www.cordenpharma.com

Experts taking care.

TIDES USAMay 2019

Mimoun Ayoub Ph. D. Head of NA and Emerging Markets

mimoun.ayoub@cordenpharma.com

Peptide CMC Approaches for a Fast and Successful IND Filing

Sales: € 380 millionEmployees: ~ 2000

Sales: € 115 millionEmployees: ~ 870

ENKA Group

CarboTech AC

Rütgers OrganicsSales: € 700 millionEmployees: ~ 2000

Sales: € 960 millionEmployees: ~ 1,200

CordenPharma Group

WeylChem Group

VYNOVA Group

IT, Accounting, Finance, Human Resources, Legal

International Chemical Investors Group (ICIG) Market Oriented Platforms

Fine Chemicals Pharma EnterprisesChlorovinyls(1)

ICIG Business Services

Corporate headquarters in Luxembourg and Frankfurt Back-office, ICIG Business Services, located in Wuppertal, 100 employees(1) Acquisition of VYNOVA Group and CordenBioChem completed in August 2015 and April 2016, consolidated pro-forma sales 2015

CordenBioChem

Supply Chain Positioning

CordenPharma covers the full GMP supply chain of pharmaceutical custom manufacturing (raw materials and non-GMP pharmaceutical intermediates partially sourced from WeylChem)

API manufacturing accounts for c.60% of net sales and usually have a shorter ramp-up phase than respective Drug Product projects

Raw Materials Non-GMP Intermediates

GMP Intermediates APIs DPs Pharma

Logistics

Lifecycle Positioning

CordenPharma focuses on all stages of a drug lifecycle with competitive advantages in clinical development and commercial production

Preclinical12 months

Phase I12-18 months

Phase II24 months

Registration12 month Commercial GenericPhase III

36 months

Value Chain Positioning

CordenPharma - Value Proposition Serving Global Pharma & Biotech

Customers

Organized under 5 Distinctive Technology Platforms

Broad Range of Expertise: API’s: Small Molecules, Peptides,

Lipids, Carbohydrates, Highly Potent, Cytotoxics, Conjugates

Drug Products: Oral, Liquids, Injectables, Highly Potents, Anti-infectives / Antibiotics

Global Coverage Allowing for Flexibility

Your Full-Service Provider from Clinical Development to Full-Scale Commercial Supply of APIs & Drug Products

Peptides, Lipids &Carbohydrates

Highly Potent & Oncology

Injectables

SmallMolecules

Antibiotics

Road-Map to Market

Pre-clinical Phase 1 Phase 2 Phase 3

Non-regulatedNon-GMP

Increasing Regulatory RequirementsGMP to Full Validation

12-36 months 12-18 months 24-36 months 24-48 months

Goal of IND and Requirements

The very top objective is to demonstrate SAFETY

Need a good process understanding and impurity control, even without a full set of QbD studies

Requires a full set of non-clinical studies• Toxicology: Maximum Tolerated Dose (MTD), chronic and accute toxicology…• Pharmacology: PK/PD, ADME…

Raw material quality. Avoid processes using toxic starting materials

Testing methods: drug substance, drug product, bioanalytical methods…

Product stability: the product should be stable during the duration of the non-clinical/clinical studies

IND Project Road-Map

Budget

Quality

Time

Alignment between Budget-Quality-Time

Compromising one will impact theother, consequences beyond IND

Risk assessment and mitigationapproach

Pay now or pay later but more…

Program Team CMC API CMC DP

Packaging labeling logistics

Non-clinical End-points

Various and complex steps

Multiple stakeholders with different skills

Project predictability. Expect challenges and be

prepared to manage them: Contingency Plan

with Time and Budget extension

The big Disconnect…

There are disconnects within each of the two pilars: between API andDP as well…Multiple partners involved

Performing non-clincial studies to nearly perfection with gaps in CMC doesn’t help

Non-clinicalTasks

CMCAPI & DP

Key Milestones

Avoid time-gaps between milestones

Data and supporting documentation

generated to be ready to transit to

next stage

Results vs. Expectations at each

milestone. Gaps and mitigation plans

Project teams for each milestone with

an overall program management

Final dossier: compiling data as you

progress

FDA Submission

API Dept. Manufact.

DP Devpt. Manufact.Labeling,

Packaging

Pre-clinical tox. And

pharmaco.

Compiling Documents

Review

Project Plan

Project Team

For Each Milestone…Ex. API Synthesis

9

Execution, monitoring

and controlingProject Closing

Follow up, improvement

• Feasibility evaluation

• Targets/milestones

• Definition of scope

• Cost calculation

• Proposal preparation

• Quote submission

• PO

• Definition of tasks

• Ressources and

capacities

• Scheduling

• Project team

building

• Kick-off

• Process research and dev´t

• Analytical dev´t• Supply chain• EHS study• Manufacturing• QC/QA release• Regulatory services• Stability study• Reporting

• Final report

• Delivery

• Project review

• Lession learned

• Further optimization

• Cost savings potential

• Know-how management

• Commercial potential

Phase appropriate development, risk assessment

Process Development

10

Technology Transfer

Manufacturing

Familia-risation

Design for Manufacturability

Process Parameter Screening

Analytical Development

Technical Package

Route Scouting Report

MasterBatch Record

Batch AnalysisMethodOptimisation / Validation

ProcessOptimisation & CharacterisationUpdated

Master Batch Record

Route scouting

CampaignReport

Commercial Manufacturing

ProcessValidation

Before Initiating the Work…

Put together a good document for the Target Product Profile TPP What needs to be achieved to end up with a good and safe drug

TPP provide a basis for a good planning of the activities and how they should be performed to address the requirements

TPP will help you identify the risks and mitigate them • Drug substance risks• Drug product risks• Non-clinical study risks, study design etc• Regulatory strategy

Mode of adminitration

Expected formulation: IV, SC, Oral (capsule, tablet, granules…), Patch…• The requirements will depend on the formulation

TPP is a living document and can be updated based on the progress and challenges

Before Initiating the Work…

Clear the intellectual property For the product itself For the planned experiments. Some of the technologies intended could be

patent protected. Seek an FTO statement Plan for enough API and finished product

Anticipate potential solubility issues and other physical and chemical challenges based on the product structure/peptide sequence:

Can the drug be formulated based on its chemical formula/structure. Hydrophobicity. Is the preclinical formulation going to be the long-term approach? Potential gaps to be assessed

Anticipated stability issues? Oxidation, ester cleavage, hydrolysis…

Manufacturing: scalability and COGS. Competitive landscape

Drug Substance CMC Requirements

The very least you need to provide:

Nomenclature and product description

Physical and chemical characteristics

Manufacturer and relevant documents

Method of synthesis: detailed flow diagram including reagents, solvents…

Structure justification, chirality, sequence

Impurities and justification. Genotoxic impurities

Specify limits for ID, purity, assay, impurity level, KF, etc. Justify why

Analytical methods: ensure the methods are aligned with the process and

can detect and quantify process and stability related impurities

Container/packaging specifications. Stability

Drug Substance Recommendations

Anticipate and identify your RSM and the criticality of their specifications

If you have ALREADY MADE the Phase 1 material, provide the CoA of both Tox and phase 1 material. Explain, justify the differences if any

Understanding the process. Process impurities vs. Stability impurities, methods, impact of raw materials (use-test?), replacing class I solvents. No need to characterize impurities for PC studies

Planning for enough material… Primary reference standard Method development, qualification Stability Formulation development Retain samples

Drug Substance Recommendations

Qualifying higher process impurities through toxicology studies. Use of a less pure API (~95%) Purity may drop during formulation Scale-up may lead to less pure material due batch size and difficulties to

keep process parameters under control

Ideally long-term process should not change too much but only optimized. Scalability of current Tox batch process to be considered

Partner should have the capacity to support throughout the product life-cycle. Switching only if really needed. Tech transfer costs, new partner not familiar with the process challenges, time for transfer…

Drug Product Requirements

Similar to API with more Drug Product specific information Components in the DP

• Excipients including novel actives (formulation technologies, delivery systems)• Primary packaging: suppliers to be listed

– For injectables:vials, stoppers, pre-filled syringes, cartridges…– Solids: blister packaging specifications, bottles…

Manufacturer, licenses Process flow diagram with emphasis on the sterilization steps Analytical methods and specifications

• Excipients and packaging materials• API• Finished product

Stability data: 1 month for US and 3 months for Europe Container closure integrity test (CCIT): to be validated for sterile products

Drug Product Requirements

Importance of the dosage form: Intravenous and Sucutaneous: sterile liquid or lyophilized to be

reconstituted Sterility is key and needs to be validated: sterile filtration, heating

cycle, container closure Inhaled products, provide information on:

• Particle size• Bioavailability• Dilution• Complex formulation (lipids nanoparticles, liposomes…): Process information• Device functionality

Oral delivery: Process information on coated, un-coated tablets, capsule…

Switching from one dosage form to another after preclinical needs tobe carefully assessed and risk-mitigated

Compressing Timelines

Good design of the studies Target indication once IND filed Plan for phase 1 studies: healthy volunteers vs. Patients (oncology) Plan to be cross-checked by a toxicologist and confirmed by a KOL Route of administration, dose Pre-IND meeting with FDA

CMC: no need for GMP API. Recommend less pure API for Tox. Leverage on synergies between API and DP

• Analytical methods• Timelines• Understanding of the API characteristics will help DP development and

manufacture• Stability data on API will help anticipate DP stability

Compressing Timelines

Overriding the requirements generates more work and causes delays

Lean project planning and avoid leaving too much gaps between

the activities. The time required is usually under estimated

The required data for filing should be generated as the project

progresses. Compiling 12-18 months of data afterwards can be a

challenge.

Analysis of the CMC risks: scale-up, stability, methods, contingency

Simple formulation possible but need to assess the risk of switching

later on.

Project management, project management, project management…

CMC Supply Chain Complexity

No matter how many CMC partners involved, there will be ONE IND Reviewer!!!

Supply Chain and Compressing Timelines

API and Drug Product Development and manufacture Automated synthesis vs. Semi-automated or manual

Drug product: level of automation in filing, labeling, packaging, inspection

Experience developing processes and similar APIs. Synergies with other similar APIs can help reducing the process development timelines

CMO/CRO level of outsourcing. The more outsourcing, the complex is the supply chain and overall project overview

Does the set-up of API and DP sourcing allows for easy use of the synergies? Integrated project plan?

Delay in API impacts the start of the formulation. Am I going to have another formulation slot soon? Impact on overall project timelines…

API and DP under the same roof. Delays in API are easier to handle in case of integrated supply. Aligning multiple partners can be a challenge

Supply Chain and Compressing Timelines

CDMOs and CROs must have a very good blend of knowledge and expertise in such services

True integrated services, no silos! CDMOs and CROs with the capabilities but working in silo mode! Overall project management: overviewing all of the activities API, DP,

coordinate with non-clinical services… Project team with clear duties and responsibilities keeping an eye on the 3

pilars: timelines, quality and budget Easy transition from one activity / stage to the next, one project team

Partner reliability: can deal with challenges. Solution oriented

The CMC gaps may have a big impact on product due dilligence for partnering or out-licensing

ProcessDevelopment Scale-Up API

Manufacturing

FormulationDevelopment Scale-Up Drug Product

Manufacturing

Compressing the Timelines Through Project Integrated Services Leverage on API know-how to transition to drug product:

Analytics, product characteristics Integrated Project Management, overview on the overall Project Plan Time and Costs saving

In vitro, ADME, Bio-

methodsToxicology,

Pharmacology

Quality & Regulatory Support

Selecting the CMC Partner

Supply of API and DP under the same roof

Scientific skills and know-how in line with your project requirement

Available capacity to support far beyond IND and avoid switching and associated risks

Capabilities: manufacturing and analytics including later stages

Regulatory history and quality system

Can manage multiple projects. Resource flexibility, can adapt to changing scenarios

Strong project management and communication

Transparency

Pricing

Pre-IND Meeting (few months before submission)

The Agency is a Partner. Work collaboratively. They provide guidance for the project

Compiling a list of questions to be addressed during the meeting. Can the data be compiled or is it spread over various CDMOs and CROs?

Few thoughts: very short summary of the dossier Product information: small molecule, peptide, biologic, vaccine… Therapeutic indication Dosage form and route of administration EXPECTATIONS FROM THE PRE-IND MEETING. What are the

questions/uncertainties to be clarified? Data to date CMC plan Non-clinical plan Phase 1 protocol, at least an idea of the next stage

IND Submission and Review Process

IND Submission

Do you have all the information required. Check-list, tick the boxes

Do you have the resources to put together the required documents

Do you have project management capabilities to feed all necessary

information generated over several months

Do you have a clear idea of the target filing date and how to get there

Don’t hesitate to seek help from consultants having experience filing

Summary

Connecting CMC development with pre-clinical development Even not completely optimized, the process strategy should be able

to supply clinical and commercial quantities after optimization Interdependent activities. Project plan is key. Integrated services are

a big plus in accelerating the program and saving costs Planning time to compile the data, not only to complete the work Some CMC activities cannot be compressed without jeopardizing the

dossier (stability, development API and DP) Specifications to be set based on process data rather than what can

be done or internal capabilities. Alignment between CQAs and CPPs

Work closely with the agency and the reviewer. Multiple CDMOs and CROs can be involved but there will be one reviewer!!! Dossier should be comprehensive

www.cordenpharma.com

Experts taking care.

THANK YOU

Mimoun Ayoub, Ph.D.Director, Head of North America and Emerging MarketsMimoun.Ayoub@cordenpharma.comCell: +41 79 937 5302www.cordenpharma.com