www.cordenpharma.com

Experts taking care.

Producing the Highly Potent Peptide

Richard Dauer, PhDDistinguished Engineer

CordenPharma Colorado

CordenPharma Overview

Full-Service CDMO Organized under 5 Technology Platforms

€ 365 Million Total Sales (2016)

11 Manufacturing Facilities in Europe / US (9 GMP Plants, 2 R&D Labs)

1,670 Employees

Your Full-Service CDMO Partner

Linking Together a Legacy of Expertise Customised Service Packages organized under Technology Platforms spanning the entire

Pharmaceutical Manufacturing Process

Specialised Technologies for the Production of Oral, Sterile & Highly Potent Pharmaceutical Drug Products and their APIs

More than 40 years of Experience in European and USA-based Pharmaceutical Manufacturing

CordenPharma Facilities are Audited and Certified by all Relevant Pharmaceutical Compliance and Approval Authorities

Commercial Supply

Registration Supply

Clinical Manufacture

Process &Analytical

Development

Process &AnalyticalTransfer

CordenPharma – Full-Service CDMO

CordenPharma - Value Proposition

Serving Global Pharma & Biotech Customers

Organized under 5 Distinctive Technology Platforms

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

Oligonucleotides, 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, Oligonucleotides, Lipids &Carbohydrates

Highly Potent & Oncology

Injectables

SmallMolecules

Antibiotics

CordenPharma Colorado

Integrated Resource for the Development & Manufacture of Advanced Intermediates and APIs for Global Pharmaceutical and Biotechnology Industries

Development & Manufacture of Complex Synthetic Peptides, Highly Active Peptides and Conjugates

Development & Manufacturing of Highly Potent, Cytotoxic & Non-Cytotoxic APIs

Excellent Track Record in Development from Early Stage to Launch

SafeBridge® IV Certified

Location: Boulder, Colorado USA Acquisition(ex Roche): September 2011 Employees: 284

Core Competencies

• Leader in Development & Manufacture of Synthetic Peptides

• Process Analytical Technology & Track Record in Regulatory Filing

• Development & Scale-up of Highly Potent & Oncology APIs

CordenPharma Boulder

Experts in the Development & Manufacture of Highly Potent Products (cytotoxic & cytostatic)

Complex Purifications Expertise

Excellent Track Record in Development from Early Stage to Launch

Successfully inspected by the US-FDA, TGA, MHRA, PDMA

Location: Boulder, Colorado USA Acquisition(ex Pfizer/Hospira): October 2017 Employees: 70

Core Competencies

• Development & Scale-up of Highly Potent & Oncology APIs

• Leader in Taxane Chemistry• Strong Regulatory Track Record

CorporateIH team founded

Corden Pharma ColoradoLong History in Highly Potent Peptides & APIs Fenprostalene/Enprostil(steroids) since 1985

25 ng/m3 OEL prostaglandins 300 g capacity

Nafarelin since 1985 1 ng/m3 OEL decapeptide 10 kg capacity

Calcitriol since 1996 10 ng/m3 OEL vitamin D analog 160 gm capacity

SyntexEarly development

of Industrial HygienePhilosophy

Corden Pharma ColoradoCMO specializing in Highly Potent Peptides and APIs

V = 6.5 X 106 m3

w = 527 ftl = 736 ft

h = 150 ft

Nafarelin OEL = 1.0 X 10-9 g/m36.5 mg

WOW!

HAC – The Challenge

Containment PuzzleThe pieces must align

ContainmentSuccess

ContainmentCulture

Occupational Health Pre-Planning

ProcessDevelopment

Containment Execution Cycle

EngineeringControls

Containment PhilosophyPresentation of the HAC?

Solids Primary exposure risk when aerosolized Types

• Precipitated and dried solids• Lyophilizate

Samples Bulk intermediates and products

Liquids and Wet Cakes Rare that risk from HAC is in the vapor phase Reduced risk to personnel Requires spill prevention, containment and response

10

Containment PhilosophyDefining and Monitoring the Hazard? Categorization of HAC – OEL (µg/m3 or ng/m3)

Structural analysis• Assess late stage intermediates• Unknowns Category D (10 µg/m3)

Testing and evaluation• Supplied by customer• Outsourced to toxicology lab (SafeBridge)

OEL conversion to surface limit

Monitoring Breathing air Swipe methods – sensitivity sufficient for surface limit Personnel health surveillance

• Blood and urine analysis

11

Containment on Scale-UpHow do we protect ourselves?

Engineering Controls PPE is a safeguard not a control Solids handling requires containment

• Hard-side for Cat 4 Location – analytical vs development vs production

Training on specific hazards & methodologies Containment Execution Cycle – monitoring corrective actions Cleaning strategies and kill solutions defined

12

Containment on Scale-UpApproach: Portable technologies applicable to standard processing equipment Flexible containment

Fast low-cost implementation Portable (un-dedicated) Versatile Can be extended by combining technologies Less cleaning Amenable to bulk handling Provides a flexible system and container Familiar to operator Disposables can be charged to product Low capital investment

Hard-side containment Required for Category 4 Cumbersome Expensive and dedicated

13

Solids OEL (μg/m3) for Routine Operations*0.0011,000 100 50 10 1 0.1 0.01

* In non-routine upset conditions PPE can add 1,000x protectionSource: Barnett International, RCC IH test data & estimates, Team Analysis

Local exhaust

Crossflow booth

Downflow booth (not used for solids at RCC)

Cone valve

Split Butterfly (typical)

Isolator (RTP)

Split Butterfly (special)

= Industry standard containment= CPC actual proven containment= CPC estimated potential containment

Dover Flexible Liners (w/ loc. exh) (w/ specific hood)

w/ shaped hood

Bulk bags

Lab hoods

Split Butterfly (w/ loc exh)

Containment Levels: Proven & Envisioned Potential

Containment on Scale-UpRisk Assessment –Team Effort

ID exposure points Minimize through development Select appropriate containment

• Sampling plant to lab to disposal• HAC loading• HAC discharge/packaging

– Customer coordination• In and post process cleaning

Implementation Containment design and installation Procedures Training

Operations Monitoring Debrief, follow-up

15

VE-250Dissolver

250Bath

VE-212Precipitator

212Bath

Apovac/vent

212Bath

PP-DH-109

Dover C/L LDPE 3 milHDPE drum

34 L

WashesLine washDisp.SlurrySlurrySlurrySpray head

Pure Product Isolation

HACSampling

Sampling

Penultimate

CTW/LTC

SE-222Wash Feed

HAC

HAC

HAC

Sprayheads

HE-232Receiver

212Bath

AirPP-PHP-02

Pure Boundary

M 1"

Solvent

M½"

WASTE2N-SRP-17

110 L Can

Solvent

StepProduct

DoverPac

HAC Risk Assessment TeamChemistProcess EngineerProject EngineerIndustrial HygienistEnvironmental EngineerOperatorArea HeadProcess Expert

Containment on Scale-UpLine Breaks and Leaks

Personnel controlled access Limit to trained personnel

Plan for line breaks Plumb for decontamination

• Flush to waste Risk assess a surface limit for process

surfaces• Monitor performance• Adjust limits as necessary

Plan for leaks Bag or line potential exposure areas Spill response Cordon off area Clean to surface limit

16

VE-250Dissolver

250Bath

VE-212Precipitator

212Bath

Apovac/vent

212Bath

PP-DH-109

Dover C/L LDPE 3 milHDPE drum

34 L

WashesLine washDisp.SlurrySlurrySlurrySpray head

Pure Product Isolation

HACSampling

Sampling

Penultimate

CTW/LTC

SE-222Wash Feed

HAC

HAC

HAC

Sprayheads

HE-232Receiver

212Bath

AirPP-PHP-02

Pure Boundary

M 1"

Solvent

M½"

WASTE2N-SRP-17

110 L Can

Solvent

StepProduct

DoverPac

FilterReplacement

SPPS or LPPS

Protected Peptide

Deprotection Folding or Modification

Purification Solids IsolationPackaging

Typical Peptide Scheme

SPPS or LPPS

Protected Peptide

DeprotectionFolding or Modification

Purification Solids IsolationPackaging

Modified Peptide Scheme

HACIsolations

HACIsolations

SPPS or LPPS

Protected Peptide

DeprotectionFolding or Modification

Purification Solids IsolationPackaging

Optimized Peptide Scheme

HACIsolation

Containment on Scale-UpProcess Modification

Containment on Scale-UpMinimization of Solids Handling

Minimize solids sampling Avoid drying

Handle the wet cake Slurry transfer from the dryer Dissolution

Avoid solids isolation Extraction

18

Work with the customer for API API transfer team

• From dryer to formulation Delump/co-mill during packaging Side samples during packaging

• Confirm batch homogeneity• Raman for RM ID

Water content and cold chain issues Coordinate shipping container

Containment PuzzleThe pieces must align

ContainmentSuccess

ContainmentCulture

Occupational Health Pre-Planning

ProcessDevelopment

Containment Execution Cycle

EngineeringControls

Minimize sampling and dry solids handling

Know yourOEL, monitoring protocols and cleaning methods

Develop a containment philosophy & extend your capabilities

Train your personnel, monitor containment

Apply your learnings& optimize your

operations

www.cordenpharma.com

Experts taking care.

Rick Dauer, Ph.D.Distinguished EngineerCordenPharma ColoradoRichard.Dauer@cordenpharma.comT: +1 303-938-6540

Inquirieswww.cordenpharma.com/contact-us/

THANK YOU!

mailto:Richard.Dauer@cordenpharma.com

Producing the Highly Potent PeptideCordenPharma OverviewCordenPharma – Full-Service CDMO CordenPharma - Value PropositionCordenPharma Colorado CordenPharma Boulder Corden Pharma Colorado�Long History in Highly Potent Peptides & APIsCorden Pharma Colorado�CMO specializing in Highly Potent Peptides and APIs�HAC – The ChallengeContainment Puzzle�The pieces must align�Containment Philosophy�Presentation of the HAC?Containment Philosophy�Defining and Monitoring the Hazard?Containment on Scale-Up�How do we protect ourselves?Containment on Scale-Up�Approach: Portable technologies applicable to standard processing equipmentContainment Levels: Proven & Envisioned PotentialContainment on Scale-Up�Risk Assessment –Team EffortContainment on Scale-Up�Line Breaks and LeaksContainment on Scale-Up�Process ModificationContainment on Scale-Up�Minimization of Solids HandlingContainment Puzzle�The pieces must align�Slide Number 21