Assay Qualification/Validation – a Reviewer’s …

1 1 Assay Qualification/Validation a Reviewer s ExpectationsSarah KennettDivision of Monoclonal AntibodiesOffice of Biotechnology ProductsOPS/CDER/FDAO ctober 20, 20102 DisclaimerThe views and opinions expressed here are my own and should not be used in place of regulations, published FDA guidances or discussions with the views reflect CDER/OPS/OBP talk is focused on analytical assays used to assess drug substance, drug product, and in-process this subject?What does FDA say officially?What do we OBP product reviewers mean by qualification and validation ?Some expectations4 Person X: Someone told me assays need to be validated to start Phase 2 studies.

2 Me: No, unless there is a scientific reason, submission of Assay validation isn t required until the BLA is submitted. However, you need to be using qualified assays from the beginning. If the assays you re using during later phases of clinical development can t be validated, you might be in trouble regarding setting of acceptance criteria and dosing/efficacy assessment. X: So, we need to show you validated assays by Phase 3. Me: Uhh, no, not exactly. Formal validation studies CAN be performed as early as you want, but with a few exceptions, the REQUIREMENT regarding timing of the original validation {exceptions include assays critical for safety!}

3 } is that it be completed prior to submission of the BLA to be included in the submission. For phase 3, you probably need to be using assays that can be validated, though, so they need to at least be well qualified. X:.. Me:..5 What does FDA say regarding BLA/NDA stage assays?The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with ..21 CFR (e) (Testing and release for distribution)At the time the application is submitted to the regulatory authorities, applicants should have validated the analytical procedures uses in the Q6 BAnalytical methods should be Q7 The stability program shall , meaningful, and specific test CFR (a)(3)

4 6 Although in each phase of the investigation sufficient information is required to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with each phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise CFR (a)(7)(i)The {IND} submission is required to contain:..the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance [drug product]..21 CFR (a)(7)(iv)(a) [21 CFR (a)(7)(iv)(b)]What does FDA say regarding IND stage assays?

5 7 One of the clearest statements FDA makes regarding a requirement for Assay validation at the IND stage is in the PROCESS validation guidance?While validated analytical methods are not required during product- and process-development activities, methods should be scientifically sound ( , specific, sensitive, and accurate), suitable, and reliable for the specified purpose. Guidance for Industry: Process validation : General Principles and Practices. FDA/CDER, CBER, CVM. vs. Qualification Are we speaking the same language?Process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.

6 Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes the process validation activities in three stages. Stage 1 Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities. Stage 2 Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of for Industry: Process validation : General Principles and Practices.

7 FDA/CDER, CBER, CVM. vs. Qualification Are we speaking the same language?LifecycleStage 1 Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up 2 Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. 10 validation vs. Qualification Are we speaking the same language?Lifecycle (borrowing from Process validation )Stage 1 Assay Design: The Assay is defined during this stage based on knowledge gained through development 2 Assay Qualification: During this stage, the Assay design is confirmed as being capable of producing reproducible results suitable for the specified purpose.

8 Stage 3 Continued Assay Verification: Ongoing assurance is gained during routine use that the Assay remains in a state of vs. Qualification Are we speaking the same language?For a bioanalytical [BA, BE, PK] method to be considered valid, specific acceptance criteria should be set in advance and achieved for accuracy and precision for the validation of QC samples over the range of the validity of an analytical method should be established and verified by laboratory studies, and documentation of successful completion of such studies should be provided in the Assay validation for Industry: Bioanalytical Method validation .

9 FDA/CDER, CVM. vs. Qualification Are we speaking the same language?Qualification: The Assay design is confirmed as being capable of producing reproducible results suitable for the specified purpose. Test how the Assay performs and decide if that performance is suitable for that point in development. If it isn t good enough, change the in progress, but scientifically sound and suitable for its : The Assay is tested against specific acceptance criteria set in advance to verify that the performance characteristics (those listed in ICH Q2(R1) and potentially others, depending on the Assay and the product) of the final method are suitable and reliable for the intended applications.

10 Documentation of successful completion of such studies should be provided in an Assay validation product, documented to meet performance acceptance vs. Qualification Are we speaking the same language?Lifecycle (borrowing from Process validation )Stage 1 Assay Design: The Assay is defined during this stage based on knowledge gained through development 2 Assay Qualification: During this stage, the Assay design is confirmed as being capable of producing reproducible results suitable for the specified purpose. Scientifically sound work in 2 - Formal Assay validation Study: The Assay is tested against specific acceptance criteria set to verify that the performance characteristics of the final method are suitable and reliable for the intended 3 Continued Assay Verification: Ongoing assurance is gained during routine production that the Assay remains in a state of control.