1. General Aspects of Quality assessment of multisource interchangeable medicines Rutendo Kuwana Technical Officer, WHO, Geneva Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

2. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 2 |2 | Topics Principles of assessment Quality by design (QbD) Pharmaceutical Development, including "Design Space" Pharmaceutical Quality System

3. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 3 |3 | Principles of assessment of Generic Products The assessors should bear in mind the general principles that the applicant, as much as possible, must use the Innovator as a reference characterises the Innovator drug product to establish pharmaceutical equivalence with their generic - primary strategy is to develop a generic using reverse engineering of the innovator - Data from these studies used to generate the target profile for the generic manufacturer. Employs the strategy of qualitative and quantitative determination of the Innovative Drug Product and reproduces this formulation As much as possible uses Pharmacopoeial or peer reviewed analytical methods Collaboration between assessors and inspectors should be established from dossier submission and during the life cycle of the product

4. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 4 |4 | Pharmaceutical Development and QbD Quality by Design Systematic approach to development that uses predefined objectives with emphasis on product and process understanding and control, based on sound science and quality risk. Ref: ICHQ8 (R1)

5. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 5 |5 | Pharmaceutical Development The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. Quality cannot be tested into products; it should be built - in by design. ICH Q8

6. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 6 |6 | Advantages of documented Pharmaceutical Development Based on information submitted or available with the applicant/Manufacturer on the level of development (scientific understanding) achieved the assessors or regulatory authority may: –Apply a risk-based approach for regulatory decisions (reviews and inspections); –Permit manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review; –Reduce requirements for post-approval submissions; –Permit real-time release testing, leading to a reduction of end- product release testing.

7. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 7 |7 | Pharmaceutical Development - Aims Comprehensive Pharmaceutical Development leads to release of a product with –an appropriate manufacturing process –a defined Quality Target Product Profile –identified critical quality attributes (CQA) of the drug product –determined quality attributes of the starting materials (drug substance, excipients) –identified control strategy

8. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 8 |8 | Elements of Pharmaceutical Development Risk assessment –Linking material attributes and process parameters to drug product CQAs Design space Control strategy: a must Product lifecycle and continual improvement: basic for the lifecycle approach of product and process quality

9. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 9 |9 | Design space - Definition The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement outside of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. ICH Q8 (R1)

10. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 10 | Design Space: possible way of illustration Multidimensional combination and interaction of input variables/process parameters demonstrated to provide assurance of quality (multivariate analysis) : operating ranges Y0 X0 Yn Z0 Zn Xn X =Temperature Y = Time Z = Water

11. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 11 | Establishment of a Design Space Establishment of the Relationship and Interaction between CPPs and CQAs. Identification of those process parameters which can influence the quality of the product Results should demonstrate within which ranges process parameters can be varied without affecting the quality of the product (quality attributes). design space provides relationships with scale up and equipment changes

12. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 12 | Elements of a Design Space Design space versus acceptance ranges –Operation within the range of a well characterised range of a process parameter, while keeping other parameters constant, will result in product meeting relevant quality criteria. Design space and edge of failure Establishment of a Control strategy

13. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 13 | Real Time Release Testing (RTRT) Bases the release of a product on product and process understanding rather than on end product testing alone and/or on the results of batch analysis. This implies –Understanding the science around the product and process Identifying the parameters (critical) of active, excipients, process that influence quality –Establishment of a risk based control strategy that monitors the important parameters influencing the CQAs; gives the basis for RTRT or reduced end product testing.

14. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 14 | Examples of RTRT Sterilisation –Injectables: compliance with the specification “sterile”: via parametric release rather than with the conventional Pharmacopeial “Sterility test”; monitoring of critical parameters (time, pressure, temperature, ….) Dissolution –Release parameters e.g. Particle size of active substance and/or excipients Hardness of the tablet Disintegration

15. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 15 | Pharmaceutical Quality System A management system that directs and controls a pharmaceutical company with regard to quality It calls for a continuous improvement of Process Performance and Product Quality

16. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 16 | Definition of Product Lifecycle Development Technology Transfer Manufacturing Product Discontinuation - Procurement of materials - Provision of facilities, utilities and equipment - Production (including packaging and labelling) - Quality control and assurance - Release - Storage - Distribution (excluding wholesaler activities) - Formulation development (including container/ closure system) - Manufacturing process development and scale-up - Analytical method development - New product transfers from Development to Manufacturing - Transfers within or between manufacturing and testing sites for marketed products - Retention of documentation - Sample retention - Continued product assessment and reporting Extracted from ICH Q10

17. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 17 | Conclusion Quality is based on a sound combination of science (enhanced scientific knowledge), use of risk management tools and the establishment of an efficient Quality System