Facility Requirements for Biotech Plants

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132-13745,1991PDA J Pharm Sci and TechDonald Hill and Michael BeatriceFacility Requirements for Biotech Plants

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COMMENTARY

F a c i l i t y R e q u i r e m e n t s f o r B i o t e c h P l a n t sDONALD HILL and MICH AEL BEATRICEFood a n d Drug Adm inistration, Rockvffle, Maryland[EDITOR'S NOTE: This document [provided to us byM s . Jeanne Devers White) represents o n e of the presentations at the First Conference on "Compliance a n d Regulatory Affairs" sponsored b y t h e Parenteral Drug A ssociation in cooperation with the FDA on September 5-6,1990inRockvilie,MD.]Introduction

Facility requirements for the manufacture of biotechnology-derived products are a significant topic of discussion since the importance of the clinical applications ofgenetically engineered drugs and biologicals is becomingwell-established within the medical community. Attention is currently focusing on the transfer of these newtechnologies from a labo ratory research setting to a commercial production environment.Complicating this transfer is the fact that the field ofbiotechnology is itself in an evolutionary state. One hasonly to look back over the last five years and see howrapidly commercial biotechnology has advanced in product development, manufacturing, and testing, as well asthe degree of sophistication in plant layout and equipmentdesign. Thus , it is difficult to keep abreast of the latestadvancements in determining the state of the art as itexists today for the manufacture of biotech-derived products, and, more importantly, to predict what it will be inthe future. If a biotech plant is built today, will it meetfacility requirements five or ten years down the road?This overview of major facility requirem ents for biotechplants is intended to provide scientists, regulatory affairsspecialists, engineers, and others, who m ay not be totallyfamiliar with the FD A regulatory review process, with ageneral understanding of how the regulatory standardsand regulations are interpreted and applied to manufacturing plants for the production of biotechnology-derivedproduc ts. Since there is no single plant layout or manufacturing process arrangem ent t hat can be used interchangeably for the production of the many different kinds ofbiotech products, this discussion will focus on regulatory-concepts rather than specific regulatory requirements.Additionally, some of the primary questions and concernsthat arise during our review of biotech facility plans willbe presented.

Received October. 1990.Correspondence address: Ms. Jeanne Devers W hite. Assistant D irector,Office of Small Business, Scientific and Trade Affairs. Office of theCommissioner. FDA. HFC-50. 5600 Fishers Lane. Rockville. MD20857.

Cha racterist ics of Biological ProductsIt is important to keep in mind that certain characteristics of biological products are in some aspects quite different from pure chemical drugs. These differences impacton the overall design considerations for a biotech plant.On too many occasions, a biotech m anufacturer has submitted floor plans of a new facility only to be informedthat the plant layout is totally inadequate for the production of biological products.What are the characteristics that make a biologicalproduct different from a pure chemical drug product? /)Biological products are derived from a living source, ei

ther human, animal, plant, or microorganism. This alsoholds true for new biotech-derived products such as recombinant DNA Interferon, where Escherichia coli mayserve as the host microorganism, or the production ofmonoclonal antibodies obtained from the ascites fluid ofmice. 2) Biological products are complex mixtures of proteins and other substances that are not easily identified orcharacterized in the final product. Components in thefinal container of most biological products cannot be identified or quantified to the same extent as pure chemicaldrugs. However, one of the exciting aspects of biotech-derived products is the degree of identification and characterization that can be employed during all phases ofmanufacturing of these products when compared to theearlier biologies manufactured by traditional methods. 3)Biological products are often heat sensitive (heat labile).For this reason, most biological products are stored continuously at 2-8C, and some are not only stored cold orfrozen but are also shipped in a frozen state, such as liveoral polio vaccine. Therefore, during biological manufacturing, certain operations may need to be performed under controlled temperatures (below 10C in some cases)depending on the nature of the product being manufactured and the length of time required to complete themanufacturing procedure(s). 4) Biological products arealso highly susceptible to microbial contamination. Asmixtures of proteins, the produ cts may be excellent vehicles for supporting microbial growth. Thus, concern formicrobial contamination must be considered at every stepduring the manufacture of a biological product, from thetime the seed cell or culture arrives in the plant to preparation of the culture media, the propagation of the productby fermentation or by a continuous cell culture system,the harvesting, concentration, and purification procedures, as well as the sterile filtration of the final bulk andaseptic filling of th e bulk intofinalcontainers. Good manufacturing practices must be employed even during the

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earliest steps in biological manufacturing operations toassure freedom from contamination.Regulating Biological Products

Biological products are regulated in this country eitheras licensed produ cts, NDA products, or medical devices.Examples of licensed products include bacterial and viralvaccines (diphtheria, tetanus, measles, rubella, mumps,polio, etc.) and human blood and derivatives (albumin,immune globulin, antihemophilic factor, etc.). Autho rityto license both the product and the manufacturing establishment is promulgated under the licensing provisions ofSection 351 of the Pub lic Health Service Act. Interferon,hepatitis vaccine, tissue plasminogen activator, and Mur-omonab-CD3 are examples of biotech-derived productswith therapeutic applications which have been licensedrecently by the FD A.

NDA regulated biologicals include antibiotics, hormones, and enzymes. NDA products are regulated underthe applicable provisions of the Federal Food, Drug andCosmetic Act as are certain biological medical deviceproducts. Examples of biotech-engineered NDA productsinclude recombinant human insulin and human growthhormone.Most biological products intended for in vitro diagnostic use are regu lated as medical devices, except for some ofthose utilized in the testing of licensed biologicals such ashuman blood and blood products. These "biological device pro ducts" include blood grouping and typing reagentsas well as reagents used to test for presence in the blood ofthe hepatitis virus or the antibody to HIV (AIDS) virus.Diagnostic monoclonal antibody and recombinant products intended for such uses are regulated as biologicalproducts subject to licensure.

Regulatory Requirements for a BiotechManufacturing PlantGeneral facility requirements for the manufacture ofbiological products are found in the biologic establishment standards, Part 600 (1) and the C urrent Good M anufacturing Practice Regulations for Finished P harmaceuticals, and Part 211 (2) of Title 21, Code of FederalRegulations. Although these FDA regulatory requirements do not directly refer to t he m anufacture of biotech-derived products, they are considered broad enough inscope to be applicable to all biologies and drugs. In ad dition, the agency's "Points to Consider" in the Production

and Testing of New Drugs and Biologicals Produced byRecombinant DNA Technology, in the Manufacture andTesting of Monoclonal Antibody Products for HumanUse, and in the Characterization of Cell Lines Used toProduce Biologicals (3) provide current knowledge gainedfrom recent research and experience with such productsand cell lines. FDA Guidelines on Sterile Drug ProductsProduced by Aseptic Processing (4) and the NIH Guidelines for Research Involving Recombinant DNA Molecules (5) may serve as useful documents in designing anappropriate biotech-manufacturing facility.

Plant Design ConsiderationsProper design of a facility intended to produce biotech-derived products by such procedures as fermentation orcontinuous cell culture should include the following considerations: /) identification of work areas where physicalcontainment of the manufacturing processes are requiredfor protection of the product, environment, and/or worker; 2) location of areas where containment isnot required,such as glassware washing areas; 3) the flow or d irectionof the air in controlled and non-controlled areas; 4) the

flow of materials, equipmen t, products, and biohazardouswaste and; 5) the flow and control of personnel, particularly in the critical work areas. Each of these design considerations merit further discussion, beginning with thecontainment areas.Why is it necessary to have containment areas? Thereare three primary reasons for containment: to protect theworkers as well as personnel in adjacent areas of the plantfrom unnecessary exposure to hazardous agents (primarycontainment), to prevent the release of such agents intothe outside environment (secondary co ntainmen t), and toprotect the product itself from the introduction of contaminating organisms or th e possible transfer of unknown or

undesired genetic material into the product. In many instances, protecting the product may be the most importantreason for requiring containment, because containmentincorporates many of the features required for asepticprocessing, such as environmental controls, systems validation, sterile technique, etc.The level of physical containment required is reallydependent on the potential hazard of the organisms/agents being used in the production processes. Such hazards would include the potential for causing disease inman or possible toxic, allergenic, or other biological effects of the organism on the workers. The level of isolationrequired for microorganisms derived by recombinant

techniques can usually be evaluated by examining theknown pro perties of the components used in the recombinant D NA process. For examp le, when DNA coding for ahighly potent toxin is to be used, special care and attentionis warranted. Thus, the level of biosafety containmentrequired must match the assessment of the risks involvedin the production of biotechnology-derived products.The descriptions of biosafety levels (BL) 1 through 4appearing in the NIH Guidelines for Research InvolvingRecombinant DNA Molecules (5) parallel those of theearlier designated P 1 through 4 categories with the BL-4or P-4 level requiring the highest degree of containment.Although these designated biosafety levels are intended

for use in a laboratory research setting, they are beingused and considered good laboratory practice standardstoday for biotech production operations. In general, thelevels for large scale (LS ) production operations (greaterthan 10 liters) are based upon th e recombinant organismwhich is being employed in production as specified in theNIH guidelines. For certain organisms for large-scalefermentation production, the appropriate physical containment co nditions need be no greater th an those for thehost organism unmodified by recombinant DNA techniques. Examples of such organisms would include E. coli133ol. 45, No. 3 / May-June 1991



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K-12 and Saccharomyces cerevisiae. However, it may beadvisabie for product protection to incorporate certainfeatures of a validated ciosed-system arrangement forthose organisms which are grown in facilities maintainedat less than a BL1-LS.Fermentation processes are usually performed in closedvessels, however, the area around the fermentor oftencannot be of clean-room quality due to the nature andscale of the operation. Frequently, fermentors for largescale production are capable of holding many thousandsof liters and may extend through two or three floors of afacility. In those instances, inoculation of the productionfermentors and harvesting should be performed in closedsystems or in an aseptic manner to protect workers and theintegrity of the product being produced.

Many companies elect to build a dedicated facility forthe manufacture of a biotech product. However, due toeconomic constraints and to maximize full utilization ofthe biotech plant, i t may be permissible to "campaign"product manufacturing, provided validated cleaning andsanitizing procedures are employed between each productmanufacturing run. The organism or particular cell lineused in each production run should also be propagated inpremises in which no other organisms or cells are handledor in contained closed system s, to minimize the c hances ofcross-contamination. The recovery and purification processes (unless the material has been completely inactivated at this stage), should also be performed in self-contained areas of the plant. Dedicated equipment should beemployed in each of these areas and if product campaigning is utilized, dedicated equipment for each product maybe necessary for certain operations. No person who hasbeen in contact with transmissible agents or experimentalanimals should enter the premises on the same day thatany such contact has been made unless they undergo avalidated regowning procedure. Depending on the natureof the product or organism being grown, controlled temperatures in certain production and purification areas(such as 2-10C) may also be required.

As described in the biological establishment standards[Title 21 , Code of Federal Reg ulations, Section 600.11(e)(3)] all work with spore-bearing microorganisms shouldbe done either in an entirely separate building or in acompletely walled-off area of the same building whichdoes not share air systems, equipment, or entrance withother manufacturing or testing areas.

In the containment areas, the ceilings, walls, and floorsshould be constructed of non-shedding material that willprovide non-porous, smooth, and easily cleanable surfaces. All joints should be sealed and all corners coved toprevent air leakage. Ceiling lights and utility outletsshould be flush mounted and sealed. There should be noexposed piping except at points of use. Only necessaryequipment and supplies should be brought into the containment areas.

In addition, particular consideration should be given tocleaning and decontaminating procedures in cases of spillsor accidents involving potentially hazardous agents. Forexample, there may be provisions incorporated in the design of the ventilation ducts, particularly the exhaust

ducts which would permit the actuai mechanical cleaningand decontaminating of the ducts. :f the ievei of contamination should warrant such action. Another examplewould be that a collection and treatment area should belocated below large scale fermentors in case of spills orleaks (i.e.. containment well). The treatment systemshould be validated as capable of immediate start-up andshould be able to handle twice the capacity of production.Written procedures should be established for handlingspills and should describe all actions to be initiated prior tore-use of the area and equipment. These written procedures and action levels become an important consideration in the environmental assessment of manufacturingfacilities.

The requirements for submission of applications forestablishment and product licensure (21 CFR 601.2) direct the applicant to submit an environmental assessmentunder Section 25.31 (21 CFR 25.31) ora claim for cate-gorial exclusion under 25.24 (21 CFR 25.24). This requirement has its origin from the President's Council onEnvironmental Quality regulations (40 CFR 1500-1508)which govern federal implementation of the National Environmental Policy Act of 1969 (NEPA). Under theabove regulations. FDA's NEPA-implementing procedures (21 CFR Part 25) were revised in a rule whichbecame effective on July 25. 1985.

These regulations require that the FDA consider theenvironmental impact of proposed actions prior to anyfinal action and that any decision regarding environmental impact be publicly disclosed. For practical purposes, amanufacturer is requested to submit an environmentalassessment (EA) as a part of their application for licensure. The assessment should include a description of theprocedures employed for containment to protect the worker, environment, or product, particularly in the event of aspill or accident, as well as the procedures for disposal ofsolid, liquid, and gaseous waste. Agency review of theadequacy of a submitted EA includes examining the information provided with that contained in the manufacturer's iicense applications and the implementation of suchprocedu res during the preiicensing inspection of the establishment. Results of this review are summarized in theagency's Sum mary of Basis for Approval (SBA ) which isa part of the final approval action documentation.

The air flow and air pressure boundaries are extremely-critical to the performance of an effective containmentbarrier. To achieve adeq uate con tainment, i t may be necessary to reverse the now of air from adjacent rooms tomove into the contained areas . The areas with the highestpotential to emit the production vector should be maintained at a lower pressure than less potentially contaminated areas including the public or uncontrolled areas.This effectively provides a negative pressure system during product manufacturing as compared to a clean roomoperation for aseptic filling of final containers where apositive pressure system should be maintained. It is important to stress that w ithin a "negative pres sure" production area, biological safety cabinets of proper classification and design may be necessary for certain open operations involving the production of the biotech product. For

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order to m inimize the risk of potential contam inants beingdischarged to the outside environment.If any portion of the production and/or purificationprocesses is conducted in an open system (exposing theproduct to the plant environmental air), such proceduresshould be performed under Class 100 air (7). Thus, airpurity, air pressure differentials, air changes, relative humidity, and temperature control are all key elements inthe design of an effective and efficient heating, ventilation, and air conditioning (HVAC) system. Since theHV AC system represents one of the most expensive costsin the construction of a manufacturing plant, it is extremely important that the system be properly designedand balanced. The establishment license applicationshould include specific drawings of the HVAC systemwith air flow and pressure differentials for each areadesignated on the layout.Water System

The quality of water required for manufacturing useand for glassware and equipment washing is also important in designing a water system for the plant.USP Waterfor Injection (WFI) (6) should be used when the watercomes in direct contact with the product including duringpurification procedures (e.g., rinsing of the resin columns), buffer preparation, product formulation and forthe final rinsing of glassware, stoppers, and equipmentused in the purification and formulation/filling operations. It may be appropriate to utilize WF I or an alternate,high pharmaceutical quality water for preparation of thegrowth media depending upon the nature of the productand its subsequent handling. The use of an uncontrolledwater source (i.e., city or well water) without subsequenttreatment for media preparation is not acceptable.

It should be noted that the USP monograph for Waterfor Injection specifies "water purified by distillation or byreverse osmosis" (6). However, recognizing that waterproduction techniques such as reverse osmosis are difficult to maintain, the section on W ater for Pharm aceuticalPurposes further states:"Purified water produced by distillation is sterile,provided the production apparatus is suitable and issterile. On the other hand, ion exchange columns andreverse osmosis units require special attention in thatthey afford sites for microorganisms to lodge, to multiply, and to enter the effluent. T hus, frequent monitoring m ay be called for, particularly with the use ofthese units following periods of shutdown for morethan a few ho urs."

The Water for Injection system should be designed sothat it can be easily sanitized both after constructionand following routine maintenance. T he system is usually designed in a m anner th at allows incoming potablewater into the plant to be pretreated by use of carbonfilters and deionization (cation and anion) beds. Afterpurification by reverse osmosis or by distillation usingan appropriate still capable of producing the qualityand quantity of WFI required for plant utilization, theWFI water is usually stored and supplied to the produc

tion areas of the plant by means of a hot loop circulationsystem in which the water is maintained at 80 C in boththe loop and storage tank s. For those production procedures requiring ambient temperature water, the watercan be passed through suitable heat exchangers thatcool the WF I as itflows hrough or by the use of a well-controlled secondary cold (ambient temperature) loop.316L or similar quality polished stainless steel shouldbe used for all piping and holding tanks to minimizepotential corrosive problems. Frequent monitoring ofall WF I points of use for microorganisms and endotoxins is essential, especially on days of use.Sterilization System

A plant facility layout should include adequate provisions for the sterilization of equipment and supplies entering the containment and aseptic processing areas. Autoclaves and dry heat ovens should be double doored topermit the direct access of the sterilized goods into eitherthe containment or aseptic processing areas. The cool-down phase for sterilized m aterials should be carried outunder controlled air, in order to further reduce the changeof microbial contamination . Class 100 air may be requiredfor this process and if the sterilized materials are cooleddown in the autoclave or oven, the cham ber air should beHEPA filtered.Provisions should also be made for the disposal andsterilization of all contaminated liquid and solid waste, aswell as the sterilization of equipment and other materialsgenerated from the biotech production process, prior toleaving the containment area. Disposed liquid wasteshould include a large enough treatment reservoir to accommodate adequately all possible loads. Provisions

should also be made for the cleaning and decontaminationof the work areas between operations. Such validatedprocedures should be detailed in written stand ard operating procedure manuals with appropriate cleaning logsbeing maintained. In order to establish baseline data tosupport the effectiveness of cleaning procedures and reagents, initial bioburden of all areas and equipmentshould be performed after qualification and should berecertified at regular intervals. Separate autoclaves fordecontamination and sterilization are recommendedbased upon the principle that clean and dirty componentpathways should never cross.Qualification/Validation ProgramThe qualification of facilities, equipment, plant systems(HVAC, WFI compressed air and gases, waste sterilization, etc.), and the validation of the actual processes (operations) should no t be an afterthought in the design of aplant for producing biotech-derived products. Rather,plans for the qualification/validation programs should bean integral part of the preliminary plant concepts andspecifications. It should not be looked upon solely as aburdensome requirement for complying with FDA regulations, but as a means of increasing productivity throughconsistently producing lots of products that meet all specifications for marketing, thereby reducing the number of

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lot rejects. Also, maintenance costs, equipment downtime, and utility costs may be reduced through a well-designed qualification/validation program. The qualification/validation program can be divided into three major parts: (/) Installation Qualification, (2) OperationalQualification, and (3 ) Process Validation.Installation qualification is the first step taken and itrelates to the proper installation of the equipment andsystems. It includes checking the equipment and systemsto see that they meet appropriate design specificationsafter installation. At this time, programs for maintaining

the systems and equipment in good working conditionmay be identified, such as preventive maintenance andequipment calibration programs. It should be noted thatcomplete reliance on outside contractors for validation ofall systems and equipme nt removes an important internalquality control check. If outside contractors are utilized,the m anufac turer's quality control unit should receive andevaluate the raw data rather than rely on a certificate ofacceptanc e. In addition, written validation procedures utilized by outside contrac tors should be a part of the m anufacturer 's SOP manual .Ope rationa l qualification relates to the actual testing of

the equipment and systems in order to determine theoperational l imits, including whether the equipment andsystems are fully capable of repeatedly performing theproduction functions for which they were intended.Process validation should not begin until all equipmentand systems have been satisfactorily tested and determined to meet established specifications. Process validation is intended to verify that the equipment and systemcan perform their intended functions within the established specifications during actual production conditionsor operations. Test runs should be performed enoughtimes to assure that the equipment, systems, and operations will consistently produce a product within accept

able established limits during all employee shifts.One of the most importan t aspects of any qualification/validation program is the documentation of the tests performed and test results. Each piece of equipment andsystem tha t is to be qualified and validated m ust first havea written protocol describing the intended objective(s), aset of instructions for performing all required tests, established specifications, and acceptance criteria. The protocol and the written results of all tests performed must bemaintained (including all raw data). Il lustrations ofplacement of testing equipment should be incorporatedinto the protocol design where applicable. For example,diagrams of the placement of thermocouples in an autoclave during heat distribution and penetration studies

should be included in the protocol packag e for such equipment. All protocols should be as complete and detailed asnecessary and all test results should be accurately recorded in order to serve as reliable references for subsequentrevalidation of the equipment and systems validation.Such documentation should be on file when an outsidecontractor is employed for equipment and system validation.Final approval of the protocol and acceptance of testresults and the system, equipment, or operation is usually-obtained from responsible personnel of the production,quality control and/or quality assurance and engineeringdepartments even if outside contractors are utilized. Oncevalidated and accepted, no significant changes in theequipment, system or operating procedure should be m adewithout written approval of authorized individuals responsible for plant operations. Major changes to theequipment or system m ay require revalidation and acceptance prior to resuming actual operations in the workarea. In addition, periodic revalidation of some systemsmay also be required at approp riate intervals.Validation of system s and processes should also includeany computer systems employed in the manufacture andtesting of the biotech product. Validation of the computerhard wa re need not be elabo rate but should be sufficient toshow confidence that it can be consistently maintained atthe level of operation demanded. Validation of computersoftware should include: {} ) simulated "worst case" testing, (2) testing of ability to give consistently reliable results (usually three separate runs), and (3) documentingall test runs. If process changes are made, then revalidation of the software may be indicated. Validation of computer systems may also include verification of computer"security" and limited access to software programs controlling the process steps during production.

References1. Code of Federal Regulations, Title 21 . Parts 60 0-680 . Revised April1.1988.2. Code of Federal Regu lations, Title 21, Parts 200-211. Revised April1.1988.3. "Points to Consider" in the Production and Testing of New Drugsand Biologicals Produced by DNA Technology (April 10, 1985), inthe Manufacture and Testing of Monoclonal Antibody Products forHuman Use (June 1987), and in the Characterization of Cell LinesUsed to Produce Biologicals (Nov. 1987).4. FDA Guidelines on Sterile Drug Products Produced by Aseptic Processing, June, 1987.5. NIH Guidelines for Research Involving Recombinant DNA Molecules, May 7, 1986 and A ug. 24, 1987.6. U.S . Pharmacopeia, 21st rev.. United States P harmacopeia! Convention, Inc., 1985.7. U.S. Federal Standard 209D, Clean Room and Work Station Re

quirements, Controlled Environment, June 15, 1988.

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Facility Requirements for Biotech Plants

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