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ISPE Seminar:
a sson u o e ,Cork
Ma 22nd 2014
Equipment Cleaning in a multipurpose API
facility and the development of a Risk Based
Approach to Cross Contamination Control
Dr. Daniel Egan
Technical Lead, API
MSD
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MSD Businesses across Ireland
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•
• Named API R&D Commercialisation site in 2005• ew ormu a on ac y opera ona n
• 430 employees + ~70 full time outside contractors
Site currently supportsworldwide revenues of
.
on new product R&D
commercialisation
25 international customers
~
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Cross Contamination Control – Using a Risk Based
Approach . Risk Identification Risk Analysis Risk Evaluation
Role of Cleaning Validation in Cross ContaminationControl Development of a new cleaning regime
ean ng pec ca ons Cleaning Validation Documentation Cleaning Execution
Using the Risk Based approach in Cleaning Validation
Key Take Aways/Challenges/Opportunities
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a y ne : qu pmen
53 vessels (reactors, extractors, tanks)
7 centrifuges (Tolhurst & Heinkel) & 2 Filter Driers 4 Rotar Dr ers
Factory 03: 25 vessels (reactors, extractors, tanks)
,
4 Conical Dryers
Both Facilities are modular: The outlet(s) of any vessel can be
Typically 25 campaigns (450 Modules cleaned per year)
including new process steps both Clinical and Commercial.
Cleaning is just one part of our overall strategy for crosscontamination control.
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ISPE Baseline Guide,
Volume 7 'Risk Based
Manufacture ofPharmaceutical Products'.
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Applying the Risk based Approach to
Cross Contamination
ep : s en ca on:
The Cross Contamination Hazards are
API’s/Intermediates/Raw Materials
Impurities
By-products Degradants
Deter ents
Solvents
Exposure) Limit.
.
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Step 2: Cross contamination Risk
ssessmen na ys s
Need to identify the quantity of the Hazard & the Failure mode Quantity
Carry over that will cause an adverse affect:
ADE*106= 0.1mg/day*106/100 = 1000mg/kg = 1.0g/Kg (0.1Kg/100kg)
Route to cross contamination Severity of the
effect
Severity ranking
based on Quanti ty
Quantity per 100Kg batch
Mix-Up Critical effect 9 > 1Kg
Retention Critical effect 9 0.05 - 1Kg
Mechanical Transfer Major effect 6 6 0.01-0.05Kg (10g-50g)
r orne rans er .
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Step 2: Cross contamination Risk
Route for CrossDefinition Examples
Mix UpMix-up is defined as
contamination at unsafe levels ofone product with another
Charge of material to the wrongequipment
Charge of incorrect material toequipment
Retention
Carry-over on product contactsurfaces from one product to
another in the same equipmentused in a se uential or cam ai n
Inadequate cleaning of equipment
Inadequate cleaning specifications
Inadequate visual inspection of
manner.equipment post cleaning
Routes by which material can betransferred from contaminatednon-product contact surfaces,
Carry-over of product on operatorclothing
Carry-over of product on equipment
MechanicalTransfer
inadvertent or transient contactwith other contaminated non-
designated product contact areasand direct contact of the product
with such surfaces as operator
Carry-over of product onwalls/ceilings/ledges
Carry-over of product on wasteappare an g oves
Airborne Transfer
Routes by which a suspension offine solid/liquid particles in air
moves to another area where it
Carry-over of product in generalventilation
Carry-over of product in the specific
on another exposed product.ventilation
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Step 2: Cross contamination Risk
ssessmen na ys s
Route to cross
contamination
Detection Detection Ranking How?
Mix-Up Very High probability 1
Detectable by procedural
controls, material balances,
analytical testing
Retention Good Probability 3Detectable by pre-
campaign checks, analytical
testing
Mechanical Transfer Low Probability 6Maybe detectable by
analytical testing
Unlikely to be caught by
low level
Occurrence is the determining factor .
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This step evaluates available data for each of the identified failure modes and determines either a
quan a ve es ma e e.g. numer ca or qua a ve escr p on e.g. g , me um or ow o
occurrence of the Failure Mode
Mix Up:
Defined as contamination at unsafe levels of one product with another.
Examples are charging of the desired material to the wrong equipment, charge of incorrect
material to desired e ui ment and accidental use of dirt e ui ment.
Review Controls Include:
Facility design (Single product rooms)
Identification procedures (both equipment and Materials)
Batch record Controls/Checks
Equipment Cleaning status
Site Audit programme
Deviation review
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.
Retention is defined as carry-over of material on product contact surfaces.
qu pmen ean ng a a on rogramme: Modular basis using pre-defined cleaning regime Solvent rinse where a ro riate swab and visual ins ection
specifications.
Detailed cleaning procedures are in place
used with the maximum carry-over using 'Health Based Calculation'.
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.Mechanical Transfer
Mechanical Transfer is the process by which material can be transferred from
• Contaminated non-product contact surfaces
• inadvertent or transient contact with other contaminated non-designated
product contact areas
•
gloves.
Procedural Controls around open product handling
Gowning/PPE (Personnel Protective Equipment)
- ,
Room cleaning Procedures
Site Audit programme
ranng
Deviation review
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.
Airborne Transfer is the process by which a suspension of
fine solid/liquid particles in air moves to another areaexposed product.
Review Controls Include: Air flows/differential pressures design and Monitoring
y : . .
Provision of HEPA filtered air (no recycling).
Air Changes per Hour (ACPH)
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.Overall FMEA Scorin Overall a Risk Priority Number (RPN) can be calculated as follows for each
failure mode.
RPN= Severity x Detection x Occurrence
Retention for non-dedicated equipment was the highest riskwith Airborne Transfer and Retention on dedicatedequipment the lowest RPN.
We understand the materials we are handling & our facility isdesigned to handle such materials
Next…..Cleaning of Multipurpose Equipment
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For a new product: Developed based on technical evaluation.
Identifying the main contaminants in each module
Solubility in water and other possible cleaning solvents (taking,
Forced degradation studies/cleaning interactions as required.
Laborator cleanin simulation.
Documented in a ‘Cleaning Technical Assessment Memo’.
Critical cleaning parameters are identified
Analytical development is completed (UV Rinse + Universal HPLCSwab Method).
solvent through all the vessel loops (out bottom, in top).
Cleaning ex Clinical Manufacture - Cleaning Verification
Cleaning ex Commercial Manufacture - Cleaning Validation
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Pre-defined justified cleaning specifications.
Set based on the ‘Health Based Cleaning’ methodology. Rinse tested to meet pre-determined specification
Swab testing to meet pre-determined specification 100mcg/25cm2
swab
Vessel visually clean (inspected when dry)
.
• Suitability of the cleaning specifications going into the process step.
• Calculation of the total carry-over for each contaminant going into thecampaign.
• The worst case carr -over is calculated based on the maximum swabspecification .
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Prior to cleaning:
Cleaning Technical assessment memo.
Cleaning Sample Keys (summary of testing requirements for the Laboratory)
Cleaning validation protocol – This documents the validation plan for the campaign. For new products: Cleaning Specification Justification including Genotoxic
assessment.
Post Campaign Flush (typically with the process solvent or Methanol) Modular approach - Each equipment module associated with a process equipment
train is cleaned se aratel to an other module in that train.
Validation status is applied to each module which is uniquely associated with the
process from which the module is being cleaned
Three successful cleanouts of a module are required for a clean-out to be deemedvalidated.
Post execution of cleaning
ean ng va a on comp e on ocumen e as pos execu on sec on o pro oco .
Includes all Laboratory cleaning Results
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Using the Risk based Approach in Cleaning
Validation
► Risk based approach to swabbing as part of cleaning validation
programme► Equipment which is not shared product contact (e.g. insides of glove-
boxes).
Question
What is the
equipment
classification?
What is the
surface area ofproduct
contact part?
What is the
potential toabsorb/adhere
product?
Is it easilyCleaned?
Is it easily
Visually
Inspected?
FinalRating
Score/Multiplier 40 20 20 15 5 100
3Direct Product
Contact>50% High potential Difficult Difficult 300
2 Auxiliary
Component10-50%
Medium
potentialModerate Moderate 200
1Proximity
Area
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Using the Risk based Approach in
ean ng a a on
► Swab Locations: Worse case assessment of hard to cleanlocations (Cannot swab all the vessel!)
► r y o me an ampa gn eng w ere s a pro emand not for all equipment.
is to be used for immuno suppressed populations,parenterals, products which are non-inhibitory to microbialgrowth.
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re- ampa gn ec s
Equipment status check (electronic tracking system) is
completed which confirms that the equipment is cleannsure con am na on rom mec an ca se -up wor oes
not impact on product quality
, .
Before Processing, Water Dummy Runs, Solvent
steps) are completed.
Not part of formal cleaning and confirm ‘equipmentreadiness’ for processing.
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ey a eaways Cross Contamination Control is not just equipment Cleaning.
Apply a Risk Based Approach and formally document the Risk
Assessmenta a e qu pmen ean ng – omp ex ys em or non-
dedicated Equipment (Multiple Modules, Multiple products all with
different processes).
Understanding of Process Contaminants and Cleaning Regimesis paramount – Should not be underestimated…
Process Understanding
Robust business systems
People with Expertise and Experience
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Challenges/Opportunities
Cleaning Verification only?
Reduced Verification Post Cleaning Validation
Turnaround: Time spent in cleaning and set up.
Science of Cleaning – Solubility only, Detergents?
–where does cleaning fit in?
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Thank You
ues ons