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Seamless Integration of ASTM E2500, Annex 15, FDA Process Validation
Guideline and Chinese GMP in Large CapEx Project in China
Daniel Nilsson
Senior Management Consultant
Agenda
• Introduction
• A state-of the-art compliant life-cycle model for Process Validation
• Case Study: Implementation Process Validation Guidelines in China
• Considerations:
– the new Chinese GMP
– FDA Process Validation Guideline
– EU GMP Annex 15 “Qualification and Validation”
– ASTM E2500
– Cultural advantages and challenges in managing projects in China
– The management and leadership aspects of a risk-based approach
• Predictions and conclusion
China Is Learning Fast: A New Approach to Design and Validation is Needed
• Incapable processes lead to high cost of quality lead to low margins and/or high consumer prices
• With global competition, it is not sustainable to allow low process capability
• Leading manufacturers in China do not look back, they want to implement world class performance from the start
Sigma ppm Defects Yield Cost of
Quality
2σ 308537 69.2% 25-35%
3σ 66807 93.3% 20-25%
4σ 6210 99.4% 12-18%
5σ 233 99.98% 4-8%
6σ 3.4 99.99966% 1-3%
Pharma
Auto
Ref. PWC 2001
A New Approach to Compliance
Verification
To market
In control
Process
Design
Process Qualification
Facility
Design
and
Equipment
Qualification
Process
Performance
Qualification
(PV)
Continued
Process
Verification
From Process Design throughout Continued Process Verification
References: FDA Process Validation: General Principles and Practices, EMA Guidelines for GMP
Annex 15 (draft issued February 2014)
Challenge
• Integrate the following guidelines and GMPs:
– ICH Q8 Pharmaceutical Development
– ICH Q9 Quality Risk Management
– ICH Q10 Pharmaceutical Quality Systems
– Chinese GMP
– Annex 15 EU GMP ”Qualification and Validation”
– US GMP and FDA Process Validation Guideline
• Align the execution of a large CapEx project for a biotech facility in China with the resulting
life cycle model
• Manage the change
• Anchor the change
The Extended V-model
Initial GMP Risk Assessment and Control Strategy
Facility and Equipment Design and Verification
Process Validation/Process PerformanceQualification
During Operations
SeamlessIntegration
Case Study
• Production of monoclonal antibodies
• Biotech API, purification, formulation, fill and finish
• Quality by design approach implemented since 2012
– Fully integrated from Process Development through commissioning, qualification and process
validation
– Creates shared values and allows the company to work together in a cross-functional way, instead
of “silo” structure
– Reduced time for validation. A fully risk-based approach was used to identify critical areas
• Domestic company looking to export to EU and the US
Case Study: Risk Identification
13
Equipment Process People
Materials Environment Management
Material
Attributes
Control of CQAs Process Design
Identification of
critical systems
and CPPs
Raw materials
SOPs
Establish and
enforce QMS
Affect
CQAs?Environmental
control
Facility design
Utilities
QC Methods
Excipients
Training
Control of
CPPs
Case Study: Risk Identification
Example: For identification of risk scenarios related to equipment, specifically
how equipment could fail to deliver desired control of CPPs and CQAs, Risk
Breakdown Structures were used to harmonize the quality of the risk
assessments and GMP Risk Control Strategies
Case Study: Control Strategies
Risk Scenario Control Strategy
Qualification Continued Process Verification/
Routine Manufacturing
Aseptic environment by batch start to
ensure growth of the target cells
(almost all other micro organisms will
grow faster than CHO)
Verify material of construction,
installation verification (surface
finish, dead legs), sprayball
coverage and cleaning/sterilization
efficiency
Sampling and evaluation of each
batch. Monitor capability of
process. Procedures for cleaning
and preventive maintenance
Agitation in order to ensure even
temperature & pH distribution without
destroying product
Installation verification, check
operating parameters of agitator,
temperature distribution verification
Procedure for preventive
maintenance
Control of CPPs is required (time,
temp, pH)
Installation verification (I/O and loop
checks), design space verification
Monitor CPPs in-line. Evaluate
trends and adjust settings within
design space
Correct information of the batch
conditions must be displayed to the
operator
Installation verification (hardware
and software), sequence of
operation verification
Calibration program covering all
instruments. Procedures for
operators and preventive
maintenance
Case Study: Control Strategies
URS Req.
No.URS Req. Description
URS
Attribute (C, N, I)
Critical
Process
Parameters /
Critical Quality
Attributes (CPP, CQA)
2.1Material of construction shall be 316L
stainless steel for all parts in product contact.C CQA: Bioassay
4.8
The temperature in the jacket shall be heated
or allowed to cool to meet the following
requirements:
* from 20°C up to 37°C within 30 min,
achieving a stable temperature at 37± 0.5°C
within 40 min
* from 121°C down to 20°C within 60 min
CCPP:
Temperature
4.4
Agitators shall be mounted at bottom of
vessel. The speed shall be variable. C
CQA: Bioassay
CPP:
Temperature,
pH
IQ Protocol Test No. OQ Protocol Test No.
16.4.9 Equipment and Piping
Stainless Steel Materials
Verification
N/A
N/A
16.6.8 Equipment
Temperature Mapping
Verification
16.7.9 Sequence of Operation
Verification
16.4.1 Piping and Component
Installation Verification
16.7.9 Sequence of Operation
Verification
Design/Function
Doc. Name
Design/Function
Doc. No.
Design/Function
Doc. Rev. No.
Design/Function
Doc. Ref.
Description
Verified in DQ
Yes/No
Material of
Construction Report
Bioreactor 04
PHD21-04-MR-01 1 Material certificateYes, doc ID:
CN2880-T-014029
Bioreactor 04 FS PHD21-04-FS-01 1Functional
specification
Yes, doc ID:
CN2880-T-014029
GA Bioreactor 04 PHD21-04-GA-01 1 Installation drawingYes, doc ID:
CN2880-T-014029
Bioreactor 04 FS PHD21-04-FS-01 1Functional
specification
Yes, doc ID:
CN2880-T-014029
Agitator 210XS series PHD21-04-DS-09 2Component
datasheet
Yes, doc ID:
CN2880-T-014029
Cultural Advantages and Challenges in Establishing a Corporate Quality Culture in China
Opportunities
• Change Management is much
easier than in Western Countries
• As long as processes are clearly
defined, end results are
excellent
• Strong education system
• Low cost
• A lot of human resources
Challenges
• No quality culture like Japan
• Lack of creativity due to corporate
culture
• Weak understanding of Line - and
Project Management
responsibilities
• Belief that responsibility for
qualification and GMP compliance
can be outsourced
• Personals relationships (“guanxi”)
Opportunity: Create the Motivated QualityOrganization
Purpose
Autonomy
Mastery
A risk-based approach delivers important
aspects to the creation of the motivated*
organization:
- Purpose. Risk-based makes it clear
why we do the acitivities what we need
to do.
- Mastery. Risk-based provides the tools
needed to channel our expertise and
realize the truly process oriented
pharmaceutical quality system
- Autonomy. Once we create control
strategies that add true value, we can
allow for more autonomy
According to ”Drive” by Daniel H Pink
Conclusions
• Chinese leading manufacturers understand both the regulatory and business drivers behind
the QbD approach
• Chinese companies manage change better than Western companies
• There are already Chinese companies that have fully implemented QbD
• China is implementing GMP at level with EU, and in the future Chinese drug development
and manufacturing will be at level or above EU
• China has issues with management, leadership, innovation and creativity that is holding
them back- for now
• Any organization would benefit from going risk-based, since it breaks up the silo structures
between R&D, Process Development, Project, and Operations
