The FDA Warning Letter Report 2023
The analysis of the FDA warning letters for fiscal year 2023 has a surprise in store when it comes to the GMP violations cited with reference to the Code of Federal Regulations, Part 211. The topic of "incoming inspection of raw materials, excipients and API components" is by far the most common in the warning letter descriptions. Of the 71 warning letters published to date, 49 describe violations of Section 211.84 of the Code of Federal Regulations - more than ever before.
Although 211.84 has always been among the sections frequently cited in warning letters, it is particularly high in fiscal year 2023 with a percentage share of 69% (see Fig. 1).
Fig. 1: Percentage of warning letters with violations of 211.84 in the last 10 fiscal years.
The distribution of the other frequently cited paragraphs corresponds to that of previous fiscal years. Here, too, you can find
- 211.22 Responsibilities of quality control unit
- 211.100 Written procedures, deviations
- 211.165 Testing and release for distribution
- 211.192 Production record review
in the top 5 of the top ten hit list (see Fig. 2).
Abb.2: Top Ten der GMP-Verstöße im Fiskaljahr 2023
211.84 - Testing and approval or rejection of components, drug product containers, and closures
This paragraph is part of Subpart E - Control of Components and Drug Product Containers and Closures of the Code of Federal Regulations and governs the procedure for testing incoming starting materials and container/closure systems used in the manufacture of finished drug products. It requires that all components necessary for the manufacture of a finished drug product - active ingredients, excipients, containers and closure systems - must be tested to the defined specifications after receipt of the goods and before release for further processing. Complete testing of all specifications can be dispensed with under the following conditions:
- A certificate of analysis from the supplier is available.
- The test results of the supplier's certificate of analysis have been validated and thus confirmed.
Recommendation
7/8 May 2024
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Even if these requirements are met, at least one identity test must be carried out for each batch!
In addition, the supplier should be qualified; this requirement is not explicitly stated in section 211.84; however, warning letters often criticize unqualified suppliers as a source of origin in this context.
Violation of 211.84 - the typical wording in the warning letters and the facts
The content of the warning letters was analyzed using a 4-part topic-related presentation according to the following structure:
- the description of the GMP violation
- the Company's response
- the FDA's feedback
- the follow-up requests for documents/evidence from the FDA
This format - an extract from the text of the warning letter - offers the advantage of a topic-centered approach, as the following two examples illustrate:
Example 1
| Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(1) and 211.84(d)(2)). |
| AG Hair Limited Coquitlam BC, Canada; 28 November 2022 |
You failed to perform adequate identity testing for each component lot used in the production of your hand sanitizer drug products, including ethanol, your active pharmaceutical ingredient. Additionally, your active pharmaceutical ingredient, ethanol, is not tested for methanol content, and your procedures did not ensure that you test glycerin for presence of diethylene glycol (DEG).
Products Containing Ethanol
You manufacture multiple drugs that contain ethanol. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide.
Recommendation
7/8 May 2024
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See FDA's guidance document Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19) to help you meet the CGMP requirements when manufacturing drugs containing ethanol at https://www.fda.gov/regulatory-information/search-fdaguidance-documents/policytesting-alcohol-ethanol-and-isopropyl-alcohol-methanol-including-during-public-health.
Products Containing Glycerin
You manufacture products that contain glycerin. The use of glycerin contaminated with diethylene glycol (DEG) has resulted in various lethal poisoning incidents in humans worldwide. See FDA's guidance document Testing of Glycerin for Diethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing glycerin at https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/testingglycerin-diethylene-glycol.
Component testing is fundamental to quality. Without adequate testing, you do not have scientific evidence that your incoming components conform to appropriate specifications before use in the manufacture of drug products.
| Company’s response |
In your response, you committed to updating component testing procedures and specifications.
| FDA’s Feedback |
Your response is inadequate. You failed to provide a detailed plan to ensure that previously distributed drug products were manufactured with incoming components that meet your updated identity and impurity testing requirements.
| What the company should provide |
In response to this letter, provide:
- The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.
- A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier's Certificates of Analysis (COA) instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier's results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
- A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.
- A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
- Methanol, […] and test results for all hand sanitizer lots released and distributed.
Example 2
| Your firm failed to conduct at least one test to verify the identity of each component of a drug product ((21 CFR 211.84(d)(1)). |
| Formology Lab Inc. Chatsworth, CA, United States, 1 March 2023 |
Your firm failed to test Active Pharmaceutical Ingredients (API) prior to use in manufacturing drug products. Specifically, at least […] drug product batches were manufactured and subsequently released, before identity testing was performed. Component testing is fundamental to drug product quality. Without adequate testing, you do not have scientific evidence that your incoming components conform to appropriate specifications before use in the manufacture of drug products.
| Company’s response |
In your response, you indicate that your firm is currently developing, reviewing, and updating all quality management system procedures and processes and assessing the roles and responsibilities of all personnel. You also indicate that procedures around testing and receiving of components will be enhanced.
| FDA’s Feedback |
Your response is inadequate. The revision of the procedure for receiving and testing components lacks details such as timelines for implementation of revised procedures and specific testing to be performed. The use of components and release of the drug products containing these components prior to conducting identity testing, and the qualification of suppliers was not addressed. An impact assessment or investigation into this practice is not provided, nor is there any evaluation if other components were inappropriately utilized.
| What the company should provide |
In response to this letter, provide:
- A comprehensive review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
- A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier's Certificates of Analysis (COA) instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier's results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
The descriptions of all 49 warning letters using this format describing GMP deficiencies in relation to 211.84 are available in the Members Area of the ECA website.
Categorization of GMP violations against 211.84
The GMP deficiencies related to incoming inspection according to 211.84 can be summarized in 2 main categories:
1. No identity verification or adequate testing of starting materials; reliance on the supplier certificate; no verification (the term "validation" is used in the warning letters) of the information on the certificate No testing of critical components for toxic impurities
2a. No testing of ethanol and isopropanol for methanol
2b. No testing of glycerin, propylene glycol, benzalkonium chloride and sorbitol solution for ethylene glycol and diethylene glycol
2c. No testing of water for USP quality
Methanol, ethylene glycol (EG) and diethylene glycol (DEG) are highly toxic impurities; in the past, the latter two have led to highprofile tragic incidents with numerous deaths (replacement of glycerine with ethylene glycol in cough syrup for children). The FDA had published the following two guidelines on methanol and EG or DEG, which are also regularly quoted in the warning letters:
- Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol
- Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19)
Product types
In the vast majority of warning letters describing violations of 211.84, inadequate testing of critical components - mainly ethanol and glycerine - plays a role. When analyzing the product types, it becomes clear why: the majority of companies produce hand sanitizers, liquid and topical dosage forms (sunscreens, ointments, etc.).
The diagram in Fig. 3 illustrates the distribution of the number of warning letters among the product types.
Fig. 3: Warning letters on GMP violations according to 211.84 in relation to product types
A tabular list of all warning letters relating to 211.84 - categorized according to GMP violations of 211.84 (core statements) and product types - provides a further overview and the possibility of indepth research in the original warning letters via the links provided.
The following table is an excerpt; the complete table is available in the ECA website's Members Area.
Hand sanitizers
| GMP Violation | Critical Components | Manufacturer |
| No identity testing of incoming material; Reliance on supplier certificate No testing for methanol | Ethanol | Beijing Xinggu Lvsan Technology Co., Ltd. |
| No testing for methanol | Ethanol, Isopropanol | McConnell Labs Inc. |
| No identity testing of incoming material; No testing for methanol | Isopropanol | Omega & Delta Co., Inc. |
| No identity testing of incoming material No testing for methanol No testing for diethylene glycol |
Ethanol Glycerine | AG Hair Limited |
Drugs – Topical Dosage Forms
| GMP Violation | Critical Components | Manufacturer |
| No identity testing of incoming material No testing for diethylene glycol and ethylene glycol | Glycerine (Benzene as an impurity in the finished medicinal product) | Accra-Pac, Inc. dba Voyant Beauty |
| No identity testing of incoming material; No proof of conformity with USP specifications | Titanium dioxide (not pharmaceutical grade) | Mr. Lulu LLC |
| No identity testing of incoming material No testing for diethylene glycol and ethylene glycol | Glycerine, propylene glycol, sorbitol solution | Orchid Lifesciences |
Drugs – Liquid Dosage Forms
| GMP Violation | Critical Components | Manufacturer |
| No proof of the suitability of the water used and the minimum quality according to the USP Purified Water Monograph. | Water | Auto-Chlor System LLC |
| No identity testing of incoming material; No testing for diethylene glycol and ethylene glycol | Propylene glycol, glycerine | Profounda, Inc. |
| No identity testing of incoming material; No testing for diethylene glycol and ethylene glycol | Potassium nitrate Glycerine | Dunagin Pharmaceuticals Inc. dba Massco Dental |
| Compilation of FDA warning letter analyses As part of the ongoing systematic analysis of the warning letters on cGMP violations published in each fiscal year, CONCEPT Heidelberg generates statistics ("Top ten lists of the most frequent GMP deficiencies") and topic-related excerpts from the warning letters in the format used in this article (e.g. on quality unit failures, stability, OOS results, etc.). Structured presentations of other relevant topics are in the works. Furthermore, a list of keywords for the fiscal year 2022 has been created, which contains important keywords on cGMP with the respective assignment to the warning letters concerned. These documents are available in the ECA Members Area. |
About the Author
Gerhard Becker is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in analytical and
compliance topics.
