Managing global release in a changing regulatory environment

An analytical testing perspective

Whether you are using an insourcing or outsourcing strategy and working with a CMO or CRO, biotechs and pharmaceutical companies are all pointing toward the same goal: rapidly achieving commercialization of their therapy. However, there are multiple approaches in early phase development that can greatly affect the process and impact the speed of global commercial release.

Learn how several analytical approaches compare and read about key considerations to avoid introducing potential early development risks that can significantly impact success when reaching commercialization.

The differences between small and large molecule development

From the perspective of analytical techniques, testing small molecules is scientifically well-known and fairly straightforward. Developing robust methods and transferring often doesn’t require in-depth expertise as compared to working with large molecules. The analytical methods for large molecules tend to have large variability and may require extra attention to be robust. Specialized laboratories supporting sponsors with small molecules may not necessarily have in-house expertise of testing large molecules. Furthermore, transferring the large molecule analytical methods can also be problematic as one laboratory may obtain slightly different results than another, often driven by subtleties in things like equipment, pipetting techniques, experience of the laboratory personnel, scientific understanding about proteins and their interactions etc.

Balancing needs in different phases

How can a sponsor best balance their development needs and avoid potential pitfalls with subpar analytical testing methods? Sponsors often look to a CRO (contract research organization) or CMO (contract manufacturing organization) to help them develop their analytical methods. Competent early-stage partners need to:

  • Offer flexibility and adaptability as a sponsor doesn’t always know the full capabilities of a method
  • Provide accessibility and regular engagement when collaborating on research and development
  • Understand regulatory approaches and be responsive to the sponsor’s end goal
  • Provide scientific understanding and experience of methodologies used previously for similar molecules to provide cost-effective and efficient solutions

On the other end of the spectrum, during later development stages, an analytical testing partner should be evaluated for a different set of requirements. Consider how an experienced late-stage partner can:

  • Leverage a regulatory track record with the FDA or MHRA
  • Offer sizable scaling for product growth
  • Provide knowledge and apply proven experience with a sponsor’s analytical methods
  • Demonstrate confidence in reproducibility of a sponsor’s methods
  • Understand the needs of the sponsor’s global commercial supply chain and inventory as it relates to the testing process

Compared to the earlier stage, late-stage and commercial analytical testing can introduce many more risks to the process. For example, if an analytical investigation halts QC testing, inventory could dwindle and patients may not be able to get their therapies. Global outreach capabilities are also important for regional testing and releases as analytical methods need to be transferred to align with different regulatory environments.

Evaluating approaches to analytical testing

Sponsors looking to develop a molecule have several options with their approaches, but they need to have a long-term vision for the applicability and transferability of their analytical methods before they approach commercialization.

  • Taking a step-by-step approach. Consider the scenario where one analytical laboratory initially supports the sponsor’s analytical testing for research and development work, but that partner may not be very compliant when it comes to meeting the standards of a global release or aligning with global supply chain management. Therefore, after the early stage, the sponsor must switch to another CRO. While this approach may seem cost effective at first, it will cost more in the long run, delay the program and introduce risks such as:
    • The new CRO lacks product knowledge as they did not contribute to the upfront development of the analytical method.
    • The new CRO may find that the previously developed method is not robust or fit for commercialization, but at the time of transfer the sponsor can’t afford any timeline delays and must proceed to launch
    • Poor pass rates with a less-than-ideal method will add extra costs and can even delay a commercial release.  
  • Using multiple parallel partners. In this scenario, consider a sponsor that works with a manufacturer in one country, where they have a laboratory and can release the drug product. A contract manufacturer could manage the release in another country. Then a third partner could provide stability testing at another location. However, with these parallel partners, a significant level of analytical variation can be introduced at each location, resulting in significant issues with determining clear scientific conclusions (e.g., is the difference in results the result of instability or the result of analytical variation between laboratories?).
  • Working with a single CMO. While a CMO can help address variability, these providers tend to utilize a platform assay approach, where the product’s standard analytical method is designed to fit within the CMO’s assay rather than adjusting to the needs of the product with custom or “bespoke” methods. This can offer short-term benefits with regard to speed but in the long term often results in assays that can overlook key structural aspects of a product. The focus on analytics to support manufacturing often results in stabilities studies and functional assay testing (e.g., cell based assay testing)  being carried out by third parties with the resulting complexity of additional subcontractors. The expertise required for drug substance and drug product manufacturing can also be very different and, unless integrated within the same organization, can result in the need to identify a third party CRO to carry out drug product testing.
  • Partnering with a single CRO. As compared to a CMO, a CRO tends to approach the analytical method development from the point of view of the product’s needs, offering a more bespoke approach and a fit-for-purpose robust analytical methodology that is not restricted within the bounds of a particular platform – and will easily transfer to support a global commercial release.  However, like CMO’s, CRO’s can offer platform methods to rapidly move through early phase development while looking for feedback during the development process of when to optimize methods for a client’s particular molecule.

Crafting a successful journey to commercialization

Given the ever increasing complexity of large molecule product, consistency and centralization of the analytical testing has become quite important. De-risking the journey toward commercialization requires working with a partner that has a long-range vision to support both early development and understand the product’s longer term commercial release needs.

Instead of building early phase expertise with just a few in-house specialists who may not have experience in late-stage requirements, utilizing a central analytical laboratory approach can help reduce analytical variation with a tailored methodology that considers all the downstream analytical needs – and doesn’t limit the sponsor’s options when they reach commercialization.

Supporting a product from the very beginning allows a sponsor’s partner to develop deep knowledge about the product and create an analytical control program that sets the sponsor up for success throughout their development spectrum.

Learn more about how Covance can help you move efficiently through your development process in a cost-effective and risk-appropriate way.

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