The World Health Organization (WHO) has released guideline for the design of hold-time studies as part of the final version of Technical Report Series 992 (TRS 992, Annex 4). The guidance covers liquids, creams, ointments and non-sterile dosage forms. It does not cover aspects for hold times in cleaning validation, or the manufacturing of active pharmaceutical ingredients (APIs) or biologicals. The guideline is a good tool when determining where to specify a hold time study.
For example, for oral tablets that are coated, the following stages may be considered:
- binder preparation to granulation – consider the granulate;
- wet granulation to drying – consider the dried granulate;
- dried granules to lubrication/blending – consider the lubricated blend;
- blend to compression;
- compression to coating – consider the tablet cores;
- coating solution to preparation – consider the coating solution;
- coating to packing – consider the bulk coated tablets;
- coating to packing in bulk;
- packing of bulk to finished packed dosage form.
The guideline recommends that a risk-based approach be used to determine the appropriate number of batches to study. Head space considerations when oxidation can cause degradation must be studied from a worst case perspective. Both physical and microbiological (where appropriate) characteristics should be considered.
Download the guideline here.