Capillary Electrophoresis in Global Emerging Markets: A Regulatory Perspective. Brian K. Nunnally, Ph.D.

Transcription

1 Capillary Electrophoresis in Global Emerging Markets: A Regulatory Perspective Brian K. Nunnally, Ph.D.

2 Agenda The Lifecycle Approach a guidance review What it really means Global Emerging Markets and their impact on the CE professional Selected questions and their answers

3 Lifecycle management guidance Health Canada published one in 2004 (GUI-0029) It was revised in 2009 The activities relating to validation studies may be classified into three phases: - Phase 1: Pre-Validation Phase or the Qualification Phase - Phase 2: Process Validation Phase (Process Qualification phase) - Phase 3: Validation Maintenance Phase Other recent guidances have been published by FDA and EMA (draft). The guidance is specific to Process Validation; however, it can be applied to analytical as well!

4 Process Validation Guidance from FDA (2011) The guidance aligns process validation activities with the product lifecycle concept and with existing FDA guidance. The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production. The concept aligns with expectations for the analytical validation and ongoing laboratory data generation

5 FDA Guidance Process validation stages Stage 1 Process Design: development and scale-up activities. Stage 2 Process Qualification: Proof of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance of process control.

6 FDA Guidance Process validation stages applied to the analytical laboratory Stage 1 Analytical Method Design: development and initial qualification activities. Stage 2 Analytical Method Qualification: Proof of reproducible commercial testing. Stage 3 Continued Analytical Method Verification: Ongoing assurance of analytical control.

7 Expectations of the CE professional Understand the sources of variation Detect the presence and degree of variation Understand the impact of variation on the process and ultimately on product attributes Control the variation in a manner commensurate with the risk it represents to the process and product

8 Understanding variability Variability comes in three forms: process, sample, and analytical. A control chart of the lot release values will encompass all three forms of variability. It is rare that all three types can be accurately quantitated without a carefully planned and executed hierarchical or similar study σ² = σ²p + σ²s + σ²t Where: σ² = Total variance. σ²p = Process variance. σ²s = Sampling variance. σ²t = Test variance.

9 Illustrating Stability If the points fall at random about the centreline and remain within the control limits, the process is deemed to be stable.

10 Illustrating Instability If this red line is the test specification, should we react to the special cause?

11 A better way Re-drawing the limits makes it easy to see!

12 Understanding the data Production Data Laboratory Controls Limits Where are set as Lies per the The usual Problem? practice, ± 3 sigma.

13 Range Range 1-Point Average 1-Point Average Understanding the data Shewhart Control Charts are Used

14 Global Emerging Markets For most life cycle management activites focus on the reference markets, e.g. US, EMA, Canada, Japan There are, of course, hundreds of other markets The prominent and fast growing are referred to as Global Emerging Markets These markets are becoming strategically important for the pharmaceutical industry

15 Global Emerging Markets Country Argentina Bahrain Bangladesh Brazil Chile China Colombia Egypt Hong Kong India Indonesia Israel Jordan Kuwait Malaysia Mauritius Mexico Morocco Nigeria IMF Next- 11/BRIC CIVETS FTSE MSCI THE ECONOMI ST S&P DOW JONES BBVA Columbia University EMGP

16 Global Emerging Markets Country Oman Pakistan Peru Philippines Qatar Russia Saudi Arabia Singapore South Africa South Korea Sri Lanka Taiwan Thailand Tunisia Turkey UAE Ukraine Venezuela Vietnam IMF Next- 11/BRIC CIVETS FTSE MSCI THE ECONOMI ST S&P DOW JONES BBVA Columbia University EMGP

17 Characteristics of GEM Regulatory Agencies Many markets expect a major market (e.g. US or EMA) approval before filing - This facilitates approval in these countries - Notable exceptions: South Africa, Brazil Requirements and expertise can vary widely, but both are increasing - Example: Azerbaijan vs Russia vs India - Example: HSA (Singapore)

18 GEM Challenges Regulations are evolving - Advances: ICH, Pharmaceutical Inspection Coop Scheme Regulations and guidelines (along with unstated expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of guidance - Pharmacopeia standards differ country to country - GMPs are not globally harmonized - Inspections are not globally harmonized - Differences exist for review/approval times, clinical trial application content, specification - Approval of changes is not harmonized - Post approval reporting requirements are not harmonized 18

19 GEM Challenges Increasing complexity with foreign countries Language, time zones, culture, FMAs, in-country testing, availability of instrumentation, technical savvy New requirements for some GEM countries IP issues Inspections Multiple approved dossier versions for a single drug - Multiple specifications, multiple item codes, different CoAs, different responses to questions Overall Global CTD not possible Understanding both the intent and expectations of questions 19

20 In-country testing Many countries require in country testing, either before approval or after launch of the product Capillary electrophoresis (among other methodologies) can be a challenge for some markets Methods need to be robust (!!) to facilitate transfer to these markets

21 In-country testing (example) Country Mandatory Requirement Full vs Partial testing * Local vs Contract Lab Small Molecules Biologicals Argentina Yes Yes Full Local Lab mandated Brazil Yes N/A Full Local Lab mandated Chile Yes Yes Partial is possible Can be contracted out Uruguay Yes Yes Theoretically full testing; selected possible Can be contracted out Mexico Yes Yes Full Testing (for n=20 batches). Then, request a Can be contracted out reduction. If tests are too expensive or require sophisticated equipment, reduction is possible. Testing is exempted for orphan drugs. Russia Yes Yes Full testing for new registrations. Laboratory assigned by MoH Turkey Yes Yes Tests performed are based on the product, but normally these include: Biological, Dissolution, Official analysis institution of TMOH Physical, physicochemical controls, Content uniformity, amount, Microbiological, purity, and ID. Ukraine Yes Yes Full testing State local laboratory assigned by the MoH Israel Yes Yes Full testing for the first imported batch and then upon MoH request Testing carried out by MOH Lab Other countries requiring testing: Costa Rica, DR, El Salvador, Ecuador, Guatemala, Honduras, Nicaragua, Panama, South Korea, etc.

22 GEM Requirements (examples) Brazil (Resolution RDC No 17, 16 Apr 2010) 22 Article 19. Qualification and validation should not be considered only exercises. After the adoption of the qualification and/or validation report, it there should have a continuous monitoring program, which must be based on periodic review. [Note: software validation and revalidation is called out as a specific self-inspection item.] Article 209, Sole Paragraph. Compendial analytical methods do not require validation, but before its implementation, there must be documented evidence of their suitability in the laboratory operating conditions. Article 312, 3. The pharmacopoeial methods should be used for the validation and performance of the sterility test. Article 463, 2 The retrospective validation is no longer encouraged and is not applicable to the manufacture of sterile products. Article 479, 2 A risk assessment should be used to determine the scope and extent of validation.

23 GEM Requirements (examples) Thailand (Q&A on ASEAN Analytical Validation) 6. Identify the conditions/scenarios when each of the following is required to be conducted: Full validation : Revalidation : Verification Refer to 1. for Full validation and Verification. According to ASEAN Guideline, revalidation may be required in the following circumstances: - Change in the synthesis of the drug substance - Change in the composition of the finished product - Change in the analytical procedure From ASEAN Guideline on Analytical Validation (consistent with ICH): The compendial methods are not required to be validated, but merely verify their suitability under actual conditions of use. 23

24 GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical Products Major Variation - No analytical examples (not counting specification changes) Minor Variation - Prior Approval (MiV-PA) - Change of test procedure to non-compendial drug substance (must at least show equivalence to former procedure) MiV-PA9 - Change of in-process controls applied during the manufacture of the drug substance (including tightening and addition of new in-process test) MiV- PA6 - Change of in-process controls applied during the manufacture of the drug product (including tightening and addition of new in-process test) MiV- PA19 Interesting note: Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way. Minor Variation - Notification (MiV-N) - No analytical examples 24

25 GEM Requirements (examples) South Africa (Amendments) Four categories: - Type A - amendments that may be implemented without intervention of or prior notification to Council - Type B - amendments that require prior notification - Type C - amendments that require prior approval - Type D - amendments that should be considered new applications Type A Biological examples - (25) Addition of release tests and /or of specifications or tightening of specifications for intermediates of the APIs Type B Biological examples - No analytical examples 25

26 GEM Requirements (examples) South Africa (Amendments) Type C Biological examples - (19B) Any change in analytical methods that results in change(s) of specification limits or modification(s) in potency, sensitivity, specificity, or purity establishes a new analytical method deletes a specification or an analytical method eliminates tests from the stability protocol; or alters the acceptance criteria of the stability protocol - (20B) Any change in production processes that may result in change(s) of specification limits or modification(s) in potency, sensitivity, specificity, or purity establish a new analytical method delete a specification or an analytical method eliminate tests from the stability protocol; or alter the acceptance criteria of the stability protocol 26

27 Analytical Validation and Method Detail (several) Question: Asked a series of questions on method details, requested method validation data for all methods used in the analytical control strategy Answer: - Provided copies of the methods and answered the specific detail questions requested. - Some requests have included providing raw data (e.g. real weight of reference standard and sample used) from validation - This detail is requested as a substitute for in-country testing thus preventing the need for in-country (repeat) testing - The procedures are not considered part of the license Result: Success

28 Method detail (South Korea) Question: Detailed test methods for API. Answer: - Provided descriptions of the assays, but not copies of the methods. - These are not considered part of the license (e.g. The detailed test methods for Drug Substance are supplied as a reference. The information provided in Module 3, Section 3.2.S.4.2 Analytical Procedures, is considered to contain the regulatory information and requirements.) Result: Success

29 Detailed data (several) Question: Provide chromatograms and electropherograms for all stability timepoints. Answer: - Provided chromatograms/electropherograms; sometimes providing only one lot instead of three lots. Result: Success

30 Conclusions Understanding analytical methods, including real time assessments of variability, are becoming increasingly important The trends toward increased globalization will create additional work and challenge for analytical professionals Global Emerging Markets will become a larger portion of the work due to increasing complexity in these markets

31 Acknowledgements Catherine Anderson Helena Madden Sue Stella

32 Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION SEAN%20PV%20(Version%203.1)%20Main%20Guide,%20without%20annexes.pdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS Draft%207.2%20(2013).pdf Thailand Q&A on ASEAN Analytical Validation &A%20analytical%20validation-25jun55.pdf ASEAN website with links to several guidances Brazil Resolution RDC No 27 Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May and Resolution RDC 27 (IDRAC ) of 17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the Good Manufacturing Practices Regulation. Australia Note for Guidance on Validation of Analytical Procedures: Text and Methodology CPMP/ICH/381/95 (pdf,183kb) Japan Excerpt from presentation: Japan has no guidance for bioanalytical method validation. The answers in these slides are the results of the discussion in the JBF kickoff meeting on March 30 (2011). Malaysia Singapore ANALYTICAL METHOD VALIDATION pdf