vp, global head of sales and key account management mimoun ... · supply chain positioning...

www.cordenpharma.com

Experts taking care.

EUROTIDES

November 12, 2019Mimoun Ayoub Ph. D.

VP, Global Head of Sales and Key Account

Management

[email protected]

Stage Appropriate CMC Overview and Requirements for a Robust Dossier

mailto:[email protected]

Sales: € 311 million

Employees: ~ 1,500


Employees: ~ 870

ENKA Group

CarboTech AC

Rütgers Organics


Employees: ~ 1,920


Employees: ~ 1,200

CordenPharma

Group

WeylChem

Group

VYNOVA

Group

IT, Accounting, Finance, Human Resources, Legal

International Chemical Investors Group (ICIG)

Market Oriented PlatformsFine 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

Highlights

CordenPharma Group represents the Pharma

platform within ICIG

Development and manufacturing of active

pharmaceutical ingredients (APIs) and drug products

(DPs)

8 cGMP manufacturing sites and 1 R&D lab in Europe

and the United States with approximately 1,870

employees

Positioned across the value chain as full-service

provider with a broad technology portfolio and

operating in five distinctive technology platforms

Strong customer base, excellent industry recognition

and strategic partner of Big & Specialty Pharma

More than two thirds of net sales generated in the API

area, especially Small Molecules and Peptides

Net Sales Development (excl. CPL)

in €m

Net Sales Breakdown by Platform

Injectables

18%

2

CordenPharma Group: At a Glance

245259

282292

311

380

2014 2015 2016 2017 2018 FC2019

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.62% of net sales and usually have a shorter ramp-up phase than

respective Drug Product projects

Raw MaterialsNon-GMP

Intermediates

GMP

IntermediatesAPIs DPs

Pharma

Logistics

Lifecycle Positioning

CordenPharma focuses on all stages of a drug lifecycle with competitive advantages in clinical

development and commercial production

Preclinical

12 months

Phase I

12-18 months

Phase II

24 months

Registration

12 monthCommercial Generic

Phase 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

Small

Molecules

Antibiotics

Compliance

Road-Map to Market

Pre-clinical

Phase 1 Phase 2 Phase 3

Non-regulated

Non-GMP

Increasing Regulatory Requirements

GMP 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 the

other, consequences beyond IND

Risk assessment and mitigation

approach

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

Program Team

CMC API CMC DP

Packaging labeling logistics

Non-clinical End-points

The big Disconnect…

There are disconnects within each of the two pilars: between API and

DP as well…Multiple partners involved

Performing non-clincial studies to nearly perfection with gaps in CMC

doesn’t help

Non-clinical

Tasks

CMC

API

& 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 Devpt. Manufact.

DP Devpt. Manufact.

Labeling, Packaging

Pre-clinical tox. And

pharmaco.

Compiling Documents

Review

Project

Plan

Project

Team

For Each Milestone…Ex. API Synthesis

1

1

Execution, monitoring

and controling

Project 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

12

Technology

Transfer

Manufacturing

Familia-

risation

Design for

Manufacturability

Process Parameter

Screening

Analytical

Development

Technical

Package

Route

Scouting

Report

Master

Batch

Record

Batch Analysis

Method

Optimisation /

Validation

Process

Optimisation &

CharacterisationUpdated

Master Batch

Record

Route

scouting

Campaign

Report

Commercial Manufacturing

Process

Validation

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 helps 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

Assumptions, Paper 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 the RSM and the criticality of their

specifications

If 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. Synthetic route to be optimized and ideally not changed.

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: Dissolution profile, Blend Uniformity, process information on

coated, un-coated tablets, capsule…

Switching from one dosage form to another needs to be 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 FDA 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

One Project Team: Easy transition from one stage to the next

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-UpAPI

Manufacturing

FormulationDevelopment

Scale-UpDrug ProductManufacturing

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-

methods

Toxicology, 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 with

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, usually underestimated

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


Experts taking care.

THANK YOU

Mimoun Ayoub, Ph.D.

VP, Global Head of Sales and Key Account Management

[email protected]

Cell: +41 79 937 5302


mailto:[email protected]