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Quality Matters

The operating environment which regulates the generics industry is undergoing dramatic and far-reaching changes on a worldwide basis. This is a result of several decisions by the European Union (EU) Commission, European Medicines Agency (EMA) and Food and Drug Administration (FDA) over recent months - which have introduced substantial changes in both US and European regulations across the globe. Building on internationally accepted International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidances Q8 (Pharmaceutical Development), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality Systems), the agencies have launched a multi-pronged attack on quality issues which are putting patients at unnecessary risk. The ICH guidances started life as purely voluntary codes, but have now been formally introduced into the regulatory landscape.

Additionally, the implementation of the Falsified Medicines Directive in Europe will ensure that active pharmaceutical ingredients (API) manufacturing meets international good manufacturing practice (GMP) in Europe. When fully in force, all APIs used in Europe will be made in accordance with GMP - with control of both drug products by the Qualified Person (QP) system, and drug substance through the importation system.

Quality by Design

To examine these changes and their impact in more detail we should start with generic products in the US. The FDA, led by Lawrence Yu, has substantially raised the expectations of the Office of Generic Drugs of new Abbreviated New Drug Applications (ANDAs) in two key areas. The first is that all ANDAs submitted from January 2013 must be based on the new Quality by Design approach and layout as set out in the FDA's published exemplars. Generic drug product developers will have to follow new ways of working, which will include establishing a new understanding of the Critical Material Attributes (of the drug substance), the Critical to Quality Attributes of the drug product and the Critical Processing Parameters of the manufacturing process. These are concepts which have not formed part of the generic product development paradigm until now, and are still under development in some areas.

Achieving a new level of understanding will take substantial extra work by the generic drugs companies (wherever they are based) and in some ways will take the submission requirements beyond those currently in place for new drugs in New Drug Applications (NDAs). Two key concessions have been negotiated by the industry with the FDA. Process development, which normally takes place on the 10-50kg manufacturing scale, will be accepted by the FDA on the 1kg scale. In addition, the expectation that generic companies will implement Process Analytical Technology (PAT) methodologies in production has been waived.

Nevertheless, in conversation with generic product developers, it is clear that these new requirements are, in many cases, poorly understood and are hard to define. The exemplar documents produced by the FDA, while helpful in terms of layout, are set out for complex products requiring very extensive development. In my view, there is an urgent need for guidance and protocols which will help companies develop simpler products using more widely used techniques.

Risk Management Principles

The second change by the FDA has also been driven by the rigorous implementation of risk management principles (see ICH Q9). This is based on the FDA's observations of a high incidence of problems with generic product stability, as seen in Field Alerts submitted to the FDA, and also on requests from manufacturers to shorten shelf lives of products which have been approved and are on the market.

It is not surprising, from a scientific viewpoint, that generic companies struggle to produce products which are as stable as those of the innovator. The amount of time and material available to generic manufacturers is always less than that available to the innovator, and there many ways in which these companies can stabilise their products which are not apparent in the summaries of product characteristics or patient information leaflet. It can, therefore, be very difficult to match the shelf life obtained by the innovator.

Under the FDA proposal, the date required at the time of submission in the US will be increased from three to six months, bringing it into line with the requirements in Europe. Perhaps the surprise here is that three months of data was ever regarded as acceptable.

It is proposed that test data will be required at ICH room temperature (25°C/60 per cent RH) as well as intermediate and accelerated conditions (30°C/65 per cent RH and 40°C/75 per cent RH). This will substantially increase the volume and cost of testing and, of course, will take longer. The change is proposed from 1st January 2014.

Taken together, these changes will have a major impact on development costs and timelines in the generics industry. They will undoubtedly improve quality standards and product understanding, but based on my teaching experiences, the learning curve will be a steep one, particularly for smaller manufacturers with limited resources.

GMP Certification

The EU and EMA are also making substantial changes to the control of drug substances imported in Europe which will have to be certified as being manufactured in accordance with GMP as set out in ICH Q7. Based on manufacturing and regulatory standards enforced in the source country, exemption from certification can be requested on a country by country basis; Switzerland is the first country to have been granted exemption. A number of other countries (Australia, Brazil, Israel and Singapore) have applied for exemption; they will have to demonstrate rigorous standards of compliance to the ICH Q7 standards.

The change is designed to improve uniformity of standards of APIs used in Europe. At present, for products imported to Europe, the QP releasing the product is also certifying that the drug substance used to make it was manufactured in accordance with GMP.

APIs used by European manufacturers should also comply with international GMP standards. The recent actions of the EU make it clear that the regulatory authorities are not sure that this is always the case. The European authorities are already taking a great deal more interest in QP certification and API sourcing than they have in the past.

The second major change in the EU is a little-commented-on update to Chapter 1 of the EU GMP guidance, which requires manufacturers to implement the ICH Q10 guidance on Quality Management Systems - so that ICH Q10, originally introduced as a purely 'voluntary' activity, is now mandatory. ICH Q9 (also initially proposed as voluntary) has also been incorporated into EU GMP as Annex 20 of the guidance.

Conclusion

It is difficult to overstate the impact of these two changes. Very few EU companies have properly implemented ICH Q9 in all areas, never mind Q10; for most companies implementation requires a substantial change in mind-set to achieve, and sets up requirements which will test the will of management and quality personnel alike. Implementation of the principles has led to greatly improved guidance from the EU in a number of other areas, and more updates are planned to achieve consistency within the EU GMP guide as a whole. However, adoption of both ICH Q9 and Q10 is wholly new to many low-cost manufacturers, many of whom struggle to comply with the previous requirements. As with the changes taking place in generic development in the US, these actions should improve manufacturing standards but achieving compliance will prove a challenge to both domestic and overseas companies.

The new guidance will be a valuable tool in raising standards and setting out what is needed, but knowing the resources available in many low-cost manufacturing centres, it is hard to see how the new standards will be achieved and maintained. The changes will greatly improve generic product quality across the world – but will also generate huge needs for training and consultancy to assist companies in making the transition. However, one only has to look to the US itself, and the ongoing meningitis tragedy with the loss of many lives as a result of poor manufacturing standards, to see the consequences of poor compliance standards which appear to have been tolerated for a decade. I look forward to continuing to work with companies dedicated to meeting current standards and making safe and effective medicines.


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Michael Gamlen is Managing Director of Gamlen Tableting Ltd. He has been working in tablet manufacturing, training and auditing for over 30 years and is the inventor of the Gamlen Tablet Press. He audits companies on a worldwide basis against EU and US manufacturing standards, and is developing standardised development protocols to assist small companies in compliance with QbD and QRM guidance and systems.

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