Insufficient Cell Bank Stability Data
Severity: criticalInformation and data provided for the Working Cell Bank (WCB) stability do not support its suitability for commercial production. The Master Cell Bank (MCB) has undergone extensive transfers, and the provided data are insufficient to account for the potential impact on MCB stability. Adequate data and information are required to confirm MCB stability, followed by qualification of a new WCB or validation of MCB use for commercial production.
Recommended response: Conduct comprehensive stability studies for both WCB and MCB, providing robust data to demonstrate their suitability for commercial production. Qualify a new WCB or validate MCB use based on confirmed stability.
Cited: General requirements for manufacturing controls and product consistency
Inadequate Fill Weight Rejection Limits
Severity: majorThe data from the Extractable Content experiment do not support that the lower limit of the fill weight range used during drug product (DP) manufacturing will consistently deliver 420 mg, as calculations show vials filled at the lower limit would not meet the label claim. The recovery data used in calculations were based on average recovery, not worst-case.
Recommended response: Tighten the lower fill weight rejection limit and provide data demonstrating that DP vials filled at this revised limit consistently deliver 420 mg of PF-05280014.
Cited: Requirements for accurate product quantity and label claims
Insufficient Commercial Shipping Validation Data
Severity: criticalThe provided information and data for commercial DP shipping validation do not assure product quality maintenance during shipping and distribution. Mechanical performance studies are not sufficiently representative of potential stresses. Leveraging stability data for allowable shipping temperature range is inappropriate. The ability of the passive pallet shipper to maintain temperature in actual shipping lanes has not been demonstrated.
Recommended response: Provide real-time or sufficiently representative simulated shipping validation data, including assessment of pre- and post-shipping DP quality. Justify simulated studies. Conduct shipping validation for the passive pallet shipper in actual shipping lanes during various seasonal conditions.
Cited: Requirements for maintaining product quality during storage and distribution
Missing or Inadequate Specifications for Critical Quality Attributes
Severity: criticalThe application lacks appropriate specifications and control strategies for several critical quality attributes. This includes implementing a validated assay for ADCC activity for DS and DP release and stability, developing and implementing an assay to control iso Asp102 levels for DS and DP release and stability, implementing an appropriate control for high mannose into the DS release specification, adding testing and quantitative acceptance criteria for Polysorbate 20 to the DP release specification, and adding the test of 'extractable content' with an acceptance criterion of 'No less than 420 mg' to the DP release specification.
Recommended response: Develop, validate, and implement appropriate assays and acceptance criteria for ADCC activity, iso Asp102, high mannose, Polysorbate 20, and extractable content for DS and DP release and stability testing.
Cited: Requirements for comprehensive product specifications and control strategies
Inadequate Justification for Release and Shelf-Life Acceptance Criteria
Severity: majorJustifications for specifications in Sections 3.2.S.4.5 and 3.2.P.5.6 are insufficient to support some release and end-of-shelf-life acceptance criteria for DS and DP. Acceptance criteria should be sufficiently narrow, based on clinical and manufacturing experience, and account for changes during storage. For some attributes, DS specifications should be tighter than DP to prevent out-of-specification results during storage. Specific attributes needing tightening include Appearance (Color) for DS, and Acidic and Basic species by CEX-HPLC for DS and DP.
Recommended response: Revise and justify acceptance criteria for release and end-of-shelf-life for DS and DP, ensuring they are sufficiently narrow, based on product understanding, and prevent out-of-specification results during storage. Specifically tighten criteria for Appearance (Color) and Acidic/Basic species by CEX-HPLC.
Cited: Requirements for robust product specifications and stability data
Lack of Data to Support Proposed Additional Storage Conditions
Severity: majorThe proposed label includes additional storage conditions (e.g., 30°C for 3 months, 2-8°C for 28 days reconstituted), but the provided information and data are insufficient to support these. Critical quality attributes like ADCC (or FcγRIIIa binding) and iso Asp102 were not assessed under these conditions.
Recommended response: Provide additional data and information, including assessment of ADCC and iso Asp102, to fully support all proposed additional storage conditions.
Cited: Requirements for stability data to support proposed storage conditions
Incomplete Method Validation for Release Assays
Severity: majorMethod transfer data were provided for reduced and non-reduced CGE assays from Pfizer St. Louis to Grange Castle, but no information or data were provided to support that these assays are validated at the Pfizer St. Louis site. Since Grange Castle is the only DP release testing site, the method validation for these assays is considered incomplete.
Recommended response: Provide comprehensive information and data to support the full method validation of the reduced and non-reduced CGE assays at the Pfizer St. Louis site.
Cited: Requirements for method validation in quality control
Unjustified Low-Risk Assessment for Manufacturing Operation
Severity: majorThe assessment that a specific manufacturing operation (b(4) operation) is low risk is disagreed with by the Agency. This operation represents a higher risk for process performance consistency and product quality. Data from commercial scale manufacturing experience and/or process validation for this operation are required.
Recommended response: Provide data from commercial scale manufacturing experience or process validation to support the proposed operation and its controls, or remove the description of the operation from the BLA.
Cited: Requirements for process validation and risk assessment in manufacturing
Missing Media Fill Simulation Data
Severity: majorMedia fill simulations used to validate (b)(4) for PF-05280014 drug product are not included in the BLA.
Recommended response: Provide summary data from three media fills performed on the fill line in the BLA resubmission.
Cited: Requirements for aseptic processing validation, including media fills
Missing Microbial Data for Maximum Hold Time
Severity: majorThe maximum hold time of PF-05280014 drug product proposed in the BLA is not supported by relevant microbiology data.
Recommended response: Provide summary microbial data from hold time studies conducted in the holding vessels used for PF-05280014.
Cited: Requirements for hold time studies and microbial control
Inadequate Capping Process Parameters and Integrity Data
Severity: majorCapping process parameters for PF-05280014 drug product and BWFI diluent vials do not specify maximum differential forces. Excessive capping differential forces may damage vials and compromise product sterility.
Recommended response: Specify a maximum differential force for each capper and provide summary results demonstrating container closure integrity after capping at this maximum differential force.
Cited: Requirements for container closure integrity and manufacturing process control
