LINKING THE “D” & “M” IN CDMO

Citation: Ross J, “Linking the “D” and “M” in CDMO”. ONdrugDelivery, Online, April 21, 2021.

John Ross looks at the role of CDMOs in product development through to commercialisation and considers the benefits of consolidated “DM” models.

“Drug manufacturers increasingly turn to integrated contract development and manufacturing organisations (CDMOs) with advanced process development and scale-up technologies to realise measurable efficiencies and cost savings without compromising patient safety and product quality.”

There is ever-increasing pressure from consumers, investors, insurance companies, regulators and governments to drive down drug development costs while improving product performance and outcomes. It is no surprise then that drug manufacturers increasingly turn to integrated contract development and manufacturing organisations (CDMOs) with advanced process development and scale-up technologies to realise measurable efficiencies and cost savings without compromising patient safety and product quality.

The notion of the CDMO was created by adding the “D” to “CMO” to capture the integrated offering of development through to commercialisation. The concept is relatively young, but since its inception in the early 2000s, more and more organisations have expanded their range of services, either organically or through merger and acquisitions (M&A) activity, to transition into end-to-end CDMOs. Ernst and Young’s Global Capital Confidence Barometer shows that 58% of pharma executives plan to actively pursue M&A during the next 12 months. Of these, more than three-quarters say that their planned M&A activity will include bolt-on acquisitions or deal-making for transitional capabilities.1,2

The appeal of outsourcing the entire development and manufacturing process to access expert support at each stage has become desirable for many drug developers, sponsors and brand owners. Sites that co-locate both development and manufacturing offer enhanced consistency in key areas, including change management, analytical testing, quality oversight and process expertise and training.

The utilisation of contract partners for early-stage analytical, stability, preformulation, formulation development and product development in the pharma industry is anticipated to increase as the strategic partnerships between drug developers and contract suppliers mature.

CDMOs position themselves as strategic partners, rather than transactional or tactical service providers, offering only niche expertise in areas sought by drug developers.

PURSUING THE CMDO MODEL

Over the last decade or so, the draw of the full-service model has led to a proliferation of organic and inorganic pursuits from CMOs and CDMOs to provide a more comprehensive offering across the lifecycle of a drug. In some cases, this has meant the “M” moving earlier in the value stream to “D”, and in others, vice versa.

“The draw of the full-service model has led to a proliferation of organic and inorganic pursuits from CMOs and CDMOs to provide a more comprehensive offering across the lifecycle of a drug. In some cases, this has meant the “M” moving earlier in the value stream to “D”, and in others, vice versa.”

Some CDMOs have expanded their global footprint to provide localised services to their clients while simultaneously entering new markets. Others have looked to expand their capabilities and capacities at existing sites to deliver greater efficiencies and provide adjacent services that benefit from co-location. Many relied on M&A activity to expand into new service areas, effectively buying access to expertise and differentiated advanced technologies. There has also been an uptick in the number of preferred partnership arrangements, allowing businesses to remain independent but customers to reap the benefits of single contract arrangements.

Finally, and arguably the rarest approach, is the embedded CDMO, where pharma companies offer their capabilities and expertise as a third-party services provider.

COMMON PITFALLS IN ADDING THE “D”

Tech Transfer Risk

An integrated CDMO is simple in concept but difficult to execute effectively.

Effective process development is essential for achieving cost-effective manufacturing operations. In particular, processes designed with scale-up to commercial volumes in mind enable smoother technology transfer, reduced manufacturing issues, fewer product quality challenges, lower processing costs and potentially, faster time to market. Every time a handoff occurs along the development through to commercialisation pathway, it adds complexity, time and risk. The most important element in a successful tech transfer is to create a solid step-wise technical plan with adequate studies, including engineering batches if required, to determine critical information before committing to the validation of the commercial process.

Most organisations get from “D” to “M” by tech transfer activities to a different site. As a result of the fractured nature of the sector and the M&A trends mentioned earlier, it is often the case that those sites came by independent acquisitions from different organisations bringing different cultures, systems and processes that may not be integrated nor optimal to the client’s needs.

Tech transfer has its own challenges, separate from clinical process development. Understanding the manufacturing process thoroughly is only one aspect needed for an effective (and efficient) tech transfer. Timing for the scale-up and transfer process is typically critical for clients and can vary depending on their approach to filing their NDA. Ensuring all necessary documents to support their filing in conjunction with the scale-up work required is essential to ensuring launch material is ready at the time of approval. Metrics Contract Services accomplish this by developing a detailed, risk-based transfer plan based on prior development work, registration batch data and collaboration with its clients to leverage this information and their target dates for filing and approval. The result is a comprehensive execution plan that ensures readiness for launch and pre-approval inspections.

Duplicating Work and Cost

“M”-only sites can struggle with non-routine requests, including the engineering, scale-up and sometimes technical evaluation stemming from product investigations or specification changes.

Often repeat manufacturing and testing studies are necessary to prepare the receiving site properly, adding time and cost. Sometimes, unintended outcomes occur during these extra steps. Such outcomes must be investigated and understood to determine if attributable to learning issues or actual product or process issues. Sometimes, these are cumbersome to resolve and challenging to navigate from a regulatory point of view.

In the oral solid dosage space, one of the worst-case scenarios in moving from separate “D” to “M” sites comes with modified-release drug products where repeated bioequivalence work is required. Not only is this costly and time-consuming, but it often creates a genuine risk to the success of the project – especially if any equipment configuration or process parameters need to change at the receiving site. Slight changes in processing between sites can impact in vitro comparative dissolution-release profiles. Maintaining the use of the same site, equipment train, processing methods and testing laboratory between development and commercial manufacturing can help mitigate this risk.

Knowledge Transfer

Separate “D” and “M” sites are also challenged to ensure tacit knowledge is passed along to prevent white spaces when continuity of the team is lost. For example, if an out-of-specification (OOS) result occurs on a batch at the receiving site, it will take time and resources to determine if the issue is associated with new analysts or operators, slight differences in materials or process, or it is actually an underlying issue with the product that was not fully understood before. Of course, any anomaly needs to be properly investigated and understood and, if part of a filing, explained to the satisfaction of the regulator to ensure the quality of the product.

When a CMO looks to enter the development space by backward integrating from being a commercial manufacturing operation first, they typically start by investing in formulation science expertise and smaller scale equipment. One of the most common errors occurs when these organisations assume that analytical needs are the same as quality control in manufacturing. Development and validation of phase-appropriate and stability-indicating methodology is needed. The solution here is experience, which is why the CDMO space is experiencing a talent war as diversifying organisations look to build up specialist teams that understand the respective “D” and “M” spaces.

CMOs also tend to rely on procedures and quality systems designed for commercial manufacturing. This can restrict speed and flexibility in the development process where it is necessary to try several prototypes using various formulations and materials to ensure that the most viable products progress.

“Consideration for downstream manufacturing must be at the front of mind within a CDMO; teams must be able to collaborate to solve technical challenges to bring products to market efficiently.”

Downstream Manufacturing

Consideration for downstream manufacturing must be at the front of mind within a CDMO; teams must be able to collaborate to solve technical challenges to bring products to market efficiently.

“D”-only sites tend to struggle to think about the commercialisation implications of manufacturing processes, such as scalability, machinability, productivity and cost.

One of the most effective strategies for addressing this is to create preliminary risk assessments and target product profiles that highlight process knowledge in the context of critical material and quality attributes for the intended drug product. This provides a template for development teams when determining priorities for development work and also ensures the process is likely to be commercially viable. With careful planning and knowledge of the commercial equipment train, the design space explored will also provide a rationale for the needed scale-up work. Where development and manufacturing groups are genuinely integrated, there is an opportunity to collaborate and develop processes on pilot equipment that are commercially appropriate, thereby minimising future scale-up work.

THE OPTIMAL CDMO MODEL

Consolidated “DM” models that leverage a single campus, with distinct parts of the operation focused on “D” and “M” co-located alongside integrated tech transfer functions, manufacturing and analytical processes offer an optimal solution to outsourcing challenges. They can reduce method-transfer activity or the re-engineering of batches, streamline project management, provide continuity of team and facilitate access to knowledge. Where there are unexpected issues, immediate technical support is available to resolve them quickly and, in the case of a pandemic such as in 2020, there is no need for travel between distant “D” and “M” locations to complete the project.

Successful CDMOs in this space have an exemplary track record of innovation, efficient scale-up and the ability to tailor plans to suit their customers’ needs.

REFERENCES

  1. “Life-Sciences-Mergers-Acquisitions”. www.ey.com, accessed June, 16, 2020.
  2. “Global Capital Confidence Barometer”. www.ey.com, accessed March 2020.

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