CENTER FOR DRUG Ev ALUATION AND RESEARCH
`
`Guidance for Industry
`
`The FDA published Good Guidance Practices in February 1997.
`This guidance was developed and issued prior to that date.
`
`Additional copies are available from:
`Office of Training and Communications
`Division of Communications Management
`Drug Information Branch, HFD-210
`5600 Fishers Lane
`Rockville, MD 20857
`
`(I'el) 301-827-4573
`(Internet) http:l!www.fda.gov/cder!guidance!index.htm
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, FOOD AND DRUG ADMINISTRATION
`
`CIPLA EXHIBIT 1009
`Page 1 of 45
`
`
`
`Guidance for Industry
`
`The FDA published Good Guidance Practices in February 1997.
`This guidance was developed and issued prior to that date.
`
`Additional copies are available from:
`Office of Training and Communications
`Division of Communications Management
`Drug Information Branch, HFD-210
`5600 Fishers Lane
`Rockville, MD 20857
`
`(I'el) 301-827-4573
`(Internet) http:l!www.fda.gov/cder!guidance!index.htm
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, FOOD AND DRUG ADMINISTRATION
`
`CIPLA EXHIBIT 1009
`Page 1 of 45
`
`
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`GUIDELINE ON STERILE DRUG PRODUCTS
`
`PRODUCED BY ASEPTIC PROCESSING
`
`June, 1987
`
`(Reprinted June, 1991)
`
`Prepared by: Center for Drug Evaluation and Research
`
`Center for Biologics Evaluation and Research, and
`
`Office of Regulatory Affairs,
`
`Food and Drug Administration
`
`Maintained by: Division of Manufacturing and Product Quality (HFD-320)
`
`Off ice of Compliance
`
`Center for Drug Evaluation and Research
`
`Food and Drug Administration (FDA)
`
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`CIPLA EXHIBIT 1009
`Page 2 of 45
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`I. PURPOSE
`
`This guideline informs interested persons on certain practices and
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`procedures for the preparation of sterile drug products by aseptic
`
`processing that constitute acceptable means of complying with certain
`
`sections of the Current Good Manufacturing Practice {CGMP)
`
`regulations for drug products {Title 21 Code of Federal Regulations,
`
`Parts 210 and 211). For biological products regulated under 21 CFR
`
`Parts 600 through 680, it should be noted that sections 210.2{a) and
`
`211.l{b) provide that where it is impossible to comply with the
`
`applicable regulations in both Parts 600 through 680 and Parts 210
`
`and 211, the regulation specifically applicable to the drug product
`
`in question shall apply. Therefore, the sterility testing of
`
`biological products, and the culture media employed for such testing,
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`must conform to the requirements under section 610.12.
`
`II. INTRODUCTION
`
`This guideline is issued under 21 CFR 10.90, and as such, it states
`
`principles and practices of general applicability that are not legal
`
`requirements but are acceptable to the Food and Drug Administration
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`(FDA). A person may rely upon this guideline with the assurance of
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`its acceptability to FDA, or may follow different procedures. When
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`Page 3 of 45
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`different procedures are chosen, a person may, but is not required
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`to, discuss the matter in advance with FDA to prevent the expenditure
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`of money and effort on activity that may later be determined to be
`
`unacceptable.
`
`This guideline may be amended from time to time as the agency· -
`
`recognizes the need through its regulatory efforts and through
`
`comments submitted by interested persons.
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`There are certain differences between the_production of sterile drug
`
`products by aseptic processing and by terminal sterilization.
`
`Terminal sterilization usually involves filling and closing product
`
`containers under conditions of a high quality environment; the
`
`product, container, and closure are usually of a high microbiological
`
`quality but are not sterile. It is important that the environment in
`
`which filling and closing is achieved be of a high quality in order
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`to minimize the microbial content of the product and to help assure
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`that the subsequent sterilization process is successful. The product
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`in its final container is then subjected to a sterilization
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`process--usually using heat or radiation.
`
`In aseptic processing, the
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`drug product, container, and closure are subjected to sterilization
`
`processes separately and then brought together. Because there is no
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`further processing to sterilize the product after it is in its final
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`container, it is critical to the maintenance of product sterility
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`CIPLA EXHIBIT 1009
`Page 4 of 45
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`that containers be filled and closed in an environment of extremely
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`high quality.
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`In addition, there are usually more variables
`
`attendant to aseptic processing than to terminal processing, a factor
`
`that can make it more difficult to attain a high degree of assurance
`
`that the end product will be sterile. For example, before aseptic
`
`assembly, different parts of the final product may have been
`
`subjected to different sterilization processes -- such as dry heat
`
`for glass containers, steam under pressure for rubber closures, and
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`filtration for a liquid dosage form -- each requiring thorough
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`validation and control, each with the possibility of error.
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`(For the
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`terminally sterilized drug product, on the other hand, there is
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`generally only one sterilization process, thus limiting the
`
`possibilities for error.) Furthermore, any manipulation of the
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`sterilized dosage form, containers, and closures immediately prior to
`
`aseptic assembly involves the risk of contamination and thus must be
`
`carefully controlled.
`
`These processing differences have led to several questions on aseptic
`
`processing regarding what FDA believes are acceptable ways of
`
`complying with certain sections of the CGHP regulations for drug
`
`products. The sections most frequently questioned concern buildings
`
`and facilities, components, containers/closures, production time
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`limitations, validation, laboratory controls, and sterility testing.
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`Because most of the questions have concerned process validation in
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`CIPLA EXHIBIT 1009
`Page 5 of 45
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`particular, this guideline addresses this area extensively. This
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`guideline is intended to respond to these questions and clarify
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`certain technical aspects of aseptic processing of sterile drug
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`products.
`
`It should be noted that this document does not address
`
`several other important aspects of aseptic pr.ocessing--such as
`
`employee hygiene, aseptic gowning, and clean room design. These and
`
`other aspects will be covered in future revisions of this guideline
`
`as needed. This guideline does not address terminally sterilized
`
`drug products, although some portions may be applicable to their
`
`preparation also.
`
`In this guideline stated CGHP requirements of certain sections of 21
`
`CFR Part 211 are followed by discussions of practices and procedures
`
`which FDA considers as acceptable means of meeting the requirements.
`
`It should be noted that not all portions of the regulations which
`
`apply to the preparation of aseptically processed sterile drug·
`
`products are identified -- only those portions for which pertinent
`
`questions have been raised. The guideline also includes a list of
`
`references which may be of value to the reader.
`
`Definitions
`
`Critical areas - Areas where sterilized product or container/
`
`closures are exposed to the environment.
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`CIPLA EXHIBIT 1009
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`Critical surfaces - Surfaces which come into contact with sterilized
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`product or containers/closures.
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`D value - The time at a given temperature needed to reduce the number of
`
`microorganisms by 90%.
`
`Overkill sterilization process - A process which is sufficient to provide
`
`at least a 12 log reduction of microorganisms having a minimum D value of
`
`1 minute.
`
`Sterilizing filter - A filter which, when challenged with the
`microorganism Pseudomonas diminuta, at a minimum concentration of 107
`organisms per cm2 of filter surface, will produce a sterile effluent.
`
`Validation - Establishing documented evidence which provides a high
`
`degree of assurance that a specific process will consistently produce a
`
`product meeting its predetermined specifications and quality attributes.
`
`Worst case - A set of conditions encompassing upper and lower processing
`
`limits and circumstances, including those within standard operating
`
`procedures, which pose the greatest chance of process or product failure
`
`when compared to ideal conditions. Such conditions do not necessarily
`
`induce product or process failure.
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`CIPLA EXHIBIT 1009
`Page 7 of 45
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`III.BUILDINGS ANO FACILITIES
`
`Requirements
`
`Section 211.42 (design and construction features) requires, in part,
`
`that there be separate or defined areas of operation to prevent
`
`contamination, and that for aseptic processing there be, as
`
`appropriate, an air supply filtered through high efficiency
`
`particulate air (HEPA) filters under positive pressure, and systems
`
`for monitoring the environment and maintaining equipment used to
`
`control aseptic conditions.
`
`Section 211.46 (ventilation, air filtration, air heating and cooling)
`
`requires, in part, that equipment for adequate control over air
`
`pressure, microorganisms, dust, humidity, and temperature be provided
`
`where appropriate and that air filtration systems, including
`
`prefilters and particulate matter air filters, be used when
`
`appropriate on air supplies to production areas.
`
`In aseptic processing there are various areas of operation which
`
`require separation and control, with each area needing different
`
`degrees of air quality depending on the nature of the operation. Two
`
`exposure areas are of particular importance to drug product
`
`quality--critical areas and controlled areas.
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`CIPLA EXHIBIT 1009
`Page 8 of 45
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`CRITICAL AREAS
`
`A critical area is one in which the sterilized dosage form,
`
`containers, and closures are exposed to the environment. Activities
`
`that are conducted in this area include manipul~tions of these
`
`sterilized materials/product prior to and during filling/closing
`
`operations. These operations are conducted in what is typically
`
`called the "aseptic core" or "aseptic processing" area.
`
`This area is critical because the product is not processed further in
`
`its inunediate container and is vulnerable to contamination.
`
`Therefore, in order to maintain the quality and, specifically, the
`
`sterility of the product, the environment in the i1t111ediate proximity
`
`of the actual operations should be of the highest quality.
`
`One aspect of environmental quality is the particulate content of the
`
`air. Particulates are significant because they may enter a product
`
`and contaminate it physically or, by acting as a vehicle for
`
`microorganisms, biologically. It is therefore important to minimize
`
`the particle content of the air and to effectively remove those
`
`particles which are present. Air in the immediate proximity of
`
`exposed sterilized containers/closures and filling/closing operations
`
`is of acceptable particulate quality when it has a per-cubic-foot
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`CIPLA EXHIBIT 1009
`Page 9 of 45
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`particle count of no more than 100 in a size range of 0.5 micron and
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`larger (Class 100) when measured not more than one foot away from the
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`work site, and upstream of the air flow, during filling/closing
`
`operations. The agency recognizes that some powder filling
`
`operations may generate high levels of powder particulates which, by
`
`their nature, do not pose a risk of product contamination.
`
`It may
`
`not, in these cases, be feasible to measure air quality within the
`
`one foot distance and still differentiate "background noise" levels
`
`of powder particles from air contaminants which can impeach product
`
`quality.
`
`In these instances, it is nonetheless important to sample
`
`the air in a manner which, to the extent possible, characterizes the
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`true level of extrinsic particulate contamination to which the
`
`product is exposed.
`
`Air in critical areas should be supplied at the point of use as HEPA
`
`filtered laminar flow air, having a velocity sufficient to sweep
`
`particulate matter away from the filiing/closing area. Normally, a
`
`velocity of 90 feet per minute, plus or minus 20%, is adequate,
`
`(Refs. 1 and 2) although higher velocities may be needed where the
`
`operations generate high levels of particulates or where equipment
`
`configuration disrupts laminar flow.
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`CIPLA EXHIBIT 1009
`Page 10 of 45
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`Air should also be of a high microbial quality. An incidence of no
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`more than one colony forming unit per 10 cubic feet is considered as
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`attainable and desirable (Ref. 3).
`
`Air is not the only gas in the proximity of fill~ng/closing
`
`operations which should be of a high particulate and microbial
`
`quality. Other gases, such as nitrogen or carbon dioxide, which
`
`contact the product, container/closure, or product contact surfaces,
`
`e.g., purging or overlaying, should be sterile filtered.
`
`In
`
`addition, compressed air should be f~ee from demonstrable oil vapors.
`
`Critical areas should have a positive pressure differential relative
`
`to adjacent less clean areas; a pressure differential of 0.05 inch of
`
`water is acceptable.
`
`CONTROLLED AREAS
`
`The controlled area, the second type of area in which it is important
`
`to control the environment, is the area where unsterilized product,
`
`in-process materials, and container/closures are prepared. This
`
`includes areas where components are compounded, and where components,
`
`in-process materials, drug products and drug product contact surfaces
`
`of equipment, containers, and closures, after final rinse of such
`
`surfaces, are exposed to the plant environment. This environment
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`CIPLA EXHIBIT 1009
`Page 11 of 45
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`should be of a high microbial and particulate quality in order to
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`minimize the level of particulate contaminants in the final product
`
`and to control the microbiological content (bioburden) of articles
`
`and components which are subsequently sterilized.
`
`Air in controlled areas is generally of acceptable particulate
`
`quality if it has a per-cubic-foot particle count of not more than
`.
`100,000 in a size range of 0.5 micron and larger {Class 100,000) when
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`measured in the vicinity of the exposed articles during periods of
`
`activity. With regard to microbial.quality, an incidence of no more
`
`than 25 colony forming units per 10 cubic feet is acceptable
`
`{Ref. 3).
`
`In order to maintain air quality in controlled areas, it is important
`
`to achieve a sufficient air flow and a positive pressure differential
`
`relative to adjacent uncontrolled areas.
`
`In this regard, an air flow
`
`sufficient to achieve at least 20 air changes per hour and, in
`
`general, a pressure differential of at least 0.05 inch of water {with
`
`all doors closed), are acceptable. When doors are open, outward
`
`airflow should be sufficient to minimize ingress of contamination.
`
`Gases other than ambient air may also be used in controlled areas.
`
`Such gases should, if vented to the area, be of the same quality as
`
`ambient air. Compressed air should be free from demonstrable oil
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`vapor.
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`CIPLA EXHIBIT 1009
`Page 12 of 45
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`In addition to these production areas, there may be certain pieces of
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`equipment which should be supplied with high quality filtered air.
`
`This is especially important where the air in the equipment will
`
`contact sterilized material or material which should have a low
`
`microbial or particulate content. For example~ bacterial retentive
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`filters should be used for lyophilizer vacuum breaks and hot air
`
`sterilizer vents to ensure that air coming in contact with a
`
`sterilized product is sterile.
`
`likewise, air admitted to
`
`unpressurized vessels containing sterilized liquid should also be
`
`filtered. Air in tanks used to hold mater)al which must be of a high
`
`microbial quality should be filtered too, and the filters should be
`
`dry to prevent wetting by condensation with subsequent blockage or
`
`microbial grow-through (two ways of achieving this are providing heat
`
`to the filter and use of hydrophobic filters.}
`
`It is important that
`
`these equipment air filters be periodically integrity tested.
`
`An acceptable system for maintaining air quality includes testing
`
`HEPA filters for integrity.
`
`Integrity testing should be performed
`
`initially when the units are first installed in order to detect leaks
`
`around the sealing gaskets, through the frames or through the filter
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`media. Thereafter, integrity tests should be performed at suitable
`
`intervals. Usually it is sufficient to perform such testing at least
`
`twice a year for critical areas; however, more frequent testing may
`
`be needed when air quality is found to be unacceptably low or as part
`
`of an investigation into a finding of non-sterility in a drug product.
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`CIPLA EXHIBIT 1009
`Page 13 of 45
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`One acceptable method of testing the integrity of HEPA filters is use
`
`of a dioctylphthalate (DOP) aerosol challenge.
`
`Inasmuch as a HEPA
`
`filter is one capable of retaining 99.97 percent of particulates
`
`greater than 0.3 micron in diameter, it is 1mportant to assure that
`
`whatever substance is used as a challenge will have a sufficient
`
`number of particles of this size range. An acceptable DOP challenge
`
`involves introducing a DOP aerosol upstream of the filter in a
`
`concentration of 80 to 100 micrograms/liter of air at the filter's
`
`designed airflow rating and then scanning the downstream side·· of the
`
`filter with an appropriate photometer prope at a sampling rate of at
`
`least one cubic foot per minute. The probe should scan the entire
`
`filter face and frame at a position about one to two inches from the
`
`face of the filter (Ref. 1). A single probe reading equivalent to
`
`0.01 percent of the upstream challenge is considered as indicative of
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`a significant leak whic~ should be repaired.
`
`Use of particle counters without introducing particles of known size
`
`upstream of the filter is ineffective for detecting leaks.
`
`The reader should note that there is a difference between filter
`
`integrity testing and efficiency testing.
`
`Integrity testing is
`
`performed to detect leaks from the filter media, filter frame and
`
`seal. The challenge is a polydispersed aerosol usually composed of
`
`particles ranging in size from one to three microns. The test is
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`done in place and the filter face is scaned with a probe; the
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`CIPLA EXHIBIT 1009
`Page 14 of 45
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`measured downstream leakage is taken as a percent of the upstream
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`challenge. The efficiency test, on the other hand, is used to
`
`determine the filter's rating. The test uses a monodispersed aerosol
`
`of 0.3 micron size particles, relates to filter media, and usually
`
`requires specialized equipment. Downstream readings represent an
`
`average over the entire filter surface. Therefore, leaks in a filter
`
`may not be detected by an efficiency test.
`
`It is also important to monitor air flow velocities for each HEPA
`
`filter according to a program of established intervals because
`
`significant reductions in velocity can increase the possibility of
`
`contamination and changes in velocity can affect the laminarity of
`
`the airflow. Airflow patterns should be tested for turbulence that
`
`would interfere with the sweeping action of the air.
`
`IV. COMPONENTS
`
`Requirements
`
`Section 211.80 (general requirements) requires, in part, the
`
`establishment of written procedures for the storage, handling and
`
`testing, and approval or rejection of components.
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`CIPLA EXHIBIT 1009
`Page 15 of 45
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`Section 211 .84 (testing and approval or rejection of components, drug
`
`product containers, and closures} requires, in part, that components
`
`liable to microbiological contamination that is objectionable in view
`
`of their intended use be subjected to microbiological tests before
`
`use.
`
`Guidance
`
`One of the most important aspects of components used in sterile drug
`
`products made by aseptic processing is mi~robiological quality. A
`
`finished drug product produced by aseptic processing may become
`
`contaminated through use of one or more components which contain
`
`microorganisms. Therefore, unless an overkill sterilization process
`
`is applied to components, it is important to routinely characterize
`
`the microbial content of each component liable to contamination and
`
`to establish appropriate acceptance/rejection limits based on this
`
`bioburden. Knowledge of this bioburden is especially significant in
`
`attaining a high degree of sterility assurance when the component is
`
`subjected.to a non-overkill sterilization process.
`
`In aseptic processing, each component may be individually sterilized
`
`or several components may be combined, with the resulting mixture
`
`sterilized. There are several methods to sterilize components, and
`
`each can be acceptable when properly validated. A widely used method
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`CIPLA EXHIBIT 1009
`Page 16 of 45
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`is filtration of a solution formed by dissolving the component in a
`
`solvent such as USP water for injection; the solution is passed
`
`through a sterilizing membrane or cartridge filter. This method can
`
`be useful where the component is likely to be adversely affected by
`
`heat. A variation of this method involves subjecting the filtered
`
`solution to aseptic crystallization and precipitation of the
`
`component as a sterile powder. However, this method involves more
`
`handling and manipulation than other methods and therefore has a
`
`higher potential for contamination during processing.
`
`If a component is not adversely affected by heat, and it is soluble,
`
`it may be made into a solution and subjected to steam sterilization ·
`
`either in a separate autoclave or within a steam-jacketed pressurized
`
`preparation vessel.
`
`Dry heat sterilization is a suitable method for components that are
`
`heat stable and may be insoluble. However, this method can pose
`
`problems of inadequate heat penetration and distribution. For
`
`example, the treatment of powders by this method necessitates
`
`suitable heat penetration and distribution studies because of the
`
`powders' insulating effects.
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`CIPLA EXHIBIT 1009
`Page 17 of 45
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`Ethylene oxide exposure is another method of sterilizing components.
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`However, its effectiveness as a primary method is questionable
`
`because of a lack of consistent penetration of the sterilant to the
`
`crystal core of a powder. Ethylene oxide may be useful for the
`
`surface sterilization of powders as a precaution against potential
`
`microbial contamination during aseptic handling.
`
`For products intended to be pyrogen free, there should be written
`
`procedures for acceptance or rejection of components which are
`
`susceptible to pyrogens. Those components found to be cont~minated
`
`with pyrogens should be rejected or processed to remove the pyrogenic
`
`properties provided that the resultant components will meet
`
`appropriate standards, specifications, and characteristics.
`
`CONTAINERS/CLOSURES
`
`Requirements
`
`Section 211.94 (drug product containers and closures) requires, in
`
`part, that drug product containers and closures be clean and, where
`
`indicated by the nature of the drug, sterilized and depyrogenated.
`
`Standards and testing methods and, where indicated, methods of
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`cleaning, sterilizing and processing to remove pyrogenic properties
`
`must be written and followed.
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`CIPLA EXHIBIT 1009
`Page 18 of 45
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`Guidance
`
`In the case of sterile drug products made by aseptic processing,
`
`preparation of containers and closures prior to filling and closing
`
`operations should go beyond mere cleaning to remove surface debris.
`
`It is critical to the integrity of the final product that containers
`
`and closures be rendered sterile and, in the case of injectable
`
`products, pyrogen free. The type of processes used to sterilize and
`
`depyrogenate will depend primarily on the nature of the material
`
`which comprises the container/closure. Any properly validated
`
`process can be acceptable.
`
`In the case of glass containers, presterilization preparation usually
`
`involves a series of wash and rinse cycles. Not only is it important
`
`that these washes effectively remove debris, it is also important
`
`that the final rinse water be of a high quality. Final rinse water
`
`is acceptable if it meets the requirements of USP water for
`
`injection. Oepyrogenation may be accomplished by a variety of
`
`methods; for example, by initial washings with chemical solutions
`
`followed by rinses with water for injection. Dry heat may be used to
`
`sterilize and depyrogenate glass containers. Validation of dry heat
`
`sterilization/depyrogenation should include heat penetration and heat
`
`distribution studies as well as use of representative process tycles
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`and loading configurations to simulate actual production practices.
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`Whatever depyrogenation method is used, the validation data should
`
`demonstrate that the process will reduce the endotoxin content by 3
`
`logs.
`
`One method of assessing the adequacy of a depyrogenation process is
`
`to simulate the process using containers having known quantities of
`
`standardized endotoxins and measure the level of reduction. However,
`
`FDA is aware of one potential problem where challenge endotoxins are
`
`used to assess certain washing process~s. The problem stems from
`
`applying the powdered endotoxin challenge directly to the surface
`
`being tested, rather than first resolubilizing the material and air
`
`drying it onto the surface. The powdered material may be much more
`
`soluble in the wash and rinse water than the reconstituted air-dried
`
`material and more so than endotoxins that may normally be present on
`
`container/closure surfaces. This could result in the perception of
`
`the process under consideration as being much more efficient at
`
`endotoxin removal than it really is. Therefore, endotoxin challenges
`
`should not be easier to remove from the target surfaces than the
`
`endotoxins that may normally be present.
`
`Plastic containers, subjected to uncontrolled handling and storage
`
`may be a source of pyrogens and should, therefore, be depyrogenated.
`
`Plastic containers may be sterilized with ethylene oxide gas.
`
`Biological indicators can be useful to monitor such processes, along
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`CIPLA EXHIBIT 1009
`Page 20 of 45
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`with monitoring and control of temperature, pressure, humidity, and
`
`ethylene oxide concentration. The potential for residues, such as
`
`ethylene oxide and its degradation products, to remain on or in the
`
`container should be assessed.
`
`Rubber compound stoppers pose another potential source of mi~robial
`
`and (of concern for products intended to be pyrogen free) pyrogen
`
`contamination. They are usually cleaned by multiple cycles of
`
`washing and rinsing prior to final steam sterilization. The final
`
`rinse should be with USP water for injection.
`
`It is also important
`
`to minimize the lapsed time between washing and sterilizing because
`
`moisture on the stoppers can support microbiological growth and the
`
`generation of pyrogens. Because rubber is a poor conductor of heat,
`
`proper validation of processes to sterilize rubber stoppers is
`
`particularly important.
`
`VI. TIME LIMITATIONS
`
`Requirements
`
`Section 211 .111 (time limitations on production) requires, in part,
`
`the establishment of time limits for completion of each phase of
`
`production, when appropriate, to assure the quality of the drug
`
`product.
`
`- 19 -
`
`CIPLA EXHIBIT 1009
`Page 21 of 45
`
`
`
`Guidance
`
`In aseptic processing of sterile drug products the establishment of
`
`time limitations is generally appropriate for several operations.
`
`The total time for the product filtration and filling operations, for
`
`example, should be limited to an established maximum in order-to
`
`prevent contamination of the filtrate by microorganisms growing or
`
`passing through the filter over a period of time. Such a limit
`
`should also prevent a significant increase in the number of
`
`microorganisms on the upstream side of the filter, which increase
`
`could lead to pyrogen formation.
`
`VII.PRODUCTION AND PROCESS CONTROLS; VALIDATION
`
`Requirements
`
`Section 211.113 (control of microbiological contamination) requires,
`
`in part, the establishment and adherence to appropriate written
`
`procedures designed to prevent microbiological contamination of drug
`
`products purporting to be sterile. Such procedures must include
`
`validation of any sterilization process.
`
`- 20 -
`
`CIPLA EXHIBIT 1009
`Page 22 of 45
`
`
`
`Guidance
`
`In order to assure the sterility of products purporting to be sterile
`
`which are prepared by aseptic processing, it is most important that
`
`two types of operations in particular be adequately validated, namely
`
`sterilization and filling/closing under aseptic conditions. The·
`
`objective of the most effective sterilization processes can be
`
`defeated if the sterilized elements of a product -- the drug, the
`
`container and closure -- are brought together under conditions that
`
`contaminate those elements. Conversely, product sterility maj' be
`
`compromised where those conditions add no contamination whatsoever,
`
`but where the product elements are not sterile at the time they are
`
`assembled.
`
`Questions have arisen as to acceptable ways of validating the aseptic
`
`assembly of sterile product elements, and the sterilization of those
`
`elements. However, the former operation is considered by some people
`
`to be the most difficult and has generated more questions.
`
`Therefore, the guidance presented places greater emphasis on
`
`validating the aseptic assembly (i.e., filling/closing) operations.
`
`- 21 -
`
`CIPLA EXHIBIT 1009
`Page 23 of 45
`
`
`
`Aseptic Assembly Operations
`
`An acceptable method of validating the aseptic assembly process
`
`involves the use of a microbiological growth nutrient medium to
`
`simulate sterile product filling operations.· This has been termed
`
`"sterile media fills". The nutrient medium is manipulated and
`
`exposed to the operators, equipment, surfaces, and environmental
`
`conditions to closely simulate the same exposure which the product
`
`itself will undergo. The sealed drug product containers filled with
`
`the media are then incubated to detect microbiological growth and the
`
`results are assessed to determine the probability that any given unit
`
`of drug product may become contaminated during actual filling/closing
`
`operations. Media filling in conjunction with comprehensive
`
`environmental monitoring can be particularly valuable in validating
`
`the aseptic processing of sterile solutions, suspensions, and
`
`powders. Filling liquid media, as part of validating the processing
`
`of powders, may necessitate use of equipment and/or processing steps
`
`that would otherwise not be attendant to routine powder operations.
`
`However, such additional efforts are valuable and important in
`
`characterizing exposure of powders to contamination.
`
`- 22 -
`
`CIPLA EXHIBIT 1009
`Page 24 of 45
`
`
`
`Several questions about media fills have been raised concerning
`
`contaminating equipment with media, frequency and number of runs,
`
`size of runs, the medium itself, environmental conditions, and test
`
`results.
`
`l. Contamination with media - Some drug manufacturers have
`
`expressed concern over the possible contamination of the
`
`facility and equipment with the nutrient media during media fill
`
`runs. However, if the medium is handled properly and is
`
`promptly followed by the cleaning, sanitizing, and, where
`
`necessary, sterilization of equipment, then media fill
`
`operations should not compromise the quality of product
`
`subsequently processed using the same facility and equipment.
`
`2.
`
`Frequency and number of runs - When a process is initially
`
`validated each separate media fill should be repeated enough
`
`times to assure that the results are consistent and meaningful.
`
`This is important because a single run may be faulty, and widely
`
`divergent results of multiple runs may signal a process that is
`
`not in control.
`
`FDA believes that, in many cases, at least
`
`three separate runs are needed: this minimum number has been
`
`recognized as a general validation principle in the industry
`
`(Refs. 6 and 7). The frequency of additional media fills needed
`
`after initial validation has been completed will vary depending
`
`- 23 -
`
`CIPLA EXHIBIT 1009
`Page 25 of 45
`
`
`
`upon a number of events and changes that may affect the ability
`
`of the aseptic process to exclude contamination from the
`
`sterilized product elements. For example, facility and
`
`equipment modification, significant changes in personnel,
`
`anomalies in environmental testing results, and end product
`
`sterility testing showing contaminated products may all be. cause
`
`for revalidating the system.
`
`In the absence of such changes or
`
`events, however, a generally acceptable frequency is at least
`
`twice each year for each shift for each filling/closing line.
`
`All personnel should take part in a media fill at least once a
`
`year. Depending upon the reason for revalidating the process
`
`using a media fill, the number of separate media fill runs per
`
`revalidation need not be as great as in the initial validation.
`
`For example, a single run may be sufficient if results are
`
`con
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