Sector Notebook Project Pharmaceutical Industry 

EPA/310-R-97-005 

EPA Office of Compliance Sector Notebook Project: 

Profile of the Pharmaceutical Manufacturing Industry 

September 1997

Office of Compliance

Office of Enforcement and Compliance Assurance

U.S. Environmental Protection Agency

401 M St., SW (MC 2221-A)

Washington, DC 20460
Sector Notebook Project Pharmaceutical Industry 

This report is one in a series of volumes published by the U.S. Environmental Protection Agency 

(EPA) to provide information of general interest regarding environmental issues associated with 

specific industrial sectors. The documents were developed under contract by Abt Associates 

(Cambridge, MA), Science Applications International Corporation (McLean, VA), and Booz-Allen 

& Hamilton, Inc. (McLean, VA). This publication may be purchased from the Superintendent of 

Documents, U.S. Government Printing Office. A listing of available Sector Notebooks and 

document numbers is included on the following page. 

All telephone orders should be directed to: 

Superintendent of Documents

U.S. Government Printing Office

Washington, DC 20402

(202) 512-1800

FAX (202) 512-2250

8:00 a.m. to 4:30 p.m., EST, M-F

Using the form provided at the end of this document, all mail orders should be directed to: 

U.S. Government Printing Office

P.O. Box 371954

Pittsburgh, PA 15250-7954

Complimentary volumes are available to certain groups or subscribers, such as public and 

academic libraries, Federal, State, and local governments, and the media from EPA’s National 

Center for Environmental Publications and Information at (800) 490-9198. For further 

information, and for answers to questions pertaining to these documents, please refer to the 

contact names and numbers provided within this volume. 

Electronic versions of all Sector Notebooks are available free of charge at the following web 

address: www.epa.gov/oeca/sector. Direct technical questions to the “Feedback” button at the 

bottom of the web page. 

Cover photographs courtesy of Pharmaceutical Research and Manufacturers of America. 

Sector Notebook Project ii September 1997 
Sector Notebook Project Pharmaceutical Industry 

Sector Notebook Contacts 

The Sector Notebooks were developed by the EPA’s Office of Compliance. Questions relating to the 

Sector Notebook Project can be directed to: 

Seth Heminway, Coordinator, Sector Notebook Project

US EPA Office of Compliance

401 M St., SW (2223-A)

Washington, DC 20460

(202) 564-7017

Questions and comments regarding the individual documents can be directed to the appropriate specialists 

listed below. 

Document Number Industry 

EPA/310-R-95-001. Dry Cleaning Industry

EPA/310-R-95-002. Electronics and Computer Industry*

EPA/310-R-95-003. Wood Furniture and Fixtures Industry

EPA/310-R-95-004. Inorganic Chemical Industry*

EPA/310-R-95-005. Iron and Steel Industry

EPA/310-R-95-006. Lumber and Wood Products Industry

EPA/310-R-95-007. Fabricated Metal Products Industry*

EPA/310-R-95-008. Metal Mining Industry

EPA/310-R-95-009. Motor Vehicle Assembly Industry

EPA/310-R-95-010. Nonferrous Metals Industry

EPA/310-R-95-011. Non-Fuel, Non-Metal Mining Industry

EPA/310-R-95-012. Organic Chemical Industry*

EPA/310-R-95-013. Petroleum Refining Industry

EPA/310-R-95-014. Printing Industry

EPA/310-R-95-015. Pulp and Paper Industry

EPA/310-R-95-016. Rubber and Plastic Industry

EPA/310-R-95-017. Stone, Clay, Glass, and Concrete Industry

EPA/310-R-95-018. Transportation Equipment Cleaning Ind.

EPA/310-R-97-001. Air Transportation Industry

EPA/310-R-97-002. Ground Transportation Industry

EPA/310-R-97-003. Water Transportation Industry

EPA/310-R-97-004. Metal Casting Industry

EPA/310-R-97-005. Pharmaceuticals Industry

EPA/310-R-97-006. Plastic Resin and Man-made Fiber Ind.

EPA/310-R-97-007. Fossil Fuel Electric Power Generation Ind.

EPA/310-R-97-008. Shipbuilding and Repair Industry

EPA/310-R-97-009. Textile Industry

EPA/310-R-97-010. Sector Notebook Data Refresh-1997

EPA/310-R-98-001. Aerospace Industry

EPA/310-R-98-002. Agricultural Chemical, Pesticide, and

Fertilizer Industry

EPA/310-R-98-003. Agricultural Crop Production Industry

EPA/310-R-98-004. Agricultural Livestock Production Ind.

EPA/310-R-98-005. Oil and Gas Exploration and Production

Industry

EPA/310-R-98-008. Local Government Operations

*Spanish translations available.

Contact Phone (202) 

Joyce Chandler 564-7073 

Steve Hoover 564-7007 

Bob Marshall 564-7021 

Walter DeRieux 564-7067 

Maria Malave 564-7027 

Seth Heminway 564-7017 

Scott Throwe 564-7013 

Jane Engert 564-5021 

Anthony Raia 564-6045 

Jane Engert 564-5021 

Rob Lischinsky 564-2628 

Walter DeRieux 564-7067 

Tom Ripp 564-7003 

Ginger Gotliffe 564-7072 

Seth Heminway 564-7017 

Maria Malave 564-7027 

Scott Throwe 564-7013 

Virginia Lathrop 564-7057 

Virginia Lathrop 564-7057 

Virginia Lathrop 564-7057 

Virginia Lathrop 564-7057 

Jane Engert 564-5021 

Emily Chow 564-7071 

Sally Sasnett 564-7074 

Rafael Sanchez 564-7028 

Anthony Raia 564-6045 

Belinda Breidenbach 564-7022 

Seth Heminway 564-7017 

Anthony Raia 564-6045 

Amy Porter 564-4149 

Ginah Mortensen (913)551-7864 

Ginah Mortensen (913)551-7864 

Dan Chadwick 564-7054 

John Dombrowski 564-7036 

Sector Notebook Project iii September 1997 
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Sector Notebook Project Pharmaceutical Industry 

Table of Contents 

List of Tables .............................................................. vii

List of Figures ............................................................ viii

List of Acronyms ........................................................... ix

I. INTRODUCTION TO THE SECTOR NOTEBOOK PROJECT ...................... 1

A. Summary of the Sector Notebook Project ................................. 1

B. Additional Information ............................................... 2

II. INTRODUCTION TO THE PHARMACEUTICAL INDUSTRY ..................... 3

A. Introduction, Background, and Scope of the Notebook ....................... 3

B. Characterization of the Pharmaceutical Industry ............................. 3

1. Product Characterization ........................................ 5

2. Industry Size ................................................. 6

3. Geographic Distribution ........................................ 11

4. Economic Trends and International Competition ...................... 13

III. INDUSTRIAL PROCESS DESCRIPTION .................................... 17

A. Industrial Processes in the Pharmaceutical Industry ......................... 17

1. Research and Development ..................................... 17

2. Production of Bulk Pharmaceutical Substances ...................... 19

3. Formulation, Mixing, and Compounding ........................... 32

B. Raw Material Inputs and Pollutant Outputs ............................... 38

1. Raw Materials ............................................... 40

2. Air Emissions and Control Systems ................................ 43

3. Wastewater ................................................. 46

4. Solid Wastes ................................................. 50

C. Management of TRI Chemicals in the Production Process .................... 51

IV. CHEMICAL RELEASE AND TRANSFER PROFILE ........................... 53

A. EPA Toxic Release Inventory for the Pharmaceutical Industry ................. 57

B. Summary of Selected Chemicals Released ................................ 68

C. Other Data Sources ................................................. 72

D. Comparison of Toxic Release Inventory Among Selected Industries ............ 74

V. POLLUTION PREVENTION OPPORTUNITIES ............................... 77

A. Material Substitutions ............................................... 79

B. Process Modifications ............................................... 83

C. Good Operating Practices ............................................ 87

D. Recycling, Recovery, and Reuse ....................................... 90

E. Pollution Prevention Research ......................................... 92

Sector Notebook Project v September 1997 
Sector Notebook Project Pharmaceutical Industry 

VI. SUMMARY OF APPLICABLE FEDERAL STATUTES AND REGULATIONS ...... 93

A. General Description of Major Statutes ................................... 93

B. Industry Specific Requirements ....................................... 105

C. Pending and Proposed Regulatory Requirements .......................... 110

D. Other Federal Regulations Affecting the Pharmaceutical Industry ............. 111

E. Other Statutes and Regulations Affecting the Pharmaceutical Industry .......... 114

VII. COMPLIANCE AND ENFORCEMENT HISTORY ........................... 117

A. Pharmaceutical Industry Compliance History ............................. 121

B. Comparison of Enforcement Activity Between Selected Industries ............. 123

C. Review of Major Legal Actions ....................................... 128

1. Review of Major Cases ........................................ 128

2. Supplementary Environmental Projects (SEPs) ...................... 129

VIII. COMPLIANCE ACTIVITIES AND INITIATIVES ........................... 131

A. Sector-related Programs and Activities ................................. 131

B. EPA Voluntary Programs ........................................... 131

C. Trade Association/Industry Sponsored Activity ........................... 138

1. Environmental Programs ....................................... 138

2. Summary of Trade Associations ................................. 140

IX. CONTACTS/ACKNOWLEDGMENTS/REFERENCES ......................... 143

Sector Notebook Project vi September 1997 
Sector Notebook Project Pharmaceutical Industry 

List of Tables 

Table 1: Summary Statistics for the Pharmaceutical Industry ........................... 8

Table 2: Pharmaceutical Industry (SIC 283) Facility Size ............................. 10

Table 3: Employment Size Distribution for Medicinals and Botanicals and Pharmaceutical

PreparationsEstablishments ............................................. 10

Table 4: Top U.S. Pharmaceutical Companies by Sales .............................. 11

Table 5: Examples of Pharmaceutical Products by Bulk Manufacturing Process ............ 20

Table 6: Pharmaceutical Dosage Forms .......................................... 34

Table 7: Summary of Typical Material Inputs and Pollution Outputs in the Pharmaceutical

Industry ............................................................ 39

Table 8: Solvents Used in the Chemical Synthesis Process ............................ 41

Table 9: Solvents Used in Biological and Natural Product Extraction .................... 42

Table 10: Solvents Used in Fermentation Processes ................................. 42

Table 11: Chemicals Discharged in Wastewater by the Pharmaceutical Manufacturing Industry 48

Table 12: Wastewater Treatment Technology Trends ............................... 49

Table 13: Source Reduction and Recycling Activity for the Pharmaceuticals Industry ....... 52

Table 14: 1995 Releases for Pharmaceutical Facilities (SIC 2833 & 2834) in TRI .......... 58

Table 15: 1995 Transfers for Pharmaceutical Facilities (SICs 2833 & 2834) in TRI ......... 62

Table 16: Top 10 TRI Releasing Pharmaceutical Manufacturing Facilities ................ 66

Table 17: Top 10 TRI Releasing Facilities Reporting Pharmaceutical

Manufacturing SIC Codes to TRI......................................... 67

Table 18: Air Pollutant Releases by Industry Sector (tons/year) ........................ 73

Table 19: Toxics Release Inventory Data for Selected Industries ....................... 76

Table 20: Five-Year Enforcement and Compliance Summary for the Pharmaceutical Industry 121

Table 21: Five-Year Enforcement and Compliance Summary for Selected Industries ....... 124

Table 22: One-Year Enforcement and Compliance Summary for Selected Industries ....... 125

Table 23: Five-Year Inspection and Enforcement Summary by Statute for Selected Industries 126

Table 24: One-Year Inspection and Enforcement Summary by Statute for Selected Industries 127

Table 25: Pharmaceutical Industry Participation in the 33/50 Program .................. 133

Sector Notebook Project vii September 1997 
Sector Notebook Project Pharmaceutical Industry 

List of Figures 

Figure 1: Percent of Total Value of Shipments by Sector .............................. 8

Figure 2: Employment in the Pharmaceutical Industry ................................ 9

Figure 3: Geographic Distribution of Pharmaceutical Facilities (SIC 2833 and 2834) ........ 11

Figure 4: World Sales of Pharmaceuticals, 1995 .................................... 14

Figure 5: Simplified Process Flow Diagram for Chemical Synthesis ..................... 22

Figure 6: Typical Design of a Kettle-Type Batch Reactor ............................. 23

Figure 7: Cross-Section of Typical Top-Suspended Centrifugal Filter ................... 25

Figure 8: Cross-Section of Typical Tumble Dryer .................................. 27

Figure 9: Simplified Process Flow Diagram for Natural/Biological Extraction ............. 29

Figure 10: Simplified Process Flow Diagram for the Fermentation Process ................ 30

Figure 11: Simplified Process Flow Diagram for Compounding and Formulating ........... 32

Figure 12: Summary of TRI Releases and Transfers by Industry ........................ 75

Sector Notebook Project viii September 1997 
Sector Notebook Project Pharmaceutical Industry 

List of Acronyms 

AFS - AIRS Facility Subsystem (CAA database)

AIRS - Aerometric Information Retrieval System (CAA database)

BIFs - Boilers and Industrial Furnaces (RCRA)

BOD - Biochemical Oxygen Demand

CAA - Clean Air Act

CAAA - Clean Air Act Amendments of 1990

CDER - Center for Drug Evaluation and Research

CERCLA - Comprehensive Environmental Response, Compensation and Liability Act

CERCLIS - CERCLA Information System

CFCs - Chlorofluorocarbons

CO - Carbon Monoxide

COD - Chemical Oxygen Demand

CSI - Common Sense Initiative

CTM - Clinical Trial Material

CWA - Clean Water Act

D&B - Dun and Bradstreet Marketing Index

ELP - Environmental Leadership Program

EPA - United States Environmental Protection Agency

EPCRA - Emergency Planning and Community Right-to-Know Act

FDA - Food and Drug Administration

FIFRA - Federal Insecticide, Fungicide, and Rodenticide Act

FINDS - Facility Indexing System

HAPs - Hazardous Air Pollutants (CAA)

HSDB - Hazardous Substances Data Bank

IDEA - Integrated Data for Enforcement Analysis

IND - Investigational New Drug

LDR - Land Disposal Restrictions (RCRA)

LEPCs - Local Emergency Planning Committees 

MACT - Maximum Achievable Control Technology (CAA)

MCLGs - Maximum Contaminant Level Goals

MCLs - Maximum Contaminant Levels

MEK - Methyl Ethyl Ketone

MSDSs - Material Safety Data Sheets 

NAAQS - National Ambient Air Quality Standards (CAA)

NAFTA - North American Free Trade Agreement

NAICS - North American Industrial Classification System

NCDB - National Compliance Database (for TSCA, FIFRA, EPCRA)

NCP - National Oil and Hazardous Substances Pollution Contingency Plan

NDA - New Drug Application

NEIC - National Enforcement Investigation Center

NESHAP - National Emission Standards for Hazardous Air Pollutants

NO2 - Nitrogen Dioxide

NOV - Notice of Violation

NOx - Nitrogen Oxides

Sector Notebook Project ix September 1997 
Sector Notebook Project Pharmaceutical Industry 

NPDES - National Pollution Discharge Elimination System (CWA)

NPL - National Priorities List

NRC - National Response Center

NSPS - New Source Performance Standards (CAA)

OAR - Office of Air and Radiation

OECA - Office of Enforcement and Compliance Assurance

OPA - Oil Pollution Act

OPPTS - Office of Prevention, Pesticides, and Toxic Substances

OSHA - Occupational Safety and Health Administration

OSW - Office of Solid Waste

OSWER - Office of Solid Waste and Emergency Response

OW - Office of Water

P2 - Pollution Prevention

PCS - Permit Compliance System (CWA Database)

PhRMA - Pharmaceutical Research and Manufacturers of America

POTW - Publicly Owned Treatments Works

RCRA - Resource Conservation and Recovery Act

RCRIS - RCRA Information System

SARA - Superfund Amendments and Reauthorization Act

SDWA - Safe Drinking Water Act

SEPs - Supplementary Environmental Projects

SERCs - State Emergency Response Commissions 

SIC - Standard Industrial Classification

SO2 - Sulfur ioxide D

SOx - Sulfur xides O

TOC - Total Organic Carbon

TRI - Toxic Release Inventory

TRIS - Toxic Release Inventory System

TCRIS - Toxic Chemical Release Inventory System

TSCA - Toxic Substances Control Act

TSS - Total Suspended Solids

UIC - Underground Injection Control (SDWA)

UST - Underground Storage Tanks (RCRA)

VOCs - Volatile Organic Compounds

Sector Notebook Project x September 1997 
Pharmaceutical Industry Sector Notebook Project 

I. INTRODUCTION TO THE SECTOR NOTEBOOK PROJECT 

I.A. Summary of the Sector Notebook Project 

Integrated environmental policies based upon comprehensive analysis of air, 

water and land pollution are a logical supplement to traditional single-media 

approaches to environmental protection. Environmental regulatory agencies 

are beginning to embrace comprehensive, multi-statute solutions to facility 

permitting, enforcement and compliance assurance, education/ outreach, 

research, and regulatory development issues. The central concepts driving the 

new policydirection are that pollutant releases to each environmentalmedium 

(air, water and land) affect each other, and that environmental strategies must 

activelyidentifyand address these inter-relationships by designing policies for 

the “whole” facility. One way to achieve a whole facility focus is to design 

environmental policies for similar industrial facilities. By doing so, 

environmental concerns that are common to the manufacturing of similar 

products can be addressed in a comprehensive manner. Recognition of the 

need to develop the industrial “sector based” approach within the EPA Office 

of Compliance led to the creation of this document. 

The Sector Notebook Project was originally initiated by the Office of 

Compliance within the Office of Enforcement and Compliance Assurance 

(OECA) to provide its staff and managers with summary information for 

eighteen specific industrial sectors. As other EPA offices, states, the regulated 

community, environmental groups, and the public became interested in this 

project, the scope of the original project was expanded to its current form. 

The ability to design comprehensive, common sense environmental protection 

measures for specific industries is dependent on knowledge of several interrelated topics. For the purposes of this project, the key elements chosen for 

inclusion are: general industry information (economic and geographic); a 

description of industrial processes; pollution outputs; pollution prevention 

opportunities; Federal statutory and regulatory framework; compliance 

history; and a description of partnerships that have been formed between 

regulatory agencies, the regulated community and the public. 

For any given industry, each topic listed above could alone be the subject of 

a lengthy volume. However, in order to produce a manageable document, this 

project focuses on providing summary information for each topic. This 

format provides the reader with a synopsis of each issue, and references if 

more in-depth information is available. The contents of each profile were 

researched from a variety of sources, and were usually condensed from more 

detailed sources. This approach allowed for a wide coverage of activities that 

can be further explored based upon the citations and references listed at the 

end of this profile. As a check on the information included, each notebook 

went through an external review process. The Office of Compliance 

appreciates the efforts of all those who participated in this process who 

Sector Notebook Project 1 September 1997 
Pharmaceutical Industry Sector Notebook Project 

enabled us to develop more complete, accurate and up-to-date summaries. 

Many of those who reviewed this notebook are listed as contacts in Section 

X and may be sources of additional information. The individuals and groups 

on this list do not necessarily concur with all statements within this notebook. 

I.B. Additional Information 

Providing Comments 

OECA’s Office of Compliance plans to periodically review and update the 

notebooks and will make these updates available both in hard copy and 

electronically. If you have any comments on the existing notebook, or if you 

would like to provide additional information, please send a hard copy and 

computer disk to the EPA Office of Compliance, Sector Notebook Project, 

401 M St., SW (2223-A), Washington, DC 20460. Comments can also be 

uploaded to the Enviro$en$e World Wide Web for general access to all users 

of the system. Follow instructions in Appendix A for accessing this system. 

Once you have logged in, procedures for uploading text are available from the 

on-line Enviro$en$e Help System. 

Adapting Notebooks to Particular Needs 

The scope of the industry sector described in this notebook approximates the 

national occurrence of facility types within the sector. In many instances, 

industries within specific geographic regions or states may have unique 

characteristics that are not fully captured in these profiles. The Office of 

Compliance encourages state and local environmental agencies and other 

groups to supplement or re-package the information included in this notebook 

to include more specific industrial and regulatory information that may be 

available. Additionally, interested states may want to supplement the 

"Summary of Applicable Federal Statutes and Regulations" section with state 

and local requirements. Compliance or technical assistance providers may 

also want to develop the "Pollution Prevention" section in more detail. Please 

contact the appropriate specialist listed on the opening page of this notebook 

if your office is interested in assisting us in the further development of the 

information or policies addressed within this volume. If you are interested in 

assisting in the development of new notebooks for sectors not already 

covered, please contact the Office of Compliance at 202-564-2395. 

Sector Notebook Project 2 September 1997 
Pharmaceutical Industry Introduction 

II. INTRODUCTION TO THE PHARMACEUTICAL INDUSTRY 

This section provides background information on the size, geographic 

distribution, employment, production, sales, and economic condition of the 

pharmaceutical industry. Facilities described within this document are 

described in terms of their Standard Industrial Classification (SIC) codes. 

II.A. Introduction, Background, and Scope of the Notebook 

The Standard Industrial Classification (SIC) code established by the U.S. 

Office of Management and Budget (OMB) to track the flow of goods and 

services within the economy is 283 for the pharmaceuticals industry. The 

industry is further categorized by four 4-digit SIC codes consisting of: 

Medicinals and Botanicals (SIC 2833) 

Pharmaceutical Preparations (SIC 2834) 

In Vivo and in Vitro Diagnostic Substances (SIC 2835) 

Biological Products, except diagnostics (SIC 2836) 

OMB is in the process of changing the SIC code system to a system based on 

similar production processes called the North American Industrial 

Classification System (NAICS). In the NAIC system, medicinals and 

botanicals are classified as NAIC 325411 and pharmaceutical preparations are 

classified as NAIC 325412. 

According to the U.S. Census of Manufacturers, in 1992 the Medicinals and 

Botanicals and Pharmaceutical Preparations categories accounted for 64 

percent of establishments and 81 percent of the value of shipments in the 

industry. In comparison, the In Vitro and In Vivo Diagnostic Products and 

Biological Products categories are relatively small. Together they accounted 

for the remaining 36 percent of establishments and 19% of the value of 

shipments in the industry. In general, the industrial processes and subsequent 

environmental impacts of the In Vitro and In Vivo Diagnostic Products and 

Biological Products categories are different from those of the Medicinals and 

Botanicals and Pharmaceutical Preparations categories. This notebook 

concentrates on the two larger categories (SIC 2833 and 2834) within SIC 

283. 

II.B. Characterization of the Pharmaceutical Industry 

As defined by its SIC Code, the pharmaceuticals industry (SIC 283) consists 

of establishments that are primarily involved in fabricating or processing 

medicinal chemicals and pharmaceutical products. The industry also includes 

establishments that formulate pharmaceutical products and are involved in 

grinding, grading, and milling of botanical products. The Census of 

Manufacturers defines an establishment as a single physical location or a 

Sector Notebook Project 3 September 1997 
Pharmaceutical Industry Introduction 

facility where manufacturing occurs. If more than one distinct line of 

manufacturing occurs at the same location, the Bureau of Census requires 

separate reports for each activity. 

Although the industry is part of the two-digit SIC code 28 for Chemicals and 

Allied Products, it differs significantly from the rest of the chemicals industry 

in its industrial processes and regulatory requirements. For example, in its 

industrial processes, the pharmaceuticals industry uses more batch operations 

than the chemicals industry as a whole. Since some of the bulk manufacturing 

operations involve extracting relatively small, highly concentrated quantities 

of active ingredients from much larger volumes of raw material, the industry’s 

production yield for these operations is correspondingly low. 

The pharmaceuticals industry also receives extensive regulatory oversight by 

the U.S. Food and Drug Administration (FDA). In 1996, the Center for Drug 

Evaluation and Research, FDA approved 131 new drug applications (NDAs), 

of which 53 were new molecular entities. According to the Congressional 

Office of Technology Assessment (OTA) in 1993, it costs an average of $359 

million to develop a new drug and complete the drug approval process. Total 

drug development and agency review time averaged 15.3 years for drugs 

approved from 1990 through 1995. More information on the typical industrial 

processes and regulatory requirements of this industry is provided in Sections 

III and VI, respectively. 

When a pharmaceutical company discovers a compound that may have 

medical potential, the company usually applies for a patent. Patents are valid 

for 20 years from the date of application. Any drug made from the compound 

may be marketed only after approval by the federal Food and Drug 

Administration (FDA). The drug development process, beginning with initial 

toxicology testing, followed by clinical trials for safety and effectiveness, and 

review of the application by the FDA averages fifteen years. When the 

company’s patent or period of exclusivity has expired, other companies may 

rely on the original manufacturer’s data on safety and effectiveness to obtain 

approval to market a generic version of the drug. Companies wanting to 

manufacture the same drug once it is off-patent are required to obtain FDA 

marketing approval, based on evidence that the generic version is 

“bioequivalent,” i.e., differs in the rate and extent of drug absorption by no 

more than 25 percent nor less than the 20 percent from the original drug 

(FDA, 1996). While companies that specialize in the development and 

marketing of brand-name, innovator drugs

1

 may have subsidiaries that 

1 The term “brand name” is used interchangeably with “pioneer drug” or “innovator’s drug product”. The terms 

reflect the fact that the drug product is the first to contain a particular active ingredient or ingredients to receive 

FDA approval for a specified use. The term “generic” drug is used to describe a product that contains the same 

active ingredients but not necessarily the same excipients (inactive ingredients) as a so-called “pioneer drug”. 

Sector Notebook Project 4 September 1997 
Pharmaceutical Industry Introduction 

manufacture generic products, most generic drug companies do not conduct 

research intended to identify and develop innovator drugs (PhRMA, 1997). 

Because of the high cost and time to approval, effective patent protection is 

an essential component in the decision to invest in drug development and 

marketing. This is especially true for international companies interested in 

marketing drugs in several countries, each with its own approval procedure 

and marketing requirements. While the International Conference on 

Harmonization is proposing harmonized rules for drug registration and 

approval for Europe, Japan and the United States, each country retains its 

own approval system. In other countries, especially developing countries, the 

issue of adequate patent protection is a central concern of pharmaceutical 

manufacturers (PhRMA, 1997). 

Discovery of new compounds followed by further research and development 

(R&D) is one of the primary functions of the industry. The pharmaceutical 

production process starts with an extensive research stage, which can last 

several years. Following the discovery of a new drug that appears to have 

efficacy in treating or preventing illness, pre-clinical tests and clinical trials are 

conducted. Then a New Drug Application (NDA) is submitted to the FDA 

for approval. According to a primary trade association for pharmaceutical 

companies producing brand name drugs, the Pharmaceutical Research and 

Manufacturers of America (PhRMA), it takes an average of 15 years to bring 

a new drug to market, from time of discovery to approval (PhRMA, 1996). 

It is only after FDA approval has been secured that market distribution in the 

U.S. can begin. 

The competition for discovering new drugs and bringing them to market is 

extremely high. As a result, a significant proportion of the industry’s sales are 

reinvested into research and development (R&D). According to PhRMA, 

total R&D expenditures, both domestically and abroad, by its members, will 

be close to $19 billion dollars in 1997. PhRMA estimates that over 21% of 

total sales will be reinvested into R&D by its members (PhRMA, 1997). 

II.B.1. Product Characterization 

The pharmaceutical industry manufactures bulk substance pharmaceutical 

intermediates and active ingredients which are further processed into finished 

products. 

Medicinals and Botanicals (SIC 2833) 

Companies in the Medicinals and Botanicals industry category are 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. The industry is made up of establishments or 

Sector Notebook Project 5 September 1997 
Pharmaceutical Industry Introduction 

facilities that manufacture products of natural origin, hormonal products, and 

basic vitamins, as well as those that isolate active medicinal principals such as 

alkaloids from botanical drugs and herbs (OMB, 1987). These substances are 

used as active ingredients for the Pharmaceutical Preparations industry 

category. Companies often produce both Medicinals and Botanicals and 

Pharmaceutical Preparations at the same facility. 

Pharmaceutical Preparations (SIC 2834) 

The Pharmaceutical Preparations industry category is made up of companies 

that manufacture, fabricate, and process raw materials into pharmaceutical 

preparations for human and veterinary uses. Finished products are sold in 

various dosage forms including, for example, tablets, capsules, ointments, 

solutions, suspensions, and powders. These are 1) preparations aimed for use 

mainly by dental, medical, or veterinary professionals, and 2) those aimed for 

use by patients and the general public (OMB, 1987). A more in depth 

discussion of these finished products is provided in Section III.A.3. 

Pharmaceutical products also are often classified in terms of their availability 

to the general public. 

Both prescription and over-the-counter (OTC) drugs are available to the 

public. Prescription drugs can be purchased only with a prescription from a 

licensed health care professional authorized to prescribe, while OTC drugs 

may be purchased without a prescription. The FDA will consider approving 

the switch of a drug from prescription to OTC when the manufacturer 

presents evidence that consumers can self-diagnose the condition for which 

the drug is approved, i.e., cold or seasonal allergy, and directions for use can 

be written for the consumer (PhRMA, 1997). 

In Vivo and In Vitro Diagnostic Substances (SIC 2835) and Biological Products (SIC 2836) 

The In Vivo and In Vitro Diagnostic Substances industry category (SIC 2835) 

includes facilities that manufacture in vivo (tested inside a living organism) 

and in vitro (tested outside of a living organism) diagnostic substances. They 

produce chemical, biological, and radioactive substances used in diagnosing 

and monitoring health. The Biological Products industry category (SIC 2836) 

produces bacterial and virus vaccines, toxoids, serums, plasmas, and other 

blood derivatives for human and veterinary use, other than in vitro and in vivo 

diagnostic substances (OMB, 1987). 

II.B.2. Industry Size 

According to the U.S. Census of Manufactures for the pharmaceuticals 

industry as a whole (SIC 283), in 1992 there were a total of 1,425 

establishments employing 194,000 people (excluding Puerto Rico). It is 

possible that some of the smaller facilities identified by the Census are actually 

Sector Notebook Project 6 September 1997 
Pharmaceutical Industry Introduction 

sales, marketing or distribution centers in which no manufacturing operations 

take place. Such possible misclassifications have no significant effect on the 

census statistics other than on the number of companies and establishments. 

(U.S. Department of Commerce, 1995) The value of total shipments was 

over $67 billion (see Table 1). Pharmaceutical Preparations (SIC 2834) was 

the largest sector in terms of number of facilities (48 percent), employment 

(63 percent), and value of shipments (75 percent). The remaining facilities, 

employment, and value of shipments were divided evenly among the 

remaining sectors within the industry. One exception is the In Vivo and In 

Vitro Diagnostic Products sector (SIC 2835) which claims a higher portion 

of employment than SIC codes 2833 and 2836. Figure 1 displays the value 

of shipments by sector, and Figure 2 displays employment by sector. 

A relatively significant number of pharmaceutical establishments are located 

in Puerto Rico. This is in part the result of the federal government’s policy 

decision to encourage job creation by offering tax incentives to manufacturers 

to locate new plants in Puerto Rico. A 1996 tax law phases-out those tax 

incentives over the next ten years. 

The effects of the tax incentive are illustrated by the concentration of 

pharmaceutical plants in Puerto Rico. According to the 1992 Economic 

Census of Outlying Areas, which covers statistics for Puerto Rico, there were 

a total of 88 establishments in Puerto Rico. Of these 88, 74 establishments 

were in the Pharmaceutical Preparations industry, 8 were in the Medicinals 

and Botanicals industry, and the remaining six establishments were in the In 

Vitro and In Vivo Diagnostic Products industry, and the Biological Products, 

except diagnostic substances industry. The total value of shipments of the 88 

establishments located in Puerto Rico was about $12 billion. Pharmaceutical 

Preparations accounted for about 92 percent of this. The pharmaceutical 

industry in Puerto Rico employed about 25,000 people in the 88 

establishments in 1992. 

Sector Notebook Project 7 September 1997 
Pharmaceutical Industry Introduction

Sector Notebook Project 8 September 1997

Figure 1: Percent of Total Value of Shipments by Sector

Source: 1992 U.S. Census of Manufacturers.

Table 1: Summary Statistics for the Pharmaceutical Industry

50 STATES PUERTO RICO

Industry

Number of

Establishments

Number of

Companies1

Value of

Shipments

(millions of

dollars)

2

Employmen

t

(000's)

Number of

Establishments

Value of

Shipments

(millions of

dollars)

2

Employment

(000's)

SIC 2833 225 208 6,438 13 8 N/A3 N/A3

SIC 2834 691 585 50,418 123 74 11,097 22

SIC 2835 234 205 6,838 40 5 477 1

SIC 2836 275 193 3,974 18 1 N/A3 N/A3

Total 1,425 1,191 67,668 194 88 11,924 25

Source: 1992 Census of Manufacturers, Industry Series: Drugs, US Department of Commerce, Bureau of the Census,

1995 and 1992 Economic Census of Outlying Areas, Manufacturers: Puerto Rico, US Department of Commerce,

Bureau of the Census, 1994.

1

Defined as a business organization consisting of one establishment or more under common ownership or control. 2

Value of all products and services sold by establishments in the pharmaceuticals industry. 3

Certain census data are not available for Puerto Rico. Information is withheld to avoid disclosing data for individual

facilities.
Pharmaceutical Industry Introduction

Sector Notebook Project 9 September 1997

Figure 2: Employment in the Pharmaceutical Industry

Source: 1992 U.S. Census of Manufacturers.

As shown in Table 2, many facilities within the pharmaceutical industry are

small. Almost 70 percent of the facilities employ fewer than 50 people.

However, a relatively small number of large companies account for a large

portion of the total value of shipments, as well as employment. For example,

according to the 1992 U.S. Census of Manufacturers, only 36 facilities (less

than three percent) employed more than 1,000 people in the 50 states(i.e., not

including Puerto Rico). However, these 36 facilities accounted for over 38%

of the total value of shipments for the industry. In comparison, 968 facilities

(almost 70 percent) employ fewer than 50 people. However, these facilities

accounted for less than four percent of the industry’s value of shipments.
Pharmaceutical Industry Introduction 

Table 2: Pharmaceutical Industry (SIC 283) Facility Size1 

Number of Employees Number of Facilities Percent of Total 

Facilities (%) 

Percent of Total Value 

of Shipments (%) 

fewer than 10 479 34 0.6 

10 to 49 489 34 3.2 

50 to 249 292 20 19 

250 to 999 129 9.1 392 

1,000 or more 36 2.5 382 

Total 1,425 100 100 

Source: 1992 Census of Manufacturers, Industry Series: Drugs, Bureau of the Census, 1995.

1 Does not include Puerto Rico - information withheld to avoid disclosing data for individual facilities. 2 Some information withheld to avoid disclosing individual facility data. Values may be somewhat higher.

Medicinals and Botanicals (SIC 2833) and Pharmaceutical Preparations (SIC 2834) 

The establishment size distributions for Pharmaceutical Preparations and 

Medicinals and Botanicals are similar (see Table 3). The Pharmaceutical 

Preparations sector, however, has a somewhat higher proportion of large 

facilities. As is the case with the pharmaceuticals industry as a whole, a 

relatively small number of large establishments account for the majority of the 

total value of shipments for the Pharmaceutical Preparations industry. Value 

of shipment data is not available by establishment size for the Medicinals and 

Botanicals sector. 

Table 3: Employment Size Distribution for Medicinals and Botanicals and 

Pharmaceutical Preparations Establishments 1 

Medicinals and Botanicals Pharmaceutical Preparations 

Number of 

Employees 

Number of 

Facilities 

Percent of 

Facilities 

Percent of 

Value of 

Shipments 

Number of 

Facilities 

Percent of 

Facilities 

Percent of 

Value of 

Shipments 

< than 10 104 46 N/A2 225 33 0.4 

10 to 49 76 34 N/A2 211 30 2 

50 to 249 35 16 N/A2 142 21 10 

250 or more 10 4 N/A2 113 16 88 

Total 225 100 100 691 100 100 

Source: 1992 U.S. Census of Manufacturers. 1

 Not including Puerto Rico. 2 Information has been withheld to avoid disclosing individual establishment data.

Sector Notebook Project 10 September 1997 
Pharmaceutical Industry Introduction 

Table 4 lists the largest U.S. pharmaceutical companies in terms of U.S. 

prescription sales. 

Table 4: Top U.S. Pharmaceutical Companies by Sales 

Rank Company 1996 Rx Sales 

(millions of dollars) 

1 Glaxo Wellcome 5,803 

2 Johnson & Johnson 5,275 

3 American Home Products 5,251 

4 Bristol-Myers Squibb 5,160 

5 Merck & Co 5,026 

6 Pfizer 4,511 

7 Novartis 3,786 

8 SmithKline Beecham 3,589 

9 Lilly 3,567 

10 Abbott 3,423 

11 Schering-Plough 3,272 

12 Hoechst Marion Roussel 2,474 

13 Roche 2,316 

14 Amgen 1,860 

15 Bayer 1,854 

Source: IMS America. 

II.B.3. Geographic Distribution 

The U.S. pharmaceuticals industry has traditionally been concentrated in New 

Jersey, California, and New York (see Figure 3). These three states account 

for about one third of the facilities, employees, and value of shipments. 

Historically, the industry concentrated here because these were vocational 

centers. Other states, such as Massachusetts, North Carolina and Maryland, 

have seen recent growth in the pharmaceuticals industry, especially in 

biotechnology and research and development. 

Sector Notebook Project 11 September 1997 
Pharmaceutical Industry Introduction 

Figure 3: Geographic Distribution of Pharmaceutical Facilities (SIC 2833 and 2834) 

Puerto Rico 

0 - 10 

101 - 123 

51 - 100 

11 - 50 

Source: 1992 U.S. Census of Manufacturers. 

A significant number of pharmaceutical establishments are also located in 

Puerto Rico. According to the 1992 Economic Census of Outlying Areas, 

which covers statistics for Puerto Rico, there were a total of 88 

pharmaceuticals establishments in Puerto Rico accounting for almost $12 

billion in shipments. Eighty two of these establishments were in the 

Pharmaceutical Preparations and Medicinals and Botanicals sectors. These 

establishments accounted for 11 percent of all employment and 15 percent of 

the value of shipments for these sectors. The driving force behind the 

pharmaceuticals industry concentrating in Puerto Rico over the years are tax 

incentives specifically directed at the industry. 

Many U.S. firms have facilities abroad or own foreign companies in which 

both R&D and production of pharmaceuticals are conducted. According to 

PhRMA, in 1996 its member firms employed close to 165,000 people 

overseas in the production of prescription pharmaceuticals. Of these, about 

42% were employed in Western Europe. The next largest region for overseas 

employment by PhRMA member companies is Latin America and the 

Caribbean, with 20 percent (PhRMA, 1996). Recently, a number of 

pharmaceutical companies are moving production to Ireland. Similarly, many 

foreign owned pharmaceutical firms operate pharmaceutical research and 

development and production facilities in the U.S. 

Sector Notebook Project 12 September 1997 
Pharmaceutical Industry Introduction 

II.B.4. Economic Trends and International Competition 

Changes in the U.S. Health Care Industry 

During the early 1990s the United States pharmaceutical industry faced major 

challenges associated with the changing nature of health care delivery coupled 

with intense market competition. In 1995 about 62 percent of prescriptions 

were paid for by insuring third parties, up from 39 percent in 1990. Third 

parties, including managed care organizations and Medicaid, consider cost in 

choosing which drugs are approved for reimbursement. Techniques such as 

substituting generic drugs for branded drugs are also used. Low priced 

generic drugs rapidly capture a large share of prescriptions once the 

originating drug’s patent expires. Likewise, intense R&D rivalries between 

companies now mean that new products may have major competition within 

months after their FDA approval, as was the case for three competing 

protease inhibitors approved between December 1995 and April 1996. 

Companies have responded to shorter product life cycles and cost 

containment pressures by forming an increasing number of strategic alliances 

and merging. However, a steady stream of new product introductions has 

contributed to steady industry growth driven by an increasing volume of 

prescriptions. In 1997, research-based companies’ net sales in the United 

States are projected to reach $66.1 billion, a 5.5 percent increase over 1996 

(PhRMA, 1997). 

Consolidation of the Pharmaceuticals Industry 

Competitive pressures are forcing many companies to restructure and form 

mergers and strategic alliances. Increasing competition from both domestic 

and foreign firms, as well as from the generic drug market, has forced mergers 

between the larger pharmaceutical companies and mid-sized companies. In 

1989, three major mergers occurred between large and mid-sized 

pharmaceutical companies. In 1995, this number increased to seven. In 1996, 

there were three mergers. 

As a result of generic competition, some brand name firms are becoming 

involved with companies that manufacture generic drugs by purchasing 

existing companies, setting up their own generic drug ventures, or forming 

partnerships (PhRMA, 1996). Also, many smaller biotech and R&D 

companies are merging with large pharmaceutical companies. Strategic 

alliances often involve domestic and foreign pharmaceutical companies, 

biotech firms, university research centers, government agencies such as the 

National Institute of Health, and contract research organizations. Such 

mergers and alliances allow companies to draw upon each others’ research 

expertise, bring products to market more rapidly, and more effectively market 

products once they are approved by FDA. 

Sector Notebook Project 13 September 1997 
Pharmaceutical Industry Introduction 

Changes in Geographical Concentrations 

An increasing number of establishments owned by U.S. companies are 

locating outside the U.S. A number of forces are driving these changes, 

including the growing international market for pharmaceutical products, 

foreign registration requirements and patent laws, laws allowing sales only if 

the products are manufactured in the country; and tax incentives. 

International Trade and Competition 

The U.S. pharmaceuticals industry accounts for about one-third of all 

pharmaceuticals marketed worldwide (see Figure 4). The major U.S. trading 

partners are Europe, Japan, Canada, and Mexico. The largest importer of 

U.S. pharmaceuticals is the European Community (EC). In 1993, the EC 

alone imported nearly 50% of all U.S. exports (ITA, 1994). Canada and 

Mexico combined imported 15 percent of all U.S. exports of pharmaceutical 

products in 1993. The North American Free Trade Agreement (NAFTA), 

however, has increased the volume of trade with Canada and Mexico in recent 

years. 

Although Japan still remains one of the largest importers of U.S. 

pharmaceuticals, Japanese pharmaceutical companies have been investing 

heavily in their own R&D, thereby reducing Japan’s import share of U.S. 

exports in recent years. 

In 1993, European and Japanese pharmaceutical companies accounted for 27 

percent and 22 percent of all pharmaceuticals marketed worldwide, 

respectively (PhRMA, 1996). China and the countries of the former Soviet 

Union are potentially large markets for U.S. pharmaceuticals. However, 

China is also increasing its production of pharmaceuticals and the former 

countries of the Soviet Union pose some major challenges for U.S. producers 

in terms of testing and licensing regulations (International Trade 

Administration, 1994). 

Major issues affecting the international competitiveness of U.S. 

pharmaceutical firms include price controls and intellectual property 

protection abroad. Other trade barriers include foreign pricing systems that 

favor locally produced pharmaceuticals, discriminatory registration 

requirements, and requirements that foreign companies enter into joint 

ventures with domestic firms. 

Sector Notebook Project 14 September 1997 
Pharmaceutical Industry Introduction 

Figure 4: World Sales of Pharmaceuticals, 1995 

Middle East 

2% 

Southeast 

Asia & China 

Canada 6%

3% 

United States 

30% 

Australasia 

1% 

Europe 

27% 

Africa 

2% 

Japan 

22% 

Latin America 

7% 

Source: Pharmaceutical Research and Manufacturers of America, 1997 

based on data provided by IMS America, 1996. 

Sector Notebook Project 15 September 1997 
Page 16 intentionally left blank. 
Pharmaceutical Industry Industrial Process Description 

III. INDUSTRIAL PROCESS DESCRIPTION 

This section describes the major industrial processes within the pharmaceutical 

industry, including the materials and equipment used, and the processes 

employed. The section is designed for those interested in gaining a general 

understanding of the industry, and for those interested in the inter-relationship 

between the industrial process and the topics described in subsequent sections 

of this profile -- pollutant outputs, pollution prevention opportunities, and 

Federal regulations. This section does not attempt to replicate published 

engineering information that is available for this industry. Refer to Section IX 

for a list of reference documents that are available. 

This section specifically contains a description of commonly used production 

processes, associated raw materials, and the materials either recycled or 

transferred off-site. This discussion, coupled with schematic drawings of the 

identified processes, provides a description of where wastes may be produced 

in the process. A more in-depth description of the major wastes produced by 

pharmaceutical manufacturing can be found in Section III.B. 

Additionally, it is important to understand the regulatory framework in which 

pharmaceutical products are manufactured. To protect the public from unsafe 

or ineffective pharmaceutical products, Congress established a stringent 

regulatory system to control the research and development, manufacture and 

marketing of pharmaceutical products. The US Food and Drug Administration 

(FDA) was delegated the responsibility for: (i) evaluating the safety and 

efficacy of new drugs; (ii) determining if the benefits of the drug outweigh the 

risks and warrant approval for sale; and (iii) reviewing toxicological 

performance of active pharmaceutical ingredients. For most new 

pharmaceutical compounds, FDA oversight begins soon after the discovery 

of the compound. 

III.A. Industrial Processes in the Pharmaceutical Industry 

The production of pharmaceutical products can be broken down into three 

main stages: 1) research and development; 2) the conversion of organic and 

naturalsubstances into bulk pharmaceutical substances or ingredients through 

fermentation, extraction, and/or chemical synthesis; and 3) the formulation of 

the final pharmaceutical product. 

III.A.1. Research and Development 

New drug development involves four principal phases: Pre-Clinical Research 

and Development; Clinical Research and Development; Review of New Drug 

Application; and Post Marketing Surveillance. Pre-Clinical Research and 

Development begins after a promising compound has been discovered and 

isolated in the laboratory. In this phase, the compound is subjected to 

Sector Notebook Project 17 September 1997 
Pharmaceutical Industry Industrial Process Description 

extensive laboratory and animal tests to determine whether the compound is 

biologically active and safe. The average time to complete this phase is six 

years. 

After completing the Pre-Clinical Research and Development and before 

testing the drug in humans, an application is filed with FDA known as an 

Investigational New Drug Application (IND). The application must show the 

results of the pre-clinical testing and detail the plans for human clinical tests. 

It must also contain information about the chemical structure of the 

compound and a general description as to how the compound is 

manufactured. 

Clinical Research and Development is typically conducted in three phases, 

with each phase involving progressively more people. The first phase, which 

typically lasts about a year, is aimed at establishing the drug’s safety and 

involves a small number of healthy volunteers. The second phase, which lasts 

about two years, helps the scientists determine the drug’s effectiveness. In the 

third phase, the drug is used in clinics and hospitals, and scientists must 

confirm the results of earlier tests and identify any adverse reactions. 

Altogether the three phases of Clinical Research and Development take about 

six years. 

In the first phase of Clinical Research and Development, a small amount of the 

compound is manufactured in a pilot plant for use in the clinical trials. This 

batch of compound is called Clinical Trial Material (CTM). At this time, the 

manufacturing steps of the compound are also optimized and improved. 

During this phase, attention to waste minimization considerations is most 

effective. 

After Clinical Research and Development is completed, the company files, 

with the FDA, a New Drug Application (NDA) containing comprehensive 

data about the compound. The NDA must include data to demonstrate that 

the drug is safe and effective for use under the conditions described in its 

labeling. FDA regulations require that the NDA contain specific and detailed 

information on: the components and composition of the drug; the methods 

and controls used in the manufacturing; processing and packaging of the drug; 

and, data from all pre-clinical and clinical investigations. In 1993, the median 

total approval time for NDAs was 21 months. This has been significantly 

reduced and in 1996, the median total approval time for NDAs was 15 

months. 

Each step in the manufacturing process, and the identity and quality of each 

ingredient used in the process, must be specified in the NDA and approved by 

the FDA. Once the NDA is approved, certain changes cannot be made 

without the filing and approval by the FDA of a supplemental application, 

known as an SNDA. The level of reporting depends on the type of change 

Sector Notebook Project 18 September 1997 
Pharmaceutical Industry Industrial Process Description 

and may require substantial investment of resources to implement. FDA 

approval may take several years to obtain depending on the nature of the 

change, and some changes even require new clinical studies. 

Based on data from a 1995 study by the Center for the Study of Drug 

Development at Tufts University, a pharmaceutical Research and 

Development (R&D) facility discovering and developing a new medicinal 

agent will evaluate approximately 5,000 to 10,000 compounds. About 250 

of these substances may hold therapeutic promise and enter preclinical testing. 

However, only about five will go on to limited human clinical testing. 

Subsequently, only one, after 15.3 years of research and development, will be 

introduced commercially as a new drug (PhRMA, 1997). 

Basic research is responsible for identifying and isolating or synthesizing each 

new chemical entity that will be evaluated for its potential therapeutic 

effectiveness. Once a lead compound has been identified and characterized, 

some 1,000 related chemical substances will be synthesized and studied by 

laboratory assay systems. These assay systems are designed to identity which 

compounds exhibit the most specific and potent biological effect. For each 

compound tested, generally some 5-10 separate chemical reactions will be 

needed to synthesize the compound. The results of biological testing will then 

guide the direction of subsequent synthetic operations. If the results are 

unsatisfactory, then the process starts anew. 

Should a substance show promise in the laboratory assays, limited animal 

studies are started. If there is no activity in the animal, other related 

compounds will be evaluated or the program will be discontinued. Once 

biologically active substances are identified, they will undergo further 

chemical modification to refine their efficacy and safety. 

Once an active candidate has been identified, it will be proposed for formal 

development. Pharmaceutical development includes the evaluation of synthetic 

methods on a larger scale and the assessment of various ways of formulating 

the drug to provide optimum delivery. Up to this point, only small amounts 

have been synthesized for evaluation. More will be needed for the extensive 

animal testing required by FDA. Even larger amounts will be required for the 

extensive clinical studies in humans required before federal approval. 

III.A.2. Production of Bulk Pharmaceutical Substances 

Bulk pharmaceutical substances typically consist of structurally complex 

organic chemical compounds which are manufactured via a series of 

intermediate steps and reactions under precise conditions. These substances 

are used in the manufacture of the dosage form of a formulated 

pharmaceutical product and are manufactured by: (1) chemical synthesis; (2) 

fermentation; (3) isolation/recovery from natural sources, or (4) a combination 

Sector Notebook Project 19 September 1997 
Pharmaceutical Industry Industrial Process Description 

of these processes. Examples of different drugs produced by each of these 

processes are presented in Table 5. 

Table 5: Examples of Pharmaceutical Products by Bulk Manufacturing Process 

Chemical Synthesis Natural Product Extraction Fermentation 

Antibiotics 

Antihistamines 

Cardiovascular Agents 

Central Nervous System (CNS) 

Stimulants 

CNS Depressants 

Hormones 

Vitamins 

Antineoplastic Agents 

Enzymes and Digestive Aids 

CNS Depressants 

Hematological Agents 

Insulin 

Vaccines 

Antibiotics 

Antineoplastic Agents 

Therapeutic Nutrients 

Vitamins 

Steroids 

Most pharmaceutical substances are manufactured utilizing “batch” processes. 

In a batch process, a particular substance or “intermediate”2

 is manufactured 

in a “campaign” for periods ranging from a few days to several months until 

sufficient material is manufactured to satisfy the projected sales demand. At 

the end of the manufacturing campaign, another pharmaceutical intermediate 

or substance is made. The same equipment with potentially different 

configurations and the same operating personnel are often used to make a 

different intermediate or substance, utilizing different raw materials, executing 

different processes, and generating different waste streams. 

When the same equipment is used for manufacturing different intermediates 

and/or different bulk substances, the equipment is thoroughly cleaned and 

validated prior to its reuse. Where cleaning of a specific type of equipment 

is difficult or where a sufficient volume of a certain intermediate or bulk 

substance is made every year, the equipment may be dedicated to the batch 

manufacturing of a particular intermediate or bulk substance. Where the 

equipment is dedicated to the production of successive batches of the same 

intermediate or bulk substance, the equipment may not be washed and cleaned 

between batches. Instead, the cleaning schedule will depend on whether there 

is a potential for carryover of contaminants or degraded materials that could 

affect the final product. 

The specific methods and materials (e.g., water, steam, detergents, and/or 

organic solvents) used to clean the equipment are based on the ability of the 

cleaning process to remove residues of raw materials, intermediates, 

precursors, degradation products, and isomers (FDA, 1996). 

2 An intermediate is a material produced during a manufacturing process that must undergo further 

molecular change or processing before it becomes a bulk pharmaceutical substance. 

Sector Notebook Project 20 September 1997 
Pharmaceutical Industry Industrial Process Description 

Raw materials are checked for their identity and quality before use in the 

manufacturing processes. Additionally, in-process testing, as well as quality 

assurance/quality control (QA/QC) testing in onsite laboratories, is performed 

during drug product manufacturing. In-process testing may include simple pH 

measurements or checks on color, while QA/QC testing typically includes 

more sophisticated analyses such as chromatography. “Upon completion of 

the manufacturing operation, batch-production records are checked by 

competent and responsible personnel for actual yield against theoretical yield 

of a batch and to ensure that each step has been performed and signed for” 

(McGraw Hill Encyclopedia of Technology). 

Chemical Synthesis 

Most of the compounds used today as pharmaceutical products are prepared 

by chemical synthesis, generally by a batch process (Watthey, 1992). 

Cardiovascular agents, central nervous system agents, vitamins, antibiotics, 

and antihistamines are just a few examples of the bulk pharmaceutical 

substances made by this process. 

The manufacture of pharmaceutical compounds using chemical synthesis 

involves a complex series of processes including many intermediate stages and 

chemical reactions performed in a step-by-step fashion. Depending on the 

process, the operator (or a programmed computer) adds reagents, increases 

or decreases the flow rate of chilled water or steam, and starts and stops 

pumps to draw the reactor contents into another vessel. At other stages in the 

process, solutions may be pumped through filters or centrifuges, recycled 

within the process, or pumped to recycling or disposal facilities. Co-products, 

such as salts, may be sold for reuse. Spent acids, metals, and catalysts may 

be recovered and reused onsite or sold for reuse. 

The material from each intermediate step may be isolated and transferred to 

the next step of the process for continued processing until the final compound 

is derived. These steps may be all conducted at the same manufacturing site, 

or if the intermediate is isolated, it may be transferred to another site for 

further processing. 

It is impossible to provide a single process flow diagram for this industry since 

each bulk pharmaceutical substance is different in its manufacture and several 

intermediates may be produced in a step-wise fashion prior to the manufacture 

of the final active ingredient. However, an example chemical synthesis 

process has been provided as Figure 5 to show the equipment used and where 

wastes or emissions might be generated. 

Sector Notebook Project 21 September 1997 
Pharmaceutical Industry Industrial Process Description 

Figure 5: Simplified Process Flow Diagram for Chemical Synthesis 

Reaction 

Vessel Chemicals 

(reactants) 

Reaction 

Residues 

Sealed - jacket 

for cooling/heating 

media 

Process 

Condenser 

Separation 

- extraction 

- decanting 

- centrifugation 

- filtration 

Spent solvents to 

recovery/disposal 

Air Emissions 

Control Device 

Solvent Vapors 

Wastewater 

Treatment 

Solvent Vapors 

Crystallization 

Process 

Condenser 

Wastewater 

Treatment 

Solvent Vapors 

Purification 

- recrystallization 

- centrifugation 

- filtration 

Drying 

Solvent Vapors 

Solvent 

vapors 

Product 

Solvent 

Vapors 

Wastewater 

Wastewater Wastewater 

Source: Adapted from Economic Impact and Regulatory Flexibility Analysis of Proposed Effluent Guidelines for the 

Pharmaceutical Manufacturing Industry, 1995. 

Reactors 

The most common type of reactor vessel is the kettle-type reactor. These 

reactors typically range in capacity from 50 to several thousand gallons. The 

vessels are made of either stainless steel or glass-lined carbon steel. 

A diagram of a typical reactor vessel is shown in Figure 6. “Reactors are 

equipped to provide a range of capabilities that may be required during the 

batch reaction step. This equipment may include: a jacket for heating and 

cooling, hookups for charging raw materials and for discharging the contents 

of the reactor, an agitation and recycle line for mixing, control systems for 

temperature and pressure, a condenser system for controlling vent losses, a 

return line for refluxing condensables, a steam ejector for vacuum operation, 

a nitrogen supply for padding and purging the reactor, and a manway for 

taking samples and adding solid catalysts, reactants, and other solid materials 

to the reactor” (USEPA 1993). 

Sector Notebook Project 22 September 1997 
Pharmaceutical Industry Industrial Process Description 

Figure 6: Typical Design of a Kettle-Type Batch Reactor 

Condensed 

Steam and 

Organics 

Pressure 

Relief Valve 

Steam-Jet 

Ejector 

Steam 

Nitrogen 

Solvent, 

Raw Material, 

and Reactant 

Addition 

Manway 

Reactor 

Jacket 

Steam 

Cooling Water 

or Coolant 

Steam 

Trap 

Condensed Steam 

Drain Valve 

Agitator 

Reactor 

Discharge 

Recycle 

Line 

Cooling Water 

or Coolant 

Source: Adapted from Control of Volatile Organic Compound Emissions from Batch Processes, EPA Guideline Series, 

1993. 

Raw materials or ingredients, including solvents, used to produce the 

intermediate or bulk substances are charged into the reactor vessel. Liquid 

ingredients are drawn into the reactor either by pumping or through vacuum 

from drums and storage tanks. Solids may be charged manually or via 

mechanical means such as through a vacuum system. 

Once the reactor vessels are charged with the raw materials, the reaction takes 

place. “The reactor can be operated at atmospheric pressure, elevated 

pressure, or under vacuum. Because of their flexibility, reactors may be used 

in a variety of ways. Besides hosting chemical reactions, they can act as 

mixers, heaters, holding tanks, crystallizers, and evaporators.” (USEPA, 

1979) Typical reactions performed include alkylations, hydrogenations, 

brominations, etc. Temperature, pressure, and the degree of mixing are 

carefully monitored to achieve the desired product and to ensure worker 

safety. 

Sector Notebook Project 23 September 1997 
Pharmaceutical Industry Industrial Process Description 

Reactors are often attached to process condensers to recover solvents from 

process operations. Theyare also often attached to other air pollution control 

devices to remove volatile organics or other compounds from vented gases. 

Depending on the reaction being carried out, a reactor may also be attached 

to a distillation column for solvent separation and recovery. 

Separation 

Several separation mechanisms are employed by the pharmaceutical industry 

including extraction, decanting, centrifugation, and filtration. These 

mechanisms may be employed jointly or individually, in multiple stages, to 

separate the intermediate or bulk substance from the reaction solution and to 

remove impurities. Crystallization is another common technique used to 

separate the desired active ingredient or intermediate from the reaction 

mixture. Because crystallization is widely used in conjunction with other 

separation techniques, it is presented separately from the other separation 

techniques shown in Figure 5 and discussed below. 

Extraction. Extraction is used to separate liquid mixtures by taking advantage 

of differences in the solubility of the mixture components. A solvent that 

preferentially combines with only one of the components is added to the 

mixture. “The resulting mixture consists of an extract (containing the 

preferentially combined material) and a raffinate (containing the residual 

phase). Extraction may take place in an agitated reaction vessel (mixersettler), in a vertical cylinder (where the solvent flows upward or downward 

through the liquid mixture), or in a column with internals to mechanically 

enhance the contact between the two liquid phases” (Crume et al., 1992). 

Decanting. Decanting is a simple process used to separate mixtures of a liquid 

and insoluble solid that has settled to the bottom of a reactor or settling 

vessel. The liquid over the solid is either pumped out of the vessel or poured 

from the vessel leaving behind the insoluble solid and a certain amount of 

liquid. 

Centrifugation. “Centrifuges are used to remove the intermediate or product 

solids from a liquid stream” (USEPA1979).Centrifugeswork on the principle 

of centrifugal force, in which an outward force is exerted on a rotating object. 

Centrifuges are cylinders with rotating baskets within them. The sides of the 

basket are perforated and covered with filter medium such as woven fabric or 

metal. As the basket rotates, a slurry solution is fed into the centrifuge via an 

inlet pipe. The centrifugal force pushes the slurry against the rotating basket, 

forcing the liquid to pass through the perforations, and the solids or filter cake 

to remain behind, accumulating on the sides of the basket. “After all of the 

slurry has been fed to the chamber, a wash liquid may be introduced to force 

the remaining slurry liquid through the cake and filter medium” (USEPA 

1993). Once the centrifuge is turned off, the solids (i.e., the intermediates or 

Sector Notebook Project 24 September 1997 
Pharmaceutical Industry Industrial Process Description 

the final bulk substance) are scraped off the sides with an internal scraper or 

manually scooped out. A diagram of a typical basket centrifuge is shown in 

Figure 7. 

Figure 7: Cross-Section of Typical Top-Suspended Centrifugal Filter 

Motor 

Slurry Inlet 

Wash Inlet 

Solids Cake 

Perforated Basket 

Removable Valve Plate 

Solids Discharge 

Casing 

Filtrate 

Discharge Adjustable Unloader 

Knife 

Source: Adapted from Control of Volatile Organic Compound Emissions from Batch Processes, EPA Guideline Series, 

1993. 

The extremely high speeds and frictional forces involved in centrifuging, 

combined with the potential build-up of combustible solvent vapors, create a 

potential for an explosive environment to develop within the centrifuge. To 

control this, an inert gas, usually nitrogen, may be introduced into the unit 

before the slurry is fed in. “Centrifuges must be carefully operated to avoid 

air infiltration by vortex entrainment. Therefore, they usually are operated 

under nitrogen blanket and kept sealed under operation” (USEPA 1993). 

VOC emissions may occur when purging the vessel before loading and 

unloading (USEPA, 1993). 

Filtration. Filtration is the separation of a fluid-solids mixture involving 

Sector Notebook Project 25 September 1997 
Pharmaceutical Industry Industrial Process Description 

passage of most of the fluid through a porous barrier (the filter medium) 

which retains most of the solid particulates contained in the mixture (Perry’s 

1984). In the pharmaceutical industry, “filtration is used to remove solids 

from a liquid, whether these solids be product, process intermediates, catalysts 

or carbon particulates (e.g., from a decoloring step)” (USEPA 1979). Batch 

filtration systems widely used by the pharmaceutical industry are the plateand-frame filter, cartridge filters, the nutsche filter, and combination 

filter/dryers. 

“The normal filtration procedure is simply to force or draw the mother liquor 

through a filtering medium. Following filtration, the retained solids are 

removed” (USEPA, 1979). The wet cake may then go through a reslurry 

process where it is washed and filtered again. “This option is usually carried 

out when a highly specialized product requiring high purity is desired or when 

solvents were not removed as part of the original slurry filtration (USEPA, 

1993). 

Crystallization 

After the reaction takes place, the intermediate or final bulk substance (which 

is usually in solid form) can be separated from the reaction solution by 

crystallization. Crystallization is one of the most common separation 

techniques and is often used alone or in combination with one or more of the 

separation techniques described above. In crystallization, a supersaturated 

solution is created in which crystals of the desired compound are formed. 

Supersaturation depends on the solubility of the desired compound. If the 

compound’s solubility increases with temperature, supersaturation can be 

achieved by cooling the solution. If the solubility is independent of or 

decreases with temperature, then evaporating a portion of the solvent will 

create supersaturation. “If neither cooling nor evaporation is desirable, 

supersaturation may be induced by adding a third component. The third 

component forms a mix with the original solvent in which the solute is 

considerably less soluble” (USEPA 1979). If crystallization is done through 

cooling of a solution there will be relatively little VOC emissions, especially 

if the equipment is fully enclosed. “However, when crystallization is done by 

solvent evaporation in a vacuum environment, there is a greater potential for 

emissions” (USEPA 1993). Further separation of the crystals from the 

supersaturated solution can be done by centrifuging or filtration. 

Purification 

Once the intermediate or the bulk substance has been separated, it may need 

to be purified. Depending on the intermediate or the bulk substance produced, 

there may be several purification steps involved to produce the desired active 

ingredient. In vitamin production, for example, there are at least three to four 

purification steps. Purification typically is achieved through additional 

Sector Notebook Project 26 September 1997 
Pharmaceutical Industry Industrial Process Description 

separation steps such as those described above. Purification is often achieved 

through recrystallization. Washing with additional solvents and filtration may 

also be used. 

Drying 

The final step in the chemical synthesis process is drying of the intermediate 

or final bulk substance. Drying is done by evaporating the solvents from the 

solids. Solvents released from drying operations may be condensed for reuse 

or disposal (USEPA 1993). 

There are several different types of dryers used by the pharmaceutical industry 

including tray dryers, rotary dryers, drum or tumble dryers, or pressure filter 

dryers. “The selection of the dryer type depends primarily on the 

characteristics of the solid” (USEPA 1993). 

Prior to 1980, probably the most common type of dryer used by the industry 

was the vacuum tray dryer. In a vacuum tray dryer, “the filtered solid is 

placed on trays which are then manually stacked on shelves in the dryer. 

When the dryer is closed, the trays are heated to remove any liquids. A 

vacuum is applied within the dryer so that drying can take place at lower 

temperatures when needed” (USEPA, 1993). 

More often today, tumble dryers or combination filter/dryers are used. In a 

combination filter/dryer “the equipment not only acts as a filter, but can also 

function as a product dryer after the slurry has been compressed and filtered 

into cake form. Heat is introduced to the filter/dryer through a hot gaseous 

medium which is blown up through the cake until the desired level of dryness 

is achieved” (USEPA 1993). VOC emissions may occur since the gas will 

entrain evaporated solvent which must be vented from the drying filter/dryer. 

Tumble dryers consist of revolving conical shells ranging in capacity from 20 

to 100 gallons. “The rotation of the dryer tumbles the product to enhance 

solvent evaporation and may also perform a blending function” (USEPA 

1979). These dryers may be operated under a vacuum or using hot air 

circulation. When operated under a vacuum, heat is supplied through 

conduction from heated surfaces. Some air will pass through the equipment 

due to inward leakage. Thus, the vacuum exhaust will contain VOCs 

(USEPA, 1993). A diagram of a simple tumble dryer is shown in Figure 8. 

Sector Notebook Project 27 September 1997 
Pharmaceutical Industry Industrial Process Description 

Figure 8: Cross-Section of Typical Tumble Dryer 

Chain Casing 

Steam or 

Hot Water 

Inlet 

Concrete 

or Structural 

Foundation 

Discharge 

Opening 

Vacuum 

Connection 

Cover 

Source: Adapted from Control of Volatile Organic Compound Emissions from Batch Processes, EPA Guideline Series, 

1993. 

Natural and Biological Product Extraction 

Natural product extraction, as the name suggests, involves isolating an active 

ingredient from natural sources, such as plants, roots, parasitic fungi or animal 

glands. This process is often used to produce allergy relief medicines, insulin, 

morphine, anti-cancer drugs, or other pharmaceuticals with unique properties. 

Blood fractionation, used to produce plasma, is also part of the natural 

product extraction process (USEPA 1995). A simplified diagram of natural 

product extraction processes and its associated wastes, is shown in Figure 9. 

The desired active ingredient, usually present in raw materials at very low 

concentrations, must be extracted for the final product. Therefore, a defining 

characteristic of this process is that the volume of finished product is often an 

order of magnitude smaller than that of the raw materials used. At each step 

in the extraction process, the volume of material being processed is reduced 

significantly. This inherent nature of the process makes it an expensive one 

Sector Notebook Project 28 September 1997 
Pharmaceutical Industry Industrial Process Description 

to utilize (USEPA 1995). 

Figure 9: Simplified Process Flow Diagram for Natural/Biological Extraction 

M ix in g & 

Wa s h i n g 

Ra w M a te r ia l 

(a n i m a l tis s u e 

p la n t t is s ue , 

ro o ts , p la s m a ) 

W a s t ew at er 

(B OD , C O D , T S S ) 

Ex t rac ti o n 

H 2 O 

Ev a p o rat io n 

W a s t ew at er 

(B OD , C O D, 

T S S , a m m oni um 

s a lts , s o lv e n t s ) 

S ludge 

(s o lv e n ts , 

or g an ic 

ma te r ia l ) 

S o lv e n t va por s 

(p h e n o l , c h lo ro fo rm , 

me th e l y n e c h lo r .) 

Ac tiv e 

Ingr e d ie nt 

T o C o m pound in g 

& F o r m u l a tio n 

O r ga n ic S o lv e n ts 

(m e th e l y n e c h lo rid e , 

c h lo ro fo rm , a l c o h o l, 

to lu e n e ) S c r ubbe r 

W a s t ew at er 

(acid ic o r 

b a s ic , s o lv e n ts ) 

H 2 O 

Source: Adapted from Economic Impact and Regulatory Flexibility Analysis of Proposed Effluent Guidelines for the Pharmaceutical 

Manufacturing Industry, 1995. 

Because of the large volume reductions involved, an assembly-line processing 

method, consisting of several operation stations is used. At each subsequent 

operation station, a little more of the inert material is removed and the active 

ingredient is extracted. As the volume of material being processed decreases, 

the size of the containers carrying the material also decreases, from containers 

capable of carrying 75-100 gallons to, in some cases, laboratory size 

equipment (USEPA 1995). 

Active ingredients are recovered by precipitation, purification and solvent 

extraction methods. In precipitation, solubility is changed by pH adjustment, 

salt formation, or addition of an anti-solvent. Solvents are used as extractive 

agents to remove the active ingredient from the raw materials, such as plant 

and animal tissues. Solvents are also used to remove fats and oils, which may 

contaminate the product (USEPA 1995). Such solvents remove the fats and 

oils, without damaging the essential active ingredient(s) found in the raw 

materials. Ammonia is also used in the extraction stages as a method of 

controlling the pH when extracting from animal and plant sources. 

Ammonium salts are used as buffering chemicals, and aqueous or anhydrous 

ammonia is used as an alkalizing agent. The high degree of solubility of 

Sector Notebook Project 29 September 1997 
Pharmaceutical Industry Industrial Process Description 

ammoniumsalts prevents unwanted precipitation. Also, ammonium salts have 

the advantage of not reacting with animal and/or plant tissues (USEPA 1995). 

Sector Notebook Project 30 September 1997 
Pharmaceutical Industry Industrial Process Description 

Fermentation 

Most steroids, antibiotics, and certain food additives (such as vitamins) are 

commonly known pharmaceuticals which are produced by fermentation. In 

fermentation, microorganisms (e.g., bacteria, yeast or fungi) are typically 

inoculated in a liquid broth supplemented with nutrients that are acclimated 

to an environment (e.g., temperature, pH, oxygen), conducive to rapid 

growth). These microorganisms produce the desired product (e.g., antibiotic, 

steroid, vitamin, etc.) as a by-product of normal metabolism. Fermentation 

involves three main steps: 1) inoculum and seed preparation, 2) fermentation, 

and 3) product recovery. A diagram of a fermentation process and the wastes 

produced in this process is shown in Figure 10. 

Figure 10: Simplified Process Flow Diagram for the Fermentation Process 

Fermentation 

Broth 

Seed 

Heat 

Filter 

H2O 

Product Dissolved 

or Precipitated 

Wastewater 

(solvents, 

copper, zinc, 

BOD, COD, TSS, 

low pH) 

Sludge 

(sugars,

starches, fermentation 

broths, corn steep 

liquor) 

Separations Active 

Ingredient 

Inoculation 

Tank 

Nutrients 

(sugars, starches) 

Gas 

(NO2CO2, sulfur) 

Solvents or 

Metal Salts 

(MiBK, Cu, Zn) 

Filter 

Cake 

Organic Solvents 

(acetone, MiBK, 

1,2-dichloroethane) 

To Compounding & 

Formulation 

Wastewater 

(solvents) 

Source: Adapted from Economic Impact and Regulatory Flexibility Analysis of Proposed Effluent Guidelines for the 

Pharmaceutical Manufacturing Industry, 1995. 

Sector Notebook Project 31 September 1997 
Pharmaceutical Industry Industrial Process Description 

Seed Preparation 

The fermentation process begins with the introduction of the microbial strain 

to a primary seed fermentation, which is commonly performed using shakingflask culture techniques at the laboratory scale. Once grown, the suspension 

is then transferred to further seed stages, which may be additional flask 

fermentations, stirred tanks or both. The purpose of this “seed-train” is to 

generate enough inoculum for the production fermentor (typically 1-10% of 

the production tank volume). Generally, special seed tanks are used for the 

fermentor inoculum which are miniature versions (1-10% of size) of the 

production fermentor. If a seed tank becomes contaminated, it is emptied, 

sterilized, and reinoculated. 

Fermentation 

Once the fermentor inoculum is ready, it is charged into a sterilized fermentor. 

During fermentation, the fermentor is usually agitated and aerated. The pH, 

temperature, and dissolved oxygen content of the fermentation broth may be 

monitored during fermentation. Fermentation may last from hours to weeks, 

depending on the process. A fermentor “broth” is produced, which is then 

filtered or centrifuged to separate out the solids (USEPA 1991). 

Product Recovery 

Filtration removes any larger residues from the broth, but it does not isolate 

the active ingredient from the residues. This must be done by product 

recovery processes. Product recovery is achievable through three different 

methods: solvent extraction, direct precipitation and ion exchange, or 

adsorption (USEPA 1995). Sometimes, the active material is contained 

within the cells of the microorganism. Cell wall breakage by heat or 

ultrasound, for example, may be required to recover the material. 

In solvent extraction the active ingredient is removed from the aqueous broth 

by contacting it with an organic solvent, in which the product is more soluble 

than it is in water. Removal of the active agent from the solvent can be 

achieved by crystallization (USEPA 1995). 

The direct precipitation method of product recovery involves precipitation of 

the active ingredient, as a metal salt from the broth using, for example, copper 

(Cu) and/or zinc (Zn) as precipitating agents. The actual choice of the 

precipitating agent depends on the properties of the desired active ingredient. 

The broth is then filtered and the product is recovered from the solid residues 

(USEPA 1991). 

Additionally, ion exchange or adsorption may be used for product recovery. 

Ion exchange resin (or alternatively, activated carbon) is contacted with the 

Sector Notebook Project 32 September 1997 
Pharmaceutical Industry Industrial Process Description 

broth and the product adsorbs onto the resin. The product is recovered from 

the resin by using a solvent or by washing the resin with an acidic or basic 

solution. It is then crystallized. 

III.A.3. Formulation, Mixing, and Compounding 

“The primary objective of mixing, compounding, or formulating operations 

are to convert the manufactured bulk substances into a final, usable form.” 

(USEPA 1995) Figure 11 shows a simplified process flow diagram for 

compounding, formulation and packaging. Common dosage forms of 

pharmaceutical products include tablets, capsules, liquids, creams and 

ointments, as well as aerosols, patches and injectable dosages. Table 6 lists 

common pharmaceutical dosage forms and their uses. 

Figure 11: Simplified Process Flow Diagram for Compounding and Formulating 

Mixing & 

Granulation 

Active Ingredient 

(Drug) 

Tableting & 

Encapsulation 

Washing 

Equipment 

Tablets and 

Capsules 

Non-Contact 

Cooling Water Excipients & 

Binders 

(sugars, starches) 

Solvent 

Emission - VOCs 

Wastewater 

(solvents, 

detergents)

Aqueous-based Solvents 

Wastewater 

(waste starches, 

sugars 

BOD, COD, TSS) 

Fugitive emissions, 

vent emissions 

Tablet 

Dust 

Source: Adapted from Economic Impact and Regulatory Flexibility Analysis of Proposed Effluent Guidelines for the 

Pharmaceutical Manufacturing Industry, 1995. 

Sector Notebook Project 33 September 1997 
Pharmaceutical Industry Industrial Process Description 

As with the bulk manufacturing operations, many final products are produced 

in batch utilizing a campaign regimen. At the end of the production campaign, 

another product may be formulated and packaged using the same equipment 

and the same personnel. Additionally, formulation and packaging is 

performed in accordance with “good manufacturing practices” (GMP). GMP 

is regulated by the FDA and sets forth the minimum methods to be used in, 

and the facilities and controls to be used for the manufacture, processing, 

packing, or holding of a drug to assure that such drug meets the safety 

requirements and the quality and purity characteristics that it purports or is 

represented to possess. 

Following formulation, the finished product may be packaged at the same site 

or it may be transferred to another site. Packaging includes placing the final 

formulated products into containers, labeling, and preparing for shipping. 

“The packaging components of a pharmaceutical product are vital to its safe 

and effective use. Besides serving the patient as a convenient unit of use, the 

composite package (unit container, labeling, and shipping components) must 

provide appropriate identification and necessary information for proper use 

including warnings and (pre)cautions and preservation of the product’s 

chemical and physical integrity” (Kirk-Othmer, 1994). 

Batch production records are used and describe each manufacturing step in 

detail. At various stages in the formulation and packaging process, quality 

control checks are utilized. All raw materials are checked prior to use in a 

process and the final dosage forms require a myriad of tests to assure 

therapeutic benefit. For example, the content uniformity, color, homogeneity, 

dissolution, stability, identity, and potency of the product must be determined 

and meet stated ranges. Representative samples are collected at the end of the 

formulation stage and submitted to the chemical and/or microbiological 

laboratories for final assaying. Representative samples are also collected 

during packaging operations. The quality control unit of the pharmaceutical 

manufacturing company has the responsibility and authority to approve or 

reject all raw materials, in-process materials, packaging materials including 

containers, closures, and labeling materials, as well as the final product. 

The equipment used to formulate and package the final product is cleaned, 

maintained, and sanitized at appropriate intervals. Actual maintenance and 

cleaning schedules and results are documented. As described under bulk 

manufacturing, the methods, equipment, and materials used (e.g., water 

wash, steam, detergents, organic solvents) to clean the equipment are 

specified on a per product basis. 

Sector Notebook Project 34 September 1997 
Pharmaceutical Industry Industrial Process Description 

Table 6: Pharmaceutical Dosage Forms 

Dosage Constituents, properties Uses 

Form 

Solids 

powders, comminuted or blended, dissolved or mixed with water external, internal 

bulk 

effervescent CO2 -releasing base ingredients oral 

insufflation insufflator propels medicated powder into body cavity body cavities 

lyophilized reconstitution by pharmacist of unstable products various uses including 

parenteral and oral 

capsules small-dose bulk powder enclosed in gelatin shell, active ingredient plus internal 

diluent 

troches, prepared by piping and cutting or disk candy technology; compounded with slow dissolution in mouth 

lozenges glycerogelatin 

compressed dissolved or mixed with water; great variety of shapes and formulations oral and external 

tablets 

pellets for prolonged action implantation 

coated tablets coating protective, slow release oral 

Liquid Solutions 

syrups sweetener, solvent, medicinal agent flavoring agent, medicinal 

spirits alcohol, water, volatile substances flavor or medicinal 

collodions pyroxylin in ether, medicinal agent (castor oil, camphor) external for corns and 

bunions 

parenteral sterile, pyrogen-free, isotonic, pH close to that of blood; oily or aqueous intravenous, intramuscular, 

solutions solution subcutaneous injection 

ophthalmic sterile, isotonic, pH close to that of tears; viscosity builder eye treatment 

nasal aqueous, isotonic, pH close to that of nasal fluids; sprays or drops nose treatment 

mouthwash, aqueous, antiseptic refreshment, short term 

gargles bacterial control 

inhalations administered with mechanical devices medication of trachea or 

bronchioles 

Liquid Dispersions 

suspensions powder suspended in water, alcohol, glycol, or an oil oral dosing, skin application 

emulsions, oil-in-water or water-in-oil oral, external or injection 

lotions 

Semisolid and plastic dispersions 

ointments hydrocarbon (oily), adsorptive water-washable, or water-soluble bases; external 

emulsifying agents, glycols, medicating agent 

pastes and ointments with high dispersed solids and waxes, respectively external 

cerates 

suppositories theobroma oil, glycinerated gelatin, or polyethylene glycol base plus insertion into body cavity 

medicinal agent 

Source: Adapted from Zanowaik, P., 1995, “Pharmaceuticals” in Kirk-Othmer, Encyclopedia of Chemical Technology, 

vol. 18, 4th edition. 

Sector Notebook Project 35 September 1997 
Pharmaceutical Industry Industrial Process Description 

Tablets 

Tablets account for the majority of solid medications taken orally in the 

United States. “Tablets can be made to achieve rapid drug release or to 

produce delayed, repeated or prolonged therapeutic action” (Kirk-Othmer, 

1994). Tablets can be compressed or molded, and may be coated. 

To prepare a tablet, the active pharmaceutical ingredient is combined with a 

filler, such as sugar or starch, and a binder, such as corn syrup or starch. The 

filler is added to ensure that the active ingredient is diluted to the proper 

concentration. A binder is needed to bind tablet particles together. A 

lubricant, such as magnesium sterate or polyethylene glycol, may be added to 

facilitate equipment operation, or to slow disintegration or dissolution of the 

active ingredient. 

Tablets are produced by compression of powder blends or granulations. In 

direct compression, the ingredients are blended and then compressed into the 

final tablet without modifying the physical nature of the material itself. “The 

most widely used and most general method of tablet preparation is the wetgranulation method” (Remington, 1995). In wet granulation, the active 

ingredient is powdered and mixed with the filler. This mixture is then wetted 

and blended with the binder, forming a solution. Coarse granules form which 

are mixed with lubricants such as magnesium stearate and then compressed 

into tablets. Slugging or dry granulation is used when tablet ingredients are 

sensitive to moisture or temperatures associated with drying or when the 

tablet ingredients have sufficient inherent binding or cohesive properties. Dry 

granulation includes weighing, mixing, slugging, dry screening, lubrication, 

and compression. Slugging requires large heavy presses to compress larger 

tablets, between 20-30 grams in weight. These large tablets are then ground 

and screened to a desired mesh size then recompressed into final tablets 

(USEPA, 1991). 

Coating may be used to offer protection from moisture, oxygen, or light, to 

mask unpleasant taste or appearance, and to impart distinctive colors to 

facilitate patient recognition. “Enteric coatings are used to delay the release 

of the active ingredient in the stomach and prolong therapeutic activity. The 

latter are used for drugs that are unstable to gastric pH or enzymes, cause 

nausea and vomiting, or irritation to the stomach, or should be present in high 

concentrations in the intestines” (Kirk-Othmer, 1994). Coating is done in a 

rotary drum. The coating solution is poured onto the tablets. In many 

operations, aqueous coating solutions are now used instead of solvent based 

(usually methylene chloride) solutions. As the drum rotates, the tablets 

become coated. Once coated, they are dried in the drum and may be sent to 

another rotary drum for polishing. Polishing works by the friction created 

Sector Notebook Project 36 September 1997 
Pharmaceutical Industry Industrial Process Description 

when the tablets rotate and rub against each other. Un-coated tablets may 

also be polished. 

Once the tablets pass quality control requirements, they may be held or sent 

directly to packaging. Coated tablets are stamped with identifying information 

(e.g., brand name, code number) in a rotary ink press. 

Capsules 

After tablets, the most common solid oral dosage form is the capsule. 

Capsules come in soft and hard shelled varieties. Hard capsules or “dry-filled” 

capsules are formed by dipping metal pins into a solution of gelatin of a 

specific temperature. The temperature controls the viscosity of the gelatin 

and hence the thickness of the capsule walls. When the pins are removed 

from the solution, a hard coating of gelatin forms on the pins. The coating is 

dried and trimmed. “These capsules are filled by introducing the powdered 

material into the longer end or body and the capsule and then slipping on the 

cap.” (Remington, 1995) 

Soft shelled capsules are formed by placing two continuous gelatin films 

between rotary die plates. As the plates are brought together, the two gelatin 

films join and seal, forming the two halves of the capsule. As the two halves 

join, the ingredients, which can be a liquid, paste or powder, are injected into 

the capsules. “Commercially filled soft gelatin capsules come in a wide choice 

of sizes and shapes: they may be round, oval, oblong, tube or suppositoryshaped” (Remington). 

Liquid Dosage 

In formulating a liquid product, the ingredients are first weighed and then 

dissolved in an appropriate liquid. The solutions are mixed in glass-lined or 

stainless steel vessels, after which they are stored in tanks before final 

packaging. Preservatives may be added to prevent mold and bacterial growth. 

If the liquid will be used for injection or ophthalmic use, sterilization is 

required. In this case, the container, which has also been previously 

sterilized/depyrogenated, is filled with liquid which has either been rendered 

sterile by aseptic filtration in a sterile environment and/or the entire container 

and its contents are terminally heat sterilized in an autoclave. 

Ointments and Creams 

Ointments are usually made byblending the bulk active ingredient with a base, 

such as a petroleum derivative or wax. The mixture is cooled, rolled out, and 

poured into tubes by machines and packaged (USEPA, 1991). 

Sector Notebook Project 37 September 1997 
Pharmaceutical Industry Industrial Process Description 

Creams are semisolid emulsions and are either oil-in-water or water-in-oil, 

rather than being petroleum based. “Generally, the ingredients of the two 

phases are heated separately, then are mixed and stirred vigorously to achieve 

emulsification” (Kirk-Othmer, 1994). 

As with all other dosage forms, equipment is washed and cleaned based on 

batch record requirements. However, because of the greasy nature of 

ointment and cream production, cleaning often is done with detergents. 

Sector Notebook Project 38 September 1997 
Pharmaceutical Industry Industrial Process Description 

III.B. Raw Material Inputs and Pollutant Outputs 

Pharmaceutical batch processes use numerous raw materials and generate 

wastes and emissions. In general, the waste and emissions generated depend 

on the raw materials and equipment used, as well as the manufacturing 

process employed. In designing bulk manufacturing processes, consideration 

is given to the availability of the starting materials and their toxicity, as well 

as the wastes (e.g., mother liquors, filter residues, and other by-products) and 

the emissions generated. A description of some of the considerations given 

is provided in Section V, Pollution Prevention Opportunities. 

When bulk manufacturing reactions are complete, the solvents are physically 

separated from the resulting product. Due to purity concerns, solvents often 

are not reused in a pharmaceutical process. They may be sold for nonpharmaceutical uses, used for fuel blending operations, recycled, or destroyed 

through incineration. 

This section describes the raw materials and associated waste streams and 

some of the more common technologies used to control these wastes. Much 

of this information is summarized in Table 7. 

Sector Notebook Project 39 September 1997 
Pharmaceutical Industry Industrial Process Description 

Table 7: Summary of Typical Material Inputs and Pollution Outputs in the Pharmaceutical Industry 

Process Inputs (examples of 

some commonly used 

chemicals provided) 

Air Emissions Wastewater Residual 

Wastes 

Chemical 

Synthesis 

- Reaction 

Solvents, catalysts, 

reactants, e.g. benzene, 

chloroform, methylene 

chloride, toluene, 

methanol, ethylene 

glycol, methyl isobutyl 

ketone (MiBK), xylenes, 

hydrochloric acid, etc. 

VOC emissions from 

reactor vents, manways, 

material loading and 

unloading, acid gases 

(halogen acids, sulfur 

dioxide, nitrous oxides); 

fugitive emissions, from 

pumps, sample 

collections, valves, tanks 

Process waste waters with 

spent solvents, catalysts, 

reactants; pump seal waters, 

wet scrubber wastewater; 

equipment cleaning 

wastewater; wastewater 

maybe high in BOD, COD, 

TSS with pH of 1-11. 

Reaction residues 

and reactor 

bottom wastes 

- Separation Separation and extraction 

solvents, e.g.. methanol, 

toluene, hexanes, etc. 

VOC emissions from 

filtering systems which 

aren’t contained; and 

fugitive emissions from 

valves, tanks and 

centrifuges 

Equipment cleaning wash 

waters, spills, leaks, spent 

separation solvents 

- Purification Purification solvents e.g.. 

methanol, toluene, 

acetone, hexanes, etc. 

Solvent vapors from 

purification tanks; 

fugitive emissions 

Equipment cleaning wash 

waters, spills, leaks, spent 

purification solvents 

- Drying Finished active drug(s) or 

intermediates 

VOC emissions from 

manual loading and 

unloading of dryers 

Equipment cleaning wash 

waters, spills, leaks 

Natural Product 

Extraction 

Plants, roots, animal 

tissues, extraction 

solvents, e.g.. ammonia, 

chloroform, phenol, 

toluene, etc. 

Solvent vapors & VOC’s 

from extraction 

chemicals 

Equipment cleaning wash 

waters, spent solvents 

(ammonia); natural product 

extraction wastewater have 

low BOD, COD, TSS and pH 

of 6-8. 

Spent raw 

materials (plants, 

roots etc.) 

Fermentation Inoculum, sugars, 

starches, nutrients, 

phosphates, fermentation 

solvents, e.g.. ethanol, 

amyl alcohol, methanol, 

MiBK, acetone, etc. 

Odoriferous gases, 

extraction solvent vapors, 

particulates 

Spent fermentor broth, 

fermentation wastewater 

containing sugars, starches, 

nutrients, etc.; wastewater 

tends to have high BOD, 

COD, TSS and have pH of 4-

8. 

Waste filter cake, 

fermentation 

residues 

Formulation Active drug, binders 

(starches), sugar, syrups, 

etc. 

Tablet dusts, other 

particulates 

Equipment cleaning wash 

waters (spent solvents), spills, 

leaks; wash waters typically 

contain low levels of BOD, 

COD, TSS and have pH of 6-

8. 

Particulates, 

waste packaging, 

rejected tablets, 

capsules etc. 

Source: Development Document for Proposed Effluent Limitations Guidelines and Standards for the Pharmaceutical 

Manufacturing Point Source Category, US EPA, Washington, DC., February 1995. 

Sector Notebook Project 40 September 1997 
Pharmaceutical Industry Industrial Process Description 

III.B.1. Raw Materials 

“The pharmaceutical manufacturing industry draws upon worldwide sources 

for the myriad of raw materials it needs to produce medicinal chemicals. 

Fermentation operations require many new raw materials falling into general 

chemical classifications such as carbohydrates, carbonates, steep liquors, 

nitrogen, and phosphorus compounds, anti-foam agents, and various acids and 

bases. These chemicals are used as carbon and nutrient sources, as foam 

control additives, and for pH adjustment in fermentation processes. Various 

solvents, acids, and bases are also required for extraction and purification 

processes. 

Hundreds of raw materials are required for the chemical synthesis processes 

used bythe industry. These include organic and inorganic compounds and are 

used in gas, liquid, and solid forms. Plant and animal tissues are also used by 

the pharmaceutical manufacturing industry to produce various biological and 

natural extraction products” (EPA, 1995). 

Each manufacturing or formulation plant is special, differing from other 

similar pharmaceutical plants in size, types of intermediates, bulk substances, 

or products produced, amounts and types of solvents used, and thus, in the 

raw materials used and wastes/emissions generated. Most bulk 

pharmaceutical reactions require organic solvents to dissolve chemical 

intermediates and reagents. Because of the high reactivity of many 

pharmaceutical reagents and intermediates, pharmaceutical solvents must be 

non-reactive, provide an environment which allows efficient heat transfer 

during endothermic or exothermic reactions, and facilitate efficient electron 

transfer. Often halogenated solvents, such as methylene chloride, provide the 

optimum choice for pharmaceutical reactions. The most commonly used 

solvent in the pharmaceutical industry is methanol, an oxygenated organic 

solvent. Other common solvents used are ethanol, acetone, and isopropanol. 

Tables 8, 9, and 10 show the typical solvents (and whether or not they are 

priority pollutants or hazardous air pollutants) used in chemical synthesis, 

biological and natural extraction, and fermentation processes, respectively. 

Final bulk substances from the bulk manufacturing processes are used in 

formulation operations, along with other raw materials or ingredients. The 

production of these ingredients is described under Section III.A.2. 

Sector Notebook Project 41 September 1997 
Pharmaceutical Industry Industrial Process Description 

Table 8: Solvents Used in the Chemical Synthesis Process 

Chemical Priority 

Pollutant 

Under the 

Clean Water 

Act 

Hazardous 

Air Pollutant 

under the 

Clean Air 

Act 

Chemical Priority 

Pollutant 

Under the 

Clean Water 

Act 

Hazardous 

Air 

Pollutant 

under the 

Clean Air 

Act 

Acetone Ethylene glycol X 

Acetonitrile X Formaldehyde X 

Ammonia (aqueous) Formamide 

n-Amyl acetate Furfural 

Amyl Alcohol n-Heptane 

Aniline X n-Hexane X 

Benzene X X Isobutyraldehyde 

2-Butanone (MEK) X Isopropanol 

n-Butyl acetate Isopropyl acetate 

n-Butyl alcohol Isopropyl ether 

Chlorobenzene X X Methanol X 

Chloroform X X Methylamine 

Chloromethane X X Methyl cellulose 

Cyanide X Methylene chloride X X 

Cyclohexane Methyl formate 

o-Dichlorobenzene (1,2-

Dichlorobenzene) 

X Methyl isobutyl 

ketone (MiBK) 

X 

1,2-Dichlorobenzene X 2-Methylpyridine 

Diethylamie Petroleum naphtha 

Diethyl Ether Phenol X X 

N,N-Dimethyl 

acetamide 

Polyethylene glycol 

600 

Diethylamine n-Propanol 

N,N-Dimethylaniline X Pyridine 

N,NDimethylformamide X Tetrahydrofuran 

Dimethyl sulfoxide Toluene X X 

1,4-Dioxane X Trichlorofloromethane 

Ethanol Triethylamine X 

Ethyl acetate Xylenes X 

Source: adapted from Development Document for Proposed Effluent Guidelines and Standards for the Pharmaceutical 

Manufacturing Point Source Category, 1995 and US Environment Laws, 1994. 

Sector Notebook Project 42 September 1997 
Pharmaceutical Industry Industrial Process Description 

Table 9: Solvents Used in Biological and Natural Product Extraction 

Chemicals Priority 

Pollutants 

under the 

Clean Water 

Act 

Hazardous 

Air 

Pollutants 

under the 

Clean Air 

Act 

Chemicals Priority 

Pollutants 

under the 

Clean Water 

Act 

Hazardous 

Air 

Pollutants 

under the 

Clean Air 

Act 

Acetone Ethylene glycol X 

Acetonitrile X Formaldehyde X 

Ammonia (aqueous) n-Heptane 

n-Amyl acetate n-Hexane X 

Amyl alcohol Isopropanol 

n-Butyl alcohol Isopropyl acetate 

Chloroform X X Isopropyl ether 

1,2-Dichloroethane X Methanol X 

Diethylamine Methylene 

chloride 

X X 

Diethyl ether Petroleum 

naphtha 

N,NDiethylformamide X Phenol X X 

Dimethyl sulfoxide n-Propanol 

1,4-Dioxane X Pyridine 

Ethanol Tetrahydrofuran 

Ethyl acetate Toluene X X 

Source: adapted from Development Document for Proposed Effluent Guidelines and Standards for the Pharmaceutical 

Manufacturing Point Source Category, 1995 and US Environment Laws, 1994. 

Table 10: Solvents Used in Fermentation Processes 

Chemicals Priority 

Pollutants Under 

the Clean Water 

Act 

Hazardous 

Air 

Pollutants 

under the 

Clean Air 

Act 

Chemicals Priority 

Pollutants Under 

the Clean Water 

Act 

Hazardous 

Air 

Pollutants 

under the 

Clean Air 

Act 

Acetone n-Heptane 

Acetonitrile X n-Hexane X 

Ammonia (aqueous) Isopropanol 

n-Amyl acetate Isopropyl 

acetate 

Amyl alcohol Methanol X 

n-Butyl acetate Methyl 

cellulose 

n-Butyl alcohol Methylene 

chloride 

X X 

Chloroform X X Methyl 

isobutane 

ketone (MiBK) 

X 

Sector Notebook Project 43 September 1997 
Pharmaceutical Industry Industrial Process Description 

Table 10: Solvents Used in Fermentation Processes 

N,NDiethylformamide X Petroleum 

naphtha 

Ethanol Phenol X X 

Ethyl acetate Toluene X X 

Formaldehyde X Triethylamine X 

Source: adapted from Development Document for Proposed Effluent Guidelines and Standards for the Pharmaceutical 

Manufacturing Point Source Category, 1995 and US Environment Laws, 1994. 

III.B.2. Air Emissions and Control Systems 

Both gaseous organic and inorganic compounds, as well as particulates, may 

be emitted during pharmaceutical manufacturing and formulation. Some of 

the volatile organic compounds (VOC) and inorganic gases that are emitted 

are classified as hazardous air pollutants (HAPs) under the Clean Air Act. 

The type and amount of emissions generated are dependent on the operations 

conducted by the facility, as well as how the product is manufactured or 

formulated. “Each (pharmaceutical) plant is unique, differing from other 

plants in size, types of products manufactured, amounts and types of VOC 

used, and air pollution control problems encountered” (EPA, 1979). 

Bulk Manufacturing 

As previously described, the industry manufactures most bulk pharmaceutical 

substances and intermediates in campaigns via batch processes. Following the 

completion of one campaign, another bulk substance or intermediate is 

typically made using the same equipment (e.g., reactors, filters, dryers). The 

reactants and solvents used in manufacturing the next bulk substance or 

intermediate may vary greatly from the ones previously used. While some 

reactions may require the use of halogenated solvents, the next reaction may 

use another solvent or no solvent at all. 

This wide variations in bulk manufacturing makes predicting typical or annual 

average emissions difficult. This is because the emission generated are 

predicated on what bulk substance or intermediate is manufactured and over 

what length of time, and which equipment and raw materials are used. Some 

bulk substances and intermediates are made frequently, while others may be 

made only once every two to three years over a one to two week period. This 

has often prevented the calculation of typical emission rates for each 

operation. However, an approximate ranking of emission sources has been 

established by EPA and is presented below in order of decreasing magnitude. 

The first four sources generally will account for the majority of emissions 

from a bulk manufacturing plant. 

�Dryers 

Sector Notebook Project 44 September 1997 
Pharmaceutical Industry Industrial Process Description 

Dryers 

�Reactors

�Distillation units

�Storage and transfer of materials

�Filtration

�Extraction

�Centrifugation

�Crystallization

are one of the largest sources of VOC emissions in bulk

manufacturing. In addition to the loss of solvent during drying, manual 

loading and unloading of dryers can release solvent vapors into ambient air, 

especially when tray dryers are used. VOCs are also generated from reaction 

and separation steps via reactor vents and manways. Centrifuges may be a 

source of VOC emissions, especially in top loading types, where solids are 

manually scooped out. 

Typical controls for these emission sources, excluding storage and transfer 

operations, include condensers, scrubbers, carbon absorbers and, on occasion, 

incinerators. “Storage and transfer emissions can be controlled by vapor 

return lines, vent condensers, conservation vents, vent scrubbers, pressure 

tanks and carbon absorbers. Floating roofs may be feasible controls for large 

vertical storage tanks” (EPA, 1979). 

Formulation 

Both particulates and VOCs may be formed during mixing, compounding, 

formulation, and packaging steps. Because these compounds may pose a 

danger to workers, through direct inhalation, they are a principal concern. 

Depending on the process and the batch record requirements, the particulates 

(e.g., tablet dusts) may be recycled back into the formulation process. 

However, sometimes the particulates are collected for destruction or disposal. 

As in bulk manufacturing, the type and quantity of compounds emitted 

depends on the operation. For example, formulation facilities may or may not 

emit VOCs. Some formulation operations do not require the use of solvents, 

some may only use solvents for cleaning, and some may use solvents in 

granulation and coating operations. In some facilities, organic compounds, 

such as ethanol or isopropyl alcohol, might be used in the formulation of the 

product and VOCs may be emitted during mixing, formulation, and/or 

packaging. 

Air Pollution Control Equipment 

More than one type of air control equipment may be used at any one time in 

any one facility. A description of the various equipment used by the industry 

Sector Notebook Project 45 September 1997 
Pharmaceutical Industry Industrial Process Description 

is provided below. 

Condensers. Condensers are widely used in the pharmaceutical industry to 

recover solvents from process operations (a process condenser) and as air 

pollution control devices to remove VOCs from vented gases. Process 

condensers differ from condensers used as air pollution control devices as the 

primary purpose of a process condenser is to recover material as an integral 

part of a unit operation. The process condenser is the first condenser located 

after the process equipment and supports a vapor-to-liquid phase change for 

the vapors produced in the process equipment. Examples of process 

condensers include distillation condensers, reflux condensers, process 

condensers in line before the vacuum source, and process condensers used in 

stripping or flashing operations. The primary purpose of a condenser used 

as an air pollution control device is to remove VOCs prior to venting. 

Condensation is the process of converting a gas or vapor to liquid. In this 

method, gas streams from vents containing VOCs are cooled to below their 

saturation temperatures, converting the gas into a VOC liquid. This removes 

some VOCs from the gas, but some remains. The amount of VOCs remaining 

in the gas depends on the temperature and vapor-liquid equilibrium of the 

VOC. Lowering the temperature of the condenser generally lowers the 

content of VOC in the gas stream. 

“In the most common type, surface condensers, the coolant does not directly 

contact condensable vapors, rather heat is transferred across a surface (usually 

a tube wall) separating vapor and coolant. In this way the coolant is not 

contaminated with condensed VOC and may be directly reused. The type of 

coolant used depends on the degree of cooling needed for a particular 

situation” (EPA, 1979). Coolants in common use are water, chilled water, 

brine, and glycol. 

Scrubbers. Scrubbers or gas absorbers are used to remove one or more 

constituents from a gas stream by treatment with a liquid. “Absorption is 

important in the pharmaceutical industry because many VOCs and other 

chemicals being used are soluble in water or aqueous solutions. Therefore, 

water, caustic or acidic scrubbers can be applied to a variety of air pollution 

problems” (USEPA 1979). 

When using a scrubber as an air pollution control device, the solubility of the 

constituents in the gas stream in the absorbing liquid must be determined. 

“The rate of transfer of the soluble constituents from the gas to the liquid 

phase is determined by diffusional processes occurring on each side of the gas 

liquid interface” (Theodore and Bonicore, 1989). 

The main types of scrubbers used are packed tower, plate or tray tower, 

Sector Notebook Project 46 September 1997 
Pharmaceutical Industry Industrial Process Description 

venturi scrubber, and spray tower. Each type of scrubber is designed to 

provide intimate contact between the scrubbing liquid and the gaseous 

constituents so that mass transfer between phases is promoted. The degree 

of control achieved is dependent on the residence time of the gas and liquids, 

the interfacial area, and the physical and thermodynamic properties of the 

VOC species involved. 

Combustion or Incineration. Another method used for controlling VOC 

emissions is combustion or incineration. “In general, factors that influence 

the efficiency of combustion are: (1) temperature, (2) degree of mixing, (3) 

residence time in the combustion chamber, and (4) type of VOC combusted. 

Since more waste streams contain dilute VOC concentrations, they require 

that supplemental fuel maintain the necessary combustion temperatures” 

(EPA, 1979). Although combustion systems can achieve high removal 

efficiencies, these systems are typically more expensive to install, operate, and 

maintain, and have secondary emissions associated with their operation. 

Additionally, a scrubber may be required to control inorganic gases produced 

as by-products of combustion. 

“Equipment used to control waste gases by combustion can be divided into 

three categories: direct combustion or flaring (not often used by the 

pharmaceutical industry), thermal oxidation, and catalytic oxidation. A direct 

combustor or flare is a device in which air and all the combustible waste gases 

react at the burner. In contrast, in thermal oxidation, the combustible waste 

gases pass over or around a burner flame into a residence chamber where 

oxidation of the waste gases is completed. Catalytic oxidation is very similar 

to thermal oxidation. The main difference is that after passing through the 

flame area, the gases pass over a catalyst bed which promotes oxidation at a 

lower temperature than does thermal oxidation” (Theodore and Buonicore, 

1989). Efficiency rates of catalytic oxidizers in destroying VOCs can reach 

close to 98% (Buonicore and Davis, 1992). 

Adsorption. Adsorption is another method for removing VOCs from gas 

streams. This method filters out the volatiles by passing them through a 

packed column of activated carbon, silicates, aluminas, aluminosilicates, or 

any other surface which is porous and has a microcrystalline structure. As the 

gas stream passes through the column, the VOCs adsorb to the surface of the 

media. The adsorption material in the column eventually becomes saturated, 

and must be either regenerated or disposed. Most sorbents may be 

regenerated repeatedly by passing hot gas or steam through the bed. VOCs 

will desorb into the gas or steam. The high VOC concentration in the gas or 

steam can then be removed through condensation. Adsorption can be about 

98% efficient in removing VOCs in the waste gas stream (Crume and Portzer, 

1992). 

Sector Notebook Project 47 September 1997 
Pharmaceutical Industry Industrial Process Description 

III.B.3. Wastewater 

Pharmaceutical manufacturers use water for process operations, as well as for 

other non-process purposes. However, the use and discharge practices and 

the characteristics of the wastewater will vary depending on the operations 

conducted at the facility. Additionally, in some cases, water may be formed 

as part of a chemical reaction. 

Process water includes any water that, during manufacturing or processing, 

comes into direct contact with or results from the use of any raw material or 

production of an intermediate, finished product, byproduct, or waste. Process 

wastewater includes water that was used or formed during the reaction, water 

used to clean process equipment and floors, and pump seal water. Nonprocess wastewater includes noncontact cooling water (e.g., used in heat 

exchangers), noncontact ancillary water (e.g., boiler blowdown, bottle 

washing), sanitary wastewater, and wastewater from other sources (e.g., 

storm water runoff). 

Based on the responses from 244 facilities to a 1990 308 Questionnaire, EPA 

estimated the average daily wastewater generation by the pharmaceutical 

manufacturing industry to be 266 million gallons. Additionally, EPA learned 

that more than half of the responding facilities have implemented water 

conservation measures. Such measures include: careful monitoring of water 

use, installation of automatic monitoring and alarm systems or in-plant 

discharges, implementation of alternative production processes, reuse of noncontact water as process makeup water and treatment of contact cooling 

water to allow reuse. 

Pharmaceutical manufacturers generate process wastewater containing a 

variety of conventional parameters (e.g., BOD, TSS, and pH) and other 

chemical constituents. The top ten chemicals discharged by the 

pharmaceutical industry are provided in Table 11. Of these compounds, two 

are “priority pollutants”3

. The top four compounds are oxygenated organic 

solvents (e.g., methanol, ethanol, acetone, and isopropanol). 

3 Priority pollutants are the pollutants listed in 40 CFR part 403, Appendix A. 

Sector Notebook Project 48 September 1997 
Pharmaceutical Industry Industrial Process Description 

Table 11: Chemicals Discharged in Wastewater by the Pharmaceutical 

Manufacturing Industry 

Constituent Name 

Quantity 

Discharged (lbs/yr) 

Percent of Total 

Loading 

# of Facilities Reporting 

Constituents 

Methanol 15,388,273 28 82 

Ethanol 6,802,384 12 97 

Acetone 4,573,766 8.4 55 

Isopropanol 4,565,370 8.4 85 

Acetic acid 4,328,691 7.9 44 

Methylene chloride 3,590,640 6.6 47 

Formic acid 2,136,059 3.9 9 

Ammonium hydroxide 1,365,741 2.5 32 

N1N-Dimethylacetamide 1,046,333 1.9 7 

Toluene 783,364 1.4 43 

Source: adapted from Development Document for Proposed Effluent Guidelines and Standards for the Pharmaceutical 

Manufacturing Point Source Category, 1995 and US Environment Laws, 1994. 

Most process wastewater receives some treatment, either in-plant at the 

process unit prior to commingling with other facility wastewater or prior to 

discharge to a permitted outfall. Table 12 provides a trend analysis prepared 

by EPA of wastewater treatment technologies used by the pharmaceutical 

industry. EPA found that “since 1986, the use of neutralization, equalization, 

activated sludge, primary clarification, multimedia filtration, steam stripping, 

secondary clarification, granular activated carbon, and oxidation have all 

increased, while the use of aerated lagoons, chlorination, waste stabilization 

ponds, and trickling filters have decreased slightly” (USEPA 1995). 

More than half of the surveyed facilities provide pH adjustment or 

neutralization to adjust the pH prior to discharge. Additionally, because 

wastewater treatment can be sensitive to spikes of high flow or high 

constituent concentration, many treatment systems include equalization. 

Advanced biological treatment is used to treat biochemical oxygen demand 

(BOD5), chemical oxygen demand (COD), total suspended solids (TSS), as 

well as various organic constituents. Biological systems can be divided into 

two basic types: aerobic (treatment takes place in the presence of oxygen) and 

anaerobic (treatment takes places in the absence of oxygen). Very few 

pharmaceutical facilities (only two) use anaerobic treatment. However, more 

than 30 percent use aerobic systems such as activated sludge, aerated lagoons, 

trickling filter, and rotating biological contactors (RBC). 

Sector Notebook Project 49 September 1997 
Pharmaceutical Industry Industrial Process Description 

Table 12: Wastewater Treatment Technology Trends 

Treatment Technology 

Percentage of Facilities Using 

Technology Prior to 1986 

Percentage of Facilities Using 

Technology in 1989/1990 

Neutralization 26.0 44.3 

Equalization 20.1 28.6 

Activated sludge 16.9 20.5 

Settleable solids removal 13.3 NA 

Primary sedimentation 12.0 NA 

Aerated lagoon 7.5 4.9 

Primary clarification 3.9 9.8 

Chlorination 3.6 2.5 

Polishing ponds 3.2 NA 

Waste stabilization pond 2.9 2.5 

Trickling filter 2.9 2.0 

Multimedia filtration 2.3 6.1 

Stream stripping 1.9 5.7 

Evaporation 1.9 NA 

Secondary clarification 1.6 20.9 

Granular activated carbon 1.3 3.3 

Oxidation 1.0 2.0 

Dissolved air flotation 1.0 NA 

pH adjustment NA 50.0 

Phase separation NA 12.3 

Note: Total percentage is not 100 because facilities may use multiple treatment technologies. 

NA - Not available. 

Source: adapted from Development Document for Proposed Effluent Guidelines and Standards for the 

Pharmaceutical Manufacturing Point Source Category, 1995 and US Environment Laws, 1994. 

Although the pharmaceutical industry has routinely utilized recovery systems 

to recover and reuse solvents, only four facilities were identified by EPA as 

using stream stripping to remove gases and/or organic chemicals from 

wastewater streams. Sixty one facilities were identified that use distillation 

either to recover a specific solvent from a process stream or to treat one or 

more process waste streams. However, according to PhRMA, it is likely that 

Sector Notebook Project 50 September 1997 
Pharmaceutical Industry Industrial Process Description 

these facilities use this method to recover a specific solvent from a specific 

process stream rather than to treat wastewater from numerous operations 

since the treatment technology is not applicable to the wide range of waste 

characteristics common in the pharmaceutical industry. 

III.B.4. Solid Wastes 

Both nonhazardous and hazardous wastes are generated during all three 

stages of pharmaceutical manufacturing. These wastes can include off-spec 

or obsolete raw materials or products, spent solvents, reaction residues, used 

filter media, still bottoms, used chemical reagents, dusts from filtration or air 

pollution control equipment, raw material packaging wastes, laboratory 

wastes, spills, as well as wastes generated during packaging of the formulated 

product. 

Filter cakes and spent raw materials (plants, roots, animal tissues etc.) from 

fermentation and natural product extraction are two of the largest sources of 

residual wastes in the pharmaceutical industry. Other wastes include reaction 

residues and filtrates from chemical synthesis processes. These wastes may be 

stripped of any solvents which remain in them, and then disposed as either 

hazardous or nonhazardous wastes. Typically, solid wastes are shipped offsite for disposal or incineration. 

A number of practices are implemented by the industry to reduce waste 

generation and material losses. Typical practices include process 

optimization, production scheduling, materials tracking and inventory control, 

special material handling and storage procedures, preventive maintenance 

programs, and waste stream segregation. 

Sector Notebook Project 51 September 1997 
Pharmaceutical Industry Industrial Process Description 

III.C. Management of TRI Chemicals in the Production Process 

The Pollution Prevention Act of 1990 (PPA) requires facilities to report 

information about the management of Toxics Release Inventory (TRI) 

chemicals in waste and efforts made to eliminate or reduce those quantities. 

These data have been collected annually in Section 8 of the TRI reporting 

Form R beginning with the 1991 reporting year. The data summarized below 

cover the years 1994 through 1997 and are meant to provide a basic 

understanding of the quantities of waste handled by the industry, the methods 

typically used to manage this waste, and recent trends in these methods. TRI 

waste management data can be used to assess trends in source reduction 

within individual industries and facilities, and for specific TRI chemicals. This 

information could then be used as a tool in identifying opportunities for 

pollution prevention compliance assistance activities. 

While the quantities reported for 1994 and 1995 are estimates of quantities 

already managed, the quantities reported for 1996 and 1997 are projections 

only. The PPA requires these projections to encourage facilities to consider 

future waste generation and source reduction of those quantities as well as 

movement up the waste management hierarchy. Future-year estimates are not 

commitments that facilities reporting under TRI are required to meet. 

Table 13 shows that the TRI reporting pharmaceutical facilities managed 

about 382 million pounds of production related wastes (total quantity of TRI 

chemicals in the waste from routine production operations in Column B) in 

1995. From the yearly data presented in Column B, the total quantity of 

production related wastes increased between 1994 and 1995. This is probably 

in part because the number of chemicals on the TRI list almost doubled 

between those years. The quantity of wastes generated was also projected to 

increase in 1996 and 1997. The effect of production increases on the amount 

of wastes generated has not been evaluated. 

Values in Column C are intended to reveal the percentage of TRI chemicals 

that are either transferred off-site or released to the environment. Column C 

is calculated by dividing the total TRI transfers and releases (reported in 

Sections 5 and 6 of the TRI Form R) by the total quantity of productionrelated waste (reported in Section 8 of Form R). Column C shows a decrease 

in the portion either transferred off-site or released to the environment from 

50 percent in 1994 to 46 percent in 1995. The waste released to the 

environment or transferred off-site for disposal decreased slightly in 1995 to 

about 10 percent of total wastes generated, as shown in Column J. This 

decreasing trend is projected to continue through 1997. 

Sector Notebook Project 52 September 1997 
Pharmaceutical Industry Industrial Process Description 

The overall proportions of wastes managed off-site (Columns D, E, and F) 

and onsite (Columns G, H, and I) change very little from year to year. About 

50 percent of the industry’s TRI wastes were managed on-site through 

recycling, energy recovery, or treatment as shown in columns D, E, and F, 

respectively. Almost all of these on-site managed wastes were recycled or 

treated on-site. Only about two percent were used in energyrecovery. Waste 

that is transferred off-site can be divided into portions that are recycled offsite, recovered for energy off-site, or treated off-site as shown in columns G, 

H, and I, respectively. The remaining portion of the production related 

wastes, 10 percent, shown in column J, is either released to the environment 

through direct discharges to air, land, water, and underground injection, or it 

is disposed off-site. 

Table 13: Source Reduction and Recycling Activity for the 

Pharmaceuticals Industry as Reported within TRI 

A B C 

On-Site Off-Site 

J 

Year 

Quantity of 

ProductionRelated 

Waste 

(106

 lbs.)

a 

% Released 

and 

Transferred b 

% 

Released 

and 

Disposedc 

Off-site 

D E F G H I 

% 

Recycled 

% Energy 

Recovery % Treated 

% 

Recycled 

% Energy 

Recovery % Treated 

1994 324 50% 13.9% 2.0% 33.5% 5.3% 21.7% 13.3% 10.8% 

1995 382 46% 16.8% 1.6% 34.3% 4.7% 21.6% 11.7% 9.7% 

1996 404 NA 18.7% 1.6% 37.1% 5.1% 18.8% 10.4% 8.4% 

1997 414 NA 20.4% 1.6% 35.9% 5.5% 18.4% 9.9% 8.3% 

Source: Toxics Release Inventory Database, 1995. a Within this industry sector, non-production related waste < 1% of production related wastes for 1995.

b Total TRI transfers and releases as reported in Section 5 and 6 of Form R as a percentage of production related wastes.

c Percentage of production related waste released to the environment and transferred off-site for disposal.

Sector Notebook Project 53 September 1997 
Pharmaceutical Industry Industrial Process Description 

Sector Notebook Project 54 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

IV. CHEMICAL RELEASE AND TRANSFER PROFILE 

This section is designed to provide background information on the pollutant 

releases that are reported by this industry. The best source of comparative 

pollutant release information is the Toxic Release Inventory (TRI). Pursuant 

to theEmergencyPlanning and Community Right-to-Know Act, TRI includes 

self-reported facility release and transfer data for over 600 toxic chemicals. 

Facilities within SIC Codes 20 through 39 (manufacturing industries) that 

have more than 10 employees, and that are above weight-based reporting 

thresholds are required to report TRI on-site releases and off-site transfers. 

The information presented within the sector notebooks is derived from the 

most recently available (1995) TRI reporting year (which includes over 600 

chemicals), and focuses primarily on the on-site releases reported by each 

sector. Because TRI requires consistent reporting regardless of sector, it is 

an excellent tool for drawing comparisons across industries. TRI data provide 

the type, amount and media receptor of each chemical released or transferred. 

Although this sector notebook does not present historical information 

regarding TRI chemical releases over time, please note that in general, toxic 

chemical releases have been declining. In fact, according to the 1995 Toxic 

Release Inventory Public Data Release, reported onsite releases of toxic 

chemicals to the environment decreased by 5 percent (85.4 million pounds) 

between 1994 and 1995 (not including chemicals added and removed from the 

TRI chemical list during this period). Reported releases dropped by 46 

percent between 1988 and 1995. Reported transfers of TRI chemicals to offsite locations increased by 0.4 percent (11.6 million pounds) between 1994 

and 1995. More detailed information can be obtained from EPA's annual 

Toxics Release Inventory Public Data Release book (which is available 

through the EPCRA Hotline at 800-535-0202), or directly from the Toxic 

Release Inventory System database (for user support call 202-260-1531). 

Wherever possible, the sector notebooks present TRI data as the primary 

indicator of chemical release within each industrial category. TRI data 

provide the type, amount and media receptor of each chemical released or 

transferred. When other sources of pollutant release data have been obtained, 

these data have been included to augment the TRI information. 

TRI Data Limitations 

Certain limitations exist regarding TRI data. Release and transfer reporting 

are limited to the approximately 600 chemicals on the TRI list. Therefore, a 

large portion of the emissions from industrial facilities are not captured by 

TRI. Within some sectors, (e.g. dry cleaning, printing and transportation 

equipment cleaning) the majority of facilities are not subject to TRI reporting 

because they are not considered manufacturing industries, or because they are 

below TRI reporting thresholds. For these sectors, release information from 

Sector Notebook Project 55 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

other sources has been included. In addition, many facilities report more than 

one SIC code reflecting the multiple operations carried out onsite. Therefore, 

reported releases and transfers may or may not all be associated with the 

industrial operations described in this notebook. 

The reader should also be aware that TRI "pounds released" data presented 

within the notebooks is not equivalent to a "risk" ranking for each industry. 

Weighting each pound of release equally does not factor in the relative 

toxicity of each chemical that is released. The Agency is in the process of 

developing an approach to assign toxicological weights to each chemical 

released so that one can differentiate between pollutants with significant 

differences in toxicity. As a preliminary indicator of the environmental impact 

of the industry's most commonly released chemicals, the notebook briefly 

summarizes the toxicological properties of the top five chemicals (by weight) 

reported by each industry. 

Definitions Associated with Section IV Data Tables 

General Definitions 

SIC Code -- the Standard Industrial Classification (SIC) is a statistical 

classification standard used for all establishment-based Federal economic 

statistics. The SIC codes facilitate comparisons between facility and industry 

data. 

TRI Facilities -- are manufacturing facilities that have 10 or more full-time 

employees and are above established chemical throughput thresholds. 

Manufacturing facilities are defined as facilities in Standard Industrial 

Classification primary codes 20-39. Facilities must submit estimates for all 

chemicals that are on the TRI list and are above throughput thresholds. 

Data Table Column Heading Definitions 

The following definitions are based upon standard definitions developed by 

EPA’s Toxic Release Inventory Program. The categories below represent the 

possible pollutant destinations that can be reported. 

RELEASES -- are an on-site discharge of a toxic chemical to the 

environment. This includes emissions to the air, discharges to bodies of 

water, releases at the facility to land, as well as contained disposal into 

underground injection wells. 

Releases to Air (Point and Fugitive Air Emissions) -- Include all air 

emissions from industry activity. Point emissions occur through confined air 

streams as found in stacks, vents, ducts, or pipes. Fugitive emissions include 

Sector Notebook Project 56 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

equipment leaks, evaporative losses from surface impoundments and spills, 

and releases from building ventilation systems. 

Releases to Water (Surface Water Discharges) -- encompass any releases 

going directly to streams, rivers, lakes, oceans, or other bodies of water. 

Releases due to runoff, including storm water runoff, are also reportable to 

TRI. 

Releases to Land -- occur within the boundaries of the reporting facility. 

Releases to land include disposal of toxic chemicals in landfills, land 

treatment/application farming,surface impoundments, and other land disposal 

methods (such as spills, leaks, or waste piles). 

Underground Injection -- is a contained release of a fluid into a subsurface 

well for the purpose of waste disposal. Wastes containing TRI chemicals are 

injected into either Class I wells or Class V wells. Class I wells are used to 

inject liquid hazardous wastes or dispose of industrial and municipal 

wastewaters beneath the lowermost underground source of drinking water. 

Class V wells are generally used to inject non-hazardous fluid into or above 

an underground source of drinking water. TRI reporting does not currently 

distinguish between these two types of wells, although there are important 

differences in environmental impact between these two methods of injection. 

TRANSFERS -- is a transfer of toxic chemicals in wastes to a facility that is 

geographically or physically separate from the facility reporting under TRI. 

Chemicals reported to TRI as transferred are sent to off-site facilities for the 

purpose of recycling, energy recovery, treatment, or disposal. The quantities 

reported represent a movement of the chemical away from the reporting 

facility. Except for off-site transfers for disposal, the reported quantities do 

not necessarily represent entry of the chemical into the environment. 

Transfers to POTWs -- are wastewater transferred through pipes or sewers 

to a publicly owned treatments works (POTW). Treatment or removal of a 

chemical from the wastewater depend on the nature of the chemical, as well 

as the treatment methods present at the POTW. Not all TRI chemicals can 

be treated or removed by a POTW. Some chemicals, such as metals, may be 

removed, but are not destroyed and may be disposed of in landfills or 

discharged to receiving waters. 

Transfers to Recycling -- are sent off-site for the purposes of regenerating 

or recovery by a variety of recycling methods, including solvent recovery, 

metals recovery, and acid regeneration. Once these chemicals have been 

recycled, they may be returned to the originating facility or sold commercially. 

Sector Notebook Project 57 September 1997 
--

Pharmaceutical Industry Releases and Transfers Profile 

Transfers to Energy Recovery -- are wastes combusted off-site in industrial 

furnaces for energy recovery. Treatment of a chemical by incineration is not 

considered to be energy recovery. 

Transfers to Treatment -- are wastes moved off-site to be treated through 

a variety of methods, including neutralization, incineration, biological 

destruction, or physical separation. In some cases, the chemicals are not 

destroyed but prepared for further waste management. 

Transfers to Disposal are wastes taken to another facility for disposal 

generally as a release to land or as an injection underground. 

Sector Notebook Project 58 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

IV.A. EPA Toxic Release Inventory for the Pharmaceutical Industry 

This section summarizes TRI data of pharmaceutical facilities reporting SIC 

codes 2833 and 2834 as the primary SIC code for the facility. Of the 916 

pharmaceutical establishments reported by the 1992 Census of 

Manufacturers, 200 reported to TRI in 1995. 

According to 1995 TRI data, the reporting facilities released (discharged to 

the air, water, or land without treatment) and transferred (shipped off-site) a 

total of 177 million pounds of pollutants, made up of 104 different chemicals. 

This represents about 3 percent of the 5.7 billion pounds of TRI chemicals 

released and transferred by all manufacturers that year. In comparison, the 

chemical industry (SIC 28) as a whole produced 1.7 billion pounds that year, 

accounting for about 30 percent of all releases and transfers. 

Of the pharmaceutical industry’s TRI releases, 57 percent go to the air, 25 

percent to underground injection, 17 percent to surface waters, and 1 percent 

to the land. This release profile differs from other TRI industries which 

average approximately 59 percent to air, 30 percent to water, and 10 percent 

to land. Table 14 lists the pharmaceutical industry’s TRI reported chemical 

releases. 

Of the pharmaceutical industry’s transfers, about 55 percent are transferred 

for energy recovery off-site, 19 percent for treatment off-site, 13 percent are 

transferred to POTWs, 12 percent for recycling off-site, and about 1 percent 

for disposal off-site. Table 15 liststhe pharmaceutical industry's TRI reported 

toxic chemical transfers. 

Of the top ten most frequently reported toxic chemicals on the TRI list, the 

prevalence of volatile chemicals explains the air intensive toxic chemical 

loading of the pharmaceutical industry. Seven of the ten most commonly 

reported toxic chemicals are highly volatile. Six of the ten are volatile organic 

compounds (methanol, dichloromethane, toluene, ethylene glycol, N,NDimethylformamide, and acetonitrile). These are primarily solvents used to 

extract active ingredients and for cleaning equipment. The primary means of 

release to the environment are from fugitive air and point air sources. Large 

quantities of methanol, N,N-Dimethylformamide, and acetonitrile, however, 

are released via underground injection. Other commonly reported chemicals 

released and transferred are acids (hydrochloric, sulfuric, and phosphoric) 

which can be used for pH control or as catalysts. 

Sector Notebook Project 59 September 1997 
Sector Notebook Project 60 September 1997 

T

able 14: 1995 Rel

eases fo

r P

har

m

aceutical F

acilities (

SIC 2833 & 2834) in T

RI, 

b

y Nu

m

ber of F

acilities Rep

o

rting 

(R

ele

ases r

eporte

d in pounds/ye

a

r) 

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Sect

or Notebook Project 61 September 1997 

Table 14, cont.: 1995 Releases for Pharmaceutical Facilities (SICs 2833 & 2934), in TRI 

by Number of Facilities Reporting 

(Releases reported in pounds/year) 

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Sect

or Notebook Project 62 September 1997 

Table 14, cont.: 1995 Releases for Pharmaceutical Facilities (SICs 2833 & 2934) in TRI, 

by Number of Facilities Reporting 

(Releases reported in pounds/year) 

CHEMICAL NAME 

# REPORTING 

CHEMICAL 

FUGITIVE 

AIR 

POINT 

AIR 

WATER 

DISCHARGES 

UNDERGROUND 

INJECTION 

LAND 

DISPOSAL 

TOTA

RELEASE

BENZOYL CHLORIDE 2 0 2 0 0 0 

BENZYL CHLORIDE 2 5 5 0 0 0 1EPICHLOROHYDRIN 2 290 50 0 0 0 34

M-XYLENE 2 1,565 571 250 0 0 2,38PHENOL 2 255 255 0 0 0 51

DIETHANOLAMINE 2 500 1,000 5 0 0 1,50

1,4-DIOXANE 2 270 260 0 0 0 53

DIMETHYLAMINE 2 23,500 15,250 250 0 250 39,25

TETRACHLOROETHYLENE 2 2,239 14,000 0 0 0 16,23

DIAZINON 2 5 278 5 0 0 28ZINC (FUME OR DUST) 2 0 2 0 0 0 

TITANIUM TETRACHLORIDE 2 5 10 0 0 0 1

HYDROGEN FLUORIDE 2 250 8,350 0 0 0 8,60

ABAMECTIN 2 0 0 16 0 0 1

ANTIMONY COMPOUNDS 1 5 5 0 0 0 1

CHROMIUM COMPOUNDS 1 0 0 0 43,000 0 43,00COBALT COMPOUNDS 1 0 0 0 0 0 SELENIUM COMPOUNDS 1 0 3 0 0 0 

FAMPHUR 1 0 0 0 0 0 

CARBON TETRACHLORIDE 1 60 400 67 0 0 52

PHENYTOIN 1 0 0 0 0 0 

DICHLORVOS 1 5 250 5 0 0 26

1,1,1-TRICHLOROETHANE 1 76,500 52,500 0 0 0 129,00

BROMOMETHANE 1 50 21 0 0 0 7

CHLOROETHANE 1 163 0 0 0 0 16

CARBON DISULFIDE 1 2,450 21,000 0 0 0 23,45

PHOSGENE 1 240 5 0 5 0 25

DIMETHYL SULFATE 1 0 8 0 0 0 

ISOBUTYRALDEHYDE 1 11 25 0 0 0 3

SEC-BUTYL ALCOHOL 1 250 71,799 0 0 0 72,04

METHYL CHLOROCARBONATE 1 250 0 5 0 5 26

QUINOLINE 1 5 0 5 0 5 1
Sect

or Notebook Project 63 September 1997 

Table 14, cont.: 1995 Releases for Pharmaceutical Facilities (SICs 2833 & 2934) in TRI, 

by Number of Facilities Reporting 

(Releases reported in pounds/year) 

CHEMICAL NAME 

# REPORTING 

CHEMICAL 

FUGITIVE 

AIR 

POINT 

AIR 

WATER 

DISCHARGES 

UNDERGROUND 

INJECTION 

LAND 

DISPOSAL 

TOTA

RELEASE

BIPHENYL 1 5 0 0 0 0 

O-XYLENE 1 2,400 54 0 0 0 2,45

1,2-DICHLOROBENZENE 1 244 2,490 0 0 0 2,73

1,2,4-TRIMETHYLBENZENE 1 250 250 5 0 0 50

CUMENE 1 250 250 5 0 0 50ACETOPHENONE 1 5 5 0 0 0 1

NITROBENZENE 1 3,891 321 0 0 0 4,21

ALLYL CHLORIDE 1 321 27 0 0 0 34CHLOROMETHYL METHYL ETHER 1 0 0 0 0 0 

MALEIC ANHYDRIDE 1 5 5 0 5 0 1

CHLOROBENZENE 1 12 11 0 0 0 2

CYCLOHEXANOL 1 93 133 0 0 0 222-ETHOXYETHANOL 1 29 91 0 0 0 12

PROPYLENE 1 5 5 0 0 0 1

N,N-DIMETHYLANILINE 1 5 35 0 0 0 4

MALATHION 1 0 2 0 0 0 

THIABENDAZOLE 1 175 3,504 0 0 0 3,67

ETHYL CHLOROFORMATE 1 250 250 5 0 5 51

1,3-DICHLOROBENZENE 1 1,200 80 0 0 0 1,28

LITHIUM CARBONATE 1 0 0 0 0 0 

N-METHYL-2-PYRROLIDONE 1 7 0 0 0 0 

TETRACHLORVINPHOS 1 5 5 5 0 0 1

TRIFLURALIN 1 6,900 250 0 0 0 7,15

BENFLURALIN 1 750 250 0 0 0 1,00

PROMETRYN 1 0 0 0 0 0 

NICKEL 1 0 0 250 0 0 25THIOPHANATE-METHYL 1 0 187 0 0 0 18SODIUM AZIDE 1 0 0 0 0 0 

VINCLOZOLIN 1 0 0 0 0 0 

PERMETHRIN 1 0 0 0 0 0 

PROPICONAZOLE 1 0 0 0 0 0 

____ _________ _________ ________ ________ _______ _______

200 6,664,939 10,500,358 4,936,137 7,438,370 375,274 29,915,07
Sect

or Notebook Project 64 September 1997 

Table 15: 1995 Transfers for Pharmaceutical Facilities (SICs 2833 & 2834) in TRI, 

by Number and Facilities Reporting 

(Transfers reported in pounds/year) 

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Sect

or Notebook Project 65 September 1997 

Table 15, cont.: 1995 Transfers for Pharmaceutical Facilities (SICs 2833 & 2834) in TRI, 

by Number and Facilities Reporting 

(Transfers reported in pounds/year) 

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Sect

or Notebook Project 66 September 1997 

Table 15, cont.: 1995 Transfers for Pharmaceutical Facilities (SICs 2833 & 2834) in TRI, 

by Number and Facilities Reporting 

(Transfers reported in pounds/year) 

CHEMICAL NAME 

# 

REPORTING 

CHEMICAL 

POTW 

TRANSFERS 

DISPOSAL 

TRANSFERS 

RECYCLING 

TRANSFERS 

TREATMENT 

TRANSFERS 

ENERGY 

RECOVERY 

TRANSFERS 

TOTAL 

TRANSFERS 

BENZYL CHLORIDE 2 5 . . 10 . 15 EPICHLOROHYDRIN 2 0 0 . . . 0 M-XYLENE 2 20 . . 87,148 78,059 165,227 

PHENOL 2 250 . . 548 . 798 DIETHANOLAMINE 2 1,500 . . . 47,916 49,416 

1,4-DIOXANE 2 4,170 2 . 300 8,960 13,432 DIMETHYLAMINE 2 0 38,000 . 2,100 . 40,100 

TETRACHLOROETHYLENE 2 0 . 510 . 49,005 49,515 

DIAZINON 2 0 1,060 . 1,609 . 2,669 ZINC (FUME OR DUST) 2 0 1,223 . . . 1,223 TITANIUM TETRACHLORIDE 2 0 . . . . 0 

HYDROGEN FLUORIDE 2 0 . . . . 0 ABAMECTIN 2 0 . . 5,582 . 5,582 

ANTIMONY COMPOUNDS 1 0 53,200 . . . 53,200 

CHROMIUM COMPOUNDS 1 250 260 . 5 . 515 

COBALT COMPOUNDS 1 2,920 . . . . 2,920 

SELENIUM COMPOUNDS 1 260 . . 13,641 . 13,901 

FAMPHUR 1 0 . . 1,540 . 1,540 CARBON TETRACHLORIDE 1 40 . . 45,782 . 45,822 

PHENYTOIN 1 0 19,300 . . . 19,300 

DICHLORVOS 1 0 250 . 250 . 500 1,1,1-TRICHLOROETHANE 1 0 . 106,250 . . 106,250 

BROMOMETHANE 1 0 . . . . 0 CHLOROETHANE 1 0 . . 2,489 . 2,489 CARBON DISULFIDE 1 1,120 . . 18 11,390 12,528 

PHOSGENE 1 0 . . . . 0 

DIMETHYL SULFATE 1 0 . . . . 0 ISOBUTYRALDEHYDE 1 0 . 8,647 640 . 9,287 

SEC-BUTYL ALCOHOL 1 0 . . . . 0 

METHYL CHLOROCARBONATE 1 0 . . . . 0 

QUINOLINE 1 0 . . 250 . 250 
Sect

or Notebook Project 67 September 1997 

Table 15, cont.: 1995 Transfers for Pharmaceutical Facilities (SICs 2833 & 2834) in TRI, 

by Number and Facilities Reporting 

(Transfers reported in pounds/year) 

CHEMICAL NAME 

# 

REPORTING 

CHEMICAL 

POTW 

TRANSFERS 

DISPOSAL 

TRANSFERS 

RECYCLING 

TRANSFERS 

TREATMENT 

TRANSFERS 

ENERGY 

RECOVERY 

TRANSFERS 

TOTAL 

TRANSFERS 

BIPHENYL 1 0 . . . . 0 

O-XYLENE 1 0 . . 100,000 61,800 161,800 1,2-DICHLOROBENZENE 1 6,480 . . 14,000 91,891 112,371 1,2,4-TRIMETHYLBENZENE 1 4,800 . . . . 4,800 

CUMENE 1 1,167 . . . . 1,167 ACETOPHENONE 1 0 . . . . 0 

NITROBENZENE 1 5 . . 5,914 . 5,919 ALLYL CHLORIDE 1 0 . . . . 0 

CHLOROMETHYL METHYL ETHER 1 0 . . . . 0 

MALEIC ANHYDRIDE 1 0 . . . . 0 

CHLOROBENZENE 1 0 . . . 179,228 179,228 

CYCLOHEXANOL 1 0 . . . . 0 2-ETHOXYETHANOL 1 4 . . 25,004 . 25,008 

PROPYLENE 1 0 . . . . 0 

N,N-DIMETHYLANILINE 1 10,000 . . . 328,000 338,000 MALATHION 1 0 26 . 273 . 299 THIABENDAZOLE 1 271 . . . 2,160 2,431 ETHYL CHLOROFORMATE 1 0 . . . . 0 1,3-DICHLOROBENZENE 1 1,400 . . . . 1,400 LITHIUM CARBONATE 1 0 . . 750 . 750 N-METHYL-2-PYRROLIDONE 1 249,000 . . . . 249,000 

TETRACHLORVINPHOS 1 0 4,200 . . . 4,200 TRIFLURALIN 1 0 18,000 . . . 18,000 

BENFLURALIN 1 0 14,000 . . . 14,000 

PROMETRYN 1 0 . . 203 . 203 NICKEL 1 0 18 400,000 . . 400,018 

THIOPHANATE-METHYL 1 0 . . 2,677 . 2,677 SODIUM AZIDE 1 0 . . . . 0 

VINCLOZOLIN 1 0 . . 1,030 . 1,030 PERMETHRIN 1 0 . . . . 0 

PROPICONAZOLE 1 0 . . 1,025 . 1,025 

____ _________ _________ _________ _________ _________ __________ 

200 19,119,179 1,394,801 18,168,783 27,330,633 81,213,752 147,239,047 
1

2

3

4

5

6

7

8

9

10

Pharmaceutical Industry Releases and Transfers Profile 

The TRI database contains a detailed compilation of self-reported, facilityspecific chemical releases. The top reporting facilities for the pharmaceutical 

industry are listed below in Tables 16. Facilities that have reported only the 

SIC codes covered under this notebook as a primary SIC code appear on the 

first list. Table 17 contains additional facilities that have reported the SIC 

code covered within this report, and one or more SIC codes that are not 

within the scope of this notebook. Therefore, the second list includes facilities 

that conduct multiple operations -- some that are under the scope of this 

notebook, and some that are not. Currently, the facility-level data do not 

allow pollutant releases to be broken apart by industrial process. 

Table 16: Top 10 TRI Releasing Pharmaceutical Manufacturing Facilitiesa 

Rank Facility 

Total TRI Releases in 

Pounds 

Pharmacia & Upjohn Co., Portage, Michigan 8,307,190 

Warner-Lambert Co., Holland, Michigan 2,594,111 

Eli Lilly & Co. - Tippecanoe Labs, Shadeland, Indiana 2,504,810 

Upjohn Mfg., Co., Barceloneta, Puerto Rico 2,001,450 

Pfizer Inc., Groton, Connecticut. 1,761,385 

Eli Lilly & Co - Clinton Laboratories, Clinton, Indiana 1,282,605 

Abbott Chemicals, Inc., Barceloneta, Puerto Rico 1,193,707 

Pfizer Inc., Southport, North Carolina 1,164,350 

Schering-Plough Products, Inc., Las Piedras, Puerto Rico 756,089 

Biokyowa Inc., Cape Girardeau, Missouri 669,869 

Source: US EPA 1995 Toxics Release Inventory Database. 

a Being included on this list does not mean that the release is associated with non-compliance with environmental 

laws. 

Sector Notebook Project 68 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

Table 17: Top 10 TRI Releasing Facilities Reporting Pharmaceutical Manufacturing SIC 

Codes to TRIa 

Rank 

SIC Codes 

Reported in TRI Facility 

Total TRI Releases in 

Pounds 

1 2834 Pharmacia & Upjohn Co., Portage, Michigan 8,307,190 

2 2819, 2834, 2842, 

2865, 2869, 2873, 

2879 

Monsanto Co., Luling, Louisiana 5,698,031 

3 2834 Warner-Lambert Co., Holland, Michigan 2,594,111 

4 2834 Eli Lilly & Co. - Tippecanoe Labs, Shadeland, 

Indiana 

2,504,810 

5 2834 Upjohn Mfg., Co., Barceloneta, Puerto Rico 2,001,450 

6 2833 Pfizer Inc., Groton, Connecticut. 1,761,385 

7 2834, 2869, 2969 Ethyl Corp., Orangeburg, South Carolina 1,284,456 

8 2833, 2834 Eli Lilly & Co - Clinton Laboratories, Clinton, 

Indiana 

1,282,605 

9 2819, 2821, 2824, 

2834, 2865, 2869, 

2879, 2979 

Dow Chemical Co., Midland, Michigan 1,228,629 

10 2833, 2834 Abbott Chemicals, Inc., Barceloneta, Puerto Rico 1,193,707 

Source: US EPA Toxics Release Inventory Database, 1995. 

a Being included on this list does not mean that the release is associated with non-compliance with environmental 

laws. 

Sector Notebook Project 69 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

IV.B. Summary of Selected Chemicals Released 

The following is a synopsis of current scientific toxicity and fate information 

for the top chemicals (by weight) that facilities within both SIC 2833 and 

2834 self-reported as released to the environment based upon 1994 TRI data. 

Because this section is based upon self-reported release data, it does not 

attempt to provide information on management practices employed by the 

sector to reduce the release of these chemicals. Information regarding 

pollutant release reductions over time may be available from EPA’s TRI and 

33/50 programs, or directly from the industrial trade associations that are 

listed in Section VIII of this document. Since these descriptions are cursory, 

please consult the sources referenced below for a more detailed description 

of both the chemicals described in this section, and the chemicals that appear 

on the full list of TRI chemicals appearing in Section IV.A. 

The brief descriptions provided below were taken from the Hazardous 

Substances Data Bank (HSDB) and the Integrated Risk Information System 

(IRIS). The discussions of toxicity describe the range of possible adverse 

health effects that have been found to be associated with exposure to these 

chemicals. These adverse effects may or may not occur at the levels released 

to the environment. Individuals interested in a more detailed picture of the 

chemical concentrations associated with these adverse effects should consult 

a toxicologist or the toxicity literature for the chemical to obtain more 

information. The effects listed below must be taken in context of these 

exposure assumptions that are more fully explained within the full chemical 

profiles in HSDB. For more information on TOXNETa , contact the 

TOXNET help line at 1-800-231-3766. 

Methanol (CAS: 67-56-1) 

Toxicity. Methanol is readily absorbed by the gastrointestinal tract and the 

respiratory tract, and is toxic to humans in moderate to high doses. In the 

body, methanol is converted into formaldehyde and formic acid. Methanol is 

excreted as formic acid. Observed toxic effects at high dose levels generally 

a TOXNET is a computer system run by the National Library of Medicine that includes a number of toxicological 

databases managed by EPA, National Cancer Institute, and the National Institute for Occupational Safety and 

Health. For more information on TOXNET, contact the TOXNET help line at 800-231-3766. Databases included 

in TOXNET are: CCRIS (Chemical Carcinogenesis Research Information System), DART (Developmental and 

Reproductive Toxicity Database), DBIR (Directory of Biotechnology Information Resources), EMICBACK 

(Environmental Mutagen Information Center Backfile), GENE-TOX (Genetic Toxicology), HSDB (Hazardous 

Substances Data Bank), IRIS (Integrated Risk Information System), RTECS (Registry of Toxic Effects of Chemical 

Substances), and TRI (Toxic Chemical Release Inventory). HSDB contains chemical-specific information on 

manufacturing and use, chemical and physical properties, safety and handling, toxicity and biomedical effects, 

pharmacology, environmental fate and exposure potential, exposure standards and regulations, monitoring and 

analysis methods, and additional references. 

Sector Notebook Project 70 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

include central nervous system damage and blindness. Long-term exposure 

to high levels of methanol via inhalation cause liver and blood damage in 

animals. 

Ecologically, methanol is expected to have low toxicity to aquatic organisms. 

Concentrations lethal to half the organisms of a test population are expected 

to exceed one mg methanol per liter water. Methanol is not likely to persist 

in water or to bioaccumulate in aquatic organisms. 

Carcinogenicity. There is currently no evidence to suggest that methanol is 

carcinogenic. 

Environmental Fate. Liquid methanol is likely to evaporate when left 

exposed. Methanol reacts in air to produce formaldehyde which contributes 

to the formation of air pollutants. In the atmosphere it can react with other 

atmospheric chemicals or be washed out by rain. Methanol is readily 

degraded by microorganisms in soils and surface waters. 

Physical Properties. Methanol is a colorless, highly flammable liquid. 

Methanol is miscible in water and has a boiling point of 147 degrees F. 

Methylene Chloride (Dichloromethane) (CAS: 75-09-2) 

Toxicity. Short-term exposure to methylene chloride (MC) is associated with 

central nervous system effects, including headaches, giddiness, stupor, 

irritability, and numbness, and tingling in the limbs. More severe neurological 

effects are reported from longer-term exposure, apparently due to increased 

carbon monoxide in the blood from the break down of MC. Contact with MC 

causes irritation of the eyes, skin, and respiratory tract. 

Occupational exposure to MC has also been linked to increased incidence of 

spontaneous abortions in women. Acute damages to the eyes and upper 

respiratory tract, unconsciousness, and death were reported in workers 

exposed to high concentrations of MC. Phosgene (a degradation product of 

MC) poisoning has been reported to occur in several cases where MC was 

used in the presence of an open fire. 

Populations at special risk from exposure to MC include obese people (due 

to accumulation of MC in fat), and people with impaired cardiovascular 

systems. 

Carcinogenity. MC is a probable human carcinogen via both inhalation and 

oral exposure, based on limited evidence in humans, and sufficient evidence 

in animals. 

Sector Notebook Project 71 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

Environmental Fate. When spilled on land, MC is rapidly lost from the soil 

surface through volatilization. The remainder leaches through the subsoil into 

the groundwater. 

Biodegradation is possible in natural waters but will probably be very slow 

compared with evaporation. Little is known about bioconcentration in aquatic 

organisms or adsorption to sediments but these are not likely to be significant 

processes. Hydrolysis is not an important process under normal 

environmental conditions. 

MC released into the atmosphere degrades via contact with other gases with 

a half-life of several months. A small fraction of the chemical diffuses to the 

stratosphere where it rapidly degrades through exposure to ultraviolet 

radiation and contact with chlorine ions. Being a moderately soluble 

chemical, MC is expected to partially return to earth in rain. 

Physical Properties. Methylene chloride is a colorless liquid. It is soluble to 

2 percent in water and has a boiling point of 104 degrees F. 

Ammoniaa (CAS: 7664-41-7) 

Toxicity. Anhydrous ammonia is irritating to the skin, eyes, nose, throat, and 

upper respiratory system. 

Ecologically, ammonia is a source of nitrogen(an essential element for aquatic 

plant growth), and may therefore contribute to eutrophication of standing or 

slow-moving surface water, particularly in nitrogen-limited waters such asthe 

Chesapeake Bay. In addition, aqueous ammonia is moderately toxic to aquatic 

organisms. 

Carcinogenicity. There is currently no evidence to suggest that ammonia is 

carcinogenic. 

Environmental Fate. Ammonia combines with sulfate ions in the 

atmosphere and is washed out by rainfall, resulting in rapid return of ammonia 

to the soil and surface waters. 

Ammonia is a central compound in the environmental cycling of nitrogen. 

Ammonia in lakes, rivers, and streams is converted to nitrate. 

a The reporting standards for ammonia were changed in 1995. Ammonium sulfate is deleted from the list and 

threshold and release determinations for aqueous ammonia are limited to 10 percent of the total ammonia present 

in solution. This change will reduce the amount of ammonia reported to TRI. Complete details of the revisions 

can be found in 40 CFR Part 372. 

Sector Notebook Project 72 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

Physical Properties. Ammonia is a colorless gas at atmospheric pressure, 

but is shipped as a liquefied compressed gas. It is soluble to about 34 percent 

in water and has a boiling point of -28 degrees F. Ammonia It is corrosive and 

has a pungent odor. 

Toluene (CAS: 108-88-3) 

Toxicity. Inhalation or ingestion of toluene can cause headaches, confusion, 

weakness, and memory loss. Toluene may also affect the way the kidneys and 

liver function. 

Reactions of toluene (see environmental fate) in the atmosphere contribute to 

the formation of ozone in the lower atmosphere. Ozone can affect the 

respiratory system, especially in sensitive individuals such as asthma or allergy 

sufferers. 

Some studies have shown that unborn animals were harmed when high levels 

of toluene were inhaled by their mothers, although the same effects were not 

seen when the mothers were fed large quantities of toluene. Note that these 

results may reflect similar difficulties in humans. 

Carcinogenicity. There is currently no evidence to suggest that toluene is 

carcinogenic. 

Environmental Fate. A portion of releases of toluene to land and water will 

evaporate. Toluene may also be degraded by microorganisms. Once 

volatilized, toluene in the lower atmosphere will react with other atmospheric 

components contributing to the formation of ground-level ozone and other air 

pollutants. 

Physical Properties. Toluene liquid with a sweet, pungent odor. It is soluble 

to 0.07 percent in water and has a boiling point of 232 degrees F. 

Sector Notebook Project 73 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

IV.C. Other Data Sources 

The toxic chemical release data obtained from TRI captures many of the 

facilities in the pharmaceutical industry. It also allows for a comparison 

across years and industry sectors. Reported chemicals are limited however to 

the approximately 600 reported chemicals. Most of the hydrocarbon 

emissions from pharmaceutical facilities are not captured by TRI. The EPA 

Office of Air Quality Planning and Standards has compiled air pollutant 

emission factors for determining the total air emissions of priority pollutants 

(e.g., total hydrocarbons, SO2, NO2, CO, particulates, etc.) from many 

chemical manufacturing sources. 

The EPA Office of Air’s Aerometric Information Retrieval System (AIRS) 

contains a wide range of information related to stationary sources of air 

pollution, including the emissions of a number of air pollutants which may be 

of concern within a particular industry. With the exception of volatile organic 

compounds (VOCs), there is little overlap with the TRI chemicals reported 

above. Table 18 summarizes annual releases of carbon monoxide (CO), 

nitrogen dioxide (NO2), particulate matter of 10 microns or less (PM10), total 

particulate (PT), sulfur dioxide (SO2), and volatile organic compounds 

(VOCs). 

Sector Notebook Project 74 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

Table 18: Air Pollutant Releases by Industry Sector (tons/year) 

Industry Sector CO NO2 PM10 PT SO2 VOC 

Metal Mining 4,670 39,849 63,541 173,566 17,690 915 

Nonmetal Mining 25,922 22,881 40,199 128,661 18,000 4,002 

Lumber and Wood 

Production 

122,061 38,042 20,456 64,650 9,401 55,983 

Furniture and Fixtures 2,754 1,872 2,502 4,827 1,538 67,604 

Pulp and Paper 566,883 358,675 35,030 111,210 493,313 127,809 

Printing 8,755 3,542 405 1,198 1,684 103,018 

Inorganic Chemicals 153,294 106,522 6,703 34,664 194,153 65,427 

Organic Chemicals 112,410 187,400 14,596 16,053 176,115 180,350 

Petroleum Refining 734,630 355,852 27,497 36,141 619,775 313,982 

Rubber and Misc. Plastics 2,200 9,955 2,618 5,182 21,720 132,945 

Stone, Clay and Concrete 105,059 340,639 192,962 662,233 308,534 34,337 

Iron and Steel 1,386,461 153,607 83,938 87,939 232,347 83,882 

Nonferrous Metals 214,243 31,136 10,403 24,654 253,538 11,058 

Fabricated Metals 4,925 11,104 1,019 2,790 3,169 86,472 

Electronics and Computers 356 1,501 224 385 741 4,866 

Motor Vehicles, Bodies, 

Parts and Accessories 

15,109 27,355 1,048 3,699 20,378 96,338 

Dry Cleaning 102 184 3 27 155 7,441 

Ground Transportation 128,625 550,551 2,569 5,489 8,417 104,824 

Metal Casting 116,538 11,911 10,995 20,973 6,513 19,031 

Pharmaceuticals 6,586 19,088 1,576 4,425 21,311 37,214 

Plastic Resins and 

Manmade Fibers 

16,388 41,771 2,218 7,546 67,546 74,138 

Textiles 8,177 34,523 2,028 9,479 43,050 27,768 

Power Generation 366,208 5,986,757 140,760 464,542 13,827,511 57,384 

Shipbuilding and Repair 105 862 638 943 3,051 3,967 

Source: U.S. EPA Office of Air and Radiation, AIRS Database, 1997. 

Sector Notebook Project 75 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

IV.D. Comparison of Toxic Release Inventory Among Selected Industries 

The following information is presented as a comparison of pollutant release 

and transfer data across industrial categories. It is provided to give a general 

sense as to the relative scale of releases and transfers within each sector 

profiled under this project. Please note that the following figure and table do 

not contain releases and transfers for industrial categories that are not 

included in this project, and thus cannot be used to draw conclusions 

regarding the total release and transfer amounts that are reported to TRI. 

Similar information is available within the annual TRI Public Data Release 

Book. 

Figure 12 is a graphical representation of a summary of the 1995 TRI data for 

the pharmaceutical industry and the other sectors profiled in separate 

notebooks. The bar graph presents the total TRI releases and total transfers 

on the vertical axis. The graph is based on the data in Table 19 and is meant 

to facilitate comparisons among the relative amounts of releases, transfers, 

and releases per facility both within and among these sectors. The reader 

should note, however, that differences in the proportion of facilities captured 

by TRI exist among industry sectors. This can be a factor of poor SIC 

matching and relative differences in the number of facilities reporting to TRI 

from the various sectors. In the case of the pharmaceutical industry, the 1995 

TRI data presented here covers 200 facilities. Only those facilities listing 

primary SIC codes falling within SIC 2833 and 2834 were used. 

Comparisons of the reported pounds released or transferred per facility in 

Table 19 demonstrate that the pharmaceutical industry is above average in its 

pollutant releases and transfers per facility when compared to other TRI 

industries. Of the twenty manufacturing SIC codes listed in the TRI database, 

the mean amount of pollutant release per facility (including pharmaceutical 

facilities) was approximately 101,000 pounds. The TRI releases of the 

average pharmaceutical facility (SIC 2833 and 2834) were 150,000 pounds, 

making the industry 1.5 times higher in per facility releases than for other 

industries. For transfers, the mean of pharmaceutical facilities was about 4.6 

times as much as that of all TRI manufacturing facilities (161,000 pounds 

transferred off-site per facility compared to 736,000 pounds per 

pharmaceutical facility). This comparison is difficult to interpret due to the 

divergent nature of the industries listed in Table 19 and the differences in the 

raw materials and processes used to manufacture the specific industry’s 

products. The batch nature and large volumes of raw materials used to 

produce the relatively small amounts of high purity pharmaceutical products 

may account for the higher rate released and transferred by the pharmaceutical 

industry. 

Sector Notebook Project 76 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

Figure 12: Summary of TRI Releases and Transfers by Industry 

0 

100 

200 

300 

400 

500 

600 

22 24 25 

2611-2631 2711-2789 2812-2819 

2821, 2823, 2824 

2833, 2834 

2861-2869 

2911 

30 32 

331 

332, 336 333, 334 

34 36 

371 

3731 

SIC Range 

Total Pounds (millions) 

Total Releases Total Transfers 

Source: US EPA 1995 Toxics Release Inventory Database. 

SIC 

Range 

Industry Sector SIC 

Range 

Industry Sector SIC 

Range 

Industry Sector 

22 Textiles 2833, 

2834 

Pharmaceuticals 333, 334 Nonferrous Metals 

24 Lumber and Wood 

Products 

2861-

2869 

Organic Chem. Mfg. 34 Fabricated Metals 

25 Furniture and Fixtures 2911 Petroleum Refining 36 Electronic Equip. and 

Comp. 

2611-2631 Pulp and Paper 30 Rubber and Misc. 

Plastics 

371 Motor Vehicles, Bodies, 

Parts, and Accessories 

2711-2789 Printing 32 Stone, Clay, and 

Concrete 

3731 Shipbuilding 

2812-2819 Inorganic Chemical 

Manufacturing 

331 Iron and Steel 

Sector Notebook Project 77 September 1997 
Pharmaceutical Industry Releases and Transfers Profile 

2821, 

2823, 2824 

Plastic Resins and 

Manmade Fibers 

332, 336 Metal Casting 

Sector Notebook Project 78 September 1997 
Sect

or Notebook Project 79 September 1997 

Industry Sector 

Table 19: Toxics Release Inventory Data for Selected Industries 

SIC 

Range 

# TRI 

Facilities 

TRI Releases TRI Transfers 

Total Releases 

+Transfers 

(million lbs.) 

Ave

Tran

Total 

Releases 

(million lbs.) 

Ave. 

Releases per 

Facility 

(pounds) 

Total 

Transfers 

(million lbs.) 

Ave. Trans. 

per Facility 

(pounds) 

Textiles 22 339 17.8 53,000 7.0 21,000 24.8 Lumber and Wood Products 24 397 30.0 76,000 4.1 10,000 34.1 Furniture and Fixtures 25 336 37.6 112,000 9.9 29,000 47.5 Pulp and Paper 2611-2631 305 232.6 763,000 56.5 185,000 289.1 Printing 2711-2789 262 33.9 129,000 10.4 40,000 44.3 Inorganic Chem. Mfg. 2812-2819 413 60.7 468,000 21.7 191,000 438.5 Plastic Resins and Manmade Fibers 

2821,2823, 

2824 

410 64.1 156,000 192.4 469,000 256.5 

Pharmaceuticals 2833, 2834 200 29.9 150,000 147.2 736,000 177.1 Organic Chemical Mfg. 2861-2869 402 148.3 598,000 208.6 631,000 946.8 Petroleum Refining 2911 180 73.8 410,000 29.2 162,000 103.0 Rubber and Misc. Plastics 30 1,947 143.1 73,000 102.6 53,000 245.7 Stone, Clay, and Concrete 32 623 43.9 70,000 31.8 51,000 75.7 Iron and Steel 331 423 90.7 214,000 513.9 1,215,000 604.6 Metal Casting 332, 336 654 36.0 55,000 73.9 113,000 109.9 Nonferrous Metals 333, 334 282 201.7 715,000 164 582,000 365.7 Fabricated Metals 34 2,676 83.5 31,000 350.5 131,000 434.0 Electronic Equip. and Comp. 

36 407 4.3 11,000 68.8 169,000 73.1 

Motor Vehicles, Bodies, Parts, and Accessories 

371 754 79.3 105,000 194 257,000 273.3 

Shipbuilding 3731 43 2.4 56,000 4.1 95,000 6.5 

Source: US EPA Toxics Release Inventory Database, 1995. 
Pharmaceutical Industry Releases and Transfers Profile 

Sector Notebook Project 80 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

V. POLLUTION PREVENTION OPPORTUNITIES 

The best way to reduce pollution is to prevent it in the first place. Some 

companies have creatively implemented pollution prevention techniques that 

improve efficiency and increase profits while at the same time minimizing 

environmental impacts. This can be done in many ways, such as reducing 

material inputs, re-engineering processes to reuse by-products, improving 

management practices, and employing substitution of toxic chemicals. Some 

smaller facilities are able to actually get below regulatory thresholds just by 

reducing pollutant releases through aggressive pollution prevention policies. 

The Pollution Prevention Act of 1990 established a national policy of 

managing waste through source reduction, which means preventing the 

generation of waste. The Pollution Prevention Act also established as national 

policy a hierarchy of waste management options for situationsin which source 

reduction cannot be implemented feasibly. In the waste management 

hierarchy, if source reduction is not feasible the next alternative is recycling 

of wastes, followed by energy recovery, and waste treatment as a last 

alternative. 

In order to encourage these approaches, this section provides both general 

and company-specific descriptions of pollution prevention activities that have 

been implemented within the pharmaceutical industry. While the list is not 

exhaustive, it does provide core information that can be used as the starting 

point for facilities interested in beginning their own pollution prevention 

projects. When possible, this section provides information from real activities 

that can be, or are being, implemented by this sector -- including a discussion 

of associated costs, time frames, and expected rates of return. This section 

provides summary information from activities that may be, or are being 

implemented by this sector. Please note that the activities described in this 

section do not necessarily apply to all facilities that fall within this sector. 

Facility-specific conditions must be carefully considered when pollution 

prevention options are evaluated, and the full impacts of the change must be 

examined to determine how each option affects air, land and water pollutant 

releases. 

The bulk manufacturing processes of the pharmaceutical industry are 

characterized by a low ratio of finished product to raw material. Therefore, 

large quantities of residual waste are generated, especially in fermentation and 

natural product extraction. Chemical synthesis processes generate wastes 

containing hazardous spent solvents and reactants, combined with residual 

wastes such as reaction residues. Equipment cleaning water and residue, often 

containing hazardous chemicals, also are a major waste stream (U.S. EPA, 

1991). 

Sector Notebook Project 81 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

Source reduction is one method by which the industry aims to reduce these 

wastes. However, source reduction methods such as process modifications 

and material substitutions may not be as easily implemented in the 

pharmaceutical industry as in other manufacturing sectors. This is because 

any significant change to the production process of an existing product, may 

need approval from the Food and Drug Administration (FDA). If a company 

wishes to change the method of making a drug or active ingredient that goes 

into it, the FDA requires the company to prove that the ‘new’ drug is of the 

same or better quality as the old drug and that any reformulation will not 

adversely affect the identity, strength, quality, purity, or bioavailability of the 

drug. The process of gathering information to support the change and 

awaiting FDA review and approval can be lengthy, time-consuming and 

expensive. 

As a result, many pharmaceutical companies are looking at ways to minimize 

waste in future production processes at the research and development stage. 

Incorporating pollution prevention at the start of a new drug development 

process is much more economical, efficient, and environmentally sound (see 

Section VI. D. for further details). The factors affecting the pharmaceutical 

industry’s pollution prevention efforts were documented byPhRMAmembers 

in a 1997 document entitled Pharmaceutical Industry Waste Minimization 

Initiatives. 

Many pharmaceutical companies have already implemented pollution 

prevention programs in their manufacturing facilities. Although pollution 

prevention may not always be a substitute for control technologies, it is often 

viable and is an increasingly popular method for meeting environmental 

compliance requirements. Some examples of innovative waste reduction 

programs that incorporate source reduction as well as recycling and reuse are 

presented in the case studies that appear in this section. 

Sector Notebook Project 82 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

V.A. Material Substitutions 

Substituting raw materials to lessen the volume and/or toxicity of waste 

generated is a type of source reduction (U.S. EPA, 1991). One of the most 

common opportunities for material substitutions in the pharmaceuticals 

industry is found in the tablet coating process. Until recently, many tablet 

coating operations involved the use of methylene chloride and other 

chlorinated solvents. By switching to aqueous-based coating films, many 

firms have reduced the hazardous waste content in their air and effluent waste 

streams, as well as the cost of purchasing chemicals. Aqueous-based cleaning 

solutions are also being used more frequently for equipment cleaning instead 

of solvent-based solutions (U.S. EPA, 1991). 

Sector Notebook Project 83 September 1997 
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Pharmaceutical Industry Pollution Prevention Opportunities 

POLLUTION PREVENTION CASE STUDIES 

Material Substitution 

� h i g-Pl ugh Pharmaceuticals will mark a ne inhaler for the treatme t f as h , 

ich i free of chlorofluo carbons (CFCs). The CF free inh ler was devel ped by 3M 

Ph icals. CF e used as a propell nt in mete ed-dose i hal r (MDI). n a new 

MDI, whi was appr ved b the FDA in A t, 1996, CFCs h ve een placed by 

hy ofl oroalkane-134a (HFA-134a). Unlik FC , HFA­ es not ete the 

ozone. The pr duct will be rketed u der t rand n me Pro nti ® HF . 

�Schering-Plough Laboratories is switching to a coated natural kraft (CNK) paperboard for 

its packagin CNK is str ng d less expensive than the previ us packagi g m terial, as 

well as recy abl d co po table. e paperb a is ot bleached wit lori , ut is 

co th white cl coat n Instead of mineral-based varni es and inks, er d soyb sed mater als are us New Jersey e, he co pany is expected t ve $225,000 

per r nd could v up to 1.2 million if the pr m expan s t t er divisions. 

� it West o , P , facility, M rc r mo 1,1,1-Trichloro tha TCA) from its 

pro n per ons. A was used in st ipping labels o f bottles an t er cleani g 

p ation t g, d manufact i g. A citrus­ ased solvent was subs it ted f 

cleani g packaging equipm t. F r cleaning manufactur n pmen , roleum-based 

solvent was sub titu d, the waste fro ich is used for en r very i f-si 

facility. 

th same fa ility, M k substit te h l for t imer l, a r u y-ba e comp nd. 

Thimerosal h d b used as a biocid o inacti ate bact a during t e i t l stages of 

rment ion i the producti of a vacci . Substi utin ph ol, hazar us, FDAappr ed bi id abled Merck t achieve an 85 percent reductio in ercury­ sed 

waste. I additio , the substituti esulted in ncreased pro yields, improved microbial 

netics, st savings f aw mat ials. 

�At i s C e ee pl nt Riverside, PA, Merc devel d innovati new manu c uring 

stry which sti ut s toluene f r dichlorom thane. e change has r sulted i a 98 

per t r duct i releases an ransf s o dichlorom thane. In tio , because 

t l en s less v ile d m re easily red, e co rols and reco ery pment on 

the new pr cess are able t tr l t luene releases such hat have in eased only 

slightly. 

Material Substitution (cont.) 

�Riker Laboratories in Northbridge, CA recently replaced several different organic solvent 

coating materials used on medicine tablets with a water-based coating material. 

Differences in the new coating material required that new spray equipment be installed. 

However, the company saves $15,000 per year not purchasing these organic solvents and 

determined that $180,000 in pollution control equipment was no longer needed. They 

estimate that the investment will pay for itself in less than one year. The substitution 

prevents 24 tons per year in organic solvent emissions, reduced exposure risks to workers, 

and has made it easier for the company to comply with strict California air emission 

standards. 

�In producing the anti-viral drug 6-aminopenicillanic acid, Bristol-Myers Squibb used to 

extract the intermediate, penicillin V from an aqueous fermentation broth. The broth was 

filtered and the intermediate then was extracted in several centrifuge steps using the toxic 

solvent methyl isobutyl ketone (MiBK). The extraction was a major source of fugitive 

emissions. The broth now is f ltered through a membrane and the intermediate is extracted 

using n-butyl acetate, a non-toxic chemical, in closed centrifuges, reducing fugitive 

emissions. The overall capital investment for this project came to almost $10 million. 

However, the annual operating cost reductions, coupled with a 10 percent increase in 

throughput, generate $4.9 million in additional cash flow. Based on this, the project will 

generate a return on investment of 28 percent and a payback period of 2.7 years. In 

addition the project reduced hazardous waste by 20,000 pounds and eliminated over one 

million pounds of MiBK releases to the air and water. 

�Glaxo-Wellcome, Inc. developed an innovative aqueous coating method that eliminated 

the use of methylene chloride, isopropyl alcohol, methanol, and ethanol in their Zantac 

tablet coating operations performed at their Zebulon, North Carolina facility. GlaxoWellcome overcame a number of obstacles before using the aqueous-based coating 

material on the Zantac production line. First, the pharmaceutical active readily degraded at 

the extreme heat and moisture encountered during aqueous coating. Also, the 

pharmaceutical active migrates through the aqueous coating causing discolorization and 

degradation of the tablet coating film. To implement the use of the substitute materials, 

Glaxo-Wellcome had to make extensive changes to the coater spray assemblies, revamped 

the coater air hand ing system with larger fans and heating coils, and installed a 

dehumidifying system. The capital investment for this equipment was $1.5 million. 

However, the company annually saves $286,800 in organic solvent purchases and 

$322,900 in disposal costs of the more than 479 tons of hazardous waste generated by the 

old system every year. The estimated payback period for the modifications is three years. 

In addition, the new system cut VOC emissions to the air from almost 15,000 pounds per 

year to zero. 

Sector Notebook Project 84 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

Material Substitution (cont.) 

�The Pharmacia and Upjohn, Inc. Sterile Manufacturing area in Kalamazoo has received 

FDA approval for a Thimerosal-free formulation of one of its products. This new 

formulation will eliminate the use of Thimerosal, a mercury based preservative, in the 

manufacture of the drug Atgam. Atgam will be manufactured without any preservative 

using new closed column chromatography and Restrictive Access Barrier technology. 

Atgam is used to prevent organ transplant rejection and in the treatment of aplastic anemia. 

�The Eli Lilly Cleaning Technology Center in late 1996 initiated a formal screening 

program to identify potential aqueous based cleaners as replacements for the various 

organic and chlorinated solvents currently used in bulk pharmaceutical manufacturing 

equipment cleanings. In one product line, 8,700 liters of acetone per cleaning was replaced 

with an alkaline aqueous based cleaner for an estimated annual reduction of 17,400 liters of 

acetone. An acid aqueous based cleaner replaced methanol in another product line, 

resulting in methanol reductions of 25,800 liters per year. In cleaning operations 

associated with another product, an alkaline aqueous based cleaner replaced 117,000 liters 

of methanol and 600 liters of ethylene dichloride per cleaning. This resulted in an 

estimated annual reduction of 368,000 liters of methanol and 1,200 liters of ethylene 

dichloride. 

Sector Notebook Project 85 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

V.B. Process Modifications 

Process modifications are alterations to or modernization of existing processes 

to reduce waste generation. Process modifications can involve re-designing 

chemical transfer systems to reduce spillage and other material losses. For 

example, in batch operations, each loading and unloading of the reactors and 

other equipment increases the risk of chemical spills and solvent vapor 

releases. Batch operations often require more frequent reactor clean outs 

using significant volumes of cleaning solution and solvents. With continuous 

operations, the reactor is loaded once and solvents and reactants are fed into 

the reactor continually, thereby reducing the risk of pollutant releases (US 

EPA, 1991). 

Thus switching from batch to continuous operations for certain products may 

potentially reduce large volumes of wastes. Switching to a continuous or 

partially continuous process may be possible for a facility that is the primary 

producer of a product which is in constant demand. For example, Hoffmann 

La Roche’s facility in Nutley, NJ is one of the primary producers of Vitamin 

E in the country. Consequently, much of their vitamin production equipment 

is dedicated and run as semi-continuous operations. 

Process changes that optimize reactions and raw material use can reduce 

waste and releases to the environment (US EPA, 1995). Modifications as 

simple as careful monitoring of reaction parameters (temperatures, pH, etc.) 

can dramatically improve manufacturing efficiency. Production inmanyofthe 

large pharmaceutical companies is computerized and highly automated. 

Computers equipped with computer aided design (CAD) programs visually 

simulate the production process on the screen. The automated system allows 

production managers to turn on the batch process and control temperatures, 

pressure, and other process parameters, from the keyboard. While, the system 

runs, production personnel are free to do other things such as check 

equipment or take product samples. Such careful automated monitoring may 

insure against the formation of fouling waste at the bottom of reactor vessels, 

thereby reducing the need for additional cleaning, as well as lessening the risk 

of damaged batches of product which have to be disposed (US EPA, 1991). 

Sector Notebook Project 86 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

POLLUTION PREVENTION CASE STUDIES 

Process Modifications 

�As part of their “Environment 2000" program, Bristol-Myers Squibb has started to look at 

Product Life Cycle (PLC) management as a way to implement pollution prevention. PLC 

involves investigating the environmental impacts of a product at every stage of production: 

R&D, manufacturing, and packaging. Pollution prevention options are now being 

investigated at the very beginning of drug development. This eliminates the possibility of 

lengthy Supplementary Drug Approval applications with FDA. Using PLC management, 

Bristol-Myers Squibb discovered the use of a filtration membrane for their 6-

aminopenicillanic acid production (see Section V.A. Case Studies). 

�At its East Hanover, NJ facility, Sandoz Pharmaceutical Co. changed processes in its 

reactors, to reduce solvent usage. An inert atmosphere above the reaction mixture is used 

during synthesis to protect the reaction from exposure to oxygen. In the previous process, 

nitrogen flowed continuously over the mixture, carrying away with it a certain amount of 

solvent vapors. The nitrogen gas blanketing process uses a non-flowing nitrogen layer that 

only bleeds out a very small amount of nitrogen and solvent. 

�In their main drug development lab in Tippecanoe, IN, Eli Lilly and Company has 

implemented a pollution prevention program. Beginning in the R&D phase, the company 

assesses the environmental impacts of every new product and determines where wastes can 

be minimized. As a result, Eli Lilly developed a new process which eliminated the use of 

methylene chloride, aluminum wastes, use of an odoriferous raw material, and all 

distillation steps from production of a drug under development for the treatment of 

osteoporosis. 

�One of Hoffmann La Roche’s major manufacturing processes uses glycol ether as an 

extractive solvent, much of which had to be disposed of as wastewater. After the product 

is recovered, the glycol ether is distilled and reused. The overhead from the distillation is 

primarily water with some glycol ether which is disposed as wastewater. The process was 

redesigned to increase per pass recycle of the glycol ether in the distillation column by 

12%. As a result, use of the chemical was reduced by about 60% and solvent releases 

decreased by 300,000 pounds per year and the batch cycle time was reduced by four hours. 

Annual savings are $250,000. 

Sector Notebook Project 87 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

Process Modifications (cont.) 

�At one of its facilities, Hoffman La Roche was using 110,000 gallons of methanol per year 

for cleaning equipment during product changeovers. Methanol was being used for all 

cleaning and rinsing stages. To reduce methanol usage and the associated waste disposal 

costs, a new method was developed whereby a two-stage water-based cleaning is done before 

a final methanol rinse. This reduced the amount of methanol used to about 30,000 gallons per 

year and saves about $49,000 per year. 

�In one of its manufacturing processes, Hoffman La Roche extracted a synthesized 

pharmaceutical intermediate from toluene into water, and then from water into chloroform. 

Because toluene was soluble in the extraction, it contaminated the chloroform and created a 

waste stream of the mixed solvents. The company eliminated the waste stream by steamdistilling the toluene from the water so that the toluene never came in contact with the 

chloroform. Chloroform use decreased by 76 percent which was sufficient to remove this 

material from the list of chemicals the facility was required to include in its Toxic Release 

Inventory report. The project saved $22,000 per year. 

�At its West Point, PA facility, Merck Co. made a simple change in the sequence of process 

steps used to manufacture a vaccine, which resulted in a substantial reduction of mercurybased wastes. Thimerisol, a mercury-based chemical, was used as a preservative during an 

intermediate process step. Thus any waste stream produced during the rest of the process 

was contaminated with mercury. A process change was initiated to add thimerosal at the end 

of the process. By elimating mercury in waste streams generated prior to the addition of 

thimerisol, mercury contaminated wastes generated during manufacturing were dramatically 

reduced. 

�At its Flint River plant in Albany, Georgia, Merck used steam jets to produce a vacuum in 

the process vessel during the production of an antibiotic. This results in dichloromethane 

being mixed with steam and subsequently evaporating into the air. The steam jets were 

replaced with liquid ring vacuum pumps which reduced air emissions. Dichloromethane 

emissions were further reduced by maintaining the vacuum pump seal fluid at subzero 

temperatures which condenses the dichloromethane vapor so it can be recycled and reused. 

�Pharmacia and Upjohn’s wastewater treatment process was modified to significantly reduce 

waste disposed by its Underground Injection Control operation. A modification suggested by 

an employee eliminated about 1 million pounds of solid waste. This modification involved 

substituting a bag filter for a precoat vacuum filter. The precoat vacuum filter used a 

diatomaceous filter medium, which generated large volumes of solid waste. The bag filter 

creates much less waste per volume of liquid filtered. The used filter bags are incinerated on 

site, thereby greatly reducing landfill wastes. 

Sector Notebook Project 88 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

Process Modifications (cont.) 

�In converting to a new process for bioconversion of a steroid intermediate, Pharmacia and 

Upjohn, Inc. has eliminated approximately 90,000 pounds of dimethylformamide waste and 

approximately 190,000 pounds of filter aid waste per year. In addition, solvent handling was 

reduced from about 6 million pounds to about 600,000 pounds and aqueous waste was 

reduced more than 4 million pounds per year. 

Sector Notebook Project 89 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

V.C. Good Operating Practices 

One of the easiest and most economical ways to achieve source reduction is 

to implement good operating practices. Pharmaceutical companies already 

follow a list of Good Manufacturing Practices (GMP) guidelines outlined by 

the FDA. In some cases these involve good operating practices that will 

reduce raw materials use and waste generation. As a result, many companies 

have developed environmental policies for all of their facilities, both in the 

U.S. and abroad. Typically, policies may be written for employee training, 

employee health and safety, hazardous chemical spill cleanup procedures, 

equipment maintenance procedures, leak detection, and emergency response 

procedures. 

Management commitment. Good operating practices start with on-site 

commitment and understanding of the need and methods for pollution 

prevention, from top management levels to the plant floor. Without facilitywide efforts to reduce pollution, source reduction may not be successful (US 

EPA, 1991). 

Employee training. An employee training program is essential to the success 

of a source reduction program. Employees should be trained in safe handling 

of equipment, chemicals, and wastes. They should also be informed of any 

potentially harmful health effects of the hazardous chemicals they handle. As 

well as being trained in proper operation of equipment and chemical handling, 

employees should be trained in spill cleanup and methods for detecting 

chemical releases (US EPA, 1991). 

Maintenance programs. Maintenance programs should target both 

preventive and corrective maintenance of equipment. This means that 

equipment should be regularly checked and cleaned to insure its proper 

functioning, and damaged equipment should be repaired quickly. Routine 

cleaning, minor adjustments, testing and replacement of parts, should be a part 

of the maintenance program. Additionally, good record keeping of equipment 

checks, repairs, cleaning, and equipment failure will help to reduce the 

likelihood of future equipment breakdowns and any associated pollution 

releases (US EPA, 1991). 

Inventory control. The wide range of chemicals used in the pharmaceutical 

industry makes it essential to instigate an efficient inventory tracking system, 

such as a “first-in, first-out” policy and chemicals must be properly labeled 

with their name, date of purchase, and date of expiration. This helps to insure 

that older, un-used chemicals do not have to be needlessly discarded (US 

EPA, 1991). In addition, having one person responsible for the distribution of 

chemicals and supplies insures a more efficient tracking system (US EPA, 

1995). Inventory tracking is a valuable and easy method for reducing wastes. 

Sector Notebook Project 90 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

Spill prevention and storage. Spill and leak prevention are critical to 

pollution prevention. Tightly secured storage tanks are a key to avoiding 

spills. Containers should have good valves with tight stopping devices to 

avoid the spilling or dripping of hazardous chemicals. Storage containers 

should have legible signs indicating the contents of the container, health 

hazard warnings (where necessary), and spill cleanup procedures in case of 

emergencies. Large drums can be raised above the ground to avoid corrosion. 

An organized storage area facilitates fast and easy removal of chemicals, as 

well as reduction and cleanup of spills (U.S. EPA, 1991). 

Sector Notebook Project 91 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

POLLUTION PREVENTION CASE STUDIES 

Good Operating Practices 

�At its Kenilworth, NJ facility, Schering-Plough Pharmaceuticals has a central warehouse 

with a computerized inventory system. Raw materials come into the warehouse in large 

volumes. Materials are weighed according to batch requirements, labeled, and then sent 

to different process areas throughout the facility. This eliminates excess raw material 

wastes and ensures that only the amounts needed are used. 

�Sandoz Pharmaceuticals has also developed a system to improve scheduling of batch 

operations in their facilities worldwide and domestically. Accurate scheduling reduces the 

chances of excess wastes and costs, which occur when a batch changeover takes place. 

�At its Nutley, NJ plant, Hoffmann La Roche was able to identify and repair more than 900 

sources of fugitive emissions. In addition, the company installed ultra-low temperature 

condensers to remove solvents from vent streams. The captured solvents are recycled or 

treated off-site. 

�The Pharmacia and Upjohn, Inc. Puerto Rico Technical Operations group was the first 

offshore location to implement the company’s pollution prevention program. The local 

pollution prevention team helps the plant set pollution prevention goals. The team reports 

progress toward meeting goals annually. As a result, the Butyl Alcohol recovery efficiency 

at the facility has been increased to 95% and Acetone to 96%. The facility has been 

tracking waste indices (Tons of waste generated vs. Kilograms of product produced) and 

results for several wastes show reductions over a four-year period. The pollution 

prevention program has been fully implemented at all Pharmacia and Upjohn U.S. sites. 

Under the program individual business units set goals and report on progress annually. 

More than 300 pollution prevention projects, many of them in the research and 

development areas, have been recorded since the program started in 1990. 

�The Chemical and Fermentation operation at Pharmacia and Upjohn, Inc. in Kalamazoo 

has begun using interlocked valve systems on jacketed coolers. The new valve systems 

help prevent the inadvertent discharge of methanol, used as refrigerant, to surface waters. 

They also have begun using new drip-less pipe couplers to reduce solvent losses and spills 

from hose connections. 

Sector Notebook Project 92 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

V.D. Recycling, Recovery, and Reuse 

“Recovery and recycling include direct reuse of waste material, recovering 

used materials for a separate use, and removing impurities from waste to 

obtain relatively pure substances” (EPA 1991). Although “strict quality 

control requirements of the pharmaceutical industry often restrict reuse 

opportunities, some do exist” (EPA 1991) and are considered valuable by the 

industry since they reduce the volume of raw materials used and the amount 

of waste generated and disposed. 

Except for in-process recycling, EPA does not consider recycling, recovery, 

and reuse to be source reduction techniques. However, in-process recycling, 

which includes the reuse or recirculation of a chemical within a process and 

may include recovery or reclamation, is considered a source reduction 

technique. The pharmaceutical industry often uses this form of recycling 

which is dedicated to and physically integrated with the pharmaceutical 

manufacturing process by means of piping or another form of conveyance. 

Recycling and recovery provides the pharmaceutical industry a great 

opportunity to reduce the volume and toxicity of spent solvents. As 

described in Section 3, solvents are used for a wide range of applications, 

from synthesis, extraction, and purification of active ingredients to cleaning 

process equipment. The types of solvent recovery employed include 

distillation, evaporation, decantation, centrifugation, and filtration. However, 

limitations exist with both on and off-site recycling and recovery since several 

types of solvents (including water), reactants, and other contaminants may be 

present. These materials must be extracted to allow the solvent to be reused 

either in a pharmaceutical process or in another process. Additionally, special 

techniques and equipment must be used to break azeotropes formed during 

the chemical reactions. 

In addition to solvents, some residual wastes may also be recovered and 

reused. For example, filter cakes from fermentation processes are usually 

disposed of in landfills. An alternative being used in some facilities is to 

collect the waste filter cakes, recover any valuable by-products, and then sell 

the cakes to be used as fertilizers or soil additives. To be used as a fertilizer, 

the nitrogen, phosphorus, and potassium content must be greater than 5%, 

which sometimes can be achieved by reducing the moisture content in the 

filter cake (US EPA, 1991). 

Sector Notebook Project 93 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

POLLUTION PREVENTION CASE STUDIES 

Recycling, Recovery, and Reuse 

�Nycomed Inc. manufactures bulk pharmaceutical products by batch processing. In 

processing a product for medical diagnostic imaging, the company installed closed loop 

distillation units to recover all of its methanol washes and methanol-containing wastewater. 

The methanol recovery system can distill approximately 2,000 gallons per day of 70 percent 

methanol to more than 99.5 percent methanol, which can be reused in the same process. 

Nycomed Inc. eliminated water discharges of methanol, reduced hazardous waste, and 

saved approximately 680,000 pounds of methanol in the first half of 1992, saving $54,438 

in the same period. 

�The Pharmacia and Upjohn, Inc. Chemical and Fermentation operation in Kalamazoo 

reuses more than 195 million pounds of solvent annually. Approximately 80% of the site’s 

total solvent requirement and 90% of the site’s chlorinated solvent requirement is met by 

reused solvent. The reused solvent demand is met through a combination of in process 

solvent reuse (150 million pounds) and distillation (45 million pounds). There are now six 

centralized distillation units. On site solvent reuse and recovery in chemical processes 

helped the company exceed its 33/50 Program goals. The achievement was commemorated 

by a National Performance Review Environmental Champion Award given to the company 

by Vice President Al Gore in 1995. 

�Pharmacia and Upjohn, Inc. Chemical Process Research and Development developed a 

proprietary distillation process for splitting Tetrahydrofuran from a mixture of alcohol, 

water, and other wastes. Without the new process, Tetrahydrofuran forms azeotropic 

mixtures with alcohol which cannot be distilled. This process now recovers approximately 

1 million pounds of THF per year. 

�Pharmacia and Upjohn, Inc. is evaluating the possibilities of reusing waste solvent 

condensate produced from their cryogenic air pollution control equipment. They have 

identified one methylene chloride rich stream to recover as a trial. An estimated 2.5 million 

pounds of this waste solvent is generated annually. Recovery by an off-site recycler or on 

site reclamation are being further evaluated. 

Sector Notebook Project 94 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

V.E. Pollution Prevention Research 

Because of comprehensive regulations from both the FDA and the EPA, 

pharmaceutical companies are continuously researching new and innovative 

ways to reduce their wastes. Many companies are starting to look at pollution 

prevention options early in development and are collaborating with 

universities and other research institutions to develop new technologies that 

will help reduce or eliminate wastes. Some of these technologies, still in the 

research and testing stages, are discussed below. 

Solvent Minimization 

One potential research area which has been identified is in supercritical 

solvents. Supercritical fluids are known to be very effective solvents and can 

function as an alternative to traditional chlorinated and other toxic solvents 

used in pharmaceutical separations. These solvents are in a supercriticalstate, 

meaning that they are at a very high temperature and/or pressure. A 

relatively small change inthe temperature and/or pressure in supercritical state 

can lead to large changes in the solubility of chemicals in the solvent. This 

increase in solubility is ideal for separations because the overall volume of 

solvent needed is reduced (NJIT, 1991). 

Separation Improvements 

Separation of active ingredients from solvents is one of the most important 

processes in the pharmaceutical industry. Research has been conducted to 

find separation methods which generate fewer by-products and less waste. 

One technology with such a potential is inorganic membrane reactors. “They 

are in effect reactors with built-in separators which may have potential for 

reaction sequences with much better reactor utilization and product 

concentrations” (NJIT, 1991). Inorganic membranes enable a continuous 

removal of product and a controlled addition of reactant. This increases the 

potential for higher yields and greater selectivity by chemicals, which could 

reduce the volume of solvents required, thereby reducing costs and wastes. 

Also, because the reaction and separation are combined in a single step, the 

emissions associated with the traditional transfer step between reaction and 

separation are eliminated (NJIT, 1991). 

Sector Notebook Project 95 September 1997 
Pharmaceutical Industry Pollution Prevention Opportunities 

Sector Notebook Project 96 September 1997 
Pharmaceutical Industry Federal Statutes and Regulations 

VI. SUMMARY OF APPLICABLE FEDERAL STATUTES AND REGULATIONS 

This section discusses the Federal regulations that may apply to this sector. 

The purpose of this section is to highlight and briefly describe the applicable 

Federal requirements, and to provide citations for more detailed information. 

The three following sections are included: 

Section VI.A contains a general overview of major statutes

Section VI.B contains a list of regulations specific to this industry

Section VI.C contains a list of pending and proposed regulations

Section VI.D contains a general overview of other federal statutes applicable

to the industry

Section VI.E. contains a general overview of state regulations affecting the

industry.

The descriptions within Section VI are intended solely for general 

information. Depending upon the nature or scope of the activities at a 

particular facility, these summaries may or may not necessarily describe all 

applicable environmental requirements. Moreover, they do not constitute 

formal interpretations or clarifications of the statutes and regulations. For 

further information readers should consult the Code of Federal Regulations 

and state or local regulatory agencies. EPA Hotline contacts are also 

provided for each major statute. 

VI.A. General Description of Major Statutes 

Resource Conservation And Recovery Act (RCRA) 

RCRA of 1976, which amended the Solid Waste Disposal Act, addressessolid 

(Subtitle D) and hazardous (Subtitle C) waste management activities. The 

Hazardous and Solid Waste Amendments (HSWA) of 1984 strengthened 

RCRA’s waste management provisions and added Subtitle I, which governs 

underground storage tanks (USTs). 

Regulations promulgated pursuant to Subtitle C of RCRA (40 CFR Parts 

260-299) establish a “cradle-to-grave” system governing hazardous waste 

from the point of generation to disposal. RCRA hazardous wastes include the 

specific materials listed in the regulations (commercial chemical products, 

designated with the code "P" or "U"; hazardous wastes from specific 

industries/sources, designated with the code "K"; or hazardous wastes from 

non-specific sources, designated with the code "F") or materials which exhibit 

a hazardous waste characteristic (ignitability, corrosivity, reactivity, or toxicity 

and designated with the code "D"). 

Regulated entities that generate hazardous waste are subject to waste 

accumulation, manifesting, and record keeping standards. Facilities must 

Sector Notebook Project 97 September 1997 
Pharmaceutical Industry Federal Statutes and Regulations 

obtain a permit either from EPA or from a State agency which EPA has 

authorized to implement the permitting program if they store hazardous 

wastes for more than 90 days before treatment or disposal. Facilities may 

treat hazardous waste stored in less-than-ninety-day tanks or containers 

without a permit. Subtitle C permits contain general facility standards such 

as contingency plans, emergency procedures, record keeping and reporting 

requirements, financial assurance mechanisms, and unit-specific standards. 

RCRA also contains provisions (40 CFR Part 264 Subpart S and §264.10) for 

conducting corrective actions which govern the cleanup of releases of 

hazardous waste or constituents from solid waste management units at 

RCRA-regulated facilities. 

Although RCRA is a Federal statute, many States implement the RCRA 

program. Currently, EPA has delegated its authority to implement various 

provisions of RCRA to 47 of the 50 States and to two U.S. territories. 

Delegation has not been given to Alaska, Hawaii, or Iowa. 

Most RCRA requirements are not industry specific but apply to any company 

that generates, transports, treats, stores, or disposes of hazardous waste. 

Here are some important RCRA regulatory requirements: 

Identification of Solid and Hazardous Wastes (40 CFR Part 261) 

lays out the procedure every generator should follow to determine 

whether the material in question created is considered a hazardous 

waste, solid waste, or is exempted from regulation. 

Standards for Generators of Hazardous Waste (40 CFR Part 262) 

establishes the responsibilities of hazardous waste generators including 

obtaining an EPA ID number, preparing a manifest, ensuring proper 

packaging and labeling, meeting standards for waste accumulation 

units, and record keeping and reporting requirements. Generators can 

accumulate hazardous waste for up to 90 days (or 180 days depending 

on the amount of waste generated) without obtaining a permit. 

Land Disposal Restrictions (LDRs) (40 CFR Part 268) are 

regulations prohibiting the disposal of hazardous waste on land 

without prior treatment. Under the LDRs program, materials must 

meet LDR treatment standards prior to placement in a RCRA land 

disposal unit (landfill, land treatment unit, waste pile, or surface 

impoundment). Generators of waste subject to the LDRsmust provide 

notification of such to the designated TSD facility to ensure proper 

treatment prior to disposal. 

Used Oil Management Standards (40 CFR Part 279) impose 

management requirements affecting the storage, transportation, 

Sector Notebook Project 98 September 1997 
Pharmaceutical Industry Federal Statutes and Regulations 

burning, processing, and re-refining of the used oil. For parties that 

merely generate used oil, regulations establish storage standards. For 

a party considered a used oil processor, re-refiner, burner, or marketer 

(one who generates and sells off-specification used oil), additional 

tracking and paperwork requirements must be satisfied. 

RCRA contains unit-specific standards for all units used to store, 

treat, or dispose of hazardous waste, including Tanks and 

Containers. Tanks and containers used to store hazardous waste 

with a high volatile organic concentration must meet emission 

standards under RCRA. Regulations (40 CFR Part 264-265, Subpart 

CC) require generators to test the waste to determine the 

concentration of the waste, to satisfy tank and container emissions 

standards, and to inspect and monitor regulated units. These 

regulations apply to all facilities that store such waste, including large 

quantity generators accumulating waste prior to shipment off-site. 

Underground Storage Tanks (USTs) containing petroleum and 

hazardous substances are regulated under Subtitle I of RCRA. 

Subtitle I regulations (40 CFR Part 280) contain tank design and 

release detection requirements, as well as financial responsibility and 

corrective action standards for USTs. The UST program also 

includes upgrade requirements for existing tanks that must be met by 

December 22, 1998. 

Boilers and Industrial Furnaces (BIFs) that use or burn fuel 

containing hazardous waste must comply with strict design and 

operating standards. BIF regulations (40 CFR Part 266, Subpart H) 

address unit design, provide performance standards, require emissions 

monitoring, and restrict the type of waste that may be burned. 

EPA's RCRA/Superfund/UST Hotline, at (800) 424-9346, responds to 

questions and distributes guidance regarding all RCRA regulations. The 

RCRA Hotline operates weekdays from 9:00 a.m. to 6:00 p.m., ET, excluding 

Federal holidays. 

Comprehensive Environmental Response, Compensation, And Liability Act (CERCLA) 

CERCLA, a 1980 law commonly known as Superfund, authorizes EPA to 

respond to releases, or threatened releases, of hazardous substances that may 

endanger public health, welfare, or the environment. CERCLA also enables 

EPA to force parties responsible for environmental contamination to clean it 

up or to reimburse the Superfund for response costs incurred by EPA. The 

Superfund Amendments and Reauthorization Act (SARA) of 1986 revised 

various sections of CERCLA, extended the taxing authority for Superfund, 

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and created a free-standing law, SARA Title III, also known as the 

Emergency Planning and Community Right-to-Know Act (EPCRA). 

The CERCLA hazardous substance release reporting regulations (40 CFR 

Part 302) direct the person in charge of a facility to report to the National 

Response Center (NRC) any environmental release of a hazardous substance 

which equals or exceeds a reportable quantity. Reportable quantities are 

defined and listed in 40 CFR §302.4. A release report may trigger a response 

by EPA, or by one or more Federal or State emergency response authorities. 

EPA implements hazardous substance responses according to procedures 

outlined in the National Oil and Hazardous Substances PollutionContingency 

Plan (NCP) (40 CFR Part 300). The NCP includes provisions for permanent 

cleanups, known as remedial actions, and other cleanups referred to as 

"removals." EPA generally takes remedial actions only at sites on the 

National Priorities List (NPL), which currently includes approximately 1300 

sites. Both EPA and states can act at other sites; however, EPA provides 

responsible parties the opportunity to conduct removal and remedial actions 

and encourages community involvement throughout the Superfund response 

process. 

EPA's RCRA/Superfund and EPCRA Hotline, at (800) 424-9346, answers 

questions and references guidance pertaining to the Superfund program. 

The CERCLA Hotline operates weekdays from 9:00 a.m. to 6:00 p.m., ET, 

excluding Federal holidays. 

Emergency Planning And Community Right-To-Know Act (EPCRA) 

The Superfund Amendments and Reauthorization Act (SARA) of 1986 

created EPCRA, also known as SARA Title III, a statute designed to improve 

community access to information about chemical hazards and to facilitate the 

development of chemical emergency response plans by State and local 

governments. EPCRA required the establishment of State emergency 

response commissions (SERCs), responsible for coordinating certain 

emergency response activities and for appointing local emergency planning 

committees (LEPCs). 

EPCRA and the EPCRA regulations (40 CFR Parts 350-372) establish four 

types of reporting obligations for facilities which store or manage specified 

chemicals: 

EPCRA §302 requires facilities to notify the SERC and LEPC of the 

presence of any "extremely hazardous substance" (the list of such 

substances is in 40 CFR Part 355, Appendices A and B) if it has such 

substance in excess ofthe substance's threshold planning quantity, and 

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directs the facility to appoint an emergency response coordinator. 

EPCRA §304 requires the facility to notify the SERC and the LEPC 

in the event of a release equaling or exceeding the reportable quantity 

of a CERCLA hazardous substance or an EPCRA extremely 

hazardous substance. 

EPCRA §311 and §312 require a facility at which a hazardous 

chemical, as defined by the Occupational Safety and Health Act, is 

present in an amount exceeding a specified threshold to submit to the 

SERC, LEPC and local fire department material safety data sheets 

(MSDSs) or lists of MSDS's and hazardous chemical inventory forms 

(also known as Tier I and II forms). This information helps the local 

government respond in the event of a spill or release of the chemical. 

EPCRA §313 requires manufacturing facilities included in SIC codes 

20 through 39, which have ten or more employees, and which 

manufacture, process, or use specified chemicals in amounts greater 

than threshold quantities, to submit an annual toxic chemical release 

report. This report, commonly known as the Form R, covers releases 

and transfers of toxic chemicals to various facilities and environmental 

media, and allows EPA to compile the national Toxic Release 

Inventory (TRI) database. 

All information submitted pursuant to EPCRA regulations is publicly 

accessible, unless protected by a trade secret claim. 

EPA's RCRA, Superfund and EPCRA Hotline, at (800) 424-9346, answers 

questions and distributes guidance regarding the emergency planning and 

community right-to-know regulations. The EPCRA Hotline operates 

weekdays from 9:00 a.m. to 6:00 p.m., ET, excluding Federal holidays. 

Clean Water Act (CWA) 

The primary objective of the Federal Water Pollution Control Act, commonly 

referred to as the CWA, is to restore and maintain the chemical, physical, and 

biological integrity of the nation's surface waters. Pollutants regulated under 

the CWA include "priority" pollutants and various toxic pollutants; 

"conventional" pollutants, such as biochemical oxygen demand (BOD), total 

suspended solids (TSS), fecal coliform, oil and grease, and pH; and "nonconventional" pollutants which are pollutants not identified as either 

conventional or priority. 

The CWA regulates both direct and indirect discharges. The National 

Pollutant Discharge Elimination System (NPDES) program (CWA §402) 

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controls direct discharges into navigable waters. Direct discharges or "point 

source" discharges are from sources such as pipes and sewers. NPDES 

permits, issued by either EPA or an authorized State (EPA has authorized 42 

States to administer the NPDES program), contain industry-specific, 

technology-based and/or water quality-based limits, and establish pollutant 

monitoring requirements. A facility that intends to discharge into the nation's 

waters must obtain a permit prior to initiating its discharge. A permit 

applicant must provide quantitative analytical data identifying the types of 

pollutants present in the facility's effluent. The permit will then set forth the 

conditions and effluent limitations under which a facility may make a 

discharge. 

A NPDES permit may also include discharge limits based on Federal or State 

water quality criteria or standards that were designed to protect designated 

uses of surface waters, such as supporting aquatic life or recreation. These 

standards, unlike the technological standards, generally do not take into 

account technological feasibility or costs. Water quality criteria and standards 

vary from state to state, and site to site, depending on the use classification 

of the receiving body of water. Most states follow EPA guidelines, which 

propose aquatic life and human health criteria for many of the 126 priority 

pollutants. 

Storm Water Discharges 

In 1987 the CWA was amended to require EPA to establish a program to 

address storm water discharges. In response, EPA promulgated the NPDES 

storm water permit application regulations. These regulations require that 

facilities with the following storm water discharges apply for an NPDES 

permit: (1) a discharge associated with industrial activity; (2) a discharge 

from a large or medium municipal storm sewer system; or (3) a discharge 

which EPA or the State determines to contribute to a violation of a water 

quality standard or is a significant contributor of pollutants to waters of the 

United States. 

The term "storm water discharge associated with industrial activity" means a 

storm water discharge from one of 11 categories of industrial activity defined 

at 40 CFR 122.26. Six of the categories are defined by SIC codes while the 

other five are identified through narrative descriptions of the regulated 

industrial activity. If the primary SIC code of the facility is one of those 

identified in the regulations, the facility is subject to the storm water permit 

application requirements. If any activity at a facility is covered by one of the 

five narrative categories, storm water discharges from those areas where the 

activities occur are subject to storm water discharge permit application 

requirements. 

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Those facilities/activities that are subject to storm water discharge permit 

application requirements are identified below. To determine whether a 

particular facility falls within one of these categories, the regulation should be 

consulted. 

Category i: Facilities subject to storm water effluent guidelines, new 

source performance standards, or toxic pollutant effluent standards. 

Category ii: Facilities classified as SIC 24-lumber and wood 

products (except wood kitchen cabinets); SIC 26-paper and allied 

products (except paperboard containers and products); SIC 28-

chemicals and allied products (except drugs and paints); SIC 291-

petroleum refining; and SIC 311-leather tanning and finishing, 32 

(except 323)-stone, clay, glass, and concrete, 33-primary metals, 

3441-fabricated structural metal, and 373-ship and boat building and 

repairing. 

Category iii: Facilities classified as SIC 10-metal mining; SIC 12-

coal mining; SIC 13-oil and gas extraction; and SIC 14-nonmetallic 

mineral mining. 

Category iv: Hazardous waste treatment, storage, or disposal 

facilities. 

Category v: Landfills, land application sites, and open dumps that 

receive or have received industrial wastes. 

Category vi: Facilities classified as SIC 5015-used motor vehicle 

parts; and SIC 5093-automotive scrap and waste material recycling 

facilities. 

Category vii: Steam electric power generating facilities. 

Category viii: Facilities classified as SIC 40-railroad transportation; 

SIC 41-local passenger transportation; SIC 42-trucking and 

warehousing (except public warehousing and storage); SIC 43-U.S. 

Postal Service; SIC 44-water transportation; SIC 45-transportation by 

air; and SIC 5171-petroleum bulk storage stations and terminals. 

Category ix: Sewage treatment works. 

Category x: Construction activities except operations that result in 

the disturbance of less than five acres of total land area. 

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Category xi: Facilities classified as SIC 20-food and kindred 

products; SIC 21-tobacco products; SIC 22-textile mill products; SIC 

23-apparel related products; SIC 2434-wood kitchen cabinets 

manufacturing; SIC 25-furniture and fixtures; SIC 265-paperboard 

containers and boxes; SIC 267-converted paper and paperboard 

products; SIC 27-printing, publishing, and allied industries; SIC 283-

drugs; SIC 285-paints, varnishes, lacquer, enamels, and allied 

products; SIC 30-rubber and plastics; SIC 31-leather and leather 

products (except leather and tanning and finishing); SIC 323-glass 

products; SIC 34-fabricated metal products (except fabricated 

structural metal); SIC 35-industrial and commercial machinery and 

computer equipment; SIC 36-electronic and other electrical 

equipment and components; SIC 37-transportation equipment (except 

ship and boat building and repairing); SIC 38-measuring, analyzing, 

and controlling instruments; SIC 39-miscellaneous manufacturing 

industries; and SIC 4221-4225-public warehousing and storage. 

Pretreatment Program 

Another type of discharge that is regulated by the CWA is one that goes to a 

publicly-owned treatment works (POTWs). The national pretreatment 

program (CWA §307(b)) controls the indirect discharge of pollutants to 

POTWs by "industrial users." Facilities regulated under §307(b) must meet 

certain pretreatment standards. The goal of the pretreatment program is to 

protect municipal wastewater treatment plants from damage that may occur 

when hazardous, toxic, or other wastes are discharged into a sewer system 

and to protect the quality of sludge generated by these plants. Discharges to 

a POTW are regulated primarily by the POTW itself, rather than the State or 

EPA. 

EPA has developed technology-based standards for industrial users of 

POTWs. Different standards apply to existing and new sources within each 

category. "Categorical" pretreatment standards applicable to an industry on 

a nationwide basis are developed by EPA. In addition, another kind of 

pretreatment standard, "local limits," are developed by the POTW in order to 

assist the POTW in achieving the effluent limitations in its NPDES permit. 

Regardless of whether a State is authorized to implement either the NPDES 

or the pretreatment program, if it develops its own program, it may enforce 

requirements more stringent than Federal standards. 

Spill Prevention, Control and Countermeasure Plans 

The 1990 Oil Pollution Act requires that facilities that could reasonably be 

expected to discharge oil in harmful quantities prepare and implement more 

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rigorous Spill Prevention Control and Countermeasure (SPCC) Plan required 

under the CWA (40 CFR §112.7). There are also criminal and civil penalties 

for deliberate or negligent spills of oil. Regulations covering response to oil 

discharges and contingency plans (40 CFR Part 300), and Facility Response 

Plans to oil discharges (40 CFR §112.20) and for PCB transformers and PCBcontaining items were revised and finalized in 1995. 

EPA’s Office of Water, at (202) 260-5700, will direct callers with questions 

about the CWA to the appropriate EPA office. EPA also maintains a 

bibliographic database of Office of Water publications which can be 

accessed through the Ground Water and Drinking Water resource center, at 

(202) 260-7786. 

Safe Drinking Water Act (SDWA) 

The SDWA mandates that EPA establish regulations to protect human health 

from contaminants in drinking water. The law authorizes EPA to develop 

national drinking water standards and to create a joint Federal-State system 

to ensure compliance with these standards. The SDWA also directs EPA to 

protect underground sources of drinking water through the control of 

underground injection of liquid wastes. 

EPA has developed primary and secondary drinking waterstandards under its 

SDWA authority. EPA and authorized states enforce the primary drinking 

water standards, which are, contaminant-specific concentration limits that 

apply to certain public drinking water supplies. Primary drinking water 

standards consist of maximum contaminant level goals (MCLGs), which are 

non-enforceable health-based goals, and maximum contaminant levels 

(MCLs), which are enforceable limits set as close to MCLGs as possible, 

considering cost and feasibility of attainment. 

The SDWA Underground Injection Control (UIC) program(40CFRParts 

144-148) is a permit program which protects underground sources of drinking 

water by regulating five classes of injection wells. UIC permits include 

design, operating, inspection, and monitoring requirements. Wells used to 

inject hazardous wastes must also comply with RCRA corrective action 

standards in order to have RCRA permit by rule status, and must meet 

applicable RCRA land disposal restrictions standards. The UIC permit 

program is primarily state-enforced, since EPA has authorized all but a few 

states to administer the program. 

The SDWA also provides for a Federally-implemented Sole Source Aquifer 

program, which prohibits Federal funds from being expended on projects that 

may contaminate the sole or principal source of drinking water for a given 

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area, and for a State-implemented Wellhead Protection program, designed to 

protect drinking water wells and drinking water recharge areas. 

EPA’s Safe Drinking Water Hotline, at (800) 426-4791, answers questions 

and distributes guidance pertaining to SDWA standards. The Hotline 

operates from 9:00 a.m. through 5:30 p.m., ET, excluding Federal holidays. 

Toxic Substances Control Act (TSCA) 

TSCA granted EPAauthority to create a regulatory framework to collect data 

on chemicals in order to evaluate, assess, mitigate, and control risks which 

may be posed by their manufacture, processing, and use. TSCA provides a 

variety of control methods to prevent chemicals from posing unreasonable 

risk. 

TSCA standards may apply at any point during a chemical’s life cycle. Under 

TSCA §5, EPA has established an inventory of chemical substances. If a 

chemical is not alreadyon the inventory, and has not been excluded by TSCA, 

a premanufacture notice (PMN) must be submitted to EPA prior to 

manufacture or import. The PMN must identify the chemical and provide 

available information on health and environmental effects. If available data 

are not sufficient to evaluate the chemicals effects, EPA can impose 

restrictions pending the development of information on its health and 

environmental effects. EPA can also restrict significant new uses of chemicals 

based upon factors such as the projected volume and use of the chemical. 

Under TSCA §6, EPA can ban the manufacture or distribution in commerce, 

limit the use, require labeling, or place other restrictions on chemicals that 

pose unreasonable risks. Among the chemicals EPA regulates under §6 

authority are asbestos, chlorofluorocarbons (CFCs), and polychlorinated 

biphenyls (PCBs). 

EPA’s TSCA Assistance Information Service, at (202) 554-1404, answers 

questions and distributes guidance pertaining to Toxic Substances Control 

Act standards. The Service operates from 8:30 a.m. through 4:30 p.m., ET, 

excluding Federal holidays. 

Clean Air Act (CAA) 

The CAA and its amendments, including the Clean Air Act Amendments 

(CAAA) of 1990, are designed to “protect and enhance the nation's air 

resources so as to promote the public health and welfare and the productive 

capacity of the population.” The CAA consists of six sections, known as 

Titles, which direct EPA to establish national standards for ambient air quality 

and for EPA and the States to implement, maintain, and enforce these 

standards through a variety of mechanisms. Under the CAAA, many facilities 

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will be required to obtain permits for the first time. State and local 

governments oversee, manage, and enforce many of the requirements of the 

CAAA. CAA regulations appear at 40 CFR Parts 50-99. 

Pursuant to Title I of the CAA, EPA has established national ambient air 

quality standards (NAAQSs) to limit levels of "criteria pollutants," including 

carbon monoxide, lead, nitrogen dioxide, particulate matter, volatile organic 

compounds (VOCs), ozone, and sulfur dioxide. Geographic areas that meet 

NAAQSs for a given pollutant are classified as attainment areas; those that do 

not meet NAAQSs are classified as non-attainment areas. Under §110 of the 

CAA, each State must develop a State Implementation Plan (SIP) to identify 

sources of air pollution and to determine what reductions are required to meet 

Federal air quality standards. Revised NAAQSs for particulates and ozone 

were proposed in 1996 and may go into effect as early as late 1997. 

Title I also authorizes EPA to establish New Source Performance Standards 

(NSPSs), which are nationally uniform emission standards for new stationary 

sources falling within particular industrial categories. NSPSs are based on the 

pollution control technology available to that category of industrial source. 

Under Title I, EPA establishes and enforces National Emission Standards for 

Hazardous Air Pollutants (NESHAPs), nationallyuniform standards oriented 

towards controlling particular hazardous air pollutants (HAPs). Title I, 

section 112(c) of the CAA further directed EPA to develop a list of sources 

that emit any of 189 HAPs, and to develop regulations for these categories of 

sources. To date, EPA has listed 174 categories and developed a schedule for 

the establishment of emission standards. The emission standards will be 

developed for both new and existing sources based on "maximum achievable 

control technology (MACT)." The MACT is defined as the control 

technology achieving the maximum degree of reduction in the emission of the 

HAPs, taking into account cost and other factors. 

Title II of the CAA pertains to mobile sources, such as cars, trucks, buses, 

and planes. Reformulated gasoline, automobile pollution control devices, and 

vapor recovery nozzles on gas pumps are a few of the mechanisms EPA uses 

to regulate mobile air emission sources. 

Title IV of the CAA establishes a sulfur dioxide emissions program designed 

to reduce the formation of acid rain. Reduction of sulfur dioxide releases will 

be obtained by granting to certain sources limited emissions allowances, 

which, beginning in 1995, will be set below previous levels of sulfur dioxide 

releases. 

Title V of the CAA of 1990 created a permit program for all "major sources" 

(and certain other sources) regulated under the CAA. One purpose of the 

operating permit is to include in a single document all air emissions 

requirements that apply to a given facility. States are developing the permit 

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programs in accordance with guidance and regulations from EPA. Once a 

State program is approved by EPA, permits will be issued and monitored by 

that State. 

Title VI of the CAA is intended to protect stratospheric ozone by phasing out 

the manufacture of ozone-depleting chemicals and restrict their use and 

distribution. Production of Class I substances, including 15 kinds of 

chlorofluorocarbons (CFCs) and chloroform, were phased out (except for 

essential uses) in 1996. 

EPA's Clean Air Technology Center, at (919) 541-0800, provides general 

assistance and information on CAA standards. The Stratospheric Ozone 

Information Hotline, at (800) 296-1996, provides general information about 

regulations promulgated under Title VI of the CAA, and EPA's EPCRA 

Hotline, at (800) 535-0202, answers questions about accidental release 

prevention under CAA §112(r). In addition, the Clean Air Technology 

Center’s website includes recent CAA rules, EPA guidance documents, and 

updates of EPA activities (www.epa.gov/ttn then select Directory and then 

CATC). 

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Pharmaceutical Industry Federal Statutes and Regulations 

VI.B. Industry Specific Requirements 

The pharmaceutical industry is affected by several major federal 

environmental statutes. In addition, the industry is subject to numerous laws 

and regulations from state and local governments designed to protect and 

improve the nation’s health, safety, and environment. A summary of the 

major federal regulations affecting the pharmaceutical industry follows. 

Clean Air Act (CAA) 

The original CAA authorized EPA to set limits on pharmaceutical plant 

emissions. Some of these new source performance standards (NSPS) apply 

to pharmaceutical manufacturers including those for flares (40 CFR Part 60 

Subpart A), and storage of volatile organic liquids (40 CFR Part 60 Subpart 

Kb). The Clean Air Act Amendments of 1990 set control standards by 

industrial sources for 41 pollutants to be met by 1995 and for 148 other 

pollutants to be reached by 2003. Under the air toxics provisions of the 

CAAA, more sources are covered including small businesses. The Hazardous 

Organic National Emissions Standard for Hazardous Air Pollutants, also 

known as HON, covers hundreds of chemicals and thousands of process units. 

The pharmaceutical industry is affected by standards for equipment leaks (40 

CFR Part 63 Subpart H), equipment leaks from pharmaceutical processes 

using carbon tetrachloride or methylene chloride (40 CFR Part 63 Subpart I), 

and standards for emissions from halogenated solvent cleaning (40 CFR Part 

63 Subpart T). The HON also includes innovative provisions such as 

emissions trading, that offer industry flexibility in complying with the rule's 

emissions goals. 

Specific industries are regulated under other National Emission Standards for 

Hazardous Air Pollutants (NESHAP). These standards are being developed 

for the pharmaceutical industry (see Section VI. C). Title V of the CAA 

introduces a new permit system that will require all major sources to obtain 

operating permits to cover all applicable control requirements. States were 

required to develop and implement the program in 1993 and the first permits 

were issued in 1994. In December 1994, Schering-Plough Pharmaceutical’s 

facility in Kenilworth, New Jersey, was the first in the nation to receive a 

facility-wide permit under this Title V program. 

Clean Water Act (CWA) 

The Clean Water Act, first passed in 1972 and amended in 1977 and 1987, 

gives EPA the authority to regulate effluents from sewage treatment works, 

chemical plants, and other industrial sources into waters. The act sets “best 

available” technology standards for treatment of wastes for both direct and 

indirect (to a Publicly Owned Treatment Works (POTW)) discharges. In 

1983, EPA proposed effluent guidelines for the pharmaceutical manufacturing 

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point source category. These guidelines are currently undergoing revisions 

(see Section VI. C). The implementation of the guidelines is left to the states 

who issue National Pollutant Discharge Elimination System (NPDES) permits 

for each facility. 

The pharmaceutical manufacturing effluent guidelines for point source 

category (40 CFR Part 439) is divided into processspecific effluent guidelines 

as follows: 

Fermentation - 40 CFR Part 439 Subpart A, 

Natural product extraction - 40 CFR Part 439 Subpart B, 

Chemical synthesis - 40 CFR Part 439 Subpart C, 

Mixing, compounding, formulation - 40 CFR Part 439 Subpart D, and 

Research - 40 CFR Part 439 Subpart E. 

Each Subpart consists of effluent limitations representing the amount of 

effluent reduction possible by using either best practicable control 

technologies (BPT), best conventional pollution technologies (BCT), or best 

available technologies (BAT). BPTs are used for discharges from existing 

point sources to control conventional and non-conventional pollutants as well 

as some priority pollutants. BCTs are used for discharges from point sources 

to control conventional pollutants. Finally, BATs are used to control priority 

pollutants and non-conventional pollutants when directly discharged into the 

nation’s waters. Standards are provided for cyanide, biologic oxygen demand 

(BOD), chemical oxygen demand (COD), total suspended solids (TSS) and 

pH. Guidelines for BCT and BAT for the research category, new source 

performance standards (NSPS), and pre-treatment standards for new and 

existing sources, are being revised and are in the final rule stage (see Section 

VI. C). 

The Storm Water Rule (40 CFR §122.26) requires pharmaceutical facilities 

discharging storm water associated with industrialactivities (40 CFR §122.26 

(b)(14)(xi)) to apply for storm water permits. 

Safe Drinking Water Act Underground Injection Control Program 

The federal Underground Injection Control (UIC) program was established 

under the provisions of the SDWA of 1974. This federal program prescribes 

minimum requirements for effective state UIC programs. Since ground water 

is a major source of drinking water in the United States, the UIC program 

requirements were designed to prevent contamination of Underground 

Sources of Drinking Water (USDW) resulting from the operation of injection 

wells. A USDW is defined as an “aquifer or its portion which supplies any 

public water system or contains a sufficient quantity of ground water to 

supply a public water system, or contains less than 10,000 milligrams per liter 

total dissolved solids and is not an exempted aquifer.” 

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Pharmaceutical Industry Federal Statutes and Regulations 

Since the passage of the Safe Drinking Water Act, state and federal regulatory 

agencies have modified existing programs or developed new strategies to 

protect ground water by establishing regulations to control the permitting, 

construction, operation, monitoring, and closure of injection wells. In 

Michigan, where all five of the pharmaceutical industry’s injection wells are 

located, the state has not sought authority to implement the federal UIC 

program but does regulate use of injection wells through state law. The EPA 

is the responsible regulatory agency for implementing the UIC program in the 

state. 

The five wells used by the pharmaceutical companies in Michigan are termed 

hazardous Class I injection wells since they inject hazardous waste into 

formations below the USDW. The process of selecting a site for a Class I 

disposal well involves evaluating many conditions with the most important 

being the determination that the underground formations possess the natural 

ability to contain and isolate the injected waste. A detailed study is conducted 

to determine the suitability of the underground formation for disposal. The 

receiving formation must be far below any usable ground waters and be 

separated from them by confining layers of rock, which prevent fluid 

migration into the ground water. The injection zone in the receiving 

formation must be of sufficient size and have sufficient pore space to accept 

and maintain the injected wastes. 

Class I injection wells are regulated in 40 CFR Part 146, Subpart G. Subpart 

G requires facilities with injection wells to submit operating reports and to 

submit plans for testing and monitoring the wastes, hydrogeologic conditions, 

condition of the well materials, mechanical integrity of the well, and ambient 

conditions in adjacent aquifers. Subpart G also sets criteria for siting Class 

I hazardous waste injection wells, construction requirements, corrective 

action procedures, operating requirements, and closure plans. 

Resource Conservation and Recovery Act (RCRA) 

The Resource Conservation and Recovery Act (RCRA) was enacted in 1976 

to address problems related to hazardous and solid waste management. 

RCRA gives EPA the authority to establish a list of solid and hazardous 

wastes and to establish standards and regulations for the treatment, storage, 

and disposal of these wastes. Regulations in Subtitle C of RCRA address the 

identification, generation, transportation, treatment, storage, and disposal of 

hazardous wastes. These regulations are found in 40 CFR Part 124 and CFR 

Parts 260-279. Under RCRA, persons who generate waste must determine 

whether the waste is defined as solid waste or hazardous waste. Solid wastes 

are considered hazardous wastes if they are listed by EPA as hazardous or if 

they exhibit characteristics of a hazardous waste: toxicity, ignitability, 

corrosivity, or reactivity. 

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Products, intermediates, and off-specification products potentially generated 

at pharmaceutical facilities that are considered hazardous wastes are listed in 

40 CFR Part 261.33(f). Some of the handling and treatment requirements for 

RCRA hazardous waste generators are covered under 40 CFR Part 262 and 

include the following: determining what constitutes a RCRA hazardous waste 

(Subpart A); manifesting (Subpart B); packaging, labeling, and accumulation 

time limits (Subpart C); and record keeping and reporting (Subpart D). 

Many pharmaceutical facilities store some hazardous wastes at the facility for 

more than 90 days, and are therefore, a storage facility under RCRA. Storage 

facilities are required to have a RCRA treatment, storage, and disposal facility 

(TSDF) permit (40 CFR Part 262.34). Some pharmaceutical facilities are 

considered TSDF facilities and are subject to the following regulations 

covered under 40 CFR Part 264: contingency plans and emergency 

procedures (40 CFR Part 264 Subpart D); manifesting, record keeping, and 

reporting (40 CFR Part 264 Subpart E); use and management of containers 

(40 CFR Part 264 Subpart I); tank systems (40 CFR Part 264 Subpart J); 

surface impoundments (40 CFR Part 264 Subpart K); land treatment (40 CFR 

Part 264 Subpart M); corrective action of hazardous waste releases (40 CFR 

Part 264 Subpart S); air emissions standards for process vents of processes 

that process or generate hazardous wastes (40 CFR Part 264 Subpart AA); 

emissions standards for leaks in hazardous waste handling equipment (40 CFR 

Part 264 Subpart BB); and emissions standards for containers, tanks, and 

surface impoundments that contain hazardous wastes (40 CFR Part 264 

Subpart CC). 

A number of RCRA wastes have been prohibited from land disposal unless 

treated to meet specific standards under the RCRA Land Disposal Restriction 

(LDR) program. The wastes covered by the RCRA LDRs are listed in 40 

CFR Part 268 Subpart C and include a number of wastes commonly generated 

at pharmaceutical facilities. Standards for the treatment and storage of 

restricted wastes are described in Subparts D and E, respectively. 

Many pharmaceutical manufacturing facilities are also subject to the 

underground storage tank (UST) program (40 CFR Part 280). The UST 

regulations apply to facilities that store either petroleum products or 

hazardous substances (except hazardous waste) identified under the 

Comprehensive Environmental Response, Compensation, and Liability Act. 

UST regulations address design standards, leak detection, operating practices, 

response to releases, financial responsibility for releases, and closure 

standards. 

Sector Notebook Project 112 September 1997 
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Comprehensive Environmental Response Compensation and Liability Act (CERCLA) 

The Comprehensive Environmental Response Compensation and Liability Act 

of1980 (CERCLA) and the Superfund Amendments and Reauthorization Act 

of 1986 (SARA) provide the basic legal framework for the federal 

“Superfund” program to clean up abandoned hazardous waste sites (40 CFR 

Part 305). The 1986 SARA legislation extended these taxes for five years and 

adopted a new broad-based corporate environmental tax, applicable to the 

allied chemicals (SIC 28) industry, which includes the pharmaceuticals 

industry. In 1990, Congress passed a simple reauthorization that did not 

substantially change the law but extended the program authority until 1994 

and the taxing authority until the end of 1995. A comprehensive 

reauthorization was considered in 1994, but not passed. Since the expiration 

of the taxing authority on December 31, 1995, taxes for Superfund have been 

temporarily suspended. The taxes can only be reinstated by reauthorization 

of Superfund or an omnibus reconciliation act which could specifically 

reauthorize taxing authority. The allied chemical industry pays about $300 

million a year in Superfund chemical feedstock taxes. Superfund’s liability 

standard is such that Potentially Responsible Parties (PRPs) may pay the 

entire cost of clean-up at sites, even though they may be responsible for only 

a fraction of the waste. 

Title III of the 1986 SARA amendments (also known as Emergency Response 

and Community Right-to-Know Act, EPCRA) requires all manufacturing 

facilities, including pharmaceutical facilities, to report annual information to 

the public about stored toxic substances as well as release of these substances 

into the environment (42 U.S.C. 9601). This is known as the Toxic Release 

Inventory (TRI). EPCRA also establishes requirements for federal, state, and 

local governments regarding emergency planning. In 1994, over 300 more 

chemicals were added to the list of chemicals for which reporting is required. 

Toxic Substances Control Act (TSCA) 

The pharmaceutical industry is specifically excluded from some of the 

requirements of TSCA. Any drugs manufactured, processed, and distributed 

in commerce are excluded by definition from the Inventory Reporting 

Regulations (40 CFR Part 710.4(c)) and the Pre-Manufacturing Notice 

requirements (40 CFR 720.30(a)) of TSCA. 

Sector Notebook Project 113 September 1997 
Pharmaceutical Industry Federal Statutes and Regulations 

VI.C. Pending and Proposed Regulatory Requirements 

Clean Air Act (CAA) 

Under the Clean Air Act, National Emissions Standards for Hazardous Air 

Pollutants (NESHAPS) are being developed for the pharmaceutical 

manufacturing industry. 

Clean Water Act (CWA) 

As part of the Clean Water Act revision process, the effluent guidelines for 

the pharmaceutical industry (40 CFR 439) are currently being revised and 

reviewed. A major part of the review considers the inclusion of limitations 

for toxic and non-conventional volatile organic pollutants. Additionally, the 

1983 New Source Performance Standards (NSPS) for conventional pollutants 

will also be reevaluated. 

Sector Notebook Project 114 September 1997 
Pharmaceutical Industry Federal Statutes and Regulations 

VI.D. Other Federal Regulations Affecting the Pharmaceutical Industry 

Food and Drug Administration (FDA) 

The Food and Drug Administration (FDA) is part of the Department of 

Health and Human Services. FDA has the statutory authority to regulate a 

wide range of products such as prescription and over-the-counter drugs, 

foods, biologics (e.g., blood plasma, vaccines), medical devices (e.g., needles, 

heart valves), veterinary drugs, cosmetics and consumer goods that emit 

radiation. This authority has been granted to FDA by Congress under various 

laws including the Federal Food, Drug and Cosmetic Act and the Public 

Health Service Act. 

There are five Centers within FDA that deal with FDA-regulated articles: 

Center for Drug Evaluation and Research (CDER), Center for Biologics 

Evaluation and Research (CBER), Center for Veterinary Medicine (CVM), 

Center for Devices and Radiological Health (CDRH), and Center for Food 

Safety and Applied Nutrition (CFSAN). The Centers review scientific 

information provided by persons wishing to place FDA-regulated articles into 

interstate commerce in order to determine whether regulatory requirements 

are met. FDA has offices throughout the U.S. where testing of FDAregulated articles is performed and where investigators are based. 

Investigators go to U.S. and foreign manufacturing facilities and other types 

of facilities involved in FDA-regulated activities to verify that they are in 

compliance with FDA regulations. 

FDA’s general approach to regulating various articles is similar, however, due 

to the diverse nature of these products, there are regulatory requirements 

tailored to each type of FDA-regulated article. Below is a summary of 

information relating to the type of products regulated by CDER. Additional 

information on other FDA-regulated articles may be located in 21 CFR or by 

contacting FDA directly. 

The manufacturing facilities that produce drugs for human use are regulated 

by CDER. The methods, facilities, and controls used for the manufacture, 

processing, and packing of a drug are reviewed by FDA to determine whether 

they are adequate to ensure and preserve the drug’s identity, strength, quality 

and purity. These characteristics are critical to ensure the safety and efficacy 

of a drug for human use. CDER conducts a scientific review of 

manufacturing methods and process controls for the drug substance and drug 

product. Field investigators conduct on-site reviews to verify the accuracy 

of the information submitted to CDER and to determine facility compliance 

with FDA’s Good Manufacturing Practices (GMPs). 

FDA’s review of a pharmaceutical facility does not include auditing 

compliance with regulations pertaining to the protection of the environment. 

Sector Notebook Project 115 September 1997 
Pharmaceutical Industry Federal Statutes and Regulations 

However, in accordance with the National Environmental Policy Act of 1969 

(NEPA), which requires all Federal agencies to assess the environmental 

impacts of their actions, CDER has integrated the consideration of the 

environmental impacts of approving drug product applications into its 

regulatory process (21 CFR Part 25). When an environmental review under 

NEPA is required, the review focuses on the environmental impacts of 

consumer use and disposal of the drug and is based on information submitted 

by the manufacturers, or on a manufacturer’s certification that an application 

falls within an established category of applications excluded from the 

requirement to submit information. 

After the original approval from CDER, an applicant may wish or need to 

make changes in the method of manufacture, testing, etc. described in their 

application. An applicant is required to notify FDA about each change in each 

condition established in an approved application (e.g., ingredients, solvents, 

processes) beyond the variations already provided for in the application (21 

CFR §314.70(a)). Depending on the type of change, the applicant notifies 

FDA about it in (1) a supplement requiring FDA approval before the change 

is made (§314.70(b)), (2) a supplement for changes that may be made before 

FDA approval (§314.70(c)), or (3) an annual report (§314.70(d)). Changes 

requiring FDA approval before they are made may include changes in the 

synthesis of the drug product or changes in solvents; the addition or deletion 

of an ingredient; and changes in the method of manufacture or in-process 

control of the drug product manufacturing process. The regulations specify 

the method of reporting certain changes. CDER also provides additional 

guidance on the method of reporting changes and documentation needed to 

support changes in guidance for industry (e.g., “Guidance for Industry, 

Immediate Release Solid Oral Dosage Forms, Scale-Up and Post Approval 

Changes: Chemistry Manufacturing and Controls, In Vitro Dissolution 

Testing and In Vivo Bioequivalence Documentation,” November 1995). 

The changes in a manufacturing process that a manufacturer may wish to 

undertake to prevent or reduce pollution would most likely be reported in a 

supplement requiring FDA approval before the change could be made (e.g., 

§§314.70(b)(1)(iv) and 314.70(b)(2)(v)). Changes such as these often require 

the manufacturer, before submitting the supplemental application to the FDA, 

to generate data that demonstrate the proposed change does not adversely 

affect the identity, strength, quality or purity of the drug. An applicant may 

ask FDA to expedite its review if a delay in making the change would impose 

an extraordinary hardship on the applicant (§314.70(b)). For changes relating 

to pollution prevention, “expedited review” is typically reserved for those 

changes mandated by the Federal, State or local environmental protection 

agencies, which must be accomplished within a specified time frame. The 

granting of an expedited review does not change the type of documentation 

that needs to be submitted to CDER to support the change. 

Sector Notebook Project 116 September 1997 
Pharmaceutical Industry Federal Statutes and Regulations 

Summary of FDA Regulations Applicable to the Pharmaceutical Industry 

Statutory Authority 

The Federal Food Drug and CosmeticAct, principally Sections 201, 301, 501, 

502, 503, 505, 506, 507, 512, 701, 704. 

CDER Regulations 

21 CFR Parts 300-499 

Manufacturing Information Submittal 

Manufacturing Information Submitted to CDER in Investigational New Drug 

Applications (INDs), New Drug Applications (NDAs), Antibiotic 

Applications, Abbreviated New Drug Applications (ANDAs), and 

Abbreviated Antibiotic Drug Applications (AADAs) 

INDs: §312.23(a)(7)(i) 

Other applications: §§314.50(d)(1)(i) and 314.50(d)(1)(ii)(a) 

Reporting Changes in Manufacturing Methods and Controls to CDER 

IND Information amendments: §312.31 

Supplements and other changes to an approved application: §314.70 

Good Manufacturing Practices (GMPs) 

Current Good Manufacturing Practice in Manufacturing, Processing, Packing, 

or Holding of Drugs; General, Part 210 

Current Good Manufacturing Practice for Finished Pharmaceuticals: Part 211 

Sector Notebook Project 117 September 1997 
Pharmaceutical Industry Federal Statutes and Regulations 

VI.E. Other Statutes and Regulations Affecting the Pharmaceutical Industry 

State Statutes and Regulations 

Most states have long-established broad-based environmental regulatory 

programs. Many of these regulatory schemes were enacted to implement 

federal programs and have been granted local primacy by the USEPA. 

Generally, the state programs are allowed to be more restrictive than federal 

requirements and, in some cases, they are. 

Some states with high concentrations of pharmaceutical manufacturing 

facilities, have their own regulations pertaining specifically to the industry. 

For example, both New York and New Jersey have Reasonably Achievable 

Control Technology (RACT) requirements for process specific volatile 

organic compound (VOC) emissions. Other states may have similar 

requirements under their own State Implementation Plans (SIPs). 

International Standards 

The U.S. Pharmaceutical industry is largely an international industry in which 

many companies have manufacturing facilities and sales and distribution 

operations in countries other than the U.S. In addition to U.S. federal statutes 

and regulations there are international laws, regulations, treaties, conventions 

and initiatives which are drivers of the environmental programs of 

pharmaceutical companies. The Basel Convention, ISO 14000 standards, the 

environmental requirements of NAFTA, and the evolving European Union 

Directives and Regulations are a few examples of important international 

environmental standards and programs which affect this industry. 

Drug Enforcement Administration Regulations 

Pharmaceutical manufacturing operations may also be regulated under the 

Controlled Substances Act. This Act regulates the manufacture, distribution, 

and dispensing of controlled substances and is enforced by the Drug 

Enforcement Administration (DEA). Examples of pharmaceutical products 

regulated under this Act include Demerol, Percodan, Ritalin, Valium, and 

Darvon. A list of controlled substances can be found in �1308 of 21 CFR. 

Sector Notebook Project 118 September 1997 
Pharmaceutical Industry Federal Statutes and Regulations 

The statute provides “closed” system for virtually every person who 

legitimately handles controlled substances, other than the ultimate user. As 

a means of controlling the distributionofregulated products, DEA sets quotas 

limiting the quantities which may be manufactured or produced to that 

amount which is necessary to meet the legitimate needs of the United States. 

The regulations set specific requirements for how such compounds are 

handled and stored at a manufacturing facility. In addition, when disposed of, 

these substances must be destroyed in the presence of DEA personnel in 

accordance with the regulations found in 21 CFR, Section 1307.21. 

Sector Notebook Project 119 September 1997 
Page 116 intentionally left blank. 
Pharmaceutical Industry Compliance and Enforcement History 

VII. COMPLIANCE AND ENFORCEMENT HISTORY 

Background 

Until recently, EPA has focused much of its attention on measuring 

compliance with specific environmental statutes. This approach allows the 

Agency to track compliance with the Clean Air Act, the Resource 

Conservation and Recovery Act, the Clean Water Act, and other 

environmental statutes. Within the last several years, the Agency has begun 

to supplement single-media compliance indicators with facility-specific, 

multimedia indicators of compliance. In doing so, EPA is in a better position 

to track compliance with all statutes at the facility level, and within specific 

industrial sectors. 

A major step in building the capacity to compile multimedia data for industrial 

sectors was the creation of EPA's Integrated Data for Enforcement Analysis 

(IDEA) system. IDEA has the capacity to “read into” the Agency's singlemedia databases, extract compliance records, and match the records to 

individual facilities. The IDEA system can match Air, Water, Waste, 

Toxics/Pesticides/EPCRA, TRI, and Enforcement Docket records for a given 

facility, and generate a list of historical permit, inspection, and enforcement 

activity. IDEA also has the capability to analyze data by geographic area and 

corporate holder. As the capacity to generate multimedia compliance data 

improves, EPA will make available more in-depth compliance and 

enforcement information. Additionally, sector-specific measures of success for 

compliance assistance efforts are under development. 

Compliance and Enforcement Profile Description 

Using inspection, violation, and enforcement data from the IDEA system, this 

section provides information regarding the historical compliance and 

enforcement activity of this sector. In order to mirror the facility universe 

reported in the Toxic Chemical Profile, the data reported within this section 

consists of records only from the TRI reporting universe. With this decision, 

the selection criteria are consistent across sectors with certain exceptions. 

For the sectors that do not normally report to the TRI program, data have 

been provided from EPA's Facility Indexing System (FINDS) which tracks 

facilities in all media databases. Please note, in this section, EPA does not 

attempt to define the actual number of facilities that fall within each sector. 

Instead, the section portrays the records of a subset of facilities within the 

sector that are well defined within EPA databases. 

As a check on the relative size of the full sector universe, most notebooks 

contain an estimated number of facilities within the sector according to the 

Bureau of Census (See Section II). With sectors dominated by small 

businesses, such as metal finishers and printers, the reporting universe within 

Sector Notebook Project 121 September 1997 
Pharmaceutical Industry Compliance and Enforcement History 

the EPA databases may be small in comparison to Census data. However, the 

group selected for inclusion in this data analysis section should be consistent 

with this sector's general makeup. 

Following this introduction is a list defining each data column presented 

within this section. These values represent a retrospective summary of 

inspections and enforcement actions, and solely reflect EPA, State, and local 

compliance assurance activities that have been entered into EPA databases. 

To identify any changes in trends, the EPA ran two data queries, one for the 

five calendar years (April 1, 1992 to March 31, 1997) and the other for the 

most recent twelve-month period (April 1, 1996 to March 31, 1997). The 

five-year analysis gives an average level of activity for that period for 

comparison to the more recent activity. 

Because most inspections focus on single-media requirements, the data 

queries presented in this section are taken from single media databases. These 

databases do not provide data on whether inspections are state/local or EPAled. However, the table breaking down the universe of violations does give 

the reader a crude measurement of the EPA's and states' efforts within each 

media program. The presented data illustrate the variations across EPA 

Regions for certain sectors.a This variation may be attributable to state/local 

data entry variations, specific geographic concentrations, proximity to 

population centers, sensitive ecosystems, highly toxic chemicals used in 

production, or historical noncompliance. Hence, the exhibited data do not 

rank regional performance or necessarily reflect which regions may have the 

most compliance problems. 

Compliance and Enforcement Data Definitions 

General Definitions 

Facility Indexing System (FINDS) -- this system assigns a common facility 

number to EPA single-media permit records. The FINDS identification 

number allows EPA to compile and review all permit, compliance, 

enforcement and pollutant release data for any given regulated facility. 

Integrated Data for Enforcement Analysis (IDEA) -- is a data integration 

system that can retrieve information from the major EPA program office 

databases. IDEA uses the FINDS identification number to link separate data 

records from EPA’s databases. This allows retrieval of records from across 

a EPA Regions include the following states: I (CT, MA, ME, RI, NH, VT); II (NJ, NY, PR, VI); III (DC, DE, MD, 

PA, VA, WV); IV (AL, FL, GA, KY, MS, NC, SC, TN); V (IL, IN, MI, MN, OH, WI); VI (AR, LA, NM, OK, 

TX); VII (IA, KS, MO, NE); VIII (CO, MT, ND, SD, UT, WY); IX (AZ, CA, HI, NV, Pacific Trust Territories); X 

(AK, ID, OR, WA). 

Sector Notebook Project 122 September 1997 
Pharmaceutical Industry Compliance and Enforcement History 

media or statutes for any given facility, thus creating a �master list” of 

records for that facility. Some of the data systems accessible through IDEA 

are: AIRS (Air Facility Indexing and Retrieval System, Office of Air and 

Radiation), PCS (Permit Compliance System, Office of Water), RCRIS 

(Resource Conservation and Recovery Information System, Office of Solid 

Waste), NCDB (National Compliance Data Base, Office of Prevention, 

Pesticides, and Toxic Substances), CERCLIS (Comprehensive Environmental 

and Liability Information System, Superfund), and TRIS (Toxic Release 

Inventory System). IDEA also contains information from outside sources 

such as Dun and Bradstreet and the Occupational Safety and Health 

Administration (OSHA). Most data queries displayed in notebook sections 

IV and VII were conducted using IDEA. 

Data Table Column Heading Definitions 

Facilities in Search -- are based on the universe of TRI reporters within the 

listed SIC code range. For industries not covered under TRI reporting 

requirements (metal mining, nonmetallic mineral mining, electric power 

generation, ground transportation, water transportation, and dry cleaning), or 

industries in which only a very small fraction of facilities report to TRI (e.g., 

printing), the notebook uses the FINDS universe for executing data queries. 

The SIC code range selected for each search is defined by each notebook's 

selected SIC code coverage described in Section II. 

Facilities Inspected --- indicates the level of EPA and state agency 

inspections for the facilities in this data search. These values show what 

percentage of the facility universe is inspected in a one-year or five-year 

period. 

Number of Inspections -- measures the total number of inspections 

conducted in this sector. An inspection event is counted each time it is 

entered into a single media database. 

Average Time Between Inspections -- provides an average length of time, 

expressed in months, between compliance inspections at a facility within the 

defined universe. 

Facilities with One or More Enforcement Actions -- expresses the number 

of facilities that were the subject of at least one enforcement action within the 

defined time period. This category is broken down further into federal and 

state actions. Data are obtained for administrative, civil/judicial, and criminal 

enforcement actions. Administrative actions include Notices of Violation 

(NOVs). A facility with multiple enforcement actions is only counted once 

in this column, e.g., a facility with 3 enforcement actions counts as 1 facility. 

Sector Notebook Project 123 September 1997 
--

Pharmaceutical Industry Compliance and Enforcement History 

Total Enforcement Actions -- describes the total number of enforcement 

actions identified for an industrial sector across all environmental statutes. A 

facility with multiple enforcement actions is counted multiple times, e.g., a 

facility with 3 enforcement actions counts as 3. 

State Lead Actions shows what percentage of the total enforcement 

actions are taken by state and local environmental agencies. Varying levels 

of use by states of EPA data systems may limit the volume of actions 

recorded as state enforcement activity. Some states extensively report 

enforcement activities into EPA data systems, while other states may use their 

own data systems. 

Federal Lead Actions -- shows what percentage of the total enforcement 

actions are taken by the United States Environmental Protection Agency. 

This value includes referrals fromstate agencies. Many of these actions result 

from coordinated or joint state/federal efforts. 

Enforcement to Inspection Rate -- is a ratio of enforcement actions to 

inspections, and is presented for comparative purposes only. This ratio is a 

rough indicator of the relationship between inspections and enforcement. It 

relates the number of enforcement actions and the number of inspections that 

occurred within the one-year or five-year period. This ratio includes the 

inspections and enforcement actions reported under the Clean Water Act 

(CWA), the Clean Air Act (CAA) and the Resource Conservation and 

Recovery Act (RCRA). Inspections and actions from the TSCA/FIFRA/ 

EPCRA database are not factored into this ratio because most of the actions 

taken under these programs are not the result of facility inspections. Also, 

this ratio does not account for enforcement actions arising from noninspection compliance monitoring activities (e.g., self-reported water 

discharges) that can result in enforcement action within the CAA, CWA, and 

RCRA. 

Facilities with One or More Violations Identified -- indicates the 

percentage of inspected facilities having a violation identified in one of the 

following data categories: In Violation or Significant Violation Status 

(CAA); Reportable Noncompliance, Current Year Noncompliance, Significant 

Noncompliance (CWA); Noncompliance and Significant Noncompliance 

(FIFRA, TSCA, and EPCRA); Unresolved Violation and Unresolved High 

Priority Violation (RCRA). The values presented for this column reflect the 

extent of noncompliance within the measured time frame, but do not 

distinguish between the severity of the noncompliance. Violation status may 

be a precursor to an enforcement action, but does not necessarily indicate that 

an enforcement action will occur. 

Sector Notebook Project 124 September 1997 
Pharmaceutical Industry Compliance and Enforcement History 

Media Breakdown of Enforcement Actions and Inspections -- four 

columns identify the proportion of total inspections and enforcement actions 

within EPA Air, Water, Waste, and FIFRA/TSCA/EPCRA databases. Each 

column is a percentage of either the �Total Inspections,” or the �Total 

Actions” column. 

VII.A. Pharmaceutical Industry Compliance History 

Table 20 provides an overview of the reported compliance and enforcement 

data for the pharmaceutical industry over the past five years (April 1992 to 

April 1997). These data are also broken out by EPA Region thereby 

permitting geographical comparisons. A few points evident from the data are 

listed below. 

�Region II has more than twice the number of pharmaceutical facilities than 

any other Region and more than half of all inspections nationally were carried 

out in this Region. The high rate of inspections in relation to the number of 

facilities is reflected in the Region’s relatively low average time between 

inspections (6 months) 

�Regions VI had only five pharmaceutical facilities (identified by the IDEA 

system) and a relatively high average time between inspections. However, in 

the past five years four enforcement actions were brought against facilities in 

the Region, giving it one of the highest enforcement to inspection rates. 

�Region X had only one pharmaceutical facility identified by the IDEA 

system. In the past five years this facility was inspected twice and had two 

enforcement action brought against it. 

Sector Notebook Project 125 September 1997 
Sector Notebook Project Table 20: Five-Year Enforcement and Compliance Summary for the Pharmaceutical Ind

A B C D E F G H I 

Region Facilities 

in 

Search 

Facilities 

Inspecte 

d 

Number of 

Inspections 

Average 

Months 

Between 

Inspections 

Facilities 

with 1 or 

More 

Enforcement 

Actions 

Total 

Enforcemen 

t Actions 

Percent 

State Lead 

Actions 

Percent Federal 

Lead 

Actions 

I 8 5 11 44 0 0 0% 0% II 60 53 624 6 21 95 84% 16% III 18 16 111 10 3 3 100% 0% IV 24 17 227 6 4 12 83% 17% V 22 16 143 9 4 5 60% 40% VI 5 5 17 18 1 4 0% 100% VII 12 8 37 19 1 1 100% 0% VIII 6 5 22 16 0 0 0% 0% IX 8 3 7 69 0 0 0% 0% X 1 1 2 30 1 2 50% 50% TOTA L 

164 129 1,201 8 35 122 80% 20% 

126 September 1997 
Pharmaceutical Industry Compliance and Enforcement History 

VII.B. Comparison of Enforcement Activity Between Selected Industries 

Tables 21 and 22 allow the compliance history of the pharmaceutical industry 

to be compared with the other industries covered by the industry sector 

notebooks. Comparisons between Tables 21 and 22 permit the identification 

of trends in compliance and enforcement records of the industry by comparing 

data covering the last five years to that of the past year. Some points evident 

from the data are listed below. 

�The pharmaceutical industry had one of the highest inspection rates as 

indicated by its relatively low average time between inspections (8 months) 

compared to other industries. 

�Compared to other sectors, the pharmaceutical industry had a relatively high 

enforcement to inspection rate (0.07) and a relatively high percent of facilities 

inspected with violations (105 percent). 

Tables 23 and 24 provide a more in-depth comparison between the 

pharmaceutical industry and other sectors by breaking out the compliance and 

enforcement data by environmental statute. As in Tables 21 and 22, the data 

cover the last five years (Table 23) and the previous year (Table 24) to 

facilitate the identification of recent trends. A few points evident from the 

data are listed below. 

�Over the past five years, about 80 percent of the industry’s inspections were 

for CAA and RCRA. Over the past year CAA and RCRA inspections 

accounted for almost 90 percent of inspections. This trend is primarily due 

to an increase in CAA inspections and a decrease in CWA and 

FIFRA/TSCA/EPCRA/Other inspections. 

�The percentage of CAA enforcement actions increased from 49 percent over 

the past five years to 71 percent in the past year. At the same time the 

percentage of CWA enforcement actions decreased from 25 percent to 14 

percent. 

Sector Notebook Project 127 September 1997 
Pharmaceutical Industry Compliance and Enforcement History 

Table 21: Five-Year E

nforcement and Com

pliance Sum

mary for Selected Industries 

J 

Enforcement 

to 

Inspection 

Rate 

0.07 

0.04 

0.05 

0.05 

0.06 

0.10 

0.04 

0.10 

0.06 

0.08 

0.09 

0.10 

0.11 0.08 

0.25 

0.06 

0.08 

0.07 

0.08 

0.11 

0.08 

0.06 

0.07 

0.13 

0.06 

0.09 0.10 

0.06 

0.02 

I 

Percent Federal 

Lead 

Actions 

47% 

11% 

21% 

23% 

10% 

30% 

19% 

20% 

12% 

26% 

24% 

20% 

35% 26% 

32% 

18% 

25% 

29% 

29% 

22% 

25% 

20% 

18% 

16% 

16% 

39% 12% 

24% 

5% 

H 

Percent 

State Lead 

Actions 

53% 

89% 

79% 

77% 

90% 

70% 

81% 

80% 

88% 

74% 

76% 

80% 

65% 74% 

68% 

82% 

75% 

71% 

71% 

78% 

75% 

80% 

82% 

84% 

84% 

61% 88% 

76% 

95% 

G 

Total 

Enforcement 

Actions 

111 

132 

309 

622 

83 

265 

91 

478 

428 

235 

219 

122 

468 

102 

763 

276 

277 

305 191 

174 

600 

251 

413 

32 

774 

70 97 

789 

66 

F 

Facilities with 1 

or More 

Enforcement 

Actions 

63 

88 

149 

385 

53 

134 

65 

150 

238 

89 

93 

35 

153 

47 

124 

178 

97 

121 113 

68 

365 

150 

253 

20 

375 

36 48 

403 

55 

E 

Average 

Months 

Between 

Inspections 

46 

52 

46 

25 

15 

15 

13 

6 

46 

9 

8 

8 

6 

12 

3 

25 

11 

5 

16 

7 

22 

17 

13 

9 

36 

38 27 

14 

95 

D 

Number of 

Inspections 

1,600 

3,748 

6,071 

12,826 

1,465 

2,767 

2,379 

4,630 

7,691 

3,087 

2,430 

1,201 

4,294 1,293 

3,081 

4,383 

3,474 

4,476 2,535 

1,640 

7,914 

4,500 

5,912 

243 

12,904 

816 

973 

14,210 

3,813 

C 

Facilities 

Inspected 

378 

741 

1,902 

2,803 

267 

473 

386 

430 

2,092 

286 

263 

129 

355 164 

148 

981 

388 

275 424 

161 

1,858 

863 

927 

37 

3,263 

192 231 

2,166 

2,360 

B 

Facilities 

in 

Search 

1,232 

3,256 

4,676 

5,256 

355 

712 

499 

484 

5,862 

441 

329 

164 

425 263 

156 

1,818 

615 

349 

669 

203 

2,906 

1,250 

1,260 

44 

7,786 

514 444 

3,270 

6,063 

A 

Industry Sector 

Metal Mining Coal Mining Oil and Gas Extraction Non-Metallic Mineral Mining Textiles Lumber and Wood Furniture Pulp and Paper Printing Inorganic Chemicals Resins and Manmade Fibers Pharmaceuticals Organic Chemicals Agricultural Chemicals Petroleum Refining Rubber and Plastic Stone, Clay, Glass and Concrete Iron and Steel Metal Castings Nonferrous Metals Fabricated Metal Products Electronics Automobile Assembly Shipbuilding and Repair Ground Transportation Water Transportation Air Transportation Fossil Fuel Electric Power Dry Cleaning 

Sector Notebook Project 128 September 1997 
Sector Notebook Project September 1997 129

Table 22: O

neYear E

nforcement and Com

pliance Sum

mary for Selected Industries

A

C

D

E

F

G

Facilities with 1 or More

Violations

Facilities with 1 or more

Enforcement Actions Total

Enforcemen

Industry Sector Actions

Facilities in

Search

Facilities

Inspected

Number of

Inspections Number

Percent* Number

Percent*

Metal Mining 1,232 142 211 102 72% 9 6% 1

Coal Mining 3,256 362 765 90 25% 20 6% 2Oil and Gas Extraction 4,676 874 1,173 127 15% 26 3% 3

Non-Metallic Mineral Mining 5,256 1,481 2,451 384 26% 73 5% 9

Textiles 355 172 295 96 56% 10 6% 1

Lumber and Wood 712 279 507 192 69% 44 16% 5

Furniture 499 254 459 136 54% 9 4% 1Pulp and Paper 484 317 788 248 78% 43 14% 7

Printing 5,862 892 1,363 577 65% 28 3% 5

Inorganic Chemicals 441 200 548 155 78% 19 10% 3

Resins and Manmade Fibers 329 173 419 152 88% 26 15% 3

Pharmaceuticals 164 80 209 84 105% 8 10% 1

Organic Chemicals 425 259 837 243 94% 42 16% 5

Agricultural Chemicals 263 105 206 102 97% 5 5% 1

Petroleum Refining 156 132 565 129 98% 58 44% 13

Rubber and Plastic 1,818 466 791 389 83% 33 7% 4

Stone, Clay, Glass and Concrete 615 255 678 151 59% 19 7% 2

Iron and Steel 349 197 866 174 88% 22 11% 3

Metal Castings 669 234 433 240 103% 24 10% 2

Nonferrous Metals 203 108 310 98 91% 17 16% 2

Fabricated Metal 2,906 849 1,377 796 94% 63 7% 8

Electronics 1,250 420 780 402 96% 27 6% 4

Automobile Assembly 1,260 507 1,058 431 85% 35 7% 4

Shipbuilding and Repair 44 22 51 19 86% 3 14% 

Ground Transportation 7,786 1,585 2,499 681 43% 85 5% 10

Water Transportation 514 84 141 53 63% 10 12% 1

Air Transportation 444 96 151 69 72% 8 8% 1

Fossil Fuel Electric Power 3,270 1,318 2,430 804 61% 100 8% 13

Dry Cleaning 6,063 1,234 1,436 314 25% 12 1% 1

*Percentages in Columns E and F are based on the number of facilities inspected (Column C). e vioccur without a facility inspection.

Table 23: Five-Year I

nspection and E

nforcement Sum

mary by Statute for Selected Industries

Industry Sector Facilities

Inspected

Total

Inspections

Total

Enforcement

Actions

Clean Air Act Clean Water Act RCRA

FI

EP

% of Total

Inspections

% of

Total

Actions

% of Total

Inspections

% of

Total

Actions

% of Total

Inspections

% of

Total

Actions

% of 

Inspec

Metal Mining 378 1,600 111 39% 19% 52% 52% 8% 12% 

Coal Mining 741 3,748 132 57% 64% 38% 28% 4% 8% 

Oil and Gas Extraction 1,902 6,071 309 75% 65% 16% 14% 8% 18% 

Non-Metallic Mineral Mining 2,803 12,826 622 83% 81% 14% 13% 3% 4% 

Textiles 267 1,465 83 58% 54% 22% 25% 18% 14% 

Lumber and Wood 473 2,767 265 49% 47% 6% 6% 44% 31% Furniture 386 2,379 91 62% 42% 3% 0% 34% 43% Pulp and Paper 430 4,630 478 51% 59% 32% 28% 15% 10% Printing 2,092 7,691 428 60% 64% 5% 3% 35% 29% 

Inorganic Chemicals 286 3,087 235 38% 44% 27% 21% 34% 30% 

Resins and Manmade Fibers 263 2,430 219 35% 43% 23% 28% 38% 23% 

Pharmaceuticals 129 1,201 122 35% 49% 15% 25% 45% 20% 

Organic Chemicals 355 4,294 468 37% 42% 16% 25% 44% 28% 

Agricultural Chemicals 164 1,293 102 43% 39% 24% 20% 28% 30% Petroleum Refining 148 3,081 763 42% 59% 20% 13% 36% 21% 

Rubber and Plastic 981 4,383 276 51% 44% 12% 11% 35% 34% 

Stone, Clay, Glass and Concrete 388 3,474 277 56% 57% 13% 9% 31% 30% 

Iron and Steel 275 4,476 305 45% 35% 26% 26% 28% 31% Metal Castings 424 2,535 191 55% 44% 11% 10% 32% 31% Nonferrous Metals 161 1,640 174 48% 43% 18% 17% 33% 31% Fabricated Metal 1,858 7,914 600 40% 33% 12% 11% 45% 43% Electronics 863 4,500 251 38% 32% 13% 11% 47% 50% 

Automobile Assembly 927 5,912 413 47% 39% 8% 9% 43% 43% Shipbuilding and Repair 37 243 32 39% 25% 14% 25% 42% 47% Ground Transportation 3,263 12,904 774 59% 41% 12% 11% 29% 45% Water Transportation 192 816 70 39% 29% 23% 34% 37% 33% Air Transportation 231 973 97 25% 32% 27% 20% 48% 48% Fossil Fuel Electric Power 2,166 14,210 789 57% 59% 32% 26% 11% 10% 

Dry Cleaning 2,360 3,813 66 56% 23% 3% 6% 41% 71% 

B

Percentages can exceed 100% becaus
Pharmaceutical Industry Compliance and Enforcement History 

Table 24: O

neYear I

nspection and E

nforcement Sum

mary by Statute for Selected Industries 

FIFR

A/TSCA/ 

EPCRA/Other 

% of 

Total 

Actions 

30% 

0% 

0% 

0% 

0% 

40% 

9% 

1% 

0% 

6% 

5% 

0% 

0% 

9% 

10% 

0% 

0% 

0% 

0% 

7% 

0% 

5% 

0% 

0% 

1% 

9% 0% 

0% 

0% 

% of Total 

Inspections 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 

0% 0% 

0% 

0% 

RCRA 

% of 

Total 

Actions 

30% 

5% 

24% 

2% 

8% 

25% 

45% 

7% 

23% 

25% 

5% 

14% 

34% 

36% 

15% 

23% 

30% 

24% 

35% 

30% 

57% 

53% 

47% 

50% 

44% 

45% 25% 

5% 

38% 

% of Total 

Inspections 

8% 

4% 

9% 

3% 

17% 

44% 

32% 

14% 

33% 

39% 

38% 

45% 

47% 

30% 

34% 

35% 

28% 

26% 

30% 

41% 

43% 

43% 

41% 

35% 

26% 

38% 57% 

9% 

30% 

Clean Water Act 

% of 

Total 

Actions 

40% 

14% 

9% 

9% 

17% 

5% 

0% 

19% 

0% 

9% 

38% 

14% 

13% 

0% 

8% 

13% 

7% 

29% 

8% 

20% 

2% 

5% 

6% 

50% 

10% 

36% 42% 

21% 

6% 

% of Total 

Inspections 

40% 

40% 

10% 

10% 

17% 

6% 

2% 

32% 

4% 

26% 

24% 

11% 

13% 

22% 

17% 

10% 

10% 

23% 

10% 

15% 

11% 

14% 

7% 

11% 

11% 

24% 15% 

32% 

1% 

Clean Air Act 

% of 

Total 

Actions 

0% 

82% 

68% 

89% 

75% 

30% 

45% 

73% 

77% 

59% 

51% 

71% 

54% 

55% 

67% 

64% 

63% 

47% 

58% 

43% 

41% 

37% 

47% 

0% 

46% 

9% 

33% 

73% 

56% 

% of Total 

Inspections 

52% 

56% 

82% 

87% 

66% 

51% 

66% 

54% 

63% 

35% 

38% 

43% 

40% 

48% 

49% 

55% 

62% 

52% 

60% 

44% 

46% 

44% 

53% 

54% 

64% 

38% 28% 

59% 

69% 

Total 

Enforcement 

Actions 

10 

22 

34 

91 

12 

52 

11 

74 

53 

31 

36 

14 

56 

11 

132 

41 

27 

34 

26 

28 

83 

43 

47 

4 

103 

11 12 

135 

16 

Total 

Inspections 

211 

765 

1,173 

2,451 

295 

507 

459 

788 

1,363 

548 

419 

209 

837 

206 

565 

791 

678 

866 

433 

310 

1,377 

780 

1,058 

51 

2,499 

141 151 

2,430 

1,436 

Facilities 

Inspected 

142 

362 

874 

1,481 

172 

279 

254 

317 

892 

200 

173 

80 

259 

105 

132 

466 

255 

197 

234 

108 

849 

420 

507 

22 

1,585 

84 

96 

1,318 

1,234 

Industry Sector 

Metal Mining Coal Mining Oil and Gas Extraction Non-Metallic Mineral Mining Textiles Lumber and Wood Furniture Pulp and Paper Printing Inorganic Chemicals Resins and Manmade Fibers Pharmaceuticals Organic Chemicals Agricultural Chemicals Petroleum Refining Rubber and Plastic Stone, Clay, Glass and Concrete Iron and Steel Metal Castings Nonferrous Metals Fabricated Metal Electronics Automobile Assembly Shipbuilding and Repair Ground Transportation Water Transportation Air Transportation Fossil Fuel Electric Power Dry Cleaning 

Sector Notebook Project 130 September 1997 
Pharmaceutical Industry Compliance and Enforcement History 

VII.C. Review of Major Legal Actions 

This section provides summary information about major cases that have 

affected this sector, and Supplementary Environmental Projects (SEPs). 

SEPs are compliance agreements that reduce a facility's stipulated penalty in 

return for an environmental project that exceeds the value of the reduction. 

Often, these projects fund pollution prevention activities that can significantly 

reduce the future pollutant loadings of a facility. 

VII.C.1. Review of Major Cases 

As indicated in EPA’s Enforcement Accomplishments Report, FY1995 and 

FY1996 publications, 5 significant enforcement actions were resolved between 

1994 and 1996 for the pharmaceutical industry. 

In the Matter of Ciba-Geigy, Inc.: On November 7, 1994, Region II issued 

an administrative consent order to Ciba-Geigy, Inc., assessing a penalty of 

$130,000 for violations of EPCRA at its Toms River, New Jersey, facility. 

The order was based upon an inspection of Ciba-Geigy’s facility that resulted 

in a sixteen count complaint alleging that Ciba-Geigy failed to report that it 

used certain of the following: copper compounds; glycol ethers; chromium 

compounds; cobalt compounds; C.I. Disperse Yellow 3; diethanolamine and 

ethylene glycol during the calendar years 1988 through 1991. 

Ciba-Geigy Superfund Site: On October 18, 1995, Region II issued an 

administrative order on consent under Sections 104, 107, and 122 of 

CERCLA to the Ciba-Geigy Corporation. The order requires Ciba-Geigy to 

perform, under EPA oversight, a feasibility study for Operable Unit Two to 

develop and evaluate remedial alternatives for approximately twenty-one 

potential source areas of groundwater contamination on the site. The 

estimated cost of the work that Ciba-Geigy will perform is $20 million. In 

addition, Ciba-Geigy will also pay all of EPA’s unreimbursed past response 

costs, $797,000, plus all of EPA’s future response costs, including oversight 

costs. 

The site is on the National Priorities List and located in Toms River, Ocean 

County, New Jersey. Groundwater at the site is contaminated with organic 

and inorganic compounds, and emanates from surface and subsurface former 

disposal areas on the site. Pursuant to a settlement with EPA in 1994, CibaGeigy is currentlyremediating the groundwater contamination. EPA recently 

completed a baseline public health risk assessment or source area surface 

soils, as well as a remedial investigation to examine the nature and extent of 

the contamination in the source areas at the site. In performing the feasibility 

study for the source areas, Ciba-Geigy has agreed to adopt EPA’s risk 

assessment and remedial investigation report. 

Sector Notebook Project 131 September 1997 
Pharmaceutical Industry Compliance and Enforcement History 

Takeda Chemical Products USA, Inc. (NC): On August 31, 1995, Region 

IV entered into a consent agreement/consent order (CACO) resolving claims 

against Takeda Chemical Products USA, Inc., for violations of RCRA at its 

vitamin manufacturing plant in Wilmington, North Carolina. As part of a 

solvent extraction process, Takeda generated a by-product referred to as 

DAS-fuel, which Takeda intended to burn for energy recovery. Prior to 

receiving any permits to burn the DAS-fuel, Takeda generated DAS-fuel and 

stored it on-site for a period in excess of 90 days without a permit or interim 

status, and later shipped it off-site. EPA determined that the DAS-fuel 

(essentially spent toluene mixed with DAS water and polymers) was F005 

hazardous waste. As a result, on September 24, 1994, Region IV issued a 

complaint for illegal storage of hazardous waste, failure to make a hazardous 

waste determination, and failure to manifest the DAS-fuel shipped off-site. 

The CACO requires Takeda to pay a civil penalty of $99,000, but allows 

Takeda to bring DAS-fuel back on-site for reprocessing, provided Takeda 

manages any waste it produces as a result as a hazardous waste. 

Abbott Laboratories: A consent agreement and final order was signed in 

September 1995, concerning Abbott LaboratoriesCorporation’s violations of 

RCRA standards applicable to the burning of hazardous waste in boilers and 

industrial furnaces (BIF) at its North Chicago, Illinois facility. Negotiations 

with Abbott Laboratories after issuance of the complaint in February 1994 

resulted in a penalty of $182,654. Abbott also agreed to conduct a 

supplemental environmental project (SEP) that will allow Abbott to recover 

and recycle the methylene chloride produced in its manufacturing processes 

and will reduce fugitive methylene chloride emissions. The SEP involves 

three separate, albeit similar, operations, replacing “wet” vacuum pump 

systems with “dry” pumps and high efficiency condensers. The projected cost 

of the SEP is $480,000. 

VII.C.2. Supplementary Environmental Projects (SEPs) 

Supplemental environmental projects (SEPs) are enforcement options that 

require the non-compliant facility to complete specific projects. Information 

on SEP cases can be accessed via the internet at EPA’s Enviro$en$e website: 

http://es.inel.gov/sep. 

Sector Notebook Project 132 September 1997 
Page 130 intentionally left blank.VIII. COMPLIANCE ACTIVITIES AND INITIATIVES 

This section highlights the activities undertaken by this industry sector and 

public agencies to voluntarily improve the sector's environmental 

performance. These activities include those independently initiated by 

industrial trade associations. In this section, the notebook also contains a 

listing and description of national and regional trade associations. 

VIII.A. Sector-related Programs and Activities 

The Pharmaceutical Research and Manufacturers of America (PhRMA) and 

EPA are considering developing compliance and regulations guides, 

concerning the interactions of EPA and FDA regulations for the 

pharmaceutical industry. 

VIII.B. EPA Voluntary Programs 

33/50 Program 

The 33/50 Program is a ground breaking program that has focused on 

reducing pollution from seventeen high-priority chemicals through voluntary 

partnerships with industry. The program's name stems from its goals: a 33% 

reduction in toxic releases and transfers by 1992, and a 50% reduction by 

1995, against a baseline of 1.5 billion pounds of releases and transfers in 

1988. The results have been impressive: 1,300 companies have joined the 

33/50 Program (representing over 6,000 facilities) and have reached the 

national targets a year ahead ofschedule. The 33% goal was reached in 1991, 

and the 50% goal -- a reduction of 745 million pounds of toxic wastes -- was 

reached in 1994. The 33/50 Program can provide case studies on many of the 

corporate accomplishments in reducing waste. 

Table 25 lists those companies participating in the 33/50 program that 

reported the SIC codes 2833 and 2834 to TRI. Some of the companies 

shown also listed facilities that are not producing pharmaceuticals. The 

number of facilities within each company that are participating in the 33/50 

program and that report pharmaceutical SIC codes is shown. Where available 

and quantifiable against 1988 releases and transfers, each company’s 33/50 

goals for 1995 and the actual total releases and transfers and percent 

reduction between 1988 and 1994 are presented. At the time of publication 

of this document (August 1997) 1995 33/50 Program TRI data were not 

available. 

Table 20 shows that 34 companies comprised of 160 facilities reporting SIC 

2833 and 2834 are participated in the 33/50 program. For those companies 

shown with more than one pharmaceutical manufacturing facility, all facilities 

may not be participating in 33/50. The 33/50 goals shown for companies with 

multiple pharmaceutical facilities, however, are company-wide, potentially 

aggregating more than one facility and facilities not carrying out 

pharmaceutical operations. In addition to company-wide goals, individual 
Pharmaceutical Industry Activities and Initiatives 

facilities within a company may have their own 33/50 goals or may be 

specifically listed as not participating in the 33/50 program. Since the actual 

percent reductions shown in the last column apply to all of the companies’ 

pharmaceutical manufacturing facilities and only pharmaceutical 

manufacturing facilities, direct comparisons to those company goals 

incorporating non-pharmaceutical facilities or excluding certain facilities may 

not be possible. For information on specific facilities participating in 33/50, 

contact David Sarokin (202-260-6907) at the 33/50 Program Office. 

Sector Notebook Project 134 September 1997 
--

--

Pharmaceutical Industry Activities and Initiatives 

Table 25: Pharmaceutical Industry Participation in the 33/50 Program 

Parent Company 

(Headquarters Location) 

Company-Owned 

Pharmaceutical 

Facilities 

Reporting 33/50 

Chemicals 

Company-wide 

% Reduction 

Goal

1

 (1988-

1995) 

1988 TRI 

Releases and 

Transfers of 

33/50 Chemicals 

(pounds) 

1994 TRI 

Releases and 

Transfers of 

33/50 Chemicals 

(pounds) 

Actual % 

Reduction for 

Pharmaceutical 

Facilities (1988 

- 1994) 

3M Minnesota Mining & 

Mfg.. Company -

St. Paul, MN 

2 70 885, 011 194, 850 78 

Abbott Laboratories -

North Chicago, IL 

6 20 3, 017, 869 2, 869, 793 5.0 

American Home Products 

Corporation -

Madison ,NJ 

19 50 1, 828, 970 930, 992 49 

Anabolic Incorporated -

Irvine, CA 

1 75 39, 602 0 100 

Baxter International Inc. -

Deerfield, IL 

8 80 921, 282 33, 312 96 

Boehringer Ingelheim Corp. 

-

Ridgefield, CT 

2 50 198, 500 247, 166 -24.5 

Bristol-Myers Squibb Co. -

New York, NY 

15 50 4, 876, 002 2, 305, 269 53 

Burroughs Wellcome Co. -

Durham, NC 

2 26 469, 075 193, 171 59 

Ciba-Geigy Company -

Tarrytown, NY 

14 50 2, 613, 266 1, 179, 471 55 

Coating Place Incorporated -

Verona, WI 

1 *** 149, 000 0 100 

Dow Chemical Company -

Midland, MI 

1 50 115, 000 109, 100 5 

Eastman Kodak Company -

Rochester, NY 

1 50 87, 350 15, 766 82 

Eli Lilly and Company -

Indianapolis, IN 

7 50 5, 749, 879 1, 194, 760 79 

Fisons Company -

Rochester, NY 

1 *** 3, 395 2, 229 34 

Ganes Chemicals Inc. -

Carlstadt, NJ 

2 *** 67, 018 19, 586 71 

Hoechst Celanese Company 

-

Corpus Christi, TX 

1 50 0 0 

Hoffmann-La Roche Inc. -

Nutley, NJ 

5 62 2, 154, 667 1, 230, 361 43 

Johnson & Johnson -

New Brunswick, NJ 

2 65 258, 090 234, 444 9 

Mallinckrodt Group Inc. -

Saint Louis, MO 

1 50 0 500 

Sector Notebook Project 135 September 1997 
--

--

Pharmaceutical Industry Activities and Initiatives 

Table 25: Pharmaceutical Industry Participation in the 33/50 Program 

Merck & Company Inc. -

Whitehouse Station, NJ 

Monsanto Company -

Saint Louis, MO 

7 

3 

50 

25 

5, 863, 293 927, 225 84 

9, 200 3, 480 62 

Par Pharmaceutical Inc. -

Spring Valley, NY 

1 *** 194, 099 0 100 

Perrigo Company -

Allegan, MI 

2 95 638, 235 0 100 

Pfizer Incorporated -

New York, NY 

10 50 2, 492, 314 3, 250, 940 -30 

Sandoz Corporation 

New York, NY 

18 50 572, 915 100, 439 82 

Schering-Plough Corp. -

Madison, NJ 

7 70 3, 181, 202 1, 867, 558 41 

Smithkline Beecham 

Americas -

Philadelphia, PA 

6 81 2, 882, 573 35, 469 99 

Solvay America Inc. -

Houston, TX 

1 * 0 36, 474 

Syntex USA Incorporated -

Palo Alto, CA 

3 33 1, 093, 051 393, 493 64 

Tishcon Corporation -

Westbury, NY 

2 ** 3, 900 113, 000 -2797 

United Organics Corp. -

Williamston, NC 

1 * 0 5, 950 

Upjohn Company -

Kalamazoo, MI 

3 50 7, 128, 339 5, 654, 150 21 

Upsher-Smith Laboratories 

Inc. -

Minneapolis, MN 

1 100 94, 000 320, 000 -240 

Warner-Lambert Company -

Morris Plains, NJ 

4 40 197, 540 242, 638 -22 

Total 160 47, 784, 637 23, 711, 586 50 

Source: US EPA 33/50 Program Office, 1996. 1995 33/50 TRI data was not available at time of publication. 1 Company-wide Reduction Goals aggregate all company-owned facilities which may include facilities not producing 

pharmaceuticals. 

* = Reduction goal not quantifiable against 1988 TRI data. 

** = Use reduction goal only. 

*** = No numeric reduction goal. 

Environmental Leadership Program 

The Environmental Leadership Program (ELP) is a national initiative 

developed by EPA that focuses on improving environmental performance, 

encouraging voluntary compliance, and building working relationships with 

stakeholders. EPA initiated a one year pilot program in 1995 by selecting 12 

projects at industrial facilities and federal installations that demonstrate the 

Sector Notebook Project 136 September 1997 
Pharmaceutical Industry Activities and Initiatives 

principles of the ELP program. These principles include: environmental 

management systems, multimedia compliance assurance, third-party 

verification of compliance, public measures of accountability, pollution 

prevention, community involvement, and mentor programs. In return for 

participating, pilot participants received public recognition and were given a 

period of time to correct any violations discovered during these experimental 

projects. 

EPA is making plans to launch its full-scale Environmental Leadership 

Program in 1997. The full-scale program will be facility-based with a 6-year 

participation cycle. Facilities that meet certain requirements will be eligible 

to participate, such as having a community outreach/employee involvement 

programs and an environmental management system (EMS) in place for 2 

years. (Contact: http://es.inel.gov/elp or Debby Thomas, ELP Deputy 

Director, at 202-564-5041) 

Project XL 

Project XL was initiated in March 1995 as a part of President Clinton’s 

Reinventing Environmental Regulation initiative. The projects seek to 

achieve cost effective environmental benefits by providing participants 

regulatory flexibility onthe condition that they produce greater environmental 

benefits. EPA and program participants will negotiate and sign a Final Project 

Agreement, detailing specific environmental objectives that the regulated 

entity shall satisfy. EPA will provide regulatory flexibility as an incentive for 

the participants’ superior environmental performance. Participants are 

encouraged to seek stakeholder support from local governments, businesses, 

and environmental groups. EPA hopes to implement fifty pilot projects in 

four categories, including industrial facilities, communities, and government 

facilities regulated by EPA. Applications are being accepted on a rolling 

basis. 

In 1996, EPA accepted a proposal by Merck to deliver superior 

environmental protection while allowing flexible operation at its 

pharmaceutical manufacturing facility near Elkton, Virginia. Merck, along 

with its stakeholders, developed a simplified air permit for the facility that will 

cap total air emissions of criteria pollutants at less than recent actual levels 

and allow the facility to make changes and additions to its manufacturing 

processes as soon as they are needed without prior approval. The upfront 

environmental benefit which will enable Merck to operate flexibly under the 

emissions cap will come from converting the coal burning powerhouse to 

natural gas. This conversion will reduce the site's actual air emissions by over 

900 tons per year of criteria pollutants, and 50 tons per year of hazardous air 

pollutants. 

Under the proposal, EPA and the Virginia Department of Environmental 

Sector Notebook Project 137 September 1997 
Pharmaceutical Industry Activities and Initiatives 

Quality (VADEQ) will adopt the Prevention of Significant Deterioration 

(PSD) permit through different mechanisms under their respective 

jurisdictions. EPA plans to promulgate a site-specific rule making in order to 

make adjustments to current applicable regulations to allow for the flexible 

operation of the permit. The Virginia State Air Pollution Control Board will 

promulgate a variance to make the PSD permit legally enforceable under state 

laws. These proposed actions and the draft permit were subject to public 

comment and it is expected that the permit will be issued to Merck during 

1997. 

For additional information regarding XL projects, including application 

procedures and criteria, see the May 23, 1995 Federal Register Notice. 

(Contact: Fax-on-Demand Hotline 202-260-8590, Web: http://www.epa.gov/ 

ProjectXL, or Christopher Knopes at EPA’s Office of Policy, Planning and 

Evaluation 202-260-9298) 

Climate Wise Program 

Climate Wise is helping US industries turn energy efficiency and pollution 

prevention into a corporate asset. Supported by the technical assistance, 

financing information and public recognition that Climate Wise offers, 

participating companies are developing and launching comprehensive 

industrial energy efficiency and pollution prevention action plans that save 

money and protect the environment. The nearly 300 Climate Wise companies 

expect to save more than $300 million and reduce greenhouse gas emissions 

by 18 million metric tons of carbon dioxide equivalent by the year 2000. 

Some of the actions companies are undertaking to achieve these results 

include: process improvements, boiler and steam system optimization, air 

compressor system improvements, fuel switching, and waste heat recovery 

measures including cogeneration. Created as part of the President’s Climate 

Change Action Plan, Climate Wise is jointly operated by the Department of 

Energy and EPA. Under the Plan many other programs were also launched 

or upgraded including Green Lights, WasteWi$e and DoE’s Motor Challenge 

Program. Climate Wise provides an umbrella for these programs which 

encourage company participation by providing information on the range of 

partnership opportunities available. (Contact: Pamela Herman, EPA, 202-

260-4407 or Jan Vernet, DoE, 202-586-4755) 

Energy Star Buildings Program 

EPA’s ENERGY STAR Buildings Program is a voluntary, profit-based program 

designed to improve the energy-efficiency in commercial and industrial 

buildings. Expanding the successful Green Lights Program, ENERGY STAR 

Buildings was launched in 1995. This program relies on a 5-stage strategy 

designed to maximize energysavingsthereby lowering energy bills, improving 

occupant comfort, and preventing pollution -- all at the same time. If 

Sector Notebook Project 138 September 1997 
Pharmaceutical Industry Activities and Initiatives 

implemented in every commercial and industrial building in the United States, 

ENERGY STAR Buildings could cut the nation’s energy bill by up to $25 billion 

and prevent up to 35% of carbon dioxide emissions. (This is equivalent to 

taking 60 million cars of the road). ENERGY STAR Buildings participants 

include corporations; small and medium sized businesses; local, federal and 

state governments; non-profit groups; schools; universities; and health care 

facilities. EPA provides technical and non-technical support including 

software, workshops, manuals, communication tools, and an information 

hotline. EPA’s Office of Air and Radiation manages the operation of the 

ENERGY STAR Buildings Program. (Contact: Green Light/Energy Star Hotline 

at 1-888-STAR-YES or Maria Tikoff Vargas, EPA Program Director at 202-

233-9178 or visit the ENERGY STAR Buildings Program website at 

http://www.epa.gov/appdstar/buildings/) 

Green Lights Program 

EPA’s Green Lights program was initiated in 1991 and has the goal of 

preventing pollution by encouraging U.S. institutions to use energy-efficient 

lighting technologies. The program saves money for businesses and 

organizations and creates a cleaner environment by reducing pollutants 

released into the atmosphere. The program has over 2,345 participants which 

include major corporations, small and medium sized businesses, federal, state 

and local governments, non-profit groups, schools, universities, and health 

care facilities. Each participant is required to survey their facilities and 

upgrade lighting wherever it is profitable. As of March 1997, participants had 

lowered their electric bills by $289 million annually. EPA provides technical 

assistance to the participants through a decision support software package, 

workshops and manuals, and an information hotline. EPA’s Office of Air and 

Radiation is responsible for operating the Green Lights Program. (Contact: 

Green Light/Energy Star Hotline at 1-888-STARYES or Maria Tikoff 

Vargar, EPA Program Director, at 202-233-9178 the ) 

WasteWi$e Program 

The WasteWi$e Programwas started in 1994 by EPA’s Office of Solid Waste 

and Emergency Response. The program is aimed at reducing municipal solid 

wastes by promoting waste prevention, recycling collection and the 

manufacturing and purchase of recycled products. As of 1997, the program 

had about 500 companies as members, one third of whom are Fortune 1000 

corporations. Members agree to identify and implement actions to reduce 

their solid wastes setting waste reduction goals and providing EPA with 

yearly progress reports. To member companies, EPA, in turn, provides 

technical assistance, publications, networking opportunities, and national and 

regional recognition. (Contact: WasteWi$e Hotline at 1-800-372-9473 or 

Joanne Oxley, EPA Program Manager, 703-308-0199) 

Sector Notebook Project 139 September 1997 
Pharmaceutical Industry Activities and Initiatives 

NICE3 

The U.S. Department of Energy is administering a grant program called The 

National Industrial Competitiveness through Energy, Environment, and 

Economics (NICE3

). By providing grants of up to 45 percent of the total 

project cost, the program encourages industry to reduce industrial waste at 

its source and become more energy-efficient and cost-competitive through 

waste minimization efforts. Grants are used by industry to design, test, and 

demonstrate new processes and/or equipment with the potential to reduce 

pollution and increase energy efficiency. The program is open to all 

industries; however, priority is given to proposals from participants in the 

forest products, chemicals, petroleum refining, steel, aluminum, metal casting 

and glass manufacturing sectors. (Contact: http//www.oit.doe.gov/access/ 

nice3, Chris Sifri, DOE, 303-275-4723 or Eric Hass, DOE, 303-275-4728) 

Design for the Environment (DfE) 

DfE is working with several industries to identify cost-effective pollution 

prevention strategies that reduce risks to workers and the environment. DfE 

helps businesses compare and evaluate the performance, cost, pollution 

prevention benefits, and human health and environmental risks associated with 

existing and alternative technologies. The goal of these projects is to 

encourage businesses to consider and use cleaner products, processes, and 

technologies. For more information about the DfE Program, call (202) 260-

1678. To obtain copies of DfE materials or for general information about 

DfE, contact EPA’s Pollution Prevention Information Clearinghouse at (202) 

260-1023 or visit the DfE Website at http://es.inel.gov/dfe. 

VIII.C. Trade Association/Industry Sponsored Activity 

VIII.C.1. Environmental Programs 

The Pharmaceuticals Research and Manufacturers of America (PhRMA) 

coordinates the research-based pharmaceutical industry’s response to 

industry-specific environmental issues, such as the pharmaceutical MACT. 

PhRMA works through an environmental committee, a series of 

subcommittees responsible for regulatory areas such as water and air, and ad 

hoc work groups to address narrowly-focused issues. 

The research-based pharmaceutical industry also relies on other broad-based 

trade associations for issues that affect the larger business community. 

Several of the PhRMA members are also members of the Chemical 

Manufacturers Association (CMA) and therefore are part of CMA’s 

Responsible Care® Initiative. 

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Pharmaceutical Industry Activities and Initiatives 

In addition, many pharmaceutical companies have been implementing their 

own environmental programs and initiatives to reduce the environmental 

impacts of their products and manufacturing processes. These programs are 

both company-wide and at the facility level. More information on such 

programs can be obtained by contacting individual companies and facilities. 

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Pharmaceutical Industry Activities and Initiatives 

VIII.C.2. Summary of Trade Associations 

Pharmaceutical Researchand Manufacturers

of America (PhRMA)

1100 15th Street, NW

Washington, D.C. 20035

Phone: (202) 835-3400

Fax: (202) 835-3414

Budget:$20,000,000 

Staff: 80 

Members: 40 companies 

Affiliates: 30 companies 

The Pharmaceutical Research and Manufacturers of America (PhRMA) is a non-profit 

organization which was established in 1958. Its main function is to assist researchbased pharmaceutical companies in discovery, development, and marketing of new 

drugs for humans. Comprised of most of the largest pharmaceutical companies in the 

United States, PhRMA members are primarily engaged in research and development 

of new medicines. To be a member of PhRMA, a company must be heavily involved 

in research and development (R&D) and must also manufacture and market finished 

dosage-form drugs under their own brand name. PhRMA member companies invest 

nearly $19 billion a year in discovering and developing new drugs. Additionally, 

PhRMA members account for approximately 90% of total pharmaceutical sales in the 

United States. 

Generic Pharmaceutical Industry 

Association 

1620 I Street, NW 

Washington, D.C. 20006-4005 

Phone: (202) 833-9070 

Fax: (202) 833-9612 

The Generic Pharmaceutical Industry Association 

Budget: $1-2,000,000 

Staff: 6 

Members: 46 companies 

(GPIA) is a primary trade 

association for manufacturers and distributors of generic drugs. Its main publication

is “GPIA News”.

National Pharmaceutical Alliance

(NPA)

421 King Street, Suite 222,

Alexandria, VA 22314

Phone: (703) 836-8816 Budget: $250-500,000

Fax: (703) 549-4749 Members: 165 companies

The National Pharmaceutical Alliance (NPA) is an organization which represents the

interests of small pharmaceutical companies and allied industries. Members of NPA

develop bioequivalent versions of major branded products, create products of

alternative combinations, strengths, and/or dosage forms, and market products which

are not produced by larger companies and which would not be available to the public

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Pharmaceutical Industry Activities and Initiatives 

otherwise. NPA assists in meeting these goals for its member companies. NPA also

publishes a bi-monthly journal called “NPA & News, Washington Report.”

American Pharmaceutical Association

(APhA)

2215 Constitution Ave. NW

Washington, DC 20037

Phone: (202) 628-4410 Budget: $12,000,000

Fax: (202) 783-2351 Members: 44,000

The American Pharmaceutical Association (APhA) is a professional society that 

includes pharmacists in all practice settings, educators, students, researchers, editors 

and publishers of pharmaceutical literature, pharmaceutical chemists and scientists, 

and food and drug officials. APhA promotes quality health care and comprehensive 

pharmaceutical care through the appropriate use of pharmacy services. APhA works 

to: represent the interests of the profession before governmentalbodies; interprets and 

disseminates information on developments in health care; and assure qualitypharmacy 

services and patient care. APhA fosters professional education and training of 

pharmacists; supports the Academy of Pharmaceutical Research and Science, the 

Academy of Pharmacy Practice and Management, and the Academy of Students of 

Pharmacy. APhA also publishes a quarterly newsletter, Academy Reporter, and 

monthly journals including, American Pharmacy (Journal of the American 

Pharmaceutical Association) and Journal of Pharmaceutical Sciences. 

United States Pharmacopeial 

Convention (USP) 

12601 Twinbrook Pky. 

Rockville, MD 20852 

Phone: (301) 881-0666 Budget: $20,000,000 

Fax: (301) 816-8247 Members: 395

The United States Pharmacopeial Convention (USP) is a recognized authority in 

medicine, pharmacy, and allied sciences. USP revises and publishes legally 

recognized compendia of drug standards including the National Formulary. 

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Pharmaceutical Industry Activities and Initiatives 

National Association of Pharmaceutical Manufacturers (NAPM)

320 Old Country Road - Suite 205

Garden City, NY 11530

Phone: (516) 741-3699

Fax: (516) 741-3696

Nonprescription Drug Manufacturers Association

1150 Connecticut Avenue, NW

Washington, DC 20036

Phone: (202) 429-9260

Fax: (202) 223-6835

National Wholesale Druggist’s Association

1821 Michael Faraday Drive

Suite 400

Reston, VA 22090

Phone: (703) 787-0000 ext. 240

Fax: (703) 787-6930

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Pharmaceutical Industry Contacts and References 

IX. CONTACTS/ACKNOWLEDGMENTS/REFERENCES 

For further information on selected topics within the pharmaceutical industry 

a list of publications and contacts are provided below: 

Contacts

a 

Name Organization Telephone Subject 

Emily Chow EPA/OECA (202) 564-7071 Chemical Industry Branch, 

Regulatory requirements and 

compliance assistance 

Joanne Berman EPA/OECA (202) 564-7064 Chemical Industry Branch, 

Regulatory requirements and 

compliance assistance 

Frank Hund EPA/OW (202) 260-7182 Regulatory Requirements (CWA) 

Randy McDonald EPA/OA (919)541-5402 Regulatory Requirements (CAA) 

Umesh Dholakia EPA Region II (212) 637-4023 Regulatory Requirements (CAA) 

Nancy Sager FDA- Center for Drug 

Evaluation and 

Research 

(301) 594-5629 Information on Human Drugs 

Daniel Kearns FDA - Center for 

Biologics Evaluation 

and Research 

(301) 827-3031 Information on Biologics 

Charles E. Eirkson, 

III 

FDA - Center for 

Veterinary Medicine 

(301) 594-1683 Information on Veterinary 

Medicine 

Mervin Parker FDA - Center for 

Devices and 

Radiological Health 

(301) 594-2186 Information on medical devices 

and radiological health 

Buzz L. Hoffman FDA - Center for 

Food Safety and 

Applied Nutrition 

(202) 418-3005 Information on foods 

Tom White PhRMA (202) 835-3546 Environmental Affairs 

CAA: Clean Air Act

CWA: Clean Water Act

OECA: Office of Enforcement and Compliance Assurance

OA: Office of Air

OW: Office of Water

FDA: Food and Drug Administration

PhRMA: Pharmaceutical Research and Manufacturers of America

a Many of the contacts listed above have provided valuable background information and comments during 

development of this document. EPA appreciates this support and acknowledges that the individuals listed do not 

necessarily endorse all statements made within this notebook. 

Sector Notebook Project 145 September 1997 
Pharmaceutical Industry Contacts and References 

REFERENCES 

Section II: Introduction to the Pharmaceutical Industry 

Opportunities and Challenges for Pharmaceutical Innovation: PhRMA Industry Profile, 

Pharmaceutical Research and Manufacturers of America, Washington, DC., 1996. 

Standard Industrial Classification Manual, 1987, Executive Office of the President, Office of 

Management and Budget, Washington, DC., 1987. 

Approved Drug Products with Therapeutic Equivalence Evaluations. FDA, Sixteenth Edition, 1996. 

United States 1992 Census of Manufacturers for Drugs, Industry Series, US Department of 

Commerce, Bureau of the Census, Washington, DC., 1992, (MC92-I-28C). 

United States Industrial Outlook 1994, US Department of Commerce, International Trade 

Administration, Washington, DC., 1994, chapter 43. 

Section III: Industrial Process Description 

Encyclopedia of Polymer Science and Engineering, Vol.6, John Wiley and Sons, Inc., New York, 

1986, p.514-515. 

Guidelines to Pollution Prevention: The Pharmaceutical Industry, US EPA, Washington, DC., 

October 1991, (EPA/625/7-91/017). 

Development Document for Proposed Effluent Limitations Guidelines and Standards for the 

Pharmaceutical Point Source Category, US EPA, Washington, DC., February, 1995, 

(EPA/821-R-95-019). 

Control of Volatile Organic Compound Emissions from Batch Processes, US EPA Guideline 

Series, Research Triangle Park, NC., November, 1993, (EPA-453/R-93-017). 

Guidance for Industry: Manufacture, Processing or Holding of Active Pharmaceutical Ingredients, 

U.S. Food and Drug Administration, August 1996. 

Kirk-Othmer Encyclopedia of Chemical Technology, Fourth Edition, John Wiley and Sons, New 

York, 1994. 

Remington: The Science of Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, 

Pennsylvania, 1995. 

Riegel’s Handbook of Industrial Chemistry, Chapter 25: The Pharmaceutical Industry, Jeffrey H. 

Watthey, Van Nostrand Reinhold, New York, 1992. 

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Pharmaceutical Industry Contacts and References 

Perry’s Chemical Engineers’ Handbook, Sixth Edition, McGraw-Hill Book Company, 1984. 

Personal Communication, Schering-Plough Pharmaceuticals, Kenilworth, New Jersey, October, 

1996. 

Air Pollution Engineering Manual - Chapter 16: Pharmaceutical Industry, Richard Crume and 

Jeffrey Portzer, eds. Buonicore, A.J., and Davis, W.T., Air and Waste Management 

Association, Van Nostrand Reinhold, New York, 1992. 

Air Pollution Control Equipment, Volume II Gases, Louis Theodore, and Anthony J. Buonicore, 

CFC Press, 1998. 

Section V: Pollution Prevention Opportunities 

Pharmaceutical Industry Waste Minimization Initiatives (White Paper), Pharmaceutical Research 

and Manufacturers of America, 1997. 

Guidelines to Pollution Prevention: The Pharmaceutical Industry, US EPA, Washington, DC., 

October 1991, (EPA/625/7-91/017). 

Profile of the Inorganic Chemical Industry, US EPA, Washington DC., September, 1995, (EPA, 

310-R-95-004). 

Pollution Prevention Research Opportunities in the Pharmaceutical Industry, New Jersey 

Institute of Technology, Emissions Reduction Research Center, New Jersey, April 1991. 

Sector Notebook Project 147 September 1997