Examples of regulatory expectations for analytical characterization and testing

Transcription

1 Examples of regulatory expectations for analytical characterization and testing AT Europe 2016, 18 March 2016 Vicki Venizelos Quality RA B.V. Leiden, the Netherlands

2 Overview What are the regulatory expectations? o Overview of global guidelines o Product life cycle o Analytical qualification/validation requirements What did the Health Authorities expect? o Examples 2

3 What do regulators expect? ICH Guidelines (EU, US, Japan): o Q1A(R2) o Q2(R1) o Q5C o Q5E o Q6B o M4Q(R1) o. Stability Testing of New Drug Substances and Products Validation of Analytical Procedures: Text and Methodology Stability Testing of Biotechnological/Biological Products Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process Specifications : Test Procedures and Acceptance Criteria for Biotechnological/Biological Products The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality (see References slide) 3

4 Analytical methods are used for: Product life cycle - I o Preclinical development Support manufacturing development Testing of preclinical batches Stability testing to support first-in-human clinical trials o Clinical development (Phase I/II, III) Support manufacturing development Characterization studies Release testing of clinical batches Stability testing Comparability 4

5 Product life cycle - II Analytical methods are used for: o Commercialization Validation of manufacturing process Characterization of key intermediates, DS, DP Release testing of commercial batches Stability testing Comparability o Post-approval Manufacturing changes Analytical method changes 5

6 Analytical method requirements Analytical methods need to be qualified/validated depending on: o Development phase Phase 1 versus commercial o Parameter to be tested Purity, impurities Strength, potency o Intended use In-process control Characterization Release testing Stability testing 6

7 Validation requirements 1 Type of analytical procedure characteristics IDENTIFICATION TESTING FOR IMPURITIES ASSAY quantitative limit content/ potency Accuracy Precision Repeatability Interm. Precision - - Specificity Detection Limit - -/+ + - Quantitation Limit Linearity Range : ICH Q2(R1)

8 Validation requirements 2 Validation of analytical procedures during clinical development is seen as an evolving process. For phase I clinical trials, the suitability of the analytical methods used should be confirmed. The acceptance limits and the parameters for performing validation of the analytical methods should be presented in a tabulated form. For phase II and III clinical trials, the suitability of the analytical methods used should be demonstrated. A tabulated summary of the results of the validation carried out should be provided (e.g. results or values found for specificity, linearity, range, accuracy, precision, quantification and detection limit, as appropriate). 2: Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials (EMA/CHMP/BWP/534898/2008) 8

9 Validation requirements 3 Proposed acceptable limits supported by simple analytical data, (e.g., IR spectrum to prove the identity, and HPLC chromatograms to support the purity level and impurities profile) of the clinical trials material should be provided Validation data and established specifications ordinarily need not be submitted at the initial stage of drug development. However, for some well characterized, therapeutic biotechnology-derived products, preliminary specifications and additional validation data may be needed in certain circumstances to ensure safety in Phase 1. 3: GfI: Content and Format of Investigational New Drug Application (INDs) for Phase 1 Studies of Drugs, Including Well Characterized, Therapeutic, Biotechnology-derived Products 9

10 Validation requirements 4 The analytical procedure (e.g., HPLC) used to support the tentative acceptance criteria should be briefly described... [in the IND] A complete description of analytical procedures and appropriate validation data should be available for the analytical procedures that are not from an FDA recognized standard reference... consider the development of stability-indicating analytical procedures that will detect significant changes in the quality of the DS 4: GfI: INDs for Phase 2 and Phase 3 Studies - Chemistry, Manufacturing, and Controls Information 10

11 Examples - #1 HA: (re: 3.2.S.3.1) The glycosylation profile can influence the pharmacokinetics and/or immunogenicity of the product and so its control should be part of the release testing unless appropriately justified. Company: The applicant agrees to implement a [modification of a characterization method used to characterize N-linked glycans] to assure control of the glycosylation profile in DS. The analytical procedure has been validated and data will be collected for DS batches used in clinical trials to establish acceptance criteria. 11

12 Examples - #2 HA: (re: 3.2.S.3.1) The complexity of glycosylation of the DS means that a relatively high number of isoforms is present. The applicant should commit to monitoring all DS batches for O-glycan profile and to complete validation of the O-glycan profile method and implement into QC release testing. Company: The applicant proposes to continue O-glycan profiling by extended characterization, by analyzing the next xx full scale DS batches. For QC release testing, an O-glycosylation site occupancy assay will be introduced. 12

13 Examples - #3 HA: (re: 3.2.P.8) The limit test for detecting oxidized species in stability should be developed and validated as a quantitative method and be implemented as a QC release test for DP. Include resolution between ox peak and main peak as a system suitability criterion. Company: The applicant will implement a QC release test upon validation of the method and include a system suitability criterion (peak-to-valley ratio, USP<621>). 13

14 Examples - #4 HA: (re: 3.2.S.2.4) In the validation of your HPLC assay, it was stated that the LOD was estimated by dividing the LOQ value by 3. The rationale behind the estimation of LOD was not provided. Provide the reason for the LOD estimated as dividing the LOQ by 3.. Company: Dividing LOQ by 3 is based on the S/N approach for analytical procedures that exhibit baseline noise as outlined in ICH Q2(R1). A S/N of 10:1 is generally acceptable for determination of the LOQ and a S/N between 3 or 2:1 for estimating the LOD is generally acceptable. The multiplication factor between 3:1 and 10:1 is about 3.3. Therefore, LOD was estimated by dividing the LOQ value by factor of 3. 14

15 Examples - #5 HA: (re: 3.2.P.8) Visible particles should be part of the stability specifications, unless otherwise justified. Company: (Disagreed) We have performed extensive characterization and monitored particles during drug development using visual inspection and micro-flow digital imaging. An extensive stability assessment has also been made including exposure to accelerated, stress, freeze/thaw, and mechanical stress conditions. There was no statistically significant increase in particles and if so, comparable to matching placebo batches. HA: Results acknowledged, however, in the light of previous history with this class of products, importance for patient safety, and limited experience with your specific product, this specification should be included in stability until more experience has been accumulated. 15

16 Conclusions Regulatory expectations are provided in global guidelines for commerical products, but also for clinical development phases Phase-appropriate method validation is required for in-process tests, release tests and stability tests (comparability) Qualification of methods is required for characterization Health Authorities have asked for characterization tests to be implemented as release tests Health Authorities have asked for a limit test used in stability to become a quantitative test implemented for release testing as well Health Authorities have asked for justification as to the validation approach and to provide this in the dossier Health Authorities have asked for the addition of a test to stability studies. 16

17 References ICH Guidelines: Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologics Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials (EMA/CHMP/BWP/534898/2008) Guidance for Industry: Content and Format of Investigational New Drug Application (INDs) for Phase 1 Studies of Drugs, Including WellCharacterized, Therapeutic, Biotechnology-derived Products Guidance for Industry: INDs for Phase 2 and Phase 3 Studies - Chemistry, Manufacturing, and Controls Information 17

18 Thank you. For questions: