Where Do Consultants Fit in to the Early Development API Supply Chain?

The Changing Landscape in Drug Discovery

Pfizer, GSK, Lilly, AstraZeneca and others have all recently announced reductions in the size of their internal R&D organizations[1]. The reasons for this have been well publicized and revolve around two issues: the impending “patent cliff,” where companies will see much of their profits evaporate as their blockbuster drugs go off patent, and the seeming lack of innovation in bringing new drugs through to replace them. To address these issues all large Pharma companies are attempting to reduce their internal research effort through externalization of their R&D. In doing so they are aiming to achieve two goals: lowering the overheads associated with maintaining large R&D sites employing staff with high average wages whilst simultaneously filling their pipelines through buying or partnering with smaller companies who, they seem to believe, to be better and more cost effective at drug hunting[2].

Over the last 10 years there has been a large increase in the number of small, start-up, Pharma companies. The strategies of these companies differ widely but most are attempting to undertake low-cost drug discovery R&D with the aim of developing any identified candidates to at least the end of Phase I, and ideally through Phase II. They are then hoping to put themselves in the position to either sell the whole company to Large Pharma or to sign licensing or co-development agreements in order to fund the hugely expensive late-phase clinical trials.

Overall, the landscape in Pharma is rapidly changing from one where major companies have huge, self-sufficient, internal R&D organizations to one where they will become increasingly reliant on a multitude of smaller, research-based, companies to find candidate drugs for them to develop and market.

The Capabilities of Emerging Pharma Companies

In order to reach a positive outcome at the end of Phase I or II trials, emerging Pharma companies need to develop a drug substance supply strategy. They will require an early development supply chain for their own needs but they should also consider how the long-term drug requirements will be met. If they hope to sell on their asset to a large Pharma company they will be subject to a due diligence audit which may, quite rightly, have a strong focus on the biological profile of the candidate and its efficacy and toxicity. However, there will also be a need to demonstrate that the compound can be synthesized and formulated to consistent standards whilst meeting reasonably long-term cost targets.

Large Pharma have always, when necessitated by a lack of internal resource or a desire to apply a specific strategy, outsourced some of their early development compound supply needs. In doing so they are outsourcing from a position of knowledge, as they have the expertise required to evaluate the process development needs, select an appropriate supplier and project manage the outsourcing activities. In contrast, these skills are often lacking in small Pharma companies that have grown up on the basis of their expertise in biological and medicinal chemistry research alone. Their need to outsource is greater, since they will very rarely have in-house process research and scale-up capability, but their experience in outsourcing API supply and process development activities is likely to be low. Unlike big Pharma, they are not outsourcing from a position of strength.

Hence, for Small Pharma, a clear need for employing the services of consultants becomes evident. They may lack the experience in identifying partners for API synthesis, setting up of contracts, etc. In addition, the lack of knowledge to understand what is required to ensure rapid project delivery through to the end of Phase II, to standards that will meet the needs of any future due diligence audits, all suggest that employing a consultant will be beneficial.

In contrast, until recently, Large Pharma companies have had little use for consultants as they believed they retained all the expertise required to fill these roles in house. However, this situation may change in the future as Large Pharma moves towards a more virtual model.

Early Development API Activities

To progress to the end of Phase 1 usually requires ~1Kg or more of API drug substance. This may seem like a relatively small quantity, however, even the modest scale up from a few mg to a Kg scale can be very challenging. There are a number of factors to be considered, including:

• Raw material sourcing to establish a potential long-term, robust supply chain of consistent materials to be used throughout the development lifetime.
• Viability of the medicinal chemistry for the initial scale up (e.g., are reagents used potentially too expensive, is it safe to operate, etc.?).
• Identifying alternative routes if the current route is not viable beyond this initial scale up. How much process R&D should be performed, and when, in order to identify a longer-term route and not delay the post-Phase I activities?
• The analytical chemistry method design and validation work is required (e.g., is there a need for impurity tracking, what potential genotoxic impurities (PGIs) are there in the process, etc.?).
• Supplier choice for the work required and why they are a good fit (e.g., are there any special requirements such as safe scale-up of hazardous reactions, large-scale chromatography, etc.?) What type of contract is needed? Which suppliers are suitable for support work such as analytical methods development, stability studies, etc.?
• Critically, the impact of the API physical properties must be studied to enable the long-term formulation objectives to be addressed early on. Although Phase I studies are often completed with simple formulations, a forward-looking strategy is very desirable if progress through development is to be rapid. What salt form is required, what polymorphs are there and what particle size is desirable by the formulators? Are there special characteristics that may require novel delivery systems e.g., water-insoluble APIs? When is data required – pre- or post-Phase I?
• How can the API and the drug formulation processes be managed to minimize timelines?

All of the above are areas within which utilizing the skills of suitably qualified and experienced consultants can pay dividends in terms of achieving the required regulatory standards, timely delivery and appropriate expenditure levels. Getting any of the above wrong could be very costly in terms of wasted resources and/or material. All of which ultimately result in lost time and more costs for the project.

The application of GMP to clinical supply at Phase I and II is a particular factor, often causing confusion, which requires special attention. The ICH Q7 guideline[3], in section 19, recognizes that the application of GMP for clinical trials material cannot be identical to that used for commercial drug substances. However, the guideline is open to various interpretations and a practical and pragmatic approach is required at the earliest phases of development. There are a plethora of QA consultants available to provide advice in the area. However, many of these have a drug product, or commercial manufacturing, background and it is therefore important to choose wisely. There is a potential GMP trap in that not doing enough can cause issues later on in the regulatory and/or due diligence processes, but insisting on a gold-plated standards will delay the project and will certainly add costs. Understanding the implications for a specific project is not always easy and this is one area where there is a need for constant review as a project moves forward through Phase I to Phase II.

There is much to consider and, for a small pharma company with little experience in addressing these issues, it can be a minefield to negotiate. As the project moves into Phase II the issues will only become more complex. Scarce management resource, and critically time, can be consumed without necessarily achieving a satisfactory outcome. Although, at first sight, it may appear to be adding costs when employing one or more consultants to advise on various aspects of the project, the reality is that in terms of overall project cost the risk mitigation this affords is value adding.

The Capabilities of CROs

There are a large number of CROs that are set up to support the process development and scale up for phase I/II studies. These range from small independent companies of <20 people to large multinationals who claim to run a full service (so-called “one-stop shops”) on all aspects of Pharmaceutical Development. All have their place and can provide a good service providing the right CRO is chosen to meet the requirements of a specific project or a specific facet of the project. Smaller CROs can often offer a much more tailored and personalized service at a lower cost for individual elements of the project, but there are potential dangers if the customer does not have a thorough understanding of what is required and does not put in place the appropriate level of project management. For the inexperienced it can appear to be better to accept a higher cost and work with a larger company which has the knowledge and resources required to handle the complex issues that can arise.

Figure 1 - Matching the capabilities of suppliers and customers

To get a Win-Win position for an individual project requires that the customer understands the CRO supply market and the capabilities of all the suppliers they might consider using. Thus the intelligent outsourcer will know what to expect and to be able to define the project brief accordingly to match the competency and structure of the chosen CROs. Figure 1 illustrates some of the potential pitfalls when choosing a supplier.

It is in the interest of the Pharma Company to increase their level of competence in order to ensure they choose the most appropriate supplier at the best available price. Employing a consultant may cost a few thousand dollars, but even the seemingly simple task of choosing the right supplier for API manufacture may save much more than this and can add real value in terms of speed of delivery.

It is also of interest to the suppliers to increase their ability to deliver what the customers want. They too may benefit from employing consultants who can help them develop their systems and procedures and/ or scientific rigor.

Integrating the Drug Substance Manufacture into the Total Project

Manufacture of the API is only one aspect of getting a target compound through to the end of Phase II and beyond. For the overall process to run smoothly and efficiently there is real need to integrate the planning of the API production schedule with any downstream activities such as formulation and toxicology. At the very least it would be extremely desirable for the API manufacturer and the drug product formulator to work closely together to ensure rapid project delivery. However, outside of the Large Pharma environment, where much of the work is performed in house, this type of project coordination is difficult to achieve.

For the inexperienced Pharma Company the use of a “one-stop shop” to deliver the whole Phase I or II project may be an attractive option. However, it is still essential to choose the right company for any individual project as even large companies with the apparent ability to manufacture and formulate the drug, carry out toxicological testing and set up clinical trials may not have the specific experiences required to deliver all aspects of a particular project in a specific therapy area or with specific chemistry, formulation or other scientific needs. As an alternative they may wish to enlist the assistance of experienced consultants who can act as project managers to set up a series of contracts with various CROs and manage the interfaces to ensure they work smoothly together.

Choosing a Consultant

The production of drug substance is usually on the critical path at the earliest stage of development and identifying and engaging the right consultant to assist in this area can be key. A consultant with a thorough understanding of the supply landscape will help to identify suitable suppliers to meet their project requirements. They may also be able to provide assistance in a number of other areas such as the definition of the supply strategy, advising on routes selection and assisting in technical meetings with suppliers, auditing of supplier’s systems (Quality and HSE) and the delivered project documentation, to help to smooth regulatory process, or setting up supply agreement, etc.

A Google search of “pharmaceutical consultant drug substance” returns over 880,000 hits. So choosing a consultant is potentially problematic. But there are some common sense steps to take and some pitfalls to avoid.

Competency of the consultant is of course key but assessing this is difficult. A personal recommendation from someone who has worked with the consultant during their career is to be recommended. However, if taking this route it is essential to make sure the person recommended has the time available to provide the attention to detail and the overall level of support required.

With the decline in the major pharma industry there are many people trying their hand at consultancy work whilst simultaneously seeking new employment. If employing a consultant it is wise to check that they are fully committed to the role and will not accept full-time employment part way through your project. Losing the person who is project managing your supply at a critical stage is not to be recommended.

Any chosen consultant must be capable of demonstrating their independence from any specific CROs, i.e., it is important to establish that they are working only in your interests. However, CROs will have likely worked with a number of consultants and asking them to recommend a suitable candidate is worth considering, especially if a CRO has already been chosen but there is a requirement for independent advice and assistance in setting up agreements and for project management.

If you intend to consider using foreign-based suppliers it is ideal to employ someone who understands the culture and nuances of doing business in both countries concerned. The world language for business is English but is not spoken in the same way in all countries and it is essential for any consultant to appreciate this.

The best form of communication is always face-to-face meetings. Employing a consultant who is prepared to travel is therefore a must unless you intend to use a CRO in close proximity to your own site. This will appear to add cost to the project but it is an essential risk mitigation technique, especially for projects involving long and complex chemistry in distant locations.

Conclusions

The landscape of drug discovery and development is rapidly changing. The experience required to progress a candidate drug through to a successful Phase II outcome are oftentimes lacking in emerging pharma companies which have their roots in biology research and medicinal chemistry. On the face of it, setting up and establishing a drug substance supply chain to meet the needs of Phase I/II may seem a simple task. However, there are many potential dangers for the inexperienced practitioner. Engaging consultants experienced in defining the strategy and project managing all aspects of early development API supply, and who can work with other experts to help to define the overall development program, is a potentially cost-effective and efficient way to progress a project through to a successful conclusion.

Disclaimer: The views expressed in this article are those of the author and do not necessarily reflect those of current or previous partners or employers.

References

1. See http://www.rsc.org/chemistryworld/News/2010/February/04021001.asp
2. See also http://social.eyeforpharma.com/story/pharma-job-cuts-there-strategy-behind-trend
3. See http://www.ich.org/LOB/media/MEDIA433.pdf

This article was printed in the July/August 2010 issue of Pharmaceutical Outsourcing, Volume 11, Issue 4. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com  and subscribe for free.