1 3) Safety Considerations Safety Overview Impart basic knowledge of pressure and the forces exerted. Understand how temperature causes burn injury. Examples.

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3) Safety Considerations

Safety Overview Impart basic knowledge of pressure and the

forces exerted. Understand how temperature causes burn injury. Examples of Safety Incidents Understand Site Safety values and systems.

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No work should be started if it cannot be completed safely.

The goal is that personnel will go home as they arrived - safe and without injury.

Personnel should not be injured in the manufacture of a product, which is designed to improve the quality of life.

Safety is a Value

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Hazardous Process Safety

Examples of Hazardous Processes Are: Vessels (Pressurized) Plant steam (60psi, 150C) Clean steam (20-30psi) WFI (Water for Injection) Compressed air (95-105psi) CIP systems (~100psi, ~80C, CORROSIVE) Solution transfer lines Oxygen and nitrogen gas (& cylinders)

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Hazardous Process Safety

Possible Hazards: Impact from a blast or release of compressed liquid or

gas Traumatic injury from flying parts

Burns from the release of hot liquid or gasses Contact with released liquid or gas (chemical burns)

Fire resulting from the escape of flammable liquid or

gas (e.g. ethyl alcohol or oxygen leaks)

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Safety Considerations

Are you aware of the hazards of pressure and temperature?

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Pressure Vessel Safety Considerations

This is a processing vessel…..

…..but its also a time-bomb, waiting to go off in your face.

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Pressure & ForceCan you get hurt with low pressure?

Force = Pressure X Area

Lets review the details

It’s like many small weights sitting on a surface (area) which add up to a large weight.

So at a given pressure,The LARGER the area, The GREATER the force

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Example 1

…this is equivalent to an object that weighs 1,639 lbs!

That's ~¾ of a Tonne (1 Tonne = 2205 lbs)

If Force = Pressure x Area, then, 14.5 psi pressure on a 12” Diameter Sight Glass surface area will produce 1,640 pounds of force. (Calculation: 14.5 x 3.14 x 62 = 1,639 lbs)

1,639 Pounds of Force

12” X 12” Square12” Dia Sight Glass

14.5 psig1 Bar

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Example 2

10 psi pressure on a 24”x24” square surface area (576 square inches) is 5,760 pounds of force! (Calculation: 576 X 10= 5,760)

This is equivalent to an object that weighs 5,760 lbs.

24” X 24” Square Door

5,760 Pounds of Force

Again, Force = Pressure X Area, so:

10 psig (~0.7 Bar)

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Example 3Even with a few PSI say 3 PSI which may not be noticeable on the Pressure gauge

150 Pounds of Force

12” X 12” Square8” Dia Sight Glass3 psig

2

4 6

8

10

40

80

120

lbf/in2

bar

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BE AWARE!Can you get hurt with low pressure?

ABSOLUTELY !Never underestimate the potential of a low pressure or vacuum

condition to cause damage.

….and be especially careful with large surfaces like manways. 1 psi may not even register on the gauge but it’s enough to send a hatch flying if the triclamp is removed and the gasket is stuck.

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Low Pressure Hazard This door had the

equivalent of 1915 lbs of force on it. And at only 2.8 psi. The door weighs about 15

pounds - much less than the 1915 lbs of force on it.

When it came loose, it slammed open seriously injuring a person.

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Over-Pressured TankThis tank was fitted with: A high level alarm, which was accepted,

and then forgotten A pressure control system, which was

out of service A pressure relief valve which was found

to be blocked ….so when the product was transferred

into the tank, it over pressured until the roof ruptured, even though the pressure was only a few psi over hydrostatic

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Vacuum Safety The same concepts apply to

vacuum. However, in vacuum systems the pressure is pushing inward, not outward.

The pressure comes from the atmosphere - we don’t feel it but a tank does when you pull vacuum on it.

Vacuum

Atmospheric Pressure

Atmospheric Pressure (at sea level) is about 14.7 psi (1 Bar), therefore full vacuum is -14.7 psi.

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Vacuum Tank Hazards When the pressure inside the vessel is lower than atmospheric pressure,

the force acts inwards, with sometimes spectacular results….

The tanker was being steam cleaned and, at the end of the job, the hatches were closed. With no vacuum breaker fitted, as the steam condensed, the tanker imploded…..

Remember with a vacuum pulled, Hatches may appear stuck - venting to Equalise Pressure, eases hatch removal. Never pressurise in an effort to remove “Stuck Hatches”

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Covered Vent This tank collapsed while being pumped out!

Painters had covered the vent with plastic sheeting. The steel tank collapsed before the plastic sucked through.

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Lack of Venting again

This tank also collapsed while being pumped out!

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Follow the Correct procedure when removing or opening vessel entry points

When removing sight glass to make chemical addition to water in media tank

Always open vent valves if possible, to ensure Pressure Equalisation.

Check the pressure gauge reading first, remember to eliminate “parallax error” from your reading. Ensure pressure has not been isolated at the regulator.

Never Pressurise a vessel to break a seal, because at just a few PSI the subsequent pressure release will be detrimental to property or the person.

Always open vent valves if Possible

Sight glass

0

2

4

6

8

bar

10

12

14

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Projectile Hazards Unsecured gauges, valves,

and probes can become “bullets” shot from tank penetrations

Double check tightness before adding pressure

Relieve pressure before disassembling by Venting Hoses Drain Systems Process Components Sampling Points

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Flailing Hoses Pressurised Hose connection that fails will

Flail. Double Check tri-clamp connection before

adding pressure to hose. Routinely check the condition of hoses for

any signs of bulging or failure. A whipping line can break bones and

damage equipment, If the line gets free leave the area

immediately and shut off flow to the line. Never attempt to grab a whipping Line or

Hose. Flexible hosing should be kept as short as

possible

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Temperature, Burns and Scalds Hot WFI at 85 Degrees C Clean Steam at 145 Degrees C Both at Pressures between 6

Bar and 1.2 Bar. High Risk of Scald injury from

hot spray or leak. High risk of Burns from

surface of hot pipe work or adjacent hot equipment.

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First Degree Burn - SuperficialInvolve the epidermis, which appears pink or red.

Are painful, don’t blister and usually heal within seven days, without scarring.

Sunburn is usually a first-degree burn.

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Partial Thickness - Second Degree BurnsPartial-thickness burns involve the epidermis and some of the dermis.

Deep partial-thickness burns involve the epidermis and deeper extension into the dermis.

Protective ability of the skin is lost.

Partial-thickness burns are painful and appear moist.

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Full Thickness – Third Degree BurnsFull-thickness burns involve the epidermis, the entire dermis and the subcutaneous tissues.

They appear white or brown, charred and leathery.

Not painful as they are deep enough to have damaged the nerve endings.

Are often surrounded by painful partial-thickness wounds.

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Incidents to take note of

Case #1: Tank Light Incident Case #2: Production Support Sight Glass Accident Case #3: Operator Burn Incident Case #4: Manway opening at less than two Bar

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Technician was removing tank light (yellow arrow)

Technician did not check pressure gauge first

Start-up engineers had pressurized tank to 15 psi

Light fixture blew off, stopped by pipe above. Sounded like shotgun

Property damage only. Luck ‘prevented’ injury.

Case # 1: Tank Light Incident

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Case # 2: Production Support Sight Glass Accident

Technician was removing sight glass to make powder addition to water in Buffer Tank

Technician did not check pressure gauge first

Vent valve usually open, but had been left closed by others from prior activity; water addition created 18 psi inside tank

Sight glass struck chin: 11 stitches and a broken tooth

Vent valve closed

Sight glass

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Case # 3: Burn Incident The Technician was opening a

Drain Valve to empty a vessel filled with 82oC WFI

The Clamp holding the Drain Valve Failed allowing the hose to disconnect.

The Operator was Sprayed with Hot Water.

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The Technician: Failed to check hoses and clamps Misread pressure gauge before

opening the drain valve Didn’t wear proper PPE

Also: Training Aids Did Not Mention PPE

Requirements for the Job. Poor arrangement of pressure

gauge and drain valve handle contributed to the Technician misreading the gauge.

Case # 2 Operator Burn IncidentCase # 3: Burn Incident

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The pressure in the vessel had risen to 24.7 PSI (1.74 Barg) during a routine operation.

Once the pressure reached 24.7 PSI, the tri-clamp was unable to keep the manway in place and the manway blew open, causing the tri-clamp to hit and damage the ceiling above.

Pressure acting on 12” Port (Surface Area = 113 Sq. Inches)

Approx. 2,800 Pounds of Force

Case # 4: Manway Opening at Less than Two Bar

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Case # 4: Manway Opening at Less than Two Bar

Tri-clamp Deformation Hole in ceiling where tri-clamp penetrated (6 ft up)

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Case # 4: Manway Opening at Less than Two Bar Failure occurred at a vessel pressure <2.0 Bar A vent valve was programmed to open when the pressure

reached approximately 1.8 Bar This valve did not open.

Both of the clamp bolts were cut prior to use (To fit) The bolt that failed was cut shorter than the other one The Operator was unable to see how well the connection was

made as dome nuts covered the thread of the bolts The Vessel was within normal operating pressures The area was open to personnel

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Safety Systems Tool Box Talks

Communications of Issues. Link Productivity with Safety and Quality. Incident communication and prevention. Learn from mistakes.

Safe Plan of Action Hazard review of the task. Involve all involved in the task. To be done on site while reviewing the hazard Where a Safe Plan is carried out – Quality and productivity follow suite

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Schedule Based Project – the risk Serious Injury or incident will affect the project

schedule. Loss time due to:

The Incident itself. Personal loss to individual and family. Incident investigation. Investigation by H.S.A or Garda. Closure of part of the project. Loss of moral. The list is endless…….

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4) Validation

Introduction What requires validation? Pre Qualification Activities Stages of Validation

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What is Validation?

Ronseal Definition Proving with documented evidence that ‘Ronseal does

exactly what it says on the tin!!’…..

Sober Definition The purpose of validation is to establish documented

evidence which provides a high degree of assurance that premises, facilities, equipment or processes have been designed in accordance with the requirements of current Good Manufacturing Practice (cGMP).

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What Areas Require Validation? All systems or just cGMP systems Analytical and Quality Procedures Instruments Critical Support Systems (e.g. HVAC, WFI) Raw Materials and Packaging Equipment Design, Installation and

Operation Facility Design, Installation and

Operation Maintenance Systems Manufacturing Processes Product Design and Development Control Systems

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Qualification Activities GMP systems and equipment qualified through documented challenge testing to verify that design intent

and user requirements have been met GMP definition includes systems and equipment used in manufacture, control, monitoring, storage and

analysis of pharmaceutical product Where appropriate, documented successful pre-qualification activities will be cited and referenced in lieu

of repeating execution steps in IQ (Installation Qualification) and OQ (Operational Qualification) IQ and OQ required for all GMP systems PQ for critical utility and manufacturing equipment

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Where do you start ?

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Validation Master Plan (VMP) Generally prepared for the start-up of a large project Serves as both a guide to the Client and is used as a review

document for regulatory agencies Develops concurrently with the project - a living document Purpose of a VMP

To briefly describe why, what, by whom, how and when the validation is to be carried out.

Provide up-to-date information about the actual state of affairs relating to validation

Demonstrate the companies commitment to carry out validation

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Pre-Qualification Activities

Purpose is to establish system / equipment installation and functionality prior to commencing formal qualification testing

Steps include: Enhanced Design Review Factory Acceptance Testing (FAT) Commissioning Site Acceptance Testing (SAT)

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Design & Design & EngineeringEngineering

ConstructionConstruction Equipment Equipment Commissioning Commissioning & Validation& Validation

Production Production Process TrialsProcess Trials

Exhibit Batches Exhibit Batches CompleteComplete

Cleaning Program phase 1Cleaning Program phase 1

Cleaning Program phase 3Cleaning Program phase 3

Start of Start of Development Development

BatchesBatches

Cleaning Program phase 2Cleaning Program phase 2

Process Validation

Example: Key Phases in a Project

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Stages of Validation

Design Qualification (DQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) Process Validation (PV) Cleaning Validation (CV) Revalidation (RV)

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Design Qualification (DQ) Provides documented evidence that the

design/ quotation acceptance satisfies the approved User Requirement Specification (URS).

Documenting that we are getting what we asked for in our design i.e. Miele Dish Washer capable of washing at temps from 25 to 80 Deg C, with air drying on a range of dirty soils with detergent capability

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Installation Qualification (IQ)

Provides documented verification that all key aspects of the installation adhere to design specification, regulatory and statutory codes and manufacturers recommendations.

Think of a dish washer at home. Checking vendor is installing it correctly as per the recommendations…Consider does this always go well?!!

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Operational Qualification (OQ)

Provides documented verification that the system and sub-systems perform as intended throughout all anticipated operating ranges.

Think of dish washer again - Proving that it is capable of running all of its cycles with process water in your house and a range of detergents …drainability, spray coverage etc

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Performance Qualification (PQ) Provides documented evidence that a GMP utility

service or process when operated or carried out within defined parameters will consistently meet pre-determined acceptance criteria. PQ will be performed on those systems or processes that require performance data for verifying proper operation.

Proving that with Production materials, i.e. dirty plates, that it will consistently clean to its pre defined criteria i.e. clean and dry within an allocated time

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Performance Qualification (PQ) Challenge testing of performance under load conditions Challenge and establish performance ranges

High & Low/ Min & Max Challenge and establish conditions of operation

Typical environmental conditions Typical working volumes Typical run durations

Sampling test plan Integration of automated control systems and individual units

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Media Simulation Important step of aseptic processing Demonstrates that the process, equipment, people and

utilities when operating together are capable of reliably producing sterile product.

Bacteria friendly food (Media) is processed through all of the equipment as a challenge. A simulation is likely to include the following steps Media compounding Sterilisation of the media by filtration Filling

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Cleaning Validation (CV) Program designed to ensure that equipment can be

cleaned to a pre-defined cleaning acceptance criteria to ensure that any carryover of product does not affect the strength, purity, identity, quality or safety of the subsequent product

Limits for cleaning based on toxiciology of product in body, and consider the risk of transferring small amounts of 1 product into another.

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Cleaning Validation (CV)

Cleaning Cycles Focus on efficacy of set parameters Validate on “worst case” basis, and provide added level of

assurance of efficacy in actual operation Execution of process parameters monitored with each execution Cleaning validation will address operations performed between

campaigns of different products Cleaning validation will address operations performed between the

manufacturing of batches of the same product

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Process Validation (PV)Irrespective of product, Process Validation is preceded by a

formal, documented development phase: Run media runs and hold studies Complete transfer / validation of test methods Challenge process and manufacturing equipment set points, ranges and

durations Evaluate efficacy of equipment cleaning processes Re-establish in-process product hold intervals Finalization and approval of manufacturing process and batch record Evaluate comparability of development batches to licensed material

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Process Validation (PV)General Requirements of Process Validation:

Can be based on successful validation and approval of the products at other licensed sites

Minimum of three production batches Evaluate manufacturing operations using qualified facilities and

equipment train, under typical processing conditions Confirm stability of product through established expiry period Demonstrate reproducible manufacturing process capable of

meeting pre-determined quality attributes Verify shipping conditions and product impact resulting from

shipment to regional packaging facility Demonstrate consistency with product specifications

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Process Validation (PV)Example: Drug Product Manufacturing Validation will focus on:

Demonstrating ability to maintain established environmental and aseptic conditions throughout the manufacturing process

Maintaining all equipment settings within established ranges Confirm performance of the formulation process Evaluation of product transfer steps:

Filling line: Capping system operation: Set up Crimping Speed Vial track Filling duration Consistency across batch

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Revalidation (RV) The action of providing documented evidence that equipment

and ancillary systems continue to operate within pre-determined and specified ranges and continue to meet user needs as established through validation testing. This is accomplished by performing planned Revalidation testing, performing Periodic Review and, where deemed necessary, Revalidation testing as a result of the conclusion from the Periodic Review performed.

Ensuring on a periodic basis that the dish Washer is still working. The worst case washing cycle would be run and documented i.e. does you dish washer work consistently !!

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Documentation Practices

Types of Documents Procedures/ Protocols for

DQ/IQ/OQ/PQ Cleaning and Process Validation

Reports summarising the validation studies providing conclusion to validated status of equipment

Deviations : raised when certain tests acceptance criteria cannot be met. These need to be investigated and closed out prior to Validation summary report approval.