Several years ago, I wrote about the relationships among date of manufacture, in-process hold times and drug product expiration date. Since then, there have been some developments that are worth revisiting.
The corresponding guidelines of EMA (The European Medicines Agency), FDA (United States’ Food and Drug Administration), PMDA (Japanese Pharmaceuticals and Medical Devices Agency) and ICH (International Committee on Harmonization) enable the production of high-quality pharmaceuticals, which fulfil the safety needs of patients. However, the assignment of the manufacturing, expiration and retest dates for drug substances and drug products are frequently encountered areas in the pharmaceutical industry which continues to lack sufficient guidance.
Drug Substance Retest Date
The drug substance retest date is when a material should be re-examined to ensure that it is still suitable for use. The drug substance retest period is the time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be retested for compliance with its specification and then immediately used.
The ICH guideline Q1E “Evaluation for Stability Data” provides recommendations on how to use stability data generated in accordance with the principles described in the ICH guideline Q1A(R2) “Stability Testing of New Drug Substances and Products” to determine a drug substance retest date.
The EMA’s questions and answers paper addresses the extension of the retest period of a drug substance with respect to ICH Q7 Section 11.6. The retest date of a specific batch can be extended based on good science and suitable long-term stability data. The retest date is assigned based on the manufacturing date and the retest period. However, it is unclear on how to assign a date of manufacture. In Section 19.8, the expiration and retest dating as defined in Section 11.6 applies to existing (commercially available) drug substances used in clinical trials. Drug substances in the early stage of clinical trials are not required to have an expiration date nor a retest period.
As mentioned in ICH Q7A “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients,” a drug substance expiration 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 (Section 11.6). If the drug substance has an assigned expiration date, the drug substance’s manufacturers expiration date cannot be extended by means of retesting.
If the drug substance is labeled with a retest date, the drug substance can be re-tested, and if retest results are in compliance with the material specification for critical attributes, such as chemical and microbiological content and purity, the batch may be immediately used. Test results must be obtained with pharmacopeial procedures or stability indicating methods, using primary reference standard. Since immediate use is not defined by the FDA, common practice in the industry is to use within thirty (30) days of the retest date. A batch of drug substance can be retested multiple times and a different portion of the batch used after each retest, as long as it continues to comply with the specification.
Under current rule, a new date for retesting beyond thirty (30) days of immediate use should be based on current retest results and supporting real time and/or accelerated stability data. Successive retest periods may not be longer than the original retest period assigned by the manufacturer of the drug substance. The re-test date must relate to the defined storage conditions specified in the label.
The retest date or the expiration date should be listed either on the container or on the Certificate of Analysis (CoA). In general, a retest or expiration date should be specified by month and year. The retest or expiration date of a blended batch of drug substance should be based on the oldest batch in the blend. For biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf-life than a retest period. The same may be true for some antibiotics.
Drug Substance Manufacture Date
Assigning a drug substance date of manufacture is not very clear. Some claim that the formation of the chemical core structure of a drug substance defines the manufacturing date. Others state that the date of the final packaging or the issuance of the CoA should be considered as manufacturing date of the drug substance.
When a drug substance is in pure form, it usually has an established chemical structure, and good chemist can, from the weakest chemical bond of the structure which would get attacked first by external energy like temperature/ heat or light or hydrolytic degradation, predict the stability of the compound. It is important to justify the manufacturing date taking into consideration the underlying chemical nature of the drug substance.
It is generally advisable to assign the manufacturing date of a drug substance to the last crystallization step performed and before any physical treatment. At this stage all physiochemical properties are settled and additionally to other parameters, the stability of the pure drug substance is established and controlled.
If the compound with the chemical structure responsible for the pharmacological activity is not immediately used in drug product manufacture and additional preparatory steps are performed, it should not be considered as drug substance.
Mixing of drug substance with an excipient or other material to aid further processing or enhance stability, i.e., physically treating the drug substance, and then holding it for a period of time before further manipulation, can be potentially considered as a starting point of drug product manufacture.
Drug Product Expiration Date
A pharmaceutical drug formulation is a different from pure drug and when there are more than a drug present in a mixture, it may increase the chances of degradations.
According to the FDA, and as explained in the stability guidelines, the expiration date assigned to a new batch of finished drug should be calculated from not later than the date of release of the batch provided that the date of release does not exceed approximately thirty (30) days from the start of manufacturing. This is understood to mean from the initial date a drug substance, preservative, or anti-oxidant ingredient is added to the batch. If more than thirty (30) days have elapsed between the date of manufacture and date of release of the batch, the expiration date should be calculated from within thirty (30) days of the date of manufacture of the batch, and not the date of release. The EMA note to the guidance on the manufacture of finished dosage forms provides essentially this same recommendation.
The maximum expiration date for drug product should not exceed five (5) years. When more than one (1) lot of drug product with different manufacture dates are packaged together, the expiration date of the complete package must not exceed that of the product batch with the shortest remaining expiration period in the package.
Extension of already manufactured and packaged drug product may be based on the following criteria which includes continuous, controlled real-time stability program that demonstrates the product to be stable to support the extended expiration dating, concurrent testing of the drug product shows little change from the original test data and is within the defined product specifications, and the desired extension is covered within the approved regulatory documentation. Expiration date assignments should be documented and maintained as part of batch or lot record.
Drug Product Manufacture Date
From an understanding of how the drug product expiration date may be determined, it then becomes clear how a date of manufacture of a drug product should be determined. The Date of Manufacture for a given batch of drug product is the date on which processing is initiated; for example, when the drug substance is mixed with or added to other materials.
A potential confounding issue is when a drug substance with known chemical, physical or biological concerns is manipulated with materials to enhance any of these characteristics before further formulation into a suitable dosage form. In these situations, data to demonstrate the stability of such an intermediate mixture is needed to demonstrate suitability for subsequent formulation into the final dosage form should this intermediate mixture be held for any length of time before final processing.
It such an instance, it may be able to justify a date of manufacture, not when the drug substance is first manipulated, but when it is combined with the materials required to produce the finished dosage form.
The dating for a combination of two or more products must be no longer than the dating of the component with the earlier manufacturing date.
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The date of manufacture for biological products, other than whole blood and blood components, must be identified in the approved biologics license application. The date should be based on the following considerations such as the potency test or another specific test as described in a biologics license application or supplement to the application, removal from animals or humans, extraction, solution, cessation of growth, final sterile filtration of a bulk solution, manufacture as described in 21CFR Part 610.50, or other specific manufacturing activity as described in a biologics license application or supplement to the biologics license application.
For licensed whole blood and blood components, the date of manufacture must be identified in the approved biologics license application or supplement to the application. The date of manufacture for whole blood and blood components should take into account the following considerations, as applicable, which are the collection date and/or time, irradiation date, the time the red blood cell product was removed from frozen storage for deglycerolization, the time the additive or rejuvenation solution was added, the time the product was entered for washing or removing plasma (if prepared in an open system), as specified in the instructions for use by the blood collection, processing, and storage system approved or cleared for such use by FDA; or as approved by the Director, Center for Biologics Evaluation and Research, in a biologics license application or supplement to the application.
References
Timko, R. J., “The Relationship among the Date of Manufacture, In-process Hold Times and Drug Product Expiration Date,” September 28 2017, https://www.RhoTauPharma.com, accessed May 10 2021
Huynh-Ba, K (Ed.). “Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies, and Best Practices,” Springer-Verlag New York, 2009
United States Code of Federal Regulations, Title 21 Sections 211.137, Expiration Dating, 211.166, Stability Testing 610.50 Date of Manufacture for Biological Products
Food and Drug Administration Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, February 1987
International Council on Harmonization Guideline Q1A(R2). Stability Testing of New Drug Substances and Products, November 2003.
International Council on Harmonization Guideline Q1E. Evaluation for Stability Data, February 2003.
International Council on Harmonization Guideline Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients – Questions and Answers, April 2018
International Council on Harmonization Guideline Q7A, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. August 2000.
Note for Guidance on Start of Shelf-life of the Finished Dosage Form, CPMP/QWP/07296, EMEA/CVMP/453/01, London, 31May2001