1、Guidance for Industryfor the Submission Documentation forSterilization Process Validation inApplications for Human and VeterinaryDrug ProductsCenter for Drug Evaluation and Research (CDER)Center for Veterinary Medicine (CVM)November 1994CMC 2TABLE OF CONTENTSI. INTRODUCTION . 1A. Purpose . 1B. Docum
2、enting Sterilization Process Validation . 2C. Remarks 2II. INFORMATION FOR TERMINAL MOIST HEAT STERILIZATIONPROCESSES . 3A. Description of the Process and Product 31. The Drug Product and Container-Closure System 32. The Sterilization Process 33. The Autoclave Process and Performance Specifications
3、. 44. Autoclave Loading Patterns 45. Methods and Controls to Monitor Production Cycles . 46. Requalification of Production Autoclaves 47. Reprocessing . 4B. Thermal Qualification of the Cycle 41. Heat Distribution and Penetration Studies . 42. Thermal Monitors 53. The Effects of Loading on Thermal I
4、nput 54. Information Included in the Batch Record . 5C. Microbiological Efficacy of the Cycle 51. Identification and Characterization of Bioburden Organisms . 62. Specifications for Bioburden . 63. Identification, Resistance, and Stability of BiologicalIndicators 64. The Resistance of the Biological
5、 Indicator Relative to Thatof Bioburden 65. Microbiological Challenge Studies . 7D. Microbiological Monitoring of the Environment . 7E. Container-Closure and Package Integrity 71. Simulation of the Stresses From Processing 72. Demonstrate Integrity Following the Maximum Exposure 83. Multiple Barrier
6、s 84. The Sensitivity of the Test 85. Integrity Over the Product Shelf Life 8F. Bacterial Endotoxins Test and Method 8G. Sterility Testing Methods and Release Criteria 8H. Evidence of Formal, Written Procedures 9III. OTHER TERMINAL STERILIZATION PROCESSES 9A. Ethylene Oxide 91. Description of the St
7、erilizer . 92. Cycle Parameters 103. Microbiological Methods 104. Stability 10B. Radiation 101. The Facility and the Process . 102. The Packaging of the Product 103. Multiple-Dose Mapping Studies . 104. Microbiological Methods and Controls . 115. Monitoring Stability . 11IV. INFORMATION FOR ASEPTIC
8、FILL MANUFACTURING PROCESSESWHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS . 11A. Buildings and Facilities . 111. Floor Plan 112. Location of equipment 11B. Overall Manufacturing Operation . 111. Drug Product Solution Filtration . 122. Specifications Concerning Holding Periods 123. Critical Operation
9、s . 12C. Sterilization and Depyrogenation of Containers, Closures,Equipment, and Components 121. Bulk Drug Solution Components That are SterilizedSeparately . 132. Sterilization Information in the Batch Records 13D. Procedures and Specifications for Media Fills . 13E. Actions Concerning Product When
10、 Media Fills Fail . 14F. Microbiological monitoring of the environment . 151. Microbiological Methods . 152. Yeasts, Molds, and Anaerobic Microorganisms . 153. Exceeded Limits . 15G. Container-Closure and Package Integrity . 15H. Sterility Testing Methods and Release Criteria . 16I. Bacterial Endoto
11、xins Test and Method . 16J. Evidence of Formal Written Procedures 16V. MAINTENANCE OF MICROBIOLOGICAL CONTROL AND QUALITY: STABILITY CONSIDERATIONS 16A. Container-Closure Integrity 16B. Preservative Effectiveness 17C. Pyrogen or Endotoxin Testing . 17VI. ADDITIONAL INFORMATION 17This guidance has be
12、en prepared by the Sterility Technical Committee of the1Chemistry Manufacturing Controls Coordinating Committee of the Center for DrugEvaluation and Research (CDER), and the Center for Veterinary Medicine (CVM), at theFood and Drug Administration. Although this guidance does not create or confer any
13、rights for or on any person and does not operate to bind FDA or the industry, it doesrepresent the agencys current thinking on sterilization process validation documentation.For additional copies of this guidance, contact the Division of CommunicationsManagement, HFD-210, CDER, FDA, 5600 Fishers Lan
14、e, Rockville, MD 20857 (Phone:301-594-1012) Send one self-addressed adhesive label to assist the office in processingyour request. An electronic version of this guidance is also available via Internet via WorldWide Web (WWW) (connect to the FDA Home Page at WWW.FDA.GOV/CDER and goto the “Regulatory
15、Guidance” section).GUIDANCE FOR INDUSTRY1FOR THE SUBMISSION OF DOCUMENTATION FOR STERILIZATION PROCESSVALIDATION IN APPLICATIONS FOR HUMAN ANDVETERINARY DRUG PRODUCTSI. INTRODUCTIONA. PurposeThis document is intended to provide guidance for the submission ofinformation and data in support of the eff
16、icacy of sterilization processes indrug applications for both human and veterinary drugs. Therecommendations in the guidance apply to applications for sterile drugproducts (new drug applications, new animal drug applications,abbreviated new drug applications, abbreviated antibiotic applications,and
17、abbreviated new animal drug applications). These recommendationsalso apply to previously approved applications when supplementsassociated with the sterile processing of approved drugs are submitted. Information and data in support of sterility assurance may also benecessary in investigational new dr
18、ug and investigational new animaldrug applications.In the FEDERAL REGISTER of October 11, 1991 (56 FR 51354), theagency published a proposed rule entitled “Use of Aseptic Processingand Terminal Sterilization in the Preparation of Sterile Pharmaceuticalsfor Human and Veterinary Use.“ This guidance is
19、 not a substitution for ora supplement to that proposed rule. Regardless of whether the applicantuses terminal sterilization or aseptic processing to manufacture a drugproduct that is purported to be sterile, certain information about thevalidation of that process should be submitted for both of tho
20、se types ofsterilization.B. Documenting Sterilization Process ValidationThe efficacy of a given sterilization process for a specific drug product isevaluated on the basis of a series of protocols and scientific experimentsdesigned to demonstrate that the sterilization process and associatedcontrol p
21、rocedures can reproducibly deliver a sterile product. Dataderived from experiments and control procedures allow conclusions to bedrawn about the probability of nonsterile product units (sterility assurancelevel). Based on the scientific validity of the protocols and methods, aswell as on the scienti
22、fic validity of the results and conclusions, the agencyconcludes that the efficacy of the sterilization process is validated. Whether a drug product is sterilized by a terminal sterilization process orby an aseptic filling process, the efficacy of the sterilization process maybe validated without th
23、e manufacture of three production batches. Sterilization process validation data, however, should be generated usingprocedures and conditions that are fully representative and descriptive ofthe procedures and conditions proposed for manufacture of the product inthe application.The Center for Drug Ev
24、aluation and Researchs (CDERs) and the Centerfor Veterinary Medicines (CVMs) review of the validation of thesterilization process consists of a scientific evaluation of the studiessubmitted in the applications. This review is conducted by FDAs reviewstaff, and is part of a cooperative effort between
25、 the review staff,compliance staff, and field investigators to ensure the overall state ofcontrol of the sterile processing of human and veterinary drug products. Information and data in support of sterility assurance may be provideddirectly to the application or by specific reference to a drug mast
26、er file(DMF), a veterinary master file (VMF), or another application. Letters ofauthorization to refer to the referenced files should be included.C. RemarksThis guidance is intended to provide recommendations for the types ofinformation applicants should include in human and animal drugapplications.
27、 Regulatory requirements for the submission of informationand data in various applications are specified in the sections listed below:1. Human Drugs:Investigational new drug applications 21 CFR 312.23(a)(7)New drug applications 21 CFR 314.50Abbreviated new drug and abbreviatedantibiotic drug applica
28、tions 21 CFR 314.94 and 314.50Supplements to NDAs and ANDAs 21 CFR 314.702. Animal Drugs:Investigational new animal drug applications 21 CFR Part 511New animal drug applications 21 CFR 514.1Supplements to NADAs 21 CFR 514.8II. INFORMATION FOR TERMINAL MOIST HEAT STERILIZATIONPROCESSESThe following t
29、ypes of information should be submitted in support of sterilityassurance for products produced using terminal moist heat sterilization. Although the following outline directly addresses moist heat processes, thesame types of information would generally pertain to other terminal sterilizationprocesse
30、s (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 themanufacture of the proposed drug product:A. Description of the Process and Product1. The Drug Product and Container-Closure SystemDescriptions o
31、f the drug product and the container-closuresystem(s) to be sterilized (e.g., size(s), fill volume, or secondarypackaging).2. The Sterilization ProcessA description of the sterilization process used to sterilize the drugproduct in its final container-closure system, as well as adescription of any ot
32、her sterilization process(es) used to sterilizedelivery sets, components, packaging, bulk drug substance or bulkproduct, and related items. Information and data in support of theefficacy of these processes should also be submitted. (See alsosections II.B. and II.C. of this guidance.) 3. The Autoclav
33、e Process and Performance SpecificationsA description of the autoclave process, including pertinentinformation such as cycle type (e.g., saturated steam, waterimmersion, and water spray), cycle parameters and performancespecifications including temperature, pressure, time, and minimumand maximum F .
34、 Identify the autoclave(s) to be used foroproduction sterilization, including manufacturer and model.4. Autoclave Loading PatternsA description of representative autoclave loading patterns shouldbe provided.5. Methods and Controls to Monitor Production CyclesMethods and controls used to monitor rout
35、ine production cycles(e.g., thermocouples, pilot bottles, and biological indicators) shouldbe described, including the number and location of each as well asacceptance and rejection specifications.6. Requalification of Production AutoclavesA description of the program for routine and unscheduledrequ
36、alification of production autoclaves, including frequency,should be provided.7. ReprocessingA description and validation summary of any program that providesfor reprocessing (e.g., additional thermal processing) of productshould be provided. Please note that the stability program is alsoaffected by
37、additional thermal processing. For further informationconcerning the stability program, reference is made to the Centerfor Drug Evaluation and Research “Guideline for SubmittingDocumentation for the Stability of Human Drugs and Biologics“and to the Center for Veterinary Medicine “Drug StabilityGuide
38、line.“B. Thermal Qualification of the Cycle1. Heat Distribution and Penetration StudiesHeat distribution and penetration study protocols and datasummaries that demonstrate the uniformity, reproducibility, andconformance to specifications of the production sterilization cycleshould be provided. Resul
39、ts from a minimum of three consecutive,successful cycles should be provided to ensure that the results areconsistent and meaningful.2. Thermal MonitorsThe number of thermal monitors used and their location in thechamber should be described. A diagram is helpful.3. The Effects of Loading on Thermal I
40、nputData should be generated with minimum and maximum load todemonstrate the effects of loading on thermal input to product. Additional studies may be necessary if different fill volumes areused in the same container line. Data summaries are acceptablefor these purposes. A summary should consist of,
41、 for example,high and low temperatures (range), average temperature duringthe dwell period, minimum and maximum F values, dwell time, run0date and time, and identification of the autoclave(s) used. Thesedata should have been generated from studies carried out inproduction autoclave(s) that will be u
42、sed for sterilization of theproduct that is the subject of the application.4. Information Included in the Batch RecordThe batch record supplied with the chemistry, manufacturing, andcontrols section of the application should identify the validatedprocesses to be used for sterilization and for depyro
43、genation ofany container-closure components. This information can beincluded in the batch record by reference to the validation protocolor standard operating procedure (SOP). Validation informationshould be provided as described above.C. Microbiological Efficacy of the CycleValidation studies that d
44、emonstrate the efficacy (lethality) of theproduction cycle should be provided. A sterility assurance of 10 or-6better should be demonstrated for any terminal sterilization process. Thislevel of sterility assurance should be demonstrated for all parts of thedrug product (including the container and c
45、losure, if applicable), whichare claimed to be sterile. The specific type of study and the methodsused to carry out the study (or studies) are product and process specificand may vary from manufacturer to manufacturer. In general, thefollowing types of information and data should be provided.1. Iden
46、tification and Characterization of Bioburden OrganismsDescribe the methods and results from studies used to identify andcharacterize bioburden organisms. The amount and type ofinformation supplied may be dependent on the validation strategychosen. For example, more information may be needed forbiobu
47、rden-based autoclave processes than for overkill processes. Information concerning the number, type, and resistance ofbioburden organisms may be necessary, including thoseorganisms associated with the product solution and the containerand closure. It may be necessary to identify the most heat-resist
48、ant bioburden organisms. 2. Specifications for BioburdenSpecifications (alert and action levels) for bioburden should beprovided. A description should be included of the program forroutinely monitoring bioburden to ensure that validated andestablished limits are not exceeded (e.g., frequency of anal
49、ysisand methods used in bioburden screening). The methodsprovided should be specific. 3. Identification, Resistance, and Stability of Biological IndicatorsInformation and data concerning the identification, resistance (Dand Z values), and stability of biological indicators used in thebiological validation of the cycle should be provided. If biologicalindicators are purchased from a commercial source, it may benecessary to corroborate the microbial count and resistance, andprovide performance specifications.4. The Resistance of the Biological
