Expiration or Retest Dating

To ensure safe and effective finished drug products, the excipients must be stable. Some excipients may be stable and may not require extensive testing, while others may be less stable and require more scrutiny. A retesting or expiration date should be identified on the container label and the COA of the raw material at the time of use. Expiration or retest dates should relate to any storage conditions stated on the label and should be supported by appropriate stability studies. 

Each batch of excipients is identified by the receiving code bar as specified in 21 CFR Part 211.80. The code bar will be used in recording the disposition of each lot. Each lot is indentified as to its status (i.e., quarantined, approved or rejected) and the date of receipt. As stated in CFR211.180, all components, production, control and distribution records that are associated with any drug product will be retained for at least one year after the expiration date of the drug product and should be available for any authorized inspection. 

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The expiration or retest date assigned to the blended API batch should be based on the manufacturing date of the oldest batch in the blend. 

An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date. 

Labeling requirements in 58.105(c) are not controversial and are the minimum to ensure against mix-up of test or control articles. The Expiration date needs to be included on the label only if one has been established. Some laboratories include a retest date on the label as a reminder of the need for periodic stability analyses. Only special storage conditions (e.g., refrigerate, protect from light, protect from freezing ) need to be included on the label. 

The stability protocol should include methodology for each parameter assessed during the stability evaluation of the drug substance and the drug product. The protocol should also address analyses and approaches for the evaluation of results and the determination of the expiration dating period, or retest period. The stability-indicating methodology should be validated by the manufacturer and described in sufficient detail to permit validation or verification by FDA laboratories. 

A stability protocol should describe not only how the stability study is to be designed and carried out but also the statistical method to be used in analyzing the data. This section describes an acceptable statistical approach to the analysis of stability data and the specific features of the stability study that are pertinent to the analysis. In general, an expiration dating or retest period should be determined on the basis of statistical analysis of observed long-term data. Limited extrapolation of the real-time data beyond the observed range to extend the expiration dating or retest period at approval time may be considered if it is supported by the statistical analysis of real-time data, satisfactory accelerated data, and other nonprimary stability data. 

Appropriately identified reserve samples representative of each lot of API should be retained for one year after the expiration date of the lot, or, for AP Is having retest dates, three years after the batch is distributed. 

Records should be maintained for all raw materials and API containers for at least one year after the expiration date of the batch. For APIs with retest dates, these records should be retained for at least three years after the API batch is completely distributed to either internal or external recipients. 

A written record of each complaint should be maintained in a file designated for APIs. The file should be kept at the establishment where the API was manufactured, processed, or packed or at another facility if the written records in such files are readily available for inspection at that other facility. Complaint records should be maintained for at least one year after the expiration date of the API, or one year after the date the complaint was received, whichever is longer. For APIs with retest dates, such written records should be maintained for at least three years after the batch is distributed. The written record should include the name of the API, batch or lot number, name and address of the complainant, nature of complaint, and reply to the complainant... 

DOT and TC state that results of required periodic inspections of a cylinder must be recorded, and a copy kept by the owner or the owner s authorized agent either until the expiration of the retest period or until the cylinder is again reinspected or retested, whichever occurs first [1, 2]. Also, a cylinder that passes the re-qualification procedure must have the date permanently stamped on the cylinder in the prescribed manner. Note An E is to follow the date (month and year) when requalification by the visual external inspection method is allowed in lieu of hydrostatic retesting. 

A reference standard must have documentation to support its use as a standard, establish its assigned assay, and defend the retest date (or expire date for chemical standards). 

Analytical reagents used in testing the excipients should be prepared and labeled following established procedures. Retest or expiration dates should be used, as appropriate, for analytical reagents, or standard solutions. Analytical methods should be validated unless the method employed is set forth in the current revision of the United States Pharmacopeia/National Formulary, Association of Official Analytical Chemists (AOAC), Book of Methods, or other recognized standard references, or detailed in the Drug Master File or approved New Drug Application and are used unmodified. 

Application of stability results Labeling of storage conditions Retest or expiration dating period Shipping and warehousing conditions Preparation, review, approval, and revision Stability coordinator, laboratory head, QA, and others as appropriate... 

The FDA Draft Stability Guidance defines an approved stability protocol as a detailed plan described in an approved application that is used to generate and analyze stability data to support the retest period for a drug substance or the expiration dating period for a drug product. 

Approved stability protocols are important for the sponsor because they may be used in developing data to support an extension of an approved retest or expiration dating period via annual reports in accordance with 21CFR314.70(d)(5). To change an approved stability protocol or to define one in an application requires a prior approval supplement. 

Retest or expiration dating period (proposed or approved)... 

Although one site-specific batch may be sufficient under certain situations, the data so generated, particularly if limited to accelerated studies, may not be amenable to statistical analysis for the establishment of a retest period or expiration dating period. Instead, the single site-specific batch may serve only to verify the stability profile of a drug substance or product that has been established based on primary stability batches at a pilot plant. 

Analytical reagents should be prepared and labeled following established procedures. Retest or expiration dates should be used, as appropriate, for analytical reagents, or standard solutions. 

A formal testing program should be established to assess the stability characteristics of APIs. The results of such testing should be used to determine appropriate storage conditions and retest or expiration dates. The testing program should be ongoing and include ... 

An adequate number of batches of each API should be tested at suitable intervals to determine an appropriate retest or expiration date. This generally includes samples from the first three commercial size batches, but fewer batches may be appropriate in the initial testing program if data from previous studies or from literature show that the API is stable for at least two years. For those biotechnological/biologic and other APIs having shelf-lives of one-year or less, stability samples should be obtained and tested monthly for the first three months, and at three-month intervals thereafter. 

A stability report is written to document the retest period, shelf life or expiration dates, and a storage statement for the registration batches for the formal stability studies. It is also used to document the shelf life for formulations that are being used in the clinic. In this case, the expiration date is generally a date when the product usage should be discontinued or that additional data are required to extend the retest period. A more detailed discussion of the information included in the stability report is given in Section lI.E. 

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