Guidance for Industry
`for the Submission Documentation for
`Sterilization Process Validation in
`Applications for Human and Veterinary
`Drug Products
`
`Center for Drug Evaluation and Research (CDER)
`Center for Veterinary Medicine (CVM)
`
`November 1994
`
`CMC 2
`
`Novartis Exhibit 2055.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 1
`
`A.
`
`B.
`
`C.
`
`Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 1
`
`Documenting Sterilization Process Validation . . . . . . . . . . . . . . . . . . .
`
` 2
`
`Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 2
`
`II.
`
`INFORMATION FOR TERMINAL MOIST HEAT STERILIZATION
`PROCESSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 3
`
`A.
`
`Description of the Process and Product . . . . . . . . . . . . . . . . . . . . . . . .
`
` 3
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`The Drug Product and Container-Closure System . . . . . . . . . .
`
` 3
`
`The Sterilization Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 3
`
`The Autoclave Process and Performance Specifications . . . . .
`
` 4
`
`Autoclave Loading Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 4
`
`Methods and Controls to Monitor Production Cycles . . . . . . . . .
`
` 4
`
`Requalification of Production Autoclaves . . . . . . . . . . . . . . . . . .
`
` 4
`
`Reprocessing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 4
`
`B.
`
`Thermal Qualification of the Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 4
`
`1.
`
`2.
`
`3.
`
`4.
`
`Heat Distribution and Penetration Studies . . . . . . . . . . . . . . . . .
`
` 4
`
`Thermal Monitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 5
`
`The Effects of Loading on Thermal Input . . . . . . . . . . . . . . . . . .
`
` 5
`
`Information Included in the Batch Record . . . . . . . . . . . . . . . .
`
`. 5
`
`C.
`
`Microbiological Efficacy of the Cycle . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 5
`
`1.
`
`2.
`
`Identification and Characterization of Bioburden Organisms . . .
`
` 6
`
`Specifications for Bioburden . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 6
`
`Novartis Exhibit 2055.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`3.
`
`4.
`
`5.
`
`Identification, Resistance, and Stability of Biological
`Indicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`The Resistance of the Biological Indicator Relative to That
`of Bioburden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
` 6
`
` 6
`
`Microbiological Challenge Studies . . . . . . . . . . . . . . . . . . . . . . .
`
` 7
`
`Microbiological Monitoring of the Environment . . . . . . . . . . . . . . . . . . .
`
` 7
`
`Container-Closure and Package Integrity . . . . . . . . . . . . . . . . . . . . . . . . 7
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Simulation of the Stresses From Processing . . . . . . . . . . . . . . . . 7
`
`Demonstrate Integrity Following the Maximum Exposure . . . . . . 8
`
`Multiple Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`
`The Sensitivity of the Test
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`
`Integrity Over the Product Shelf Life . . . . . . . . . . . . . . . . . . . . . . 8
`
`Bacterial Endotoxins Test and Method . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`
`Sterility Testing Methods and Release Criteria . . . . . . . . . . . . . . . . . . . . 8
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`Evidence of Formal, Written Procedures . . . . . . . . . . . . . . . . . . . . . . . . 9
`
`III.
`
`OTHER TERMINAL STERILIZATION PROCESSES . . . . . . . . . . . . . . . . . . . . 9
`
`A.
`
`Ethylene Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`
`1.
`
`2.
`
`3.
`
`4.
`
`Description of the Sterilizer
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`
`Cycle Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
`
`Microbiological Methods
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
`
`Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
`
`B.
`
`Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
`
`1.
`
`The Facility and the Process . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
`
`li
`
`Novartis Exhibit 2055.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2.
`
`3.
`
`4.
`
`5.
`
`The Packaging of the Product
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . 10
`
`Multiple-Dose Mapping Studies . . . . . . . . . . . . . . . . . . . . . . . . . 10
`
`Microbiological Methods and Controls
`
`. . . . . . . . . . . . . . . . . . . 11
`
`Monitoring Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`
`IV.
`
`INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES
`WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS
`. . . . . . . . . . . 11
`
`A.
`
`Buildings and Facilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`
`1.
`
`2.
`
`Floor Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`
`Location of equipment
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`
`B.
`
`Overall Manufacturing Operation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`
`1.
`
`2.
`
`3.
`
`Drug Product Solution Filtration . . . . . . . . . . . . . . . . . . . . . . . . . 12
`
`Specifications Concerning Holding Periods . . . . . . . . . . . . . . . . 12
`
`Critical Operations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
`
`C.
`
`Sterilization and Depyrogenation of Containers, Closures,
`Equipment, and Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
`
`D.
`
`E.
`
`F.
`
`1.
`
`2.
`
`Bulk Drug Solution Components That are Sterilized
`Separately . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
`
`Sterilization Information in the Batch Records . . . . . . . . . . . . . . 13
`
`Procedures and Specifications for Media Fills . . . . . . . . . . . . . . . . . . . 13
`
`Actions Concerning Product When Media Fills Fail . . . . . . . . . . . . . . . 14
`
`Microbiological monitoring of the environment
`
`. . . . . . . . . . . . . . . . . . . 15
`
`1.
`
`2.
`3.
`
`Microbiological Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
`
`Yeasts, Molds, and Anaerobic Microorganisms . . . . . . . . . . . . . 15
`Exceeded Limits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
`
`iii
`
`Novartis Exhibit 2055.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`G.
`
`H.
`
`I.
`
`J.
`
`Container-Closure and Package Integrity . . . . . . . . . . . . . . . . . . . . . . . 15
`
`Sterility Testing Methods and Release Criteria . . . . . . . . . . . . . . . . . . . 16
`
`Bacterial Endotoxins Test and Method . . . . . . . . . . . . . . . . . . . . . . . . . 16
`
`Evidence of Formal Written Procedures . . . . . . . . . . . . . . . . . . . . . . . . 16
`
`V.
`
`MAINTENANCE OF MICROBIOLOGICAL CONTROL AND QUALITY:
`STABILITY CONSIDERATIONS
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
`
`A.
`
`B.
`
`C.
`
`Container-Closure Integrity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
`
`Preservative Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`
`Pyrogen or Endotoxin Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`
`VI.
`
`ADDITIONAL INFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`
`iv
`
`Novartis Exhibit 2055.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`GUIDANCE FOR INDUSTRY1
`
`FOR THE SUBMISSION OF
`
`DOCUMENTATION FOR STERILIZATION PROCESS
`VALIDATION IN APPLICATIONS FOR HUMAN AND
`VETERINARY DRUG PRODUCTS
`
`I.
`
`INTRODUCTION
`
`A.
`
`Purpose
`
`This document is intended to provide guidance for the submission of
`information and data in support of the efficacy of sterilization processes in
`drug applications for both human and veterinary drugs. The
`recommendations in the guidance apply to applications for sterile drug
`products (new drug applications, new animal drug applications,
`abbreviated new drug applications, abbreviated antibiotic applications,
`and abbreviated new animal drug applications). These recommendations
`also apply to previously approved applications when supplements
`associated with the sterile processing of approved drugs are submitted.
`Information and data in support of sterility assurance may also be
`necessary in investigational new drug and investigational new animal
`drug applications.
`
`In the FEDERAL REGISTER of October 11, 1991 (56 FR 51354), the
`agency published a proposed rule entitled "Use of Aseptic Processing
`and Terminal Sterilization in the Preparation of Sterile Pharmaceuticals
`
` This guidance has been prepared by the Sterility Technical Committee of the
`1
`Chemistry Manufacturing Controls Coordinating Committee of the Center for Drug
`Evaluation and Research (CDER), and the Center for Veterinary Medicine (CVM), at the
`Food and Drug Administration. Although this guidance does not create or confer any
`rights for or on any person and does not operate to bind FDA or the industry, it does
`represent the agency’s current thinking on sterilization process validation documentation.
`For additional copies of this guidance, contact the Division of Communications
`Management, HFD-210, CDER, FDA, 5600 Fishers Lane, Rockville, MD 20857 (Phone:
`301-594-1012) Send one self-addressed adhesive label to assist the office in processing
`your request. An electronic version of this guidance is also available via Internet via World
`Wide Web (WWW) (connect to the FDA Home Page at WWW.FDA.GOV/CDER and go
`to the “Regulatory Guidance” section).
`
`Novartis Exhibit 2055.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`for Human and Veterinary Use." This guidance is not a substitution for or
`a supplement to that proposed rule. Regardless of whether the applicant
`uses terminal sterilization or aseptic processing to manufacture a drug
`product that is purported to be sterile, certain information about the
`validation of that process should be submitted for both of those types of
`sterilization.
`
`B.
`
`Documenting Sterilization Process Validation
`
`The efficacy of a given sterilization process for a specific drug product is
`evaluated on the basis of a series of protocols and scientific experiments
`designed to demonstrate that the sterilization process and associated
`control procedures can reproducibly deliver a sterile product. Data
`derived from experiments and control procedures allow conclusions to be
`drawn about the probability of nonsterile product units (sterility assurance
`level). Based on the scientific validity of the protocols and methods, as
`well as on the scientific validity of the results and conclusions, the agency
`concludes that the efficacy of the sterilization process is validated.
`Whether a drug product is sterilized by a terminal sterilization process or
`by an aseptic filling process, the efficacy of the sterilization process may
`be validated without the manufacture of three production batches.
`Sterilization process validation data, however, should be generated using
`procedures and conditions that are fully representative and descriptive of
`the procedures and conditions proposed for manufacture of the product in
`the application.
`
`The Center for Drug Evaluation and Research's (CDER's) and the Center
`for Veterinary Medicine's (CVM's) review of the validation of the
`sterilization process consists of a scientific evaluation of the studies
`submitted in the applications. This review is conducted by FDA's review
`staff, and is part of a cooperative effort between the review staff,
`compliance staff, and field investigators to ensure the overall state of
`control of the sterile processing of human and veterinary drug products.
`Information and data in support of sterility assurance may be provided
`directly to the application or by specific reference to a drug master file
`(DMF), a veterinary master file (VMF), or another application. Letters of
`authorization to refer to the referenced files should be included.
`
`C.
`
`Remarks
`
`This guidance is intended to provide recommendations for the types of
`information applicants should include in human and animal drug
`applications. Regulatory requirements for the submission of information
`and data in various applications are specified in the sections listed below:
`
`-
`
`Novartis Exhibit 2055.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`1.
`
`Human Drugs:
`
`Investigational new drug applications
`New drug applications
`Abbreviated new drug and abbreviated
`antibiotic drug applications
`Supplements to NDA's and ANDA's
`
`21 CFR 312.23(a)(7)
`21 CFR 314.50
`
`21 CFR 314.94 and 314.50
`21 CFR 314.70
`
`2.
`
`Animal Drugs:
`
`Investigational new animal drug applications
`New animal drug applications
`Supplements to NADA's
`
`21 CFR Part 511
`21 CFR 514.1
`21 CFR 514.8
`
`II.
`
`INFORMATION FOR TERMINAL MOIST HEAT STERILIZATION
`PROCESSES
`
`The following types of information should be submitted in support of sterility
`assurance for products produced using terminal moist heat sterilization.
`Although the following outline directly addresses moist heat processes, the
`same types of information would generally pertain to other terminal sterilization
`processes (e.g., ethylene oxide or radiation). (See section III of this guidance.)
`The following information should be submitted for each facility to be used in the
`manufacture of the proposed drug product:
`
`A.
`
`Description of the Process and Product
`
`1.
`
`The Drug Product and Container-Closure System
`
`Descriptions of the drug product and the container-closure
`system(s) to be sterilized (e.g., size(s), fill volume, or secondary
`packaging).
`
`2.
`
`The Sterilization Process
`
`A description of the sterilization process used to sterilize the drug
`product in its final container-closure system, as well as a
`description of any other sterilization process(es) used to sterilize
`delivery sets, components, packaging, bulk drug substance or bulk
`product, and related items. Information and data in support of the
`efficacy of these processes should also be submitted. (See also
`sections II.B. and II.C. of this guidance.)
`
`3
`
`Novartis Exhibit 2055.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`3.
`
`The Autoclave Process and Performance Specifications
`
`A description of the autoclave process, including pertinent
`information such as cycle type (e.g., saturated steam, water
`immersion, and water spray), cycle parameters and performance
`specifications including temperature, pressure, time, and minimum
`and maximum F . Identify the autoclave(s) to be used for
`o
`production sterilization, including manufacturer and model.
`
`4.
`
`Autoclave Loading Patterns
`
`A description of representative autoclave loading patterns should
`be provided.
`
`5.
`
`Methods and Controls to Monitor Production Cycles
`
`Methods and controls used to monitor routine production cycles
`(e.g., thermocouples, pilot bottles, and biological indicators) should
`be described, including the number and location of each as well as
`acceptance and rejection specifications.
`
`6.
`
`Requalification of Production Autoclaves
`
`A description of the program for routine and unscheduled
`requalification of production autoclaves, including frequency,
`should be provided.
`
`7.
`
`Reprocessing
`
`A description and validation summary of any program that provides
`for reprocessing (e.g., additional thermal processing) of product
`should be provided. Please note that the stability program is also
`affected by additional thermal processing. For further information
`concerning the stability program, reference is made to the Center
`for Drug Evaluation and Research "Guideline for Submitting
`Documentation for the Stability of Human Drugs and Biologics"
`and to the Center for Veterinary Medicine "Drug Stability
`Guideline."
`
`B.
`
`Thermal Qualification of the Cycle
`
`1.
`
`Heat Distribution and Penetration Studies
`
`Heat distribution and penetration study protocols and data
`
`4
`
`Novartis Exhibit 2055.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`summaries that demonstrate the uniformity, reproducibility, and
`conformance to specifications of the production sterilization cycle
`should be provided. Results from a minimum of three consecutive,
`successful cycles should be provided to ensure that the results are
`consistent and meaningful.
`
`2.
`
`Thermal Monitors
`
`The number of thermal monitors used and their location in the
`chamber should be described. A diagram is helpful.
`
`3.
`
`The Effects of Loading on Thermal Input
`
`Data should be generated with minimum and maximum load to
`demonstrate the effects of loading on thermal input to product.
`Additional studies may be necessary if different fill volumes are
`used in the same container line. Data summaries are acceptable
`for these purposes. A summary should consist of, for example,
`high and low temperatures (range), average temperature during
`the dwell period, minimum and maximum F values, dwell time, run
`0
`date and time, and identification of the autoclave(s) used. These
`data should have been generated from studies carried out in
`production autoclave(s) that will be used for sterilization of the
`product that is the subject of the application.
`
`4.
`
`Information Included in the Batch Record
`
`The batch record supplied with the chemistry, manufacturing, and
`controls section of the application should identify the validated
`processes to be used for sterilization and for depyrogenation of
`any container-closure components. This information can be
`included in the batch record by reference to the validation protocol
`or standard operating procedure (SOP). Validation information
`should be provided as described above.
`
`C.
`
`Microbiological Efficacy of the Cycle
`
`Validation studies that demonstrate the efficacy (lethality) of the
`production cycle should be provided. A sterility assurance of 10 or
`-6
`better should be demonstrated for any terminal sterilization process. This
`level of sterility assurance should be demonstrated for all parts of the
`drug product (including the container and closure, if applicable), which
`are claimed to be sterile. The specific type of study and the methods
`used to carry out the study (or studies) are product and process specific
`
`5
`
`Novartis Exhibit 2055.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`and may vary from manufacturer to manufacturer. In general, the
`following types of information and data should be provided.
`
`1.
`
`Identification and Characterization of Bioburden Organisms
`
`Describe the methods and results from studies used to identify and
`characterize bioburden organisms. The amount and type of
`information supplied may be dependent on the validation strategy
`chosen. For example, more information may be needed for
`bioburden-based autoclave processes than for overkill processes.
`Information concerning the number, type, and resistance of
`bioburden organisms may be necessary, including those
`organisms associated with the product solution and the container
`and closure. It may be necessary to identify the most heat-
`resistant bioburden organisms.
`
`2.
`
`Specifications for Bioburden
`
`Specifications (alert and action levels) for bioburden should be
`provided. A description should be included of the program for
`routinely monitoring bioburden to ensure that validated and
`established limits are not exceeded (e.g., frequency of analysis
`and methods used in bioburden screening). The methods
`provided should be specific.
`
`3.
`
`Identification, Resistance, and Stability of Biological Indicators
`
`Information and data concerning the identification, resistance (D
`and Z values), and stability of biological indicators used in the
`biological validation of the cycle should be provided. If biological
`indicators are purchased from a commercial source, it may be
`necessary to corroborate the microbial count and resistance, and
`provide performance specifications.
`
`4.
`
`The Resistance of the Biological Indicator Relative to That of
`Bioburden
`
`Studies characterizing the resistance of the biological indicator
`relative to that of bioburden may be necessary. Resistance in or
`on the product (i.e., in the product solution, or on the surface of
`container or closure parts or interfaces) should be determined as
`necessary. If spore carriers are used (e.g., spore strips), the
`resistance of spores on the carrier relative to that of directly
`inoculated product should be determined, if necessary.
`
`e
`
`Novartis Exhibit 2055.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`5.
`
`Microbiological Challenge Studies
`
`Microbiological validation studies should be submitted that
`demonstrate the efficacy of the minimum cycle to provide a sterility
`assurance of 10 or better to the product under the most difficult to
`-6
`sterilize conditions (e.g., the most difficult to sterilize load with
`biological indicators at microbiological master sites or in master
`product or both). Use of a microbiological master product or site
`should be supported by scientific data. Microbiological master
`sites or solutions are those sites or solutions in which it is most
`difficult to kill the biological indicator under sterilization cycles that
`simulate production conditions.
`
`D.
`
`Microbiological Monitoring of the Environment
`
`Section 211.160 of the Code of Federal Regulations requires, in part, the
`establishment of scientifically sound and appropriate specifications,
`standards, sampling plans, and test procedures designed to ensure that
`components, drug product containers, closures, in-process materials, and
`drug products conform to appropriate quality standards. Therefore, a
`microbiological monitoring program for production areas along with a
`bioburden monitoring program for product components and process water
`should be established. Process water includes autoclave cooling water.
`Applicants should provide information concerning this program.
`Frequency, methods used, action levels, and data summaries should be
`included. A description of the actions taken when specifications are
`exceeded should be provided.
`
`E.
`
`Container-Closure and Package Integrity
`
`An applicant should provide scientific validation studies (and data) in
`support of the microbial integrity of the drug packaging components. The
`following types of information should be included:
`
`1.
`
`Simulation of the Stresses from Processing
`
`Experimental designs should simulate the stresses of the
`sterilization process, handling, and storage of the drug and their
`effects on the container-closure system. Physical, chemical, and
`microbiological challenge studies may be necessary.
`
`2.
`
`Demonstrate Integrity Following the Maximum Exposure
`
`Container-closure integrity should be demonstrated on product
`
`,
`
`Novartis Exhibit 2055.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`units that have been exposed to the maximum sterilization
`cycle(s). If a product is exposed to more than one process, then
`exposure to the maximum cycle of all processes should be
`incorporated into the study design.
`
`3.
`
`Multiple Barriers
`
`Each barrier that separates areas of the drug product claimed to
`be sterile should be separately evaluated and validated.
`
`4.
`
`The Sensitivity of the Test
`
`The sensitivity of the experimental method used for container-
`closure integrity testing should be specified and provided.
`
`5.
`
`Integrity Over the Product Shelf Life
`
`Microbial integrity of the container-closure system should be
`demonstrated over the shelf life of the product. (See section V.A.
`of this guidance.)
`
`F.
`
`Bacterial Endotoxins Test and Method
`
`The bacterial endotoxins test used for the product should be described.
`The description should include qualification of the laboratory, inhibition
`and enhancement testing and results, determination of noninhibitory
`concentration and maximum valid dilution. For further information see the
`agency guidance entitled "Guideline on Validation of the Limulus
`Amebocyte Lysate Test As An End-Product Endotoxin Test for Human
`And Animal Parenteral Drugs, Biological Products, and Medical Devices."
`
`G.
`
`Sterility Testing Methods and Release Criteria
`
`Sterility test methods should be described and should include the protocol
`for the selection of representative units during production. When test
`methods differ significantly from compendial test methods, a
`demonstration of the equivalency to the compendial method should be
`provided. Testing performed within barrier systems should be described,
`and information concerning validation of the barrier system may be
`necessary.
`
`H.
`
`Evidence of Formal, Written Procedures
`
`8
`
`Novartis Exhibit 2055.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Section 211.113(b) of the Code of Federal Regulations requires that
`written procedures, designed to prevent microbiological contamination of
`drug products purporting to be sterile, be established and followed. Such
`procedures should include validation of any sterilization process.
`Therefore, evidence should be provided that there are formal, written
`procedures describing the elements listed above and that these
`procedures are followed. Such evidence may consist of SOP's, listing of
`SOP's, and protocols submitted as part of these elements.
`
`III. OTHER TERMINAL STERILIZATION PROCESSES
`
`Although the information above (sections I.A. through I.G. of this guidance)
`directly addresses moist heat processes, the same type of information would
`pertain to other terminal sterilization processes used singly or in combination to
`sterilize a drug product. The types of information outlined are, in general, also
`applicable to ethylene oxide and radiation (gamma and electron beam). These
`other processes should be addressed as each applies to the drug product,
`sterile packaging and in-process sterilization of components. Examples of such
`information might include: descriptions of loading configurations; qualification
`and validation of master load configurations; determination and validation of the
`efficacy of the minimum cycle to provide sterility assurance at the product
`master sites; requalification of the cycle; provisions for resterilization;
`specifications and monitoring program for product bioburden; and container-
`closure integrity. Specific examples are provided below to demonstrate the
`application of these concepts to other sterilization processes.
`
`Additional information relating to the effects of the sterilization process on the
`chemical and physical attributes of the drug substance or drug product may be
`applicable, and should be supplied to the chemistry, manufacturing, and controls
`section of the application.
`
`A.
`
`Ethylene Oxide
`
`1.
`
`Description of the Sterilizer
`
`The sterilizer(s) and controlled site(s) for prehumidification and
`aeration of the product load should be described.
`
`I
`
`Novartis Exhibit 2055.0014
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2.
`
`Cycle Parameters
`
`The parameters and limits for all phases of the cycle, e.g.,
`prehumidification, gas concentration, vacuum and gas pressure
`cycles, exposure time and temperature, humidity, degassing,
`aeration, and determination of residuals should be specified.
`Specific procedures used to monitor and control routine production
`cycles to assure that performance is within validated limits should
`be provided.
`
`3.
`
`Microbiological Methods
`
`The microbiological methods (growth medium, incubation
`temperature, and time interval) for cultivating spores from
`inoculated samples during validation experiments should be
`described as well as the microbiological methods used as part of
`routine production cycles.
`
`4.
`
`Stability
`
`The program for monitoring the stability of packaging and the
`integrity of the container-closure system barrier over the claimed
`shelf life should be described.
`
`B.
`
`Radiation
`
`1.
`
`The Facility and the Process
`
`The radiation facility should be identified. The radiation source,
`method of exposure (i.e., movement through the irradiator), and
`the type and location of dosimeters used to monitor routine
`production loads should be described. If the low dose site is not
`used for routine monitoring, data that show the dose relationship
`between the two sites should be provided.
`
`2.
`
`The Packaging of the Product
`
`The packaging of the drug product within the shipping carton and
`within the carrier should be described.
`
`3.
`
`Multiple-Dose Mapping Studies
`
`Multiple-dose mapping studies for identification of low and high
`dose sites and demonstration of uniformity and reproducibility of
`
`18
`
`Novartis Exhibit 2055.0015
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`the process should be described.
`
`4.
`
`Microbiological Methods and Controls
`
`The microbiological methods and controls used to establish,
`validate, and audit the efficacy of the cycle should be described.
`
`5.
`
`Monitoring Stability
`
`The program for monitoring the stability of packaging and the
`integrity of the container-closure system barrier over the claimed
`shelf life should be described.
`
`IV.
`
`INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES
`WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS
`
`The following types of information should be submitted in support of sterility
`assurance for products manufactured by aseptic processing.
`
`A.
`
`Buildings and Facilities
`
`A brief description of the manufacturing building and facilities should be
`provided. The following information should be included:
`
`1.
`
`Floor Plan
`
`A floor plan of the areas holding the aseptic filling facilities
`including preparation and holding areas, filtering and filling areas,
`and gowning rooms should be included. The air cleanliness class
`of each area should be identified (e.g., Class 100, Class 10,000,
`Class 100,000). Isolators or barrier systems should be identified.
`
`2.
`
`Location of Equipment
`
`The placement of all critical equipment, including, but not limited to,
`laminar flow hoods, autoclaves, lyophilizers, and filling heads,
`should be identified. Equipment within barrier or isolation systems
`should be noted.
`
`B.
`
`Overall Manufacturing Operation
`
`The overall manufacturing operation including, for example, material flow,
`filling, capping, and aseptic assembly, should be described. The normal
`
`II
`
`Novartis Exhibit 2055.0016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`flow (movement) of product and components from formulation to finished
`dosage form should be identified and indicated on the floor plan
`described above. The following information should be considered when
`describing the overall manufacturing operation:
`
`1.
`
`Drug Product Solution Filtration
`
`The specific bulk drug product solution filtration processes,
`including tandem filter units, prefilters, and bacterial retentive
`filters, should be described. A summary should be provided
`containing information and data concerning the validation of the
`retention of microbes and compatibility of the filter used for the
`specific product. Any effects of the filter on the product formulation
`should be described (e.g., adsorption of preservatives or active
`drug substance, or extractables).
`
`2.
`
`Specifications Concerning Holding Periods
`
`Section 211.111 of the Code of Federal Regulations requires, in
`part, when appropriate, the establishment of time limits for
`completing each phase of production to ensure the quality of the
`drug product. Therefore, specifications concerning any holding
`periods between the compounding of the bulk drug product and its
`filling into final containers should be provided. These
`specifications should include, for example, holding tanks, times,
`temperatures, and conditions of storage. Procedures used to
`protect microbiological quality of the bulk drug during these holding
`periods should be indicated. Maintenance of the microbiological
`quality during holding periods may need verification.
`
`3.
`
`Critical Operations
`
`The critical operations that expose product or product contact
`surfaces to the environment (such as transfer of sterilized
`containers or closures to the aseptic filling areas) should be
`described. Any barrier or isolation systems should be described.
`
`C.
`
`Sterilization and Depyrogenation of Containers, Closures,
`Equipment, and Components
`
`The sterilization and depyrogenation processes used for containers,
`closures, equipment, components, and barrier systems should be
`described. A description of the validation of these processes should be
`provided including, where applicable, heat distribution and penetration
`
`1Z
`
`Novartis Exhibit 2055.0017
`Regeneron v. Novartis,