Example conference posters

Introduction

Galapagos Quality Strategy in Non-Regulated Research

Frank Giots, Karen Schoonis

Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen, Belgium

E-mail: frank.giots@glpg.com

HowdoesQualityspellinyourResearchorganization?Thisquestionisoften addressedtoQualitySpecialistssupportingResearchorganizationsinthe PharmaceuticalIndustry.

TheanswerislessstraightforwardasspecificqualityguidanceonResearch operationsislimitedinanareathatiscommonlyconsiderednon-regulated humanmedicinalproductdevelopment.

Objective

StartingfromacompleterevisionofthecurrentGLPGResearchQuality ManagementSystem(QMS),a desiredQMS isdesignedbasedupon:

1) GLPGQualitymodeldescribedinourR&DQualityPolicy

2) BenchmarkanalysiswithcommonIndustryguidelinesfornon-regulated ResearchinaBiotechnologycompany(seeReferences)

ThefutureQMSwillbedefinedasaGLPGResearch QualityFramework reflectingapplicable“GoodScientificPractices”andcorresponding quality E2Eprocesses.Suchprocessesshallensurevalidity&integrityofResearch dataandcontributetoasmoothtransitiontotheGLPGDevelopment organization(anticipatingcompliancewithGxP-regulatedprocesses).

CompliancewithResearchE2Equalityprocesses(asdescribedintoGLPG procedures)willbeverifiedthroughspecific QualityMonitoringPrograms resultingintocontinuousimprovementoftheactualQMS,whereapplicable.

IndustryBenchmarkAnalysisOutcome:

GLPG“GoodScientificPractices”(GSP)

Strategy&Approach

 Centralization: one global Quality project across all Research sites

 Global Harmonization: aiming for standardized quality practices between all Research sites

 Global Action Plan: remediation plan in response to QMS gap analysis to align with defined “Good Scientific Practices”

 Pilot Projects: new process design and/or implementation focusing first at one Research site and subsequentlyhaving consolidated implementation across all Research sites

 Subject Matter Experts: assignment of key experts in Research liaising with Quality with the aim of familiarizing with Research “Ways of Working”

Methodology,Techniques&Tools

Phasedapproachof ChangeManagement,coveringthefollowingstages:

 Diagnosis:analysis&evaluationofthesituationbeforechangeinordertoidentify whatmustbekept,whatshouldimprove,andtoallowanestimationofchangeimpact

 Design:conceptualphaseofchangedevelopmenttakingintoaccounttheexpectations &requirements(technical,organizationalandlegal)forthefuturesituation

 Implementation:actualroll-outofdesignedprocesses,typicallyincludinganextensive learningphase(formatdependentoncomplexityofthechange)priortorelease  Grow&Improve:everychangewillrequireadap tationtothenewsituationand eventuallycontinuousre-evaluationofthesituationmustallowforfurtherimprovement

References

GuidelinesforQualityinNon-RegulatedScientificResearch,2008 Handbook:Qualitypracticesinbasicbiomedicalresearch,2006

QualityAssuranceforResearchandDevelopmentandNon-routine Analysis,1998

Results

Laboratoryequipmentmanagement atGLPGResearchhasbeenentirely revisedfollowingexplainedchangemanagementmethodologyandtodaya newlydesignedE2Eprocessisinplaceandinusefollowingaspecific implementationplan.

GlobalActionPlan

AQuality&ComplianceGlobal ActionPlanisinplaceaimingfor QMSremediation through revisionandintroductionofE2E qualityprocessesinalignment withdefined“GoodScientific Practices”andfollowingSenior Managementendorsement& agreedprioritization.

Conclusions

SimilarE2Eprocessdesign,QMSimprovementandphasedimplementation hasbeenachievedforGLPGResearchcovering Researchstudydesign, conduct&reporting and chemicalcompoundmanagement.Other GSPkeyareaswillfollow,asagreedperGlobalActionPlan.

UsingbenchmarkanalysiswithIndustryguidelines, an adaptedQualityFramework forGLPG Research hasbeendefined&introduced.Based uponachangemanagementmethodology, QMS continuousimprovement issoughtandsuccessful implementationwillbemonitoredovertime.

Capitalizing on Regulatory Change for Optimizing Quality-System Effectiveness: A Case Study on the Practical Implementation of a New Global Quality Process

Paul Hastwell, Tegan Francis, Jane Winter

Quality Change Methodology Guiding Principles

• Coordination of initiatives across the organization to minimize disruption

• Integrated planning around future landscape to minimize effort

Can I capitalize on regulatory changes to drive innovation in the organization?

• Proactive assessment of industry/business issues

• Formulate creative solutions

• Align industry trends to business strategy

• Cross-functional approach to scenario planning and solutions building

Innovative Solutions

• Assimilation of change topics into single initiative

How do you manage regulatory change for effective adoption?

• Implement changes into current processes

• Maintain quality requirements

• Subject-matter expertise drawn upon to create innovative solutions

• Governance Committee includes active participants across business functions

Case Study: Risk-Based Strategy to Support Confidence in QMS Case Study: Development of a SOP Framework Case Study: Implementation of a Global Serious Breach Process

Value Outcome: Providing an external perspective with hands-on experience to ask the right questions

Situation Prompted by site audit findings, our client wanted to develop a future state “risk-based” strategy to improve quality, effectiveness, and performance of site audits

Action

• Through conducting a series of discovery workshops, surveys, and interviews with cross-functional stakeholders, we sought to answer the following key questions:

1. What does a risk-based, site-audit strategy need to encompass?

2. How do measure being in control?

Results

• Defined strategy for proactive risk-impact assessments, risk plans, risk-assessment methods, issue escalation, and ownership of risks/issues

Value Outcome: Increased speed of change adoption

Global organization with little consistency in QA system wanted to simplify and optimize the current SOPs for clinical operations

• After “current-state” process was mapped, we brought the project team together prior to beginning “future-state” definition to consider the key requirements for the SOP update

• Developed framework for SOP updates that enables successful adoption of the change through effective change management, training, and communications

Value Outcome: Reduced change burden for EU Clinical Trial Regulation readiness

Serious Breach notification to be extended from the UK to EU under Regulation (EU) 536/2014

• New process design, including a new “Serious Breach Assessment Committee,” bringing together people from Quality, Study Management, Regulatory, Drug Safety, and Medical functions

• Designed new roles and IT system to support the new process

• Implementation planning for the new process across all stakeholders

• Cross-functional steering committee

• Global enterprise stakeholder collaboration and adoption

• Increased compliance now and ready for future

Virtually in Charge: Quality Management System (QMS) for a Virtual Company Christopher Rush, President, FDAQRC

Risk Evaluation

Major Risk: Inspection by a Health Authority reveals no QMS when one is required resulting in regulatory action

Major Risk: Audit by client reveals no QMS resulting in loss of business

Major Risk: Quality issues detected through compliant investigation demonstrates noncompliance to the regulations

Minimum Elements of QMS

The following are a list of minimum elements to a QMS for a virtual company:

1. Documentation Controls which includes the appropriate guidance on which documents and records need to be maintained and the retention period for those documents.

2. Change Controls to establish a uniform process for controlling the creation and issuance of new documentation (including SOPs), and changes to existing documentation and labeling. This process also incorporates the approval and distribution methods in order to comply with the Quality Manual, the Quality System Regulation, and/or any applicable International Standards.

3. Personnel training is to ensure that all employees obtain the necessary training in order to correctly perform the duties of their job position. These procedures shall be prepared in accordance with the regulatory requirements, International Standards, and Quality Manual.

4. Material and Vendor management to define the process for the selection, approval, and continued evaluation of suppliers of products.

5. Non-conformances and Out Of Specifications to define the oversight requirements and processes to be followed for the control of product or materials that do not meet specified requirements.

6. Deviation and Corrective and Preventative Action (CAPA) to describe the process for oversight, identification and handling of product and material deviations that may occur.

7. Clinical Trial Material (CTM) / Investigational Product(IP) lot release to describe the expectations for and circumstances under which IP may be released for shipment to approved clinical research sites.

The Road Map

What process are we performing?

How could this be viewed by a Regulator?

What oversight are we performing?

Do we need a Quality Management System?

What risks are involved if we do not implement a QMS?

Ensuring ICH GCP Compliance in Semi-Virtual Clinical Trials Using Direct to Patient (O -Site) Research Nurses –Practical Considerations for Sponsors and CROs

Background

Number of trials involving “home care”, “direct to patient” or “O -Site” component has been steadily increasing over the past 20 years. The use of o -site Research Nurses has further increased with the move towards virtual (or site-less) trials. Although technology has driven the change to this more decentralised trial model, the use of o -site Research Nurses is a key component of the more patient centric model.Following the ICH E6 (R2) update, European Medicines Agency (EMA) Inspectorate Working Group (WG) issued two new posts on the Q&A website in Dec 2018 to further clarify how compliance with ICH E6 (R2) can be achieved and what steps must be taken when including an external O -Site Nursing provider (“Provider”) in any trial model.

Objectives

The intention is to identify di erent categories of actions and responsibilities from the Sponsor/ Contract Research Organisation (CRO), Investigator Site (“Site”) and Provider, to comply with ICH GCP E6 (R2).

Methods

The available guidance was reviewed and interpreted by the members of the Illingworth Quality Assurance department, with further input and clarification from the Medicines and Healthcare products Regulatory Agency (MHRA), EMA and Health Research Authority (HRA) was obtained. The results were categorised, and responsibilities assigned to each stakeholder (Sponsor/CRO, Site and Provider).

Conclusions

Sponsors/CROs looking to implement virtual and semi-virtual trial models to achieve patient centricity should ensure early engagement of both the Site and the Provider.

This will allow for open communication and appropriate, documented division of responsibilities across all parties, in turn ensuring regulatory compliance.

Essential Documents Approvals & Permissions

Study design, patient condition and drug indication support and justify o -site services. Protocol and other key documents (e.g. Lab Manual) identify procedures to be carried out o -site. Informed Consent Documentation reflective of o -site process including data sharing (with provider and partners e.g. courier).

Sponsor/CRO

Contracts & Agreements

IRB/IEC and Competent Authority approval of Protocol and ICD containing O -Site procedures.

Essential Documents Approvals & Permissions

Sponsor/CRO and Site agreement (e.g. mCTA) refers to the Provider and how delegation of Investigator duties will be documented.

Financial agreement between Sponsor and Provider.

Contracts & Agreements

PI review of Provider Nurse’s CV and acceptance of proposed resource.

Patient Safety Data Integrity Oversight

Risk Management Plan to include risks associated with o -site procedures.

Site

Written agreement confirming delegation of Investigator duties, as well as assurance of pre-engagement checks (training and experience) between the Site and Provider.

Other Institution requirements (e.g. insurance or indemnification arrangements).

Essential Documents

Develop instructions for the O -Site Nurses based on the protocol and relevant manuals. Due diligence checks on the Protocol, ICD and other documentation to ensure OSite procedures are adequately described.

Approvals & Permissions

Contracts & Agreements

Strict pre-engagement checks for each potential O -Site Nurse.

Review of source data worksheet template. Ensuring Provider has procedures for quality control and quality assurance (vendor qualification). Monitoring of data.

Regular communication with the -Site and Provider.

Patient Safety Data Integrity Oversight

Pre-visit handover between Site and O -Site nurse to ensure all relevant safety information is completed.

Provider

Financial agreement with the Sponsor, delegation agreement with the Investigator (may be per trial or a master agreement with individual scope of work). OR Tri-partite agreement including all stakeholders.

Pre-agreed timelines for return of completed worksheets.

Regular contact between O -Site Nurseand Site.

Patient Safety Data Integrity Oversight

Strict process to ensure protection of Subject Identifiable Information. Detailed country-specific due diligence to ensure compliance with data protection regulations.

Ensuring Life Support training of O -Site Nurses. Study specific risk assessment for o -site visits. Health and safety risk assessments for conducting osite visits.

“Meet the Patient” visits at Site prior to the first o -Site visit. StaySafe® platform for emergency notifications. Procedure for direct reporting of SAEs and other AEs of interest to the Site.

Quality control processes for data collected o -site. Timelines for data provision to sites. Secure storage of worksheets before return to Site.

O -Site Nurse attending Site Initiation Visit and periodically visiting the site. Regular communication between Site and Provider to schedule visits and exchange feedback.

Natalia Janik and Nikki Cooper, Quality Assurance Managers at Illingworth Research Group Ltd.

Consideration of appropriate management of the GLP computerized system for data integrity

-Analysis of data integrity issues from FDA warning letters -

IsaoWatanabe: Shin Nippon Biomedical Laboratories, Ltd. Drug Safety Research Laboratories (SNBL DSR), Kagoshima, Japan

Co-author: Japan Society of Quality Assurance (JSQA), GLP Division, Study Group 3, Subgroup 2, Team A

Introduction

Globally, data integrity findings have been issued

Method

Step 1

Collected the FDA warning letters of data integrity issues related to computerized systems

Search on FDA website

Warning letters from April 2016 to August 2019

33warning letters from 9 countries in cGMP

Step 2 Categorized the data integrity issues of the FDA warning letters to the 5 phases of the data lifecycle

Result

Data integrity issues according to data lifecycle phase

What should be the focus point to improve data integrity at the GLP facilityinJapan?

Is staff training sufficient ?

Are effective controls in place for legacy systems ?

62 issues were categorized into the 5 phases

Discussion and Conclusion

In facilities where sufficient training on data integrity is not provided to staff, there is a concern that a lack of understanding will cause data integrity issues. Also, many facilities use legacy systems (insufficient functionality) and effective controls are required to ensure data integrity in such systems. Therefore, we adopted the methods described herein to consider appropriate management of the GLP computerized system focused on data integrity in Japan.

Purpose

To identify the focus point to improve data integrity based on categorizing according to the data lifecycle.

PhaseMain finding

*One issue may be classified into multiple phases

Inadequate control of computer clock or audit trail

Sharing a username and password

Storing on separate storage from the reported data

Multiple integrations or data deletion without just ification System administrator rights are assigned to staff with a direct interest in the data

Only the passing result was reported in the officia l record.

The extracted findings from the FDA warning letters were categorized into the 5 phases of data lifecycle. About 85% of data integrity issues extracted from FDA warning letters were categorized in the early phases of data lifecycle (generation and processing). Data integrity issues are likely to occur in the early phases of data lifecycle and may be the inspector's focus point. As a result, it is considered that the priority for GLP facilities to improve its response to data integrity should be focusing on the generation and processing phases of the data lifecycle. We plan to conduct activities to propose to Japan GLP facilities, measures for data integrity focusing on the generation and processing phases of the data lifecycle and to establish procedures for that purpose.

Certificates of Analysis can be manipulated or deleted

Unable to retrieve the data

Focus point of the data lifecycle to improve data integrity at the GLP facilityfrom this approach

(There were no applicable issues in this phase.)

Regulatory inspection

Increasing compliance for global medical coverage for clinical trials

Hugh Devine1, Stephen Ferrell1

1Promedim UK

Objective

Insu cient medical oversight is a common finding in regulatory inspections. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) requires that medical oversight be ‘readily’ available.1

Previous best practice relies on a paper rota or pager system or handing around a single mobile phone with regulators checking paper testing documentation at audits.

We set out to enable sponsors and contract research organisations (CRO) to demonstrate an audit trail and to learn how compliance and e ciency can be improved in provision of 24/7 medical monitoring, whilst having a user-friendly solution for on-call study physicians.

Method

We looked at the problem and designed a solution with technology, compliance and usability for all parties in mind i.e. provision of high utility for sponsors and physicians alike whilst providing a continuous audit trail.

As a 21CFR part 112 and Annex 11 compliant3 cloud-based solution the technology allows management of study physicians who can log in and out depending on availability and can access the latest study documentation remotely through an iOS or android app.

Results

This cloud-based technology and associated medical services have now been utilised in global studies with over 1000 patients worldwide.

Case study 1

An innovative biotech company, developing new medicines in the critical care setting, required immediate medical helpline support for investigators in a complex study. The support was focused on enrolling patients and helping to correctly titrate the study drug. This 24/7 solution integrated the extensive company team with additional external medical resources to support sites around the clock on 3 continents. This enabled potential patients to be assessed by the sponsor in real-time and drug titration to be managed in collaboration with the sponsor. The technology allowed coordination of the medical support team from the sponsor together with a CRO to ensure no calls were missed despite very high call volumes.

Case study 2

Cloud-based app

Site

Conclusion

A technology enhanced medical monitoring solution can supplement in-house medical resource for global studies allowing;

• Physicians to have easy to access study documentation through an app.

• Sponsors to have visibility of the medical resource whilst ensuring a continuous audit trail to assure GCP 24/7 medical coverage.

References

A small biotech company with limited medical resource was starting a global study in a gastro-intestinal indication. They required their Chief Medical O cer to be supported by externally contracted medics to ensure global, round-the-clock provision with maximal cost e ectiveness. The continuous medical coverage was demonstrated through instant reports accessed through the app.

1. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM073122.pdf (Accessed March 2017)

2. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11 (Accessed March 2017)

3. http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-4/ annex11_01-2011_en.pdfcfm?CFRPart=11 (Accessed March 2017)ww

Multi-point access to a cloud-based app allows physicians to control availability and access secure study protocols, and sponsors to access a continuous audit trail.

A trial patient presents to a medical site, an emergency call is made to the provider control centre

The global control centre accesses the cloud-based app to view available physicians

Control centre contacts study physician, who is showing as available via the app

Study physician takes call direct from site and accesses relevant study documents via the secure database

query answered and contact report generated and sent to sponsor

Sponsor can constantly monitor physician availability, ensuring compliance and transparency throughout the study

Typical emergency response workflow

CHALLENGES FOR GLP QA IN AUDITING AND MONITORING OF IN VITRO STUDIES

Dr. Labhu U. Sanghani, and Smit J. Patel, smit.patel@jrfonline.com

sanghanilu@jrfonline.com

Jai Research Foundation, India, www.jrfglobal.com

INTRODUCTION

In vitro studies are conducted to obtain data on the safety of various chemicals with respect to human health and the environment, mainly in the genetic toxicity testing. The hazard assessment based on data derived from in vitro studies, to a large extent, is gaining prominence as alternative or supplement to in vivo safety testing.

As GLP Principles require QA to inspect especially the critical phases of a study, it is important that QA should be well aware of what constitutes critical phases (and critical aspects) of in vitro. The Standard Operating Procedures (SOPs) for QA inspections should be developed in co-operation with Study Directors, Principal Investigators, and study personnel pertaining to the relevant functions. For a better understanding and effective auditing of in vitro studies, QA personnel should be trained and educated on specific aspects of studies which will help them to recognize potential challenges in specific areas of in vitro testing.

QA AUDITS

Audits of raw data, statestical analysis & report

Review of acceptance criteria, interpritation of results

Requirements of Regulatory Guidelines

QA AUDITORS TRAINING FOR IN-VITRO STUDIES

Development of audit checklist, audits of critical phase (s)

Study specific SOPs and safety in in-vitro lab

Study plan verification and identification of critical phase(s)

Equipment/instruments PQ

IN-VITRO FACILITY AUDIT v and acceptance criteria

v SOPs/instruction

Manual/guidance documents

v Staff training & competency

v Test system (maintenance, identification and characterization)

v Cryopreservation and reconstitution of cells/tissues

v Sterility of materials and supplies

v Cleaning and decontamination of facilities/equipment

v Adequate separation of activities

v Environmental monitoring (pathogens in the air and on surfaces)

IN-VITRO STUDIES STUDY PLAN AUDIT

v Regulatory/guidelines requirements

v Study acceptance criteria

v Criteria for assay repetition

v Details of test system & test item

v Positive/negative control/vehicle control

v Experimental procedure

v Special requirement to be considered (sponsor/study plan)

AUDIT OF CRITICAL PHASE(S) OF STUDY

v phases

Identification of critical

v Availability and adherence of SOPs

v Test system record (chronology of custody, passage number of cell lines, culture conditions and sub cultivation intervals, freezing/thawing conditions, etc.)

v Procedures for freezing and thawing of cells and tissues

v Maintenance of aseptic condition during experimental work

v Procedure to check the responsiveness of test system and its records

v Raw data documentation

AUDIT OF RAW DATA , CALCULATION AND STATISTICAL ANALYSIS

v are attributable, legible, contemporaneous, original, accurate & complete

Establish that the raw data

v Verification of doses, calculation and statistics

v Record of test system used

v Records of test item, positive control, negative control used

v Records of disposal of culture, reagents, formulations

v Repeatability of assay

v Criteria to assess the viability, suitability and responsiveness of test system and records of such evaluation

v Documentation of problems with test system, if any and its impacts

AUDIT OF REPORT

COMPLIANCE & CONCLUSION

Accuracy in transfer of

v data identification of test system, test item, positive and negative controls

v Characterisation status of test system and test items used

v Study plan amendment(s) and deviation(s), if any

v Acceptance criteria in line with study plan, SOPs and test guidelines

v Content of repot in line with respective test guidelines and study plan requirements

Qualified, trained &

v competent QA auditor

v Well developed QA SOPs

v Indepth QA check list for critical phase(s) audit

v Data and report review in line with acceptance criteria

FDA 483 Responses: Do You Have What it Takes?

Many Warning Letters are issued by US FDA because a company’s response letter did not address the finding and/or include evidence of the corrective and preventative actions taken for the FDA to evaluate to determine if the situation was appropriately addressed.

When responding to a 483, your objectives should focus on the following three things

Good Response

We have opened CAPA 123 to investigate and fully understand the root cause of this issue and to develop comprehensive corrective actions in order to prevent recurrence. As immediate corrections to this observation, we have taken the following actions:

• We have revised our XYZ procedure to address the specific example in the 483 as well as the other areas where this issue may arise (see Attachment 1 for revised procedure).

• We have retrained all applicable employees on this procedure to ensure it is implemented appropriately (see Attachment 2 for evidence of re-training to the revised procedure).

• We have quarantined the product referenced in the example and will disposition it in accordance with our procedures by 31-Oct 2018.

• We have arranged for a retrospective review of other products that may have been impacted by this same issue to be performed and will ensure they are also appropriately dispositioned. This retrospective review will be completed by 30-Npv 2018 and the results will be provided in our monthly update to this response.

The CAPA 123 root cause investigation is currently underway; a copy of the CAPA investigation and corrective action plan will be provided in our next monthly response.

 Objective evidence provided for completed actions

 Immediate corrections made, timelines provided for longer term corrective actions

Bad Response

 Addressed example in 483, but also looked to see what other product could be impacted

 Commits to providing updates on a periodic basis

 Commits to performing a retrospective review for other potentially impacted product

We have reviewed our process as described in the 483 and we respectfully disagree with this finding as procedure XYZ has been in place for many years with no issue and we believe it to be compliant as is. However, we have revised the procedure to address the specific example listed in the 483 and we have retrained all applicable employees on this procedure to ensure it is implemented appropriately. We have also quarantined the product referenced in the example and will disposition it in accordance with our procedures.

REGULATION DESCRIPTION

TIP APPROACH

100% ideal; should be risk based. May apply σ based upon risk and 95-99% CI

QMS Stats

100% ideal; should be risk based. May apply σ based upon risk and 95-99% CI

ANSI Z1.4 | ISO 2859 AQL sampling

I’m 95% confident you…

ANSI Z1.9 | ISO 3951

AQL sampling

If device cannot be fully tested, the manufacturing process Gage R&R (ANOVA, random efects model)

Statistical tools not needed if no variation, if variation tolerance analysis or worst case testing

Can be achieved through simulated (bench testing) or real use testing (IND)

Should link to complaints, nonconformances

Can be adapted from incoming inspection of variables/attributes

Should link to nonconforming material and complaints

National Institute of Standards and Technology (NIST) Handbook on sample sizes

National Institute of Standards and Technology (NIST) Handbook on sample sizes

Trend for root cause individual / departmental responsibility or process

AQL sampling plans #nonconforming vs. #conforming (trend for degree and frequency)

# scrap (reworked / returned) vs #conforming, # use as is vs. # scrapped and variations of each

Collect data, code per FDA problem codes for trend analysis

Analyze service records as relates to CAPA, complaints and MDR per appropriate CI (95% - 99%)