evolution of isolator technology over the last decades and

CASE STUDY… INSIGHTS INTO STATE-OF-THE-ART STERILE FILL FINISH APPLICATIONS

(FOR ASEPTIC AND HIGH POTENT DRUGS)

Jürgen Michael Metzger

North Bethesda, MD

18 - 19 Mar

Connecting Pharmaceutical Knowledge ispe.org

Agenda

Introduction

Drivers for combination of “aseptic” and “high-potent” drug manufacturing isolator line

Key considerations

Project example

State-of-the-art

Summary

… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs

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Agenda

Introduction


Key considerations

Project example

State-of-the-art

Summary


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Introduction

This talk will provide insights into how a CDMO - located in North America - grew from a small legacy

facility into a world-class medium-sized facility, based on a project example from 2012.

The overview will include the main drivers for this particular project, key considerations, line design,

qualification measures, aseptic processing, and long-term experience since 2013.

Furthermore we browse through the current state-of-the-art aseptic filling technology.

Attendees will benefit from insights into design concepts, selection process,

sophisticated isolator equipment, and advanced aseptic technology.


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Agenda

Introduction


Key considerations

Project example

State-of-the-art

Summary


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Drivers for combi of “aseptic” and “high-potent” drug manufacturing isolator line

It was a rising demand for different types of drugs already applicable in 2012.

The idea was, that one manufacturing line could cover all types of drugs (toxic and non-toxic) in the future.

The Worldwide Total Prescription Drug Sales

shows an CAGR of about +7% since 2012.

The factors driving market growth include rising importance of generics, rapidly increasing geriatric

population, increasing prevalence of cancer and increasing incidence of chronic diseases.


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Drivers for combi of “aseptic” and “high-potent” drug manufacturing isolator line


• Be prepared for the demands of the future

• Highest flexibility for different types of drugs in fill finish process

• Best possible protection for drugs and operators

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Agenda

Introduction


Key considerations

Project example

State-of-the-art

Summary


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Key considerations … What´s the product like?

• Liquid / solid dosage form (intravenous, oral,..)

• Product specifics Viscosity, sensitivity (temp, oxygene, light,..),..

Toxicity, ADC, HP-API, harmful aerosols

Adequate fill solution (foaming proteins, decompounding,..)

Storage conditions, process monitoring, ..

• Container form (vial, syringe, ampoule, cartridge,..) Bulk or pre-sterilized (nested or tray)


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Key considerations … Drug categorization


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Key considerations … Drug categorization

Product categorization• BSL / OEB

It’s said that 50% of new chemical entities are classified as potent (OEL <10μg / m³) • OEB level 4, isolator recommended.

Trend towards an increased number of highly toxic drugs (OEL < 1μg / m³) • OEB level 5 or higher is becoming more and more standard

• Containment isolator recommended


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Key considerations … Risk management

• Risk reduction per design, material studies (adsorption / desorption)

• Product and operator protection, cross-contamination

• Cleaning process considerations, cleaning media


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Key considerations … RABS vs Isolator


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Key considerations … RABS vs Isolator

Isolator operation in a grade C (D) room (ISO8)

Return of invest in 1.5 … 4 years (depending on frequency of production)

compared to RABS system, what´s operated in grade B (ISO7)

• The higher initial investment for an Isolator can be covered well by lower running

costs compared to a RABS system in a grade B room (energy consumption, air

exchange rates, filter changes, gowning time and costs, trainings,..)


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Key considerations … Transfer technology

• The transfer of materials into and out of aseptic core is one of the greatest potential sources of contamination.

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Key considerations … Qualification and validation activities on isolators

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Key considerations … What else


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Key considerations … What should be considered (at a glance)

Definition and specification of drug and fill finish equipment

Type of barrier system and ambient room classification

Ergonomic aspects, hygienic design, accessibility and cleanability, mock-up

Qualification and validation activities, documentation, batch reporting

Vendor selection, lead-time and overall project schedule, risks & costs


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Key considerations … What should be considered (at a glance)

Definition and specification of drug and fill finish equipment

• Upstream / downstream equipment: washer, depyrogenation, external vial washer, inspection, labeling,..

Facility design, room layout, infrastructure, media supply, internal supply chain, cooling chain,..

• Which solution fits best to the requirements, product specifications, fill solution and accuracy,..

• LYO, sterilizers, formulation, sterility testing, (pure) media supply, wash-down, single-use vs stainless steel, CIP/SIP, WFI, steam, air

• Transfer systems, air locks, RTU, RTP, biodecontamination process,..

Type of barrier system and ambient room classification (LF Hood, RABS, cRABS, isolator, Containment)

• Make-up air / process air specifications

ISO 7 vs ISO 8

• Line configuration adequate for aseptic and high potent application?!

Extra safety factors e.g. triple sealed single glass doors (1 static seal, 2 active vacuum seals) for highest operator and drug protection,

Safe Change Filters, Wash-down, ..

Ergonomic aspects, hygienic design, accessibility and cleanability, mock-up

• Line design and overall accessibility, cleanability

Qualification and validation activities, documentation, batch reporting

Vendor selection, lead-time and overall project schedule, risks & costs

• Best requirement fulfillment and best overall equipment competency, project confidence and process safety, transparency


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Agenda

Introduction


Key considerations

Project example

State-of-the-art

Summary


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2 FDA approved vial filling lines for liquid and lyo products

2 containment isolators, freeze dryer integration, lyo loading /

unloading,

Capping in containment ITP, fully integrated VHP System, triple

sealed vacuum doors,

High-potent application, semi automatic wash-down,

Disposable filling equipment (PreVAS) in combination with

peristaltic pumps,

Output rate 120/min with 100% IPC, unloading of lyo up to

200/min,


Project example … As built and in production since 2013

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Project example … Grade C environment line layout

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Project example … Room design

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Project example … Technical area design

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Project example … Transfer ports

• Considerable the RTP dimension: 105 mm, 110 mm (biosafe), 190 mm + 270 mm (material / caps / stoppers / waste), 350 mm, 460 mm

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Project example … Pre-sterilized (single use) filling equipment

• Single-use (ready to use) equipment vs hard piped product supply [SART & PreVAS vs CIP/SIP]

SART - System

PreVAS - System

Advantages of single use equipment:

Easier cleaning process, reduction of cross contamination,

no CIP/SIP, less process risks,..

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Project example … Monitoring equipment and integration

• Integration of monitoring system in HMI and line batch report vs separated system integration under drug manufacturer control

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Project example … Batch to batch

experience, changeover procedures(as of 2013!)

- Line are able to run with LYO path or without LYO (3 cycles a week),

Total preparation time for batch therefore in total 9 or 15 hours.

Lots of things have improved since that!

• Reduction of cycle time to ~1h

• Less format parts

… follow me on the next pages through the

state-of-the-art aseptic filling technology.

Step ActionTime (~)

ITP - DoorsMin. Max.

filler isolator LYO transfer isolator

0 End of previous batch

10Removal of monitoring equipment

end monitoring

10

(90)

10

(120)closed

20

(Optional CIP filling duct)

Only done biannually,

as there´s no need for CIP duct or filter

--> use of PreVAS

(40) (90) closed

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Wash-down (detergent, WFI, comp. air),

additional manual cleaning with wipes

WFI & detergent only for toxic products, all other products are manual

wipe down, using 70:30 IPA and / or WFI.

30

(40)

60

(70)

closed

40 Removal of filters 15 20 closed

50Removal of filling equipment,

gassing station equipment, format parts (2 or 4 people)30 60 opened

60Additional manual cleaning and drying

(2 or 4 people)45 90 opened

70 isolator glove test

Done monthly, but do a manual

inspection before each batch.

8 hours for filler- & transfer- isolator

opened

80

Replacing of format parts

mechanical functional test of filler / line

4h is budgeted, can be completed in 2h with strong technicians.

120 240 opened

90Load and prepare isolator for new batch

(according to Q&A check list)60 90 opened

100 Biodecontamination cycle isolator(s) 180 240 closed

110

• Installation of PreVAS fill equipment,

gassing station equipment

(Optional SIP)

20

(30)

30

(40)

closed

120Prepare monitoring equipment, bulk loading setup,

SCADA, IPC batch, weight setup50 60 closed

130 Start new batch closed

Duration (average) ~ 9 h ~ 15 h

Optional CIP/SIP

Optional wash-down for toxic products

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Project example … Batch to batch experience, changeover procedures

The line preparation depends on SOPs and is mostly done by 2 people.

It can take up to 2 shifts, depending on product type (LYO isolator involved or not), cleaning efforts, room preparation and

other human factors.

The goal to reduce the changeover time starts with the machine design, by optimizing machines and lines (accessibility,

cleanability, hygienic design,..).

This also depends on defined procedures at the drug manufacturer site to handle the changeover

(Risk analyses and cleaning studies to be done, PQ, media fills, SOPs needs to be written, process needs to be mimicked

successfully).

Highly sophisticated lines can often be running in at least 2 shifts, 5 – 7 days a week. Sometimes a line needs to be

prepared multiple times a week for different products and the efficiency of changeover time is crucial.

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Agenda

Introduction


Key considerations

Project example

State-of-the-art

Summary


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State-of-the-art … Aspects to be considered in future projects

• Bulk containers vs pre-sterilized nested vials, syringes, cartridges,..

Advantages of pre-sterilized containers:

Less space requirement, less energy / media supply costs, reduced process risk.

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• Safe change filters (BiBo filters) vs point of use return air filters


Point of use return air filter

Simplifies filter change and duct installations, less space requirement,

reduces contamination risk and cleaning efforts,

no wash-down needed for return air ducts,..

Filter location direct in return air duct

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• Standard valves vs (H2O2) sterilizable aseptic valves in formulation / compounding applications


Mostly used in formulation / compounding applications to guarantee sterile (aseptic) transfer of (potent) powder into e.g.

product vessels or to connect powder bags / product vessels to a isolator system.

Usage of aseptic ports reduces clean room classification A to C(D) and minimizes risk of contamination.

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• Wire based test equipment integration vs fully integrated wireless glove test system


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• One solution fitting a variety of products vs highest flexibility of combi filling stations by having to multiple product types matching solutions

Like TPF / peristaltic- / rolling diaphragm- / rotary piston- / mass flow- / … pumps

By considering viscosity, fill accuracy, avoiding negative effects (e.g. degradation of ingredients, spills, foaming,..)


Improvement

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State-of-the-art … Aspects to be considered in future projects (at a glance)

• H2O2 injection point above LF-Hepa filters vs underneath LF-Hepa filters (above CG-screens)

• Catalytic converter combined with air recirculation for best biodecontamination cycle-time and energy

efficiency

• Bulk containers vs pre-sterilized nested vials, syringes, cartridges,..

• Safe change filters (BiBo filters on-top of isolator) vs point of use return air filter (direct in return air duct)

• Semi-automated or manual vs fully automated wash down

• Standard valves vs H2O2 sterilizable aseptic valves in formulation / compounding applications

• Wire based test equipment integration vs fully integrated wireless glove test system

• One solution fitting a few products vs highest flexibility of combi filling stations by using multiple product

matching solutions


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Agenda

Introduction


Key considerations

Project example

State-of-the-art

Summary


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Summary

• More time in the planning phase leads to a better design, higher efficiency and less frustration in

daily operation later.

• An experienced engineering firm and a trusted (single source) vendor with full line competency

leads to higher success.

• Cost and lead-time is a strong driver in most businesses, ideally both could be covered well.

• Technology is improving steadily, latest and greatest technology is always a compromise of nice-

to-have vs needs and costs .

• Competency of partners and quality of highly sophisticated solutions pay off during the years.

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RESEARCH LIST:

• PREPARING-TOMORROW-S-PHARMACEUTICAL-CHALLENGES

• RESTRICTED ACCESS BARRIERS VS. ISOLATORS: AN ENERGY CONSUMPTION COMPARISON

• GOOD MANUFACTURING PRACTICE GUIDE FORACTIVE PHARMACEUTICAL INGREDIENTS Q7

https://www.chemanager-online.com/en/topics/plant-engineering-components/preparing-tomorrow-s-pharmaceutical-challenges

https://www.pharmaceuticalonline.com/doc/restricted-access-barriers-vs-isolators-an-energy-consumption-comparison-0001

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q7/Step4/Q7_Guideline.pdf

RELEVANT NORMS TO CONSIDER (AT A GLANCE)

ISO (INTERNATIONAL ORGANIZATION FOR STANDARDIZATION)

— ISO 10648-2 CLASSIFICATION ACCORDING TO LEAK TIGHTNESS AND ASSOCIATED CHECKING METHODS

— ISO 11135 (STERILIZATION OF HEALTH CARE PRODUCTS

PART 1: REQUIREMENTS FOR DEVELOPMENT, VALIDATION AND ROUTINE CONTROL OF A STERILIZATION PROCESS FOR MEDICAL DEVICES)

— ISO 14161 (STERILIZATION OF HEALTH CARE PRODUCTS - BIOLOGICAL INDICATORS)

— ISO 13408-6 (ASEPTIC PROCESSING OF HEALTH CARE PRODUCTS)

— ISO 14644 (CLEANROOMS AND ASSOCIATED CONTROLLED ENVIRONMENTS)

ISO 14644-1 CLASSIFICATION OF AIR CLEANLINESS

ISO 14644-2 CLEANROOM TESTING FOR COMPLIANCE

ISO 14644-3 METHODS FOR EVALUATING AND MEASURING CLEANROOMS AND ASSOCIATED CONTROLLED ENVIRONMENTS

ISO 14644-4 CLEANROOM DESIGN AND CONSTRUCTION

ISO 14644-5 CLEANROOM OPERATIONS

ISO 14644-6 TERMS, DEFINITIONS AND UNITS

ISO 14644-7 ENHANCED CLEAN DEVICES

ISO 14644-8 MOLECULAR CONTAMINATION

ISO 14644-9 SURFACE CLEANLINESS BY PARTICLE CONCENTRATION

ISO 14644-10 SURFACE CLEANLINESS BY CHEMICAL CONCENTRATION

— ISO 14698 (BIOCONTAMINATION)

ISO 14698-1 BIOCONTAMINATION: CONTROL GENERAL PRINCIPLES

ISO 14698-2 BIOCONTAMINATION: EVALUATION AND INTERPRETATION OF DATA

ISO 14698-3 BIOCONTAMINATION: METHODOLOGY FOR MEASURING EFFICIENCY OF CLEANING INERT SURFACES

— ISO 14971 (MEDICAL DEVICES -- APPLICATION OF RISK MANAGEMENT TO MEDICAL DEVICES)

— ISO 10648 (CONTAINMENT ENCLOSURE, PART 1 DESIGN PRINCIPLES, PART 2 CLASSIFICATION ACCORDING TO LEAK TIGHTNESS AND ASSOCIATED CHECKING METHOD)

DIN EN (DEUTSCHES INSTITUT FÜR NORMUNG, GERMAN INSTITUTE FOR STANDARDIZATION)

— DIN EN 13697 (CHEMICAL DISINFECTANTS AND ANTISEPTICS)

— EN 14175 BIOSAFETY CABINET (PART 1,2,3 AND 6)

ISA (INTERNATIONAL SOCIETY OF AUTOMATION)

— ISA S88 / ISA S95 (BATCH REPORTING AND PROCESS CONTROL) AND HOW TO INTEGRATE

GUIDELINES

— VDI 2083 CLEANROOM TECHNOLOGY BARRIER SYSTEMS (ISOLATORS, MINI-ENVIRONMENTS, SEPARATIVE DEVICES)

QUESTIONS?

THANK YOU VERY MUCH!

JÜRGEN MICHAEL METZGER

BARRIER SYSTEMS & ISOLATOR PROCESS SPECIALIST

ROBERT BOSCH PACKAGING TECHNOLOGY GMBH

[email protected]

evolution of isolator technology over the last decades and

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