Harmonizing Manufacturing across Multiple Sites and Regions

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


There must be clear rules for:

Proposing,

Classifying,

Reviewing,

Approving,

Implementing,

Closing,

Follow-up, and

Reporting of Changes


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.


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


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


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


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


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


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


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.


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


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


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


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


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??

Documents

Harmonizing Manufacturing across Multiple Sites and Regions