illev Pharma East has a highly educated and dedicated team of international experts with many years of experience in Pharmaceutical industry.

21 November 2022

US FDA Warning Letters of the fiscal year 2022 

In fiscal year (FY) 2022 (October 2021 – September 2022), US FDA issued 62 warning letters and 23 import alerts related to drugs, excluding compound related actions. The number of warning letters prompted by onsite inspections increased dramatically in FY 2022; 42 (67.7%) of the warning letters followed onsite inspections, while 16 (25.8%) resulted from inspecting samples and four (6.5%) were the result of a records request. In FY 2021, fewer warning letters followed onsite inspections, as the pandemic halted many inspections, except for those deemed mission critical. In FY 2021, 21 (25.3%) of such warning letters followed onsite inspections. The remainder stemmed from alternative tools: 59% were from testing samples, and 13.3% emanated from a records request, while 2.4% were from a refusal of a section 704 records request (FDA Officials: Growing number of enforcement actions stem from inspection alternatives).


US FDA emphasized the importance of on-site inspections as gold standard because they allow more holistic snapshot of a company operations, while alternative methods only allow to see a fraction of the firm’s operations.

The systematic analysis of the GMP deficiencies recorded during an inspection reflects on the one hand, what US FDA inspectors focus on and, on the other hand, provides clues for preparing for an upcoming inspection by the US FDA. The sometimes quite detailed descriptions of the GMP violations are facilitated by topic-related statistics, which are carried out annually by Concept Heidelberg in the context of the respective completed fiscal year.


Looking ahead, US FDA will be taking a hard look at management responsibility and risk management in upcoming inspections, as per the Agency’s recently updated compliance policy guideline on good manufacturing practice (GMP) preapproval and post-approval surveillance inspections (FDA addresses alternative inspecting tools, expectations for nitrosamine assessments in updated CPGs). Using a risk-based model to decide on which firms to inspect next and for industry side US FDA expects formal implementation of risk management programs so that they can have better assurance over the quality system of the product being manufactured.


In the FY 2022, a total of 42 Warning Letters were sent to medicinal product manufacturers, each explicitly describing the GMP deficiencies in connection with the paragraphs of 21 CFR 211. Ten most frequently cited GMP deficiencies are as follows:


First on this list is paragraph 211.22 Responsibilities of quality control unit, which sets out the requirements for the quality assurance unit in terms of its responsibilities. The GMP violations described in the 23 Warning Letters can be grouped as follows:

  • QA review of batch documentation and batch release
    • QA releases batches that have been tested using non-validated methods.
    • QA releases batches prior to review of manufacturing documentation.
  • Responsibilities of the Quality Unit towards contract manufacturers and contract laboratories
    • There are no quality agreements.
    • There is no release procedure for starting materials or components for product manufacture at the contract manufacturer.
    • QA does not ensure that the test methods of the contract laboratory are validated.
  • QA’s responsibility for procedural instructions, SOPs, GMP documents
    • Procedural instructions for the following GMP-relevant processes are missing:
      • batch release
      • Quality-critical manufacturing processes, operation of production equipment
      • clarification of deviations in the laboratory (OOS results)
      • microbiological tests on the product
      • Implementation of CAPAs
      • Dealing with complaints, returns and recalls
      • Evaluation of changes
      • Ongoing stability tests
      • Annual product review
  • QA responsibility for root cause analysis in case of deviations
    • Root cause analysis does not take place; instead, unjustified, and not scientifically sound corrective measures are taken (e.g., increasing the preservative content ensures that the previously too high microbial count in the product is again in compliance with specifications).
  • QA responsibility for trained personnel
    • QA does not take care of the training of staff in quality-critical areas such as processing complaints from customers, returns processing, etc.


Billev Pharma East experts can offer gap analysis of Quality Management Systems, providing a comprehensive report citing the sections of GMP that the site is deficient in and offering suggestions for appropriate CAPA. Our experts will work with yourself and the site to remedy any problematic areas identified during gap analysis. Additionally, Billev Pharma East can also offer on-site support if any significant issues are found during health authority inspections.