Skip Testing in Pharmaceutical Industry

INTRODUCTION:

As per WHO, “Performance of specified tests at release on preselected batches and/or at predetermined intervals, rather than on a batch-by-batch basis, with the understanding that those batches not being tested still meet all acceptance criteria established for that product. This presents a less than full schedule of testing should therefore be justified and presented to and approved by the regulatory authority prior to implementation”.

All pharmaceutical industries have their internal Standard Operating Procedure (SOP) for the implementation of periodic or skip testing. The frequency for the implementation of Periodic testing or Skip testing may be one batch per twenty batches or the first batch manufactured every year (whichever is earlier) and it may vary from one company to another.

Where to Apply ?

Periodic testing or skip testing should be implemented after performing sufficient risk evaluation and assessment of product quality during drug product development. It should be implemented at commercial level only after gaining sufficient confidence. Periodic or skip testing approach and stages are represented in the Figure:

Periodic (Pt) or Skip Testing (St) Selection Considerations:

PT or ST can be selected and implemented for the testing of regular commercial batches. For selecting the periodic or skip tests, the following points should be considered,

1. Whether materials are received from the approved supplier.
2. A documented history of satisfactory results for material supplied and performance of supplier is available.
3. A documented history of satisfactory performance for the process and product is available.
4. Compliance with specific regulatory requirements of testing is ensured.
5. Sufficient development data for the specified tests is available.
6. Scientific justification can be provided.
7. To be implemented for tests which are not critical to assess the product quality.
8. Batch to batch retesting to be stored in the event of failure and it should be properly investigated and closed.
9. An impact assessment of the PT or ST should be undertaken.
10. Does the specification or method provide information about the purity or potency of the finished product? If not, the specification or method should be reconsidered.
11. Analytical method should predict or prevent the compliance issue.
12. What would be the regulatory impact of eliminating or reducing the test ?

Implementation of the PT or ST concept for the important test:

Implementation of the PT or ST concept for the important test items such as description, loss on drying, purity test and microbial testing etc. The list of recommended test items are represented in the below table for active ingredients, excipients and packing materials.

Skip or periodic testing cannot be implemented for finished product testing.

Skip Testing Strategy:

The proposed strategy for implementing skip-testing implementation can be broken down into a four-stage procedure:

STAGE-I: Selection of attributes via risk assessment

STAGE-II: Assessment of attributes

STAGE-III: Routine application of skip testing

STAGE-IV: Change control and remediation

STAGE-I: Selection of attributes via risk assessment

• Risk assessment: Impact of not testing a batch that fails specification (patient outcome, quality, yield, batch recall strategy, etc.)
• Related tests: the ability of an alternative test (that will be performed) to predict the ‘skipped’ test
• Robust control strategy: a strategy is in place to control the attribute, implying that an out-of-control process is not expected
• Historical knowledge: previous knowledge suggests the attribute routinely passes specification.

STAGE-II: Assessment of attributes

Candidate attributes are assessed to confirm the process is under control for that attribute. This can be achieved by fully testing a sufficient number of batches so that the common-cause variability of the process attributes can be estimated under standard operating conditions, using multiple batches of starting material, etc. The number of batches tested should be selected in order to obtain a reasonable estimate but also to increase the chance of identifying any sources of special-cause variability. The time span required to collect these batches should be sufficient and also include commonly-occurring process variables, for example, all starting material sources.

STAGE-III: Routine application of skip testing

If the conditions described so far are satisfied, then skip-testing can be implemented. Stage 3 involves the routine running of the process, with ongoing verification to confirm there are no batch failures or significant trends observed. To begin with, the frequency of skipping will be selected to ensure that the probability of not testing an attribute which misses specification is small.

This frequency should align with the number of batches that can be held, e.g., testing one in every 12 batches (per interval) because 12 batches are manufactured each day. Additionally, the choice of which batches to test and which to skip should be made randomly within each interval, ensuring those tested do not align with other systematic factors, e.g., always testing the batches manufactured on a Monday. All skipped batches can either be held until the next batch tested is confirmed to have passed or released with acceptance that there is a very small risk that they may need to be recalled. If, after a suitable period of time, the process has remained under control and capable, and the skip strategy has proved successful, the frequency of testing may be reduced further (the level of increased skipping will depend on the process). During this stage, along with testing the batches to confirm the attributes are within specification, a check is also made that the process is still under control and capable. It was decided that initially one in 10 batches (which relates to one per day) would be tested. In practice, on each day one of the 10 batches was selected at random for testing prior to manufacture to avoid any unforeseen time-related effects affecting the assessment. If, one year later, the process continues to remain under control and capable, with the skip strategy thus proven to be successful, the level of testing could be reduced further.

STAGE-IV: Change control and remediation

If an attribute fails to meet specification during the ongoing verification of tested batches, then skip-testing should be suspended and full specification testing reinstated. The batches that were not tested (between the previous batch tested, where the attribute passed specification, and the latest batch that has failed) also need to be tested. An investigation can be performed to identify why the attribute failed to meet specification. Once identified and preventative action has been taken, the testing strategy can return to Stage 2. The number of batches tested may be reduced from the original total assessed in Stage 2, depending on the cause of the failure, the outcome of the investigation and the knowledge of the process gained since the initial assessment. In the example presented earlier, up to 200 further batches (this number being dependent on the cause of the failure) may be tested and the process re-evaluated. During the assessment of process changes (both planned and unplanned deviations), it is important that the assessment of the change considers any impact on the skip-testing strategy. In the event of a process deviation or if another routinely tested attribute (which is not part of the skip-testing regime) fails specification, then any impact on skipped batches will be assessed and full testing of all skipped batches should be considered. This change control process may also be followed if there is a potentially impactful change to the process.

Periodic or Skip Testing for in-Process Samples:

Periodic or Skip Testing for API, Excipients and Packing Materials:

USFDA Prospective:

As per the USFDA recommendations, PT or ST implementation has to be submitted as a supplement to an approved application. Some changes may not require approval before implementation and some changes may require an approval before implementation.

Major-Prior Approval Supplement (PAS):

PAS submission is required for implementation of PT or ST for in-process testing of the finished product. We cannot implement PT or ST for in-process testing of the drug product unless agency approves the supplement.

Moderate-Changes Being Effected 30 Days (CBE-30):

Relaxing an acceptance criterion or deleting a test for raw materials used in the manufacture of the drug substance, in-process materials prior to the final intermediate, starting materials introduced prior to the final drug substance intermediate, or drug substance intermediates.

CBE 30 days:

The CBE (Changes being effected) 30 supplement serves as a notification to the FDA that a change will be implemented in the process, analytical techniques/technologies. The Agency has 30 days from the day of receipt to respond to the applicant. This is usually a minor change which does not impact final product quality. The FDA has 30 days to respond as to whether the changes are satisfactory. If the manufacturer does not receive any response within the 30-day period, it may be assumed that the change is acceptable.

Minor (Annual Report):

For DS/DP, the addition or revision of an alternative analytical procedure that provides the same or increased assurance of the quality being tested as the analytical procedure described in the approved product or deletion of an alternative analytical procedure. Annual report: For the above change, applicant should provide the sufficient data in the annual report.

EU Variations (Type-IA):

As per EMA recommendations, Type IA variations do not require approval by the authorities before their implementation by the holder. However, within 12 months from the date of implementation, the holder must submit simultaneously to all national competent authorities.

The specification parameter does not concern a critical parameter, for example any of the following: assay, impurities, any critical physical characteristics e.g. particle size, bulk or tapped density, identity test, water, any request for skip testing.

Conclusion:

Periodic Testing or Skip Testing can be implemented for testing of products which are intended for commercialization. Generally, the industry has to assess the possibility of acceptance of the parameters by the regulatory agency. Generally parameters are proposed for PT or ST for a minimum of 20 and 30 lots/batches of packaging material and excipient etc. If the change is accepted by the agency then the company should follow the internal SOP on PT/ST for the implementation of PT/ ST. As per USFDA, these changes are addressed under PAS, CBE-30 or annual reportable category. As per EMA, these changes come under type-IA (annual reporting) variation. As per USFDA, if the change is major then the applicant should submit the prior approval supplement, if the change is moderate then the applicant should follow the CBE 30days procedure and if the change is minor then the applicant can include the change in the annual report. If the variation is accepted then PT/ST may be implemented. But if the variation is rejected by the agency then the sponsor should immediately stop the implementation.