Manufacturing, Impurities, and Characterization Methods Are Key Regulatory Focal Points for Peptides and Oligonucleotides


The manufacturing process, the control of impurities – in the starting materials, the API and the drug product – and the analytical methods for characterization are focal points for regulators during CMC reviews of both synthetic peptide and oligonucleotide (oligo) therapeutics.

Why these three areas are key concerns and what reviewers will be looking for in addressing them were explored at the opening session of USP’s Therapeutic Peptides and Oligonucleotides Workshop, held virtually in March 2021.

During the first workshop session, regulators from FDA and Europe as well as experts from industry focused on the oligo/peptide CMC regulatory issues.

USP’s previous workshop on peptides and oligos, held at its Rockville, Maryland headquarters in November 2019, also began with a regulatory-focused session (see IPQ July 23, 2020). The discussions at this year’s workshop allowed the industry, agency and pharmacopeia participants to further explore the regulatory/CMC similarities and differences between the two treatment paradigms in view of the recent developments in this rapidly evolving arena.

Peptides and oligos are similar, the presenters pointed out, in being complex molecules that are difficult to synthesize and characterize, prone to impurities, and posing a variety of regulatory challenges. Both classes can be manufactured by solid phase synthesis followed by chromatographic purification. Furthermore, ICH Q3 impurity limits do not directly apply for these classes. They present additional regulatory challenge in falling between the classifications for small-molecule drugs and large-molecule biologics.

Also emerging into relief during the workshop discussions were meaningful differences between the two modalities and how they are playing out in the CMC regulatory context.

The field of therapeutic peptides is considerably more established, with licensed products and generics on the market for decades. The peptide regulatory framework is correspondingly well-established as are the manufacturing processes and procedures for handling of impurities.

In contrast, oligonucleotides represent a more nascent product class, and as such, the regulatory framework is still taking shape. Additionally, oligos present many unique regulatory challenges, including: ● a lack of ICH guidelines that specifically address the quality expectations and standards ● their considerable diversity, which complicates the setting of standards ● the lack of limits for the reporting and identification of oligo impurities, and ● the many challenges that exist for impurity characterization.


USP BIO1 Expert Committee Active in Peptide Arena

The March workshop opened with welcoming remarks by USP Global Biologics Education and Training Senior Scientific Fellow Maura Kibbey, who explained the role of USP’s Biologics 1 (BIO1) expert committee on peptides and oligonucleotides, which helped organize the workshop.

The BIO1 focus includes supporting and expanding the existing portfolio of USP monograph and reference standards, which entails reviewing and prioritizing: ● existing products for which no public standard exists, and ● monographs and general chapters for modernization.

Also in the committee’s purview are developing broadly applicable performance standards for raw materials and impurity standards, as well as advancing the quality, standards and science in the peptide/oligo arena through workshops, roundtables and white papers and other publications.

Kibbey pointed out the peptide monographs and reference standards that are new or under development (see below).

She noted that during its 2015-2020 cycle, USP published chapter <1503> on the quality considerations for peptide drug substances, and is now working on chapters addressing the quality of raw materials. “We are also building some impurity standards that may not be tied to a specific compendial monograph,” she said – “so again, trying to broaden that impact beyond the monographs themselves.”

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A brief overview of the workshop was then given by BIO1 expert committee member and workshop chair, Lilly Bioproduct Research and Development Distinguished Research Fellow Michael DeFelippis. [A link to the meeting agenda is provided below.] He also provided an introduction to session one and moderated the corresponding panel discussion and Q&A.


Workshop Sessions 2&3 Focus on Analytical and Manufacturing Considerations

The second session, held on day two of the workshop, focused on advances in analytical tools to ensure oligo quality.

It began with industry consultant Marc LeMaitre, also a member of the workshop steering committee and USP’s BIO1 expert committee, providing a brief recap of the first day’s discussions. LeMaitre had reviewed the strategies for developing oligonucleotides at the previous USP peptide/oligo workshop [see Part IV of IPQ July 23, 2020].

The leadoff presentation was on Biogen’s use of a risk-based platform for the specification and release tests for antisense oligos. Further advanced analytical techniques covered at this session included the use of NMR spectroscopy and LC-MS for oligo characterization, and the use of LC-MS for the characterization of oligo degradation products.

A summary of the session two discussions was provided at the beginning of the third day by BIO1 vice chair and workshop committee member Gerhard Haas, who serves as quality VP for Bachem in Europe. [Haas’ summary of the second session is appended below.]

Session three featured manufacturing and formulation approaches for peptides and oligos.

It opened with a presentation on various synthetic methodologies under development to enable environmentally friendly chemistry for oligo manufacturing. Lilly researchers then discussed a novel hybrid process for the high-volume synthesis of complex peptides, based on native chemical ligation.

Also discussed at the third session were specific considerations and challenges associated with the terminal sterilization of oligos, with reference to the recommendations from a position paper being prepared by the European Pharma Oligonucleotide Consortium (EPOC) on this topic.

Insights were then provided into the latest developments in peptide formulation, with a presentation on novel drug delivery systems, including non-parenteral delivery routes.

[Editor’s Note: USP’s Kibbey has published reviews of the workshop discussions on peptides and oligos, respectively, which include further coverage of sessions two and three. Links to her reviews are provided below.]

IPQ Spotlights Opening Regulatory Session

IPQ’s coverage focuses on the opening regulatory session at the workshop, and is divided into four parts:

● Part I reviews the lead-off presentation by CDER’s Lawrence Perez on the CMC/regulatory challenges for oligonucleotides. Addressed are issues the agency is seeing in INDs and NDAs regarding the manufacturing, characterization, and control of the drug substance.

● Part II continues with a discussion of the comparability challenges that present themselves in developing generic peptide and oligonucleotide drug products.

Following Perez at the USP workshop was former CDER official Jeff Jiang, who reviewed the challenges specific to generic peptides. His review encompassed comparative studies on the API and drug product, as well as immunogenicity analysis – an issue Jiang had the opportunity to elaborate on in the Q&A that followed.

Included in Part II is a review of the immunogenicity issues relating to generic peptides by CDER’s Eric Pang at a September 2020 FDA workshop on advancing generic drug development. Complementing Jiang’s and Pang’s remarks are two releases from FDA: a draft guidance on ANDAs for peptides of rDNA origin; and a FY2020 “GDUFA Science and Research Report,” which includes coverage of oligo/peptide-related analytical issues.

FDA held a workshop in late June 2021 to further the dialogue with industry on the research priorities for complex generics, and the discussion related to oligo and peptide issues at that workshop is also reviewed in this part of the story. Weighing in are Acting Commissioner Janet Woodcock, who provided the workshop introduction, Sandoz’ Zdenko Časar, on the characterization and analysis challenges for oligonucleotide and liposomal drug products, and CDER’s Rachel Dunn and Darby Kozak, reviewing the agency’s GDUFA-funded research on the analytical challenges for complex generics.

● Part III shifts the vantage point to that of a European regulator – in this case, BfArM René Thürmer. Following Jiang at the USP workshop, Thürmer provided insights on the similarities and differences in the CMC issues that face peptides and oligos regarding the manufacturing process, characterization, impurities, and sterilization.

● Part IV presents an industry perspective on the CMC/quality and regulatory strategies for setting flexible specifications for oligo synthesis starting materials, which was provided at the USP workshop opening session by Roche’s Dominik Altevogt. Addressed are typical starting materials for oligo synthesis and the control of and the acceptance limits for impurities.


USP March 2021 Peptide/Oligo Workshop Agenda

● Maura Kibbey’s Two Reviews on USP March Workshop: ● on Peptideson Oligonucleotides

[CLICK HERE for Haas’ Day 2 summary at the USP workshop.]

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