#Hold time study an important aspect in pharmaceutical industry.

Hi All,

In this article I'll take you through the key points included in the WHO’s TRS 992 Annex 4: general guidance on hold time studies for non-sterile solid dosage forms.

What is hold time study:

It is the study which is used to determine the time limit under which the material remains in defined specification prior to final packaging.

When is it required to perform and why it is required?

Hold times should normally be determined prior to marketing of a product. It is required because it helps in establishing the time limits for holding the materials at different stages of production to ensure that the quality of the product does not produce results outside the acceptance criteria during the hold time.

When is it recommended to perform?

Hold-time studies shall be included during development on pilot-scale batches (a small-scale batch of a drug product that is manufactured during the development phase of a new drug) or during scale-up and should be confirmed during process validation of commercial-scale processing.

Alos, when there is a change in processes, equipment, storage conditions, starting or packaging materials a risk assessment shall be performed and based on the assessment further hold-time studies should be performed

How to perform?

Manufacturing process of the product shall be thoroughly reviewed, break each step of the manufacturing process to identify the critical steps. This critical step shall be evaluated based on the time required to store the material (basically pause time) between the two processes during the manufacturing. Below are the steps which are involved during the drug product manufacturing and the sample from this step can be used to perform the hold time study,

-??????? 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.

A representative sample batch of material or product subjected to the hold-time study should be held for the defined hold period. The hold period for each category of material should be established on the basis of the study by keeping the material in either the original or simulated container used in production. The containers in which hold-time samples are stored should be the same pack as is used in production.

For testing of pooled samples, care must be taken to avoid masking potential issues, such as uneven moisture distribution in granules.

How many batches are required to perform the Hold time study?

Typically, one or more batches of a material, intermediate or product can be used for determining hold times or on the risk-based approach, more numbers of batches can be used for this study.

The amount of sample required should be calculated based on the batch size, the intervals, and the tests to be performed.

Results of hold time study shall be compared with the initial data of the control sample.

What is the requirement for Hold time study?

A well written, well designed and approved protocol is required to perform the Hold time study which shall include,

The activities to be performed,

Test parameters and acceptance criteria appropriate to the material or product under test.

Acceptance criteria shall be kept more stringent than registered specifications, to provide assurance that the material is well within control.

What information protocol and report should have?

The protocol and report should generally include the following:

a title; reference number; version; date; objective; scope; responsibility; procedure; description

of the material or product; sample quantities; sampling method and criteria.

acceptance limits; frequency of sampling; sampling locations; pooling of samples.

storage conditions; type of container; methods of analysis; results; conclusion.

recommendation; signatures; and dates.

Required time period for Hold time study:

Benefits of Hold time study?

Below are the benefits of the hold time study,

• Research and Development:?Data from hold time studies provides valuable insights during the research and development phase. It guides the formulation of products that exhibit greater stability and longevity, leading to enhanced patient outcomes.
• Optimizing Production Processes:?By determining the optimal hold time for each product, organizations can streamline their manufacturing processes. This reduces waste, enhances resource allocation, and contributes to cost-effectiveness.
• Ensuring Product Integrity:?Hold time studies verify the stability of pharmaceutical products over extended periods. This ensures that products remain effective, safe, and suitable for patient use, safeguarding both consumer health and the pharmaceutical company’s reputation.
• Risk Mitigation:?Hold time studies identify potential risks associated with product degradation or instability. This proactive approach enables companies to take corrective measures before issues arise, mitigating the likelihood of recalls or market withdrawals.
• Regulatory Compliance:?Regulatory agencies require thorough documentation of a product’s stability and shelf life. Hold time studies provide experiential data that demonstrate compliance with these regulations, preventing legal and financial consequences.
• Continuous Improvement:?Hold time studies promote a culture of continuous improvement. Regularly revisiting and updating these studies enables companies to adapt to evolving regulations, technology, and best practices.

Reference: The World Health Organization’s TRS 992 Annex 4: general guidance on hold time studies for non-sterile solid dosage forms.

I've tried to capture key points from the above reference documents for more details about Hold time study refer above mentioned WHO guideline.

Thanks for reading.

Regards,

Shailesh Mewada