Transcript Slide 1

Introduction to PAT
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Current State of Pharmaceutical
Manufacturing
• Conventional pharmaceutical manufacturing is generally
accomplished using batch processing with laboratory
testing conducted on collected samples to evaluate
quality.
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20th Century Process Validation
• Establishing documented evidence that provides a high
degree of assurance that a specific process will
consistently perform as intended.
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Desired State
• Product quality and performance achieved and assured
by design of effective and efficient manufacturing
processes.
• Product specifications based on mechanistic
understanding of how formulation and process factors
impact product performance
• Continuous "real time" assurance of quality
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US drug products are of high
quality, BUT..
• The introduction of new technologies has not been
facilitated in
• the US market slowing innovation, and modernisation of
cGMP
• resulting in:
• An increasing burden on FDA resources:
• Handling ~ 4,000 manufacturing supplements submitted yearly
• FDA inspectors unable to meet statutory biannual GMP inspection
requirement
• Lower scrutiny of non-domestic industry
• Cost implications for the industry from:
• Low manufacturing and QA efficiency
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Overall
• The current approach to risk is probably delivering as
much as is reasonably possible in respect of Safety,
Efficacy
• But at significant cost from a :
• Regulatory perspective
• Manufacturing perspective
• Cost ultimately borne by the consumer
• Regulatory uncertainty has had a negative impact on
innovation
• In an environment where customer awareness of
different industry sector’s performance is changing their
expectation of the industry’s deliverables
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PAT Guidance
• Released September 29, 2004
• Scientific principles and tools supporting
innovation
•PAT Tools
•Process Understanding
•Risk-Based Approach
•Integrated Approach
• Regulatory Strategy accommodating
innovation
•PAT Team approach to Review and
Inspection
•Joint training and certification of staff
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Process Analytical Technology Defined
• System for designing, analyzing, and controlling manufacturing
• through timely measurements (during processing) of critical quality and
performance attributes of raw and in-process materials and processes, with the
goal of ensuring final product quality.
• The term analytical in PAT
• includes chemical, physical, microbiological, mathematical, and risk analysis
conducted in an integrated manner.
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What PAT means
• Understanding the process
•A process is well understood when:
•all critical sources of variability are identified and
explained.
•variability (e.g. raw materials) is managed by the
process
•product quality attributes can be accurately and reliably
predicted.
• Timely measurement (i.e. during processing).
• Control of critical quality and performance
attributes.
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What PAT is
• An enabling framework
• Science based not procedure based.
• Risk based
• An integrated systems approach
• Flexible
• Voluntary
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What PAT is not.
• It is NOT a regulation (CFR).
• It is NOT mandatory.
• It is not just adding a new sensor.
• It is NOT a technique that must be applied
throughout. It may be applied to part or all of a
process
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Why PAT? What is wrong?
• Most processes are fixed with variable materials,
resulting in variable quality of product.
• Most processes are not well understood.
• Existing procedural approach has created a “climate of
fear” stifling innovation.
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The Potential Benefits
• Reduced scrap
• Improved quality of product (every time, by design)
• Faster production
• Quicker development, faster scale up
• Encourages innovation
• Reduced regulatory burden
• Real-time release
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Process Control System in a PAT
Context
• Often requires new sensors (NIR, RAMAN, acoustics ...)
for direct measurement of product attributes (e.g.
moisture content, particle size, content uniformity, etc.)
• New multi-variate data analysis performed “at-line” or
“in-line”
• Data records are “different”.
• Feedback/feedforward within and between phases.
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Multivariate Data Analysis
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How the process might change
• More design of experiments during development to
understand the process.
• More data may be collected to continuously analyse it.
• Process may be modified during its life, without
revalidation.
• Equipment may be added/removed/changed without
validation.
• Move from batch to continuous processing
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The FDA
• The FDA have trained a few inspectors (4), more(50) are
being trained.
• The FDA are encouraging draft submissions.
• The FDA wish to establish an open dialogue during
development of a PAT process. (No more hiding data)
• The Pat principle is very well supported by other
regulatory agencies (e.e. EMEA)
• One NDA has been Pat based (Aventis)
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PAT, Process Control, MVDA and
Eurotherm ? Multi-variate data Analysis Tools
Eurotherm
NIR etc. Sensor(s)
Plant
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And Finally…
• The goal of PAT is to understand and control the
manufacturing process
• to ensure appropriate control of all relevant critical
attributes of in-process materials (e.g., using process
endpoints) to allow the process to manage the inherent
variability of material attributes that can impact the
quality of the output
• Proactive science-based approach. Continuous
validation (every lot is a validation lot) versus discrete 3lot exercise.
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End Slide