Organisations are outsourcing their active pharmaceutical ingredient (API) manufacture more often than ever before, so selecting a contract manufacturing organisation (CMO) is of increasing importance
Choosing a CMO is not straightforward, but the rewards for building a successful relationship can be high in both the short- and the long-term. The challenges of outsourcing are faced by a range of organisations, from first-time biotechnology companies to Big Pharma; but, irrespective of the nature of the sponsor, the principles remain the same.
This article looks at factors to take into account when outsourcing the production of material for first in human (FIH) studies. I work in the peptide CMO sector, so the article is written through the eyes of a supplier in that field. But, this should give the sponsor valuable insight into the factors that help to shape a successful manufacturing programme. I will cover three main topics: defining the project, conducting process and analytical method development, and project implementation and management
Clear project definition or scope is crucial to ensure that both the sponsor and the CMO are in agreement regarding the work to be done. The project scope will be written in the proposal provided by the CMO; it may take several iterations and revisions to reach the point when scope is agreed. It is very useful for the sponsor to have a clear understanding of what they need, and a well-structured Request for Proposal (RFP) helps to reach clarity — as well as enable comparison between competitor proposals. Essential elements of an RFP are shown in Table I.
The proposal should describe all development activities during the manufacturing process and analytical methods, manufacturing activities and support work, such as characterisation or stability studies. The proposal should include clear deliverables and assumptions, and provide information on prices and timeline estimates. A 2-week turnaround from the point of providing the RFP is reasonable.
It is important to understand whether the CMO will outsource any activities; it’s likely that some activities may be outsourced, such as specialist analytical tests. The concept of a “one-stop-shop” is very attractive, and integrated services is a very appealing proposition to save cost and time. It is worth doing some homework to understand the true extent of integration.
Are manufacturing and formulation activities, for example, conducted on the one site, or is the proposition simply an umbrella organisation, wherein activities are performed on different sites, countries or even continents? Multisite projects aren’t necessarily a bad thing, but it’s worth understanding how the project will be managed.
The proposal will normally need refinement to a greater or lesser extent, and will require investment in time on the part of the sponsor and CMO to ensure the details are finalised. Calls, or even better, face to face visits help to reach an agreement on the project scope, and a site visit to see the facilities and get a feel for the culture of the organisation is highly recommended. An audit of the CMO’s quality systems will certainly be required.
FIH campaigns present something of a dilemma to sponsors when it comes to conducting development work. On the one hand, it is important that the manufacturing process and supporting analytical methods are sufficiently robust to ensure a successful manufacturing campaign. On the other hand, it is not appropriate to invest too heavily in development at this early stage — as the molecule may not proceed beyond the FIH study.
A pragmatic approach is required. There will not be time to understand the criticality of every process parameter, but it is important to demonstrate that the process is sufficiently robust and agree which process steps will be conducted under GMP. Similarly, with analytical method development, the standard approach is to focus on limited validation of the purity method (usually HPLC/UPLC) and use generic methods for other analytical tests. The detail of the development work undertaken will depend on the sponsor’s preference — based on experience from previous programmes and approach to risk. Reaching agreement with the CMO regarding the extent of development work to be performed is crucial to ensure that expectations are met.
And, sometimes things go “wrong” during development. A product that is sticky during filtration is no one’s fault, it’s just the property of the molecule. Development is just that. It’s about getting a better understanding of the molecule and the controls required to ensure successful production. Sometimes, more development work is required than planned to overcome difficulties.
Some difficulties may be overcome by generating a package of physicochemical information on the API, as such information can impact the processability of the molecule. Information on characteristics such as solubility, stability and morphology needs to be gathered so that choices can be made regarding factors such as formulation and storage. For example, in the world of peptides, a key question is the nature of the counterion employed. The acetate salt is often chosen by default, but others may improve the physical characteristics of the molecule … or make manufacturing easier.
In FIH studies, when timelines and budgets are often tight, such physicochemical studies are often ignored, or at least put back. This may be an entirely reasonable course of action, but may result in important data being missing.
Choosing the CMO is just the beginning of the relationship, and effort is required by both the sponsor and the CMO to make a success of the project. The first step, ensuring the scope of work is clear, is achieved in the written proposal, but successful project implementation arises from effective interactions throughout the project’s duration, and effective project management is crucial.
I would suggest that the sponsor should expect the CMO to provide technical expertise, generate knowledge and information, and be flexible and reliable. Underpinning this is a strong project management base: communication, co-ordination and control. Establishing regular calls, providing written reports and conducting face to face meetings all help to manage progress. It is good for the CMO to be kept alert by communicating with the sponsor, and tends to result in a much more effective relationship than if the sponsor is passive. The days of signing a project and then receiving no further communication until product is shipped 9 months later are long gone!
Early stages in development programmes can be very challenging. Assuming the CMO has done its work professionally and diligently, how challenges are dealt with is an important indicator of its approach and attitude. Does the CMO immediately share the issue with the client? Are the causes clearly understood? What actions are being taken? Understanding how issues will be dealt with is an important element to establish at the outset of the project, which is why understanding the scope of work at the outset is critical. Overcoming challenges is worth it in the long run — a good CMO will value the relationship and work hard to deliver on promises and maintain trust.
CMOs generate a great breadth and depth of knowledge through exposure to a wide range of projects. This puts the CMO in a very privileged position as a whole range of projects come through its doors. A successful CMO is continuously improving its technical and regulatory knowledge, as well as its operational practices to meet the demands of the industry. Investing time during an FIH programme to work closely with the CMO will certainly bear fruit in the long-term.