Pfizer's Strategy for the Development and Manufacture of Linker-Payloads in Antibody Drug Conjugates

Pfizer’s Strategy for the Development and

Manufacture of Linker-Payloads in

Antibody-Drug Conjugates

Jeffrey B. Sperry, Ph.D.

HPAPI Development & Manufacturing Summit 2014

Outline

• Discuss how Pfizer classifies HPAPIs

– Occupational Exposure Band (OEB) values

• Internal guidance for the handling and manufacture of HPAPIs

– Internal versus external manufacture options

• Outsourcing relationships for the manufacture of HPAPIs

– Leveraging external expertise

– Case example: ADCs

Pfizer Confidential │ 2

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Pfizer Occupational Exposure Values

Occupational Exposure Limits (OELs)

An 8 hour time-weighted average concentration of a substance in air to which it is

believed that employees may be exposed, without personal protective equipment,

for eight hours per day, 40 hours per week, without adverse effect.

Occupational Exposure Bands (OEBs)

Occupational Exposure Bands (OEBs) are hazard classifications that correspond

to specific [order-of-magnitude] airborne concentration ranges.

OEBs are intended to protect workers from the hazardous properties of the

compound during handling.

The OEB system separates substances into different hazard categories when the

available data are sufficient to do so, but inadequate to establish an Occupational

Exposure Limit (OEL).

• Small molecules assigned Occupational Exposure Bands (OEBs),

• Large molecules (Biologics) assigned to Biotherapeutic Occupational

Exposure Bands (B-OEBs)

OEB Criteria Matrix for Small Molecules


Pfizer Definitions

• Compounds handled within a research environment are “born” as

unclassified from an occupational toxicology perspective unless data

indicates otherwise. Unclassified compounds are handled as Occupational

Exposure Band 4 (OEB 4s).

• This requirement applies to all Laboratories, Vivarium and Clinical

Manufacturing activities.

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Type Occupational

Exposure Level

(OEL)

Occupational

Exposure Band

(OEB)

Biotherapeutics

Occupational

Exposure Band (B-

OEB ) based on ADI

Potent

Compound

<10 μg/m3 (0.01 mg/m3) OEB 4 B-OEB 4

(10-100 μg/day)

Highly Potent

Compound

<1 μg/m3 (0.001 mg/m3)

OEB 5

B-OEB 5 (<10μg/day)

ADI – Allowable Daily Intake

OEB 5 Compounds

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• Certain criteria and or concerns drive more conservative handling:

• Projected potency of < 0.5 mg (or lower end of potency range < 0.5)

• Analogy to other similar highly potent compounds

• Mechanism of action – known or suspected to affect rapidly dividing

cells

• Classification is usually compound specific but in some cases is made for

classes of compounds (Vitamin D analogs, ADCs)

• An OEB 5 or B-OEB 5 classification stays with the compound in all

physical states (solid, solution, formulated product), it does not change

unless the data set drives a re-classification

• The exposure potential varies depending upon the physical state, amount

being handled and effectiveness of controls available

Compound Classification Process

Pfizer employs a Global Compound Classification Process:

– Conducted by EH&S

– Compound classification decisions are made in partnership with

Research Project Teams to ensure all relevant data is considered.

– Classification is initiated in line with R&D development stage-gates.

– Pharmacological (or toxicological) data points used (mechanism of

action, potency projections, and structural analogy)

– As compounds move through the development process and

information is generated on their toxicological profile, further

evaluations are undertaken for worker safety endpoints


Risk Assessment Process for Containment

1. Form

– Solid or liquid

2. Activity

– Structurally similar compounds with similar potency

3. Quantity

– Small-scale (< 1 g) manufacture

– Large-scale (500+ g) manufacture

4. Quality

– DSI, DS, or DP

5. Available Facilities

– Research Labs

– Kilo-lab

– Pilot Plant


Case Study: Linker-Payload Manufacture for

Antibody-Drug Conjugates (ADCs)


What is an ADC?


What is an ADC?


What is an ADC?


ADC Manufacturing Strategy


mAb is a Drug Substance

Intermediate



Linker-Payload is a Drug Substance Intermediate



Small Molecule:



Small Molecule:

ADC:



Small Molecule:

ADC:





Manufacturing Challenges


Payloads are complex “small molecules”

• High MW (~1000 amu)

• Contain minimum of 8 stereocenters

• Consist of natural and synthetic amino acids

Payloads and Linker-Payloads (LPs) are classified as OEB5

• Cytotoxic (IC50 values <1 nM)

• High potency (Projected ADC dose 1 to 10 mg)

• Maximum 10g handling limit for solids in CRD

Isolations challenging

• Linkers and intermediates require chromatography

• Final linker-payloads require RP-HPLC or RP-MPLC purification to meet high purity

requirement (>98%)

Linkers, payloads, and LPs are required across multiple programs

• Multiple LPs entering early tox and FIH studies for each program

• Need to be flexible with synthesis design and manufacturing capacity



Payloads are complex “small molecules”

• High MW (~1000 amu)

• Contain minimum of 8 stereocenters

• Consist of natural and synthetic amino acids

Payloads and Linker-Payloads (LPs) are classified as OEB5

• Cytotoxic (IC50 values <1 nM)

• High potency (Projected ADC dose 1 to 10 mg)

• Maximum 10g handling limit for solids in CRD

Isolations challenging

• Linkers and intermediates require chromatography

• Final linker-payloads require RP-HPLC or RP-MPLC purification to meet high purity

requirement (>98%)

Linkers, payloads, and LPs are required across multiple programs

• Multiple LPs entering early tox and FIH studies for each program

• Need to be flexible with synthesis design and manufacturing capacity

Can an external partnership be developed to meet the project deliveries?

Supplier Considerations


• Short-list criteria

– Capabilities

• GMP API manufacturing

• GMP HPAPI manufacturing

• Chromatography

– HP GMP

• Strong analytical

• Peptide Experience

• Good standing in Pfizer systems

– Geography: Not a requirement; L-P is not API so not bound by Import-for-Export

limitations



• “Small molecules” classified as OEB4 (no high potency handling precautions)

• Sourced from several vendors

• All are available in 100g to >1kg quantities



• “Small molecules” classified as OEB4 (no high potency handling precautions)

• Sourced from several vendors


• “Small molecules” classified as OEB5

• Sourced from vendors capable of HiPo API production


Payload Manufacturing












Both products classified as OEB5

Linker-Payload Manufacturing


10 Steps from amino acid building blocks

• 6 non-HP steps

• 4 HP steps

Linker-Payload Manufacturing


40% of steps require containment


• 6 non-HP steps

• 4 HP steps

Linker-Payload Manufacturing – New Route








“Tetramer “

• classified as OEB4

• Requires 6 non-HiPo steps




• 6 non-HiPo steps

• 2 HiPo step vs.

Decreased cost and production time!


• 6 non-HiPo steps

• 4 HiPo steps


How do we support multiple programs, each with unique Linker-Payloads

and separate timelines?


How do we support multiple programs, each with unique Linker-Payloads

and separate timelines?

Through strategic sourcing of intermediates!

Challenges Supporting Multiple Programs




Must balance:

• Production time required to make LPs

• Cost to store OEB4 intermediates

• Cost to store OEB5 intermediates

• Producing too much of “wrong” intermediate













Strategic sourcing allows for more rapid execution of synthesis,

and in some instances, fewer HiPo steps

Conclusions

• Pfizer employs a Global Compound Classification Process for Highly Potent APIs:

• Compound classification decisions are made in partnership with Research Project Teams to

ensure all relevant data is considered.

• Pharmacological (or toxicological) data points used (mechanism of action, potency projections,

and structural analogy)

• As compounds move through the development process they are frequently evaluated for worker

safety endpoints

• Within Pfizer, several types of exposure limits or Occupational Exposure Values are developed:

• Occupational Exposure Limits (OELs) define the amount (concentration in µg/m3) of compound

that you can be safely exposed to over an 8-hour day, 5 days per week without experiencing

adverse effects

• Exposure Bands define an airborne concentration into which the OEL is reasonably expected to

fall (once data becomes available)

• CRD has developed working relationships with outside vendors to support the ADC programs

• Payloads and Linker-Payloads are classified as OEB5

• LPs can be assembled in a linear fashion via linking of payload or in a convergent fashion via

tetramer

• Utilize strategic sourcing to support multiple programs and provide a wide range of linker-

payloads in a timely fashion


Acknowledgements

CRD

Dan Bowles

Phil Dent

Cheryl Hayward

Jason Kiser

Hayden Thomas

Analytical

Mike Lovdahl

Jared Van Haitsma

Sourcing

Mari Stephan

Jeff Raggon

Purification

Manisha Patel

Frank Riley

Chris Foti

Todd Zelesky

Melissa Wagenaar

Medicinal Chemistry

Chris O’Donnell

Alex Porte

Andreas Maderna

Russell Dushin

Hud Risley

Chakrapani Subramanyam,

Matt Doroski

mAb Production

Frank Loganzo

Mark Pozo

Christine Smith

Bo Arve

Leo Letendre

Kevin King

Steve Max

Birte Nolting

Anthony Barry

Durgesh Nadkarni

EH&S

Sarah Jones

Jean Ferris

Eric Watters

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Occupational Exposure Bands

Occupational Exposure Bands:

– Small molecules

– Airborne concentration range, limited

hazard data (LOAEL, NOAEL)

– Exposure controls focused on

inhalation exposures

Biotherapeutic Occupational Exposure

Bands (B-OEBs)

– Large molecule / biotherapeutic entities

– ADI (μg/day) calculated from Lowest

Therapeutic Dose (LOAEL)

– Exposure controls focused on parenteral

exposures (sharps) and liquid aerosols

Bands separate compounds into one of five different hazard categories

Exposure control and containment strategy = Handling Guidelines

OEB 4 = default in both schemes

Pfizer's Strategy for the Development and Manufacture of Linker-Payloads in Antibody Drug Conjugates

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