3rd Dimension of Product Translation: Industrialization BioMARC 3rd Dimension of Product Translation: Industrialization Becky Rivoire, B.S., RAC Director, BioMARC Department of Microbiology, Immunology & Pathology Colorado State University Regional Training Center for Product Translation Short-Course: Product Translation and Related Regulations December 10, 2008

Translational Critical Path for Medical Product Development http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html

Translational Critical Path Initiative IND BLA, NDA, 510k The template we will use was published by the FDA in 2004 and updated in 2006. It is called the translational critical path initiative. It depicts the progression of a product from basic research, through a prototype to preclinical and clinical development to get to the stage of submitting an application for a commercial license. It is broken into three dimensions: safety, medical utility, and industrialization. Good laboratory Practice (GLP) falls between the prototype and preclinical stage, current good manufacturing practice (CGMP) falls between preclinical and clinical development, and good clinical practice (GCP) is followed during clinical development. The IND application is submitted after preclinical trials and the BLA, NDA or 510k applications are submitted following Ph I/II/III clinical trials. The PDM Core is only geared to provide services to help move a product into preclinical and phase I/II clinical trials, to provide data to leverage industrial partners to move the project into a Phase III clinical trial, if appropriate. www.fda.gov/oc/initiatives/critical path/whitepaper.pdf 3

Industrialization Physical Design Bird’s Eye View Physical Design Characterization, Small Scale Production Preclinical lot (GLP grade material) Manufacturing Scale-up, Refined Specifications Clinical lots (cGMP grade material) Phase I Clinical Trial Phase II Clinical Trial Phase III Clinical Trial Mass Production Commercial lots

current Good Manufacturing Practice (cGMP) cGMPs apply to the entire production process, from raw material to final product, for any approved drug, licensed biologic, or clinical trial material.

cGMP Continuum (Increased compliance required at each subsequent phase) Phase I - Manufactured under the spirit of cGMP with all procedures properly documented Phase II - Begin to fine tune the process: develop and refine assays, perform stability studies, begin process validation for removal of impurities Phase III – Approaching full cGMP: final release strategies formulated, products manufactured in facility where commercial production occurs Phase I - Manufactured under the spirit of cGMP with all procedures properly documented Phase II - Begin to fine tune the process: develop and refine assays, perform stability studies, begin process validation for removal of impurities Phase III – Approaching full cGMP: final release strategies formulated, products manufactured in facility where commercial production occurs Commercial Production – Manufactured under full cGMP

Physical Design Process Feasibility Scalability

Quality Considerations Production Facilities and Equipment Materials Laboratory Control Product Labeling Guidance for Industry, Quality Systems Approach to Pharmaceutical cGMP Regulations, September 2006 http://www.fda.gov/CDER/guidance/7260fnl.htm 21CFR211 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211

Manufacturing Campaign Documentation & Risk Assessment Gowning Cleaning Environmental monitoring Materials receipt/quarantine/release Sterilization of media/buffers Production run Testing for release Product labeling Product storage/Accountability Quality Assurance oversight

Documentation Specification Sheets PDM Core Experience Specification Sheets Raw material Equipment Product Master Batch Production and Control Records Standard Operating Procedures (SOPs) Laboratory Cleaning and Use Logs Equipment Cleaning, MainT, Calibration and Use Logs Distribution Records Deviation Logs Inspection Reports Complaint Files Refer to 21CFR 211, Subpart J – Records and Reports

Gowning ISO 8 Clean Room Ms. Emily Stump; PDM Core Manufacturing Manager

Gowning ISO 7 & 5 Clean Rooms

Cleaning Fumigant SporKlenz Disinfectants Conflict Vesephene LpH RACAL Respirator Emily Stump Jessica Mierkey

Environmental Monitoring Rodac Plate Surface Sampler - Tryptic Soy Agar (TSA)

Environmental Monitoring Biotest RCS Microbial Air Sampler TSA Strips API Strips Biomerieux Inc. Isolate Identification Genus:species

Environmental Monitoring Metone handheld Particle Counter

Sterilization ISO 8 Clean Room

Successful Industrialization Preclinical grade material; characterization GLP compliant Animal studies Safety and efficacy Clinical grade material; refine specifications cGMP compliant Human studies Phase I – safety/dose ranging Phase II – safety/efficacy Phase III – safety/efficacy Commercial grade material Licensed facility Licensed product

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