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Dr Saranjit Singh
National Institute of Pharmaceutical Education and Research SAS Nagar 160 062 India
ssingh@niper.ac.in
Indian Pharmacopoeia
Test Design and Expression of Limits for Known and Unknown Impurities
IP 1996
Total number of monographs Monographs with HPLC assay methods Monographs with Test for Related Substances TLC methods HPLC methods 1253 139 448 391 57
IPC
Established: 9 December 2004
Mandate of IPC
To
bring new editions and supplements of Indian Pharmacopoeia at regular intervals accelerate the process of preparation, certification and distribution of IP reference substances develop understanding with International Pharmacopoeial agencies
To
To
Vision Statement of
IPC
To promote the highest standards for drugs for use in humans and animals within practical limits of the technologies available for manufacture and analysis
In total 5500 enterprises, with differences in technological capability for manufacture and analysis
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
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
So important for the Government to ensure continued supply of medicines at an affordable cost
Price comparison of some well known drugs in INR
Drug Name
Ciprofoxacin 500 mg (10s) Norfloxacin 400mg (10s) Diclofenac 50 mg (10s)
Price in
India
29.00 20.70 3.50
Pakistan
423.86 168.71 84.71
Price in
Indonesia
393.00 130.63 59.75
Price in
Price in
US
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
An objective of IPC
(Adopted 8 July 2006)
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.
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,Ndimethylalinine in cloxacillin sodium, <20ppm)
IPC
to take care that Related Substances test in new monographs received from industry has no barrier element all situations, the test must be possible in Government and Private Laboratories
In
IP 2007: INTRODUCTION
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
2007
1253 -13 +257
=
1253
139 448 391 57
1497
General Chapter
Acceptance criteria for impurities in drug substances:
Each identified specified impurity Each unidentified impurity Total impurities Not more than 0.5 per cent Not more than 0.3 per cent Not 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
(cont)
Provided it has been determined that the impurities are not toxic. Higher limits may be set if scientifically justified.
(cont..)
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.
(cont..)
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.
What
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
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, LCNMR, etc., which are being used for impurity profiling and structure characterization
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
Summing up
AVAILABILITY
of
AN AFFORDABLE COST
Our belief is
GOOD QUALITY of drugs and products can be well assured by recently adopted approach of IPC on impurities
Somehow
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
EP 5.0 (2005)
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%
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?
So overall,
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
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
Thanks so much