ISPE Seminar:
Radisson Bl
Blu Hotel
Hotel,
Cork
Mayy 22nd 2014
Equipment Cleaning in a multipurpose API
facility and the development of a Risk Based
Approach
pp
to Cross Contamination Control
Dr. Daniel Egan
Technical Lead, API
MSD
MSD Businesses across Ireland
MSD Ballydine Site
• Established API manufacturing plant in 1976
• Named API R&D Commercialisation site in 2005
• New
N
fformulation
l ti R&D ffacility
ilit operational
ti
l iin 2010
• 430 employees + ~70 full time outside contractors
Site currently supports
worldwide revenues of
approx €8bn and focuses
approx.
on new product R&D
commercialisation
25 international customers
~30
30 shipments/month
Agenda
Cross Contamination Control – Using a Risk Based
Approach
} Steps in applying the Risk based approach.
} Risk Identification
} Risk Analysis
} Risk Evaluation
Role of Cleaning Validation in Cross Contamination
Control
}
}
}
}
}
Development of a new cleaning regime
Cl
Cleaning
i S
Specifications
ifi ti
Cleaning Validation Documentation
Cleaning Execution
Using the Risk Based approach in Cleaning Validation
Key Take Aways/Challenges/Opportunities
MSD B
Ballydine
ll di (API)
(API):Equipment
E i
t
} Factory 01/Pilot Plant:
} 53 vessels (reactors, extractors, tanks)
} 7 centrifuges (Tolhurst & Heinkel) & 2 Filter Driers
} 4 Rotary Dryers
} Factory 03:
} 25 vessels (reactors, extractors, tanks)
} 2 Cogeim Filter Dryers,
Dryers & 2 Heinkel Centrifuges
} 4 Conical Dryers
} Both Facilities are modular: The outlet(s) of any vessel can be
connected to the inlet(s) of any other vessel in the building
} Typically 25 campaigns (450 Modules cleaned per year)
including new process steps both Clinical and Commercial
manufacture.
manufacture
} Cleaning is just one part of our overall strategy for cross
contamination control.
Risk based Approach
ISPE Baseline Guide,
Volume 7 'Risk Based
Manufacture of
Pharmaceutical Products'.
Applying
y g the Risk based Approach to
Cross Contamination
St 1:
Step
1 Risk
Ri k Identification:
Id tifi ti
The Cross Contamination Hazards are
¾
¾
¾
¾
¾
¾
API’s/Intermediates/Raw Materials
Impurities
By-products
Degradants
Detergents
Solvents
Severity of the Hazard is determined by the ADE (Acceptable Daily
Exposure) Limit.
Facility does not handle Antibiotics or Highly Active compounds
compounds.
Step 2: Cross contamination Risk
A
Assessment
tA
Analysis
l i
Step 2: Risk Analysis:
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)
MDD
Route to cross contamination
Severity of the
effect
Severity ranking
based on Quantity
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)
Airborne transfer
Negligible effect
1
Quantity < 0
0.01Kg
01Kg (<10g)
Step 2: Cross contamination Risk
Assessment Analysis
Route for Cross
Contamination
Definition
Examples
p
Mix Up
Mix-up is defined as
contamination at unsafe levels of
one product with another
Charge of material to the wrong
equipment
Charge of incorrect material to
equipment
Accidental use of dirty equipment
Retention
Carry-over on product contact
surfaces from one product to
another in the same equipment
used in a sequential or campaign
manner.
Inadequate cleaning of equipment
Inadequate cleaning specifications
Mechanical
Transfer
Routes by which material can be
transferred from contaminated
p
contact surfaces,
non-product
inadvertent or transient contact
with other contaminated nondesignated product contact areas
and direct contact of the product
with such surfaces as operator
apparell and
d gloves
l
Carry-over of product on operator
clothing
Carry-over
y
of p
product on equipment
q p
Carry-over of product on
walls/ceilings/ledges
Routes by which a suspension of
fine solid/liquid particles in air
moves to another area where it
deposits in significant quantities
on another exposed product.
Carry-over of product in general
ventilation
Airborne Transfer
Inadequate visual inspection of
equipment
i
t postt cleaning
l
i
Carry-over of product on waste
Carry-over
y
of p
product in the specific
p
ventilation
Step 2: Cross contamination Risk
A
Assessment
tA
Analysis
l i
► Failure Modes and Detection:
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
3
Detectable by precampaign checks, analytical
testing
Mechanical Transfer
Low Probability
6
Maybe detectable by
analytical testing
Airborne transfer
Remote Probability
9
Unlikely to be caught by
analytical testing at such a
low level
► Severity and detection rankings result in equivalent scores =>
Occurrence is the determining factor.
Step 3: Risk Evaluation
This step evaluates available data for each of the identified failure modes and determines either a
quantitative
tit ti estimate
ti t (e.g.
(
numerical)
i l) or qualitative
lit ti d
description
i ti ((e.g. hi
high,
h medium
di
or llow)) off
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 equipment and accidental use of dirty equipment.
Review Controls Include:
} Facility design (Single product rooms)
} Identification procedures (both equipment and Materials)
} Batch record Controls/Checks
} Equipment Cleaning status
} Site Audit programme
} GMP Training
} Deviation review
Risk Evaluation Contd.
Contd
Retention
Retention is defined as carry-over of material on product contact surfaces
from one product to another in the same equipment
equipment.
E i
Equipment
t Cleaning
Cl
i Validation
V lid ti Programme:
P
} Modular basis using pre-defined cleaning regime
} So
Solvent
e t rinse
se ((where
e e app
appropriate),
op ate), sswab
ab a
and
d visual
sua inspection
spect o
specifications.
} Detailed cleaning procedures are in place
} Compare Swab specifications and total surface area of the equipment
used with the maximum carry-over using 'Health Based Calculation'.
Risk Evaluation Contd.
Contd
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
•
Direct contact of the product with such surfaces as operator apparel and
gloves.
Review Controls Include:
¾ Procedural Controls around open product handling
¾ Gowning/PPE (Personnel Protective Equipment)
¾ IH (Engineering) controls (glove
(glove-bags,
bags continuous liners etc)
¾ Room cleaning Procedures
¾ Site Audit programme
¾ GMP T
Training
i i
¾ Deviation review
Risk Evaluation Contd.
Contd
Airborne Transfer
Airborne Transfer is the process by which a suspension of
fine solid/liquid particles in air moves to another area
where it deposits in significant quantities on another
exposed product.
Review Controls Include:
¾
¾
¾
¾
Air flows/differential pressures design and Monitoring
Facilit design:
Facility
design e.g.
e g Airlocks
Provision of HEPA filtered air (no recycling).
Air Changes per Hour (ACPH)
Risk Evaluation Conclusions.
Conclusions
Overall FMEA Scoring
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 risk
with
t
Airborne
bo e Transfer
a se a
and
d Retention
ete t o
on ded
o
dedicated
cated
equipment the lowest RPN.
We understand the materials we are handling & our facility is
designed to handle such materials
Next…..Cleaning of Multipurpose Equipment
Development of a Cleaning Regime
¾ For a new p
product: Developed
p based on technical evaluation.
¾ Identifying the main contaminants in each module
¾ Solubility in water and other possible cleaning solvents (taking
operational cost and environmental factors in account)
operational,
¾ Forced degradation studies/cleaning interactions as required.
¾ Laboratory cleaning simulation.
¾ Documented in a ‘Cleaning Technical Assessment Memo’.
¾ Critical cleaning parameters are identified
¾ Analytical development is completed (UV Rinse + Universal HPLC
Swab Method).
¾ Executed on a modular basis and involve circulating the cleaning
solvent through all the vessel loops (out bottom, in top).
¾ Cleaning ex Clinical Manufacture - Cleaning Verification
¾ Cleaning ex Commercial Manufacture - Cleaning Validation
Cleaning Specifications
Pre-defined justified cleaning specifications.
ƒ Set based on the ‘Health Based Cleaning’
g methodology.
gy
ƒ Rinse tested to meet pre-determined specification
ƒ Swab testing to meet pre-determined specification 100mcg/25cm2
swab
ƒ Vessel visually clean (inspected when dry)
Each New product is confirmed to be within existing specification.
specification
• Suitability of the cleaning specifications going into the process step
are confirmed.
confirmed
• Calculation of the total carry-over for each contaminant going into the
campaign.
carry-over
over is calculated based on the maximum swab
• The worst case carry
specification .
Cleaning Validation Documentation
Prior to cleaning:
¾
¾
¾
¾
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.
Execution Of Cleaning
¾ Post Campaign Flush (typically with the process solvent or Methanol)
¾ Modular approach - Each equipment module associated with a process equipment
p
y to anyy other module in that train.
train is cleaned separately
¾ Validation status is applied to each module which is uniquely associated with the
process from which the module is being cleaned
¾ Three successful cleanouts of a module are required for a clean-out to be deemed
validated.
Post execution of cleaning
¾ Cleaning
Cl
i validation
lid ti completion
l ti
d
documented
t d as postt execution
ti section
ti off protocol.
t
l
¾ Includes all Laboratory cleaning Results
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 of
product
contact part?
What is the
potential to
absorb/adhere
product?
Is it easily
Cleaned?
Is it easily
Visually
Inspected?
Final
Rating
Score/Multiplier
40
20
20
15
5
100
3
Direct Product
Contact
>50%
High potential
Difficult
Difficult
300
2
Auxiliary
Component
10-50%
Medium
potential
Moderate
Moderate
200
<10%
Low potential
Easy
Easy
100
1
Proximity
Area
Using the Risk based Approach in
Cl
Cleaning
i V
Validation
lid ti
► Swab Locations: Worse case assessment of hard to clean
locations (Cannot swab all the vessel!)
► Dirty
Di t h
hold
ld titime and
dC
Campaign
i L
Length
th where
h
it iis a problem
bl
and not for all equipment.
► Tracking of Clean hold time/sanitizations where equipment
is to be used for immuno suppressed populations,
parenterals, p
p
products which are non-inhibitoryy to microbial
growth.
P C
Pre-Campaign
i Ch
Checks
k
¾
¾
¾
¾
¾
Equipment status check (electronic tracking system) is
completed which confirms that the equipment is clean
E
Ensure
contamination
t i ti ffrom mechanical
h i l set-up
t
work
kd
does
not impact on product quality
Water dummy run,
run visual cleanliness is confirmed
confirmed.
Before Processing, Water Dummy Runs, Solvent
Dummy Runs and physical matter flushes (for pure
steps) are completed.
Not p
part of formal cleaning
g and confirm ‘equipment
q p
readiness’ for processing.
K T
Key
Takeaways
k
¾ Cross Contamination Control is not just equipment Cleaning.
¾ Apply a Risk Based Approach and formally document the Risk
Assessment
¾ Validated
V lid t d E
Equipment
i
t Cl
Cleaning
i – Complex
C
l S
System
t
ffor non-
dedicated Equipment (Multiple Modules, Multiple products all with
different processes).
¾ Understanding of Process Contaminants and Cleaning Regimes
is paramount – Should not be underestimated…
¾ Cleaning Validation requires:
‰ Process Understanding
‰ Detailed documentation
‰ Robust business systems
‰ People with Expertise and Experience
Challenges/Opportunities
¾ Cleaning Verification only?
¾ Reduced Verification Post Cleaning Validation
¾ Turnaround: Time spent in cleaning and set up.
¾ Equipment issues versus cleaning issues
¾ Science of Cleaning – Solubility only, Detergents?
¾ Link between R&D and Commercial manufacture –
where does cleaning fit in?
¾Thank You
¾Questions?
Q
ti
?