US FDA's Compliance Program for Drug Quality Assurance, with a focus on Active Pharmaceutical Ingredient (API) process

The USFDA released a document on 01 August 2025 outlining a Compliance Program for Drug Quality Assurance, with a focus on Active Pharmaceutical Ingredient (API) process inspections. The program aims to ensure that APIs are manufactured following Current Good Manufacturing Practice (CGMP) standards, thereby protecting the quality, identity, and purity of the drugs.

Key Elements

  1. Purpose: To detail a risk-based inspection strategy for API manufacturing facilities, ensuring compliance with CGMP standards.
  2. Scope: Applies to the manufacturing of APIs for human drug products, including small molecules, polypeptides, antibiotics, and other APIs produced by chemical synthesis or microbial fermentation. Excludes APIs for blood, vaccines, allergenics, tissues, and cellular and gene therapies.
  3. Implementation Date: 09/02/2025
  4. Revisions: Includes elements from the International Council for Harmonisation (ICH) guidances for industry, specifically Q9(R1) Quality Risk Management (May 2023), Q10 Pharmaceutical Quality System (April 2009), and Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (May 2021).

 

I. Background

Introduction:

  • The compliance program uses a risk-based inspection strategy for API manufacturing facilities to ensure effective inspection coverage and optimal use of resources.
  • Inspection depth is determined by risks associated with a firm's operations, including compliance history, technology, and API characteristics.
  • An API is defined as any component intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease.
  • API production processes include multistep chemical synthesis, fermentation, purification, crystallisation, drying, milling, packing, labelling, and testing.

Applicable Statute, Regulations, and Guidance:

  • API manufacturers must register their establishments with the FDA and list their APIs in commercial distribution.
  • APIs are subject to the adulteration provisions of section 501(a)(2)(B) of the FD&C Act, which requires all drugs to be manufactured in conformance with CGMP requirements.
  • FDA has not published specific CGMP regulations for APIs but considers the concepts in the CGMP requirements for drug products (parts 210 and 211) as valid for API manufacturing.
  • ICH Q7 provides guidance on CGMP for APIs and is used by investigators as a guideline for inspecting API manufacturers.
  • The program also incorporates principles from ICH Q9(R1) (Quality Risk Management), ICH Q10 (Pharmaceutical Quality System), and ICH Q12 (Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management).

Scope of APIs Covered:

  • The program applies to the manufacture of APIs for human drug products, including small-molecule APIs, polypeptides, and antibiotics.
  • It does not cover APIs for blood, vaccines, allergenics, tissues, and cellular and gene therapies.

Definitions:

  • Active Pharmaceutical Ingredient (API): Any component intended to furnish pharmacological activity.
  • API Production Process: A series of operations resulting in the preparation of an API.
  • API Starting Material: A raw material, intermediate, or an API that is used in the production of an API and is incorporated as a significant structural fragment into the structure of the API.
  • Bulk Finished Product: A drug material manufactured similarly to an API but does not undergo further processing.
  • Intermediate: A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. 

II. Implementation

Objective:

  • To provide comprehensive CGMP inspectional coverage of API manufacturing establishments through system-based inspections.
  • To determine whether a manufacturer is operating in a state of control, ensuring adequate quality, identity, and purity of APIs.

Program Management Instructions:

  • Selecting Sites: CDER uses a risk-based site selection model to identify API firms for routine surveillance inspections.
  • Selecting Investigators: Inspections should be conducted by experienced investigators with sufficient education and training related to the type of API production process.
  • Selecting Inspection Types: There are two basic types of CGMP inspections: surveillance and for-cause.
  • Selecting Systems: The general scheme of systems for inspecting API manufacturers includes:

Quality System

Facilities and Equipment System

Materials System

Production System

Packaging and Labeling System

Laboratory Control System

  • Selecting APIs: Inspections should cover any APIs referenced in the assignment and, as appropriate, any other representative APIs based on their level of risk.
  • Selecting Profile Classes: Profile class codes or APIs selected for coverage should represent all of the APIs manufactured at the firm.

 

III. Inspectional

Operations:

  • Investigators should understand the general inspection strategy and carefully plan their inspection strategy at each firm.
  • Investigators should review the firm's rationale for the point at which API production begins, as described in ICH Q7 and the ICH guidance for industry Q11.

Inspection Approaches:

  • Surveillance inspections have two options: a full inspection and an abbreviated inspection.
  • For-cause inspections can provide focused coverage or be expanded to abbreviated or full inspections at OII's discretion.
  • A full inspection includes an in-depth evaluation of the establishment's conformance with CGMP requirements.
  • An abbreviated inspection efficiently updates the evaluation of an establishment's conformance with CGMP requirements.

System Coverage:

  • This section provides a detailed description of each system and the areas for coverage, including:

Quality System

Facilities and Equipment System

Materials System

Production System

Packaging and Labeling System

Laboratory Control System

Preparing the Inspection Strategy:

Select two or more systems for inspection coverage.

Select significant APIs for inspection coverage if APIs are not specified in the assignment.

Review the impurity profile for each API production process.

Verify conformity to any compendial monographs.

Determine if the firm has made process changes by comparing current operations against the EIR for the previous inspection.

Reporting:

  • Investigators should describe their inspection coverage and findings in the EIR.
  • The EIR must include a list of APIs manufactured, an explanation for the APIs selected for coverage, and, for foreign API manufacturers, information on the U.S. Agent and a report of all APIs imported into the United States in the last two years.

Special Instructions for Responding to a Form FDA 483:

  • Investigators should instruct management to submit an electronic response to a Form FDA 483 with appropriate documentation via email.

 

IV. Analytical

  • API samples collected for quality evaluation should be submitted to the appropriate servicing laboratory.

V. Regulatory/Administrative Strategy

  • If one or more systems are documented as not in a state of control, OII should endorse an OAI inspection report.
  • Recommendations for regulatory action for API CGMP deficiencies should cite the statute (section 501(a)(2)(B) of the FD&C Act) and not the drug product regulations in parts 210 and 211.
  • Examples of deficiencies that may result in an inspection that is classified as OAI include:

  1. Contamination of APIs
  2. Failure to show that API batches conform to established specifications
  3. Failure to ensure the accuracy and integrity of data
  4. Failure to comply with commitments in drug applications or DMFs
  5. Distribution of an API that does not conform to established specifications
  6. Deliberate blending of API batches
  7. Failure to demonstrate that all materials are chemically and microbiologically suitable
  8. Lack of adequate validation for critical steps in the API production process
  9. Implementation of retrospective process validation when the process has changed significantly
  10. Failure to establish an impurity profile for each API production process
  11. Failure to show that a reprocessed batch complies with established standards
  12. Failure to test for residues of solvents used during manufacturing
  13. Failure to have a formal process change control system
  14. Failure to maintain batch and quality control records
  15. Incomplete stability studies
  16. Use of inadequate laboratory test methods
  17. Packaging and labeling in a way that introduces a significant risk of mislabeling

VI. References, Attachments, and Program Contacts

  • This section lists references to compliance programs, draft guidances for industry, guidances for industry, and ICH guidances for industry.
  • It also provides program contacts for CGMP or quality-related policy questions, enforcement-related guidance or policy questions, labeling requirements and policies, registration and drug listing requirements, inspection-related questions, and sampling of APIs.

In summary, this compliance program provides a structured approach for the FDA to inspect API manufacturing facilities, ensuring adherence to CGMP standards and safeguarding the quality and safety of drug products. The program emphasises risk-based inspections, system-based evaluations, and compliance with relevant regulations and guidance documents.

The link from the USFDA website can be found here.


Location: Mumbai, Maharashtra, India

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