PIONEERING DI AGNOSTICS

Increase Productivity with Rapid Micro Methods in a Pharma EnvironmentTechnology – Implementation & Validation

Michael Wasmann

Business Development Director

Rapid Micro Methods and Blood Banks

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A Pasteurian tradition: Marcel Mérieux worked with Louis Pasteur in 1894.

A commitment that transcends four generations: ever since the creation of

Institut Mérieux, a generation has worked after another to expand its legacy.

AN HISTORIC FAMILY COMMITMENT TO

MEDICINE AND PUBLIC HEALTH WORLDWIDE

Marcel Mérieux

1897 - Creation of Institut Mérieux

Dr Charles Mérieux

1937 - Dr Charles Mérieux

took up the reins

Dr Alain Mérieux

1963 - Creation

of bioMérieux

Alexandre Mérieux

2017 - Chairman &

CEO of bioMérieux

Marcel Mérieux

1894 - Student of Louis Pasteur

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Designing, developing, manufacturing

and marketing diagnostic solutions:

OUR EXPERTISE

CLINICAL FIELD INDUSTRIAL FIELD

80%of sales

20%of sales

Improving patient health

especially in infectious diseases

Ensuring consumer safety,

product quality and animal health

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2008

Only 2 biologicswere in the top ten sellingtherapeutic (Enbrel, Neulasta).

2016

8 of 10 best selling productsare biologics(Humira, Enbrel, Rituxan, Remicade, Avastin, Herceptin, Lantus, Prevnar).

2018-2019

100% of the best sellingproducts will be biologics

EVOLUTION OF BIOPHARMACEUTICAL DRUGS

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USP <71>

Ph.Eur. 2.6.1

JP16 4.06

14 day test

Subjective (sometimes difficult)

interpretation

Suited only to long shelf-life

pharmaceuticals and sterile

medical devices

TRADITIONAL (COMPENDIAL) STERILITY TEST

Harmonized

Pharmacopoeias

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BLOOD PRODUCTS

Platelet concentrate

bacterial screening

NEW CHALLENGES: SHORT SHELF LIFE PRODUCTS

CELL THERAPIES

Sterility testing of

cellular therapeutics

CORD BLOOD

Contamination testing

of umbilical cord blood

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OTHER SHORT SHELF-LIFE THERAPIES

COMPOUNDING STERILE PHARMA

Bespoke cocktails of cytotoxic and antimicrobial

therapeutics for cancer

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Many cell based or compounding products can

not be preserved or stored without affecting

viability and potency. These products tend to

have short shelf life and administration of the

final product is often necessary before a final

sterility test result is available.

14 days incubation required for the compendial

sterility test is too long.

Many of these products have small batch size,

for which USP <71> and EP 2.6.1 typical test

volumes and sample size may be unsuitable.

COMPENDIAL STERILITY TESTA CHALLENGE TO SHORT SHELF LIFE PRODUCTS

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ALTERNATIVE METHODS VALIDATION

European Pharmacopoeia, chapter 5.1.6 “Alternative Methods for the

Control of Microbiological Quality”

USP, chapter 1223 “ Validation of Alternative Microbiological Methods”

PDA, Technical Report 33, “The Evaluation, Validation

and Implementation of New Microbiological Methods”

3 standards on the validation of alternative microbiological methods:

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Installation and Commissioning • Instrument is installed and calibrated in accordance with requirements

Installation Qualification (IQ)• Instrument conforms to the manufacturer’s description and installation requirements

Operational Qualification (OQ)

• Instrument meets the operational expectations and specifications. Includes security tests, conformance tests, challenge tests or stress tests

Training of Operators• On-site training by vendor Field Application Specialist

Performance Qualification (PQ)

• Verify the analytical performances of the system in concordance with Pharmacopeia and the equivalence of the results obtained with the current reference method for a given product

CLASSICAL IMPLEMENTATION OF AN RMM METHOD

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ADVANTAGES OF A COMPENDIAL STERILITY

MICROBIAL CONTAMINATION TEST

It would address the microbiological safety needs of short shelf-lived ATMPs, PET or

compounded sterile products.

It may be implemented after successful completion of a method suitability testing without

validation comparison with the traditional method.

It may be implemented without prior regulatory approval of the test method.

The barrier of entry into the test instrumentation market will be lowered.

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USP MICROBIOLOGY EXPERT COMMITTEE

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USP EXPERT PANEL MEMBERS

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PUBLISHED ARTICLE BY THE PANEL MEMBERS

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USP <1071> RAPID MICROBIAL TESTS FOR

RELEASE OF SHORT LIFE STERILE PRODUCTS

Information chapter based on the outcome of the Modern Microbial Methods (MMM) panel discussion

and review of the stimuli article.

Contains sections on:

User Requirement Specifications.

Concept of Risk-Based Microbiological Monitoring and Release Testing.

Situations when the <71> Sterility Tests are Unsuitable for Product Release Testing.

Examples of Rapid Sterility Tests Technologies.

Method Suitability Testing

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USP <1071> CANDIDATE TECHNOLOGIES

Operational Parameters of Candidate Technologies:

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BENEFITS OF RAPID MICRO METHOD IMPLEMENTATION

✓ Benefits for the Laboratory. Microbial quality controls are no more the bottleneck of a safe

product release process. Rapidity

. Automation

. Standardization

. Traceability

✓ Benefits for the Quality Department. Reduce Non-Quality costs

. Reduce safety stock

. Test sterility within hours up to few days instead of 2 weeks

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BENEFITS OF RAPID MICRO METHOD IMPLEMENTATION

✓ Benefits for the Manufacturing Department. Reduce lead time

. Improve production capacity

. Rapidly response to contamination incidents

✓ Benefits for the Supply Chain. Release products faster

. Save up to 13 days on quarantine time and decrease the required

storage area

. Decrease end product inventory costs

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WHEN PROFITABILITY AND QUALITY COME TOGETHER

Benefits for the financial department. Decrease working capital requirements

. Increase cash flow

Global benefits for the companyDown to 6 months return on investment with

significant operational costs savings

Traditional Method Rapid Micro Method

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FILTERABLE & NO PARTICLESSOLID PHASE CYTOMETRY

TWO COMPLEMENTARY RMM SOLUTIONS

NON-FILTERABLEAUTOMATED GROWTH BASED CO2

DETECTION

• Compounding products

• WFI & process water

• Infusion fluids

• Small molecule therapeutics

• In-process products

• Blood products

• Cellular therapies

• Large molecule biotherapeutics

• In-process products

Results in 4 hours instead of 14 days Results in 1-7 days instead of 14 days

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SOLID PHASE CYTOMETRY - WORKFLOW

Filter1

Label2

Scan & Confirm3

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WORKFLOW - FILTER

Performed under laminar flow ISO 5 (14644-1)

or Cleanroom Grade A (GMP Annex 1) using filtration ramp

Filter1

Filter Apparatus Options▪ Fluorassure Integral Filtration Unit (FIFU)

▪ Cyclo Black 04 Porosity (CB04)

Track-Etched Membrane (TEM)▪ Polyester (non-fibrous)

▪ 0.4µ pores

▪ Organism(s) remain on surface for labeling

▪ Black color reduces fluorescence interference

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WORKFLOW - LABEL

Counterstain (background fluorescence, block particles and dead cells)

Pre-labeling step (activates dormant and spore cells)

Viability substrate added and enters the cells passively

Label2

Criteria of Viability▪ Enzymatic activity

▪ Membrane activity

Labeling is not

destructive

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WORKFLOW – SCAN & CONFIRM

Membrane is transferred to the solid-phase cytometer

Complete surface of the membrane is scanned (0.5 miles) with an Argon neon

laser within 3 minutes

The total # of living cells on the membrane are displayed. The scan map and

microscope attachment allow for visual confirmation

Scan & Confirm3

Fluorescent Signal

515 nm

(Green)

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SOLID PHASE CYTOMETRY - RESULTS

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AUTOMATED MICROBIAL DETECTION SYSTEM

The automated microbial detection systems are non-destructive, growth based, dual temperature, that

may be used as an alternative to the traditional sterility test method (EP 2.6.1, USP <71>, JP 54) .

Incubation at 20-25°C and 30-35°C.

Samples are measured objectively

• No need to visually inspect for turbidity

• Continuous monitoring

• Detection typically occurs within 24-72 hours

Aligned with compendial methods

• Two broths (aerobic/anaerobic) – Two temperatures

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AUTOMATED MICROBIAL DETECTION SYSTEM

WORKFLOW

Scan

Touch

Load

Anywhere

Control Module

Simplifies work flow

Simultaneous bottle handling and data management

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COLORIMETRIC CO2 SENSOR TECHNOLOGY

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NEW EP CHAPTER 2.6.27.

EP 2.6.27. describes how automated, growth based

methods may be validated for cell-based

biopharmaceutical products.

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NEW EP CHAPTER 2.6.27.

EP 2.6.27. major validation steps

▪ Growth Promotion Test

▪ Method suitability

▪ Conditions to be used

▪ Microorganisms to be used for validation

Contains:

PIONEERING DIAGNOSTICS