BioProcess Technology Consultants, Inc

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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)


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?


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


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


Thank you!

BioProcess Technology Consultants, Inc.289 Great Road, Suite 303

Acton, MA 01720

www.bioprocessconsultants.com

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BioProcess Technology Consultants, Inc