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User Experiences With Pre-Fabricated

Containment Solutions

Ed HolmesBrian Ward

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• The inspiration for this presentation comes from a Project Manager who was leading a $167 million (1993 era) construction project

• During a lull in engineering design he asked every Engineer to go back and visit the last project that they worked on

• He encouraged the Engineers to talk to the site Engineers/Process Chemists/R & D Chemists and most important the operators

• Find out what the site had to fix after they left the project

• What a radical concept!

• I hope that what Ed and I present will help you to avoid some of the learning that we had to go through the hard way

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What We Plan To Deliver:• 1) Share experiences encountered during

application of containment solutions from conception, design, prototype, testing, and final reduction to practice.

• 2) Illustrate the roles/responsibilities of the practitioner, the designer, the vendor, and the continued support during installation and operation.

• 3) Share critical learning points and their outcomes.

• 4) Show opportunities for partnerships with suppliers and industry peers.

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•We will be presenting experiences gained using:

•1) Rigid containment, e.g. Gloveboxes

•2) Airflow balanced containment, e.g. Downflow Booths, Benchtop enclosures, and Restricted Access Barriers (RAB’s)

•3) Flexible Barriers

•4) Hybrid Systems, e.g. Half Suit Isolator

•&

•5) An engineering performance measuring technique for instantaneous evaluations

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•The legacy that we inherit:

•Historically traditional containment comes from 60+ years of learning in the nuclear industry

•Expertise - sadly only gained from the school of hard knocks, i.e. experience

•Personally I’ve made more mistakes than most people wish to encounter - but stayed around long enough to either resolve or solve the problems

•The product value or hazard in other containment using industries is the primary driver, e.g. in the semi-conductor chip industry containment is primarily for quality purposes because the product value is comparable with Pharmaceuticals, while in the lithium battery industry it is used to maintain the argon atmosphere surrounding the raw material

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•When you deal with:

•1) Conventional Architectural & Engineering providers

•2) Vendor consultants,

• or

•3) An independent subject matter expert

•you need to be assured that they have extensive hands-on experience with containment in the Pharmaceutical Industry

•Even more important is their experience in dealing with challenges in the specific application, e.g. bulk, dispensing, parenteral & sterile, tabletting, biotechnology, or R & D from laboratory through bench scale studies to pilot plant scale

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• Let me start off with a perspective:

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• 2011 has been the declared:

• THE INTERNATIONAL YEAR OF CHEMISTRY

• as I’m sure you are all aware!

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• In deference to our chemists, allow me to give you just a little education:

• In 2009, the International Union for Pure and Applied Chemistry (IUPAC) changed the value of a long established physical value namely:

• Avogadro’s Number - the number of molecules in a gram mole

• This was a long overdue recognition of the fact that the basic reference for atomic weights has been changed progressively from Hydrogen, to Carbon 14, and most recently to Oxygen 16 all of which have different atomic weight relationships

• The change was from 6.023 X 1023 to 6.022 X 1023

• This may not seem a significant change: 1 X 1026 represents a decrease of >0.000166molecules/g moles

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The change in value represents an equivalent change of 0.3g in 200g of a product having a molecular weight of 200, and with a detection

limit of ng/sample you can see that the change is well within our actual sampling and analysis

range

• Current performance measurements using standard Occupational Health sampling and measurement techniques for equipment qualification are <2ng/m3

for conventional test agents - which is orders of magnitude more sensitive than this change

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• Learning gained on the source of MATERIAL LEAKAGE OR MIGRATION - A Half Suit Isolator used for seeding a reactor

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• During testing from when the operator entered the half suit to completing the operation and exiting the suit (15 - 25 minutes) he experienced a material exposure level >10 times the permissible short term ceiling level

• The suit was cleaned and measurements repeated with the same result!

• Conclusion - the suit is leaking

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• After changing the suit twice more the same results were observed

• Conclusion - a leaking seal between the suit and the enclosure

• But measurements taken inside the suit after the operation and during the internal purge of the enclosure (24 hours) were significantly lower than the operator measurements

• What’s happening?

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• It wasn’t until facility wide monitoring was carried out using long term (8 hour) simultaneous air sampling that the answer became obvious

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• Sampling results showed that material was migrating from the Ground Floor processing room, throughout the passageways and stairways to the third floor seeding room

• The operator was carrying contaminants on his person from one process to another and contaminating the entire processing suite

• But how could this happen when the operator is fully garbed in a standard air supplied full containment suit during operations in the processing room?

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• The problem was in the floor plan layout of the Filter/Dryer room

• After completing open sampling of the filter/dryer the operator entered the shower and performed a suit decontamination, then walked across the room before doffing the suit

• While doffing and disposing of the suit, the operator contacted the newly contaminated exterior of the suit

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Ground Floor Processing Room- Filter/Drying with Sample Collection

• Processing room layout

∆P= 0.6 in w.g.

∆P= 0.2 in w.g.

∆P= 0.2 in w.g.

DeconShower

Zwag Filter/Dryer

Gown/Degown

WasteDrum

Access HallwayReference Pressure

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• Solutions:

• 1) install a sampling glovebag enclosing the sampling manway

• 2) relocate the shower to the exit adjoining the doffing airlock

• 3) reverse the pressurization to negative inside the room

• 4) share the information with the operators

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Processing Room after Modification

DeconShower

Zwag Filter/Dryer

Reference Pressure Access Hallway

∆P= -0.8 in w.g.

∆P= -0.5 in w.g.

∆P= -0.2 in w.g.WasteDrum

SamplinSampling g

glovebaglovebag g

attached attached to to

manwaymanway

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This may seem a simple case but it is one that is still being repeated: • Have you ever had a piece of equipment

fail when using the SMEPAC/ISPE test protocol?

• The most common cause of failure (>$25,000/test cycle) is contamination due to the operator

• Unless great care is taken in the performance of the test the operator can be the dirtiest item in the test enclosure contributing to the ‘failure’ of the containment equipment

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Learning gained due to the PRESSURE VARIABLES

present during bulk manufacturing

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Glovebox Set-up for Testing

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Mid 1990’s Statistical Sampling Approach

Vacuum Vacuum sampling sampling manifoldmanifold

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Situation 1:

Sample locations

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Simulation Outcome:• A bulk material packaging study using a bag-over-bag procedure in the lower enclosure for connecting the final package

• The entire system was initially at ambient pressure, i.e. no stress due to pressure differentials

• With almost no material transferred from the overhead ‘hopper’, the neck of the bulk package released from the connection allowing the test powder to fill the lower box

• This was a simulation of a planned procedure without undue stress due to the pressure differenceCatastrophe

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Situation 2:• In 1993 a Glovebox vendor proposed two

Gloveboxes at >$75,000 each to accommodate:

• 1) Collection of bulk seed material from a Filter/Dryer

• 2) Dispensing of seed crystals into a Reactor

• Careful assessment allowed a single multi-purpose Glovebox ($80,000) to accommodate both tasks and minimize material transfer for dispensing and repackaging

• The Glovebox operation was to be conducted at reduced internal pressure 30

• During a seed charge the garbed operator was working at the Glovebox while another operator was positioned at the reactor manway. Vessel vacuum was applied to the seed source to facilitate material transfer (trapped vacuum transfer) from the Glovebox to enable both seed transfer and the solvent wash used to recover residual seed crystals

• The initial seed transfer proceeded without incident

• When the operator at the Glovebox opened the solvent valve inside the enclosure...........................

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• 1) The relief valve on the top of the Glovebox BLEW OPEN allowing an instantaneous powder release which snowed down throughout the entire room

• 2) The Glovebox condition immediately stabilized

• 3) The blower motor which was set to ramp up speed in the event of a pressure change to maintain negative pressure NEVER CHANGED SPEED

• 4) The pressure surge, and release, was of such short duration that the control system integration time DID NOT SENSE THE EXCURSION AS AN EVENT

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LESSON LEARNED:•In a dynamic process where processing conditions can change rapidly such as:

•1) vacuum transfer

•2) opening a manway

•3) lack of vigilance on the part of the operator

Reliance on Glovebox pressure controls can

lead you into a false sense of security

So let’s compound the situation........

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Situation 3:• A new building with 12+ 1 spare Gloveboxes was

completed and initial PQ runs planned using bulk surrogate materials

• The Gloveboxes were made in the US but much of the control hardware came from Europe

• Two weeks before the first solvent ticket trial the system was in shake-down mode when someone realized that the blowers for the Glovebox negative pressure control system were not operational

• The power transformers for the blowers had not been ordered!

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• Hurry up and get the transformers here!

• But the blowers are from Germany!

• The requirement is single phase 240 volt!

• Unavailable in the US!

• Delivery time 9 months if even expedited with money!

Disaster?

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Let’s think about this!• 1) We are planning to charge ~350Kg of bulk material from an overhead rigid or flexible Intermediate Bulk Container (IBC)

• 2) We will be delivering the charge into a Reactor connected to the site vent system running under negative pressure

• 3) After connecting the IBC to the Glovebox transfer port, the delivery point from the IBC will be connected to the Glovebox discharge to the Reactor

• 4) The connection within the glovebox will be secured using a flexible thin (20 mil) transfer chute

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• 5) The transfer chute will experience negative pressure due to the Reactor Vent System

• 6) and........ the stress due to ~350 Kg of material from the overhead charge

• 7) and........ now we are going to exert a negative controlled vacuum inside the Glovebox

• 8) and........ the flexible polyethylene chute is the only barrier between the internal pressure(s) due to the process and the control pressure inside the GloveboxHaven’t we been there before?

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Somethings wrong with this picture!

• But this cannot be avoided!

• The variables can however be minimized if we allow the Glovebox to act ballistically

• Replace the blowers with high performance HEPA filters at the air supply and exhaust vents

• Let the Glovebox pressure equalize passively when under stress

Engineering 101 - never allow three different pressures

to meet at a single point!!!!!!!!!!!

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The outcome is:• 1) Reduced pressure stress inside the Glovebox which

in turn is not attempting to forcibly ‘suck’ the flexible transfer chute into the open-flow condition

• 2) HEPA filters function better when subjected to low airflow conditions when they act more as brownian diffusion collectors (aka. mist eliminators) to capture the sub-micron (<0.2 μm particle diameter) which normally pass through conventional HEPA’s with

>95% efficiency - but cannot be validated so call

them diffusional barriers• 3) This system has been in use for both charging and

packaging for over 13 years of production without incident due to the Glovebox operating condition

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Situation 4:• There was a potential and one serious disconnects several years

after start-up:

• 1) Enough operational time had passed that experienced building operators had moved on to new assignments leaving the building with third generation operations staff without dedicated containment oversight

• The safety personnel decided that the systems had been in operation without review by the vendor

• A vendor audit found that the Glovebox blower system was inoperative, and recommended that be remedied - SOP!

• Fortunately an experienced operator was visiting the building when plans were being made to retrofit the Gloveboxes and was able to influence the decision

• 2) Without consulting a design team member or design records (the archives), the building engineers designed around two separate operating departments sharing a common vent system with disastrous consequence

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Learning point from these experiences -among many others:

• Building design and operational decisions should be kept in an archive in the building and not on a vendors computer server which is subject to major software changes with time

• Design records should be reviewed before any operational changes are made

• Qualify your ‘expert’ resources to be sure that their experience is in a familiar operating environment

• Try to ensure that your ‘subject matter expert’ will be available to the facility throughout the entire start-up and operational mode.....and as far beyond that as possible with a succession plan in place

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Situation 5:

• So if the Glovebox didn’t fail, how and why did this packaging system vent material?

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Engineering Group had acquired 4 identical research grade particle monitoring instruments which were exercised for the first time in the packaging room - 3 located in the room and one in the hallway as a control reference

• While sampling packaging of the fourth production lot the particle count for the sample taken at the exhaust air intake showed a sudden increase in particle count

• The operation was immediately terminated and personnel evacuated from the process room

• The particle count rapidly decreased to pre-

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• The feather edged gasket seals on the Glovebox rapid transfer port were the immediate suspect because α-β flanges are notorious for failing when used for powder transfer control

• The operators garbed up and re-entered the room and examined the seals

• No visual damage was apparent but the α-β flange gaskets were lightly lubricated and returned to service as a precautionary measure

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• The actual cause was not identified until conventional airborne particulate sample data was received from the laboratory

• During the study a standard cassette sample had been located at the top bearing of the screw drive transporting the finely divided product up the flight tube from the loss-in-weight hopper, which discharged into the Glovebox for final packaging

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Packaging Room Layout

Room Size: 9m x 9m x 7m20 Air changes/hr

Packaging Packaging GloveboxGlovebox

Loss in weight Loss in weight hopperhopper

Screw Screw FeederFeederMaterial

pass-through

People pass-

through

Decon Decon showershower

Exhaust air Exhaust air intakeintake

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Packaging Delivery system

• Line drawing of the loss in weight hopper, screw feeder, and packaging Glovebox attached through the HEPA system to the vent system

Screw Feeder

Loss-in-

weight hopper

Packaging glovebox

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• On this particular evening it was getting rather late

• The engineer was still doing some system shake-down so he was controlling the material flow out of the cone dryer into the loss-in-weight hopper

• As the time approached 11 pm (10:42 pm), he was becoming anxious because he had an early morning engagement

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The outcome was:• He fed material into the hopper to a higher level than

normal

• Under normal operation the product flowed past the flukes of the screw feeder, consequently the speed of the motor drive was ramped up to overcome backflow of product

• In this case the hopper was filled above the height of the top bearing of the screw feeder

• The product flowed like water up the flight tube and out through the small leak path provided by the top bearing

• When the packaging operation resumed the product in the hopper had already been dispensed and the release minimized

• The long term retrofit was to enclose the top bearing in a flexible enclosure vented through a small HEPA filter

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These issues all relate to bulk processing where dynamic operating conditions are frequently encountered

• When the loss-in-weight equipment vendor was later consulted they explained that they would never recommend this mechanical train for such an operation

• Were the engineers at the A & E firm in a position to know this, or did their subject matter experts just follow ‘normal’ practice?

• As you can see the learning was a continuous progression of incidents that were outside the realm of conventional daily operations experienced in the traditional experience base -the Nuclear Industry

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• Unfortunately the engineers from the A & E firm were not involved in the actual start-up and operational trials beyond Operational Qualification so their learning was not cumulative

• Whether the equipment vendor was aware of the project is uncertain, but they certainly weren’t in a position to learn from the experience until >8 years later

• This is not unique to Pharmaceutical bulk material manufacturing because parenteral (positive pressure) and clean environment operations such as dispensing, formulation and tabletting all have their nuances

• Unlike the Nuclear Industry, the Pharmaceutical Industry does not operate on a 40 year disposable basis, but rather on rapid turnaround which is becoming ever more critical in the wake of multiple product batch operations

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• These events have served to strengthen my belief that experienced practitioners are your lifeline because of their breadth of knowledge and learning under fire!

Select your practitioner with care!

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Beginning our foray into airflow balanced containment:•Venturing into the laboratory -

•During comparative testing (1997) of a variety of laboratory scale containment devices the following approach was taken:

•The airflow dependent containment systems - laboratory hoods and open front enclosures were all performance qualified according to vendor and ASHRAE criteria

•ASHRAE testing was conducted by an independent qualified consultant

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• A particle generation system was assembled to provide a 4 mg/m3 airflow feed of ≤3μm diameter lactose particles at a feed rate of 8 liters/min for a 30 minute duration study

• The generator was enclosed in a Glovebag located adjacent to the device under test

• The lactose was dispersed into the test enclosure using a particle effuser modeled after the standard SF6 diffuser - which during these studies demonstrated that the diffuser &/or effuser does not behave like a boiling beaker as conceived for the standard ASHRAE test procedure

• Sampling followed the same strategy for each device

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Sampling Array at a Flow Booth

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≤3μm Particle Generator

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Particle Effuser in Flow Hood

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Particle Effuser Operating in the Biological Safety Cabinet

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• All of the devices (2 different Lab Hoods, 2 Flow Hoods and a Biological Safety Hood, a Glovebox, and a Glovebag) exceeded our expectations on control of particulate release based on both quantitative analysis (quantitation limit <10ng/m3 based on a 30 minute sample) and particle count

However the story doesn’t end there.......

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Deposition inside Face of Flow Booth

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Deposition with Manufacturer Recommended Aerofoil

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Deposition with Manufacturer Recommended Aerofoil

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Deposition on face of Second Flow Hood

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What are the issues:• 1) While the flow hoods exhibit no release outside the enclosure they all experience particle transport across the working zone immediately in front of the personnel

• 2) Throughout testing the mannequin was static, unlike laboratory personnel whose hands and arms are in motion across the particle deposition area

• 3) The apparent particle focussing in the flow hoods was traced to the cut-outs in the side of the test enclosure which are provided for power and data cable entry

TRAIN PERSONNEL TO KEEP OBSTRUCTIONS OUT OF THE ENCLOSURES AND TO WEAR DISPOSABLE SLEEVES WHEN WORKING INSIDE THE ENCLOSURES

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• Moving on to performance engineering measurement and balanced air control systems:

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• How can you measure the performance of a containment device or system?

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Occupational Exposure Measurements:• All are average measures of the particulate challenge over the sampling period

• All are subject to laboratory method sensitivity

• All personal samples are a measure of only an individuals challenge concentration

• Area samples are not a measure of the personal challenge

• Most are subject to some size selectivity, i.e. non-isokinetic

• IOM samplers do not ‘vacuum’ the air around them like regular closed face cassettes

• None are spontaneous measures of change

• Conventional personal and area samples form the basis of the SMEPAC/ISPE equipment performance evaluation

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Real Time Measurements:

• Particle counters use light scattering to count particle transit

• Not all instruments have the same sensitivity

• Careful instrument selection can give you the answer you want, i.e. conservative readings for compliance purposes, or ultra sensitive readings for diagnostic measurements

• Samples are averaged over a usable range of 40 seconds or more to minimize instrument noise artifacts

• Typical airflow is at 1 ACFM and quality instruments use an inlet size of 37 - 39 mm resulting in an effective inlet flow of ~90 linear ft/min, comparable with the IOM sampler (~95 linear ft/min) to minimize isokinetic artifacts

• Non-research instruments measure particles down to 0.3μm diameter (spherical equivalent), while research instruments can measure particles down to 0.15μm diameter over a 5 minute sample

• 0.15μm diameter is the physical limit. Anything smaller is less than the wavelength of visible light

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Particle Counting:• BENEFITS:• Understood in its basic form

• Incredibly sensitive - without need for laboratory analysis (and feedback delay)

• Almost instantaneous readout - every 40 seconds

• Measures change in particle challenge

• CONCERNS:• Cost of the instrument, i.e. payback time (the typical ~$100 cost

of a single conventional sample with assay approximates to ~50 particle count readings based on instrument cost and labor)

• Cannot provide Occupational Exposure data

• Conversion of data to mass equivalents is very empirical (±500% at best) and must be used with extreme caution

• Needs skill in interpretation

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APPLICATIONS:• Primary, secondary, R & D, equipment development, dispensing, and any applications where material handling and transfer are involved

• Diagnostic phases of OQ and PQ before formal documentation becomes necessary

• Performance of Airlocks, Pass-throughs, annexes and hallways, and entire facility monitoring

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• The plant was located in Ireland

• 16 sample points were located throughout a new building, primarily in areas deemed sensitive to particulate releases

• 3 ‘control locations’ were sampled routinely to observe normal background changes

• One of the control points was located in the Utilities room and rendered worthless because of a continuous spread of emissions of sub-micron particle throughout the room due to the ‘industry standard’ of black iron Steam and Ethylene Glycol fittings

A long standing question whether particle counters ‘see’ water

droplets was answered during the shake-down of a facility wide

FMS (particulate Fingerprint Monitoring System)

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• A progressive increase in background counts was noted in the 0.3 - 0.5 μm particle range at every sample location even though no open processing was occurring

• Between 2pm and 3pm the counts increased with each 40 sec. sample until the total particle count finally overwhelmed the counting capability of the instrument (1,000,000 events/second)

• In spite of this there was no visible haze in the facility

Data logging of the succession of measurements from each

randomized sample point was being observed on a

pleasant fall day.

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• 1) Be extremely careful when interpreting particle count measurements because any minor, i.e. unobservable, fugitive emission from any random source such as utility piping fittings, can lead to erroneous conclusions

• 2) The obvious marker is that the counts/min will steadily increase rather than displaying the surge and recovery due to processing emissions

• 3) Do not attempt to install a full scale FMS system in a building with no air conditioning

LEARNING POINTS:

But at ~5pm a light sea-fog rolled in, increasing to a

heavy fog overnight

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DEL (Design Exposure Limit)

•Ed Holmes•Central HSE•Industrial Hygiene

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Central Position- acceptability

• Chemical exposures–The concept of the OEL is what defines and is

used as acceptable exposure to chemicals–An OEL is a maximum exposure, averaged over

an 8-hour day, at which it is believed the majority of workers can be exposed, day after day, for a working lifetime without significant effects on their health

• We are obliged to stay below the OEL in order to be at acceptable exposure levels

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Principles of protection

• Working Practices (and Procedures)

• “Hardware” (ECM)–Local Exhaust Ventilation–Containment–Isolation

PerformanceProcedures

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The value of the OEB

• OEB: is an invention of the pharma industry–Applies to pharmaceuticals (“white” dust)–Groups or bands of similar OEL values –We use 5 bands (others?)–Communication tool

• Equipment suppliers: “on the bandwagon”–Adoption of band concept–Easy “marketing” tool – no science

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DEL Basics

• Definition of what we need – OUR business• Equipment suppliers – supply what we need

–DEL concept – a target for suppliers• Basic principle – 1/3rd of the OEL

[Widely used and accepted; takes account of natural variability]

–Valid for:Pure APIs8-hour (working day) exposures

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Example 1 - API

• We need to specify an inline milling operation in Aramon to finish Product A.

• task needs one day, Product A with OEL: 95ug/m3

• DEL = 1/3 x 95, = 32 i.e. 30ug/m3

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Example 1 -API

• DEL = 1/3 x 95, ie 30ug/m3

• Would the same installation be suitable for–Product B?

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DEL Basics

• Basic principle – 1/3rd of the OEL–Valid for:

Pure APIs8-hour (working day) exposures

• Mathematical manipulation for:–Pharmaceutical formulations–Combinations of APIs–Shorter-term exposures–Multiple exposures

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Example 2 – Tabletting

• We need to specify a tabletting machine for making Product C tablets in Karachi

• Task duration (all) day, Product C 8-hr OEL: 10ug/m3

• [There are 3 different formulations in Karachi, with, respectively, 25, 37 and 50% active]

• Use worst case (highest conc), = 50%*• DEL = 1/3 x 10 x 100/50*, ie 7ug/m3

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Exposure “pictures”

A “day’s” exposure is a cumulative total of the individual task exposures, averaged over the whole day

COMPLIANCE with the OEL is managed by monitoring exposure over 8 hours – accuracy is CRITICAL

CONTROL of exposure is managed by knowledge of the relative sizes of the peaks (task-related). Accuracy is much less important

For this reason, a knowledge of BOTH is vital!

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Exposure “picture”

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Example 3 – Dispensing

• We need to dispense 10kg of Product D in Laval

• teriflunamide 8-hr OEL: 3ug/m3• Task duration 15-20 minutes• Can use derived STEL, 3x TWA = 9ug/3• DEL = 1 or 3ug/m3 depending on OEL used…

• BUT…

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Example 3 – Dispensing

• BUT

we have assumed NO FURTHER exposure in the day–In the image shown, dispensing*– adds ~8% of the day’s total exposure–Therefore a DEL for the dispensing operation in

the process depicted = 8% of 3 ie 0.24ug/m3

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DEL Conclusions

• DEL is a theoretical exposure “target”which can be calculated

• In-house info for URS supplier • Knowledge of task-related timing and

frequencies essential • May often need IH specialist

knowledge

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Containment - cannot use OEBs to predict controls

• Misunderstanding/ misuse of the role of OEB

• Attempts to control “hazard”• Ignores “risk”, and its assessment• Prescriptive, “one size fits all”• Inappropriate technology• High cost, limited comprehension

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For the same OEBLow

containment Scale DustinessProcess Energy

API content

Tonne

Kilogramme

Gramme Coated tablets

Tablets

Wet Cake

Granules

Powders

Micronised

Weighing/ Dispensing

Charging/ discharging

Milling/ sieving

1%

10%

100%

Increasedcontainment 98

Containment - preliminary thoughts• OEB 4/5 (HAPs) may be achievable using moderate or

readily available control technologies, especially when using small quantities (eg R&D)

•• Control technologies can be incorporated into general

guidelines but further work is always necessary on the detail

• Does not remove the need for specialist support

• Need to (greatly) improve training and communication of control technologies across the businesses

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Containment - the ECM approach1. Proposal

• Create categorised matrix for controls• Introduce ECM-A to ECM-C and terminology• Clarify application of risk assessment to select

ECM• Clarify that matrix can be used for lab, pilot plant

and manufacturing• Improve communication and understanding of

ECM: - ECM does not equal OEB• Improve use of specialist support

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Containment - the ECM approach2. Basics

• Engineering Control Measures/ Expositions Collectivement Maitrisees = ECM

• 3 recognisable categories of control, A, B, and C

• Technologies fitted into the categories, BUT continuum concept

• No linear link between OEB and control technology

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Control MatrixR

isk

Ass

essm

ent:

eg. P

roce

ss, S

cale

,Pe

rcen

tage

Act

ive,

Dus

tines

s of

Mat

eria

l OEB 1

OEB 2

OEB 3

OEB 4

OEB 5

>1000-5000

>100-1000

>10-100

>1-10

</=1

µg/m3

Eng

inee

ring

& a

dmin

istra

tive

Per

form

ance

spe

cific

atio

n

Actual performance depends critically on behaviour

Per

form

ance

cap

abili

ty

Room Ventilation

Local Extract

Partial/Enclosure

Hightech

Isolation/

L

H

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Containment – The use of OEBs

• OEBs used for GENERAL guidance• Very simple and ignores reality• Unscrupulous marketing• IH expertise

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Containment - the ECM approachBroad Classifications

• ECM-A Traditional: General ventilation/HVAC and Extraction - LEVs, Vac transfer, simple downflow booths, bin systems

• ECM-B Advanced: Partial / Enclosure - M/C enclosures, in-line transfers, glovebags and boxes, fume and dust control cupboards, contained dust collection, bi-bo

• ECM-C Sophisticated: Isolation / High-Tech. - multi-chamber isolators, Remotes and robotics, Absolute dedusting systems 103 104

The ECM conceptLow

containment Time CategoryReduction

Factor Cost

Days

Hours

Minutes A

B

C

10s

100s

1000s100%

Increasedcontainment

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Our products

• What do we make?• HOW do we make them?

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Tablet manufacture in the 1970s

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Product manufacture

• HOW do we make them?• 80s? 90s??• 21st century….

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21st century vision

Closed system

In-line transfers by gravity

No interventions

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ECM- Matrix

• ECM-A Traditional: • General ventilation/HVAC and Extraction

–simple downflow booths, – vac transfer, – LEVs,– bin systems (IBCs)…

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Introduction

• The downflow booth is an important, maybe a critical feature of our industry.

• Designed to protect product, and reduce or prevent operator exposure to powders .

• Good ones do both, essential design features

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Introduction

• The Problem…• … is that we have a great

number of such installations which do not appear to work (properly)

• Background: –Downward laminar flow–Interpretation reg. Q demands–Home-grown solutions

Wh t’ ith DIY?

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Objectives• To establish the magnitude and scope of the

problem–Audit and inspection

• To raise awareness amongst users and sites – targets

• To begin implementation of an effective training programme

• To prioritise and initiate a programme of remediation

• To control exposure, and protect workers’health

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FOUR types

• There are four basic types of such installations

• They work in different ways

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Four types – type 2 (benchtop type)

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Type 3 – horizontal laminar flow

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Type 4 – laminar flow “appliance”

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– Important, type 1, walk-in booth

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High quality type 1 booth

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Important Technical Points

–Air-supply nozzles, or grilles–Filter performance–Velocity–“Safe working” line–Exhaust grilles, or vents

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– schematic, type 1, show tech points

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Downflow booth interior

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“downflow” booths

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Important Behavioural Points

–Obstacles and furniture–Operator(s) positions–Good and bad practices

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Downflow booth checklist

• Original specification/ history• General cleanliness• Filter(s) condition (dial information)• Airflow at vent face• Worker position(s) relative to operating

line and task• Smoke capture at operating line

perimeter

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Conclusions

• A GOOD booth, properly used, will give ~ 50-100ug/m3 (into OEB3).

• Internal features, or a flexible barrier, will improve this, to ~5ug/m3.

• A GENERIC, badly designed or badlyperforming booth may not give

ANY protection at all! 126

LEV – what it is, what it SHOULD be!

• The “vacuum cleaner”concept.

• Air from where?• Enough?• How could we improve?

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Improve the ventilation• Old • New

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FBCs and IBCs

Big-Bags, good for up to OEB2/3

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Bag-over-bag applicationChemistry – API transfer (OEB4)

“Crimp and Cut”

“Shower Cap”

“Bag tricks”129 130

HiCoFlex (Buck) Bags•

High Containment Flexible CouplingHigh Containment Flexible Coupling

Application for Application for ““dust freedust free”” charging charging and discharging (per manufacturer)and discharging (per manufacturer)

Coupling provides a Coupling provides a ““selfself--locking locking and sealing, closing and docking and sealing, closing and docking mechanismmechanism

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An excellent application – OEB4

• Tabletting

• Packaging

• Development….

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ECM Matrix• ECM-B Advanced: • Partial / Enclosure

–M/C enclosures,– in-line transfers, – fume and dust control cupboards,

– glovebags and boxes,– contained dust collection, – bi-bo.

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The third zone concept!

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Three zones and the barrier principle

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Lab scale powder-handling (RABS)

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Flexible isolator (glovebag)

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Flexible isolator applications PSD – packaging (tablets containing

OEB5)

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ECM Matrix

• ECM-C Sophisticated: • Isolation / High-Tech.

–multi-chamber isolators– remotes and robotics – absolute dedusting systems

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Split butterfly

A valve which “breaks” in half

Valve surfaces stay “clean”

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“Single-pot” processing

• MGD• No transfer

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Two-chamber isolator for in-process checks

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Isolator systems

•jetmill

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Jet-mill enclosure

• Can work at 10ng/m3, all day

• 8m height

• 780.000€ (for the isolator)

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Realistic Case StudyYou have been asked to propose “something” for dispensing Product 5, a powerful growth-regulating hormone.

• Define the material(s)• Define the task(s) to be contained• Apply the ECM philosophy

• L-thyroxine is a fine white powder. It has an OEL of 0.2 ug/m3 (8-hr TWA), and thus is an OEB5 material

• The task we are looking at is dispensing the active ingredient for a batch, in this case 1.8kg

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Use the DEL approach

Can we define a DEL for the task?

Maybe. We CAN use the STEL value because dispensing is a short-term task (~ 15 minutes) and only happens once per batch

By convention the STEL is 3x the OEL (so 3x 0.2 =0.6)

Also by convention the DEL is a third of our exposure limit, in this case the STEL/3 (0.6/3 = 0.2) A value for the DEL could be 0.2ug/m3

However, what about if there is further exposure possible during the day?

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Which equipment can reach below the DEL?

• Downflow booth – with curtain and gloves– without?

• Powder control cabinet?

• Fume cupboard

• Glovebox

• Isolator – flexible

– fixed

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Which are feasible?

• At first sight, ALL of them!

• Are they practicable?The answer depends critically on step2, “Define the Task”

• Downflow booths? Size?

• Fume cupboard? Use of air?

• So, we have 4 options left148

How would we choose?*“Fixed” Isolator (100,000€)Costs, ergonomics High protectionMonovalence, “bottleneck” Cleaning?

*Flexible Isolator (1,000€ per batch)“Bottleneck” High ProtectionCleaning Robust? Disposable

Glovebox (20,000€)Cleaning Transfers in/out?

Protection?

*PSC (12,000€)Protection sufficient? Easy to use/ clean

There is no SINGLE answer, here there are (at least) THREE

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Other, “rhetorical” questions• Could we use it for other tasks?• We want to weigh 18kg (rather than 1.8Kg)• Would it be suitable for 2kg of other materials, all

OEB4, every day?

• It depends!• Changes affect exposure potential, and therefore

risk. A risk assessment of the proposed change(s) will better enable a response.

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Technical supports and tools• G.506 to outline the approach

• E-catalogue (ECM e-room)

•Two-chamber lab isolator (130,000€)

•PROs Very high containment (1-5ng)

•CONs Bottleneck, inflexible, ergonomy

•Vitry, Dagenham

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Is it possible to combine technology?

• Yes, in fact sometimes a combination is the best.

• This approach is valuable for multi-purpose or multi-product equipment

• It can eliminate some of the shortcomings of other technologies

• It may be cheaper, 152

Chemical Pilot – OEB4 - use of OEL as a design criterion (the DEL)

Elephant trunk LEV at manholeElephant trunk LEV at manhole

Results of centrifuge unloading Results of centrifuge unloading –– 145 to 624 mcg/m3145 to 624 mcg/m3

Need to get 1mcg/m3 DELNeed to get 1mcg/m3 DEL

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Chemical Pilot – OEB4; application of combined containment techniques

Results: <0.052 mcg/m3; N=3; 15 min.154

What value does this bring?• « Wrong » containment – too much?• « Wrong » containment – not enough?• No containment• Quality considerations• Site-site consistency• Inadvertent or side effects

• It is a key strategic issue for our future.

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Conclusions

• Understand continuum of containment• Understand limitations of OEBs• Understand combinations of technologies• Business integration – decisions• Training/ information • High-tech operators

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Back to Flexible Barriers:• We’ve had the opportunity to work with 4 of the

principal suppliers

• We’ve also had the luxury of making mistakes using the in-house Fabrication Shop which was only available for prototype development -although it paid for itself on a major project in less than 3 months

• Flexible Barriers are frequently viewed as cosmetically less acceptable than rigid containment but convenient for interim purposes - even though they can match rigid containment in execution and performance

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What you do need to understand, especially your Purchasing Agent:

• 1) You don’t get something for nothing! Surprise!

• 2) How you pay for design work is all a matter of the relationship you have with your supplier

• 3) EITHER you pay up front for design work, especially the first prototype and changes

• 4) OR you accept that the supplier ostensibly provides free design work but adds the cost as an increment to every device that you buy ad infinitum - they do have to cover for their design overhead

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•I’ve been involved with vendor R & D projects in one form or another more than anybody else I know since 1993. Along with upper management support

• I’ve probably dedicated >$3.5 million of development costs pursuing Flexible Barrier applications

•I’ve also been partially responsible for the involvement and growth of 3 of the 4 suppliers currently serving the Pharmaceutical Industry in the US

•Am I biased? I use all 4+ forms of containment as appropriate but find Flexible Barriers to be most accommodating, cost effective, and virtually irreplaceable for retrofit purposes where space and access is at a premium, and for batch operations where cleaning would be a major cost factor. Selection of vendors is based on process needs

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So what are the shortcomings of using Flexible Barrier Fabricators?

• 1) You need to be sure of what, and how, you are paying for their service

• 2) The fact that their goods are relatively cheap, i.e. not capitalized items, so there is a major hurdle to convincing management that their use is viable

• 3) Because of their relatively low cost, fabricators would prefer to sell a new barrier than retrofit an existing one

• 4) While this makes sense from a business case it all too often lets the user down

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Let me review some of my issues:

1) I have an inventory of Flexible Barrier items for which I now have a new design. It would be nice to retrofit my stock items where possible, if the cost of double shipping and supplier labor was cost effective. Suppliers do not like to do this -case dependent

• 2) I have a Barrier that is already installed and contaminated and I need to continue work without a loss of production time. Time for teardown, decontamination of the entire workspace, disposal of the old Barrier and used items, order and/or redesign, wait for fabrication & shipping, then reinstall could take up to 6 weeks or more

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• 3) Supplier retrofit of the existing Barrier is incompatible because I can’t send contaminated goods to the supplier

• 4) All of this costs me much loss of production time

• 5) This can be in the thousands of $ for hold time. If this is a critical project holding up clinical trials the cost of lost lead time can be of the order of 10’s of thousands of $

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A real situation that could have been traumatic:• Working in a pilot plant facility in Belgium

• The original request was for a reactor enclosure for manway nozzle charging and sampling for one lot of material

• During the planned processing step management made available more raw material with a request for two more lots immediately

• There was no time to order and have a new enclosure delivered

• The in-house support was 4,000 miles from home base with no readily accessible supplies

• Fortunately the site had ordered Flexible Enclosures for another project

• The expedient solution was to cannibalize the spares by removing sample sleeves and pass-through sleeves

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Glass Reactor Manway Enclosure

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Charging and Sampling Nozzle

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• The outcome was successful preparation of three full lots of usable material within 8 days without decommissioning or loss of containment

• Although two perfectly good Flexible Enclosures were sacrificed, the project was not held up and the overall cost was kept to a minimum in terms of deliverable product

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• A similar project in the US involved enclosing a combination of a walk-in-hood adjacent to a bench hood

• None of the ~40 hoods in the facility was deemed capable for small scale potent compound preparation involving 20 liter glass vessels and a laboratory scale vacuum drying oven

• How to proceed without using third party manufacturing?

• Two enclosure with full floors were installed with an interconnect between the two hoods to allow material transfer

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Walk-in Hood Enclosure with Airlock

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Bench Hood Enclosure With Pass-through and Vacuum Oven Annex

TextText

TextText

Pass-through

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Weighing and Packaging Bench

170

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•A similar circumstance to the Belgium situation - one lot planned but request for 2 more lots immediately

•The enclosures were already contaminated from the first lot synthesis

•Because of an oversight the design was missing access to two critical components: 1) stirrer motor access on the front panel of the walk-in hood 2) access to the purified water valve by the storage doghouse

•Even though the site had ordered and received a back-up enclosure setup, it did not have the desired change (although the supplier did accept and modify the spare enclosure later)

•What to do:

•Shut down operations until a modified enclosure was shipped by the supplier and then decontaminate, etc.

This was unacceptable!

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• Hardware stores are your best resources when in a crisis

• On-line search of a hardware supplier showed that an attachment for connecting a glove sleeve to a fiberglass rigid glovebox was still available - albeit the price had now increased from $115 (1993) to $360 (2007) for a pair of rings

• Full sleeve gloves were also available at much lower cost ($80 for a pair of Hypalon gloves) than conventional suppliers and compatible with the attachment rings

• A pair of these were ordered, delivered, and installed within three days in the existing contaminated enclosure without loss of containment - just after completion of drying and packaging the first lot

Prior experience came in to play:

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• Once the gloves and rings were available it took approximately two hours to install both gloves and resume processing

• The Project was completed without further delay

• Cost of enclosure ~$1,600

• Cost of gloves and rings ~$450 (2006)

• Alternative cost of a single days delay >$4,000 plus lost opportunity

• The improvisation saved much time, minimized decontamination waste and expedited the project

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• Since that time a vendor is now providing a simple clamping system enabling attachment of a sleeve to a flexible film wall

• Alternatively your supplier could provide a supply of glove and bagout sleeves for attachment to the skin of an enclosure as was performed in the Belgian small scale operation

• Similar needs (and opportunities) exist for suppliers to make available other retrofit items for your specific barrier design, e.g. extending airlocks, bag-in bag-out sleeves, coupling ring attachments to extend the use of a barrier without decommissioning, to cite just a few

Vendor opportunities:

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Working away from your home base creates a lot of stress:• The same Belgian facility that I described earlier was under

pressure to show capability to manufacture small lots of potent compound or be furloughed

• The facility was built ca. 1960 and the processing equipment was of a similar age - not designed for containment

• The site was given 5 months warning to produce the first lot of a potent product

• Vendors were invited to present proposals

• One vendor immediately disqualified themselves by proposing that a product delivery pipe be welded onto the existing Filter/Dryer - obviously no comprehension of equipment validation

• One vendor was selected to design, fabricate, and deliver a performance tested filter/dryer

• None of the other containment proposals were acceptable in either time frame, cost or viability

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• The US based in-house containment resources visited the site and designed a complete containment system for the entire dry processing and packaging operation situated on the ground level

• The cost of goods if provided by a US based vendor was ~8,000 Euros along with ~3,000 Euros in-house installation cost

• The site wished to establish a working relationship with a European provider to complete the design, fabricate the completeenclosure, and install the system

• The provider requested an installation date 2 weeks after the contractual commitment, and finally agreed to deliver one week late, but delayed a further 4 days until late on a Thursday before a National Holiday weekend which caused a minor crisis, however the site could still meet delivery commitment assuming that processing went as planned

• The installed cost was 45,000 Euros plus travel costs

• Three pre-fabricated enclosures (with no backup provision) were delivered (with ~250% mark-up) but fabricated by the same US supplier that the US team normally select

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Proposed Enclosure Layout

Deconshower

Robingairlock

Filter/dryer

Dry productpackaging room

Overheadreactor

Reactor Reactor skirtskirt

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The supplier sent two installation technicians to the site

• They had not been shown how to install the enclosure components, nor had they had previous experience with this type of flexible containment

• Their truck contained a large roll of polyethylene film, double sided adhesive carpet tape, a selection of scaffolding components (the spare parts were still back in the shop), and the three packaged pre-fabricated enclosures from the US supplier -none of which had ever been laid out and even less assembled

• They were assured that I would be able to show them how to assemble the system - that I had never seen before

• The scaffolding was to form an internal support which meant thatit would have to be disassembled inside the contaminated enclosure and disposed of into a roll-off after the project was completed

• The pre-fabricated (US) enclosures were a decontamination shower with attached airlock, a skirt to enclose the bottom of the reactor penetrating through the floor above, and a separating wall with a doorway 184

• Stretching roll film and securing over the scaffolding at the entry airlock, installing the shower/airlock, and attaching the reactor skirt took about 14 hours on Saturday

• I was only available for this one day due to their late arrival so the bulk of the installation had to take place before my departure early the next morning

• When attaching the roof of the enclosure to the reactor skirt, Imisjudged the size of the roof cut-out making it too large and leaving a large gap

• The suppliers personnel left for supper with the expectation that the installation would be abandoned, while I paced around trying to find a solution which was simple, i.e. fold the roll film partially back over the hole and re-cut the opening before completing the rest of the enclosure

• After the holiday weekend they returned to complete the installation according to my guidance and the enclosure was up and running two days later allowing the site to deliver product on time and prevent a site closure

• In spite of the sites desire to establish a working relationship with technical staff who had worked on site, the providing Company laid off one of the technicians that I had trained within two weeks of the installation

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Complete Enclosure with Pass-Throughs & Skirt

185 186

Vessel Skirt with seam overlap

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points, but with the additional observations:

• When working at a distance from your principal place of work, e.g. with third party contractors and/or third world country resources, the learning points become even more critical when you don’t have normal resources available

• Keep in mind the 5 P’s: Proper Prior Planning Prevents Poor Performance

• Provider prior experience and qualification is ever more critical when you have no local advice

• Be very judgmental on the overall project cost and know exactly what you are paying for (with or without penalty clauses)

• Have a clear understanding of the providers responsibilities, deliverables, and most important the project due date, and hold them to it

• Make sure that you have a back-up plan for future needs and technical support, also including existing design details. In the present economy the provider may no longer be in business withina couple of years, or providing the complete service and supportthat you need

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• Let me add a 6th P -

• Proper Prior Planning• Possibly• Prevents Poor Performance

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The Quality Organization has been my most recent challenge

• The issue of Materials of Construction has become contentious because of misleading claims by vendors that you must use a specific, single source, certified, flexible film in all material handling operations

• A truly certified product contact film has to undergo the expensive stability performance testing as if it were to be used for long term packaging and warehousing, assuming product contact is critical and more than transitory, i.e. about $½ million in testing over three months for accelerated testing and 2 or 3 years of storage testing.

This is regardless of the film source

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• Most anti-stat additives are volatile and bleed out of the polymer with time creating a reduced shelf life -beware extraneous materials in your product!

• All film polymers can be considered for transitory use, i.e. short term containment inside a flexible barrier, where all product actually adhering to the film becomes waste - the film must only meet local regulatory and processing requirements of conductivity, solvent compatibility, incendivity, etc

• Film materials listed as a Drug Master File (DMF) entry are qualified to some degree as to their applicability and can be selected as appropriate for transitory material handling without further testing

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Maintenance issues:• When properly designed, a process will normally operate without fugitive releases

• So why do we need containment?

• Containment is provided to control emissions during materials transfer, equipment adjustments and maintenance such as line breakages and process turnaround as well as major breakdown and repair

• Effective decontamination of external surfaces is virtually impossible

• Drive equipment, e.g. drive shafts, gearboxes, motor drives, should be kept out of the enclosure whenever possible!!!!!

• The last item should be a cause to challenge your vendors knowledge of our industry

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A Seemingly Impossible Request:

•Situation:•An animal antibiotic blending operation in a third world country was operating in a totally unacceptable manner

Challenge:Provide a low cost barrier solution and eliminate operator sensitization

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• The active material was an animal antibiotic

• The process involved blending and packaging large lot sizes of the antibiotic with animal feed and oil

• At any given time all of the operators were restricted due to allergenic response

• The operators were only conversant in Portuguese

• How to improve the process to eliminate fugitive releases?

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• 1) Dispensing was performed directly from the tote of Active material into the mixer

• 2) Make and break connection during charging/dispensing of all raw materials was achieved using a custom made electropolished connecting canister for all additions

• 3) A US based flexible barrier supplier provided an inventory of spare enclosures for production purposes

• 4) Immediately after charging add the process oil to the blending process - the active material becomes stabilized and is no longer dusty

Solution:

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• 5) The packaging machine was contained using flexible film bonded to the operating jaws of the load cell system to make the built-in exhaust system more effective

• 6) Respirators were still used as a precaution even though the charging operation became shirt sleeve capable

• 7) Production was increased to 2 lots/day and no further sensitization was observed as long as the operators took the time to follow procedures

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199 200

• The process was scaled up to a 10 ton capacity using a rotary mixer into which the raw materials were charged

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Rotary Mixer with Bagging Equipment

201 202

Bagging Actuator

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LEARNING POINTS FROM THESE AND MANYMORE EXPERIENCES:• In any project involving Flexible Barrier design you are

a partner with the provider regardless of how the work is to be paid for

• You need a committed collaborative long term partner for a major design project and implementation - be it your supplier, an A & E firm, or an independent subject matter expert

• Make sure that your collaborator is qualified to provide input into your project

• Be sure that your provider is not taking advantage of the opportunity to have you pay for training their technical staff while developing their new product line and capabilities, i.e. you can end up teaching them the work that you are paying for204

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If you are paying up front for design work you need to own the final design

• If your supplier provides design work be sure that you have a contractual agreement that you have design ownership - they may not be in this business 2 years down the road!

• Be aware of alternative ways to achieve your end result - and always have a backup plan

• Challenge claims that seem unreasonable to you even if the Quality argument is implied

• The mark of a good ‘expert’ is their detailed knowledge of Pharmaceutical operations including decontamination and maintenance needs 206

•Eds e-mail address:

•edholmes@hotmail.fr

•Brians e-mail address

•w_brian@sbcglobal.net

•Web address for pdf update:•http://idisk.mac.com/briangward-Public?view=web

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