Validation Change Control Maintaining The Validate State-09-2015

Process Validation and Change Control:
The Validation Life Cycle

and
Maintaining The Qualified State
Gamal Amer, Ph. D.
Principal
Premier Compliance Services, Inc.
All rights reserved. Do not copy without permission.
VALIDATION
Establishing documented evidence which provides
a high degree of assurance that a specific process
will consistently produce product meeting its
predetermined specifications and quality attributes
(old definition Focus on documentation Event approach)
Process Validation: The collection and evaluation

of data, from the process design stage throughout
commercial production, which establishes
scientific evidence that a process is capable of
consistently delivering quality products.
(FDA Guidance to Industry Jan 24, 2011-Focus on understanding and data collection as
well as analysis Life cycle approach)
FDA Guidance:
Process Validation: General
Principles and Practices
Replaces the guidance issued in 1987
Quality of the product cannot be assured by
simply inspecting or testing in-process and
finished products. It must be built into the
product-process a-priori.
Focusing exclusively on the qualification effort
without understanding the process and ensuring
the process is maintained in a state of control may
not lead to adequate assurance of quality.
FDA Guidance To Industry

January 2011
Three Stages of Process Validation
Process Design Stage (process is defined based
on development and scale-up)
Process Performance Qualification (PPQ) Stage
(Design is confirmed as being capable of
reproducible production)
Continued Verification and improvement
(Continuously gaining assurance the process
remains in a validated state of control)
Regulatory Imperatives
The process and equipment must be
carefully designed and selected
You must have procedures to prevent
contamination
You must validate the process
A qualification protocol is required
Regulatory Imperatives (Cont.)

You must establish criteria for initiating
and performing out-of specification
investigations
Revalidation/re-qualification when there
are changes
Procedures for reprocessing
Change control and maintaining the
validated state
Conducting Qualification
Define critical process and utility systems (based on Risk analysis)
Ascertain correct equipment was obtained and installed correctly
Establish confidence that equipment is capable of consistently achieving
product specifications by performing adequately within the operating
limits of the process
Establish evidence that the process is both effective and reproducible
through rigorous testing and documentation
Test parts of the process that may affect product quality or may cause
variability
Summarize results
Ensure that process remains in a qualified state through verification,
maintenance, and a change control system
Qualification Approach
Stage 1 Information
Stage 2 Qualification
Design
Review
QMP/VMP
Manuals, P& ID,

SOPs
Protocol
Preparation
Protocol
Execution
Summary
Report
Preparation
Engineering Drawings
Specifications
IOQ (Verification), PQ
Weld Logs, Certifications,

Analytical and Integrity Tests
Executed
protocols
IOQ (Verification) &

PQ Reports
Qualification
Record
Product Data
Stage 3 Monitor & Improve
Validated/Qualified State
A system is in a validated/Qualified state if:
Properly qualified/validated originally.

Same equipment used.
Same procedures followed
Equipment maintained in original state.
Instruments and controls are calibrated.
Process inputs (raw material, etc.) the same.
No significant changes were made.
Need For Change
Process Improvement
Improved technology and science
Improved equipment
Equipment maintenance issues
Correct/Prevent Deviations & Nonconformances
Improved raw materials and intermediates
10
Where Do Changes Happen

Changes Happen in:
Facility, Utilities and Process
Configuration/Equipment
Material/Services and Suppliers
Procedures and Training
Could be anywhere or to any component of the
operation, Etc.
11
Types of Changes Encountered

Changes Can Be:
Planned
Emergency
Major
Minor
12
Regulatory Requirements
You must have a procedure for change
control
You must invoke the procedure each time a
change is contemplated
You must follow the procedure
You must use scientific reasoning and risk
analysis for changes and the actions to be
taken to address them
13
The Qualification Life Cycle

-
Qualified System
Change Control
System
Implement Change
Modified System
14
What is a Change Control

System?
It is a formal system which is designed not to
prevent change, but rather document and control it.
Its main purpose is to ensure that a
system/process/operation is always in a GMP
compliant and validated state, regardless of changes
made to it. It is usually implemented using a
procedure.
15
Importance of Change Control
Not to prevent change.

To control and document change.
Required by the regulations.
Identify GMP and validation implications.
Ascertain process remains in a state of
control.
Must be implemented using a procedure.
16
Controlling Change
How to maintain a validated/qualified state after
change (implementing change control):
Evaluate for impact on GMP compliance.
Evaluate for impact on validation.
Knowledgeable assessment of requirements to maintain
compliance and validation (commensurate with risk
level).
Develop plan to implement requirements.
Implement requirements and maintain a compliant and
validated system.
Monitor to ensure change gave intended result and did
not introduce unexpected issues
17
The ASTM E2500 Process Verification

Good Engineering Practices
Company
Quality Req.
Acceptance &
Release
Verification
Regulatory
Requirements
Specification
& Design
Process
Knowledge
Requirements
Product
Knowledge
Operation &
Continuous
Improvement
Risk Management
Design Review
Change Management
18
Process Validation: General

Principles and Practices
Guidance to industry issued by the FDA in
January 2011.
Outlines the life cycle approach to validation.
Inline with the principles advanced in ICH Q8,
ICH Q9, ICH Q10 and in ASTM E2500.
Defines PROCESS VALIDATION as the
collection and evaluation of data, from the process
design stage throughout production, which
establishes scientific evidence that a process is
capable of consistently delivering quality
products.
19
FDA Guidance to Industry

January 2011
Three Stages of Process Validation
Process Design Stage (process is defined based on
development and scale-up)
Process Qualification Stage (Design is confirmed
as being capable of reproducible production)
Continued Verification and improvement
(Continuously gaining assurance the process
remains in a state of control)
20
The Life Cycle Approach to Process

Validation
Planning &
Design (ICH Q8)
PAT
ICH Q9
Continuous
Verification &
Improvement
Implementation
& Qualification
ICH Q9, CAPA, PAT &
Change Control
ICH Q10
The Quality System
21
Stage 1: Process Design
Understanding the science

Understanding the risk
Building Quality into the process
Establishing Control Strategy
22
Stage 2: Implementation and Process

Qualification
Qualification of utilities and equipment
Process Performance Qualification (PPQ)
protocol
Protocol execution and report
23
Stage 3: Continued Process

Verification
(ensure process remains in a validated state of control)
Monitoring appropriate parameters to ensure

process in a state of control.
Use CAPA, PAT and change control as well as
data collected in monitoring to maintain the
validated state and continually improve the
process.
Proper maintenance of the facility, utilities, and
process equipment
24
Stage 3 of Guidance Stipulates

Process must remain in a state of control (or in the
Qualified/validated State)
This is accomplished by verifying that it is, through a system
to detect unplanned departures (monitoring).
If trends are observed, then you must take action to correct.
Every time you take action to correct (e.g. PAT, CAPA) you
maintain the validated state and you are improving the
operation.
Use Statistics to identify trends and review such using SME.
Quality unit to review the information.
Use data collected to identify ways to improve process.
25
Stage 3 of Guidance Stipulates

Quality unit to meet with manufacturing periodically
to evaluate data.
Monitor beyond process parameter (e.g complaints,
OOS, deviations, etc.).
Use data collected to identify ways to improve
process.
Maintenance of the facility, utility and equipment is
of critical importance for maintaining the validated
state.
26
Monitoring
Need to know the right Critical Quality
Attributes (CQAs) of product
Need to know the Critical Processing
Parameters (CPPs) which affect CQAs
Monitor the CPPs and CQAs
Insure you take actions when you see a
deviation or observe a trend.
27
Data from variable being monitored should conform to a

random pattern around the target value, and should be within the
action limits to indicate that the system/process/condition is
under control.
Failure
Action Level
Function
*
Being
Monitored
* * *
*
*
*
Alert Level
*
Target Value
*
*
*
*
*
Alert Level
Action Level
Time
28
Monitoring ensures trends towards failure are identified

in time
Trend begins
Action Level
Function
*
Being
Monitored
* * *
*
*
*
*
*
Alert Level
*
* *
*
*
*
*
*
*
Alert Level
Action Level
29
Correct the negative trend by manipulating the proper

CPP
Begin Manipulating
CPP
Action Level
Function
Being
Monitored
* * *
*
*
*
*
*
*
* *
* * **
Alert Level
*
*
*
*
* *
***
* **
Alert Level
Action Level
30
PAT CAN DO IT
Product Quality= f (input property, intermediate property, processing conditions, quantity
and quality of processing input, etc.)
Result of analysis
or reading
Control signal
Process Analyzer
Computer Model
Manipulate process into
desired state
Critical
Sample/Reading
Result of analysis
or reading
Input (material, heat,

agitation, etc.)
Input
Processing step
Processing step
Processing step
Process analyzer
Product quality reading
Final step
Product of acceptable
quality
31
Example Monitoring data

Negative event
CAPA
32
CAPA
CAPA= Corrective Action Preventive
Action
A process which uses many of the existing
quality system components to ensure
process remains in a state of control.
Action is taken to correct a deviation or non
conformance (quality event), based on level
of risk.
33
CAPA
As issues are corrected or prevented from
happening again you return the process into a
state of control and improve the process
In cases of intolerable risk action is taken to
prevent the reoccurrence of the quality event.
Many of these actions require changes, which
should be implemented after invoking the
change control system to insure system
remains in a validated state of control.
34
CAPA
Use risk assessment and your knowledge of the
process to determine the degree of corrective
and preventive action to be taken.
The level of effort, its formality and the level
of documentation should be commensurate
with the level of risk and be based on science.
Many of the actions taken correct or prevent a
processing problem require changes to the
operation-Use Change Control to manage
them.
35
Change Control System

Change
Identified
GMP
Issues?
YES
YES
Emergency?
NO
NO
Implement as
Maintenance
Obtain
Approvals
Implement
Compliance
Requirements
Document
Change
Initiate
Change
Control
Implement
Change
36
Change Control Procedure

Initiate change (simple form with
justification, technical information and drawings).
Review and approval (quality unit, user

group, engineering, validation professional,
regulatory affairs, safety and environmental).
Identify GMP implications

37
Change Control Procedure

(cont.)
Define what is needed to make the
change permanent.
Identify revalidation requirements, if

any, and implement.
Change permanent.
38
Initiating Change
A short and concise form
Should have space for comments and
approvals
Should have all information needed to
render judgment
Should have space to define requirements
for implementing change
39
Change Request Form

Page 1
Originators Information
Date
Short Title
Reason for Requesting Change
Description of Requested Change
Known or Suspected GMP Implications
Add support documentation and/or drawings
40
Change Request Form

Page 2
Review, Requirements, and Approval
Technical review and comments by engineering,
technical services, operation, regulatory, safety,
environmental, and QA-recommend approval/disapproval
Review and approval by Change Control Committee
(needed if disagreements occur above)
Define requirements to be satisfied for change
implementation; validation, document or drawing
modification, procedure modification, etc.
41
Change Control procedure

Change required
Generate
Change Request
GMP
Implications?
No
Implement Change
Maintenance
End
Yes
Requalification?
Revalidation?
No
Implement Change
& Insure GMP
Requirements Done
Issue GMP
Report
Obtain
Approvals
Change is
Permanent
Obtain Approval
Yes
Requalify
Revalidate &
Issue Reports
Change is
Permanent
End
42
Emergency Changes
Implement Change
Fill out paper work and circulate for comments
and approval (within 48 hours)
Implement GMP required actions immediately
Release is contingent on additional testing and
implementation of GMP requirements.
Keep a close eye on the lots released once
distributed and facilitate fast customer feedback.
43
Post Change Monitoring and its

Importance
Once change is implemented and becomes
permanent you must continue to monitor the
changed part to ensure
a) change achieved its objective and
b) that no unintended issues arise.
Do a lot of monitoring in the beginning to

establish background information, then scale back
to a statistically appropriate level.
Look at variation for the batch and also for batch
to batch variations.
Always be quantitative and use statistical methods
when ever possible.
44
Data from post change monitoring should conform to a random

pattern around the target value, and should be within the action
limits to indicate that the system/process/condition is under
control.
Failure
Action Level
Function
*
Being
Monitored
* * *
*
*
*
Alert Level
*
*
*
*
*
Alert Level
Action Level
Time
45
Make sure data does not show trending towards failure

Post Change?
Action Level
Function
*
Being
Monitored
* * *
*
*
*
*
*
Alert Level
*
* *
*
*
*
*
*
*
Alert Level
Action Level
46
Example Monitoring data

Address as Deviation -CAPA
Thanks Brian Nunnally
47
Trends and Not Single Event

CAPA
Thanks Brian Nunnally
48
ASTM E2500 View of Change Control
Copied with permission D. Petko, Presentation to ISPE

Delaware Valley Chapter, April 2008
49
Maintenance the Third Leg

Maintenance is defined as all actions which
have the objective of retaining or restoring
an item in or to a state in which it can
perform its required function
50

Ensure equipment remain viable throughout
the life of the product (continue to use the
same equipment)
Maintaining the facility and equipment for
both utility and process in their original
condition to ensure they still operate as
originally intended
Proper maintenance ensures equipment does
not contaminate, or introduce objectionables
into, the product.
51

Types of maintenance:
Preventive Scheduled - Planned
Corrective Unscheduled - Unplanned
Preventive maintenance is the routine recurring

work required to keep a facility, equipment,
utilities and other production related systems in
such condition that it may be continuously
used, at its original or designed capacity and
efficiency for its intended purpose
52

Preventive maintenance is implemented using
procedures and a schedule with proper ticklers.
Normally it is based on equipment
Manufacturers recommendations
Preventive maintenance is designed to avoid
failure of equipment unexpectedly
Electronic systems used to support preventive
maintenance programs should be part 11
compliant and validated.
53

Corrective maintenance requires experienced
personnel familiar with the equipment
Corrective maintenance results in down time
and possibly product failure
Maintaining a stock of common
replacement/spare parts can help with quick
resolution of more common and known
maintenance problems and thus maintaining
the operation in a state of control
54

Replacing equipment, as a maintenance
approach, should implemented through
change control if such replacement has a
GMP or a Validation impact.
Maintenance is a regulatory required activity to
ensure the process remains viable and in a state
of control.
55
In Summary
You must always maintain your processes in a GMP compliant
and validated state
This can be achieved by monitoring the process to identify
trends and correcting them, by having a change control system
in place, and by properly maintaining your equipment and
facility.
Monitoring, change control, and proper maintenance of your
facility & equipment are regulatory requirements.
Change control as well as maintenance are implemented using
procedures.
You must invoke the change control system every time you
contemplate a change to an approved and validated process.
The change control system should not be designed to prevent
making changes to your operation, but rather to control and
document such changes.
56

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Process Validation and Change Control:

The Validation Life Cycle

Gamal Amer, Ph. D.

Process Validation: The collection and evaluation

FDA Guidance To Industry

Regulatory Imperatives (Cont.)

All rights reserved. Do not copy without permission.

Manuals, P& ID,

Weld Logs, Certifications,

IOQ (Verification) &

All rights reserved. Do not copy without permission.

Properly qualified/validated originally.

All rights reserved. Do not copy without permission.

Need For Change

Where Do Changes Happen

All rights reserved. Do not copy without permission.

Types of Changes Encountered

All rights reserved. Do not copy without permission.

The Qualification Life Cycle

All rights reserved. Do not copy without permission.

What is a Change Control

All rights reserved. Do not copy without permission.

Importance of Change Control

Not to prevent change.

The ASTM E2500 Process Verification

Process Validation: General

FDA Guidance to Industry

The Life Cycle Approach to Process

All rights reserved. Do not copy without permission.

Stage 1: Process Design

Understanding the science

All rights reserved. Do not copy without permission.

Stage 2: Implementation and Process

All rights reserved. Do not copy without permission.

Stage 3: Continued Process

Monitoring appropriate parameters to ensure

Stage 3 of Guidance Stipulates

Stage 3 of Guidance Stipulates

Data from variable being monitored should conform to a

Monitoring ensures trends towards failure are identified

All rights reserved. Do not copy without permission.

Correct the negative trend by manipulating the proper

All rights reserved. Do not copy without permission.

Input (material, heat,

Example Monitoring data

All rights reserved. Do not copy without permission.

Change Control System

All rights reserved. Do not copy without permission.

Change Control Procedure

Review and approval (quality unit, user

Identify GMP implications

Change Control Procedure

Identify revalidation requirements, if

Change Request Form

Change Request Form

Change Control procedure

All rights reserved. Do not copy without permission.

Post Change Monitoring and its

Do a lot of monitoring in the beginning to

Data from post change monitoring should conform to a random

Make sure data does not show trending towards failure

All rights reserved. Do not copy without permission.