Storage Time of Oral Solid Preparations

FDA declaration 3.2.P.3.4 includes three contents.

1. Acceptance criteria and test results of registered batches;

2. Comparison table of equipment and control standards used in registered batches and commercial batches;

3. Intermediate storage information.
   The contents of the first and second items may be familiar to everyone. Therefore, this article mainly introduces the third item, the key point of intermediate storage information, in combination with WHO and GMP.

Why do we need to check the storage time?

GMP requires that the used raw materials, intermediate powders or granules, finished products to be packaged and final finished products are stored under appropriate storage conditions. Therefore, the selected storage conditions should ensure that the raw materials, intermediates or samples to be packaged are stored properly. Safety (such as related substances, microorganisms), expiration date (such as content), and at the same time, it is necessary to ensure that these non-final products can proceed smoothly and stably in the follow-up production process, and will not affect the follow-up production process (here refers to the verified , The established production process). Therefore, if it is a non-continuous production sample, during the transition period after production and before the next step of production, it should be ensured that the maximum storage time is effective and will not produce any side effects that affect the quality and process. The determination of this time requires data to support, so that our samples stored in this time will not affect the entire production cycle.

When will the storage time survey be established?

The investigation and study of the storage period (or time) should be determined before the product goes on the market. Its research process can be carried out in the pilot scale or scale-up process in the research and development process, and verified and confirmed in the commercial-scale process verification, and it can also consider collecting more information from the deviation investigation in the production process. In addition, the risk assessment involving changes in processes, equipment, storage conditions, starting materials and packaging materials should also include whether the storage cycle needs to be studied.

We can borrow a complete process flow chart to review and review the entire production process, and then divide the key processes of the production process according to whether special storage and processing time are required, and whether there is a potential impact on the environment and storage conditions. Generally speaking, materials will stop during the production cycle. Next, taking common oral solid tablets as an example, the production process of oral tablets includes ingredients, (raw materials) sieving, pre-mixing, granulation, drying, After the lubricant is added, the total mixing, tableting, coating, to the final packaging of the finished product. For the production of this coated tablet, the yellow part in Figure 2 can be considered for storage cycle inspection. The inspection items are as follows:

Adhesives used for granulation: the test items that can be considered include microorganisms, appearance, and viscosity;

Dry particles after drying: The test items that can be considered include properties, content, related substances, LOD, moisture content, PSD, bulk density, tap density, angle of repose;

Mixed particles after adding lubricant: The test items that can be considered include microbial testing, LOD, BU, PSD, bulk density, and tap density;

Plain tablets after tableting: the test items that can be considered include properties, hardness, tablet thickness, friability, disintegration time limit, dissolution/dissolution curve, content, related substances, dose uniformity, and microorganisms;

Coating liquid or coating suspension used for coating: The test items that can be considered include physical properties, specific gravity, viscosity, sediment, pH, and microorganisms;

Coated tablets after coating (unpackaged): The test items that can be considered include properties, hardness, tablet thickness, friability, disintegration time limit, dissolution/dissolution curve, content, related substances, moisture content, and microorganisms;

Other points to note about storage time

Generally speaking, one batch or multiple batches of raw materials, intermediates, and samples to be packaged can be used to determine their storage time. The environmental conditions of the sample storage should be the same as the conditions of the temporary storage area or production process. The packaging materials used in the storage time inspection should be the same as the packaging used in actual production. For example, the plain sheet should be placed in a double-layer polyethylene bag before the next step. The research is carried out in a vinyl bag, not in a bottle or other container.

The research on the storage time should be based on the research and development of the materials in the original or simulated containers used in the production, and then establish and follow a sampling plan to sample and test at different time intervals. The data measured at the time of inspection of the sample should be compared with the initial data (0-day data), and the acceptable storage period of the sample should be predicted through the analysis of the final result.

The content described in this article is mainly for the design strategy of non-sterile solid preparations, and some of the principles can also be applied to other dosage forms (such as liquid preparations, emulsions, ointments, etc.). In addition, the storage cycle inspection content described in this article does not apply to the storage cycle inspection issues in the cleaning verification (such as the storage cycle inspection of cleaned equipment), nor does it apply to the storage cycle inspection in the production process of APIs and biological agents.

In addition, the hold-time investigation described in this article is only a guiding role, not a specific process. And the final choice of the longest storage time should be supported by corresponding data, rather than relying on other experience.