Process Hold Times: What is it and Why is it Important?

According to the European Medicines Agency (EMA) and the World Health Organization (WHO), process hold times (PHT) “can be considered as the established time period for which materials (dispensed raw materials, prepared media and buffers, intermediates and bulk dosage form awaiting final packaging) may be held under specified conditions and will remain within the defined specifications” (1,2). Both agencies state that “manufacturing durations of critical steps and hold times should be stated and justified,” so supportive data and confirmatory validation studies can be inferred as being required.

This seems simple, except when you come to a more detailed analysis of what you are really looking for and asking about when it comes to holding times, such as the examples below:

1. Is moving from one step to another within the manufacture of an intermediate also a hold time?
2. What if the intermediate does not have a registered specification?
3. What about total processing time for the manufacture of the final drug substance (DS)?
4. What is the interplay between “in-process holds” (during processing) and “storage holds”?
   1. Between the end of intermediate(s) production and the start of DS manufacture
   2. End of DS manufacture and start of Drug Product (DP) manufacturing
   3. Start of formulation of DP and filling into final container activities (including lyophilization)
   4. End of DP and labelling & packaging
   5. End of packaging and entry into the cold chain (if needed), and initiation of the stability time period

Additionally, there is little guidance relating to when to start validating process hold times. Many companies apply the 24-hour rule on process holds and only validate after 24 hours of process hold. But where does this standard come from? For example, why is 24 hours important in the context of a biological process, and why is it important in terms of chemical stability?

The prevailing thinking is that if companies do not see anything adverse happening in the 24 hours from a quality and yield perspective, then there must be no impact, and the hold is considered just another step in a series of ongoing processing steps. But each time a process step is finished, and the subsequent step does not occur immediately, as indicated previously, a type of variable process hold is occurring for which the individual and cumulative impact is unknown as it was not validated.

There is also a lot of uncertainty concerning what and how to validate. Based on the example below, how should firms design their studies to validate and verify hold times? Firms are faced with options one or two, but there may be some other effects of PHT on the process unit operations hold time.

1. PHTt = PHT1+PHT2+…+PHTn i.e. cumulative or,

2. PHT1, PHT2, …, PHTn i.e. separate validations

Why are process holds considered important by the agencies (i.e. EMA and WHO)? The answer lies in the possibility of product quality degradation concerning either chemical or microbiological impacts. As PDA Technical Report. 60-3 Process Validation: A Lifecycle Approach (3) states, “The biochemical stability of process intermediates needs to be validated...” and that there needs to be "...relevant data for establishing intermediate hold times from the standpoint of chemical stability.” TR No. 60-3 states that for low bioburden DS processing “Hold steps provide a potential source of bioburden risk since growth of any present bacteria or fungi could occur.”

Other factors that can play a role in this risk topic of “degradation” can include storage in single-use systems, where extractable and leachable data needs to be assessed, and the use of solutions and buffers in storage periods, which also need to have their stability documented and assessed.

Conclusion

PHT must be validated for biological and chemical reasons. TR No. 60-3 gives great guidance as to what to look for to match the WHO and EMA regulatory requirements (the “what” but not the “how”). What is lacking is a comprehensive definition of “What is a Hold Time, and what is ongoing processing”? As stated previously, many companies consider the 24-hour hold time an ongoing processing step and do not risk assessing or validating anything.

The authors of this article would be very interested in receiving feedback on the concepts expounded above and assessing whether there is an appetite within the industry for expanded guidance requested from PDA in the form of a new Points to Consider document (or similar). Click here for the survey.

References

1. Supplementary guidelines on GMP: General guidance on hold-time studies. In: WHO Expert, Committee on Specifications for Pharmaceutical Preparations: forty-ninth report. Geneva: World Health Organization; October 2015: Annex 4 (WHO Technical Report Series, No. 992)
2. EMA/CHMP/QWP/245074/2015: Committee for Human Medicinal Products (CHMP) - Guideline on manufacture of the finished dosage form July 2017
3. PDA Technical Report No. 60-3 – Process Validation: A Lifecycle Approach; – Annex 2: Biopharmaceutical Drug Substances Manufacturing – March 2021; https://www.pda.org/bookstore/product-detail/6044-tr-60-3-process-validation-annex-2