controlling

Process Analytical Technologies: Tools for
the Easement of the Regulatory Approval
Process
John T. Davis
Etcetera Consulting Services, LLC
[email protected]
Etcetera Consulting Services, LLC
Theory of
Process Analytical Technology
and
Quality by Design
“…a system for designing, analyzing,
and controlling manufacturing through timely
measurements of critical quality and
performance attributes of raw and in-process
materials and processes, with the goal of
ensuring final product quality…
 The goal of PAT is to understand and control the
manufacturing process … acceptable endproduct at the completion of the process…”
 PAT is the enabling tool for QbD.

(Reference Web site:
http://www.fda.gov/AboutFDA/CentersOffices/C
DER/ucm088828.htm
P ublished by the FDA in Septem ber 2004
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Goal
• Monitor, understand, and control manufacturing processes
•
Primary Methodology
• DMAIC (Define, Measure, Analyze, Improve, Control)
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Common Tools
Process Mapping
Failure Modes and Effects Analysis
Regression Analysis
Design of Experiments
Multivariate Data Analysis
Control Charts/SPC
Control Plans
Stabilizing N ew and Legacy P rocesses
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
Process
Monitoring
Process
Improvement
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State of the art technology
Rapid analysis
On-line/in-line/at-line monitoring
Process
Understanding
Process
Control
• Multivariate data analysis
• Critical parameters
• Transfer functions/Models
• Process and endpoint control tools
• Multivariate control strategies/Adaptive
P rocess Understanding, Control, and I m provem ent
W ith perm ission of Serj Vartanian and Leslie Gilbert, Bax ter BioScience
Sigma
SixSix
Sigma
Provides
Provides
PAT
PAT
Provides
Provides
= f(X)
Y =Yf(X)
Monitoring
Monitoring&&Control
Control
P AT and Six Sigm a Enable Each Other
W ith perm ission of Serj Vartanian and Leslie Gilbert, Bax ter BioScience
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Desired state of pharmaceutical manufacturing

(FDA Guidance for Industry, Sept 2004):
•
Product quality and performance are ensured through the
design of effective and efficient manufacturing processes
•
Product and process specifications are based on a mechanistic
understanding of how formulation and process factors affect
product performance
(Reference Web site: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm088828.htm
Quality N eeds to be Built into , not Tested into, the P roduct

Staging is proposed as an exercise in:
 Assessing current process capabilities
 Defining PAT integration opportunities
 Evaluating PAT strategies
 new on-line instrumentation (to replace existing offline methods)
 demonstration of equivalence (to off-line methods)
 Technology transfer plan

What process data do you currently collect?
 On-line (fermentation)
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pH
Mass
Temperature
Pressure
Agitation rate
Dissolved oxygen
 Off-line (fermentation)
 pH
 Cell density
 Nutrient concentration
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Bioburden
Purity
 Identification of impurities
 Amounts of impurities
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Step recovery / yield
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Continuously (during and immediately following
each run)
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Discontinuously (weekly, monthly, quarterly…)
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Are the data stable?
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Do the data show process capability?
 Should have been established in earlier development
and validation stages.
 May have deviated from the validated state – due to
factors that should be identified and corrected.
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If you can conclude that:
specific process variables are stable
positively correlate to product quality and
yield
can you discontinue intermediate product
testing?
What if individual process variables appear to be
stable and capable, but outputs (I.e., product yield
or quality) are highly variable?
You may not be tracking the right variable(s)
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To identify the major contributors to variation
(in input).
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To identify relationships between variables, as
relate to outputs.
STOP!
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Conclude that, because it is a “biological”
process, it is inherently unpredictable,
highly variable and uncontrollable.
This has been the most common conclusion in
the bioprocess industry – and is NOT TRUE!
Drill down – to include input variables that
have not been considered.
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Raw materials
Equipment changes
People (training level, competencies, etc…)
Procedure changes (SOPs, BRs, etc…)
Metrics/measures
If CPP is identified and brought under control, go
back to individual CPPs and re-evaluate.
Continue this process until you have
demonstrated a high state of process control – of
inputs and outputs!
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Soundness of methodologies employed
Appropriateness of tools selected and
implemented
Appropriateness of instrumentation selected
and implemented
If you satisfy these requirements, then
regulatory approval will be highly more likely.