PEPTIDES & PROTEINS are becoming an increasingly common method for conjugation
• Chemical orthogonality : Introducing multiple variations to a peptide backbone will require this to ensure reaction specificity
• Ability to analyse : Complex modifications , such as the incorporation of PEG to enable halflife extension , introduce significant analytical challenges due to physical and spectroscopic properties There are likely to be multiple alternative synthetic routes to a given target molecule . It may be appropriate to perform a route-selection phase of work to compare potential synthetic approaches . This can become an extensive exercise and the tradeoffs between gaining valuable information and cost or time will have to be considered .
Physical properties
Understanding the physical properties of a lead early on can have a significant positive impact on the programme , saving issues further on . With the right guidance and assessment , it is relatively straightforward to build a package of data that informs later decisions , for example around counterion choice and formulation . Some of the aspects to be considered are :
• Physico-chemical properties : pI determination , counterion selection & lyophile stability
• Determination of solubility & stability in a range of pharmaceutically acceptable buffers
• Identification of degradation pathways
• Freeze-thaw stability determination
• Aggregation determination Of these , perhaps the most important characteristic to consider is the nature of the counterion . Most research grade peptides are manufactured as the TFA as a consequence of the manufacturing process . It is usually desirable to move away from the TFA salt and the acetate or chloride is often selected by default . The nature of the counterion can dramatically affect properties such as solubility and stability , and it is worth taking the time to consider counterion alternatives . This can be achieved by a quick and straightforward screening process , which can be highly informative .
Preparing for first in human
Building up to a first-in-human clinical trial is a significant milestone for any development project and API supply is very much on the critical path . The IP clock is ticking and there is significant incentive to reach this milestone as quickly as possible . However , there is a tradeoff between process knowledge and cost or time . A phase-appropriate approach is recommended .
There is a clear link between time invested and process knowledge . The more time spent on developing a manufacturing process , the greater the process knowledge . It is likely that during the research phase , limited time has been spent on the manufacturing process . There may be competing forces when transitioning from research to development ( Figure 2 ), but manufacture for Phase I does not have the time available to develop a fully understood process . It is not required , or desired , to invest in a validated package for a first-in-human trial . The manufacturing process used need only be fit for purpose and demonstrated to be sufficiently robust to be performed under GMP . It is not expected that every process detail is fully understood . One key aspect that needs to be sufficiently understood is control aspects around the generation of impurities . It is wise to ensure a clear progression from the quality of GLP tox material to clinical material . It is prudent to ensure that the GLP tox material is of a lower overall purity than the clinical batch , such that process impurities can be appropriately qualified . If too high a purity is used for tox or early clinical batches , then it can introduce process challenges later in clinical development when larger quantities of material are required .
Conclusion
The field of peptide therapeutics is alive and well , and the landscape has changed to incorporate creative solutions to some of the disadvantages they present as a class of molecule . Giving consideration to a few concepts can help smooth transition from research to the clinical arena . •
Dr Alastair Hay
VICE-PRESIDENT PEPTIDES
ALMAC GROUP
Figure 2 - Competing perspectives in process development
J j alastair . hay @ almacgroup . com www . almacgroup . com
47