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BioProcess Technology Consultants, Inc.

BioProcess Technology Consultants, Inc.






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    BioProcess Technology Consultants, Inc. BioProcess Technology Consultants, Inc. Presentation Transcript

    • Managing Vendor Selection Through the RFP Process Susan Dana Jones, Ph.D. Senior Consultant BioProcess Technology Consultants, Inc. IBC Conference “Outsourcing Biopharmaceutical Manufacturing” March 7, 2005
    • CMO Selection Process Define critical parameters and create list of suitable vendors Contact vendors to determine interest and availability Create short list of vendors and sign CDAs • CMOs will insist on CDA prior to submitting proposals with timeline or financial information Prepare and circulate Request for Proposal (RFP) to vendors Compare proposals Site visits to top 2-3 vendors Selection Entire selection process takes 2-3 months per major activity From clone to clinicTM
    • Example of Critical Parameters Definition Technical • Mammalian cell culture experience, preferably including some non-antibody products • Process Development and scale-up experience • 500L clinical GMP manufacturing capacity • Analytical development capability Other • Location? • Availability of PD and manufacturing capacity • Perceived cost • Responsiveness to customer inquiries and requests From clone to clinicTM
    • Use of the RFP Method RFP will ideally outline all activities for which a time and cost estimate is required • Omission of desired SOW in RFP leads to proposals that are not easily comparable RFP should be sent to candidate vendors at same time, with same deadline for response • Ability to meet the initial deadline indicative of future responsiveness of CMO • Deadline must be realistic and allow time for CMO to prepare project-specific timeline and budget Decision making mechanisms should be in place and process and timing of final decision should be known From clone to clinicTM
    • Biopharmaceutical Manufacturing Vendors Manufacture of Bulk Drug Substance (DS) • GMP suites will contain bioreactors and harvesting equipment • Downstream processing equipment in separate suite • Analytical methods to support all stages of manufacture Manufacture of Final Drug Product (DP) • Fill/finish facilities will contain compounding rooms for formulation (dilution, addition of excipients) • One or more GMP filling lines for aseptically filling product into final containers (vials, syringes) • Potentially will contain lyophilization capability Analytical Methods Development and Stability Testing • Usually performed by the DS or DP vendor From clone to clinicTM
    • Biopharmaceutical Manufacturing Vendors Formulation Development • Must have strong analytical capability to support formulation decision making experiments • Must have stability chambers for forced degradation and accelerated stability Packaging, Labeling, and Distribution • May be provided by Drug Product CMO • Offered by some vendors as separate service • Capability to distribute within countries targeted for clinical trials or commercial license essential From clone to clinicTM
    • Request for Proposal Content of RFP depends on activity being outsourced and clinical development phase of program • RFP for cell line and early stage program contains desired process yields, timelines, and scale • RFP for clinical distribution contains complete description of clinical program for blinded labeling and coding RFP may be composite or single focus • Analytical and formulation development often performed at same CMO • Benefits to single RFP and proposal but may take more time to negotiate • Fill/finish and distribution may be combined • Vendor can provide quotation on those areas that are within the CMO’s capability From clone to clinicTM
    • Outsourcing Early Stage Activities for Drug Substance Production Construction of expression vector and isolation of production cell line • Often performed in-house, prior to outsourcing • May not be a strength of late stage manufacturing organizations Develop initial cell culture and purification process • Benefit to outsource for “platform” products such as antibodies − Utilizing a generic process at an experienced CMO often saves time and money • For unique products with unknown performance, in-house early development activities can be more cost-effective From clone to clinicTM
    • Outsourcing GMP Manufacturing of DS Cell line and process already developed in-house • CMO and client often disagree on definition of a “developed process” Outsource GMP production • Minimal development activities necessary at CMO • Technology transfer through documentation and in-person transfer meetings • Adapt process to run using equipment at CMO − Different scale bioreactors − Alternate instrumentation for HPLC, pH, etc. Deliverable is fully released active DS, ready for fill/finish From clone to clinicTM
    • Analytical Methods Development Outsourcing Key component necessary to support process development and monitor product stability • In process assays to monitor yield and performance critical for effective decision making during process development • Determine key product release assays • Analytical development usually initiated in-house with methods transfer to CMO for final development and qualification (or validation) Some methods are routine and CMOs have generic SOPs • pH, osmolality, appearance, endotoxin, particulate matter Analytical methods different for different products • Specific binding to therapeutic target • Bioassay is essential to determine potency From clone to clinicTM
    • Formulation Development Outsourcing Knowledge of protein properties essential to initiate formulation development • Observed stability at various pH, temperatures, other conditions • Tendency to aggregate, dissociate (multimers), oxidize, or degrade through proteolytic cleavage Stability analysis performed rigorously by CMO using existing knowledge as a basis for experimental design • Prior formulation development experience essential • Proper stability testing will insure selection of optimal formulation Analytical method development and execution essential From clone to clinicTM
    • Drug Product Manufacturing Outsourcing Fill/finish is often outsourced even when DS produced in- house Selection criteria based on desired presentation of final product • Lyophilized or liquid • Vial or pre-filled syringe • Storage temperature Analytical capabilities essential for DP manufacturing CMO Deliverable is product in final configuration, ready for shipment to distribution facility or clinic • DP vendors may provide packaging and distribution services, or this may be outsourced to a third vendor From clone to clinicTM
    • Preparing an Effective RFP: A DS Example Expected deliverables • When material needed and how much? • Analytical methods development, qualification, or validation? • Overall program timeline • Desired scale of final process Process details • More detail will enable vendors to provide accurate pricing and timelines • Information about desired product and potential variants essential − Yield and purity obtained thus far in process development, if known From clone to clinicTM
    • DS Manufacturing Decisions Prior to preparation of RFP for DS GMP manufacturing services, customer must determine the following: • Production host − Different CMOs have experience in mammalian cell culture, microbial fermentation, or both • Desired product quantity to support preclinical and clinical activities − Determines scale and number of GMP runs; therefore determines which CMOs can meet the demand • Timing of preclinical and clinical activities − Customers often unrealistic about necessary development times − CMOs often offer timelines that are difficult to achieve, in order to obtain the business From clone to clinicTM
    • Effective Project Description for Drug Substance Manufacturing RFP Statement of work with specific tasks and goals outlined • Prepare CHO production cell line using vector provided by client − Deliverable: Fully characterized MCB (and WCB?) • Develop cell culture process with yield of at least 1.0 g/L − Deliverable: Master batch record defining process • Develop purification process with acceptable viral clearance and >50% product yield − Deliverable: Master batch record, results of scale-down viral clearance study • Scale process to >200L scale; provide material from engineering run to client for tox studies − Deliverable: 100 gm Bulk Drug Substance From clone to clinicTM
    • Sample RFP Table of Contents for Early Stage DS Manufacture 1. Background and Objectives 2. Scope of Services Requested • A. Analysis of Product Provided Material • B. Construction of Expression Vector, Cell Line, and RCB • C. Preparation of Master (and Working) GMP Cell Banks • D. Development and Scale-up of Cell Culture Process • E. Development and Scale-up of Purification Process • F. Quality and Analytical Support Services • G. Production of DS for Tox Studies and Phase 1 Trials • H. Documentation Required 3. Project Estimates and Fee Schedule 4. Qualifications 5. Deadline for Submission of Proposals 6. Appendices From clone to clinicTM
    • Process Information for RFP Production cell line • Host cell system • Current productivity and conditions in which that productivity is obtained (shake-flask, small bioreactor?) • Factors known to influence productivity Purification methods • Number and types of chromatography steps utilized • Any information on viral clearance using existing process • Filtration or other steps currently used − Scaleability of filtration and centrifugation steps From clone to clinicTM
    • Analytical Methods Information for DS RFP Lot release tests and specifications if known • All methods and specifications should be listed • Provide product-specific or unusual methods to help CMO provide accurate timeline and pricing Status of method development • Will assays be transferred in only or is development needed at the vendor? • Assays should be qualified or validated? Analytical methods for MCB testing • Must meet regulatory guidelines • Additional testing desired • Known issues with chosen host cell (if unusual) From clone to clinicTM
    • Ineffective Project Description for Drug Substance Describe product and clinical approach in detail General statement of work with no delineated activities, deliverables or timelines: “We need the product to be manufactured for our tox studies by June of 2006 and for the clinic by Dec 2006” • Is there a cell line? • Desired (realistic) yield and purity of process? • Analytical methods? Minimal process details: “The product is produced in CHO cells and purified in a 2-column procedure” • Scale and yield thus far? • Perfusion or fed-batch? • Type of columns? From clone to clinicTM
    • Comparison of Proposals for DS Manufacture Approximate CMO Pricing for Process Development and Early Stage GMP Manufacturing Vendor A Vendor B Vendor C Vendor D Technolology Transfer $ 90,000 Process Development $ 650,000 $ 1,500,000 $ 1,500,000 $ 1,100,000 Viral Clearance $ 200,000 $ 200,000 $ 200,000 $ 200,000 (including viral testing) Analytical Development $ 150,000 included in PD $ 295,000 included in PD non-GMP $ 300,000 included in GMP $ 625,000 $ 800,000 Process Demonstration manufacturing cGMP Manufacturing $ 1,275,000 $ 3,600,000 $ 850,000 500,000 Total $ 2,665,000 $ 5,300,000 $ 3,470,000 $ 2,600,000 From clone to clinicTM
    • Conclusions Effective RFPs for any outsourced activity should generate proposals that can be compared Detailed description of desired service essential Use Scope of Work format in RFP and request line by line responses in proposal from CMO • CMO not always cooperative in providing breakdown pricing Request quality/compliance history • Formal pre-selection audit should be performed after receipt of proposals and before final choice All manufacturing activities can be outsourced • Client has final responsibility for product quality, timeline, and budget From clone to clinicTM
    • Thank you! BioProcess Technology Consultants, Inc. 289 Great Road, Suite 303 Acton, MA 01720 www.bioprocessconsultants.com From clone to clinicTM