Brian Mullan is the chief technical officer of Yposkesi, an SK Pharmteco company.

Brian Mullan

In the past 20 years, the contract development and manufacturing organization (CDMO) sector has grown strongly—initially in chemical manufacturing (outsourcing capacity for specialized manufacturing chemistries) and more recently for biopharmaceutical manufacturing, as parts of this sector have matured (e.g., monoclonal antibody therapeutics [mAbs]) (1).

When (or whether) to work with a CDMO for all or part of bioprocessing development needs, or whether to keep these activities in-house, has been the subject of many articles, reviews, and discussions (2–9). These reviews, principally in the trade media, have dealt extensively with thematics such as scope, expertise, capacity, quality systems, and risks when evaluating whether to develop and/or manufacture biotherapeutics in-house or outsource these activities to an external partner.

Among many of these factors that could be considered (2–9), this decision comes down to some key considerations (see also 

 Determine whether the necessary expertise/capabilities exist in-house. This can include at a minimum scientific and technological expertise but can also extend to associated expertise, such as the ability to translate the manufacturing and analytical technology into current good manufacturing practice (CGMP) mode, scale it up, or support regulatory activities (e.g., dossier submission).

 Is the analytical and manufacturing technology at the necessary scale and standard to develop and/or produce the product at the required volumes? Is this capacity available now, or is it being built and will only come online in a couple of years’ time?

 Is the product pipeline sufficiently developed to utilize internal capacity (based on current or future anticipated capacity needs)? What is the financial capacity of the organization? Is it sufficient to carry idle manufacturing capacity until the pipeline matures to fill this capacity? Is there enough activity to maintain a workforce engaged and in a sufficiently-trained state? Are the process and analytical technologies used rapidly evolving and require frequently updated equipment, methods, training, etc.? An organization must also determine whether there is a budget to maintain state-of-the-art manufacturing technology.

If the decision is to partially or fully outsource the activity based on the assessment of these various factors, the choice then becomes which CDMO to work with. In many sectors of bioprocessing technology, there are usually many contract service providers to choose from, and some larger CDMOs offer services across a disparate range of technologies and platforms.

The area of cell and gene therapies (CGTs) is an interesting case to consider for “make versus buy” decisions. The field is immature but evolving rapidly. While products have been developed since 2000, approvals have only started in earnest since 2017. Even with six product approvals in 2021 (10), the peak of such approvals is yet to come (10, 11). The understanding of how the products work is currently weak (e.g., dosing as well as the adeno-associated virus empty/full capsids issue [10]), which manifests in a general sentiment around chemistry, manufacturing, and control (CMC) challenges for these programs. As this continues to rapidly evolve, it will have a profound effect on the choice of manufacturing and analytical technology (10). This complexity and state of product understanding also put a premium on the quality of any partnership with a CDMO (i.e., capability, experience, and reliability).

Concerns about the perceived high costs of CGT manufacturing and the level of control over the CMC program are frequently evoked, as many programs are currently outsourced to CDMOs as developers build up their own internal capabilities. There is also a strong sentiment around the lack of available capacity, which is more specifically related to slot availability and turnaround time. For example, a requested turnaround time of six to nine months from an order to batch completion, as opposed to a proposed 12- to 18-month turnaround time, may not be coherent with overall program timelines.

The costs of working with a CDMO in the CGT area can sometimes appear to be high but may, in fact, not be so different from the comparative costs of doing this internally. In general, even for large pharmaceutical companies using a sufficiently platformed process and operating in an efficient manner, the cost for manufacturing biopharmaceutical drug substance batches (e.g., mAbs) is often in the millions of euros per batch, and 50–70% of this cost can be additionally charged for the associated drug product batch. The key drivers for these costs are facility utilization (asset costs and depreciation, utilities, etc.), people, and raw materials. The economic efficiency of the process can be quoted as X$ per Z gram of DS (or X$/DP vial), with the process deemed to be more efficient with higher yields, and the X$/Zg or vial can be benchmarked across similar drug categories (e.g., for mAbs). This approach is typically applied more rigorously for commercial supply of biopharmaceuticals, whereas in the clinical supply phase costs are more typically on a per-batch basis with sometimes no guarantee of fixed yields as the process may be under development and its performance continuously evolving. As a drug developer, these costs may seem elevated—especially if associated with no commitment to final yield—when presented with them for the first time by a contract service provider. But in many cases, these costs are similar to or lower than the developer would otherwise experience doing everything in-house.

When considering perceptions around control, it is often a point of frustration for product developers that issues arise at contract service providers that create problems for their programs. It is true that such setbacks can have a serious impact on the overall product development timeline and even the financial viability of the company. This may lead to the belief that CGT CMC activities are better performed in-house, as this enables more direct control and—as such—more reliable outcomes.

This may not always be true. It is unlikely that quality standards or reliability are significantly lower at CDMOs than for comparative internal performance. For larger pharmaceutical companies, whether in new product platforms or on more mature product classes, everything doesn’t always work perfectly all the time. Sometimes, mistakes are made. It is important to consider how issues arising externally at CDMOs would be viewed if they occurred internally. As such, the bar may be set higher for a CDMO in relation to what would be accepted in-house.

Deciding whether to outsource or insource

Let’s break this down and examine working with CDMOs from the perspective of a large organization as well as from the perspective of small biotech companies. For a large company with the financial means and a deep and promising product pipeline, it might make more sense to do this internally if a company has the financial capital to construct, buy, or reconvert the necessary facilities (manufacturing and testing) and recruit, train, and develop the different supporting teams. Depending on how companies with scale and financial means see their pipeline developing in the coming years, perhaps the “make” decision is the best one. But with all of this (facilities, trained personnel, etc.), large companies must be ready on time for their product pipeline and also consider their competitors’ products (and their anticipated arrival to market). If the timing is not coherent with the product milestones, maybe a medium-term partnership with a contract service provider can be a prudent choice (a “hybrid” model). This could allow a company to continue to develop a product internally in alignment with their chosen platform (manufacturing and analytical) while supplying clinical material via a CDMO. CDMOs are generally quite flexible in this regard and can adapt to different platforms.

On the other end, many younger and/or smaller biotech companies may not have the relevant skill set or experience to guide their own CMC activities. In some cases, the team is focused on the direct product aspects (clinical evaluation, fundraising, etc.) and does not have the capacity or experience to develop and drive the CMC program. An experienced CMC professional can be brought on board to enable the company to develop the CMC program, but they may not have experience in all relevant areas. As such, working with a CDMO may be the prudent choice here. A key consideration for these companies may be manufacturing and analytical portability, as the company or its product assets may be acquired in the future by another company that already has internal CMC capabilities or is working with a different preferred provider, and the transfer to another provider should not be a blocking point for a potential deal (between the biotech company and the acquiring company).

Many product developers today are looking to enter into a partnership with a CDMO, and not just a transactional relationship. There is a profound difference between these two approaches: fee for service versus a partnership based on trust, understanding, and shared view that is intended to run over a longer term (whether for one product or several products based on similar technology). The outcomes of these two models are not always the same for companies who work with large or complex products (such as gene therapies), as serious issues can result in a need to change the manufacturing site, which is a costly endeavor that can create significant delays to overall product development programs. As such, many product developers assess potential CDMOs over a longer-term horizon, even though the initial phase of work may only entail early process development or the generation of material for pre-clinical evaluation. Oftentimes, the evaluation process, even for early phase activities, can include an assessment of how the program can evolve over different stages of development, three to five years into the future.

The following questions are often raised to CDMOs for early-stage programs (and lead to long-term success for product development):

How do you approach process characterization and process validation?

Can you support us with regulatory dossier writing?

What prior experience do you have in doing this?

Lastly, one key advantage of working with CDMOs that merits highlighting is that they have generally gained a lot of experience across multiple different projects. In many cases, they have seen and learned things in previous projects that can be of benefit to your project (while maintaining client confidentiality and respecting IP). It’s the type of experience that other companies may not yet have gained in-house, but it may be key to the success of a program. This usually has many benefits when evaluating concerns around control and costs, which are both related to experience and capabilities.

In summary, choosing whether to internally develop and manufacture biopharmaceutical products or to outsource these activities is a complex and high-stakes decision, which can have a profound impact on the success of a product development program. Many factors should be considered in such an evaluation; but in many cases, this comes down to key considerations around expertise, capacity/technology, and economics. CGT products raise additional dilemmas. Different situations, such as internal capacities and capabilities, may direct companies toward different choices, either in the short or long term. If the decision is to outsource, a quality-focused, partnership-based approach is critical to future success given the complexity of the products and the technological and regulatory evolution of the CGT sector.

 DOI:10.3389/fbioe.2022.841420 (March 2022).

2. Pharmaceutical Online, “Choosing A CDMO: If You Can't Answer 'Yes' to These 3 Questions, Walk Away,” 

3. Outsourced Pharma, “Selecting A CDMO: Strategies to Ensure a Successful Partnership,” 

4. American Pharmaceutical Review, “Risk Minimization Through Careful Cdmo Selection,” 

5. Bioprocess Online, “CMC and Quality Considerations When Engaging Your CDMO,”

6. Pharmaceutical Online, “Betting the House: CDMO Selection for Emerging Pharma,” 

7. The Medicine Maker, “So, You Want to Become a CDMO,” 

8. BioProcess International, “Developing Advanced-Therapy Products Through Global CDMOs,” 

9. BioProcess International, “Will In-House Manufacturing Capabilities Give Cell and Gene Therapy Developers Competitive Advantages?”, 

10. J .Lynch Lambert, “Regenerative Medicine: New Paradigms,” 

online, DOI:10.18609/cgti.2022.018 (Feb. 1, 2022).

Regenerative Medicine: Disrupting the Status Quo


Vol. 46, No. 10
October 2022
Pages: 60–64

When referring to this article, please cite it as B. Mullan, “Choosing the Right CDMO for CGT Programs," 

Articles

Whether biologic manufacturers decide to outsource or develop products internally, the quality of a CDMO partnership is critical to success, especially for cell and gene therapy products.