Covid-19: What Does Lockdown Mean for Chromatograph Qualification and Calibration?

This article focuses on maintaining the calibration and qualification of chromatographs to ensure data integrity of results during the Covid-19 pandemic and is based upon an article published in LCGC North America¹.

During this pandemic it can be easy to forget that we are a regulated industry and that chromatographs must be qualified, calibrated and maintained. If service engineers cannot travel to a site or are not admitted how will you keep your chromatographs operating reliably and ensuring data integrity?

What Happens Now with Regulatory Inspections?

The FDA have postponed both foreign and domestic inspections^2,3 and MHRA will only conducting GXP inspections for the UK's response to Covid-19, all other inspections are 4 with the expectation that compliance is maintained⁵.

What happens if you have a chromatograph that is due a preventative maintenance visit and annual Operational Qualification (OQ) and an engineer can't reach you? Grace periods for instruments typically only last for 1 - 4 weeks and regulations require:

Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used⁶.

Repair and maintenance operations should not present any hazard to the quality of the products⁷.

What happens if you have a chromatograph that requires a PM and OQ now? At the end a grace period, it does not necessarily mean that a qualification pixie waves a magic wand and all chromatographs are no longer qualified and must not be used. However, there is a deviation from the maintenance and qualification schedule that must be documented and continued use justified.

The risks associated with any action are dependent on the context that the actions are considered from. So, in this instance, the risks to the patient associated with failure to supply pharmaceuticals must be balanced against the risks which result from instruments which cannot be fully maintained or qualified.

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If a decision is made to continue using instruments outside of maintenance and qualification grace periods, the principle types of risk associated with this action include:

• Breakdown - Unmaintained instruments are more likely to break down
• Regulatory - Justification of actions:
  Defending the decision to continue using the instruments
  -Documenting scientifically that using instruments without PM and OQ were controlled and trending of test results under GMP Chapter 6.9 [8] are used to support this
• Patient - Potential risk that sub-standard or over-strength pharmaceutical may be released
  

This decision must be documented carefully and in a transparent manner. The worst way to document a sensitive decision would be to hide it but this would be interpreted as running a secondary quality system from a data integrity perspective⁹.

Figure 1: Detecting Performance Drift of a Chromatograph if there is no Preventative Maintenance or Operational Qualification

 

What Can Go Wrong with an HPLC?

You need to perform an enhanced risk assessment to support continued use. Smith and McDowall discussed risk assessment of an HPLC by discussing the main failures and their detection¹⁰ e.g.:

• Catastrophic failure of the chromatograph is where the instrument becomes inoperative and no further work is possible
• Variable performance results in detectable variable chromatography
• Slow performance drift resulting in method values being outside of set points would be much harder to detect and potentially more serious as shown in Figure 1.
• How does PQ demonstrate that the instrument meets its intended use as defined in the laboratory URS required by USP <1058>¹¹?
  

This principle applies to other instruments (How can an instrument fail? Can it be detected? What action should be taken?).

Enhanced Role of PQ

PQ is defined by USP <1058> as:
PQ …. demonstrate that an instrument consistently performs according to the specifications defined by the user, and is appropriate for the intended use¹¹.
Many of the parameters that would be measured directly in the OQ can be indirectly measured in the PQ as long as they are related to the URS^12,13. If a laboratory has an integrated AIQ continuum of URS, OQ and PQ, it will help them remain compliant, e.g. meaningful SST parameters linked to user requirements make it easier to justify continuing to use instruments with expired OQs.

SSTs measuring only column plate count or retention time, will find it difficult to provide scientifically sound evidence to justify using a chromatograph as there is link to the URS. There will be interesting times when inspections resume.

A Holistic HPLC PQ Test

There should be a holistic PQ test that can show user requirements are still being met. Analytical procedures should routinely be designed to be as robust as possible¹⁴. However, the principle of a holistic PQ test is an analytical procedure that is sensitive to instrument performance (which is the opposite of normal analytical science) e.g. Performance Verification Testing of dissolution baths. Ideally, the procedure must use stable model compounds, with simple, stable and robust chromatography to minimize analytical variance12. Standard solutions and mobile phases should be prepared gravimetrically, again to reduce variance, so that instrument performance and issues have a greater probability of being detected. These overall holistic standards allow limits to be set for:

• Detector reproducibility and linearity
• Autosampler precision
• Pumping system and oven

Unlike an analytical balance where calibrated masses are used to confirm the instrument performance in OQ and PQ, this is not possible with an HPLC. A holistic PQ test should ideally be conducted immediately after an OQ so that the holistic PQ test can be directly equated with the OQ and hence to the URS. Consistency of retention time over a sequence implies that the pump and the oven (if used) are working consistently.

Self Service for Minor Repairs

Minor repairs e.g. replacement of pump seals can be performed inhouse as long as there is an SOP and that includes requalification to demonstrate the chromatograph works correctly. Suppliers can provide help with phone and video calls to help service chromatographs. It is important that regulatory requirements related to training records are considered, or the work performed may be hard to defend during the next audit. The problem, resolution and requalification work must also be recorded in the instrument log book in chronological order as required by 21 CFR 211.182⁶, EU GMP Chapter 4.31¹⁵ and discussed in an article¹⁶.

There is also on-line technical support or trouble shooting guides to diagnose problems, some of which are shown below:

• https://community.agilent.com 
• https://sciex.com/community/ 
• https://support.waters.com/
• https://www.shimadzu.com/an/support/index.html 
• https://web.vscht.cz/~schulzov/HPLC/Troubleshooting%20HPLC.pdf

Update Your Qualification Procedures

Grace periods can only be extended for so long as mentioned earlier in this article. Therefore, your procedures will need to be updated and justified to perform any extension without a PM service and requalification of your chromatographs. Whatever is done remember that under 21 CFR 211.160(b)⁶ and ICH Q7 / EU GMP Part 2 clause 11.12¹⁷ any work must be scientifically sound.

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MHRA Guidance on Instrument Service

MHRA have published advice on their web site if it is not be possible for service personnel or external engineering support to operate as normal¹⁸.

• If an engineer can be on-site: ensure social distancing for the engineer to work and documentation can be signed electronically
• If an engineer is available remotely: a suitably trained analyst can perform work with guidance but risk assess the impact of this.
• If no engineer is available: raise a deviation and risk assess the delay to the calibration or maintenance task 
• Off-site calibration/maintenance: it may be possible to ship an instrument to the supplier but this would require IQ and OQ upon return. 
•  Substitution of laboratory equipment 

Returning to Normal?

What happens when we return to normality? If a laboratory has deviated from approved SOPs that are designed to ensure the safety and efficacy of drugs with no justification, there will be a regulatory reckoning. Instead of blaming Covid-19 for a lack of compliance, companies who have a well thought out policy of appropriate risk based changes that justify controlled deviation from procedures will fare much better. As inspectors expect to see compliance maintained⁴ even in these difficult times, effective risk management and sound science is the only way to achieve this, especially if service engineers are conspicuous by their absence.

 

Author:
R. D. McDowall
... is Director of R.D.McDowall Limited, Bromley, UK.

Source:
¹ R.D.McDowall, Data Integrity Focus 4: Covid-19 and Data Integrity: What Does Lockdown Mean for Chromatograph Qualification and Calibration? LC-GC North America, 2020. 38(5): p.
291-298, 307, 308
² Coronavirus Disease 2019 (COVID-19) Update: Foreign Inspections. 2020; Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-disease-2019-covid-19-update-foreign-inspections
³ Coronavirus (COVID-19) Update: FDA Focuses on Safety of Regulated Products While Scaling Back Domestic Inspections. 2020; Available from: https://www.fda.gov/news-events/pressannouncements/coronavirus-covid-19-update-fda-focuses-safety-regulated-products-while-scaling-back-domestic .
⁴ New arrangements for MHRA Good Practice (GxP) inspections due to coronavirus (COVID-19) 2020; Available from: https://www.gov.uk/government/news/new-arrangements-for-mhragood-practice-gxp-inspections-due-to-coronavirus-covid-19--2 .
⁵ Guidance for Good Laboratory Practice (GLP) facilities in relation to coronavirus (COVID-19) 2020; Available from: https://www.gov.uk/guidance/guidance-for-good-laboratory-practiceglp-facilities-in-relation-to-coronavirus-covid-19 .
⁶ 21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceutical Products. 2008, Food and Drug Administration: Sliver Spring, MD.
⁷ EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines, Chapter 3 Premise and Equipment. 2014, European Commission: Brussels.
⁸ EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines, Chapter 6 Quality Control. 2014, European Commission: Brussels.
⁹ P.Baker, Personal Comminication. 2019.
¹⁰ P.Smith and R.D.McDowall, Life Cycle Risk Assessment of HPLC Instruments. LC-GC Europe, 2015. 28(2): p. 110-117.
¹¹ USP 41 General Chapter <1058> Analytical Instrument Qualification. 2018, United States Pharmacopoeia Convention Rockville, MD.
¹² P.Smith and R.D.McDowall, Data Integrity and USP <1058>: Part 3: Monitoring and Requalification. LC-GC Europe, 2019. 32(1): p. 28-32.
¹³ R.D.McDowall, Data Integrity Focus V: How Can USP <1058> Help Data Integrity? LC-GC N.America, 2019. 37(5): p. 312–316.
¹⁴ R.D.McDowall, Data Integrity Focus 3: Understanding the Lifecycle Approach for Analytical Procedures. LC-GC N. America, 2020. 38(4): p. 233-240.
¹⁵ EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines, Chapter 4 Documentation, E. Commission, Editor. 2011: Brussels.
¹⁶ R.D.McDowall, The Humble Instrument Log Book. Spectroscopy, 2017. 32(12): p. 8-12.
¹⁷ EudraLex - Volume 4 Good Manufacturing Practice (GMP) guidelines, Part 2 - Basic Requirements for Active Substances used as Starting Materials. 2014, European Commission: Brussels.
¹⁸ Guidance for Manufacturers and Good Practice (GxP) laboratories on exceptional flexibilities for maintenance and calibration during the coronavirus COVID-19 outbreak 2020; Available
from: https://www.gov.uk/guidance/guidance-for-manufacturers-and-good-practice-gxp-laboratories-on-exceptional-flexibilities-for-maintenance-and-calibration-during-the-coronavirus-co?utm_source=369ad22e-bfe9-426b-8b98-088e0d3c0e31&utm_medium=email&utm_campaign=govuk-notifications&utm_content=weekly .