BRIEFING
〈316〉 Gel Permeation Chromatography Molecular Weight and Polydispersity Determination for Lactide or Lactic Acid and Glycolide or Glycolic Acid Polymers Using Universal Calibration. On the basis of USP's validated methods of analysis, a new chapter is being proposed by the Excipient Test Methods Expert Committee (ETM EC).
Lactide (or lactic acid) and glycolide (or glycolic acid) (LG) polymers have unique characteristics of biodegradation, which enables controlled release formulations with varied drug release periods. LG polymer excipients have been used in many complex extended-release drug products and medical devices approved by the 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 these complexities, sameness evaluations of LG polymers are 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 four monographs in PF.
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 chromatography (SEC) with three detectors (multiangle light scattering, refractive index, and viscometer) and nuclear magnetic resonance (NMR) spectroscopy.
USP has been expanding the current compendial monograph standards development process by using iterative approaches to standard development. USP published several standalone general chapters (GCs) including Molecular Weight Determination for Alginates 〈312〉, Molecular Weight and Polymer Chain Length Determination for Polypropylene Glycol Fatty Ethers 〈313〉, and Molecular Weight Determination for Copolymers Containing Alkyl Methacrylate or Alkyl Acrylate 〈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. The three GCs are currently official, but none of the three GCs are applicable to any USP–NF monographs. According to USP General Notices, 3.10 Applicability of Standards, “Applicable general chapters” means general chapters numbered below 1000 or above 2000 that are made applicable to an article through reference in General Notices, a monograph, or another applicable general chapter numbered below 1000. Because these GCs have not been referenced in any of these manners, the methods in the three GCs are not applicable to any USP–NF monographs.
Using the same standalone GC iterative approach, USP is proposing this chapter and NMR Spectroscopy Number-Average Molecular Weight Determination for Lactide or Lactic Acid and Glycolide or Glycolic Acid Polymers 〈315〉, which appears elsewhere in this issue of PF.
As part of USP's stakeholder engagement model, on December 29, 2023, USP published general chapter prospectuses for 〈315〉 and 〈316〉, which outlined the background for developing these two chapters.
On the basis of comments received on the prospectus, the ETM EC provided the following key points:
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As mentioned above, USP is proposing 〈315〉 and 〈316〉 using the same standalone GC iterative approach as 〈312〉, 〈313〉, and 〈314〉 and has no plan to make these two chapters applicable to any USP–NF monographs currently.
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The current scope of this proposed chapter only covers analysis of LG polymers of an 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.
This chapter proposal contains the following method:
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GPC method for molecular weight and polydispersity determination for LG polymer using universal calibration
The method is based on validated GPC methods of analysis performed with the Tosoh TSKgel G4000Hhr brand of column with L21 packing with the Tosoh TSKgel guard column before the column. The typical retention times for the polystyrene standard with a peak molecular weight of approximately 13,000 Da (g/mol) and dl-Lactide and Glycolide (50:50) Copolymer 12000 with acid or ester end group are about 7.6 and 7.7 min, respectively.
Stakeholders are encouraged to contact USP to discuss any additional methods for characterization of LG polymers.
(ETM: P. Zhang)
Case ID—SUB-226