THE NEW QUALITY PARADIGM OPPORTUNITIES AND EXPECTATIONS IN ICH Q8 Q9 Q10 Q11 DR. FRITZ ERNI

Transcription

1 THE NEW QUALITY PARADIGM IN ICH Q8 Q9 Q10 Q11 OPPORTUNITIES AND EXPECTATIONS DR. FRITZ ERNI

2 THE NEW PARADIGM OR QUALITY BY DESIGN Why do we need it! Some background Information

3 The impact of ICH GLOBAL HARMONISATION (ICH+GCG) Expert Working Groups (EWG) WHO Global Cooperation Group APEC ASEAN PANDRH SADC 3

4 THE ROLE OF PROCESS UNDERSTANDING Pharma Air Plane 4

5 Typical Ingredients of a Tablet Active 5µm Lactose 100µm Corn Starch 30µm Microcrystalline Cellulose µm Dr. Susanne Keitel 5

6 Q8 Annex The New Paradigm Quality by Design THE ICH CONCEPT OF THE NEW PARADIGM The new Paradigm Pharmaceutical Development Q8 Defines what is the minimum (Basel Line) The role of Process Understanding Defines what is a Design Space Defines Regulatory Flexibility Pharmaceutical Development Q8 Annex Defines what is Quality by Design The role of a Systematic Approach Defines Critical Quality Attribute Examples of Design Space Defines Control Strategy Development of Drug Substances Q11 Defines what is the minimum (Basel Line) The traditional and enhanced Approaches Defines Critical Quality Attributes (CQA s) How to use Quality Risk Management 6

7 A PROCESS IS WELL UNDERSTOOD WHEN all critical sources of variability are identified and explained; variability is managed by the process; and, product quality attributes can be accurately and reliably predicted over the design space The PAT Guidance 7

8 ICH Q8(R) : DEFINITION Quality by Design: A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. 8

9 WHAT IS QUALITY BY DESIGN Elements of a QbD Systematic Development Approach Formulation Understanding Process Understanding Packaging Understanding Application of Quality Risk Management Advanced Control Strategy 9

10 TRADITIONAL VERSUS ENHANCED DEVELOPMENT

11 Conventional PD Mainly empirical approach Quality assured by endproduct testing and inspection Process is fixed, disallowing changes Focus on process reproducibility often avoiding or ignoring variability Limited and simple IPC Control Strategy based on end product testing Quality by Design(ideal) A systematic approach Quality assured by well understood product and process, moving controls upstream without relying only on endproduct testing justified in a Control Strategy Flexible process within design space, allowing continuous improvement Focus on formulation and process robustness understanding and controlling variability Extended PAT tools replacing the need for end product testing Extended Control Strategy based on QRM 11

12 Q8 GENERAL CONCEPTS: REGULATORY FLEXIBILITY This scientific understanding facilitates establishment of an expanded design space. In these situations, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate: risk-based regulatory decisions (reviews and inspections); manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review; reduction of post-approval submissions; real-time quality control, leading to a reduction of 12

13 POSSIBLE REGULATORY FLEXIBILITY Continuous Improvement Real time release Reduced or elimination of routine end product testing Expanded design space Independence on scale Independent of equipment Independent of site Independent from drug substance manufacturing if within spec Process Validation Process validation replaced by Concurrent Process Verification using validated methods (qualified controls) Stability Testing Reduced confirmation stability studies for any changes within the design space Reduced annual stability batches 13

14 ADDITIONAL BENEFITS OF QBD Faster Development Better Formulations Better Process Less Rejects and OOS/OOE Less QA investigations More consistent and reliable Quality Reduced manufacturing cost Less Transfer problems 14

15 Q8 GENERAL CONCEPTS WHAT IS MINIMAL REQUIREMENT At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. 15

16 Q8 GENERAL CONCEPTS WHAT IS CRITICAL? Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product. 16

17 ICH Q11 17

18 Q11 SCOPE For Drug Substance from Chemical Origin Biotech Origin 18

19 MINIMUM REQUIREMENTS Manufacturing process development should include, at a minimum, the following elements: Identifying potential CQAs associated with the drug substance so that those characteristics having an impact on product quality can be studied and controlled; Defining an appropriate manufacturing process; Defining a control strategy to ensure process performance and drug substance quality (see Section 6 on Control Strategy). 19

20 Q11 ENHANCED APPROACH An enhanced approach to manufacturing process development would additionally include the following elements: A systematic evaluation and scientific understanding of the manufacturing process, including use of QRM; Determination of the functional relationships and relevant multivariate interactions that link material attributes and process parameters to drug substance CQAs; Using the enhanced approach in combination with QRM to establish a more focused control strategy which can include proposals for a design space(s). 20

21 IMPORTANCE OF IMPURITIES For drug substance development a major focus is knowledge and control of impurities 21

22 THE ROLE OF RISK MANAGEMENT (QRM) Risk assessment can be used during development to identify those parts of the process likely to impact potential CQAs and drive process improvement to mitigate quality risk. Further risk assessments can be used to focus development work in areas where better understanding of the link between process and quality is needed 22

23 ENHANCED APPROACH Identify potential sources of process variability; Identify the material attributes and process parameters likely to have the greatest impact on drug substance quality. This can be based on prior knowledge and risk assessment tools; Design and conduct experiments and/or mechanistic studies (e.g., multivariate Design of Experiments, simulations, modelling) to identify and confirm the links and relationships of material attributes and process parameters to drug substance CQAs; Conduct analysis of the data to establish appropriate ranges, including establishment of a design space if desired. 23

24 6. CONTROL STRATEGY Every drug substance manufacturing process, whether developed through a traditional or an enhanced approach (or some combination thereof), has an associated control strategy. A control strategy can include, but is not limited to, the following: Controls on material attributes (including raw materials, starting materials, intermediates, reagents, primary packaging materials for the drug substance, etc.); Controls implicit in the design of the manufacturing process (e.g., choice of reagents or media, sequence of operations); In-process controls (including in-process tests and process parameters); Controls on drug substance (e.g., release testing). 24

25 POINTS TO CONSIDER

26 ICH Q8/Q9/Q10/Q11 Q&A S

27 POST APPROVAL CHANGE MANAGEMENT PROTOCOLS Strategy + Results Strategy + Results Currently Evaluation of a proposed variation as a whole (Strategy + Results) Early Step 1: Submission of a Change Management Protocol Fast Step 2: Reporting of implementation of a change in accordance with an approved protocol Type II Variation Type IA IN or IB Variation

28 CONTENT OF A POST APPROVAL CHANGE MANAGEMENT PROTOCOL Support of the proposed change company should submit all relevant information that can demonstrate that it has acquired adequate knowledge to prepare and manage the impact of the change. The content of the protocol could include depending on the nature of the change: Justification that there is a definite recognised future need for the specific change, within a reasonable timeframe, and that adequate knowledge has been acquired to appropriately evaluate and manage the change for the specific product concerned. Justification should also be provided for the proposed evaluation strategy.

29 SUMMARY Q8, Q9, Q10, Q11 define a new Paradigm Systematic Development Approach Formulation Understanding Process Understanding Packaging Understanding Application of Quality Risk Management Advanced Control Strategy

30 QUALITY BY DESIGN: The Future has started QbD submissions approved in US and EU including Real Time Release NEW : also for BIOTECH Products! 30