[DOCKET NO. 95N-0200] GUIDANCE FOR THE SUBMISSION OF CHEMISTRY, MANUFACTURING, AND CONTROLS INFORMATION AND ESTABLISHMENT DESCRIPTION FOR AUTOLOGOUS SOMATIC CELL THERAPY PRODUCTS January, 1997 For further information about this document, contact: Center for Biologics Evaluation and Research (HFM-630) Food and Drug Administration 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 301-594-3074 Submit written comments on this document to: Dockets Management Branch (HFA-305) Food and Drug Administration Rm. 1-23 12420 Parklawn Dr. Rockville, MD 20857 Submit requests for single copies of this document to: Office of Communication, Training and Manufacturers Assistance,(HFM-40) Food and Drug Administration 1401 Rockville Pike, suite 200N Rockville, MD 20852-1448 301-827-1800 FAX (Automated Information System) 800-835-4709 INTERNET CBER_INFO@A1.CBER.FDA.GOV Comments and requests should be identified with the docket number found in brackets at the heading of this document. This guidance is an informal communication that reflects the best judgment of FDA at this time. It does not create or confer any rights, privileges or benefits for or on any person, nor does it operate to bind or obligate FDA in any way. _________________________________________________________________ GUIDANCE FOR THE SUBMISSION OF CHEMISTRY, MANUFACTURING, AND CONTROLS INFORMATION AND ESTABLISHMENT DESCRIPTION FOR AUTOLOGOUS SOMATIC CELL THERAPY PRODUCTS January, 1997 Center for Biologics Evaluation and Research ________________________________________________________________ TABLE OF CONTENTS GENERAL INFORMATION..........................................1 PART 1 -- CHEMISTRY, MANUFACTURING, AND CONTROLS SECTION I. INTRODUCTION............................................2 II. BIOLOGICAL SUBSTANCE/PRODUCT............................2 A. Description and Characterization.................2 B. Manufacturer(s)..................................4 C. Method(s) of Manufacture.........................6 D. Process Controls.................................9 E. Specifications/Analytical Methods...............10 F. Container/Closure Systems/Shipping Containers...11 G. Biological Substance Stability..................12 III. BIOLOGICAL PRODUCT.....................................12 A. Method(s) of Manufacture and Packaging..........12 B. Specifications and Test Methods for Final Biological Product..............................13 C. Biological Product Stability....................13 D. Container and Closure System....................14 E. Microbiology....................................14 IV. ENVIRONMENTAL ASSESSMENT...............................14 V. METHOD VALIDATION......................................14 PART 2 -- ESTABLISHMENT DESCRIPTION SECTION I. INTRODUCTION..........................................15 II. GENERAL INFORMATION...................................15 III. WATER SYSTEMS.........................................16 A. General description of water system(s).........16 B. Validation summary.............................16 C. Routine monitoring.............................16 IV. HEATING, VENTILATION AND AIR CONDITIONING (HVAC) SYSTEMS...............................................16 A. General description of the HVAC system(s)......16 B. Validation.....................................17 C. Routine monitoring.............................17 V. CONTAMINATION/CROSS CONTAMINATION ISSUES..............17 A. Cleaning procedures and validation.............17 B. Containment features...........................18 REFERENCES.................................................19 *Note: Page numbering may vary for documents distributed electronically. ________________________________________________________________ GUIDANCE FOR THE SUBMISSION OF CHEMISTRY, MANUFACTURING AND CONTROLS INFORMATION AND ESTABLISHMENT DESCRIPTION FOR AUTOLOGOUS SOMATIC CELL THERAPY PRODUCTS January, 1997 GENERAL INFORMATION Over the last several years, the Food and Drug Administration (FDA) has worked to clarify its approach to the regulation of products that are comprised in whole or in part of living cellular materials. FDA issued a notice in the Federal Register of October 14, 1993 (58 FR 53248), entitled "Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Cell Therapy Products", which explains the regulatory frame work for somatic cell and gene therapy products but does not provide detailed technical guidance. More recently, in the May 28, 1996, issue of the Federal Register, FDA published a notice announcing the availability of a guidance document entitled "Guidance on Applications for Products Comprised of Living Autologous Cells Manipulated Ex Vivo for Structural Repair or Reconstruction" (61 FR 26523). The May 1996 guidance document describes the regulatory requirements, including clinical studies, needed for market approval of a subset of autologous somatic cell therapy products called manipulated autologous structural cell products (MAS cell products). CBER has determined that for the purposes of this guidance document it is not necessary to distinguish between MAS cell products and other autologous somatic cell therapy products. This guidance document is intended to assist manufacturers of all autologous somatic cell therapy products, whether used for structural repair or reconstruction, or for other purposes. As noted in the May 1996 guidance document, the biologics license application (BLA) may be submitted in lieu of the product license application (PLA) and an establishment license application (ELA). This document, therefore, serves to provide guidance to manufacturers in the preparation of the chemistry, manufacturing and controls (CMC) and establishment description sections for a BLA, or in the preparation of a PLA and ELA, for autologous somatic cell therapy products, including MAS cell products. An interim form for the submission of the BLA, FDA Form 3439, is available from CBER's Office of Communication, Training and Manufacturers Assistance at the address provided at the beginning of this guidance document. This guidance document outlines the information which should be submitted in the CMC section and establishment description section of the application and describes the information that FDA would consider significant in the review of manufacturing issues for autologous somatic cell therapy products. Because of the broad range of products encompassed by the term autologous somatic cell therapy products, if any part of this guidance is not applicable, the manufacturer should state this in the application and provide explanation. FDA may amend this guidance periodically, as needed. Because the FDA is in the process of revising 21 CFR 10.90(b), this document is not being issued under the authority of 21 CFR 10.90(b), and the document does not bind the agency and does not create or confer any rights, privileges, or benefits for or on any person. Manufacturers may follow the guidance or may choose to use alternative procedures not provided in this guidance document. If a manufacturer chooses to use alternative procedures, they may wish to discuss the matter further with the agency to prevent expenditure of resources on activities that may be unacceptable to the FDA. PART 1 - CHEMISTRY, MANUFACTURING AND CONTROLS INFORMATION I. INTRODUCTION Part 1 of this guidance describes the information to be submitted in the CMC information section of applications for autologous somatic cell therapy products, and may assist in complying with the requirements in Title 21, Code of Federal Regulations (21 CFR) Parts 210, 211, 601 and 610. Part 2 of this guidance includes a description of the information on the establishment that should be included in the establishment description section of the application. II. BIOLOGICAL SUBSTANCE/PRODUCT In most cases, the biological substance and biological final product will be the same for all autologous somatic cell therapy products. If this is not the case, an explanation of the distinction should be provided by the manufacturer and information similar to section II should be provided for the final biological product under section III. If the substance and final product are the same, most of section III will be merely a reference to section II. (See specifics in section III.) A. Description and Characterization 1. Description a. Names Provide a clear description of the biological substance. This description may include, but is not limited to: name(s) and, as appropriate and available, the established (generic) and proprietary (brand) names or synonyms. b. Biological representation Provide the cell type, cell origin, or other applicable information that succinctly characterizes the biological substance. For most autologous somatic cell therapy products, the biological substance and biological product will be the same. The terms should be interchangeable in most cases. In those cases where they may not be, the distinction should be noted. c. Lot/batch definition. Define a batch and/or lot. In many cases, these will be the same; i.e., one patient's cells will be both a batch and lot. This should be stated and exceptions carefully explained. 2. Characterization A rational choice of appropriate specifications is founded on thorough analytical and biological characterization of the biological product under consideration. The objective of such an analysis is to establish which product and process characteristics are useful in ensuring the safety and effectiveness of the product, so that appropriate specifications and process controls can be developed. Thus, the set of tests chosen will vary from product to product, and should be guided by preclinical and clinical safety and effectiveness data as much as possible. a. Biological Characterization: i. Include a description of the selection of cell type and harvesting procedures. ii. If a reference cell culture is used as a standard for product characterization, describe the reference cell culture and include the results of all the analytical testing performed on it (standard lot or test lot). iii. Include a description of tests that establishes the identity, homogeneity profile, stability and consistency of manufacture for the biological substance. An illustrative, though not exhaustive, list includes: -expiration/stability -cell morphology -cell viability -molecular phenotypic characterization -PCR -immunoassay (cell surface, cell product) -other tests as appropriate -bioburden, sterility (or equivalent) -endotoxin -residuals (e.g., antibiotic, foreign proteins) iv. All test methods should be fully described and the results provided. These should match those listed in iii above. The application should include the data and results, such as chromatograms, photomicrographs of cell morphology, photographs of SDS-PAGE or agarose gel or immunoblot analysis, FACS analyses, ELISA data, etc., as applicable. The sponsor should specify whether testing is on cells, cell culture, cell supernatant, or lot if these differ and provide the justification for the testing procedures. v. At this time, autologous somatic cell therapy products are known to be harvested, processed and reimplanted within a relatively short time period. In those cases where cells may be frozen and stored for future or multiple uses, the manufacturer should refer to available guidances for these procedures, such as, Points to Consider -- Characterization of Cell Lines Used to Produce Biologicals, 7/12/93. This document may contain relevant information depending on the processing employed and should be considered by the manufacturer only as it applies to their product. vi. Provide a brief description of the environment in which cells are to be implanted. One example would be a surgical suite using aseptic technique. b. Biological Activity: A description and results of all relevant in vivo and in vitro biological testing performed on the manufacturer's reference cell culture (standard lot or test lot, where applicable) and compared to the autologous somatic cell therapy product lot to show the cell viability, activity, and, where appropriate, potency of the biological substance should be provided. The description of the bioassays should include the methods and standards used and the variability and acceptable limits of the assay. Validation and system suitability information should be provided and specifications for such tests and assays should be stated. This section should also include in-process storage and testing descriptions and procedures (See section II.D.) B. Manufacturer(s) 1. Include the name(s) and address(es), FDA registration number if available, and other pertinent organizational information for each manufacturer responsible for any portion of the manufacture or testing operations (e.g., the processing, packaging, labeling, or control operations) for the biological substance (e.g., performs the isolation, purification, testing, processing, packaging, or labeling). This may include contractors or other company subsidiaries serving as contractors, or other location/sites owned and operated by the applicant. Include a brief description of the operations(s) performed by each party and the responsibilities conferred on each party by the applicant. 2. For each manufacturing location, a floor diagram should be included that indicates the general facilities layout. This diagram need not be a detailed engineering schematic or blueprint, but rather a simple drawing that depicts the relationship of the subject manufacturing areas, suites, or rooms to one another, and should indicate other uses made of adjacent areas that are not the subject of the application. This diagram should be sufficiently clear that the reviewer may visualize the flow of production of the biological substance and would be able to identify areas or room "proximities" that may be of concern for particular operations, e.g., segregation of operations. Room numbers or other unique identifiers should be provided; however, the location of processing equipment within rooms and areas is not necessary. Reference can be made to manufacturing flow information presented in previous sections or in the establishment description (Part 2) section. 3. A comprehensive list of all additional products or different lots of the same product to be manufactured or manipulated in the areas used for the product in question should be provided. The applicant should indicate in which rooms the additional products will be introduced and the manufacturing steps that will take place in the room. An explanation should be given as to whether these additional products will be introduced on a campaign basis or concurrently during production of the product which is the subject of the application. Indication should also be given as to which additional products may share product contact equipment with the product in question (dedicated vs. multi-use equipment/areas should be delineated for each process step, in this section or other appropriate sections of the application). A brief description should be provided as to the type and developmental status of the additional products. 4. For all areas in which operations for the preparation of cell cultures and cell processing are performed, the following information concerning precautions taken to prevent contamination or cross-contamination should be provided: a. The air quality classification of room or area in which operations are performed as validated and measured during operations. b. A brief, narrative description of the procedures and/or facility design features for the control of contamination, cross-contamination and containment (air pressure cascades, segregation of operations and product, etc.) - this is of particular importance for multi-use areas or for different lots of the same product. c. General equipment design description, e.g., does design represent an open or closed system or provide for a sterile or non-sterile operation. d. A description of the in-process controls performed to prevent or to identify contamination or cross contamination. (See section II.C.3.b. and section II.D.1.) The manipulation of more than one cell culture product or two different products in a single area or piece of equipment, either concurrently or on a campaign basis, should be indicated and measures to ensure prevention of cross contamination should be discussed. (See Part 2, section V.) Reference other sections as appropriate. C. Method(s) of Manufacture 1. Raw materials and reagents A list of all components used in the manufacture (i.e., collection, processing, isolation and culture) of the biological substance, and the tests and specifications or reference to official compendia should be provided. For purchased raw materials, representative certificates of analysis from the suppliers and the manufacturer's own acceptance testing results should be included in the submission. Process gases (e.g., air, carbon dioxide) and water are considered raw materials. Include a list with tests and specifications of all special reagents and materials used in the manufacture of the biological substance, e.g., culture media, buffers, sera, antibiotics, preservatives. In some cases a detailed description of their preparation and characterization may be required. Submit a description of the tests and specifications for materials of animal source that may potentially be contaminated with adventitious agents, such as Bovine Spongioform Encephalopathy agent (BSE) for bovine derived products and other adventitious agents of human or animal origin. Information (validation data) or certification supporting the freedom of reagents from adventitious agents should be included in the submission. 2. Flow Charts A complete visual representation of the manufacturing process flow should be provided. This flow chart should indicate the step in production, the equipment and materials used, the room or area where the operation is performed (may reference the simple diagram requested in section B.2.) and a complete list of the in-process controls and tests performed on the product at each step. This diagram should also include information (or be accompanied by a descriptive narrative) on the methods used to transfer the product between steps, e.g., open transfers under laminar flow units. Such transfers should be described for movement of product between equipment, areas/rooms, buildings and sites. References can be made to previous sections or the establishment description (Part 2) section of the application for more detailed process information. 3. Detailed Description a. Cellular Sources: i. A list of all cellular starting materials, specifically, the acceptance criteria for the cells used in the manufacture of the biological substance should be included. Provide a detailed description of the collection and harvesting method for patient cells prior to isolation and expansion. The shipping conditions and types of containers for these cells should be described (or referenced if described elsewhere.) ii. Provide a description of the infectious disease tests and screening of patients for human viral pathogens. Describe labeling of positive samples as a biological hazard. Circumstances when this is not appropriate should be described in detail. Include a description of procedures for the containment of products from donors known to be positive for infectious disease agents, e.g., HIV and hepatitis. iii. Provide validation data that the culture methods and the cell types do not introduce viral or other human pathogens. iv. Provide validation data for storage conditions. Note distinctive conditions or procedures, such as freezing of cells, and provide appropriate data to confirm acceptability of these conditions or procedures if employed. Reference guidance as appropriate to the procedure such as, Points to Consider -- Characterization of Cell Lines Used to Produce Biologicals, 7/12/93. b. Cell growth, cell culture and harvesting: i. Provide a detailed description of the processes of cell or tissue sampling, propagation, expansion, and/or growth, including precautions taken and testing implemented to ensure prevention of contamination or cross contamination (or reference to other sections where this is described). Methods to standardize the enumeration of cells should also be included. iii. The composition of the medium, equipment preparation and sterilization, as well as cell culture medium sterilization or sterile filtration, should be described. For all stages of any cell culture process,the procedures which prevent contamination with adventitious agents should be described. iv. The stages of cell growth and/or processing should be described in detail including acceptance criteria for cells at each stage, propagation, and established and proposed (if different) batch/lot size. All operating conditions and in-process controls should also be described and appropriate ranges for operating and control parameters, such as culture time, cell doubling time, cell culture purity, cell viability, pH, CO2, etc., established. v. If the culture is stored prior to processing, data supporting its stability during storage should be provided. The manipulation of more than one cell culture product or cell line or in a single area or piece of equipment, either concurrently or on a campaign basis, should be indicated and measures to ensure prevention of cross contamination should be discussed or reference to other sections where this is described. (see Part 2, section V.) c. Purification and downstream processing: Provide a detailed description of any purification or downstream processing steps, including a rationale for the chosen methods, and the precautions taken to ensure containment and prevention of contamination or cross-contamination; in-process bioburden and endotoxin limits should be specified where appropriate. Any reprocessing using a validated reprocessing method and the conditions for batch/lot eligibility should be described. If applicable, indication should be made as to the multi-use nature of areas and equipment (e.g., campaigning vs. concurrent manufacture; dedicated vs. shared equipment) used for these procedures. A brief description of the controls employed to ensure segregation and prevent cross-contamination should be provided or reference to other sections where this information is described. 4. Batch records A completed (executed) batch record of the process of production of the biological substance should be submitted. (It is understood that each lot may have its own batch record for these products. If so, this should be stated for clarification purposes.) D. Process Controls This section focuses on validation of the process. In some cases, references to other sections may be appropriate. The testing procedures and limits of acceptance should be included and the rationale for these limits explained. 1. In-process controls A description of the methods used for in-process controls, e.g., those involved in culture, harvesting and any downstream processing, should be provided. 2. Process validation A description of the validation studies should be provided. For each study, data should be provided. If the process was changed for commercial production and involved changes in the cell culture steps, re-validation for consistency and stability during growth should be described, as in the previous section, and the data and results provided. a. Validation studies for the cell growth and harvesting process: Provide a description of the validation studies and data summary which identify critical parameters to be used as in-process controls, to ensure the success of routine production. Refer to the flow diagrams as appropriate. b. Validation studies for the purification process: A description should be provided, where appropriate, of the validation of the purification process and data summary to demonstrate adequate removal of extraneous substances such as antibiotics, particulates, cellular debris, media components, endotoxin, etc. c. Microbiology: Include a description of the validation studies and data for any processes used for media sterilization, inactivating cells prior to their release to the environment, if such inactivation is required, etc. If the biological substance is intended to be sterile, information should be submitted as described in the "Guidance for Industry for the Submission of Documentation for Sterile Process Validation in Applications for Human and Veterinary Drug Products", as applicable. E. Specifications/Analytical Methods The characteristics described in section II.A.2. should be used to support the selection of an appropriate set of lot release specifications and quality assurance procedures. 1. Biological substance specifications and tests a. Specifications and analytical methods used for lot release testing, shelf life and distribution should be described. Provide a full description of the specifications and analytical test methods for the biological substance sufficient to assure its identity, purity, homogeneity, safety and where applicable, potency. Such assurances may include cell viability, cell number, metabolic measurements, etc. Since some parameters may vary from patient to patient, and therefore lot to lot, acceptable ranges for the process should be defined and explained. Validation of the analytical systems and the data should be provided for non-compendial methods to demonstrate suitability. b. Provide certificates of analysis, if applicable, and analytical results for at least 3 lots of the biological substance. For many autologous somatic cell therapy products, the useful lifetime of the therapeutic material may be short. Certain tests, (e.g., mycoplasma cultures) may require too much time to make them feasible for lot release. Nevertheless, lot sampling for tests falling into this category should provide useful information regarding overall process integrity. Thus, while individual patient's cells would not be held pending the test result, the appearance of a positive or series of positives would prompt immediate investigation of manufacturing process integrity. In addition, if sampling reveals contamination early in the manufacturing process, this result may be used to reject a particular lot downstream. If some test results are not available until after product release, indicate the length of time to obtain these results. c. For some autologous somatic cell therapy products, replacing a batch/lot of autologous cells and the importance and/or timing of the therapy may make it acceptable to have flexible acceptance criteria and a tighter process control specification for some characteristics (e.g., cell viability). The manufacturer may wish to develop separate sets of specifications for acceptance criteria from those of process controls. Both sets of specifications should be indicated and the rationale for their acceptability included. Additionally, actions that would be taken if specifications are not met should be described. 2. Impurities profile a. A discussion of the impurity profiles, with supporting analytical data, should be provided. Profiles of variants of the biological substance as well as non-product related impurities (e.g., process reagents and cell culture media components) should be included. Safety tests for endotoxin should also be included where appropriate. b. For culture methods and cell types which support the growth of viral pathogens, provide a description of the assays used to determine viral load and include validation data for assays. The specification for viral load on end-of-production cells should be provided and should be no more than that of the starting material using the data obtained on individual samples with validated assays. Any deviations from this should be explained. c. For culture methods and cell types which may contain impurities from adventitious agents (e.g., bacterial contamination), provide a description of the assays that determine the absence or presence of such agents. Provide the specification(s) for possible adventitious agents and explain the rationale for such a specification. F. Container/Closure Systems/Shipping Containers Include a description of the container and closure system, and its compatibility with the biological substance. Submit detailed information concerning the supplier, address, and the results of available compatibility, toxicity and biological tests. Provide evidence of container and closure integrity. This information should be included on containers transporting incoming patient cells, those shipping the final product, and all container systems used in production and storage of intermediate products. Provide assurance of the container's suitability for shipment and delivery of the biological substance. G. Biological Substance Stability 1. A description of the storage conditions, study protocols and results supporting the stability of the biological substance should be submitted in this section (Refer to ICH document, Stability Testing of Biotechnological/Biological Products or other FDA documents such as Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics for specific information.) Data from tests to monitor the biological activity or viability and degradation products, if any, should be included as appropriate. Data supporting any proposed storage of intermediates should also be provided. Intermediate stability and viability should include compatibility with storage conditions. 2. If cells are transported from one site to another before, during or after processing, stability during transport should be described. Measures taken to ensure that adequate conditions are maintained during transport should also be described. III. BIOLOGICAL PRODUCT This section is meant to address any process not included in the biological substance section which applies only to the final biological product. If these processes have been previously described then reference the appropriate sections only. If the biological substance and product are one and the same, then the manufacturer should state this and need not provide further information where it has already been included (reference section II as appropriate.) A. Method(s) of Manufacture and Packaging 1. A complete description of the final biological product, if different from the biological substance, should be provided. Accompanying this narrative, a flow chart should be provided that indicates the production step, the equipment and the materials used, the room or area where the operation is performed (may reference simple diagram in section II.B.2.) A listing of the in-process controls, including analytical tests performed on the product at each step of manufacture, should also be provided. Reference to previous sections is recommended as necessary. Any additional processing for the final product should be emphasized. Reprocessing operations that can be anticipated should be described. 2. Container and Closure System -- Provide full information about the characteristics of, and test methods used for, the container-closure or other component parts of the biological product package to ensure their suitability for packaging. Also include a description of the packaging operation and relevant in-process controls. Reference other sections as appropriate. B. Specifications and Test Methods for Final Biological Product 1. Description Provide a full description of the specifications and all analytical test methods necessary to assure the identity, purity, homogeneity, safety and where appropriate, potency. Such assurances may include cell viability, cell number, metabolic measurements, etc., for the proposed shelf life of the final biological product. The methods and standards of acceptance, including the sampling plan and the accuracy and precision of the analytical methods, should be sufficiently detailed to permit duplication and verification. It is recognized that autologous somatic cell therapy products will likely have a short shelf life to implant time. If shelf life and/or product expiry release specifications and analytical results differ please specify. If such methods do not apply to a specific product, then include an explanation as to why they are not applicable. Reference other sections as appropriate (e.g., II.D.,II.E., III.D.) 2. Samples found to be positive on microbiological testing Issues arising from positive sample results and steps to be taken in the face of positive results should be stated. For example, if a culture is positive for mycoplasma, what steps will be taken and when to inform the physician, modify or investigate the manufacturing process, etc. Re-validation of procedures after corrective action should also be described. 3. Lot Test Failures Issues arising from lot test failures and steps to be taken in face of out of specification results should be stated. C. Biological Product Stability Provide a description of the storage conditions, study protocols and results supporting the stability of the biological product, including information showing the suitability of the analytical method(s) used. Describe any additional stability studies underway or contemplated. Stability data should be submitted for the biological product as packaged in the container in which it is to be marketed. State the expiration dating period proposed to be shown on the label. If the biological product is to be shipped under conditions considered to maintain cell viability, data supporting the shipping process which demonstrate that the product is stable under the conditions used should be included. The proposed shelf life of the biological product should be stated and the data for stability and methods included. D. Container and Closure System Provide a description of the container and closure system, and its compatibility with the biological product. Submit detailed information concerning the supplier, address, and the results of compatibility, toxicity and biological tests. Alternatively, a Master File can be referenced for this information. For sterile product, evidence of container and closure integrity should be provided for the duration of the proposed expiration period. E. Microbiology Information should be submitted as described in the "Guidance for Industry for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products" and/or the "Guideline on Sterile Drug Products Produced By Aseptic Processing." IV. ENVIRONMENTAL ASSESSMENT An environmental assessment should be prepared as outlined in 21 CFR Part 25. Provide a description of the action that is being considered and address all the components involved in the manufacture and disposal of the product (including the ultimate use of the product.) Documents prepared by manufacturers to address state and local environmental concerns may submitted in lieu of 21 CFR Part 25. A statement of categorical exclusion may be provided, if applicable. V. METHOD VALIDATION The methods validation package should be made up of photocopies of information from various pertinent sections of the application and should retain the original pagination of the sections from which the photocopies are taken. _________________________________________________________________ GUIDANCE FOR THE SUBMISSION OF CHEMISTRY, MANUFACTURING AND CONTROLS INFORMATION AND ESTABLISHMENT DESCRIPTION FOR AUTOLOGOUS SOMATIC CELL THERAPY PRODUCTS January, 1997 PART 2 - ESTABLISHMENT DESCRIPTION I. INTRODUCTION Part 2 of this document provides guidance on information that should be submitted in section 15, Establishment Description, regarding establishments and related good manufacturing practice (GMP) controls in a BLA, or PLA and ELA, for autologous somatic cell therapy products and may assist in complying with the requirements in Title 21, Code of Federal Regulations (21 CFR) Parts 200 and 600. This guidance applies to manufacturers of all autologous somatic cell therapy products, whether used for structural repair or reconstruction or for other purposes. This document serves to provide to manufacturers FDA's current expectations regarding the information describing establishment standards and GMP controls in place for the manufacture of these products which should be submitted as part of the BLA, or PLA and ELA. II. GENERAL INFORMATION For each manufacturing location, a floor diagram should be included that indicates the general production facility layout. The following information should be provided on each flow diagram and/or in an accompanying narrative: A. Product, personnel, equipment, waste and air flow for production areas. B. An illustration or indication of which areas are served by each air handling unit. C. Air pressure differentials between adjacent areas. Alternatively, this information may be illustrated on the floor diagram requested in part II.B.2. of the CMC section. The manufacturing flow chart requested in part 1, section II.C.2. of the CMC section may also be referenced as applicable. III. WATER SYSTEMS The following information for systems used in the production of water for manufacturing and rinsing of product contact equipment should be provided: A. General description of water system(s) General description including major components and general discussion of what type of water is used for each stage of processing. This need not be extremely detailed. B. Validation summary 1. Narrative description of the validation (or protocol) and certification that Installation Qualification (IQ) and Operational Qualification (OQ) have been completed. 2. Length of the validation period 3. Parameters monitored and tests performed 4. Frequency of monitoring each point of use during the validation period 5. Validation data summary 6. Explanation of all excursions or failures, including deviation reports and results of investigations C. Routine monitoring 1. Narrative description of program including tests performed and frequencies. 2. Alert and action limits, summary of actions taken when limits are exceeded. IV. HEATING, VENTILATION AND AIR CONDITIONING (HVAC) SYSTEMS The following information on HVAC Systems should be provided: A. General description of the HVAC system(s) Number and segregation of air handling units, once-through or recirculated air, containment features, air changes/hour - information required for some of these features is described below in greater detail in the contamination/cross contamination section of this outline. Reference may be made to information in the CMC section. B. Validation 1. Narrative description of validation (or protocol) and certification that IQ, OQ and certification of filters has been completed. 2. Length of the validation period. 3. Validation data summary (validation data should include data accumulated during actual processing). 4. Explanation of all excursions or failures, including deviation reports and results of investigations. C. Routine monitoring 1. Narrative description of the program, including tests performed and frequencies for viable and nonviable particulate monitoring parameters. 2. Viable and nonviable particulate action and alert limits for production operations for each manufacturing area, and a summary of corrective actions taken when limits are exceeded. V. CONTAMINATION/CROSS CONTAMINATION ISSUES The following information regarding methods to prevent contamination and cross-contamination should be provided to supplement the information requested in part 1, section II.B.4. of the CMC section of this application. A. Cleaning procedures and validation 1. For dedicated equipment, the following information should be provided: a. Brief description of cleaning procedures and cleaning reagents used. b. Certification that cleaning validation for removal of product residuals and cleaning agents has been successfully completed. 2. For shared equipment, including equipment that will be used for processing more than one patient's cells, the following information should be provided: a. Brief description of cleaning procedures and cleaning reagents used. b. Rationale for cleaning procedures chosen; effectiveness for residual products to be removed. c. Validation report describing cleaning validation procedures for removal of product residuals and cleaning agents, sampling methods and analytical methods including sensitivities and specificities. B. Containment features 1. Describe segregation and containment procedures for areas, manufacturing operations, personnel, equipment and waste materials designed to prevent contamination of products. Air pressure differentials between adjacent manufacturing areas, segregation of air handling units, a description of air supply and return (recirculated, once-through, HEPA filtered out, etc.) and use of airlocks should be discussed if these features are employed to maintain segregation and containment. Reference to part 2, section II, and Part 1, section II.B.4. of this application may be made as necessary. Information included in the CMC section should not be duplicated here. Only additional information should be included here. 2. In cases where cleaning reagents are required for decontamination or inactivation, a validation report should be provided which demonstrates the effectiveness of the decontamination/inactivating agent(s). 3. Manipulation of more than one cell line or cell culture product in the same area at the same time may only be acceptable if validation has been performed and data provided to demonstrate cross contamination will not occur and that the proper controls are in place to prevent cross contamination. If requesting such procedures, a description of the validation procedures and summary data should be submitted in this section. An explanation of any failures which occurred during the validation should also be provided. 4. Clearance procedures for successive lots in each hood or area should be briefly described or reference to the CMC section. REFERENCES Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products (58 FR 53248) Interim Final Rule: Human Tissue Intended for Transplantation (58 FR 65514) Guidance for Industry for the Submission of Documentation for Sterile Process Validation in Applications for Human and Veterinary Drug Products Points to Consider--Characterization of Cell Lines Used to Produce Biologicals ICH document: Stability Testing of Biotechnological/Biological Products Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics Guideline on Sterile Drug Products Produced By Aseptic Processing