Holdtime can be considered as the established time period for which materials (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging) may be held under specified conditions and will remain within the defined specifications.
- What tools do pharmaceutical companies have to establish hold times?
- What are the GMP requirements?
- What do the GMPregulations say about hold times?
21 CFR 211.111 Time Limitations on Production states:
When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable, if such deviation does not compromise the quality of the drug product.
Such derivation shall be justified and documented.
The FDA expectations were further described in a 2004 guidance document.
FDA’s Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice states:
When appropriate, time limits must be established for each phase of aseptic processing (§ 211.111). Time limits should include, for example, the period between the start of bulk product compounding and its sterilization, filtration processes, product exposure while on the processing line, and storage of sterilized equipment, containers and closures. The time limits established for the various production phases should be supported by data.
The 2004 guidance further states:
- The total time for product filtration should be limited to an established maximum to prevent microorganisms from penetrating the filter.
- Such a time limit should also prevent a significant increase in upstream bioburden and endotoxin load. Because they can provide a substrate for microbial attachment, maximum use times for those filters used upstream for solution clarification or particle removal should also be established and justifier.
Examples of Manufacturing Processes with Time Limitations
- Drug product manufacturing, i.e., compressed tablet manufacturing
- Downstream processing during biopharmaceutical product manufacturing
- Generic sterile injectable product manufacturing
The first step to take would be conducting a general risk assessment of the inherent stability of the product intermediate.
Next, the data generated during process development and validation would be evaluated.
Conducting a range study may help do this. With a multivalent process, using a statistical tool like Design of Experiments may be useful.
A hold time study protocol should contain all the appropriate study parameters for the material in question, the acceptance criteria for the analysis, the type of storage container, the volume of sample, the storage conditions, the frequency of sampling, the method of analysis and other required information.
- Hold Time Study Guidelines for Pharmaceutical Industry
- Bracketing and Worst Case Rating in Cleaning Validation
Resource Person: BARBARA PIROLA