Dr. Santosh Kumar Narla, Senior Manager,

Formulation Regulatory Affairs, Laurus Labs Limited, Hyderabad.

santoshmph@yahoo.com

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Key points of discussion: Data Integrity: Beware or Be aware?, Decades of regulatory history, International regulatory perspective and collaboration, Common misconceptions, Enforcement actions, Inspections and ANDA approvals, Risk reducing strategies, Regulatory challenges.

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Data Integrity: Beware or Be aware It is not new … don’t be panic ….. BUT .. be aware of the requirements…

Treat EVERYDAY as a AUDITABLE DAY…

Know the BASIC regulatory requirements…

Refresh your company policies / systems (SOPs/handling procedures)..

Always consult your superiors / guide your sub-ordinates…

Learn from the Audit findings…

Stay on regulatory updates and warning letters…

Watch with your EARS too ….

ALWAYS follow your company policies……

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Decades of Regulatory History……… It is not a new requirement… and not only related to some regulated countries…

Above 60% of Warning Letters in 2015 and 2016 involved data integrity lapses Problem is continuing to till date………….

USFDA: 21 CFR Parts 11, 211, 803: Electronic Records, Signatures - 1997, 2003. Data integrity key concepts are inherited from 21 CFR 11, 210, 211 and 212. “Data Integrity and Compliance with cGMP”, draft guidance for industry (April 2016).

EMA: EudraLex Vol 4 Chapter 4 Documetation & Annex 11: Computerized systems: 2011. GMP guidance (Q&A) to ensure the integrity of data: Aug 2016.

MHRA: MHRA GxP Data Integrity Definitions and Guidance for Industry 2015/2016.

WHO: WHO Technical Report Series 996 Annex 5, Guidance on good data and record management practices: May 2016.

Health Canada: Letter to Stakeholders -Responsibilities and Obligations with Respect to the cGMP – Feb 2015.

ICH: Q7: Computerized Systems (5.4) & Q9: Quality Risk Management: 2005.

PIC/S: Good Practices for Data Management and Integrity In Regulated GMP/GDP Environments, Aug 2016.

India: CDSCO Offers Risk-Based Checklist for Indian Pharma Manufacturing Inspections

The above list is not limited ……….. There are MORE country requirements and guidelines.

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In 2015: “a new look at an old topic”

In 2003, TGA suspended 219 products of Pan Pharma, Australia and instructed to recall immediately…..due to DI WORLD BIGGEST PRODUCT RECALL – 219 products recalled, 1650 export products cancelled……

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Data integrity issues and importance is increasing….

Warning Letters Citing Data Integrity Deficiencies FY2013 FY2014 FY2015 FY2016

Total warning letters 38 22 19 46

US sites with DI deficiencies

0% 0% 33% 73% (0 of 13) (0 of 4) (1 of 3) (8 of 11)

Outside US sites with DI deficiencies

40% 67% 81% 81% (10 of 25) (12 of 18) (13 of 16) (29 of 35)

Total number of warning letters citing DI

deficiencies

26% 55% 74% 79%

(10 of 48) (12 of 22) (14 of 19) (37 of 46)

Note: Compounding warning letters excluded.

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2016 — A year of data integrity issues and pharma non-compliances

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International Regulatory Perspective and Collaboration

International convergence in data integrity guidance

Cooperation between regulators Exchange of information Joint inspections Coordinated market actions

Inspectorates better equipped to Identify data integrity failures Manage post-inspection actions and remediation plans

Widespread inspectorate training in DI principles and techniques

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Common Misconceptions

Why we need to worry?

It is important ONLY in Pharma? 2015: Volkswagen Emission scandal for diesel cars in US

The result: VW’s CEO lost his job; billions were wiped from the company’s shares; and the German economy faced a bigger threat than the Greek crisis.

My department is perfect… 1000 drugs reviewed/ 700 rejected: May 2014. Over 700 medicines were recommended for suspension by the EMA based on DI concerns, over clinical studies conducted at GVK Biosciences.

Volkswagen GVK Biosciences Timeline September 18, 2015 May 19, 2014 The issue Installation of a ‘defeat device’ software on cars

to fool emission tests Falsification of electrocardiograms detected in each and every one of the 9 trials inspected

The regulator US Environmental Protection Agency (EPA) French agency on medicinal products (ANSM) The impact About 11 million cars About 700 different medicines suspended The financial impact

EPA penalties could reach US $ 18 billion India’s export loss estimated US $ 1.2 billion

Severity of problem

Car engines emitted nitrogen oxide pollutants up to 40 times above what is allowed in the US

Falsification of ECGs was performed by at least 10 individuals and took place between 2008 and 2013 11

Enforcement actions

Enforcement tool Action 2016

statistics

Regulatory Meetings

FDA may use the regulatory meeting after a follow-up re-inspection 27

Injunctions FDA may seek injunctions against individuals / corporations to prevent them from violating the Act

Consent Decrees

Agreement between FDA and drug maker, proving via third party. 27

Import Alerts Prevent violated products from being distributed in the US. 47 Seizures Removal of specific violated goods from commerce.

Warning Letters

Noted violations, requesting a written response. 54

Untitled Letters

Noted violations (not in the threshold of warning letter), requesting a written response.

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FDA Form 483

Official Action Indicated (OAI)

Voluntary Action Indicated (VAI)

No Action Indicated (NAI)

Office of Compliance Office of Manufacturing Quality (OMQ)

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Inspections and ANDA Approvals

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Where and When, Data Integrity is applicable…….

Applies to Entire Product Lifecycle

Risk Reducing Strategies

Internally identified DI issue: Disclose to regulators, documented evidence of remediation or commit to voluntary

remediation.

Discrepancy found in the batch record / QC document: Report it with a valid risk assessment and detailed justification – Follow SOPs.

Identify the resources where risk is HIGH : Risk based approaches /Internal audits /double review need to be utilized.

Follow ALCOA+ (Used by FDA, MHRA and WHO): A – Attributable: Records and data linked to the individual or system performing the action L – Legible: Records and data, readable and traceable across the lifecycle C – Contemporaneous: Records and data reported at the time it has occurred O– Original: Records and data are the primary source (or true copy) A – Accurate: Records and data are correct and free from errors/manipulations + - WHO added: complete, consistent, enduring and available .

Stay UPDATED: Always stay updated with recent audit news, warning letters ….. Stay tuned for guidelines and regulation updates ….. Fine tune your SOPs / policies based on your Internal Audit Findings….

Plan Data Integrity Specific Internal Audits… Beware / Be Ready for Whistle-Blowers ……….

Whistle Blowers: 2016: Ranbaxy: Dinesh Thakur 2014: GVK: Narayan Konduru Reddy 2010: GSK: Cheryl Eckard

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Data Integrity

R&D QA

Soft wares, Systems and Audits

Quality culture and Training

Policies and User controls

Management and department leads

Individuals

Operations QC RA

Pillars of Data Integrity

All other parties linked with development, manufacturing, distribution and selling are also responsible.

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Regulatory Challenges

In 2016, 40% ANDAs approval is delayed due to manufacturing issues (received CRL).

2016: Semler’s data integrity concerns made regulators question the equivalency of over 110 generic drug applications. Concerns were raised by the US FDA, EMA and the WHO.

In 2015, USFDA issued a warning letter to Sipra Labs, a testing laboratory. There are also instances of lapses on data integrity.

Regulatory department will also play an important role:

Data integrity checks before dossier submission.

Internally identified data integrity issues: Understand the out come and analyze the impact on dossiers/Product

Propose required regulatory action (product recall? / Notification to agencies?)

Review of Deviations, OOS and validation summaries..

Supporting during regulatory audits with submitted information…..

FDA's Pre Approval Inspection Program 7346.832:

18 Incorrect Handling of OOS Results found in 10 FDA Warning Letters in 2011

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Cost of Data Integrity Lapses………

FDA-483 Observations Warning letters Import alerts Withheld product approvals Cancellation of government contracts Product recalls Seizure Consent decree of permanent injunction

Civil money penalties Suspension or revocation of licenses Prosecution (temporary or permanent debarment, if found guilty) Damage to company’s reputation Loss of sales Loss of jobs Loss of Share Value Closing or take-over company

Data integrity is about more than compliance with regulations; it’s about protecting life-saving research and products for human use.

Cost of compliance is cheaper than facing non-compliance issues…

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�-� November - Hyderabad

Conference � Workshop ����

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Ensuring Product Quality And Patient Safety

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Ensuring Product Quality And Patient Safety

EXPERT SPEAKERS

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Dr.Ambrish SrivastavaVP Medical Affairs,ClinicalResearch and Regulatory

Alkem Labs Ltd

Suveer ShrivastavaVice president-QualityMylan Laboratories

Yogesh Joshi

Associate VP-QC

Ajanta Pharma

Sophia Lily Head Quality, API and Nutrition

Piramal Enterprises Limited

Chandra Sekhar

VP Quality Reliance life sciences Pvt.Ltd.

Dr. Upendra k Jani

VP- Quality Assurance

Hester Biosciences

Dr Nimita Limaye

CEO Nymro Clinical

Consulting Services

Dr Ravisekhar Kasibhatta

Sr.VP -Clinical Research

Lupin Limited

Arun Mendiratta

Associate VP-QC

Aurobindo pharma

Dr.Prashant Pandya

GM-Program Management

Reliance Life sciences Pvt.Ltd.

Kiran Kumar Merusomayajula

Senior Manager, CQA

Aurobindo Pharma

Dr.Mahesh BhalgatExecutive Director � COO

Sanofi

Dr. Santosh Kumar Narla

Group Head- Europe

Laurus Labs

Dr. Jayam Ravi Global Compliance Head Clinical � Pharmacovigilance

Dr. Reddy�s Laboratories

Sanjit GhoshWorks Manager

Shine Pharmaceuticals

Raghuvirsinh Parmar

Sr Executive, Analytical Quality

Sunpharma

Tapas Joshi

Executive MirobiologyLupin

Arani ChatterjeeSenior Vice President, Clinical Research

Aurobindo Pharma

Dr.Sambi Reddy Kurre

Associate Vice PresidentAurobindo Pharma

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Ensuring Product Quality And Patient Safety

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SESSION �

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SESSION �Data Integrity risk management Data Integrity in Clinical Research

Why Data integrity issues happen�Data integrity risk factorsConsequences of non-complianceApproach to Data Integrity complianceRisk Management strategies

Dr.Prashant PandyaGM-Program Management

Reliance Life sciences Pvt.Ltd.

CRO � Sponsor RelationshipProtocol � EC � Local FDA � Investigator managementSubjects � Volunteers � ICF ProcessGxP ImplementationRegulatory Inspection readiness

Dr Ravisekhar Kasibhatta

Sr.VP -Clinical Research Lupin Limited

Data Integrity and cGMP compliance for successful Inspections

DI audit trends through review of recently issued ���swarning letters on Data IntegrityCase study: How to respond to ���s and Warning letters Satya Chandra Sekhar

VP Quality

Reliance Life sciences Pvt.Ltd.

Data Quality Management in Clinical ResearchEnd to End Process for Managing Quality, Validity and Integrity of DataBasis of GCPData Management PlanData � Safety Monitoring in Clinical TrialsRole of QA � QCBringing it All Together

Dr.Ambrish SrivastavaVP Medical Affairs,ClinicalResearch and Regulatory

Alkem Labs Ltd

SESSION �

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Regulations Impacting Data Integrity:

The Cost of Poor Data Integrity

Dr Nimita Limaye CEO

Nymro Clinical Consulting Services

Industry reaction on DIBeginning of DI issues..Understanding DI…Industry understanding�s at the beginningPreparing from Others Mistakes.Types of reaction based on size … Business volume

Entire industry got together to address DIToday�s Industry stand on DIFormation of Remediation teams..Mock audits and role of Management , Consultants as out come to address DI

Yogesh JoshiAssociate VP-QC

Ajanta Pharma

Creating A Culture of Quality For Data Integrity

Discussing GCP GMP GLPleadership emphasis, message creditability,peer involvement and employee ownership of quality issues.Dr. Upendra k Jani

VP- Quality AssuranceHester Biosciences

Data management perspective & challenges for the Pharmaceutical MSME Sector in India

Sanjit GhoshWorks Manager

Shine Pharmaceuticals

Data integrity - Analytical Laboratory perspective

The increasing focus of FDA on Data integrity. Data integrity and Human factor. Case study and Examples of recent Data integrity highlights.Raghuvirsinh Parmar

Sr Executive, Analytical QualitySunpharma

Overview of DI non conformance from regulators, impact and remediation perspective � or

�Cultivating the culture to avoid DI shortfalls Sophia Lily

Head Quality, API and Nutrition

Piramal Enterprises Limited

Data integrity-Essential Part of Quality:Reduce manual entries possibilitiesContinual state of validationSecurity of electronic dataAdherence of SOP to guidelines�regulationsAdherence of practices to SOPs

Arun Mendiratta Associate VP-QC

Aurobindo Labs

Data Integrity: Regulatory Perspective and ChallengesData Integrity: Beware or Be aware�,Decades of regulatory history,International regulatory perspective and collaboration,Common misconceptions,

Enforcement actions,Inspections and ANDA approvals,Risk reducing strategies,Regulatory challenges. Dr. Santosh Kumar Narla

Group Head- Europe Laurus Labs

MHRA , US FDA requirements for data integrity in clinical studies

Arani ChatterjeeSenior Vice President, Clinical Research

Aurobindo Pharma

Data Integrity on the Manufacturing floor: SAP, MES, DCS, PLC

Dr.Sambi Reddy KurreAssociate Vice PresidentAurobindo Pharma

Mahesh Bhalgat

Executive Director and Chief Operating OfficerShantha Bioethics

Tapas JoshiExecutive Mirobiology

Lupin

Dr. Jayam Ravi

Global Compliance Head Clinical � Pharmacovigilance Dr. Reddy�s Laboratories

Kiran Kumar Merusomayajula

Senior Manager, CQA

Aurobindo Pharma

SESSION ��

Suveer ShrivastavaVice president-Quality

Mylan Laboratories