A Framework for Technology Transfer to the
Emerging Markets to Satisfy the New
Process Validation Guidance
Bikash Chatterjee
Pharmatech Associates
ISPE Commuter Conference
February 21, 2012
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Agenda
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Introduction
Comparing the New Process Guidance to the 1987 Guidance
Pharmatech's Roadmap
Case Study
Considerations for the Emerging Markets- China
Questions
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Overview of the New PV Guidance
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Issued in January 2011
Based on experience gathered by the FDA since 1987
Radical departure from the original concept of process validation
Scientific understanding in order to control process variability
Integrates basic principles of ICH Q8 and Q9
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Who is Affected by the Guidance
Manufacturers will be directly affected by the changes if they sell
products into FDA regulated markets in the following categories:
• Human drugs
• Veterinary drugs
• Biological and biotechnology products
• Drug constituent of a combination drug/device
• Both finished product and active pharmaceutical ingredient (API)
manufacturers are affected
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Process Validation Definition
• For years, many in the industry have been able to recite the
FDA’s 1987 definition of process validation. The 2011 guidance
has updated the definition and shifted the focus from
documentation to “scientific evidence” throughout the product
life cycle
1987 Definition
2011 Definition
“establishing documented evidence
which provides a high degree of
assurance that a specific process will
consistently produce a product meeting
its pre-determined specifications and
quality characteristics”
“the collection and evaluation of data,
from the process design stage
throughout production, which establishes
scientific evidence that a process is
capable of consistently delivering quality
products”
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Ramifications of the Validation Product
Lifecycle
• The life cycle approach to validation has significant impact on
manufacturers who previously have seen validation as a discreet effort
at the commencement of product commercialization
• For many companies, core validation activities have been IQ, OQ, PQ
and 3 process validation batches. The FDA is keen to move firms away
from this thinking. Indeed the guidance states:
“Focusing exclusively on qualification efforts without also
understanding the manufacturing process and associated variations
may not lead to adequate assurance of quality.”
• Verifying adequate assurance of quality will involve assessment of all
three stages described in the guidance. This will significantly increase
emphasis on prequalification activities such as product development, as
well as assessment of procedures for, and results of ongoing process
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verification
The New Process Validation Guidance
Stage 1
Process
Design
2011
FDA Process
Validation
Guidance
Stage 3
Process
Monitoring
Stage 1: Process Design
• Define the Knowledge Space
• Identify Critical Process
Parameters
• Determine Control Strategy
Stage 2
Process
Qualification
Stage 2: Process Qualification
• Equipment/Utility/Facility
Qualification
• Process Performance Qualification
Stage 3: Continuous process
Monitoring
• Monitoring of Critical process
Parameters as part of APR and
other Monitoring programs
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Typical Activities by Stage- Stage 1
Stage
Intent
Typical Activities
Process
Design
To define the commercial process
on knowledge gained through
development and scale up
activities. The outcome is the
design of a process suitable for
routine manufacture that will
consistently deliver product
that meets its critical quality
attributes
A combination of product and
process design (Quality by Design)
Product development activities.
Experiments to determine process
parameters, variability and
necessary controls, risk
assessments. Other activities
required to define the
commercial process
Design of Experiment testing
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Typical Activities by Stage- Stage 2
Stage
Intent
Typical Activities
Process
Qualification
To confirm the process
design as capable of
reproducible commercial
manufacturing
Facility design
Equipment & utilities qualification
Process Performance qualification
(PPQ)*.
Strong emphasis on the use of
statistical analysis of process data to
understand process consistency and
performance
* Note: The term “Process Performance Qualification” or PPQ has been carried over from the 1987 guidance. This term is
analogous with the traditional concept of ‘process validation’, as multiple batches of product made at commercial scale
under commercial manufacturing conditions. It is not the same as the concept of ‘equipment performance qualification’.
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Typical Activities by Stage- Stage 3
Stage Intent
Typical Activities
Continued
Process
Verification
Proceduralised data collection from
every batch
Data trending and statistical analysis
Product review
Equipment and facility maintenance
Calibration
Management review and production
staff feedback
Improvement initiatives through
process experience
To provide ongoing
assurance that the
process remains in a
state of control
during routine production
through quality
procedures and
continuous improvement
initiatives
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Equipment Qualification
What has happened to the concept of IQ, OQ and PQ for
equipment?
• It has widely been recognized that there is no mention of the terms
installation, operational or (equipment) performance qualification in
the new guidance. Does this mean that equipment IQ, OQ and PQ
are no longer required?
• The answer is both yes and no! Yes, in that there is no expectation
expressed in the guidance for the preparation of three stages of
qualification documents for critical equipment. No, in that there is a
clear expectation that equipment will be qualified, and that the
qualification will include all the aspects that have traditionally fallen
into the IQ/OQ/PQ categorization
• The new guidance shifts the focus from completing a suite of
qualification documents, to ensuring that equipment and utility 11
qualification activities are appropriate and complete
Equipment Qualification
• While there is now less focus on what equipment qualification activities
are called, there is little difference between the requirements of the old
and new guides, as illustrated in the table below
1987 Guidance
2011 Guidance
Describes “Installation Qualification”
which, in practical terms, refers to IQ,
OQ and arguably equipment PQ. The
1987 guide does not mention OQ or
equipment PQ
Describes “Equipment Qualification”
which, in practical terms, refers to IQ,
OQ and equipment PQ
Describes “Process Performance
Qualification” which, in practical terms,
refers to equipment PQ (if not previously
covered) and prospective process
validation batches
Describes “Process Performance
Qualification” which, in practical terms,
refers to what we would think of as
prospective process validation
batches
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The Three Golden Batches
• The new guidance makes it clear that it is the manufacturer’s
responsibility to provide assurance that the process is
adequately qualified. The use of statistical methods to provide
objective evidence of this is strongly recommended
• In practice, this may mean that 3 batches is sufficient to provide
the necessary data, or it may be that more are required (it is
unlikely to be less). The manufacturer needs to assess, justify
and clearly state those requirements during the preparation of
the PPQ protocol
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Revalidation
• The 1987 guidance included the concept of revalidation of
processes when changes to a process are introduced (e.g.
changes in formulation, raw material, equipment), or when
process variation is detected
• The 2011 guidance has revised this concept with the
introduction of Continued Process Verification. This involves the
ongoing assessment of process data (in-process, finished
product, equipment parameters, etc.) against variability limits
established during the first two stages of process validation
• The sorts of changes which previously required revalidation may
now be adequately addressed through a company’s Continued
Process Verification procedure, incorporating the use of
statistical and qualitative methods, as well as risk assessment 14
Matrix Approach
• The 1987 guidance expressly discouraged matrix approaches to
process validation, where multiple similar products,
presentations or equipment are grouped together
• Conversely, the 2011 guidance provides specific acceptance of
the practice, stating:
“Previous credible experience with sufficiently similar
products and processes can also be considered”.
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Concurrent and Retrospective Validation
• The concept of concurrent validation was not included in the
1987 guidance
• The new 2011 guidance provides information on the precise
circumstances under which concurrent release of validation
batches is acceptable. These include:
1. infrequent product manufacture
2. necessarily low volume or short shelf-life manufacture
(e.g. radiopharmaceuticals)
3. manufacture of medically necessary products in short
supply
• The FDA expects that concurrent validation approaches will be
used rarely. If used, the approach must be fully justified and
additional expectations for customer feedback and stability are
required
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Legacy Products
• The 2011 FDA guidance states: “Manufacturers of
legacy products can take advantage of the knowledge
gained from the original process development and
qualification work as well as manufacturing experience
to continually improve their processes. Implementation
of the recommendations in this guidance for legacy
products and processes would likely begin with the
activities described in Stage 3.”
• In the end there can only be one standard for validated
products
• Firms must develop a plan to bring all products up to the
same level of control
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Establish
PAR/NOR
CPPs/Risk
Assessment
PPQ
Prerequisites
– Point...
Historical
Performance
Equipment
Design
Characterization
Studies
– Point...
– Point...
– Point...
PPQ
–
–
–
–
Point
Point
Risk
Point
Assessment
Point
Process Monitoring
Product
Design
Process Reproducibility
Process Understanding
Pharmatech’s Technology
Transfer Roadmap
Continuous
Improvement
Risk
Assessment
Verification
Verification
Change Control
and Stage 3
Recommendation
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CASE STUDY
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Case Study Application
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Lexicon
• Critical Process Parameter (CPP): A process parameter
whose variability, within defined limits, has an impact on a
critical quality attribute and therefore should be monitored or
controlled to ensure the process produces the final drug product
quality
• Critical Quality Attribute (CQA): A physical, chemical or
microbiological property or characteristic that should be within a
predetermined range, range or distribution to ensure the desired
final product drug quality
• Critical To Quality Attribute (CTQ): An in-process output
parameter that is measured and/or controlled that should be
within a predetermined range, range or distribution to ensure the21
desired final product drug quality
Stage 1 Process Understanding
• Product Design
• Process Risk Assessment
• Equipment/Process Characterization Studies
– Sampling Plans
– Sampling Techniques
– Method Robustness
• Design Space Establishment
• Validation Master Plan
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Product Design
• Why go back to product design?
– Understand what is important: Product
Requirement Specification (PRS)
– Have solid grasp of formulation and product
design rationale
• Formulation may provide insight as to which processing
steps are critical downstream
• Rationale for product design helps define how the
formulation, raw materials and process steps are related
to achieving desired product performance
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Key PRS Specifications
Key criteria from the PRS include:
• Greater than 50 percent Active Pharmaceutical
Ingredient (API)
• Round 200 mg tablet
• Coated to mask taste
• 12-hour drug release with the following specifications:
– 4 hour dissolution 20-40 percent
– 8 hour dissolution 65-85 percent
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Raw Material and API Considerations
• Consider existing qualified Suppliers when choosing
excipients
• Includes a review of products with similar PRS
requirements
• Foundation for Knowledge Management effort
• API characterization includes Supply Chain and
Quality Engineering feedback from current products
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Tablet Formulation
Raw Material
API
Microcrystalline cellulose
Povidone K 29-32
Lactose
Mg Stearate
Purified water
Coating Solution Raw Material
Eudragit Coating Solution
Triethyl Citrate
Talc
Water
%w/w
60
22
5
12
1
QS
%w/w
12
1
1.5
QS
Function
Active ingredient
Excipient filler
Granulation binder
Excipient filler
Lubricant
Solvent
Function
Controlled release
polymer
Plasticiser
Glidant
Solvent
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Process Risk Assessment
• Helps identify which processing steps could affect
process stability in Stage 2
– Process map to capture inputs, outputs, and
control variables
– Process FMEA’s to prioritize key process steps
and KPIV’s
– Critical to Quality Attributes(CTQs) identified
• Helps focus characterization studies
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Risk Assessment Process Map
• Identify formulation
driven PRS
requirements
• Establish boundaries
for the process step
risk assessment
Develop Process Map
• Identify controlled and
uncontrolled variables
• Establish basic
measurement approach
• Separate between scale
independnet and
dependent varaibles
Identify
CPP/CTQ/CQAs
• Conduct risk map
• Review development
data
• Analyze historical
performance to set
acceptance criteria
Development/
Historical
Data Gap Analysis
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Process Unit Operation Risk Assessment
CQA
Appearance
Assay
Impurity
Blend
Uniformity
Drug Release
Particle Size
Distribution
Justifications
for High
Rating
Process Steps
Blending
Low
Medium
Low
High
Granulation
Low
Low
Low
Low
Drying
Low
Low
Low
Low
Milling
Low
Low
Low
Medium
Low
Medium
Low
Low
Low
High
N/A
N/A
Milling screen
size and
speed can
affect the PSD
and therefore
the powder
flow and tablet
fill weight
control
Compression
Medium
Low
Low
High
Coating
High
Low
Low
Low
Medium
Low
Medium
Low
High
Low
Blending can
affect blend
uniformity, assay,
and drug release
profile
Compression can
affect drug
uniformity in the
tablet based upon
particle size
variability and flow
The final
appearance
and drug
release rate are
affected by the
coating quality
and
reproducibility
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Relationship Between Proven Acceptable
Range and Normal Operating Range
Max Set Point
Run(s)
Variability of actual data
around set point
PAR
Target Set Point
NOR
Limit of individual
excursions
Min Set Point
Run(s)
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Duration of process
Historical Analysis
• The absence of development data establishing the PAR and
NOR for the CPP can be ascertained to some extent by
evaluating the historical behavior of each parameter along with
the corresponding behavior of the CQAs for the unit operation
• Data should be extracted from multiple batch records to
determine whether the process is stable within lot and between
lots
• The team went back into the batch records of approximately 30
lots across a period of one year to extract the necessary data.
This exercise also gave some indication as to whether the
parameter was truly a CPP, based upon whether it had an
impact on the corresponding CQA for the unit operation
• Evaluate scale independent and scale dependent parameters
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Control Charts
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Process Capability Analysis
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I Chart of PSD
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Correlation Plot
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Equipment Design Considerations
• Compare underlying equipment design and
configuration differences
• Focus on impact of equipment design on scale
dependent parameters
• Objective during transfer and scale-up is to
understand where equipment can affect the PAR And
NOR for the transferred process
• Also consider final PV considerations such as
sampling plans, sampling technique, and method
robustness
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Historical data Review Conclusion
• Dissolution testing of uncoated tablets across the
process range were 100% dissolved in 3 hours
• Storage studies determined bulk granulation and
uncoated tablets were sensitive to humidity
• Operating characteristic (OC) curves developed for
each unit operation to understand the relationship
between sampling size and sampling risk (AQL vs.
LTPD)
• Highlight sampling challenges prior to design space
activity
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Tech Transfer Equipment Comparison
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Unit Operation
Compounding
Fluid Bed
Granulation/Drying
CPP
Mixing speed
Water temperature
Addition rate
Spray Rate
Inlet Air Humidity
Atomization
pressure
CTQ
Fully DissolvedVisual
Granulation PSDd10, d50, d90
Moisture content
LOD
CQA
Content
Uniformity
Potency
Bulk/Tapped
Bulk Density
Milling
Blending
Compression
Coating
Screen size
Mixing Speed
Mixing Time
Pre-compression
force
Compression force
Spray Rate
Atomization Air
Pressure
Inlet Air
Temperature
Summary of
CPP/CTQ and
CQA Assumption
for Tech Transfer
PSD
Tablet Thickness
Tablet Weight
Tablet Hardness
Friability
Percent Weight
Gain
Appearance
Content
Uniformity
Potency-Assay
Dissolution
profile
Content
Uniformity
Potency-Assay
Dissolution
Percentage at 4
and 8 hours
Potency-Assay
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Tech Transfer-Sampling Qualification
• Sampling Methodology Qualification
Gage R&R conducted with sampling equipment for each
unit operation. GRR< 20%, Distinct Categories > 5
• Sampling Plan Development
Could use ANSI Z1.4-2008 or Zero-Acceptance Plan.
Used Power calculation, e.g. Powered at 80% with 5% as
significant difference for a known SD
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Tech Transfer Characterization Study
• Historical review concluded final product CQA for
dissolution is not affected by upstream process
before coating
• Confirmation DOEs are required to establish PAR
and NOR upstream with a focus on process
predictability
• Coating process DOE’s designed to demonstrate
comparability, confirm CPP’s, and provide supportive
data for PAR and NOR
• Also included commercial studies, e.g. solution hold
time, pan load studies, etc.
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Drug Dissolution Dependence on Coating Weight
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Validation Master Plan
• Summarizes the rationale for Process performance
Qualification
– CPPs, CTQs and CQAs
– Summarizes the impact of controlled variables
– Introduces approach for understanding impact of
uncontrollable parameters
• Justifies sampling plan based upon process risk
• Defines acceptance criteria based upon product
CQA’s
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Stage 2- Process Qualification
• Demonstration phase of the PV cycle
• Precursors to this stage
– Facility and utilities that support the process must be in
state of control
– Process equipment must be qualified (i.e. IQ, OQ, PQs are
complete)
– In-process and release methods used for testing must be
validated and their accuracy and precision well understood
– Cleaning validation is complete
– Essential to have precursors completed to ensure
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unknown variability is due to process alone
Stage 2 Process Qualification (cont.)
• New term: Process Performance Qualification (PPQ)
– Intended to include all known variables from the
manufacturing process
– Focused on demonstrating reproducibility. This drives
the acceptance criteria
– Cumulative understanding of Stage 1 and Stage 2
– No more three lots and we’re done
– Performed as many lots needed to demonstrate a clear
understanding of variables and process is in control
– Data derived from studies will be used to measure
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manufacturing process in Stage 3
Establishing Acceptance Criteria
• Based upon reproducibility criteria
• For example if the Stage 1 performance for the 4 hr.
dissolution was 32% ± 2% against a specification of
20-40%:
– Acceptance criteria could be: 95% confidence
interval applied to a spec of 32 ± 6%
– Used a 2 sided t-Test with an α = 0.05 (0.025 on
the HA for < comparison)
– We used the ± 6% because it is 3 x std. dev. In a
normal distribution this covers 99.7 of the data
variability for a controlled process
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Why Can’t I Just Compare My Result
Against the Acceptance Limits?
• We did not know the true mean and standard deviation of the
population That is the premise behind the t-test. If we knew it we
would use the z-test
• We only knew the behavior of our sample population and we
must infer that the process population behaves the same. That
is why we apply the confidence interval to the assessment and
apply the alternative hypothesis to test if the variability and
mean is within what has historically seen
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Stage 3 Continuous Process Verification
• Goal of this stage is to show assurance that the
process remains in control
• Need monitoring program to detect gradual or
unplanned departures from the process
• Program should be derived from the understanding
and knowledge from Stage 1 and 2 to establish alert
and action limits
• Use statistical analysis to determine performance
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Stage 3 Continuous Process Verification
(cont.)
• All parties involved in the development, analysis and
evaluation of the data and process should have a
solid understanding of past performance and its
implications on process stability and product
performance
• Consolidating the information in a central document
or repository will ensure some continuity of learning
and will allow continuous improvement or CAPA
activities to build upon best practices of the past
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Process Validation DeliverablesLegacy Products
Stage 2
Process
Qualification
• Data gathering protocol
• Reporting Dashboard/ SOP
• Summary report
Stage 3
Continuous Process
Verification
Go/No Go
Decision
• PPQ Prerequisite reports
• Tech Transfer
characterization studies to
establish PAR/NOR
• Risk map confirmation
• PPQ studies and
recommended CPPs
Go/No Go
Decision
Stage 1
Process Design
Go/No Go
Decision
• Review historical
performance and risk
map
• Identify predicate process
PAR and NOR
• Identify knowledge gaps
for scale dependent
variables
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The Emerging Markets- China
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Demographics
• Population - 1.3 billion people
• “One Child” policy to limit growth, but
social impact
• Population will peak at 1.6 billion in 2030
• 70% of population located in south and
east coastal regions
• 70% of population lives on the land
• Population and Employment – China
must create 13 million new jobs each
year
• Population Trends – Aging population
and declining births
• Han Chinese make up 92% of population
– 55 different minorities
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Business Culture
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General Principles
Relationships
Great Family – hierarchy
Ritual and protocol
Risk Taking – acceptance of responsibility
Trial and Error
Initiative
Fear of negative reporting
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Cultural Paradox’s
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General vs. Specific
Man vs. Law – Guangxi and relationships (Trust)
Group vs. Individual – core group is the family
Family vs. Common Good
Intuitive vs. Scientific
Hierarchy vs. Matrix – clean chain of command
Form vs. Substance - issue of FACE
Face vs. Results
Shame vs. Guilt
Order vs. Chaos
Hustle vs. Planning
Concrete vs. Abstract – impact on services
Indirect vs. Direct
Backward looking/conservative vs. Forward looking
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Common Errors
• Irrational Exuberance
• Trust but no verification
• Failure to take proper legal and financial
precautions
• Acceptance of “This is the way we do it in China”
• Worry about offending Chinese hosts
• Believing in “Friendship”
• Not getting the home office on board
• Failure to recognize the cultural/systemic
differences between China and the home market
• Not establishing company culture and values
• Not knowing when to say NO
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Trends and Opportunities
• Infrastructure Development
• Environmental and Energy
Efficiency
* Renewable Energy * Clean Coal *Waste
Management
• Pre-Clinical Product
Development and R&D
• Manufacturing and Packaging
• Clinical Studies
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Challenges for Foreign Businesses
• The need to understand the role of the
Government
• The constancy of Change
– Regulations and Standards- GMP 10
– Authorities
– Market conditions
• Corruption, IP Protection and rule of law
• Increasing Economic Nationalism
• Managing control and Compliance across the
board
• Pace and depth of Local Talent
• The right Organizational Structure
• Corporate Engagement
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Government Relations
Key Objectives
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Reputation enhancement
Problem/Issue resolution
Policy watch and regulatory shaping
Direct Commercial Support
Where possible align your goals with those
of the government
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Common Errors
• The Role of Guanxi - particularly the belief
that a company must rely on someone
with connections to achieve its goalsmake it difficult for companies to conduct
government affairs effectively
• The successful government affairs
professional in China places greater
emphasis on interpersonal communication,
analytical, and critical thinking skills than on
personal relationships or contacts
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Positioning for Growth - Partnerships
• Partnering with local firms will in some
cases be necessary and now in many
cases feasible
* Local firms : have the home court
advantage in terms of cost and
resources
Focus on:
* Intellectual rather than physical capital
* Firm that have licenses
* Channel enlargement – but never easy
* Private firms that demonstrate good
management
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Negotiation Strategies
• Anything is possible…everything is difficult and
remember - the negotiation is never done
• Know the Objective – know the other side
• Understand and set limits – don’t be anxious –
don’t get involved in a pure price discussion
• Explain your position – be clear be direct - make
concessions reluctantly – stress shared
responsibility/gain
• Dig in or flex - don’t get emotional – decide before
hand where to give
• Always support your team – no public
disagreement
• Always have your own interpreter
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Conclusion
• Technology Transfer must consider the new PV
guidance at the outset in order to be able to meet the
requirements for Stages 1, 2 and 3
• The framework described works equally well for legacy
products and newly developed products
• No single answer to the question of demonstrating
process capability. Each firm must define and justify its
approach and acceptance criteria for demonstrating
reproducibility
• Quality’s role is much more complex in determining
suitability and compliance
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Questions?
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Thank You for Your Attention!
Bikash Chatterjee, President & CTO
Pharmatech Associates, Inc.
3847 Breakwater Avenue
Hayward, CA 94545
510-732-0177
bchatterjee@pharmatechassociates.com
Or visit our website at:
www.pharmatechassociates.com
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