Challenges in the Changing Peptide Regulatory Landscape

Although therapeutic peptides have a rich and long history, starting in 1923, when insulin from an animal origin was administered for the first time to a diabetic patient, the regulation requirements by the authorities with regards to generic synthetic peptides are still much less established compared to those applied to small molecules.

For a long time European Pharmacopoeia limited the maximal content of each impurity in the synthetic peptides to not more than 0.5%.

On the other side of the ocean, the FDA only recently published new guidance for the industry on “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin”, which details the agency’s view on the expected quality of generic peptides.

According to this guide each impurity present at a level above 0.10%, if not present in RLD, should be assessed for immunogenicity. Factually this requirement directs the process development to have APIs with as little as possible new impurities at a level above 0.10%.

This new desired level of control leaves behind even the most well-known requirements for small molecules, where each identified impurity can be present at a level of up to 0.15%.

To address this challenging demand, a strict control strategy should be in place, both at upstream and downstream levels of the peptide production process. Such control starts from the protected amino acids, the basic building blocks used for solid-phase peptide synthesis.

Each impurity present in a commercial amino acid can potentially enter the peptide sequence and form a peptide impurity, which should be then purified, wasting the resources and reducing the product yield. In general, the smaller the molecule, the easier to control its quality and higher the control efficiency.

Another class of impurities obtained during peptide production are synthesis-related, such as omissions and extra-insertions of amino acids, incomplete deprotection, oxidation of amino acid residuals, oligomers formation, and so on.

Thorough process understanding and systematic reaction optimization makes it possible to maximally reduce the formation of these impurities thus simplifying the downstream purification, making it predictable and reproducible.

Peptide synthesis strategy, where several short fragments, all of which are first synthesized in a solid phase, are then linked between them in solution, called hybrid synthesis. This approach is especially effective for production of long sequences (> 30 amino acids).

The longer the peptide sequence, the more potential impurities can be present in the product. At some stage, notwithstanding the state-of-art analytical technology, it’s difficult to resolve all the potential impurities from the main peak.

In these cases the control of impurities content can be done in intermediate (shorter) fragments and the final material includes control of impurities, originating only from the coupling of short fragments.

Downstream processing of the synthesized sequence is the last gatekeeper of the peptide production process. During chromatographic purification(s) the peptide quality is polished to achieve the target content of impurities.

Substantial amount of material and time resources is consumed particularly at purification step. Continuous purification technology, which became available lately, has a potential to reduce significantly the time required for chromatographic purification and to increase the process yield.

The combination of tight control strategy and state-of-art production and analysis technology makes the synthetic peptides products competitive and quality consistent.

About the author

Pavel Parkhomyuk holds a PhD in Biophysical Chemistry from Ben-Gurion University. Pavel has been working at Teva for over 19 years, and is currently Complex API Science, Technology and CMC Manager at Teva api R&D. His previous roles include: Coordinator in Analytical R&D, and DMF-to-Launch R&D Group Leader.