Disposal Inorganic chemical with/without

heavy metal

Organic chemical with/without
heavy metal

Biological

Flammable

Explosive

— Deep-well injection Disposal Only liquids can be disposed of in
this manner; all those listed for
land disposal, with the excep-
tion of explosives, are disposable
in this manner with proper pre-
cautions.

— Ocean dumping Disposal Inorganic chemical with/without
heavy metal
Organic chemical with/without
heavy metal
Flammable
Explosive

—— Engineered storage Storage All as in land burial

Source: Colonna, R.A., and McLaren, C., "Appendix D. Hazardous Wastes," Decision-Makers Guide
in Solid Waste Management, Environmental Protection Agency, 1974, p. 146.

107

TABLE 4.2.7-B
WASTE TREATMENT PROCESSES USED TO SEPARATE
AWASTET DESTINED FOR LAND DISPOSAL

 

Function Resource Recovery

Process Performed* Types of Waste** Capability
Physical Treatment:

Carbon Sorption Se 1, 3, 4 Yes

Dialysis Se 1, 2, 3, 4 Yes

Electrodialysis Se 1, 2, 3, 4, 6 Yes

Evaporation Se 1, 2 Yes

Filtration Se 1, 2, 3, 4 Yes

FIoccuIation/Settling Se 1, 2, 3, 4 Yes

Reverse Osmosis Se 1, 2, 4, 6 Yes

Ammonia Stripping Se 1, 2, 3, 4 Yes
Chemical Treatment:

Calcination 1, 2 Yes

Ion Exchange Se, De 1, 2, 3, 4 Yes

Neutralization De 1, 2, 3, 4 Yes

Oxidation De 1, 2, 3, 4 Yes

Precipitation Se 1, 2, 3, 4 Yes

Reduction De 1, 2 Yes
Thermal Treatment:

Pyrolysis VR, De 3, 4, 6 Yes

Incineration De, Di 3, 6, 7, 8 Yes
Biological Treatment:

Activated Sludge De 3 No

Aerated Lagoon De 3 No

Waste Stabilization Ponds De 3 No

Trickling Filter De 3 No
Disposal/Storage:

Deep-well InjectionT Di 1, 2, 3, 4, 6, 7 No

*Se — segregation VR — volume reduction

De — detoxification Di — disposal
”1. Inorganic chemical without heavy metal

2. Inorganic chemical with heavy metal

3. Organic chemical without heavy metal

4. Organic chemical and heavy metal

5. Radiological”

6. Biological

7. Flammable

8. Explosive

T A waste is formed either when solids must be filtered out, or when a substance must be precipitated
out because of chemical incompatibility with substances underground.
TT Use and disposal of radiological wastes within the pharmaceutical industry is not discussed in this
report.
Source: Colonna, RA. and McLaren, C., “Appendix D. Hazardous Wastes,” Decision-Makers Guide in
Solid Waste Management, Environmental Protection Agency, 1974, p. 146.

108

The most common air pollution control device for removing acidic gases is a wet
scrubber like the venturi. A significant operating cost for these incinerators may be incurred
in providing the caustic scrubbing liquors for the venturi such as lime, sodium hydroxide, or
ammonia for removal of halogens from off-gases. Disposal of the scrubber liquors is usually
via introduction into wastewater treatment systems. This means that a significant load of
dissolved solids may be imposed. Although the effectiveness of liquid injection incinerators
may vary widely in the destruction of solvent-type wastes, the efficiency of destruction is
relatively high in a properly operated incinerator. In general, the liquid injection incinerators
need auxiliary fuel for solvents with low heating values. Consequently, the disposal costs are
inversely related to the heating values of the wastes: the higher the heating value of the
solvent, the lower the disposal cost. Some waste solvents can be recovered for their fuel
value. The wastes then have a net worth; thus increasing attention is being given to their
recovery, especially by some of the contract waste disposers that have sophisticated systems
for recovery and conversion. Instead of paying for the disposal of some waste solvents, they
can be sold. However, the industry often uses high heating value wastes (i.e., solvents) to
destruct low heating value waste (watery wastes) in company-owned facilities. As regula-
tions regarding disposal become stricter, an increasing number of companies are contracting
for waste disposal. This is true especially where a variety of liquids as well as solid wastes
must be destroyed.

4.2. 7.3 Incineration of Solid Wastes

The incinerator furnace provides the environment for controlled combustion of solid
wastes with air. The waste is processed by controlled oxidation with the liberation of heat,
producing flue or combustion gases and a residue or ash. Most incineration furnaces have
either a refractory hearth to support the burning waste, or a variety of grate-type hearths
which stroke the waste. Neither the stationary hearth nor the rotary kiln furnace systems
have grates. The typical stationary hearth furnace has a refractory floor which may have
openings to let slightly pressurized air in underneath the burning wastes. Stationary hearth
furnaces are used for commercial and small industrial incinerators. For hospital wastes, they
are equipped with auxiliary gas or oil burners to maintain the furnace temperature above
1200 to 1600°F, At these temperatures, the combustible solids and vapors will be
completely eliminated as long as high oxygen content air is well dispersed throughout the
gas. This may require auxiliary fuel burners in the secondary combustion chamber.

The rotary kiln incinerator has been used for several hundred years in the pyropro-
cessing industry. Unless special provisions are made for air or water cooling, the metal
cylinder is lined with refractory material to prevent overheating of the metal. The move-
ment of the solids being processed is controlled by the speed of rotation of the kiln which is
inclined toward the discharge end. The rotary kiln normally requires all the air for
combustion to enter with the waste at the feed end.

109

Because of their versatility in handling solids, sludges, and containers, rotary kiln
incinerators are being used increasingly for the thermal destruction of wastes. The incinera-
tors are used by a number of contractors and individual plants. Since the feed rates of wastes
cannot be controlled closely, as is done in liquid injection incinerators, the rotary kiln
incinerator usually operates less thermally efficient than the liquid injection incinerators to
ensure effective destruction while meeting air pollution regulations. However, these incinera-
tors are especially sensitive to erratic conditions, such as the rupture of containers. Any
volatile substances which are released cause oxygen deficiencies in the reaction chamber and
consequently smoke forms. Thus, extensive afterburner chambers and control methods are
required to prevent smoke.

The most common off-gas cleaning systems for rotary kiln incinerators like those used
in liquid injection incinerators are wet scrubbers. Because of their versatility in handling
different forms of wastes, especially wastes with high heating values, use of the rotary kiln
incinerator is expected to increase. As in the case of the liquid injection incinerator, the
costs generally are inversely related to the heating value of the wastes; the higher the heating
value of the waste, the lower the disposal cost. Because tarry substances take longer to burn,
they will cost more to dispose of than the non-tarry substances.

Stationary grates have been used in incinerator furnaces for a long time. The original
stationary grates consisted of metal bars or rails supported in the masonry sides of the
furnace chamber. Subsequently, these bars were replaced with cast metal or fabricated metal
grates with provisions for rotating the grate sections to permit dumping of the ash residue.
Such stationary grates are still used in many of the older incinerators.

Mechanically operated grates installed in batch-type furnaces evolved from the station-
ary grates in batch-type furnaces. Many of the new, small-capacity incinerators still utilize
batch-fed furnaces either with stationary or mechanically operated grates. Although other
thermal destruction systems such as multiple hearths or fluidized beds might be used for
waste disposal, especially sludges from wastewater treatment plants, filter cakes or centri—
fuge solids, these are not used much in the pharmaceutical industry.

Conventional incinerator furnaces are made from refractories such as fire bricks,
metals, and refractory-covered metals, such as castable or fire brick refractory linings 1 to 9
inches thick.

A rotary kiln furnace may be lined either with castable refractories or with kiln blocks.
Alternatively, if the kiln is unlined, it must be cooled externally with air or water with an
optional water film on the inside of the cylinder. Since furnaces are subject to temperature
changes, refractory linings are susceptible to damage from spalling, fluxing, or slagging.
Corrosion must also be considered for any incinerator furnace material whether refractory
or metal.

110

Many incinerator design specifications require a secondary combustion chamber. In the
primary combustion chamber wastes are ignited, vaporized, and burned above the incinera-
tor grates. The secondary combustion chamber may consist of a separate down stream
chamber wherein gases emitted from the primary chamber containing soot, hydrocarbons,
and other combustibles are burned. They will be completely eliminated as long as the gases
in the secondary combustion chamber are heated above 1500 to 1600°F. After complete
incineration of the waste, the ash residue drops into an ash chamber or chute from the end
of the grate or kiln, directly into a container, onto conveyors for disposal, or into water for
quenching and cooling.

Wastewater at incinerator installations comes from various sources such as chamber
sluicing, the quenching of ash, and parts of the ash conveyor system, the flue gas cooling
chamber, or the flue gas scrubbers. Because of the costs of water treatment facilities
required to prevent water pollution, this wastewater flow is minimized. For example, ash
can be quenched with air near the discharge end of the grate or in a separate ash cooler; gas
can be cooled with a gas-to-air heat exchanger or by total evaporation of fine water sprays;
and dry dust collection systems can be used instead of wet ones.

Acceptable ash residue can only be achieved by prudent operation. This requires
teamwork on the part of the entire staff. Materials must be mixed to provide a relatively
homogeneous feed stream. The furnace operator must constantly check and adjust the air
ratio, the degree of agitation, the temperature of the furnace, and the residence time of the
waste flowing through the furnace. Such an operation requires constant attention and, when
waste is difficult to burn, waste flow may be reduced. Knowing the composition of the
residue is important as a diagnostic aid to detect operational problems, determine complete-
ness of combustion, and identify potential water pollutants.

A well operated modern incinerator will burn out 97 percent of the combustible
materials. The water solubility of the residue is of interest primarily to evaluate potential
groundwater pollution, because this fraction will, to some extent, be leached from the ash
over long periods of time and may contaminate groundwater. Such leaching may or may not
be harmful, depending upon the materials which are dissolved and the rate of solution. In
general, the amount of water-soluble materials in the ash will be quite small and will reflect ‘
the composition of the waste burned and the operating practices of the incinerator. The
extent to which groundwater contamination occurs depends primarily on the fill operation,
the local rainfall, drainage patterns, and geology all of which vary widely. Each fill site is
different.

The organic-soluble fraction of the residue will support undesirable forms of life such
as insects, rodents, and bacteria. If the level of these materials is found to be over 1 percent
of the residue ash, the incinerator is not being operated properly. All organic materials are
combustible. Increased residence time in the furnace, high temperatures, good agitation, and
proper air distribution will reduce these materials to less than 1 percent of the residue ash.
To determine if living organisms are in the ash, samples of the ash can be incubated. If

11]

organisms are present, they should be classified to establish which fraction is pathogenic.
Fungi or bacteria indicate that burn out of the ash is not complete.

The air pollutants associated with incinerators fall into three categories: particulates
(both mineral and combustible), combustible gases (which include carbon monoxide and
hydrocarbons), and non-combustible gases (including nitrogen oxides, sulfur oxides, and
hydrogen chloride).

4. 2. 7.4 Land Disposal

The disposal methods used by many industries are those used for residential and
commercial wastes: landfill and incineration. Landfills are either dumps, land burial opera-
tions, or sanitary landfills. Dumps and land burial operations are generally unsuitable
disposal methods, land burial being a dump that is covered. Sanitary landfilling is defined as
an engineering method of disposing of solid waste on land in a manner that minimizes
environmental hazards by spreading the waste in thin layers, compacting the wastes to the
smallest practical volume, and applying the compacting cover material at the end of each
operating day.

Where land is available, a sanitary landfill is usually more cost-effective than incinera-
tion for disposing of solid wastes. A number of pharmaceutical companies are located in
areas where land availability is not a problem. On the other hand, in areas such as New
Jersey, there is increased difficulty in locating landfill operations willing to accept industrial
wastes.

Current practice dictates that the potential sanitary landfill site be examined for soil
condition and proximity of groundwater. Because so little is known of the properties of
chemical wastes in landfills, an effective monitoring system for toxic waste disposal areas
may become a routine requirement.

A safety hazard exists with landfilling organic waste. Fires and explosions occur in
landfills which handle liquid organics. Further, the California Water Pollution Control Board
found that water that has gone through landfilled incinerator ash will leach alkalies and salts
from the fill. Gases such as methane, ammonia, and hydrogen sulfide are produced in land
disposal areas. Because landfilling of materials with high water content can produce adverse
effects within a landfill, States such as Indiana and New Jersey are considering, or have
instituted, strict requirements on landfill operations. As regulations on a State and local
level become effective, the number of landfills accepting organic liquids is expected to
decrease.

Increased consideration will be given to thermal destruction as regulatory agencies
establish more stringent rules and regulations for landfill disposal. There are economic
reasons for landfill disposal. Costs of landfilling range from $4 to $10/ton of solids because
of relatively low capital investment and energy requirements, while incineration costs fall in

112

the range of $25 to $50/ton of solids. Incineration of solid wastes is capital- and energy-
intensive. Additional fuel is required when the wastes have low heating values. Therefore, in
spite of increasing pressure to minimize landfill, the rapidly escalating energy costs and
capital investment requirements for thermal destruction will mean that landfill costs will
continue to be more economically attractive than thermal destruction.

Secure chemical landfills (i.e., lined landfills, limited to chemical wastes, with adequate
local soil conditions and often using leachate control) will probably be an important aspect
of long-term disposal of selected pharmaceutical wastes. Inorganic salts and other sub—
stances, such as metallic compounds, which cannot be converted into innocuous substances
will present continuing disposal problems. The magnitude of these problems will be
determined by the volume and toxicity of the substances. Among these problem wastes are
mercury, arsenicals, chromium, copper, and zinc. Since some of these substances, such as
mercury, arsenic, and zinc would be vaporized in thermal destruction facilities, and perhaps
widely dispersed by atmospheric transport, careful consideration must be given to the
methods for their disposal. The “concentrate and contain” philosophy of land disposal will
have to be exercised for these wastes which cannot be altered in toxicity or hazardousness.

4.2.7.5 Recovery for Reuse

There are many processes for resource recovery. Important factors in deciding which
method to use include type, form, and volume of waste, as well as the economics of the
processes. Solvents are now recovered for economic reasons. Heavy metals, on the other
hand, may be removed to keep them out of the wastes to be disposed.

Within the pharmaceutical industry, most recovery operations, with the exception of
solvent recovery, are performed off—site by contractors. In our study, we found that firms
handling recovery were often reluctant to discuss the source and potential market for
recovered materials. The competition for recovery appears to be great in areas such as New
Jersey and Illinois.

4.2. 7. 6 Wet Oxidation

Wet oxidation is oxidation of organic materials in a liquid state under high pressure at
moderate temperatures. Sulfur, nitrogen, and halogen breakdown products are retained in
the liquid effluent. Waste treatment techniques, such as wet oxidation, are found infre-
quently in the pharmaceutical industry. However, this particular technique is used when the
total energy content of the wastes is too low for cost-effective incineration. In wet
oxidation a complex mixture of organic materials may be degraded to a more simple series
of components which are amenable to further treatment by well-established processes such
as biochemical treatment. This method is usually employed for slurries and sludges with the
concomitant need to dispose of solids which, of course, are much more stable and of less
potential environmental concern than the original waste. This process may be a candidate
for those wastes which have inhibitory effects on biochemical systems. Its utilization will

113

require an assessment of the specific waste compositions. Treatment costs range from $1 to
$20 per thousand gallons.

4. 2. 7. 7 Deep-well Injection

Deep-well injection for disposal of industrial wastes became popular during the late
1950’s. Of the approximately 300 wells drilled in the United States, close to 200 are still in
use, mostly in Texas and Michigan. To be effective the wells must have a complete and
permanent separation between the stratum being used for disposal and useful strata. The
rock must have the desired porosity and permeability at the level the waste is to be injected.
Approximately 30 new wells are being built each year. Deep-well injection is a method of
aqueous liquid waste disposal. It was investigated because a limited number of pharma-
ceutical plants manufacturing active ingredients use deep-well injection for their wastewater,
and often solid wastes are formed while preparing the liquid for injection. In addition, if
deep-well injection were to be banned, these companies would have to find some alternate
method of disposal. The pollutants typically sent to deep-wells are difficult to remove using
standard biological methods. Chemical methods such as precipitation or adsorption would
probably be used, forming a potentially hazardous solid waste for land disposal.

Since Michigan’s Department of Natural Resources officials have indicated that deep-
well injection will continue, we investigated only those solid wastes produced prior to
injection to meet the limitations of deep-well disposal. That is, wastes must be compatible
with the brine naturally occurring in the selected porous rock stratum. If they are not
compatible, solids which can plug the pores of the rock will precipitate. For example, if the
stratum were a limestone, sulfates, phosphates, and aluminum salts would not be com-
patible.

4.3 ANALYSIS OF ON-SITE/OFF-SITE DISPOSAL METHODS

The pharmaceutical industry makes extensive use of waste disposal contractors. Eight-
five percent of the pharmaceutical industry’s total process waste and 60 percent of the
hazardous wastes are disposed of off-site by contractors. Contractors either haul and dispose
of the wastes, or in areas such as northern New Jersey, trucking firms transport the waste
from the pharmaceutical plant to the disposer. Within the State of New Jersey independent
licenses are granted for transporting wastes and disposing of wastes. Occasionally, the
pharmaceutical company delivers the waste to the disposal site.

Waste disposal contractors contacted indicated that pharmaceutical companies segre-
gated their wastes and provided information on the constituents’ characteristics and recom-
mended handling techniques. Their work relationship appears to be open and functional.
The pharmaceutical companies take considerable care to ensure that reliable methods of
final disposal are used by their contract disposers. Hazardous wastes are usually landfilled in
areas of low soil permeability, and are often encapsulated and segregated from other wastes.

114

Contract disposers are very visible and are rapidly coming under the strict regulations
of air, water, and hazardous waste authorities. Because contract disposal operations are
susceptible to shutdowns that can last hours or months, the larger pharmaceutical com-
panies are tending toward installation of their own liquid and solid incineration capacity.

A large amount of the general process wastes, such as mycelia from fermentation, is
landfilled. Most of the landfilling is handled by private commercial operations. In total,
about 80 percent of the pharmaceutical industry process wastes disposed of by contractors
are landfilled. Some of the remaining wastes are recovered, but most are incinerated.
Eighty-five percent of the hazardous waste handled by contractors are incinerated or
recovered. Most of this waste is solvent. While some contractors are set up to recover
valuable products from this waste, most is incinerated. Most of the remainder of the
hazardous wastes are landfilled. These wastes include potentially hazardous high inert
content wastes, such as filter cakes, and heavy metal wastes.

Of those hazardous process wastes disposed of on-site, all except 8 percent are
incinerated either in liquid injection incinerators or in solid-waste incinerators.

Table 4.3 summarizes current on—site/off—site disposal methods and indicates the
amount of wastes by specific category.

4.4 SAFEGUARDS USED IN DISPOSAL

Numerous safeguards were found to be used in waste disposal. Table 4.4 summarizes
the use of the various safeguards.

4.5 TREATMENT AND DISPOSAL TECHNOLOGY LEVELS AS APPLIED TO LAND-
DESTINED HAZARDOUS WASTE STREAMS FROM THE PHARMACEUTICAL
INDUSTRY

The various levels of technology within the pharmaceutical industry are described in
this subsection for those hazardous waste streams identified in Section 3. They are described
on the basis of EPA definitions for the industry studies:

Technology Level] — This level encompasses the broad average of technologies
which are currently used in typical facilities. There may be more than one Level I
technology used by the facilities in an industry section. Although the possible
variations within a technology are often numerous, Level I is defined broadly to
distinguish between technologies such as incineration and landfill or chemical
landfill and sanitary landfill.

115

911

TABLE 4.3

ANALYSIS OF ON-SlTE/OFF-SITE DISPOSAL METHODS‘H

Current Disposal Methods

 

 

 

 

 

 

 

 

 

 

 

On~$ite Off-Site (Contractors)
Total Hazardous Waste Incineration Other incineration Landfill Recovery‘
Industry Segment (metric tons per year) Quantity % Quantity % Quantity _;%_ Quantity % Quantity %
O R&D
Solvent 1,500 450 30 — — 1 ,050 70 — — — —
Animals _ x — X” — — — - — — —
Heavy metals _ — — — — — — — — x —
0 Active Ingredient Production
— Organic medicinal chemicals
Non-halogenated waste solvent 23,800 9,300 40 — — 14,500 60 — — — —
Halogenated waste solvent 3,400 800 24 — — 2,600 76 — — - —
High inert content wastes
— containing flammables only 850 225 26 — — 200 24 425 50 - —
— containing heavy metals or corrosives 850 — — —— — — -— 850 100 — -—
Heavy metal wastes 2,585 — — — — — — 2,010 78 575 22
Organic chemical residues 13,600 5,440 40 1,360” * 10 5,100 38 1,700 12 — —
— Inorganic medicinal chemicals
Heavy metal wastes 200 — — — — — — 200 100 —- —
— Fermentation Products
Waste solvent concentrate 12,000 5,000 42 — — 7,000 58 — — — —
— Botanicals
Aqueous solvent 1,000 400 40 — — 600 60 — -— — —
. Waste halogenated solvent 50 5 10 — — 45 90 — — — —
Non—halogenated solvent 120 50 40 —— — 70 60 — — — —
— Drugs from animal sources
Aqueous alcohol 800 260 33 40 5 500 62 -— — — -
— Biologicals
Aqueous alcohol 250 100 40 — — 150 60 — —— -— —
Antiviral vaccines 300 100 33 100* 33 100 33 — — — —
Other biologicals (toxoids, serum) 200 — — 2001 100 — -- — — — --
0 Pharmaceutical Preparations 500 50 10 100 20 — — 350 70 — —
Total 62,005 22,180 36 1,800 3 31,915 51 5,535 9 575 1

*Solvent recovery is a very common practice onsite at pharmaceutical plants; it has been excluded from this study as a waste treatment process. The recovery discussed here is heavy metal
recovery from waste.
”Small animals are often autoclaved if they cannot be incinerated immediately.
*“Dilute and sent to on-site biological wastewater treatment.
1 Autoclaved.

H Source: Interviews and Arthur D. Little, lnc., estimates.

 

 

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Technology Level II — This level includes the best technologies which are cur-
rently used in at least one pharmaceutical facility, that is, they are the soundest
treatment or disposal methods on a commercial scale from an environmental and
health standpoint. In some cases the technologies may be the same as in Level 1.
Pilot and bench-scale installations are not considered.

Technology Level III — This level includes the technologies which are necessary to
provide adequate health and environmental protection. Existing pilot or bench-
scale processes that have high potential for meeting the needs of the industry if
scaled up are considered.

Tables 4.5.1-A through 4.5.5 describe the technology levels and provide relevant
information such as current usage of the identified levels of technology, present adequacy,
future adequacy based upon waste stream volume, composition, suitability for retrofit, non
land-related environmental impact such as energy and water requirements, residual wastes
finally disposed of on land, problems, limitations and reliability of the technology, imple-
mentation time, and environmental impact.

As a basis for calculating the number of facilities employing various treatment and
disposal technologies, we estimated that approximately 54 company operations large
enough to have significant wastes participate in the manufacture of pharmaceutical active
ingredients. Another 175 operations large enough to produce significant wastes formulate
and package these and other ingredients into final pharmaceutical preparations. The derived
estimates of facilities using the various treatments appear in the following sections.

4.5.1 Treatment and Disposal Levels for Halogenated and Non-Halogenated Waste Solvents

ADL estimates that 39,470 metric tons of non-halogenated waste solvents are gener-
ated annually by the pharmaceutical industry. This amount includes 1500 metric tons from
research and development, 23,800 metric tons from organic medicinal chemicals, 12,000
metric tons from the production of fermentation products, 1000 metric tons of aqueous
solvent concentrates (720 metric tons on a dry basis) from the production of botanicals and
an additional 120 metric tons of non-aqueous solvents from botanicals, 800 metric tons
from the production of drugs from animal sources, and 250 metric tons from the produc-
tion of biologicals.

In our survey of the industry, we found that approximately 50% of the industry
facilities had onsite incineration capability; the remainder used contractor incineration to
dispose of these solvent wastes. These two treatment technologies, therefore, are defined as
Level I in Table 4.5.1-A. Both of these disposal techniques are presently adequate. A
limitation of this kind of incineration is that liquid incinerators cannot handle a high
inorganic salt content waste.

Because there are a number of contractors who provide energy and resource recovery
at their own sites, we have included this technology in our Level II discussion. By energy
recovery we mean that the contractor has the capability to produce steam during

118

TREATMENT AND DISPOSAL TECHNOLOGY LEVELS

TABLE 4.5.1—A

FOR NON-HALOGENATED WASTE SOLVE NTSf

Amount of Waste:* 39,470 Metric Tons per Year

Hazardous, Physical, and Chemical Properties of Waste: Flammable organic liquid.

Technology

Current Usage
— Percent of Industry
Facilities

— Number of Facilities
Risk

— Risk from Fires or
Explosions

— Transport Risks

— Pollution Risk

Present Adequacy

Future Adequacy

Residual Waste**

Reliability of Technology

Limitations or Problems

Suitability for Retrofit
Non-Land Related Impact

Implementation Time

Level I

 

1) Incineration on-
site

2) Contractor in-
cineration

1) 50
2) 50
1) 27
2) 27

Moderate

Minimized with
on-site incinera-
tion

Minor

1) Excellent
2) Excellent

1) Good
2) Good

0

1) Good

2) Many reliable
contract dis-
posal firms

1) Cannot handle
high inorganic
salt content

2) Same as 1) above

Excellent

None, excepting
salt plume

1) Two years
2) Minimal

Level II

 

1) As Level |

2) Includes energy
and resource re-
covery at the
contractor's site.

1) 50
2) 12

1) 27
2) 6

Moderate

Minimized with on-
site incineration

Minor
1) (2) Excellent

1) Good
2) Excellent

0
As Level I

 

V

*Generated, i.e., prior to treatment or disposal (see Table 4.2.2).

HFinally land disposed.

1) As Level I***
2) As Level ||***

 

0
As Level I

None

Technology not
yet proven for salt
removal by scrubbing

***With scrubber for salts when they are present in concentrations that require scrubbing.

Source: Interviews and Arthur D. Little, lnc., estimates.

119

incineration of the waste. Resource recovery is possible if the contractor produces a
low-grade, salable fuel from the various waste solvents that he collects. We estimate that
approximately 12% of the pharmaceutical facilities are currently using contractors which
are using energy and resource recovery techniques.

The Level III technology is the same as Levels I and II, except that a scrubber is added
to handle salts when they are present in concentrations that require scrubbing. Although
there have been numerous attempts to work out this technological problem, there is
currently no proven method for complete salt removal by scrubbing. In Table 4.5 .l-B we
discuss the treatment and disposal technology levels for halogenated waste solvents. There
are approximately 3450 metric tons of halogenated waste solvents generated annually in the
pharmaceutical industry. These materials are usually flammable and the halogen is typically
chlorine.

In our survey of the industry, we found that those facilities which had incineration
capability onsite either diluted the halogenated solvents with their other solvents, or they
had them incinerated by a contractor. Those plants which had no incineration capability
onsite also had their waste solvents incinerated by contractor. In both cases, the contractor
had the capability for scrubbing for HCl. We have estimated that about 35% of the industry’s
facilities with this kind of solvent waste were diluting and incinerating onsite. In so doing
they were meeting current air pollution control regulations. A specific limitation on this
kind of incineration, however, is that it tends to corrode the incinerator. Because we had
identified offsite facilities which used incineration and energy- and resource-recovery tech-
niques, we have included energy and resource recovery as a technology level within Level 11.
About 10% of pharmaceutical industry facilities utilize offsite contractor incineration with
energy and resource recovery. As long as care is taken to maintain proper operating
conditions, Level I and Level 11 technology provides adequate waste disposal.

It takes approximately two years to design and install an onsite incinerator within a
pharmaceutical plant. However, there is an adequate supply of reliable contract disposal
firms in most areas of the country. Also, under Levell we believe that the incineration
onsite that is accomplished by dilution of the halogenated solvent with other solvents is
satisfactory, because the use of halogenated solvents within the pharmaceutical industry
does not constitute a major portion of the solvents.

4.5.2 Treatment and Disposal Levels for Organic Chemical Residues

Based on its 1973 production level, we estimate that the pharmaceutical industry
generates 13,600 metric tons of organic chemical residues annually. By far the majority of
these residues results from the production of the active ingredients used in organic medicinal
chemicals. We further estimate that about 10% of these residues are disposed of onsite by
methods other than incineration; for example, by mixing the residue with plant wastewater
prior to its treatment. We have not cited this method as a unique technology level because
we found it to be used for only a small amount of waste within a given plant, and only when

120

TABLE 4.5.1 —B

TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
FOR HALOGENATED WASTE SOLVENTSf

Amount of Waste:* 3450 Metric Tons per Year

Hazardous, Physical, and Chemical Properties of Waste: Flammable, Chlorinated Organic

 

 

Liquid.
Level | Level II Level III
Technology 1) Incineration on- 1) as Level l*** 1) as Level l***

Current Usage

site (diluted with

other solvents)

2) Contractor incin- 2) With energy and

eration with

scrubbing for HCI

I'ESOU I’CB recovery

— Percent of Industry 1) 35 1) 35
Facilities 2) 65 2) 10
— Number of Facilities 1) 19 1) 19
2) 35 2) 5
Risk
— Risk from Fires or 1) Moderate 1) Moderate
Explosions 2) Moderate 2) Moderate

— Transport Risks

Minimized by on-

*Prior to treatment or disposal.

Minimized by on~site

site incineration incineration
— Pollution Risk 1) Moderate 1) Moderate
2) Slight 2) Slight
Present Adequacy Good 1) Good
2) Excellent
Future Adequacy Good 1) Good
2) Excellent
Residual Waste** Nil Nil
0 Reliability of Technology Good Good
0 Limitations or Problems 1) Corrosion and
pollution may
occur at high
percentage
chlorine.
0 Suitability for Retrofit Good Good
0 Non-Land Related Impact — —-
Implementation Time 1) Two years 1) Two years
2) Minimal 2) Minimal

2) as Level II

 

i

HFinally land disposed.
"*Assuming that the relatively small percentage of halogenated solvents will continue.

tSource: Interviews and Arthur D. Little, lnc., estimates.
1 21

the waste was compatible with the onsite treatment. The other methods currently used to
dispose of these residues are onsite and contractor incineration and landfill.

Only the smaller facilities are likely to place these materials in a landfill. We estimate
that 40% of the industry facilities use onsite incineration and another 40% use contractor
incineration. The present adequacy of the incineration method is excellent, while the
landfill can be defined as only fair. In many instances, little is known about the constituents
in organic chemical residues. For that reason we have described the future adequacy of
the landfill method as poor. There is little residual waste from the incineration of these
materials. Often the amount of solvent in the residue is maintained at a level that allows it
to remain pumpable, so that it can be incinerated in a liquid-feed incinerator. In the past,
the residue was allowed to flow into a steel drum while still hot. As the material cooled, it
turned into a hard, glassy substance which was then landfilled. A potential for groundwater
contamination is inherent in this method. With Level 11, either onsite or contractor incinera-
tion is recommended, and Level III is the same as Level II.

Table 4.5.2 provides information on the contractor-recommended levels of treatment
and disposal of organic chemical residues.

4.5.3 Treatment and Disposal Levels for Potentially Hazardous High Inert-Content Wastes,
Such as Filter Cakes

To discuss these high inert-content wastes effectively, we divided such as filter cakes, in
two classes, one of which contains flammable solvent, and the other which contains
corrosives or trace amounts of heavy metals. Based on information obtained in our
interviews, we estimate that approximately half of the wastes contains solvents and the
other half heavy metals and corrosives. These materials are either semi-solid or solid. The
inert content may be filter aid or materials, such as charcoal.

In Table 4.5.3-A, we discuss the wastes which contain flammable solvent. Currently,
about one half of the plants generating this kind of waste send the material to contractor
landfill. The others have some means of incinerating, generally in rotary kilns or multiple
hearth furnaces. The content in these wastes ranges from under five to as much as 60
percent solvent.

The present adequacy of the landfill method is only fair and its future adequacy has
been determined to be poor because of the possibility of fires in the disposal area. On the
other hand, incineration provides an excellent means of making the waste inert as it burns
off all solvent and the only residual is the inert ash. A facility for the incineration of these
materials would take about two years to design and install.

For Level II technology, we are recommending incineration as the best method

currently used. Because it provides an environmentally acceptable method for disposing of
these materials, we have also stated that Level III should be incineration. In Table 4.5.3-B,

122

TABLE 4.5.2

TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
FOR ORGANIC CHEMICAL RESIDUES?

Amount of Waste:* 13,600 metric tons per year

 

 

 

 

Level I Level II Level III
0 Technology 1) On-siteincinera- 1) On-site incinera- as Level II
tion tion
2) Contractor in- 2) Contractor in-
cineration cineration
3) Landfill
0 Current Usage
— Percent of Industry 1) 40 1) 40
Facilities 2) 40 2) 4O
3) 20
— Number of Facilities 1) 22 1) 22
2) 22 2) 22
3) 11
0 Risk
— Risk from Fires' or 3) Yes Moderate
Explosions
— Transport Risks 2) Moderate 2) Moderate
3) Moderate
— Pollution Risk 3) Yes Nil
0 Present Adequacy 1) (2) Excellent Excellent
3) Fair
0 Future Adequacy 1) (2) Excellent Excellent
3) Poor
0 Residual Waste” 1) (2) Minimal” Minimal
0 Reliability of Technology 1) (2) Good Good
3) Unknown
0 Limitations or Problems 1) (2) None None
3) Landfill ade-
quacy unknown
0 Suitability for Retrofit 1) GoodTH Good
0 Non-Land Related Impact 3) Potential Nil
groundwater
pollution
0 Implementation Time 1) Two years 1) Two years
”Generated, i.e., prior to treatment or disposal. '

MFinally land disposed.
TSince smaller facilities are more likely to use landfilling, it is included here.
TTlf enough solvent remains to keep waste pumpable, it can be incinerated in liquid-feed
incinerator with little residual waste.
TTTHeated feed to existing liquid injection incinerator is possible.

1.Source: Interviews and Arthur D. Little, lnc., estimates.

123

TABLE 4.5.3—A

TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
FOR POTENTIALLY HAZARDOUS HIGH INERT CONTENT WASTES1

(such as filter cakes, which contain flammable solvent)
Amount of Waste:* 850 Metric Tons per Year

3 Hazardous, Physical, and Chemical Properties of Waste: Flammable, Semi-Solid or Solid
with High Inerts Contents

 

Level I Level II Level III
Technology 1) Landfill
2) Incineration Incineration as Level II
Current Usage
— Percent of Industry 1) 50 50
Facilities 2) 50 27
— Number of Facilities 1) 27 27
2) 27
Risk
— Risk from Fires or 1) Yes Minimal
Explosions
— Transport Risk Slight Slight
— Pollution Risk 1) Yes Nil
Present Adequacy 1) Fair Excellent
2) Excellent
Future Adequacy 1) Poor Excellent
2) Excellent
Residual Waste” 1) All Inert ash
2) Inert ash
Reliability of Technology 1) Unknown Excellent
2) Excellent
Limitations or Problems Fire risk None
Suitability for Retrofit 1) Not recome Good
mended
2) Good
0 Non-land Related Impact — —-
0 Implementation Time 2) Two years Two years V

*Prior to treatment or disposal
HFinally land disposed

fSource: Interviews and Arthur D. Little, Inc., estimates.

124

TABLE 4.5.3—B

TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
FOR POTENTIALLY HAZARDOUS HIGH INERT CONTENT WASTESJr
(such as filter cakes, which contain heavy metals or corrosives)
Amount of Waste:* 850 Metric Tons per Year

Hazardous, Physical, and Chemical Properties of Waste: Toxic, Semi-Solid or Solids with
high inerts content (may contain solvent)

 

 

Level I Level II Level III
0 Technology 1) Secure chemical Neutralize or pre. as Level II
landfill cipitate heavy
2) Sanitary land- metal, then place
fill in secure chemical
landfill
0 Current Usage
— Percent of Industry 1) 40 20
Facilities 2) 4O
— Number of Facilities 1) 22 11
2) 22
0 Risk
— Risk from Fires or Slight Slight
Explosions
-— Transport Risks Slight to moderate Slight
- Pollution Risk 1) Slight Slight
2) Moderate***
0 Present Adequacy 1) Good Good
2) Fair
0 Future Adequacy 1) Fair Good
2) Poor
0 Residual Waste** All More stable
0 lReliability of Technology 1) Good Good
2) Fair
0 Limitations or Problems 1) (2) Soil con- Soil conditions
ditions
O Suitability for Retrofit — -
O Non-Land Related Impact — —
0 Implementation Time — —
*Prior to treatment or disposal.

 

HFinally land disposed. '
***Anaerobic conditions can occur in sanitary landfill which will dissolve heavy metals and
make them mobile.

tSource: Interviews and Arthur D. Little, |nc., estimates.

125

we outline our evaluation of treatment and disposal of those high inert-content wastes
which contain corrosives or trace amounts of heavy metals. We estimate that the pharma-
ceutical industry generates 850 metric tons of these wastes annually. Because they contain
corrosives, they are generally not incinerated.

Because these materials cannot be incinerated, they are currently landfilled. We
estimate that about 40% of the facilities dispose of these wastes in sanitary landfills, which
means that wastes other than chemical wastes are being disposed of. We estimate that a
second 40% disposes of these wastes in a secure chemical landfill that is both limited to
chemical wastes and has to be lined with some material to ensure that materials do not leach
into groundwater. The present adequacy of the sanitary landfill method is only fair and is
not recommended for future disposal. Anaerobic conditions can occur in sanitary landfills
which will dissolve heavy metals and make them mobile.

Secure chemical landfills provide better environmental conditions, but even these can
create problems because of local soil conditions. Level 11 technology, which is currently
used by about 20% of the facilities, involves the neutralization of the corrosive material or
precipitation of the trace amounts of heavy metal. Then, the material which is less soluble
and less toxic is placed in a secure chemical landfill. Because of the nature of these wastes
and the inability to recover the trace amounts of heavy metal, we have recommended this
Level 11 treatment as Level III also.

4.5.4 Treatment and Disposal Levels for Heavy Metal Wastes

ADL estimates that the pharmaceutical industry generates 2875 metric tons of heavy
metal wastes annually. Pharmaceutical facilities which produce these heavy metal wastes are
not common within the industry. In fact, we estimate that only 15 pharmaceutical plants
generate heavy metal wastes. About 80% of these facilities currently convert the heavy
metal wastes into their most insoluble form, place them in drums, and then bury them in a
secure chemical landfill. All the plants we visited that used landfill for disposal used a secure
chemical landfill for their heavy metal wastes. However, we believe that a small percentage
of the heavy metal wastes may be placed in normal sanitary landfills. As we mentioned
before, anaerobic conditions can occur in sanitary landfills which may dissolve the heavy
metals and make them mobile.

About 20% of the industry facilities currently subject their heavy metal wastes to a
recovery process at an offsite contractor location. From an environmental control view-
point, this technique is excellent, since only a small portion of the wastes is then disposed of
on land. The limitations of this kind of disposal include the economics of the recovery and
the market for the recovered metal. For Level III, we recommend both the recovery as
described in Level II and engineered storage. However, in our survey, we did not find any4
one utilizing engineered storage. We include engineered storage in this Level III technology
because there are some heavy metal wastes which do not lend themselves to recovery and
therefore must be subjected to some secure method of disposal.

1 2’6
1

LV

Table 4.5.4 provides information on our recommended levels of treatment and disposal
of heavy metal wastes.

4.5.5 Treatment and Disposal Levels for Returned Goods and Reject Materials
from Formulation

ADL estimates that the pharmaceutical industry annually generates 500 metric tons of
waste from returned goods and reject material from formulation operations. The technology
most commonly used within the industry for handling these wastes is to crush the material
and dispose of it in a sanitary landfill. We estimated that approximately 60% of the industry
facilities use this method. Because more information is needed on the effects of these
materials being landfilled, we have described their present adequacy as good, but have
recommended other treatment for Level II.

In Level 11 technology in our survey we have found that these wastes were both being
incinerated by either a contractor or at a company—owned facility and also treated in an
onsite biological wastewater treatment system. Approximately 10% of these facilities
currently use incineration and about 20% use the biological treatment. The residual from
the incineration is a non-hazardous ash.

The problems and limitations associated with these two methods involve the avail-
ability of either incineration or onsite biological treatment. We have described Level III to
be the same as Level 11, because we believe these two methods provide environmentally
adequate methods of disposal.

Table 4.5.5 provides information on our recommended levels of treatment and disposal
of returned goods.

127

TABLE 4.5.4

TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
FOR HEAVY METAL WASTES”

Amount of Waste: *

Technology

Current Usage

— Percent of Industry
Facilities

— Number of Facil-
itiesi

Risk

— Risk from Fires or
Explosions

— Transport Risks
— Pollution Risk

Present Adequacy
Future Adequacy
Residual Waste“
Reliability of Technology

0 Limitations or Problems

Suitability for Retrofit
0 Non-land Related Impact

0 Implementation Time

*Prior to treatment of disposal

HFinally land disposed

Level I

Convert heavy metal to
most insoluble form,
drum, and place in se-
cure chemical landfill

80

12

Slightly
Moderate

Good

Good

All

Good

Soil conditions

2875 Metric Tons per Year

Level II
1) Recovery off-site
2) As Level I

***

1) 20
2) 80

1) 3
2) 12

1H2) Slight

1) Minimal
2) Moderate

1) Excellent
2) Good

1) Excellent
2) Good

1) Some
2) As Level 1

1) (2) Good

1) Market for heavy
metal
2) Soil conditions

1) Minimal

1 ) Two years

1) Recovery off-site
2) Engineered storage

1) 20
2) 0

H3
2)0

1)(2) Slight

1) Minimal
2) Slight

1) (2) Excellent

1) (2) Excellent

1) Some
2) All

*“All of the plants we visited that used landfill for disposal used a secure chemical landfill for their heavy
metal wastes. We believe, however, that a small percentage of the heavy metal wastes may be land-

filled in sanitary landfills.

T1‘5 pharmaceutical plants are estimated to have heavy metal wastes.

”Source: Interviews and Arthur D. Little, |nc., estimates.

128

TABLE 4.5.5

TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
FOR POTENTIALLY HAZARDOUS RETURNED GOODS AND
REJECT MATERIAL FROM FORMULATION”

Amount of Waste:* 500 Metric Tons per Year

H“More information needed.

Technology

Current Usage
— Percent of Industry
Facilities

— Number Of Facilities

Risk
— Risk from Fires or
Explosions

- Transport Risks

— Pollution Risk

Present Adequacy

Future Adequacy
Residual Waste”
Reliability of Technology
Limitations or Problems
Suitability for Retrofit
Non-Land Related Impact

Implementation Time

 

 

 

Level I Level II Level III
Crush on-site and 1) Incineration by as Level II
landfill in sanitary contractor or at
landfill. company-owned

faciIity.

2) Treatment in on-
site biological waste-
water treatment
system.

60 1) 10

2) 20
122 1) 15

2) 30
None 1) (2) None
None 1) (2) None
Slight 1) (2) None
Good 1) (2) Excellent
*** 1) (2) Excellent
All 1) 60 percent of wasteT
Good 1) (2) Good
*** 1) (2) Availability

*Prior to treatment or disposal.

“Finally land disposed.

TNon-hazardous ash.

 

HSource: Interviews and Arthur D. Little, Inc., estimates.

129

GENERAL BIBLIOGRAPHY
Section 4.0

Achinger, W. C. and L. E. Daniels. An Evaluation of Seven Incinerators, Proceedings of the
1970 National Incinerator Conference, p. 32.

Adinoff, J. “Waste Disposal,” Industry and Power, July 1953, p. 80.

B1ack&Veatch and Rafael A. Domenech&Associates. “Industrial Waste Survey, Bar-
celoneta Region, Puerto Rico,” Prepared for the Puerto Rico Aqueduct and Sewer
Authority, Commonwealth of Puerto Rico, July 1973.

Breaz, Emil. “Drug Firm Cuts Sludge Handling Costs,” Water and Waste Management,
January 1972, p. A—22.

Bridge, D. P. and J. D. Hammel. “Incinerator Design Specifically to Burn Waste Liquids and
Sludges,” Proceedings of 1972 National Incinerator Conference, p. 55.

Colonna, Robert A., and Cynthia McLaren. “Appendix D, Hazardous Wastes,” Decision-
Makers Guide in Solid Waste Management, Environmental Protection Agency, 1974,

p. 146.

Danielson, C. N., W. G. Robrecht. “Deep-well Disposal of Chemical Wastes: Solid Backbone
of a Total Waste Control Program.”

Davis, Ken E. and Rabey J. Funk. “Deep-Well Disposal of Industrial Wastes,” Industrial
Wastes, Vol. 21, No. 1, January/February 1975, p. 28.

Eckenfelder, W. Wesley, Jr., and Edwin L. Barnhart. “Biological Treatment of Pharma-
ceutical Wastes,” Biotechnology and Bioengineering, Vol. IV, 1962, p. 171.

Heaney, Frank L., and Charles V. Keane, Solid Waste Disposal (Camp, Dresser and McKee
Company).

Hescheles, C. A. “Ultimate Disposal of Industrial Wastes,” Proceedings of 1970 National
Incinerator Conference, p. 235.

Kroneberger, G. F. “Porteous Conditioning of Sludges for Improved Dewatering,” Solid
Waste Treatment, Vol. 68, No. 122, p. 176.

Kumar, J. and J. A. Jedlicka. “Selecting and Installing Synthetic Pond-Linings,” Chemical
Engineering, February 5, 1973, p. 67.

130

Laboratory Waste Disposal Manual, Manufacturing Chemists Association, Revised July
1974.

Lawson, J. Ronald, Michael L. Woldman, and Paul P. Eggermann. “Squibb Solves Its
Pharmaceutical Wastewater Problem In Puerto Rico,” Chemical Engineering Progress
Symposium Series, 1970, p. 401.

McGill, Douglas L., and Elbridge M. Smith. “Fluidized Bed Disposal of Secondary Sludge
High in Inorganic Salts,” Proceedings of 1970 National Incinerator Conference, p. 79.

Mead, Berton E., and William G. Wilkie. “Leachate Prevention and Control from Sanitary
Landfills,” Presented at the 68th National Meeting of the American Institute of
Chemical Engineers, March 2, 1971, p. 1.

Melcher, R. R. “Experience with Pharmaceutical Waste Disposal by Soil Injection,” Speech
presented at the American Chemical Society, September 7, 1961.

“Ocean Dumping,” Federal Register, Environmental Protection Agency, Part 11, Volume 38,
No. 94, May 16, 1973.

Proposed Solid Waste Management Authority Development Plan, Solid Waste and Noise
Control Program, Office of the Governor, Commonwealth of Puerto Rico, p. 69.

Quane, D. E. “Air Pollution Control Techniques: Reducing Air Pollution at Pharmaceutical
Plants,” Chemical Engineering Progress, V01. 70, No. 5, May 1974, p. 5.

Routson, R. C. and R. E. Wildung. “Ultimate Disposal of Wastes to Soil,” Chemical
Engineering Progress Symposium Series, No. 97, V01. 65, Winter, 1969, p. 19.

Rules of the Bureau of Solid Waste Management, New Jersey Department of Environmental
Protection, July 1, 1974.

Santoleri, Joseph J. “Chlorinated Hydrocarbon Waste Recovery and Pollution Abatement,”
Proceedings of 1972 National Incinerator Conference, p. 66.

Scurlock, Arch C., Alfred W. Lindsey, Timothy Fields, Jr., and David R. Huber. “Incinera-
tion in Hazardous Waste Management,” Division of the Environmental Protection
Agency, April 1974.

“Solid Waste Management in the Drug Industry,” Prepared for the Environmental Protec-
tion Agency, 1973.

Sorg, Thomas J. “Industrial Solid Waste Problems,” AIChE Symposium Series, No. 122,
Vol.68, 1972, p. 1.

131

Stone, Ralph. “Sanitary landfill Disposal of Chemical Petroleum Waste,” Solid Waste
Treatment, AIChE Symposium Series, No. 122, Vol. 68, p. 35.

“Synthetic Organic Chemicals, United States Tariff Commission, United States Production
and Sales, 1971, p. 101.

“The Form of Hazardous Waste Materials,” Rollins Environmental Services, September 7,
1972.

Walker, William H. “Monitoring Toxic Chemicals in Land Disposal Sites,” Pollution Engi-
neering, September 1974, p. 50.

Witt, Philip A., Jr. “Disposal of Solid Wastes,” Chemical Engineering, October 4, 1971,
p. 61.

132

5.0 COST ANALYSIS
5.1 BACKGROUND

Total production of active ingredients within the pharmaceutical companies in 1973 is
estimated at 45,000 metric tons. Overall, production of these ingredients is expected to
grow at a rate of 3 percent per year through 1977 and at a 7 percent rate thereafter.* Waste
generated and destined for land disposal in 1973 for the pharmaceutical industry is
estimated at 244,000 metric tons per year. The hazardous waste represents about 25 percent
of the total waste or 61,000 metric tons per year in 1973. Wastes are expected to grow to
400,000 metric tons per year of total wastes and to 100,000 metric tons per year of
hazardous wastes by 1983. Approximately 85 percent of total wastes and 60 percent of
hazardous wastes are estimated to be treated and disposed of by contractors.

Approximately 54 company operations estimated to be large enough to have signifi-
cant wastes participate in the manufacture of pharmaceutical active ingredients. Another
175 operations large enough to produce significant wastes formulate and package these and
other ingredients into final pharmaceutical preparations. In order to calculate total industry
costs, we used the above estimates of company operations in conjunction with industry
production estimates and treatment and disposal costs per ton of product.

5.2 SUMMARY OF COSTS FOR CONTROLLED TREATMENT AND DISPOSAL OF
LAND-DESTINED HAZARDOUS WASTES

Tables 5.2-A, -B, and -C summarize the costs of end-of-pipe treatment and disposal
systems either currently in use or recommended for future use in pharmaceutical production
facilities. No costs are given for in-process changes made to minimize or change the
hazardous character of the wastes. Because typical plants were used to develop an estimate
of the total industry cost of treatment and disposal of hazardous wastes, the total industry
costs should be taken only as an indication of the order of magnitude of such costs rather
than as the outcome of a detailed industry survey of the costs. Issues such as site specific
costs, different products or product mixes, local disposal rates, and available disposal
methods were not included in this estimate. Where it is necessary to reflect different
economics of large versus small plants and separate hazardous waste streams, costs have been
developed typically for more than one plant in each industry section. These product-specific
analyses are presented in Tables 5.4.2.1 to 5.4.3.

5.3 RATIONALE AND REFERENCES USED IN COST ESTIMATING

Eighty-five percent of the total pharmaceutical industry process waste are disposed of
through contractors. The onsite disposal facilities are liquids incinerators and solids incinera-
tors. However, almost 70 percent of the incineration capability are located offsite with
contractors. There is, however, a trend toward onsite incineration. In our survey, we
contacted numerous pharmaceutical companies that had recently installed incineration

‘ *The industry growth rate is discussed in Section 2.7.
133

capacity or were planning installation. Because of the patterns of offsite disposal, costs in
this report have usually been determined for representative plants on the basis of contractor
disposal. In addition, there is information presented on the cost of onsite incinerators for
solids. The data are presented for various size ranges. Installation of these units is usually
determined by individual company location and policy. Where industry in an area is sparse,
there may be limited availability of contractor incineration. On the other hand, in some
areas, pharmaceutical companies may find an adequate supply of disposers, but find that
they are constantly on the brink of being shut down by local regulatory agencies for air or
water regulation violations. These pharmaceutical companies may decide in favor of onsite
incineration to ensure that they have a reliable disposal method.

TABLE 5.2-A
PERSPECTIVE ON THE PHARMACEUTICAL INDUSTRY:

TREATMENT AND DISPOSAL COSTS PE R UNIT OF HAZARDOUS WASTE?
($/metric ton)

Product Category Level I Level II Level III

 

0 Bulk Active Ingredient

— Organic Medicinal Chemicals

Non-halogenated waste solvent 68 68 68

Halogenated waste solvent 184 184 184

High inert content wastes 26 43 43

Heavy metal waste 50 50' 60

Organic chemical residues 100 100 100
-— Inorganic Medicinal Chemicals

Heavy metal waste 50 50 60
— Fermentation Products

Waste solvent concentrate 120 120 120
— Botanicals

Aqueous solvent 144 144 144

Waste halogenated solvent 180 180 180

Non-halogenated waste solvent 68 68 68
—- Drugs from Animal Sources

Aqueous alcohol 142 142 142
— Biologicals

Aqueous alcohol 142 . 142 142

Antiviral vaccine 3O 30 30

Other biologicals (toxoids, serum) 30 30 30
0 Pharmaceutical Preparations 28 67 67

fSource: Arthur D. Little, lnc., estimates.

134

TABLE 5.2-3

PERSPECTIVES ON THE PHARMACEUTICAL INDUSTRY:
HAZARDOUS WASTE TREATMENT AND DISPOSAL COSTS‘I

Product Category

0 Bulk Active Ingredient
— Organic Medicinal Chemicals

Non-halogenated waste solvent
Halogenated waste solvent
High inert content wastes
Heavy metal wastes
Organic chemical residues
- Inorganic Medicinal Chemicals***
Only one hazardous waste identified
- Fermentation Products
Waste solvent concentrate
— Botanicals

Aqueous solvent
Halogenated waste solvent
Non-halogenated waste solvent

—— Drugs from Animal Sources
Aqueous alcohol
— Biologicals

Aqueous alcohol
Antiviral vaccines
Other biologicals (toxoids serum)

0 Pharmaceutical Preparations

Partial Total+

 

Estimated
Total Annual Costs ($000)“
1.9.72 117.7 19%
1,620 1,820 2,585
630 705 1,000
45 80 1 10
145 160 275
1,360 1,530 2,170
1,440 1,620 2,300
145 160 230
10 10 15
10 10 15
1 15 130 180
35 40 60
. 10 10 15
5 10 10
15 40 50
5,585 6,325 9,015

*Based on average treatment costs and pharmaceutical industry waste esti-

mates.
* * December 1973 dollars.

***|ncluded in heavy metal wastes under organic medicinal chemicals

+Excludes R&D costs.

ISource: Arthur D. Little, lnc., estimates.

135

TAB LE 5.2—C

PERSPECTIVES ON THE PHARMACEUTICAL INDUSTRY:

COST IMPACT OF HAZARDOUS WASTE TREATMENT AND DISPOSAL?

Estimated Hazardous Waste
Control Cost as Percent of Price"

 

 

 

1973
Selling Price
Product Category I $/kg Level 1 Level II Level Ill'
0 Bulk Active Ingredient
Organic Medicinal Chemicals 22 0.2% 0.22% as Level II
Inorganic Medicinal Chemicals ** — — — -
Fermentation Products 44 0.34% as Level I as Level |
Botanicals ***
Drugs from Animal Sources *** <0.1% as Level I as Level I
Biologicals ***

* Manufacturers selling price in the case of pharmaceutical preparations; value of sales, that
is, the net selling value FOB plant or warehouse, or delivered value, whichever represents
the normal practice for bulk active ingredient.

** Representative data not available because most inorganic medicinal ingredients that might
produce a hazardous waste are purchased from the chemical industry.
*** Data not available; the selling price of many of these products is stated in terms of
biological activity.

1.Source: Arthur D. Little, lnc., estimates.

In each of the representative operation cost analyses, typical plant situations are
identified in terms of production capacity, process waste load, hazardous waste load, and
product value. Annual capital costs have been assumed to be a constant percentage (10
percent of fixed investment). Depreciation costs have been calculated on the straight—line
method (10 percent per year) over 10 years, even though the physical life is longer. Taxes
and insurance are included as 1-1/2 percent of the capital investment. All estimates are
reported in December 1973 dollars. The Engineering News Record (ENR) Construction Cost
Index (1158) and the Chemical Engineering (CE) Plant Cost Index (148.2) have been used
to prepare these estimates. Land requirements for onsite treatment are not significant;
therefore, no cost allowance has been made. Offsite treatment and disposal land require-
ments are not considered directly. Land costs are included in the contractor’s charges.
Cost-effectiveness relationships are implicit in the calculation of these costs, together with
the technology levels achieved. For example, when considering a small pharmaceutical plant,
the use of contractor disposal is more cost-effective because of the economies of scale and
the potential for energy and resource recovery. With larger pharmaceutical operations,
onsite and Offsite incineration have approximately equal cost-effectiveness. The major issue
in these instances would be the availability of capital.

136

Table 5.3-A presents costs for transporting wastes for offsite disposal:

TABLE 5.3-A

COST OF TRANSPORTING WASTES?

 

Distance Liquids Solids
(miles) ($/m3 l ($l1000 gal) ($lmetric ton)
5 0.92 3.50 1.85
10 1.02 3.85 2.10
20 1.48 5.60 2.70
40 1.94 7.35 3.40
50 2.03 7.70 3.70

1Source: Arthur D. Little. lnc., estimates.

A number of contractors were contacted in this study, primarily in EPA Regions II and V
where concentrations of the pharmaceutical industry are found. Table 5.3-B summarizes the
information obtained, supplemented and checked by ADL estimates. No factors are in-
cluded for areas of the country, as no obvious differences were found in our analysis.

TABLE 5.3-B

CONTRACT DISPOSAL CHARGES FOR HAZARDOUS WASTES.r

Method $lMetric Ton
General Landfil|* 8
Secure Chemical LandfillM 17
Approved Secure Landfill*** 30
Incineration

Non-halogenated solvents (organic

content 85% and over) 90

Solids 30
Neutralization (or precipitation of
components) of Wastes 30

*Operated as sanitary landfill.
H'Lined landfill limited to chemical wastes.
*** Lined landfill limited to hazardous wastes with monitoring.

1'Source: Interviews and Arthur D. Little, lnc., estimates.

137

Also, the costs for Offsite disposal vary, depending upon the amount of waste to be
disposed, the collection frequency, and the onsite storage facilities. Figure 5.3-A gives an
example of how these factors affect costs. Figure 5.3-B presents capacity ranges and
investment costs for industrial solid waste incinerators, and Table 5.3-C presents background
information. Figure 5.3-C gives operating costs in terms of dollars per metric ton.

5.4 COSTS FOR TREATMENT AND DISPOSAL OF HAZARDOUS WASTES
5.4.1 Research and Development

The hazardous wastes produced within the R&D section of the industry include both
waste solvents and test animals. Waste solvents can be incinerated either by contractors or in
company-owned facilities for about $0.30 per gallon. A research facility with 100 re-
searchers will produce about 2000 gallons of waste solvent annually. The cost of incinerat-
ing that waste will be approximately $600 annually.

Most pathological incineration capacity for test animals within the R&D section of the
industry is installed. It is not discussed here.

5.4.2 Production of Active Ingredients (SIC 2831 and 2833)
5. 4. 2. 1 Organic Medicinal Chemicals

Of the 27,200 metric tons of waste solvent produced by the pharmaceutical companies
in the manufacture of organic medicinal chemicals, about 10,100 metric tons per year can
be incinerated onsite by the industry. Onsite incineration capacity and its associated
pollution control equipment (both air and water) are expected to increase.

Offsite contractors dispose of the remainder of the waste solvent, about 17,100 metric
tons per year. After surveying the disposers, we found the typical charge for incineration of
pharmaceutical waste solvents to be $0.20 to $0.35 per gallon for a solvent of medium-range
Btu content, depending mainly on the Btu content. The purer solvents can potentially be
recovered and sold, reducing the disposal charge, or used as a fuel for the incineration of
wastes with a higher water content. Those lower Btu content wastes may vary from $0.35 to
$0.60 per gallon for those with high water content; perhaps up to $1.00 for those with high
chlorine content as well.

Since the actual quantities of medicinals which are produced in an operation are often
difficult to determine, we based the plant size on the number of production workers. A
typical operation producing organic medicinal chemicals has 300 production workers. In
other industries, the production is related to the number of production workers. That ratio
remains relatively constant from plant to plant within an industry. Within the pharma-
ceutical industry, where the number of intermediate production steps can range from 1 to

‘138

 

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TAB LE 5.3C

CAPiTAL INVESTMENT FOR INDUSTRIAL SOLID WASTE INCINERATIONf

Capacity
Annual Capacity (single-shift operation)
Type
Capital Cost
Incinerator
Freight
Installation+ (includes foundations,
electrical, plumbing, oil storage)

Total Fixed Capital Investment (FCI)
Engineering @ 10% of FCl
Contractor's Fee @ 7% of FCl
Contingency @ 15% FCl

Total

*410 metric tons
H820 metric tons

"*1700 metric tons

600 lb/hr
450 tons*
Batch

$25,000
2,000

5,000

32,000
3,000
2,000
5,000

$42,000

1200 lb/hr 2500 lb/hr
900 tonsH 1875 tons***
Batch Semi-Automatic
$45,000 $1 00,000
3,000 5,000
8,000 1 5,000
56,000 120,000
5,000 1 2,000
3,000 8,000
8,000 1 8,000
$72,000 $158,000

+Installation costs for an incinerator within an operating plant are lower than those for
for an incinerator located in areas where these facilities are not already available.

TSource: Arthur D. Little, lnc., estimates.

140

15, we studied the various plants for which production figures were available and found that
for operations of approximately the same complexity the production per production worker
stays relatively constant also. Ratios varied from 8000 pounds per year per production
worker* to 30,000 to 40,000 pounds per year per production worker for large-scale
operations making relatively simple products such as aspirin.

The costs of treatment and disposal of hazardous wastes from organic medicinal
chemical active ingredient production for, a typical plant of 300 production workers are
presented in Tables 5.4.2.1-A,—B,—C, and -D. There are smaller operations in the industry
ranging down to almost 100 production workers. Few facilities can operate with fewer than
this number. Some of the larger operations employ close to 1000 production workers. The
problems and the associated costs per amount of waste are generally of the same magnitude
as the typical plant.

5.4.2.2 Inorganic Medicinal Chemicals

No individual costs have been developed for the treatment and disposal of inorganic
medicinal chemical wastes. We found only one hazardous waste in our survey. We have
included its treatment and disposal cost in the overall number for the organic medicinal
chemical hazardous waste treatment and disposal cost. We have estimated that the treatment
and disposal cost for this waste is approximately $50 per metric ton.

5.4. 2.3 Fermentation Products

As we have indicated in Tables 5.4.2.3-A and -B, although the plant size varies, both
the large and small plants incur the same average treatment and disposal cost of 14¢/kg of
product and $120/metric ton of waste to dispose of a material which is a waste solvent
concentrate containing about 50% solids.

5. 4. 2. 4 Bo tanicals

We have identified three hazardous wastes from the production of botanicals, specifi-
cally alkaloids. These materials are an aqueous solvent with 50% solids, a halogenated waste
solvent, and a non-halogenated waste solvent. Each of these waste streams was disposed of
by incineration. Although there are onsite facilities for incineration of these wastes, as our
example we have chosen a typical plant which is using incineration by contractor offsite.
The average treatment and disposal costs of these wastes range from $68/metric ton of
waste for the non—halogenated waste solvent to $144/metric ton of waste for the aqueous
solvent to a high of $180/metric ton of waste for the halogenated waste solvent. Tables
5.4.2.4—A, -B, and -C describe the costs associated with a typical botanical production
operation.

* For operations making widely diverse products in batch operations where many products were made only
once per year with the production lasting anywhere from one day to three months.

141

5.4.2.5 Drugs from Animal Sources

For our typical plant we have chosen a plant with 20 employees manufacturing insulin.
The hazardous waste stream from this production facility is an aqueous alcohol with organic
solids. It is typically 25% alcohol, 25% solids, and 50% water. This waste is disposed of by
incineration by a contractor offsite. The costs average $50/kg of product or $142/metric
ton of waste. Table 5.4.2.5 describes the costs associated with a typical operation in which
drugs are produced from animal sources.

5. 4. 2. 6 Biologicals

Producing plasma protein fractions represents a typical production scenario for a
biological products plant. We have based our estimates of disposal costs on such a plant. The
representative production capacity for this plant is a SOC-liter batch of input plasma. The
associated hazardous waste load from this batch is about 2500 liters of aqueous alcohol.
This corresponds to a hazardous waste load per unit of production of 5 liters of waste per
liter of plasma. This results in an average treatment and disposal cost of 40¢/liter of input
plasma. Table 5.4.2.6 describes the costs associated with a typical biological operation.

5.4.3 Formulation and Packaging (SIC 2834)

Finished pharmaceutical preparations are made in the formulation and packaging
operation. The hazardous waste stream from this operation consists of a portion of the
returned goods and reject materials. A typical plant would have 200 production employees
and would operate 250 days per year. Because of the variety of products, it is difficult to
assign a representative plant capacity to these operations. We have therefore described the
plant capacity both in terms of the value of shipments and the value added in that
processing operation. The representative plant we have chosen has $1 1,000,000 value added
and a $14,000,000 value of the shipments. The average product value added annually per
employee is $55,000; the average value of shipment annually per employee is $70,000. The
hazardous waste load from this facility annually is about 18 metric tons of returned goods
and reject material. Under Level I technology, which is described as crushing this material
onsite and having a contractor handle the landfill and the sanitary landfill offsite, the cost
amounts to about $28 per metric ton of waste. Incineration of this waste by a contractor
offsite raises the average treatment and disposal cost to $67 per metric ton of waste.

Table 5.4.3 describes the waste volume and treatment costs of a typical formulation
and packaging operation.

142

TABLE 5.4.2.1-A
TREATMENT AND DISPOSAL COSTS:

ACTIVE INGREDIENT PRODUCTION; ORGANIC MEDICINAL CHEMICALS
WASTE STREAM — NON-HALOGENATED WASTE SO LVENTT

Plant description: plant with 300 employees

Representative production schedule, days/year: 250
Representative plant capacity: million kg/year: 1.0
Average product value per unit of production, $/kg 22

Process hazardous waste load in million kg/year:

Waste solvent, non-halogenated; 0.7
Waste solvent, halogenated; 0.1
Potentially hazardous high inert content wastes; 0.05
Heavy metal waste —
Organic chemical residues 0.4
Hazardous waste load (Non-halogenated waste solvent)
million/kg year: 0.7
Hazardous waste load per unit of production: kg/kg 0.7

Levels of Treatment

 

Cost — ($I Level I Level II Level III
Transportation 1,000 as Level I as Level I
Contract disposal charges 46,400
Total Annual Costs 47,400
Average Treatment/ Disposal Cost
per Unit of Production, $/kg $0.047
per metric ton of waste $68
Level I — Incineration by contractor off-site
Level II — as Level I
Level III —— as Level I

tSource: Arthur D. Little, |nc., estimates.

143

TABLE 5.4.2.1-B
TREATMENT AND DISPOSAL COSTS:

ACTIVE INGREDIENT PRODUCTION: ORGANIC MEDICINAL CHEMICALS
WASTE STREAM — HALOGENATED WASTE SOLVENT?

PIant=descriptionz plant with 300 employees

Representative production schedule, days per year 250
Representative plant capacity: million kg/year: 1.0
Average product value per unit of production, $/kg 22
Process hazardous waste load in million kg/year:
Waste solvent, non-halogenated; ' 0.7
Waste solvent, halogenated; 0.1
Potentially hazardous high inert content wastes; 0.05
Heavy metal waste —
Organic chemical residues 0.4
Hazardous waste load (halogenated waste solvent)
million kg/year: 0.1
Hazardous waste load per unit of production: kg/kg 0.1

Level of Treatment

 

Cost — ($) Level I Level II Level III
Transportation 160 as Level I as Level I
Contract disposal charges 18,280
Total Annual Costs 18,440
Average treatment/disposal cost
per unit of production, $0.018/k9
per metric ton of waste $184
Level I — Incineration by contractor off-site
Level II — as Level I; with energy and resource recovery at contractor’s site
Level III - as Level II
1'

Source: Arthur D. Little, lnc., estimates.

144

TABLE 5.4.2.1-C
TREATMENT AND DISPOSAL COSTS:

ACTIVE INGREDIENT PRODUCTION, ORGANIC MEDICINAL CHEMICALS
WASTE STREAM: POTENTIALLY HAZARDOUS HIGH IN ERT CONTENT WASTES

Plant description: plant with 300 employees

Representative production schedule, days per year 250
Representative plant capacity: million kg/year: 1.0
Average product value per unit of production, $/kg 22
Process hazardous waste load: million kg/year:
Waste solvent, non-halogenated; 0.7
Waste solvent, halogenated; 0.1
Potentially hazardous high inert content wastes; 0.05
Heavy metal waste -—
Organic chemical residues 0.4
Hazardous waste load (potentially hazardous high inert
content wastes), million kg/year: 0.05
Hazardous waste load per unit of production: kg/kg 0.05

Levels of Treatment

 

 

 

Cost— ($) Level 1 Level II Level III
Transportation Cost 163 163 as Level II
Contractor Incineration Charge 730 730
Contractor Landfill Charge ' 198 198
Neutralization Cost —— 730
Contractor Secured Landfill Charge 438 438

Total Annual Costs 1,529 2,259
Average treatment/disposal cost
‘ per umt of production 1000 kg 1000 kg
per metric ton of waste $26 $43
Level I — Incineration by contractor off-site for solvent containing waste; disposal by contractor

in secure chemical landfill for waste containing corrosives or trace amounts of
heavy metal.‘

Level II —- Incineration by contractor off-site for solvent containing waste; treatment (neutrali-
zation) by contractor prior to disposal by contractor in secure chemical landfill for
waste containing corrosives or trace amounts of heavy metal.

Level III — as Level II

*If this plant were to landfill the solvent containing waste (as described in Table 4.5.3—A) and ‘
landfill the waste containing corrosives or trace amounts of heavy metal, then the associated
costs for treatment and disposal would be $0.77 per 1000 kg product ($13 per metric ton of
waste).

tSource: Arthur D. Little, lnc., estimates.

-145

I

TABLE 5.4.2.1-D
TREATMENT AND DISPOSAL COSTS:

ACTIVE INGREDIENT PRODUCTION; ORGANIC MEDICINAL CHEMICALS
WASTE STREAM -— ORGANIC CHEMICAL RESIDUES...

Plant description: plant with 300 employees

Representative production schedule, days/year: 250
Representative plant capacity: million kg/year: 1.0
Average product value per unit of production: $/kg 22
Process hazardous waste load in million kg/year:
Waste solvent, non-halogenated; 0.7
Waste solvent, halogenated; 0.1
Potentially hazardous high inert content wastes; 0.05
Heavy metal waste -
Organic chemical residues 0.4
Hazardous waste load (organic chemical residues)
million kg/year: 0.4
Hazardous waste load per unit of production: kg/kg 0.4

Levels of Treatment

 

 

Cost - ($I Level I Level II Level III
Transportation . 600 as Level l as Level I
Contract disposal charges 39,400
Total Annual Costs 40,000
Average treatment/disposal cost
per unit of production $0.04/kg
per metric ton of waste $100
Level | — Incineration by contractor off-site”
Level II — as‘Level | .
Level III - as Level I

*If this plant were to landfill these wastes as described in Table 4. 5. 2, the associated costs
for treatment and disposal would be $0. 0034 per kg product ($8. 50 per metric ton of waste)
Larger facilities, such as the one described on this page, do not landfill these residues.

TSource: Arthur D. Little, |nc., estimates.

146

TABLE 5.4.2.3-A

ACTIVE INGREDIENT PRODUCTION; FERMENTATION PRODUCTS; PENICILLIN
WASTE STREAM— WASTE SOLVENT CONCENTRATE (50% SOLIDS”.

Plant description: small plant (with solvent extraction)

Representative production schedule, days per year: 350
Representative plant: 200,000-gallon fermentor capacity.

Product, million kg/year: 0.95
Average product value per unit of production, $/kg 22
Hazardous waste load (waste solvent concentrate, 50% solids),

million kg/year: 1.14
Hazardous waste load per unit of production: kg/kg 1.20

Levels of Treatment

 

Cost - ($l Level I Level II Level III
Transportation 1,730 as Level I as Level I
Contract disposal charges 133,000

Total Annual Costs 134,730
Average treatment/disposal cost

per unit of production $0.14/kg

per metric ton of waste $120
Level I - Incineration by contractor off-site
Level II -— as Level |

Level III — as Level I

1Source: Arthur D. Little, |nc., estimates.

147

TABLE 5.4.2.3-3

TREATMENT AND DISPOSAL COSTS:
ACTIVE INGREDIENT PRODUCTION; FERMENTATION PRODUCTS; PENICILLIN
WASTE STREAM - WASTE SOLVENT CONCENTRATE (50% SO LIDSIT

Plant description: large plant (with solvent extraction)

Representative production schedule, days per year:

350

Representative plant: 600,000-gallon fermentor capacity

Product, million kg/year:

Average product value per unit of production, $/kg

Hazardous waste load (waste solvent concentrate, 50%

solids), million kg/year:

Hazardous waste load per unit of production: kg/kg

Cost — ($I

Transportation
Contract disposal charges
Total Annual Costs

Average treatment/disposal cost
per unit of production
per metric ton of waste

Level I — Incineration by contractor off~site
Level II - as Level I
Level III — as Level I

TSource: Arthur D. Little, lnc., estimates.

148

Level I

5,280
406,000
41 1,280

$0.14/kg
$120

2.9
22

3.48
1.20

Levels of Treatment

 

Level II Level III
as Level l as Level |

TABLE 5.4.2.4-A

TREATMENT AND DISPOSAL COSTS:
ACTIVE INGREDIENT PRODUCTION; BOTANICALS; ALKALOIDS
WASTE STREAM — AQUEOUS SOLVENT WITH SOLIDS (30% SOLVENT, 20% WATER,
50% SOLIDsl'r

Plant description: typical size industrial plant with 20

employees

Representative production schedule, days per year: 250
Representative plant capacity, kg/year: 680
Average product value per unit of production, $/kg 11,000
Process hazardous waste load in thousand rn3 /year:

Aqueous solvent with 50% solids 0.09

Halogenated waste solvent ems

Non-halogenated waste solvent 0.020

Hazardous waste load (aqueous solvent with solids 30%
solv‘ent, 20% water, 50% solids) thousand m3/year: 0.09

Hazardous waste load per unit of production: m3 /kg 0.13

Levels of Treatment

 

Cost — ($) Level I Level II Level III
Transportation 160 as Level I as Level I
Contract disposal charges 12,500

Total Annual Costs 12,760
Average treatment/disposal cost

per unit of production $18.8/kg

per metric ton of waste $144
Level | —— Incineration by contractor off-site
Level II — as Level I

Level Ill —- as Level I

tsource: Arthur D. Little, lnc., estimates.

149

TABLE 5.4.24-3

TREATMENT AND DISPOSAL COSTS
ACTIVE INGREDIENT PRODUCTION; BOTANICALS; ALKALOIDS
WASTE STREAM - HALOGENATED WASTE SOLVENT?

~ Plant description: typical size industrial plant with 20 employees

Representative production schedule, days per year: 250
Representative plant capacity: kg/year: 680
Average product value per unit of production, $/kg 11,000
Process hazardous waste load in thousand m3/year:

Aqueous solvent with 50% solids 0.09

Halogenated waste solvent 0.005

Non-halogenated waste solvent 0.020
Hazardous waste load (halogenated waste solvent, thousand

m3/year): 0.005

Hazardous waste load per unit of production: ma/kg 0.007

Levels of Treatment

 

Cost - ($I Level I Level II Level III
as Level I as Level |
Transportation 20
Contract disposal charges 1,000
Total Annual Costs 1,020
Average treatment/disposal cost
per unit of production $1.5/kg
per metric ton of waste $180
Level I — Incineration by contractor off-site
Level II — as Levell
Level III — as Level I

fSource: Arthur D. Little, lnc., estimates.

150

TABLE 5.4.2.4-C

TREATMENT AND DISPOSAL COSTS:
ACTIVE INGREDIENT PRODUCTION; BOTANICALS; ALKALOIDS
WASTE STREAM — NON-HALOGENATED WASTE SOLVENTI

Plant description: typical size industrial plant with 20

employees

Representative production schedule, days per year: 250
Representative plant capacity, kg/year: 680
Average product value per unit of production, $/kg 11,000
Process hazardous waste load in thousand rn3 /year:

Aqueous solvent with 50% solids 0.09

Halogenated waste solvent 0.005

Non-halogenated waste solvent 0,020
Hazardous waste load (non-halogenated waste solvent,

thousand m3 /year): 0.020
Hazardous waste load per unit of production: ma/kg 0.03

Cost - ($I

Transportation
Contract disposal charges
Total Annual Costs

Average treatment/disposal cost
per unit of production
per metric ton of waste

Level I — Incineration by contractor offsite
Level II — as Level I
Level III — as Level I

ISource: Arthur D. Little, lnc., estimates.

151

Levels of Treatment

 

Level I Level II Level III
80 as Level I as Level I
1,040
1,120
$1.60/kg
$68

TABLE 5.4.2.5

TREATMENT AND DISPOSAL COSTS:
ACTIVE INGREDIENT PRODUCTION; DRUGS FROM ANIMAL SOURCES; INSULIN
WASTE STREAM — AQUEOUS ALCOHOL WITH ORGANIC SOLIDS
(25% ALCOHOL, 25% SOLIDS, 50% WATER).r

Plant description: typical size industrial plant with 20

employees
Representative production schedule, days per year: 250
Representative plant capacity, kg/year: 284
Average product value per unit of production, $/kg 11,000
Hazardous waste load (aqueous alcohol with organic solids,
25% alcohol, 25% solids, 50% water), thousand m3/year: 0.10
Hazardous waste load per unit of production: m3/kg 0.35

Levels of Treatment

 

 

 

Cost — ($I Level | Level II Level III
Transportation 400 as Level I as Level I
Contract disposal charges 13,900
Total Annual Costs 14,300
Average treatment/disposal cost
per unit of production $50/kg
per metric ton of waste $142
Level | — Incineration by contractor off-site
Level II — as Level I
Level III —— as Level I

1lsource: Arthur D. Little, |nc., estimates.

152

TABLE 5.4.2.6

TREATMENT AND DISPOSAL COSTS:
ACTIVE INGREDIENT PRODUCTION; BIOLOGICAL PRODUCTS;
PLASMA PROTEIN FRACTIONS
WASTE STREAM — AQUEOUS SOLVENT?

Plant description: typical size industrial plant

Representative production schedule, days/year 250
Representative production capacity: 500liter batch of

input plasma
Average product value per unit of production, $/kg N.A.*
Hazardous waste load (aqueous alcohol, liters/batch) 2,500

Hazardous waste load per unit of production: liters/liter
of plasma 5

Levels of Treatment

 

Cost — ($I Level I Level II Level III
Contract disposal charges per batch 200 as Level l as Level I
Average treatment/disposal cost $0.40/liter of

per liter of plasma input plasma
Level | — Incineration by contractor off-site
Level II — as Level I
Level III — as Level I

*N.A. = not available

1'80”“: Arthur D. Little, lnc., estimates.

153

TABLE 5.4.3

TREATMENT AND DISPOSAL COSTS:
FORMULATION AND PACKAGING (FINISHED PHARMACEUTICAL PREPARATIONS)
WASTE STREAM — RETURNED GOODS AND REJECT MATERIAL?

Plant description: plant with 200 employees
Representative production schedule, days/year: 250

Representative plant capacity: $11 million value added
$14 million value of shipments

Average product value added per employee, $/year $55,000
Average value of shipments per employee, $/year $70,000
Hazardous waste load, returned goods and reject material,
metric tons/year 18
kg/year/employee 90

Levels of Treatment

 

 

 

Cost — ($l Level I Level II Level III
Crushing 100 — as Level II
Transportation 200 200
Landfill Charge 200 —
Incineration Charge — 1,000
Total Annual Costs 500 1,200
Average treatment/disposal cost
per metric ton of waste $27.80 $66.70
per pound of waste $0.013 $0.03
Level | — crush on-site and landfill in sanitary landfill off-site by contractor

Level II — Incineration by contractor off-site

Level III —— as Level H

1.Source: Arthur D. Little, lnc., estimates.

154

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

APPENDIX A*
DESCRIPTION OF HAZARD GRADES
HAZARD CATEGORY I — FIRE
Insignificant Hazard: Includes chemicals that are essentially noncombustible.

Slightly Hazardous: Includes chemicals having a closed-cup flash point
above 140°F (60°C).

Hazardous: Includes combustible chemicals having a closed-cup flash point
below 140°F (60°C) and above 100°F (37.8°C).

Highly Hazardous: Includes flammable liquids having a closed-cup flash
point below 100°F (37.8°C) and a boiling point under standard conditions
above 100°F (37.8°C).

Extremely Hazardous: Includes volatile liquids or liquefied gaseous materials
having a flash point below 100°F (37.8°C) and a boiling point below 100°F
(37.8°C).

*National Academy of Sciences Hazard Classification Scheme.

155

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

HAZARD CATEGORY II — LIQUID CONTACT WITH SKIN AND EYES

Insignificant Hazard: Liquids in this category are all those not described
below.

Slightly Hazardous: Liquids that are corrosive to the eyes according to the
definition in 16 CFR 1500.3(c) (3) and the test procedure in 16 CFR
1500.42

Moderately Hazardous: Liquids in this category are:

a. Liquids that are corrosive according to the test procedure described in
46 CFR 146.23-1.

b. Materials that are transported as liquids at 140°F (60°) or above.
0. Liquefied gases that are capable of causing freeze burns.

Highly Hazardous: Liquids in this category have an LD50* of more than
20 mg/kg of body weight when administered by continuous contact for 24
hours or less with the bare skin of rabbits, according to the test procedure
described in 21 CFR Section 191.10 of the Code of Federal Regulations.

Extremely Hazardous: Liquids in this category have an LD50* of 20 mg/kg
or less or body weight when administered by continuous contact for 24
hours or less with the bare skin of rabbits, according to the test procedure
described in 21 CFR Section 191.10 of the Code of Federal Regulations.

*LDso : that dose likely to kill one-half of a group of animals within 14 days.

156

HAZARD CATEGORY III — INHALATION OF VAPORS
(Occasional Short-Term)

Grade 0 Insignificant Hazard: Liquids in this category are all those not described
below.
Grade 1 Slightly Hazardous: Liquids in this category cause dizziness and unsteadiness

in 30 minutes or less upon exposure to an atmosphere saturated with vapor
at 122°F (50°C)."‘

Grade 2 Moderately Hazardous: Liquids in this category have an LC50** in air of
more than 200 ppm, but not more than 2000 ppm by volume of vapor; or
more than 2 mg/l, but not more than 20 mg/l of mist when administered by
continuous inhalation for one hour or less to both male and female albino
rats (young adults), provided the Coast Guard finds that such concentration
is likely to be encountered by man under any reasonably foreseeable condi-
tion of transportation.*

Liquids in this category may produce sufficient imitation of the eyes or
respiratory tract to cause temporary incapacitation. This includes lachryma-
tors and those corrosive liquids as defined above in Hazard CategoryI that
have a vapor pressure at 122°F (50°C) or 10 mm Hg or more.*

Grade 3 Highly Hazardous: Liquids in this category have an LC50** in air of more
than 50 ppm but not more than 200 ppm by volume of vapor, or more than
0.50 mg/l, but not more than 2 mg/l, of mist when administered by con-
tinuous inhalation for one hour or less to both male and female albino rats
(young adults), provided the Coast Guard finds that such concentration is
' likely to be encountered by man under any reasonably foreseeable condi-
tion of transportation.*

Grade 4 Extremely Hazardous: Liquids in this category have an LC50** in air of
50 ppm by volume or less of vapor, or 0.5 mg/l or less of mist when admin-
istered by continuous inhalation for one hour or less to both male and
female albino rats (young adults), provided the Coast Guard finds that such
concentration is, likely to be encountered by man under any reasonably
foreseeable condition of transportation.

*During transportation emergencies involving liquids (ruptures, spills, etc.) the degree of personnel hazard
is increased by rapid evaporation. If the ratio of the evaporation rate for the test material to that of
n-butyl acetate at 122°F (50°C) under the same test conditions is 0.8 or less, the test material should be
given the next higher rating with a notation to this effect. An appropriate test procedure has been
described.

MLC”: that concentration which, over a given period of time, is likely to kill one-half the test animal
species.

157

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

HAZARD CATEGORY IV — GAS INHALATION
Grade 0 is not applicable since no gas has an insignificant hazard.

Slightly Hazardous: Gases in this category are all those not described below,
since the release of a gas into a confined space may displace sufficient
oxygen to create a significant hazard to life.

Moderately Hazardous: Gases in this category have an LCS o * in air of more
than 200 ppm, but not more than 2000 ppm, by volume of gas when admin-
istered by continuous inhalation for one hour or less to both male and fe-
male albino rats (young adults). Gases in this category may product suffi-
cient irritation of the eyes or respiratory tract to cause temporary incapacita-
tion. This includes lachrymators.

Highly Hazardous: Gases in this category have an LC50* of more than 50
ppm, but not more than 200 ppm as described in Grade 3 of Hazard
Category III.

Extremely Hazardous: Gases in this category have an LCS 0* of 50 ppm or
less as described in Grade 4 of Hazard Category III.

‘ HAZARD CATEGORY V** — HAZARD RATING FOR PREPARED 1

INHALATION OF GASES AND VAPORS

Insignificant Hazard: Materials in this category are all those not described
below and having standards established by the US Department of Labor,
Occupational Safety and Health Administration (OSHA), as in 29 CFR Sub-
part G, Section 1910.93, of 1000 ppm or more.

Slightly Hazardous: Materials in this category have standards established by
OSHA of 100 ppm or more, but less than 1000 ppm.

Moderately Hazardous: Materials in this category have standards established
by OSHA of 10 ppm or more, but less than 100 ppm.

Highly Hazardous: Materials in this category have standards established by
OSHA of 1 ppm or more, but less than 10 ppm.

Extremely Hazardous: Materials in this category have Occupational Safety
and Health Standards established by OSHA of less than 1 ppm.

*LCso: that concentration which, over a given period of time, is likely to kill one-half the test animal

species.

"OSHA standards are applicable to a normal working situation, i.e., 8 hours per day, 5 days per week. i

158

Grade

 

AWN—'0

Grade

 

AWNI—d

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

HAZARD CATEGORY VI — WATER POLLUTION RATING —
HUMAN TOXICITY

 

Description LDs o
Insignificant Hazard Above 5000 mg/kg
Slightly Hazardous 500-5000 mg/kg
Moderately Hazardous 50-5 00 mg/ kg
Highly Hazardous 5—50 mg/kg
Extremely Hazardous Below 5 mg/kg

HAZARD CATEGORY VII — AQUATIC TOXICITY RATING

Description TLm Concentration
Insignificant Hazard >1000 mg/l
Practically Nontoxic 100-1000 mg/l
Slightly Toxic 10-100 mg/l
Moderately Toxic 1-10 mg/l
Highly Toxic <1 mg/l

HAZARD CATEGORY VIII — WATER REACTION RATING
Insignificant Hazard: No known hazardous reaction with water.

Slightly Hazardous: Chemical or physical reaction with water may occur.
Unlikely to be hazardous under conditions of water transportation.
Examples are chlorine, bromine, ethylene oxide, propylene oxide, propionic
anhydride, stabilized benzoyl chloride, and acetic anhydride.

Hazardous Reaction: Examples are anhydrous ammonia, hydrogen fluoride,
and hydrogen chloride.

Highly Hazardous (Vigorous Reaction): Examples are oleum, 72%—98% sul-
furic acid, ethyl trichlorosilane, and chloroacetyl chloride.

Extremely Hazardous (Violent Reaction): Likely if mixed with water.

Examples are sulfur trioxide, chlorosulfonic acid, aluminum triethyl, unstab-
ilized benzoyl chloride, methyl trichlorosilane, and acetyl chloride.

159

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

HAZARD CATEGORY IX — SELF-REACTION RATING
Insignificant Hazard: No appreciable self-reaction.

Slightly Hazardous: Chemicals known to undergo polymerization or other
self-reaction under certain conditions. Due to low reactivity or low heat
evolution, they are unlikely to lead to a hazardous situation in bulk water
transportation.

Hazardous: Chemicals that may undergo polymerization or other self-
reaction if contaminated-by an initiator for such process. The results may be
hazardous. They are not considered to require a stabilizer or inhibitor for
safe shipment under normal conditions.

Highly Hazardous: Chemicals that may underto a hazardous self-reaction and
are considered to require special handling, such as incorporation of a sta-
bilizer or polymerization inhibitor to ensure safety in bulk water transporta-
tion.

Extremely Hazardous: Chemicals that can undergo self-oxidation, and/or
polymerization, possibly causing explosions or detonations.

160

APPENDIX B
PROPERTIES OF HAZARDOUS CONSTITUENTS
EXPLANATION OF SPECIAL TERMS

Several of the terms used in the following tables may not be clear to the average reader.
Therefore, we have prepared short explanations that will be useful in interpreting the data.

0 Physical Form — The statement indicates whether the chemical is a solid,
liquid, or gas after it has reached equilibrium with its surroundings at
“ordinary” conditions of temperature and pressure (15°C and 1 atmo-
sphere).

0 Specific Gravity — The Specific gravity of a chemical is the ratio of the
weight of the solid or liquid to the weight of an equal volume of water at
4°C (or at some other specified temperature).

0 Flash Point ~ The flash point is defined as the lowest temperature at which
vapors above a volatile combustible substance will ignite in air when exposed
to a flame. Depending on the test method used, the values given are either
Tag closed cup (C.C.) (ASTM D56) or Cleveland open cup (O.C.)
(ASTM D93). The values give an indication of the relative flammability of
the chemical. In general, the open-cup value is about 10° to 15°F higher
than the closed-cup value.

0 Boiling Point at 1 Atmosphere — This value is the temperature of a liquid
when its vapor pressure is 1 atmosphere. For example, when water is heated
to 100°C (212°F), its vapor pressure rises to 1 atmosphere and the liquid
boils.

O Melting Point— The melting point is the temperature at which a solid
changes to a liquid.

0 Chemical Composition — This has been limited to a commonly used one-line
formula.

0 Molecular Weight— The value. given is the weight of a molecule of the
chemical relative to a value of 12 for one atom of carbon.

0 Heat of Combustion — The value is the amount of heat liberated when the
specified weight is burned in oxygen at 25°C. The products of combustion,
including water, are assumed to remain as gases; the value given is usually

161

referred to as the “lower heat value.” The negative sign before the value
indicates that heat is given off when the chemical burns. Units are calories
per gram.

0 Solubility — The value represents the grams of a chemical that will dissolve
in 100 grams of pure water. Solubility usually increases when the tempera-
ture increases. The following terms are used when numerical data are either
unavailable or not applicable:

“Miscible” means that the chemical mixes with water in all proportions.
“Insoluble” usually means that 1 gram of the chemical does not dissolve
entirely in 100 grams of water.

0 TL m (Aquatic Toxicity) — TLm (Median Tolerance Limit) means that ap—
proximately 50% of the fish will die under the conditions of concentration
and time given. The form of data presentation used by the Environmental
Protection Agency’s “Oil and Hazardous Material-Technical Assistance Data
System (OHM-TADS)” is used here. Reading from left to right and separated
by slashes (/) are the following data:

Concentration in parts per million by weight (or milligrams per liter) at
which the chemical was tested;

Time of exposure in hours;
Name of the aquatic species studied (only data on fish are given here);

0 TLV (Threshold Limit Value) — The threshold limit value is usually ex-
pressed in units of parts per million (ppm) — i.e., the parts of vapor (gas) per
million parts of contaminated air by volume at 25°C (77°F) and atmospheric
pressure. For a chemical that forms a fine mist or dust, the concentration is
given in milligrams per cubic meter (mg/m3 ). The TLV is defined as the
concentration of the substance in air that can be breathed for five consecu-
tive eight-hour workdays (40-hour work week) by most people without
adverse effect.* As some people become ill after exposure to concentrations
lower than the TLV, this value cannot be used to define exactly what is a
“safe” or “dangerous” concentration.

0 L050 (Oral Toxicity) - The term LD50 signifies that about 50% of the
animals given the specified dose by mouth will die. All LD5 0 values listed
are for rats.

 

*American Conference of Governmental Industrial Hygienists, “Threshold Limit Values for Substance in
Workroom Air, Adopted by ACGIH for 1972."

162

TABLE B-1

PROPERTIES OF ACETONE

Physical & Chemical Properties

Physical form: Liquid Chemical composition: CH3COCH3
Specific gravity: 0.791 Molecular Weight: 58.08

Flash Point: 4°F 0.0., 0°F c.c. Heat of Combustion: -6808 cal/g
Boiling point at 1 atm: 56.1°C Solubility: Complete

Melting point: -94.7°C Odor: Sweetish

% Cl:

Biological Properties

Toxicity:

TLm: 13,000 ppm/48 hr/mosquito fish
TLV: 1000 ppm

LD5 03 > 5000 mg/kg

TABLE B-2

PROPERTIES OF ACETONITRILE

Physical & Chemical Properties

Physical form: Liquid Chemical composition: CH3CN
Specific gravity: 0.787 Molecular Weight: 41.05

Flash Point: 42°F O.C. Heat of Combustion: ~7420 cal/g
Boiling point at 1 atm: 81.6°C Solubility: 'Miscible

Melting point: 45.7°C Odor: Sweet, ethereal

96 Cl:

Biological Properties

Toxicity:

TLm: 1150 ppm/24 hr/fathead minnow
TLV: 40 ppm

LD5 oi 500-5000 mg/kg

163

TABLE B-3

PROPERTIES OF AMYL ACETATE

Physical & Chemical Properties

Physical form: Liquid

Specific gravity: 0.876

Flash Point: (n-) 91°F, C.C., (iso-) 69°F C.C.
Boiling point at 1 atm: 146°C

Melting point: <-100°C

% Cl:

Biological Properties
Toxicity:

TLm:

TLV: 100 ppm

TABLE 84

Chemical composition: CH3COOC5 H, 1
Molecular Weight: 130.19

Heat of Combustion: -7423 cal/g
Solubility: Insoluble

Odor: Banana-l ike

PROPERTIES OF BENZENE

Physical & Chemical Properties
Physical form: Liquid
Specific gravity: 0.879

Flash Point: 12°F C.C.
Boiling point at 1 atm: 801°C
Melting point: 55°C

% CL:

Biological Properties
Toxicity:

TLm: 20 ppm/24 hr/sunfish
TLV: 25 ppm

LD5 0: >5000 mg/kg

164

Chemical composition: C6 H5
Molecular Weight: 78.11

Heat of Combustion: -9698 cal/g
Solubility: Insoluble

Odor: Aromatic

TABLE B-5

PROPERTIES OF CH LOROFORM

Physical & Chemical Properties

Physical form: Liquid Chemical composition: CHC|3
Specific gravity: 1.49 Molecular Weight: 119.39
Flash Point: - Heat of Combustion: ——

Boiling point at 1 atm: 612°C Solubility: Insoluble
Melting point: -63.5°C Odor: Ethereal
% Cl: 89.09

Biological Properties
Toxicity:

TLm: —

TLV: 25 ppm

LD50: >5000 mg/kg

TABLE B-6

PROPERTIES OF CHROMIC ANHYDRIDE

Physical & Chemical Properties

Physical form: Solid Chemical composition: Cr03
Specific gravity: 2.70 Molecular Weight: 100.01
Flash Point: — Heat of Combustion: ——
Boiling point at 1 atm: Solubility: Very soluble
Melting point: - Odor: —

%Cl‘:

Reactivity: Reacts with organic materials rapidly; may cause ignition

Biological Properties

- Toxicity:

TLm: 52 ppm/96 hr/goldfish
TLV: —

LD5 01 50-500 mg/kg

165

TABLE B-7

PROPERTIES OF COPPER SULFATE

Physical & Chemical Properties

Physical form: Solid Chemical composition: C‘uSO4 .5H30
Specific gravity: 2.29 ' Molecular Weight: 249.7

Flash Point: — Heat of Combustion: '—

Boiling point at 1 atm: Solubility: Soluble

Melting point: — Odor: —

% Cl:

Biological Properties

Toxicity:

TLm: 3.8 ppm/24 hr/rainbow trout
TLV: —

LDso: 50-500 mg/kg

7

TABLE B-8

PROPERTIES OF ETHANOL

Physical & Chemical Properties

Physical form: Liquid Chemical composition: CgHsoH
Specific gravity: 0.790 Molecular Weight: 46.07

Flash Point: 55°F C.C., 64°F 0.C. Heat of Combustion: ~6425 cal/g
Boiling point at 1 atm: 78.3°C Solubility: Miscible

Melting point: -114°C Odor: Like whiskey

%C|: —

Biological Properties
Toxicity:

TLm: 250 ppm/6 hr/goldfish
TLV: 1000 ppm

LDs o: >5000 mg/kg

166

TABLE B-9

PROPERTIES OF ETHYLENE DICHLORIDE

Physical & Chemical Properties

Physical form: Liquid Chemical composition: CICH2CH2C|
Specific gravity: 1.253 Molecular Weight: 98.96

Flash Point: 60°F O.C., 55°F C.C. Heat of Combustion: 1900 cal/g
Boiling point at 1 atm: 835°C Solubility: Insoluble

Melting point: -35.7°C Odor: Ethereal

% Cl: 71.66

Biological Properties
Toxicity:

TLm: 150 ppm/ */pin perch

TLV: 50 ppm
LDso: 500-5000 mg/kg

*Time of exposure unknown.

TABLE B-10

PROPERTIES OF ETHYLENE GLYCOL MONOMETHYL ETHER

Physical & Chemical Properties

Physical form: Liquid Chemical composition: CH3OCH2CH2 OH
Specific gravity: 0.966 Molecular Weight: 76.10

Flash Point: 120°F O.C., 107°F C.C. Heat of Combustion: 5,500 cal/g

Boiling point at 1 atm: 124.5°C Solubility: Miscible

Melting point: -85.1°C Odor: Mild ethereal

% Cl: —

Biological Properties
Toxicity:

TLm: —

TLV: 25 ppm

167

TABLE 3-"

PROPERTIES OF HEPTANE

Physical & Chemical Properties

Physical form: Liquid Chemical composition: CH3(CH2)5CH3
Specificgravity: 0.6838 Molecular Weight: 100.21

Flash Point: 250° F C.C. Heat of Combustion: -10,650 cal/g
Boiling point at 1 atm: 98.4°C Solubility: Insoluble

Melting point: -90.6°C Odor: Gasoline

% Cl: -

Biological Properties

Toxicity:

TLm: 4924/24 hr/mosquito fish
TLV: 500 ppm

LDso: >15000 mg/kg

TABLE B-12

PROPERTIES OF ISOPROPYL ALCOHOL

Physical 8t Chemical Properties

Physical form: Liquid Chemical composition: CH3CH(OH)CH3
Specificzgravity: 0.785 Molecular Weight: 60.10

Flash Point: 65°F O.C., 54°F C.C. Heat of Combustion: -7,201 calls
Boiling point at 1 atm: 823°C Solubility: Soluble

Melting point: -88.5°C Odor: Like ethyl alcohol

% CI: —

Biological Properties

TLm: 900-1000 ppm/24 hr/chab
TLV: 400 ppm

LDso: >5000 mg/kg

168

TABLE 343

PROPERTIES OF MERCURY

Physical & Chemical Properties
Physical form: Liquid
Specific gravity: 13.55

Flash Point: —

Boiling point at 1 atm: 357°C
Melting point: -38.9°C

% Cl: —

Biological Properties

Toxicity:

TLm: 0.29 ppm/48 hr/marine fish
TLV: 0.05 ng/m3

LDso: —

Chemical composition: Hg
Molecular Weight: —
Heat of Combustion: —
Solubility: Insoluble
Odor: —

TABLE B~14

PROPERTIES OF METHANOL

Physieel & Chemical Properties
Physical form: Liquid

Specific graVity: 0.792

Flash Point: 59°F c.c., 61°F o.c.
Boiling point at 1 atm: 645°C
Melting point: -97.8°C

% CI: —-

Biological Properties
Toxicity:

TLm: 250/4 hr/goldfish
TLV: 200 ppm

LDso >5999 mg/kg

Chemical composition: CH3 UH
Molecular Weight: 32.04

Heat of Combustion: -4677 cal/g
Solubility: Miscible

Odor: Faintly sweet

169

TABLE B-15

PROPERTIES OF METHYL ISOBUTYL KETONE

Physical & Chemical Properties
Physical form: Liquid

Specific gravity: 0.802

Flash Point: 73°F C.C., 75°F O.C.
Boiling point at 1 atm: 116.2°C
Melting point: -84°C

% Cl: —

Biologiml Properties
Toxicity:

TLm: >1000 ppm
TLV: 100 ppm

LD5 0: 500-5000 mg/kg

Chemical composition: (CH3)2CHCH2 COCH3
Molecular Weight: 100.16

Heat of Combustion: -5800 cal/g

Solubility: 2%

Odor: Pleasant ketonic

TABLE 3-16

PROPERTIES OF METHYLENE CHLORIDE

Physical & Chemical Properties:
Physical form: Liquid

Specific gravity: 1.322

Flash Point: —

Boiling point at 1 atm: 393°C
Melting point: -96.7°C

% Cl: 83.49

Biological Properties
Toxicity:

TLm: —

TLV: 500 ppm

LDso: 500-5000 mg/kg

Chemical composition: CH2C|2
Molecular Weight: 84.93

Heat of Combustion: ——
Solubility: Insoluble

Odor: Aromatic

170

TABLE B-17

PROPERTIES OF NAPHTHA (STODDARD SOLVENT)

Physical & Chemical Properties

Physical form: Liquid Chemical composition: (mixture)
Specific gravity: 0.78 Molecular Weight: —

Flash Point: 110°F c.c. Heat of Combustion: -10,100 cal/g
Boiling point at 1 atm: 160-199°C Solubility: Insoluble

Melting point: — Odor: Like kerosene

% Cl: -—

Biological Properties
Toxicity:

TLm: —

TLV: 200 ppm

TABLE B-18

PROPERTIES OF n-BUTANOL

Physical & Chemical Properties

Physical form: Liquid Chemical composition: CH3(CH2)2 CHOH
Specific gravity: 0.810 Molecular Weight: 74.12

Flash Point: 84°F C.C.,l97°F C.C. Heat of CombustiOn: -7906 cal/g

Boiling point at 1 atm: 117.7°C Solubility: Slightly soluble

Melting point: -89.3°C Odor: Alcohol-like

% CI: -

Biological Properties

Toxicity:

TLm: 1000 ppm/29 hr/goldfish
TLV: 100 ppm

171

TABLE 8-19

PROPERTIES OF n-BUTYL ACETATE

Physical & Chemical Properties

Physical form: Liquid Chemical composition: CH3COO(CH2)3CH3
Specific gravity: 0.875 Molecular Weight: 116.16

Flash Point: 99°F o.c., 75°F c.c. Heat of Combustion: -7294 cal/g

Boiling point at 1 atm: 126°C Solubility: insoluble

Melting point: -73.5°C Odor: Fruity in low concentrations

% Cl: —

Biological Properties
Toxicity:
TLm: —
TLV: 150200 ppm

LD50: >5ooo mg/kg

TAB LE B-20

PROPERTIES OF o-XYLENE

Physical & Chemical Properties

Physical form: Liquid Chemical composition: o-C6H4(CH3)2
Specific gravity: 0.880 Molecular Weight: 106.16

Flash Point: 63°F o.c., 75°F 0.0. Heat of Combustion: -9754.7 cal/g
Boiling point at 1 atm: 144.4°C Solubility: Insoluble

Melting point: -25.2°C Odor: Benzene-like

% Cl: -—

Biological Properties
Toxicity:

TLm: —

TLV: 100 ppm

LDso: 50-500 mg/kg

172

TABLE B-21

PROPERTIES OF TOLUENE

Physical & Chemical Properties

Physical form: Liquid Chemical composition: C6H5CH3
Specific gravity: 0.867 ‘Molecular Weight: 92.14

Flash Point: 40°F c.c., 55°F 00. Heat of Combustion: -9686 cal/g
Boiling point at 1 atm: 110.6°C Solubility: Insoluble

Melting point: -95.o°c Odor: Aromatic

% Cl: —

Biological Properties

Toxicity:

TLm: 1180 ppm/96 hr/sun fish
TLV: 100 ppm

TABLE B-22

PROPERTIES OF ZINC CHLORIDE

Physical & Chemical Properties

Physical form: Solid Chemical composition: ZnC12
Specific gravity: 2.91 Molecular Weight: 136.28
Flash Point: — Heat of Combustion: -
Boiling point at 1 atm: — Solubility: Soluble

Melting point: 283°C Odor: —

% Cl: 52.03

Biological Properties
Toxicity:

TLm: 7.2 ppm/96 hr/bluegill
TLV: 1 mg/m3 (dust)

LD50: 50-500 mg/kg

173

 

GLOSSARY OF TERMS
Activated Sludge Treatment — A wastewater treatment process in which biological orga-
nisms convert soluble and insoluble pollutants to biological mass (activated sludge)

which is then usually removed from the treated wastewater by settling.

Active Ingredient —— The chemical constituent in a medicinal which is responsible for its
activity.

‘ Analgesics — Pain-relieving medicinals.
Ataraxics — Tranquilizers

Alkaloids —— Basic (alkaline) nitrogenous botanical products which produce a marked physio-
logical action when administered to animals (or humans).

Ampoule — A small, sealed-glass container for one dose of a sterile medicine to be injected
hypodermically.

Antibiotic — A substance produced by a living organism which has the power to inhibit
multiplication of , or to destroy, other organisms, especially bacteria.

Biological Products — In the pharmaceutical industry, medicinal products derived from
animals or humans, such as vaccines, toxoids, antisera and human blood frac-
tions.

Blood Fractionation — The separation of human blood into its various protein fractions.

BOD — Biochemical Oxygen Demand— A measure of the amount of oxygen required (and,
therefore, the concentration of the pollutants present) in the destruction of pollu-
tant(s) by microorganisms (i.e., activated sludge).

Botanicals — Drugs made from a part of a plant, such as roots, bark, or leaves.

Capsules — A gelatinous shell used to contain medicinal chemicals; a dosage form for admin-
istering medicine.

Chemical Residues — Waste materials, such as still bottoms and chemical process “muds”
or waste slurries.

Control Technology — Method for treatment or disposal for wastes such as neutralization,
landfill, and incineration.

Diatomaceous Earth — A fine material of uniform particle size used to aid in filtration.

175

Ethical Products — Pharmaceuticals promoted by advertising to the medical, dental, and
veterinary professions.

Fermentation — Decomposition or conversion of complex substances to other substances
by enzymes produced by microorganisms.

Fermentor Broth — A slurry of microorganisms in water containing nutrients (carbohydrates,
nitrogen) necessary for the microorganism’s growth.

Filter Cakes — Wet solids generated by the filtration of solids from a liquid. This filter cake
may be a pure material (product) or a waste material containing additional fine solids
(i.e., diatomaceous earth) that has been added to‘ aid in the filtration.

Halogenated Solvent — An organic liquid chemical containing an attached halogen (chlorine,
fluorine, etc.) used for dissolving other substances.

Hazardous High-Inert Content Wastes - Those high inert content wastes which contain
corrosives, trace amounts of heavy metals, or flammable solvents. ‘

Hazardous Wastes — No final judgments are intended by such a classification. Additional
information will be required before a definition of hazardous waste can be made.

Heavy Metals — Originally defined as a group of metals including lead, zinc, arsenic, mer-
cury, selenium, cadmium, and copper which have an atomic weight greater than iron.
In more recent usage, the toxic metals, chromium and vanadium, are also considered
to be “heavy (toxic) metals.”

High-Inert Content Wastes - Waste materials such as filter cakes which contain large
amounts of diatomaceous earth, filter aid or activated carbon used to remove color or

trace impurities.

Hormone — Any of a number of substances formed in the body which activate specifically
receptive organs when transported to them by the body fluids.

IMCO System — Intergovernmental MaritimeConsultative Organization hazardous material
determination system.

Incineration - Burning under controlled combustion conditions.

Injectables — Medicinals prepared in a sterile (buffered) form suitable for administration by
injection.

ISO-Electric Precipitation ,‘ Adjustment of the pH (hydrogen ion concentration) of a solu-
tion to cause precipitation of a substance from the solution.

176

 

Land-Destined Process Wastes — Solids, slurries and liquids currently or previously disposed
on land. The term is used to distinguish these wastes from water or air effluents.

Land Disposal — Placing waste materials into the land in a specific manner as a method of
treatment, storage, or disposal.

LD50 ~—- A dosage level that is lethal to 50% of the test animals to which it is administered.
Medicinal Chemicals — Chemicals which have therapeutic value.

Mycelia — A mass of filaments which constitutes the vegetative body of fungi. In the indus-
try, the term is commonly used to designate the mixture of cells, filter aid, undigested
grain solids, etc., that is filtered off and discarded from all types of fermentations.

Pharmaceutical — A medicinal chemical which has been processed into a stable useful dosage
form.

Plasma — The fluid part of the lymph and of the blood, as distinguished from the co»-
puscles.

PMA — Pharmaceutical Manufacturers Association, which represents 110 pharmaceutical
manufacturing firms which, in turn, account for approximately 95 percent of the
ethical pharmaceuticals sold in the United States.

Priority I — Hazardous Waste — Includes all “elementary” toxic materials, viz., materials
which are potentially harmful, regardless of their state of chemical combination. This
also includes materials which owe their hazardous properties to their molecular
arrangement — and which fall in hazard grades 3 or 4 in Table 3.1 .2A.

Priority II — Hazardous Waste — These wastes owe their hazardous properties to their
molecular arrangement and fall in hazard grades 1 or 2 in Table 3.1.2A.

Proprietary Products — Pharmaceuticals promoted by advertising directly to the consumer.

Sanitary Landfill — A sanitary landfill is a land disposal site employing an engineered

method of disposing of solid wastes on land in a manner that minimizes environmental
hazards by spreading the wastes in thin layers, compacting the solid wastes to the
smallest practical volume, and applying cover material at the end of each operating
day.

Secure Chemical Landfill — A landfill that is lined and limited to chemical wastes.

Serum — Blood serum containing agents of immunity, taken from an animal made immune
to a specific disease by inoculation; it is used as an antitoxin.

177

SIC Codes — Standard Industrial Classification. Numbers used by the US. Department of
Commerce to denote segments of industry.

Steroid — Any one of a large group of multicyclic ring chemical substances related to
various alcohols occurring naturally in plants and animals.

Still Bottom — The residue remaining after distillation of a material. Varies from a watery
slurry to a thick tar which may turn hard when cool.

Tablet — A small, disc-like mass of compressed medicinal powder used as a dosage form for
administering medicine.

Technology Level I — A waste treatment or disposal method that is the broad average of
technologies which are currently used in typical facilities.

Technology Level II — A waste treatment or disposal method which is the best technology
from an environmental and health standpoint that is currently used in at least one
pharmaceutical facility.

Technology Level III — A waste treatment or disposal method that provides adequate health
and environmental protection.

TLm — Median Tolerance Limit — This measure of aquatic toxicity means that approxi-
mately 50 percent of the fish will die under the conditions of concentration and time
given.

Toxoid — Toxin treated to destroy its toxicity, but still capable of inducing antibody forma-
tion.

Vaccine - A preparation of dead or modified live virus or bacteria introduced into the body
to produce immunity to a specific disease by causing the formation of antibodies.

Virus — Any of a group of ultramicroscopic or submicroscopic infective agents that cause
various diseases; viruses are capable of multiplying in connection with living cells.

Wastewater — Process water contaminated to such an extent it is not reusable in the process
without repurification.

Also please note terms appearing in Appendix B.

1101318
SW-508

178 fi U. S. GOVERNMENT PRINTING OFFICE : 1976 623—300/498

anti-k. .

u.c. BERKELEY LIBRARIES

 

 

 

 
 

 

 

 

 

 

 
 

 

 
 

 

 

 

 

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