TM: What’s the single most important issue facing the API manufacturing sector today?
SM: In my opinion the most important issue facing the API manufacturing sector today is the very large number of players operating in the sector, which means that the FDA and other regulatory bodies have to avoid the occurrence of ‘regulatory oversight’ such as problems like the recent issues with Heparin supply. Companies have to play by the rules, and problems like these mean that there will be more regulations coming in the future. Regulations in general add a level of complexity to how the industry operates but they are necessary to avoid errors and minimise potential injury to patients. Remember, we are here to protect people.
TM: Is there any particular issue that’s important specifically for the high-potency APIs sector rather than for the API manufacturing sector in general?
SM: In the high-potency sector the most important issue, particularly for smaller companies, is capital expenditure. This is because the production of high-potency APIs is an expensive business and you have to decide whether to invest in barrier isolation technology or to use the more traditional personal protective equipment procedures. For smaller companies, how they deploy their capital is a crucial issue for success. PPE items such as moon suits are, of course, safe but they are cumbersome for the operator: barrier isolation technology is better but more expensive.
TM: How did ASI develop its particular expertise in high-potency APIs?
SM: Ash Stevens started business as a US Government contractor working for the National Insitiutes of Health and in particular for the National Cancer Institute, so the company was involved with anti-cancer drugs from a very early stage. This experience has given us a real advantage in the high-potency APIs area, and about ten years ago we started thinking about contained processes and ways to minimise operator exposure. In fact, ASI was one of the first companies to install Walker-Carlisle filtration systems. We took a novel approach: we worked through the operating procedures in a mock-up system using placebos so there was no risk of exposure to hazardous material and then asked the operators to advise on which procedures and designs worked best for them. This included both manufacturing and equipment cleaning procedures. The result was a smoothly operating system for manufacture of high-potency APIs.
TM: Why are fast-track approvals so important in the anti-cancer area and what is ASIs experience and expertise in this field?
Ash Stevens CEO Dr. Stephen Munk
SM: Under the 1997 FDA Modernization Act, the fast-track approvals system was developed to allow patients rapid access to treatments for life-threatening conditions and for the approval of new treatments for unmet medical needs. A good example is Velcade, the first FDA-approved protezome inhibitor. However for these drugs, quality still has to be validated as in the normal approvals procedure, the manufacturing process needs to be fully understood, and a full development report produced just like before. This means the same amount of work needs to be done in a much shorter time, maybe in as little as a third of the time for a normal approval. ASI has a lot of experience in this area and has developed strong management skills, enabling us to have as many as three fast-track projects running simultaneously.
One of the methods that allows us to achieve this is the on-track performance of analytical work and process development using commercial software packages in which a very large number of operational parameters such as temperature, stoichiometry, stir rates, heat transfer characteristics etc can be analysed using statistical design methods to optimise the process quickly. What we need to do is complete the same amount of process development work as in a non-fast-track project but by working intensely in a short time period. Smaller companies like ASI can achieve this because of their flexibility and their ability to shift gear and complete multiple tasks concurrently.
TM: What are the issues related to how materials handling practices and cleaning protocols meet the requirements of health & safety legislation?
SM: There aren’t any formal OHSA regulations with respect to barrier isolation technology as yet but there are issues in that the equipment is complicated and therefore so are the cleaning procedures. What you need to do is ensure that the cleaning procedures themselves are fast-tracked so the equipment can be used for more than one product and you need to be able to measure the cleaning efficiency. The best procedure is to use product-specific cleaning methods and analyses, for example swab transfer processes with HPLC analysis based on retention times to determine the presence or absence of material. Tests need to be specific, for example HPLC or UV analysis, not just general ones like TOC (total organic carbon). Cleaning is just as much of an issue as chemical process development.
When working with a client we look at the toxicology data and do a hazard assessment. Operators tend to be suited up more for charging operations: in discharging operations barrier isolation technology is preferred. Small companies need to look at their capital expenditure and decide which combination of PPE and barrier isolation technology is best for their high-potency API manufacturing process, bearing in mind that environmental and safety issues are just as important as FDA drug product requirements.
Equipped for high-potency
TM: What outsourcing opportunities are there for European companies with US-based contractors? How have these activities developed/expanded in recent decades and how do you see these activities developing in the future?
SM: Of late there has been a big increase in business for USA-based contract manufacturers because of the weakness of the dollar with respect to both the euro and the pound Sterling. Another factor is that Chinese and Indian contract manufacturers are no longer able to offer the same low prices as in the past because of the increased regulatory requirements they have to meet. Other factors are the lower time differences and closer cultural similarities between the USA and Europe compared to those with Asia. There has been substantial activity from European companies seeking US partners.
TM: Are there any other technical innovations you see impacting the high-potency APIs sector in the near future? What are the prospects for the sector in the medium to longer term?
SM: Clever engineering in valves, materials transport, packaging, plus new high-throughput approaches to safer process development, for example the use of parallel synthesis methods, are issues for all API manufacturers but in high-potency manufacture it’s in the engineering that the major breakthroughs will be. Anti-cancer APIs will remain a good business to be in, provided you make the right capital investments and pay attention to detail. Effective project management and development of reproducible procedures are the keys to success. For companies with staying power and a strong capital structure, it’s now a good time to be in the business. I’m proud to be involved in what ASI and others are doing in the high-potency oncology drugs field.
Further information
Dr Stephen A. Munk
Ash Stevens Inc
5861 John C. Lodge Freeway
Detroit, MI 48202
USA
Tel: +1 313 872 3621
Fax: +1 313 872 6841
Internet Links:
Email: samunk@ashstevens.com
Web: www.ashstevens.com
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