In a recent FDA inspection, investigators noted that a firm failed to conduct hold time studies for bulk drug substances transferred between manufacturing sites. This observation poses extreme risk to product quality with potentially far-reaching implications.
“Your firm does not conduct hold time studies for bulk […]. Your firm manufactures bulk […] at one location and transfers it to another location for further processing into […] finished product. There is a gap of […] days between the production of the bulk […] and the production of the finished […] product.”
Over a five-year period, the firm released multiple batches without scientific justification for the length of time the intermediate product was held before final processing.
Hold time studies determine the maximum allowable time a product or intermediate can be stored before it must be used or further processed, without compromising its identity, strength, quality, or purity. In the absence of such data, firms are essentially guessing that product quality remains stable, which directly violates 21 CFR 211.111, requiring time limits to be established for each production phase “to assure the quality of the drug product.”
Without validated hold times, microbial growth may go unchecked in aqueous solutions or other sensitive materials. In addition, chemical degradation may affect potency, rendering the API or final product ineffective or unsafe. Batch-to-batch variability may increase without established hold times, making root cause analysis harder in the event of complaints or failures.
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