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
`
`Actavis - IPR2017-01103, Ex. 1009, p. 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
`
`Actavis - IPR2017-01103, Ex. 1009, p. 1 of 45
`
`
`
`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
`
`Actavis - IPR2017-01103, Ex. 1009, p. 2 of 45
`
`
`
`I. PURPOSE
`
`This guideline informs interested persons on certain practices and
`
`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,
`
`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
`
`(FDA). A person may rely upon this guideline with the assurance of
`
`its acceptability to FDA, or may follow different procedures. When
`
`-
`
`l -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 3 of 45
`
`
`
`different procedures are chosen, a person may, but is not required
`
`to, discuss the matter in advance with FDA to prevent the expenditure
`
`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.
`
`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
`
`to minimize the microbial content of the product and to help assure
`
`that the subsequent sterilization process is successful. The product
`
`in its final container is then subjected to a sterilization
`
`process--usually using heat or radiation.
`
`In aseptic processing, the
`
`drug product, container, and closure are subjected to sterilization
`
`processes separately and then brought together. Because there is no
`
`further processing to sterilize the product after it is in its final
`
`container, it is critical to the maintenance of product sterility
`
`- 2 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 4 of 45
`
`
`
`that containers be filled and closed in an environment of extremely
`
`high quality.
`
`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
`
`filtration for a liquid dosage form -- each requiring thorough
`
`validation and control, each with the possibility of error.
`
`(For the
`
`terminally sterilized drug product, on the other hand, there is
`
`generally only one sterilization process, thus limiting the
`
`possibilities for error.) Furthermore, any manipulation of the
`
`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
`
`limitations, validation, laboratory controls, and sterility testing.
`
`Because most of the questions have concerned process validation in
`
`- 3 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 5 of 45
`
`
`
`particular, this guideline addresses this area extensively. This
`
`guideline is intended to respond to these questions and clarify
`
`certain technical aspects of aseptic processing of sterile drug
`
`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.
`
`- 4 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 6 of 45
`
`
`
`Critical surfaces - Surfaces which come into contact with sterilized
`
`product or containers/closures.
`
`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.
`
`- 5 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 7 of 45
`
`
`
`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.
`
`- 6 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 8 of 45
`
`
`
`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
`
`- 7 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 9 of 45
`
`
`
`particle count of no more than 100 in a size range of 0.5 micron and
`
`larger (Class 100) when measured not more than one foot away from the
`
`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
`
`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.
`
`- 8 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 10 of 45
`
`
`
`Air should also be of a high microbial quality. An incidence of no
`
`more than one colony forming unit per 10 cubic feet is considered as
`
`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
`
`- 9 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 11 of 45
`
`
`
`should be of a high microbial and particulate quality in order to
`
`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
`
`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
`
`vapor.
`
`-
`
`l 0 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 12 of 45
`
`
`
`In addition to these production areas, there may be certain pieces of
`
`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
`
`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
`
`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.
`
`- 11 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 13 of 45
`
`
`
`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
`
`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
`
`done in place and the filter face is scaned with a probe; the
`
`- 12 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 14 of 45
`
`
`
`measured downstream leakage is taken as a percent of the upstream
`
`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.
`
`- 13 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 15 of 45
`
`
`
`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
`
`- 14 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 16 of 45
`
`
`
`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.
`
`- 15 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 17 of 45
`
`
`
`Ethylene oxide exposure is another method of sterilizing components.
`
`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
`
`cleaning, sterilizing and processing to remove pyrogenic properties
`
`must be written and followed.
`
`- 16 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 18 of 45
`
`
`
`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
`
`- 17 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 19 of 45
`
`
`
`and loading configurations to simulate actual production practices.
`
`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
`
`- 18 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 20 of 45
`
`
`
`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 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 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 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 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 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 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 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 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 -
`
`Actavis - IPR2017-01103, Ex. 1009, p. 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.
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
