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Galit Weil EM Team Leader

November 2016

Environmental Monitoring Policy and Implementation

in BTG-Ferring Pharmaceuticals

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Presentation Contents

• BTG – Ferring Pharmaceuticals - Background • BTG Products • EM sampling frequency during routine production • EM program for initial qualification of cleanrooms • Rationale for determination of routine sampling locations • EM sampling frequency during routine production • Sampling and testing procedures • Establishment of alert and action limits • EM Deviation investigation • Identification of microorganisms • Trending of results • EM related 483

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BTG – Ferring Pharmaceuticals – Background (1)

‣ Ferring was first founded in Sweden in 1950 by

Dr. Frederik Paulsen

‣ Ferring Headquarters : Saint-Prex Switzerland

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‣ Research, development, manufacturing and marketing innovative products in the fields of reproductive health, urology, gastroenterology, endocrinology and orthopaedics.

‣ Manufacturing and R&D Centers: Argentina, China, Czech Republic, Denmark, Germany, Japan, India, Israel, Mexico, Scotland, Switzerland, USA.

‣ Products available in 110 countries

BTG – Ferring Pharmaceuticals – Background (2)

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‣ BTG produces biopharmaceuticals, primarily recombinant products, based on microbial fermentation and mammalian cell culture

‣ The manufacturing facility has been approved by regulatory bodies worldwide, including the U.S. FDA, European Regulatory Authorities, the Israel Ministry of Health, Health Canada, the Australian TGA and others.

‣ 2005 - Ferring acquires Bio-Technology General

1980 Bio-Technology General - founded as one of the

first biotechnology companies in Israel

BTG – Ferring Pharmaceuticals – Background (3)

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‣ ZOMACTON® (somatropin)

used to treat Growth Hormone

Deficiency (GHD) in children

‣ REKOVELLE® (uFSH) is a

highly purified human-derived

FSH indicated for the treatment

of female infertility

Drug Substances used in:

BTG Products – Two Types manufactured by biotechnology methods (1)

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‣ EUFLEXXA ®(in Israel, Arthrease®) is intended for intra-articular injection for the treatment of joint pain due to osteoarthritis

‣ Biolon® is used in ophthalmic surgical procedures to protect corneal endothelium

Medical devices manufactured by aseptic filling

BTG Products – Two Types manufactured by biotechnology methods (2)

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‣ ISO 14644-1/2/3/4 Cleanrooms and associated controlled environments

‣ ISO 14698-1/2:2003 Cleanrooms and associated controlled environments – Biocontamination control

‣ ISO 13408-1 Aseptic processing of health care products

‣ Sterile Drug Products Produced by Aseptic Processing – cGMP; FDA Guideline

‣ USP <1116> “Microbiological Evaluation of Clean Rooms and Other Controlled Environments”.

‣ Current EU Guide to GMP Revision to Annex 1 “Manufacture of Sterile Medicinal Products”.

EM Regulatory Guidelines

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Frequency of Air Monitoring in Classified Areas (operational)

(Operational)

EM Program During Routine Production for Clean Rooms (1)

Room

classification EU

Grade/ISO

Examples of Areas/ Activities Frequency of Testing

A / ISO 5

Critical aseptic / sterile activities

UDAF areas surrounded by

Grade B/ sterile activities

Continuous / Duration of activity

UDAF surrounded by Grade C

or unclassified / API filtration Before work begins

B / ISO 7 Direct support area to critical aseptic

processing (e.g. gowning room) Daily

B / ISO 7

Indirect support zone to critical aseptic

processing (e.g. formulation),

Background to UDAF areas used for

final filtration of Drug Substances.

Weekly

C ISO 8

Downstream (Purification)

Manufacturing facilities Weekly

Upstream (Fermentation, harvest,

recovery) Manufacturing facilities;

General & Support areas

Monthly

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Frequency of Contact Monitoring in Classified Areas

(operational)

EU Examples of Activities / Areas Frequency of Testing

A / ISO 5

Critical aseptic activities During and at the completion of

activity.

UDAF / sterile activities & API

filtration

Before and at the completion of

work unless specified otherwise

B / ISO 7 Direct support area to critical aseptic

processing (gowning room) Each operational day

B / ISO 7

Indirect support zone to critical aseptic

processing (e.g. formulation),

Background to LFH used for final

filtration of APIs.

Weekly

C / ISO8 Manufacturing and General & Support

areas Quarterly

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‣ All employees present during aseptic activities are monitored at the end of the activities and, when applicable, during the activity itself according to relevant SOPs.

‣ Gowning re-certification is performed annualy

Routine Personnel Monitoring Sampling Plan

EM Program During Routine Production for Clean Rooms (3)

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Yearly trend of recovery results in aseptic operations

Trending of gowning during aseptic operations by employee

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• Active Air sampler (MAS 100) –

active monitoring of airborne viable counts

• Air sampler (PMS LASAIR III®) –

airborne non-viable monitoring

• LMS system for the whole duration of

aseptic assembly and filling process

Equipment and sampling technologies

EM Program During Routine Production for Clean Rooms (1)

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‣ Air-settling plates – passive monitoring of airborne viable counts

‣ Contact plates - surfaces and personnel monitoring

‣ ICR swabs – filling needles surfaces

Equipment and sampling technologies

EM Program During Routine Production for Clean Rooms (2)

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‣ Sampling is performed according to SOPs

‣ EM sampling is performed by qualified personnel from manufacturing and QC

‣ Gowning used during the sampling activities are in conformance with the sampled room classification

‣ Single use sterile gloves are worn for all sampling activities; during aseptic assembly and filling single-use sterile sleeves are added at grade A

‣ TSA plates are used per sampling location for the relevant tests

‣ SDA plates are used on a quarterly basis

EM Program During Routine Production for Clean Rooms (3)

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‣ Instalation qualification should be performed on new or modified facilities, systems and equipment

‣ Operational qualification includes tests on the HEPA system in terms of filters integrity, air flow velocitiy and patterns (smoke tests), particle concentration etc.

‣ Demonstrating the room is suitable for production and consistently meets classification limits under both static and dynamic conditions under normal operating conditions

EM program for initial qualification of cleanrooms

IQ

OQ

PQ

Static &

Dynamic

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‣ Sampling locations are determined by a multi-disciplinary team consisting of representatives from: - QA - QC-EM - Engineering - Production

‣ Flows of equipment, personnel, and product

‣ process step and exposure to the environment

‣ The routine sampling locations are determined following the successful completion of the PQ.

‣ Locations are chosen according to the “Worst case” results obtained from the PQ study.

Rationale for Determination of Sampling Locations

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‣ Action Limits – when exceeded should trigger immediate investigation of the cause, and corrective action

‣ Alert Limits – set by BTG as ~50% of the action limit and give an early warning of possible drift from normal conditions, resulting in increased attention to the process

EM Action Limits were established

according to:

• EU Annex 1

• USP <1116>

• FDA guidance document: “Sterile Drug Products

Produced by Aseptic Processing – cGMP”

BTG Alert and Action Limits

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Routine trending

‣ As part of EM deviation investigation, a trend of previous 8 EM samplings is reviewed

‣ 3 consecutive alerts in a room triggers GLIMS to automatically open an investigation

Periodic trending

‣ EM Annual Product Review is conducted as part of the Annual Site Quality Review

‣ Selected trends are presented to the management on a quaterly basis during the QRB

Trending of Results

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‣ Investigation of environmental monitoring procedure

‣ Inquiery with manufacturing personnel present at the time of sampling

‣ Verification of all other EM results from the day of the deviation

‣ Microorganism identification*

‣ IPC bioburden results

‣ Cleaning verification

‣ Physical parameters verification (pressure, temperature, humidity)

‣ Trend of last EM 8 samplings results in the room

‣ Results of next EM

‣ Other potentially related deviations

Action limit violation Deviation

EM Deviation investigation

1 .Probable causes 2. Risk assessment

Isolated event / no findings

CAPA

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‣ A valid and current database of contaminants present in the facility is established

‣ Top 10 microorganisms are used for:

‣ Growth promotion tests of media

‣ Efficacy testing of disinfecting agents

Identification of Environmental Monitoring Microorganisms

‣ Microorganisms from all EM recoveries from class A and B areas : aseptic filling and gowning room, UDAF/LFHs, sterility laboratory and its gowning room.

‣ In other grade B and C areas microorganisms are identified in case of a repeating deviation

‣ A risk assessment for the identified microorganism is performed

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During sterility testing:

EM Related 483

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EM Related 483

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Questions?

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