Transcript Transfer Validation Requirements

Transfer Validation Requirements
Morning Session #2
Robert Beall, PMP
Introduction
Robert Beall
Hometown:
Home:
Family:
Hobbies:
Education:
Syracuse, NY
Providence, RI
Günther (Son), Maren (Daughter),
Calvin (Son)
Sailing, Travel, Olympic Weightlifting
RIT BS - Engineering
PMP
Transfer Experience
Solids Transfer Engineer for Optimization in North America (OPINA) 132 Product transfers
Managed Europe to USA NDA product transfers for 3 blockbuster product lines.
Head of International transfers between Germany, US and India for WW distribution 18 products
Head of Life-Cycle product transfer for parenteral manufacturing 64 products.
Solids Transfer Manager for animal Healthcare products – 32 products
Medical Device Transfer Consultant – 4 products
Biological product transfer leader – 4 products
2 Confidential
2
Agenda
Lifecycle Validation Requirements
1. Regulatory Standards
2. Stage 1 – Development
3. Stage 2 - Validation
4. Stage 3 – Lifecycle
3 Confidential
3
Lifecycle Validation Requirements
US Regulatory Standards for Validation
Solid Oral Dose / Biological Prod*
Medical Device
211.100 (a)
211.110(b)
211.160 (b)
211.165 (a,d)
211.84 (b)
211.180 (e)
ISO 13485
* These requirements were included in CDER/CBER/ CVM Jan 2011
Process Validation General Principles and Practices.
4
Audience Quick
Benchmarking Poll #1
• How many of you have read the 2011 FDA
Guidance on Process Validation?
– Yes or No
5
Process Improvement?
Grandpa’s
Car
Future
Grandkid’s
Car
6
Guidance Evolution
from 1987 to 2011
1987
•
•
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•
•
•
•
•
Single protocol approach
Static event, disconnected
3 batch requirement almost
explicit
More deliberately prescriptive
Simply a confirmation
Criticality is binary (yes or no)
It is what it is
Final report jumps to
conclusions
2011
•
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•
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3 phased approach
Lifecycle evolution, sustainable
No longer a magic run number
Risk-based decision-making
Emphasizes up front learning
Criticality is a continuum
Greater clarity of expectations
Allowing the final report to
“return” to process design
allows for learning
7
Learning Progression
Poor design,
planning, process and
understanding
Unexplained variation, Product
and process problems, Process
not in control. Major Learning!
Potential substandard product
on market
PQ checklist exercise
w/ little
understanding
Poor, minimal design
Good planning,
expected result
Continued Verification,
Process Learning and
improvement
Sound, thorough process
Qualification confirms
design
Comprehensive process
design, Scientific process
understanding
Borrowed from Grace E. McNally
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Approach to Process Validation
Process validation involves a series of activities
taking place over the lifecycle of the product and
process. The guidance describes the process
validation activities in three stages.
9
Audience Quick
Benchmarking Poll #2
• Does the Process Validation Guidance only
apply to Product or Device manufacturing?
– YES or NO?
10
Lifecycle Staged Approach
STAGE 2
PROCESS
QUALIFICATION
STAGE 1
PROCESS
DESIGN
COMMERCIAL
DISTRIBUTION
Confidential
STAGE 3
CONTINUED
PROCESS
VERIFICATION
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Process Validation Stages
Stage 1
Process
Design
Building and
capturing
process
knowledge
Establishing a
control
strategy
Stage 2
Process
Qualification
Design of
facility and
qualification
of utilities &
equipment
(IQ/OQ/PQ)
Process
Performance
Qualification
(PPQ)
Stage 3
Continued
Process
Verification
Implement
control
strategy
12
Audience Quick
Benchmarking Poll #3
• How many have a life cycle approach
documented at their facilities?
– Yes or No
13
Audience Quick
Benchmarking Poll #4
• How many just have what we recognize as
a Phase 2 approach?
– Yes or No
14
Audience Quick
Benchmarking Poll #5
• How many have a developed Phase 3
program in place?
– Yes or No
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Schematic of Stages
(New Process or Product)
Stage 2
Stage 1
Process Design
Evaluate/Confirm
Process Qualification (PQ)
Design of
Facilities &
Qualification
of Equipment
and Utilities
Process
Performance
Qualification
(PPQ)
Stage 3
Distribute
Continued
Process
Verification
Ref: Grace E. McNally FDA (Guide Leader) Sept 15, 2010
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What does this mean?
• Lifecycle approach – product conception
through commercialization
Focusing exclusively on qualification efforts
without also understanding the manufacturing
process and associated variations may not lead
to adequate assurance of quality.
- FDA Guideline Section IIB
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Schematic of Stages
(Legacy Process or Product)
Stage 2
Stage 1
Process Design
Evaluate/Confirm
Process Qualification (PQ)
Design of
Facilities &
Qualification
of Equipment
and Utilities
Process
Performance
Qualification
(PPQ)
Variation Detected
Stage 3
Distribute
Continued
Process
Verification
Ref: Grace E. McNally FDA (Guide Leader) Sept 15, 2010
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STAGE 1: PROCESS DESIGN
Building and Capturing Process
Knowledge (Stage 1 – Process Design)


Thoughtful planning very early in Development
Sources of knowledge prior to Stage 1
o Previous experience with similar processes (e.g. platform
process)
o Product and process understanding from clinical and preclinical activities
o Analytical characterization
o Published literature
o Engineering Studies/batches
o Clinical Manufacturing
• Process development and characterization studies
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STAGE 1: PROCESS DESIGN
Deliverables from Stage 1
of Process Validation


Early Stage 1 – Process Development
o Establish Target Product Profile and Quality Target Product
Profile (QTPP) – Living Documents
o Identify Critical Quality Attributes (CQAs)
o Define the Manufacturing Process
Late Stage 1 – Process Characterization
Scale up, Tech Transfer and Set Design Space Boundaries
(optional)
o Perform Quality Risk Assessment Initial Categorization of
Parameters
o Perform Process Characterization Experiments (eg DOE,
multivariate, univariate)
o Final Categorization of Parameters Based on Criticality and
Establish Control Strategy
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STAGE 1: PROCESS DESIGN
Quality Target Product Profile (QTPP)

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
This is done at the initiation of Stage 1
Periodically updated to incorporate any new data that may have been
generated during development
Addresses relevant characteristics that include:
o Intended use in a clinical setting
o Drug substance quality attributes appropriate to the drug dosage
form being developed (e.g. physical, chemical and biological
properties)
o Drug product quality attributes for the intended marketed product
(e.g. purity/impurities, stability, sterility, physical and chemical
properties)
o Pharmacokinetic characteristics (e.g. dissolution, aerodynamic
performance)
o Excipient and component quality attributes, drug –excipient
compatibility, and drug container compatibility that affect the
process ability, stability or biological effect of the drug product
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STAGE 1: PROCESS DESIGN
Quality Target Product Profile (QTPP)

Does not include (this is contained in the TPP)
o Dosage forms and strengths
o Contraindications
o Warnings and Precautions
o Adverse Reactions
o Drug interactions
o Abuse and dependence
o overdose
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STAGE 1: PROCESS DESIGN
Critical Quality Attributes (CQAs)

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Physical, chemical, biological or microbiological properties or
characteristics that should be within an appropriate limit, range
or distribution to ensure the desired product quality
CQAs are NOT synonymous with specifications
Several CQAs may be detected by a single test method
CQAs with corresponding Criticality Risk Assessment and desired
confidence
CQAs are subject to change in the early stages of product
development (risk management should allow for an evolution of
product and process knowledge
CQAs for commercial products should be defined prior to
initiation of Stage 2 activities
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STAGE 1: PROCESS DESIGN
Define the Manufacturing Process


Designed to consistently provide a product that will meet its required quality
attributes
Process Description showing process inputs, outputs, yields, in-process tests
and controls, and process parameters (set points and ranges) for each unit
operation
o Process requirements including raw materials, scale and order of
operations
o Set points and ranges for process parameters
o Identification and quantity of all material flows (addition, wastes and
product streams)
o Testing, sampling and in-process controls
o Hold times and hold conditions for product and addition solutions
o Estimated yields and durations
o Sizing for equipment including chromatography columns, filtration units,
etc.
o Specific identification (manufacturer, part number) for manufacturing (e.g.
filters) and product components (e.g. vials, stoppers, etc.)
o Other information necessary to successfully reproduce the process
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STAGE 1: PROCESS DESIGN
Define the Manufacturing Process
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Process solution formulas, raw materials, specifications
Batch Records and production data from laboratory or pilot
scale production
Knowledge management is key at this stage
This stage is where the Technology Transfer package should
begin
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STAGE 1: PROCESS DESIGN
Analytical Methods

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Analytical methods are important not only in process and product
characterization (and should be referred to in the Process
Characterization Plan)
They also become key aspects of the Process Control Strategy
Methods should be developed and documented as qualified for
the following
o product
o intermediates
o raw materials
Don’t forget that analytical instrument in and of themselves also
need to be calibrated, qualified and maintained
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STAGE 1: PROCESS DESIGN
Risk Assessment and
Parameter Criticality Designation
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ICH Q8 defines a Critical Process Parameter as “one with variability
that has an impact on a CQA, and therefore, should be monitored
or controlled to ensure that the process produces the desired
quality.”
Risk assessment serve the following purpose in the PV lifecycle
o Structured means for documenting data and rationale
associated with the risk outcome
o Document process development history
Risk assessments should be done as an iterative process as more
process and product knowledge is gained
Quality Risk Assessment – initial risk-based categorization of
parameters prior to process characterization
Criticality and Risk Assessments – identification of Process
Parameters with corresponding criticality and risk analysis
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STAGE 1: PROCESS DESIGN
Risk Assessment and
Parameter Criticality Designation


Parameter or Attribute
o Parameters: Process variables that are directly controllable process
input parameters can theoretically contribute to process variability
o Attributes: Process outputs that are not directly controllable. They
are monitored and may be indicative of process performance or
product quality.
Parameters
o CPP – If impact is suspected or if data show variability in a
parameter could impact a CQA, the parameter is designated as a
CPP
o KPP – Potential impact to process performance or consistency if run
outside of defined range
o nKPP – Parameter has little impact to the process over a wide range
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STAGE 1: PROCESS DESIGN
Process Characterization
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Defined as: A set of documented studies in which operational
parameters are purposely varied to determine their effect on
product quality attributes and process performance
Include: Process Characterization Plan and Protocols. May utilize:
o Univariate approaches to find PAR
o Multivariate approaches to find interactions between process
parameters/ material attributes
Useful in:
o defining ranges beyond NOR
o Setting acceptance criteria for PPQ
Study Data Reports
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STAGE 1: PROCESS DESIGN
Process Characterization

Scale up/scale down approach (Evaluation/Qualification of Laboratory
Models)
o Laboratory models need to be verified and justified for full scale
 Biotech Chromatography scale down models should compare to full
scale including the following parameters:
 Yield
 Eluation Profile
 Elution Volume
 Retention Time
 Should analyze Product Quality such as
 Pool Purity
 Process related impurities
 Host cell related impurities
 Small Molecule Pilot Scale Modeling
 Solid and liquid oral dosage forms
o 10% of commercial size or
o 100,000 units
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STAGE 1: PROCESS DESIGN
Product Characterization Test Plan

Characterization tests not included in the product Release Test
panel
o Tests on Drug Substance, Drug Product and/or Critical
Intermediates
o E.g.: Residual DNA levels beyond safety clearance
requirements
o Whatever testing is necessary to claim a comprehensive
understanding of the product and process
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STAGE 1: PROCESS DESIGN
Control Strategy
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Establishing a control strategy is one of the most important outcomes of Stage 1
Development of an effective control strategy is an iterative process
Needs to take into consideration all unit operations in the process
All Attributes, Critical or not, are included in the process control strategy (PCS)
Raw material / Component Specifications
o Characterized based on their potential risk for
 Introducing variability
 Introducing contaminants
o Potential sources in CQA variability
o Potential sources of process variability
 E.g.: Yield, Reaction kinetics, filterability or non-product, quality related
effects
o Raw material selection should consider grade (e.g.: purity, chemical and
physical characteristics, microbial specifications and endotoxins)
o Relationship of raw materials to product and process essential to controlling
variability
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STAGE 1: PROCESS DESIGN
Control Strategy
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
In-process and Release specifications
o Relationship to product safety, efficacy and product consistency
o Confirmed failure of these specifications should disqualify the product
from use in clinical or commercial applications
o More information can be found in ICH Q6a and Q6b
 Q6a = Specifications: Test Procedures and Acceptance Criteria for
new drug substances and new drug products: Chemical Substances
 Q6b = Specifications: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products
In-process Control limits
o Inputs to the process
o Checks performed during the production for monitoring and adjusting
o Ensures intermediates or product conform to defined specification
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STAGE 1: PROCESS DESIGN
Control Strategy
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Process Parameters
o Process outputs that cannot be controlled
o Indicators of proper process performance
o E.g.: peak cell density/viability or tablet/capsule disintegration
Process Parameter set points and ranges
o Knowing NOR and PAR (with supportive data) can be used to
assess the severity of process deviations caused by parameter
excursions
Routine monitoring requirements (including sampling and testing)
o Data collection and analysis should begin in Stage 1 and will
become integral parts of Stage 2 and eventually evolves into
Stage 3
o E.g.: Flow rates, temperatures, volumes, pH, etc.
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STAGE 1: PROCESS DESIGN
Control Strategy
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Storage and time limitations
o Necessary for all intermediates, prepared process solutions and process
steps, drug substance and drug product
o These are key to the process control strategy
Process Analytical Technology (PAT)
o Maybe used to implement the Process Control Strategy
o CQAs may be monitored in real time (in-line and/or at-line)
o May be used to adjust CPPs to decrease product variability
o PAT=process knowledge + equipment automation + analytical
instrumentation
o PAT requires a thoroughly characterized process
 Including mathematical models of the relationship of CPP to CQAs
 Stage 1 must deliver a scheme and algorithm for adjusting CPPs based
on process response
o Design and qualification of instrumentation becomes more key in control
systems
o Qualification of PAT control methods must also be conducted
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STAGE 1: PROCESS DESIGN
Clinical Manufacturing Experience –
Batch Records and Production Data
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Not all the final controls may be implemented
Experience is valuable for evaluating process performance
May be used to support ranges and limits
Clinical batch data should be included in the final process
design report
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STAGE 1: PROCESS DESIGN
Process Design Report –
Development Document

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Deliverable or Output from Stage 1
Intended to be a revisable document
Support data for PCS and justification of ranges
Data gathered from process change control should be incorporated here
The document should include:
o CQAs and supporting risk assessments
o Process flow diagrams
o Process description tables
 Inputs (in process controls)
 Outputs (in process tests and limits, in process specifications)
o Process Parameters and ranges
o Classification of parameters for risk of impact to CQAs and process
performance
o Design space, as appropriate
o Justification and data supporting all parameter ranges
 Characterization data
 Development studies
 Clinical manufacturing history
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STAGE 1: PROCESS DESIGN
Process Validation Master Plan
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Should be initiated during Stage 1
Outlines validation strategy and supporting rationale
Typically includes
o Process characterization plan
o Description of the manufacturing process and control strategy
o Functions and responsibilities
o PQ or PPQ plan
o PPQ
 strategy (examples may include)
 Single unit operations or a combination of unit
operations
 Bracketing
 Family
 Matrix
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STAGE 1: PROCESS DESIGN
Process Validation Master Plan
 List of individual protocols (examples may include)
 Mixing
 Media preparation
 In process pool hold time
 Resin lifetime
 List of equipment and facilities to be used
 List of analytical methods and their status
 Sampling plan
o Proposed timeline and schedule of deliverables
o Procedures for handling deviations and revisions
o Continued Process Verification Plan
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STAGE 1: PROCESS DESIGN
Stage 1 Manufacturing and
Technology Considerations


Beyond equipment capabilities; material compatibility should be
studies in Stage 1
Equipment surface interactions (e.g. extractables, leachables,
adsorptions)
o Extractables come off materials under force
o Leachables come off materials under normal conditions of use
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STAGE 1: PROCESS DESIGN
Expectations
1) Define risk based methodology and team structure
2) Define CQA
3) Perform Risk Assessment
4) Design of Experiments & Quality by Design
4) Define applicable CPPs
5) Determine analytical process variation
6) Demonstrate variation correlation
7) Establish control strategy
8) Assess data
Best Practice
1) Engage Process Development Scientist &
Engineers early
2) Get it in writing
3) Ensure scalability
4) Create event driven Process Flow
5) Get an early start on Method Validation
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Quick Case Study /
Knowledge application
Process
• Weighing two solids (active
and stabilizer)
• Dissolving in Water for
Injection
• Sterile Filtration
• Fill into Single use bottles
– Type answers here
List the CPPs
42
Process Risk Assessment
Tracking
Perform Risk
Assessment and
List RPN
List Process
Steps and CPP /
CQA
Process
Flow
CPP
Evaluate
Rationale for
Specification
Determine MS
Validation Status
Check Data Quality,
Process State of
Control
Risk
Measure
System
Validated
Spec
Rationale
Process
Quality
Data
updated
Statistical Capability Assessment
RPN
< 100
Yes / No
Yes / No
Spec Range
Yes / No
Control Charts
Capability Assessment
Pattern
Analysis
Average /
Standard
deviation
Distribution
K2
PPK
CQA
Monitor
In Normal
Product
(Yes / No)
analysis
Raw Material
Release –
Alkylating
Agents
48
Yes – MVR 1234
Yes – USP
1280
Yes –
Report 102
NA
99.3/ 0.4
X - Normal
3.0
1.49
No – NIR
planned for
2015
Mixing
RPM
Time
Feed rate
Impeller
selection
383
No
Yes
No
Yes
Linearity
Matrix
Limits
Tech sheet
Mix Report
1200
Due 10/13
Due 11/13
Due 12/13
4.26
0.93
Protein– No
pH- Yes
Filter
Bubble
point
110
Yes – MVR
4321
Tech sheet
Yes Report 102
In process
Chi Square
3.1
0.99
No – flow
meter due
9/13
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STAGE 1: PROCESS DESIGN
Expectations
Stage 1 Summary
Report
Best Practice
1) Defined process
2) Completed CPP/CQA Matrix including rationale
3) Completed risk assessment
4) Defined control strategy including limits
and monitoring methods
5) Defined risk reduction plan
6) Summary of test method validation
7) Statistical assessment
8) Process variation
1)
2)
3)
4)
Make it accessible
Make it searchable
Make it clear!
Allow amendments
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STAGE 2: PROCESS QUALIFICATION
• Addresses 2 primary areas
– Design and qualification of the facility, equipment, and
utilities
– Demonstrating the ability to produce product that meets
predetermined quality attributes; demonstrating control
of variability
• In current terminology: Process Performance
Qualification (PPQ)
• Stage 2 activities may be in progress in parallel
with Stage 1
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STAGE 2: PROCESS QUALIFICATION
Strategies for System Design and Qualification
•
Qualification of Systems (facilities, utilities,
and equipment)
• Performed per Qualification Plan
• Confirm suitability for intended use
• Completed prior to PPQ
• For equipment
• verify operational parameters suitable
to support intended process
• verify performance when applicable
46
STAGE 2: PROCESS QUALIFICATION
• Sequence of phases
– Design / Engineering
• Utilize information from Stage 1 Process Design
(process parameters, control strategy, performance
requirements, etc)
– System Level Impact Assessment
– Risk Assessment
– Design Review/Qualification
– Installation
• FAT/SAT
47
STAGE 2: PROCESS QUALIFICATION
• Sequence of phases
(Continued)
– Start up
• SAT/Commissioning
– Verification/Qualification
• Test Functions
– Based on process design, engineering studies
– Should demonstrate consistency of operating parameters
• Acceptance Criteria
– Based on sound, documented, scientific rationales
– Should be significant, specific, and measurable
• May leverage commissioning data if acceptable (GEP, GDP,
oversight by Quality Unit)
• Studies/tests to ensure equipment supports process requirements
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STAGE 2: PROCESS QUALIFICATION
• Process Performance Qualification (PPQ)
• PPQ Readiness
• Confirm all support facilities, utilities and
equipment qualified
• Implement Process Control Strategy
•
CPPs and CQAs
• Process Risk Assessment
• Analytical Methods
• Process Design Report
49
STAGE 2: PROCESS QUALIFICATION
• PPQ Design Strategy Considerations
• Prior Knowledge/ Stage 1 Data to support PPQ
• Data from process characterization studies,
clinical/stability/pilot manufacturing batches
• PPQ Design considerations/approaches
• Number of Batches
• No pre set number (traditional 3 batches)
• Based on combination of prior knowledge,
process complexity, process variability,
type and amount of data needed to confirm
process design, control strategy, and
operational proficiency at commercial scale
• Use statistical methods when practical
50
STAGE 2: PROCESS QUALIFICATION
• PPQ Design considerations/approaches
• PPQ at Normal Operation Conditions
• Demonstrate state of control; assess expected
variability
• PPQ Using Individual Unit Operation Studies
• Individual protocols for each unit operation
• Final drug substance/product meets all
specifications and predefined acceptance criteria
• PPQ using Bracketing, Matrix and Family Approaches
• May group operations with similar or identical
processes or equipment
51
STAGE 2: PROCESS QUALIFICATION
• PPQ Design considerations/approaches
• Bracketing Approach
• Can be used for processes that represent
extremes of process variables
• Matrix Approach
• Can be used when configurations of same
process/product have > one variable
• Family (Grouping) Approach
• Appropriate when related but different
processes are represented by one of the group
which demonstrates the common properties or
is worst case
52
STAGE 2: PROCESS QUALIFICATION
• PPQ Protocol
• Introduction
• Purpose and Scope
• References
• Equipment and Materials
• Responsibilities
• Process Description
• Sampling Plan
• Analytical Testing
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STAGE 2: PROCESS QUALIFICATION
• PPQ Report
• Introduction
• Methods and Materials
• Deviations/Nonconformances
• Results
•
Data Summary
•
Data Analysis
• Conclusions
54
STAGE 2: PROCESS QUALIFICATION
• Transition to Continued Process Verification
• Plan or Protocol for CPV
• Assess body of data from PPQ; select key
indicator parameters/attributes to monitor
• May include enhanced level of PPQ level
sampling for a period of time following
completion of PPQ
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STAGE 2: PROCESS QUALIFICATION
Expectations
1) Confirm Facility, Equipment, Utilities “fit for purpose”
check
2) Develop PPQ Protocol including:
a) Definition of testing methodology and team
structure
b) Definition of statistical terms and formulas
c) Applicable references to stage 1 summary
report
d) Control strategy
e) Number of batches
f) Sampling Plan
g) Create control charts
h) Acceptance Criteria / Investigation process
for both intra and inter batch variability
i) Training record
56
STAGE 2: PROCESS QUALIFICATION
Expectations
Best Practice
3) Train Operations and Analytical Team
a) Manufacturing Processes
b) Statistical Process Control trending or charting begins
c) Updated SOPs
d) Batch record review
e) Risk assessment review
f) CPP/CQA Matrix review
4) Execute Protocol
5) Revise risk assessment and CPP/CQA
1) Plan extra runs
2) Prepare for deviations & conduct ‘in control’ approvals
3) Follow in-process results closely
57
Knowledge Check
• When should you get the Quality Unit
involved on the team?
–
–
–
–
A. When Process Equipment is Qualified
B. At Stage 2
C. At Stage 1
D. Never 
58
Using your scientific mind…
• What else can lead to failure?
– Type answers here
• Variation can come from all sources!
• Let’s explore
59
Variability Assessment
60
Why PPK and not CPK?
PPK:
• Index based on Long Term Variation
• Calculated using overall standard deviation
• Indicates the overall performance of a process
including special causes of variation
• PPK captures both within-batch and between-batch
variation
• Usually used when the state of statistical control is
unknown
61
STAGE 2: PROCESS QUALIFICATION
Expectations
1)
2)
3)
4)
5)
6)
Summary of results
Confirm Process Performance value
List of CPP’s by Risk Priority Number
Control system
Determine confidence intervals
Justification for reduced testing (“hand-shake” to Stage 3)
Stage 2 Summary
Report
Best Practice
1) Compile results in real time
2) Utilize someone well versed in statistical
methods
3) Leave a well documented rationale as to
which Attributes to monitor and why
62
Commercial Distribution
• Basis for Commercial Distribution
“Each manufacturer should judge whether it has
gained sufficient understanding to provide a high
degree of assurance in its manufacturing process
to justify commercial distribution of the product.”
FDA Guideline Section IIB
63
STAGE 3: CONTINUED PROCESS VERIFICATION
Incorporation of Feedback from CPV Monitoring
•
•
Validation CPP and CQA’s checked – A Risk
Assessment is conducted to confirm future state.
Lock validated parameters
64
STAGE 3: CONTINUED PROCESS VERIFICATION
Examples of Monitored Biological Parameters
• Pre-Harvest Hold Time
• Operating Temperature
• Operating Centrifuge Speed
• pH
• Operating Flow Rate
• Osmolality
• Solids shot volume
• Conductivity
• Steady stat centrate backpressure
• Centrate hold tank temperature
• Storage temperature
• Column bed heights
• Column volumes
• Fluid velocity
65
STAGE 3: CONTINUED PROCESS VERIFICATION
Examples of Monitored Biological Parameters
Validation Batch Results
66
STAGE 3: CONTINUED PROCESS VERIFICATION
Examples of Monitored Biological Parameters
+/- 3 Sigma control lines
67
STAGE 3: CONTINUED PROCESS VERIFICATION
Examples of Monitored Fluid Bed Parameters
• Inlet Temperature
• Exhaust temperature
• Inlet Humidity
• Exhaust Humidity
• Fluidizing flow rate
• Time
68
Continued Process Verification
CGMP requirements:
The collection and evaluation of information and
data about the performance of the process will
allow detection of undesired process
variability. Evaluating the performance of the
process identifies problems and determines
whether action must be taken to correct,
anticipate, and prevent problems so that the
process remains in control
(§ 211.180 e).
69
Continued Process Verification
• Goal – to continually assure that process remains in a
state of control
• Collection and evaluation of data will allow detection of
process drift
• Evaluation should determine whether action must be
taken
• On-going program to collect and analyze data must be
established
• Statisticians can develop the data collection plan &
methods
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EU Continuous Process Validation
• An alternative approach in which manufacturing
process performance is continuously monitored and
evaluated.
• In-coming materials or components, in-process
material and finished products
• Verification of attributes, parameters and end points,
and assessment of CQA and CPP trends
• Use of tools to support (PAT, NIR, etc.)
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EU Continuous Process Validation
•
Other Factors
 Compliance with GMP principles & requirements
 Prior development & manufacturing knowledge
 Complexity of product/manufacturing process
 Process should be verified on commercial-scale
batches prior to marketing
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Is there a conclusion?
•
•
•
•
•
•
•
Know your process
Understand your variability
Build a Control Strategy early
Establish a lifecycle
Revisit your Risk Assessment
Monitor the process and analyze your results
Continued process improvement will lead you to
the Future!
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