Solution Oligonucleotide APIs: Regulatory Considerations

Therapeutic Innovation & Regulatory Science, vol. 56, pp. 386–393

Abstract

Manufacture of oligonucleotide active pharmaceutical ingredients (APIs) typically consists of solid-phase synthesis, deprotection and cleavage, purification and filtration, and isolation from aqueous solutions through lyophilization. In the first step of drug product manufacture, the API is dissolved in water again and excipients are added. While isolation of oligonucleotide APIs can be meaningful in many cases, there may be cases where keeping the API in solution provides benefit, and multiple technical aspects must be taken into account and balanced when determining the appropriate API form. A significant factor is whether an API in solution will contain additional components. While APIs in solution containing additional components (so-called formulated APIs) are well established for biological products, there are regulatory guidelines in place that represent hurdles for industry to using a formulated API approach for oligonucleotide drugs. The present communication outlines conditions where a formulated API approach can be chosen in compliance with existing guidelines. Relevant aspects pertaining to risk management, GMP standards, facility design, control strategies, and regulatory submission content are discussed. In addition, the authors propose that existing guidelines be modernized to enable the use of a formulated API approach for additional reasons than the ones described in the existing regulatory framework. The manuscript aims to promote a dialog with regulators in this field.

Authors 12

1. Christian Wetter corresponding

   Roche (Switzerland)

   Affiliation as printed

   Pharma Technical Regulatory, F. Hoffmann - La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland. christian.wetter.cw1@roche.com

   Pharma Technical Regulatory, F. Hoffmann – La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland

2. Chris Chorley

   Biogen (United States) · Biogen (United Kingdom)

   Affiliation as printed

   Global Regulatory CMC, Biogen Idec Limited, Innovation House, 70 Norden Road, Maidenhead, SL6 4AY, Berkshire, UK

3. Corrine Curtis
   Affiliation as printed

   Global Regulatory Affairs CMC, Janssen Research and Development, 965 Chesterbrook Blvd, Wayne, PA, 19087, USA

4. Nicole del Canto

   Biogen (United States)

   Affiliation as printed

   Global Regulatory CMC, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA

5. J. Gair Ford

   AstraZeneca (United Kingdom)

   Affiliation as printed

   CMC Regulatory Affairs, AstraZeneca, Charter Way, Macclesfield, SK10 2NA, UK

6. Jennifer L. Franklin

   Ionis Pharmaceuticals (United States)

   Affiliation as printed

   CMC Regulatory Affairs, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA

7. Cinzia Gazziola

   Roche (Switzerland)

   Affiliation as printed

   Pharma Technical Regulatory, F. Hoffmann - La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland

   Pharma Technical Regulatory, F. Hoffmann – La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland

8. Michael T. Jones

   Pfizer (United States)

   Affiliation as printed

   Pharmecuetical Sciences, Pfizer Inc., 875 Chesterfield Parkway West, Chesterfield, MO, 63017, USA

9. Judy Lee

   Novartis (United States)

   Affiliation as printed

   Regulatory Affairs CMC, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA

10. Arnold McAuley

    Amgen (United States)

    Affiliation as printed

    Process Development, Amgen, Inc, Thousand Oaks, CA, 91320, USA

11. Florence C. E. Sarabèr Aachen CMC Leadership and Dossier Development and Operations

    Janssen (Netherlands)

    Affiliation as printed

    CMC Leadership and Dossier Development and Operations, Janssen Biologics B.V., Einsteinweg 101, 2333 CB, Leiden, The Netherlands

12. Janine K. Tom

    Amgen (United States)

    Affiliation as printed

    Process Development, Amgen, Inc, Thousand Oaks, CA, 91320, USA