Extended in process hold times for drug product intermediates could have an overall impact on the commercial ‘shelf-life’ (not expiry date) of your product.

Establishing Date of Manufacture

According to FDA, a 30-day period from the Date of Manufacture to the completion of the packing into the commercial image, e.g. bottles, blister, vials, syringes, etc. does not require additional justification. Any in-process ‘hold times’ which extend this 30-day manufacturing interval must be suitably justified with appropriate data. Companies should have a SOP which defines how hold times are defined and justified for various unit operations as part of their overall Quality System.

The Date of Manufacture for a given batch of drug product is the date on which processing is initiated; for example, when the Active Pharmaceutical Ingredient (API) is mixed with, or added to the other materials. It is not generally acceptable to claim a Date of Manufacture as the date the last processing operation is completed.

For a typical tablet product, processing may include weighing, dry blending, wet granulation, drying, screening (milling), blending, tableting, coating and packing into, for example, bottles and blisters.

Expectation of Continuation

The expectation is that the process operations are a continuum, one occurring one after the other without extended delays (hold times) between each of the unit operations.  So, from start of weighing to completion of tablet coating, one could nominally expect that these unit operations for a batch-type process could be completed within about 5-10 days for a given batch (maximum 30 days as previously discussed). This is how most pharma manufacturing operations work.  Many companies perform ‘hold time’ studies on the bulk finished tablets usually for 1-3 and sometimes, up to 6 months, to allow for any delays of packing into the commercial presentations, e.g. bottles and/or blisters.

Stability Studies on Commercial Packaged Product define the Commercial Drug Product Expiration Date. Ideally, such studies are initiated within 1-2 months after packaging as not all drug substance have ‘rock-like’ stability and the intent is to maximize expiration dating.

A commercial drug product expiration date for a given drug product batch is assigned from its date of manufacture. The Date of manufacture is generally defined by a Month/Year and with a similar format for an drug product Expiration Date (Month/Year). So, for example, if a batch of drug product initiated manufacture in November 2017 and there is an assigned drug product expiry date of 2 years, the expiry date for this batch should be October 2019. An SOP as part of a company’s Quality System should define how expiration dates are defined, formatted and assigned to drug product batches.

So, with a Drug Product having a commercial expiry date of 2 years (which start the Date of Manufacture e.g. weighing, or best case, with justification, combining of the API with excipients (a couple days difference is inconsequential), it is or should be desirous to minimize the time from start of manufacture to the date of commercial packing. The longer the intermediate hold times for each unit operation, the less time a given batch has to be available for sale for a given approved expiry date.

Example Manufacturing Timeline

An example manufacturing timeline for a tablet product, where hold time studies might occur are as follows:

Day 1 – Weighing of excipients, drug substance – nominal usage within 24-48 hours should not require any hold time studies unless significant issues with temperature, moisture, or light once materials are removed from original packaging and put into other containers for processing.

Day 1/ 2 – Preparation of Granulation Solution, Dry Blend, Wet Granulation, Drying – Potential Hold Time for granulating solution if not used within 12-24 hours – mostly a pmicrobiological concern, Potential Hold Time for wetted granulation if not immediately dried – potential for micro issues and wet massed particle size to change

Day 3 – Dried granulation Milling, Final Blending – Potential Hold Time study for dried granulation and final blend – Dried granulation – potential for change in assay, moisture content, or other physical or chemical properties. If final blend is held for an extended period time before tableting, the main concerns would be for segregation, and moisture pick-up.

Day 4 – Tableting – Potential Hold Time for uncoated tablets after compression and before coating – Possible change in assay, physical characteristics – dissolution, hardness, etc.

Day 5/6 – Coating Solution Preparation and Coating – Potential Hold Time for coating solution if held more than 12-24 hours – Potential micro concerns, Coated tablets before packaging – Change in assay, physical characteristics – dissolution, etc.

Day ? – Packing into commercial image bottles, blisters, etc. includes stamping of Lot Number and Expiration Date onto label

Drug Product Date of Manufacture, In-Process Hold Times and Drug Product Expiry Date, should be discussed, explained/defined and justified as part of the NDA/MAA documentation. it is important that there is a clear understanding of these terms, their meanings and their implications for each drug individual product.