GLP Update and Hot Topics - s3.amazonaws.com€¦facility holds a GLP compliance statement ... differences and is not a detailed comparison of the technical content. ... New advisory

GLP Update and Hot

Topics

RQA Annual ConferenceMark Goodwin

9 Nov 2016

Introduction

• International GLP Updates

– OECD including MAD Agreement

– EC/ EMA

– US FDA & US EPA

• UK GLP Update

– MHRA

– MHRA GLP Deficiencies 2015

• Hot Topics

• RQA GLP Committee Activities

OECD GLP Working Group

• Chair of WG - Japanese PMDA representative

• Vice Chair of WG - Swiss representative

• Meeting was held in April 2016.

OECD GLP Working Group Headlines

• OECD FAQ Page: RQA Members are encouraged to view this page, as the FAQs are agreed by consensus across OECD. New FAQs will be reviewed at the OECD WG meeting in 2017.

International GLP News: Mutual Acceptance of Data (MAD)

Current Adherents OECD Countries

Argentina

Brazil

India

Malaysia

South Africa

Singapore

Provisional Adherents Thailand

• Argentina-MAD applies to industrial chemicals, pesticides and biocides only

• Thailand is likely to be evaluated in the near future

• Russia was striving for OECD MAD status but little progress recently

• China is not a provisional adherent although the OECD continues to work with China; China reps are Observers at OECD Working Party meetings

UK position on non-OECD GLP claims

Non MAD adherent countries

•The UK GLPMA will not support claims of compliance for GLP studies made by facilities located in non MAD adherent countries even if the facility holds a GLP compliance statement issued by a monitoring authority from a MAD adherent country.

National Regulatory Receiving Authorities

•The UK GLPMA advise national regulatory receiving authorities to request regulatory study audits of all studies (performed in non MAD adherent countries) that are deemed to be pivotal to an application. However it should be noted that final decision whether or not to accept or reject data rests with the regulatory receiving authority.

Regulatory Update: OECD

OECD Series on GLP No.18 issued on 2 Sep 2016: Position Paper regarding the Relationship between the OECD GLP Principles and ISO/IEC 17025.

Draft was made available for industry comment –no comments from the GLP Committee review

The paper explains the general (often philosophical) differences and is not a detailed comparison of the technical content


• OECD GLP Discussion Group: 3 themes

QA activities

QA statement content

Who should sign QA statement?

Audit of the QA department

Access to QA reports

Identification and characterisation of test items

New advisory document planned to “clear up a lot of uncertainty”.

Likely to be issued in 2017

Issues relating to advances in IT technology

OECD Advisory Document No 17: Application of GLP to Computer Systems

Issued 22 April 2016 and replaces OECD Monograph No 10.


‘Re-opening’ a GLP study, post issue of the final report.

Reporting requirements following the early termination of a GLP study.

Method validation completion relative to initiation of a GLP study.

Standards applicable to method validations

4 questions added to FAQ on OECD website…

EC / EMA Update

• EMA currently considering Advanced Therapies and how they affect GLP

• EC GLP Group currently establishing a working agreement with the European Food Safety Authority (EFSA) regards study audits

• The possibility of EU developing data integrity guidance to be discussed at EU GLP working group meeting in spring 2017

EC / EMA Update

• EMA issued a document entitled "Triggers for Audits of GLP studies". Effective in March 2015 but only reached our attention in Dec 2015

- It includes a checklist for Regulatory Assessors to check the GLP compliance status of the studies.

- EMA might reject ‘GLP’ studies conducted at facilities outside a national GLP Compliance programme or if they have not been inspected by the national GLPMA

Regulatory Update: US FDA

FDA have a notice of proposed rule making in development for 21 CFR Part 58:

Review• All industry comments were reviewed

Clearance• Proposed draft issued in August 2016

Comment• Industry given 90 days to comment

Issue• New (Final) Regulations expected in 2018

Regulatory Update: US FDA

• Non-GLP Data

– If non-GLP data are included as part of a GLP submission it will be included in the scope of inspection (although not ‘held’ to GLP standards)

• FDA have increased their scrutiny of test facility responsibility regarding the compliance status and integrity/quality of data from subcontractors. The SD needs to be assured of the quality and integrity of the data from GLP compliance test sites used on multi-site studies, including sponsor test sites.

Regulatory Update: US EPA

• Modified Inspection program has resolved any questions by OECD GLP Working party

– Consists of desk-top inspection but still doing mix of conventional inspections

– Geographical bundle of inspections to reduce travel time and costs

Regulatory Update: US EPA

Letter of IntentEPA• This has been signed with the Chinese Ministry of

Agrochemicals (ICAMA) to mutually recognise each others GLP Programme

Inspection Closure LettersEPA• These must not be used in marketing as these are

not approval of a facility

MHRA GLP Update

• Organisation

• Information form StEM meeting

• 2015 GLP Inspection Information

• MHRA Symposium, Sep 2016

• MHRA Guidance Documents

Inspection, Enforcement & Standards DivisionInspectorate

Unit Manager, Inspectorate Operations

GLP/GCP/GDP

Andrew Gray

Operations Manager GCP

Jenny Martin

(maternity cover)

Operations Manager GDP

Peter Coombs

Operations Manager GDP

Phillip Neale

Senior Inspectors

Lesley Graham

Jason Wakelin-Smith*

Emma Whale*

Inspectors

Michael McGuinness

Martin Reed

Lisa Ottowell

* GCP/GLP Inspector

Senior Inspectors

Andy Fisher

Kathleen Meely

Inspectors

Mandy Budwal-Jagait

Balall Naeem

Hayley Dixey

Operations Manager

GLPMA/Labs Group

Stephen Vinter

MHRA Organisation

• Chris Gray is Operations Manager GMP, reporting to Richard Andrews, a Unit Manager, Inspectorate Operations (responsible for GMP Inspectorate and GPvP Inspectorate).

Regulatory Update: UK GLPMA

Risk-based approach now embedded

• based on inspection history, intelligence and other risk factors (mainly volume and nature of work)

High risk facilities

• No change and are inspected every 12 months although there may be some flexibility for facilities with high compliance

Low risk facilities

• May be subject to a 30 month inspection cycle (rather than 24 months)

Monitoring Inspections

Regulatory Update:

• Stakeholder Engagement Meeting (StEM) held 8 Sep 2016

• Covered:

- MHRA GxP document on data integrity

- International and UK GLPMA updates

- Industry questions

• BREXIT

– No comments on this at the moment!

• All statements will be dealt with at an Agency level, through the Policy Division.

• Remember, GLP works through OECD Agreements

MHRA Regulatory Update…


• 2015 GLP Inspection Summary

– 48 inspections conducted (53 in 2014)

– 4 Critical deficiencies

– 28 Major deficiencies (11 study conduct, 6 QA, 6 computerised systems)

– 593 Deficiencies


• 2015 GLP Inspection: 4 Critical deficiencies

- 1 Failure to comply with own procedures

- 2 Study Management

- 1 Multi-site aspects

General comments

• High impact of critical findings

• Increased inspection findings related to data and computerised systems

UK GLPMA (2015 Inspection Metrics)

Item 2013 2014 2015

Number of deficiencies (total) 713 711 625

Number of critical deficiencies (% of total) 6 (0.84) 2 (0.28) 4 (0.64)

Number of major deficiencies (% of total) 38 (5.3) 23 (3.2) 28 (4.5)

Number of deficiencies (% of total) 669 (93.8) 686 (96.5) 593 (96.5)


• Focus on Bioequivalence Studies (GCP) has increased – particularly overseas inspections

• 2014 – 2016: 3 critical findings

- Clinical Sample Analysis

- QA

- Data Integrity


Bioequivalence Studies (GCP)

• 17 major findings

- 2 Computer Systems validation

- 2 Data Integrity

- 2 CRF Data / Source Data

- 2 QA

- 2 Quality System

Regulatory Update: UK GLPMASign up to get up-to-date informationhttps://www.gov.uk/government/news/new-mhra-inspectorate-blog


A number of projects to develop internal systems resulting in changes to GLP documents

- Notification Form

- GLP Certificate

- Harmonised reports for GLP facilities and GCP laboratories

MHRA GLP Symposium 2016

• MHRA GLP and GCP Laboratory Symposium 22 September 2016.

• Topics

- Regulatory Compliance for Computer Systems

- Data Integrity

- Data Integrity – hot topics and example findings from inspection

- Bioanalytical, Regulatory and Inspection (hot topics)

- Panel session


Computer Systems

‘Off the shelf’ – risk assessment; utilise vendor validation effort

‘Bespoke’ – complexity will determine how much validation

Raw data – for any system other than simple systems, print-outs are not representative of original data (i.e. electronic data is the raw data)


Data Integrity

- Inspectors will expect the GxP Guidance to be followed on issue of the document

- should at least be an implementation plan in place (timelines; gap analysis; risk assessment)

- data governance and risk assessment key elements of DI

- DI failures: deletion, amendment, duplication, processing, fabrication


Bioanalytical topics

- Justifiable reasons for repeat runs

- SOP required covering QCs set up

- SOP required covering review of internal standards performance

- Justifiable reasons for rejection of standards

- Integration process needs to be transparent, audit trailed, reviewed and SOP controlled

Regulatory Update: UK GLPMA: Guidance Documents

Set up QA Programme based on documented

Risk assessment

Out of scope are study plan and amendments, report and facility audits

Allows resources to target areas of high risk, and is therefore value adding

The Guidance does not mandate a risk based QA

programme!

Risk Based QA Programme


Selection and use of GLP test sites located outside the UK

(issued April 2016)

Expectation that test site is located in a country that is signatory to MAD and

subject to periodic inspections

If not, this must be stated in SD statement and no claim of GLP

Compliance made for that phase of the study


Draft MHRA GxP

Guidance on Data Integrity

Released in July, for

consultation by Industry

Comments deadline 31st

October, 2016

Organisation & Personnel

Identification of the individual(s) comprising Test

Facility Management

PI/SD Interaction &

Communication

Job descriptions must mention

the requirement to work to GLP

Training Records

Demonstration of Training

leading up to Roles

• QA

– Tolerance for Conduct of Facility Inspections

• If “Annual” in SOP, carried out in Q1 one year and Q4 next year, is this in compliance with SOP?

• Test item

– Expiry vs. retest dates

– Formulation stability must be assessed under GLP

• Sample Storage Conditions

– Impact assessment if storage temperature outside required range

• Data Integrity

– Conflict of Interest around Computer System Administrator also the primary user / SME

– Valid documented reasons for repeats and for not reporting data

– Justification of acceptance of results if do not fully meet predefined acceptance criteria (in study records and report)

– Data scrutiny – e.g. Gaps in acquisition times; changes in data filenames

RQA GLP Committee News

• Two new publications

– GLP in the Analytical Laboratory (now available)

– Practical Guide on the Roles and Responsibilities of the Study Director (awaiting publication)

• Distance learning course being developed on the Role and Responsibilities of the Study Director

• Number of webcasts in preparation

• Representation on the OECD GLP Discussion Group

• Review of MHRA GxP DI Guidance and review of new (proposed) FDA GLP Regulations

RQA GLP Committee News

• GLP Discussion forum is being well used on www.therqa.com

– lots of postings (and answers)

– Please keep them coming!

• If you know of any activities or topics you feel the GLP Committee should be involved in then let us know

– we are here to support the RQA membership!

http://www.therqa.com

Thanks very much for your time….

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