Skip testing is a process employed to reduce the analytical drugs testing burden and lends itself to processes with high-frequency batch production. Rather than test all batches within a given interval, pre-selected batches are assessed and the other batches are ‘skipped’. This reduction is justified as it is shown that there is a low risk of any batches failing specification.
Periodic Testing or Skip Testing
- Skip or periodic testing is defined by The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) as conducting ‘‘specified tests at release on pre-selected batches and/or at predetermined intervals, rather than on a batch-to-batch basis, with the understanding that those batches not tested should still meet all the acceptance criteria established for that product’’.
- 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.
Implementation
- Skip testing must only be implemented for low risk scenarios. This could be based upon a strong scientific rationale detailing why the skip-test is inherently unlikely to fail and/or using process capability data to show that the process is under control. Ongoing verification should also be applied to confirm the process is still capable of meeting specification. In addition, the following should be documented prior to implementation:
- Alternative measures which are in place to control the quality attribute if it is no longer to be confirmed through testing every batch;
- Scientific rationale which shows that the quality attribute has a low impact on safety and/or efficacy;
- Scientific rationale (supported by risk assessment) which demonstrates that the attribute is not critical to quality (i.e., it is not a Critical Quality Attribute )
- Justification of skip testing intervals and batch selection
- Process to be followed if a batch selected for testing fails to meet specification.
- These tests can be implemented for
- Active Pharmaceutical Ingredients (APIs),
- Excipients,
- Packing materials
- In-process testing of finished products analysis.
- Skip or periodic testing cannot be implemented for finished product testing.
- Implementation of PT or ST for API, excipient and packaging material can be approached according to SOP which would be available for an audit by the regulatory agencies.
- The implementation of PT for in-process testing of finished product can be undertaken only after seeking concurrence from the regulatory either during the review of a marketing authorization application or after approval of the application.
- A suitable supplement or variation needs to be submitted to the agency for its review if PT is to be implemented for in-process testing.
ALSO READ: SOP for Reduce Testing for Raw Material
Implementation of the PT or ST concept for the important test
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Raw Materials |
|
|
API |
Description
(DS), Identification (ID), Loss on Drying (LOD), water content, particle
size, bulk density, assay, purity test and microbial test. |
|
Excipients |
DS, ID, particle size, bulk density,
powder fineness and microbial test |
|
Packing Materials |
|
|
Al. foil
paper back |
DS, ID*, Total grammage and width |
|
Al. foils
plain |
DS, ID* and
width |
|
Al. foils
printed |
DS, ID*, width, printing matter and
shade |
|
Ampoules |
DS,
dimensions and weight* |
|
Closures |
Type of closure, dimensions, heat seal and
pulp lines |
|
Cold
formable foil |
DS, ID*,
width and shade |
|
Laminated
Al foil pouch |
DS, ID*, dimensions and printing |
|
Molecular
sieves |
DS and
adsorption capacity |
|
Plastic
containers |
DS and physical parameters |
|
Poly Bag |
DS and
dimensions |
|
Purified
cotton/Rayon filter |
DS, ID, water content |
|
PVC and
PVDC |
DS, ID,
width and shade* |
|
PVC Aclar |
DS, ID*, width, total grammage |
|
Rubber
stopper |
DS,
dimensions and absorbance |
|
Silica gel
bag |
DS and weight |
|
Silica gel
canister |
DS,
dimension and adsorption capacity |
|
Vials |
DS, dimensions, weight* |
|
Carton |
DS, printing
matter and shade |
|
Leaflets |
DS and printing |
|
Self-adhesive
label |
DS, Text and
Color |
* If applicable this test can be recommended
Note: Key identification test only required.
Skip Testing Strategy
- The proposed strategy for implementing skip-testing implementation can be broken down into a four-stage procedure.
1. Selection of attributes via risk assessment
- Risk assessment must be carried out for all suppliers of the material being assessed. Where there is more than one supplier for a particular material, then each supplier must be assessed individually.
- A periodic review must be conducted to ensure that the risk assessment and PT or ST schemes remain valid. Where an assessment has identified a significant risk it must be appropriately mitigated.
3. Routine application of skip testing
4. Change control and remediation
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 the commercial level only after gaining sufficient confidence. Periodic or skip testing approaches and stages are represented in the Figure.
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,
- Whether materials are received from the approved supplier.
- A documented history of satisfactory results for the material supplied and the performance of the supplier is available.
- A documented history of satisfactory performance for the process and product is available.
- Compliance with specific regulatory requirements of testing is ensured.
- Sufficient development data for the specified tests is available.
- Scientific justification can be provided.
- To be implemented for tests that are not critical to assess the product quality.
- Batch-to-batch retesting to be stored in the event of failure and it should be properly investigated and closed.
- An impact assessment of the PT or ST should be undertaken.
- 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.
- The analytical method should predict or prevent compliance issue.
- What would be the regulatory impact of eliminating or reducing the test?
Periodic or Skip Testing for in-Process Samples
- Skip testing can be implemented for in-process samples of all categories of finished drug products such as tablets, capsules, semi-solids and liquids.
- This can be implemented after review of data for 20 to 30 consecutive batches which have been manufactured without any change in process, formula, equipment or specification.
- PT/ST can be implemented after approval from the respective regulatory agency.
- After implementation of PT or ST if the process, formula, equipment etc. is changed then the skip testing procedure should be reevaluated.
- If any OOS/incident is encountered due to process quality and the Root Cause Analysis indicates in-process testing or a change in the process, specification or test procedures, then complete testing needs to be performed on few consecutive batches without any change.
- The internal quality assurance team will be responsible to perform the risk assessment.
Periodic or Skip Testing for API, Excipients and Packing Materials
- After analyzing 30 to 40 batches, periodic testing or skip testing may be implemented if data is found satisfactory and without much variation.
- If any OOS/incident is encountered then complete testing of few consecutive batches is to be performed and the quality assurance team needs to perform the risk assessment.
Approval
- PT or ST may be implemented for API's, excipients and packaging material after a favorable review of sufficient batch data and by preparing SOP's which would be available for an audit by the regulatory agencies.
- For the implementation of PT for in-process testing of the finished product concurrence from the agency during the review of an application or after approval is necessary.
- A suitable supplement or variation needs to be submitted to the regulatory agency for its review if PT is to be implemented for in-process testing of the finished product post-approval.
Tags
Quality Assurance
