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
ssingh@niper.ac.in
Indian Pharmacopoeia
Available Edition: 1996
Supplements: 2000, 2002 and 2005
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
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
A Typical Example - TLC Method
Indian Pharmacopoeia
Commission
IPC
Established: 9 December 2004
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
Vision Statement of
IPC
(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’
Why mention of:
……..practical limits of
technologies available for
manufacture and analysis?
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
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
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 $1 a day

Population below poverty line: 25-29%

80% of the health care payments borne
by individuals
So important for the Government to
ensure continued supply of medicines
at an affordable cost
Price comparison of some well known drugs in INR
Drug Name
Price in
Price in
Price in
Price in
India
Pakistan
Indonesia
Ciprofoxacin
500 mg (10s)
29.00
423.86
393.00
2352.35
Norfloxacin
400mg (10s)
20.70
168.71
130.63
1843.66
Diclofenac
50 mg (10s)
3.50
84.71
59.75
674.77
Source: OPPI website, 45 INR = 1$
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
The perspectives of IPC
on impurities in
pharmaceuticals in future
editions of compendia
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)
Other perspectives of
on Impurities
IPC
 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
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”
IP 1996 versus 2007
1996
2007
Total number of
monographs
Monographs with HPLC
assay methods
1253
1253 -13 +257
139
139+……
Monographs with test of
Related Substances
448
448+~100
391
~390
TLC methods
HPLC methods
57
=
1497
57+~100
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 naturallyproduced 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
General Chapter
Acceptance criteria for impurities in drug
substances:
Each identified specified
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 not
toxic. Higher limits may be set if scientifically justified.
General Chapter
(cont…)
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 products
Not 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.
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’
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.”
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.”
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
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
Current Dynamics
of
Indian
Pharmaceutical
Industry
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, LCNMR, etc., which are being used for impurity
profiling and structure characterization
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.
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
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
Summing up…
For a country with >1.2 billion people
The priority is
AVAILABILITY
of
GOOD QUALITY DRUGS
at
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
A glimpse of emerging
standards….
European Pharmacopoeia 5.0, 2005
EP 5.0 (2005)
(Ph Eur monograph 0906)
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%
Moreover, a moot point….
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