Outsourcing Formulation Development for High-Potency Compounds

There is a trend emerging in drug discovery for new compounds to be increasingly more selective in their pharmacological activity. The manufacturing activities associated with highly potent compounds are becoming more difficult to manage with respect to safe handling of the compounds and also achieving reproducibility of dosing. Many companies are consequently choosing to outsource the development and manufacture of highly potent drugs to contract development and manufacturing organizations (CDMOs) with the necessary skills and capabilities in this area. But what should one look for in a CDMO if they wish to outsource the formulation development of a highly potent drug?  It is almost impossible to find every box ticked by a CDMO; therefore, building a risk-based approach to selection is required. The following five key areas should be considered when deciding to outsource a high-potency project.

Safety
When selecting a CDMO, the first thing to check is that they have the necessary infrastructure for ensuring safe handling of highly potent compounds. Many organizations are now choosing to conduct a safety audit of a CDMO’s facility in addition to the usual technical and quality audits. In particular, the following should be checked:

Risk assessment procedure. It has become common practice within the industry to define the handling requirements for a drug according to an occupational exposure banding (OEB) system (1). Typically, OEB systems categorize compounds from low potency to high potency and define the handling/containment requirements dependent upon the OEB category. Banding systems are often used in cases where there is insufficient data available to define an occupational exposure limit (OEL) for a compound (e.g., new potential drug candidates). Depending upon its pharmacological attributes (e.g., dose and toxicology), a compound can be placed into an OEB category that defines the implications for operator exposure and the actions required for safe handling. An example of a typical potency classification system is shown in Figure 1.With this in mind, it’s worth checking what risk assessment process is followed by the CDMO for the introduction of a new project, particularly one involving a highly potent compound, and whether the outcome of each risk assessment is documented.

Process containment. Are there suitable containment practices in place to prevent operator exposure and cross-contamination within the facility? The industry preference is for “containment at source” rather than reliance on personal protective equipment (PPE). The activities where the drug is being handled (e.g., preparation of formulation or analytical samples) should be conducted in suitable isolators or extraction cabinets (2, 3). Procedures for handling contaminated waste materials should be in place.

In many cases, the project will progress to current good manufacturing practice (cGMP) manufacture of product for clinical trial use. Consideration should, therefore, also be given to the containment practices within the manufacturing facility. Is the manufacturing equipment that would be required at the next phase able to be appropriately contained?  

Expertise
High potency generally means low dose, and formulation development for low-dose products usually demands particular knowledge and skill. The main challenge is often achieving satisfactory drug content uniformity per unit dose. The CDMO’s track record in developing low-dose formulations is, therefore, a factor that must be taken into consideration. Ask about the experience and technical skills of the people who would be responsible for the project from the initial development of an appropriate formulation to the clinical manufacture. Ultimately, for clinical manufacture, it is important that appropriate training procedures are in place for safe handling of potent materials. No matter how well designed the facility is for containment, the weakest link will always be the people using it. More than anything, you need to feel confident in your CDMO partner.

Processing capabilities
Formulations for highly potent compounds will often contain only a few milligrams of drug and could contain as little as a few micrograms of drug substance. For very low dose requirements, it may be appropriate to consider dissolving the drug in a liquid vehicle and filling into capsules (4). Alternatively, to maximize the drug-to-excipient ratio, minitabs may be an option. Another option is to pre-dissolve the drug in a suitable liquid vehicle and to spray this solution onto carrier particles to produce coated granules. One crucial consideration is whether the potential CDMO has the requisite development expertise and range of processing capabilities for developing such low-dose products.

When outsourcing a formulation development project to a third party, most vendors will prefer for the CDMO to also be responsible for provision of products for clinical trial use. It is, therefore, worthwhile to confirm that the CDMO has capability for scale-up of processes from benchtop to early-phase cGMP manufacture. In reality, most CDMOs will have a maximum scale they can produce with respect to equipment capabilities, the flexibility of the facility, and resource availability. Discuss with your CDMO potential tech-transfer and/or scale-up options should the project continue to expand.

Analytical capabilities
Formulating and manufacturing for potent/low dose products is challenging, but so too is the analysis of these products. Detection of very low concentrations of drug in the product can be an issue. If the drug molecule contains a strongly absorbing chromophore, then analysis of unit doses for drug content and degradation products can be achieved using standard high-performance liquid chromatography (HPLC) ultraviolet (UV) detectors. However, for determination of degradation products or drug residues for cleaning verification purposes, it may be necessary to achieve levels of detection at nanogramme or even picogramme levels. For very low-level detection, liquid chromatography-mass spectroscopy (LC-MS) is the most appropriate analytical method for cleaning verification purposes (5). Consider the CDMO’s analytical techniques for low-level detection and what criteria are used for cleanliness verification for processing equipment.

The International Society for Pharmaceutical Engineering’s Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) process (6) is being widely adopted to manage the risk of cross-contamination to achieve and maintain an appropriate balance between product quality and operator safety. Furthermore, a recent EMA guideline (7), based on the principles of Risk-MaPP, introduces the practice of determining the permitted daily exposure (PDE) of a compound for calculation of acceptable residue levels for equipment following cleaning. This approach replaces the traditional practice of applying 1/1000th of the lowest clinical dose or 10 ppm to derive acceptance criteria for cleaning limits. Ask whether the CDMO is familiar with these guidelines and how they are used.

Project management
Even if a CDMO has what appears to be the required blend of skills, experience, and processing capability, it does not necessarily guarantee your project will be in safe hands. One aspect that can have the most influence on a successful outcome (or otherwise) of an outsourced development programme is project management. Enquire how projects are typically inducted, run, and completed by the CDMO. Who will be your point of contact and who will be the project team members? Work closely with your CDMO to create an outline of how the contract partner visualizes the breakdown of the programme of work and how each stage will be scheduled to ensure you are both aligned. Agree on means and frequency of communication as well as expected response times upfront to help manage expectations.

Conclusion
Although the five points given in this article may provide some guidance in assessing potential vendors for a formulation development project, the reality is that no CDMO is likely to meet every need perfectly, and early discussions to find appropriate options is advised. Away from the technical aspects, there are many other softer selection criteria that are more difficult to define and quantify. For instance, how engaging and enthusiastic are the representatives from the CDMO at initial discussion stages?  Do the technical discussions provide a sense of trust in the ability of the CDMO to fulfil the requirements of the project brief and to work collaboratively to meet the yet unforeseen hurdles?

Handing over any project to a third-party contractor includes risks, and outsourcing development of products containing highly potent drugs is particularly risky, both from a safety aspect and also because of the technical challenges. Ideally, your chosen CDMO will not only tick many of the more mechanical selection criteria, but will also demonstrate an enthusiastic and collaborative attitude to helping reach your project goals.

References
1. J.P. Farris,  A.W. Ader, and R.H. Ku, Chem. Today 24, 5-10 (2006).
2. D. Bormett, “High-Potency APIs: Containment and Handling Issues,” Pharm. Technol., Pharmaceutical Ingredients Supplement (September 2008).
3. M.J. Faber  et al.,   Chemica Oggi - Chemistry Today 32 (3) 34-38 (2014).
4. J. Carey and A. Dixon, “Challenges in the Secondary Manufacture of Encapsulated High-Potency Drugs,” Pharm. Technol. Supplement (April 2008).
5. L. Liu and B.W. Pack, J. Pharm. Biomed. Analysis 43, 1206-1212 (2007).
6. ISPE, ISPE Baseline Guide: Risk-based Manufacture of Pharmaceutical Products (Bethesda, MD, 2010).
7. EMA, Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, EMA/CHMP/ CVMP/ SWP/169430/2012. 

Article DetailsPharmaceutical Technology European Outsourcing Outlook
Vol. 28, No. 13
Pages: 8–10

Citation:
When referring to this article, please cite it as R. Harris, “Outsourcing Formulation Development for High-Potency Compounds," Pharmaceutical Technology European Outsourcing Outlook 28 (13) 2016.