Vol 6 - Handbook of Pharmaceutical Manufacturing Formulations Sterile Products (Volume 6 of 6)/1751_C01.pdf

Part I

Sterile Manufacturing Practice

1

Inspection of Sterile Product Manufacturing Facilities

I. INTRODUCTION

Typically, a sterile drug contains no viable microorgan-isms and is nonpyrogenic. Drugs for intravenous injection,for irrigation, and those used as ophthalmic preparationsmeet these criteria. In addition, other dosage forms mightbe labeled as sterile, for instance, an ointment applied toa puncture wound or skin abrasion.

Parenteral drugs must be nonpyrogenic, because thepresence of pyrogens can cause a febrile reaction inhumans. Pyrogens are the products of the growth of micro-organisms. Therefore, any condition that permits bacterialgrowth should be avoided in the manufacturing process.Pyrogens may develop in water located in stills, storagetanks, dead legs, and piping, or from surface contamina-tion of containers, closures, or other equipment. Parenter-als may also contain chemical contaminants that producea pyretic response in humans or animals although no pyro-gens are present.

The sterile product manufacturing system includesmeasures that minimize the hazard of contaminationwith microorganisms and particulates of sterile drugs.This chapter describes what manufacturers should eval-uate about their facilities regarding compliance with theexisting (and, in some instances, upcoming) standardsof inspection. Highlighted in this chapter are the areasof concern to regulatory inspectors, the problem areas,the often overlooked systems, and, above all, theattributes where most inspections fail. It is assumed thatthe manufacturer is fully cognizant of the existing cur-rent good manufacturing practice (cGMP) complianceconditions as described in the Code of Federal Regula-tions (CFR).

This chapter includes an outline of the general cGMPcompliance requirements (particularly those laid out bythe U.S. Food and Drug Administration [FDA]) for sterilemanufacturing areas, detailed description of complianceproblem areas regarding aseptic processing, terminal ster-ilization, blow-fill sealing, lyophilization, and the qualityof water systems. Portions of the watch list provided hereare still in the draft phase at the regulatory agencies, butmight be fully adopted by the time this book is published.The guidelines given therefore present state-of-the-artsterile product manufacturing inspection auditrequirements.

II. cGMP COMPLIANCE BASICS

A. P

ERSONNEL

Greater emphasis is placed by regulatory agencies on thetraining of personnel involved in the manufacturing ofsterile products than any other type. The company mustalways assure that the training program ensures that per-sonnel performing production and control procedures haveexperience and training commensurate with their intendedduties. It is important that personnel be trained in asepticprocedures. The employees must be properly gowned anduse good aseptic techniques.

B. B

UILDINGS

The nonsterile preparation areas for sterile drugs shouldalso be controlled. Refer to Subpart C of the proposedCurrent Good Manufacturing Practice Requirements(CGMPRs) for large volume parenterals (LVPs) for furtherdetails. Evaluate the air cleanliness classification of the area.For guidance in this area, review Federal Standard #209Eentitled Airborne Particulate Cleanliness Classes in Clean-rooms and Clean Zones. The formulation practices or pro-cedures used in the preparation areas are important in min-imizing routes of contamination. It is best to minimizetraffic and unnecessary activity in the preparation area. Thefilling rooms and other aseptic areas should be so con-structed as to eliminate possible areas for microbiologicalor particulate contamination, for instance, in the dust-col-lecting ledges or porous surfaces. Detailed plans of thecleaning and maintenance of aseptic areas should be devel-oped and appropriate records kept assuring compliance.

C. A

IR

Air supplied to the nonsterile preparation or formulationarea for manufacturing solutions prior to sterilizationshould be filtered as necessary to control particulates. Airsupplied to product exposure areas where sterile drugs areprocessed and handled should be high-efficiency particu-late air (HEPA) filtered under positive pressure. The sys-tem description for HEPA filters should include certifica-tion or dioctyl phthalate (DOP) testing, indicating thefrequency of testing, or both.

The compressed air system requires that the air befiltered at the point of use to control particulates. Diagrams

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4

Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products

of the HEPA-filtered and compressed air systems shouldbe made and be readily available for inspection.

D. E

NVIRONMENTAL

C

ONTROLS

Specifications for viable and nonviable particulates mustbe established. Specifications for viable particulates mustinclude provisions for both air and surface sampling ofaseptic processing areas and equipment. A comprehensiveenvironmental control program, specifications, and testdata should be available, particularly the procedures forreviewing out-of-limit test results. Review of environmen-tal test data should be included as a part of the releaseprocedures. (

Note

: In the preparation of media for envi-ronmental air and surface sampling, suitable inactivatingagents should be added; for example, the addition of pen-icillinase to media used for monitoring sterile penicillinoperations and cephalosporin products.)

E. E

QUIPMENT

Instructions should be available on how the equipmentoperates, including cleaning and maintenance practices.How the equipment used in the filling room is sterilized,and if the sterilization cycle has been validated, should beproperly documented. The practice of resterilizing equip-ment if sterility has been compromised should be clearlydescribed.

A listing of the type of filters used; the purpose of thefilters; and how they are assembled, cleaned, and inspectedfor damage should be maintained. Microbial retentive fil-ters require an integrity testing (i.e., bubble point testingbefore and after the filtration operation).

F. W

ATER

FOR

I

NJECTION

Water used in the production of sterile drugs must becontrolled to assure that it meets USP (United States Phar-macopoeia) specifications. A detailed description of waterquality systems is presented later in the chapter. Thedescription of the system used for producing Water forInjection (WFI) storage and of the delivery system shouldbe present in a written form and in sufficient detail for theoperators to understand it fully. The stills, filters, storagetanks, and pipes should be installed and operated in amanner that will not contaminate the water. The proce-dures and specifications that assure the quality of the WFIshould be periodically audited for compliance and recordsof audit available for inspection.

G. C

ONTAINERS

AND

C

LOSURES

The system for handling and storing containers and clo-sures should be established to show that cleaning,sterilization, and depyrogenization are adequate and havebeen validated.

H. S

TERILIZATION

1. Methods

Depending on the method of sterilization used, appropri-ate guidelines should be followed. A good source of ref-erence material on validation of various sterilization pro-cesses is the

Parenteral Drug Association TechnicalReports

. For instance, Technical Report #1 covers valida-tion of steam sterilization cycles. Establish that the vali-dation data are in order.

If steam under pressure is used, an essential controlis a mercury thermometer and a recording thermometerinstalled in the exhaust line. The time required to heat thecenter of the largest container to the desired temperaturemust be known. Steam must expel all air from the sterilizerchamber to eliminate cold spots. The drain lines shouldbe connected to the sewer by means of an air break toprevent back siphoning. The use of paper layers or linersand other practices that might block the flow of steamshould be avoided. Charts of time, temperature, and pres-sure should be filed for each sterilizer load.

If sterile filtration is used, establish criteria for select-ing the filter and the frequency of changing. Review thefilter validation data. Know what the bioburden of the drugis and develop the procedures for filter integrity testing.If filters are not changed after each batch is sterilized,establish data to justify the integrity of the filters for thetime used and that grow through has not occurred.

If ethylene oxide sterilization is used, establish testsfor residues and degradation. A record of the ethyleneoxide (EtO) sterilization cycle, including preconditioningof the product, EtO concentration, gas exposure time,chamber and product temperature, and chamber humidityshould be available.

2. Indicators

Establish which type indicator will be used to assure ste-rility, such as lag thermometers, peak controls, SteamKlox, test cultures, or biological indicators. (

Caution:

When spore test strips are used to test the effectiveness ofethylene oxide sterilization, be aware that refrigerationmay cause condensation on removal to room temperature.Moisture on the strips converts the spore to the moresusceptible vegetative forms of the organism, which mayaffect the reliability of the sterilization test. Do not storethe spore strips where they could be exposed to low levelsof ethylene oxide.)

If biological indicators are used, assure that the currentUSP guidelines on sterilization and biological indicatorsare followed. In some cases, testing biological indicatorsmay become all or part of the sterility testing.

Biological indicators are of two forms, each incorpo-rating a viable culture of a single species of microorgan-ism. In one form, the culture is added to representative

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Inspection of Sterile Product Manufacturing Facilities

5

units of the lot to be sterilized or to a simulated productthat offers no less resistance to sterilization than the prod-uct to be sterilized. The second form is used when the firstform is not practical, as in the case of solids. In the secondform, the culture is added to disks or strips of filter paper,or metal, glass, or plastic beads. Data on the use of bio-logical indicators include:

Surveys of the types and numbers of organismsin the product before sterilization.

Data on the resistance of the organism to thespecific sterilization process.

Data used to select the most resistant organismand its form (spore or vegetative cell).

Studies of the stability and resistance of theselected organism to the specific sterilizationprocess.

Studies on the recovery of the organism usedto inoculate the product.

If a simulated product or surface similar to thesolid product is used, validation of the simula-tion or similarity. The simulated product or sim-ilar surface must not affect the recovery of thenumbers of indicator organisms applied.

Validation of the number of organisms used toinoculate the product, simulated product, orsimilar surface, to include stability of the inoc-ulum during the sterilization process.

Because qualified personnel are crucial to the selectionand application of these indicators, their qualifications,including experience dealing with the process, expectedcontaminants, testing of resistance of organisms, andtechnique, should be frequently reviewed and recordskept current. Policies regarding use, control, and testingof the biological indicator by product, including adescription of the method used to demonstrate presenceor absence of viable indicator in or on the product, shouldbe established.

Check data used to support the use of the indicatoreach time it is used. Include the counts of the inoculumused; recovery data to control the method used to demon-strate the sterilization of the indicator organism; countson unprocessed, inoculated material to indicate the stabil-ity of the inoculum for the process time; and results ofsterility testing specifically designed to demonstrate thepresence or absence of the indicator organism for eachbatch or filling operation. In using indicators, assure thatthe organisms are handled so they do not contaminate thedrug manufacturing area and product.

3. Filled Containers

Challenge the procedure of how the filled vials orampoules leave the filling room. Is the capping or sealing

done in the sterile fill area? If not, how is sterility main-tained until capped? Review the tests done on finishedvials, ampoules, or other containers to assure proper filland seal, for instance, leak and torque tests.

Keep a good record of examinations made for partic-ulate contamination. Know that inspectors can quicklycheck for suspected particulate matter by using a polari-scope. Practice this in-house on a representative sampleof production frequently. Employees doing visual exami-nations online must be properly trained. If particle countsare done by machine, this operation must be validated.Know that even when 100% inspection is performed,defective vials and ampoules are picked up afterward.

I. P

ERSONNEL

P

RACTICES

Establish how employees sterilize and operate the equip-ment used in the filling area. Be critical of filling roompersonnel practices. Are the employees properly dressedin sterile gowns, masks, caps, and shoe coverings? Estab-lish the gowning procedures, and determine whether goodaseptic technique is maintained in the dressing and fillingrooms. Check on the practices after lunch and otherabsences. Is fresh sterile garb supplied, or are soiled gar-ments reused? If the dressing room is next to the fillingarea, how employees and supplies enter the sterile area isimportant.

J. L

ABORATORY

C

ONTROLS

Pharmaceutical quality-control laboratories are subject tostrict guidelines established by the FDA. Review theFDA Guide to Inspections of Pharmaceutical QualityControl Laboratories and the FDA Guide to Inspectionsof Microbiological Pharmaceutical Quality Control Lab-oratories. Clear standard operating procedures (SOPs)should be established.

1. Retesting for Sterility

See the USP for guidance on sterility testing. Sterilityretesting is acceptable provided the cause of the initialnonsterility is known, thereby invalidating the originalresults. It cannot be assumed that the initial sterility testfailure is a false positive. This conclusion must be justifiedby sufficient documented investigation. Additionally,spotty or low-level contamination may not be identifiedby repeated sampling and testing. Review sterility testfailures and determine the incidence, procedures for han-dling, and final disposition of the batches involved.

2. Retesting for Pyrogens

As with sterility, pyrogen retesting can be performed pro-vided it is known that the test system was compromised.It cannot be assumed that the failure is a false positive

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6

Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products

without documented justification. Review any initial pyro-gen test failures and establish a justification for retesting.

3. Particulate Matter Testing

Particulate matter consists of extraneous, mobile, andundissolved substances other than gas bubbles uninten-tionally present in parenteral solutions. Cleanliness spec-ifications or levels of nonviable particulate contaminationmust be established. Limits are usually based on the his-tory of the process. The particulate matter test procedureand limits for LVPs in the USP can be used as a generalguideline. However, the levels of particulate contamina-tion in sterile powders are generally greater than in LVPs.LVP solutions are filtered during the filling operation.However, sterile powders, except powders lyophilized invials, cannot include filtration as a part of the filling oper-ation. Considerable particulate contamination is alsopresent in sterile powders that are spray dried due tocharring during the process.

Establish the particulate matter test procedure andrelease criteria. Have available production and controlrecords of any batches for which complaints of particulatematter have been received.

4. Production Records

Production records should be similar to those for otherdosage forms. Critical steps, such as integrity testing offilter, should be signed and dated by a second responsibleperson. The production records must ensure that directionsfor significant manufacturing steps are included and reflecta complete history of production.

III. ASEPTIC PROCESSING

A. I

NTRODUCTION

There are basic differences between the production ofsterile drug products by aseptic processing and by terminalsterilization. Terminal sterilization usually involves fillingand sealing product containers under conditions of a high-quality environment; the product, container, and closurein most cases have low bioburden but are not sterile. Theenvironment in which filling and sealing is performed isof high quality in order to minimize the microbial contentof the in-process product and to help ensure that the sub-sequent sterilization process is successful. The product inits final container is then subjected to a sterilization pro-cess such as heat or radiation. Due to their nature, certainproducts are aseptically processed from either an earlierstage in the process or in their entirety. Cell-based therapyproducts are an example. All components and excipientsfor these products are rendered sterile, and release of thefinal product is contingent on determination of sterility.

In aseptic processing, the drug product, container, andclosure are subjected to sterilization processes separately,as appropriate, and then brought together. Because thereis no further processing to sterilize the product after it isin its final container, it is critical that containers be filledand sealed in an environment of extremely high quality.

Manufacturers should be aware that there are morevariables associated with aseptic processing than with ter-minal sterilization. Before aseptic assembly, differentparts of the final product are generally subjected to dif-ferent sterilization processes, such as dry heat for glasscontainers, moist heat sterilization for rubber closures, andsterile filtration for a liquid dosage form. Each of theprocesses of the aseptic manufacturing operation requiresthorough validation and control. Each also introduces thepossibility of error that might ultimately lead to the dis-tribution of contaminated product. Any manual ormechanical manipulation of the sterilized drug, compo-nents, containers, or closures prior to or during asepticassembly poses a risk of contamination and thus necessi-tates careful control. The terminally sterilized drug prod-uct, on the other hand, undergoes a single sterilizationprocess in a sealed container, thus limiting the possibilitiesfor error. Nearly all drugs recalled due to nonsterility orlack of sterility assurance from 1980 to 2000 were pro-duced via aseptic processing. Manufacturers should havea keen awareness of the public health implication of dis-tributing a nonsterile drug purporting to be sterile. PoorcGMP conditions at a manufacturing facility can ulti-mately pose a life-threatening health risk to a patient.

B. B

UILDINGS

AND

F

ACILITIES

Section 211.42, Design and Construction Features, ofCFR requires, in part, that aseptic processing operationsbe performed within specifically defined areas of ade-quate size. There shall be separate or defined areas for theoperations to prevent contamination or mix-ups. Asepticprocessing operations must also include, as appropriate,an air supply filtered through high efficiency particulateair (HEPA) filters under positive pressure, as well assystems for monitoring environmental conditions andmaintaining any equipment used to control aseptic con-ditions. Section 211.46, Ventilation, Air Filtration, AirHeating and Cooling, states, in part, that equipment foradequate control over air pressure, microorganisms, dust,humidity, and temperature shall be provided when appro-priate for the manufacture, processing, packing or holdingof a drug product. This regulation also states that airfiltration systems, including pre-filters and particulatematter air filters, shall be used when appropriate on airsupplies to production areas.

In aseptic processing, various areas of operationrequire separation and control, with each area having dif-ferent degrees of air quality depending on the nature of

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Inspection of Sterile Product Manufacturing Facilities

7

the operation. Area design is based on satisfying micro-biological and particulate standards defined by the equip-ment, components, and products exposed as well as theparticular operation conducted in the given area. Criticaland support areas of the aseptic processing operationshould be classified and supported by microbiological andparticulate data obtained during qualification studies. Ini-tial clean room qualification includes some assessment ofair quality under as-built and static conditions, whereasthe final room or area classification should be derived fromdata generated under dynamic conditions, that is, withpersonnel present, equipment in place, and operationsongoing. The aseptic processing facility-monitoring pro-gram should assess on a routine basis conformance withspecified clean area classifications under dynamic condi-tions. Table 1.1 summarizes clean-area air classifications.

1

Two clean areas are of particular importance to sterile drugproduct quality: the critical area and the supporting cleanareas associated with it.

1. Critical Area (Class 100)

A critical area is one in which the sterilized drug product,containers, and closures are exposed to environmentalconditions designed to preserve sterility. Activities con-ducted in this area include manipulations (e.g., asepticconnections, sterile ingredient additions) of sterile mate-rials prior to and during filling and closing operations.This area is critical because the product is not processedfurther in its immediate container and is vulnerable tocontamination. To maintain product sterility, the environ-ment in which aseptic operations are conducted should beof appropriate quality throughout operations. One aspectof environmental quality is the particulate content of theair. Particulates are significant because they can enter aproduct and contaminate it physically or, by acting as avehicle for microorganisms, biologically. Particle contentin critical areas should be minimized by effective airsystems.

Air in the immediate proximity of exposed sterilizedcontainers or closures and filling or closing operations isof acceptable particulate quality when it has a per-cubic-foot particle count of no more than 100 in a size range of0.5

m

m and larger (Class 100) when counted at represen-tative locations normally not more than 1 ft away fromthe work site, within the airflow, and during filling orclosing operations. Deviations from this critical area mon-itoring parameter should be documented as to origin andsignificance.

Measurements to confirm air cleanliness in asepticprocessing zones should be taken with the particle count-ing probe oriented in the direction of oncoming airflowand at specified sites where sterilized product and con-tainer/closure are exposed. Regular monitoring should beperformed during each shift. Nonviable particulate mon-itoring with a remote counting system is generally lessinvasive than the use of portable particle counting unitsand provides the most comprehensive data.

Some powder-filling operations can generate high levelsof powder particulates that, by their nature, do not pose arisk of product contamination. It may not, in these cases, befeasible to measure air quality within the 1-ft distance andstill differentiate background noise levels of powder par-ticles from air contaminants. In these instances, air shouldbe sampled in a manner that, to the extent possible, charac-terizes the true level of extrinsic particulate contaminationto which the product is exposed. Initial certification of thearea under dynamic conditions without the actual powder-filling function should provide some baseline informationon the nonproduct particle generation of the operation.

Air in critical areas should be supplied at the point ofuse as HEPA-filtered laminar flow air at a velocity suffi-cient to sweep particulate matter away from the filling orclosing area and maintain laminarity during operations.The velocity parameters established for each processingline should be justified, and appropriate to maintain lam-inarity and air quality under dynamic conditions within a

TABLE 1.1Air Classifications

a

Clean-Area Classification >0.5-

mmmm

m Particles/ft

3

> 0.5-

mmmm

m Particles/m

3

Microbiological Limit

b

CFU/10 ft

3

CFU/m

3

100 100 3500