Type of Posting: General Chapter Prospectus
Posting Date: 29-Dec-2023
Expert Committee: Excipient Test Methods (ETM)
Proposed New Title: <316> GPC Molecular Weight and Polydispersity Determination for LG Polymers using Universal Calibration
Input Deadline: 28-Jan–2024
Suggested audience: Excipient manufacturers, users, and regulators
Estimated proposal PF: 50(5) [Sep.–Oct. 2024]
Background and objectives:
LG polymers refer to biodegradable polyesters made from lactide (or lactic acid) and glycolide (or glycolic acid) monomers.
LG polymer excipients have been used in many complex extended-release drug products and medical devices approved by FDA. LG polymer-based generic drug products have been facing regulatory challenges due to many complexities in formulation, characterization, and evaluation of test products. Among the factors, sameness evaluation of LG polymer is very challenging. USP hopes to address concerns by providing advanced quality testing methods and monographs for excipient selection and regulatory evaluation.
USP and the LG Polymer Joint Subcommittee (JS) have been working with multiple sponsors on developing LG polymer compendial standards. So far, USP has published two stimuli articles and three monographs in Pharmacopeial Forum.
Molecular weight methodologies received from sponsors have been varied, with no clear compendial method emerging. USP has been utilizing internal resources to develop and validate advanced quality testing methods for LG polymers. The advanced techniques that USP has been focusing on include gel permeation chromatography (GPC)/size exclusion chromatograph (SEC) with three detectors (multi-angle light scattering, refractive index, and viscometer) and NMR.
USP published several stand-alone general chapters (GC) including <312>, <313>, and <314> to enable stakeholders to use advanced analytical methods to enhance characterization and quality of polymeric excipients, prior to the methods being ready to be included in related official monographs. <313> and <314> are currently official and <312> will be official, but none of the three general chapters are applicable to any USP-NF monographs. According to USP General Notices (GN) 3.10, “Applicable general chapters” means general chapters numbered below 1000 or above 2000 that are made applicable to an article through reference in GN, a monograph, or another applicable GC numbered below 1000. Because these general chapters have not been referenced in any of these manners, the methods in the three general chapters are not applicable to any USP–NF monographs.
Using this same stand-alone GC iterative approach, USP is working on developing two test method general chapters for LG polymers:
- Proposed <315> NMR number-average molecular weight determination for LG polymers.
- Proposed <316> GPC molecular weight and polydispersity determination for LG polymers using universal calibration.
USP’s first LG polymer stimuli article in PF 48(2) offers guidelines for naming and testing LG polymers. USP’s second LG polymer stimuli article in PF 49(6) offers USP’s responses to the comments received on the first article, clarifications regarding performance-related tests of LG polymers and USP’s scope of work for LG polymers, and updates on USP’s recent activities pertaining to LG polymers. These updates include development of the two chapters mentioned above. USP is also working on developing additional methods for LG polymers using GPC with the three detectors and NMR and exploring some other technologies mentioned in the first article.
Description of scope and application:
The scope of this proposed general chapter includes GPC methods for determination of molecular weights and polydispersity for LG polymers using universal calibration.
The general chapter is intended to be applicable for LG polymers of L:G ratio of 50:50 and weight-average molecular weight ranging from 7000 to 17000. USP will consider adding methods for other LG polymers with different ratios and higher molecular weights in the future with supporting validation data.
Preliminary outline:
- Introduction
- Procedure
- Solutions preparation (including standard and sample solutions)
- Instrumental system
- System suitability requirements
- Analysis
Anticipated activities: USP is requesting early input from stakeholders on this proposal of a new general chapter General Chapter <316> GPC Molecular Weight and Polydispersity Determination for LG Polymers Using Universal Calibration which is planned to be published for comments in Pharmacopeial Forum.
Contact: Peng Zhang, Ph.D., (301-692-3454, PGZ@usp.org)