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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)
5/15/2015 2
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
5/15/2015 3
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.
5/15/2015 4
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
5/15/2015 5
Regulation References to Know
5/15/2015 6
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
5/15/2015 7
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
5/15/2015 8
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
5/15/2015 9
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
5/15/2015 10
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
5/15/2015 11
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
5/15/2015 12
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
5/15/2015 13
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.
5/15/2015 14
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
5/15/2015 15
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)
5/15/2015 16
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
5/15/2015 17
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
5/15/2015 18
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?
5/15/2015 19
Important to Understand
Roles and Responsibilities
GMPQuality
Business Areas
Operations
Technical
Others
GLP
Quality
Study Director
Archivist
Sciences
Laboratories
Others
5/15/2015 20
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
5/15/2015 21
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
5/15/2015 22
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
5/15/2015 23
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
5/15/2015 24
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