Regulatory Compliance for Global Pharma Market

1. Regulatory Compliance for Global Pharma Market Dr Rajiv A. Desai President – Quality Dishman Pharmaceuticals and Chemicals Ltd Ahmedabad , INDIA Workshop Organised by Ahmedabad, Gujarat 18th December 2012

2. Basics of Business What is the main aim of doing a business ? Earn Profit ! When customer is ready to pay a good price, What is expected ? • Consistency • Quality • Value for money Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

3. Pharma share around the world Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

4. Generic Pharmaceutical Industry Generic Drug substances and drug products allowed after patent expiration A big business opportunity within the Pharmaceutical Industry Cost of Generic drugs significantly lower than the Innovators Generic Pharmaceutical companies look for opportunities targeting the patent expiration dates Around the world , various countries and geographies provide lucrative markets in the pharmaceutical space Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

5. Patent expiration of drugs (year wise ) Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

6. Opportunities in the US Market US Pharma market size is approx USD 320 billion Generic substitution approximately 75 % One of the largest and most matured market, globally Reforms initiated by the US Government to reduce health care spending Many Indian companies have ANDA filings, in-line with patent expiration Para IV / FTF have formed a major share for many Indian Pharma companies Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

7. Opportunities in the Europe Market European Generics market is diverse Regulations and Generics penetration varies across Countries Several governments have implemented measures at reducing healthcare spending Generic Penetration in Europe Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

8. Opportunities in the Japanese Market Reforms on reducing health care spending by Japanese Government is opening up new opportunities for Generics Consumer mindset strongly towards brands Generics market was around 23% at the beginning of 2012 This has gone up to ~ 30% by end of 2012 Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

9. Opportunities in the Emerging Market Emerging Market represent the fastest growing segment of the Global Pharma Industry Total spending on health care likely to grow from approx USD 150 Billion to USD 300 Billion by 2015 Russia, South Africa, Latin America (Brazil, Mexico ) and South East Asia are fast growing regions Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

10. Increase in DMF submissions with the US FDA Number of DMF submissions Reference : US FDA presentation on GDUFA Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

11. Increase in ANDA submissions with the US FDA Number of ANDA submissions Year 2011 saw the highest number of submissions Reference : US FDA presentation on GDUFA Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

12. Backlog of ANDAs Reference : US FDA presentation on GDUFA Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

13. Reference : US FDA presentation on GDUFA Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

14. Reference : US FDA presentation on GDUFA Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

15. US FDA outside USA Why ? Many overseas manufacturing facilities Large quantum of Outsourcing of manufacturing and clinical trials Imports coming from countries with less well developed regulatory systems Inspections should not be done at the borders of USA Borders must be placed at the point of manufacturing Engage more effectively aboard in order to be more effective at home ( Beyond the Borders ) India Office operational since January 2009 Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

16. Reference : US FDA presentation on GDUFA Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

17. US DMF filings from India India has more than 2600 DMFs filed with the US FDA, highest number in the world !! More than 300 facilities have been inspected and accepted for manufacturing in India Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

18. ANDA filings from India During the year 2007 to 2011 2244 ANDA were approved from around the world Contribution from India 694 ANDAs During the year 2011 431 ANDAs approved Contribution from India 144 ANDAs Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

19. US FDA will now charge fees ! • Generic Drug User Fee Act (GDUFA) • Fees for DMF (Drug Master file) $ 21,340 • based on expected 700 DMFs to be filed • Fees for ANDA ( Abbreviated New drug Application) $ 51,520 • based on expected 850 ANDA to be filed • Fees for PAS ( Prior Approval Supplement ) $ 25,760 • based on expected 576 PAS submissions • Assumption of number of submissions based on previous year’s data • Fees calculations , updated by US FDA on 25th Oct 2012 • The rates will be effective till Sept 2013 Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

20. Why facility audits are required ? Driven by National Health Services for cheap medicines, market for Generic API has increased. 70% of all APIs consumed in Europe are imported from China and India Aggressive competition amongst the manufacturers for lowering the price has led to cases of compromising Quality of the APIs. Unknown impurities are a major concern for provoking side effects and adverse reactions. “Chinese Heparin” which caused more than 100 death in USA was attributed to adulteration to bring down price and shortage of actual source of Heparin. Cases of use of uncertified outsourcing increasing Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

21. Recent European Union Directive European Parliament and Council of European Union published a Directive 2011/62/EU on 8th June 2011 on Falsification of Medicinal products Local drug Regulatory authorities must certify the products exported by manufacturers maintain Quality and follow cGMP as prescribed by EU drug regulations Such certificate should be in place even after the manufacturing facility and products get all regulatory clearances from EU drug regulatory authorities The directive promoted with the aim of protecting EU patients from falsified medicines This certification should be in place by 2nd July 2013, applicable for drug substance intended for human consumption Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

22. Format to be used for the Certification as per EU

23. Current format as used by the FDCA, Gujarat

24. Initiative by the CDSCO on the EU directive Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

25. Mutual Recognition Agreement awaited … The European Fine Chemicals Group (EFCG) is proposing a global harmonisation of the rules and regulations governing the manufacture of active pharmaceutical ingredients (APIs) Expected to provide consistency of Quality of APIs and Medicines will meet the high standards as recognized by ICH This should be achieved by mandatory inspections of all global API manufacturers by a Mutual Recognition Agreement (MRA) and managed by a National Regulatory authorities to share limited inspection resources and avoid duplication Reference : EFCG news release dated 12th Nov 2012 Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

26. Opportunities Big opportunities bring big profits High Quality standards expected Big Opportunities also brings in fierce competition Cost cutting / Cost saving Problems with compromised Quality Risk to patients Government responsibility increases to ensure safe medicines Regulatory audits and inspections become strict Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

27. Why is an audit done ? • Protect Consumers ( Patients ) • Collect evidence Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

28. Why an audit is required ? Physical inspections of the manufacturing facility Check operations in the manufacturing area Verify written procedures v/s actual practice Check capability of people Check controls on material management Check the Process development activities Check packaging and logistics Ensure quality products to patients Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

29. Importance of an audit • Site inspections are one of the primary means by which the regulatory authorities interface with companies • Systematic preparation for an audit will have a positive inspection • A favorable inspection also helps build confidence and credibility with the regulatory agency including • Product Approval • Customer Loyalty • Business Impact Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

30. Audit methodologies • Walk though the material flow within the site • Check for the SOPs being used at the site by various departments • Review the activities of the site and compare the SOP for compliance • This is a slow and tedious process !! Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

31. New approach of auditing • It’s a known fact that nobody is perfect, problems will be faced, • lets see how the problems are handled …. • Deviations / Non-conformance • Change controls • OOS • Reprocess / Rework • Rejections • Complaints • Preventive maintenance Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

32. Auditor’s wish list • What will satisfy an auditor ? • List of various deviations and OOS • Full documented evidence of Investigation reports • Identification of possible root cause • Corrective and preventive actions • What will make the auditor uncomfortable ? • No documented evidence of any incidences • Improper investigations • Investigations not based on Scientific rationale • It is difficult to predict what a specific auditor would want to see • But, its possible to prepare well ! Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

33. Audit preparation • Be on-line • Last minute preparation should be avoided • Concentrate on…. • Team members • Facilities • Documents Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

34. During the audit • Investigation • Quality records and documents are reviewed • Documents and the actual practices are cross verified Remember …. What was not documented, was not done US FDA is well known to emphasise on documents European Regulatory agencies focus more on the facilities and spend more time at the shop floor talking to employees Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

35. What do Auditors evaluate ? • Auditors observe body language • Non-verbal and verbal behavior, looking for some mistakes • Look out for typical style of the auditee for • Too anxious or polite • Defensive • Rationalizing • Apologetic • Quiet • Posture and body position • Restless • Very Rigid • Rapid changes in posture • Avoids eye contact Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

36. During the audit • Listen to the question, if it isn’t clear… ask again • Answer all questions honestly • Don’t answer what is not asked • Don’t ever guess • Don’t volunteer information • Don’t be afraid of silence Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

37. During the audit • Demonstrate a cooperative, polite and professional attitude • Speak with confidence • Answer with supporting facts and evidence • Restrict the number of team members interacting with the auditor. • Every thing that is said to the auditor will go on record and will be part of the report Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

38. During the audit – Unacceptable points • Become Defensive and start an argument • Make blunt refusals on the requests • Respond to questions outside your expertise • Attempt to answer a hypothetical question • Intentionally mislead or lie • Start blaming others or departments for the mistakes • Make any personal comment on the quality of the investigator Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

39. During the audit – Unacceptable points • Agree or disagree if the Auditor points out a potential problem or concern • Claim to be an expert in Good Manufacturing Practices (GMP) or other regulations • Generate questions by offering un-requested information or asking questions of the Investigator • Feel obligated to fill silence (pauses) with further clarification or talk • Say something is impossible or could not happen • Ask a team member additional questions in front of the Investigator • Allow the use of audio or video recording devices by the investigator (without first getting approval from site management) Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

40. Response to the audit observations • Ensure that the audit response is sent before the agreed date • Response should include • Root cause analysis • Correction, Corrective action, Preventive action, • Proof of actions taken • Evaluation of other similar areas not seen by the auditor • An updated response would be required , in case of a delayed completion of the corrective action. • Keep the language as soft as possible • Try to get the proper understanding of the observations so that the response is appropriate for the point made. • Seek clarifications on the observations during the audit Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

41. Response to the audit observations • Respond clearly and completely to the observations and show that the observation was properly understood and addresses the issue in full • Response should have the full story, because the response is read by other members within the regulatory agency who were not part of the audit. • Provide a confidence that by responding to the observation , all the applicable laws and regulations are followed • Provide corrective actions, taking into consideration impact to product, processes and Quality System • Explain how corrective and preventive actions will be monitored to ensure effectiveness Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

42. Quality standard comparison Pharmaceutical Semiconductor Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

43. Setting high standards for Quality Voluntary recall of formulations by Pharma companies in US US FDA database Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

44. Regulatory guidelines Regulatory Agencies update their websites with the latest requirements What’s known today becomes obsolete after a few months. Misinterpretation of guidelines Over reacting to Regulatory guidelines Simple problems have simple solutions Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

45. Expectations Members working in Research and Manufacturing should consider a job rotation in Quality Assurance and Regulatory Affairs Universities and Institutes should proactively update their post graduate syllabus to include QA and Regulatory topics Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

46. Communication is important Communication, Interaction and Support between Manufacturers and Regulators Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

47. Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

48. Let us strive to develop, manufacture, comply safe sale and availability of medicines Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012

49. Thank you