QbD for Better Method Validation and Transfer
Just as process validation can benefit from a QbD and a product lifecycle approach, so can analytical method validation and transfer
By Phil Nethercote, Phil Borman, Tony Bennett, GSK; Gregory Martin, Complectors Consulting LLC, and Pauline McGregor, PMcG Consulting
The extent of the IQ phase may vary depending on the level of pre-existing knowledge of the routine testing laboratory with the product, method or technique. For example, the laboratory that originally developed the method may merely ensure that other personnel who will use the method are trained.
The Method Operational Qualification phase is focused on demonstrating that the method meets its design intent. It is similar to “traditional method validation.” In the lifecycle approach, however, the focus is not about performing the traditional check box exercise to demonstrate compliance with ICH Q2. Instead, it is about demonstrating that the method meets the specific requirements that have been pre-defined in the Analytical Target Profile. A fundamental principle of this stage is that it should build on information that may have been generated in experiments already performed; for example, evidence of the selectivity or limit of quantification of a method may already exist from studies performed as part of method design.
The final stage in the qualification phase is to perform a MPQ exercise. At this stage, the actual manufactured supply samples are tested in facility, equipment and by personnel that will be used for routine analysis. The method should be operated exactly in accordance with the defined method controls and local operating procedures. As with the IQ stage above, the extent of the PQ exercise could vary, and would include for example confirming system suitability criteria are being routinely met.
Stage 3 - Continued Method Verification
The goal of this stage of the method lifecycle is to continually assure that the method remains in a state of control. This should include an ongoing program to collect and analyze data that relate to method performance---for instance, by setting criteria for replication of samples or standards during the analysis, by trending system suitability data or by trending the data from the regular analysis of a reference lot.
This activity aligns with the guidance in USP chapter 1010 on system performance verification. Close attention should also be given to any out of specification (OOS) or out of trend (OOT) results generated by the method once it is being operated in its routine environment. Ideally, using the new approach, laboratories should encounter fewer OOS results. If they do, it will be easier for staff to determine their root cause.
During the lifecycle of a product, both the manufacturing process and the method are likely to experience a number of changes brought through unintentional deviations, continuous improvement activities or the need to operate the method and\or process in a different environment. It is essential that all changes to the method operating conditions be considered in light of the knowledge and understanding that exists on the method performance. If the method operating conditions are modified such they fall outside the known method operable region (determined as part of ‘method understanding’ during the original design phase) then the Method Qualification should be revisited. Likewise if the process changes and samples contain analytes at levels outside those covered in the method operational qualification exercise or have new interferences, a new ATP would need to be generated and a partial re-qualification exercise will be required to ensure the method is still capable of producing consistent and reliable results for the extended range or modified sample.
Where a method needs to be transferred to new location, appropriate Method Installation Qualification activities (including knowledge transfer) will need to be performed in addition to a Method Qualification exercise.
Consistent with QbD principles, the extent of requalification should be driven by scientific principles, as described previously
The approach to method qualification described above focuses on the activities that would typically be performed when a method is developed and used within a single company. Other scenarios exist where a laboratory may need to use a method for which it has no access to the original method design or qualification information such as in a contract testing laboratory. In these situations, it is important that an ATP is defined and documented. An appropriate qualification study is then performed to demonstrate that the method meets its ATP. This approach could also be applied to qualification of a pharmacopoeia method. By applying the lifecycle approach to pharmacopoeia methods it is envisaged that there would be no need for a separate USP chapter on method verification (USP <1226> Verification of Compendial Procedures).
Another scenario that needs to be considered is when a method is used to support drug development rather than drug manufacturing activities. In this case the method will still need to produce data that is scientifically sound - particularly as it may be used to release material for clinical supplies, support stability studies or support the development of process understanding. At this point in the product lifecycle however the focus is on understanding the method performance rather than demonstrating that it meets predefined acceptance criteria.
A key advantage of this approach for the above scenarios is the flexibility to perform a qualification against the specific ATP defined for the intended use of the method. This eliminates the current desire to create a qualification document against ICHQ2 in a check box manner which can lead to unnecessary headaches and additional work.
Since there is the potential for this approach to be adopted for all users of analytical methods, it also offers the potential to standardise the multiple, misrepresented terminology which currently exists within the industry. It would result in a harmonised method qualification approach with standardised terminology which would remove the current state of confusion between the terms; method validation transfer and verification and the many interpretations as to what is actually required for each.