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

APIs/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 Severity ranking Quantity per 100Kg batch
effect based on Quantity

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
Definition Examples
p
Contamination
Charge of material to the wrong
Mix-up is defined as equipment
Mix Up contamination at unsafe levels of Charge of incorrect material to
one product with another equipment
Accidental use of dirty equipment

Carry-over on product contact Inadequate cleaning of equipment

surfaces from one product to
Retention another in the same equipment
used in a sequential or campaign
manner.
Inadequate cleaning specifications
Inadequate visual inspection of
equipment
i t postt cleaning
l i

Routes by which material can be Carry-over of product on operator

transferred from contaminated clothing
p
non-product contact surfaces, Carry-over
y of p
product on equipment
q p
inadvertent or transient contact Carry-over of product on
Mechanical
with other contaminated non- walls/ceilings/ledges
Transfer
designated product contact areas
and direct contact of the product
Carry-over of product on waste
with such surfaces as operator
apparell and
d gloves
l

Routes by which a suspension of Carry-over of product in general

fine solid/liquid particles in air ventilation
Airborne Transfer moves to another area where it
Carry-over
y of p
product in the specific
p
deposits in significant quantities
ventilation
on another exposed product.
 Step 2: Cross contamination Risk
A
Assessment tA
Analysis
l i
Failure Modes and Detection:
Route to cross Detection Detection Ranking How?
contamination

Detectable by procedural
Mix-Up Very High probability 1 controls, material balances,
analytical testing

Detectable by pre-
Retention Good Probability 3 campaign checks, analytical
testing

Maybe detectable by
Mechanical Transfer Low Probability 6
analytical testing

Unlikely to be caught by
Airborne transfer Remote Probability 9 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:

Procedural Controls around open product handling
Gowning/PPE (Personnel Protective Equipment)
IH (Engineering) controls (glove
(glove-bags,
bags continuous liners etc)
Room cleaning Procedures
Site Audit programme
GMP T Training
i i
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:

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
For a new p
product: Developed
p based on technical evaluation.
Identifying the main contaminants in each module
Solubility in water and other possible cleaning solvents (taking
operational cost and environmental factors in account)
operational,
Forced degradation studies/cleaning interactions as required.
Laboratory cleaning simulation.
Documented in a Cleaning Technical Assessment Memo.
Critical cleaning parameters are identified
Analytical development is completed (UV Rinse + Universal HPLC
Swab Method).
Executed on a modular basis and involve circulating the cleaning
solvent through all the vessel loops (out bottom, in top).
Cleaning ex Clinical Manufacture - Cleaning Verification
Cleaning ex Commercial Manufacture - Cleaning Validation
 Cleaning Specifications

Pre-defined justified cleaning specifications.

Set based on the Health Based Cleaning

g methodology.
gy
Rinse tested to meet pre-determined specification
Swab testing to meet pre-determined specification 100mcg/25cm2
swab
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.
The worst case carry
carry-over
over is calculated based on the maximum swab
specification .
 Cleaning Validation Documentation
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.

Execution Of Cleaning
Post Campaign Flush (typically with the process solvent or Methanol)
Modular approach - Each equipment module associated with a process equipment
p y to anyy other module in that train.
train is cleaned separately
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 deemed
validated.

Post execution of cleaning

Cleaning
Cl i validation
lid ti completion
l ti d
documented
t d as postt execution
ti section
ti off protocol.
t l
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).
What is the What is the
What is the Is it easily
surface area of potential to Is it easily Final
equipment Visually
Question product absorb/adhere Cleaned? Rating
classification? Inspected?
contact part? product?

Score/Multiplier 40 20 20 15 5 100

Direct Product
3 >50% High potential Difficult Difficult 300
Contact

Auxiliary Medium
2 10-50% Moderate Moderate 200
Component potential

Proximity
1 <10% Low potential Easy Easy 100
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 hhold
ld titime and
dCCampaign
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 ChChecks
k

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
kddoes
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 ppart of formal cleaning
g and confirm equipment
q p
readiness for processing.
 K T
Key Takeaways
k
Cross Contamination Control is not just equipment Cleaning.
Apply a Risk Based Approach and formally document the Risk
Assessment
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).
Understanding of Process Contaminants and Cleaning Regimes
is paramount Should not be underestimated
Cleaning Validation requires:
Process Understanding
Detailed documentation
Robust business systems
People with Expertise and Experience
 Challenges/Opportunities

Cleaning Verification only?

Reduced Verification Post Cleaning Validation
Turnaround: Time spent in cleaning and set up.
Equipment issues versus cleaning issues
Science of Cleaning Solubility only, Detergents?
Link between R&D and Commercial manufacture
where does cleaning fit in?
Thank You

Questions?
Q ti ?