bioprocess technology consultants, inc
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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
From clone to clinicTM
CMO Selection Process
Define critical parameters and create list of suitable vendorsContact vendors to determine interest and availabilityCreate short list of vendors and sign CDAs• CMOs will insist on CDA prior to submitting proposals with
timeline or financial informationPrepare and circulate Request for Proposal (RFP) to vendorsCompare proposalsSite visits to top 2-3 vendorsSelection
Entire selection process takes 2-3 months per major activity
From clone to clinicTM
Example of Critical Parameters DefinitionTechnical• 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 comparableRFP 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 budgetDecision making mechanisms should be in place and process and timing of final decision should be known
From clone to clinicTM
Biopharmaceutical Manufacturing VendorsManufacture 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 stabilityPackaging, 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 codingRFP 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
organizationsDevelop 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 cleavageStability 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
formulationAnalytical method development and execution essential
From clone to clinicTM
Drug Product Manufacturing Outsourcing
Fill/finish is often outsourced even when DS produced in-houseSelection criteria based on desired presentation of final product• Lyophilized or liquid• Vial or pre-filled syringe• Storage temperature
Analytical capabilities essential for DP manufacturing CMODeliverable 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 Objectives2. 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 Schedule4. Qualifications5. Deadline for Submission of Proposals6. 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 pricingStatus 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 detailGeneral 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
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(including viral testing)
$ 200,000 $ 200,000 $ 200,000 $ 200,000
Analytical Development $ 150,000 included in PD $ 295,000 included in PD non-GMPProcess Demonstration
$ 300,000 included in GMP manufacturing
$ 625,000 $ 800,000
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
Approximate CMO Pricing for Process Development and Early Stage GMP Manufacturing
From clone to clinicTM
Conclusions
Effective RFPs for any outsourced activity should generate proposals that can be comparedDetailed description of desired service essentialUse 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 choiceAll 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