Guidance for FDA Reviewers and Sponsors

Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)

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Additional copies of this guidance are available from the Office of Communication, Training, and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at http://www.fda.gov/cber/guidelines.htm.

For questions on the content of this guidance, contact the Office of Cellular, Tissue, and Gene Therapies at 301-827-5102.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
April 2008

Contains Nonbinding Recommendations

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Table of Contents

1. INTRODUCTION
   1. How will FDA Reviewers and Sponsors Use this Guidance?
   2. How is this Guidance Organized?

2. ADMINISTRATIVE INFORMATION TO BE DOCUMENTED BY FDA REVIEWERS
3. PRODUCT MANUFACTURING AND CHARACTERIZATION INFORMATION TO BE SUBMITTED BY SPONSORS AND DOCUMENTED BY FDA REVIEWERS
1. Product Manufacturing - Components and Materials
1. Cells
2. Reagents
3. Excipients
4. Additional Considerations
2. Product Manufacturing - Procedures
1. Preparation of Autologous or Allogeneic Cells
2. Process Timing and Intermediate Storage
3. Final Formulation
4. PRODUCT TESTING
1. Microbiological Testing
1. Sterility Testing (Bacterial and Fungal Testing)
2. Mycoplasma
3. Adventitious Agent Testing
2. Identity
3. Purity
1. Residual Contaminants
2. Pyrogenicity/Endotoxin
4. Potency
5. Other
1. General Safety Testing
2. Viability
3. Cell Number/Dose
5. FINAL PRODUCT RELEASE CRITERIA TESTING
6. PRODUCT STABILITY
7. OTHER ISSUES
1. Product Tracking
2. Labeling
3. Container/Closure
4. Environmental Impact
5. Qualification of the Manufacturing Process
6. Biostatistics
8. PRECLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS
9. CLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS
1. Protocol Title
2. Subject Population
3. Route of Administration
4. Dose
5. Frequency
6. Genetic, Biochemical, and Immunological Testing
7. Informed Consent
10. RECOMMENDATION TO BE DETERMINDED BY FDA REVIEWERS
11. COMMENTS TO SPONSOR GENERATED BY FDA REVIEWERS
1. Clinical Hold
2. Non-Clinical Hold
12. REFERENCES

APPENDIX A - PRODUCT REVIEW TEMPLATE

APPENDIX B - CONSIDERATIONS FOR DEVELOPMENT OF FINAL PRODUCT RELEASE CRITERIA SPECIFICATIONS AND STABILITY PROTOCOLS

1. Development of Release Acceptance Criteria
2. Development of Acceptance Criteria Analytical Procedures
3. Development of Stability Protocols

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Guidance for FDA Reviewers and Sponsors
Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)

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 appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

1. INTRODUCTION

This guidance document provides to you, sponsors of a human somatic cell therapy investigational new drug application (IND), recommendations on the chemistry, manufacturing, and control (CMC) information to include in an original IND. This guidance also applies to combination products that contain a human somatic cell therapy biological product in combination with a drug or device as part of the final product. Also, this guidance instructs FDA CMC reviewers about the information to record and assess as part of an IND review, taking into consideration the various manufacturing challenges for these products.

In order to deliver a safe and effective product, human somatic cell therapies present many manufacturing challenges. Some of these challenges include the variability and complexity inherent in the components used to generate the final product, such as the source of cells (i.e., autologous or allogeneic), the potential for adventitious agent contamination, the need for aseptic processing, and the inability to "sterilize" the final product because it contains living cells. Distribution of these products can also be a challenge due to stability issues and the frequently short dating period of many cellular products, which may necessitate release of the final product for administration to a patient before certain test results are available.

This guidance finalizes the draft guidance entitled, "Guidance for Reviewers: Instructions and Template for Chemistry Manufacturing, and Control Reviewers of Human Somatic Cell Therapy Investigational New Drug Applications" dated August 2003 (68 FR 49488; August 18, 2003).

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the FDA'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 FDA's guidances means that something is suggested or recommended, but not required.

1. How will FDA Reviewers and Sponsors Use this Guidance?

FDA's primary objectives in the review of INDs are to help ensure the safety and rights of human subjects in all phases of an investigation and, in Phases 2 and 3, to help ensure that the quality of the scientific evaluation of the investigational product is adequate to permit an evaluation of its safety and effectiveness (21 CFR 312.22(a)). This guidance will help sponsors and FDA reviewers to assess, given the phase of the investigation, whether sufficient information is provided to assure the proper identification (identity testing), quality, purity, and strength (one aspect of potency) of the investigational product (21 CFR 312.23(a)(7)(i)). These principles apply to investigational biological products and drugs; however, specific terms, such as safety, identity, purity, and potency, are generally understood to be applicable to biological products and are used throughout this document.

If you are a FDA reviewer, you will use this guidance as you assess the safety, identity, purity, and potency of an investigational product and you will use the format of the human somatic cell therapy CMC review template (Appendix A) in preparing your reviews. Because of the wide variability of the contents of IND amendments, you are only expected to use the attached template during review of original IND submissions. However, you should consult this document for guidance throughout the investigational new drug development process.

The human somatic cellular therapy CMC review instructions and template described in this guidance are tools to assist FDA in the review of human somatic cellular therapy INDs. They are designed to serve as a guide to help ensure that all applicable regulatory requirements are reviewed at the appropriate stage of product development. In addition to the CMC review instructions and template, some general considerations are discussed in Appendix B that should be helpful in assessing proposed release criteria testing and specifications. Section 10.70 (21 CFR 10.70) provides further instruction to FDA reviewers regarding documentation of review decisions.

If you are a sponsor of a human somatic cell therapy IND, you may use this guidance in developing an IND submission that will be adequate to permit FDA reviewers to make an assessment of the safety, identity, purity, and potency of your investigational product. Other regulatory documents that may be relevant are listed in the references (see Section XII below).

2. How is this Guidance Organized?

This guidance is organized in a format that generally corresponds to the sections in the CMC review template provided in Appendix A. In each section, where necessary, we (FDA) provide recommendations as to the information you may submit in your original IND submission. As necessary throughout this document, we give specific instructions to FDA reviewers concerning their documentation and assessment of an IND submission during the CMC review. Many of the instructions for FDA reviewers provided in this guidance are distinguished by the designation "Note to FDA Reviewers."

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2. ADMINISTRATIVE INFORMATION TO BE DOCUMENTED BY FDA REVIEWERS

Note to FDA Reviewers: Document in your review all of the IND information listed below. Most of this information should be available on Form FDA 1571, the sponsor's cover letter, or the reviewer assignment notice from the Regulatory Project Manager (RPM) of the application division.

• BB-IND Number (assigned by Center for Biologics Evaluation and Research (CBER) after receipt);
• Date of submission;
• 30-day review due date;
• Sponsor - name, address, title, phone, fax;
• Sponsor point of contact (sponsor's authorized representative) - name, address, title, phone, fax;
• Title of IND;
• Proposed use;
• Product description;
• Phase of study;
• Cross-referenced INDs, investigational device exemptions (IDEs), and master files (MFs): List all regulatory files (IND, IDE, MF) that the sponsor has obtained permission to cross-reference in support of this file. The file under review must contain a letter signed by the person who submitted the cross-referenced file (21 CFR 312.23(b)), giving FDA permission to cross-reference the file. This letter should identify the nature of the information being cross-referenced (e.g., pre-clinical, product manufacturing, and/or clinical) and where it is located within the file being cross-referenced. You should verify that the cross-referenced information satisfies the IND requirement for which the information is cited. If the letter of cross-reference is absent or inadequate, or the cross-referenced information is inadequate for the purpose cited, the RPM or the reviewer should notify the sponsor to obtain additional information;
• Key words: Include three to four words that can be used to identify the product, indication, and any materials, components, or devices that may be part of the final product or used in the manufacturing process. These key words should be general enough to be used in a database search;
• Introduction/rationale: Summarize relevant information on the development of the product if the sponsor provides this information. In addition, document and assess, as appropriate, the sponsor's scientific rationale and justification for using the product for the indication under review; and
• Study objectives.

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3. PRODUCT MANUFACTURING AND CHARACTERIZATION INFORMATION TO BE SUBMITTED BY SPONSORS AND DOCUMENTED BY FDA REVIEWERS

As described in the following sections, you should provide a detailed description of where and how the cell therapy product is manufactured. You should include all of the components and materials used during the manufacture of the cellular product, such as cells, cell bank systems, and any reagents or excipients. In addition, you should describe all procedures used during the manufacturing process. Examples of these procedures may include recovery and processing of tissues or cells, purification, and other preparation of cells, donor screening and testing, including final formulation of the product. This information will allow us to assess the identity, quality, purity, and potency of your product. For further information, refer to the "Guidance for Human Somatic Cell Therapy and Gene Therapy" (Ref. 1) and the guidance on "Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products" (Ref. 2). In addition, you may refer to the other documents listed in the references (see Section XII below).

We also encourage sponsors to use the format and headings described in Appendix A to facilitate an efficient review by FDA.

Note to FDA Reviewers: Document and assess product manufacturing and characterization information in your IND reviews. Organize the CMC review using the format and headings described in Appendix A and below, as appropriate.

1. Product Manufacturing - Components and Materials

Note to FDA Reviewers: Document the source of all materials and components and summarize the testing performed on those materials and components, and review the specific instructions and recommendations set out below.

Your IND must include a list of all components used in manufacturing of your product (21 CFR 312.23(a)(7)(iv)(b)). The sections below detail the information on manufacturing components that we recommend you submit in an IND.

1. Cells

1. Allogeneic and/or Autologous Cell Components

You should describe the following information in your IND:

• Cell source: tissue and cell type (e.g., colon, hematopoietic, neuronal, T-cells);
• Mobilization protocol: document whether or not donor cells are mobilized or activated in vivo in the donor;
• Collection or recovery method: state the procedure used to obtain cells (e.g., surgery or leukapheresis indicating the device used if possible), the name and location of the collection facility, and transport conditions if shipped to a processing facility for further manufacturing; and
• Donor screening and testing: the donor screening and testing that is performed to determine donor eligibility. Requirements for screening and testing donors of human cells and tissues are described in 21 CFR Part 1271 (see final rule, "Eligibility Determination for Donors of Human Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps)") (Ref. 3). When appropriate, you should document the donor safety testing that is performed. In addition, FDA has published a final "Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)" (Ref. 4). We recommend that you review this guidance to ensure that the donor qualification criteria described in your IND are consistent with current recommendations.

1) Autologous

You are not required to make a donor eligibility determination or to perform donor screening for cells and tissues for autologous use (21 CFR 1271.90(a)(1)). However, you should determine whether your manufacturing procedures increase the risk of propagation of pathogenic agents that may be present in the donor. If so, you should document whether the donor is reactive for specific pathogens. Also, you should describe precautions to prevent the spread of viruses or other adventitious agents to persons other than the autologous recipient (see Ref. 3).

2) Allogeneic

You must perform donor screening and testing as required in 21 CFR Part 1271 for all allogeneic cells or tissues except those that meet the exceptions in 21 CFR 1271.90(a). Donors of all types of cells and tissues must be screened and tested for HIV-1, HIV-2, hepatitis B virus (HBV, surface and core antigen), hepatitis C virus (HCV), Treponema pallidum (syphilis), and CJD (screening only). Donors of viable leukocyte-rich cells or tissues should be screened and tested for human T-lymphotropic virus types 1 and 2 (HTLV-1, HTLV-2) and CMV. In addition, you should document whether FDA-licensed, cleared, or approved test kits are used in these detection assays and document which tests are used. Include a description of the type of serological, diagnostic, and clinical history data obtained from the donor. You should consider other issues such as typing for polymorphisms and human leukocyte antigen (HLA) matching, where appropriate. If cord blood or other maternally derived tissue is used, you should describe testing and screening performed on birth mothers.

Note to FDA Reviewers: Communicate with the clinical reviewer regarding any issues or concerns relating to the screening or testing of the donor cells.

2. Cell Bank System

You should describe pertinent information, as described in sections 1) and 2) below, relating to the cell bank system (i.e., master cell bank (MCB), and working cell bank (WCB)) used in product manufacture. In addition, you should describe the history, source, derivation, characterization of each cell bank (both MCB and WCB), and the frequency at which testing is performed. For further information, refer to the document on "Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals" (Ref. 5). See also ICH document Q5D, "Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products" (Ref. 6), and, where applicable, "Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans" (Ref. 7) and the "PHS Guideline on Infectious Disease Issues in Xenotransplantation" (Ref. 8).¹

Note to FDA Reviewers: Document and assess the testing that is performed on each cell bank. Determine if the most relevant and critical testing for the particular cellular product has been performed. Appropriate tests should be performed depending on the species of origin used to derive the cell bank.

1) Master Cell Bank (MCB)

You should include in the IND information regarding MCB history, source, derivation and characterization, including testing to adequately establish the safety, identity, purity, and stability of the cells. This section will likely address:

• Product microbiologic characteristics, including sterility, mycoplasma, in vivo and in vitro testing for adventitious viral agents, as appropriate (see Section IV below);
• Freedom from the presence of specific pathogens, including, for human cells, testing for CMV, HIV-1 & 2, HTLV-1 & 2, EBV, B19, HBV, and HCV, as appropriate. For cell lines that are exposed to bovine or porcine components (e.g., serum, serum components, trypsin), appropriate testing would include testing for bovine and/or porcine adventitious agents. See further discussion of bovine components and reagents in Section III.A.2.a;
• Identity of the cells, including tests to distinguish the specified cells through physical or chemical characteristics of the cell line (i.e., phenotype, genotype, or other markers);
• Purity of bank cells, including identification and quantification of any contaminating cells;
• Testing for activity of cells (e.g., activated lymphocytes, dopamine secretion, insulin secretion) and cell maturation (e.g., dendritic cells). This should be performed if activity is relevant to the therapeutic nature of the product; and
• Processes critical to product safety, as applicable, including:
• Culture conditions used, including documentation of all media, and reagents/components used during production, with copies of relevant certificates of analysis (COA);
• Cryopreservation, storage, and recovery of the MCB, including information pertaining to cell density, number of vials frozen, storage temperature, and cell bank location; and
• Genetic and phenotypic stability of the MCB after multiple passages as well as viability of cells after cryopreservation. We recommend that, while the IND is in effect, you perform a stability assessment on the end of production cells (EOP) as a one-time test. This testing is usually performed later in product development and would be included as part of the biologics license application (BLA).

2) Working Cell Bank (WCB)

WCB may have been derived from one or more vials of the MCB. As discussed in the guidance documents referenced in Section III.A.2.b, the amount of information needed to document characterization of the WCB derived from the MCB is usually less extensive than that needed to document characterization of the MCB. If there is a two-tiered cell bank system in place (MCB and WCB), we recommend that you test the WCB for:

• In vitro adventitious viral agent testing;
• Bacterial and fungal sterility;
• Mycoplasma; and
• Limited identity testing (e.g., Southern blot, flow cytometry).
2. Reagents

You must list in your IND any reagents used in manufacturing the product (21 CFR 312.23(a)(7)(iv)(b)). For the purpose of this guidance, reagents are those materials that are used for cellular growth, differentiation, selection, purification, or other critical manufacturing steps but are not intended to be part of the final product. Examples include fetal bovine serum, trypsin, digestion enzymes (e.g., collagenase, DNAse) growth factors, cytokines, monoclonal antibodies, antibiotics, cell separation devices, and media and media components. These reagents can affect the safety, potency, and purity of the final product, especially by introducing adventitious agents. For monoclonal antibodies, refer to the guidance on "Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use" (Ref. 9) for further information.

1. Tabulation of Reagents Used in Manufacture

We recommend that you provide the following information on all reagents used during product manufacturing:

• concentration of the reagent at the manufacturing step at which it is used;
• vendor/supplier;
• source:
• human: If human albumin is used, you should have procedures in place to ensure that no recalled lots were used during manufacture or preparation of the product. If using human AB serum, ensure serum is obtained from an approved blood bank and meets all blood donor criteria. For all other reagents that are human derived you should identify whether it is a licensed product, or clinical or research grade, and provide a COA or information regarding testing of the donor and/or reagent.
• porcine: If porcine products are used, a COA or other documentation that the products are free of porcine parvovirus.
• bovine: If a reagent is derived from bovine material, you should identify the bovine material, the source of the material, information on the location where the herd was born, raised, and slaughtered, and any other information relevant to the likelihood that the animal may have ingested animal feed prohibited under 21 CFR 589.2000. It may be that bovine material is introduced at different points in production of a reagent; the information described above should be provided for all bovine materials used. For more information see, "Proposed Rule: Use of Materials Derived from Cattle in Medical Products Intended for Use in Humans and Drugs Intended for Use in Ruminants," (72 FR 1581; January 12, 2007) found at http://www.fda.gov/cber/rules/catruminant.htm. In addition, you should provide a COA to document that bovine materials are compliant with the requirements for the ingredients of animal origin used for production of biologics described in 9 CFR 113.53.

Note to FDA Reviewers: For all animal derived products, enter the following information in the animal components database: source organism, supplier/vendor, country of origin, and stage of manufacture. Additionally, the information provided on bovine materials should be evaluated to determine whether, for informed consent that is adequate under 21 CFR Part 50, the subject should be informed of the potential risk that TSE agents have been introduced into the final product.

• Reagent quality: We recommend that you use FDA-approved or cleared, or clinical grade reagents whenever they are available.

Note to FDA Reviewers: If the reagent is regulated as a biological product, drug, or device, consider whether a consultative review should be obtained. See Section III.A.4.b below for further information about consultative review process.

• COA or cross-reference letters: If you are using a research grade (not FDA-approved or cleared) reagent as part of the manufacturing process, we recommend that you provide information verifying the source, safety, and performance of the reagent. If the vendor of the reagent has a regulatory file with the FDA, a cross-reference letter from the sponsor may be provided in the IND. If a COA from the reagent manufacturer is used, you may assess whether the testing performed is adequate (see "Qualification Program" below) and provide that information in the IND.

Note to FDA Reviewers: For letters of cross-reference, include the regulatory file number and consider the need for a consultative review to determine whether there are any safety concerns or other outstanding issues.

2. Qualification Program

If the reagent is not FDA-approved or cleared, additional testing may be needed to ensure the safety and quality of the reagent. We recommend that you establish a qualification program that includes safety testing (sterility, endotoxin, mycoplasma, and adventitious agents), functional analysis, purity testing, and assays (e.g., residual solvent testing) to demonstrate absence of potentially harmful substances. The extent of testing will depend on how the specific reagent is used in the manufacturing process.

3. Determination of Removal of Reagents from Final Product

You should test the final product for residual manufacturing reagents with known or potential toxicities and describe the test procedures you use to detect residual levels of these reagents in the final product. We recommend that you determine whether a qualification study is sufficient to document their removal, or whether lot release testing is appropriate prior to initiation of clinical trials.

4. Other Concerns

Because some patients may be sensitive to penicillin, we recommend that you do not use beta-lactam antibiotics during the manufacturing of a therapeutic product for humans. If beta-lactam antibiotics are used, we recommend that you provide a rationale for their use and describe precautions to prevent hypersensitivity reactions.

Note to FDA Reviewers: If beta-lactam antibiotics are used during manufacturing, consult with the clinical reviewer concerning appropriate exclusion criteria for the study and proper informed consent to address potential patient sensitivity. Discuss with the sponsor the rationale for using beta-lactam antibiotics and whether an alternative to beta-lactam antibiotics can be used as an appropriate substitute.

3. Excipients

For the purpose of this guidance, an excipient is any component that is intended to be part of the final product, such as human serum albumin or Dimethyl Sulfoxide (DMSO). You must list in your IND all excipients used during manufacture of the product that are intended to be present in the final product. (21 CFR 312.23(a)(7)(iv)(b)). You should include the concentration and source of the excipients. Also, you must provide information regarding the qualification of all excipients that are present in the final product (21 CFR 211.84(a)). For further information, please see Sections III.A.2 above on reagents.

4. Additional Considerations

1. Combination Products

This guidance also applies to combination products that contain a human somatic cell therapy biological product in combination with a drug or device as part of the final product.² When intended for a different use, the drug or device component may already have FDA marketing approval or clearance (e.g., new drug application (NDA), a premarket approval application (PMA), or a premarket notification (510(k)), or it may be previously unstudied.

If information describing the drug or device component has already been submitted to FDA (e.g., in another IND, IDE, or Master File), you may submit a letter of authorization authorizing FDA to reference the previous submission for CMC or other information related to the drug or device component of your product.

Note to FDA Reviewers: Determine the regulatory status of the drug or device either by contacting the RPM from the center with jurisdiction for the drug or device or the sponsor directly, if necessary. If the drug or device has been approved for any use, confirm and document this in your review. In most cases, request a consultative or collaborative review from the Center for Drug Evaluation and Research (CDER) or the Center for Devices and Radiological Health (CDRH) even if the drugs or device components were previously approved for another use. Confer with your supervisor if it is unclear whether a consultative or collaborative review is needed. Once an adequate letter of authorization is submitted, verify that the referenced file contains the needed information. Inform the consultative or collaborative reviewer that the information referenced in the letter of authorization should be reviewed as part of the application.

2. Consultative Reviews

Note to FDA Reviewers: Follow the standard operating procedures and policies (SOPP) on the "Intercenter Consultative/Collaborative Review Process" (Ref. 10). Specify the questions the consultative reviewer should address, identify the specific sections of the IND applicable to those questions, and request a date for completion of the consultative review. The requested date should be determined by coordinating with the consulting review center and be based on timeframes mandated by statute, the priority of the consultative review request, and the workload of the designated reviewer. The RPM will request the consultative or collaborative review from the appropriate Center/Division using the form in Appendix 1 of the SOPP. Given the tight IND deadlines, work with the RPM to contact the appropriate Center/Division before sending the consult request to identify the appropriate reviewer and ensure that the review can be completed within the time requirements. Also, as described in the SOPP, the RPM should send to the Office of Combination Products a copy of the consultative/collaborative request for monitoring/tracking purposes. The RPM should follow up with the consultative reviewer to confirm that essential documents are received along with the consultative review request. If problems that affect the timeliness of the consultative review occur during the consult review period, discuss with your supervisor how to share these experiences with the Office of Combination Products, which is responsible for monitoring the efficiency and effectiveness of the intercenter consultative/collaborative review process.

3. Review of Device Components

Note to FDA Reviewers: In the device consultative/collaborative review request, describe the device component, and where to find relevant information in the submission. You should ask the consultative reviewer to identify concerns with how the device component will be used, to determine whether appropriate types of biocompatibility and other device testing were performed adequately, and to assess testing of any hardware and software controlling the hardware. In addition, if the sponsor asserts barrier or performance claims, identify information relative to these claims for the consultative reviewer to assess. Document in the review basic information concerning the device, such as the device name, vendor or source, purpose, regulatory status, and a brief description of the device. When the consultative/collaborative review is completed, and signed off by the appropriate CDRH supervisory chain, attach it to your review and communicate any outstanding issues to the sponsor.

4. Review of Drug Components

Note to FDA Reviewers: In the drug consultative/collaborative review request, describe the drug component of the combination product and state where to find relevant information on the component in the submission. Ask the consultative/collaborative reviewer to identify any concerns with how the drug will be used and also to evaluate the methods of manufacturing and the adequacy of results from testing of the drug substance and/or drug product. Document in your review basic information concerning the drug component, such as the drug name, vendor or source, purpose, regulatory status, and a brief description of the use of the drug. When the consultative/collaborative review is completed and signed off by appropriate CDER supervisory chain, attach it to your review and communicate any outstanding issues to the sponsor.

5. Summarize Any Areas of Concern to be Addressed

Note to FDA Reviewers: Summarize any areas of concern identified during the review of the product components. Discuss these concerns with the sponsor and/or communicate them in a letter to the sponsor, as described in Section XI, "Comments to Sponsor Generated by FDA Reviewers".

2. Product Manufacturing - Procedures

You should include a detailed description (list or summary) of all procedures used during the collection, production, and purification of the cellular therapy product. We believe that a schematic of the production and purification process, and in-process and final product testing, helps to provide more clearly this information.

Note to FDA Reviewers: If provided by the sponsor, append a copy of the process schematic to the IND review. If a schematic is not included, briefly summarize the processing steps used during product manufacturing. In addition, summarize any areas of concern identified during the review of any submitted product manufacturing procedures. Discuss these concerns with the sponsor and/or communicate to the sponsor in a letter, as described in Section XI, "Comments to Sponsor Generated by FDA Reviewers".

1. Preparation of Autologous or Allogeneic Cells

We recommend that you describe the following procedures:

1. Method of Cell Collection/Processing/Culture Conditions

You should describe the volume and number of cells collected. You should include any mechanical or enzymatic digestion steps used, and describe the use of any cell selection device or separation device, including density gradients, magnetic beads, or fluorescence activated cell sorting (FACS). You should include a description of culture systems (flasks, bags, etc.) and state whether the system is closed or open. Also, you should describe any in-process testing that will be performed during these procedures.

2. Irradiation

If the autologous or allogeneic cell product is irradiated before injection, you should provide data to demonstrate that the cells are rendered replication-incompetent, but still maintain their desired characteristics after irradiation. You should describe the documentation of calibration of the cell irradiator source.

3. Final Harvest

You should provide a detailed description of the final harvest. You should inform FDA whether the final cell harvest is centrifuged prior to final formulation, and if so, describe the wash conditions and media used. You should also inform FDA in your IND submission whether the cells are cryopreserved after formulation or formulated immediately and given to the patient. If the final harvest is stored, you should describe the storage conditions and the length of storage, and provide appropriate supporting data (see Section VI below).

2. Process Timing and Intermediate Storage

You should report the approximate time elapsed for each step from cell collection to final harvest. It is important to know the time limit of each step in production to determine what, if any, in-process testing to perform. If cells are cryopreserved before injection into patients, you should include this information along with any stability studies initiated (see Section VI.A.1 below). Also, you should describe the time and conditions of storage prior to patient administration.

Note to FDA Reviewers: Describe and assess the procedures in place to ensure the stability of the bulk harvest while in storage.

3. Final Formulation

You must describe the formulation of the final product, including excipients such as growth factors or human serum albumin (21 CFR 312.23(a)(7)(iv)(a)). You should state the source of these components (see Section III.A.3 above). You should identify the vendor and final concentration of these excipients and describe the cell density or cell concentration used in the final product. If the final product is delivered to the clinical site frozen, you should include a description of how the product will be shipped and data to show that the product can be thawed with consistent results. In addition, if the product is shipped, you should provide data on product stability during shipping (see Section VI.A.2 below).

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4. PRODUCT TESTING

We recommend that product testing for cellular therapies include, but not be limited to, microbiological testing (including sterility, mycoplasma, and adventitious viral agent testing) to ensure safety and assessments of other product characteristics such as identity, purity (including endotoxin), viability, and potency. We recommend that you perform this testing throughout the manufacturing process, including on the manufacture of cell banks, to evaluate the manufacturing process itself and to ensure the quality and consistency of the product. You should describe the specifications used for intermediate acceptance criteria and final product release criteria. Specifications are the quality standards (i.e., tests, analytical procedures, and acceptance criteria) that confirm the quality of products and other materials used in the production of a product. Acceptance criteria mean numerical limits, ranges, or other attributes or variables for the tests described. Specifications should be appropriate to the stage of product development, because release criteria should be refined and tightened as product development progresses toward licensure (see Appendix B). You should submit test results related to lot release, characterization testing, MCBs, and WCBs in tabular form including the lot number or identifier, date of manufacture, test, test method, the sensitivity and specificity of test methods and, when appropriate, release criteria.

Product testing is an integral part of ensuring control of the manufacturing process and lot to lot consistency. Therefore, it is important to identify critical parameters in the manufacturing process and critical product attributes to ensure the desired clinical effect of the final product. Refer to the "FDA Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-Derived Products" (Ref. 11) for additional information.

Note to FDA Reviewers: Document the testing performed. Assess the appropriateness of that testing and the acceptance criteria, based on any results previously obtained by the sponsor.

1. Microbiological Testing

We recommend that you perform microbiological testing on cell banks, in-process intermediates, and the final product, as appropriate.

1. Sterility Testing (Bacterial and Fungal Testing)

Current practices for sterility testing.

1. Test Method

Suitable sterility tests include the test described in 21 CFR 610.12 and the test described in United States Pharmacopoeia (USP) <71> Sterility Tests (23rd edition, 1995) (Ref. 12). Later versions of the USP<71> are also suitable. If you are using another test method, you should describe its suitability. Note that under 21 CFR 610.9, prior to product licensing, the alternative method must be shown to provide assurances of the safety, purity, potency and effectiveness of the biological product equal to or greater that the assurances provided by the method or process specified in the 21 CFR 610.12 method.

If you use antibiotics in manufacturing, you should provide documentation that the antibiotics were removed prior to sterility testing. If the antibiotics cannot be removed from the final product, we recommend that you assess the validity of the sterility assay using the bacteriostasis and fungistasis testing as described in USP <71> Sterility Tests. Use of this assay is designed to ensure that any residual antibiotic present in the product does not interfere with the results of sterility testing.

2. Note to FDA Reviewers: If the Sponsor proposes to use an alternative method in place of the traditional sterility methods described in 21 CFR 610.12, then you will need to assess the adequacy of this alternative test method and the data provided to provide assurances of the safety, purity, potency and effectiveness of the biological product equal to or greater than the assurances provided by the method or process specified in the general standard (21 CFR 610.9). The completeness of the validation study for the alternative method used during the product development should reflect an assessment of risk associated with the application of the method (e.g., stage of the manufacturing process).
3. Test Timing

Sponsors frequently perform in-process sterility testing at critical points during manufacturing, such as during extended culture periods, or after cells have undergone activation or other modification. You should identify when in-process sterility testing is performed during manufacturing and the test method used. The test method that you choose for in-process sterility testing should be adequate to provide assurance of product sterility.

If you freeze the final product before its use, we recommend that you perform testing on the product prior to cryopreservation, so that results will be available before the product is administered to a patient. However, if the product undergoes manipulation (e.g., washing, culturing) after thawing, particularly if procedures are performed in an open system, you may need to repeat sterility testing. You should incorporate the results of in-process sterility testing into your acceptance criteria for final product specifications.

If your product has a short dating period and must be administered to patients before sterility test results of the final product are available, then you will need to develop an alternate approach to provide sterility assurance. As an alternative approach, we recommend that you perform all of the following tests:

• in-process sterility testing on a sample taken 48 to 72 hours prior to final harvest or after the last re-feeding of the cell cultures
• a rapid microbial detection test such as a Gram stain or other procedure on the final formulated product
• sterility testing compliant with 21 CFR 610.12 on the final formulated product.

Under this alternative approach the release criteria for sterility would be based on a negative result of the Gram stain and a no-growth result from the 48 to 72 hour in-process sterility test. Although in this situation the results of the sterility culture performed on the final product will not be available for product release, this testing will provide useful data. A no-growth result will provide assurance that aseptic technique was maintained. A positive result will provide information for the medical management of the subject, and trigger an investigation of the cause of the sterility failure. The sterility culture on the final formulated product and when possible the in-process culture should be continued to obtain the full 14 day sterility test result even after the product has been given to the patient.

In all cases where product release is prior to obtaining results from a full 14 day sterility test, the investigational plan should address the actions to be taken in the event that the 14 day sterility test is determined to be positive after the product is administered to the subject. You should report the sterility failure, results of investigation of cause and any corrective actions, in an information amendment submitted to your IND in a timely manner, within 30 calendar days after initial receipt of the positive culture test result (21 CFR 312.31).

The investigator should evaluate the subject for any signs of infection that may be attributable to the product sterility failure. If the patient experiences any serious and unexpected adverse drug experience that could be from administration of the sterility failure of the cellular product, then you must report this information to FDA in an IND safety report no more than 15 calendar days after your initial receipt of the information (21 CFR 312.32). If you determine that an investigational drug presents an unreasonable and significant risk to subjects, you must discontinue those investigations that present the risk, notify FDA, all Institutional Review Boards, and all investigators (21 CFR 312.56(d)).

2. Mycoplasma

There are several potential sources of mycoplasma contamination. Two major sources include animal serum products used in culture and the culture facility environment, particularly with open culture systems. We recommend that you perform mycoplasma testing on the product at the manufacturing stage when the test is most likely to detect contamination, such as after pooling of cultures for harvest but prior to cell washing. Testing should be conducted on both cells and supernatant. We recommend that you inform FDA whether there is in-process testing for mycoplasma during extended culture procedures. Due to the limited dating period of many cellular products, it is frequently not feasible for a sponsor to perform the recommended culture-based assay (see Ref. 5) for release testing. In those cases, we recommend the use of polymerase chain reaction (PCR)-based mycoplasma assays or another rapid detection assay during product development. As part of your BLA, you should submit appropriate data to demonstrate that the PCR or alternative test has adequate sensitivity and specificity.

3. Adventitious Agent Testing

As appropriate, you should perform and describe in your IND adventitious agent testing as set out below. For more information on adventitious agent testing, refer to "Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals" and ICH guidance Q5A: "Guidance on Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin" (Refs. 5 and 13).

1. In Vitro Viral Testing

When cell lines are used, you should describe the cell lines and perform in vitro viral testing. In vitro viral testing should be performed on the MCB, WCB, and as a one time test on the EOP cells. Testing should be conducted by inoculating the test sample (MCB) onto various susceptible indicator cell lines such as the human cell line MRC-5 or Vero cells which are primate in origin. The choice of cells used would depend on the species of origin of the product to be tested. An appropriate test should include monolayer cultures of the same species and tissue as that used for production of the product, as well as a human and a non-human primate cell line susceptible to human viruses. In addition, the test should include a measure of both cytopathic and hemadsorbing viruses.

2. In Vivo Viral Testing

When cell lines are used, we recommend that you perform and submit data on in vivo viral assays carried out by inoculating the test sample (MCB) into animals such as adult and suckling mice and embryonated hen eggs. You should consider whether to include additional testing of guinea pigs, rabbits, or monkeys. Such studies would assess the test animals for any indication of illness. If such additional testing is appropriate, you should describe and explain the suitability of the animals used.

3. Selected Species-Specific Testing for Adventitious Viruses

We recommend that you test your MCB for appropriate, species-specific viruses. You should describe the testing that is performed, the different stages of manufacturing where those tests are performed (e.g., cell banks, final product), and the test methods used. If human cell lines are used in the therapeutic product, we recommend that you perform testing for human pathogens (CMV, HIV-1 & 2, HTLV-1 & 2, EBV, HBV, HCV, B19), and other human viral agents, as appropriate. We recommend such testing because these cells are manipulated (cultured for extended time periods) and human pathogens can be introduced or propagated during the extended culture periods. Human viral agents may be tested using a PCR-based test system. (Refer to Section III.A.1.b.1)

2. Identity

We recommend that you verify the identity of the MCB, WCB, and the final product by assays that will identify the product and distinguish it from other products being processed in the same facility. For the final product, identity testing is important to ensure that the contents of the vial are labeled appropriately. For additional information on labeling, refer to Section VII.B below.

If the final product consists of one or more cell lines, we recommend that you establish identity tests and/or controls that distinguish between the multiple cell lines used, and describe those tests and/or controls. Tests may include assays for cell surface markers or genetic polymorphisms (see Ref. 1 for additional information).

3. Purity

Product purity is defined as relative freedom from extraneous material in the finished product, whether or not harmful to the recipient or deleterious to the product (21 CFR 600.3(r)). Purity testing includes assays for pyrogenicity/endotoxin (see below), residual proteins or peptides used to stimulate or pulse cells, reagents/components used during manufacture, such as cytokines, growth factors, antibodies, and serum, and unintended cellular phenotypes.

1. Residual Contaminants

The appropriate purity testing should include assays for residual peptides, and proteins used during production and purification, and reagents used during manufacture, such as cytokines, growth factors, antibodies, beads, and serum. Appropriate purity testing should include a measurement of contaminating cell types or cell debris. For further information, refer to ICH Q3 on "Impurities" (Ref. 14). You should describe in your IND the purity testing you conduct and your specifications for release.

2. Pyrogenicity/Endotoxin

The rabbit pyrogen test method is the currently required method for testing biological products for pyrogenic substances (21 CFR 610.13). Although the pyrogenicity test is required, there may be specific cases where this test method can not be performed for release due to properties of the cellular product (i.e., short product shelf life, toxicity of product in rabbits). Under these circumstances, a test method such as the Limulus Amebocyte Lysate test method (LAL) may be used as an alternative method, but prior to licensure must be shown to provide equal or greater assurances of safety, purity, and potency (see 21 CFR 610.9). The 1987 FDA Guideline on Validation of the Limulus Amebocyte Lysate (LAL) Test as End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices sets forth acceptable conditions for use of LAL.

For any parenteral drug, except those administered intrathecally, we recommend that the upper limit of acceptance criterion for endotoxin be 5 EU/kg body weight/hour. For intrathecally-administered drugs, we recommend an upper limit of acceptance criterion of 0.2 EU/kg body weight/hour. You should describe in your IND the pyrogenicity/endotoxin testing you conduct, and your acceptance criterion for release.

Note to FDA Reviewers: Document in your review the specification for pyrogenicity/endotoxin testing and verify that testing is on the final product and that results are available prior to lot release.

4. Potency

You should describe and justify all assays you will use to measure potency. We recommend that these assays be quantitative, but in addition, they may include a qualitative biological assay. By the end of Phase 2, we recommend that the potency assay consist of in vivo or in vitro tests that measure an appropriate biological activity. If development of a quantitative biological assay is not possible, then a quantitative physical assay which correlates with and is used in conjunction with a qualitative biological assay can be used. Note that potency assays are part of lot release and should be validated prior to licensure.

5. Other

1. General Safety Testing

Cellular therapy products are exempt from general safety testing under 21 CFR 610.11(g)(1).

2. Viability

You should establish minimum release criteria for viability. For somatic cellular therapies, the minimum acceptable viability specification is generally set at 70 percent. If this level cannot be achieved, we recommend that you submit data in support of a lower viability specification, demonstrating, for example, that dead cells and cell debris do not affect the safe administration of the product and/or the therapeutic effect. For further information, see Ref. 1.

3. Cell Number/Dose

You should develop specifications for the minimum number of viable and functional cells as part of product testing and release. We recommend that you inform FDA whether a maximum number/dose of cells to be administered has been established and the basis for that level.

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5. FINAL PRODUCT RELEASE CRITERIA TESTING

The final product is the final formulated product used for administration to human subjects. Final product release criteria testing should be performed on each lot of product manufactured. In some situations, each dose could be considered a single lot, depending on the manufacturing process. The results from final product release criteria testing should be available prior to administration to a human subject. If results from final product testing will not be available prior to release, we recommend that you clearly indicate this in the IND, together with your specifications, and include a description of the reporting notification process if the acceptance criteria are not met. We recommend that you provide, in table format, all of your proposed specifications (tests for safety, purity, potency, and identity as described in Section IV, test methods, and acceptance criteria), including test sensitivity and specificity, where appropriate, for the final product. (Note that, before the product may be licensed, these parameters must be validated (21 CFR 211.165(e)).

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6. PRODUCT STABILITY

Stability testing must be performed during early phases of the clinical trial to establish that the product is sufficiently stable for the time period required by the study (21 CFR 312.23(a)(7)(ii)). Data supporting a final formulation and dating period will be necessary for licensure. You should describe the stability measures you will use to support your studies. For further information, refer to ICH Q5C: "Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products," (Ref. 16), ICH Guideline Q1A(R): "Stability Testing of New Drugs and Products" (revised guideline) (Ref. 17), ICH Guideline Q1E: "Evaluation of Stability Data" (Ref. 18).

Note to FDA Reviewers: Assess the product development plan in the IND review to determine how much stability data are needed for the current phase of investigation and whether sufficient data are included in the submission. If submitted, include preliminary data in your review. Assess whether proposed expiration dating is appropriate.

Stability Testing

Under 21 CFR 312.23(a)(7)(ii), you must conduct stability testing in all phases of the IND, to demonstrate that the product is within acceptable chemical and physical limits for the planned duration of the proposed clinical investigation. If a very short term clinical investigation is proposed, the stability data submitted may be correspondingly limited. You should submit a stability protocol and data for both in-process material and the final cellular product. A proposed stability protocol should include a measure of product sterility, identity, purity, quality, and potency. For each test conducted, you should describe the test method, sampling time points (there should be a zero-time point), testing temperature, and other appropriate information, including your justification of the assays used to indicate product stability, measuring those parameters for the duration of storage required by the clinical protocol. We recommend sterility testing be performed at zero-time, end of stability study, and at an intermediate point during the study.

Note to FDA Reviewers: If the sponsor plans to use the product past the duration of the clinical trial (e.g., for a separate trial being conducted after the initial trial), verify that testing establishes stability throughout the relevant time period.

1) In-Process Stability Testing

If cells are cryopreserved, you should describe the stability protocol that will be used to ensure that the product is stable during the period of cryopreservation, measuring the parameters described in Section VI.A, as appropriate. A comparison is often made of analyses carried out pre-freeze and post-thaw. You should describe any stability testing performed on the product during the holding steps, such as cryopreservation of cells and storage of bulk product.

2) Final Product Stability Testing

You should include any data that demonstrate that the product is stable between the time of product formulation and infusion to subjects to aid in establishing an expiration-dating period. We recommend that you conduct the testing at the appropriate temperatures and at time points consistent with predicted storage times. If the product is shipped from the manufacturing site to the clinical site, describe the time and shipping conditions (e.g., packaging, temperature). Your stability protocol should be adequate to demonstrate that product integrity, sterility, and potency are maintained under the proposed shipping conditions. We further recommend that validation studies using conditions that stress the system be initiated by Phase 3 and completed prior to submission of a BLA.

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7. OTHER ISSUES

1. Product Tracking

For all products, you should establish a product tracking and segregation system. An adequate system should allow identification of the therapeutic product from collection to administration of the product and should include procedures to ensure that the product is segregated from other products in incubators, hoods, and cryopreservation units. You must establish and maintain a system of tracking that enables the tracking of all products from the donor to the consignee or final disposition, and from consignee or final disposition to donor (21 CFR 1271.290(b)). In INDs for somatic cell therapy products, typically the processor would consign the product to the investigator, thus the investigator is the consignee.

2. Labeling

You should describe the product labeling used throughout the manufacturing process and on the final product container. As described in 21 CFR 312.6(a), the label for an investigational product must contain the following statement: "Caution: New Drug - Limited by Federal law to Investigational Use." To minimize the potential for mix-ups for products manufactured in multi-use facilities and for patient-specific products, we recommend that the product label contain the date of product manufacture, storage conditions, expiration date and time (if appropriate), product name, and two non-personal patient identifiers. As HCT/Ps, labeling for somatic cell therapy products must meet the requirements in 21 CFR 1271.250. For autologous donors and other situations described in 21 CFR 1271.90(a) for which a donor eligibility determination is not required, you must include the applicable required labeling in 21 CFR 1271.90(b). For example, for autologous cells intended for autologous use you must label the product "FOR AUTOLOGOUS USE ONLY" (21 CFR 1271.90(b)(1)), and "NOT EVALUATED FOR INFECTIOUS SUBSTANCES" if donor testing and screening is not performed (21 CFR 1271.90(b)(2)). For more information, refer to Ref. 4.

3. Container/Closure

You should describe the types of container and closure used, and that you have determined that the containers and closures are compatible with the product. For more information, refer to "Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics; Chemistry, Manufacturing, and Controls Documentation" (Ref. 19) and "Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, Questions and Answers" (Ref. 20).

4. Environmental Impact

Under 21 CFR 312.23(a)(7)(iv)(e), you must submit either a claim for categorical exclusion under 21 CFR 25.30 or 25.31, or an environmental assessment under 21 CFR 25.40. Such categorical exclusion is ordinarily granted, absent extraordinary circumstances indicating that the specific proposed action might significantly affect the quality of the human environment. Extraordinary circumstances are described in 40 CFR 1508.27 and may include actions that create a potential for serious harm to the environment and actions that adversely affect a species or the critical habitat of a species determined to be endangered, threatened, or entitled to special protection (21 CFR 25.21). See the "Guidance for Industry: Environmental Assessment of Human Drug and Biologics Applications" (Ref. 21) for additional information.

Note to FDA Reviewers: Document in your review whether the sponsor has claimed a categorical exclusion or evaluate the sponsor's assessment of any extraordinary circumstances using this product.

5. Qualification of the Manufacturing Process

The manufacturing process for somatic cell therapy products entails the use of reagents and source materials of differing complexity, variability and risk for introduction of adventitious agents. Qualification of reagents and source materials, as well as ensuring that appropriate controls are in place for monitoring manufacturing consistency and product quality, are key elements in ensuring that subjects receive a product that is consistently safe, pure, and potent. We recommend that, prior to production of clinical lots and initiation of clinical studies, you establish and implement written procedures to ensure proper manufacturing oversight. This includes the responsibilities and procedures applicable to the quality control unit. We recommend that you establish a quality control (QC) plan and document that plan in writing. For example, a sound QC plan must provide for the following functions:

• Responsibility for examining the various components used in the production of a product (e.g., containers, closures, in-process materials) to ensure that they are appropriate and meet defined, relevant quality standards (21 CFR 211.84(a));
• Responsibility for review and approval of production procedures, testing procedures and acceptance criteria (21 CFR 211.22(c));
• Responsibility for releasing or rejecting each clinical batch based on a cumulative review of completed production records and other relevant information (21 CFR 211.22(a), 21 CFR 211.165, 21 CFR 211.192); and
• Responsibility for investigating and initiating corrective actions if unexpected results or errors occur during production (21 CFR 211.22(a), 21 CFR 211.192).

You should summarize the QC plan that is in place to prevent, detect, and correct deficiencies that may compromise product integrity or function, or that may lead to the possible transmission of adventitious infectious agents. We recommend that QC responsibilities be performed independently from production responsibilities by dedicated QC personnel who are familiar with QC principles. You should conduct internal audits at planned intervals to evaluate effective implementation of the quality plan and to determine if processes and products meet established parameters. You should develop and document audit procedures to ensure that the planned audit schedule takes into account the relative risk of the various QC activities, the results of previous audits and corrective actions, and the need to audit the entire operation at least annually.

Note to FDA Reviewers: Document that you have reviewed the summary of the QC plan. Note each individual who has authority over the QC unit and the individual's assigned duties. Document the date of the most recent internal audits of the manufacturing operations and those of contract manufacturers, vendors, or other parties.

You should describe the changeover procedures that are followed to ensure that no cross-contamination occurs among cells intended for an individual subject and other products stored or produced in the same facility. You should describe the use of PCR assays for detecting area clearance, cleaning and decontamination reagents and segregation of activities, and the qualification of aseptic processing steps. Because most cellular therapy products are not subject to final sterile filtration prior to infusion, you should manufacture these products under aseptic conditions. A media fill is an appropriate method to qualify that the process produces a sterile product. Refer to the "Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice" (Ref. 22) for further information.

Note to FDA Reviewers: Obtain consultative reviews from the Division of Manufacturing and Product Quality, CBER, to assess any data submitted by the sponsor on facilities and environmental issues such as decontamination and cleaning validation.

6. Biostatistics

Note to FDA Reviewers: Obtain consultative reviews for relevant portions of the CMC section from the Division of Biostatistics to ensure the adequacy of proposed experimental designs and analytic plans. There are many significant design and analysis issues in the areas of assay validation, establishing specifications, evaluation of product potency, and evaluation of product stability. Proper statistical design and analysis of such studies are essential to ensure reliable documentation of the safety, purity, and potency of the product. If applicable, document in your review recommendations from the Biostatistics consult.

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8. PRECLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS

Note to FDA Reviewers: Document information provided by the sponsor to support the scientific rationale underlying the proposal. Include a brief summary of preclinical data that was generated using in vivo animal studies and/or in vitro studies to assess the product's activity, efficacy, and any safety issues observed during the study. Also include the route of administration and dosage used in the proof of concept studies.

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9. CLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS

Note to FDA Reviewers: Provide a brief description of the following in the CMC review:

1. Protocol Title

Name of the protocol.

2. Subject Population

Define the population; e.g., size, gender, race, age, etc.

3. Route of Administration

Define; e.g., oral, intravenous, intramuscular, etc.

4. Dose

Include the dosing regimen and whether there is a dose escalation. Document the dosing range and number of subjects enrolled in each dose. Describe the plans for dose escalation and what time interval/data evaluations occur between dose increases.

5. Frequency

Include the frequency of dose injections per treatment cycle and the number of proposed cycles.

6. Genetic, Biochemical, and Immunological Testing

Assess, in conjunction with the clinical reviewer, whether all genetic and/or product-specific biochemical and immunological testing of subjects is appropriate for the stage of clinical investigation. Evaluate the sensitivity and specificity of the test methods used to demonstrate biological activity (e.g., immunological assay, PCR) and document this information in your review.

7. Informed Consent

If the informed consent document is submitted for your review, verify that the product is described accurately and completely.

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10. RECOMMENDATION TO BE DETERMINDED BY FDA REVIEWERS

Note to FDA Reviewers: Describe any information that is missing or incomplete, and issues that require additional clarification. Provide an overall assessment from the CMC perspective of whether the trial may proceed or should be placed on clinical hold. Document all information obtained from the sponsor through telephone conversations or faxes. Note this documentation in the Recommendation Section of the Product Review Template, throughout the review document, or as an attachment to the review, as appropriate. Upon completion, sign and date the review and then obtain concurrence from your supervisor.

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11. COMMENTS TO SPONSOR GENERATED BY FDA REVIEWERS

Note to FDA Reviewers: Draft letter comments on unresolved issues as discussed below. Refer to SOPP 8201, "Issuance of and Response to Clinical Hold Letters for Investigational New Drug Applications" (Ref. 23), for additional information. After you have obtained supervisory concurrence on your review, forward your comments to the RPM for inclusion in a letter to the sponsor.

1. Clinical Hold

Clinical hold comments are comments that the sponsor must satisfactorily address prior to allowing clinical studies to proceed after FDA has imposed a clinical hold. These comments must meet the criteria listed in 21 CFR 312.42(b).

2. Non-Clinical Hold

Non-clinical hold comments are comments that the sponsor should address as product development progresses. In some cases, a sponsor may need to address specific manufacturing issues by a certain point in clinical development, such as prior to initiation of Phase 3 studies.

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12. REFERENCES

1. Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy, March 1998, http://www.fda.gov/cber/gdlns/somgene.pdf.
2. Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products, November 1995, http://www.fda.gov/cder/guidance/phase1.pdf.
3. Final Rule: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products, (69 FR 29786, May 25, 2004), http://www.fda.gov/cber/rules/suitdonor.pdf.
4. Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), August 2007, http://www.fda.gov/cber/gdlns/tissdonor.pdf.
5. Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals, July 12, 1993, http://www.fda.gov/cber/gdlns/ptccell.pdf.
6. ICH Guidance on Quality of Biotechnological/Biological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products, (63 FR 50244, September 21, 1998), http://www.fda.gov/cber/gdlns/qualbiot.pdf.
7. Guidance for Industry: Source Animal, Product, Preclinical and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans, April 2003, http://www.fda.gov/cber/gdlns/clinxeno.htm.
8. PHS Guideline on Infectious Disease Issues in Xenotransplantation, January 19, 2001, http://www.fda.gov/cber/gdlns/xenophs0101.htm.
9. Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use, February 28, 1997, http://www.fda.gov/cber/gdlns/ptc_mab.pdf.
10. Manual of Standard Operating Procedures and Policies: Intercenter Consultative/Collaborative Review Process, Version 4, dated June 18, 2004, http://www.fda.gov/oc/ombudsman/intercentersop.pdf.
11. FDA Guidance Concerning Demonstration of Comparability of Human Biological Product, Including Therapeutic Biotechnology-derived Products, April 1996, http://www.fda.gov/cber/gdlns/comptest.pdf.
12. United States Pharmacopoeia (USP), Chapter <71> Sterility Tests, 23th Edition, 1995, http://www.usp.org.
13. ICH Guidance on Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin, (63 FR 51074, September 24, 1998), http://www.fda.gov/cber/gdlns/virsafe.pdf.
14. ICH Topic Q3. Impurities.
    Guidance for Industry: Q3A Impurities in New Drug Substances, February 2003, http://www.fda.gov/cber/gdlns/ichq3a.pdf.
    Guidance for Industry: Q3B(R2) Impurities in New Drug Products, July 2006, http://www.fda.gov/cber/gdlns/ichq3br.pdf.
    Guidance for Industry: Q3C Impurities: Residual Solvents, December 1997, http://www.fda.gov/cber/gdlns/q3cresolvent.pdf.
15. 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, 1987, http://www.fda.gov/cber/gdlns/lal.pdf.
16. Guideline for Industry: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products, July 1996 (ICH Q5C), http://www.fda.gov/cder/guidance/ichq5c.pdf.
17. Guidance for Industry: Q1A(R2): Stability Testing of New Drug Substances and Products (Revision 2), November 2003, http://www.fda.gov/cber/gdlns/ichstab.pdf.
18. Guidance for Industry: Q1E: Evaluation of Stability Data, June, 2004, http://www.fda.gov/cber/gdlns/ichstabdta.pdf.
19. Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics; Chemistry, Manufacturing, and Controls Documentation, May 1999, http://www.fda.gov/cber/gdlns/cntanr.pdf.
20. Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, Questions and Answers, May 2002, http://www.fda.gov/cber/gdlns/cntanrq&a.pdf.
21. Guidance for Industry: Environmental assessment of Human Drug and Biologics Applications, Revision 1, July 1998, http://www.fda.gov/cber/gdlns/environ.pdf.
22. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, September 2004, http://www.fda.gov/cber/gdlns/steraseptic.htm.
23. Manual of Standard Operating Procedures and Policies Investigational New Drug; Issuance of and Response to Clinical Hold Letters for Investigational New Drug Applications, SOPP 8201, Version #3, April 27, 1999, http://www.fda.gov/cber/regsopp/8201.htm.

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APPENDIX A - PRODUCT REVIEW TEMPLATE (SOMATIC CELL THERAPY)

Supervisor Concurrence/Date
IND:	XXXX	Sponsor's Submission Date:		Month DD, YYYY
		30 Day Review Due Date:		Month DD, YYYY
		STATUS:		Pending
DATE:		Month DD, YYYY
REVIEWER:		Your Name Your Title, OCTGT/DCGT/Your Branch
THROUGH:		Branch Chief Name Branch Chief, OCTGT/DCGT/Branch
SPONSOR:		Name: Address: Title: Phone: Fax:
SPONSOR POINT OF CONTACT:		Name: Address: Title: Phone: Fax:
TITLE OF IND:
PROPOSED USE:
REVIEW TEAM:		Clinical: Pharm-Tox: RPM: Consults:
PRODUCT DESCRIPTION:
PHASE OF STUDY:
CROSS-REFERENCED INDS, IDES, MFS:
KEY WORDS:

INTRODUCTION / RATIONALE:

STUDY OBJECTIVES:

PRODUCT MANUFACTURING AND CHARACTERIZATION:

Product Manufacturing - Components

Cells

Allogeneic or Autologous Cell Components

Cell Source:

Method of Collection:

Donor Screening:
Description

Tabulation of Testing

Cell Bank System - If Applicable

Master Cell Bank (MCB)
Description

Tabulation of Testing

Working Cell Bank (WCB)

Description

Tabulation of Testing

Reagents

Tabulation of Reagents Used in Manufacture

Reagent/Excipient

Concentration at use

Source

Grade

Vendor

COA

Qualification Program

Determination of Removal of Reagents from Final Product

Combination Products - If Applicable

Drug or Device Components - If Applicable

Consult Review Issues:

Areas of Concern for Components:

Product Manufacturing - Procedures

Preparation of Autologous or Allogeneic Cells

Method of Cell Collection/Processing/Culture Conditions

Irradiation - If Applicable

Process Timing & Intermediate Storage

Final Harvest

Timing/Methods/Wash Procedure

Final Formulation

Formulation/Infusion Buffer

Excipients

Cell Density/Concentration in the Final Product

Storage Method Prior to Use

Areas of Concern for Manufacturing

PRODUCT TESTING

In-Process Testing and Criteria

Tabulation of Tests, Manufacturing Step, Test Methods, Criteria, and Test Sensitivity & Specificity

Test	Manufacturing Step Where Performed	Method	Criteria	Sensitivity	Specificity
Sterility
Mycoplasma
Purity (endotoxin)
Purity (other contaminants)
Identity
Potency
Others (cell dose)
Others (cell viability)

Description of Test Methods

FINAL PRODUCT RELEASE CRITERIA/SPECIFICATIONS

Tabulation of Final Product Release Criteria Tests, Test Methods, Criteria, Test Sensitivity & Specificity

Test	Method	Criteria	Sensitivity	Specificity	Results Available Prior to Release

Description of Test Methods

PRODUCT STABILITY

    In-Process Stability Testing

Cryopreserved Cells

Other Intermediate Holding Steps

    Final Product Stability Testing

Product Formulation to Patient Infusion

Shipping Conditions

OTHER ISSUES

Product Tracking

Labeling and Containers

In-Process Labeling

Final Product Labeling

Container Closure & Integrity

Environmental Impact

Validation and Qualification of the Manufacturing Process

QA/QC Program

Manufacturing Process Validation

Biostatistics

PRECLINICAL STUDIES

CLINICAL STUDIES

Protocol Title

Subject Population

Route of Administration

Dose

Frequency

Genetic, Biochemical, and Immunological Testing

Informed Consent

RECOMMENDATION

COMMENTS TO SPONSOR

Clinical Hold
Non-Clinical Hold

Signature Reviewer Name

Date:____________________

Return to Table of Contents

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APPENDIX B - CONSIDERATIONS FOR DEVELOPMENT OF FINAL PRODUCT RELEASE CRITERIA SPECIFICATIONS AND STABILITY PROTOCOLS

Specifications are the quality standards (i.e., tests, analytical procedures, and acceptance criteria) that confirm the quality of products and other materials used in the production of a product. Acceptance criteria are the numerical limits, ranges, or other criteria for the tests described. For additional information, see ICH Guideline Q6B: "Test Procedures and Acceptance Criteria for Biotechnological/Biological Products".³ We believe that certain release specifications, such as those related to product safety, should be in place prior to initiating Phase 1 clinical studies. As product development proceeds, additional specifications for product quality and manufacturing consistency are developed and implemented. For additional discussion of manufacturing quality control, see "Guidance for Industry: Guideline on the Preparation of Investigational New Drug Products"⁴ and "Guidance for Industry: IND Meetings for Human Drugs and Biologics; Chemistry, Manufacturing and Controls Information".⁵

1. Development of Release Acceptance Criteria

We recommend that proposed release acceptance criteria for the final product be based on scientific data and manufacturing experience obtained during development of the product as described below:

• Phase 1 - Based on data from lots used in preclinical studies.
• Phase 2 - Refine and tighten based on data generated during Phase 1.
• Phase 3 - Based on information collected during product development.
• Licensure - Based on information collected during product development using validated assays.
2. Development of Acceptance Criteria Analytical Procedures

We recommend that proposed analytical procedures be based on scientific data and manufacturing experience as described below:

• Phase 1-3 - Usually based on Code of Federal Regulation (CFR) methods or alternative methods, if appropriate.
• Phase 2 - If an alternative to the CFR method is used, we recommend that the sponsor initiate validation of the alternative by Phase 3.
• Licensure - The product specification should be in place and established under a validated assay.
3. Development of Stability Protocols

In order to develop adequate stability data for timely submission in a license application, we recommend that a sponsor implement and expand the stability program as described below:

• Phase 1 - 3 - Preliminary data on product stability must indicate whether the product or components are likely to remain stable for the duration of the clinical trial. Note: the regulations require that the IND contain these data at each stage of the clinical trial (21 CFR 312.23(a)(7)(ii)).
• Phase 2 - We recommend that the sponsor initiate a stability protocol to accumulate additional data.
• Phase 3 - We recommend that the sponsor begin to establish the dating period, storage conditions, and shipping conditions based on data derived from the stability protocol.

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Footnotes

¹ If a feeder cell line of animal origin is used to propagate human cells (i.e., human and non-human animal cells are co-cultivated), the final product falls within the definition of a xenotransplantation product (see both Refs. 8 and 9).

² Regulations on combination products are found in 21 CFR Part 3, which describes how we will determine which component of FDA has primary jurisdiction for the premarket review and regulation of a combination product. Note to FDA Reviewers: If you have any concerns regarding the appropriateness of the jurisdictional assignment or regulatory mechanism, you should contact the Office of Cellular, Tissues, and Gene Therapies' jurisdictional officer.

³ Guidance for Industry: Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products, August 1999, http://www.fda.gov/cder/guidance/Q6Bfnl.pdf.

⁴ Guidance for Industry: Guideline on the Preparation of Investigational New Drug Products (Human and Animal), dated March 1991, reprinted November 1992, http://www.fda.gov/cder/guidance/old042fn.pdf.

⁵ Guidance for Industry: IND Meetings for Human Drugs and Biologics; Chemistry, Manufacturing and Controls Information, May 2001, http://www.fda.gov/cber/gdlns/ind052501.htm

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