Consortium activities on developing a strategy for the implementation of Modern Microbiological Methods in

place of traditional testing for new products

• Karen Capper Astra Zeneca • Paul J Newby , Microbiology Modernisation Lead, GSK R&D

Outline

• Introducing the Microbiology Modernisation Cross-industry Consortium (MMCC) • The GSK experience post Pharmig 2017 with MHRA Innovation office

• Challenges for implementation in place of traditional methods • Modern methods, potential applications and readiness levels • Implementation strategies

• The AZ experience • MHRA regulatory engagement and the benefits of early engagement and using the

innovation centre • Consortium contact details

MICROBIOLOGY MODERNIZATION CROSS -INDUSTRY CONSORTIUM (MMCC)

THE PURPOSE OF THE CONSORTIUM (MMCC) IS TO CATALYSE TRANSFORMATIONAL CHANGE IN

MICROBIOLOGY TESTING BY ESTABLISHING STRATEGIC PARTNERSHIPS TO ENABLE IDENTIFICATION AND

INDUSTRIALISATION OF STANDARDISED TECHNOLOGY PLATFORMS AND WAYS OF WORKING.

MMCC Key areas of collaboration and vehicle for change include, but are not restricted to:

• Foster collaboration and communication between

key stakeholders in the precompetitive space

• Share knowledge on new technologies

• Develop best practices

• Speak with a united voice to the regulators to

stimulate acceptance of new validated

technologies

• Speak with a united voice at conferences and

industry fora to provide direction to the suppliers

in the development of their technologies

• Develop an effective business case tool

• Progress similar innovations with comparable

benefits profiles

• Develop strategic alliances with key suppliers and

institutions

• Share insights and input on implementation of new

technologies

• Create sub-teams to progress individual projects

• Centralise validation protocols for new

technologies

CONSORTIUM AREAS OF INTEREST

• Drivers for modernisation of microbiology methods

• Challenges for implementation in place of traditional methods

• Modern methods, potential applications and readiness levels

• Implementation strategies

• MHRA regulatory engagement and the benefits of early engagement and using the

innovation centre

• Consortium purpose, status and activities

Modernisation of Microbiological Testing in GSK

Paul Newby – Future Analytical &

Control Technology (FACT)

Alice Laures - FACT

Philip Butson – Quality Assurance

Sandra Kite - CMC Regulatory

Julian Kay – Quality Assurance

MHRA 16th Aug 2018

Confidential

RMMs already in use (but needs more uptake)

Regulators are keen to support innovation

Help the regulator to understand

Caution

Be careful what you ignore

Still need the right knowledge

Additional tool in the tool box does not necessarily replace existing tools

Talk to Regulators!

Andrew Hopkins, MHRA senior inspector – Pharmig

conference Nov 2017

Presentation title

Modernising Microbiology Discussion with MHRA Innovation Office,

• Phil Butson, Director, Quality Futures

• Sandra Kite, Director Global CMC Regulatory

• Alice Laures, Manager Future Analytical & Control

Technologies

• Paul Newby, Microbiology Modernisation Lead

• Sarah Gomersal, Pharmacopoeial Scientist

• Andrew Hopkins (via phone), Expert GMDP Inspector

• Nafisa Potrick, Scientific Innovation Lead

• Ian Rees, Unit Manager, Inspectorate, Strategy & Innovation

• Ioana Venet, Pharmaceutical Assessor

Innovation Office, MHRA, Canary Wharf, 16 Aug 2018

• GSK ATTENDEES

• MHRA/BP ATTENDEES

Meeting Aims and objectives

Meeting objectives were :

• To provide the IO with an awareness of the drivers, status and future plans for

modernization of microbiological testing within GSK, including environment

monitoring, and a focus on rapid sterility testing.

• To obtain feedback to help enable the implementation and uptake of modern

microbiological testing technologies.

• Discussion topics

– GSK’s RMM technology roadmap

– Alternative approaches to sterility testing

What did we want to get out of our meeting with the Innovation Office (IO)?

9 Confidential

Introduction

GSK has identified 2 main drivers

• Near/Real time analysis

Real time or near real time microbiological analysis of product quality is the desired state but not possible with

conventional growth-based methods.

• Direct Data Capture (Data Integrity considerations)

Microbiological test platforms with integrated data capture functionality. This is the desired state for environmental,

process and product analysis.

Drivers for modernisation

Confidential 10

These considerations have led to the development of a microbiology testing technology roadmap

which was discussed with the IO and feedback provided.

Guiding Principles Drivers Alignment

Rea

din

ess

Ind

ex*

Standard technology platforms

Dir

ect

Dat

a ca

ptu

re

Rea

l tim

e/ n

ear

real

tim

e

ster

ile p

rod

uct

an

alys

is

Nea

r re

al t

ime

envi

ron

men

tal

mo

nit

ori

ng

Rea

l tim

e /

nea

r re

al t

ime

tro

ub

le

sho

oti

ng

inve

stig

atio

ns

Smal

l Mo

lecu

les

Bio

Ph

arm

Ad

van

ced

Th

erap

ies Network Alignment

Automation

GMP compliant

Data integrity standards met

LIMS compatible

End user driven

Enab

ling

Pla

tfo

rms Growth Direct 2nd Gen

Strong Strong 7

Automated plate readers Strong Strong

6

HVLD (E-Scan 625) Strong Strong

9

RaSTA (ParaDNA & ddPCR) Strong 4

Growth Direct for Sterility testing Strong Strong Strong 6

BacT/ALERT 3D Dual Temp

Strong Strong Strong 9

Microbiology testing - technology Roadmap

HVLD = High Voltage Leak Detection

RaSTA = Rapid Sterility Test Approach

LIMS: Laboratory Information Management System

* On a scale from 1 to 9 with 1 being an idea in academia and 9 being

a commercial instrument

Overview of current main areas of interest – short to medium term

11

Confidential

Sterile products Container Closure Integrity (CCI)

12

High Voltage Leak Detector (HVLD)

Stability Sterility Test Surrogate

• EMA outlined in 2009 that sterility testing should be performed at least at the end of shelf life but it could be replaced by testing of container closure integrity (CCI).

• Substitution of sterility testing by CCI for interim time points has been accepted by some markets but it appears that uptake as an approach is slow.

• GSK is investigating HVLD for CCI as an alternative to Dye immersion/microbial ingress for interim time point testing of steriles due to

– Suitable for wider product range

– More objective end point (turbidity, dye detection)

– Simplification

Q – Does the IO have a view as to why uptake of using CCI for interim stability testing appears to

GSK to have been slow?

Q – What would MHRA specifically need to justify the use of HVLD for interim stability testing?

Q – Would HVLD for CCI be an acceptable approach at interim stability timepoints in lieu of sterility

testing ?

Confidential

Rapid sterile products testing

GSK is using BacT/ALERT for Advanced therapy products and is investigating its use for small molecules sterility testing where membrane filtration is not applicable.

However, our ambition is to use it as our first intent sterility test including small molecules.

Challenges

• Direct inoculation only – sample size restricted to 10ml per canister

• Not a compendial method as yet

• Slow uptake by industry for sterile small molecule release testing – Previously single temp system – GSK use recent dual temperature system

• Equivalence testing interpretations in USP, EP, BP

BacT/ALERT

Q – What would be the appropriate validation requirements?

e.g. would following the USP guidance on equivalence testing satisfy the requirements from EP and

BP? 13

Q – Given the BacT/ALERT is designed as a direct inoculation technique, would MHRA & BP support a

position to use BacT/ALERT for filterable solutions?

Confidential

Innovation Office meeting outcomes

• The meeting provided a very informal opportunity to talk to MHARA and BP

• It was very informative on both sides

• MHRA

– Underlined the importance of cross industry groups in generating more data from more players

– The importance of data integrity and validation in pharmaceutical microbiology

– The need for ongoing dialogue especially in areas not directly involved in regulatory submissions eg.

Environmental monitoring technologies

– The importance of product based justifications for technologies such as BacTalert for small molecule,

filterable products

– Willingness to review but not author experimental protocols for technology innovations

AstraZeneca Approach to the Modernisation of Microbiology

Karen Capper PharMIG Conference November 2018

AstraZeneca’s Main Drivers for Modernisation

• Increased process understanding, knowledge and robustness

• Ability to introduce the engineering technology available to us to

improve patient protection and reduce waste due to batch

rejection

• Reduction in cycle times

• Reduction in time to results

• Reduce in time to batch release or the ability to move stages of

the production process on faster

• Faster supply chains

• Reduce data integrity issues

• Increase sustainability

Product Release Tests

Our diverse range of products means we need a diverse

range of solutions

Challenges of Traditional Methods • Slow • Will only detect a fraction of actual

bioburden • Prone to data integrity issues • Can only respond to an issue/event days

after

Modern Micro Methods Can be; Qualitative Quantitative Identification

Growth Based platforms reduce time to detection of organism, use conventional media, therefore same application that traditional methods are used for can be applied to growth based alternatives

Viability-based use viability stains and laser excitation

Cellular component-based rely on detection & analysis of portions of the cell

Micro-Electro-Mechanical Systems (MEMS)

18

Challenges of Traditional

Methods

• Slow

• Will only detect a fraction of

actual bioburden

• Prone to data integrity issues

• Can only respond to an

issue/event days after

• Difficult to identify root

causes due to time lapse &

lack of understanding of

baseline

Environmental monitoring

Traditional plate techniques

Rapid techniques to read plates

Growth Direct

EviSight

Others?

Continuous viable

monitoring

BioTrak

BioLas

Others?

Water systems

At-line continuous monitoring

Sentinel MOBA

Mettler RMS7000

Biovigilance IMD-W

Traditional plate techniques

Rapid techniques to read plates

Rapid methods

Growth Direct

ChemScan RDI

MuScan

Milliflex Quantum

Others?

Support Monitoring – Environmental and Waters

IT Systems

To trend data

Support Monitoring – Steriliser/Decontamination

verification VHP verification

Traditional biological indicators

Standardization of approach to Bis

2018

Enzyme Indicators

Initial assessment complete

Extended validation/equivalency studies to performed

Routine use in cycles

VHP; Challenges of

Traditional Methods

• Live organisms taken into

controlled areas for

routine revalidation

• Yes/no answer

• Cycle design slow, as

need to wait for answers;

Leads to over-use of VHP

& extended aeration

cycles

• Long cycle times reduces

availability of isolators

• Limited knowledge of

cycle robustness

• Cannot use Bis to verify

every cycle

• Maintenance of BI &

verification time

consuming – prone to DI

risks

Example Implementation

The Challenges with Endotoxin Testing

Natural Assay = variable

2-20% invalid test rate

i.e. at some sites 20% of our tests are repeated due to invalid results, typically 8-12%

6 different iterations

used across AZ

Issues at one site could not easily be supported by

other sites

Different costs for

consumables & equipment

Even at country level

Cost dependent on 3 (main)

reagent suppliers

Time consuming

Lots of manual steps

Time to result – not an issue in small molecule world, but is an

issue at some of our biologics

sites.

Data integrity risks high

Manual prep

Manual Result interpretation

More parenterals

in our pipeline

Increased testing burden

One test may not suit all products

Capability gap

More parenterals globally increases

cost of goods

Reliance on a natural resource

Horseshoe Crab survival is out of

our hands

More parenterals globally

The Business Case for Charles River Endosafe®

• 12 sites doing endotoxin testing on water

• Spend >5000 hours testing these samples

• Use >17L HSC Lysate • >10% retest rate

• Switch water testing to Endosafe® • Testing time reduced <2000 hours • Lysate <1 L • Retest rate approx. 2%

Implementation Plan; • CRL Multi-cartridge system in use for >5 years at one site • Selected for new facility and currently under validation • Strategic implementation of Nexus robot for automation at higher volume sites • Target water testing to get technology in and “easy” regulatory path • Will transfer product over on a case by case basis, depending on the file • Implementation of instruments planned between 2018 and 2020

AstraZeneca Interaction with the MHRA Innovation Centre

• AstraZeneca visited the innovation centre to discuss with MHRA their advice and opinion on a proposed approach for an existing product sterility assurance continuous improvement program.

• AstraZeneca was in the early stages of planning additional improvements and investment in the manufacturing of this product relating to sterility assurance and wanted to seek input from MHRA on prioritisation of these improvement projects by using data from microbiology technical studies and risk assessments to focus improvements in highest risk areas.

• Two key areas AstraZeneca was interested in using as part of risk assessments included: Evaluation of heat treatment step in the process as a decontamination step. Assessment of the container closure integrity testing of a device which would not pass a typical container closure test.

Benefits of this Interaction

• MHRA gave advice on the microbiological aspects of the experimental design.

• Organism types • Expansion of the study to the whole process • Suggestions on how we might challenge the process with micro organisms • Suggestions on how to make the study robust to questions from regulators • Learning shared from other industry projects that had similar challenges and gave good

advice on non standard process. • When the agency then visited the site during inspection they were aware of both

studies, we shared results and progress. Advised on potential next steps to implement the findings of the studies and mitigate any risks.

24

• The agency have engaged in the facility and new line design and visited the wooden mock ups of the facility.

• Given advice on environmental

monitoring locations and risk assessment and area classification.

• Much smoother approval of the line

and a joined up approach to ensure the risks identified were assessed appropriately and mitigated with the correct containment and barriers appropriate for the product and patient.

• Facility recently inspected by MHRA.

Very smooth inspection.

MICROBIOLOGY MODERNISATION CROSS-INDUSTRY CONSORTIUM

Final comments

MMCC FUTURE PROJECTS • Hold regular technology update meetings

• Increase cross-company membership

• Expand expert network

• Engage with suppliers, academics & experts

• Regulatory advocacy – MHRA Innovation Office, EMA,

FDA Emerging Technology Team

• Sustainability initiative – Endotoxin testing

• Container Closure Integrity (CCI)

• Initiate revision of Pharm Europa chapter 5.1.6

MMCC COMPANY REPRESENTATIVES

• Miriam Guest AstraZeneca

• Karen Capper AstraZeneca

• Andrew Ray AstraZeneca

• Paul Newby GlaxoSmithKline

• Alice Laures GlaxoSmithKline

• Lisa Wysocki GlaxoSmithKline

• Sven Deutschmann Roche

• Wolfgang Eder, Roche

• Mousumi Paul Merck

• Philip Breugelmans JnJ

• Cedric Joossen JnJ

• Heike Merget-Millitzer JnJ

• Scott Weiss J&J

• Thierry Bonnevay Sanofi Pasteur

• Jeffrey Weiss Pfizer

INTERESTED?

• Karen Capper Karen.Capper@astrazeneca.com

• Paul Newby, paul.j.newby@gsk.com

• Alice Laures, 2018 chair – alice.2.laures@gsk.com

• Miriam Guest Miriam.Guest@astrazeneca.com

MMCC Contacts in the UK