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 Pharma Auto Ref. PWC 2001 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%
A New Approach to Compliance From Process Design throughout Continued Process Verification Process Design Verification Process Qualification Facility Design and Equipment Qualification Process Performance Qualification (PV) To market Continued Process Verification In control References: FDA Process Validation: General Principles and Practices, EMA Guidelines for GMP Annex 15 (draft issued February 2014)
Integrate the following guidelines and GMPs: ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality Systems Chinese GMP Challenge 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 Performance Qualification
During Operations
Seamless Integration
Production of monoclonal antibodies Case Study 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 Equipment Process People Control of CQAs Process Design SOPs Control of CPPs Material Attributes Raw materials Excipients Identification of critical systems and CPPs QC Methods Environmental control Facility design Training Establish and enforce QMS Affect CQAs? Utilities Materials Environment Management 13
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 Aseptic environment by batch start to ensure growth of the target cells (almost all other micro organisms will grow faster than CHO) Agitation in order to ensure even temperature & ph distribution without destroying product Control Strategy Qualification Verify material of construction, installation verification (surface finish, dead legs), sprayball coverage and cleaning/sterilization efficiency Installation verification, check operating parameters of agitator, temperature distribution verification Continued Process Verification/ Routine Manufacturing Sampling and evaluation of each batch. Monitor capability of process. Procedures for cleaning and preventive maintenance Procedure for preventive maintenance Control of CPPs is required (time, temp, ph) Correct information of the batch conditions must be displayed to the operator Installation verification (I/O and loop checks), design space verification Installation verification (hardware and software), sequence of operation verification Monitor CPPs in-line. Evaluate trends and adjust settings within design space Calibration program covering all instruments. Procedures for operators and preventive maintenance
Case Study: Control Strategies URS Req. No. URS Req. Description Critical Process URS Design/Function Parameters Design/Function / Design/Function Attribute IQ Protocol Test No. OQ Protocol Test No. Doc. Name Critical Quality Doc. No. Doc. Rev. No. (C, N, I) Attributes (CPP, CQA) Design/Function Doc. Ref. Description Verified in DQ Yes/No 2.1 4.8 16.4.9 Material of construction shall be 316L Material Equipment of and Piping Stainless Construction C Steel Report CQA: Materials Bioassay PHD21-04-MR-01 N/A 1 Material certificate stainless steel for all parts in product contact. Verification Bioreactor 04 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, N/A achieving a stable temperature at 37± 0.5 C within 40 min * from 121 C down to 20 C within 60 min 16.6.8 Equipment Temperature Mapping CPP: Bioreactor C 04 FS PHD21-04-FS-01 Verification 1 Temperature 16.7.9 Sequence of Operation Verification Functional specification Yes, doc ID: CN2880-T-014029 Yes, doc ID: CN2880-T-014029 4.4 Agitators shall be mounted at bottom of vessel. The speed shall be variable. GA Bioreactor 04 PHD21-04-GA-01 1 Installation drawing CQA: Bioassay 16.7.9 Sequence of Operation 16.4.1 Piping and CPP: Component Functional Bioreactor C 04 FS PHD21-04-FS-01 Verification 1 Installation Verification Temperature, specification ph Component Agitator 210XS series PHD21-04-DS-09 2 datasheet Yes, doc ID: CN2880-T-014029 Yes, doc ID: CN2880-T-014029 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 Quality Organization 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 Autonomy Mastery Purpose 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
Thank you for your attention! Questions? daniel.nilsson@aregab.se