Colin MacKay

	There is an increasing number of new drugs in development that require handling of materials classified as highly potent or cytotoxic. Many of these drugs can also be highly toxic, hence, requiring extreme care and specialist knowledge. This article discusses some of the issues and challenges when developing such products.


	The handling of highly potent and cytotoxic materials that require containment capabilities is a tricky business especially if the material is a new chemical or biological entity that has not been used in humans before. Drug substances can be categorized by their potency by using occupational exposure limits (OELs). However, if potency is not yet established because the product is only at the development stage, the first challenge can be in getting the material manufactured to understand if there is safety and efficacy in the proposed indication.

	There are many challenges to handling materials that require containment for personal protection, the first of which is an understanding of what high potency actually means. This interpretation can vary depending on the different viewpoints. Moreover, there is no standard classification that is globally accepted for high potency materials. As a result, many large pharma companies have developed their own in-house classification systems for materials to try to clarify and categorize the types of controls and handling procedures required for adequate personal protection and potential for cross-contamination.  

	There have been efforts across the industry to interpret these various classifications; SafeBridge is a widely recognized good example of such, but there are also many other categorization systems including the Merck system, the Roche system, and the Affygility system. Nevertheless, there remains no “one-size-fits-all” system across the pharmaceutical industry, which adds complexity to the issue. With a wider need for the industry to move away from time-heavy tasks and constant duplication of efforts to become more efficient, agreeing on and standardizing the classification of highly potent and cytotoxic materials would be a good starting point.


	Interpretation of the potential hazards is required by many different types of organizations for classification of potent materials for containment during handling processes. Communication and information sharing between companies developing new drugs and those seeking to handle potent materials on a contract basis are crucial. Ensuring potential hazards are identified and understood, and that risk is adequately managed for people who handle such materials in the process of manufacturing a drug product for first-in-human use, are key aspects in the product development phase.

	Potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. But if the effects are not yet fully established, as in the case of a new drug to be evaluated in clinical trial, that process for assessment of the potency is less easily applied. Clearly, the potency of materials is one thing, but exposure is another. Specialist facilities are required for handling potent materials, including dedicated areas for containment and segregation. There must be clear processes for risk assessment, ensuring adequate staff training, and understanding of risks. Controlled waste-stream management is required to control materials after the main manufacturing process.

	Developing and manufacturing highly potent and cytotoxic drugs tend to be more complex than most products, with challenges in terms of classification, handling, and selecting the right contract manufacturing organization. A more collaborative approach in supply-chain management, information sharing, risk identification, and agreed standards would go a long way in helping overcome these challenges.

Articles

Highly potent or cytotoxic drugs require special handling

Best Practice: Developing Drugs that are Highly Potent

	The past six months has seen some major changes to the sterile manufacturing landscape in Europe. There have been a number of exits and acquisitions that have no doubt grabbed headlines, but has anything really changed?

	At an industry level, the demand for sterile injectable manufacturing capability is evident. Industry publications regularly publish indicators of growth in the market. There are many factors driving this demand, including shifting trends towards the development of oncology therapies and the increasing number of large-molecule drugs in development, which require an injectable route of administration. Additional data generated by absolute bioavailability studies to support regulatory submissions where a proven relationship exists between the pharmacodynamics and the pharmacokinetics at therapeutic dose further drive this growth.

	Market growth in response to the increasing demand for sterile manufacturing has triggered some high-profile activity in recent months. The acquisition of the Aptuit fill/finish facility in Glasgow by AMRI, for example, although interesting, is unlikely to significantly affect the United Kingdom or European market. This is because neither the number of drug-development companies or the number of manufacturing facilities providing sterile injectable manufacturing services will actually change as a result of the acquisition. There is no doubt this deal is evidence of further consolidation in the aseptic manufacturing space following the acquisition of OsoBio by AMRI in 2014. The wider market, however, still remains relatively fragmented.

	Moving forward, we can expect to see other large contract development and manufacturing organizations (CDMOs) prompt further deals of this type as the competitive landscape continues to evolve. Nonetheless, it is unlikely that the market will change significantly, other than clients potentially having fewer options, in that they will have to choose between large one-stop CDMOs or specialist sterile service providers. Specialist contract manufacturing organizations (CMOs), such as Symbiosis, are often more able to provide operational flexibility and move their clients through the clinical development stages more quickly than the larger, more cumbersome CMOs/CDMOs.

	Interestingly, given the recent corporate activity by the larger CMO/CDMOs, it appears that the “all-under-one-roof drug-development capability organizational model” (which is similar to the one that Big Pharma had in-house a generation ago and prior to the advent of the more efficient modern drug-development outsourcing model of today) is in danger of being resurrected.

	Having said that, as the market continues to develop, it’s not just about organizational size but more about the level of service excellence that a CMO/CDMO can deliver to its customers, including the ability to demonstrate absolute regulatory compliance to the highest standards. Size really doesn’t matter in this sense. For the smaller providers of sterile fill/finish services, the key to growth will be to retain a clear focus on what they are good at and delivering exactly what their customers need.

	With the requirements of drug-development projects constantly changing, the freedom to choose from a number of smaller drug-development service providers with true expertise in their field may be the most time-efficient and cost-effective way of not only successfully achieving drug-development milestones, but also of generating value for stakeholders. This trend will continue to drive the growth of specialist, smaller players in the market and ensure healthy competition.

	In short, the sterile manufacturing market is certainly changing and will continue to do so, but as ever, customers are faced with the choice of engaging a one-stop-shop service provider or going with a smaller, more specialist, flexible, and time-conscious partner. Ultimately for clients, it’s all about getting to clinical trials in the safest and quickest route possible.

is CEO of Symbiosis Pharmaceutical Services

The past six months has seen some major changes to the sterile manufacturing landscape in Europe. There have been a number of exits and acquisitions that have no doubt grabbed headlines, but has anything really changed?