Waste Minimization Assesment

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EPA/625/7-9l/017

October 1991

Guides to Pollution Prevention

The Pharmaceutical Industry

Risk Reduction Engineering Laboratoryand

Center for Environmental Research InformationOffice of Research and DevelopmentU.S. Environmental Protection Agency

Cincinnati, Ohio 45268

Printed on Recycled Paper


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Notice

This report has been subjected to the U.S. Environmental Protection Agencys peer and administrativereview and approved for publication. Mention of trade names or commercial products does not constituteendorsement or recommendation for use.

This document is intended as advisory guidance only to pharmaceutical manufacturers in developingapproaches for pollution prevention. Compliance with environmental and occupational safety and healthlaws is the responsibility of each individual business and is not the focus of this document.

Worksheets are provided for conducting waste minimization assessments of pharmaceutical manufac-turing plants. Users are encouraged to duplicate portions of this publication as needed to implement awaste minimization program.

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Foreword

Pharmaceutical manufacturing plants generate a variety of wastes during manufacturing, maintenanceand housekeeping operations. While maintenance and housekeeping activities are similar from one plant tothe next, the actual processes used in pharmaceutical manufacturing vary widely. The pharmaceuticalindustry is also highly competitive, so companies are often unwilling to divulge details pertaining to their

processes. With this diversity of processes comes a similarly diverse set of waste streams. Typical wastestreams include spent fermentation broths, process liquors, solvents, equipment washwaters, spilled materi-als, off-spec products, and used processing aids.

Reducing the generation of these wastes at the source, or recycling these wastes, will benefitpharmaceutical manufacturers by increasing product yields, reducing raw material needs, reducing disposalcosts, and reducing the liabilities associated with hazardous waste management. This guide provides an

overview of several pharmaceutical manufacturing processes and operations that generate waste andpresents options for minimizing the generation of waste materials through source reduction and recycling insuch cases where suitable opportunities exist. Because of the confidential nature of each companysspecific operation, only very general discussion of material substitution and process modification can begiven. The intent is to stimulate the thinking of manufacturers about their own processes, rather than

provide a comprehensive set of detailed recipes for reducing waste.


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Acknowledgments

This guide is based on a waste audit study for the pharmaceutical industry performed by ICFTechnology Inc. for the California Department of Health Services, under the direction of Benjamin Fries ofthe Alternative Technology Section, Toxic Substances Control Program. Teresa Harten of the U.S.Environmental Protection Agency, Office of Research and Development, Risk Reduction EngineeringLaboratory, was the project officer responsible for the preparation of this manual, which was edited and

produced by Jacobs Engineering Group Inc. Denise Luckhurst served as author of this manual.

The following individuals contributed substantially to the development of this document:

Mr. Laurence Della Vecchia, Ciba-Geigy Pharmaceuticals;Mr. Melvin Friedman, Boehringer-Ingelheim Pharmaceuticals;

Mr. Charles Sawyer, Camargo Associates;Ms. Cheryl Sutterfield and Mr. Tom White, Pharmaceutical Manufacturers Association.

Their contributions are hereby gratefully acknowledged.Much of the information in this guide that provides a national perspective on the issues of waste

generation and minimization for pharmaceutical manufacturers was provided originally to the U.S. Envi-ronmental Protection Agency by Versar, Inc. and Jacobs Engineering Group Inc. in Waste Mi nimizat ion -I ssues and Opt ions, volume It, report NTIS NO. PB87-114369 (1986).

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Contents

Section Page

Notice ........................................................................................................................................................... ii

Foreword.. .......................................................................................................................................................iii

Acknowledgments.. .........................................................................................................................................iv

Introduction.. .............................................................................................................................................1

Overview ofWaste Minimization....................................................................................................l

Waste Minimization Opportunity Assessment .................................................................................1

References .........................................................................................................................................3

Pharmaceutical Industry Profile ...............................................................................................................5

Industry Description ..........................................................................................................................5

Process Descriptions.. ........................................................................................................................5

Waste Streams ...................................................................................................................................8

References .........................................................................................................................................9

Waste Minimization Options for Pharmaceutical Facilities ..................................................................11

Source Reduction ............................................................................................................................11

Recovery and Recycle.. ...................................................................................................................13

References .......................................................................................................................................14

Waste Minimization Assessment Worksheets .......................................................................................17

Appendix A

Pharmaceutical Manufacturing Plant Assessments: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Case Studies of Plants A, B and C

Appendix B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... ....... 41

Where to Get Help: Further Information on Pollution Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

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Section 1Introduction

This guide is designed to provide pharmaceutical indus-try personnel with waste minimization options appropriatefor this industry. It also provides worksheets for carrying outa waste minimization assessment of a pharmaceutical manu-facturing plant. It is envisioned that this guide be used by

pharmaceutical companies, particularly their plant operatorsand engineers. Others who may find this document usefulare regulatory agency representatives, industry suppliers, andconsultants.

In the following sections of this manual you will find:

. A profile of the pharmaceutical industry andthe processes used by the industry (Section 2);

. Waste minimization options for pharmaceuticalfirms (Section 3);

. Waste minimization assessment guidelines andworksheets (Section 4);

. Appendices, containing:- Case studies of waste generation and waste

minimization practices of pharmaceuticalfirms;

- Where to get help: additional sources of in-formation.

The worksheets and the list of waste minimization op-

tions were developed through assessments of three pharma-ceutical manufacturing companies commissioned by the Cali-fornia Department of Health Services (Calif. DHS 1989).The operations, manufacturing processes, and waste genera-tion and management practices were surveyed, and theirexisting and potential waste minimization options were char-acterized.

Overview of Waste M in imi zation

Waste minimization is a policy specifically mandated bythe U.S. Congress in the 1984 Hazardous and Solid WastesAmendments to the Resource Conservation and RecoveryAct (RCRA). As the federal agency responsible for writingregulations under RCRA, the U.S. Environmental ProtectionAgency (EPA) has an interest in ensuring that new methodsand approaches are developed for minimizing hazardous wasteand that such information is made available to the industriesconcerned. This guide is one of the approaches EPA is usingto provide industry-specific information about hazardous wasteminimization. The options and procedures outlined can also

be used in efforts to minimize other wastes generated in abusiness.

In the working definition used by EPA, waste minimiza-tion consists of source reduct ion and recycling. Of the two

approaches, source reduction is considered preferable to re-cycling. While a few states consider treatment of waste anapproach to waste minimization, EPA does not, and thustreatment is not addressed in this guide.

Waste M inimization Opportuni ty Assessment

EPA has developed a general manual for waste minimi-zation in industry. The Waste M ini mizati on Opportuni tyAssessment M anual (USEPA 1988) tells how to conduct awaste minimization assessment and develop options for re-ducing hazardous waste generation at a facility. It explains

the management strategies needed to incorporate waste mini-mization into company policies and structure, how to estab-lish a company-wide waste minimization program, conductassessments, implement options, and make the program anongoing one.

A Waste Minimization Opportunity Assessment(WMOA), sometimes called a waste minimization audit, is asystematic procedure for identifying ways to reduce or elimi-nate waste. The four phases of a waste minimization oppor-tunity assessment are: planning and organization, assess-ment, feasibility analysis, and implementation. The stepsinvolved are shown in Figure 1 and presented in more detail

below. Briefly, the assessment consists of a careful review

of a plants operations and waste streams and the selec-tion of specific areas to assess. After a particular wastestream or area is established as the WMOA focus, a numberof options with the potential to minimize waste are devel-oped and screened. The technical and economic feasibilityof the selected options are then evaluated. Finally, the most

promising options are selected for implementation.

Planning and Organization Phase

Essential elements of planning and organization fora waste minimization program are: getting managementcommitment for the program; setting waste minimizationgoals; and organizing an assessment program task force.

Assessment PhaseThe assessment phase involves a number of steps:

l Collect process and site data;. Prioritize and select assessment targets;. Select assessment team;. Review data and inspect site;. Generate options; and. Screen and select options for further study.

Coll ect pr ocess and sit e data. The waste streams at amanufacturing plant should be identified and characterized.

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Figure 1. The Waste Minimization Assessment Procedure.

The Recognized Need to Minimize Waste

Planning and Organization Phase

l Get management commitment

l Set overall assessment program goals

l Organize assessment program task force

Assessment Organization &Commitment to Proceed

Assessment Phase

- Collect process and site data

- Prioritize and select assement targets

- Select people for assessment teams

- Review data and inspect site

l Generate options

l Screen and select options for further study

l Technical evaluation

l Economic evaluation

- Select options for implementation

Final Report, includingRecommended Options

Implementation Phase

. Justify projects and obtain funding

. Installation (equipment)

. Implementation (procedure)

. Evaluate performance

Successfully ImplementedWaste Minimization Projects

2

Select New AssessmentTargets and ReevaluatePrevious Optlons

Repeat the Process


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Information about waste streams may be available from haz-ardous waste manifests, National Pollutant Discharge Elimi-nation System (NPDES) reports, routine sampling programsand other sources.

Developing a basic understanding of the processes thatgenerate waste at a site is essential to the WMOA process.Flow diagrams should be prepared to identify the quantity,types and rates of waste generating processes. Also, prepar-

ing material balances for the different processes can be use-ful in tracking various process components and identifyinglosses or emissions that may have been unaccounted for

previously.

Prioritize and select assessment targets. Ideally, allwaste streams in a manufacturing plant should be evaluatedfor potential waste minimization opportunities. If resourcesare limited, however, the plant manager may need to concen-trate waste minimization efforts in a specific area. Suchconsiderations as quantity of waste, hazardous properties ofthe waste, regulations, safety of employees, economics, andother characteristics need to be evaluated in selecting thetarget streams or operations.

Select assessment team. The team should include peoplewith direct responsibility for and/or knowledge of the par-ticular waste stream or area of the facility being assessed.Equipment operators and people involved in routine wastemanagement should not be ignored.

Review data and inspect site. The assessment teamevaluates process data in advance of the inspection. Theinspection should follow the target process from the pointwhere raw materials enter to the point where products andwastes leave. The team should identify the suspected sourcesof waste. This may include the production processes, main-tenance operations, and storage areas for raw materials, fin-ished products, and work in progress. The inspection may

result in the formation of preliminary conclusions aboutwaste minimization opportunities. Full confirmation of theseconclusions may require additional data collection, analysis,and/or site visits.

Generat e opti ons. The objective of this step is to gener-ate a comprehensive set of waste minimization options forfurther consideration. Since technical and economic con-cerns will be considered in the later feasibility step, nooptions are ruled out at this time. Information from the siteinspection, as well as from trade associations, governmentagencies, technical and trade reports, equipment vendors,consultants, plant engineers, and operators may serve assources of ideas for waste minimization options.

Both source reduction and recycling options should beconsidered. Source reduction may be accomplished throughgood operating practices, technology changes, input materialchanges, and product changes. Recycling includes use andreuse of water, solvents and other recyclable materials, whereappropriate.

Screen and select options for further study. This screen-ing process is intended to select the most promising optionsfor a full technical and economic feasibility study. Througheither an informal review or a quantitative decision-making

process, options that appear marginal, impractical or inferiorare eliminated from further consideration.

Feasibility Phase

An option must be shown to be technically and eco-

nomically feasible in order to merit serious consideration foradoption at a facility. A technical evaluation determineswhether a proposed option will work in a specific applica-tion. Both process and equipment changes need to be as-sessed for their overall effects on waste quantity and productquality. A major concern is the impact of any proposedchanges on the product license. Minor changes may beimplemented rather easily, but major changes may requirereview and approval of the revised process by the FDA. Thetime required for this activity may render some options non-feasible.

An economic evaluation is carried out using standardmeasures of profitability such as payback period, return on

investment, and net present value. As in any other project,the cost elements of a waste minimization project can bebroken down into capital and operating costs. Savings andchanges in revenue also need to be considered, as do presentand future cost avoidances. In cases of increasingly stringentgovernment requirements, actions that increase the cost of

production may be necessary.

Implementation Phase

An option that passes both technical and economic feasi-bility reviews should be implemented. The project can beturned over to the appropriate group for execution while theWMOA team, with management support, continues the pro-cess of tracking wastes and identifying other opportunities

for waste minimization. Periodic reassessments may beconducted to see if the anticipated waste reductions wereachieved. Data can be tracked and reported for each imple-mented idea in terms such as pounds of waste per productionunit. Either the initial investigations of waste minimizationopportunities or the reassessments can be conducted usingthe worksheets in this manual.

References

Calif. DHS. May 1989. W aste audi t study : drugmanufacturing and processing industry. Reportprepared by ICF Technology Inc., Universal City,California for the Alternative Technology Section, ToxicSubstances Control Division, California Dept. of Health

Services.USEPA. 1988. Waste minimization opportunity assessment

manual. Hazardous Waste Engineering ResearchLaboratory, Cincinnati, Ohio. EPA/625/7-88/003.


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Section 2Pharmaceutical Industry Profile

I ndustry Description

The primary charter of the pharmaceutical industry is toproduce substances that have therapeutic value for humansand animals. The industry employs about 170,000 peopleand produces goods valued at over 39 billion dollars in 1987(USDC 1989). Products of the industry are split into fourcategories, based on the Standard Industrial Classification(SIC) system (USOMB 1987). including medicinal chemi-cals and botanical products (SIC 2833) pharmaceutical prepa-rations (SIC 2834), in vitro and in vivo diagnostic substances(SIC 2835) and biological products, except diagnostic sub-

stances (SIC 2836).

Process Descriptions

The pharmaceutical industry utilizes a vast array ofcomplex batch-type processes and technologies in the manu-facture of pharmaceutical products. Due to the diversity ofthese processes, it is impractical to provide a general set ofwaste minimization guidelines that would apply to all drugmanufacturing. Along with research and development, fourcommon methods used in the manufacture of pharmaceuti-cals are considered:

1) research and development,2) chemical synthesis,

3) natural product extraction,4) fermentation, and5) formulation.

The processes, raw materials, and wastes of these fiveareas arc discussed in the following sections.

Research and Development

Research and development (R&D) in the pharmaceuticalindustry encompasses several fields, including chemical re-search, microbiological research, and pharmacological re-search. The development of a new drug requires the coop-erative efforts of a large number of trained personnel special-izing in medicinal, organic, and analytical chemistry; micro-

biology; biochemistry; physiology; pharmacology; toxicol-ogy; chemical engineering; and pathology. As a result ofthis diverse nature of pharmaceutical research and develop-ment, a wide range of chemical and biological laboratorywastes are produced. Examples of the more common chemi-cal wastes produced from pharmaceutical research and de-velopment include halogenated and non-halogenated solvents,

photographic chemicals, radionuclides, bases, and oxidizers(Zanowiak 1982). Biopharmaceutical research also gener-ates significant amounts of waste materials, including bio-logical and medical wastes.

Chemical Synthesis

Most drugs today are produced by chemical synthesis.In a typical manufacturing plant, one or more batch reactorvessels is used in a series of reaction, separation and purifi-cation steps to make the desired end product. Numeroustypes of chemical reactions, recovery processes, and chemi-cals are employed in order to produce a wide variety of drug

products, each conforming to its own rigid product specifica-tion.

Within a drug manufacturing plant, reaction vessels and

ancillary equipment are often arranged into separate, dedi-cated process units, with these dedicated units being used forthe highest throughput products. Some pharmaceutical prod-ucts are manufactured in single product campaigns, whichmay last a few weeks or a few months depending upon themarket for the product. During a campaign, operators orcomputerized controllers add the required reagents and moni-tor process functions (i.e., flow rate, pH, temperature) ac-cording to good manufacturing practice (GMP) protocols.At the end of a campaign, process equipment is thoroughlycleaned. Campaign schedules are tightly controlled to ensuretimely product delivery and availability of raw materials and

process equipment.

Chemicals used in chemical synthesis operations rangewidely and include organic and inorganic reactants and cata-lysts. In addition, manufacturers use a wide variety ofsolvents listed as priority pollutants (USEPA 1983); theseare used for product recovery, purification, and as reactionmedia.

Waste streams from chemical synthesis operations arecomplex due to the varied operations and reactions em-ployed. Virtually every step of an organic synthesis gener-ates a mother liquor that contains unconverted reactants,reaction byproducts, and residual product in the organicsolvent base. Acids, bases, cyanides, and metals may also begenerated. Typically, the spent solvents are recovered on-site by distillation or extraction (Cooper 1983), which alsogenerate solvent recovery wastes such as still bottom tars.The use of volatile solvents can also result in air emissions,which may be reduced by employing scrubbers or condens-ers to reclaim the solvent vapors. An aqueous waste streamresults from miscible solvents, filtrates, concentrates, equip-ment cleaning, wet scrubbers, and spills. Because of thewaste stream concentration or toxicity, pretreatment may berequired prior to sewer discharge. Waste waters from syn-thesis processes typically have high biological oxygen de-mand (BOD), chemical oxygen demand (COD), and total

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suspended solid (TSS) levels and pHs from 1 to 11 (USEPA1983).

Natural Product Extraction

Natural product extraction is the production of pharma-ceuticals from natural material sources such as roots, leaves,and animal glands. Such pharmaceuticals, which typicallyexhibit unique pharmacological properties, include allergyrelief medicines, insulin, morphine, alkaloids, and papaver-ine. Another characteristic of natural product extraction isthat the amount of finished drug product is small comparedto the amount of natural source material used. During each

process step, the volume of material being worked can greatlydiminish to the point where final purification may occur onvolumes less than one-thousandth of the initial volume. Be-cause of these volume reductions, conventional batch andcontinuous processes typically are not suitable for naturalextraction operations.

Product recovery and purification processes include pre-cipitation, with lead and zinc being used as precipitatingagents, and solvent extraction, where common solvents in-clude ketones and alcohols. Solvents are used in product

recovery to dissolve fats and oils which would contaminatethe product. Ammonia, in solution or anhydrous forms, isoften used for pH control, as are the hydroxides of variouscations.

Wastes from natural product extraction include spentraw materials such as leaves and roots, water-soluble sol-vents, solvent vapors and waste waters. Extraction wastewaters typically have low BOD, COD and TSS levels and apH in the range of 6 to 8 (USEPA 1983).

Fermentation

Steroids, Vitamin B,,, and antibiotics are typically pro-duced using batch fermentation processes (Resource Integra-

tion Systems et al.). Overall, fermentation processes consistof two major steps: inoculum and seed preparation andfermentation, followed by crude product recovery and purifi-cation.

Sterile inoculum preparation begins in the lab with acarefully maintained population of a microbial strain. A fewcells from this culture are matured into a dense suspensionthrough a series of test tubes, agar slants, and shaker flasks.For further propagation, the cells are then transferred to aseed tank which operates like a full scale fermenter and isdesigned for maximum cell growth. The final seed tankvolume occupies from 1 to 20 percent of the volume used infull scale production.

To begin fermentation, a sterilized fermenter is chargedwith material from the seed tank through a series of sterilizedlines and valves. Once these sterilized nutrient materials areadded to the vessel, fermentation commences. During fer-mentation, the vessel contents are usually agitated and aer-ated with sterile air via a sparger. Dissolved oxygen content,pH, temperature and several other parameters are carefullymonitored throughout the fermentation cycle.

Following cell maturation, the fermenter broth is oftenfiltered to remove the solid residues resulting from the fer-

mentation process. The filtrate is then processed to recoverthe desired product using solvent extraction, precipitation,and ion exchange or adsorption chromatography (Bailey andOllis 1977).

In solvent extraction, the aqueous filtrate is contactedwith an organic solvent, typically methylene chloride or

butyl acetate, to transfer the product into the solvent phase.The product is recovered by further extraction processes,

precipitation, or crystallization. In precipitation processes,the product is recovered directly from the treated fermenterbroth. Ion exchange resins are used to remove products fromthe treated broth for additional purification steps prior tofinal isolation.

The fermentation process generates large volumes ofwastes such as the spent aqueous fermentation medium andsolid cell debris. The aqueous medium is very impure,containing unconsumed raw materials such as corn steepliquor, fish meal, and molasses. Filtration processes result inlarge quantities of solids in the form of spent filter cakewhich includes solid remains of the cells, filter aid, and someresidual product. After product recovery, spent filtrate isdischarged as waste water, augmented by waste water fromequipment cleaning operations and fermenter vent gas scrub-bing. Waste waters from fermentation operations typicallyhave high BOD, COD and TSS levels with a pH range of 4to 8 (USEPA 1983). Volatile solvents used in productrecovery operations may release vapors to the air.

Formulation

Pharmaceutical formulation is the preparation of dosageforms such as tablets, capsules, liquids, parenterals, and creamsand ointments. These formulations are discussed in thissection and a complete listing of dosage forms is presentedin Table 1.

Tablets account for over 90 percent of all medications

taken orally (Zanowiak 1982) and are produced in threevarieties: plain compressed, coated, and molded. The tabletform depends upon the desired release characteristics of theactive ingredient, which can be slow, fast, or sustained. Oneway of controlling the release characteristics involves spray-ing or tumbling the tablets with a coating material.

Tablets are produced by blending the active ingredientwith fillers, such as starch or sugar; and binders, such as cornstarch. The blend is compressed following one of three

production methods, including wet granulation, direct com-pression, or slugging. In wet granulation, the powderedactive ingredient and filler are blended and then wetted witha binder solution. Coarse granules are formed, dried, and

mixed with lubricants, such as magnesium stearate. The mixis then compressed into tablets.

Direct compression utilizes a tablet press in which a dieholds a measured amount of material and a punch com-

presses the tablet. Multi-layered tablets are produced usingpresses with several feed hoppers. The tablet is partiallycompressed each time a layer is added and is completelycompressed after the final layer is added.

Slugging is a process used for drugs that are unstableunder wet granulation procedures or for formulations that

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Table 1. Pharmaceutical Dosage Forms

Dosage Form

Liquid solutionsaromatic waters

liquors or solutions

syrups

elixirs

Constituents, Properties Uses

volatile solids or oils, water

water, chemicals

sweetener, solvent, medicinal agent

sweetened hydroalcoholic solution,may be medicated

flavoring agents, carminative action

internally or externally formulating aids

flavoring agent, medicinal

spirits, essences

tinctures

collodions

alcohol, water, volatile substances

natural drugs, extracted with appropriate solvent

pyroxylin in ether, medicinal agent (castor oil,camphor)

liniments

mucilages

parenteral solution

ophthalmic

oily or alcoholic solutions, suspensions

colloidal polymer solutions

sterile, pyrogen-free, isotonic, pH close tothat of blood; oily or aqueous suspension

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

nasal

otic

mouthwash, gargles

nhalations

enemas, douches

aqueous, isotonic, pH close to that of nasalfluid; sprays or drops

glycerol-based

aqueous, antiseptic

administered with mechanical devices

aqueous solution or suspension, may includemedicinal agent

Liquid dispersionssuspensions powder suspended in water, alcohol, glycol,

or an oil; viscosity builders, wetting agents,preservatives

emulsions, lotions

gels, jellies, magmas

gaseous solutions,dispersions

oil-in-water (o/w), or water-in-oil (w/o)

viscous, colloidal dispersions

delivered in atomizers. nebulizers. aerosols,inhalers

Semisolid and plasticdispersionsointments

pastes and cerates

hydrocarbon (oily), absorptive water-washable, or water-soluble bases;emulsifying agents; glycols; medicating agent

ointments with high dispersed solids or waxes,respectively

suppositories theobroma oil, glycerinated gelatin, or

polyethylene glycol base plus medicinal agent

Solidsbulk powder cornminuted or blended, dissolved in or

mixed with water

effervescentpowder

dusting powder

insufflations

CO,-releasing base ingredients

contain also absorbents

insufflator propels medicated powder intobody cavity

lyophilized powders reconstitution by pharmacist of unstable products

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flavor or medicinal

flavor or medicinal

external or internal

external for corns and bunions

external with rubbing

formulation adjuvant

intravenous, intramuscular, subcutaneous injection

eye treatment

nose treatment

ear treatment

refreshment, short-term bacterial control

medication of trachea or bronchioles

irrigation of body cavity

oral dosing, skin application

oral, external or injection

internal (oral), external

external or internal

external

external

insertion in body cavity

external, internal

oral

skin treatment

body cavities

various uses, including parenteral and oral


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Table 1. (continued).

Dosage Form Constituents, Properties Uses

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

massed or molded solidpills adhesive or binding agents facilitate compounding;

prepared by massing and piping external

troches, lozenges, pastilles prepared by piping and cutting or disk candytechnology; compounded with glycero-gelatin slow dissolution in mouth

tablet triturates small molded tablets intended for quick completedissolution (e.g., nitroglycerin) oral

granules particle size larger than powder oral

compressed tablets dissolved or mixed with water; great variety ofshapes and formulations oral and external

pellets for prolonged action implantation

coated tablets coating protective; slow release oral

Source: Zanowiak 1982

cannot be directly compressed. Slugging requires heavyduty tablet presses to compress relatively large 20 to 30 gramtablets which are ground and screened to a desired mesh size,then recompressed into final tablets.

After tablets, capsules, prepared in hard or soft form, arethe next most widely used oral dosage form for solid drugs.Hard capsules consist of two separate pieces which are formed

by dipping pins into a solution of gelatin maintained at aspecified temperature. When removed, a gelatin film isdeposited on the pins. The temperature of the gelatin affectsthe viscosity and, hence, the wall thickness of the capsule.After drying and trimming, the separate sections of the cap-sule are filled and joined.

Unlike hard capsules, soft capsules are prepared by plac-ing two continuous gelatin films between rotary die plates.As the plates are brought together and sealed to form the twohalves of the capsule, the drug, usually a nonaqueous solu-tion or soft mass, is injected into the capsule.

The third type of pharmaceutical formulation is the liq-uid dosage form prepared for injection or oral use, whichincludes solutions, syrups, elixirs, suspensions, and tinctures,all of which are usually prepared by mixing the solutes with

a selected solvent in a glass-lined or stainless steel vessel.Solutions are then filtered and pumped into storage tanks forquality control inspection prior to packaging in final contain-ers. Suspensions and emulsions are frequently preparedusing colloid mills and homogenizers.

Liquid dosage forms are prepared with preservatives toprevent mold and bacteria growth, but they do not requiresterilization if they are intended for oral or topical use.However, prescriptions and formulations for ophthalmic usemust be sterilized, and are, therefore, prepared in a mannersimilar to parenteral products.

Parenteral dosage forms are injected into the body eitherintramuscularly, intravenously, or subcutaneously. Parenteralsare prepared as solutions, as dry solids which are dissolvedimmediately before injection, as suspensions, as dry insolublesolids which are suspended before injection, and as emul-sions. The injection vehicle is usually aqueous but can benonaqueous. Terminal sterilization of parenteral dosages isperformed as soon as possible after tilling and sealing of theproduct container, usually using moist heat in a steam auto-clave. Products which are degraded by heat can be passed

through bacteria-retaining filters into sterile containers, whichare then sealed under aseptic conditions.

Ointments and creams, the fifth formulation type, aresemisolid dosage forms prepared for topical use. Ointmentsare usually prepared by melting a base, which is typically the

petroleum derivative petrolatum. This base is then blendedwith the drug and the cooled mixture is passed through acolloid or roller mill. Creams are oil-in-water or water-in-oilemulsions, rather than being petrolatum based, and are manu-factured in a similar manner.

Waste Streams

The wastes generated during these various formulation

processes result from cleaning and sterilizing equipment,chemical spills, rejected products and the processes them-selves. During mixing or tableting operations, dusts can begenerated which are recycled back into the formulation pro-cess, though small amounts of waste dust may be generated.The primary waste water source is equipment washwaterwhich may contain inorganic salts, sugars, and syrups andtypically has low BOD, COD, and TSS, with near neutral

pH. Air emissions may result from the use of any volatilesolvents in the formulation process. Table 2 lists typicalwaste and their process origins.

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Table 2. Pharmaceutical Process Wastes

Waste Description

Process liquors

Spent fermentation broth

Spent natural productraw materials

Spent aqueous solutions

Leftover raw materialcontainers

Scrubber water frompollution control equipment

Volatile organic compounds

Process Origin

Organic syntheses

Fermentation processes

Natural productextraction processes

Solvent extraction processes

Unloading of materialsinto process equipment

Dust or hazardous vaporgenerating processes

Chemical storage tanks,drums

Composition

Contaminated solvents

Contaminated water

Leaves, tissues

Contaminated water

Sags, drums (fiber, plastic,metal), plastic bottles

Contaminated water

Solvents

Off-spec or out-dated products

Spills

Waste water

Manufacturing operations

Manufacturing and laboperations

Equipment cleaning,extraction residues

Miscellaneous products

Miscellaneous chemicals

Contaminated water

Spent solvents

Used production materials

Solvent extraction orwash practices

Manufacturing operations

Used chemical reagents

Natural gas combustionproducts

R & D operations

Steam boilers

Contaminated solvents

Filters, tubing,diatomaceous earth

Miscellaneous chemicals

Carbon compounds, oxidesof nitrogen and sulfur

References w aste abat ement, reuse, recycle and reducti on

Bailey, J.E. and D.F. Ollis. 1977.Biochemicalopportunit ies in industry .

engineering fundamentals, McGraw-Hill, New York.USDC. 1989. U.S. Department of Commerce 2987 census

Calif. DHS. 1989. Waste audi t study : drug manufactur ingof manufacturers, preli mi nary r eport of i ndust ry seri es.

and processi ng industr y. Report Prepared by ICFUSEPA. 1983. U.S. Environmental Protection

Technology Inc. for the California Department of HealthAgency. Development document for effluent limitations

Services, Alternative Technology Section, Toxicguidelines and standards for the pharmaceutical

Substances Control Division.manufacturing point source category. EPA/440/1-83/084.

Cooper, C.M. 1983. Solvent Recovery, In: Ki rk -USOMB. 1987. U.S. Government Office of Management

Ot hmer encyclopedi a of chemi cal t echnology, Vol 21.and Budget. Standard industrial classification manual.

Third Edition.Zanowiak, P. 1982. Pharmaceuticals, In: Ki rk -

Resource Integration Systems Ltd., Ontario ResearchOthmer encyclopedi a of chemi cal t echnology, Vol 17,

Foundation, J.L. Richards and Assoc. Ltd., and TheThird Edition.

Proctor and Redfern Group. No Date. Technical manual:

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Section 3Waste Minimization Options

Pharmaceutical Facilitiesfor

Introduction

The pharmaceutical industry is characterized by a lowratio of finished products to raw materials (USEPA 1983), in

particular, among drugs produced by natural product extrac-tion and fermentation. Depending on the processes andmaterials involved, large amounts of extraction waste andfermentation media are generated which may contain hazard-ous components. The primary waste streams associated with

pharmaceutical operations are listed in Table 3, along withsuggested waste minimization options. Source reduction is

always the most desireable option with recycling, the reuseor reclamation of part or all of a waste stream, being the nextdesired option. Both source reduction options and recyclingoptions suited to pharmaceutical manufacturing are discussedin this section.

In addition to the specific recommendation providedbelow, rapidly advancing technology makes it important thatcompanies continually educate themselves about improve-ments that are waste reducing and pollution preventing. In-formation sources to help inform companies about suchtechnology include trade associations and journals, chemicaland equipment suppliers, equipment expositions, conferences,and industry newsletters. By keeping abreast of changes and

implementing applicable technology improvements, compa-nies can often take advantage of the dual benefits of reducedwaste generation and a more cost efficient operation.

Source Reduction

Source reduction of hazardous wastes can be achieved inindustry through changes in products, raw materials, processtechnologies, or procedural and organizational practices.Various source reduction alternatives, including material sub-stitution, process modification, and good operating practices,are provided here. Pharmaceutical manufacture is a diverseand highly competitive industry. Because of the highlyspecific and often confidential nature of each companysspecific operations, only very general discussions of material

substitution and process modification can be given. Theintent is to stimulate the thinking of manufacturers abouttheir own processes.

Material Substitution

Material substitution is a change in one or more of theraw materials used in production in order to reduce thevolume or toxicity of waste generated. For the pharmaceuti-cal industry, however, product reformulation is likely to bevery difficult due to the testing required to ensure that thereformulation has the same therapeutic effect, stability and

purity profile as the original drug. Furthermore, a consider-

able amount of time is required for FDA approval of thereformulated drug. An additional concern is the effect ofreformulation on the products aesthetic qualities becausechanges in characteristics such as taste, color, or dosage formcould result in customer rejection of the product.

Material substitution has been used successfully in phar-maceutical tablet coating operations to reduce hazardouswaste generation. In one manufacturing plant, developmentof a water-based solvent and new spray equipment for atablet coating application eliminated the need for expensive

($180,000) air pollution control equipment. The resultingsavings in solvent make-up cost was $15,000 per year (ILSR1986). Another tablet coating operation reduced methylenechloride usage from 60 tons per year to 8 tons per year byconverting from conventional film coating to aqueous filmcoating (Wayman and Miller 1987).

Other material substitutions that may be suited to phar-maceutical manufacturing include the use of aqueous-basedcleaning solutions instead of solvent-based solutions and thereplacement of chlorinated solvents with non-chlorinated sol-vents. Because of the reformulation difficulties encounteredin the production phase, waste minimization should be intro-duced at the research and development (R & D) phase.

Careful examination of all materials which can be used inmanufacturing or formulating a pharmaceutical with the aimto reduce toxicity of residuals should be an integral part of R& D activities.

Process Modificaiton

Besides investigating material substitution options, a phar-maceutical manufacturer can look for source reduction op

portunities that can be accomplished through modification ormodernization of the existing process. In most cases, the

product/process yield determines the product/waste ratio.Reasons for high byproduct yield include inadequate feedrate control, mixing or temperature control. By controllingreaction parameters, reactor efficiency can be improved and

byproduct formation reduced. Increased automation can alsoreduce operator errors. For example, automated systems formaterial handling and transfer, such as conveyor belts for

bagged materials, can help reduce spillage.

Fouling deposits on interior equipment surfaces are causedby crystallization, sedimentation, polymerization and corro-sion. These deposits reduce process operating efficienciesand increase waste generation. Proper agitator design andoptimization of operating temperatures can inhibit foulingdeposits.

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Table 3. Waste Minimization Methods for the Pharmaceutical Industry

Waste Stream

Containers

Waste Minimization Methods

Return empties to supplierThoroughly empty and triple rinse with minimal waterUse containers with recyclable linersSegregate solid wasteCollect and reuse plastic from in-house molding

Air Emissions Control bulk storage air emissions (e.g. internal floating roofs).

Use dedicated dust collectors and rework dust back into productOptimize fossil fuel combustionUse dedicated vent condensers and return condensate to source, where possibleMaintain N2 purge rates at minimum through vapor space of agitated reactors

Equipment Cleaning Wastes Maximize number of campaigns to reduce cleaning frequencyUse final rinse as prerinse on next cleaning cycleUse wiper blades and squeegees and rework remainders into products

Use low volume, high efficiency cleaning (e.g. spray heads)

Spills and Area Washdown Use dedicated vacuum systemsUse dry cleaning methodsUse recycled water

Off-spec Products Rework off-spec materialUse automated processing systems

Solvents Substitute aqueous systems where possibleReduce quantity of solvent usedRegenerate/recover spent solvent

Production Materials Validate cleaning and reuse

Another process modification option is to redesign chemi-cal transfer systems to reduce physical material losses. Forexample, replacing gas pressurization with a pumped transfereliminates the tank pressurizing step and its associated mate-rial losses (ICF 1987). Other design considerations for waste

minimization include modifying tank and vessel dimensionsto improve drainage, installing internal recycle systems forcooling waters and solvents, selecting new or improved cata-lysts, switching from batch to continuous processes for sol-vent recovery, and optimizing process parameters-to increaseoperating efficiency.

In one case, excessive solvent emissions from the purg-ing of autoclaves used for the manufacture of synthetic ste-roids were considerably reduced by installing rotameterswith integral needle valves to control nitrogen flow into thereactor. Nitrogen flow and resulting solvent vapor pickupwere reduced by a factor of six, compared to the baselinesituation where nitrogen flow was not controlled and oper-

ated in an on/off fashion without throttling.While process modification can result in significant waste

reduction, there may be major obstacles to this approach towaste minimization. Extensive process changes can be ex-

pensive; downtime will occur when production is stopped fornew equipment installation; and new processes must be testedand validated to ensure that the resulting product is accept-able. In addition, to the extent that processes and processequipment are specified in an approved drug application,FDA approval is likely to be required prior to instituting anychanges.

Good Operating Practices

The good operating practices listed in Table 4 can helpreduce hazardous and other waste generation and materiallosses.

Management I ncent i ves. Because of rising disposal costsand environmental responsibilities, many firms are now in-stituting environmental programs. Management initiativescan encourage new ideas from knowledgeable employees,which result in reduction or recycling of waste.

Employ ee Trai ning. To be effective, a waste manage-ment program must contain an employee training program sothat all personnel operating equipment or handling wastes aretrained in safe operating procedures, proper equipment use,

process control specifications, and industrial hygiene. Thistraining should occur prior to job assignment and continueduring the period of employment for all supervisors, lead

persons and operators.

Employees need to be informed of the materials thatthey will handle and the possible health effects from expo-sure to these materials. They should be fitted for any neces-sary protective equipment and trained in proper equipmentcare, equipment operation, material handling, and spillcleanup. Employees should be taught methods for detectingchemical releases and be briefed on regulatory requirements.

Regularly scheduled drills and safety meetings are anecessary part of employee training, as is supervisory reviewof industrial hygiene, material handling, and emergency prac-tices. Employees should be aware of waste disposal costs

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Table 4. Good Operating Practices

Plant Management: Waste Management:

Management incentives Waste/environmental auditsEmployee training Waste stream segregation

Closer supervision Waste handling and storage procedures

Production schedulingAdditional documentation

Materials Handling:

Materials tracking and inventory controlSpill preventionMaterial handling and storage proceduresPreventive maintenance

and liabilities, and they should understand the causes ofwaste generation and potential process upsets.

Closer Superv i sion. Closer supervision of plant person-nel and operations can increase production efficiency andreduce waste generation by reducing material losses, spills,

and production of off-spec products. Coordination withinthe overall plant operation can, in turn, increase opportunitiesfor early detection of mistakes.

Product ion Schedul ing. Effective production and main-tenance scheduling can help reduce waste generation. Properscheduling ensures raw materials are used before expirationand products are recovered and processed efficiently, whilemaintenance scheduling makes sure that work is done onequipment at a time least likely to result in product losses.Minimization of equipment cleaning requirement should beone of the objectives of production scheduling.

Addit ional Documentati on. Documentation of processprocedures ensures that job duties are precisely dcfincd. A

good operating manual informs employees how each job fitsinto the overall process. It describes startup, shutdown,emergency, special, and normal operating procedures; con-trol parameters; job responsibilities; and potential personnelhazards. The manual also should outline effluent sampling

procedures and equipment failure procedures. Having andusing accurate procedural guidelines will reduce waste gen-eration during maintenance or emergency shutdowns.

M aterial s Tracking and Inventory Cont rol . A signifi-cant contributor to hazardous waste generation is overstock-ing inventory. Accurate material, product, and waste track-ing improves material handling and storage procedures. Acomputerized inventory system can assist in controlling and

tracking materials and thus in reducing overstocking. Usinginventory on a first-in/first-out basis minimizes waste fromexpired chemicals. Some suppliers will take back expiredchemicals.

Spil l Preventi on. Spillage or leakage of hazardous chemi-cals generates hazardous wastes: liquid waste from washingspilled toxic chemicals, and solid waste from cleanup usingabsorbent materials. Spill and leak prevention are critical towaste minimization, and a properly trained and equippedspill control team is needed to prevent or contain spills.Methods of reducing or preventing spills include: conduct-

ing hazard assessment studies; using properly designed stor-age tanks and process vessels; equipping all liquid containerswith overflow alarms; and testing alarms periodically. Also,steps should be taken to maintain the physical integrity ofcontainers; set up administrative controls; and install suffi-cient secondary containment. Other preventive measuresinclude having a good valve layout; having interlock devicesto stop flow to leaking sections; not allowing the operators to

bypass interlocks or alter set points; and isolating equipmentor process lines that are not in service. Finally, spills andtheir related dollar values should be documented in relationto overall operating efficiency.

Mat eri al H andl ing and St orage Procedures. Properhandling and storage ensures that raw materials reach the

production process and products and wastes leave the pro-cess without spills, leaks, or other forms of waste generation.For small operations, proper storage of hazardous materialsincludes adequate spacing between rows of drums, storage

based on chemical compatibility, insulating electrical cir-cuitry, raising drums off the ground to prevent corrosion, andusing large drums (greater than 55 gallons) for storage. Allstorage containers should clearly identify the material in thecontainer and display health hazard warnings, storage, han-dling, first aid, and spill procedures. Material Safety DataSheets (MSDSs), which provide proper handling and safetyinformation, should be available to all employees workingwith hazardous materials.

M ain t enance Programs. A proper maintenance pro-gram, which includes preventive as well as corrective main-tenance, can minimize waste generation caused by equip-ment failure or mechanical breakdown and can cut costsstemming from equipment repairs, waste disposal, and busi-ness interruptions.

Preventive maintenance programs can reduce the inci-

dence of equipment breakdown and malfunction by routinelycleaning, making minor adjustments, lubricating, testing, mea-suring, and replacing minor parts. Typically, equipment datacards, master preventive maintenance schedules, deferred

preventive maintenance reports, equipment history cards, andequipment breakdown reports are used as record-keepingdocuments.

Corrective maintenance repairs the unexpected failuresas they occur and collects data for use in determining mainte-nance demand. Maintenance and operating data sheets should

be prepared for each piece of equipment.

Waste St ream Segregat i on. Hazardous waste hauledoff-site is often a mixture of two or more waste streams.

Waste stream segregation involves separating hazardous ma-terials from nonhazardous materials; sorting hazardous waste

by contaminant; and separating liquid from solid waste. Thissegregation reduces waste haulage volumes, simplifies dis-

posal, and facilitates recovery and recycle.

Recovery and Recycle

Recovering and recycling includes direct reuse of wastematerial, recovering used materials for a separate use, andremoving impurities from waste to obtain relatively puresubstances. The goal is to recover materials for reuse in the

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process or for reuse in a different application. The strictquality control requirements of the pharmaceutical industryoften restrict reuse opportunities, though some do exist. Af-ter a high degree of purification, materials recovered frommanufacturing processes may be reused. Recycling can be

performed either on-site or off-site. On-site recycling can beeither integral to an operation or in a separate operating area.

Advantages include:

reduced waste leaving the plant;management control of reclaimed material purity;reduced cost and liability of waste transportedoff-site;

reduced reporting requirements; andlower unit costs for raw materials use.

Disadvantages include:

capital expenditure for recycling equipment;additional operating and maintenance costs;

potential additional permitting requirements;increased operator training; andincreased risks to workers.

The last three disadvantages do not apply when recy-cling is included in the initial design of a process.

Off-site recycling, performed at commercial recyclingfacilities, is well suited for small quantity generators andfirms which cannot accept the technical, economic, and mana-gerial requirements of on-site recycling. The recycler maycharge the generator a straight fee or may base fees on wastevolumes and in some instances, may credit the generator forthe value of saleable wastes. The value of a waste dependson the type, market, purity, quantity and frequency of gen-eration, and distance between the generator and the recyclingoperation.

The decision to recycle on-site or off-site depends on thecapital investment, operating costs, and expertise needed. Ifwaste volumes are small or in-house expertise is unavailable,off-site recycling is more likely to be the alternative chosen(Calif. DHS 1986). Because generators can be held liable forfuture clean-up cost of wastes leaving their plants, it isimportant to select a recycler that is reliable.

Solvent Waste Recycling

Solvents are used for equipment cleaning, reaction me-dia, extraction media, and coating media. Processes forsolvent recovery from concentrated waste streams includedistillation, evaporation, liquid-liquid extraction, sedimenta-

tion, decantation, centrifugation, and filtration. Many stan-dard references provide a good description of these unitoperations. Table 5 lists some commonly used and recycledsolvents.

The following steps can improve solvent wasterecyclability:

Segregate solvent wastes as follows:

chlorinated from non-chlorinated solvent wastes;aliphatic from aromatic solvent wastes;

Table 5. Solvents Commonly Used In Pharmaceutical Manufacturing

Acetone

Cyclohexane

Methylene Chloride

Ethyl Acetate

Butyl Acetate

Methanol

Ethanol

isopropanol

Butanol

Pyridine

Methyl Ethyl Ketone

Methyl lsobutyl Ketone

Tetrahydrofuran

Source: Calif. DHS 1986.

chlorofluorocarbons from methylene chloride; andwater wastes from flammables.Minimize solids concentration in solvent wastes.

Label all solvent wastes and record compositions andmethods of generation.

Waste Exchanges

An alternative to recycling is waste exchange, whichinvolves the transfer of a waste to another company for useas is or for reuse after treatment. Waste exchanges are

private or government-subsidized organizations that help toidentify the supply and demand of various wastes. AppendixB lists exchanges currently in operation.

Three types of waste exchanges are available: informa-tion exchanges, material exchanges, and waste brokers. In-formation exchanges are clearing houses for informationon supply and demand, and typically publish a newsletter orcatalog. Material exchanges take temporary possession of awaste for transfer to a third party, in contrast to waste

brokers, who do not take possession of the waste but chargea fee to locate buyers or sellers.

Because of their high recovery value, metals and sol-vents are the most frequently recycled materials via waste

exchange. Other wastes commonly recycled through wasteexchanges include acids, alkalis, salts and other inorganicchemicals, organic chemicals, and metal sludges. Of thetotal materials listed with waste exchanges, approximately 20to 30 percent are actually exchanged (Calif. DHS 1989).

References

Calif. DHS. 1989. Waste audit study: drug manufacturingand pr ocessi ng industry . Report Prepared by ICFTechnology Inc. for the California Department of HealthServices, Alternative Technology Section, Toxic

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Substances Control Division.Calif. DHS. 1986. Guide to solvent w ast e reducti on

alternatives. Prepared by ICF Consulting Associates,Inc. for California Department of Health Services,Alternative Technology Section, Toxic SubstancesControl Division.

ICF Technology Inc. May 1987. Waste Identi f icationand M ini mi zati on: A Reference Guide.

ILSR. 1986. Proven profit s from pollut ion preventi on:

case stud i es in resour ce conserv at i on and w aste

reduction, Case Study 14. Institute for Local Self-Reliance.

USEPA. September 1983. Devel opment document for ef-fl uent l imi tat ions guideli nes and standards for thepharmaceuti cal manufacturi ng point source category.

EPA/440/1-83/084.Wayman, C.H. and K.S. Miller. November 18, 1987. Waste

minimization through the adaption of coatings conversionand catalytic oxidation,presented at the PMA workshop

on waste minimization practices in the pharmaceuticalindustry.

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Section 4Waste Minimization

Assessment Worksheets

The worksheets provided in this section are intended toassist pharmaceutical manufacturers in systematically evalu-ating waste generation processes and in identifying wasteminimization opportunities. These worksheets include onlythe waste minimization assessment phase of the proceduredescribed in the Waste Minimization Opportunity Assessment

Manual. A comprehensive waste minimization assessmentincludes planning and organization, gathering backgrounddata and information, a feasibility study of specific wasteminimization options, and an implementation phase.

In addition, performance of a material balance on eachmajor waste generating process is recommended. For a fulldescription of waste minimization assessment procedures,refer to the manual.

Table 6 lists the worksheets that are provided in thissection. After completing the worksheets, the assessmentteam should evaluate the applicable waste minimization op-tions and develop an implementation plan.

Table 6. List of Waste Minimization Assessment Worksheets

NO. Title Description

1. Waste Sources

2a. Waste Minimization: Material Handling

2b. Waste Minimization: Material Handling

2c. Waste Minimization: Material Handling

3. Input Materials Summary

4. Products Summary

5. Option Generation: Material Handling

6a. Process Description

6b. Process Description

6c. Process Description

6d. Process Description

6e. Process Description

7a. Waste Stream Summary

7b. Waste Description

6. Waste Minimization: Reuse and Recovery

9. Option Generation: Process Operation

10. Waste Minimization: Good Operating Practices

11. Option Generation: Good Operating Practices

Checklist of significant wastes

Questionnaire for material handling techniques

Questionnaire on bulk liquids handling

Questionnaire on drums, containers and packages

Questionnaire on raw materials and supplies

Questionnaire on products manufactured

Waste minimization options checklist

Questionnaire on processing operations





Relative importance of sources

Questionnaire on waste stream characteristics

Checklist of waste reuse and recovery techniques

Waste minimization options for process operations

Checklist for waste minimization techniques

Waste minimization options for good operating practices

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Appendix APharmaceutical Manufacturing Plant Assessments

Case Studies of Plants A,B, and C

In 1989 the California Department of Health Servicescommissioned a waste minimization study of three pharma-ceutical manufacturers. The objectives of the waste minimi-zation assessments were to:

. Gather site-specific information concerning thegeneration, handling, storage, treatment, anddisposal of hazardous wastes;

. Evaluate existing waste reduction practices;

. Develop recommendations for waste reductionthrough source reduction and recyclingtechniques; and

. Assess costs/benefits of existing andrecommended waste reduction techniques.

The first steps in conducting the assessments were se-lecting and contacting the plants to solicit voluntary partici-

pation in the assessment study. Plant selection emphasizedsmall businesses which generally lack the financial and/orinternal technical resources to perform a waste reductionassessment. One relatively large plant was also selected forstudy because it offered the opportunity to evaluate a widevariety of manufacturing operations, as well as a number ofin-place waste reduction measures.

During each of the plant visits, the team observed manu-

facturing processes; inspected waste management facilities;interviewed the plant manager, environmental compliancepersonnel, and operations supervisors; and reviewed and cop-ied records pertinent to waste generation and management.From the three assessments that were conducted, it wasevident that employee knowledge of waste streams, wasteminimization approaches and the hazardous waste regulatorystructure varied greatly. Most of their technical expertisecame from on-the-job experience or vendor contacts. Recordsof hazardous waste generation wcrc sketchy, and there was

little understanding of the importance of waste minimization.In all three plants, accurate material balances often could not

be prepared because of inadequate record-keeping.

It should be noted that the information presented hererepresents procedures which are being conducted by thethree pharmaceutical manufacturing companies. These procedures and the suggested waste minimization options shouldnot be construed to represent recommendations of the U.S.Environmental Protection Agency. In addition, these wastemanagement techniques are specific to the California firms.State regulations vary and alternate techniques may be re-

quired elsewhere.

This Appendix presents both the results of the assess-ments of the plants (here identified as A, B, and C) and the

potentially useful waste minimization options identifiedthrough the assessments. Also included are the practicesalready in use at the plants that have successfully reducedwaste generation from past levels. The original assessmentsmay be obtained from:

Mr. Benjamin FriesCalifornia Department of Health ServicesAlternative Technology DivisionToxic Substances Control Program

714/744 P StreetSacramento, CA 94234-7320(916) 324-1807

In addition, the results of the waste assessments wereused to prepare waste minimization assessment worksheetsto be completed by other pharmaceutical manufacturers in a&f-assessment process. Examples of the worksheets areincluded at the end of this Appendix.

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Plant AWaste Minimization Assessment

Plant Description

Plant A produces erythromycin base and erythromy-cin derivatives using batch fermentation. Erythromycin de-rivatives include erythromycin thiocyanate, erythromycinstearate, and erythromycin estolate. Large quantities of base

product and its derivatives are manufactured in bulk for saleto industry for further processing. At the time of the wasteassessment, Plant A was producing erythromycin thiocya-nate. Erythromycin thiocyanate is used as a growth promoterand disease preventative in animal feed or can be sold forfurther processing.

The plant recently changed ownership and full scaleproduction had not yet been implemented. At the time of thewaste assessment, Plant A was operating at approximately 50

percent of full production capacity.

Raw Materials

The raw materials used by Plant A include the inoculumorganisms and nutrients for fermentation; solvents for prod-uct recovery; ammonium thiocyanate and acetic acid for

processing; a diatomaceous earth filter aid for fermentationbroth processing; and sodium carbonate, sulfuric acid, andsodium hydroxide for pH control. Raw material storage andmanagement procedures are designed to be in compliance

with current Good Manufacturing Practices as detailed in 21CFR 211.

Powdered nutrient materials (e.g., sugar, flour, and fill-ers) are purchased in bulk and arrive in bags on pallets.Upon delivery, nutrient materials are kept segregated and arestored in an on-site warehouse. The identity of each compo-nent is verified by quality control inspection and materialsare kept in quarantine before they are released for produc-tion.

Solvents used at Plant A for product extraction andprocessing consist of acetone and amyl acetate. Acetone isused for product recovery during erythromycin base cam-

paigns and amyl acetate is used during base derivative cam-paigns. During processing, spent solvents are sent to stripperand distillation units for recovery, then placed in storagetanks prior to release and reuse.

Process Description

The following paragraphs present a generalized descrip-tion of the manufacturing process in use at Plant A. FigureA-l shows a block flow diagram for this process.

A lab culture of inoculum is delivered to a sterile 2,000-gallon seed tank containing nutrients in an aqueous media.

After an initial fermentation period, seed tank componentsare transferred to a 67,000-gallon fermentation vessel. Solu-tion transfer lines are steam-sterilized prior to transfer. Thefermentation cycle runs for seven days with nutrients beingadded over the course of the fermentation. During the cycle,the vessel contents are aerated and mechanically stirred whilesterility is monitored and fermentation off-gases are ventedto the atmosphere via a sub-micron filter. Upon maturation,harvest solution containing erythromycin base is transferredto a holding tank for further processing. Under currentscheduling, an average of five batches is harvested eachweek. This rate will approximately double when full scaleoperations commence.

To separate erythromycin base from the fermentationbroth, rotary vacuum filtration is used. Filtration units areprecoated with an aqueous slurry of filter aid and the aque-ous filtrate from the filter aid application step is dischargedto the sewer. After the filtration is complete, the solid cakeis scraped from the filter drum, dropped onto conveyor belts,and collected in a large disposal bin for removal from the

plant by a waste hauler. Filtrate containing the erythromycinbase, free of any suspended solids, is sent to the solventextraction process.

Erythromycin base is removed from the filtrate using a

multistage countercurrent liquid-liquid extraction process. Therich organic solvent layer and the raffinate, a water layercontaining some solvent, are sent to their respective recoveryunits for recovery and recycle of the solvent.

The erythromycin-rich extract is then sent to a crystalliz-ing unit for product recovery. Crystallized erythromycin

base is then separated by centrifugation and the resultingcentrifuge cake is sent to a fluid bed dryer. The centrate orspent solvent is again recovered and recycled. Dried productis drummed and sent to the warehouse for storage and qualitycontrol inspection with dryer off-gases being vented to theatmosphere. Approximately one-half of one percent of alldried product fails to meet the required product specifica-

tions. This off-spec product is stored on-site and saved forsubsequent reworking.

To produce erythromycin thiocyanate. erythromycin baseis reacted with ammonium thiocyanate prior to crystalliza-tion. Erythromycin thiocyanate is then crystallized, centri-fuged, and dried. Dried product is drummed and stored inthe warehouse.

Waste Streams and Waste Management

The principal waste streams generated at Plant A includethe following:

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Figure A-l: Plant A Process Flow Diagram

Filt rat ion Process Wastes

To remove erythromycin base from the fermentationbroth, harvests are filtered using rotary vacuum filters coatedwith diatomaceous earth. Waste streams from this processconsist of the aqueous precoat filtrate and the wet filter cake.The precoat material is applied continuously at a rate ofapproximately 1,100 kg/hr during the precoat operation andthe filtrate is discharged into the local sewer. During filtra-tion, each rotary vacuum unit generates solid filter cakewaste continuously at a rate of 1,243 kg/hr. The filter cake,consisting of mycelia and filter aid, is mechanically scrapedoff the filter drum and dropped onto a conveyor belt system.The wet waste cake is directed into large waste bins fordisposal in shipments ranging from five to 10 tons per load,with an average weight of nine tons per load. The filter cakematerial is a nonhazardous waste and is disposed of in amunicipal landfill.

generated, Plant A is investigating replacing the rotary vacuumfilters currently in use with an ultrafiltration process. Vol-ume reduction will be accomplished by elimination of the

requirement for diatomaceous earth filter aid.

Solvents

Spent solvents are generated from recovery and purifica-tion operations. Two to three thousand gallons of solvent areused in processing a single fermentation harvest. Undercurrent management practices, spent solvent solutions aretransferred to storage tanks, then recovered and recycled

back into the production process. This solvent recoveryprocess generates an average of two 55-gallon drums of stillbottoms per week. A discussion of solvent recovery opera-tions and an estimate of savings is presented later in thissection.

Equipment Cleaning WastesBecause of the volume of material produced, the wet Process equipment is thoroughly cleaned between manu-

filter cake is the major waste stream generated by Plant A. facturing campaigns to ensure product purity and to main-Filter cake disposal is contracted out to a waste hauler at a tain operating efficiency. Washwaters are generated

price of $160 for the first six tons plus $16 per ton for each intermittently around these campaigns depending upon prcd-ton thereafter. Seven to 10 loads (five to 10 tons each) are uct scheduling. Periodically, a caustic solution is used todisposed of each week, with the amount of filter cake waste clean out the fermentation vessels. Washwaters are routinelyexpected to increase significantly as Plant A reaches full discharged into the local sewer system but the quantity ofscale production. To reduce the amount of filter cake waste washwater being discharged is undetermined.

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Spills

Spills are the result of inadvertent material dischargeduring operations. Two types of spills were noted during the

plant visits: spillage of dry filter aid material and wet filtercake waste. Prior to filtration, the aqueous filter aid slurry ismade by mixing a powdered filter aid material with water.The filter aid material is purchased in bags, and spills canoccur as a result of the bags being handled. During the

assessment, it was noticed that a small amount of the filteraid material was falling onto the ground and onto adjacentequipment in the filtration area. The amount of spilled filteraid was not quantified.

As noted earlier, wet filter cake is scraped from thefiltration unit surface and allowed to fall onto a conveyor beltlocated beneath the scraper bar. During operation, smallquantities of filter cake, relative to that which is generated,fail to land on the conveyor belt and fall to the ground below.Spilled filter cake material is either shoveled up for disposalor washed into sewer sumps with water. Filter cake materialaccumulating in the sumps is periodically shoveled up fordisposal.

Waste Minimization and Management Alternatives

This section presents waste minimization and manage-ment alternatives developed for Plant A. The alternatives

presented apply to specific waste streams identified duringthe waste assessment. Waste minimization and managementalternatives for each of these waste streams are presented

below along with a summary of the generation rate, currentdisposal practice and disposal cost.

Al ternati ves for F il tration Process Wastes

Filtration process wastes consist of the liquid precoatcarrier and waste filter cake. As discussed earlier, the liquidmaterial is not a hazardous waste and no pretrcatmcnt is

required prior to sewer discharge Because of this, the liquidwas not considered a high priority for waste minimizationand alternatives are not presented for this waste stream.(Editors note: While early waste minimization assessmentsfocused on hazardous waste reduction, EPA now encouragesattention to all wastes generated using a multi-media ap-proach.)

Alternate uses for waste filter cake could result in sig-nificant reductions of waste quantities. At current produc-tion rates, the average quantity of waste is seven to 10 loads

per week, or 364 to 520 loads per year. Assuming anaverage load weight of nine tons, this results in 3,276 to4,680 tons per year of filter cake waste being disposed of in

landfills. According to plant personnel, filter cake wastegeneration will increase significantly when full scale produc-tion is achieved.

Using the waste quantities specified above and a dis-posal cost of $208 per nine-ton load, the current yearlydisposal cost for filter cake waste is between $76,000 and$108,000. The estimated disposal cost for filter cake duringfull scale production is approximately $250,000 per year. Toreduce the amount of material disposed of via landfilling andthe associated disposal cost, byproduct uses of filter cakematerial should be examined. These savings would be aug-

mented by the additional revenue generated from the sate ofthe filter cake material.

Potential uses include:

Use as a Fert il izer

According to the USDA, in order for a byproduct to beconsidered usable as a fertilizer, the nitrogen, phosphorous,and potassium (N+P+K) content must be greater than fivepercent. Based on mineral analyses, the N+P+K content ofthe filter cake is less than two percent. Therefore, it isunlikely that the filter cake generated at Plant A is directlyusable as a fertilizer.

Use as a Soil Addit iv e

To evaluate the potential for use as a soil additive, soilspecialists from the University of California campuses atDavis and Riverside were contacted. Both sources believedthe analyses of the filter cakes showed that the material hasthe basic components of regular soil and recommended usingthe material as a soil additive.

The KC Mattson Company, a fertilizer manufacturer in

San Marino, California, expressed interest in utilizing thefilter cake as a soil additive. Concerns affecting the potentialfor use as a soil additive included the amount of odor pro-duced by the material, the moisture content, and the price perunit. As the filter cake is moist (approximately 64 percentwater) and does generate an odor, additional treatment may

be required before use as a soil additive. Water content maybe reduced by heating the filter cake as it is transported alongconveyor belts to the disposal bins or by batch drying. Asample of the filter cake would be needed in order for the KCMattson Company to fully evaluate this alternative.

Al ternati ves for Solvents

Under current waste management practices, spent sol-vent solutions of amyl acetate and acetone are recycled. Inaddition, small quantities of spent solvent which remain afterproduct recovery are also recycled. Solvent recovery pro-cesses include the use of a stripping column, an evaporator,and a rectifying column. Recovery operations result in therecycle of over 99 percent of solvents processed.

The solvent requirement per harvest is two to threethousand gallons. Based on a cost of $1.78 per gallon of rawsolvent, a savings of approximately $3,520 to $5,290 perharvest is achieved with a 99 percent recycle of spent sol-vents. These estimated savings are offset by operating costsof the recovery units, still bottoms disposal, and makeup fornon-recovered solvent. Solvent recovery operations on aver-

age generate two 55-gallon drums per week of still bottoms.Solvent recovery wastes are disposed of by off-site incinera-tion at a cost of $250 to $300 per drum, depending on thesolvent being recovered. With current recycle processesoperating in excess of 99 percent, additional solvent recoveryor recycle is a low priority at this time and is not pursued as anew waste minimization alternative.

Al ternatives for Equipment Cleaning Washwaters

Washwaters generated during equipment cleaning arenonhazardous and require no treatment prior to sewer dis-

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charge. Therefore, washwaters are not considered a highpriority for waste minimization, and alternatives are notdeveloped for this waste stream. (Editors note: As previ-ously stated, EPA now encourages attention to all wastesgenerated.)

Another source of spilled material at Plant A is the dryfilter aid used to prepare the rotary vacuum filters. Goodoperating practices will keep filter aid spillage to a mini-mum.

Recommendations

Al ternatives for Spil l Reduction Based on the waste assessment and the discussion of

As noted previously, filter cake from fermentation broth alternatives presented above, the following recommendations

filtration is scraped from rotary vacuum filters onto conveyor for waste management were prepared for Plant A:belts for collection and disposal. During this operation,some of the filter cake material misses the conveyor beltsand falls to the ground. The amount of filter cake falling tothe ground could not be determined but is believed to besmall compared to the total amount of material generated.Under current practices, spilled filter cake is periodicallyshoveled up and placed into bins for disposal.

Because the filter cake may have value as a byproduct, itwould be beneficial to prevent the filter cake from falling onthe ground. Spillage could be prevented by installing v-shaped guides beneath the rotary vacuum filters which directthe scraped filter cake onto the center of the conveyor belt.

Installation would require little capital investment, no opcrat-ing cost, and could be accomplished bctwcen filtration batches.

Provide KC Mattson Company and Kruse OHGrain and Milling with filter cake samples andany other data required to establish theusefulness of the material as a soil additive.Identify any subsequent treatment required andthe potential value of the material as a byproduct.Investigate methods for reducing water contentand odor levels in filter cake wastes.Install guides beneath each rotary vacuum filterto prevent filter cake materials from missingthe conveyor belts and falling onto the ground.

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Plant BWaste Minimization

Plant Description

Plant B produces a wide range of dermatologic andophthalmic products. These pharmaceutical compounds areformulated in the production section after having been thor-oughly researched by the R & D section. The R & D sectionis divided into two major groups, the synthetic chemistrydivision, and the product development division.

Raw Materials

Production

The raw materials used by Plant B in the productionsection consist of a large variety of active ingredients andfillers. Fillers include oils, fatty acids, surfactants, alcohols,and water used to prepare the various ointments and liquid

bases. Raw material storage and management procedures aredesigned to be in compliance with Good ManufacturingPractices.

R & D

The R & D section uses a large number of chemicals insmall quantities. The materials in use at a given time willvary depending upon the focus of the R & D program.Chlorinated and non-chlorinated solvents such as chloro-form, methylene chloride, methanol, acetonitrile, acetone,

ethyl ether, xylene and hexane are commonly used for ex-traction and analyses. Acetonitrile and methanol are exten-sively used as carrier liquid in high performance liquid chro-matography (HPLC) with annual consumptions of 400 gal-lons of acetonitrile and 991 gallons of methanol. Sulfuricacid is the most widely used acid at an annual consumptionof 450 gallons. In addition, a large quantity of sulfuric acidis used during glassware washing at an annual acid consump-tion of approximately 1,080 gallons.

Process Description

Production

The following categories of products are formulated by

the ophthalmic section:Contact lens cleaners;saline solutions;ophthalmic ointments;eye drops; anddisinfecting solutions.

The following categories of products are formulated bythe dermatologic section:

Shampoos, including dandruff shampoos;creams;

Assessment

suntan lotions;acne medications; anditch soothing preparations.

Ophthalmic and dermatologic compounds are producedin batches where the raw materials are mixed in 1,000-gallonvessels according to detailed batch records. To avoid spill-age, raw materials are carefully poured into the vessels dur-ing formulation. The finished compounds are sampled andanalyzed by the QA/QC laboratory where the dermatologicsection has found that none of the batches were rejected in

the previous 15 months as a result of tight QA/QC during theformulat

Waste Minimization Assesment

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