News Archive

2021 News

Mark Goodwin, GLP Committee

Notes from the MHRA GLP Stakeholder Engagement Meeting (GLP Consultative Committee Meeting), 19th May 2021, MS Teams

These notes have been generated by the RQA representatives and are not the official minutes of the meeting. The latter will be issued by the MHRA and posted on their website.

MHRA Updates

The focus of the MHRA has been on COVID-19 based activities to support approval of treatments and vaccines. The GLPMA have contributed to this process as required.

The UK GLPMA maintained regulatory oversight during the pandemic through a hybrid inspection approach using remote and on-site inspections where appropriate. Remote inspection approaches were developed including employment of software to enable review of analytical data and use of MS Teams as a document sharing platform and for facilitating inspections. The MHRA appreciated the efforts of test facilities in accommodating the remote inspection approach.

There have been no recent changes in the UK GLPMA organisation; the most recent inspector joined the MHRA two years ago as a GMP Inspector and is now cross training to undertake GLP Inspections.

Incident of Fraud (outside the UK)

Fabricated reports were used to support a new product application outside of the UK. Report templates from a UK test facility were copied, data inserted and presented as having been generated by the Test Facility. The UK Test Facility had no involvement in the fraudulent activity.

The reported data was submitted by an organisation outside the UK and therefore the fraud is outside MHRA jurisdiction and hence there are no UK legal implications. All OECD MAD member countries have been made aware of the incident and of the impacted data, such that the data will be rejected if included in any other submissions. Facilities are asked by the GLPMA to contact them in the event they identify they may be involved in similar situations.

Performance Metrics and Future Inspection Strategy

The laboratories group conducted 58 GLP inspections in 2020-2021 (mainly remote) compared with 46 GLP inspections in 2019-2020. Inspections of larger facilities were postponed to allow for the remote approach to become embedded.

Two critical findings were reported during 2020-2021.

• A test item was used outside its expiry date with no supporting information available
• A report amendment was issued that removed key information originally reported.

It was recognised that remote inspections take place over a longer period (three to four days equivalent to two days for on-site inspections with the same scope). In addition, closure of the conduct of a remote inspection is less clearly defined than an on-site inspection, but in most cases the closing meeting represented the end of the ‘fieldwork’. It was clarified that any additional requests made after the closing meeting were in relation to deficiencies identified during the inspection, primarily with the purpose of assisting in report writing or assessing the impact.

It is likely that going forward, a hybrid but flexible approach to inspections will continue, with some of the inspection being performed remotely, including pre-read of QMS documents, and the remaining time spent on-site.

Other MHRA Activities

The MHRA Guidance Documents are being reviewed with the revisions expected later this year.

There has been limited opportunities for engagement work, for example the planned 2021 symposium was cancelled. Some engagement was possible, including remote attendance at conferences as presenters and meetings with receiving authorities and compliance monitoring authorities.

International and Engagement Activities

The OECD GLP Working Group is now known as the OECD GLP Working Party. The Working Party met remotely in April 2021.

The OECD GLP DI Guidance is undergoing the next round of OECD Working Party review; it is anticipated that only minor changes will be required. The issue date has yet to be determined but is likely to be later this year. This document will override the MHRA GxP DI Guidance with respect to GLP.

The revision of OECD Consensus Document No. 4 on QA is making progress. The draft will be made available for industry consultation once ready.

The OECD GLP Working Party is involved in emerging technology discussions and is using industry feedback from the questionnaire.

There is no change to the status of China in terms of progressing towards OECD MAD.

The OECD FAQs on the website is considered a good mechanism for providing guidance on small or focused GLP items for which an Advisory Document is not appropriate. In the near future, industry will be invited to submit further questions that might be included as a FAQ on the website.

Questions Submitted by Industry
Representatives with MHRA Answers

Question 1: EC Directives: is there confirmation that following BREXIT the EC Directives relating to GLP (most notably EC Directives 2004/09/EC and 2004/10/EC) no longer apply to UK Test Facilities? Is it inappropriate for UK Test Facilities to reference these EC Directives in Study Plans and Final Reports (GLP Compliance Statement and/or body of the report)?

Answer 1: It is no longer appropriate for test facilities in Great Britain to reference EC Directives in GLP documentation such as protocols and reports. The EC Directives in Northern Ireland remain applicable.

Question 2: Test Item Supply: For supply of a biopharm test item (e.g. MABs) for use in GLP studies, would it be acceptable to routinely perform characterisation to an internal quality standard rather than GLP or GMP? If not acceptable on a routine basis, would it be considered appropriate in limited circumstances and, if so, are there any examples of such circumstances?

Answer 2: Test facility management should ensure there is appropriate supporting documentation. The study director needs to ensure that the test item is fit for use on their study by assessing the characterisation data and being informed of the quality system that underpinned the generation of the data.

If test item characterisation is conducted to a company’s internal quality standard (i.e. not GLP or GMP), the Study Director would need sufficient detail of the quality system to allow for impact assessment and to satisfy themselves that it was fit for purpose.
In addition, it is recommended that if a quality system other than GLP was used to generate test item characterisation data, this should be indicated in the Final Report.

Question 3: Many sponsors would like to use digital pathology to undertake peer reviews. However, with the different approach between the UK and USA with regard to GLP Programme membership it raises the issue of an uneven playing field in that US based sponsor pathologists have an advantage in that they are able to make claims of compliance for peer review GLP studies from non-GLP inspected facilities. With the emerging technology of digital path peer review, the location of the pathologist becomes more important, especially where there is a need to consider validated systems. Given the trend for sponsors to leave GLP compliance monitoring programmes for their pathology activities, this leaves UK pathologists at a disadvantage, should they wish to deploy digital pathology for peer review in a GLP compliant manner.
As sponsors may be reluctant to re-join or maintain membership of GLP compliance monitoring programmes solely for the purposes of pathology peer review, how would the MHRA inspectorate and regulatory reviewers view routine GLP exceptions for pathology peer review of GLP studies?

We believe that resolution of this issue is important to avoid impeding advances in technology such as digital peer review, where the flexibility provided may allow for a more robust peer review process, and to prevent an apparent dichotomy between pathologists options from countries sharing OECD membership.

Answer 3: OECD Advisory Document No. 16 allows for some flexibility of approach. If the pathology peer review is not conducted to GLP, this should be indicated in the GLP Compliance Statement in the Final Report. The UK GLPMA do not consider it a deficiency to routinely include such a disclaimer in the GLP Compliance Statement.

Question 4: Expectations on retention of electronic media from decommissioned systems?

Answer 4: The Data Integrity guidance includes details around the system life span. There is a need to consider the importance of data and the need to retain it. If data cannot be migrated to maintain the data, meta data and audit trail, test facility management need to assess the impact of the migration on the studies. The retirement plan for a system needs to consider how data can be accessed and ensuring not only access but including sufficient instruction on how to access it.

Question 5: Claims of compliance when sample stability information is not generated?

Answer 5: A lack of stability information affects compliance and the validity of the study. The preferred option is to wait for the stability information to be ready and if not, add as an exception on the GLP Compliance Statement and include narrative relating to the lack of sample stability information in the body of the Final Report.

Question 6: Conduct of remote/hybrid inspections?

Answer 6: This was considered answered previously in the meeting.

Question 7: Where exploratory samples are collected in a GLP study for future possible analysis, do the results need to be reported in the GLP study?

Answer 7: Details of the samples should be included in the Study Plan. The report should reference that the samples were collected and there is no need to include the results in the report. However, if those results did have an impact on the study results, this should be considered.

AoB

Question: What is the position if a non-GLP facility was used where a GLP facility exists that could have undertaken the work but the sponsor had had previous negative feedback on the GLP facility?

Answer: The MHRA guidance on this matter is that non-GLP facilities can only be used in exceptional circumstances but the key action is to contact the MHRA on the issue.

Further discussion on the characterisation of the test item ensued with regard to quality standard and GLP compliance. There is an expectation that the quality standard employed is reflected in the report (refer to OECD No.19). MHRA will endeavour to cover this in the next MHRA Symposium, (provisionally scheduled to be in H1 2022).

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GLP Regulatory Update

Mark Goodwin and Peter Connaughton, GLP Committee

The OECD GLP Working Party has been busy over recent months. The Advisory Document (No. 22) of the Working Party on Good Laboratory Practice on GLP Data Integrity was issued on 20th September 2021. The document contains good information and useful guidance, however some of the expectations will be challenging to test facilities and some of the content is open to interpretation, particularly around risk assessment. The Guidance was discussed in detail during the GLP Clinic at the RQA International QA Conference. An MHRA blog (27th September 2021) confirmed that for GLP test facilities based in the UK, the OECD document takes precedence over the MHRA GxP Data Integrity Guidance.

The OECD also released the draft revision of OECD Document No. 4 (QA and GLP) to industry members of the OECD GLP Discussion Group for consultation. The review period was relatively short with a submission date for comments of 29th October. Comments have been submitted following review of the document by RQA GLP Committee members. The draft document is quite lengthy (30 pages) as it incorporates information from OECD FAQs and Guidance Documents. There are several references to test facility management responsibilities and comprehensive coverage of the risk-based approach to QA auditing.

In the near future there is likely to be an invitation for industry to submit more GLP FAQs for the OECD website, again through the OECD GLP Discussion Group. The OECD GLP Working Party is also considering emerging technology using information gained from industry.

The US FDA re-commenced on-site inspections in July; during the pandemic such inspections were confined to ‘Mission Critical’. Remote inspections are not considered to be full inspections by the FDA. With respect to the new GLP Rule (GLP Regulations), industry comments are still undergoing review.

The MHRA GLP Guidance Documents are undergoing review with the revisions expected to be ready by the end of 2021. MHRA GLP on-site inspections resumed in July. The MHRA shared some GLP inspection metrics at the RQA Conference. A summary is provided below for the 2019-2020 period (total of 43 GLP Inspections).

MHRA GLP Inspection Metrics 2019-2020

Number of Deficiencies in each Severity Classification (from 43 inspections)

No. of Critical Deficiencies: 13

No. of Major Deficiencies: 46

No. of Deficiencies (Other): 398

Nature of the Critical Deficiencies

Study Management and Conduct

1. It was not possible for the study director to demonstrate oversight of the study.

2. The multi-site study included a claim of compliance for work which was performed by a facility who had not been inspected by their national GLPMA.

3. A collection of issues associated with the outsourced analytical phase which were not adequately impact-assessed by the study director. This included:

• Work performed ahead of study plan finalisation
• Incorrect storage during transfer of samples
• Issues with the principal investigator phase compliance statement and QA coverage at the test site.

4. A piece of equipment/analyser was being used despite not being validated. It was being used under an ‘at risk’ rating.

5. A final report was not issued for a completed study with the data archived and considered completed on the Master Schedule.

Test Facility Management Responsibilities

6. The commitments made in response to previous inspection reports had not been completed. This included the commitment made in response to critical and major deficiencies.

7. A repeat of 6.

8. An additional repeat of 6.

9. There were issues identified with test facility management’s oversight and management of the quality system. This included issues with training, computerised system validation and availability of technically valid SOPs.

10. Test facility management failed to notify the GLPMA of a facility relocation and work was undertaken at the new address prior to assessment by GLPMA. Issues with the move were subsequently identified which undermined GLP studies.

Quality Assurance

11. Inadequate Quality Assurance audit coverage of studies (in life).

Laboratory Facilities and Equipment

12. Issues with facility relocation relating to temperature excursions which affected TI samples during transit.

Data Integrity

13. A number of significant issues were identified which prevented the reconstruction of the study and undermined the reported results:

• Lack of raw data and audit trials
• Failure of procedural controls
• Unreported results.

League table for Major Deficiencies (top 7)

Data Integrity Controls: 7

Study Management and Conduct: 6

Lab Facilities and Equipment: 6

Quality Assurance: 6

Computer Systems: 4

Source/Raw Data: 3

Archiving: 3

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October 2020 Updates
Mark Goodwin, GLP Committee

OECD Update

The OECD GLP Working Group has been particularly active in recent months. A summary of the outcomes from these activities is highlighted below.
OECD Document (No. 21) entitled ‘OECD Position Paper Regarding Possible Influence of Sponsors on Conclusions of GLP Studies’ was issued on 7th May 2020. More detailed commentary 
on this paper is given at the foot of this update.

There’s been no recent update on progression of the OECD GLP Data Integrity Guidance document, however information from a few months ago indicated that it could be issued by the end of 2020. Andrew Gray (MHRA) will be providing an update at the RQA International QA Conference in November.

Through the OECD GLP Discussion Group, industry has been requested to complete a brief survey on emerging technologies. Completed surveys need to be submitted by 31st December 2020: Survey
 
The FAQ document on the OECD website was updated on 15th June 2020 and included several new Q&As.
www.oecd.org/chemicalsafety/testing/glp-frequently-asked-questions.htm

Some of the more interesting additions are:
Test items, reference items and samples/specimens (including biotechnology, GMOs, etc.) section:
No. 4: How should samples/specimens collected during a GLP study for exploratory research outside of the GLP study be handled and reported?
No. 5: Can the residual samples from bioanalysis be retained for a limited period, outside the archive, after the report is finalised and then be destroyed provided this is clearly stated in the study plan and report?
Management of Study: DI section:
No. 1: In the last few years, guidance on data integrity has been developed in the fields of Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP). Could similar guidance on data integrity in GLP be developed?
Histopathology: Digital Histopathology section:
No. 1: Is there any objection from the GLP compliance monitoring authorities to implement digital pathology in GLP studies?
No. 2: Should digitised slides be retained in the archives if used in GLP studies?
Archives:
No. 1: Can a system administrator conduct electronic archiving 
of GLP data?
No. 2: How is GLP applied to traceability and archiving of communications between study director, sponsor, principal investigators and pathologists in the context of new information technology tools (such as client portals, encrypted documents, electronic messaging, social networks tools)?
 

MHRA Update

The MHRA Stakeholder Engagement meeting, sometimes referred to as the GLP Consultative Committee meeting originally scheduled for 22nd June was postponed; the meeting has yet to be rescheduled. There has been a number of communications from the MHRA relating to COVID-19 that impact the GLP and GCP clinical laboratory communities. Links to these are provided below with a brief summary of the key message or content.

MHRA, 20th March 2020
MHRA only conducting key inspections. Expectation that GxP compliance is maintained.
New arrangements for MHRA Good Practice (GxP) inspections due to coronavirus (COVID-19): www.gov.uk/government/news/new-
arrangements-for-mhra-good-practice-gxp-inspections-due-to-coronavirus-covid-19--2

MHRA, 23rd March 2020
MHRA only conducting remote inspections except:
MHRA will only conduct on-site inspections linked to the UK Government’s COVID-19 response or any other potential serious public health risk, and where remote assessment is not possible.
https://mhrainspectorate.blog.gov.uk/2020/03/23/mhra-good-practice-gxp-inspections-during-the-covid19-outbreak/

MHRA, 30th March 2020

• Confirmation that a statement of GLP compliance will be issued following closure of a remote inspection
• GLP compliance must be maintained
• Any issues encountered due to COVID-19 that could 
potentially impact the GLP status of a study should be managed, fully assessed and documented via existing amendment and deviation procedures
• Adequate QA programme essential. Impact of any missed 
QA inspections must be assessed by the study director. 
Alternative QA approaches (e.g. remote observation) should be risk assessed to ensure similar level of oversight as a physical inspection.
• Guidance for Good Laboratory Practice (GLP) facilities in relation to coronavirus (COVID-19):

www.gov.uk/guidance/guidance-for-good-laboratory-practice-glp-
facilities-in-relation-to-coronavirus-covid-19

MHRA, 7th April 2020
Maintenance and calibration of equipment – guidance provided for various scenarios:

• If an engineer is available to attend site
• If an engineer cannot attend site but is available either by 
telephone or video call
• If an engineer is not available to attend site and remote 
supervision is not possible
• Off-site calibration/maintenance
• Substitution of laboratory equipment.

Guidance for manufacturers and GxP laboratories on exceptional flexibilities for maintenance and calibration during the coronavirus COVID-19 outbreak: www.gov.uk/guidance/guidance-for-
manufacturers-and-good-practice-gxp-laboratories-on-exceptional-
flexibilities-for-maintenance-and-calibration-during-the-coronavirus-co 

MHRA, 9th April 2020
Approval of GxP documents when working from home during COVID-19 outbreak:

• Use existing validated systems that support electronic signatures (if available)
• For alternative methods to wet ink signatures, a signature applied remotely should be equivalent to the handwritten signature
• A number of risks are associated with remote approval (see link for details).

www.gov.uk/guidance/approval-of-gxp-documents-when-working-from-home-during-the-coronavirus-covid-19-outbreak

MHRA, 16th April 2020
Guidance for industry on flexible approaches to regulation the MHRA are taking during the COVID-19 outbreak. Guidance covering a number of disciplines/GxPs.

MHRA regulatory flexibilities resulting from coronavirus (COVID-19): www.gov.uk/guidance/mhra-regulatory-flexibilities-
resulting-from-coronavirus-covid-19

MHRA, 23rd July 2020
The MHRA announced the resumption of on-site GxP inspections in the UK, starting in September scaling up to the full programme in October 2020.
https://mhrainspectorate.blog.gov.uk/2020/07/23/mhra-planning-for-
return-to-on-site-good-practice-gxp-inspections/

WHO Update

WHO Guidance on Data Integrity (version 2) was made available for industry consultation. The submission deadline for comments has now passed.

OECD Position Paper Regarding Possible Influence of Sponsors on Conclusions of GLP Studies, Lesley Graham

OECD GLP working group is the global regulatory voice on all things GLP. Their most recently published document is a position paper that discusses the expectations of sponsor influence on the outcome and conclusions of GLP studies. The working group is made up of heads of GLP Monitoring Authorities (in excess of 50 global representatives). The foundations of the OECD GLP Mutual Acceptance of Data Agreements (MAD) is based on global harmonisation of the GLP Principles and mutual recognition of inspections between countries, all in the pursuit to reduce barriers 
to trade. In summary, what this means is anything they produce 
we need to pay close attention to in order to remain compliant. 
The key messages, points to note and actions have been summarised and presented here: 
Key Messages and points to note:
This is a position paper and the 2nd position paper published by the GLP Working Group. This is significant as it means there was no consultation with industry or other OECD stakeholders and is a clear communication as to their expectation and requirements. The fact that the Principles of GLP or the country specific GLP regulations have not been updated with specific requirements for a sponsor, is not a good enough reason to overlook these requirements and/or not comply as it will not prohibit GLP inspectors raising findings in this area.
The document is pitched and aimed at study directors (SD) on the basis they are ultimately responsible for the integrity, scientific validity and GLP compliance of the study. The document will also provide clarity to sponsors who may not be fully aware of the GLP regulations and expectations. Therefore, this document is intended to be used to support a SD position in the event that a sponsor was deemed to be either exerting undue pressure and influence on the study results and outcomes or was unaware of the requirements.
Section 6 makes it clear that comments and correspondence on the draft report by the sponsor should be retained by the test facility and recommends QA audit the final report after the sponsor’s comments have been integrated. The reason for this is to be transparent and to be able to demonstrate the extent of any influence the sponsor’s comments had on the final report and being able to reconstruct the study activities.
Section 6.2 discusses interim reports and makes the point that GLP Principles recognise only final reports that contain a SD compliance statement. The paper allows interim reports, but the expectation is that if interim reports are issued, they should not contain a GLP statement of compliance unless specifically requested to by a receiving authority.
Page 14 includes an expectation that if exploratory research is part 
of the study plan then it should be included in the report.

Suggested Actions
GLP QA groups should consider including the following checks within their audit of reports:

•     Has the sponsor reviewed the SD final report or principal 
investigator (PI) phase report?
•     Is the evidence of their review maintained and is this report audited after all their comments?
•     Are their comments and requests appropriate?

Link to full document: www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2020)5&doclanguage=en

 

September 2019 GLP Updates

Regulatory Updates

A number of regulatory documents / information have become available in recent months.

ICH M10 Bioanalytical Method Validation – Draft, June 2019

Although this document is of more interest to the scientific community it could impact working practices in laboratories that conduct GLP and GCP Clinical Laboratory analysis. Comments from industry are to be provided by end of 2019.

 Modernising FDA’s New Drugs Regulatory Program, June 2019 update

In 2017, FDA’s Center for Drug Evaluation and Research (CDER) embarked on an initiative to modernize the New Drugs Regulatory Programme. The modernization of the New Drugs Regulatory Programme will be a long-term process of continuous improvement involving multiple initiatives; implementation of some initiatives has begun and will continue over the course of 2020. The modernisation focuses on six strategic objectives:

• Scientific Leadership: Grow our scientific expertise and clarify pathways to regulatory approval
• Integrated Assessment: Critically, collaboratively, and consistently assess whether information in drug approval applications meets legal and regulatory requirements.
• Benefit-Risk Monitoring: Systematically monitor the benefits and risks of approved drugs pre- and post- approval to effectively protect the American public
• Managing Talent: Attract, develop, and retain outstanding people
• Operational Excellence: Standardize workflow, business processes, roles, and responsibilities to improve operational efficiency, and enable our scientists to focus on science
• Knowledge Management: Facilitate the identification, capture, distribution and effective use of information

Draft FDA Document: Pathology Peer Review in Nonclinical Toxicology Studies: Question and Answers, July 2019

Industry comments were required for submission by 30 Sep 2019. Some of the more interesting questions that are answered include:

• Can pathology peer review be conducted at a non-GLP compliant site for a GLP compliant study
• How should the nonclinical laboratory staff document the peer review and what should be included in the peer review statement
• Should the signed peer review statement be included in the final study report
• How can the Agency be assured that the study pathologists interpretive findings are not unduly influenced during the pathology peer review process

EC Notice to Stakeholders: Withdrawal of the UK & EU Rules in the Field of GLP, June 2019

It has always been known that the two key EC Directives relating to GLP (2004/9/EC and 2004/10/EC) would no longer apply to the UK when the UK leave the EU. The document in the link below provides official confirmation. There is little impact on the UK since the UK operates within the framework of OECD MAD.

https://ec.europa.eu/info/files/good-laboratory-practice_en

OECD Series on Principles of GLP and Compliance Monitoring Number 20: Guidance Document for Receiving Authorities on the Review of the GLP Status of Non-Clinical Safety Studies, July 2019

Although this document is for use by regulatory reviewers, it provides industry with an insight into the expectations of Regulators around the GLP status of submitted non-clinical safety data and the checks that the reviewers will perform to verify the GLP compliance status. The key checks are the compliance status of the facility (and any test sites if applicable) and the GLP requirements of the final report. Any significant concerns could lead to a request for a directed (study) audit with the outcome determining whether the data is accepted or rejected.

No. 20: Guidance for Receiving Authorities on the Review of the GLP Status of Non-Clinical Safety Studies

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MHRA GLP Consultative Committee Meeting 19th October 2018

Unofficial minutes recorded by Lisa Heely and Vanessa Grant, RQA

MHRA Updates

Personnel Changes

Mark Birse has been seconded to the Medical Devices Division for 18 months as Group Manager of MHRA Devices Safety and Surveillance Group & Devices Software and Apps. Andrew Gray has moved into Mark’s previous position as Inspectorate Group Manager.

Post meeting note: During this time, Stephen Vinter will take the role of Head of the GLPMA. 

BREXIT

There have been no changes yet pending an agreement on the conditions for leaving the EU. Updates will be published in the inspectorate blog and online. It was clarified that as the UK are members of the OECD MAD programme then Brexit does not alter the acceptance of UK GLP data within Europe or on a Global basis. 

Inspection Metrics

Metrics gathered from deficiencies arising from MHRA GLP inspections in 2017 were published at the end of 2018. 

There was a significant jump in critical deficiencies raised (8 in 2016 compared with 16 in 2017). These are mainly in the categories of Study Management and QA, and include such things as:

Study Management

• Lack of transparency

• Misleading compliance statements

• Data integrity controls

• Inability to reconstruct the study

• Lack of method validation, but study director has indicated validity of data

• Lack of checking use of non-GLP facilities.

QA

• Insufficient audit coverage

• Critical phases not inspected by study based or process-based inspections

• Failure to identify deficiencies

• Failure to address corrective and preventative actions

• Insufficient QA resource.

On the basis that poor close out of CAPA and QA resourcing are often outside of QA’s control, a new finding category of Test Facility Management is being introduced for use where applicable.

There has also been a jump in major deficiencies predominantly in the same areas. Data integrity major deficiencies have risen from 4 to 15 and include issues such as what is the raw data, access rights and audit trail management and review.

The MHRA explained that these deficiencies are not in areas which have been newly introduced by the Data Integrity Guidance but are pre-existing GLP requirements. The inspectorate does not believe that the rise in critical and major deficiencies is due to a shift in the grading of inspection deficiencies, however, a greater understanding of processes and a greater focus on electronic data may be contributing factors. The MHRA stressed that all deficiencies are peer reviewed and there is consistency of deficiency gradings.

The MHRA have updated the definitions of the categories and are now more aligned with GCP definitions by introducing clarity about escalations if they see insufficient CAPA or repeats of deficiencies. 

The MHRA indicated that whilst there is no requirement for a formal CAPA system, they do expect organisations to have a mechanism for implementing corrective actions in response to inspection deficiencies.

Laboratories Symposium

A symposium covering GLP and GCP/GMP laboratories was held on 13th March 2019 at Novotel, Hammersmith. The symposium covered GLP, GCP and GMP facilities. Topics on the draft agenda include data integrity and QA/QC interactions as well as an agency update. The afternoon was split into bioanalytical validation, tired approach and cross GxP quality.

Email Address

There is a new contact email address for GLP, GCP and GMP labs gxplab@mhra.gov.uk. The previous email address will continue to work for a period of time and will be monitored during the transition.

Fees

Fees for next year are being reviewed. In the event of a change in fees there will be a consultation period with stakeholders.

Guidance Document Update

Interim Reports

The MHRA have issued a draft position paper on interim reports with GLP compliance claims. As outlined in the laboratories symposium in 2018, the MHRA position and majority EU GLP working party is that interim reports should not include a claim of compliance. There is a problem if compliance is claimed for interim reports where data is significantly incomplete, or where data acquisition methods have not yet been fully validated. In these cases, it is difficult and inappropriate for the study director to indicate validity of the data and therefore a claim of GLP compliance. The MHRA has approached all the UK assessors to understand if they require interim reports to include GLP claims and all have indicated that not only do they not require it, but they they would prefer not to have such claims. However, there are some receiving authorities within the OECD that require compliance statements to be included in interim reports. There is no issue with having QA audits of the interim reports and the inclusion of a QA statement. If a receiving authority does ask for a claim of compliance, it must be supported by a full review of data and a QA audit.

The comments that have been received will be incorporated into the draft position paper before it is circulated for further comment. 

Use of Non-GLP Data in GLP Studies

The position outlined in the guidance on the use of non-GLP facilities remains unchanged. If the work is critical to a study it should be GLP compliant and any non-GLP data should be clearly excluded from the compliance statement. Conclusions from the study cannot be drawn from non-GLP data. There was some discussion around including non-GLP data as an addendum to the report but this is not widely agreed by receiving authorities. The GLPMA agreed that non-GLP data can be included in the body of the report but it should be unequivocally identified in the report as being ‘non-regulatory’ data.

An update may be issued by the MHRA to clarify further.

International Regulatory Update

Every year, the MHRA attend an EU GLP Working Group in February and the OECD GLP Working Group in March. 

EU GLP

UK and NL are looking at differences in the way OECD GLP Working Group members deal with the fact that there is no routine inspection programme in the US. They are also looking at the way members deal with facilities in third countries which have been inspected by an OECD member country. Focus is on what is allowed under national law with respect to study director claims of compliance. The results of this exercise may be published when it is completed but this would need to be agreed by all Working Group members. 

There is an agreed process for audit requests by EMA, EFSA and ECHA of planned inspections so that they can routinely ask for random studies to be reviewed. 

OECD GLP

Thailand was subject to assessment late 2018 and the results of the report from the assessment will be discussed at the next OECD Working Group meeting. China remains an observer and there is a lot of effort to engage at OECD level. MOFCOM in China are coordinating with different ministries, but it remains difficult to move forward. It may mean that each ministry will be approached individually.

OECD have set up a drafting group to convert the UK data integrity guidance into an OECD advisory document. Work on this is ongoing. The document will be checked for consistency with OECD Advisory Document 17 and then go out to public consultation once the working group have agreed the draft version. There may be differences from the MHRA document, in which case the OECD document will take precedence.

It was confirmed that QSAR requirements falls outside the scope of GLP.

There is interest to see how much the OECD MAD programme saves industry. As such they are reaching out to industry trade associations.

US FDA Centre for Veterinary Medicine (CVM) Submissions

A question was submitted from RQA regarding the FDA CVM requirement to submit all study raw data and supporting data and whether this undermines OECD MAD. If RQA and SLA put this question in writing, the MHRA will pass to US FDA.

Data Integrity on Inspection

Major deficiencies are being raised where there appear to be no plans in place to address gaps to meet the Data Integrity Guidance Document. The inspectors are being pragmatic where there are plans and evidence of progress. Where there is a lack of management commitment then findings will be raised. The expectations for small companies and large companies are the same.

Examples have been found where a risk assessment has been undertaken but the remediation done in the wrong order, with high risks left until last including older systems with paper data. In such cases appropriate checks and balances should be implemented until the system is upgraded. 

It is no longer acceptable to define the paper printout as the raw data. If data integrity issues have been identified during an MHRA inspection, the expectation is that they will have been addressed by the next inspection.

Questions and Answers

The GLPMA will publish their responses to the following questions in the near future:

Question 1. How should complex mixtures be characterised?

Discussion included that the guidance given in OECD Advisory Document 19 (Management, Characterisation and Use of Test Items) should be followed. This is intended to foster a risk-based approach.

Supplementary question: if a formulated product has not been characterised, what should be reported and how? 

Discussion included that the MHRA expect deviations to be reported in the study director’s compliance statement and the report. Study director statement should assess the impact. Detailed information on scientific rationale can be elsewhere in the report, i.e. study director statement highlights it and report discusses it.

Question 2. The EMA seems to be moving towards a more pragmatic approach to long-term retention of electronic data. What are the MHRA expectations for migration of data?

Discussion included that a risk-based approach should be adopted. What is the risk of long-term data retention versus the dynamic readability of data. If you have a process to migrate to paper data, the expectation is that you need to have access to the dynamic data for at least three years. Inspectors expect to access the electronic data so it should be available for review at the very least up to the time of marketing authorisation application. 

Question 3. How should small companies validate software?

Discussion included that companies should understand what they are buying, its functionality and the vendor support available. Validation should be appropriate i.e. validate only what you will use. Companies do too much and overcomplicate the validation process. Software must be validated and size of company does not influence the validation requirements.

Question 4. How should companies validate cloud-based storage?

Discussion included that a clear, robust contract is required. Facilities should understand the data-flow process and how the data is managed. Advice should be sought from knowledgeable IT people. Security and control are key in a cloud-based system.

Question 5. In what circumstances would inspectors look at QA reports? 

Discussion included that inspectors usually only look at inspection dates and the description of what was inspected. QA reports are only inspected if there are concerns regarding whether the QA programme is effective. 

Any Other Business

The MHRA are establishing a StEM for GCP laboratories in May 2019 and will shortly be inviting attendees.