FDA 483s and Warning Letters concerning Stability Testing


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Medicinal products must comply with their specifications throughout their entire shelf life. Stability is therefore one of the crucial quality attributes.

Stability tests are designed to determine how a drug product or active ingredient changes under certain conditions - temperature, humidity, exposure to light - during a specified period of time. Possible changes can occur in the area of physical properties (crystal form, particle size, melting point, etc.), chemical properties (formation of decay products, decrease in content) and microbiological properties (germ growth). All of these changes in properties can negatively affect efficacy.

In the marketing authorization application, drug manufacturers must specify a shelf life, based on the stability studies performed, from which the expiration date to be specified for the medicinal product is determined. In addition, storage instructions must be derived from the results of the studies. Stability must also be continuously monitored after market launch in order to be able to identify stability-related problems at an early stage. For the EU, a corresponding requirement can be found in the EU GMP Guideline Part I, for example. There, chapter 6.27. states: "The purpose of the on-going stability programme is to monitor the product over its shelf life and to determine that the product remains, and can be expected to remain, within specifications under the labelled storage conditions.”

Stability testing is thus important at all stages of the life cycle - in development, during marketing authorization and during the commercial phase.

Setting Specifications AND Stability Testing


Barcelona, Spain22-24 October 2024

Setting Specifications AND Stability Testing


There are a large number of regulations that deal with stability testing requirements. The following documents are examples:

  • ICH Quality Guidelines: Q1A – Q1F Stability1
  • EMA Guideline on declaration of storage conditions2
  • WHO Technical Report Series, No. 953, 2009, Annex 2: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products3
  • WHO Technical Report Series 1010, 2018, Annex 10: WHO guidelines on stability testing of active pharmaceutical ingredients and finished pharmaceutical products4

Regulatory requirements in the USA

Products entering the U.S. market must comply with FDA requirements. The agency has summarized these requirements in various guidance documents, for example:

  • ANDAs: Stability Testing of Drug Substances and Products, June 20135
  • ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers, May 20146
  • Center for Veterinary Medicine (CVM), Drug Stability Guidelines, December 20087

Legal requirements regarding stability studies are defined in the Code of Federal Regulations (21 CFR Part 211.166 Stability testing). The following general requirements can be derived from this:

  • Existence of a written test program containing specifications on sample size and test intervals, storage conditions and suitable test methods;
  • Storage of a sufficient number of batches of each drug product;
  • Determination of sample size and testing intervals based on statistical criteria;
  • Testing of the drug product in the same container-closure system in which the drug product is marketed.

There is also a requirement in 21 CFR Part 211.194 Laboratory records. Under 21 CFR 211.194(e), complete records shall be maintained of all stability testing performed.

Stability Testing for Drug Substances and Drug Products


Barcelona, Spain23/24 October 2024

Stability Testing for Drug Substances and Drug Products

FDA 483s

Deficiencies observed during an FDA inspection are documented on the FDA Form 483. In the Inspection Observations section of the FDA website, various tables can be accessed with compilations of the observations listed on the 483 forms generated by the FDA system.8 These tables indicate the number of deficiencies found on specific GMP requirements with reference to the respective locations in the U.S. Code.

In the "Drugs" area, the total number of reports issued in recent years was as follows:

  • Fiscal year 2018 (between Oct. 01, 2017 and Sept. 30, 2018):
    716 FDA 483 forms
  • Fiscal year 2019 (between Oct. 01, 2018 and Sept. 30, 2019):
    779 FDA 483 forms
  • Fiscal year 2020 (between 10/01/2019 and 9/30/2020):
    349 FDA 483 forms
  • Fiscal year 2021 (between Oct. 01, 2020 and Sept. 30, 2021):
    215 FDA 483 forms
  • Fiscal year 2022 (between Oct. 01, 2021 and Sept. 30, 2022):
    466 FDA 483 forms

The total number of 483s was at a rather low level in 2020 and 2021, compared to previous years, which is likely related to the Corona pandemic and associated cuts in inspections.

Of the forms issued, a quite relevant number relate to the topic of stability. The table  below summarizes an evaluation carried out in this regard.

It is apparent that there were findings in almost all subsections of 21 CFR part 211.166 in the inspections of the last five fiscal years. In each case, the most common finding was that "There is no written testing program designed to assess the stability characteristics of drug products".

FDA Warning Letters

If FDA inspectors find relevant deficiencies and document them in a 483 report, these deficiencies can lead to a warning letter if the response from the companies concerned is unsatisfactory.

A systematic analysis of warning letters published in the GMP Journal for fiscal years 2017 to 2021 (October 2016 to September 2021)9 showed that the most frequent GMP deficiencies in the quality control area affected pre-release product testing and stability testing. Accordingly, deficiencies in the area of stability testing were cited particularly frequently in fiscal year 2021. The topic of stability studies also has a certain significance in connection with the investigation of OOS results. From another analysis, also published in the GMP Journal10, it can be deduced that time and again OOS results were not or only insufficiently investigated in stability tests.

Warning letters are published on the FDA homepage and are thus freely accessible to everyone. A database with filter and search functions is available for the period from 2018. There is also the possibility for a full text search11.

As of June 27, 2023, the database contained a total of 3,138 entries, although these do not relate exclusively to the pharmaceutical sector, as "Tobacco Retail Warning Letters" are also included.

A search for the keyword "stability", also conducted on June 27, 2023, returned a total of 260 results. If we look at the warning letters issued in the period from January to the end of June 2023, we find the following main violations:

  • "You lack a stability program and stability data."
  • "Adherence to a stability program." / "You did not perform stability testing at the intervals required by your procedure."
  • "Your firm did not provide evidence of long-term stability."
  • "You did not provide assurance that your test methods are stability indicating."
  • "The temperature storage condition is not monitored throughout the study and there are no protocols for humidity."
  • "Establishment of an adequate ongoing stability program."
  • "Your firm did not place an appropriate number of batches of each drug product formulation on stability."
  • "You failed to investigate out-of-specification (OOS) assay results during stability checks for several batches."
  • "Your stability program lacked appropriate testing of your drug products, including testing of active ingredients, impurities, and other degradation products."

In summary, it can be concluded that despite the requirements for GMP-compliant stability testing, which have been known for a long time and have remained unchanged in principle, deficiencies still occur regularly in this area.


1 https://www.ich.org/page/quality-guidelines
2 https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-declaration-storage-conditions_en.pdf
3 https://apps.who.int/iris/bitstream/handle/10665/44553/WHO_TRS_953_eng.pdf
4 https://cdn.who.int/media/docs/default-source/medicines/norms-and-standards/guidelines/regulatory-standards/trs1010-annex10-who-stability-testing-of-active-pharmaceutical-ingredients.pdf
5 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/andas-stability-testing-drug-substances-and-products
6 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/andas-stability-testing-drug-substances-and-products-questions-and-answers
7 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-5-drug-stability-guidelines
8 https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/inspection-observations
9 https://www.gmp-journal.com/current-articles/details/the-most-frequent-gmp-deficiencies-in-quality-control.html
10 https://www.gmp-journal.de/aktuelle-artikel/details/out-of-specification-results-im-fokus-von-fda-inspektionen-eine-analyse-der-warning-letters-der-letzten-5-jahre.html (German)
11 https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters


About the Author
Dr Markus Funk
... joined CONCEPT HEIDELBERG in October 2019 as operational director and is in charge of the topics GDP and analytics.

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