FDA 483s due to Deficiencies in the Stability Program: Evaluation of Fiscal Year 2023

Observations made by the inspector during an FDA inspection are listed on the FDA Form 483. Spreadsheets summarizing the areas of regulation cited on FDA's system-generated 483s are available by fiscal year on the FDA's homepage in the subsection on "Inspection Observations". These spreadsheets represent the area of regulation and the number of times it was cited as an observation on a Form FDA 483.

Stability studies of pharmaceuticals are a well-established discipline and, of course, an important regulatory requirement. Nevertheless, as you could read in provious articles, deficiencies in the stability program were mentioned in numerous FDA 483s in fiscal years 2019 to 2021 as well as in fiscal year 2022.

The FDA has now published the data for the fiscal year 2023 (October 2022 to September 2023). As in previous years, we have again performed an evaluation with regard to deficiencies in the stability programme.

Evaluation

In the area of "Drugs", the following number of reports have been issued in the past years:

  • Fiscal year 2019: 779 FDA 483 forms
  • Fiscal year 2020: 349 FDA 483 forms
  • Fiscal year 2021: 215 FDA 483 forms
  • Fiscal year 2022: 466 FDA 483 forms
  • Fiscal year 2023: 510 FDA 483 forms

Requirements for stability studies and stability testing are defined in the Code of Federal Regulations, mainly in 21 CFR Part 211.166. In addition, stability testing is also mentioned in 21 CFR Part 211.194.

The following table gives an overview of typical deficiencies related to stability testing:

Reference Number Short Description Frequency (fiscal year 2019) Frequency (fiscal year 2020) Frequency (fiscal year 2021) Frequency (fiscal year 2022) Frequency (fiscal year 2023)
21 CFR 211.166(a) Lack of written stability program 67 18 15 30 18
21 CFR 211.166(a) Written program not followed 29 13 12 19 13
21 CFR 211.166(a) Results not used for expiration dates, storage cond. 10 4 2 6 6
21 CFR 211.166(a)(1) Sample size - test intervals 4 1 0 3 5
21 CFR 211.166(a)(2) Stability sample storage conditions described 3 1 2 4 1
21 CFR 211.166(a)(3) Valid stability test methods 22 5 5 11 11
21 CFR 211.166(a)(4) Testing in same container - closure system 0 0 1 2 5
21 CFR 211.166(a)(5) Testing of reconstituted drugs 0 0 0 0 1
21 CFR 211.166(b) Adequate number of batches on stability 8 1 4 11 6
21 CFR 211.166(b) Accelerated stability studies 0 1 0 4 1
21 CFR 211.166(b) Tentative expiration date 1 1 0 0 0
21 CFR 211.166(c)(1) Homeopathic drugs, assessment of stability 3 2 1 1 2
21 CFR 211.166(c)(2) Homeopathic drugs, same container - closure 0 0 0 0 1
21 CFR 211.194(e) Stability testing records not included 0 0 0 1 0

Looking at the ratio of 483s in stability relative to the total number of 483s in the area of Drugs, the percentage in fiscal year 2023 is six percentage points less than in the previous year, and thus at the level of 2020:

Fiscal year 2019 Fiscal year 2020 Fiscal year 2021 Fiscal year 2022 Fiscal year 2023
FDA 483 forms in total (Drugs)

779

349 215 466 510
FDA 483 in the area of stability 147 47 42 92 70
Percentage 19% 13% 20% 20% 14%

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