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Setting Impurity Standards for APIs and Dosage Forms: An IP Perspective. Dr Saranjit Singh National Institute of Pharmaceutical Education and Research SAS Nagar 160 062 India [email protected] Indian Pharmacopoeia. Available Edition: 1996 Supplements: 2000, 2002 and 2005.

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Setting Impurity

Standards for APIs

and Dosage Forms:

An IP Perspective

Dr Saranjit Singh

National Institute of Pharmaceutical Education and Research

SAS Nagar 160 062 India

[email protected]


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Indian Pharmacopoeia

Available Edition: 1996

Supplements: 2000, 2002 and 2005


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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




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Indian Pharmacopoeia CommissionIPC

Established: 9 December 2004


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Mandate of IPC

  • 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


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Vision Statement ofIPC (Adopted 8 July 2006)

‘To promote the highest standards for drugs for use in humans and animals within practical limits of the technologies available for manufacture and analysis’


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Why mention of:

……..practical limits of technologies available for manufacture and analysis?


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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


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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


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Other local compulsions

  • Large population of the country ~1.2 billion

  • Very low gross national income ~$620

    (US $41,400)

  • 390 millionlive on less than $1 a day

  • Population below poverty line:25-29%

  • 80% of the health care payments borne

    by individuals


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So important for the Government to ensure continued supply of medicines at an affordable cost

Price comparison of some well known drugs in INR

Source: OPPI website, 45 INR = 1$


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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


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The perspectives of IPC

on impurities in pharmaceuticals in future editions of compendia


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An objective ofIPC(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 toxicimpurities of the concerned drug.’


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Basic decisions of IPCon 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.…


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Other perspectives of IPC on Impurities

  • 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


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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”



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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.


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General Chapter

Acceptance criteria for impurities in drug substances:

Provided it has been determined that the impurities are not toxic. Higher limits may be set if scientifically justified.


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General Chapter (cont…)

Acceptance criteria for degradation products in drug products:

Provided it has been determined that the impurities are not toxic. Higher limits may be set if scientifically justified.


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Viewpoints in the General Chapter

‘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’


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Viewpoints in the General Chapter(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.”


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Viewpoints in the General Chapter(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.”


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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


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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


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Current Dynamics

of

Indian

Pharmaceutical Industry


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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


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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.


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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


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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



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For a country with >1.2 billion people

The priority is

AVAILABILITY

of

GOOD QUALITY DRUGS

at

AN AFFORDABLE COST



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GOOD QUALITY

of drugs and products can be well assured by recently adopted approach of IPC on impurities



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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




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EP 5.0(2005)

(Ph Eur monograph 0906)


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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%



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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?



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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


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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



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