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SOPP 8408.1: Development of Testing Plans and Release of Lots as Part of the Approval Process

Version #1

Effective Date: March 15, 2011
 


 

  1. Purpose 

    This SOPP provides procedures for Center for Biologics Evaluation and Research (CBER) staff for the review of manufacturer’s lot-specific testing data and the conduct of any CBER testing of sample(s) submitted pursuant to 21 CFR 601.2(a) Applications for biologics licenses; procedures for filing.

  2. Scope

    This procedure covers CBER-regulated products during the biologics license application (BLA) approval process and during changes to existing biological license(s) through the biologics license supplement (BLS) approval process. 
     
  3. Background

    1. In accordance with 21 CFR 601.2(a), to obtain a biologics license under section 351 of the Public Health Service Act for any biological product, the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research. Manufacturers are required to submit various information, including information and data related to representative samples of the product meant for interstate commerce. As such CBER evaluates the summaries of results and also determines whether to perform any testing of its own.
    2. In accordance with 610.2(a), samples of any lot of licensed product together with the results of applicable tests may at any time be required to be sent to the Director, Center for Biologics Evaluation and Research. Lots shall not be distributed until the lot is released by the Director, Center for Biologics Evaluation and Research. CBER will not issue a notification for lot release except when deemed necessary for the safety, purity or potency of the product.
    3. CBER's position on whether to require lot release post-licensure and if determined to be necessary, how to evaluate product for distribution post-licensure is initially determined during the BLA or BLS review process. This position may include a decision on the test methods and test results to be submitted by the manufacturer in a lot release protocol, as well as a determination of the need for any confirmatory testing to be conducted by CBER.
    4. Product test results generated by CBER in support of regulatory decisions are acquired under the tightly controlled requirements of the CBER Laboratory Quality System (LQS) program.
       
  4. Definitions

    1. Confirmatory Testing – Testing of regulated products conducted by CBER in order to verify results reported by the manufacture
    2. Data Monitoring Plan – For the purposes of this SOPP, control chart or other method used by CBER to monitor manufacturer’s lot release test results over time.
    3. Exempt from Lot Release – Condition of licensure whereby the manufacturer is not required to submit lot-specific protocols or samples to CBER for review. The manufacturer may distribute lots without a release notification from CBER. Summary lot release data may be submitted and reviewed in Annual Reports.
    4. Laboratory Quality System (LQS) program – Organizational structure, policies, procedures, processes and resources needed to conduct regulatory testing activities in a secured and controlled environment using appropriately qualified and validated methods for generating data supportive of Center regulatory activities.
    5. Launch Lots – Lots of product available for distribution into interstate commerce at the time of BLA or BLS approval. Launch lots have also been known as exhibit lots.
    6. Lot Release – Condition of licensure whereby the manufacturer is required to submit lot-specific protocols and possibly samples to CBER for review. The manufacturer may not distribute individual lots until receiving a release notification from CBER.
    7. Lot Release Program – CBER activities, resources, and processes engaged in fulfilling CBER’s rights and obligations under 21 CFR 610.2, including products subject to either Lot Release or Surveillance.
    8. Lot Release Protocol – Manufacturer’s summary document sent to CBER for the purpose of obtaining CBER’s permission to release a lot of product into distribution, per 21 CFR 610.2(a); typically containing lot-specific manufacturing information and testing results.
    9. Lot Release System (LRS) – Database of information supporting the Lot Release Program.
    10. Lot Release Testing Plan – Documentation of CBER's current approach to evaluating a licensed product including the circumstances under which CBER would or would not conduct testing
    11. Protocol Review Worksheet – Tool used by CBER during the routine lot release process to facilitate the review and trending of data provided in the manufacturer’s lot release protocols.
    12. Regulatory Testing Activities - Laboratory activities performed by CBER consisting of: 1) Official testing (as defined in CBER’s Lab Quality Policy Manual [LQPM]) – testing that has a direct impact on a regulatory position (i.e. licensure of new products, routine release of products into the marketplace, approval of changes to licensed products, compliance action, or formal international collaboration and 2) associated activities – development and evaluation of reference materials/standards, studies evaluating a manufacturer’s reference standard, or assay.
    13. Surveillance – Condition of licensure, usually conferred by the approval of a BLS, whereby the manufacturer is required to submit lot-specific protocols and possibly samples to CBER for review. The manufacturer may distribute lots at their own risk without waiting for a release notification from CBER.
    14. Testing Lab – for purposes of this SOPP, any CBER laboratory that tests regulated product, pre- or post-licensure, for the purposes of licensing, Lot Release or Surveillance.

      NOTE: In all but the most unusual circumstances, testing lab activities should be performed under the Laboratory Quality System program by OCBQ/DPQ or OVRR/DBPAP/LIB.
       
  5. Policy

              Pre-Licensure 
    1. The timely review of test results and lot release protocols are an important part of the approval process for biological products. Early communication and collaboration, both internally and with manufacturers, is essential during the approval process with respect to review of manufacturing protocols, sample requirements and the development of validated, LQS program-compliant testing procedures at CBER.
    2. Failure to identify lot numbers of biological products which are available for submission in-support of licensure to CBER in the BLA may be considered as a basis for issuance of a Refusal to File letter to the applicant per 21 CFR 601.2. 
    3. For new products or manufacturing changes, protocols and lot samples should be submitted to CBER only after a CBER issued submission tracking number (STN) has been assigned to the application or supplement.
    4. Testing performed in support of licensing, supplements, amendments to licenses, and routine lot release are conducted under the CBER LQS program.

      Post-Licensure 
    5. As part of the review process, CBER develops a Lot Release Testing Plan for post market evaluation of each product. Lot Release Testing Plans are intended to remain flexible over time in order for CBER to respond appropriately to protect public health in the face of new information. In developing Lot Release Testing Plans, CBER does not relinquish any rights or obligations under 21 CFR 610.2(a).
    6. Per 21 CFR 610.2(a), CBER may require sample and protocol submission for the purposes of Lot Release only when necessary to ensure the safety, purity or potency of products. Prior to requiring sample submission as a condition of licensure, CBER develops and approves a Lot Release Testing Plan describing how and under what conditions CBER intends to test the samples.
       
  6. Responsibilities  
     
    1. Center Lab Quality Manager (CLQM)
      1. Manages the Lab Quality System program
      2. Reviews and, after confirming that the plan is complete and meets the requirements of the CBER LQS program, approves the Lot Release Testing Plan.
         
    2. CMC Reviewer/Product Lead
      1. Proposes, with justification, any need for CBER testing in support of the submission.;
      2. Reviews both manufacturer and any CBER lot-specific testing data
      3. Proposes and discusses as appropriate:
        1. test methods and product specifications to be included in manufacturer’s post-licensure lot release protocols,
        2. role and identity of post-licensure lot release protocol reviewer(s)
        3. content for the Protocol Review Worksheet(s)
        4. content for a Data Monitoring Plan, and
        5. any use of CBER’s confirmatory testing post-licensure
           
        • Refer to SOPP 8401.4: Review Responsibilities for the CMC Section of Biologic License Applications and Supplements for additional information.
           
    3. Committee Chair
      1. Communicates requirements for samples and testing data to the manufacturer, if appropriate, following Office Director (designee) approval.
      2. Confirms with applicant the availability of launch lots concurrent with approval, if appropriate.
      3. Requests product testing by CBER, as appropriate, through form PRB-101.
      4. Requests the manufacturer submit a lot release protocol template as part of the submission
      5. Facilitates discussions on:
        1. the development of the Lot Release Testing Plan;
        2. content and format of the manufacturer’s lot release protocol;
        3. role and identity of lot release protocol reviewers (post-licensure).
           
    4. Division of Product Quality (OCBQ/DPQ) or Laboratory of Immunobiochemistry (OVRR/DBPAP/LIB)

      Note: DPQ staff performs these responsibilities for all products other than allergenic products in which case LIB staff fulfills these responsibilities.
      1. Summarizes review committee discussions and decisions on whether CBER will test samples provided in support of a submission.
      2. Discusses as appropriate:
        1. test methods and product specifications to be included in manufacturer’s post-licensure lot release protocols;
        2. role and identification of post-licensure lot release protocol reviewer(s); and
        3. any potential post-licensure confirmatory testing by CBER
      3. Summarizes Center discussions and decisions on whether to conduct confirmatory testing post-licensure
      4. Prepares and routes the finalized Lot Release Testing Plan for approval
      5. Inform the review team of any issues needing follow up during a pre-license inspection
         
    5. OCBQ, Division of Manufacturing and Product Quality (DMPQ) Director
      1. Reviews and, after confirming that DMPQ/PRB is prepared to receive this product post-licensure, approves the Lot Release Testing Plan
         
    6. OCBQ/DMPQ/Product Release Branch (PRB
      1. Serves as the Center Sample Custodian as described in 21 CFR 600.2(c) and as manager of the Lot Release Program (Branch Chief)
      2. Provides the necessary processing of samples and protocols as part of the approval process.
      3. Clears launch lots for release at the time of approval.
      4. Recommends format for post-licensure manufacturer’s lot release protocol, as necessary.
      5. Discusses role and identity of any post-licensure lot release protocol reviewer(s)
      6. Prepares, as needed, to receive and manage product post-licensure.
      7. Archives documentation in appropriate database or, if paper, with DCC.
         
    7. Product Office Director (or designee)
      1. Decides, based on the recommendations of the review team and Committee Chair and the outcome of Center-wide negotiations:
        1. Whether the product will be subject to Lot Release, Surveillance or Exempt from Lot Release;
        2. Any CBER testing activities to be included in the Lot Release Testing Plan; and
        3. Role and identity of any post-licensure lot release protocol reviewer(s) (accomplished through the product Lab/Branch Chiefs).
        4. If the Office Director does not concur with the review committee recommendation, the Office Director must create a separate review memo stating the reasons for disagreement.
      2. Approves the final lot release testing plan prior to the approval of a new product or product class, or new testing methods or product specifications for existing licenses.
      3. Provides resources sufficient for testing assignments stipulated in the Lot Release Testing Plan.
        1. Confirms the plan represents an appropriate use of public resources per the CBER LQS program, FDA Staff Manual Guide 2350.1, and Office of Personnel Management circular A-123
           
    8. Protocol Reviewer(s)
      1. Develops and finalizes the Protocol Review Worksheet and Data Monitoring Plan
         
    9. Regulatory Project Manager (RPM)
      1. Ensures that communications between the committee members and the manufacturer or between the committee members and other Center representatives are recorded and included in the file.
      2. Ensures the appropriate language describing any need for post-licensure lot release responsibilities are included in the Approval Letter.
         
    10. Review Team Members (including DPQ or LIB representative)
      1. Proposes and negotiates whether approval of the submission should be conditional based on manufacturer participation in the Lot Release Program.
      2. Determines any need for CBER testing of samples submitted in support of the submission.
      3. Recommends whether CBER should perform confirmatory testing post-licensure.
         
    11. Statistician
      1. Discusses as appropriate:
        1. product specifications to be included in manufacturer’s post-licensure lot release protocols,
        2. content for a Data Monitoring Plan,
        3. content for the Protocol Review Worksheet
           
    12. Testing Lab(s)
      1. Performs product testing as requested, pre- or post- licensure
      2. Documents results in appropriate database
      3. Documents results of testing conducted in support of the submission in the Testing In-Support Results Memo using Regulatory Template T-910.03:Testing In Support Results Memo
      4. Communicates results of testing conducted in support of the submission to the review committee
         
    13. Testing Lab Division Director
      1. Reviews and, after confirming testing labs are prepared to conduct assigned testing, approves the Lot Release Testing Plan
         
  7. Procedures

    Activities described in this section may be performed concurrently as outcomes of steps in one section may influence steps in other sections.

    1. Prior to the filing decision, determine whether or not samples are available to be submitted in-support of the application. If samples are not available, this could be considered grounds for refusing to file the application. [Committee Chair]

    2. B. Propose as a starting point for Center-wide discussion whether this product should be subject to Lot Release, Surveillance, or Exempt from Lot Release. Regulatory Job Aid 900.04: Reviewer Considerations for Post-Market Product Assessment can be used as a guide to help with the decision making process [Review Committee]

      Note:
      Consider holding one review committee meeting, soon after the filing meeting, at which steps B, C1, D1, E1, and F1 are all discussed.
       
    3. CBER Testing In Support of approval of the submission
      1. Determine, after the filing decision, whether to test samples provided in support of the submission. Refer to Regulatory Job Aid 900.05: Reviewer Considerations for CBER Product Testing in Support of Licensing Action. (Refer to the flowchart in Appendix 1 for additional information.)

        1. Propose any test(s) to the review committee with product analysis and defend the need for the test(s). [CMC Reviewer/Product Lead]
        2. Discuss and decide whether to test sample(s) provided in support of the submission. (Review Committee)
      2. If testing will not occur, proceed to Step 3. If testing will occur:

        1. Identify appropriate laboratory to perform testing. Questions may be referred to the DPQ member of the review committee. [CMC Reviewer/Product Lead, PRB, Testing Lab(s), and DPQ or LIB]
        2. Estimate the number of samples required [Testing Labs and CMC Reviewer/Product Lead]
        3. Request the manufacturer provide samples for testing in support of the submission. Samples should be submitted to the Sample Custodian and the manufacturer’s lot-specific testing data should be provided as an amendment to the submission. [RPM, Committee Chair and PRB]
        4. Route manufacturer’s lot-specific testing data to the CMC Reviewer/Product lead. [RPM]
        5. e. Notify the Committee Chair and RPM when the samples have been received. Provide Forms PRB-101 “Request for Control Tests” and PRB-201 “Sample Request Form” to the Committee Chair to record testing requests. [PRB]
        6. Complete, sign, and enter form PRB-101 into RMS-BLA and import into CBER’s EDR. Send form PRB-201 in an email with the Subject line: “Sample Request” to “CBER Lot Clearance” mailbox within 10 days of receipt. [Committee Chair]
        7. Distribute samples with a copy of the completed form PRB-101 to Testing Lab(s) [PRB]
        8. Perform testing according to PRB-101. [Testing Labs]
        9. Record testing outcome(s) in LRS. Refer to LRS Users’ Guide. [Testing Labs]
        10. Prepare a memo to the Committee Chair reporting the test results using Regulatory Template T 910.03: Testing In Support Results [Testing Labs]

          1. In the case of unanticipated or unusual test results, also report results to PRB Chief. [Testing Lab]
          2. Communicate unanticipated or unusual test results to the manufacturer. [PRB, CMC Reviewer/Product Lead, Committee Chair, and Testing Lab]
        11. Enter the test results memo into RMS –BLA and import into CBER’s EDR; notify the Committee Chair. [Testing Labs]
      3. Summarize in a memo to the file (referred to as a Testing In Support Summary memo) the factors which the review committee considered while making the decision on whether to request CBER testing in support of the submission, including any disagreements. Reference by title and location subsequent test results memo(s) if appropriate. Enter this memo into RMS-BLA and import into CBER’s EDR. [DPQ or LIB]
      4. Enter into the Lab Quality Database (LQDB) a reference to the ‘Testing In Support’ summary memo referred to in step number three (3) above. [DPQ or LIB]
      5. Track and dispose of any samples received in support of the application, whether tested or not, according to Lab Quality System policies and procedures, after final decision on approval. [PRB and Testing Labs]

        Note:
        Once distributed, samples may not be returned to PRB.

      6. Review manufacturer’s lot-specific testing data and CBER test results, if any. [CMC Reviewer/Product Lead]

    4. Manufacturer’s Lot Release Protocol

      This section does not apply to products Exempt from Lot Release. (Refer to the flowchart in Appendix 2 for additional information.)

      Per 21 CFR 610.2(a), CBER may require sample and protocol submission for the purposes of Lot Release only when necessary to ensure the safety, purity or potency of products. 

      1. Determine the post-licensure manufacturer’s lot release protocol requirements before the mid-cycle review meeting. Refer to Regulatory Job Aid 900.06: Reviewer Considerations for Manufacturer’s Lot Release Protocol Content. [CMC Reviewer/Product Lead, Committee Chair, DPQ or LIB, PRB, Statistician]
      2. Discuss lot release protocol requirements with manufacturer, as necessary. Request the manufacturer provide a finalized template for the lot release protocol to be used post-licensure as an amendment to the submission. [Committee Chair, PRB, DPQ or LIB]
      3. Route the finalized manufacturer’s lot release protocol template to PRB, and DPQ or LIB. [RPM]
      4. Record finalized lot release test specifications in a controlled document within the LQDB. [DPQ or LIB]
      5. Enter into the LQDB a reference to the finalized manufacturer’s lot release template in the EDR. [DPQ or LIB]
      6. Facilitate discussion among Lab/Branch chiefs with product responsibility, CMC Reviewer/Product lead, PRB, and DPQ or LIB on the role and identity of post-licensure lot release protocol reviewers. [Committee chair]
      7. Develop the Protocol Review Worksheet template(s) the protocol reviewer(s) will use post-licensure when reviewing lot release protocols. Refer to Regulatory Job Aid JA 900.07: Protocol Review Worksheet Example. [Protocol Reviewer(s) with input from CMC Reviewer/Product Lead and Statistician]

        Note:
        In cases where more than one protocol reviewer is identified, reviewers can choose to create one combined template or multiple reviewer-specific templates.

        Note: It is strongly recommended that this worksheet template be created using spreadsheet or database software in order to facilitate statistical analyses. CBER QAS can provide guidance on using the LQDB if the protocol reviewer is interested in creating the worksheet template in that database. 
         
      8. Forward the Protocol Review Worksheet template to DPQ or LIB for inclusion in the LQDB. [Protocol Reviewer]
      9. Define the Data Monitoring Plan(s) the protocol reviewer(s) will use post-licensure to trend manufacturer’s data as reported in lot release protocols. [Protocol Reviewer(s) with input from CMC Reviewer/Product Lead and Statistician]
      10. Forward the Data Monitoring Plan(s) to DPQ for inclusion in the LQDB. [Protocol Reviewer(s)]
      11. Update LRS as needed to reflect protocol requirements and reviewers. [PRB]
      12. Provide a copy of the final lot release protocol Routing Slip to DPQ or LIB. [PRB] 
         
    5. Lot Release Testing Plans
      1. Propose to the review committee whether or not CBER should maintain testing methods for the post-marketing evaluation of production lots for release under 21 CFR 610.2. Refer to Regulatory Job Aid JA 900.03: Reviewer Considerations for Product Testing Post-Licensure. (Refer to the flowchart in Appendix 3 for additional information) [CMC Reviewer/Product Lead and DPQ or LIB]
      2. Record committee recommendations, for or against, in a draft Lot Release Testing Plan, by the mid-cycle review meeting. [DPQ or LIB]
      3. Negotiate within the Center the details of the Lot Release Testing Plan. [Committee Chair, DPQ or LIB, CMC Reviewer/Product Lead, Office Director or designee, Testing Lab(s) as appropriate, and Statistician]
      4. Summarize in a memo to the file (referred to as a Testing Post Licensure Summary memo) the factors which the Center considered while making this decision, including any disagreements. Enter this memo into RMS-BLA and import into CBER’s EDR. [DPQ or LIB]
      5. Enter into the LQDB a reference to the Testing Post Licensure Summary memo referred to in step number four (4) above. [DPQ or LIB]
      6. Prepare and route the finalized Lot Release Testing Plan for approval. [DPQ or LIB]
      7. Review, approve, and forward the Lot Release Testing Plan to the Product Office Director. [Testing Lab Division Director]
      8. Review, approve, and forward the Lot Release Testing Plan to the Director, DMPQ. [Product OD]
      9. Review, approve, and forward the Lot Release Testing Plan to the CLQM. [DMPQ Division Director]
      10. Review, approve, and forward the Lot Release Testing Plan to DPQ or LIB. [CLQM]
      11. Update the LQDB document control records, enter the Testing Plan into the RMS-BLA, import into the EDR, and notify the RPM that these steps have been completed. [DPQ or LIB]
      12. Include appropriate language in the Approval Letter describing any post-licensure needs, as determined by the product Office Director, for the manufacturer to submit lot release protocols and, if appropriate, samples to the Sample Custodian. Please refer to CBER’s Review Template Letters on CBER’s Intranet Web page for the most recent approved template. [RPM]

    6. Launch Lots

      This section does not apply to products exempt from lot release.

      This section will apply if launch lots will be released at the time of approval. Launch lots are not a requirement for approval.

      1. Discuss with the manufacturer, after the filing decision, any potential launch lots and lot release protocols. [Committee Chair, CMC Reviewer/Product Lead, DPQ or LIB, PRB, and RPM]
      2. Consider, during the mid-cycle review meeting, if samples and manufacturer’s lot-specific testing data provided in support of the submission represent suitable launch lots and lot release protocols. [Committee Chair]
        1. It is not an absolute requirement that the lot-specific testing data supplied to the file by the manufacturer be in the final Lot Release Protocol format in order to be considered acceptable launch lot release protocols. The Committee Chair, after appropriate review committee discussion, will exercise judgment as to whether or not the information required in a lot release protocol can be determined from the information provided.
        2. Likewise, any CBER testing performed on samples in support of the application does not have to mirror the CBER testing as written in the approved Lot Release Testing Plan in order for the lots to be considered acceptable launch lots. Again, the Committee Chair should exercise judgment as to whether or not the goals of the Lot Release Testing Plan have been met.
      3. Notify PRB whether or not any samples provided in support of the submission represent acceptable launch lots. [Committee Chair]
        1. If samples are suitable, label as “For Lot Release” the samples previously received. [PRB]
        2. If samples are not suitable as launch lots or if no samples have been submitted, request the manufacturer submit samples and lot release protocols representative of suitable launch lots to the Sample Custodian. [Committee Chair]
      4. Send the Short Summary information from RMS-BLA in an email with the Subject line: “Lot Clearance” to “CBER Lot Clearance” mailbox prior to beginning the approval process. Be sure to include all relevant lot numbers. [Committee Chair]
      5. Verify that launch lots are available for release at the time of approval and that the appropriate review and signoff on the lot release protocols have been completed. [PRB]
        1. Record this step on the Licensing Action Recommendation Memo (LARM) at the time of approval. [PRB]
      6. Fax or email the signed approval letter to PRB on the day of approval. [RPM]
      7. Update PRB files with approval letter and notify DPQ or LIB. [PRB]
      8. Generate and deliver notification of release as appropriate for launch lots. [PRB and DMQP Division Director]
      9. Update LQDB document records with reference to PRB-filed approval letter. [DPQ or LIB]

  8. Appendix
    1. Appendix 1: flowchart: CBER Testing In Support of Approval of the Submission
    2. Appendix 2: flowchart: Manufacturer’s Lot Release Protocols
    3. Appendix 3: flowchart: CBER Lot Release Testing Plans
       
  9. References
    1. References below are located on CBER's Intranet Web Page unless otherwise noted
      1. Regulatory Job Aid JA 900.03: Reviewer Considerations for CBER Product Testing Post-Licensure
      2. Regulatory Job Aid JA 900.04: Reviewer Considerations for Post-Market Product Assessment
      3. Regulatory Job Aid JA 900.05: Reviewer Considerations for CBER Product Testing In Support of Licensing Action
      4. Regulatory Job Aid JA 900.06: Reviewer Considerations for Manufacturer’s Lot Release Protocol Content
      5. Regulatory Job Aid JA 900.07: Protocol Review Worksheet - Example
      6. Regulatory Template T 910.03: Testing In-Support Results Memo
      7. Product Release Branch (PRB) Form 101: Request for Control Tests (obtained from the PRB)
      8. Product Release Branch (PRB) Form 201: Sample Request Form (obtained from the PRB)
      9. Lot Release System User Guide (found in the LRS)
      10. Laboratory Quality System Policy Manual (found in the LQDB)
         
    2. Web links to the references below can be found in the list following the History Section
      1. SOPP 8401: Administrative Processing of Biologics License Application (BLA)
      2. SOPP 8401.4: Review Responsibilities for the CMC Section of Biologic License Applications and Supplements
      3. FDA Staff Manual Guide 2350.1 Guidance for the Implementation of the Federal Managers’ Financial Integrity Act (FMFIA)
      4. OMB revised Circular A-123, dated December 21, 2004 Management’s Responsibility for Internal Control
      5. 21 CFR
         
  10. History

    Written/Revised
    Approved By
    Approval Date
    Version Number
    Comment
    Jansen, DixonRobert A. Yetter, Ph.D.February 18, 20111Separated SOPP 8408 into SOPP 8408.1 and SOPP 8408.2