evolution of isolator technology over the last decades and ... · disposable filling equipment...
TRANSCRIPT
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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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
3
Connecting Pharmaceutical Knowledge ispe.org
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.
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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
5
Connecting Pharmaceutical Knowledge ispe.org
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.
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
6
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Drivers for combi of “aseptic” and “high-potent” drug manufacturing isolator line
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
• 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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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
8
Connecting Pharmaceutical Knowledge ispe.org
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)
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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Key considerations … Drug categorization
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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Key considerations … RABS vs Isolator
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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,..)
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
14
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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
Key considerations … Qualification and validation activities on isolators
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Key considerations … What else
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
19
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
20
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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,
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
Project example … As built and in production since 2013
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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
Project example … Grade C environment line layout
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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
Project example … Room design
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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
Project example … Technical area design
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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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
30
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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… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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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
30
Connecting Pharmaceutical Knowledge ispe.org
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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.
31
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State-of-the-art … Aspects to be considered in future projects
• Safe change filters (BiBo filters) vs point of use return air filters
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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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State-of-the-art … Aspects to be considered in future projects
• Standard valves vs (H2O2) sterilizable aseptic valves in formulation / compounding applications
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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.
33
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State-of-the-art … Aspects to be considered in future projects
• Wire based test equipment integration vs fully integrated wireless glove test system
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
34
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State-of-the-art … Aspects to be considered in future projects
• 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,..)
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
Improvement
35
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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
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
36
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
37
Connecting Pharmaceutical Knowledge ispe.org
… Insights into state-of-the-art sterile fill finish applications for aseptic and high potent drugs
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
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