Perspective on Current Industry Control Strategies for Synthetic Peptides
Jeremy Manheim, Ph.D. Associate Principal Scientist, Merck
Oligo Sector’s Scattershot Analytics Reflects Lack of Regulatory Consistency, Says IQ
The lack of regulatory consensus on oligonucleotides is reflected in a wide variety of analytical techniques used in the industry, according to research by an IQ Consortium team tasked with establishing a “best practices” framework.
The issue was raised at TIDES USA by Jeremy Mannheim, an associate principal scientist at Merck, (MSD outside of the U.S. and Canada) and a member of IQ’s analytical peptide working group, who said developers would benefit from a regulatory harmonization on oligos.
“So when is your API considered a small molecule versus a peptide versus a biologic? Well, as we know, it kind of depends on who you ask. Small molecules have a clear guidance and ICH guidelines, and then your API can be considered a peptide if it has more than four amino acids, according to the EMA.
“But that size delineation is not really spelled out by the FDA. If you have two amino acids coupled together, then it can be considered a peptide. And when you’re considering a peptide, those guidances aren’t very clear.”
Mannheim added, “There is a draft EMA guidance out there that we hope comes out soon, but at the time, there’s not much guidance available for peptides.” Similarly, while a peptide API composed of more than 40 amino acids can be a biologic by the FDA, the EMA threshold isn’t considered for synthetic peptides by the EMA.
“There’s a lack of kind of guidance out there of what you’re supposed to do if you’re considering your API a peptide.”
Analytical practices
The absence of regulatory consistency is impacting analytics practices, according to Mannheim, who said a recent survey of 10 member companies illustrates the current lack of industry consensus on techniques and thresholds.
“The main takeaway from all 129 questions [was that] while there was some consensus amongst the responses we received, not a single question received a unanimous response. That’s kind of really showing that there is a lack of alignment amongst what our pharmaceutical industry practices are.”
Mannheim cited the range of techniques being used to test oligonucleotide purity as an example, explaining that while most respondents use reverse phase HPLC, a significant proportion uses size exclusion chromatography. And even among those that use SEC, there is a lack of consistency.
“Only four companies said they are even using [SEC] as a release test. But even the responses for the limits being set are split amongst the industry. Two companies are saying they have limits of 1% to 4.9%. And two other companies indicated they use point five 2.9%.
“And the rationale for this was the first time that the size of the peptide was used as a way to determine these limits. So the company said that if the peptide had less than or equal to 40 amino acids, they would set a limit of point five 2.9% — kind of in line with the unspecified impurity limit of the EP guidance. But if the peptide had more than 40 amino acids, they would set this aggregate range here of 1% to 4.9%.”
The findings were similar for questions related to drug products, where again a range of analytical techniques and limits were reported.
Furthermore, Mannheim said, “You can see that there is a lack of alignment amongst the pharmaceutical industry created mostly by this ambiguity and lack of consistency in the guidances available.
“So what we’re going to hopefully come to next is define a unified appropriate science-based approach for the control strategy of synthetic peptides.”