E-drug: Re: ICH guidelines (cont)
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Further to my posting 17 February, here is the poster of the study as
presented at the FIP congress in Nice in September 2002. Abbreviations
explained at the end. [Long posting].
PUBLIC HEALTH OR BUSINESS STRATEGY?
A comparison of international guidelines on the quality of pharmaceutical
products, with special emphasis on ICH and WHO documents
Ragnar Salm�n, Kirsten Myhr, Patrice Trouiller M�decins sans Fronti�res
(MSF)
The poster summarises the results of an initiative under the MSF campaign
for access to medicines
INTRODUCTION
It has been claimed that the steadily increasing requirements for
documentation of the quality of pharmaceutical products in OECD countries
may be technology driven rather than driven by a real need for more
sophisticated quality control methods, and that this process is an obstacle
to the development of pharmaceutical industry in developing countries. We
tested this claim by comparing the present quality requirements in the ICH
documents with the WHO requirements; WHO being considered as the only
organisation mandated to issue �world standards� in this field.
METHOD
Simple comparison of ICH guidelines, other quality related guidelines used
in the ICH regions, WHO guidelines.
The documents were rearranged where appropriate in order to facilitate a
paragraph by paragraph comparison.
The following areas of pharmaceutical quality assurance were covered:
- Good manufacturing practices (GMP) for active pharmaceutical ingredients
(APIs)
- GMP for finished dosage forms
- Validation
- Stability
- Impurities
Safety and efficacy issues were not covered and we did not aim at discussing
the relevance of specific requirements.
OBSERVATIONS
Starting materials
WHO wishes to see a strong regulation of starting materials. The present WHO
API guidelines are not, as demonstrated also by the PIC/S 1996 initiative
(new API GMP), considered adequate. The ICH API GMP is very detailed,
leaving little room for interpretation. WHO has guidelines for excipients
which does not have any counterpart in the ICH and which imposes
requirements on excipient manufacturers that at least the EU inspectors�
working party have been unwilling to impose on EU manufacturers.
Finished products GMP
The general parts of the WHO and PIC/S or EU GMP guidelines are, though
different in layout, essentially similar. The annexes, however, are quite
different in the sense that PIC/S or EU annexes cover more than WHO.
Validation
ICH, EU and PIC/S guidelines focus on validation of critical processes or
process parameters. WHO states that few processes are sufficiently
�non-critical� to escape validation; thus it is seen as common practice to
extend validation to all processes. The most recent validation guideline
(EU) is, due to its increased stringency, far more useful as a standard than
the older ones, particularly that of WHO, which mainly may serve as textbook
documents.
Analytical validation
ICH and WHO guidelines cover more or less the same objects, main differences
being that WHO offers an explanation of the relevant terms but gives little
further guidance on the practical issues and ICH gives more detailed
instructions for what is expected from a validation study.
Stability
A few differences in testing frequency and duration of the stability studies
were identified. As the ICH guideline is intended for new substances,
additional requirements needed to establish sufficient knowledge of the
substance are covered by ICH. The present ICH guideline covers only climatic
zones I-II, WHO also zones III-IV. ICH plans to extend its coverage,
building on the WHO guideline. Considering the somewhat different scope of
the two guidelines, the documents appear essentially similar.
Impurities
ICH, as opposed to WHO, introduces exact limits for impurities. However, as
the WHO guidelines on impurities state that generic copies should not be of
lower quality than the original (comparator) product, and as most new
products are developed in the richest countries, WHO guidelines are
effectively imposing the requirements of the richest countries upon the rest
of the world.
DISCUSSION
Part of the criticism raised against priorities set by the pharmaceutical
industry in the richest countries may stem from the discrepancy between the
pharmaceutical industry�s focus on developing drugs against �life style
diseases� and the perceived lack of interest in developing life saving drugs
for the poor.
Undoubtedly, a very high quality and safety level must be required for �life
style drugs�. Requiring an equally high quality/safety level for new
life-saving drugs for otherwise incurable diseases may not always be
reasonable.
Not bearing these nuances in mind, a conspiracy theory that harmonises well
with traditional assumptions regarding the rich countries� exploitation of
the poor is easily constructed. The assumption would be that by establishing
unnecessarily rigid quality/safety/efficacy standards for medicinal
products, the established pharmaceutical industry would effectively build
barriers to newcomers from less developed countries. This would sustain the
rich world�s dominance over the poor world in the long term, also with
respect to the health of the poor. The fact that the establishment of such
standards takes place in closed interest groups, like the ICH, instead of
being introduced through a worldwide consensus based system like WHO, adds
fuel to the fire.
CONCLUSIONS
We have shown that ICH guidelines are not stricter than WHO guidelines. On
the contrary, in several cases WHO enforces stricter requirements than the
ICH or other relevant comparison documents.
WHO documents are often less well organised and to some extent inconsistent
with each other.
The inconsistency found in the WHO guidelines regarding validation is
particularly unfortunate, as a fair and consistent evaluation of a company�s
validation efforts may represent some of the more difficult tasks for
pharmaceutical inspectors and other regulatory personnel.
Criticism of the ICH process and its de facto influence on the rest of the
world�s pharmaceutical regulations may be well founded seen from a decision
making point of view. However, the practical consequences of running the
process one way or the other seem negligible.
WHO guidelines are not necessarily more adapted to developing countries than
their counterparts written in the ICH region.
In terms of �regulatory imperialism�, the criticism of the ICH process may
not be particularly well founded.
RECOMMENDATIONS
Appreciating that international trade is a key factor for economic
development for all but (possibly) the very largest countries, our
recommendations are to
- accept that harmonisation of regulatory requirements is good for increased
international trade;
- support training of DRA officials, particularly in the field of
pharmaceutical inspection, e.g. in line with the PIC/S approach, in order to
increase the confidence in national drug regulatory authorities and, hence,
the national pharmaceutical industry;
- promote activities intended at modernising selected pharmaceutical plants
in developing countries, thus achieving a good basis for national self
supply of relevant drugs and increasing the export opportunities;
- investigate the possibilities for increasing the confidence in
pharmaceutical manufacturers in developing countries by offering assistance
with GMP inspections and surveillance of the quality of marketed products;
- when the necessary quality is achieved by local manufacturers, assist in
the promotion of the idea that locally produced, reasonably priced products
are as good as expensive, high profile international brands.
Abbreviations
API: Active Pharmaceutical Ingredient
DRA: Drug Regulatory Authority
EU: European Union
FDA: United States Food and Drug Administration
GMP: Good Manufacturing Practice
ICH: International Conference on Harmonisation
PIC/S: Pharmaceutical Inspection Co-operation Scheme
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Kirsten Myhr, MScPharm, MPH
Head, RELIS Ost Drug Information Centre
Ulleval University Hospital
0407 OSLO, Norway
Tel: +47 23 01 64 11 Fax: +47 23 01 64 10
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