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 : giusti_mauro@lilly.com

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

giusti_mauro@lilly.com

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