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WHO publishes revised draft on the Guideline on  - 10 Apr 2014

The definition of hold times for intermediates and bulk products is a key GMP requirement in pharmaceutical manufacturing.  Although the scope of this document is the manufacture of solid dosage forms the principles applies also to liquids and semi-solid dosage forms.  Manufacturing of active pharmaceutical ingredients is not in scope, and neither have manufacture of sterile dosage forms mentioned.  The objective of the paper is to ensure understanding of the aspects that have to be taken into consideration when designing hold time studies.  The primary focus is on intermediates and bulk products; however the document also references raw materials and packaging materials.

Hold-time studies establish the time limits of holding the materials at different stages of production by assuring that the quality of the product does not deteriorate during the hold time.  Data to justify the hold times can be systematically collected during development, on pilot scale or validation batches.  It may also be gained from knowledge following an investigation of a deviation.  In addition, data from one batch may be sufficient for this.  Alternatively, a risk-based approach is used to determine the appropriate number of batches to be tested.

Hold times should normally be determined prior to marketing of a product. However, for products already marketed there is the possibility of retrospective risk-based, hold-time determination.  For carrying out the study, the material to be tested should be kept in either the original or simulated container used in production. If the headspace plays a role the material to be tested should be stored with the maximum possible headspace. The data received should be evaluated by statistical means in order to recognise trends and to be able to establish limits.

The draft guideline also contains a list of examples with permissible maximum hold times for the different stages of tablet production that do not necessitate hold time studies (such as 2 – 30 day for the granulate).  However, this appears to contradict the preceding pages which require investigational studies for the determination of hold times.  There is also a new paragraph providing information on cumulative hold times.  Generally, a cumulative hold time of 90 days is acceptable without the need for further data. In the case where cumulative hold times individually add to >90 days, but there is an additional provision that time from dispensing of the ingredients to the final top coating will not exceed 30 days, further justification of the cumulative hold time is considered unnecessary.

The draft guideline can be found here.


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