Expectations for Early Phase cGMP Andra Miller The Biologics Consulting Group 301-871-1259
CBER’s Expectations for cGMP Compliance • GMPs expected throughout clinical studies • Level of compliance should increase as phases of study progress (stepwise approach) • Important early: adequate facility, QC/QA, aseptic processing, documentation • GMPs that develop with clinical studies: • Process validation, Methods validation, Process controls
Early Phase cGMP How to define the essential elements?
How to define? Early Phase • Identify critical steps in function of facility and in process • Develop controls
Vector Production Facility Hood Incubator Supplies Storage Waterbath In/Out Production Final Product Storage
Vector Production Facility Training Cleaning Monitoring Hood Incubator Supplies Storage Waterbath In/Out Production Equipment Receipt Storage Final Product Storage Distribution Release testing DOCUMENTATION
Documentation • Procedures • Standard Operating Procedures (SOPs) • Facility cleaning • Manufacturing • Records • Log of procedures performed • Batch production records • Lab records • Cleaning log
Procedures • Standard Operating Procedures- SOPs • Details of operations/ instructions • Written • Accessible to those doing work • File should be historical- tracks changes to procedures • Eventually all functions impacting product manufacture should be documented in SOP • Drafted by appropriate organizational unit, reviewed and approved by QA unit.
Records • Document accuracy of implementation of procedure • Filled out in real time • QA review and authorization of completed records on routine basis
Documentation- General • Must reflect reality • Must be followed • SOP Change Control • Procedure for modifying an SOP- proactive change • Process, authorization, implementation • Deviation reports • Documents a change from SOP that was not proactive • Record and justify on a separate form- signed • Store with relevant record
Documentation- General • Investigation reports • Documents investigation into reason for deviation, conclusions and follow-up • Example: positive sterility • Quality assurance review and authorization of SOPs and Records
Importance of Documentation • Allows control of the Facility • Allows control of Manufacturing Process • Tracking of Product Lots • Reviewed Upon FDA Inspection- demonstrates control
Vector Production Facility Training Monitoring Cleaning Hood Incubator Supplies Storage Waterbath In/Out Production Equipment Receipt Storage Final Product Storage Release testing Distribution DOCUMENTATION
Training • Each person involved in preparation of drug product shall have the education, training or experience to perform the assigned function. • Training should be in particular operation and cGMPs. • Anyone entering facility needs training & supervision (not a research lab)
Training- Procedures • SOP for training-when, how and content • Particular operations - individualized • GMPs – ongoing, repeated • Training conducted by qualified individual on a continuing basis • Formal courses, in-house program, on-the-job • Personnel at all levels should have appropriate training • Management, scientific staff, technical staff, maintenance/custodial staff.
Training- Records • Record of training program elements and materials – serves as documentation and reference • Record for each personnel: • Job description • Training requirements (based on activities) • Documentation of training completed • Curriculum vitae
Cleaning and Sanitization- SOP • Describe cleaning and sanitization process, agents, frequency/schedule, personnel responsible • For Phase I, cleaning agents selected based on manufacturer’s specifications – no formal validation • Gather information on effectiveness to control organisms in facility via environmental monitoring (alter as needed). • Use more than one cleaning agent in program
Cleaning and SanitizationRecords • Log to verify that cleaning and sanitization performed according to SOP • For each individual activity/ room • Date • Time • Signature
Environmental Monitoring • SOP to monitor: • Viable and non-viable particulates, surfaces, personnel • Methods, Location, Frequency, Responsible party • Define alert limits and action limits and procedure for follow-up • Records/logs: • Date, location, method, result, signature
Entering Facility • Since bi-directional, need SOP for entry and exit to give temporal separation • Personnel • Waste • Gowning Procedure • Protective clothing used and order of gowning • Available for reference • Records- Log of personnel entering to maintain control
Receipt and Storage of MaterialsSOP • Record Date of Receipt, Lot number in a Log • Visual inspection upon receipt • Damage, proper labeling • Storage in quarantine, pending release • Label as to status of material (quarantined) • Segregate from released materials • Qualifying materials for use • Inspection or test as needed (identity, purity, quality) by QC unit • Must conform to written specification • Release from quarantine • Re-label as to status of material (released or rejected) • Stored with released materials
Receipt and Storage of MaterialsRecords • Log for each material received • Date of receipt • Lot number • Date of quarantine • Result of qualification testing • Release date, signature
Equipment Qualification and Maintenance • SOP • For cleaning, maintenance, qualification for use • Testing Water bath temperature, and maintenance • Cleaning procedure and schedule of maintenance for Biosafety Cabinet • Records • Log documenting each activity was carried out • For each piece of equipment, log recording the batch processed (date, time, product and lot number)
Manufacturing ProcessSOP • Detailed instructions and protocols for each step in the manufacturing process • To assure uniformity from batch to batch • Documentation of deviations • Change SOP
Manufacturing ProcessRecords • Batch Production Record (BPR) • Prepared for each batch produced • Complete information relating to production and control of each batch • Documentation that each significant step in manufacturing, processing, packaging or holding were accomplished • Record of materials and equipment used • Reviewed and approved by QA unit to determine compliance with SOP prior to release and distribution.
Product Storage and Quarantine • Written SOP for storage of products, pending release including: • Requirements for Quarantine before release by QC unit • Requirements for storage under appropriate conditions so identity, purity, and quality are not affected • Records to reflect quarantine of product pending release (product, lot number, date)
Testing and Release for Distribution- SOP • Written procedures for sampling and testing • QC testing for identity, potency, purity, and safety • Established specifications/ acceptance criteria • Product must meet specifications for release
Testing and Release- Records • Laboratory records- include complete data derived from tests • Description of sample • Method used, calculations performed • Record of all data • Testing results and signature of “tester” • Certificate of Analysis listing all tests performed, specification and result for product- tabular format • Record of product movement from quarantine to release status • QA review and approval for product release
Product Distribution –SOP • Written procedures describing the distribution of products including: • Procedure for oldest approved stock to be distributed first • A system by which the distribution of each lot can be readily determined to facilitate its recall if necessary
Product Distribution- Records • Name and strength of product • Description of dosage form • Name and address of consignee • Date and quantity shipped • Lot number • Documentation of receipt by consignee • Return mail • Date, amount received, conditions of product and signature
Product Tracking • Extends from who was in facility, reagents, materials, equipment used in production through storage, release and distribution • Trace entire product “history” • Important if any problem occurs • Assay result • Malfunction of equipment • Patient adverse event • Product recall • Control over entire process
Summary • cGMP is important at all phases of development but can be implemented in a step-wise approach • Early phase cGMP requires attention to the facility, documentation and QC/QA. • Early phase cGMP elements can be defined by identifying steps in the facility and the manufacturing process that are critical for control over the process and seem logically necessary for production of a safe and consistent product