While pharmaceutical validation studies are typically performed at full scale, in most cases scale - down or laboratory – scale models were used to initially develop the manufacturing process.
Consequently, scale - down process pre-characterization and characterization studies are considered crucial to successful process validation for both API and drug product manufacturing schemes.
In engineering terms, characterization studies identify the critical parameters useful for dimensional analysis that enable successful process scale - up.
In fact, scale - up is probably the most difficult manufacturing challenge for traditional small molecules, let alone biopharmaceuticals. Issues such as homogeneous mixing, bulk product holding and technology transfer, and sterile filtration could all be potentially compounded due to the increased scale and introduced stress.
However, a QbD approach to rational drug design should enable simplified process scale - up and validation. This is only true if experimental design approaches have been utilized to identify the design space for the processes involved in the production of the molecule. This is also where the greatest benefit of developing empirical phase diagrams early in development could materialize.
The FDA defines process validation as “establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined quality attributes”.
As per FDA Guideline,
For Tablets/Capsules: Two of the three batches should be of at least 10 percent of the proposed production batch or 100,000 finished dosage units, whichever is greater (i.e., pilot scale batches). The third batch can be smaller than the 10 percent of the proposed production batch, but should not be less than 25 percent of the pilot scale batch.
For Powders/Solutions/Suspensions: Two of the three batches should be at least 10 percent of the proposed maximum size commercial batch. The third batch can be smaller than 10 percent of the proposed commercial batch, but should not be less than 25 percent of the pilot scale batch.
For Solutions/Powders for Solutions (lyophilized cakes)/Suspensions/Sterile Topicals (Ophthalmic and Otic drug products): Two of the three batches should be at least (a) 10 percent of the proposed maximum size commercial batch (i.e., pilot scale size), (b) 50 L (per batch if the fill volume configurations per vial is larger than 2.0 mL), or (c) 30 L (per batch if the fill volume size is up to 2.0 mL) whichever is larger including packaging.
When multiple fill volume sizes are proposed by the applicant (e.g., 1 mL, 2 mL, and 3 mL), then 50 L per batch size is recommended. The third batch can be smaller than 10 percent of the proposed commercial batch, but should not be less than 25 percent of the pilot scale batch (with packaging).
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