Inspection ReadinessGMP/GLP for Computerized/Automation Systems

5/15/2015

Presenters: Joyce Morrow and Paula EggertGlobal Quality Assurance – Computerized/Automation SystemsMerck Manufacturing Division Public Information

Agenda

Share Overview:

Inspection readiness process for computerized/automation

systems for regulated inspections.

Scope:

Potential to affect product quality/patient safety (GMP) and

preclinical environment (GLP).

Applicable to pharmaceutical and biopharmaceutical manufacturing systems both new and existing computerized/automation systems that include: (GMP)

Facilities/utilities, Materials, Production and Process Monitoring, Packaging and Labeling, and

Laboratories

Applicable to pharmaceutical and biopharmaceutical pre-clinical studies including both new and

existing computerized/automation systems that include: (GLP)

Facilities/Utilities, Incoming Materials, Study Conduct, Analysis, and Reporting, Formulation and Laboratories (GLP)

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Outline

Facilitated discussion GLP/GMP Regulatory Inspections

A readiness approach for computerized/automation systems

Background of GLP/GMP regulatory inspections:

GLP/GMP review for inspection types

Regulatory references - GLP/GMP for computerized/automation systems

What you need to know to prepare for inspections – Inspection readiness

General Overview

Inspection Process Overview

Inspection Types

What is requested during inspections

How it relates to Computer System Validation

Interactive Discussion for audience

Conclusion

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Background

We will review the inspection readiness process for RegulatedInspections overall with a focus on computerized/automationsystems with considerations for the following:

GLP - Pre-clinical GMP - Product manufacturing

Applicable to both new and existing pre-clinical andmanufacturing systems and applies to a system throughout itssystem lifecycle.

So why do we do inspections….catastrophic events for GMPsand mishandling of animals;

For a more detailed history, please visit the FDA centennial website at

http://www.fda.gov/centennial/history/history.html

and

Guidance for Industry Good Laboratory Practices Questions and Answers

1979 and updated 2007 minor editorial comments.

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Discussion

Today allot of the training regarding inspection readiness is how to teach personnel how to respond to an inspector.

While this is an important aspect our focus today will be how do we get this space and what do we need to know before we are in the inspection process and speaking.

We will highlight the general inspection process and focus computerized/automation systems during the inspection process and HOW to Prepare utilizing Public Information

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Regulation References to Know

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Good Laboratory Practices (GLP)

Preclinical

21 CFR Part 11

21 CFR Part 58

OECD

Good Clinical Practices (GCP)

21CFR Part 11

21 CFR Part 50

21 CFR Part 54

21 CFR Part 56

21 CFR Part 312

21 CFR Part 314

ICH E2A and E6

Good Manufacturing Practices (GMP)

21CFR Part 11

21 CFR Part 210

21 CFR Part 211

ICH Q7 – Q10

EU Annex 11

Inspection Readiness Tool-kit

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References Link Guidance for Industry Computerized Systems Used in Clinical InvestigationsMay 2007

http://www.fda.gov/cder/guidance/index.htm

CPG Sec. 425.300 Computerized Drug Processing; Source Code for Process Control Application Programs Issued: 4/16/87

Go to FDA website and search Compliance Policy Guideline

CPG Sec. 425.500 Computerized Drug Processing; Identification of "Persons" on Batch Production and Control RecordsIssued: 11/2/82 and Reissued: 9/4/87

Go to FDA website and search Compliance Policy Guideline

Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP RegulationsSeptember 2006

http://www.fda.gov/cder/guidance/index.htm

FOOD AND DRUG ADMINISTRATION COMPLIANCE PROGRAM GUIDANCE MANUAL PROGRAM CPGM: 7346.832 , New EvaluationCPGM: 7348.808, Good Laboratory Practices (Nonclinical Laboratories) CPGM: 7356.002, Drug Manufacturing Inspections (CDER)CPGM: 7345.848, Inspection of Biological Drug Products (CBER)

http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/default.htm

FDA searchable inspection database http://www.accessdata.fda.gov/scripts/inspsearch/

GUIDE TO INSPECTIONS OF COMPUTERIZED SYSTEMS IN THE FOOD PROCESSING INDUSTRY http://www.fda.gov/cder/guidance/index.htm

Inspection Guides > Computerized Systems in Drug Establishments (2/83) http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074869.htm

GLOSSARY OF COMPUTERIZED SYSTEM AND SOFTWARE DEVELOPMENT TERMINOLOGY Go to FDA website and search Glossary of Computerized System terms

General Principles of Software Validation; Final Guidance for Industry and FDA StaffDocument issued on: January 11, 2002

http://www.fda.gov/cder/guidance/index.htm

Note for Guidance: This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance.

References -

Current Topics of Interest

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United States FDA Homepage – Query Topic of Interesthttp://www.fda.gov/default.htm

Application Data Integrity policy http://www.fda.gov/downloads/ICECI/EnforcementActions/ApplicationIntegrityPolicy/UCM072631.pdf

International Conference Harmonization – Query Topicshttp://www.ich.org/home.html

Pharmaceutical Cooperation Inspection Scheme (PICS) http://www.picscheme.org/publication.php?id=4

Good Automated Manufacturing Practices References – GAMP http://www.ispe.org/cs/gamp_publications_section/gamp_publications_overview

Eudralex – European Requirements & Computerized Systems see Annex 11http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

Inspection Process

Regulated inspections occur annually by Food and

Drug Administration and out Country Agencies

For Example:

Center for Drug Evaluation Review (CDER)

Center for Biologics Evaluation Review (CBER)

Other Centers exist however, will not be our focus

today.

Europe Regulations Apply to Chapters and what

are termed Annex topics, for example Annex 11

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Types of Inspections

Routine Inspections (GLP/GMP)

Every 2-3 years (GLP Study/General Site)

Unannounced inspection

For-Cause Inspections (GLP/GMP)

Unannounced inspection

Pre-approval Inspections (GMP)

Focus on facility ready to be fully operational

Announced inspections

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Before we begin lets review the general

process so we all begin on same page.

Focus of inspections generally include review for

Risk and Science based process for manufacturing and

equipment systems that potentially affect product

quality and patient safety. (GMP) and Preclinical (GLP)

Computerized/automation systems

Applies to Specification, design, and verification

Demonstrates fit for intended use with managed risk

Support continuous process capability improvement

Enable innovation for Process Analytical Technology

Process and operational – maintained state of control

Including configuration management and change control

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Inspection Steps – Arrival

Notice of Inspection

Provided in US it is form 482

Site security is notified of inspection

Company Lead verifies credentials

Site notice is issued regulators on site

Leadership gathered for opening meeting Purpose/scope of audit, product, safety, and study impact

Areas of follow-up from past inspections is communicated

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Inspection Steps – Initiate Investigators provide initial requests

Company provides Overview

Site size, number of employees, operational hours

Site facilities and Utilities

Products

Areas of renovation and safety considerations

Agency submits requests for tour areas Training for safety or area pre-entry criteria completed

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Inspection Process – Tours

Generally these include the following areas for GMP

Facilities/Utilities,

Incoming Materials,

Production and Process Monitoring,

Packaging and Labeling,

Laboratories and

Warehouse/Distribution.

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Inspection Process – Tours

Generally these include the following areas for GLP

Facilities/Utilities,

Incoming Materials,

Formulation,

Study Conduct and Testing,

Study Analysis and Reporting,

GLP Archive and Laboratories

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Inspection Room

Inspection Process - Points to Consider

May be many days with many investigators

Daily goal is to review findings with a focus to resolve any discrepancies and misunderstandings

Company maintains daily update for notes and next day activities

Document listings internally for what is pending and groups to meet and plan for – ready approval to present topics.

Inspection close-out – receive summary and findings (483s)

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Post Inspection Process Observations are received by organization

Internal Teams are formed to review observations and response writing begins

Company responses provided to agency for review, comment, acceptance of response

Company begins commitment process for CAPA, corrective action and preventative actions.

FDA issues also Establishment Inspection Report (EIR) in addition to 483 post inspection. This includes summary details of inspection process

Agency follow-up completed

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So where do computerized/automation systems fit

and why is this important ?

First impression during inspection process.

Tour, walkthroughs and interviews Organization Charts SOP Lists Equipment and System Inventory Training Material Flow diagrams Product Process flow diagrams Product listings (GMP) Master Schedule (GLP) Listing of Study Protocols Change control/Deviations – as requested

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So why is this important to know?

Tours

During this time equipment selected for further review – maintained in state of control

Questions during Tour

During this time general questions are asked to ensure personnel are trained, demonstrate they know overview of area, primary functions, areas of importance.

Relational Review to systems

Questions are asked, what is the system you are using, name? What is company name, common name, type of system, what does it interface to, how do you access, what do you do if something goes wrong or an alarm goes off, please sign-in. How do you back up system? What if your SOP is incorrect, what do you do?

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Important to Understand

Roles and Responsibilities

GMPQuality

Business Areas

Operations

Technical

Others

GLP

Quality

Study Director

Archivist

Sciences

Laboratories

Others

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Computer System Validation

Validation (GLP/GMP)

System development lifecycle methodology may differ by company relating to phases and required documentation. Key point – understand what is requested by investigator

System Architecture Topology

Data Flow Data capture, process, storage and archive

Network Infrastructure

Configuration Management

Change Control Processes

Security – User Access and System Administration

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Specification, Design, and Verification Process copyright by ASTM

Good Engineering Practice

Product knowledge

Process knowledge

Regulations

Company Quality Requirements

Requirements Specification

and

Design Verification

Acceptance and

Release

Operations Continuous

Improvement

Retirement

Risk Management

Design Review

Change Management

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Inspection Readiness -

What to Anticipate for Discussion

Topics to Prepare:

Demonstration –online

Disaster Recovery

Business Continuity

Backup

Electronic Record & Signature

Audit Trail

GLP archive – electronic records

Multiple computer support groups

Trigger: Causing Deliverable Requested

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Audience Participation – Interactive what are other items that

should be included for Inspection Readiness for

Computerized/Automation Systems

GLP

• Audience response – add text

GMP

• Audience response – add text

Other

• Audience response – add text

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