1. 1 Quality Management for 21 st Century S. Srinivasan CEO & Managing Director Matrix Laboratories Limited

2. 2 Indian Pharmaceutical Companies – geared up for global market Quality Management for 21 st Century Quality Risk Management Product Development Process Analytical Technology (PAT) Regulatory Review Conclusion

3. 3  Current size of the global Pharma market is around US$ 800 billion –  Generic market US$ 93 billion &  the API market US$ 37 billion (Source: Espicom business intelligence)  Global demand of APIs is expected to increase at CAGR of over 8% over the next 5 years (Source: Chemical Pharmaceutical Association (CPA))  A recent study by E&Y indicates projected growth in Pharma outsourcing out of India of over 40%.  India projected as an excellent destination for cost efficiency in manufacturing, coupled with strong supply of skilled manpower, in comparison to China, Eastern Europe, Puerto Rico, Singapore & Ireland Indian Pharmaceutical Companies – geared up for global market

4. 4  India has maximum number of USFDA approved plants outside the US and last few years filed the maximum number of DMFs.  Indian companies play a predominant role in the WHO pre-qualification programme related to Malaria, TB and HIV/AIDS.  Indian pharmaceutical and API players are well positioned to take advantage of this market opportunity.  Indian companies have created good infrastructure with cGMP compliant plants over the last decade. Indian Pharmaceutical Companies – geared up for global market

5. 5 Indian Pharmaceutical Companies – geared up for global market Quality Management for 21st Century Quality Risk Management Product Development Process Analytical Technology (PAT) Regulatory Review Conclusion

6. 6 Quality Management for 21st Century  An integrated quality system should cross into all areas of operations.  QMS to be designed to assure quality into the manufacturing and control processes.  ICH Q10 is not intended to create any new expectation beyond current regulatory requirements. This guideline has been formed by integrating GMP requirements (ICHQ7) and ISO QMS guidelines. It serves as a bridge between regional requirements, facilitating harmonization of pharmaceutical quality system.  Implementation of ICH Q10 should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities.

7. 7 Main objectives of Q10 are :  To achieve product realization  Establish and maintain a state of control, and  Facilitate continual improvement Pharmaceutical quality system should include the following elements -  Process performance and product quality monitoring  Corrective and preventive actions  Change management and management review  Key performance indicators should be identified and used to monitor effectiveness of processes. These indicators can be derived during the development process and also from manufacturing experience. They can be used as enablers for continual improvement. Quality Management for 21st Century

8. 8 The quality management system presents continuous validation -concept to replace the current three-batch process validation concept, i.e. move from paradigm of “testing to assure quality” to “designing to assure quality” and increase process capability to minimize risk. Implementation of this framework will place tremendous responsibility on the pharmaceutical manufacturers to have the Operations and Quality teams well- trained in quality management initiatives In integrated QMS, there is an interplay of several ICH guidelines - - ICHQ8 on Product Development - ICHQ9 on Quality Risk Management Quality Management for 21st Century

9. 9 Indian Pharmaceutical Companies – geared up for global market Quality Management for 21st Century Quality Risk Management Product Development Process Analytical Technology (PAT) Regulatory Review Conclusion

10. 10  ICH Q9 should serve as a foundation and complement existing quality practices, standards and guidelines within the pharmaceutical industry.  Appropriate use of quality risk management can facilitate regulatory compliance to a substantial degree and also improve quality of communication between industry and regulators.  A rational approach to risk management has to begin with the question “What is the impact on the product?” Quality Risk Management

11. 11 This guideline provides a framework that may be applied to all aspects of pharmaceutical business, including  development, manufacturing and distribution  inspection and submission /review processes throughout the lifecycle of drug substances, biological and biotechnological products and  use of raw materials, solvents, excipients, packaging and labeling materials. Quality Risk Management

12. 12 Risk Management is about:  knowing our processes (manufacturing and business)  understanding what is truly important  not spending time on a low risk activity, process, event or system because it just doesn’t matter!  focusing our money, time, energy and people on the things that are really important  focusing our efforts and resources on the things that provide quality assurance to our customers Risk Management is not about:  making do with insufficient time, money or people  providing an excuse not to do the right things  deciding what to do based on what might be observed during an inspection Quality Risk Management

13. 13 It is imperative therefore, that we as API manufacturers are able to and perform a scientific and practical risk management process as a part of the quality management and  document the observations  the actions and other related details based on current knowledge about assessing the probability  the severity and detectability of the risk. Output of a risk assessment could either be a quantitative estimate of risk or a qualitative description of a range of risks. Quality Risk Management

14. 14 Based on the risk analysis, one could arrive at appropriate risk control measures to reduce and /or accept risks. Training of industry personnel in quality risk management process provides for greater understanding of decision making processes and builds confidence in quality risk management outcomes. Quality Risk Management

15. 15 Example 1 : Quality Risk Management Recent examples of improper evaluation of manufacturing processes ( Source : http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viracept/Viracept-H-164-Z-109-AR.pdf ) Nelfinavir  Europe wide recall of the HIV drug Nelfinavir  Patients reported strange smell on the tablets  Investigation revealed high level of Ethyl Mesylate (EMS) a potential genotoxic impurity  Investigation at the manufacturing plant identified ethanol contamination in a holding tank of Methane Sulphonic Acid (MMS)  Ethanol was used as a cleaning solvent which was not part of a regular procedure  Residual ethanol got converted to EMS in presence of MMS  Lack of knowledge & understanding of the manufacturing process

16. 16 Example 2 : Quality Risk Management Recent examples of improper evaluation of manufacturing processes (Source : http://www.ibc-asia.com/GenericsAsia/Day%201/Ron%20Tomer.pdf ) Terbinafine  A potential impurity was identified in the manufacturing process of the API  Launch of the Generic version was delayed due to lack of knowledge  Impurity was expected to be generated due to two starting materials (Acrolein and PCl 5 )  EDQM initially set a limit of 6 ppm and after additional studies fixed the limit at 500 ppm  This impurity now appears as a listed impurity in the EP monograph

17. 17 Indian Pharmaceutical Companies – geared up for global market Quality Management for 21st Century Quality Risk Management Product Development Process Analytical Technology (PAT) Regulatory Review Conclusion

18. 18  Another integral part of the new quality management system is ICHQ8 on 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.  The information and knowledge gained from pharmaceutical development and manufacturing experience provide scientific understanding to support the establishment of specifications and manufacturing control.  Information from pharmaceutical development studies can be a basis for Quality Risk Management Product Development

19. 19  Changes in formulation and manufacturing processes during development and lifecycle management are opportunities to gain additional knowledge.  Movement out of the “controls window” should be considered a change and would normally initiate a regulatory post-approval change process. Product Development

20. 20 Example 3 : Trend Analysis before CAPA

21. 21 Example 3 : Trend Analysis after CAPA

22. 22 Indian Pharmaceutical Companies – geared up for global market Quality Management for 21st Century Quality Risk Management Product Development Process Analytical Technology (PAT) Regulatory Review Conclusion

23. 23 Process Analytical Technology (PAT)  Process analytical technology approach should encourage voluntary development and implementation of innovative approaches to pharmaceutical manufacturing and quality assurance.  Many new technologies that provide information on physical, chemical, biological characteristics of materials will help in improving process understanding, predict quality and performance.  Regulatory expectations are so high that manufacturers are expected to use such technologies to improve efficiency and effectiveness of process design, manufacturing controls and quality assurance.

24. 24 Gains in quality and efficiency from PAT could vary and are likely to come from:  reducing production cycle times by using on-line measurements and controls  preventing rejects, scrap and re-processing  real time release  increased automation to improve operator safety and reduce human errors  improving energy and material use and increasing capacity  facilitating continuous processing to improve efficiency and manage variability The integrated quality system orientation affords a flexible regulatory approach for implementation of PAT under the facilities’ own quality system Process Analytical Technology (PAT)

25. 25 Indian Pharmaceutical Companies – geared up for global market Quality Management for 21st Century Quality Risk Management Product Development Process Analytical Technology (PAT) Regulatory Review Conclusion

26. 26 Regional differences in the regulatory review processes such as filing of changes are adding complexity to manufacturers during the product life cycle. Now considerable emphasis is being placed on :  Assessment of possible Genotoxic impurities  Crystal characteristics  Polymorphism  Enantiomeric purity besides residual solvents, organic and inorganic impurities  Metal catalytic residues Regulatory Review

27. 27  The regional differences in the regulations and the different requirements for the same monograph as per different Pharmacopoeias pose its own challenge to the Industry.  Compelling necessity to develop a bank of reference standards  Increasing emphasis by the WHO and its expectation for the APIs for WHO markets to be compliant with the international pharmacopoeia, has raised an additional point of complexity.  One hopes that WHO also joins the initiative of harmonization and international pharmacopoeia gets harmonized with other standards of reference.  It is important for the manufacturers to design and develop their operations with the aim of avoiding excessive changes to their products during its lifecycle.  This would save precious time as well as resources for the organization. Regulatory Review

28. 28 Indian Pharmaceutical Companies – geared up for global market Quality Management for 21st Century Quality Risk Management Product Development Process Analytical Technology (PAT) Regulatory Review Conclusion

29. 29 Quality Guru Deming has the following to say on variability & inspection - “Depending on inspection is like treating a symptom while the disease is killing you. The need for inspection results from excessive variability in the process. The disease is variability. Ceasing dependence on inspection means you must understand your processes so well that you can predict the quality of their output from upstream activities and measurements. To accomplish this, you must have a thorough understanding of the sources of variation in your processes and then work toward reducing the variation. Ceasing dependence on inspection forces you to reduce variability.” Conclusion

30. 30 To conclude, the API industry needs to evolve to a desired quality system: Present FocusDesired Focus DocumentationTrend Data analysis Have SOPsUnderstand parameters that are critical to quality attributes Follow SOPsMeasure process capability Validate processPerform continuous quality verification Meet specifications & don’t change Undertake continuous improvement Conclusion

31. 31 Thank you