DR. SARANJIT SINGH by hedongchenchen


									 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

 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   1253
Monographs with HPLC assay   139
Monographs with Test for     448
Related Substances
  TLC methods                391
 HPLC methods                57
A Typical Example - TLC Method
  Indian Pharmacopoeia


Established: 9 December 2004
         Mandate of IPC
   To bring new editions and supplements
    of Indian Pharmacopoeia at regular

   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
 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     US
   Ciprofoxacin       29.00       423.86        393.00    2352.35
   500 mg (10s)
   Norfloxacin        20.70       168.71        130.63    1843.66
   400mg (10s)
   Diclofenac          3.50           84.71     59.75     674.77
   50 mg (10s)
  Source: OPPI website, 45 INR = 1$
       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
 Fornew monographs, impurity control directed
 to be a part of Related Substances test
 Both   TLC and HPLC methods acceptable
          limit, if an impurity is toxic and/or
 Stringent
 named impurity is to be controlled (e.g., N,N-
 dimethylalinine in cloxacillin sodium, <20ppm)
       Other perspectives of   IPC
             on Impurities

 IPCto take care that Related Substances
 test in new monographs received from
 industry has no barrier element
   all situations, the test must be
 In
 possible in Government and Private

“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
      IP 1996 versus 2007

                          1996     2007
Total number of           1253   1253 -13 +257
monographs                       = 1497

Monographs with HPLC      139    139+……
assay methods
Monographs with test of   448    448+~100
Related Substances
   TLC methods            391    ~390
 HPLC methods             57      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 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
           General Chapter
  Acceptance criteria for impurities in drug

  Each identified specified    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 Not more than 1.0 per cent
  Each unidentified            Not more than 0.5 per cent
  degradation products
  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

 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
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
 Top Indian Companies – Way Ahead

 Exportoriented 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
 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

   This is happening without intervention of
    local pharmacopoeial and regulatory
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

Our belief is…
of drugs and products can be well
    assured by recently adopted
   approach of IPC on impurities
   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
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
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
So overall,
1. There is a need to ponder
   whether the forensic analysis
   of pharmaceuticals is all that
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
Thanks so much

To top