Quality Application within BioProcess Lifecycle R&D to Commercialization Eileen Cortes February 5, 2018
Agenda • Take Away • Background: Baseline Concepts • Process Development Lifecycle • Application of Quality Practices by Phase of Development • Quality by Design (QbD) • Quality Risk Management (QRM) • Process Validation • CMOs • Open Discussion
Take Away… • How to live QUALITY throughout a BioProduct Lifecycle, from its Introduction to its Commercialization. • Identification of “how much Quality” within PD stages • Identification of “Quality Risks” – Cumulative Risk Awareness • Quality Control & Maintenance
Background
Baseline Concepts Internal Quality Program Industry Guidelines & Standards Law
Baseline Concepts GxP Across the Organization • GxP’s Building Blocks • Basic Fixed Principles • Record and Documentation requirements for the materials being produced or processed • Establishment of appropriate Quality Systems • Variable Principles • Contamination requirements and controls • Facility Requirements • Design Requirements • Defect detection programs • Monitoring of Process and Suppliers • Material controls • Validation and Qualification Practices
Baseline Concepts • Product Development Lifecycle • During Clinical Phases of PD, supplies of a new drug are manufactured. • These IND’s (investigational new drugs) shall be safe for use in humans and have the quality attributes necessary for an appropriate clinical product evaluation. What How Product Process Development Development In pa In parall llel Commercially Feasible Process that is fully in compliance with cGMPs
Baseline Concepts GCP GMP • International quality • GMP is a system for ensuring standard provided by ICH that products are • Reference: E6 Good Clinical consistently produce and Practice controlled according to • Enforces tight guidelines on Quality Standards. ethical aspects of a clinical study. • Enforce by the FDA to assure • Comprehensive safety and efficacy of drug documentation for the products. clinical protocol, record keeping, training and facilities including computer and software. • Quality Assurance ensure that these standards are met.
Process Development Lifecycle
Goal of Process Development • Main Goal • DESIGN, DEVELOP and CHARACTERIZE a PROCESS that can be TRANSFERRED to a COMMERCIAL ENVIRONMENT • SUPPORT a Manufacturing Process that will yield a Quality Product on a CONSISTENT basis • CONTINUE after approval to INCREASE PROCESS UNDERSTANDING, IMPROVE Process throughout product life- time, MITIGATE risk of potential product defects and Disruption to Supply
How? Partnership -Integration of CMC and cGMP’s *Figure for PDA Technical Report No. 56 “Application of Phase Appropriate Quality Systems and cGMP to the Development of Ther apeutic Protein Drug Substance
Integration of CMC & cGMP Quality Systems • Quality Systems in place to ensure that: • CMC requirements are described in proper documentation submitted to authorities to gain approval of clinical study start. • cGMP requirements have to take the CMC requirements into account, derived from regulations/guidelines that allows consistent production and testing of a quality product (purity, safety, potency). Product ICH Q8, Q9, Q10 & Q11 CMC cGMP
How CMC and cGMP can work together? Focus Submission/Dossier Facility/Manufacturing/ Testing Industry Role Setting criteria and Implementing controls for manufacturing and manufacturing and testing practices quality designed to meet manufacturing and quality standards Guidance ICH Q1 to Q6 ICH Q7 Agency Role Assessment and Verification of approval of conformance to cGMP manufacturing and and to regulatory quality standards and submission/dossier controls standards through facility inspections; evaluation of quality system Note: Validation summary data is included in regulatory application.
Quality Practices by Phase of Development
Application of Quality Practices by Phase of Development • Phase-Approach – 5 Stages 1. Research and Development – At Laboratory Environment 2. Toxicity Studies • Effective documentation and characterization • Similar/representative material 3. Phase 1 trials • Goal: Start to show that quality has / is designed into the process 4. Phase 2 trials • Goal: Increase Quality and cGMP expectations 5. Phase 3 trials • Goal: Validated Processes, Methods and Controls
cGMP & Quality per Phases
cGMP by Stage of Development • Recommendations for the implementation of cGMP and quality system for products under development through Phase 3 reflect a graded phase approach in where cGMP expectations increases as development approaches later phases. • Recommendations are per FDA defined Systems: • Facilities • Equipment • Materials • Production • Laboratory • Packaging / Labeling • Quality
cGMP by Stage of Development System R&D Phase 1 Phase 2 & 3 • • Quality Unit must be in place. • Responsibilities are governed by Personnel with Quality science Product is release by QA/QP cGMP. • Quality • QA/QP ensures proper approval of background and after satisfactory review of Management trained in GLPs. batch records and data, deviations and CAPAs. • Documentation • • Quality standards in place. Awareness of analytical results, COA, • Product Release GMPs. environmental and water results • Change • Failures should be and compliance with IND Management investigated to registration. • Deviations/CAPA increase process • Auditing knowledge. • Quality Agreements • • Facilities suitable for • Facilities suitable for intended use. Appropriate for Facilities • Includes: laboratory intended use • Critical Utilities • • Critical utilities should be • Controlled of Use of high • Non critical quality water (WFI qualified manufacturing utilities • Facility cleaning and or RO), bioburden areas, segregation, • Water reduction sanitization program in place pressure • Process Gases filtration with differentials • Segregation/contai • Critical utilities testing for nment endotoxin should be • Maintenance/Sani commissioned and tization qualified • PMs in place • Alarm strategy in place
cGMP by Stage of Development System R&D Phase 1 Phase 2 & 3 • • Equipment should be • Critical equipment should be fully Equipment Equipment maintained, commissioned, calibrated, qualified prior to PPQ or process • Qualification cleaned, and and monitored to ensure fit validation runs. • Maintenance • Preventive maintenance, calibrated as per for use. • Cleaning • Equipment used for process vendor cleaning/sanitization/sterilization • Calibration recommendations should be sterilized by a process and calibration program • Computerized validated process or sterile should be in place and fully Systems disposable equipment. documented per ICH Q7. • Records of equipment • Cleaning/sanitization/sterilization cleaning should be generated should be validated prior and maintained. Computer conformance lots. • Computer systems for critical GMP systems should be qualified for the intended use. equipment should be validated. • Alert and action alarm limits for deviations from set points and process parameters should be defined based on risk assessment.
cGMP by Stage of Development System R&D Phase 1 Phase 2 & 3 • CoA and expiry • • Same controls from phase 1 Good controls over Materials • Incoming items and • Suppliers should be fully qualified materials is required to • General controls documentation ensure proper receipt, • Receipt & (logbooks) storage, release and Quarantine • Equipment/Units integrity. • Sampling and • used with regular Release of materials based Testing calibration/mainten on CoA • Storage and ance expiry • Warehouse procedures • Supplier Qualification
cGMP by Stage of Development System R&D Phase 1 Phase 2 & 3 • Quality by Design • Process and equipment • Same as Phase 1 Production • Routine • Acceptance ranges for CPPs should scaled based on size of • Production documentation and projected clinical batch. be established operations • Batch records most capture • Batch records should be quality practices • Hold Times • Procedures and process steps and main data. implemented • In process • IPC should be recorded (note: • Acceptance ranges for IPC should Equipment logs sampling and • Area Clearance and acceptance criteria for in- be defined controls segregation process controls and results • Pooling criteria • Reliability of are not yet set). • Contamination • Initial acceptance ranges suppliers controls defined for CPPs. • Cross- • Process flow charts. contamination controls
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