This section contains only new information from FY2016. For background scientific information and outcomes from previous years on this research topic, please refer to the FY15 Regulatory Science Research Report on Complex Mixtures and Peptides.

Introduction

One category of complex generics has complex active ingredients such as peptides, complex mixtures, or natural source products. For complex active ingredients, our research goal is to apply modern analytical and quantitative analysis methods to characterize product-specific attributes so that the sameness of the active ingredient can be established between the RLD and the proposed generic drug. For most peptide drugs, the active ingredient is clearly defined and can be well characterized. However, characterizing the impurity profile of peptide-related substances and assessing the associated safety risks, including immunogenicity of a proposed generic product, is challenging; this also is a goal of our current research.

Research

In 2016, ORS worked closely with the Office of Testing and Research (OTR) and the Office of Biotechnology Products (OBP) on a number of internal and external (supported by grant mechanisms) research projects. Through such collaborations, OTR developed a UPLC-HRMS based method that has much higher resolution than the conventional HPLC-UV method for peptide-related impurity analysis and is suited for peptide drug quality control. OBP developed cell based assays to detect innate immune response due to impurities in therapeutic products, which can be applied to assess the immunogenicity risk of impurities in peptide drug products. In addition, salmon calcitonin nasal spray products were selected and used as a case study in which multiple lots of the RLD and generic products were collected, and their peptide-related impurity profiles were analyzed using the established UPLC-HRMS method. Currently they are being tested in cell based assays for innate immune responses.

Additionally, ORS coordinated with the Office of Pharmaceutical Quality previously and issued three grants to characterize complex drug products containing complex mixtures and develop mathematical models to assess critical quality attributes through external grants. Specific complex drug products including pentosan polysulfate and crofelemer are currently being studies under these grants. As an extension to existing projects, another research contract was issued to develop bioanalytical method for pentosan polysulfate in 2016. Collectively, these research activities advance FDA’s understanding of complex drug products containing complex mixtures, help establish product-specific guidance on active ingredient sameness, and provide critical inputs to regulatory review and decision-making processes.

ORS staff facilitating research in this area

• Xiaohui Jiang, Meng Hu, Deyi Zhang, and other ORS staff members

Projects and Collaborators

• Integrated approach to determine equivalence in complex drug mixtures, Massachusetts Institute of Technology
  • Site PI: Ram Saisekharan
  • Grant #: 1U01FD005291

• Development of an integrated mathematical model for comparative characterization of complex molecules, University of Kansas Lawrence
  • Site PI: David Volkin
  • Grant #: 1U01FD0058285

• Statistical methodology for characterization of macromolecular similarity, Battelle Pacific Northwest Laboratories
  • Site PI: John Cort
  • Grant #: 1U01FD005288

• Mass Spectrometry Profiling of Pentosan Polysulfate in Urine, Battelle Pacific Northwest Laboratories
  • Site PI: John Cort
  • Contract #: HHSF223201610114C

• Internal Project: Characterization of impurities in salmon calcitonin
  • FDA Collaborator: Jamie Dunn
  • FDA Center/Office/Division: CDER/OPQ/OTR/DPA

• Internal Project: Characterization of sequence and impurity of H.P. Acthar gel
  • FDA Collaborator: Ashley Gucinski
  • FDA Center/Office/Division: CDER/OPQ/OTR/DPA

• Internal Project: Characterization of host-cell protein impurities in peptide products of rDNA origin
  • FDA Collaborator: Sarah Rogstad
  • FDA Center/Office/Division: CDER/OPQ/OTR/DPA

• Internal Project: Assessment of innate immune response modulating impurities in peptide drugs
  • FDA Collaborator: Daniela Verthelyi
  • FDA Center/Office/Division: CDER/OPQ/OBP

 

Outcomes

• Draft Guidance on Sevelamer Carbonate Tablet (Sep 2015)

• Draft Guidance on Colesevelam Hydrochloride Tablet (Sep 2015)

• Draft Guidance on Colesevelam Hydrochloride Suspension (Jan 2016)

• Draft Guidance on Glatiramer Acetate Injection (Jan 2016) 

Resources For You

• Office of Generic Drugs FY 2016 Regulatory Science Research Report