It is important to ensure that a reserve sample representative of each lot or batch of drug product is retained and stored under conditions consistent with the product labeling, as per the Code of Federal Regulations (CFR) section 21 CFR 211.170 Reserve Samples. The retain samples must be stored in the same immediate container-closure system in which the drug product is and should consist of at least twice the quantity necessary to perform all the required tests, except those for sterility and pyrogens. It is also necessary to visually examine reserve samples at least once a year for any evidence of deterioration unless it would affect the integrity of the reserve sample. Any evidence of reserve sample deterioration should be investigated in accordance with 21 CFR 211.192, and the results of the examination must be recorded and maintained with other stability data on the drug product.
A company recently received the following observation:
….. Written records are not always made of investigations into unexplained discrepancies.
Specifically, during your review of retain samples of … products from lots … and …, … sample from each lot were found discolored as dark brown in color. According to the specifications listed on the Product Test Results & “C” OF A” sheet, the product passes the “Appearance Test” when it is …. There are no complete investigations conducted to determine the root cause of the discoloration. … has a … shelf-life and approximately … number of lots were released for commercial U.S. distribution over the last 3 years. The finished product is not subjected to any related substances/impurity testing during release and/or during stability testing.
To view more observations pertaining to retain samples, refer to the following GMP Trends® Issues: 1132, 1129, 1122, and 1121.
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