Transfer Validation

Requirements
Morning Session #2
Robert Beall, PMP

Introduction
Robert Beall

Hometown:
Home:
Family:
(Daughter),

Syracuse, NY
Providence, RI
Gnther (Son), Maren
Calvin (Son)
Sailing, Travel, Olympic

Hobbies:
Weightlifting
Education:
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

Agenda
Lifecycle Validation Requirements
1. Regulatory Standards
2. Stage 1 Development
3. Stage 2 - Validation
4. Stage 3 Lifecycle

Confidential

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.

Audience Quick
Benchmarking Poll #1

How many of you have read the 2011 FDA

Guidance on Process Validation?
Yes or No

Process Improvement?

Grandpa
s Car

Future
Grandkid
s Car
6

Guidance Evolution
from 1987 to 2011
1987

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

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

Learning Progression

Poor design,
planning, process
and
understanding
Unexplained variation,
Product and process
problems, Process not in
control. Major Learning!
Potential substandard
product on
PQmarket
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

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.

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
11

Process Validation Stages

Stage 1
Process
Design

Building
and
capturing
process
knowledg
e

Establishin
g a control
strategy

Stage 2
Process
Qualification

Design of
facility and
qualificatio
n of
utilities &
equipment
(IQ/OQ/PQ)

Stage 3
Continued
Process
Verification

Process
Performanc
e
Qualificatio
n (PPQ)

Implemen
t 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

15

Schematic of Stages
(New Process or Product)
Stage 2

Stage 1

Process
Design

Evaluate/Confir
m

s
ge
an
Ch

Ch
an

ge
s

Stage 3

Distribut
e

Continued
Process
Verification

Process Qualification
(PQ)
Design of
Facilities &
Qualificatio
n of
Equipment
and Utilities

u
b
i
r
t
Dis
e

Process
Performanc
e
Qualificatio
n (PPQ)

Ref: Grace E. McNally FDA (Guide Leader) Sept 15, 2010

16

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

17

Schematic of Stages
(Legacy Process or Product)
Stage 2

Stage 1

Process
Design

Evaluate/Confir
m

s
ge
an
Ch

Ch
an

ge
s

Process Qualification
(PQ)
Design of
Facilities &
Qualificatio
n of
Equipment
and Utilities

Process
Performanc
e
Qualificatio
n (PPQ)

Variation Detected
Stage 3

Distribut
e

Continued
Process
Verification

u
b
i
r
t
Dis
e

Ref: Grace E. McNally FDA (Guide Leader) Sept 15, 2010

18

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

19

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
20

STAGE 1: PROCESS
DESIGN

Quality Target Product Profile (QTPP)

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
21

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

22

STAGE 1: PROCESS
DESIGN

Critical Quality Attributes (CQAs)

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

23

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
24

STAGE 1: PROCESS
DESIGN

Define the Manufacturing Process

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

25

STAGE 1: PROCESS
DESIGN

Analytical Methods

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
Dont forget that analytical instrument in and of themselves also
need to be calibrated, qualified and maintained

26

STAGE 1: PROCESS
DESIGN
Risk
Assessment and

Parameter Criticality Designation

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
27

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

28

STAGE 1: PROCESS
DESIGN

Process Characterization

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

29

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
30

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

31

STAGE 1: PROCESS
DESIGN

Control Strategy

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
32

STAGE 1: PROCESS
DESIGN

Control Strategy

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

33

STAGE 1: PROCESS
DESIGN

Control Strategy

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.

34

STAGE 1: PROCESS
DESIGN

Control Strategy

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
35

STAGE 1: PROCESS
DESIGN
Clinical
Manufacturing Experience
Batch Records and Production Data

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

36

STAGE 1: PROCESS
DESIGN
Process Design Report
Development Document

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
37

STAGE 1: PROCESS
DESIGN
Process
Validation Master Plan

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
38

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

39

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

40

STAGE 1: PROCESS
DESIGN

Expectations

Best Practice

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
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
41

Quick Case Study /

Knowledge application
Process
List the CPPs

Weighing two solids (active

and stabilizer)
Dissolving in Water for
Injection
Sterile Filtration
Fill into Single use bottles

Type answers here

42

Process Risk Assessment

Tracking
Perform Risk
Assessment
and List RPN

List Process
Steps and
CPP / CQA
Proces
s
Flow

CPP

Determine MS
Validation
Status

Ris
k

Measure
System
Validate
d

Spec
Rational
e

Process
Quality
Data
updated

RPN
<
100

Yes / No

Yes / No
Spec
Range

Yes / No

Evaluate
Rationale for
Specification

Check Data
Quality, Process
State of Control

Statistical Capability Assessment

Control Charts
Pattern
Analysis

Average /
Standard
deviation

Distribution

Capability Assessment
K2

PPK

analysis

CQA
Monitor
In
Normal
Product
(Yes /
No)

Raw
Material
Release

Alkylati
ng
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

43

STAGE 1: PROCESS
DESIGN

Expectations

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

Best Practice

1)
2)
3)
4)

Make it accessible
Make it searchable
Make it clear!
Allow amendments

44

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

45

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

48

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

53

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

55

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!

Lets 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

Best Practice

1)
2)
3)
4)
5)
6)
to

Summary of results
Confirm Process Performance value
List of CPPs by Risk Priority Number
Control system
Determine confidence intervals
Justification for reduced testing (hand-shake
Stage 3)

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 CQAs 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

70

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.)

71

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

72

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!

73