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regulatory compliance
Legacy Products and Process Validation
Prioritization Scheme
The first practical dilemma most companies face when moving to compliance
with the 2011 guidance is how to evaluate and prioritize existing commercial
products. There can only be one standard
for process validation and eventually all
products have to meet it. Even so, it can
be difficult to gain organizational consensus to establish a practical path forward.
One simple framework for incorporating
diverse prioritization criteria is to employ
a Pugh Matrix. A Pugh Matrix is a structured, semi-quantitative tool for evaluating alternatives. Like all risk frameworks,
the primary advantage of a Pugh Matrix
is to establish a common criterion for
evaluation, minimizing subjectivity while
providing sufficient quantitative criteria
for measurement. Factors to consider
include:
1. Patient Criticality life sustaining
drugs
2. Product Volume percentage of the
sites manufacturing volume
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PHARMACEUTICAL ENGINEERING
regulatory compliance
Legacy Products and Process Validation
Alternative Concepts
Criteria
Rating (1-10)
Product 1
Product 2
Product 3
Product 4
Product 5
Product 6
Product 7
Patient Criticality
10
Product Volume
Business Risk
Process Complexity
Process Quality
History
Sum of Positives
Sum of Negatives
Sum of Sames
10
15
17
24
17
19
10
12
29
22
Implementation
The process to this point has identified CPPs for each
product in the prioritization matrix that is suitable for CPV.
Moving to implementation, there are four elements that
comprise an effective CPV program:
1. Defining a data capture strategy
2. Establishment of a CPV monitoring and reporting plan
3. Determine alert and action limits
4. Enhanced monitoring components
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regulatory compliance
Legacy Products and Process Validation
Data of Interest
Possible Analysis
Development
Reports
Product Design
Critical Raw
Material Tests
Design Space
Sampling Plan
Method Capability
Product Design
Pre-Hazard
Analysis
Process Risk
Analysis
Design Space
Data
Master Batch
Records
Unit operation
control ranges and
data
Control Charting
IMR Chart
Process Capability
IP and Release
Test Data
Individual and
summary test data
Mean and
standard deviation
analysis
Trend Analysis
X-Y curves
Deviations
Recurring failures
Method capability
issues
Trend Analysis
Raw Material
Supplier
CAPAs
Identify process
and control
strategy
corrective actions
implemented
Root Cause
analysis data and
the methodology
Change
Controls
Quality
assessment
related to changes
Validation criteria
evaluated
Correlation
analysis between
changes and
process stability
or product
performance
Are changes
adding instability
to process
Annual
Product
Reviews
Product CQA
trends analysis
Correlation
between product
performance,
deviations, and
change controls
Is product
performance
capable?
Prior Validation
Testing
Sampling Plan
Process capability
Control Strategy
Baseline process
control charting
T-test comparison
of means
CPP baseline data
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PHARMACEUTICAL ENGINEERING
1. Creating additional sampling and testing procedures and records which can
be used to manually capture the data
required
2. Data acquisition through equipment
PLC and microprocessors
3. SCADA systems for equipment process monitoring
regulatory compliance
Legacy Products and Process Validation
Conclusion
Legacy products represent the largest compliance risk
against the new PV guidance for an API, pharmaceutical and
biotech manufacturer. Establishing a formalized process for
risk management, process evaluation and on-going monitoring will permit the organization to prioritize and address legacy products that are not in control while integrating those
that are in control into a formalized monitoring program.
References
1. ISPE Discussion Paper: Topic 2 Stage 3 Process
Validation: Applying Continued Process Verification
Expectations to New and Existing Products, www.ispe.
org.
2. PDA Technical Report No. 60: Process Validation A
Lifecycle Approach, Parenteral Drug Association, www.
pda.org.
3. Code of Federal Regulations Citation: 21CFR211.80(e).
4. Mitchell, M., Determining Criticality-Process Parameters and Quality Attributes Part I: Criticality as a Con-
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