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R.D. McDowall is principal of McDowall Consulting and director of R.D. McDowall Limited, and "Questions of Quality" column editor for LCGC Europe, Spectroscopy's sister magazine.
In September, the World Health Organization (WHO) issued a new guidance document on Good Chromatography Practices. What guidance does it contain and is it useful? Has the document failed its system suitability test (SST) acceptance criteria?
In September 2020, the WHO issued a guidance document on Good Chromatographic Practices (1). The scope, content, and sections of the document dealing with the system and its set up were discussed in Part 1 (2). In this part, we’ll take a close look at the sections dealing with chromatography analysis and see if any additional bouts of lalochezia occur.
Let’s get down to some chromatography, as the remainder of the guidance document is focused on analysis of samples, as shown in Figure 1, and
has the following sections:
I am at a loss to understand the difference between processing and peak integration in Sections 12 and 13 respectively? Especially as there is no mention of processing in Section 12!
OK, competition time! What’s missing from the list above? Give up? Quite a lot! Figure 2 shows the contents of the GChromP document (green boxes) mapped against a generic analytical process (yellow boxes) with the main missing
tasks (red boxes). Presented in this way you can see the areas that the WHO guidance omits. The dashed lines indicate partial coverage in the WHO guidance document. There is no mention of the following that I believe should be part of a chromatography guidance to ensure data integrity:
How much a guidance document goes into detail is at the discretion of the authors. However, if items are to be omitted from the scope of a guidance document then it is the responsibility of the authors to state this. In this respect the authors and quality oversight for the document have failed. Please excuse me while I have another bout of lalochezia.
Reagents and Column Management
Section 9 deals with solvents, buffers, and mobile phases and is relatively straightforward except for one phrase. Clause 9.1 covering the use of these items states in the last sentence: These should be used within appropriate, scientifically justifiable timelines. Why not simply say that expiry dates should be justified scientifically?
Section 10 covers column management and provides general advice about column management, from purchase to how to handle the column in the laboratory and keeping records of each one’s use. However, there should be a warning that if a column is used for different analytical methods, it may change the chromatographic properties over time. Ideally it is better to have dedicated columns, though cost may be a factor in some laboratories.
Clause 10.4, requiring chromatograph tubing and fittings to be appropriate (but you are left to define that!), is in the wrong place and should be in Section 3 on chromatographs. Given the organization of the document...
Clause 10.5 suggests that the only method of monitoring a column performance is to calculate the theoretical plates. In my experience, very few laboratories use plate count to measure column performance—it is an academic exercise because it depends on the separation in question. For example, if separation of two closely running peaks is required, then peak resolution is a better criterion. You could have a situation where the plate count is acceptable but peaks are not resolved. Perhaps a better way of expressing this is that the criteria for monitoring any column’s performance should be scientifically sound. This leaves the laboratory to select and monitor appropriate criteria through system suitability tests (SSTs). On the topic of SSTs, clause 4.8 mentions that on SST failure there should be a (corrective action and preventative action) CAPA generated. This is stupid. What must happen is that the failure must be documented, investigated, and appropriate action agreed which may include a CAPA plan but not necessarily so. Consider a pump leak as the source of SST failure: document, replace the seal, requalify, and get on with the analysis, there is no need for a CAPA. It raises the question: how many of the authors have actually worked in an analytical laboratory?
Sample Management and Preparation
Sample management is presented in overview but sampling and the sample plan is omitted, and so is reference to the overall analytical procedure. Notwithstanding, the outline of sample preparation and placing the vials in the correct order to match the sequence file order is presented well. However, from 11.9 to 11.13 we move into SST injections and analysis of the samples before discussing the chromatographic method in Section 12 and therefore these are in the wrong sequence (sorry!). Unfortunately, manual entry of sample information such as identity, lot number, weight, dilution factor, and standard purity, which can be a source of transcription errors, is not even considered.
Clause 11.9 is badly phrased and states that trial or system check injections that are not specified as an injection sequence is not recommended. (Normally, only standard solutions may be used for this purpose, unless otherwise needed and justified (e.g. biologics). This is similar to the approach that Heather Longden and I discussed in a recent Questions of Quality on peak integration (7) but is written more clearly. There is a Level 2 guidance question and answer on the FDA website that goes into more detail about this topic by asking question 17: Is it ever appropriate to perform a “trial injection” of samples?
No. ..... This is in contrast to the appropriate practice where an injection of a standard is performed with the sole intention of determining if the chromatographic system is fit for purpose. The injection of trial samples is not acceptable, in part, because all data from analysis of product samples must be retained and reviewed...
Column conditioning does not involve injecting a sample from a lot and is not considered a trial injection. When its use is scientifically justified, column conditioning should be fully described in the method validation package as to the conditions needed to make the measurement (i.e., based on data from the method validation) and should be clearly defined in an approved and appropriate procedure. Only validated test methods that demonstrate accuracy, sensitivity, specificity, and reproducibility may be used to test drugs (21 CFR 211.165[e]). Consistent and unambiguous injection nomenclature should be used, and all data from the column conditioning, including audit trail data, should be maintained and subject to review (8).
Using standard injections to confirm that the column is conditioned is an acceptable practice BUT it needs to be scientifically justified, included in the method validation report and MUST be part of complete data for the second person review under 21 CFR 211.194(a), clause 8 (9). There are no excuses or justifications for taking any different approach.
Section 12 is titled Chromatographic Methods (acquisition and processing) but there is not much in this section about acquisition and nothing about data processing. The order of clauses is random and confusing (lucky dip time or a chat after a session at the bar?):
At this point in the document, even an extended bout of lalochezia fails to work and I’m getting depressed as I’ve still got two more sections to review.
Hope springs eternal and I’m hopeful that I’ll find something positive to say about this part of the document. Clause 13.1 with its scientifically sound approach to integration raises my hopes, but they are dashed when I get to clause 13.2. Here I find that I should connect the chromatograph to a CDS—sorry—to computerized chromatographic data capturing and processing systems. What is this and why do we need to connect a chromatograph to two of them? Again, the document organization is appalling with an abject failure in technical understanding as well as editorial and quality oversight.
After discussing some of the types of integration and the ideal peak shape for integration (symmetrical) we come to manual integration. Here procedures for manual integration should be followed and records, including the authorization and justification for manual integration, should be maintained. The guidance fails to define what is manual integration: manual positioning of the baselines by an analyst (7,10,11).
From the wording in the guidance it appears that authorization is required each time that manual integration is needed. This is too draconian and manual integration must be justified in the validation report and the analytical procedure. Manual integration can occur daily if a method is analyzing biologicals, contrast media, or impurities. Scientific justification not regulatory diktat must be applied for manual integration. The PDA TR80 guidance (10) is the best guidance for integration as it has figures illustrating both good and bad integration practices, coupled with the differentiation between manual intervention and manual integration (11,12).
Most of the section covers managing the administration of the computerized chromatographic data capturing and processing system (singular, this time!) better known as a CDS. The guidance does not say who is responsible but ideally this should be an IT function. True to form, there is another clause out of place with 14.2 requiring that data should be timely processed and reviewed, posing the question of why is this clause here and not under peak integration? If compliance with ALCOA+ requirements is required, why is there not a separate section for second person review, as this is where mistakes and errors should be caught in the laboratory. Clause 14.5 notes that printed records may be retained. May? May?? What planet are these writers on??? Strike three and out for quality and technical oversight and cue an extended bout of lalochezia.
There are three WHO references listed at the end of the document but these are only referenced to clause 14.1, which is most unhelpful. References to the United States and European Pharmacopoeias are equally unhelpful especially the specific chromatography and instrument qualification general chapters are not mentioned explicitly, for example, USP <621> (13), USP <1058> (14) and EP <2.2.46> (15).
The question posed by the title of these two columns is, “What is good about the WHO Good Chromatography Practices guidance?” Very little is my answer, and the document fails its SST criteria (if it had any). From the organization of the document, clauses in the wrong place, missing topics, wrong approaches to computerized system validation (CSV), to the inability to call a chromatography data system a CDS, it is a document that has been cobbled together without knowledge of the subject coupled with a total lack of technical and quality oversight. I’m not sure who this is written for and by whom.
This is a dangerous document if you were relying on it as your sole guide for good chromatography practices in a regulated laboratory. The writing is just too vague, generic and imprecise to be of real value: there is just one must and over 120 should statements in the document.
There is a need for a guidance document for Good Chromatographic Practice. However, with the problems and omissions presented here, the WHO guidance is not it. The current guide needs to be extensively rewritten, reorganized and expanded, ideally to highlight best practices that a laboratory should aim towards, if they do not work this way now.
I would like to thank Chris Burgess and Paul Smith for helpful review comments on the two parts of this column.
1) WHO Technical Report Series No.1025, Annex 4 Good Chromatography Practices (World Health Organization, Geneva, 2020).
2) R.D. McDowall, LCGC Eur. 33(11), 579–584 (2020).
3) T. Schofield, et al., “Distinguishing the Analytical Method from the Analytical Procedure to Support the USP Analytical Procedure Life Cycle Paradigm”, Pharmacopeial Forum, 45(6) (2019). Online only.
4) WHO Technical Report Series No.929, WHO Guidelines for Sampling of Pharmaceutical Products and Related Materials (World Health Organization, Geneva, 2005).
5) US Food and Drug Administration, Guidance for Industry: Out of Specification Results (FDA, Rockville, Maryland, USA, 2006).
6) R.D. McDowall, LCGC N. Am. 38(7), 411–419 (2020).
7) H. Longden and R.D. McDowall, LCGC Eur. 21(12), 641–651 (2019).
8) US Food and Drug Administration, Questions and Answers on Current Good Manufacturing Practices—Laboratory Controls (FDA, USA, 2019). Available from: https://www.fda.gov/drugs/ guidances-drugs/questions-and-answers-current-good-manufacturing-practices-laboratory-controls.
9) US Food and Drug Administration, 21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceutical Products (FDA, Silver Spring, Maryland, USA, 2008).
10) Parenteral Drug Association, Technical Report 80: Data Integrity Management System for Pharmaceutical Laboratories (PDA, Bethesda, Maryland, USA, 2018).
11) R.D. McDowall, LCGC Eur. 28(6), 336–342 (2015).
12) R.D. McDowall, Validation of Chromatography Data Systems: Ensuring Data Integrity, Meeting Business and Regulatory Requirements (Royal Society of Chemistry, Cambridge, UK, 2nd ed., 2017).
13) United States Pharmacopoeia General Chapter <621> “Chromatography” (United States Pharmacopoeia Convention, Rockville, Maryland, USA).
14) United States Pharmacopoeia General Chapter <1058> “Analytical Instrument Qualification” (United States Pharmacopoeia Convention, Rockville, Maryland, USA).
15) General Text 2.2.46 “Chromatographic Separation Techniques,” European Pharmacopoeia (Strasbourg, France, 2005), pp. 69–73.
“Questions of Quality” Column Editor Bob McDowall is Director of R.D. McDowall Limited, Bromley, Kent, UK. He is also a member of LCGC Europe’s editorial advisory board. Direct correspondence about this column to the Editor‐in‐Chief, Alasdair Matheson: email@example.com