Guidance for Industry
`
`Sterile Drug Products
`Produced by Aseptic Processing(cid:173)
`Current Good Manufacturing Practice
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`Office of Regulatory Affairs (ORA)
`
`September 2004
`Pharmaceutical CGMPs
`
`Regeneron Exhibit 1036.001
`
`

`

`Guidance for Industry
`Sterile Drug Products
`Produced by Aseptic Processing
`Current Good Manufacturing Practice
`
`Additional copies are available from:
`Office of Training and Communication
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
`http://wwwjda.gov/cder/guidance/index.htm
`
`or
`
`Office of Communication, Training and
`Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research
`Food and Drug Administration
`1401 Rockville Pike, Rockville, MD 20852-1448
`http://wwwjda.gov/cber/guidelines.htm.
`(Tel) Voice Information System at 800-835-4709 or 301-827-1800
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`Office of Regulatory affairs (ORA)
`
`September 2004
`Pharmaceutical CGMPs
`
`Regeneron Exhibit 1036.002
`
`

`

`Contains Nonbinding Recommendations
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ............................................................................................................. 1
`BACKGROUND ............................................................................................................... 2
`II.
`A. Regulatory Framework ................................................................................................................. 2
`
`B. Technical Framework .................................................................................................................... 2
`
`SCOPE ............................................................................................................................... 3
`III.
`BUILDINGS AND FACILITIES .................................................................................... 4
`IV.
`A. Critical Area - Class 100 (ISO 5) ................................................................................................. 5
`
`B.
`
`Supporting Clean Areas ................................................................................................................ 7
`
`C. Clean Area Separation .................................................................................................................. 7
`
`D. Air Filtration .................................................................................................................................. 8
`
`1. Membrane ........................................................................................................................................ 8
`2. High-Efficiency Particulate Air (HEPA) ......................................................................................... 8
`E. Design ............................................................................................................................................ 10
`
`PERSONNEL TRAINING, QUALIFICATION, & MONITORING ........................ 12
`V.
`A. Personnel ....................................................................................................................................... 13
`
`B. Laboratory Personnel .................................................................................................................. 15
`
`C. Monitoring Program .................................................................................................................... 15
`
`VI. COMPONENTS AND CONTAINER/CLOSURES .......................................................... 15
`A. Components .................................................................................................................................. 16
`
`B. Containers/Closures ..................................................................................................................... 17
`
`1. Preparation .................................................................................................................................... 17
`2. Inspection a/Container Closure System ........................................................................................ 18
`VII. ENDOTOXIN CONTROL ................................................................................................. 19
`VIII. TIME LIMITATIONS ...................................................................................................... 20
`IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION .................. 20
`A. Process Simulations ..................................................................................................................... 20
`1. Study Design ................................................................................................................................. 21
`2. Frequency and Number of Runs .................................................................................................... 22
`3. Duration of Runs ............................................................................................................................ 22
`4. Size of Runs .................................................................................................................................... 23
`5. Line Speed ...................................................................................................................................... 23
`6. Environmental Conditions ............................................................................................................. 24
`7. Media ............................................................................................................................................ 24
`8. Incubation and Examination of Media-Filled Units ...................................................................... 24
`9. Interpretation a/Test Results ......................................................................................................... 26
`B. Filtration Efficacy ........................................................................................................................ 27
`
`Regeneron Exhibit 1036.003
`
`

`

`Contains Nonbinding Recommendations
`
`C. Sterilization of Equipment, Containers, and Closures ............................................................. 28
`
`1. Qualification and Validation ......................................................................................................... 29
`2. Equipment Controls and Instrument Calibration .......................................................................... 30
`LABORATORY CONTROLS ...................................................................................... 31
`
`X.
`
`A. Environmental Monitoring ......................................................................................................... 32
`
`1. General Written Program ............................................................................................................. 32
`2. Establishing Levels and a Trending Program ............................................................................... 33
`3. Disinfection Efficacy ...................................................................................................................... 34
`4. Monitoring Methods ...................................................................................................................... 34
`B. Microbiological Media and Identification ................................................................................. 35
`
`C. Prefiltration Bioburden ............................................................................................................... 36
`
`D. Alternate Microbiological Test Methods ................................................................................... 36
`
`E. Particle Monitoring ...................................................................................................................... 36
`
`XI.
`
`STERILITY TESTING .................................................................................................. 37
`
`A. Microbiological Laboratory Controls ........................................................................................ 38
`
`B. Sampling and Incubation ............................................................................................................ 38
`
`C.
`
`Investigation of Sterility Positives .............................................................................................. 39
`
`XII. BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION ........ 42
`
`APPENDIX 1: ASEPTIC PROCESSING ISOLATORS ....................................................... 44
`
`APPENDIX 2: BLOW-FILL- SEAL TECHNOLOGY .......................................................... 49
`
`APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS .... 52
`
`REFERENCES ............................................................................................................................ 54
`
`RELEVANT GUIDANCE DOCUMENTS ............................................................................... 55
`
`GLOSSARY ................................................................................................................................. 56
`
`Regeneron Exhibit 1036.004
`
`

`

`Contains Nonbinding Recommendations
`
`Guidance for Industry1
`Sterile Drug Products Produced by
`Aseptic Processing - Current Good Manufacturing Practice
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
`and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
`implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
`number listed on the title page of this guidance.
`
`I.
`
`INTRODUCTION
`
`This guidance is intended to help manufacturers meet the requirements in the Agency's current
`good manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211) when
`manufacturing sterile drug and biological products using aseptic processing. This guidance
`replaces the 1987 Industry Guideline on Sterile Drug Products Produced by Aseptic Processing
`(Aseptic Processing Guideline). This revision updates and clarifies the 1987 guidance.
`
`For sterile drug products subject to a new or abbreviated drug application (NDA or ANDA) or a
`biologic license application (BLA), this guidance document should be read in conjunction with
`the guidance on the content of sterile drug applications entitled Guideline for the Submission of
`Documentation for Sterilization Process Validation in Applications for Human and Veterinary
`Drug Products (Submission Guidance). The Submission Guidance describes the types of
`information and data that should be included in drug applications to demonstrate the efficacy of a
`manufacturer's sterilization process. This guidance compliments the Submission Guidance by
`describing procedures and practices that will help enable a sterile drug manufacturing facility to
`meet CGMP requirements relating, for example, to facility design, equipment suitability, process
`validation, and quality control.
`
`FDA's guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`1 This guidance was developed by the Office of Compliance in the Center for Drug Evaluation and Research
`(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) and the Office of Regulatory
`Affairs (ORA).
`
`1
`
`Regeneron Exhibit 1036.005
`
`

`

`Contains Nonbinding Recommendations
`
`The text boxes included in this guidance include specific sections of parts 210 and 211 of the
`Code of Federal Regulations (CFR), which address current good manufacturing practice for
`drugs. The intent of including these quotes in the text boxes is to aid the reader by providing a
`portion of an applicable regulation being addressed in the guidance. The quotes included in the
`text boxes are not intended to be exhaustive. Readers of this document should reference the
`complete CFR to ensure that they have complied, in full, with all relevant sections of the
`regulations.
`
`II.
`
`BACKGROUND
`
`This section describes briefly both the regulatory and technical reasons why the Agency is
`developing this guidance document.
`
`A.
`
`Regulatory Framework
`
`This guidance pertains to current good manufacturing practice (CGMP) regulations (21 CFR
`parts 210 and 211) when manufacturing sterile drug and biological products using aseptic
`processing. Although the focus of this guidance is on CGMPs in 21 CFR 210 and 211,
`supplementary requirements for biological products are in 21 CFR 600-680. For biological
`products regulated under 21 CFR parts 600 through 680, §§ 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
`supercede the more general regulations.
`
`B.
`
`Technical Framework
`
`There are basic differences between the production of sterile drug products using aseptic
`processing and production using terminal sterilization.
`
`Terminal sterilization usually involves filling and sealing product containers under high-quality
`environmental conditions. Products are filled and sealed in this type of environment to minimize
`the microbial and particulate content of the in-process product and to help ensure that the
`subsequent sterilization process is successful. In most cases, the product, container, and closure
`have low bioburden, but they are not sterile. The product in its final container is then subjected to
`a sterilization process such as heat or irradiation.
`
`In an aseptic process, the drug product, container, and closure are first subjected to sterilization
`methods separately, as appropriate, and then brought together.2 Because there is no process to
`sterilize the product in its final container, it is critical that containers be filled and sealed in an
`extremely high-quality environment. Aseptic processing involves more variables than terminal
`sterilization. Before aseptic assembly into a final product, the individual parts of the final product
`
`2 Due to their nature, certain products are aseptically processed at an earlier stage in the process, or in their entirety.
`Cellular therapy products are an example. All components and excipients for these products are rendered sterile, and
`release of the final product is contingent on determination of sterility. See Appendix III.
`
`2
`
`Regeneron Exhibit 1036.006
`
`

`

`Contains Nonbinding Recommendations
`
`are generally subjected to various sterilization processes. For example, glass containers are
`subjected to dry heat; rubber closures are subjected to moist heat; and liquid dosage forms are
`subjected to filtration. Each of these manufacturing processes requires validation and control.
`Each process could introduce an error that ultimately could lead to the distribution of a
`contaminated product. Any manual or mechanical manipulation of the sterilized drug,
`components, containers, or closures prior to or during aseptic assembly poses the risk of
`contamination and thus necessitates careful control. A terminally sterilized drug product, on the
`other hand, undergoes final sterilization in a sealed container, thus limiting the possibility of
`error.3
`
`Sterile drug manufacturers should have a keen awareness of the public health implications of
`distributing a nonsterile product. Poor CGMP conditions at a manufacturing facility can
`ultimately pose a life-threatening health risk to a patient.
`
`III.
`
`SCOPE
`
`This guidance document discusses selected issues and does not address all aspects of aseptic
`processing. For example, the guidance addresses primarily finished drug product CGMP issues
`while only limited information is provided regarding upstream bulk processing steps. This
`guidance updates the 1987 Aseptic Processing Guideline primarily with respect to personnel
`qualification, cleanroom design, process design, quality control, environmental monitoring, and
`review of production records. The use of isolators for aseptic processing is also discussed.
`
`Although this guidance document discusses CGMP issues relating to the sterilization of
`components, containers, and closures, terminal sterilization of drug products is not addressed. It
`is a well-accepted principle that sterile drugs should be manufactured using aseptic processing
`only when terminal sterilization is not feasible. However, some final packaging may afford
`some unique and substantial advantage (e.g., some dual-chamber syringes) that would not be
`possible if terminal sterilization were employed. In such cases, a manufacturer can explore the
`option of adding adjunct processing steps to increase the level of sterility assurance.
`
`A list ofreferences that may be of value to the reader is included at the conclusion of this
`document.
`
`3 Nearly all drugs recalled due to nonsterility or lack of sterility assurance in the period spanning 1980-2000 were
`produced via aseptic processing.
`
`3
`
`Regeneron Exhibit 1036.007
`
`

`

`Contains Nonbinding Recommendations
`
`IV.
`
`BUILDINGS AND FACILITIES
`
`21 CFR 2 l l .42(b) states, in part, that "The flow of components, drug product containers, closures, labeling,
`in-process materials, and drug products through the building or buildings shall be designed to prevent
`contamination."
`
`21 CFR 211.42( c) states, in part, that "Operations shall be performed within specifically defined areas of
`adequate size. There shall be separate or defined areas or such other control systems for the firm's operations
`as are necessary to prevent contamination or mixups during the course of the following procedures: * * *
`(10) Aseptic processing, which includes as appropriate: (i) Floors, walls, and ceilings of smooth, hard
`surfaces that are easily cleanable; (ii) Temperature and humidity controls; (iii) An air supply filtered
`through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or
`nonlaminar; (iv) A system for monitoring environmental conditions; (v) A system for cleaning and
`disinfecting the room and equipment to produce aseptic conditions; (vi) A system for maintaining any
`equipment used to control the aseptic conditions."
`
`21 CFR 2 l l .46(b) states that "Equipment for adequate control over air pressure, micro-organisms, dust,
`humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or
`holding of a drug product."
`
`21 CFR 211. 46( c) states, in part, that "Air filtration systems, including prefilters and particulate matter air
`filters, shall be used when appropriate on air supplies to production areas * * * ."
`
`21 CFR 211.63 states that "Equipment used in the manufacture, processing, packing, or holding of a drug
`product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its
`intended use and for its cleaning and maintenance."
`
`21 CFR 21 l.65(a) states that "Equipment shall be constructed so that surfaces that contact components, in(cid:173)
`process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety,
`identity, strength, quality, or purity of the drug product beyond the official or other established
`requirements."
`
`21 CFR 21 l.67(a) states that "Equipment and utensils shall be cleaned, maintained, and sanitized at
`appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength,
`quality, or purity of the drug product beyond the official or other established requirements."
`
`21 CFR 211.113 (b) states that "Appropriate written procedures, designed to prevent microbiological
`contamination of drug products purporting to be sterile, shall be established and followed. Such procedures
`shall include validation of any sterilization process."
`
`As provided for in the regulations, separate or defined areas of operation in an aseptic processing
`facility should be appropriately controlled to attain different degrees of air quality depending on
`the nature of the operation. Design of a given area involves satisfying microbiological and
`particle criteria as defined by the equipment, components, and products exposed, as well as the
`operational activities conducted in the area.
`
`4
`
`Regeneron Exhibit 1036.008
`
`

`

`Contains Nonbinding Recommendations
`
`Clean area control parameters should be supported by microbiological and particle data obtained
`during qualification studies. Initial cleanroom qualification includes, in part, an assessment of
`air quality under as-built, static conditions. It is important for area qualification and
`classification to place most emphasis on data generated under dynamic conditions (i.e., with
`personnel present, equipment in place, and operations ongoing). An adequate aseptic processing
`facility monitoring program also will assess conformance with specified clean area
`classifications under dynamic conditions on a routine basis.
`
`The following table summarizes clean area air classifications and recommended action levels of
`microbiological quality (Ref I).
`
`TABLE 1-Air Classificationsa
`
`Clean Area
`Classification
`(0.5 um particles/ft3
`100
`1000
`10,000
`100,000
`
`)
`
`ISO
`Designationb
`
`::::0.5 µm
`particles/m3
`
`5
`6
`7
`8
`
`3,520
`35,200
`352,000
`3,520,000
`
`Microbiological
`Active Air Action
`( cfu/m3
`Levels0
`)
`le
`7
`10
`100
`
`Microbiological Settling
`Plates Action Levels0 ·d
`(diam. 90mm; cfu/4 hours)
`le
`3
`5
`50
`
`a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.
`b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle
`concentration is equal to Class 100 and approximately equals EU Grade A.
`c- Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological action
`levels due to the nature of the operation or method of analysis.
`d- The additional use of settling plates is optional.
`e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.
`
`Two clean areas are of particular importance to sterile drug product quality: the critical area and
`the supporting clean areas associated with it.
`
`A.
`
`Critical Area - Class 100 (ISO 5)
`
`A critical area is one in which the sterilized drug product, containers, and closures are exposed to
`environmental conditions that must be designed to maintain product sterility(§ 21 l.42(c)(l0)).
`Activities conducted in such areas include manipulations (e.g., aseptic connections, sterile
`ingredient additions) of sterile materials prior to and during filling and closing operations.
`
`This area is critical because an exposed product is vulnerable to contamination and will not be
`subsequently sterilized in its immediate container. To maintain product sterility, it is essential
`that the environment in which aseptic operations (e.g., equipment setup, filling) are conducted be
`controlled and maintained at an appropriate quality. One aspect of environmental quality is the
`particle content of the air. Particles are significant because they can enter a product as an
`extraneous contaminant, and can also contaminate it biologically by acting as a vehicle for
`microorganisms (Ref 2). Appropriately designed air handling systems minimize particle content
`of a critical area.
`
`Air in the immediate proximity of exposed sterilized containers/closures and filling/closing
`operations would be of appropriate particle quality when it has a per-cubic-meter particle count
`
`5
`
`Regeneron Exhibit 1036.009
`
`

`

`Contains Nonbinding Recommendations
`
`of no more than 3520 in a size range of 0.5 µm and larger when counted at representative
`locations normally not more than I foot away from the work site, within the airflow, and during
`filling/closing operations. This level of air cleanliness is also known as Class I 00 (ISO 5).
`
`We recommend that measurements to confirm air cleanliness in critical areas be taken at sites
`where there is most potential risk to the exposed sterilized product, containers, and closures. The
`particle counting probe should be placed in an orientation demonstrated to obtain a meaningful
`sample. Regular monitoring should be performed during each production shift. We recommend
`conducting nonviable particle monitoring with a remote counting system. These systems are
`capable of collecting more comprehensive data and are generally less invasive than portable
`particle counters. See Section X.E. for additional guidance on particle monitoring.
`
`Some operations can generate high levels of product ( e.g., powder) particles that, 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 levels of particles from air
`contaminants. In these instances, air can be sampled in a manner that, to the extent possible,
`characterizes the true level of extrinsic particle contamination to which the product is exposed.
`Initial qualification of the area under dynamic conditions without the actual filling function
`provides some baseline information on the non-product particle generation of the operation.
`
`HEPA-filtered4 air should be supplied in critical areas at a velocity sufficient to sweep particles
`away from the filling/closing area and maintain unidirectional airflow during operations. The
`velocity parameters established for each processing line should be justified and appropriate to
`maintain unidirectional airflow and air quality under dynamic conditions within the critical area
`(Ref 3). 5
`
`Proper design and control prevents turbulence and stagnant air in the critical area. Once relevant
`parameters are established, it is crucial that airflow patterns be evaluated for turbulence or eddy
`currents that can act as a channel or reservoir for air contaminants (e.g., from an adjoining lower
`classified area). In situ air pattern analysis should be conducted at the critical area to
`demonstrate unidirectional airflow and sweeping action over and away from the product under
`dynamic conditions. The studies should be well documented with written conclusions, and
`include evaluation of the impact of aseptic manipulations (e.g., interventions) and equipment
`design. Videotape or other recording mechanisms have been found to be useful aides in
`assessing airflow initially as well as facilitating evaluation of subsequent equipment
`configuration changes. It is important to note that even successfully qualified systems can be
`compromised by poor operational, maintenance, or personnel practices.
`
`Air monitoring samples of critical areas should normally yield no microbiological contaminants.
`We recommend affording appropriate investigative attention to contamination occurrences in this
`environment.
`
`4High Efficiency Particulate Air filter
`
`5 A velocity of0.45 meters/second (90 feet per minute) has generally been established, with a range of plus or minus
`20 percent around the setpoint. Higher velocities may be appropriate in operations generating high levels of
`particulates.
`
`6
`
`Regeneron Exhibit 1036.010
`
`

`

`Contains Nonbinding Recommendations
`
`B.
`
`Supporting Clean Areas
`
`Supporting clean areas can have various classifications and functions. Many support areas
`function as zones in which nonsterile components, formulated products, in-process materials,
`equipment, and container/closures are prepared, held, or transferred. These environments are
`soundly designed when they minimize the level of particle contaminants in the final product and
`control the microbiological content (bioburden) of articles and components that are subsequently
`sterilized.
`
`The nature of the activities conducted in a supporting clean area determines its classification.
`FDA recommends that the area immediately adjacent to the aseptic processing line meet, at a
`minimum, Class 10,000 (ISO 7) standards (see Table 1) under dynamic conditions.
`Manufacturers can also classify this area as Class 1,000 (ISO 6) or maintain the entire aseptic
`filling room at Class 100 (ISO 5). An area classified at a Class 100,000 (ISO 8) air cleanliness
`level is appropriate for less critical activities (e.g., equipment cleaning).
`
`C.
`
`Clean Area Separation
`
`An essential part of contamination prevention is the adequate separation of areas of operation.
`To maintain air quality, it is important to achieve a proper airflow from areas of higher
`cleanliness to adjacent less clean areas. It is vital for rooms of higher air cleanliness to have a
`substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. For
`example, a positive pressure differential of at least 10-15 Pascals (Pa)6 should be maintained
`between adjacent rooms of differing classification (with doors closed). When doors are open,
`outward airflow should be sufficient to minimize ingress of contamination, and it is critical that
`the time a door can remain ajar be strictly controlled (Ref 4).
`
`In some cases, the aseptic processing room and adjacent cleanrooms have the same
`classification. Maintaining a pressure differential (with doors closed) between the aseptic
`processing room and these adjacent rooms can provide beneficial separation. In any facility
`designed with an unclassified room adjacent to the aseptic processing room, a substantial
`overpressure (e.g., at least 12.5 Pa) from the aseptic processing room should be maintained at all
`times to prevent contamination. If this pressure differential drops below the minimum limit, it is
`important that the environmental quality of the aseptic processing room be restored and
`confirmed.
`
`The Agency recommends that pressure differentials between cleanrooms be monitored
`continuously throughout each shift and frequently recorded. All alarms should be documented
`and deviations from established limits should be investigated.
`
`Air change rate is another important cleanroom design parameter. For Class 100,000 (ISO 8)
`supporting rooms, airflow sufficient to achieve at least 20 air changes per hour is typically
`acceptable. Significantly higher air change rates are normally needed for Class 10,000 and Class
`100 areas.
`
`6 Equal to 0.04-0.06 inches of water gauge.
`
`7
`
`Regeneron Exhibit 1036.011
`
`

`

`Contains Nonbinding Recommendations
`
`A suitable facility monitoring system will rapidly detect atypical changes that can compromise
`the facility's environment. An effective system facilitates restoration of operating conditions to
`established, qualified levels before reaching action levels. For example, pressure differential
`specifications should enable prompt detection (i.e., alarms) of an emerging low pressure problem
`to preclude ingress of unclassified air into a classified room.
`
`D.
`
`I.
`
`Air Filtration
`
`Membrane
`
`A compressed gas should be of appropriate purity (e.g., free from oil) and its microbiological and
`particle quality after filtration should be equal to or better than that of the air in the environment
`into which the gas is introduced. Compressed gases such as air, nitrogen, and carbon dioxide are
`often used in cleanrooms and are frequently employed in purging or overlaying.
`
`Membrane filters can be used to filter a compressed gas to meet an appropriate high-quality
`standard. These filters are often used to produce a sterile compressed gas to conduct operations
`involving sterile materials, such as components and equipment. For example, we recommend
`that sterile membrane filters be used for autoclave air