No detailed regulatory guidelines or standards exist for manufacturing synthetic peptides. They are subject to general ICH guidelines, but otherwise fall into a somewhat blurry zone between biotherapeutics and small molecule drugs.
“We need official guidelines for peptides from the FDA or EMEA,” says Hagopian. The current guidance for organic molecules—not including synthetic peptides, at least for now—requires identification of any impurity present at a level of >0.1%. But some in the industry suspect a shift in direction by the regulatory agencies.
At present, “the interpretation of the guidelines is the issue, and that depends on the reviewer,” says Hagopian. Most of the “impurities” result from truncation of the growing peptide molecule or the deletion of amino acids. More stringent guidelines could require companies to generate a detailed impurity profile.
Some peptide drug developers take a conservative approach and request GMP quality product for use in preclinical toxicology and pharmacokinetic studies.
The lack of any regulatory guidance regarding impurity profiles of complex peptides is a source of major concern in the peptide industry for both CMOs and customers.
Rodney Lax of PPL describes two extremes, with some customers treating peptides like small molecules, even in the early stages of development, and insisting on the ICH Q3A specifications for impurities throughout. This not only makes the peptides more expensive, especially for very long peptides, but also the need to meet the stringent specifications associated with these guidelines presents significant challenges. For example, complex peptide species containing single amino acid deletions “are unlikely to separate from the main product peak,” notes Lax. “Moreover, the guideline limits are often close to the limits of detection as well as the theoretical achievable purity for solid-phase procedures.”
At the other extreme, “underkill” is a problem for some other customers who do not address the issue of impurity profiles until later in development, when it can become more difficult to implement changes to make the synthesis protocol more robust and to minimize impurities.
According to Lax, no single regulatory recommendation would likely be suitable for all peptide APIs, which can range from as few as 2 to 50 or more amino acids in length. Risk assessment should take into account the complexity of the peptide and the expected human dose.