Jon Sutch, PhD, is manager of formulation development at Patheon’s Milton Park facility, UK, jon.sutch@patheon.com.

Jon Sutch

Early development is a crucial stage in the drug product lifecycle. Key milestones include demonstrating the safety profile of a new molecule or the proof of concept. This challenging space is occupied by Big Pharma and emerging pharmaceutical companies alike. For a new chemical entity, the clinical path is often being defined along with the API synthetic route and process while the doses are determined based on emerging preclinical data. At the same time, the ultimate goal is to develop a fit-for-purpose drug product. 

Europe has seen an increasing number of emerging specialist companies over the years, but despite being experts in their own therapeutic field, these companies often require support in the chemistry, manufacturing, and control (CMC) area. From a drug product point of view, a fast and flexible provider with expertise covering the whole of the development lifecycle is advantageous. There is clearly a need for early development expertise with end-to-end pharmaceutical manufacturing capabilities in Europe. 


  A scientific approach is as essential during early development as it is for Phase III evaluation or batch registration. While the drug product does not need to be as elegant and the target product profile may not be so well defined, it needs to be fit for purpose so that the molecule has the best chance for clinical success. Developing fit-for-purpose formulations involves understanding the target product profile for the clinical trial, evaluating the physicochemical data of the API, and using tools such as risk assessment to help design the right sort of formulation, as opposed to using an off-the-shelf or platform-type approach that may be quick but does not necessarily give the molecule an optimum opportunity in the clinic. By using a science-led approach, time can be saved from reworking a formulation due to poor stability that may have been predictable or even repeating a whole clinical study because the bioavailability of the formulation is suboptimal.


  The introduction of new technologies in the pharmaceutical arena is starting to have an impact on the way early development projects are carried out in Europe. Traditionally, early development has been largely focused on establishing proof of concept on the first physical form of an API identified. Once this milestone has been achieved, salt or polymorph screens would then be introduced to ensure that the optimal form is taken forward to the next development stages. With high throughput screening techniques, polymorph or salt screening can be simplified and brought forward in the development chain, thereby, allowing early phase formulation studies to be conducted on the optimized chemical form, therefore, reducing the risks at later development stages.

Another key trend resulting from the introduction of new technologies in drug discovery is the use of high throughput screening for APIs. The challenges in modern drug discovery are well documented. The increasing number of compounds with poor solubility and high potency has been reflected in the majority of projects seen in early development. As a result of this shift in the types of API coming through development pipelines, investment in new capabilities to meet these more demanding customer needs is a necessity for any company wanting to stay ahead in the drug development arena.

Working with highly potent molecules has become particularly relevant at early phase. At this stage, toxicity data are less well defined and conservative toxicity categorization would, therefore, mean that many early-phase molecules must be handled as potentially highly potent or highly toxic. Dedicated safety systems that are commonly used in late-stage development, such as wash-in-place or isolator-based technologies, are less common or incompatible with a fast and flexible early phase offering. High potency can also be a challenge for an analytical cleaning verification method because the limits of quantification and the limits required to demonstrate the equipment as clean are so low. One solution to these issues is the use of disposable technology.

As an example, at Patheon’s Milton Park facility in the UK, the standard approach during early development is for all product contact equipment to be disposable. This approach includes obvious items such as weighing boats to more complex items such as blending vessels or sieves, where the risks and the costs of verifying the items as clean is outweighed by the cost of the equipment themselves. The result is that faster development times can be achieved with less equipment down times and lower cost to the customers. The use of disposable technology has also been extended to product contact parts of a tablet press in a patent held by Patheon designed to extend this benefit to more sophisticated dosage forms (1). Single-use containment is also a feature of disposable manufacturing technologies. Flexible glove bags are designed to accommodate specific equipment or processes and to ensure complete containment of highly potent APIs. In addition, these systems can be used to protect moisture- or oxygen-sensitive APIs from the environment, enabling the manufacture of early-phase drug products within an inert environment. Once again, as these systems are single use, they can be disposed of, and the risk of cross contamination is, therefore, eliminated

Transitioning from early- to late-phase development 


  Patheon’s Milton Park site is part of a much larger network that spans from preclinical through early phase to Phase III and commercialization. An advantage of working within such a network at early phase is the simplification of 
transition into later-phase clinical trials. The prior knowledgegained as a result of the science-based approach used during the early phases ensures that the formulation for late phase and registration is designed on a firm foundation.

Depending on the indication and patient population, an early-phase formulation can be scaled up to support later phases. Patheon’s end-to-end capabilities, for example, enable both sterile and non-sterile drug products to go all the way from preclinical to commercial manufacture within the network, following well-understood scale-up routes. Formulation and processes developed at early phase can be designed to ensure that scale up or technology transfer is as smooth as possible. By knowing the equipment and capabilities of the later-phase sites, scalable processes can be developed. This approach overcomes one of the key errors encountered during scale up. A formulation that is designed simply to get through Phase I may be completely unsuitable for Phase II and consequently, require significant reformulation.

For companies intending to extend their early phase capabilities, the key when adding in new equipment is to ensure that the operating principle of the equipment is the same as similar equipment at larger scales to enable a smoother scale-up transition. One way is to use the same manufacturer and, therefore, the same dosing mechanism for capsules as an example. The other alternative is by understanding the critical variables that need to be
measured when scaling up a formulation (e.g., tablet ejection force and dwell times or granulation speeds and spray rates). The integration of equipment, instrumentation, and science throughout the end-to-end network offers a smoother transition between the scales, an easier regulatory filing, and a better outcome for customers. 


  Early-phase drug development is faced with many variables in an increasingly challenging discovery landscape. To help work through this process, it is important to partner with a CDMO that is prepared to understand the specific issues and risks of the API and to quickly and flexibly create solutions to produce a fit-for-purpose early phase formulation. The pressure, however, does not end there, and a CDMO with end-to-end capabilities, knowledge, and experience of scale-up will aid formulation development while minimizing time and keeping the drug product off the critical path.


  1.	Patheon, “Rapid low-cost manufacture of tablets using disposable equipment,” US Patent 20110187016, filed August 2009. 


Jon Sutch, PhD, is manager of formulation development at Patheon’s Milton Park facility, UK, jon.sutch@patheon.com.

Articles

Despite the growth of specialist companies with capabilities across various therapeutic areas in Europe, there is still a need for early development expertise with end-to-end pharmaceutical manufacturing capabilities.