For academic groups or small biotech companies primarily focused on drug discovery, taking products into clinical development can be a daunting task. The requirements for process development and analytical development which enable GMP manufacturing can appear to be extremely expensive steps in the development path. This article highlights how investment in early-phase process and analytical development can significantly increase the value of products in clinical development, as well as increasing the value of the sponsor company.
In 2017 it was estimated that there were globally ca. 15,000 drugs in development, of which approximately 38% (5,700) were biologics (Pharmaprojects Pharma R&D Annual Review, 2017). This number has increased by 2.5-fold since the start of the century. This ever-increasing pipeline of new biological Investigational Medicinal Products (IMPs) has significantly increased the demand for early-phase process development, analytical development and GMP manufacturing. However, during the same time-frame the amount of capital investment into the biopharm sector has been disproportionally modest, producing a situation where many small companies or researcher groups, especially in Europe are “product rich” but “cash poor.” Hence, it has become imperative for many to advance their clinical pipeline products in the most cost-effective manner possible. One solution to this problem which has become ubiquitous in the biotech sector over the last 20 years is the outsourcing of process and analytical development and GMP manufacturing to biologics Contract Manufacturing Organisations (CMOs). The outsourcing of these activities, which are generally outside of the experience of most small biotech companies and academic groups, allows them to deploy internal resource to their core activities within drug discovery. It also allows the sponsor to “buy-into” the experience of the biologics CMO which can help significantly accelerate the projects route into the clinic. As most funding rounds within academia or biotech companies are milestone related, getting a lead product through Phase 1 clinical trials using grant or initial investment has become important for further fund-raising opportunities. Successful early-phase process development and manufacturing can not only significantly increase the ability to raise further funding, but also the partnering value of a potential product when it comes to licencing. Therefore, choosing the right CMO partner and maintaining a good working relationship with them has become a vital activity for early-phase development groups, even though they may not have expertise within these areas.
The limited financial resources of many groups can cause conflicting priorities when it comes to early-phase process and analytical development. On the one hand it is important to support suitably detailed development studies to provide a sound basis on which later-phase manufacturing processes and analytics can be built. But at the same time, the resource allocation must be controlled as the product has yet to prove itself in first-in-man clinical trials. Hence, a balance of suitable and sufficient development must be achieved in a cost-effective manner. Strategies to achieve this need to be developed early in the product development planning stage, which can be very difficult without experienced input. Therefore, obtaining experienced input at an early planning stage can ensure that resources are planned appropriately to each stage in product development.
When a New Biological Entity (NBE) is first identified as a candidate for clinical development it is common for the molecule to be produced in very small quantities, in a laboratory process by research scientists who have little or no experience of process development and scale-up suitable for transfer to GMP manufacturing. Similarly, the research product may be analysed by standard “off-the-shelf” analytical techniques by the same research scientists. At the early-phase all experience with a molecule and any data generated on it is important to act as a basis for process and analytical development to start in earnest. As mentioned above, the aim of process and analytical development should be to carry out suitable and sufficient studies in order to support each stage of product development. Detailed Pharmaceutical Development approaches have become regulatory expectations; for example, as set out in ICH Q8. Initial Phase 1 development studies should be carried out in sufficient detail to allow Phase 1 GMP manufacturing and release to be successful and at the same time, act as a basis for later-stage development and manufacturing. Two areas which are frequently overlooked during early-phase planning are process consistency and toxicology (tox.) batch production. Early in a products development lifecycle experience with its characteristics are obviously limited and the same is true for the production process. For clinical batch production to progress rapidly, the process should be demonstrated to be consistent and produce a product with the expected characteristics, before it is transferred to GMP manufacturing. It is not uncommon for less experienced sponsors to wish to transfer the process into manufacturing with only one integrated process having been run at an intermediate scale. This is a very high-risk strategy which can lead to program delays and increased overall cost. Therefore, a strategy for how reproducibility will be demonstrated should be decide upon during program planning. In similarity to process consistency, for a clinical development program to advance rapidly, the tox. batch frequently needs to be produced at a relatively early stage in the project, often before development activities are complete. However, it is a regulatory requirement that the tox. material is “representative” of the clinical material to help assure patient safety. The tox. batch also frequently acts as the first reference standard for product release and analytical comparability. So, it is imperative that suitable strategies around tox. batch production are put in place to support the product development program. These two often overlooked aspects of early-phase development programs can be addressed in parallel, for example by producing three larger-scale development batches before transfer to GMP manufacturing.
But how can small companies or academic groups, with limited resources ensure that they carry out suitable and sufficient development work? The answer to this question lies partly in tapping into expertise already gained in the biopharm industry and partly in executing “smart,” rapid development campaigns. The basis of which will be discuss in more detail in my next article. At a high level, process and analytical development for Phase 1 should to be carried out in such a manner that it not only provides assured supply of GMP material for First-in-Man studies but can also act as a solid basis for later-phase product development. By following this development approach, if the product is successful time is saved through such an iterative process, rather than time consuming re-development being required at each stage. Another advantage to this approach is that it can also help prevent the requirement for expensive comparability studies during later-phase development. Overall, a coherent, forward-thinking approach to development decreases cost and time; both critical variables for sponsors entering clinical development.
Early investment in process and analytical development not only has the effect of increasing the likelihood of successful GMP manufacturing to enable first-in-man clinical trials, but also the value of the product. When partnering a product in clinical development it is common for the acquiring company to ask four basic questions during due diligence:
- Does the product work?
- Can it be made?
- How much does it cost?
- Is it protected?
Process development, analytical development and successful GMP manufacturing can offer answers to three of these four vital questions viz. “Does the product work?” “Can it be made?” and “How much does it cost?” Without suitable answers to these questions and appropriate supporting data, the partner is unlikely to acquire the asset or will only do so at a significant discounted price. It is also not uncommon for the same four questions to be raised during funding rounds, whether they are for grant funding or equity financing. This demonstrates quite clearly the importance and value of development activities to the future of a product in development. So, an investment in resources early in the development life-cycle of a new product will reap rewards later. Previously, it has been quite common for early-phase sponsors to carry out very limited development at the early-phase and assume that the company who eventually commercialises the product will carry out the required development studies at a late-stage. This however is a high-risk strategy and unless it can be demonstrated to a partner company that the product can be produced and analysed reproducibly at a reasonable cost, they are unlikely to licence or purchase it. Therefore, producing and following a “phase appropriate” development plan early in the product development life-cycle will help provide assurance that the product is indeed manufacturable at a reasonable cost.
In conclusion, the true value of carrying out suitable and sufficient process and analytical development work at an early-stage may not be apparent to many sponsors entering clinical product development for the first time. Especially when the associated costs run into several hundred thousand pounds or dollars. However, the expense should be viewed as a sound investment in the future of the product and company, which will gain true value when either partnering the product or raising further funding for its continued development.
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