Webinar Highlights – Pharmacopeial Modernization: How Will Your Chromatography Workflow Benefit?

By October 17, 2018


On September 27, Waters partnered with United States Pharmacopeia (USP) experts to host a webinar discussing the upcoming changes in the pending USP General Chapter <621> on chromatography that will provide increased flexibility for gradient methods. Additionally, Waters highlighted a case study that leverages USP <621> allowable adjustments to illustrate the benefits of modernizing methods without the need to revalidate.

In addition, we have transcribed many of the questions and answers that followed the webinar and provided some related resources on this important topic below.

Did you miss the live webinar? Watch it now.

Slides from the webinar are also available on Slideshare:



Answers are from the webinar presenters, Leonel Santos, Director of the Chemical Medicines Department at USP, Dr. Horacio Pappa, Director of the General Chapters Department at USP, and Amanda Dlugasch, an applications chemist at Waters. Some questions have been edited for clarity.

Could you please confirm that the AQUITY Arc System can be used through 15,000 PSI?

The ACQUITY Arc System does not have an upper pressure limit of 15,000 PSI. The pressure limit of the Arc System is 9,500 PSI. The ACQUITY UPLC H-Class System, however, has an upper operating pressure of 15,000 psi.


Is the decreased run time for the gradient method moving from HPLC to UPLC an example of typical reductions one would expect in scaling a gradient method? Or is the amount of time reduced highly variable?

The reduction of run time when scaling a gradient method will be gradient specific. Since the quetiapine impurity example is geometrically scaled, it represents a good example of how much time can be approximately reduced when scaling.


Has Waters tried to scale many methods and what is the success/fail rate?

Typically when scaling a method, success can be achieved. There may be other adjustments or modifications, depending upon the method, that need to be made during the scaling process. Other examples of successful method scaling can be found in various application notes on our website.


In chapter <621> the paragraph about monographs indicates: “If adjustments of operating conditions are necessary in order to meet system suitability requirements, each of the items in the following list is the maximum variation that can be considered, unless otherwise directed in the monograph; these changes may require additional verification data.”  Are the new changes applicable only to pharmacopoeia methods as well as to product specific methods developed in-house and not reported as compendial in pharmacopoeias?

Technically speaking, USP chapters apply only to USP monographs, however many companies use to adopt <USP>chapters in their internal documents (e.g. SOPs).  In other words – it is a company decision.


What type of regulatory submission is needed to update this type of method change?

You should contact the applicable regulatory authority with this request.


Can you clarify what you meant by proving efficiency of the solid-core particle column vs. totally porous for a specific method. Is it equivalent plate counts?

The adjustment of particle size allowed in <621> is based on the L/dp  ratio as an estimation of efficiency. In core shell columns, the particle diameter is not indicative of the effective separation section of the particle, thus the efficiency of these columns  (plate count) should be evaluated in some other way.


Karl Fischer Titration for water content determination uses health hazardous reagents and solvents. Are there any plans from USP to replace Karl Fischer Titration?

Presently, there is no plan to replace the Karl Fischer  Titration.  The Karl Fischer Titration is cross-referenced in more than 1000 USP monographs.  USP is thinking of adding alternative method(s) in the determination of water  for pharmaceutical articles.


What is the USP approach for updating for monographs that exist for API and preparations product when the methods are not similar, e.g., mometasone furoate?

One of the ways USP modernize the drug substance and drug product monographs is to include the test for Organic impurities.  In some cases, where USP receive submission(s) from pharmaceutical manufacturers updating the drug product monograph(s) but not the drug substance.  For mometasone furoate drug substance, USP is modernizing the TLC organic procedure to HPLC for alignment with drug product monographs.


Can validated alternative LC methods be used in place of compendial titration methods?

Yes, the USP General Notices 6.30. Alternative and Harmonized Methods and Procedures allow the use of any method or procedure other than the compendial method or procedure for the article in question.


What would I consider when a monograph do not specify the particle size used?

The best way to consider when a monograph do not specify the particle size used is to verify with USP science staff or email to STDSMONOGRAPHS [at] usp.org.


What approach has to be followed if we change column from totally porous to monolith for product described in USP monograph?

There is no guideline in changing the column from totally porous to monolith for drug product described in the USP monograph.  The best approach is to use the specific column used in the validation of the test procedure.  If using a different brand of column, the important requirement to consider is to use the same type of packing, GC phase or support.  Please verify column equivalency database on USP website.


What % of total monographs is currently based on outdated methods, for example, TLC, titration etc.? What % of monographs needs to have impurities or related substance tests added? What % of these is highlighted for modernization?

Approximately, about 65% of monographs are complete with modernization.  In general, 33% of monographs targeted for modernization needed organic impurity tests.


How will the method modifications be accepted by the regulatory bodies? How can the method modifications be used during method transfer?

Revisions to USP monographs are published in Pharmacopeial Forum for 90 days for public review and feedback from various stakeholders including regulatory agency (US-FDA).  For Method Transfer or Transfer of Analytical Procedures, please refer to  General Chapter <1224> which describes several approaches for method  modifications (i.e.  Comparative Testing, Covalidation, and Revalidation).



Additional resources and related content:

Categories: Pharmaceutical