Product file stability

For products that are prepared extemporaneously at a regular basis or even for a limited stock, a product specific documentation (product file) is needed. This will include specifications, instructions, and records but also a pharmaceutical assessment of safety data, toxicity, biopharmaceutical aspects, stability, and product design. The product file should also include a product review as soon as a product is used repeatedly or over longer periods. 

Part II relates to the quality of the product and gives details of its chemical, pharmaceutical and biological testing. Data should be provided in respect of qualitative and quantitative particulars of the constituents, description of the method of preparation, control of starting materials, control tests on intermediate products, control tests on the finished product and stability tests. In cases where the active ingredient is made by a manufacturer other than the applicant or the product manufacturer, some of the information required in Part II may be presented in a separate file, the Drug Master File, to maintain the confidential nature of the synthetic process. 

For a standardised preparation the product file may be quite extensive. There is need for a more elaborate evaluation of the topics discussed above, and the product file should also include information on the validation of the preparation and on the stability and shelf life of the preparation. The product file of pharmacy preparations that are distributed on a relatively large scale should be the most extensive. The various topics of the product file in its most extensive form will be discussed in detail in the following subsections. At the end of each section an example of 12.5 mg diclofenac suppositories is used, assuming that diclofenac is not available in this strength as licensed medicine. 

This section of the product file should give information about the stability of the product and the choices that have led to its shelf life and the storage conditions. In most cases a shelf life for the unopened package is defined, as well as for the container after opening. Also the storage temperature is specified, and if applicable special conditions, for example protect from light or in a well closed container . 

For infrequently prepared products the analysis of some expired batches may also provide usefiil support for the shelf-hfe of a preparation. A more detailed product file should include data from a thorough stability study. Stability testing should ideally be performed prospectively, but it can also be performed concurrently by following the first batches produced, this can be particularly useful if accelerated storage at an elevated temperature is included in the study. The product shelf life can be increased during the study as more data becomes available. The design of a stability study is described in Sect. 22.5. 

For products described in a pharmacopoeia, the official specifications can and should be used for the product file, with referral to the official source. The same applies to preparations from standard formulatimis, in which quality requirements are included. For in-house formulations, the quality requirements have to be set by an appropriately competent person internally. Useful information can be found in the formulatimi or validatimi studies. The results of stability studies may be useful when setting the quality requirements for the product, because the premise is that a preparation should comply to the quality requirements throughout the whole shelf life. An overview of the applicable quality requirements, including supporting information, has to be included in the product file. In addition it should be specified how the packaging and labelling are checked, and how and with what analytical method the product quality is controlled. Additionally the validation of the analytical methods is included in this section of the product file. 

Finally, the registration stability batches were manufactured within a 6-month time period of transfer initiation. During the entire transfer process the marketed product had to have uninterrupted commercial supply, with minimal impact on the regulatory file (Anon, 2012). The product was subsequently manufactured at the production facility for a further 6-years, with good operating metrics (>95% on-time-in-full metrics). 

General information Product, including description (e.g., tablet, dose) method name, including revision and technique (e.g., HPLC) project information concerning sample(s) (e.g., stability samples three months) date of test and lot number equipment identifier column raw data file name of computerized system and analyst. This general information will be transferred to each spreadsheet. 

The polymers described above have been chemically pure, although physically helerodisperse. It is oflen possible lo combine two or more of these monomers in the same molecule to form a copolymer. This process produces still further modification of molecular properties and, in turn, modification of the physical properties of file product. Many commercial polymers are copolymers because of the blending of properties achieved in this way. For example, one of the important new polymers of the past ten years has been the family of copolymers of acrylonitrile, butadiene and styrene, commonly called ABS resins. The production of these materials has grown rapidly in a short period of time because of their combination of dimensional stability and high impact resistance. These properties are related to the impact resistance of acrylonitrile-butadiene rubber and the dimensional stability of polystyrene, which are joined in the same molecule. 

Additional stability studies may also be undertaken if there is an increase in the number of complaints for a product or if there is a change in the grade and/or supplier of a raw material, manufacturing process, and/or equipment, even if stability is not required for a regulatory filing. 

Stability Protocol A postapproval stability protocol should be submitted documenting future plans. It should include information on time points and storage conditions to be evaluated, and indicate whether extensions of expiration dating are intended based on sponsor evaluation of data obtained following the protocol. These data will still have to be submitted, as well as the details of the extensions of expiration dating being implemented, in the annual reports filed with FDA. Also indicate how many batches of drug product will be placed on stability in a year. 

Typically, a stressed sample of about 10 to 20% degradation is used to demonstrate file resolution among degradation products. A 10 to 20% degraded sample is used because it has a sufficiently high concentration level of critical related substance. Therefore, fiiese related substances can be detected easily. In addition, 10 to 20% degradation is not too excessive, and file related substance profile should be close to that of a typical stability sample. 

---