ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Møde i Industrifarmaceut foreningen 15/

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1 ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Møde i Industrifarmaceut foreningen 15/ Nanna Aaby Kruse Team Manager, Biologics. BWP Vice-chair. Member of BMWP, PAT and CAT

2 Presentation Outline ICH in general Objectives of ICH Q12 Content of ICH Q12 How far are we and next step Questions and discussion 2

3 3 ICH Q12 EWG Team Moheb Nasr, Former GSK, Rapporteur of Q12 EWG for step 1 document Ashley Boam, FDA, Rapporteur of Q12 EWG after step 1 Founding Regulatory Members EC, Europe FDA, US MHLW/PMDA, Japan Founding Industry Members EFPIA JPMA PhRMA Standing Regulatory Members Health Canada, Canada Swissmedic, Switzerland Regulatory Members ANVISA, Brazil MFDS, Republic of Korea HSA, Singapore NMPA, China TFDA, Chinese Taipei Industry Members BIO IGBA WSMI Standing Observers IFPMA WHO Legislative or Administrative Authorities CDSCO, India CECMED, Cuba COFEPRIS, Mexico INVIMA, Colombia MMDA, Moldova National Center, Kazakhstan NPRA, Malaysia Roszdravnadzor, Russia SAHPRA, South Africa SCDMTE, Armenia TGA, Australia TITCK, Turkey Regional Harmonisation Initiatives (RHIs) APEC ASEAN EAC GHC PANDRH SADC International Pharmaceutical Industry Organisation APIC International Organisation regulated or affected by ICH Guideline(s) Bill & Melinda Gates Foundation CIOMS EDQM IPEC PIC/S USP

4 4 This is a GLOBAL guideline

5 History of ICH Q : First phase of drafting June 2017: Q12 Step 1 document signed by technical experts October 2017: Q12 Sep 2a and 2b* Public consultation launched in EU: 18 Dec 2017 Deadline for comments: 18 Dec

6 Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management ICH Q12 is intended to complement the existing ICH Q8, Q9, Q10 and Q11 Guidelines Using the opportunities offered in ICH Q12 is optional This guideline is not intended to introduce new requirements necessitating changes to the regulations in the regions 6

7 Guideline Objectives Objectives* include: Harmonize change management in a more transparent and efficient manner across ICH regions Facilitate risk-based regulatory oversight Emphasize control strategy as a key component of the dossier Support continual improvement and facilitate introduction of innovation Enhance use of regulatory tools for prospective change management enabling strategic management of post-approval changes 7 *From the ICH Q12 concept paper. July 2014

8 How to archive that? EWG Team representing European Commission: Jean-Louis Robert (former QWP chair), Topic Lead Nanna Aaby Kruse (Vice-chair BWP), Regulatory Chair for step 2 Joined in June EWG meeting in Fukuoka, Japan Brian Dooley (EMA Quality Office) 8

9 Content ICH Q12 (step 2 document) - Two Documents A. Q12 Core guideline 1. Introduction/Scope 2. Categorisation of post-approval CMC changes 3. Established conditions (ECs) 4. Post-approval change management protocol (PACMP) 5. Product lifecycle management (PLCM) 6. Pharmaceutical Quality System (PQS) and Change Management 7. Relationship between assessment and inspection 8. Post-approval changes for marketed products 9. Glossary 10.References Appendix 1: CTD sections that contain ECs Appendix 2: Principles of change management B. Annex Examples on Established Conditions, PACMPs, PLCM 9

10 Chapter 1 Guideline Scope Pharmaceutical drug substances (i.e., active pharmaceutical ingredients) Pharmaceutical drug products, including marketed chemical, and biotechnological/biological products Note: While it is understood that ATMPs are biological products, how the tools described in Q12 could be used (or not) for ATMPs can be elaborated during regional implementation of the guideline (e.g. via question and answers or specific guidance document) Drug-device combination products that meet the definition of a pharmaceutical or biotechnological/ biological product Changes needed to comply with revisions to Pharmacopoeial monographs are not in the scope of this guideline ICH Q12 is not mandatory If not applied regional regulation has to be followed 10

11 Chapter 2 (1) Categorisation of Post-Approval CMC changes Regulatory communication between a MAH and the Regulatory Authority for potential changes which need regulatory action (category, information requirements and associated time frames) Drug regulatory authorities are encouraged to utilize a system that incorporates risk-based mechanisms for (a) requesting approval from the regulatory authority, (b) notifying the regulatory authority, or (c) simply recording CMC changes, with associated information requirements and, where applicable, timeframes for decision. Describes high level the different categories of changes Prior-approval (tell and do): Notification (do and tell): moderate to low risk No reporting (do and record) Essentially the EU Variation Classification Guideline 11

12 12 Chapter 2 (2) Remember: EU Variation classification guideline

13 Chapter 2 (3) EU Variation classification guideline Changes not requiring prior approval Changes requiring prior approval within a Design space PQS Type IA Type IB Type II Extension Do and Tell Tell, wait and do Variations Annual report Immediate notification 13 Evaluation Procedure adapted to the level of risk

14 Chapter 3 (1) Definition Established Conditions (ECs) ECs are legally binding information (or approved matters) considered necessary to assure product quality As a consequence, any change to ECs necessitates a submission to the regulatory authority All regulatory submissions contain a combination of ECs and supportive information Supportive information is not considered to be an EC, but is provided to share with regulators the development and manufacturing information at an appropriate level of detail, and to justify the initial selection of ECs and their reporting category 14

15 Chapter 3 (2) Established Conditions ECs in a submission are either implicit or explicit*: Implicit ECs are elements that are not specifically proposed by the marketing authorisation holder (MAH) but are derived from and revised according to regional regulation or guidance related to post-approval changes. Explicit ECs are specifically identified and proposed by the MAH together with their proposed reporting category as part of a regulatory submission Appropriate when either the proposed EC or reporting category is different than regional guidance or regulation Not required, but if proposed, should be justified 15

16 ECs for manufacturing processes: Chapter 3 (3) Established Conditions Generally include unit operations and the sequence of steps Considering the overall control strategy, include those inputs (e.g., process parameters, material attributes) and outputs (may include in-process controls) necessary to assure product quality: o critical process parameters (CPPs, as defined in ICH Q8(R2)) o key process parameters (KPPs) new* parameters of the manufacturing process that may not be directly linked to critical product quality attributes, but need to be tightly controlled to assure process consistency as it relates to product quality 16

17 Chapter 3 (4) Established Conditions ECs for manufacturing processes fall on a continuum based on extent of development: A parameter-based approach, in which product development prior to regulatory submission provides a limited understanding of the relationship between inputs and resulting quality attributes, will include a large number of inputs (e.g., process parameters and material attributes) along with outputs (including in-process controls). An enhanced approach with increased understanding of interaction between inputs and product quality attributes together with a corresponding control strategy can lead to identification of ECs that are focused on the most important input parameters along with outputs, as appropriate. In certain cases, applying knowledge from a data-rich environment enables a performance-based approach in which ECs could be primarily focused on control of unit operation outputs rather than process inputs (e.g., process parameters and material attributes). 17

18 Chapter 3 (5) Established Conditions ECs and reporting category for changes: After identifying ECs, MAH proposes reporting category for post-approval changes May follow existing regional regulations and guidance or propose alternate reporting category Reporting category is dependent on the potential risk to quality o Risk assessment activities should follow approaches described in ICH Q9 o Consider the overall control strategy and any possible concurrent changes 18

19 Figure 1. Decision Tree for Identification of Established Conditions and Associated Reporting Categories for Manufacturing Process Parameters Chapter 3 (6) Established Conditions 19

20 Chapter 3 (7) Established Conditions Topics for further discussion * * : After identifying ECs, MAH proposes reporting category for post-approval changes May follow existing regional regulations and guidance or propose alternate reporting category Reporting category is dependent on the potential risk to quality o Risk assessment activities should follow approaches described in ICH Q9 o Consider the overall control strategy and any possible concurrent changes 20

21 Chapter 3 (8) Established Conditions Identification of Established Conditions: Analytical method ECs related to analytical procedures should include elements which assure performance of the procedure Appropriate justification should be provided to support the identification of ECs for analytical procedures. The extent of ECs could vary based on the method complexity, development and control approaches. 21

22 Identification of Established Conditions: Analytical method Chapter 3 (9) Established Conditions The extend varies with the method complexity, development and control approach Where the relationship between method parameters and method performance has not been fully studied at the time of submission, ECs will incorporate the details of operational parameters including system suitability. When there is an increased understanding of the relationship between method parameters and method performance defined by a systematic development approach including robustness studies, ECs are focused on method-specific performance criteria (e.g., specificity, accuracy, precision) rather than a detailed description of the analytical procedure. A suitably detailed description of the analytical procedures in Module 3 is expected to provide a clear understanding regardless of the approach used to identify ECs for analytical procedures. Use of this guideline should not lead to providing a less detailed description of analytical procedures in the MAA 22

23 Chapter 4 (1) Post Approval Change Management Protocols (PACMPs) Already part of EU Variation legislation A PACMP describes the change post approval- a firm would like to implement during the lifecycle of a product, how it would be prepared and verified, including assessment of the impact of the proposed CMC change, and the suggested reporting category in line with regional requirements. Lower reporting category Shortened review period It is a regulatory tool that provides predictability and transparency in terms of the requirements and studies needed to implement a change 23

24 Chapter 4 (2) Post-Approval Change Management Protocol Step 1 Submission of a written protocol proposed change(s) with rationale(s) risk management activities proposed studies and acceptance criteria to assess the impact of the change(s) other conditions to be met the proposed reporting category any other supportive information Approved by regulator in advance of execution Step 2 Carry out tests and studies outlined in the protocol If results/data generated meet the acceptance criteria in the protocol and any other conditions are met, submit this information to the regulatory authority according to the category in the approved protocol Depending on the reporting category, approval by the regulatory authority may or may not be required prior to implementation of the change. 24

25 Chapter 4 (3) Post-Approval Change Management Protocol Acknowledement: Mats Welin, MPA 25

26 Chapter 5 (1) Product LifeCycle Management (PLCM) document Product Lifecycle Management (PLCM) document Serves as a central repository for ECs, reporting category for making changes to approved ECs, PACMPs (when proposed), and any post-approval CMC commitments Provides a high level summary of product control strategy to clarify and highlight which elements of the control strategy should be considered ECs. Facilitates and encourages a more strategic approach to lifecycle management Intended to enable transparency and facilitate continuous improvement 26

27 Chapter 5 (2) Product LifeCycle Management (PLCM) document Submitting the PLCM document o o Initial PLCM document is submitted with the original Market Authorization Application, or with a supplement/variation for marketed products where defining ECs may facilitate regulatory change management. Maintenance of the PLCM Document o o Updated PLCM document should be included in post-approval submissions for CMC changes. MAH should follow regional expectations for maintaining a revision history for the PLCM document. Format and Location of PLCM Document* * o o Tabular format recommended, but not mandatory. Location is based on regional recommendations 27

28 Chapter 6 (1) Pharmaceutical Quality System and Change Management ICH Q10 describes principles for the effective management of CMC changes under the PQS This section articulates the importance of timely communication across multiple sites (outsourced or not), and between the MAH and the regulators on manufacturing changes Appendix 2 elaborates on Q10 principles and describes how the PQS can be utilized effectively in the application of Q12 concepts 28

29 Chapter 6 (2) Pharmaceutical Quality System and Change Management Assessment Inspection MAH Quality System Change Management ECs & PCMP Product Specific Lifecycle Management (PSLCM) MAH as manufacturer Rapid information flow 29

30 Chapter 6 (3) Pharmaceutical Quality System and Change Management Assessment Inspection BR Packagers MAH Quality System QC FP Manufacturers ECs & PCMP Change Management Product Specific Lifecycle Management (PSLCM) API Manufacturers FLOW OF INFORMATION???? 30

31 Chapter 6 (4) Pharmaceutical Quality System and Change Management Assessment Inspection MAH BR Packagers Quality System QC FP Manufacturers ECs & PCMP Change Management API Manufacturers Product Specific Lifecycle Management (PSLCM) 31 FLOW OF INFORMATION???? GLOBAL MANUFACTURE

32 Chapter 6 (5) Pharmaceutical Quality System and Change Management An effective PQS as established in ICH Q10 and in compliance with regional GMPs is the responsibility of a firm (manufacturing sites and MAH where relevant) It is not the intent of this guideline to require a specific inspection assessing the state of the PQS before the firm can use the principles in this guideline. Some challenges: Regulatory action when a company meet minimum standards but not sufficient for Q12? Demonstration of an effective PQS Change during life-cycle!? Relationship: MAH and Manufacture Outsourcing 32

33 Chapter 7: Relation Assessment and Inspection Regulatory assessment and inspection are complementary activities and their fundamental roles remain unchanged by this guideline Encourages communication between assessors and inspectors to facilitate implementation of Q12 33

34 Chapter 8 (1) Post-Approval Changes for Marketed Products This chapter describes a strategy for a structured approach for frequent CMC changes (e.g., analytical methods) and data requirements for CMC changes (e.g., stability): Structured Approach to Analytical Procedure Changes (8.1) obasically to provide a recommendation how to make changes to an analytical procedure in a structured manner to allow a notification process ( Do and Tell ) Data Requirements to Support CMC Changes (8.2) - Stability 34

35 Chapter 8 (2) Post-Approval Changes for Marketed Products Structured Approach for Analytical Procedure Changes * The intent of this chapter is to incentivize structured implementation of equivalent analytical procedures that are fit for purpose. An approach wherein specific criteria are defined for changes to analytical procedures used to test marketed products is described below. If this approach is followed and all criteria are met, the analytical procedure change can be made with immediate or other post-implementation notification, as appropriate, to the relevant regulatory authorities. Out of Scope Procedure where the specification does not adequately reflect the complex information provided by the method. Change(s) to a test method based on a biological/immunological/ immunochemical principle or a method using a biological reagent (e.g., bioassay, binding assay, ELISA, testing for viral adventitious agents). Changes to predictive models used with multivariate methods. The flexibility provided by the structured approach may not be available in all regions and in all situations; some specific changes may require prior approval as defined in regional guidance* JP 35

36 Structured Approach for Analytical Procedure Changes In order to use the Structured Approach, a set of principles should be met. Principles: Chapter 8 (3) Post-Approval Changes for Marketed Products High level description of the new and old methods should be same (e.g., chromatography with spectroscopic detection) Test results obtained using the original method and revised method should be equivalent to each other Demonstrate equivalency or better through validation studies System suitability requirements should be established for the revised method No change to acceptance criteria (unless allowed by regional regulation) Approach may not be used if toxicological or clinical data are required as a result of the method change 36

37 Chapter 8 (3) Post-Approval Changes for Marketed Products Structured approach: step wise procedure Step 1: Method description: A distinction has been included to differentiate column chromatography (hplc, uhplc) and plate chromatography (tlc); Therefore a change from tlc to hplc is not necessarily considered a minor change. Changes to spectroscopic procedures should remain within same specific technology, e.g., UV to UV, NMR to NMR; a change from UV to NMR is not considered a minor change. Step 2: Based mainly on a prospective analytical validation protocol, comparison on the current and proposed method (results) Step 3: Consideration of suitability criteria Step 4: Execution of validation protocol and comparison to pre-determined acceptance criteria Step 5: Consideration of new product information (specifications) Step 6: Written summary Step 7: Internal change process (PQS) Step 8: Post implementation notification per regional reporting requirements Step 9: Post-change monitoring Step 10: All information available on site

38 Appendices 1. CTD sections that contain ECs 2. PQS: principles of change management 38

39 Annex Annex 1: illustrative examples ECs IA: chemical product IB: biological product o Parameter based-, Enhanced-, and Performance based approach Annex II: PACMPs Annex III: Product lifecycle management document 39

40 Nov 2017 Q12 Step 2 document signed by European Commission, with a legal disclaimer inserted: In certain ICH regions, the current ICH Q12 guideline is not fully compatible with the established legal framework with regard to the use of explicit Established Conditions ('EC') referred to in Chapter 3 and with the Product Lifecycle Management ('PLCM') referred to in Chapter 5 as outlined in this guideline. These concepts will, however, be considered when the legal frameworks will be reviewed and, in the interim, to the extent possible under the existing regulation in these ICH regions 40

41 Next steps Deadline for comments: 18/12/2018 Guideline to be found on EMA homepage Regional discussion of comments within different Working Parties/ Committees /industry Interim Q12 EWG meeting in Japan Feb 2019 ICH EWG meeting in June 2019 in Amsterdam Finalisation of guideline June or Nov or summer ? 41

42 42 This is a GLOBAL guideline

43 Thank you for your attention 43