12/13 September 2024
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, an evaluation of the last two fiscal years shows that deficiencies in the stability program are mentioned in numerous FDA 483s.
Requirements for stability studies are defined in the Code of Federal Regulations (21 CFR Part 211.166):
Sec. 211.166 Stability testing
(a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:
(1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability;
(2) Storage conditions for samples retained for testing;
(3) Reliable, meaningful, and specific test methods;
(4) Testing of the drug product in the same container-closure system as that in which the drug product is marketed;
(5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.
(b) An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained. Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates provided full shelf life studies are not available and are being conducted. Where data from accelerated studies are used to project a tentative expiration date that is beyond a date supported by actual shelf life studies, there must be stability studies conducted, including drug product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration date determined.
(c) For homeopathic drug products, the requirements of this section are as follows:
(1) There shall be a written assessment of stability based at least on testing or examination of the drug product for compatibility of the ingredients, and based on marketing experience with the drug product to indicate that there is no degradation of the product for the normal or expected period of use.
(2) Evaluation of stability shall be based on the same container-closure system in which the drug product is being marketed.
(d) Allergenic extracts that are labeled “No U.S. Standard of Potency” are exempt from the requirements of this section.
779 FDA 483 forms were issued in the area of "Drugs" during the fiscal year 2019 and 349 during the fiscal year 2020.
The following table gives an overview of typical deficiencies in the area of stability. It can be seen that there were findings in inspections of the last two fiscal years for almost all subparagraphs of 21 CFR Part 211.166.
|Reference Number||Short Description||Frequency (fiscal year 2019)||Frequency (fiscal year 2020)|
|21 CFR 211.166(a)||Lack of written stability program||67||18|
|21 CFR 211.166(a)||Written program not followed||29||13|
|21 CFR 211.166(a)||Results not used for expiration dates, storage cond.||10||4|
|21 CFR 211.166(a)(1)||Sample size - test intervals||4||1|
|21 CFR 211.166(a)(2)||Stability sample storage conditions described||3||1|
|21 CFR 211.166(a)(3)||Valid stability test methods||22||5|
|21 CFR 211.166(b)||Adequate number of batches on stability||8||1|
|21 CFR 211.166(b)||Accelerated stability studies||0||1|
|21 CFR 211.166(b)||Tentative expiration date||1||1|
|21 CFR 211.166(c)(1)||Homeopathic drugs, assessment of stability||3||2|