Presentation - Current FDA Considerations for the Assessment of Sub-Visible Particles
MORNING SESSION
The 24th CMC Strategy Forum (Jan 9, 2011 - Washington DC, USA) focused on the analysis and immunogenic potential of aggregates and particles. The morning discussion was directed around the analytical needs and challenges which exist. During this discussion, Barry Cherney (USFDA - CDER) presented industry with the "Current Regulatory Considerations for the Assessment of Sub-Visible Particles."
In this presentation, the following topics were covered:
- Background on subvisible particulates and immunogenicity
- Risk assessments
- Risk reduction control strategies
- Current Recommendations
Specifically, recommendations were made regarding the characterization of subvisible particles in the micron range.
"I think it is pretty clear that particulates in this range can be detected and appropriately quantified by various analytical techniques. Micro-Flow Imaging [among other technologies] can be used to characterize and quantitate these." - B.Cherney, PhD
A detailed report on the morning session has been published by International Pharmaceutical Quality (IPQ). This report includes a transcription of Dr. Cherney's oral presentation. The full article can be found here:
For those who are also interested in reviewing Dr. Cherney's presentation slides, they are publicly available here:
Presentation - Latest FDA Perspectives re. the Immunogenic Potential of Aggregates in Therapeutic Protein Products
AFTERNOON SESSION
The afternoon discussion was directed around the immunogenic potential of protein aggregates and testing. During this discussion, Amy Rosenberg (USFDA - CDER) gave a presentation on the immunogenic significance of aggregates in protein therapeutic products.
In this presentation, Dr. Rosenberg:
- Defines aggregates
- Givesan overview of the immune system
- Covers historical research into the immunogenicity of protein aggregates
- Provides conclusions and advice to manufacturers of therapeutic proteins
In her conclusions, Dr. Rosenberg expressed the need to characterize, quantify and control aggregates.
"Aggregates, particularly large molecular weight aggregates and particulates, pose a clear risk to the safety and efficacy of protein therapeutic products and are considered a critical quality attribute. Aggregates, including protein particles, should be characterized, quantified and controlled in therapeutic protein products at release and on stability." - A.Rosenberg, M.D.
A detailed report on the afternoon session and specifically on Dr. Rosenberg's presentation has been published by International Pharmaceutical Quality (IPQ). The full article can be found here:
For those who are also interested in reviewing Dr. Rosenberg's presentation slides, they are publicly available here:
Scientific Publication - Evaluation of the Effect of Syringe Surfaces on Protein Formulations
AUTHORS
Sumit Majumdar, Brandi M. Ford, Kevin D. Mar, Vince J. Sullivan, Robert G. Ulrich*, Ajit Joseph M. D'Souza.
BD Technologies, RTP North Carolina USA, * USAMRIID, Fort Detrick, Maryland USA
Published online in Journal of Pharmaceutical Sciences DOI: 10.1002/jps.22515
IN THIS ARTICLE:
Limitation of SEC...
"SEC does not always provide sufficient sensitivity for quantifying the protein loss due to particle formation because the protein aggregates and subvisible particles amount to an extremely small fraction of the total protein mass that cannot be detected using SEC."
Value Provided by MFI...
"In this study, it was found that MFI, a technique relatively new to the pharmaceutical formulator, provided great value in imaging some of the aggregates formed and characterizing the behavior of silicone oil used in prefillable syringes. For instance, the rPA monomer content, as measured using SEC, was not influenced by whether the formulation was stored in SGS, NSGB, or BD-42-coated syringes. MFI, however, clearly showed the formation of additional particles in the formulation stored in SGS. In addition, the ability to clearly image particles above 20μm was very valuable. The results presented here clearly demonstrated that substantial information can be derived regarding the stability of protein formulations and their compatibility with storage containers by the use of techniques aimed at measuring particle size, concentration, and assessing their shapes."
Authors Conclusions...
"SEC analysis may not provide a complete picture of the instability in the protein solution,
requiring that additional techniques be used to characterize the stability. Subvisible particle analysis using MFI can help present a more complete picture of the solution and in some cases also help to identify the origins of the particles."
The complete article can be found at:
Journal Article: Evaluation of the Effect of Syringe Surfaces on Protein Formulations
Authors Commentary...
"While scouring for the techniques that can effectively monitor aggregates/particles larger than 2 micron, MFI by Brightwell stood out from the rest due to its user friendly features and ability to analyze small volumes of liquid with reasonable accuracy and precision. Actual appearance of the particles/aggregates gave us an opportunity to identify the origin of the particles in some cases. Importantly enough, where other techniques failed to differentiate various samples (e.g. by monitoring soluble protein content) this technique proved to be quite useful. The principle behind this technique, we believe, makes it suitable for monitoring partly translucent protein aggregates." - S.Majumdar, PhD - BD Technologies, Feb 2011
Brightwell Poster Hall - Latest Additions
Brightwell's MFI Poster Hall is a collection of posters that were presented at various events and that utilized Micro-Flow Imaging in the course of the study. Authors are invited to display their poster free of charge and viewers have access to posters in downloadable PDF format. If you have a question about a specific poster, complete the form at the bottom of the specific abstract. Your question will be forwarded to the corresponding author who will respond to you directly.
Click here to see poster listing
This Month's Featured Posters:
Formulation Optimization to Minimize sbVP & VP Formation in a High-Concentration mAb
Particle Analysis as a Formulation Development Tool
Upcoming Events
241st ACS National Meeting and Exposition - March 27-31, 2011
Anaheim Convention Center, Anaheim CA, USA
- Brightwell Presentation - Analysis of Subvisible Particles in Protein Therapeutics Using Micro-Flow Imaging.
- Location - Anaheim Marriott - Platinum II
- Date/Time - Wed Mar 30, 4:00pm, pub# 353.
- Conference website - 241st ACS Annual Meeting
7th BioProcess International Europe - April 6-7, 2011
Nice Acropolis Des Congres, Nice, FRANCE
7th PEGS Summit - May 9-13, 2011
Sheraton Boston Hotel, Boston MA, USA
- Brightwell Poster - To be announced.
- Exhibit Booth - 516
- Conference website - 7th PEGS Summit
2011 AAPS National Biotechnology Conference - May 16-18, 2011
Hilton San Francisco Union Square, San Francisco CA, USA
- Brightwell Poster #1 - Qualification of MFI for Subvisible Particle Analysis in Protein Formulations.
- Brightwell Poster #2 - Development of a Protein Surrogate Reference Material for MFI Instrument Calibration and Field Verification.
- Exhibit Booth - 104
- Conference website - 2011 AAPS National Biotechnology Conference
Brightwell Seminar @ AAPS NBC - May 17, 2011, 8:00-12:00pm
Title: Characterize, Quantify and Control Subvisible Particles and Aggregates
The USFDA has affirmed the immunogenic potential of aggregates and have indicated that these particles must be characterized, quantified and controlled. Brightwell's Micro-Flow Imaging™ (MFI™) has been identified as suitable and validatable for this purpose. The MFI analysis principle, application case studies and latest Brightwell innovations shall be presented.
(Registration to open soon!!!)
