The FDA routinely sends specific requests for information to drug companies during BLA reviews to assess compliance with 21 CFR Part 4, particularly regarding management responsibility, design controls, corrective and preventive action (CAPA), and purchasing controls. Below are examples of such requests, organized by topic, with direct references to actual FDA communications:

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1. Management Responsibility (21 CFR 820.20)

Typical FDA Requests:

• Provide a summary of how your firm's management has established responsibility to assure that the combination product is manufactured in compliance with all applicable CGMP requirements (see 21 CFR Part 4).
• Provide a description of the functions and responsibility of each facility involved in the manufacturing of the combination product and its constituent parts.
• Describe the management structure with executive responsibility for those who manage, perform, and assess work affecting quality of the product and related controls to ensure that your quality policies are appropriately implemented and followed, and the product appropriately designed and manufactured in conformance with CGMP requirements ^14421433718.

Example Requests:

• "Please provide a summary of how your firm's management has established responsibility to assure that the combination product is manufactured in compliance with all applicable CGMP requirements (see 21 CFR Part 4). Also, provide a description of the functions and responsibility of each facility involved in the manufacturing of the combination product and its constituent parts." ⁴²¹⁴³
• "Provide a summary of your management structure with executive responsibility for those who manage, perform, and assess work affecting quality of the product and related controls to ensure that your quality policies are appropriately implemented and followed, and the product appropriately designed and manufactured in conformance with CGMP requirements, including quality system requirements met, per 21 CFR 820.20." ¹⁴¹⁸⁴³

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2. Design Controls (21 CFR 820.30)

Typical FDA Requests:

• Provide a summary of your design control system under 21 CFR 820.30 for the device constituent part and combination product.
• The design control information should include initial design, planning and development, design input, design output, design review, design transfer, design verification, design validation that meets the proposed intended use of the final combination product, design changes, and design history file.
• For changes made to the device constituent part, the impact of the design changes on the overall combination product performance should be considered and documented. All the design control activities must be documented in the Design History File (DHF) and subjected for design reviews. ^142130374118

Example Requests:

• "Please provide detailed summary for the Design Control per 21 CFR 820.30 as it relates to [product]." ⁹³⁰⁴¹
• "Please provide your design verification reports for the [device]." ¹⁸
• "Please provide your risk analysis assessment used for the design of your final drug product with respect to the device design." ¹⁸
• "The procedures' descriptions must include how the requirements for design and development planning, design input, design output, design review, design verification, design validation, design transfer, design changes, and design history file are fulfilled. Please provide a copy or a summary of the plan used to design the combination product." ²¹³⁰⁴¹

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3. Purchasing Controls (21 CFR 820.50)

Typical FDA Requests:

• Provide a summary of the procedure(s) for purchasing controls.
• Describe your supplier evaluation process and describe how it will determine the type and extent of control you will exercise over suppliers.
• Define how you maintain records of acceptable suppliers and how you address the purchasing data approval process.
• Explain how you will balance purchasing assessment and receiving acceptance to ensure that products and services are acceptable for their intended use.
• Explain how the procedure(s) will ensure that changes made by contractors/suppliers will not affect the final combination product. Provide a description of how you apply the purchasing controls to the suppliers/contractors used in the manufacturing of the combination product (e.g., through supplier agreement). ^{4213041141833}

Example Requests:

• "Please provide a summary of the procedure(s) for purchasing controls. The summary should: a. Describe your supplier evaluation process and describe how it will determine type and extent of control you will exercise over suppliers. b. Define how you maintain records of acceptable suppliers and how you address the purchasing data approval process. c. Explain how you will balance purchasing assessment and receiving acceptance to ensure that products and services are acceptable for their intended use. Please explain how the procedure(s) will ensure that changes made by contractors/suppliers will not affect the final combination product. Provide a description of how you apply the purchasing controls to the suppliers/contractors used in the manufacturing of the combination product." ^4213041
• "Provide a summary of your purchasing control system per 21 CFR 820.50 to demonstrate controls and documentation for components, products, or services (e.g., sterilization) received at your facility for use in the manufacture of the combination product. The summary should include your evaluation process of your suppliers that meet the manufacturing acceptance criteria of the combination product specifications. Notification of changes made by the suppliers should be considered in your Purchasing/Supplier agreement as changes to incoming specification that can impact the safety and effectiveness of the final combination product." ¹⁴

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4. Corrective and Preventive Action (CAPA, 21 CFR 820.100)

Typical FDA Requests:

• Please summarize the procedure(s) for your Corrective and Preventive Action (CAPA) System.
• The CAPA system should require:
  • Identification of sources of quality data and analysis of these data to identify existing and potential causes of nonconforming practices and products;
  • Investigation of nonconformities and their causes;
  • Identification and implementation of actions needed to correct and prevent recurrence of nonconformities;
  • Verification or validation of the actions taken.
• CAPA activities for the analysis of sources of quality data to identify existing and potential cause of nonconformances, related investigations, and actions considered to correct and prevent recurrences of problems and non-conformances, including the verification or validation of the actions must be documented under your CAPA System as described in 21 CFR 820.100. ^{421221447606163}

Example Requests:

• "Please summarize the procedure(s) for your Corrective and Preventive Action (CAPA) System. The CAPA system should require: a. Identification of sources of quality data and analysis of these data to identify existing and potential causes of nonconforming practices and products; b. Investigation of nonconformities and their causes; c. Identification and implementation of actions needed to correct and prevent recurrence of nonconformities; and d. Verification or validation of the actions taken." ^{421223047606163}
• "Provide a summary of your corrective and preventive actions (CAPA) system per 21 CFR 820.100. CAPA procedures are used to determine the cause of problems and non-conformances, and the appropriate measures used to correct and prevent such problems and non-conformances from recurring. The CAPA system must account for investigations into failures in the device constituent." ¹⁴⁶³

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Summary Table of Example Requests

Area	Example Request Language	Sources
Management Responsibility	Provide a summary of management structure, executive responsibility, and facility functions for quality and CGMP compliance.	414182143
Design Controls	Provide a summary of design control system, including all phases (inputs, outputs, verification, validation, changes, DHF, etc.).	91418213041
Purchasing Controls	Provide a summary of purchasing controls, supplier evaluation, change notification, and application to contractors/suppliers.	4141821303341
CAPA	Summarize CAPA procedures, including data analysis, investigation, corrective/preventive actions, and verification/validation.	4141821223047606163

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Conclusion

The FDA's information requests during BLA reviews for Part 4 compliance are highly structured and typically require sponsors to provide:

• Detailed summaries and/or SOPs for management responsibility, design controls, purchasing controls, and CAPA systems.
• Descriptions of how these systems are implemented, maintained, and documented.
• Evidence of compliance, often in the form of procedures, organizational charts, risk analyses, and design history documentation.

These requests are consistent across multiple BLA reviews and are often accompanied by references to specific sections of the eCTD submission where the information should be placed.

References:
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