Qualification
Qualification // Validation
Validation
Quality
Quality Risk
Risk Assessment
Assessment in
in the
the
Pharmaceutical
Pharmaceutical Industry
Industry
-- Challenges
Challenges and
and Opportunities
Opportunities --
Andreas Brutsche
Novartis Switzerland
GMP Conference, 11.06.04, Istanbul
GMP-Conference / 10.-11. June 2004 / Istanbul
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Qualification,
Qualification, Validation,
Validation, Calibration
Calibration
Validation/Qualification Iceberg
Visible Process
Unvalidated
Process
GMP-Conference / 10.-11. June 2004 / Istanbul
New System
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‹ Validation / Qualification Approach
User Requirement
Specifications
Performance
Qualification
related to
Functional
Specifications
related to
Design
Specifications
Operational
Qualificaton
Installation
Qualification
System Build
GMP-Conference / 10.-11. June 2004 / Istanbul
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Quality
Quality Risk
Risk Assessment
Assessment in
in the
the
Pharmaceutical
Pharmaceutical Industry
Industry
Risk Assessment has become a key concept in the
decision making process of today’s pharmaceutical
industry. Its impact affects many disciplines including:
‹ Engineering
‹ Manufacturing
‹ Project Management
‹ Quality
‹ Safety
‹ Environmental
GMP-Conference / 10.-11. June 2004 / Istanbul
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People
Quality
QualityRisk
RiskAssessment
Assessment
Associated Systems
Utilities
Analytical Testing
Equipment
Validation
Manufacturing
Process
Validation
Validation of
the analytical
method
Product
Quality
Equipment
Qualification
Qualification /
Validation
Qualification
Part 11
Computer
Water / Air /
Process gases
Training
GMP-Conference / 10.-11. June 2004 / Istanbul
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Risk
Risk Assessment:
Assessment:
Each step in a process is assessed on its
influence on product quality.
• Critical steps have to be validated/qualified
• Uncritical steps Æ no activities are required
GMP-Conference / 10.-11. June 2004 / Istanbul
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Equipment
Equipment Qualification
Qualification
• User Requirement Specifications (URS)
• Design Qualification
• Conceptual Design
• Basic Design
• Detail Design
• Installation Qualification
GMP-Conference / 10.-11. June 2004 / Istanbul
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Equipment
Equipment Qualification
Qualification
• Operational Qualification
• Performance Qualification
¿ Calibration and Maintenance Programs
¿ Retrospective Qualification
GMP-Conference / 10.-11. June 2004 / Istanbul
;
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Equipment
Equipment Qualification
Qualification
Design Qualification
“Defining the quality parameters required of the
equipment and manufacturer”
GMP-Conference / 10.-11. June 2004 / Istanbul
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Equipment
Equipment Qualification
Qualification
Installation Qualification
“Assurance that the intended equipment is
received as designed and specified.”
GMP-Conference / 10.-11. June 2004 / Istanbul
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Equipment
Equipment Qualification
Qualification
Operational Qualification
“Confirmation that the equipment functions as
specified and operates correctly.”
GMP-Conference / 10.-11. June 2004 / Istanbul
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Equipment
Equipment Qualification
Qualification
Performance Qualification
“Confirmation that the equipment consistently
continues to perform as required”.
GMP-Conference / 10.-11. June 2004 / Istanbul
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Validation
To prove that a process works is, in a
nutshell, what we mean by the verb to
validate.
E. Frey, FDA
GMP-Conference / 10.-11. June 2004 / Istanbul
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Validation
‹
‹
‹
‹
‹
Process Validation
Cleaning Validation
Computer system Validation
Validation of Analytical Methods
Part 11 Compliance
‹ Risk based approach is key !!!
‹ Focus on Product, not only on technology
GMP-Conference / 10.-11. June 2004 / Istanbul
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Link between Validation/ Qualification
Product
Risk Analysis
Equipment Qualification
GMP-Conference / 10.-11. June 2004 / Istanbul
Risk Analysis
Process Validation
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Quality
Quality Risk
Risk Analysis
Analysis
Flow
FlowChart
Chartfor
foraaSolid
SolidDosage
DosageForm
FormProcess
Process
Weigh Active Agents
Weigh Excipients Add Binder
Water / Solvent
Weigh Excipients
Dry Mix
Wet Mix / Granulate
Dry
Dry Granulate
Weigh Lubricant Add Lubricant
Blend
Compress
Solution Preparation
Coat (optional)
GMP-Conference / 10.-11. June 2004 / Istanbul
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Quality
Quality Risk
Risk Analysis
Analysis
Key
Key Parameters
Parameters
Process Stage
Parameter
Worst Case Values
___________________________________________________________________________________________________________________________________________
__________________
Raw materials
Particle size
Active agent
Surface area
Wet mixing Binder temperature
Binder volume
Mixing time
Drying
Granule moisture
Blending
Granule particle size
Compression
Compressor speed
Coating
GMP-Conference / 10.-11. June 2004 / Istanbul
Pre-compression
pressure
Inlet air temperature
Spray rate
Min-Max values
Target +/- x°C
Min-Max used in Pilot Scale
Normal time +/- x minutes
Upper-lower in process spec
Upper-lower in process spec
Normal production range
(e.g. 100000/hr-150000/hr)
Min-Max
Target + / - x
target rate + / - x
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Quality
Quality Risk
Risk Analysis
Analysis
Critical
Critical Process
Process Parameter
Parameter
Parameters:
Colette gral mixer
Agitator - Speed 2
Chopper - off
Mixing time - 5 minutes
Sampling
Regimen:
After mixing take 12 samples from the mixing bowl using a
sample thief. Samples to be taken 4 top, 4 middle, 4
bottom. Sample to be 300 mg approx.
Testing:
Analyse each sample for active agent content
Acceptance
All individual values to be within + 7 - 10 % of the group Crite
mean RSD to be less than 6 %. The mean to be within
+ 7 - 5 % of the theoretical value
________________________________________________________________
______
Solid dosage form
GMP-Conference / 10.-11. June 2004 / Istanbul
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Tool
Tool box
box
Risk
Risk Assessment
Assessment
• FMEA (= Failure Mode and Effect Analysis)
• HACCP (= Hazard Analysis Critical Control Points)
• FTA (= Failure Tree Analysis)
• System Kepner-Tregoe
•
Analysis of the situation
• Analysis of the problem
• Analysis of the decisions
• Analysis of potential problems
GMP-Conference / 10.-11. June 2004 / Istanbul
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Tool
Tool box
box
Risk
Risk Assessment
Assessment
• FMEA (Failure Mode and Effect Analysis)
→ Define the “Risk Priority number” ( - RPN)
Example: Steam sterilisation Process
- Steampressure / Temperature in the autoclave
Risk
- Sterilisation Time
- Measures to avoid air in the autoclave
- Treatment of the product before and after the
decreasing
process
GMP-Conference / 10.-11. June 2004 / Istanbul
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FTA
FTA (Failure
(Failure Tree
Tree Analysis)
Analysis)
Basic Concept:
Undesired
Incident
Basic
Incident 1
Basic
Incident 2
GMP-Conference / 10.-11. June 2004 / Istanbul
Basic
Incident 3
Basic
Incident 4
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Risk
Risk Assessment
Assessment
Key Success Factor:
Training and Skills of people
•
Scientific skills
•
Broad - Experience in pharmaceutical Industry
•
Leadership, Responsibilities
GMP-Conference / 10.-11. June 2004 / Istanbul
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Change
Change // Deviation
Deviation
“Change” usually refers to a planned alteration which is
documented and considered before implementation. Normally,
changes are either permanent or have a fixed period of validity.
“Deviation” represents a change which may occur for a variety of
reasons during operations, or may be observed to have happened
after the operation.
Normally, deviations are not permanent and represent single events
“Planned Deviations” ??
GMP-Conference / 10.-11. June 2004 / Istanbul
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Documentation
‹
‹
‹
‹
‹
‹
‹
Validation Master Plan
Qualification Master Plan
GMP Risk Analysis
Validation Protocol
Test protocol (including specification)
Validation Report
Summary of Deviations / Issues
GMP-Conference / 10.-11. June 2004 / Istanbul
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Change
Change Management
Management
Who made the change
Why was the change necessary
When was the change implemented
What international consequences arise:
- Risk / benefit assessments
- Cost / benefit assessments
- Regulatory impact
Who gave approvals
_____________________________________________________________________________________________________________________________________
_____________
Changes are necessary - Uncontrolled changes are dangerous
GMP-Conference / 10.-11. June 2004 / Istanbul
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Computer Simulations
in Conventional Clean Rooms (Sterile Manuf.)
‹ To be in compliance with all microbiological and particulate
requirements, the design of the sterile facilities plays the
most important role.
‹ Computer simulation studies of air flows should be used to
analyse the most critical areas.
‹ Detailed analysis was made with regard to conflicting areas of
class 10`000 and critical class 100 areas in order to prevent
any possible contamination of the product.
‹ Detailed qualification of the balance is a prerequisite for a
successful implementation of these design concepts.
5
GMP-Conference / 10.-11. June 2004 / Istanbul
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Initial Air Handling Design
Picture shows air inlets (units) and air exhaust systems
Laminar flow units
Exhaust
Unformatting
table
Filling
station
Formatting
table
Loading
buffer
Unloading
buffer
Freeze
dryer 2
Freeze
dryer 1
Transfer cart with
horizontal laminar flow
GMP-Conference / 10.-11. June 2004 / Istanbul
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Improved Air Handling Design
Picture shows new and modified air inlets (LF units) and air exhaust
systems
New exhaust
Modified
exhaust
Additional laminar flow units
New inlets (background area)
New exhaust
New exhaust
New exhaust
Modified
inlet on cart
New exhaust
GMP-Conference / 10.-11. June 2004 / Istanbul
New exhausts
on cart
New exhaust
Modified exhaust
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