1. Dr Saranjit Singh National Institute of Pharmaceutical Education and Research SAS Nagar 160 062 India ssingh@niper.ac.in Setting Impurity Standards for APIs and Dosage Forms: An IP Perspective

2. Indian Pharmacopoeia Available Edition: 1996 Supplements: 2000, 2002 and 2005

3. Control of Impurities in IP 1996 and Supplements  Tests for Related Substances  Specific Tests for the Named Impurities  General Tests for Unnamed Impurities  Total Impurity limits  Test Design and Expression of Limits for Known and Unknown Impurities

4. IP 1996 Total number of monographs1253 Monographs with HPLC assay methods 139 Monographs with Test for Related Substances 448 TLC methods391 HPLC methods57

5. A Typical Example - TLC Method

7. Established: 9 December 2004 Indian Pharmacopoeia Commission IPC

8.  To bring new editions and supplements of Indian Pharmacopoeia at regular intervals  To accelerate the process of preparation, certification and distribution of IP reference substances  To develop understanding with International Pharmacopoeial agencies Mandate of IPC

9. ‘To promote the highest standards for drugs for use in humans and animals within practical limits of the technologies available for manufacture and analysis’ Vision Statement of IPC (Adopted 8 July 2006)

10. ……..practical limits of technologies available for manufacture and analysis? Why mention of:

11. Indian industry is fragmented into:  Indian multinationals  Large Companies  Medium sized  Small scale In total 5500 enterprises, with differences in technological capability for manufacture and analysis

12. Regulatory laboratory set-up is also fragmented:  Central Laboratories  State Laboratories  Approved Private Test Laboratories Presently differ in technological capability for analysis, though Central/State Laboratories are being upgraded with same brands of state-of-art sophisticated analytical instruments under Capacity Building Project

13. Other local compulsions  Large population of the country ~1.2 billion  Very low gross national income ~$620 (US $41,400)  390 million live on less than $1 a day  Population below poverty line: 25-29%  80% of the health care payments borne by individuals

14. So important for the Government to ensure continued supply of medicines at an affordable cost Drug NamePrice in India Price in Pakistan Price in Indonesia Price in US Ciprofoxacin 500 mg (10s) 29.00423.86393.002352.35 Norfloxacin 400mg (10s) 20.70168.71130.631843.66 Diclofenac 50 mg (10s) 3.5084.7159.75674.77 Source: OPPI website, 45 INR = 1$ Price comparison of some well known drugs in INR

15. In this scenario The drug quality standards need to be rational, practical and simple The products sold in the country presently comply to standards laid down in Indian Pharmacopoeia 1996, the monographs of which meet the above requirements

16. The perspectives of IPC on impurities in pharmaceuticals in future editions of compendia

17. ‘To give special attention to the methods of manufacture used by the indigenous industry in selecting the pharmacopoeial tests for monitoring the toxic impurities of the concerned drug.’ An objective of IPC (Adopted 8 July 2006)

18. Basic decisions of IPC on Impurities  Minimum change in existing monographs  For new monographs, impurity control directed to be a part of Related Substances test  Both TLC and HPLC methods acceptable  Stringent limit, if an impurity is toxic and/or named impurity is to be controlled (e.g., N,N- dimethylalinine in cloxacillin sodium, <20ppm) Cont.…

19.  IPC to take care that Related Substances test in new monographs received from industry has no barrier element  In all situations, the test must be possible in Government and Private Laboratories Other perspectives of IPC on Impurities

20. “The use of chromatographic methods has been greatly extended to cope with the need for more specificity in assays and in particular, in assessing the nature and extent of impurities in ingredients and products” IP 2007: INTRODUCTION

21. IP 1996 versus 2007 19962007 Total number of monographs 1253 1253 -13 +257 = 1497 Monographs with HPLC assay methods 139139+…… Monographs with test of Related Substances 448448+~100 TLC methods391~390 HPLC methods57 57+~100

22. IP 2007 General Chapter on Impurities 5.5 Impurities This chapter provides guidance on the control of impurities in drug substances and formulated preparations. It applies mainly to totally synthetic organic medicinal substances and those substances obtained by synthetic modification of a naturally- produced precursor; it is not necessarily relevant to other organic substances e.g. those of plant or animal origin, biological and biotechnological products, inorganic substances and pharmaceutical excipients. It provides an approach to the setting of limits for impurities in articles for which the individual monographs do not provide either a test or specific limits. An impurity is defined as any component of a drug substance for pharmaceutical use or of a drug product that is not the chemical entity that defines the substance, or in the case of a drug product, not an excipient in the product. It includes among other things, degradation products of the drug substance that may develop on storage and in the case of dosage forms, those that may also be formed during manufacture and storage.

23. Acceptance criteria for impurities in drug substances: Each identified specified impurity Not more than 0.5 per cent Each unidentified impurityNot more than 0.3 per cent Total impuritiesNot more than 1.0 per cent Provided it has been determined that the impurities are not toxic. Higher limits may be set if scientifically justified. General Chapter

24. Acceptance criteria for degradation products in drug products: Each identified degradation product Not more than 1.0 per cent Each unidentified degradation products Not more than 0.5 per cent Total degradation productsNot more than 2.0 per cent Provided it has been determined that the impurities are not toxic. Higher limits may be set if scientifically justified. General Chapter (cont…)

25. ‘Although a primary objective of the Pharmacopoeia is to guarantee the identity, strength, purity and quality of official articles, it is not possible to include in each monograph a test for every impurity or contaminant or even an adulterant that might be present’ Viewpoints in the General Chapter

26. “The exclusion of a limit for impurities in a monograph does not absolve the manufacturer of providing assurance to the user on the safety of a drug. It is incumbent on the manufacturer to follow good manufacturing practices (GMP) and to ensure the limitation of impurities based on knowledge of the properties of the chemical entity and the likelihood of related substances being associated with the end product during production and subsequent storage.” Viewpoints in the General Chapter (cont..)

27. “Material found to contain an impurity not detectable by the prescribed tests of a monograph may be deemed to be not of pharmacopoeial quality particularly if the nature of the impurity(ies) found is not compatible with GMP. In any case, the specifications should in course of time be refined to include tighter and more specific limits in the light of experience with production batches and a better understanding of the manufacturing process.” Viewpoints in the General Chapter (cont..)

28. So, an overall perspective of IPC CONTROL OF IMPURITIES is more stronger regulatory and GMP issue, than compendial So only reasonable control in IP, except for those related substances that are known or even doubted to adversely influence safety of the product

29. What IPC aspires for Information on impurities associated with side effects or toxic reactions, including genotoxicity, so that specific named tests can be added in existing or new monographs of Indian Pharmacopoeia Simple tests for these impurities

30. Current Dynamics of Indian Pharmaceutical Industry

31. Top Indian Companies – Way Ahead  Export oriented Indian companies, which have world class facilities, completely comply to stringent International regulatory expectations on impurities  Some of the Indian companies have more than 600 HPLC systems, change 100 columns per day, and are equipped with most sophisticated instruments, like LC-MS, LC- NMR, etc., which are being used for impurity profiling and structure characterization

32. An Example of Maturity of Indian Industry FDAnews Drug Daily Bulletin Nov. 16, 2007 | Vol. 4 No. 226 Generic Firm Commences Gabapentin Recall Due to Excessive Impurities Ranbaxy Pharmaceuticals initiated a voluntary Class III recall of 73 million gabapentin tablets because the allowed level of impurities in the tablets exceeded their specification limits, according to FDA documents. Gabapentin is the active ingredient in Pfizer’s antiseizure drug Neurontin, which is off patent. The affected dosage strengths include the 600- and 800-mg tablets. Ranbaxy’s abbreviated new drug application (ANDA) for the tablet formulation is for those two strengths and the firm holds approval for a capsule formulation as well. The company could not comment on whether the recall will create a shortage of its tablets.

33. A Few Distinct Advantages  The drive of export-oriented Indian Pharma companies, to meet stringent quality and impurity control expectations of International agencies, has lead not only to creation of excellent facilities and trained manpower, it has been indirectly responsible for improvement of quality of pharmaceuticals sold within the country, as the same companies hold 70% share in the local market  This is happening without intervention of local pharmacopoeial and regulatory agencies

34. The Benefit of Indian System as a Whole The Indian system encourages the big players, but it also protects medium and small scale enterprises, which are very much needed in the chain of supply of drugs to large population of the country with marked differences in paying capacities

35. Summing up…

36. For a country with >1.2 billion people The priority is AVAILABILITY of GOOD QUALITY DRUGS at AN AFFORDABLE COST

37. Our belief is…

38. GOOD QUALITY of drugs and products can be well assured by recently adopted approach of IPC on impurities

39. Somehow…

40. We at IPC are not fully convinced on the trend in USP, EP, BP, etc. on searching impurities in each and every product, even old and well established, at ICH thresholds, which we consider is guided more by protectionist approach of big players in Pharmaceutical industry

41. A glimpse of emerging standards….

42. European Pharmacopoeia 5.0, 2005

43. EP 5.0 (2005) (Ph Eur monograph 0906 )

47. Due to tropical environmental conditions in India, it may not be reasonable to expect Industry to control individual degradation products in formulations at 0.1 or 0.15%

48. Moreover, a moot point….

49. If there is no emphasis on impurities in kilogram(s) and liters of food taken by an individual in a day Then how come it is a so serious issue for few milligrams of drug(s) consumed in a tiny pill daily?

50. So overall,

51. 1. There is a need to ponder whether the forensic analysis of pharmaceuticals is all that necessary 2. Something, which is real toxic and difficult for our bodies to handle, must be controlled but not every type of minutiae

52. 3. The compendia require innovative thinking, wherein impurities are classified drug-wise as ‘toxic’ and ‘safe’, with emphasis only on those that might be harmful 4. Compendia must pursue policy of exclusion rather than inclusion, unlike the trend being pursued currently

53. Thanks so much