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Harmonizing Manufacturing across Multiple Sites and Regions
ISCT North America Regional Meeting Philadelphia, Pennsylvania Byron T. McAllister B.T. McALLISTER ASSOCIATES, INC. Tuesday, 10 September 2013
Harmonizing Manufacturing across Multiple Sites and Regions
The Change Control Management Process (A Tutorial):
An Essential Element for Successful Transition to Commercialization (Read: Product Approvals, Prescriptions Equal Positive Cash Flow)
It must include:
1. Prospective written and approved change management plan;
2. Project management deliverables; and
3. Periodic effectiveness checks.
The Change Control Management Process
Why You Need A Comprehensive Change Control Management Process
To ensure that all changes to GMP and GMP-related activities are:
Documented,
Reviewed,
Approved,
Implemented, and
Controlled
The Change Control Management Process
There must be clear rules for:
Proposing,
Classifying,
Reviewing,
Approving,
Implementing,
Closing,
Follow-up, and
Reporting of Changes
The Change Control Management Process
CCMP applies to: The management of changes to a GMP or GMP-related activity
CCMP Does Not apply to: Unexpected / unplanned result or action (deviation) occurring
during a GMP or GMP-related activity, which must be treated through the Deviation Management Process N.B.: Yes, the CCMP process may be invoked as part of the deliverables in terms of Corrective and / or Preventive Action(s) (CAPA) as the result of a material Deviation [legal definition], but this is a topic for another day
Pre-scheduled calibration and preventative maintenance events.
The Change Control Management Process
DEFINITIONS:
A Change: Is any prospective addition, modification or deletion with respect to raw material, components, process, product, method, equipment (including computerized system), specification, responsibility and / or facility used to perform a GMP related activity
The Change Control Management Process
GMP Related Activity
Any activity/system which may potentially impact the equipment or system design and operation, validation status, process performance, safety or product quality attributes
The Change Control Management Process
When Is GMP Compliance Expected / Required? The Process / Product Development Life Cycle
EU versus U.S. FDA
Controversy remains, but
Flexibility in Design Decision-Making Is Paramount
Patient Safety and “First-in-Man” considerations
Validity of Tests
Sterility, Apryrogenicity, Freedom from Other Adventitious Agents
The Change Control Management Process
What Is A “Locked” Process? Processes Related To Patient Safety for Phase 1
Objectively, Processes Related To Manufacturing and Control for Phase 2 and beyond
Certainly, for Phase 3 Pivotal Efficacy Trials
Absolutely, for Product Consistency Batch Production Bio-Batches, Demonstration Batches, Process Validation Batches
Pre-Approval Inspection (PAI) to Demonstrate Full GMP Compliance
The Change Control Management Process
Examples of Different Types of Quality System Changes: Administrative Change: change to a document- format, spelling,
typographical error correction, or clarification which does not include any change to the intent or meaning
Emergency Change: change which must be implemented immediately due to an issue of safety or immediate product loss
Local Change: a change in which the scope is limited to one site/facility only
Permanent Change: change is not temporary in nature.
Major Change: any change that impacts a regulatory filing or commitment (i.e., the “Registered Details”)
Minor Change: any change that does not impact regulatory filings
Multisite Change: a change that impacts more than one site
Temporary Change: any change of a specific duration or number of batches after which the initial conditions will be restored
Multi-Site Change Control Management
Why Is Multi-Site Change Control Management So Complicated?
Changes May Originate From Many Different Sources
A Request for Change may be initiated by:
1. Sponsor 2. Supplier (manufacturer of the raw or starting material)* 3. Clinical site* 4. CMO, CRO or CTL*
* Must be accepted and implemented by the Sponsor in any event
Multi-Site Change Control Management
Drivers of Complexity:
Never Be Single Sourced
“Golden Rule” of Quality Assurance
Catastrophe Backup Planning
Additional Site(s) of Manufacture
Manufacturing Formula Master Control
One Product for Worldwide Market
Raw Materials and Components
Grades and Quality Specifications
Products Requiring Manipulation at Clinical Administration Site
Sponsor Must Supply Everything Needed for Consistency
Multi-Site Change Control Management
Regulatory Categories: Classification of regulatory action required before a
change can be made effective. Type A: Changes can be implemented immediately and need no
notification of the Health Authorities
Type B1: Changes can be implemented immediately, but require subsequent notification of the Health Authorities.
Type B2: Changes can be implemented immediately AFTER notification of the Health Authorities.
Type C: Changes require approval by Health Authorities PRIOR to implementation.
Multi-Site Change Control Management
Process Elements for the CCMP: Request Must Have a Proponent
Drives the entire process
QA is only the information “traffic controller”, i.e., facilitator, communicator
Implementation Planning Deliverables (a comprehensive Project Management list of
all affected processes and products)
Expected Timeline (Often a matter of hurry up and wait!)
Actions to maintain quality and compliance to GMP
Validation considerations
Stability confirmation
Multi-Site Change Control Management
Review of Multi-Site Changes:
Requests Must Be Reviewed by the Respective Heads of QA and RA
Assess the Impact On Each Site
Data Requirements for Eventual Submission
Approve or Deny the Change Request
Multi-Site Change Control Management
Process Elements for the CCMP (Cont): Implementation of the Change
Material Quarantined Until Changes Verified
All Activities Completed
All Deliverables Available and Approved
Changes Made Effective
Date of First Implementation
Batch Number(s) Involved
Multi-Site Change Control Management
Process Elements for the CCMP (Cont): Effectiveness Checks
Audit, Audit, Audit!
Corrective Action Where Necessary
See the CAPA Process
Close Out the Change Request
Archive
Update the “Registered Details” as appropriate
See Ongoing Process / Product Monitoring Management Process
Multi-Site Change Control Management
The Value Proposition: The Obvious:
GMP Compliance, it’s the Law!
ICH Q10 requires it
Departmental System Owner of the GMP System/Activity for technical approval of comprehensive implementation plan, identification of deliverables, revalidation requirements, if applicable, etc.
Local/Site QA for accuracy, adequacy, completeness and compliance to Quality Policies, Standards and SOP’s.
If you are a CMO or CRO or CTL, customer approval of implementation plan, revalidation requirements, etc. (as required)
Safety, Health & Environment (SHE) for compliance to applicable company and regulatory SHE requirements.
The Value Proposition (Con’t):
The Not So Obvious:
Provides for a continuum of process and product
development progress (Development History), and
Provides for a link back to the original R&D Scientist(s)
And Finally...
QUESTIONS??
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