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

• 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

• 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 verification 6

2011 FDA Process

Validation Guidance

Stage 1 Process Design

Stage 2 Process

Qualification Stage 3 Process

Monitoring

Stage 1: Process Design • Define the Knowledge Space • Identify Critical Process

Parameters • Determine Control Strategy 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

The New Process Validation Guidance

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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

To provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement initiatives

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

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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 qualification activities are appropriate and complete

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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 17

Pharmatech’s Technology Transfer Roadmap

– Point... – Point... – Point... – Point...

– Point – Point – Point – Point

Product Design

CPPs/Risk Assessment

Historical Performance

Equipment Design

Characterization Studies

Establish PAR/NOR

PPQ Prerequisites

PPQ

Risk Assessment Verification

Change Control and Stage 3

Recommendation

Pro

cess

Und

erst

andi

ng

Pro

cess

Rep

rodu

cibi

lity

Continuous Improvement

Risk Assessment Verification P

roce

ss M

onito

ring

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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 the desired final product drug quality

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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 %w/w Function API 60 Active ingredient Microcrystalline cellulose 22 Excipient filler Povidone K 29-32 5 Granulation binder Lactose 12 Excipient filler Mg Stearate 1 Lubricant Purified water QS Solvent Coating Solution Raw Material %w/w Function Eudragit Coating Solution 12 Controlled release

polymer Triethyl Citrate 1 Plasticiser Talc 1.5 Glidant Water QS 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

• Identify controlled and uncontrolled variables

• Establish basic measurement approach

• Separate between scale independnet and dependent varaibles

• Conduct risk map • Review development

data • Analyze historical

performance to set acceptance criteria

Develop Process Map

Identify CPP/CTQ/CQAs

Development/ Historical Data Gap Analysis

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Process Unit Operation Risk Assessment

CQA Process Steps Granulation Drying Milling Blending Compression Coating

Appearance Low Low Low Low Medium High Assay Low Low Low Medium Low Low Impurity Low Low Low Low Low Low Blend Uniformity

Low Low Medium High High Low

Drug Release Low Low Low Medium Medium High Particle Size Distribution

Medium Low High Low Low Low

Justifications for High Rating

N/A

N/A

Milling screen size and speed can affect the PSD and therefore the powder flow and tablet fill weight control

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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Target Set Point

Max Set Point Run(s)

Min Set Point Run(s)

PAR NOR

Limit of individual excursions

Duration of process

Variability of actual data around set point

Relationship Between Proven Acceptable Range and Normal Operating Range

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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 31

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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Summary of CPP/CTQ and CQA Assumption for Tech Transfer

Unit Operation CPP CTQ CQA Compounding Mixing speed Fully Dissolved-

Visual

Water temperature Addition rate Fluid Bed Granulation/Drying

Spray Rate Granulation PSD- d10, d50, d90

Content Uniformity

Inlet Air Humidity Moisture content Potency Atomization

pressure LOD

Bulk/Tapped Bulk Density

Milling Screen size PSD Blending Mixing Speed Content

Uniformity Mixing Time Potency-Assay Compression Pre-compression

force Tablet Thickness Dissolution

profile Compression force Tablet Weight Content

Uniformity Tablet Hardness Potency-Assay Friability Coating Spray Rate Percent Weight

Gain Dissolution Percentage at 4 and 8 hours

Atomization Air Pressure

Appearance Potency-Assay

Inlet Air Temperature

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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. 41

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

unknown variability is due to process alone 44

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

manufacturing process in Stage 3 45

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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• Review historical performance and risk map

• Identify predicate process PAR and NOR

• Identify knowledge gaps for scale dependent variables

• PPQ Prerequisite reports • Tech Transfer

characterization studies to establish PAR/NOR

• Risk map confirmation • PPQ studies and

recommended CPPs

• Data gathering protocol • Reporting Dashboard/ SOP • Summary report

Stage 1 Process Design

Process Validation Deliverables-Legacy Products

Stage 2 Process Qualification

Stage 3 Continuous Process Verification G

o/N

o G

o D

ecis

ion

Go/

No

Go

Dec

isio

n

Go/

No

Go

Dec

isio

n

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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

• 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 • 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

• 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 goals-make 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 61

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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