GMP Hot Spots as seen in the Warning Letters - Stability Testing
Stability tests on finished medicinal products and their components, active ingredients and excipients, are an essential part of GMP-compliant manufacturing and provide the data to justify the shelf life of the product. Stability tests are required in national regulations worldwide and are explained in the respective guidelines, directives, etc., in some cases in great detail. For the US economic area, §211.166 contains the regulations for carrying out stability tests. These are used by FDA inspectors as a basis for on-site inspections.
Further detailed specifications for conducting stability tests are described in the following ICH regulations:
- Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003)
- Q1B Photostability Testing of New Drug Substances and Products (March 1996)
- Q1C Stability Testing for New Dosage Forms (May 1997)
- Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (January 2003)
- Q1E Evaluation of Stability Data (June 2004)
- Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products (July 1996)
There are two guidelines specifically for the stability testing of generic drugs...
- ANDAs: Stability Testing of Drug Substances and Products (June 2013)
- ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers (May 2014)
... and for the stability testing of solid dosage forms containing iron, one guideline:
- Expiration Dating and Stability Testing of Solid Oral Dosage Form Drugs Containing Iron (July 1997)
Testing the integrity of the container/closure system of sterile medicinal products is part of the stability protocol for these products. The requirements are described in the following guideline:
Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products (February 2008)
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Finally, there is a series of Compliance Policy Guides (CPGs) in which GMP deficiencies are described. The content of the CPGs is addressed to FDA inspectors, who should focus on potential deficiencies during an inspection. The CPGs are also used by the relevant departments of the Office of Pharmaceutical Quality Operations (OPQO) as a basis for decision-making when issuing a warning letter. There are two CPGs on the subject of stability testing:
- CPG Sec. 480.300 Lack of Expiration Date of Stability Data (March 1995)
- CPG Sec. 480.100 Requirements for Expiration Dating and Stability Testing (March 1995)
Even though the requirements are so clearly described in numerous regulations and have been publicly available for many years, deficiencies in the performance of stability tests appear time and again in the texts of the warning letters.
The graph in figure 1 shows the percentage of warning letters addressed to pharmaceutical manufacturers over a period of 5 years in which this deficiency - with reference to §211.166 - is described.
Fig. 1: Percentage of warning letters with deficiency notices on stability testing according to 21 CFR 211.166 for fiscal years 2019 2023
With the exception of the peak value of 44%, the percentage of warning letters describing GMP violations of §211.166 lies at around 25%. This means that every fourth warning letter contains complaints about stability testing.
Categorization of GMP deficiencies in stability testing
The following analysis of GMP violations related to stability testing includes a total of 31 warning letters: 19 warning letters from fiscal year 2023 and 12 warning letters from the current fiscal year 2024 to April 2024.
The deficiencies in the stability check described in the warning letters can be divided into the following categories:
Incomplete stability testing data
Almost half of the warning letters (15) addressing the issue of stability testing refer to a lack of data to justify the declared shelf life. Data on chemical and microbiological stability and, in some cases, data on physical stability and long-term stability are missing.
The inspectors were either unable to obtain any stability study at all or they received data from outdated stability studies (different active ingredient supplier, different production site).
No stability testing program in place
In 16 of the warning letters examined, the complete lack of data on stability testing was criticized; in many cases, no stability testing program was established at all in the production facilities. In 12 of the 16 warning letters, this deficiency was listed as a failure of the quality assurance unit with reference to 211.22 as a sub-item of several other GMP violations that are the responsibility of the quality assurance unit (e.g. incoming inspection of components; 211.84; release inspection; 211.165; employee training; 211.25 etc.).
The standard wording in the warning letters is: "Your quality unit (QU) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure the following:".
In some cases, the companies do not even have a quality assurance unit and therefore do not have a stability testing program.
The companies in which the inspectors found no testing program or no QA unit are almost exclusively manufacturers of hand disinfectants.
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Follow-up requests from the FDA
Following an inspection that resulted in a warning letter, the FDA requires the submission of various documents related to the area in which the GMP violation was found. This compilation of evidence requested by the FDA in the warning letters provides evidence that can be useful in preparing for an FDA inspection. In the case of deficient stability testing, the following documents are standard:
- A complete, independent assessment including CAPA plan of the stability testing program. The assessment must include evidence that the program is capable of performing stability testing.
- Specification of stability indicating procedures
- Stability studies of all products destined for the U.S. market in final packaging prior to release for shipment
- Ongoing stability studies to which representative batches are added annually to demonstrate the declared shelf life.
- A precise definition of the quality attributes to be tested at each point in time
- A compilation of all procedures describing the revised stability testing program.
During an inspection in which these documents can be presented, the topic of "stability testing" should not cause any problems.
| Note: You can find the complete analyses of the warning letters for the 2022 and 2023 fiscal years and other relevant documents in this context in the ECA member 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.
