Rieckermann Engineering Operations - Introduction To Containment Technology (Don Grubb)

ENGINEERING
OPERATIONS
OSD Seminar
Jakarta
26th September 2018
AN INTRODUCTION TO CONTAINMENT
CONTAINMENT TECHNOLOGY
DEFINITION
A STRUCTURE OR SYSTEM DESIGNED TO ACHIEVE THE

ISOLATION OF COMPOUNDS/PRODUCT FROM OTHER
PRODUCTS, PEOPLE AND THE ENVIRONMENT.
RIECKERMANN Group | 21/09/2018 | Slide 2 ENGINEERING OPERATIONS

AN INTRODUCTION TO CONTAINMENT TECHNOLOGY
MIND MAP

WHY?
ACTIVE PHARMACEUTICAL INGREDIENTS (API’S) ARE BIOLOGICALLY ACTIVE.
 Vital not to expose operators to levels that could cause adverse biological effects.
“So far as reasonably practicable, the prevention or adequate control of exposure of

employees to a substance hazardous to health shall be secured by measures other than the
provision of personal protective equipment.”
“The first duty of every employer is to prevent the exposure of employees to substances
hazardous to their health. The company may implement additional personal preventative
measures only there where this cannot be guaranteed by suitable technical options.”
(COSHH 2002 Control of Substances Hazardous to Health)
WHY?
CONTAINMENT PHILOSOPHY
ELIMINATE OPERATOR EXPOSURE
BEST DEPENDENT ON
 Eliminate by process design;
SYSTEMS
DESIGN TO BE
HERE
 Use Containment Technology;
 Ventilation/Extraction
 Reliance on SOPs;
 Use Personal Protective Equipment

LAST (PPE). DEPENDENT ON
RESORT DMDW OPERATORS
WHY?
USE CONTAINMENT TECHNOLOGY
 Contain API’s at source, prevent escaping into workplace;
 Isolate the product from personnel;
 Protect the product, the operators and the environment;
 Comply with Health Safety & Environment (HSE) legislation;
 Protect against insurance claims.

WHY?
CONTAINMENT TECHNOLOGY OVERVIEW

WHEN & HOW MUCH?
 Occupational Exposure Limit (OEL)
 OELs for the protection of workers around since 1939 when
workplace exposure limits first published in America;
 In 1970 US Occupational Safety and Health Act these became
enforceable limits;
 For commonly used industrial chemicals, few APIs listed;
 System adopted by many Pharmaceutical Companies to protect
workers from developing deleterious health effects caused by
exposure to chemicals;

WHEN & HOW MUCH?
 Occupational Exposure Limit (OEL) - see Material Safety Data Sheets
(MSDS). The OEL determines how much containment is needed;
 The maximum permissible concentration of chemical agent in the
air in the workplace to which workers may be exposed, either in
relation to an 8 hour (time weighted average (TWA) exposure or a
15 minute short term exposure limit (STEL) reference period;
 Compliance checked using air samplers located near the operators
breathing zone during operation;
 Adhering to OELs effective and proven way to protect workers from
the effects of chemicals if appropriately determined and
periodically monitored for in the workplace air;
 Setting OELs?

WHEN & HOW MUCH?
 Occupational Exposure Limit (OEL);
 The higher the potency of an API the lower the OEL;
 OEL ≤100µg/m3 a potent API;
 OEL ≤10µg/m3 a very potent API.
 Occupational Exposure Limit (OEL);
 Paracetamol 1000µg/m3
 Steroids - Ethinyl estradiol 0.035µg/m3
 Oncology Drugs - Doxorubicin has an occupational exposure limit of
0.5 µg/m3;
 Consider the effect of dilution – Rosuvastatin 0.5µg/m3;
 With the OEL design a Containment Strategy.
WHEN & HOW MUCH?
OCCUPATIONAL EXPOSURE BAND (OEB)
10,000 to 1,000 to
100 to 10 10 to 1 1 to 0.01
OCCUPATIONAL 1000 100
microgms/ microgms/ microgms/
microgms/ microgms/
EXPOSURE LIMIT m3 m3 m3
m3 m3
OCCUPATIONAL
OEB 1 OEB 2 OEB 3 OEB 4 OEB 5
EXPOSURE BAND

WHEN & HOW MUCH?
CONTAINMENT STRATEGY (PART OF CONCEPT DESIGN)
 With the batch size analysis & the OEL(s)

 Process flow diagram – identify exposure points
 Containment description and strategy
 Process cartoon (like story-boarding a movie or play)
 Isolator requirement
 Risk analysis
 Equipment list
 User Requirement Specifications (URSs)

WHEN & HOW MUCH?
CONTAINMENT DESCRIPTION
Exposure Point
with reference
Number
Isolator
to PFD
Potential Exposure
Process Description Resolution
Point
Dispensing is carried out in a negatively pressurised isolator, complete with pass box for materials
1 Dispensing of API API weighed for batch processing in and a continuous liner system for bagging materials and waste out and an RTP for material
transfer option to the next step in the process.
Monitoring
Operation Sampling Cleaning Waste Maintenance
Isolator washed with a spray hose and

for materials Operation carried out in Samples bagged out Waste bagged out Isolator and equipment rinsed and decontaminated
base free draining to mobile waste water
isolator therefore powder through the continuous through the first. Safe change filters, push push or bag in bag
decontamination tank that is moved to the
contained at source. liner or RTP port. continuous liner. out.
wash room for discharge.

WHEN & HOW MUCH?
RISK ANALYSIS
 ICH Q 9 using the FMEA methodology for risk ranking and prioritising
 Risks assigned risk numbers
Risk/Numbers 1 2 3 4 5
Severity Insignificant Minor Moderate Major Catastrophic
Probability Rare Unlikely Possible Likely Almost certain

Almost never Rarely Sometimes Repeatedly Always
Detectability
overlooked overlooked overlooked overlooked overlooked
 Risk Priority Number (RPN) = Severity x Probability x Detectability

 Classification of RPN defined as Risk
Low Medium High
Class
RPN 1 - 24 25 - 57 60 - 125

CONTAINMENT STRATEGY (SUMMARY)
 API - OEL
 Batch size & quantities

 Process design and identification of exposure points;
 With the OEL & the nature, quantity & time of handling then a risk analysis can be carried out on
every stage in the process (operation / cleaning / maintenance) for all potential exposure points.
 Containment equipment and techniques;
 Operation  Cleaning  Maintenance
 Sampling  Waste
 Training
 Occupational hygiene (the anticipation, recognition, evaluation, control and prevention of
hazards from work that may result in injury, illness, or affect the well being of workers).
 Validation impact
 Best equipment for the job
CONCEPT DESIGN
WITH CONTAINMENT
STRATEGY =  Best factory for the job
 Value for money – neither over nor under-specified

ISOLATOR DEFINITION

USE AND OBJECTIVE

HISTORY & APPLICATIONS

CHOICE OF STERILE PROCESSING TECHNOLOGY
OPEN RABS
 Unidirectional air to provide Grade A
 Surrounding room Grade B
 Disinfection of all interior surfaces before start of production
 Consider procedure
 Door opening a significant event
 Following door opening - Line clearance vs. disinfection
 Consider quality reason for RABS
 No automated disinfection thus simpler to validate
 Significant improvement to existing conventional facility

CHOICE OF STERILE PROCESSING TECHNOLOGY
ISOLATOR (CLOSED RABS)

 Unidirectional air to provide Grade A
 Surrounding room Grade C
 Disinfection of all interior surfaces automated
 Consider procedure
 New validation methods
 Extensive training
 New SOPs
 Consider quality reason for Isolators
 Significant improvement in sterility assurance to existing conventional facility and
open RABS

HISTORY & APPLICATIONS

THE ISOLATOR

THE ISOLATOR

THE ISOLATOR
VENTILATION & FILTRATION
 With air handling system air entering and leaving HEPA filtered.
 Arrangement and type of fans, filters and control system determines
pressure, air changes and classification.
 Turbulent air flow may be from c20+ air changes per hour.
 Unidirectional air flow with a velocity of 0.45m/s in the chamber gives
an air change rate of over 1,000 per hour.
 Negative Isolator typical pressure -40 to -150Pa.
 Positive Isolator typical pressure +40 to +80Pa.
 Provide very good quality clean environments – no human
contamination.
 Containment breach system.
 Bio-decontamination systems e.g. Vaporised Hydrogen Peroxide for
validated bio-decontamination.
THE ISOLATOR
MANIPULATION/ACCESS DEVICES
 Human access to isolators through remote manipulators, robots,
glove ports, half or full suits.
 Gloves and gauntlets preferred & most common way of gaining

access to the materials to be manipulated inside the isolator.
 Most critical components of the isolator being the most vulnerable

components, prone to wear and leakage and require special
consideration.
 Position determined by ergonomics.

THE ISOLATOR
GLOVES & GAUNTLETS – THE WEAK LINK
 Choice critical for durability / comfort / dexterity /

sensitivity / impermeability & resistance / clean ability /
cost.

THE ISOLATOR
 Contain hands – hands can be highly contaminated/susceptible to
toxic materials, also hands sweat - always wear inner gloves.
 Come into close proximity with the process.
 Vulnerable – thin/prone to wear and tear/prone to physical/chemical

damage & when changing.
 Studies have shown that cytotoxic solutions pass through all glove
materials given time thus gloves should be changed regularly as
matter of course do not wait for a failure.
 Allow operator to lift about 5Kg over a radius of about 500mm.

THE ISOLATOR
 Training in glove use critical.
 Leaks difficult to detect, glove testing essential. All leak detection

methods show limitations.
 Visual inspection by trained operators, pressure test and routine

changing.
 Most gloves produced by dipping hand-shaped formers into a

liquefied material so note that thickness will vary on the glove when
inspecting for defects. Critical points are finger tips, the spaces
between fingers and at the connection to the glove port.

THE ISOLATOR
HALF SUITS – FOR GREATER LIFTING & REACHING
ABILITY
 Reach to 1200mm lifting up to 15Kg.
 Work from standing position or with stool.
 Breathing air supply – never enter when air off, leave if air fails.
 Never enter during gas sanitisation and run for at least 30 minutes
before entering after gassing cycle as gas can diffuse through the
suit material depending on the gassing time.
 Kept on support rings in isolator for gassing, storage and ease of
entry.
 Inspection, and leak detection important.

THE ISOLATOR
TRANSFER DEVICES
 Used for the transfer of materials into and out of isolators and
between isolators without the transfer of unwanted contamination.
Each application has its own particular requirements but must fully
achieve their objective of product or operator protection or both.
 A variety of equipment can be integrated with or linked to an isolator

for the transfer of components and product. E.g. Sterilising tunnels,
autoclaves, ovens.
 Air locks, conveyors and pass through hatches are also used.
 Major differences with traditional processes are the use of Bagging

Systems, RTPs and Split Butterfly Valves .
THE ISOLATOR
TRANSFER DEVICES – BAGGING SYSTEMS
 Bag ports
 Continuous liner
 Loading - Keg loading
 Unloading – Keg Pack off
 Bag in bag out systems
 Waste
 Maintenance
 Transfer

THE ISOLATOR
TRANSFER DEVICES – BAG TIE TECHNIQUE
1. Carefully bunch the bag together.
2. Twist to form a sausage.
3. Tape the twist.
4. Apply two ties close together and tighten.
5. Cut the bag between the two ties.
6. The bag is cut and can be taken to the next step in the process.

THE ISOLATOR
TRANSFER DEVICES
 Rapid Transfer Port – RTP
 Split Butterfly Valve

WHEN & HOW MUCH?
OCCUPATIONAL EXPOSURE BAND
TECHNOLOGY
OEB 1 OEB 2 OEB 3 OEB 4 OEB 5
Isolators
Protective Liner Systems
SBV with RIP
SBV with Extraction
SBV
RTP
Bag Tie Technique
Downflow Booth
IBC with Butterfly Valve
LEV
10,000 to 1,000 to
100 to 10 10 to 1 1 to 0.01 SBV – SPLIT BUTTERFLY VALVE
OCCUPATIONAL 1000 100
RIP – RINSE IN PLACE
microgms/ microgms/ microgms/
EXPOSURE LIMIT microgms/ microgms/ RTP – RAPID TRANSFER PORT
m3 m3 m3
m3 m3 LEV – LOCAL EXHAUST VENTILATION
WHEN & HOW MUCH?
AVAILABLE CONTAINMENT TECHNOLOGIES
 0.01 µg/m3 - Isolator/Barrier Containment

 20 µg/m3 - Down Flow Booth
 1,000 µg/m3 - Local Exhaust Hood
 Rapid Transfer Port or Alpha/Beta Port (down to <1 µg/m3).
 Split butterfly valve (down to <1 µg/m3).
 ‘Bag Tie’ Technique (100 to <1 µg/m3). Operator performance critical.

 Pass Through Chambers / Air locks for materials in (down to 1 µg/m3).
Operator performance critical.
THE ISOLATOR

AN INTRODUCTION TO CONTAINMENT TECHNOLOGY

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ENGINEERING

A STRUCTURE OR SYSTEM DESIGNED TO ACHIEVE THE

RIECKERMANN Group | 21/09/2018 | Slide 2 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 3 ENGINEERING OPERATIONS

“So far as reasonably practicable, the prevention or adequate control of exposure of

ELIMINATE OPERATOR EXPOSURE

 Use Personal Protective Equipment

USE CONTAINMENT TECHNOLOGY

 Contain API’s at source, prevent escaping into workplace;

 Isolate the product from personnel;

 Protect the product, the operators and the environment;

 Comply with Health Safety & Environment (HSE) legislation;

 Protect against insurance claims.

RIECKERMANN Group | 21/09/2018 | Slide 6 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 7 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 8 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 9 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 11 ENGINEERING OPERATIONS

 With the batch size analysis & the OEL(s)

RIECKERMANN Group | 21/09/2018 | Slide 12 ENGINEERING OPERATIONS

Operation Sampling Cleaning Waste Maintenance

Isolator washed with a spray hose and

RIECKERMANN Group | 21/09/2018 | Slide 13 ENGINEERING OPERATIONS

Severity Insignificant Minor Moderate Major Catastrophic

Probability Rare Unlikely Possible Likely Almost certain

 Risk Priority Number (RPN) = Severity x Probability x Detectability

RIECKERMANN Group | 21/09/2018 | Slide 14 ENGINEERING OPERATIONS

 Batch size & quantities

RIECKERMANN Group | 21/09/2018 | Slide 15 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 16 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 17 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 18 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 19 ENGINEERING OPERATIONS

ISOLATOR (CLOSED RABS)

RIECKERMANN Group | 21/09/2018 | Slide 20 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 21 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 22 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 23 ENGINEERING OPERATIONS

 Gloves and gauntlets preferred & most common way of gaining

 Most critical components of the isolator being the most vulnerable

 Position determined by ergonomics.

RIECKERMANN Group | 21/09/2018 | Slide 25 ENGINEERING OPERATIONS

 Choice critical for durability / comfort / dexterity /

RIECKERMANN Group | 21/09/2018 | Slide 26 ENGINEERING OPERATIONS

 Come into close proximity with the process.

 Vulnerable – thin/prone to wear and tear/prone to physical/chemical

 Allow operator to lift about 5Kg over a radius of about 500mm.

RIECKERMANN Group | 21/09/2018 | Slide 27 ENGINEERING OPERATIONS

 Leaks difficult to detect, glove testing essential. All leak detection

 Visual inspection by trained operators, pressure test and routine

 Most gloves produced by dipping hand-shaped formers into a

RIECKERMANN Group | 21/09/2018 | Slide 28 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 29 ENGINEERING OPERATIONS

 A variety of equipment can be integrated with or linked to an isolator

 Major differences with traditional processes are the use of Bagging

 Loading - Keg loading

 Unloading – Keg Pack off

 Bag in bag out systems

RIECKERMANN Group | 21/09/2018 | Slide 31 ENGINEERING OPERATIONS

RIECKERMANN Group | 21/09/2018 | Slide 32 ENGINEERING OPERATIONS

 Rapid Transfer Port – RTP

 Split Butterfly Valve

RIECKERMANN Group | 21/09/2018 | Slide 33 ENGINEERING OPERATIONS