No manufacturing firm can design a process where they don’t need to hold the various dispensed, in-process, bulk and finished products for few hours to many months. The duration for which the various materials can be hold under specific environmental conditions shall be established by the manufacturer as it directly impacts the product quality.

It’s an obvious fact that the temperature, humidity, light etc. have an impact on materials physical and chemical attributes. Hence, a pharmaceutical manufacturer shall ensure that the dispensed raw materials and packaging materials, intermediate products, bulk and finished products are stored under appropriate storage conditions, so that, it does not have deleterious effects on the subsequent processing, stability, safety, efficacy or quality of starting materials, intermediate products and bulk products prior to final packing.

It is therefore expected that a manufacturer shall establish maximum acceptable holding periods to ensure that intermediates and bulk product can be held for a certain duration before the next processing step, without producing results outside the acceptance criteria for the quality of the material.

Hold time may be defined as an established time period for which materials may be held under specified conditions and will remain within the defined specifications for the said period.

Hold time studies shall be conducted during development stage of a product and finalized during the process validation of commercial batches. Hold time may vary due to change in storage conditions, processes, equipment, starting or packaging materials etc. Hence, the additional studies may also be conducted depending upon the risk assessment of the change. Even market complaints, deviations, out of specification, investigations etc. may also lead to generation of additional data.

Manufacturers shall review the manufacturing procedure and shall break the process into various critical steps. The critical steps may be identified on the basis of the time period required for the particular storage and processing stages, typical pauses in the manufacturing campaign, and the potential impact of storage with reference to environmental and storage conditions. Wherever required the manufacturer may use a flow chart.

To understand it better, the example as provided in WHO TRS 992 is reproduced below:

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.

Hold time studies

 

The establishment of hold time shall be done as per protocol-based study and enough data shall be generated to support the established hold time. The protocol shall include all the steps, where the material may be required to store during various stages of production. Expected holding time shall be considered while designing the protocol.

The study protocol shall include the activities to be performed, test parameters and acceptance criteria appropriate to the material or product under test. The test protocol and subsequent report shall clearly mention the sampling stage, sampling procedure, tests to be performed, acceptance criteria, sampling frequency, sampling locations, storage conditions, methods of analysis; results; conclusion; recommendations etc. It should be noted that the studies may extend beyond the chosen maximum but it is not necessary to extend testing to determine the extreme limits at which failure occurs.

Acceptance criteria are typically more stringent than registered specifications, to provide assurance that the material is well within control. When setting the specifications, any known stability trends will need to be taken into account. Wherever required, microbiological aspects should also be considered and included. All testing of bulk intermediates and product should be performed using validated stability‑indicating methods.

A manufacturer must adopt a risk‑based approach, considering the characteristics of the materials and other relevant aspects to determine the appropriate number of batches to be used for carrying out hold time study. A representative sample of the batch of material or product for which hold time is to be established, shall be kept in either the original or simulated container used in production. The sample shall be kept for the intended hold period. In case, the pack is exceptionally large, the sample shall be kept in a smaller container which is constructed of the same material and using the same closure system as the production packaging system. However, the firm shall justify the reduction in the size of container.

Headspace is an important criterion while establishing the hold time especially for the materials which are potentially at a risk of degradation due to oxidation, hence, the hold‑time studies should represent worst‑case conditions. Accordingly, the test protocol shall clearly specify the ratio of headspace to contents in the test containers. It should be at least as great as the maximum that is possible in routine production. The environmental conditions for sample storage should be the same as those of the quarantine area/manufacture stage. A sampling plan should be established and followed for taking samples for testing at the different intervals. The amount of sample required should be calculated based on the batch size, the intervals, and the tests to be performed. Results should be compared with the initial baseline data on the control sample. Samples may be pooled for analysis where appropriate, e.g. when the analysis of a composite sample will not lead to issues that would be detectable in single samples being missed when the samples are pooled.

The firm shall conduct the statistical analysis of the data generated to identify trends and to justify the limits and hold time set.

Batches of finished products made from intermediates or bulk products and subjected to a hold‑time study should be considered for long‑term stability testing if data show adverse trending or shifting patterns during the intermediate time points up to the end of the shelf‑life. The shelf‑life of the product – irrespective of hold times – should be measured from the time the active ingredients are mixed with other ingredients. Normally, intermediate and bulk products should not be stored beyond the established hold time.

Examples of stages, study times and tests that may be considered for a coated tablet.

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Reference: General Guidance on hold time studies – Annexure 4 of WHO Technical Report Series 992