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ProSys Containment

ISOLATOR CONTAINMENT TECHNOLOGY FOR THE MANUFACTURE OF

ANTIBODY DRUG CONJUGATES (ADCS)

OCTOBER 2015

Pharmaceutical Market in Transition

Targeted Drug Therapies (Personalised Treatment)

◦ Mabs, (Monoclonal Antibodies)

◦ ADCs, (Antibody Drug Conjugates)

◦ CART (Chimeric Antigen Receptor T) Cell Immunotherapy

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ADC IN ACTION !

� ADC Monoclonal antibody (mAb) + cell-killing cytotoxic drug

� mAb Delivery system which selectively targets the tumour cells

It has high binding specificity for tumour-specific antigens

� Once in the tumour, the ADC releases its cytotoxic payload by chemical or enzymatic processes, eventually leading to the death of the targeted cell

Components of ADC

COURTESY: (GENENTECH INC., 2015)

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Clinical Landscape of ADCs

COURTESY: ROSTAMI, S., I. QAZI, AND R. SIKORSKI, THE CLINICAL LANDSCAPE OF

ANTIBODYDRUG CONJUGATES. ADC REVIEW. AUGUST 1, 2014.

Isolator Definition

A separative device that provides assured protection by using physical

and dynamic barriers to create separation between operation

(product) and operator/exterior environment.

Containment Aseptic

Operator protection Product protection

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Containment Performance Target (CPT) & Occupational Exposure Limit (OEL)

CPT measured in ‘ µg/m³ or ng/m³@’ at 8 hours Time weighted average (TWA)

CPT= Containment capacity in terms of airborne concentration (µg/m3) of the isolator based on the OEL of the compound/API to be handled

OEL = Airborne concentration of a compound/API to which nearly all workers can be repeatedly be exposed 8 hours a day, 40 hours a week, without adverse effects.

ADC projects Customer Location : Cambridge, USATarget CPT : ≤10ng/cubmAchieved CPT: ≤5ng/cubm

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ADC projects Customer Location : California, USATarget CPT : 10 nanogram/cubm

MSB Isolator

Achieved CPT: 8ng/cubm

VSE Isolator

Achieved CPT: 10ng/cubm

CASE STUDYCASE STUDYCASE STUDYCASE STUDYCustomer Location : Dublin, IrelandTarget CPT : 50ng

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Project ObjectiveProject ObjectiveProject ObjectiveProject Objective

To develop a Production Suite for the contained manufacture of HPAI of an ADC

Project Drivers

EHS Achieve appropriate OEB 5 containment levels – less than

50ng/m3

EHS/GMP Prevent escape of airborne material from the suite or ingress

of material to the suite

GMP GMP improvements over existing cleanrooms (class and bio-

burden)

Production Maintain production during project execution

Concept Concept Concept Concept studystudystudystudy

2 processes:

� Lyophilisation of liquid API

� Lyophilisation of API Salt

Review existing process, equipment and SOP’s with production staff –decide what is sacrosanct and what can be changed.

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Process No.1 Process No.1 Process No.1 Process No.1 ----Lyophilisation of liquid API Lyophilisation of liquid API Lyophilisation of liquid API Lyophilisation of liquid API

Lyophilisation of liquid API Lyophilisation of liquid API Lyophilisation of liquid API Lyophilisation of liquid API

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Process No.2 Process No.2 Process No.2 Process No.2 ----Produce API Salt Produce API Salt Produce API Salt Produce API Salt

Produce API salt Produce API salt Produce API salt Produce API salt

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Key success factors for achieving Key success factors for achieving Key success factors for achieving Key success factors for achieving ng ng ng ng containment containment containment containment levelslevelslevelslevels

� Isolation technology

� Transfer technology

� Minimise number of transfers

� Minimise internal dust levels

� Perform transfers after cleaning where possible

� Effective cleaning

Key Equipment requirements to satisfy Key Equipment requirements to satisfy Key Equipment requirements to satisfy Key Equipment requirements to satisfy driversdriversdriversdrivers

� Separate units in independent rooms

� Achieve CPT of 50ng/m3

� Test in accordance with ISPE good practice guide

� Analyse results in accordance to EN 689

� Fit within available footprint (long and thin)

� Adhere to product registration –final package format

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Biggest isolator design challengesBiggest isolator design challengesBiggest isolator design challengesBiggest isolator design challenges

� Parallel development of isolator and process equipment

� Integration of 3rd party equipment (4 suppliers)

� Ergonomics

� Layout to provide logical process flow with minimum footprint

Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) ––––Design considerations Design considerations Design considerations Design considerations ----ergonomicsergonomicsergonomicsergonomics

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Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) ––––Design considerations Design considerations Design considerations Design considerations ----ErgonomicsErgonomicsErgonomicsErgonomics

Conclusion:

Integrate into isolator

base, accessed from

half-suit

Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) ––––design design design design considerations considerations considerations considerations ----ergonomicsergonomicsergonomicsergonomics

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Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) ––––design considerations design considerations design considerations design considerations ---- ergonomicsergonomicsergonomicsergonomics

Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) Isolator (unit 1) –––– design considerations design considerations design considerations design considerations ----ergonomics ergonomics ergonomics ergonomics

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Unit 1 Unit 1 Unit 1 Unit 1 ––––Concept Design LayoutConcept Design LayoutConcept Design LayoutConcept Design Layout

Unit 1 Unit 1 Unit 1 Unit 1 ––––Concept Design LayoutConcept Design LayoutConcept Design LayoutConcept Design Layout

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Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) ––––design considerations design considerations design considerations design considerations ----ergonomicsergonomicsergonomicsergonomics

� Non-hazardous dispensing outside isolator: Solids and liquids in VBE.

� Need Peristaltic Pump connections

Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) ––––design considerations design considerations design considerations design considerations ----ergonomicsergonomicsergonomicsergonomics

50 l vessels

� ergo issues similar to unit 1 mixing vessel

� 2 vessels require agitator and weigh cells

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Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) ––––design considerations design considerations design considerations design considerations ----ergonomicsergonomicsergonomicsergonomics

� Need to be able to inspect internals

� Need to be able to remove basket

� Need a filtrate receiver

Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) ––––design considerations design considerations design considerations design considerations ----ergonomicsergonomicsergonomicsergonomics

Conclusions:

� Access OK for door opening and tray loading

� Access not OK for cleaning and inspection

� Half-suit preferred

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Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) –––– design considerations design considerations design considerations design considerations ---- ergonomics ergonomics ergonomics ergonomics

Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) Isolator (unit 2) ––––design considerations design considerations design considerations design considerations ----ergonomicsergonomicsergonomicsergonomics

Same design as Unit 1

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Unit 2 Unit 2 Unit 2 Unit 2 ––––Concept Design LayoutConcept Design LayoutConcept Design LayoutConcept Design Layout

Unit 2 Unit 2 Unit 2 Unit 2 –––– Concept Design LayoutConcept Design LayoutConcept Design LayoutConcept Design Layout

Vessels Centrifuge

Sieve

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Post Procurement Post Procurement Post Procurement Post Procurement ––––detailed design phasedetailed design phasedetailed design phasedetailed design phase

� Initial GA / P&ID review

� Ergonomic review of physical model

� Design documents review –

◦ Design specification

◦ FDS

◦ Software design and testing

�Testing

P&ID P&ID P&ID P&ID ––––Unit 1Unit 1Unit 1Unit 1

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Ergonomic reviewErgonomic reviewErgonomic reviewErgonomic reviewSuccess factors:

� Involve people with good process knowledge

� Involve people of different heights

� Step through process, cleaning and maintenance

� Simulate activity durations

� Identify control element locations

� Use actual equipment or weights

� Use gloves and half-suits

� Take photos

� Take minutes and agree during review

97 design points minuted for unit 1

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Unit 1 Unit 1 Unit 1 Unit 1 ––––Sectional planSectional planSectional planSectional plan

Unit 1 Unit 1 Unit 1 Unit 1 ––––Sectional elevationSectional elevationSectional elevationSectional elevation

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Unit 2 Unit 2 Unit 2 Unit 2 ––––Sectional planSectional planSectional planSectional plan

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Unit 2 Unit 2 Unit 2 Unit 2 ––––Sectional elevationSectional elevationSectional elevationSectional elevation

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Factory TestingFactory TestingFactory TestingFactory Testing

� Get protocols signed off early

� Pre-FAT recommended

◦ 149 items on unit 1 punch list

� Ensure vendor has completed testing

� Allow time in your schedule

◦ Pre-FAT, FAT, remedial work, Re-FAT -8 wks

◦ Bespoke solutions

Factory Testing Factory Testing Factory Testing Factory Testing ----challengeschallengeschallengeschallenges� Started too early –schedule driven

� Design errors of minor components

◦ bespoke designs

�Leak rate tests

�Cleanroom recovery tests

�Vessel Weigh cells

�Vessel agitators interface

�Peristaltic pump interface

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Layout Layout Layout Layout

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Installation Installation Installation Installation ––––Unit 1Unit 1Unit 1Unit 1

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Installation Installation Installation Installation ––––Unit Unit Unit Unit 2222

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Surrogate Testing

� Conducting air sampling and surface sampling to determine how much dust escapes from the containment.

� The sampling results provide a means of estimating how effectively the equipment will contain the API under similar conditions of use.

�Evaluate containment performance without potential exposures to potent Active Pharmaceutical Ingredients (APIs)

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Surrogate Materials

Containment testing Containment testing Containment testing Containment testing ----SATSATSATSAT

CPT: 50ng/m3

Geometric mean target: <25ng/m3

Equipment accepted.

Further actions: Test during operation

Consider using worker activity multiplier if necessary

Note: Operational results with product may be higher or lower

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ScheduleScheduleScheduleSchedule

High pointsHigh pointsHigh pointsHigh points

� Met the goals

� Successful integration of third party equipment

� Use of 3D to interrogate design

� Ergonomics

� Project on budget and schedule

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Low PointsLow PointsLow PointsLow Points

� Integration of Weighing and pump control system

� FAT time

� SAT time

Thank You

Contact Details

Michael McLoughlin

Managing Director

Email: mmcl@prosys.ie

Tel: +353 (0)21 4853900

Web: www.prosys.ie

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ProSys Containment HQ, Ireland

Our Clients

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Our Vision Our Vision Our Vision Our Vision (purpose)(purpose)(purpose)(purpose)

Our Vision is to be the Preferred Supplier of Custom Containment Equipment to the Global Pharmaceutical Production

Industry

Strategy StatementStrategy StatementStrategy StatementStrategy Statement

To be the Preferred Supplier of Custom Containment Equipment to the Global Pharmaceutical Production Industry

by

Delivering High Quality Engineered Solutions

by

Providing a responsive, can-do service driven by a sense of urgency to exceed customer expectations

by

Leading innovation in Containment Technology

by

Developing lean agile processes across the organization

by

Keeping our Promises

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ProSys Core ValuesProSys Core ValuesProSys Core ValuesProSys Core Values

Customer Orientation

Innovation

Flexibility

Communication - Face to Face Interaction

Co-operation & Knowledge Sharing

Accountability

Cost Conscious