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Implementation of ICH Q12 Tools and Enablers for Post-Approval CMC Changes in Drug Products and Combination Products (DRAFT)

This guidance clarifies how ICH Q12 tools and enablers can be implemented within the U.S. regulatory system for managing post-approval chemistry, manufacturing, and controls (CMC) changes. It applies to drug substances and drug products that are subject to NDAs, BLAs, ANDAs, and their supplements regulated by CDER and CBER, including combination products with device constituent parts.

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By ReguVirta
3 min read

This is a draft guidance. Not for implementation.

What You Need to Know? 👇

What are Established Conditions (ECs) in ICH Q12 and how do they differ from traditional regulatory requirements?

Established Conditions are legally binding information considered necessary to assure product quality. Unlike traditional approaches, ECs allow applicants to propose specific parameters requiring regulatory submission when changed, potentially reducing reporting burden for non-critical changes while maintaining quality assurance.

How should medical device companies approach ECs for combination products with device constituent parts?

Device constituent parts should focus on “primary characteristics” essential for safe use, dose delivery, and drug product quality. Consider design features, manufacturing processes, and control strategies that ensure these characteristics as potential ECs, using risk management principles to justify selections.

What reporting categories apply to postapproval CMC changes under ICH Q12 implementation?

FDA uses Prior Approval Supplement (PAS) for high-risk changes, CBE-30 for moderate notification changes, CBE-0 for low notification changes, and annual reports for lowest risk changes. The lowest risk changes are managed within the pharmaceutical quality system without reporting.

Yes, applicants may propose reduced reporting categories for changes to ECs if supported by increased understanding of quality risk. However, justification must demonstrate that the proposed category appropriately reflects the actual risk to product quality.

What is required in the Product Lifecycle Management (PLCM) document for ICH Q12 submissions?

The PLCM document should include proposed ECs, reporting categories, comparability protocols, and postapproval commitments in tabular format. It must reference specific eCTD locations for scientific justifications and indicate manufacturing sites by FEI numbers where ECs apply.

How does pharmaceutical quality system effectiveness impact approved ECs and reporting flexibility?

An effective PQS is essential for ICH Q12 tools. Inspection findings raising PQS concerns may require modification of previously approved ECs or reporting categories until effectiveness returns to acceptable levels. New manufacturing sites require reassessment of relevant ECs.

What You Need to Do 👇

  1. Determine if specific ECs will be proposed or if changes will follow standard regulations/guidance
  2. If proposing ECs:
    • Include appropriate statements in cover letter and eCTD section 3.2.R
    • Provide scientific justification for EC selection and reporting categories
    • Create PLCM document with complete EC listing
    • Consider device constituent part requirements for combination products
  3. Establish effective PQS to support EC management
  4. Maintain up-to-date documentation of analytical procedures in annual reports
  5. Update PLCM document with each supplement/annual report that changes approved ECs
  6. Reassess ECs when introducing new manufacturing sites
  7. Monitor PQS effectiveness through inspections and quality metrics
  8. Consider using structured approaches for frequent CMC changes as described in ICH Q12

Key Considerations

Safety

  • For device constituent parts, functions essential for safe use based on risk management principles must be considered as primary characteristics
  • Risk assessment process and criticality assessment must be documented to determine impact of parameters on product quality

Other considerations

  • Established Conditions (ECs) are legally binding information necessary to assure product quality
  • Changes to ECs require regulatory submission
  • ECs can be proposed in original applications or Prior Approval Supplements (PAS)
  • Complete list of proposed ECs must be included in Product Lifecycle Management (PLCM) document
  • Scientific justification required for selection of ECs and their reporting categories
  • For combination products, device constituent parts must consider primary characteristics related to:
    • Essential functions for safe use
    • Design features for drug delivery
    • Characteristics impacting drug quality attributes
  • Effective Pharmaceutical Quality System (PQS) necessary to support EC management
  • Changes to approved ECs can be made through supplements, PACMPs, or fulfillment of post-approval commitments

Relevant Guidances đź”—

Related references and norms đź“‚

  • ISO 14971:2019: Medical devices—Application of risk management to medical devices
  • ISO 13485:2016: Medical devices—Quality management systems—Requirements for regulatory purposes

Original guidance

  • Implementation of ICH Q12 Tools and Enablers for Post-Approval CMC Changes in Drug Products and Combination Products
  • HTML / PDF
  • Issue date: 2021-05-20
  • Last changed date: 2021-09-10
  • Status: DRAFT
  • Official FDA topics: Chemistry, Pharmaceutical Quality, Medical Devices, Manufacturing, Drugs, Biologics, and Controls (CMC)
  • ReguVirta ID: ae1bf4a700f4c2c91d6328e2d30c3108
FDA guidance, Draft
Chemistry Pharmaceutical Quality Medical Devices Manufacturing Drugs Biologics and Controls (CMC)
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