Tim
Sandle offers his thoughts on the development of pharmaceutical regulatory
harmonization, outlining the benefits and coming changes.
What are the benefits of harmonization?
The
benefits of harmonization are multi-faceted. The benefits include ensuring that
there is one standard, or set of standards, across different countries and,
where applicable, across different industries. This helps with trade. It also
helps consumers, patients and clients to know that the equipment produced or
tests conducted have been undertaken to a supra-national or internationally
recognized benchmark.
Harmonization
also allows technologists and scientists an opportunity to shape and adjust
guidelines and methods to make sure that they are meaningful and generate the
most appropriate results in a consistent manner. Consistency is key really; it
is important to know that tests are reliable and that results can be
reproduced.
Harmonization
benefits drug manufacturers in being able to share data, studies, process
technologies; and to use established test methods. This can lead to time and
cost savings.
There
are also benefits to consumers and patients in either getting faster access to
medicines, or access to previously unavailable medicines, and to safer and
better quality products.
To
draw an example, the World Health Organization has been an institution which
has arguably promoted harmonization for the longest time across a range of
health and drug initiatives. Recognition in relation to life-enhancing drugs in
relation to HIV/AIDS, TB, and malaria are cogent examples. There are, however,
a multitude of other areas in the pharma and healthcare fields which fall
outside the WHO scope and where harmonization would be an advantage.
Acknowledging
these various activities, I would surmise the benefits using three words:
quality, safety and efficacy.
What are the ultimate goals of the
harmonization movement?
First
off, harmonization is part of globalization and a reflection of the greater
interconnectedness of nations and people which has been evolving with a fast
momentum over the past few decades. This underpins many of the initiatives.
The
goals of harmonization will be different depending upon which stakeholder
offers their view. Politicians and businesses will see economic advantages, and
to an extent with quality and safety.
Scientists, like myself, will see harmonization as the means by which
quality can be inbuilt into tests and processes to peer reviewed international
standards.
The
goals is in finding ways for regulatory representatives from drug manufacturers
and researchers to work together to raise standards and to push through drug
approvals.
What are the main challenges of harmonization?
The
overarching challenge is with integrating national standards with international
standards in ways which will be universally acceptable. This task leads to the
main challenges which are, foremost, dealing with the different views of
national committees and attempting to move beyond the parochialism of
"we've always done it this way".
After these come the various technical challenges in reaching points of
agreed understanding and developing agreed methodologies. Then comes the complexities of the review
process and finalization. Good review
practices help to promote transparency and consistency.
Once
these barriers have been overcome, there are challenges between what the
scientific consensus may be and the resultant costs to industry.
One
of the reasons that the international cleanroom standards ISO 14644 parts 1 and
2 were sent back to the drawing board were because those interested in the
statistics of sampling and with a focus upon contamination control proposed,
wisely in my view, that the number of locations for monitoring within a
cleanroom should be increased to make the sampling of airborne contaminants
more representative. This was opposed, however, my certain pharmaceutical
companies who saw the added costs to their operations. Over this there was, to
a degree, a divide between the European delegation and the North American
delegation. The dispute has pushed the revision of the standard back at least
eighteen months.
What the obstacles standing in the way
of harmonization?
Time
is, as with many major projects, an obstacle. Time in the sense that some areas
of harmonization take years and years to achieve. Drawing on cleanrooms again,
it took over a decade to move away from the old Federal Standard (FS209E) to
ISO 14644. Even then, this was in two waves, with most of the world adopting
the new standard in 1999, whereas the US waited until 2004.
Time,
in the other sense, relates to competing demands. There are only so many
projects which can be run at any one time.
Another
obstacle is lack of interest or will, which is why there are several different
American and European standards .
A
further obstacle is failure to achieve scientific consensus. One example here
are the complexities of mutual recognition (which have a political dimension as
well as a scientific one).
Drawing
upon a specific technical example: the standard for the evaluation of
disinfectants, the European 'norms' focus heavily on evaluating what happens
when a disinfectant solution is challenged with a micro-organism (how quickly
is the microbe destroyed and by what quantity); whereas the US standards are
more interested in what happens when micro-organisms are on surfaces and
whether the disinfectant and wiping process can effectively inactive or remove
the microbes. The consequence of this is
that a simple biocide, used to prepare process equipment, may not be recognized
in one region of the world or another.
Which areas of drug development and
commercialization should be harmonized ?
A
key area is with clinical trials and with overcoming the quite considerable
delays in getting products approved across multiple countries. This involves
licensing and regulatory agencies in working together. Likewise there is still
work to be done in relation to marketing applications, to avoid putting
together multiple applications, invariably with the same data presented
differently, to different regions.
There
is much that can be done in building upon the work of regional agencies. A
number of bodies. like APEC (across Asia) and PANDRH (South America), have
helped to facilitate research and trade within their respective regions. What
is important is taking this to the next level and for these bodies to work more
closely together.
What are some examples where
harmonization has been successful and useful?
The
most successful examples of harmonization, in my view, relate to the
pharmacopeias. With the biological chapters the European, United States and
Japanese pharmacopeias have worked effectively together in relation to
sterility testing (a key batch release test for aseptically filled products),
microbial limits (which applies to many non-sterile products, like creams and
ointments where there is a concern with pathogens), and with bacterial endotoxin
(which is a test for microbial by-products which can cause fever).
For
these developments, various expert groups have worked very effectively
together. A parallel example is with the ISO standards, although there is not
always a compulsion to take these up and given the vast range these can be
picked and chosen to some extent. With ISO quality standards, like ISO 9001,
however, these have near universal acceptance and the resultant quality audit
initiatives have helped to shape drug safety.
Another
key area is with the ICH (International Conference on Harmonization). The ICH
kicked things off with breaking down barriers in relation to regulated markets.
The ICH has also made some progress with stability data to assess the
shelf-life of medicines, which enables studies in one region to be recognized
and accepted by another.
More
recently it has done some sterling work in relation to quality management and
risk management. This has introduced a whole set of tools for evaluating and
mitigating risks to the industry and a common set of objectives. This has been
to the benefit of more efficient processes and, ultimately, patient safety.
A
further example has been with regulatory guidance and inspection. Here a body
like PIC/S (Pharmaceutical Inspection and Co-operation Scheme) has been
instrumental. PIC/S has traditionally been strong in co-ordinating regulatory
best practice across European and Australian territories, but its course of
action was strengthened considerably when the FDA joined in 2011.
Posted by Tim Sandle
Some useful links to pharmacopoeia and regulators.
