Manufacturing Process of the Drug Substance

Specific submission and stability issues will be addressed in detail in a separate forthcoming guidance dealing with postapproval changes for drug substances. 

For a move of the manufacturing site within an existing facility or a move to a new facility on the same campus using similar equipment and manufacturing processes, submission of stability data on the drug product in the new facility before implementation is generally not necessary. 

Change in Packaging Site for Solid Oral Dosage-Form Drug Products 

A packaging site change for other than solid oral dosage-form drug products is considered a manufacturing site change, and the data package that should be submitted for approval is indicated in Section IX.C.2. 

An analytical testing laboratory site change may be submitted as a Changes Being Effected Supplement under certain circumstances. No stability data are required. 

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Contaminants 2 Any adventitiously introduced materials (e.g., chemical, biochemical, or microbial species) not intended to be part of the manufacturing process of the drug substance or drug product.2... 

For a continuous SMB process, the specific identified amount or batch produced is defined by unit of time in such a way that ensures a homogeneous material and quality within specified limits. In the case of a continuous SMB production run a batch is defined by the amount produced in a fixed time interval. A time limitation during manufacturing using SMB is established by the same fixed time interval as the batch. The duration of the production phase is thus established, which does not affect the quality of the drug substance [66]. 

Manufacturing process The descriptions of the manufacturing steps for the drug substance and product should include process flow diagrams and discussions of critical scale-up steps and process development history and process validation activities, together with assessment of the equivalence or differences in batches used for various studies. 

As the stability data can be affected by many factors like formulation, manufacturing, storage conditions, in-process and GMP controls, analytical methods, and process validation, the biggest challenge is to figure out the source of the variability in the stability results. At least three batches of the drug substance or product are required to establish the acceptance criteria for future production batches as a measurement... 

By understanding the manufacturing process and the stability of the drug substance, whether from synthetic, natural, or recombinant sources, the chemist is able to identify, control, and measure the impurities, and so the quahty of the drug substance and reproducibility from production batch to batch are maintained. 

The physical characteristics, particularly the particle size of the drug substance, are very important for suspensions. As with topical products in which the drug is suspended, particles are usually very fine to micronized (to <25 microns). For syrup, elixir, or solution dosage forms in which there is nothing suspended, particle size and physical characteristics of raw materials are not that important. However, they can affect the rate of dissolution of such raw materials in the manufacturing process. Raw materials of a finer particle size may dissolve faster than those of a larger particle size when the product is compounded. 

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