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Views on Quality System Advances and their Impact on Manufacturing of the Future
PDA Italy Chapter
Manufacturing trend of parenterals: a glance to the future
Bari, October,5-6th , 2017
Michele Simone
Bracco Suisse S.A.,
Corporate Quality
Director
2
Pharmaceutical companies have used cutting-edge science to discover medicines, but they have manufactured them using techniques dating to the days of the steam engine.
Manufacturing processes are falling behind other industries in terms of technology and efficiency. To keep pace with this phenomenon pharmaceutical
companies will need to look at their manufacturing operations and adjust to this new model.
Regulation of the future will also need to meet these challenges, by incorporating new scientific information into regulatory standards and policies.
To embed quality in everything companies do, integration of Quality Risk Management, Quality Management Review and Knowledge Management for a
Comprehensive Quality Program has to be ensured.
Looking into the Future….
3
The new era of manufacturing: highly agile, networked enterprises
Massive use of data and analytics tools – real-time collection of data
Skilled individuals, new technologies and modern machinery
Turning data into information, resource efficiency and scalevariations will increase in their importance
High quality thanks to automation: full or reduced automation enables personnel to be deployed in an optimal way, process steps to be executed correctly, and releases to be done based on a shared and regulated plan. This is beneficial for the quality of affected documentation, and thus for compliance with all internal and regulatory requirements.
Manufacturing of the Future
4
4
Road map for pharmaceutical manufacturing:
Paradigm shift in manufacturing and quality
envisioned
0
12
No Knowledge
Management
and Quality
Risk
Mnagement
Incomplete
Knowledge
Management
and informal
or
retrospective
Quality Risk
Mnagement
Knowledge
Management +
Quality Risk
Management=
Integrated
Quality
Management
Review
5
Supply chain quality and reliability: two key dimensions to product quality.
If quality issues then lack of drug safety and supply continuity are
experienced
How to resolve these quality issues?
Industry Progress and Challenges
General solution:improving quality risk management, pharmaceutical quality systems, and business processes.
Product-specific solution: focusing on processes, modalities, and platforms; as well as operational and technical/analytical considerations.
“Use of knowledge management and quality risk management will enable a
company to implement ICH Q10 effectively and successfully. These enablers
will facilitate achievement of the objectives described in Section 1.5 above by
providing the means for science and risk based decisions related to product
Quality ”.
ICH Q10 Section 1.6
6
What do I know?
Now what is the message there? The message is that there are known "knowns." There are things we know that we know. There are known unknowns. That is to say there are things that we now know we don't know. But there are also unknown unknowns. There are things we do not know we don't know. So when we do the best we can and we pull all this information together, and we then say well that's basically what we see as the situation, that is really only the known knowns and the known unknowns. And each year, we discover a few more of those unknown unknowns.
Donald Rumsfeld at a press conference at NATO Headquarters, Brussels, Belgium, June 6, 2002
Knowledge Management
7
”Knowledge management is a conscious strategy of getting the right knowledge
to the right people at the right time and helping people share and put
information into action in ways that strive to improve organizational
performance. Knowledge management is a complex process that must be
supported by a strong foundation of enablers. The enablers for KM are strategy
and leadership, culture, measurement, and technology. Each of these must be
designed and managed in alignment with the other and in support of the
process. The process usually involves several of the following stages or sub-
processes in the use of knowledge: create, identify, collect, organize, share,
adapt, and use”
APQC, 2000
Knowledge Management
What is Knowledge?
8
Knowledge Management
What is Knowledge?
Data is a collection of facts, such as values or
measurements.
Information relates to description, definition, or
perspective (what, who, when, where).
Knowledge comprises strategy, practice, method, or
approach (how).
Wisdom embodies principle, insight, moral, or archetype
(why).
http://www.systems-thinking.org/kmgmt/kmgmt.htm
Types of knowledge:
– Tacit, implicit unwritten, unspoken, and hidden vast storehouse of knowledge
held by practically every normal human being, based on his or her
emotions, experiences, insights, intuition, observations and internalized
information.
– Explicit Articulated knowledge, expressed and recorded as words,
numbers, codes, mathematical and scientific formulae and musical notations.
9
Knowledge Management
Why Knowledge Management (KM) exists?
Problems needexperts and experience
Silos: We don’tknow what we
know.
Knowledge iswalking out the
door.
Not transferringbest practices.
Not using lessonslearned.
10
International Conference Harmonization (ICH) Q9 – Quality Risk Management
European Medicines Agency (EMA)▪ Eudralex – Volume 4, Good
Manufacturing Practice (GMP) Guidelines
▪ Guide presented in 3 parts
ICH Q9 and ICH Q10 have been adopted as Part III of the EU GMP Guide
FDA▪ Guidance for Industry – Q9 Quality
Risk Management
▪ Represents FDA’s current thinking
Others, e.g. ISO, WHO, PIC/S, UK MHRA and Australia
Quality Risk Management: Regulatory
Requirements - Summary
Quality Risk Management (QRM) is a systematic process for the assessment, control, communication & review of risks to quality of the drug product across the product lifecycle
Primary Principles
▪ The evaluation of the risk to quality should be based on scientific knowledge & ultimately link to the protection of the patient and
▪ The level of effort, formality & documentation of the quality risk management process should be commensurate with the level of risk
Proactive use to identify and control risk
Support decisions through lifecycle
Integrate into key parts of PQS, e.g. change mgt, CAPA, GMPs -Validation, etc
Help set meaningful specifications / Control points ensure product quality attributes are met
11
QRM
Phase I – “Where Is the Risk?”
ITHR
Legal
Sales
Regulatory strategy
ManufacturingOperations
PharmaceuticalOperations
CustomerFulfillment
Quality
Marketing
Vendor managementFinance
12
Cultural Risk Management improvement
12
No QRM
Informal
QRM
Most
retrospective
/corrective
QRM
Prospective,
preventive
QRM
Integrated
QRM
13
Knowledge Management & Quality Risk
Management over the lifecycle
Product and ProcessDevelopment
TechnologyTransfer
CommercialManufacturing
Product and ProcessDevelopment
Product Lifecycle – What is it?
▪ Develop knowledge of product and process.
▪ Utilize QRM principles to identify and control risk toproduct quality.
▪ Developfurtherknowledge.
▪ Refine QRM strategies.
▪ Knowledge iscontinuallyexpanded.
▪ QRM processconsistentlyused.
Manage the terminal stage of the product lifecycleusing a pre-definedapproach (e.g., productcomplaint management,stability studies,documentation).
14
Quality Risk Management as enabler for a
sustainable Quality System
15
This is not EMA regulatory requirement
Medicines and Healthcare products Regulatory Agency (MHRA) -Good Manufacturing Practice ‐ QRM Frequently Asked Questions Question ‐ Should sites have a formal risk register and management process?
Yes, a risk register (or equivalent title document) should list and track all key
risks as perceived by the organisation and summarise how these have been
mitigated. There should be clear reference to risk assessments and indeed a
list of risk assessments conducted should be included or linked to the register.
A management process should be in place to review risk management – this
may be incorporated into the quality management review process.
Risk register – what is the expectation?
16
So what are the key elements?
➢ GMPs
➢ Management Responsibility
➢ Continual Improvement
➢ Products and Processes
➢ PQS itself
➢ Quality Risk Management
➢ Knowledge Management
➢ Lifecycle approach
➢ Opportunities for science and risk-based regulatory
approaches
Quality Management Review as tool for
Continual Improvement: ICH Q10
What QMR shall include?
➢ Report identified risks and control mitigation solutions
➢ Detect and monitor variations in product quality
➢ Measure quality system effectiveness at manufacturing sites
➢ Show the state of quality, establish performance goals across industry, and better communicate internally and externally
➢ Minimize potential for unintended consequences through KPI trend monitoring
➢ Predict market quality
17
17
Innovation and Continuous Improvement in
Pharmaceutical
1818
Innovation and Continuous Improvement in
Pharmaceutical
Extract, Transform and Load
SAP PES LIMS Other TrackWise
a b ea ab bc c cd d
Metadata
ea b c d
Metadata
ea b c d
Metadata
ea b c d
System Engine
Enterprise
reportingDashboards Specific applicationsAlerts & Proactive
Notification
Thanks
Back Up
21
Knowledge Management
KM DESIGN PRINCIPLES: BEST PRACTICES?
▪ Start your efforts with focus on the knowledge that matters to the business.
▪ Don’t reinvent KM best practices.
▪ Embed knowdlege sharingapproaches in the flow of work.
▪ People approaches make systemapproaches work.
▪ Balance «connect» and «collect».
▪ Demonstrate tangible value.
▪ Think enterprise-wide.
22
Knowledge Management
Nonaka‘s SECI Model of Knowledge Transfer
http://powerknowledge.edublogs.org/2010/08/10/seci-time-d/
By understanding the transfer mechanisms it is now possible to develop the necessary
strategy for knowledge management
23
Knowledge Management & Quality Risk
Management over the lifecycle
➢ Knowledge increases throughout the product lifecycle Must be captured, transferred and
used systematically.
➢ Quality risk management: Provides proactive approach to
identifying and controlling risksthroughout the lifecycle.
24
The QRM Process
24
RiskAssessment
RiskReview
RiskControlTo
ols
Ris
kC
om
mu
nic
ati
on
Continuous Feedback for New or
Existing Risks
Todd Kapp June 25, 2009
Overcoming Quality and Regulatory
Challenges of Implementing Single-Use
Pharmaceutical Manufacturing
Janmeet Anant, Ph.D.,
Board Member of Bio-Process
Systems Alliance (BPSA)
Agenda
BPSA Introduction
Regulatory Background and Introduction
Risk Assessment Model and Factors
EPICS solutions
Other activities
Bio-Process Systems Alliance
Trade association of suppliers and users: 56 Members
Facilitates implementation of single-use via:
▪ Networking opportunities: Annual Summits
▪ Safe harbor for dialogue: among
industry/business leaders
▪ End-user / supplier forums
▪ Best practice guides/projects
5
Evolving and Compounding Regulatory Expectations
UPCOMING:
ICH Q12 – Technical and Regulatory Considerations for Lifecycle and Change Management
USP <665> - Plastic Components and Systems Used in Pharmaceutical Manufacturing
Evolving Biopharmaceutical Development Expectations
Enhanced approach
Define set points/operat
ing ranges
Demonstrate Process
Reproducibility
Test to meet established acceptance
criteria
Traditional Approach
Process Risk
Assessment
Design Space
Control Critical
Material and Process Parameters
Mitigate Risk
Drug Product CQAs
7
FDA / EU GMP General Guidelines
“Production equipment shall not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be
reactive, additive or absorptive to such an extent that it will affect the quality of
the product and thus present any hazard.”
FDA, Code of Federal Regulations, Part
211, “Current Good Manufacturing Practice
for Finished Pharmaceuticals”, Part 211.65,
“Equipment Construction”, 2005
European Commission, EUDRALEX Volume 4, “Good Manufacturing
Practices, Medicinal Products for Human and Veterinary Use”, Chapter 3, “Premise and Equipment”, 2003
“Equipment shall be constructed so that
surfaces that contact components, in-process
materials, or drug products shall not be
reactive, additive, or absorptive so as to alter
the safety, identity, strength, quality, or purity of
the drug product beyond the official or other
established requirements.”
8
Supply Chain Quality Key Regulatory Concern for
Single-Use Systems
End users have cited* that regulatory concerns have shifted from
VALIDATION requirements for stainless steel (multi-use) systems,
to…
SUPPLY CHAIN Quality and Transparency for single-use systems.
Regulatory agencies are still coming up to speed….
9
How do you know X, Y, and Z?
How is it manufactured?
How is it controlled?
(“Trust, but Verify)
Extractables
Leachables
Particulates
Change
Understanding the quality and variability of
raw materials is critical
*SOURCE: 2015 ISPE Annual Meeting, Philadelphia, USA, “Things your Mother Didn’t Tell You:
Lessons Learned from Implementing Single-Use Technology in Scale-up from Clinical to Commercial
Manufacturing”, November 9, 2015.
Monitor and Control SUS Quality
via Partnership with Supplier
“SUS can eliminate equipment assembly, cleaning and sterilization and much of the value
from single use systems comes from this “ready to use” status. However, to be successful
end users must ensure that these value added activities were done effectively and that
can only happen by developing quality systems which can monitor and control SUS quality
throughout the SUS Supply chain. Only a partnership with a SUS supplier can ensure that
quality is as good as, or better than what is achieved with traditional systems.”
- Robert Repetto, Pfizer (Co-Author of PDA Technical Report 66)
10
Supplier
•Material/Component Knowledge
•Assembly Qualification and Design
•SUS Manufacturing and Controls
•Assembly Handling Best Practices
•Experience with many customer processes
End User
•Process and Manufacturing Knowledge
•System Design and Operation
•Product and Patient Knowledge
• Internal Procedures and Controls
•Risk Tolerance / Past Experience
ELSIE presentation October 20, 2016
A Lot of Organizations Involved
11
ELSIE presentation October 20, 2016
A Summary of Current SUS Activities
12
Source: http://bioprocessinstitute.com/wordpress/wp-content/uploads/2016/09/Revised-SUS-Newsletter_SEP-2016_Issue-13_160726.pdf
Risk Model for Aseptic Process
13Source: James Oliver, 3D risk assessment model, JVT, Autumn 2008, page 70-76.
3D RISK ASSESSMENT MODEL
Distance along the product stream
Distance from product stream
System complexity
ICH Q9 is a useful
reference for a detailed
description of risk
assessment
14
Factors Influencing Risk Assessment of Single-Use
Manufacturing Systems
Compatibility
Residual
Solvents
Elemental
Impurities
Adsorption
Functional / Fit for Purpose
Residual Impurities
Drug Product Dependent
Sterile
Barrier
In Concert with our Members:Seeking EPICSolutionsTM to Today’s Challenges
Extractables Consensus Test Standards
Particulates Sources and Controls
Integrity and Leak Testing and Quality Assurance
Change Notification and Control
Sustainability/Disposal: “It’s Not Easy Being Green”
BUT ALSO:
Sustainable Educated SUT Workforce for the Long Term
Sustainability of SUT Growth and Adoption
BPSA: the Single Voice for Single-Use
Extractables Today –
2 Organizations are Driving the Industry
• Mandatory regulatory implications
• Second Draft USP 665 published
• Comments period ended Sept. 30, 2017
• Finalization of USP 665 planned
• Scientific risk based approach (3 model solvents and 1 time point for high risk applications)
• Large biopharmaceutical manufacturers
consensus
• Extractables standards agreed upon by 17
major BPOG members, which are multi-
national biopharmaceutical manufacturers.
• Extensive testing requirements (6 model
solvents with 4 time points.
BPOG – Extractables Protocol
BPOG Published a Protocol in Nov 2014
• BPOG is a 28 company member forum that works
together on initiatives important to the
biopharmaceutical industry.
• In 2012, a Disposables working group was formed to
work on standardized protocols for extractables for
single use systems.
• Consensus standardized extractables testing protocol
for SUS based on survey of 17 major BPOG
companies
• BPOG published an extractables protocol in
Pharmaceutical Engineering in November 2014.
BPOG – Extractable Protocol
BPOG guidelines better reflect the real world application of the filtration devices and single use
assemblies.
Six Streams for Extraction:
50% EtOH, 1% PS-80, 5M NaCl, 0.5N NaOH,
0.1 M H3P04, WFI
Additional Analysis:
pH, Total Organic Carbon (TOC), Non-Volatile Residue
(NVR), Conductivity
Dynamic Mode of Extration
Extensive Analysis:
GC/MS-HS, GCMS-DI, HPLC-PDA-MS, ICP-MS,
FTIR, IC
Four time points:
T=0, 24 Hours,
7 Days, 70 days
19
The manufacturing system should be:
Composed of materials and components that are safe
for use with the pharmaceutical or biopharmaceutical
product and all process intermediates and/or process
streams
Compatible with the pharmaceutical or
biopharmaceutical product and all process intermediates
and process streams
Functional
USP <665>
20
Initial Assessment
21
Risk Matrix
organic solvents (by
volume)
surfactants (by
weight)
blood/blood-
derived
substances (by
weight)
lipids and
proteins (by
weight)
Aqueous
Level 1<5% <0.1%
blood-derived
<1%<1%
Somewhat organic
Level 25-40% 0.1-0.5%
blood-derived 1-
25%1-5%
Highly organic
Level 3>40% >0.5%
blood or blood-
derived >25%>5%
If the process streams contain multiple solubilizers,
e.g. protein and surfactant, the risk is compounded.
Process stream
Temperature duration
Temperature (°C) Duration
Level 1 Frozen (<-10) < 24 hrs
Level 2
refrigerated (2-8)
Ambient (15-25) 1-7 days
Level 3 Elevated (>30) > 7 days
Processes such flushing a component to prepare for use can
reduce risk of extractables
Additives (by weight)Treatment for
sterilizationProcessing
Inert
Level 1<0.1%
Intermediate
Level 20.1-1%
chemical
adhesives/bonding of
component's
materials
Reactive
Level 3>1%
irradiation/chemi
cal treatment
chemical
adhesives/bonding of
component's
materials
Material
Clearance and clinical mitigating factors must be take into account when
establishing the characterization level
22
Testing Requirements Based on Risk Level
Risk Level Assessment
Level
Testing Requirements
Material Component
A Baseline Testing All individual materials of construction comply with ⟨661.1⟩ as follows:
Identity
Biological Reactivity Tests, In Vitro ⟨87⟩ Physicochemical characteristics
Extractable metals
Additives are addressed by proper reference to 21 CFR §174–179 Indirect Food
Additive regulations
USP ⟨87⟩
B Expanded
baseline testing
All individual materials of construction comply with ⟨661.1⟩ as follows:
Identity
⟨87⟩ and ⟨88⟩ , plastic class VI designation
Physicochemical characteristics
Extractable metals
Additives determined by testing as specified in ⟨661.1⟩
⟨87⟩ and ⟨88⟩ , plastic class VI
designation
Extractable metals
C Full testing All individual materials of construction comply with ⟨661.1⟩ as follows:
Identity
⟨87⟩ and ⟨88⟩ , plastic class VI designation
Physicochemical characteristics
Extractable metals
Additives determined by testing as specified in ⟨661.1⟩
⟨87⟩ and ⟨88⟩ , plastic class VI
designation
Full extractables profiling
24
Solvent Type USP <665> BPOG
1 Common solvent WFI
2 Organic 50% EtOH 50% EtOH
3 Low pH 0.2M KCl, pH 3 0.1M H3PO4, pH
~1.8
4 High pH 0.1M Phosphate
buffer, pH 10
0.5N NaOH, pH >
13
5 High Salt 5M NaCl
6 Surfactant 1% PS-80
Organic Extractables
Dynamic extraction, 4 timepoints
Dynamic extraction, 1 timepoint
Low pH solvent in Standard solvents can be substituted with justification unlike the High pH solvent
25
The timeline:
Comment Deadline Sept 30, 2017
Expert Panel, address comments and revise (if necessary)
Final chapters are submitted to Expert Committee for vote in Oct 2017
If enough votes are received the chapters will appear in USP 41 1st
Suppl March 1, 2018
Official Aug 1, 2018
Communication from USP
Particles-BPSA Particulates Guide
▪ Recommendations for Testing, Evaluation and Control of Particulates From Single-Use Process Equipment
▪ Published in September 2014
▪ The BPSA 2014 Particulates Guide was a dedicated 18-month project funded and executed by BPSA under the guidance of a volunteer member committee of subject-matter experts representing the following companies:
Csilla Kollar, Dow Corning Corp.
Mark A. Petrich, Merck & Co., Inc.
Eric Isberg, Entegris
Ernie Jenness, EMD Millipore
Helene Pora, Pall Life Sciences
James D. Vogel, The BioProcess Institute
John Stover, AdvantaPure/New Age Industries
Ken Davis, Value Plastics, Inc.
Kirsten Strahlendorf, Sanofi Pasteur
Mike Johnson, Entegris
Patrick Evrard, GSK Vaccines
Maureen Eustis, The BioProcess Institute
Environment
SUTComponents
PeopleEnvironment
SUTComponents
People
TIME
controls controls controls
“Initial”Particulate Profile
“Final” Particulate Profile
“Perfect World” Particulate Profile
“Target” Particulate Profile
Particles-BPSA Particulates Guide
The 12-chapter compendium was derived from a recognized need in the single-use technology (SUT) industry to address issues such as:
▪ Why particulates are an issue with SUT:
▪ Why particles in SUT may be a contamination risk to a formulated product and/or the patient treated with the product;
▪ How one can control particulates; and
▪ What steps to take when particulates are found and attributed to SUT.
Next Steps:
Need SUT Particulate Measurement Method.
Better defined application-specific requirements.
Create industry-wide catalog of particles.
Conduct particulate generation studies.
Create a formal SUT Best Practices Guide.
Establish supplier/end-user Quality Agreements of SUT Acceptance Criteria.
Environment
SUTComponents
PeopleEnvironment
SUTComponents
People
TIME
controls controls controls
“Initial”Particulate Profile
“Final” Particulate Profile
“Perfect World” Particulate Profile
“Target” Particulate Profile
Particles-BPSA Particulates Guide
What is happening now?
Most SUS manufacturers rinse their single-use assemblies, then measure the extracted liquid for subvisible particulates using methods described in USP <788>. However, such tests are not to be confused with true USP <788> measurements because extraction conditions for single-use components are not standardized. This is the same issue with USP <790> for visible particulates.
ASTM is making an effort to develop a standard extraction method for SUS. The committee’s working draft is titled, Standard Practice for the Extraction of Particulate Contamination from the Fluid-Contacting Surfaces of Single-Use Components (WK 54630).
Source: Vogel and Wormuth. Particulate Contamination in Single-Use Systems: Challenges of Detection, Measurement, and Continuous Improvement, BioProcessInternational. August 28, 2017.
USP <667> will be announced as a new general chapter on particulate controls for polymeric pharmaceutical manufacturing systems.
Integrity Assurance – BPSA Guide
▪ Design, Control and Monitoring of Single-Use Systems for Integrity Assurance
▪ Published in Summer 2017
▪ The BPSA 2017 Integrity Assurnce Guide was a project funded and executed by BPSA under the guidance of a volunteer member committee of subject-matter experts representing the following companies:
Integrity Assurance – BPSA Guide
Executive Summary
BPSA recognized the need for a guide on the integrity assurance of single-use
systems and formed a working group from suppliers and end user to discuss the
topic and recommend best practices.
This document divides practices into 2 separate but complementary sections.
1. A risk-based approach requiring a risk assessment of the total process from
design development and manufacture by the supplier through to packaging
and transportation and finally installation and operation by the end user.
2. The complementary section covers practical testing of components and systems.
Two types of tests are described: (1) Pressure based tests, using either a
pressure decay or flow measurement method; (2) Trace gas tests, typically using
helium.
Integrity Assurance – SUS product life cycle
Integrity Assurance – SUS product life cycle
Level of System Complexity and Test Suitability
Integrity Assurance – Best Practices for Risk Mitigation
Change Notification Practices
▪ Objective: Created a “practice” (2016-2017) document that describes means by which suppliers may handle change notification of Single Use products in such a manner that the changes may be managed effectively and in a timely manner by end-users.
▪ People/Companies Involved:
▪ Joint effort with BioPhorum Operations Group
▪ Small group of representatives from each of BPOG and BPSA
Complexity Level of Change
Change Notification Practices
▪ Outcome or Current Status: In the initial stages of documenting problem statement, objective statement and deliverables have been completed.
▪ Next Steps: Implementation of standard templates and procedures.
Sustainability
Sustainable Single-Use Disposal/Recycling Committee
This committee was formed to provide member stakeholders with information about the
environmental impact of Single-Use Technology and to take actions to show that sustainability
is important to BPSA. The team’s immediate goals include organizing member tours of waste
management sites, developing an effective social media program, summarizing available SUS
studies, compiling a list of existing recycling/reuse programs, investigating related efforts by
similar groups, and other projects as agreed to by BPSA membership.
Committee Chair- Mark Petrich, Merck & Co., Inc.
Follow Committee on LinkedIn
https://www.linkedin.com/groups/12038145
In Concert with our Members:Seeking EPICSolutionsTM to Today’s Challenges
Extractables Consensus Test Standards
Particulates Sources and Controls
Integrity and Leak Testing and Quality Assurance
Change Notification and Control
Sustainability/Disposal: “It’s Not Easy Being Green”
BUT ALSO:
Sustainable Educated SUT Workforce for the Long Term
Sustainability of SUT Growth and Adoption
BPSA: the Single Voice for Single-Use
BPSA European Advisory Council
The European Advisory Council (EAC) was formed in 2016, due to the success of
BPSA’s first European Summit, held in September 2016 in Barcelona, Spain. The
EAC was formed to identify specific challenges or areas of interest within Europe
regarding single-use manufacturing technologies used in the production of
biopharmaceuticals and vaccines. The EAC will also be tasked with shaping the
2018 BPSA European Summit’s program and location. (BPSA will host a European
Summit every other year.)
Committee Chairs-
Hélène Pora, Pall Life Sciences
Stephen Brown, Biological E. Ltd.
Follow Committee on LinkedIn
https://www.linkedin.com/groups/12042724
Cell and Gene Therapy (CGT) Committee
BPSA has created the cell and gene therapy (CGT) committee with the purpose of
taking the lessons learned from adopting single use technologies in bio-processing of
proteins and Mabs and applying them to the CGT market. We also have recognized
the complexity involved with CGT and the more precision approach to smaller
population therapies which require new issues to be addressed in single use
technologies. As a result, bringing suppliers of the technology together with users will
allow us to provide best practice guidelines to aid in the creation of new CGT’s.
Committee Chair- Dominic Clarke, Charter Medical
Follow Committee on LinkedIn
https://www.linkedin.com/groups/12038106
Todd Kapp June 25, 2009
TO JOIN: www.bpsalliance.org
Questions
The journey of the isolator technologies
Implications, benefits and watch-outs
PDA Italy Chapter
Manufacturing trend of parenterals: a glance to the future
Bari, October,5-6th , 2017
Dr. Mauro Giusti
Director,
Techn. Svcs/Mfg Science
& Mfg Sourc./Vendor Mngt
Eli Lilly Italia Email : [email protected]
2
• Describe the experience of Lilly Italia in the Isolator Journey
• Share lessons learnt along the way and get comments
Objectives of presentation
3
Eli Lilly Italia was established in 1959 and the plant built in 1961
Eli Lilly Italia became a global Manufacturing Site for dry and parenteral products in the mid ’90s.
In 2003 a decision was made to change the plant mission to biotechnology products.
3
1990 2000
Lilly Italy - Manufacturing
4
Isolator – Lilly Italia History
Date Activity
1999 Transfer, validation and start up of a Flexible wall sterility testing isolator
2003 Purchase of 3 brand new rigid wall sterility testing isolators to replace flex one
2003-2005
Discussion whether to install a RABS or an Isolator for high speed filling –
decision Isolator!
2009 Install., Qualif., Media fill and first Proc. Valid. for Isolator Cartridge Line 1
2012 Install., Qualif., Media fill and first Proc. Valid. for Isolator Cartridge Line 2
2015 Install., Qualif., Media fill and first PV for RABS Cartridge Line 3
2017-2019 Plan
Planned IQ/OQ/PQ/MF and 1° PV for Isolator Line 1 Prefilled Syringe
We have gained experience both in lab and production isolators
5
Isolator technology - achievements
Sterility
testing
Cartridge
filling
• Quality = zero sterility test failures, low EM hits
• Productivity = faster cycle, easier segregation
• Availability = 3 smaller isolators better than a large one
• Quality = zero sterility test failures, zero EM hits in
filling area
• Training = simplification to train new recruit
• Productivity:
• Validated a 22 days campaign and 9 lot changes
(one campaign consists of nearly 7 million carts)
• Less time to gown (higher people availability)
• Reduced costs for EM materials and gowning
• Reduced costs for Utilities (HVAC)
• People Engagement = less stressful for personnel
Overall a great success story!
6
• Cleaning and sanitisation Yes Yes
• Equipment set-up Yes NO
• Interface with Tunnel/Lyo Yes (Fill) NO
• Decontamination Yes Yes
• Materials introduction/removal Yes, many Yes, less
• Isolator integrity/ openings (Typically) Open Closed
• Glove use, inspection, testing Yes, many Yes, few
• Aseptic interventions Depends Many
• Maintenance interventions Possible Rare
• EM monitoring (Viable, Non viable) Yes, many Yes, few
• Interlot/ campaigning procedures Yes Depends
Main Operations to be carried out
Production
Isolator
Testing
Isolator
7
Example of a filling line using isolator
Loading,
washing and
possible
siliconization of
glass
containers
Depyrogenation
TunnelSampling &
inspection
MTC
Isolators
Connection
Mat transfer
Filling
Filling
Hot chambers
Cooling Chambers
8
Isolators HVAC machines - Example
9
Isolator technology – Lessons learnt in steps
1- Design
2- Qualifications
3- Media
Fill
4- Process
Valid.
5- Routine
Ops.
6- Campaign
Elongation
Ops.
Filling Isolator – the pathway
10
Lessons learnt - Isolation Technology Design
DO’s- Ensure project team with adequate capabilities.
- Perform benchmarking
- Verify product compatibility with VPHP, suitability of
technology for line portfolio
- Define isolation technology:
- Robust HVAC design
- VPHP thru or bypass HEPA filters
- Closed or open loop
- VPHP elimination/reduction technology
- Select right vendor
- Know-how of isolator cycle/VPHP
generation
- Integration with Filler
- Possibility to perform tests during FAT
- Possibility to perform mock up
- Possibility to assist during cycle
development and start-up
- Define construction material suitable for VPHP
- Define material and process flow during operations
- Define EM sampling points and technology
- Define interventions including maintenance ones
- Quality by design in the automation logic
DONT’s- Lack of careful evaluation of products vs
technology
- Vendor selected with :
- Insufficient HVAC power
- Having little know-how on VPHP
- Inadequate documentation
- Not flexible to accept data integrity
and automation requirements from
customer
- With deficient post sales services
- Selling older technology
- In case of 2 vendors, lack of
integration between them
- Not having possibility to test
VPHP cycle during FAT
- Delay mock-up and other verifications after
FAT or even worse after equipment delivery
11
Lessons learnt - Isolation Technology Qualification
DO’s- Define upfront C&Q approach (e.g. ISO2500)
- Ensure site people participation
- Decide extent of FAT tests vs tests on site
- Repeat on site Cycle development with facility
qualified and in operation status
- Special focus on the automation part, as sometimes
software bugs may be discovered too late
- Special focus on qualification of decontamination for
sterile materials to be introduced
- Special focus on cleaning /sanitisation of RTP doors
- Ensure to perform Line integrated PQ at the end of
individual PQs and prior to Media fill to verify:
- Integration of Isolator with Tunnel
- Integration with Filler
- Integration with Glove testing
- EM operations (viable + non viable)
- Impact of facility/operations (i.e. Delta P
and Temperature fluctuation,etc)
- Strong technical knowledge and reasonable criteria
for initial and periodic validation of the cycle
- Good know-how and qualification of Biolog. Indicat.
DONT’s- Unclear C&Q approach
- Complete delegation to contractors
- Inadequate Cycle development studies
- Insufficient/not capable process automation
resources
- Insufficient tests to prove reproducibility of
isolator cycle
- Inadequate/absent Integrated line PQ
- Define very difficult criteria for cycle
validation, forgetting to address possible
isolated Biolog. Indic. failures.
- Not reliable supply of Biolog. Indic.
12
Lessons learnt - Isolation Technology Media Fill
DO’s- Define upfront Media fill strategy:
- To get started
- End in mind to match planned output
- Define upfront allowed interventions
- Design media fill
- starting from formulation
- simplest media fill to match all possible
combination of products and containers
(hybrid approach)
- Bundling interventions
- Filling MF units after each bundle
- Avoiding filling too many units
- Prepare people with training including aseptic
practices (isolator does require aseptic practices)
- Perform detailed PFMEA to define upfront what to
do in case of issues:
- Broken gloves
- Loss of overpressure
- Leaks
- Etc…..
DONT’s- Unclear Media fill strategy (often outcome
of unclear Operations strategy)
- Assuming to replicate as is the aseptic
approach
- Focus on isolator distracting from critical
formulation/product transfer processes
- Insufficient/not capable surveillance of MF
execution
- Lack of instructions in case of issues
13
Lessons learnt - Isolation Technology Routine Ops
DO’s- Define type of support required (Eng/Maint., QA,
Steril Assur, TS)
- On shift
- On days
- Define capabilities required for each function
- Define process monitoring parameters
- Define periodic reviews of data and actions:
- Broken gloves
- EM viable and not viable
- Alarms
- Cycles
- Pressure fluctuation
- Leaks
- Etc…
- Define program to include unplanned interventions
in media fill program
- Define criteria to break isolator sterility in case of
issues
- Have clear “end in mind” for campaign definition
- Ensure a reliable supply of BI with low variability
DONT’s- Unclear definition of support
- Unclear roles and responsibilities
- People not capable
- Excessive trust in isolator leading to lack to
follow aseptic practices
- Lack of periodic reviews and actions
- Do not pay enough attention to BI order,
incoming and qualification, as this could
trigger validation failure during annual
verification.
14
Detailed operational aspects for discussion
• Cleaning and sanitisation
• Equipment set-up
• Interface with Tunnel/Lyo
• Decontamination
• Materials introduction/removal
• Isolator integrity/ openings (Typically)
• Glove use, inspection, testing
• Aseptic interventions
• Maintenance interventions
• EM monitoring (Viable, Non viable)
• Interlot/ campaigning procedures
We can select the detailed operational aspects
of more interest to you
15
Cleaning and sanitisation
Why = remove debris and dirt, then sanitize, to allow decontamination to
occur successfully on surfaces based on microcondensation.
Who/When = Operators and Lab technicians, at end of each significant
operation, or when isolator is opened
How
1- Clearance of debris (using special vacuum cleaner when isolator closed)
2- Cleaning with non particle shedding cloth and detergent
3- Same as 2 but with sterile sanitizer.
Notes
- Precaution about avoid releasing of particles from body of people (gowning)
- Use of standard technique for wiping (unidirectional)
16
Cleaning and sanitization - Pictures
Cleaning of gasket
of RTP door
Vacuum cleaner to
perform clearance
Bowl, cleaned in washers, bioburden reduced in autoclave,
Assembled during machine set-up, then VPHP decontaminated in place.
17
Equipment set-up
Why = some equipment needs to be washed in washers, then reassembled
Who/When = Operators or Mechs, prior to restart
How
1- Determine washing and bioburden reduction cycles for large parts (e.g. bowl)
2- Determine set-up process for small parts (CIP/SIP vs Aseptic assembly)
3- Perform non aseptic set-up and verify machinability, then clear line, sanitize
surfaces and start decontamination Cycle.
4- Equipment set up fine tuning after decontamination to be an exception
Notes
- precaution about avoid releasing of particles from body of people (gowning)
- have some materials set aside for machinability trials
- maximize campaigning to avoid risks related to set-up variability
18
Equipment set-up - Pictures
19
Interface with Tunnel
Why = Need to ensure sterility continuity (differential pressure, cold chamber
sterilization, curtain to segregate during decontamination phase of cycle)
Who/When = Equipment design, typically fully automated
How
1- Perform cold chamber sterilization by dry heat
2- Close curtain to segregate Isolator from Tunnel during gassing
3- Re-open curtain and ensure pressure balancing between the 2 equipment
4- Load containers and fill the accumulating table
Notes
- Validation of Dry Heat requires good Biological Indicators and good technique
- Tunnel for isolator has given characteristics (e.g. Hepa filters heat resistant)
Interface with Tunnel - Pictures
Interface with Tunnel - Pictures
Decontamination
Why = Key Operation to achieve sterility inside isolator, and to decontaminate
surfaces
Who/When = Equipment design, typically fully automated
How
1- Dehumidification (to achieve proper T and RH)
2- Conditioning (Gassing phase where we ramp up to a specific concentration)
3- Decontamination (Gassing phase with fairly stable concentration)
4- Aeration
Notes
- Several slides to follow
- During preliminary design study, any MOC should be evaluated for suitability
22
Decontam- – Cycle Development strategy
• If possible, perform pre-cycle development at supplier shop. Reasons:
• Ensure equipment is functioning as expected
• Acquire knowledge of the specific VPHP evaporation system
• Determine reference values for some parameters
(injection rates and VPHP quantities, T, RH, Aeration time)
• Perform cycle development of the line once installed in final location starting
from the parameters defined at supplier shop line. Expect some changes!
• Cycle development consisting of :
• BIs in stainless steel and MOC (if not tested before separately), enveloped
• Concentration of spores above 1 x 10 exp 6
• Calculation of D-Value both in a lab ref. isolator and in the large one
• Air flow pattern (smoke studies and air velocity)
• Temperature mapping both of surfaces and of air
• H2O2 distribution through chemical indicators
• Determination of aeration time to achieve less than 1 ppm
23
Decontamination – Strategy for Mapping with BIs
•Identification of worst case locations with 3 BIs per location.
•Identification of cycle parameters resulting in NLT 5% Positive BIs.
•Identification of cycle parameters resulting in only 1-2 positive BIs.
•Identification of cycle parameters with Total Kill (3 BIs per location).
•Verification of defined cycle parameters with SS BIs.
24
Decontamination– Total Kill parameters
example - 19 cubic meter isolators
Initial parameters: Drying
Air Humidity (%rh) ≤ 20
Air velocity (m/s) 0,2 ± 0,1
Temperature (air)(°C) 30
Concentration H2O2 solution (%) 35
Parameters of SAFE VAP
Inj.
Rate
(g/m)
Total
(g)
Conditioning 35 1000
Biodecontamination 30 900
Aeration time(m)
120
25
Decontamination Cycle
Evaporators
temperature
Humidity
Ppm H2O2
Overpressure
26
Decontamination Cycle
Typical approach for Qualification:
- Total kill cycle with some extra margin = the Validation Cycle
- Production cycle = Validation cycle plus 20% during decontamination
- Validation of decontamination = 3 successful consecutive runs with
SS BIs, using the Validation cycle (worst case)
- Validation of aeration = 3 runs with Production cycle, NMT 1 ppm
-Typical approach for Periodic Requalification
- Annual
- HEPA filter integrity, Chem. Indicat., Air velocity, T mapping
- 1 run with SS BIs using the Validation cycle
- Verification of trends for aeration (6 cycles) or 1 aeration run
27
Material introduction/ removal
Why = Need to introduce components, connections, tools, EM material, wipes
Who/When = typical a manual or semiautomatic operation
How
1- Shuttle isolators/Transfer Chamber/CPS vessels/RTP bags for Primary packaging
components (Stoppers, plungers, disc seals, beads, etc..)
2- Shuttle isolators or Transfer chamber for EM material (packaged pre-sterilized)
3- RTP canisters or Processor vessels for Steam sterilized components, tools, wipes
Notes
- Material introduction requires ability to understand RTP doors principles
- Assurance about integrity of package of pre-sterilized material prior to introduction
- Material removal requires sterilization of Vacuum cleaners or vacuum wound
28
Introduction/removal pictures
RTP Canisters
29
RTP Door
Beta Side
Introduction pictures - CPS Vessels RTP
30
Introduction pictures - CPS Vessels RTP
RTP Door
Alfa Side
31
RTP Doors Principle/Pictures
32
Isolator Integrity/openings
Why = Production isolators have to allow container flow in and out.
Sterility isolators are typically a closed system.
Who/When = typical a automatic operation.
How
1- Prod isolators = control of Tunnel gate and of mouse hole, then overpressure.
2- Sterility Isolators = control of main doors and overpressure.
3- Possible issues = glove integrity breach, flexible wall breach, carter removal,
loss of pressure on gaskets for doors.
Notes
- Main cause for lack of integrity are blackouts, so UPS coverage advisable.
- Avoid maintenance operations potentially triggering contamination.
- Experience shows small glove punctures unlikely to trigger microb. issues.
33
Glove use, inspection, testing
Why = Key technical feature. Need to be robust, material suitable for sterilant, and also not
offering cavities for bacteria. Can be single piece or 2-piece (sleeve and glove).
Who/When = operators inspect visually, plus some automatic testing at start and end of
campaign.
How
1- Visual inspection is able to detect quickly and immediately visible holes.
2- Automatic testing based on several principles, main one is pressure test.
Notes
- Main cause for glove issues are broken glass, connections, stretching moves
- Glove position and length to be defined at design time
- Uniformity of “people size” (arm length/height) helps reduce issues (Quality/Ergonomics)
- Potential Microbiol. issues due to glove breach can be minimized wearing sterile gloves .
34
Glove - pictures
2-piece glove
glove
2-piece glove
sleeve
Single piece
glove
35
Aseptic interventions
Why = Operation performed to remove debris, components blocked, broken containers,
adjustment or replacement of parts, set-ups.
Who/When = operators or mechanics when needed
How
1- Principles of aseptic technique also apply in isolators
2- Need to have sterilized tools (tweezers, scissors, sticks) available. Do NOT use gloves
3- Should never lead to exposure of surfaces not decontaminated
4- Potentially contaminated units to be discarded
Notes
- All interventions needs to be accounted and included in Media fill program
-Typical, unavoidable interventions are
- Execution of EM viable sampling
- Removal of blocked/broken components
- Introduction of materials (tools, wipes, etc..)
36
Maintenance interventions
Why = Operation performed to adjust or replace parts
Who/When = mechanics/electricians/automation/operators when needed
How
1- Need to determine if intervention is putting at stake isolator sterility
2- Need to determine if it is covered by Media fill program
3- Exposure of not decontaminated surfaces may require launch of a new
decontamination cycle
Notes
- All interventions needs to be accounted and included in Media fill program
- Typical interventions are
- Adjustments of stoppering station, chute and bowl
- Adjustment/straightening of dosing needles
- Adjustment of crimping station, chute and bowl
37
Environmental monitoring
Why = comply with Annex 1 and GMP, verify viable and non viable cleanliness
Who/When = Operators (under Q supervision) or Q/EM technicians
How
1- Fixed positions inside isolator for Viable and non Viable
2- Non viable continuous monitoring
3- EM swabs for surfaces at end batch, active and settling plates during batch
4- End of batch EM may include contact parts
Notes
- All viable data obtained in isolators are typically zero
- Rare instances of EM hits often result in artifacts
- Frequent instances of EM hits indicate significant problems in isolator
- Integration of active EM system with filler and isolator is advisable
- Spikes of not viable typically related to interventions
38
Campaign Operation (vs single lot)
• Correct initial set-up minimize machinability
risks due to set-up change
• Reduce microbial and particle fluctuations
• Better efficiency which makes technology
affordable
• Feasible if it is possible to replenish materials
• Feasible if working with same/similar product
Campaign convenient when intercampaign is long, not so convenient
when intercampaign is short.
Current testing isolators with fast cycle mostly operates with single lot
batch, whereas production isolators for high volume/similar products
mostly operate in campaign (up to 20-25 days).
• Elongates the batch/test release process
• In case of issues, bigger business impact
• Requires validation with Media fill
Pro’s Con’s
39
Conclusions
Isolator technology properly designed and managed ensures better
sterility assurance and quality standardization (e.g. ensuring less
dependence from people).
For sterility testing it is becoming the standard equipment.
However it requires a higher investment in both capital and
people competences and it can be somewhat less flexible (e.g.
sensitivity of products to sterilant). RABS could be an alternative.
Isolator or RABS technology should be the next steps from standard
aseptic cleanroom.
40
Acknowledgement
TSMS Validation Sr. Mngr
Eli Lilly Italia
TSMS Sterility Assurance Sr Consultant
Eli Lilly Italia
41
Questions??
Discussion!
Pls feel free to email questions/comments to
Final Discussion
Isolation and Disposable Technologies, Data Automation
How these transform Site Operations
PDA Italy Chapter Bari, October,5-6th , 2017Manufacturing trend of parenterals: a glance to the future
M. Mannini, C. GianiGSK
2
Isolation and Disposable Technologies, Data Automation20 Years Evolution
• The last 20 years in Sterile Operations has dramatically changed Site capability and capacity
• Technology evolution provided multiple solutions to implement changes which allowed gradually to transform sterile operations, facility design, site organization and governance
• Increased Quality requirements imposed growing restrictions on interaction of Humans during execution of critical activities
• Operations control and recording requirements gradually requires a larger amount of data with consequences on process documentation, data storage, batch release; significant impact on resources has been observed with consequential supporting functions grown
2007 2012 20172000 2020+
Volumes (M units)
30 – 50 70 75 80 100 – 120
Technologies
LAF Passive -RABS Active-RABS Isolation
Data Management Automation & Process ControlFully on paper CFR 21– Mixed system Paper/OSI e-BPR
Limited information SCADA OSI-Pi reporsitory data
Filling Batch Size
50K 120K 200K 350K 500K
Disposable & Single Use
Open process Formulation Closed Connections Full Closed Process
Isolation and Disposable Technologies, Data Automation20 Years Evolution
Starting From:
• Open Formulation process executed into conventional Facility
Design (Grade C / Grade B rooms)
Arriving to:
• Fully closed Formulation process through usage of Aseptic
Connectors and SUS into facility provided with only Grade C Rooms
Advantages
• Increased Sterility Assurance Level
• Reduced issues on material preparation and sterilization , focusing
on added values activities
• Reduced Cleaning Validation issues
• System Integrity fully tested
Challenges
• Operators expertise in managing SUS
• Extractable & Leachables Studies
• Introduction of Changes in already registered processes
• System integrity
• Rely on supplier (shortage of critical components)
Isolation and Disposable Technologies, Data AutomationChanges in Technologies – Disposable in Formulation
Starting from:
Conventional Grade B filling rooms with segregated Grade A zone with
frequent or continous Human interactions in critical operations
Arriving to:
Fully contained Grade A zone in Isolators with no Human interaction in
critical operations
Advantages
• Increased Sterility Assurance Level
• Longer manufacturing time with no operators fatigue and increased
batch sizes
• System Integrity fully tested
• Reduction in critical EM excursion during process
Challenges
• Rely on high engineerized equipment
• Personnel competencies and skills
• Technical Support and edeep expertise on specific topics (i.e. Hidden
Surfaces, VHP, contamination carriers in ISO technology..)
• Long setup time and change over, loss of flexibility, reduced capacity
Isolation and Disposable Technologies, Data AutomationChanges in Technologies – RABS & Isolators
6
Modular Concept Facility – Isolator Technology ( Video )
380000 PFS
Isolation and Disposable Technologies, Data AutomationChanges in Technologies – New Facility Design
Isolation and Disposable Technologies, Data AutomationChanges in Technologies – Developing skill for personnel
Challenges
• Changes of personnel qualification
and training program and different
skills required in new personnel
• Needs of SMEs for each new topics
or technology (SUS, Integrity
testing, VHP, Isolators, Automation
etc..) with limited time availability
• Conversion of «old» operators to
different needs to perform
manufacturing activities and to
control them
• Increased need of Integrated
functions to support routine
operations (QA, Engineering,
Validation)
• Rely on Suppliers knowledge or
network SMEs
• Fully Integrated Facility
into SCADA for managing
operations
• Reduced Lead time
• Control from Remote
locations
• Data repository (Osi-Pi) to
avoid printing, paper
management, Data
Handling
• Fully Integrated Facility
into SCADA for managing
operations
• Reduced Lead time
• Control from Remote
locations
• Data repository (Osi-Pi) to
avoid printing, paper
management, Data
Handling
Isolation and Disposable Technologies, Data AutomationChanges in Technologies – Automation & Process Control
Opportunities
Batch Reports
Dashboarding
Execution
Control
Data Storage
Challenges
• Fully dependent on IT
systems and their perfect
functioning
• Data recovery , Data loss
and Data integrity
• Utilization more complex
for most of personnel
Challenges
• Fully dependent on IT
systems and their perfect
functioning
• Data recovery , Data loss
and Data integrity
• Utilization more complex
for most of personnel
9
• Utilization of high speed capacity lines and Isolators led to much larger
batches
• Same shift pattern for Operators and manufacturing / Quality team allow
to produce approx 3x volumes in the same timeframe
• Reduced number of batches / year at the facility allow to optimize
manufacturing areas and equipment utilization with more opportunity to
recover in case of issues
• Reduced ancillary activities like reviewing BPRs and managing Deviations
lead to an indirect cost saving
• Reduced cost for Quality testing, due to approx half of batches to be tested
at constant volumes output
Isolation and Disposable Technologies, Data AutomationChanges in Technologies – impact on Cost of Goods
10
Isolation and Disposable Technologies, Data AutomationChanges in Technologies - Conclusion & Lessons Learnt
Changes running at different speed...
• Computer Technologies, Information Technology running faster than any others
• Technologies innovation provide multiple solutions to increase standards and
efficiency, but their implementation require a clear path and well structured
plan
• Quality, Regulatory and Compliance requirements continously increase, once
you have capabilities, standards will be higher than before...
• Organizational Changes not always are implemented on time and often does
not fit with the purposes
• Knowledge management (skills, competencies, expertise, SMEs) should be built
in advance; payback sometimes could be very low in the expected time
• Cultural mindset, needs to plan for a sound plan to anticipate and manage
what is needed to sustain such changes
Thank You!!!Questions?
Isolator technology: a new challenge
Subtitle
PDA Italy Chapter
Manufacturing trend of parenterals: a glance to the future
Bari, October,5-6th , 2017
E. Matarrese, A.Calvano
Merck
2
✓ Why using isolator;
✓ Design of the vial line;
✓ Bio-Decontamination for isolators;
✓ Isolator Validation activities approach: cycle development and cycle validation;
✓ Study on going for H2O2.
✓ Environmental Monitoring Program;
✓ Day by day improvements.
Index
Aseptic processing using isolation systems separates the external cleanroom environment from the aseptic processing line and minimizes its exposure to personnel. A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control, offers tangible advantages over traditional aseptic processing, including fewer opportunities for microbial contamination during processing. However, users should remain vigilant to potential sources of operational risk. [FDA Guidance for Industry]
Isolator:
Why to implement this new technology?
Integrated biodec. system
Separation of product and process from the
operators (main contamination source)
Excellent
Product
safety
Vial line overview
Vial loading system in class D
✓ 3 independent isolators;
✓ 3 completely separated systems for the generation of the H2O2 used for isolators sterilization;
✓ 1 rapid transfer chamber for material introduction (ISS) with dedicated H2O2 bio-decontamination system;
✓ “Cross” shape of the line allows capping and filling in parallel of two different batches high rate of flexibility and quite unique shape within Pharma Companies for a vial line.
Filling
Lyo 1 loading/
unloading
Lyo 2 loading/
unloading
Capping
Isolator
Open RABS
Vial line machines (1/2)
✓ Machine can process vials from 3ml to 100ml both liquid and freeze dried;
✓ Filling machine speed: 24000 vials/h for 3ml vial;
✓ Capping machine speed: 27000 vials/h for 3ml vial;
✓ LYO capacity increased from 52.000 to 80.000 vials/batch.
Vial line machines (2/2)
Bosch: Washing Machine and Tunnel Bosch: Filling Unit
✓ The machine consists of the following main components and processing steps air containing H2O2 is not recirculated. No catalytic converter are installed
Main characteristic of the isolator (2)
8
Bio-decontamination in our Isolators
The bio-decontamination process with H2O2 vapour inactivates a potential microbiological contamination inside the isolation system
Bosch SafeVAP (open loop system)Liquid H2O2 evaporates out of the isolator and is transported in the isolator via piping.There, the recirculation takes place. In order to create air balance exhaust air need to be opened.
ITP 8711Surface = 3,5 m² Volume = 5,2 m³
ITP 8711Surface = 3,5 m² Volume = 5,2 m³
ITP 6211Surface = 9,2 m² Volume = 3,5 m³
ISS 1000 Volume = 0,35 m³
9
Isolator Integration with SafeVAP Process
• The injection point is above the HEPA filter, double filtration of the air and safe decontamination of the filter
• To achieve a fast and entire decontamination a homogenous distribution of the H2O2 steam is necessary
• H2O2 steam is injected via preheated distribution-pipes
• An homogeneous concentration is accomplished with only one generator
10
Bosch SafeVAP Process
• H2O2 is pulled through a venturi by sterile filtered compressed air and forms a spray of micro-droplets
• Spray is injected into a heated evaporator
• Vapour is mixed with dry, warm air which acts as carrier
• Transport of H2O2 vapour through pre-heated distribution pipework
11
Phases0 Preparation Place all items as designed (utensiles, monitoring devices, gloves)
1 Drying / Preheating Preparation of starting conditions:• Leak test• Relative humidity [%]• Air velocity [m/s]• Temperature [°C]
2 Conditioning Injection of H2O2 with a high rate to achieve a high gas concentration
3 Bio-decontamination Injection of H2O2 with a high rate to achieve a high gas concentration (get a stable H2O2 concentration)
4 Aeration Injection of H2O2 with a high rate to achieve a high gas concentration Time to reduce the residual concentration of H2O2 [ppm] in the chamber <1 ppm
• The bio-decontamination process with H2O2 vapour inactivates a potential microbiological contamination inside the isolation system
• The inactivation depends on the exposure and concentration of H2O2 inside the isolation system
Bio-Decontamination Cycle with H2O2
12
CoP Aseptic Processing F2F Meeting
Isolator Validation activitiesPerformance Qualification Approach
1 Cycle Development
2 Cycle Validation
Physical Evaluation
13
Bio-Decontamination Cycle
Chemical Evaluation
Biological Evaluation Safety Evaluation
1 Cycle Development 2 Cycle Validation
BiologicalSystemCharacterization
Worst location CIs
for H2O2
DistributionTemperature
Mapping
Air flow verification
Critical design considerations
Worst location withtriplicate BIs
Worst locationBIs 3 times
EvaluateAeration
time
14
Objective:✓ To determine the quantity of H2O2 adsorbed by primary packaging materials (empty vials
and stoppers) and by the formulated solution when exposed into the isolator. ✓ Different H2O2 levels tested
Procedure (test 1 – empty vials): ✓ Heat sterilization of vials✓ Autoclaving of stoppers✓ Incubation of the following empty vials per concentration (0.03 / 0,1 / 0,5 / 1 ppm)
o5 vials 2Ro5 vials 50R
✓ Exposition for 18 h✓ After exposition, filling with 3 ml (2R) and 3 ml (50R) of water (HPLC grade)✓ Filling of 5 unexposed vials with 3 ml (2R) and 3 ml (50R) of water (HPLC grade) as negative
control✓Mixing of the vials to remove H2O2 from the surfaces✓ Analysis of H2O2 concentration with AmplexRed Assay, 3fold per vial
Study on going at Bosch (1)
15
Procedure (test 2 – pre-filled vials): Prior to testing, the products will be kept at 2-8°C. During testing, the product will be exposed to room conditions (22-25°C).✓ Heat sterilization of vials✓ Prefilling vials with product✓ Incubation of the following vials per concentration
o 5 vials Product 1 (freeze dried) open DIN 2R 3ml vials – filling volume 0,5mlo 5 vials Product 1 (FD) partially stoppered DIN 2R 3ml vials – filling volume 0,5mlo 5 vials Product 2 (FD) open DIN 2R 3ml vials – filling volume 0,88mlo 5 vials Product 2 (FD) partially stoppered DIN 2R 3ml vials – filling volume 0,88mlo 5 vials Product 3 (liquid) open DIN 50R vials – filling volume 61,2ml
✓ Exposition for 3h✓ Full stoppering of all vials; vials that were exposed without stopper, will be closed with
stoppers not exposed to H2O2 before✓ Analysis of H2O2 concentration in the vials with AmplexRed Kit, 3fold per vial✓ Analysis of unexposed product solutions as negative control
Study on going at Bosch (2)
16
Procedure (test 3 – stoppers):
✓ Autoclaving the stoppers✓ Exposition of 10 stoppers to 0.03 / 0,1 / 0,5 and 1 ppm, respectively✓ Exposition time 18 h✓ Closing of unexposed, heat treated vials filled with 3 ml of water with the stoppers✓ Turning vials upside down✓ Analysis of H2O2 concentration in the solution after 1 h, 3 h and 6 h
Study on going at Bosch (3)
17
Summary of the updake study (1/3)
18
Summary of the updake study (2/3)
19
Summary of Results: Uptake Studies (3/3)
• Total uptake largely depends on H2O2 concentration in isolator atmosphere and vial orifice cross-sectional area
o Seems to be a diffusion controlled process
o Impact by convection/air flow very likely (strongly dependent on isolator characteristics!)
• Stoppers impact is negligible stoppers around detection level at 1 ppm, below detection level at 0,5 ppm;
• High fill volumes are rather low risk because the amount of H2O2 taken up dilutes into a larger volume (favourable surface-to-volume ratio)
• Small fill volumes reach very high H2O2 concentrations even at low isolator atmosphere levels
o 3 h line stoppage seems impossible/unlikely to be achieved, even if product is reasonably stable towards normal H2O2 levels
• Composition of the product to be carefully evaluated during development selecting excipient to reduce oxidation effect
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✓ Why using isolator;
✓ Design of the vial line;
✓ Bio-Decontamination for isolators;
✓ Isolator Validation activities approach: cycle development and cycle validation;
✓ Study on going for H2O2.
✓ Environmental Monitoring Program;
✓ Day by day improvements.
Index
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Environmental Monitoring Program
Isolator technology is pretty new, no detailed guideline is available to define a fixed environmental monitoring program.
In any case, a comprehensive Environmental Monitoring program (particulate and microbialmonitoring), based on the applicable sampling methodologies, will be essential to guaranteecompliance of products with the Pharmacopoeial requirements for “Sterility” and “Foreign andParticulate Matter” in parenterals.
The strategy defined for environmental monitoring program in the new vial isolator line will beconceptually analogous to the current «classical» filling clean room, taking into account the specificcharacteristics of the isolators, providing meaningful information on the quality of the asepticprocessing environment within the isolators, promptly identifying potential routes of contaminationand providing application in capturing adverse events or drifts, allowing for implementation ofcorrections, before product contamination occurs.
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Environmental Monitoring Program
Particulate monitoring will be performed continuously during operations.
Microbial monitoring will be performed by means of active air sampling semicontinuously duringoperations. Semicontinuous monitoring will be representative of the total validated exposuretime (e.g. 4 hours covering the entire filling time).
Microbial sampling of surfaces will be performed in post operation condition, with qualifiedmethod.
With regards to microbial sampling of isolator gloves, the ones that will be used by the operatorswill be sampled by means of contact plates at the end of the operations and following a riskbased approach for selecting gloves to be sampled.
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EM material handling
With the use of isolators, personnel is excluded from the aseptic processing environment andmanipulations are made using glove-and-sleeve assemblies.... Personnel have far less impact onthe microbial quality of the environment within an isolator enclosure in a clean roomenvironment
At the date, a new support, totally made in stainless steel, has been finalized in order to permitan easier replacement of the traditional impactor in stainless steel with a disposal one.
Acknowledgements