International pharmaceutical harmonization

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