iqpc 12th contract manufacturing for pharmaceuticals & biotech1 workshop c: tools for a...

IQPC 12th Contract Manufacturing for Pharmaceuticals & Biotech 1

Workshop C: Tools for a Successful Outsourcing Program

Paul WoitachManaging Partner

Pharmaceutical Advisors LLC316 Wall Street, Research Park

Princeton, NJ 08540609-688-1330

[email protected]

Workshop ApproachWorkshop Approach

• Management perspective• Not a development planning discussion per se

– Assume you know what to do BUT some insights• Checklists and tools• Tips and suggestions• Assuming all can read so will speak to the key points rather

than discuss every bullet• Geared for first GMP but applicable to all stages and

commercial• Structured to leverage the experience of CMOs and

Sponsors in the workshop– Discussion, Debate & Reconciliation / Group hugs

• Help you to walk away with a robust package• Using term CMO and Vendor interchangeably – can often

apply to packaging, analytical etc.


AgendaAgenda

1. Case study examples and tools for developing an outsourcing program, whether it’s a single compound or you need more structure to managing multiple programs

2. Understanding how to find CMOs, contract with them, and maintain leverage and look after your interests in structuring the business and technical relationship

3. How to be a good business client for speed and value

4. Anticipate and handle specific problems with outsourcing

5. Case Studies - Bumps in the road that others have had and what you can learn from them

6. Tips on running programs with a limited internal budget and resources



If You Are Just Starting to Outsource…If You Are Just Starting to Outsource…

Nomination PhI PhII PhIII NDA/MAA Approval

LaunchAPI/DPEnabling Technology &Supply Manufacturer

API/DPTechnology/Supplies

RM API DP

PhIII Supplies

RM API DPLaunchPlanning

RM DP DP StabilityAPI PAIn Planning

RM API DP ICH Stability ICH DP StabilityPlanning

DP Technology

API Technology

Raw Materials API Activities DP Activities Enabling

EvolvingEvolving

API…API…

& Drug Product…& Drug Product…

DemandDemand

Demand

Lead Times and Need to Be PreparedLead Times and Need to Be Prepared

• If you are starting to outsource manufacture of DS or DP– Lead times can be

• 3-6 months to ID and secure CMOs for CTM or more• Can be longer for commercial

– Many factors can add up / compound the issue• Screening / ID CMOs true capabilities takes time• CDAs can take time• 2-4 weeks to prepare a good response to RFP• Timing of scheduling site visits and audits depends on working around

existing client schedules• No two CMOs are exactly alike• Sometimes technologies / unit opps are not ubiquitous or all in the same

location• The CMO you want may not be interested or feel comfortable with your

project• Negotiations & Contracting iterations• Seasonal factors can stretch lead times further


Tools on The ChecklistTools on The Checklist

Descriptions and Tips


Tools - Outsourcing Checklist for SuccessTools - Outsourcing Checklist for Success

Item Comments Integrated

Development PlanCore Enabler – Always changes but think it through before you start to write RFP

The Right SOPs Core Enabler some before RFP, others in time for GMP

Data Plan Core Enabler - think it through before you write RFP

Resources to Manage Core Enabler - before you start to write RFP

Process for Selection Core Enabler – now you have one

Know Your Requirements

Varies by project but aim to not change after the RFP

Finding CMO Candidates

Varies by Project

Selection Criteria Varies by Project

RFP Template Varies by Project – now you have one

Contracting / Ts & Cs Be prepared to integrate your needs with CMO’s

Quality Agreement Be prepared to integrate your needs with CMO’sIQPC 12th Contract Manufacturing for Pharmaceuticals & Biotech 7

1. Integrated Development Plans1. Integrated Development Plans

You’d be amazed at how infrequently we see them!

•Integrate DS & DP at the very least

•Tox and clinical timelines and quantities are important for your planning

– Create a strawman assumptions if you cant get answers

•Consider impact on today’s and tomorrow’s needs of– Approval & Investment Strategy

– Development Plan beyond IND

•Factor in Lead times– CMO selection & contracting

– Product release across CMOs and report turnaround times

– Experimental failures

•Not Doing it is a huge source of problems– Beware of oversimplified plans / rules of thumb

– Make communication across functions happen! Even if its just with yourself!



Symptoms of a Planning Gap to be FilledSymptoms of a Planning Gap to be Filled

Dangerous Assumptions We Hear…• “We don’t need to think about that because we’re

going to license out in Phase II…”• “Our licensing partner will worry about that…”• “Let’s just get GMP material for everything…”• “We’re going to use GLP material…”• “We’ll get a consultant to write the CMC section

when the time comes…”• “We need a Quality Manual? But We’re virtual…”• “It’s too early to be thinking about a Quality

Agreement – it’s just development work…”

2. The Right SOPs2. The Right SOPs


• Not a thick binder but a few enabling tools– Leverage Contractors Quality System & SOPs

– Minimal core internal Policies and SOPs to enable running through contractors

• Can also invest proactively in your Quality Agreement Template and Roles & Responsibilities Matrix to reduce need for certain SOP detail

• Important to understand what you need in place before contracting and before GMP activity

• It’s still your product with your responsibilities

Pre-Outsourcing SOP Gap AnalysisPre-Outsourcing SOP Gap Analysis

IQPC 12th Contract Manufacturing for Pharmaceuticals & Biotech

11

Area for Policies and/or Procedures Now Soon Later ApproachQuality Unit Responsibilities SOP Modify existing or create newAuditing SOP Modify existing or create newBatch Disposition Pol/SOP Modify existing or create newBuildings and Facilities Pol Use contractors’ SOPsChange Control Pol/SOP Modify existing or create newComplaint Handling X Contractors - Approval of GXP Contractors & Consultants SOP Modify existing or create newCorrective and Preventive Actions Pol Use contractors’ SOPsDeviations Pol Use contractors’ SOPsDocumentation Creation, Mods & Control SOP Modify existing or create new

Use contractors’ SOPsEquipment Pol Use contractors’ SOPsLabeling Control X Use contractors’ SOPsLaboratory Control SOP SOP Modify existing or create new

Use contractors’ SOPsManagement & Employee Quality Responsibilities X Materials Management & Purchasing Control Pol Modify existing or create newPackaging, Labeling, Storage, Shipping and Distribution Pol Use contractors’ SOPsProduction and Process Controls Pol Use contractors’ SOPsQualification and Validation Pol Use contractors’ SOPsRecalls and Product Withdrawals X Records and Records Retention X Returned and Salvaged Goods X Specifications SOP Modify existing or create newStability Pol/SOP Modify existing or create newTraining SOP Modify existing or create new

Leveraging the Contractors SOPs in Your SOPs

Pre-Outsourcing SOP Gap AnalysisPre-Outsourcing SOP Gap Analysis


Area for Policies and/or Procedures Now Soon Later ApproachQuality Unit Responsibilities SOP Modify existing or create newAuditing SOP Modify existing or create newBatch Disposition SOP Quality Agreement. Create SOPBuildings and Facilities Pol Use contractors’ SOPsChange Control Pol/ SOP Quality AgreementComplaint Handling X Contractors - Approval of GXP Contractors & Consultants SOP Modify existing or create newCorrective and Preventive Actions Pol Quality AgreementDeviations Pol Quality AgreementDocumentation Creation, Mods & Control SOP Modify existing or create newEquipment Pol Quality AgreementLabeling Control Quality AgreementLaboratory Control SOP SOP Quality AgreementManagement & Employee Quality Responsibilities X Materials Management & Purchasing Control Pol Modify existing or create newPackaging, Labeling, Storage, Shipping and Distribution Pol Quality AgreementProduction and Process Controls Pol Quality AgreementQualification and Validation Pol Quality AgreementRecalls and Product Withdrawals X Records and Records Retention X Returned and Salvaged Goods X Specifications SOP Modify existing or create newStability Pol /SOP Quality AgreementTraining SOP Quality AgreementQuality Agreement X

Leveraging Your Quality Agreement

3. Data Plan3. Data Plan

• You are not just buying supply, you are buying– Material – Technology & Other IP– Registration Enabling Information

• Understand data needed for submission, to make decisions and to achieve objectives with future partners or for your commercial objectives– Where will it come from– Who will write what– In what form do you need– Implications for your RFP / Requirements– How will you file and access the info


Often Overlooked Data Consideration Often Overlooked Data Consideration

• Development Reports – Deliverable of detailed development, analytical,

and production report – What was tried, results, and evolution of the

procedure, linked to notebook records and preliminary reports.

– You then have a good record of what works and doesn't work

– How the process and analytical procedures evolved into a manufacturing process and quality control test methods

– Enable learning / problem solving & QBD for registration


4. Internal Resources -Small Molecule4. Internal Resources -Small Molecule

Internal expertise needed: Medchem Process chemistry & API Manufacturing Dosage form Development Dosage form manufacturing Pharm Tox Legal Analytical Quality Packaging CTM logistics TPL Management Sourcing Regulatory Project Management


4. Internal Resources - Biologics4. Internal Resources - Biologics

Internal expertise needed: Bulk - Cell line development & selection, Fermentation, DSP Dosage form Development Lyophilization Dosage form manufacturing Pharm Tox Legal Analytical Quality Packaging CTM logistics including cold chain TPL Management Sourcing Regulatory Project Management



Action Plan & Key Indicators

of Success

Company Needs

Resources

Timing

Program Requirements

Project Requirements

Internal issues

Long list of candidates

Short list

Finalists and selected

CMO

RelationshipRelationship& Project& Project

ManagementManagement

Kick-off & Tech

Transfer

Proactive Management

Leverage and

Alignment

SourcingSourcing& Selection& Selection

ProcessProcess

Requirements &

CMO ID

ScreeningRFP

& Selection

Negotiation Contracting

& Scope

Integrated Integrated DevelopmentDevelopment

PlansPlans

Clinical & Safety

Drug Substance & Drug Product

Regulatory and other

StrategicStrategicContextContext

Boundaries

Investment Strategy

StrategicSkills

Approval & Regulatory

5. Structured Process for Selection5. Structured Process for Selection


Overall Sourcing & Selection Process TableOverall Sourcing & Selection Process Table


6. Your Requirements – Some Variables6. Your Requirements – Some Variables

Technical Package and Tech Transfer Technical Package and Tech Transfer

Drug Substance•Technology•Raw Material specs & vendors•Unit Operations as practiced•PD History, if any•Batch Manufacturing History•Current IPCs at R&D stage, rationale and CPPs •Storage requirements for raws, in process and final product•Mass Balance as complete as possible•EH&S info; Process Risks and Controls – incl waste streams, MSDS•Analytical Requirements•Dev Reports, Methods protocols, tech trans plans, & validation reports, if ready•Proposed specs for API•Batch size assumptions – CTM, Reg batch, validation batch, commercial and projected forecast

Drug Product•API and Excipient grades & suppliers•Batch Mfg. History •Specs for API and excipients incl micro •Excipient functionality•EH&S info, risks, incl waste streams,•Detailed characterization •PD History Report •Current IPCs and rationale and CPPs •MBR & , ancillary batch docs•Storage for raws, wip & final product•Dev. Reports, Methods protocols, tech trans plans, & validation reports, if ready•Stability information (API, intermediates and final product)•Cleaning procedures and tests: operator exposure, disposal etc.•Packaging

•Batch size assumptions – CTM, Reg batch, validation batch, commercial and projected forecast


7. Finding CMO Candidates7. Finding CMO Candidates

• Quickly Getting Some Material Made…It’s just kit & people right?

• Don’t assume one stop shops actually exist– Tech transfer has to happen across scale anyway– DP & DS are different disciplines– Technical specialization needs– Skills & Creativity across disciplines– Service oriented culture– Right business model, business size (to align with you) – Capital structure / health– Location

• Very few direct capability overlays in comparing CMOs• And the golf course issue…• Plan on 3-6 months for development and potentially longer

for commercial


Tips for Making it EasierTips for Making it Easier

• Start with your requirements…– For this project and the follow-on…if you are successful

• Create a Long List– Capabilities & specialties– Capacity– Location– Reputation

• Information Resources– Your functional team members / consultants– Peers– Industry directories i.e. Contract Pharma– Trade-Shows & Conferences

• AAPS, Informex, Interphex, Chemspec, CPhI, Contract Pharma, DCAT IQPC, etc.

– Create and maintain a “living list”



““Living” List of Potential Vendors is an AssetLiving” List of Potential Vendors is an Asset

• Document and refresh findings on candidates– Lack of fit today may not apply to the next

project– Reduce search time later– Decide what you will share and what stays

internal– Compile for various functions i.e. DS & DP etc.– A strategic asset

This knowledge often “walks out the door” when employees or key consultants move on

8. Criteria – Often Overlooked8. Criteria – Often Overlooked

• Capacity / Scale – Stage now vs. later needs and implications

• Overall Capability– Tech Transfer ( in and out)– Experience updating the CMC sections– Understand ability to source of all raw materials

• Project Specific Technical Capability– For development, unique technical deliverables and their “transportability”– Response to RFP and scientific approach

• Quality– Capabilities / FDA inspections or approvals– Import / export processes of material for CTM & Commercial – Strength of their Vendor Qualification Program

• Location– Your capacity to manage distance and cultural issues– Internal tech transfer capability across locations.

• Proprietary technology/tech transfer

– Does CMO propose to use proprietary technology and what is impact on royalty rate burden or ability to transfer process or qualify back-up CMO

• Other– Adequately capitalized– Must be able and willing to produce references



9. RFP Package9. RFP Package

• The Package – Workscope– Technical and Timing Requirements– Terms & Conditions– Quality Agreement

• The RFP should be structured to – Enable objective and complete comparison of the candidates– Expedite the development of a contract – Help CMO to understand required scope, potential for expansion /

change and their risk– Help CMO to understand their risk

• Avoid taking on a project with more scope that visible• Understand potential impediments to meeting timeline• Fit with their skills and schedule

• Both the RFP and CMO response should be complete enough to provide the basis for workscope, pricing and terms


RFP Contents – DP & DSRFP Contents – DP & DS

• Brief description of your company (optional)• Brief description of the product (along with Material Safety Data Sheet

and handling instructions)• Overall project objectives and timeline• Detailed scope for CMO’s portion of the project:

– Process description with flow chart and bill of materials– In-process and product test methods and target specifications– What will be delivered to CMO and by when– What the CMO is expected to deliver back and when– Desired pricing structure (i.e., fixed price versus time and materials, mass

unit price versus batch price, etc.)• Requests for information, including:

– Financial status of the company and description of pharmaceutical development and commercialization programs, if any.

– Confirmation of absence of conflicts of interest– References, inspection history– Manufacturing success rate

• RFP response instructions (due date for submission of response, name and address of person to whom the responses should be directed, etc.)

10. Contracting and Negotiations10. Contracting and Negotiations

• The contract is critical to the balance of leverage in a relationship.

• Negotiation is part of relationship management, and should be considered part of the selection process, not a formality– Behavior demonstrated during negotiation of challenging

aspects of the contract is a good indication of how the other party will behave during challenging points in the relationship.

– Goodwill and trust are critical to productivity of inter-organizational relationships.

– Often contentious negotiations are not contained and impact the project team members perceptions of the other party.

• Anticipate, understand and balance risks on both sides as they change from development to commercial stage activities

• Integration with Quality Agreement saves time and money and operationalizes the relationship quickly



Master Services Agreement ConceptMaster Services Agreement Concept

• The future needs of a project cannot be fully anticipated at the outset of a project

• A “Master Services Agreement”, provides flexibility – General terms of the relationship between the parties

– Scope of Segments of the project(s) can be described,

– Can provide a basis for amendments combine refined or new scope and already agreed pricing structures

• Can be overkill for some one-offs BUT a balanced MSA can be executed rapidly and accelerate things later on

Business Checklist for ContractingBusiness Checklist for ContractingItem Tips

Scope • Clear Scope or if an MSA, clear description of what’s in a workorder

Scope change process • Clarity

CMO Accountability • Project management process / interactions

Subcontracting • Control of subcontracting

Ownership of Materials • Ownership of materials and responsibility when held at CMO

Handling of data • Timing, duration

Ownership of IP • Clarity

Tech Transfer support • Support tech transfer to another facility at sponsor sole discretion

Exclusivity? • For discussion if warranted

De-barred personnel • None

Deliverables • Commitment to timing, conformance to spec and not just CofA

Rejection • Rejection and recourse for missed deliverables

Bumping • Protect yourself - Prevention of / Mitigation for bumping

Title • Transfer and when and how title changes

Facilities • Commitment to provide facilities and capacity to complete obligations

Facility change • Lead-time on change of facility or right of refusal / first look

Legalese • Ins., Indemnification, Confidentiality are business decisions, don’t abdicate

Effect of termination • Cost controls and process on effect of termination. Fees on cancellation

Conflict resolution • Have a process - a 3rd party not always good

Permits • Responsibility for cost of permits, waste removal etc.IQPC 12th Contract Manufacturing for Pharmaceuticals & Biotech 29

Other Business Agreement Elements Other Business Agreement Elements

Future issues can be avoided by anticipating needs and building them into contract terms•Provision for future supply and/or additional projects•The right of the client to all IP and know how required to produce the product•Rights to process and analytical methods and technology•The right of the client to transfer the production technology and qualify other sites to produce the product •Pricing to manage risk

– Payment obligations that are triggered by acceptance of deliverables (i.e., reports, QA release, etc.)

– Fixed pricing on each segment of the project as its scope becomes well defined (i.e., both parties are motivated to complete the work in a timely fashion)

– Bonus payments for development and demonstration of specific process yields, which in turn tie to lower unit pricing for product supply

•Dealing with risk of loss– Ability to negotiate assumption of risk of batch failure increases with process maturity,

validation– Typically, fill-Finish and DP CMOs do not add enough value to take on risk of loss of API

value


11. Quality Agreement11. Quality Agreement

• Clearly articulate technical and regulatory roles and responsibilities

• Phase appropriate differences• Integrated with Terms and Conditions,

MSA or Supply Agreement• Roles and Responsibilities matrix is

more easily read and used by operating personnel than a legalese document


Quality Agreement R&RQuality Agreement R&R


Item Issues & Responsibilities, Drafting, Review & Approval

Org and Personnel Be aligned on role of Quality Group and training

Facilities Commitment to compliance, access control, prevention of cross contamination

Equipment Qualification, cleaning logs & control

Materials & packaging Spec setting, testing, retention, approval of suppliers

Production Development, review and approval of MBR, BR, specs, deviations, reprocessing / rework, EM, retention, definition and handling of deviations

Analytical Specs, methods, sampling, OOS / Investigations, Turnaround time, validation, Right to participate in investigations

QC CofA, Product Disposition at various stages

Label, Pkg, Ship & Storage

Label text, layout, retention, retest dates, storage conditions, shipping, inspection. Consider if need is more than 5 years and receiving at end of the period.

Stability Plan, reporting and approval

Change Control Clarity on process

QA Complaints, recalls, MSDS, Auditing, release

Audits and Inspections Access to facility for Audits

Reg Inspections Notifications, Communications, timing

Reg Filings Initial, annual and ad hoc

Expiry R&R

Being a Good Client Being a Good Client

…and how to anticipate and proactively work to avoid issues


Other Side of the Desk – The CMOOther Side of the Desk – The CMO

• Contract manufacturing is a very challenging and often “lumpy” business – Scarcity of capacity can sometimes drive price

more than level of quality• It costs real money to generate a proposal• CMOs focus on doing what customers ask

– Don’t expect them to stop you from making mistakes - It’s Your Development Plan

– Will they stop you from making process changes that affect impurity profiles or bioavailability?

• Development Stage vs. Commercial Stage CMO needs

• Differences between US, EU, India and China


Challenges CMOs Face in Serving YouChallenges CMOs Face in Serving You

• CMOs are a service business and you are one of many clients – CMOs can be very service oriented but need to balance your

project needs and changes with all those of all other clients– CMOs do not always have resources, capacity and schedule

availability to meet all needs exactly when required. • CMOs do not have unlimited surge capacity

– Ability to add FTEs is limited – Ability to go back when there are significant technical hurdles or

unplanned failures may not be immediate • Lead times impact on responsiveness may not be their doing

– RM not always available when required• Flexibility is not always possible

– The best CMOs often don’t have much flexibility– Clients that keep changing their mind create a ripple effect of cost– Be wary CMOs offering too much flexibility!


Maximizing By Being a Good ClientMaximizing By Being a Good Client

• Success enablers are often set before kick-off

– Provide Well considered specificity - “Cocktail Napkin” TIPS Cost Your Money and Time!

– Have realistic expectations of timing

– Apply adequate internal resources for CMO guidance, oversight and to cover distance & cultural issues

– Proactive management & metrics

• Planning - only certainty is that things will go wrong so plan accordingly

– Plan with contracting and scheduling lead times in mind

– Build in scheduling lead-times for when problems occur and iterations for to-be-demonstrated technology

• Execution

– On-site involvement early in the relationship and more time on-site up front, less time fixing things later

• Proactive vs. Reactive

• In-person builds relationship & personal commitment

– Clear project management and information flow BUT do not impede scientist-to-scientist interaction when needed

– Strive to be easy to do business with while being clear and firm on your requirements

• Understand how your changes impact the CMO


Issues Good Clients Can Anticipate & AvoidIssues Good Clients Can Anticipate & Avoid

Issue Comments

CMO “Performance” and commitment falls short

• Don’t always assume the CMO is motivated to deliver for you over an alternative

• Invest time and effort up front in contracting and relationship management

Cost and delay of back and forth to get data

• Don't underestimate the analytical rigor required to complete a filing

• Plan ahead for site specific and product specific post-run data checklists

Cost surprise on follow-on

• Consider separation of development / CTM to simplify earlier contracts but get ROM quotes based on assumptions

CMO has some IP or know-how that is needed in the future

• Protect your right to all IP and know how required to produce your product

• Secure rights to process and analytical methods and technology

• The right to transfer the production technology and qualify other sites to produce the product

Need for unplanned technical work on a previously per-batch cost project

• Consider having that work charged on a transparent time and materials basis with the ability to review and cancel on 30 days notice. IQPC 12th Contract Manufacturing for Pharmaceuticals & Biotech 37

Issues Good Clients Can Anticipate & Issues Good Clients Can Anticipate & AvoidAvoid


Issue Comments

Delays in finalizing deliverables

• Consider Payment obligations that are triggered by acceptance of deliverables (i.e., reports, QA release, etc.)

• Fixed pricing on each segment of the project as its scope becomes well defined (i.e., both parties are motivated to complete the work in a timely fashion)

Your time or cost constraints will be hard for CMO to meet

• Consider bonus payments for development and demonstration of specific process yields, which in turn tie to lower unit pricing for product supply

Stalemate on issues such as responsibility for failed batch

• Include terms which delineate the obligations of the parties in terms of communication and interactions, including arbitration

Cost increases when you feel there’s no scope-creep

• Risk of surprise should decrease as project progresses• A step past which cost increases can not be passed on except

for unforeseen and unavoidable technical issues is not unreasonable

Deviation and investigation report charges

• Should not constitute a scope change• Clarify up front in Quality Agreement or contract

Issues Good Clients Can Anticipate & Issues Good Clients Can Anticipate & AvoidAvoid


Bumping or Failure • If CMO is fairly busy, the opportunity cost of their capacity is high.

• Want to avoid ability to bump and then use “best efforts” to catch-up later and not be penalized

• Penalty fees in general are a common practice and not unreasonable to include

• Can trade-off some termination fee for equitable penalties for non-delivery based on things that they should to anticipate or control

Bumping or Failure – if it DOES Happen

• Consider the Pragmatic approach to the reality• Usually advisable to avoid forcing payment of fees from a

CMO • Identify a win-win which maximizes the outcome and gain

back time • Typically faster to recoup at contractor than to start over

elsewhere• Have the contractor provide raw materials for another batch • Have contractor bump someone else in order to slot your

work ahead • If CMO actions resulted in failure, CMO could redo at their cost• If results in significant timeline impact and work at a different

CMO, consider RM at CMO’s expense or finished material for cost of materials alone without a processing fee


Metrics & ManagingMetrics & Managing

• Keep metrics simple• Understand how your demands

change as you progress– Consider impact on the CMO

• Put in the effort to be a good client• It’s Your program – you need to lead

the CMO• Get on-site early

– Less investment needed avoiding vs. solving

Tips for Outsourcing with Tips for Outsourcing with Limited Internal BudgetLimited Internal Budget

…And Tips to Help the Timeline


Keys to Managing to a Lean BudgetKeys to Managing to a Lean Budget

• Have the right expertise on YOUR side of the desk – Knowledgeable internal resources

• Invest in being prepared– Specificity & minimize scope change, rework, risk ID

• Be proactive – Get on-site early

• Convert fixed costs to variable where possible– Right level of functional team members– Complement your internal expertise – Requires hard-to-find mix of hands-on AND strategic– Need experience with outsourcing and current

knowledge of CMO performance– Seek to minimize your coordination costs of all the

resources


FTE Effort ExamplesFTE Effort Examples

Function Effort CommentsMedchem .25

Process Chem & Mfg. .15-.25 Higher during ID & Selection

Form Dev. & Mfg. .15-.25 Higher during ID & Selection

Pharm - Tox .25-.33 Peaks during on-sites and documents

Legal Varies Can limit with good operational contracts

Analytical .15-.25 Methods, data

Quality Varies Audits, release

Packaging Varies Special situations or efficient use of packaging vendors

CTM logistics or TPL Varies Depends on trial or Supply Chain complexity

Sourcing Varies Special situations

Regulatory Varies Strategy, documents ( Operational)

Project Management <.1-.15 (Better team, less PM needed)


FTE Effort ExamplesFTE Effort ExamplesFunction Effort Comments

Cell line Varies

Fermentation .10-.15 Peaks during documentation

DSP .10-.15 Peaks during documentation

Lyophilization Varies

Form Dev. & Mfg. .15-.25 Higher during ID & Selection

Pharm - Tox .25-.33 Peaks during on-sites and documents

Legal Varies Can limit with good operational contracts

Analytical .15-.25 Methods, data

Quality Varies Audits, release

Packaging Varies Cold Chain, Special situations or efficient use of packaging vendors ( DP)

CTM logistics or TPL Varies Depends on trial or Supply Chain complexity

Sourcing Varies Special situations

Regulatory Varies Strategy, documents ( Operational)

Project Management <.1-.15 (Better team, less PM needed)


Driving Down Internal FTEsDriving Down Internal FTEs

• Leverage FTEs– Make sure there’s operational regulatory

experience in the functional team members, not just technical

– Can put PM responsibility into one of the functions until there is critical mass / portfolio need• Supply is ongoing so CMC or CTM logistics can make

sense

– Better the quality and the better integrated team, the less specialized PM you need

• Build and maintain internal tools – Templates– Vendor database


Hub and SpokeHub and Spoke

• Can surround a limited internal core team / individual with internal functional experts

• Can serve as Advisors in the background or use the ring of Advisors to each run all the various functions

• Can have external Project Management Advisor as well


Drive Down Total Resource UseDrive Down Total Resource Use

• Can reduce overall and individual FTEs with the right cross–functional experience to take on informed, broader roles in adjacent functions

• PM effort can also be led by one of the functional team members

• Can enable success efficiently with an almost completely virtual “internal” team


Other Sources of Cost Reduction or SpeedOther Sources of Cost Reduction or Speed

• A detailed well constructed RFP– Have the tech transfer package ready to go

• Realistic expectations and requirements– Take rework and risk out

• Compress Contracting Time and Get Started– Do good pre-screen Get Ts & Cs and Quality Agreements across the table

early • Legal and purchasing review – especially with larger sponsors and CMOs is a

bottleneck

– Can break up workscope to start under a PO

• Ask the CMO– They can contribute ideas

• Production– Can reduce # of batches i.e. no demo batch if comfortable with the

technology and tox risks

• Submissions– Sponsors routinely underestimate the analytical rigor and effort required for

a filing – plan ahead


For Discussion …For Discussion …

• One stop shops• Global outsourcing• Centralized analytical• Taking on risk


Bumps in the Road Others Have Had…Bumps in the Road Others Have Had…

…and what you can learn from them


Case 1Case 1

What they Did What happened Prevention

• Sponsor with a project outside of their manufacturing know-how needed development from a US based CMO

• Worried about getting started quickly, sponsor signaled early in negotiations that the CMO was their first choicefor the project

• Sponsor took CMO recommendations without critical review and would defer to CMO rather than their consultants

• CMO was opportunistic on scope and pricing

• CMO made unilateral development decisions and forced a sub-optimal process which hurt yield be gave better throughput for the CMO. Some decisions led to a batch failure

• Once sponsor involved a consultant, the CMO would take direction only from the sponsor, despite sponsor directives to the contrary, creating mixed messages

• Treat CMO like a valued team member but don’t confuse with partnership and manage negotiations

• Adequately resource technical project oversight

• If a consultant, make sure internal lines of communication are clear

• Do not expect CMO to make technical decisions that are 100% aligned with sponsors best interest


Case 2Case 2



Quality Agreement not specific enough on aspects such as

•Changes to raw material suppliers

•Process changes

Sponsor saw changes in impurity profile that took significant resources and time to ID the root cause (new RM supplier)

Sponsor saw changed metabolic conditions ( low DO2) and RM changes which altered fermentation. Took many weeks to solve and address

In each the CMO was operating within its agreement

Proactively ensure Quality Agreement is specific enough to address the uncertainties

OK to use CMOs Quality Agreement, as long as all that you need is inserted

Case 3Case 3



Cash constrained and needing to show progress, Sponsor felt they could not afford to pay a CMO with development capabilities to take their cell culture process from literature and make it “CMO ready”

Sponsor felt they could not afford the time for an academic lab to do so either

Selected an emerging, low-cost CMO with limited development resources

Resulted in timeline delays, failures and iterations

Additional cost of having a fermentation consultant coach the CMO staff through follow-on iterations

Do the work up front to have your process ready for the type of CMO you have selected

Summary and KSFsSummary and KSFs

Not rocket science but not easy either

1.A little planning & structure – it’s NOT bureaucracy, its your friend

2.Honest understanding and documentation of yourself and your Requirements

3.The right internal expertise in the right amounts at the right time. Does not mean big infrastructure

4.Structured and forward looking RFPs & Contracting

5.Be a good client and anticipate understand what can go wrong. Many more things can be prevented than actually are!


Supplemental InformationSupplemental Information

Development Decision Variables and Trade-Offs to Consider as You

Plan Your Outsourcing



Development Strategy AlternativesDevelopment Strategy Alternatives-Different Approaches to Managing Risk-Different Approaches to Managing Risk

Alternatives Development Implications

When Developing toEfficacy in Man

•Work to “Get into man”•Worry less about restarts•Delay process optimization, scale up tasks•Consider minimizing early formulation development efforts •Minimize analytical method validation•Design stability programs on a cost per pull point basis to allow discontinuation and cost recovery

When Developing toCommercial

Launch

•Work to “Deliver the First Pill Sold”•Minimize restarts•Don’t delay process optimization•Don’t delay dosage form optimization•Be more willing to incur process development & validation cost earlier if efforts reduce risk long term•May accelerate scale-up & move to commercial vendor earlier if efficacy risks are reduced


Outsourcing Implications of Outsourcing Implications of Development Strategy AlternativesDevelopment Strategy Alternatives

Alternatives Implications

To Registration •Consideration of Commercial Supply•Different development vendors vs. scale-up vs. commercial?•Process data for scale-up•Rate of investment in technology knowledge vs. scale-up•Final process definition•Knowledge transfer•Ability of vendor to develop a process that will be transferred to other vendors•Raw material strategies

To POC / Human Efficacy Data

•Potentially less need for investment in process data•Ability of vendor to develop a process that will be transferred to other vendors•Ability of vendor to tech transfer•Some need for analytical validation and stability indicating methods

Other •Varying need for analytical characterization, technology development•Potentially less need for investment in process data


Outsourcing Implications of Outsourcing Implications of Approval Strategy AlternativesApproval Strategy Alternatives

Alternatives Implications

Fast-Track / Accelerated

•Consideration of Commercial Supply•Process data for scale-up•Rate of investment in technology knowledge vs. scale-up•Final process•Knowledge transfer•Limited tech-transfers•Concurrent activities•More at-risk investment•Higher API cost in clinic•Earlier attention to formulation•Supply more critical•Additional internal management•Plan for analytical bottleneck•Potential for pre NDA process validation•Earlier planning for commercial supplier & materials

Standard Approval

•Increased ability to postpone investment in technology


Outsourcing Implications of Outsourcing Implications of Investment Strategy AlternativesInvestment Strategy Alternatives

Alternatives ImplicationsInvest-at-Risk to ensure commercializable technology

•Increased initial cash burn rate•Increases initial in-house demand for vendor management•May need to repeat analytical tasks if API salt form or formulation, or DS/DP mfg process changes •Plan DS synthesis to enable targeted changes without effecting entire synthesis – choose earlier what to lock down

Develop DS & DP suitable for exposure in humans to efficacyDelay investment in technology and information until efficacy data available

•Reduces initial cash burn rate •Reduces initial in-house demand for vendor management•May allow non-robust processes to be used for Phase III CTM mfg but may delay registration•Increase risk of DS/DP process changes and hence attributes during or after efficacy trials•Increases risk of need for clinical bridging studies should DP attributes change during clinical development

Invest in Inventory •Ability to campaign•Ability to realize batch-size cost benefits earlier•Ability to do multiple sourcing earlier


Outsourcing Implications of Outsourcing Implications of Development Plan AlternativesDevelopment Plan Alternatives

Alternatives ImplicationsNeed for small quantity quickly

•Requires suitable technology in place to deliver multi-kg •Documentation less regulated but still critical•Wider variety of facility choices•May increase eventual need for tech transfer•non-GMP material can be used for animal safety studies and drug development work. Key issue is whether or not it makes sense to prepare non-GMP material after initial lot.

Need for large quantity quickly

•Increases opportunity/need to ID Phase III/commercial vendor early•Increases importance for early vendor compliance assessment •Increases importance of early vendor commercial assessment

Need for non- GMP or GMP

•Can significantly increase speed and reduce cost of API mfg if non-GMP material can be used for toxicology and formulation development•May increase risk of impurity profile changing between toxicology and CTM batches leading to bridging tox need


Outsourcing Implications of the Outsourcing Implications of the Level of Technology DifficultyLevel of Technology Difficulty

Alternatives ImplicationsSimple •Internal skills still needed

•Analytical skills required same as complex•Wider choice of vendors & scale•Shorter timeline •Lower cost

Complex •Variety of technical internal skills needed•Potentially more limited choice of vendors or for multiple vendors•Longer timelines•Greater effort needed to manage impurity profile for CTM material. •Challenge of scale up increases, increasing time & technology risk•Increased need for process safety management•Compounded if BOTH DS & DP have difficult technology

Developed •Vendor choice more purely technology / hardware & work processes driven•Faster mfg process development timeline

Undeveloped •Vendor choice depends on development AND technology capability•Implications for Safety and Clinical results•Slower mfg process development timeline


Outsourcing Implications of Outsourcing Implications of Unique Technology NeedsUnique Technology Needs

Alternatives ImplicationsHigh Potency / Exposure Management

•More limited vendor choices•More costly API•If volume is low, single vendor for development & commercial

High Chemical Reactivity i.e. Exo-Endothermic, High Pressure Hydrogenation Processes

•Is new technology required?•More limited vendor choices•More costly API•Greater scale up challenges

Biologics •Expression systems IP•Scale & yield•Product by process (hard to characterize equivalence)

Need for multiple dosage forms

•Timing of formulation work•Timing of / flexibility in salt selection•Early experimentation •Increased risk of need to show bioequivalence through additional PK, bridging tox or clinical studies

Novel Drug substance Technology/Issues – i.e. Not Scalable

•Early design of experiments•Vendor capabilities•Need for new chemistry / route ID capability

Novel Physical Pharmacy/Dosage Form Issues

•Timing of formulation work•Flexibility in salt selection•Tox & clinical plan •GRAS issues with regulatory agencies

Other •Different development & commercial vendors / more tech transfers?•Need for and control of new IP to solve development problems


Leverage with VendorsLeverage with Vendors

Alternatives ImplicationsMultiple Projects •Ability of vendor to learn common platform and enable

speed•Potential convergent synthesis of APIs•Location of facilities•Other functions to consolidate at vendor (analytical development, sourcing, process safety mgmt.)•Contracting and quality system costs•Overall leverage potential and >15-20 FTEs per year•Allows priorities to be set within context of more than one project •Ability for speed over data generation or visa versa•Risk for approval may be reduced on follow-on projects•Vendor changes•Risk of overtax vendors technical capability & sub-optimization

Level of investment in internal resources

•More efficient use of internal resources•Ability to manage•Knowledge transfer•Cost & time•Still must do technology audit for each vendor

iqpc 12th contract manufacturing for pharmaceuticals & biotech1 workshop c: tools for a...

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pharmaceuticals biotech6

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