Dr. Saranjit Singh

8/2/2019 Dr. Saranjit Singh

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Dr Saranjit SinghNational Institute of Pharmaceutical Education and Research

SAS Nagar 160 062 India

[email protected]

Setting Impurity

Standards for APIsand Dosage Forms:

An IP Perspective


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Indian Pharmacopoeia

Available Edition: 1996Supplements: 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 Limitsfor Known and Unknown Impurities


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IP 1996

Total number of monographs 1253

Monographs with HPLC assay

methods

139

Monographs with Test forRelated Substances

448

TLC methods 391

HPLC methods 57


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A Typical Example - TLC Method


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Established: 9 December 2004

Indian PharmacopoeiaCommission

IPC


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To bring new editions and supplementsof Indian Pharmacopoeia at regularintervals

To accelerate the process ofpreparation, certification and

distribution of IP reference substances

To develop understanding withInternational Pharmacopoeial agencies

Mandate ofIPC


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To promote the highest standardsfor drugs for use in humans andanimals within practical limits of

the technologies available formanufacture and analysis

Vision Statement ofIPC(Adopted 8 July 2006)


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..practical limits oftechnologies available formanufacture and analysis?

Why mention of:


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Indian industry is fragmented

into: Indian multinationals Large Companies Medium sized Small scale

In total 5500 enterprises, withdifferences in technological capabilityfor 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/StateLaboratories are being upgraded with samebrands of state-of-art sophisticated analyticalinstruments 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 borneby individuals


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So important for the Government toensure continued supply of medicinesat an affordable cost

Drug Name Price inIndia

Price inPakistan

Price inIndonesia

Price inUS

Ciprofoxacin500 mg (10s)

29.00 423.86 393.00 2352.35

Norfloxacin400mg (10s)

20.70 168.71 130.63 1843.66

Diclofenac50 mg (10s)

3.50 84.71 59.75 674.77

Source: OPPI website, 45 INR = 1$

Price comparison of some well known drugs in INR


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In this scenario

The drug quality standards need to be

rational, practical and simple

The products sold in the countrypresently comply to standards laid

down in Indian Pharmacopoeia1996, the monographs of which meetthe above requirements


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The perspectives ofIPC

on impurities inpharmaceuticals in futureeditions of compendia


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To give special attention to the

methods of manufacture used bythe indigenous industry in selectingthe pharmacopoeial tests for

monitoring the toxicimpurities ofthe concerned drug.

An objective ofIPC(Adopted 8 July 2006)


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Basic decisions ofIPCon ImpuritiesMinimum 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,


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IPC to take care that Related Substances

test in new monographs received fromindustry has no barrier element

In all situations, the test must be

possible in Government and PrivateLaboratories

Other perspectives ofIPC

on Impurities


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The use of chromatographicmethods has been greatly extended

to cope with the need for morespecificity in assays and in particular,in assessing the nature and extent of

impurities in ingredients andproducts

IP 2007: INTRODUCTION


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IP 1996 versus 2007

1996 2007Total number of

monographs

1253 1253 -13 +257= 1497

Monographs with HPLCassay methods

139 139+

Monographs with test of

Related Substances

448 448+~100

TLC methods 391 ~390

HPLC methods 57 57+~100


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IP 2007General Chapter on Impurities

5.5 ImpuritiesThis chapter provides guidance on the control of impurities indrug substances and formulated preparations. It applies mainlyto totally synthetic organic medicinal substances and those

substances obtained by synthetic modification of a naturally-produced precursor; it is not necessarily relevant to otherorganic substances e.g. those of plant or animal origin,biological and biotechnological products, inorganic substances

and pharmaceutical excipients. It provides an approach to thesetting of limits for impurities in articles for which the individualmonographs do not provide either a test or specific limits.

An impurity is defined as any component of a drug substancefor pharmaceutical use or of a drug product that is not the


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Acceptance criteria for impurities in drugsubstances:

Each identifiedspecified

impurity

Not more than 0.5 per cent

Each unidentified impurity Not more than 0.3 per cent

Total impurities Not more than 1.0 per cent

Provided it has been determined that the impurities are nottoxic. Higher limits may be set if scientifically justified.

General Chapter


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Although a primary objective of thePharmacopoeia is to guarantee the

identity, strength, purity and quality ofofficial articles, it is not possible toinclude in each monograph a test for

every impurity or contaminant or evenan adulterant that might be present

Viewpoints in the General Chapter


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The exclusion of a limit for impurities in amonograph does not absolve the manufacturer ofproviding assurance to the user on the safety of a

drug.

It is incumbent on the manufacturer to follow goodmanufacturing practices (GMP) and to ensure thelimitation of impurities based on knowledge of theproperties of the chemical entity and the likelihoodof related substances being associated with theend product during production and subsequentstorage.

Viewpoints in the General Chapter(cont..)


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So, an overall perspective ofIPC

CONTROL OF IMPURITIES is more strongerregulatory and GMP issue, than compendial

So only reasonable control in IP, except forthose related substances that are known or

even doubted to adversely influence safetyof the product


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WhatIPCaspires 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 haveworld 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 mostsophisticated 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 of73 million gabapentin

tabletsbecause the allowed level of impurities in the tablets exceeded their specification limits,

according to FDA documents.

Gabapentin is the active ingredient in Pfizers antiseizure drug Neurontin, which is off patent.

The affected dosage strengths include the 600- and 800-mg tablets. Ranbaxys abbreviated newdrug 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 Pharmacompanies, 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 indirectlyresponsible 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 mediumand small scale enterprises, which are

very much needed in the chain of

supply of drugs to large population ofthe country with marked differences in

paying capacities


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Summing up


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For a country with >1.2 billion people

The priority is

AVAILABILITYof

GOOD QUALITY DRUGS

atAN AFFORDABLE COST


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Our belief is


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GOOD QUALITY

of drugs and products can be well

assured by recently adoptedapproach ofIPCon impurities


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Somehow


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We atIPCare not fully convincedon the trend in USP, EP, BP, etc. onsearching impurities in each and every

product, even old and well established, atICH thresholds, which we consider is

guided more by protectionist approach

of big players in Pharmaceutical industry


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A glimpse of emerging

standards.

E Ph i 5 0 2005


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European Pharmacopoeia 5.0, 2005


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EP 5.0(2005)(Ph Eur monograph 0906)


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Moreover, a moot point.


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If there is no emphasis on

impurities in kilogram(s)and liters of food taken byan individual in a day

Then how come it is aso serious issue for fewmilligrams of drug(s)

consumed in a tiny pilldaily?


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So overall,


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1. There is a need to ponderwhether the forensic analysisof pharmaceuticals is all thatnecessary

2. Something, which is real toxicand difficult for our bodies to

handle, must be controlled butnot every type of minutiae


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3. The compendia require innovative

thinking, wherein impurities areclassified drug-wise as toxic andsafe, with emphasis only on those

that might be harmful

4. Compendia must pursue policy of

exclusion rather than inclusion,unlike the trend being pursuedcurrently


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Documents

Dr. Saranjit Singh