Expediting IND Submission

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The global pharma industry has changed dramatically over the last decade, and innovation has moved away from just a Big Pharma domain and increasingly towards smaller and medium sized companies (especially during the earlier stages of trials) (1), and encouragingly this has led to increasing numbers of drug approvals (2). Looking behind the curtain, while Big Pharma has improved its speed of development, many of the approved new chemical entities (NCEs) have been developed by these smaller more nimble players, empowered by funds from the capital markets. But another change has expedited approvals, namely the growth and increased capabilities of global contract development and manufacturing organizations (CDMOs).

Strong demand for CDMOs

Unlike Big Pharma companies that have substantial in-house resources, smaller innovators may have limited or no in-house resources and experience in running full chemistry, manufacturing, and controls (CMC) programs. The importance of having a clear CMC strategy must not be overstated. Limited resources are often the cause of quick and dirty proof-of-concept studies—methods that will provide a compound but are unsuitable/sustainable at higher volumes—as companies look to cut development times or conserve their budget. However, this approach can lead to failures in identifying inadequate analytical testing, unscalable processes, or formulations that don’t deliver a clinically effective therapeutic dose. If the innovator’s goal is to sell or license assets, then it is in their best interest to conduct CMC due diligence. Companies will not want to invest in a new drug if it potentially has a host of undiscovered liabilities.

The current outsourcing model is most often predicated on a minimum of two CDMOs—one for drug product and one for drug substance, plus in many cases a further packaging provider for clinical distribution (3). This multi-provider model was established due to the historical development capabilities of the contract services industry as specialists, with drug product and substance CDMOs having only recently transitioned to becoming full-service providers. The multi-provider model allows for cost comparisons of individual services; however, innovators risk possible delay, even failure, as well as integration costs. Materials have to be transported between global locations meaning travel, export documentation and alignment and/or repetitive testing.

So, while the ‘multi-provider model’ has been successful in helping biotechs progress further into drug development than before, it still presents several bottlenecks—perhaps the biggest of which is lost knowledge and communication between providers (3). In fact, through using an ‘integrated provider model’ as an alternative, it may be possible to save between four and six months on development timelines of an investigational new drug (IND) program, which is highlighted in the visual representation of the prospective pathway of a product shown in Figure 1.

Figure 1(a): A visual representation of a chemistry, manufacturing, and controls (CMC) program implemented using a multi-provider model.

Figure 1(b): A visual representation of a chemistry, manufacturing, and controls (CMC) program implemented using an integrated-provider model.

Advantages of an integrated provider

The first advantage of running an integrated CMC package with a single provider is that it largely removes the logistical challenges, so any time delays occurring as a result of the cross-functional work between drug substance and drug product can be shortened. Equally significant is the fact that an integrated provider model also expedites the two-way transfer of knowledge between the drug substance and drug product teams—this is particularly important because vital information from the formulation study is used to adjust the parameters of good manufacturing practice (GMP) production and release specification setting of the API. On examination of the alternative model—using multiple contract providers—due to intellectual property (IP) issues, all communication will have to go back through the sponsor or more likely the CMC consultant, adding an extra layer of complexity to information dissemination. And, of course, that is without considering the geographic locations of each party involved, meaning that companies must consider varying time zones for exchanging information and transit time for material shipping.

By using a single CDMO from one site, it is easier for the teams to meet in person more frequently to ensure sufficient communication and increased flexibility. Should there be some challenges in formulation or additional API is needed, the teams can quickly meet and adjust schedules so that IND submission can still be achieved rapidly. Conversely, if the production of the API is delayed by some unforeseeable reasons, capacity can be adjusted with the drug product team to ensure that once ready, formulation work can begin immediately—whereas in a non-integrated, multiple-CDMO approach the customer may have to wait for a new drug product slot if API delivery is delayed. This benefit provides for timeline and capacity flexibility, as well as an added layer of robustness (i.e., both API and drug product teams will talk directly on the same site and can adopt plans together). This is particularly important when biotechs are working towards development goals that might have sizable investment implications (e.g., milestone payments).

Another advantage is that an integrated provider can involve CMC writing work from project start and collect/review the data once the required tests are completed to avoid any gaps along the process. Otherwise, the sponsor will need to request documentation from two different providers—often a lengthy and complicated process. In addition, different tests running with different quality and control systems will further generate risks and potentially delay timelines (4). Furthermore, with a multi-vendor model, if the drug substance and product vendors do not have fully aligned analytical testing methods, the extra time taken from GMP release to clinical trial manufacture can add one and a half to two months on average (4).

Management of multi-provider models will also often require an experienced CMC specialist to coordinate the outsourced providers and deal with the complexities of submission—very rarely will the biotech possess this expertise in-house. Therefore, when considering the CMC roadmap holistically, an integrated partner can simplify the coordination between drug substance and drug product R&D and manufacturing teams, and can gain efficiencies through unified and coordinated quality and analytical teams.

For a global industry with tremendous complexity, diverse innovator capabilities and high regulatory burdens, efficiencies through this integrated CMC model is another step towards delivering faster, more robust development pathways—and ultimately more therapies to global patients.

References

1. W. Rushing, “Designing Phase-Appropriate CMC Analytical Programs,” Pharmaceutical Technology Outsourcing Resources Supplement (August 2019).
2. FDA, “Drug Approvals and Databases,” fda.gov [accessed 22 Feb. 2021].
3. C. Shaffer, “Making the Most of a CDMO Relationship,” GEN, 1 April 2020.
4. J.A. DiMasi, Z. Smith, and K.A. Getz, “Assessing the Economics of Single-Source vs. Multi-Vendor Manufacturing,” Tufts Center for the Study of Drug Development, October 2017.

About the Author

Xueqiang (Cliff) Yin is executive director, CMC Project Management, STA Pharmaceutical, a WuXi AppTec Company (WuXi STA).