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FDA: diastereomer acceptance criteria are review issues; multiple methods may be required for complex oligonucleotides
Summary
FDA reviewers said acceptance criteria for diastereomeric composition are determined during review and that sponsors may need multiple analytical methods—particularly for complex oligonucleotides like ASOs—while separable diastereomers may allow individual comparisons for some products.
Sponsors asked about setting diastereomeric composition acceptance criteria for sameness evaluations and routine controls. Dr. Liang said the adequacy of acceptance criteria is a review issue that will be evaluated case‑by‑case during the review process.
Dr. Liang explained that some oligonucleotide types have few diastereomers and individual diastereomers can be separated and compared to reference material, which can simplify establishing acceptance criteria. For products with many diastereomers (for example antisense oligonucleotides), analytical methods often produce a profile rather than discrete separations, and single methods may not be sensitive to all composition changes. "So it really depends on whether that method is capable of accurately determine and and sensitively determining the composition... If that is not the case, then multiple methods may be required," he said.
He recommended sponsors engage the agency through a development meeting request or controlled correspondence to discuss proposed acceptance criteria and analytical approaches. Post‑approval, sponsors might propose reducing routine tests if they can show consistent manufacturing and method sensitivity sufficient to detect meaningful composition changes.
