Professional Documents
Culture Documents
11Sep2013
Presented by:
Dawn Tavalsky
Sr. Director QA, genzyme, a Sanofi Company
Dawn.tavalsky@genzyme.com
Outline:
2
Definition of Cleaning Validation
3
Definition of Cleaning Validation (Cliff Notes)
Removing:
all components of the previous product (antigen, Hg, Al, egg
proteins, etc)
Bioburden
Endotoxin
Detergents
Down to levels that are “safe”
have no impact on the next product or the patient with a
large safety factor built in
Prior to using the equipment for the next product
4
Why do we need Cleaning Validation?
5
Why do we need Cleaning Validation?
6
Scope of Cleaning Validation Program
7
Product Contact
Equipment
VS
Equipment that is
Contacted by
Product
Scope of Cleaning Validation Program (cont)
9
The Cleaning Validation Team Mascot
10
The Manufacturing Process
from a Cleaning Validation Perspective
The closer you get to the patient, the more stringent
your cleaning validation criteria become –
Sanofi Example
Processing Stage 1 - those phases of a manufacturing process that
precede the purification steps. Stage 1 process equipment includes the
preparation of raw materials, the fermentation or culture process and
primary filtration steps.
12
Where do I begin?
13
14
Where do I begin?
15
Validation Master Plan:
The establishment of a dynamic
written plan that defines the overall
approach to a validation discipline or
project. It will define the terminology
to be used in all subsequent
documentation, and outline
descriptions of the facility site, the
manufacturing processes, and the
scope and implementation of the
validation sequence.
Where do I begin?
17
Where do I begin?
18
Trace Matrix
Equipment ID Product
Step Material(s) of Cleaning SWI
Step Reference Room Equipment Number (if Soil Contact Cleaning SWI(s) Cleaning Validation Report(s) Soils Encountered
Description Construction Notes
applicable) (D, I, N)
Seed Culture
Unknown N/a Flu Seed Culture N/a Not Found N/a Not Found N/a
Vials
MR0023, Flu
9mL Vial Unknown N/a D Not Found N/a Not Found N/a
Seed Culture
MR0023, Flu
99mL Vial Unknown N/a D Not Found N/a Not Found N/a
Seed Culture
C000540 (BSA WSH)*if Thimerosal ● N. meningitides
Glass or
20L Inoculum MR0023, Flu SS●C002004 & C002011 (BSA Polysaccharide
Stainless 1970 D J000722 (sec 8 & 11) To Service Area
Bottle Seed Culture WSH)*if GLASS●C002077 & Depolymerized Concentrate
Batch Production Steel
C002078 (BSA WSH)*if GLASS ● TET Toxin
Record
Inoculum J000722 (sec 8 & 11),
#3030413, 109 Magnetic Stirring MR0023, Flu C001815 (BSA ULT)●C000540 Meninge Conjugate ●
Preparation Plastic N/a D J000491, J000823, & To Service Area
section 1; Bar Seed Culture (BSA ULT) Thimerosal
J000575
PFD3030044FA
J000722 (sec 8 & 11),
Inoculum Bottle MR0023, Flu C000540 (BSA ULT)●C000540
Silicone N/a D J000491, J000823, & To Service Area Thimerosal ● Thimerosal
Stopper Seed Culture (BSA WSH)
J000575
J000722 (sec 8 & 11),
Automatic
Stainless MR0023, Flu J000536 (sec 5), J000491 C001815 (BSA ULT)●C001159 Meninge Conjugate ●
Inoculum Bottle N/a D To Service Area
Steel Seed Culture (sec 6), J000823, & (B37 ULT)●C000540 (BSA ULT) Harvest Fluids ● Thimerosal
Siphon
J000575
Bottle Stopper MR0023, Flu C000540 (BSA ULT)●C000540
Unknown N/a I Not Found N/a Thimerosal ● Thimerosal
Clamp Seed Culture (BSA WSH)
Batch Production
Egg Unloading, Record
"Warm
Storage, and #3030413, N/a N/a N/a N/a N/a N/a N/a N/a N/a
Room"
Pre-Inoculation section 2;
PFD3030044FA
In-Process
Punch/Needle Stainless J000722 (sec 8 & 11),
N/a Monovalent D To Service Area C001159 (B37 ULT) Harvest Fluids
Assembly Steel J000823, & J000575
Vaccine
In-Process J000722 (sec 8 & 11),
Stainless
Inoc. Manifold N/a Monovalent D J000525 (sec 5), J000491, To Service Area C006108 (B37 ULT) Influenza Inoculum
Steel
Vaccine J000823, & J000575
In-Process
Needle Rinsing Stainless J000491, J000823, &
N/a Monovalent D To Service Area C006108 (B37 ULT) Influenza Inoculum
Manifold Steel J000575
Vaccine
In-Process
Rinsing Manifold
Unknown N/a Monovalent D Not Found N/a Not Found N/a
Tubing
Vaccine
In-Process Meninge Conjugate ●
Stainless C001815 (BSA ULT)●C001159
Forceps N/a Monovalent D Not Found N/a Harvest Fluids & Virus
Steel (B37 ULT)
Vaccine Subunit Fluids
In-Process
Batch Production Replacement Stainless J000491, J000823, &
N/a Monovalent D To Service Area C001159 (B37 ULT) Harvest Fluids
Record Punch Steel J000575
Vaccine
#3030413,
Inoculation 144 In-Process
section 3; SWI Replacement Stainless J000491, J000823, &
N/a Monovalent D To Service Area C001159 (B37 ULT) Harvest Fluids
J000722; Needle Steel J000575
Vaccine
PFD3030044FA
In-Process
4L Collection C002077 & C002078 (BSA TET Toxin ● Tetanus Toxoid
Glass N/a Monovalent D J000491(sec 6) & J000569 To Service Area
Bottle WSH)●C006476 (BSA WSH) (NT0151)
Vaccine
Stainless In-Process
Inoculum Volume C006108 (B37 ULT)●C001159 Influenza Inoculum ● Harvest
Steel or N/a Monovalent D Not Found N/a
Cup Tray (B37 ULT) Fluids
Plastic Vaccine
In-Process
Stainless
Inoculator 7491 & 335 Monovalent D J000722 (sec 8 & 11) Manual Cleaning Not Found N/a
Steel
Vaccine
N. meningitides
20L Inoculum In-Process C002004 & C002011 (BSA
Polysaccharide
Bottle (from Unknown 1970 Monovalent D J000722 (sec 8 & 11) To Service Area WSH)*if GLASS●C002077 &
Depolymerized Concentrate
previous step) Vaccine C002078(BSA WSH)*if GLASS
● TET Toxin
In-Process
10mL Graduated Plastic or
N/a Monovalent D Not Found N/a C00540 (BSA WSH) Thimerosal
Cylinder Glass
Vaccine
19
First:
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Hydrolyzing
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Dissolving
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Saponifying
This mechanism is used for the chemical cleavage and degradation of lipids, in the
form of tri-glycerides, which are not freely soluble in aqueous solutions.
Saponification involves a hydration reaction where free hydroxide breaks the ester
bonds between fatty acids and glycerol of tri-glycerides, resulting in free fatty acids
and glycerol.
The resultant materials are both soluble in aqueous solutions.
As lipids are nearly always present in some stage of a process, especially those
involving cell growth and separation, saponification is an important cleaning
mechanism for residue removal from process equipment surfaces.
24
De-Mineralizing
25
Neutralizing
26
Chelating
27
Virus
28
Raw Meat and Prions
29
Formalin Sodium Citrate
Triton X-100
Sucrose
Aluminum
Mercury
30
Allantoic Fluid
31
Your Soils may Change with Heat/pH/Time
32
Gelatin
33
Antifoam
34
Bacteria
•Gram-positive bacteria
•Gram-negative bacteria are pathogenic,
meaning they can cause disease in a host
organism. This pathogenic capability is usually
associated with certain components of Gram-
negative cell walls, in particular the
lipopolysaccharide (also known as LPS or
endotoxin)
35
Endotoxin
36
Viral Material after Cleaning and/or
Disinfection
37
Protein Folding / Protein Surface Bonding
38
Evaporative Dispersion
39
Soil Lists from in-process Streams
Use the PFD and list all of the components that are
present on the equipment just prior to cleaning – and
then assign “that” soil a name
40
Obtain Subjective Data
41
Obtain Subjective Data
Rank from 1 - 5 with 1 being easiest to clean and 5 being hardest to clean
DtabP, Absorbed 3 3 3 3 3 3 0
(biken)-1 DS Pres
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Product Information
Concentration
Freely
P.B.S 0.006M Soluble Slightly Toxic 52.55405564 52.55405564 52.55405564 50.46327387 ml
60/40
Isopropano
l soluble Slightly Toxic 1.943832433 1.943832433 1.943832433 0.050560013 ml
43
Now – Onto Soil Grouping
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One Example of Soil Grouping
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Example Continued
Group 1 Soil:
Soil containing proteins, nucleic acids and other components of viral origin.
Group 1 soils may also contain cellular debris from viral culture, and components
derived from in-process activities (e.g., inorganic salts, formaldehyde).
Group 2 Soil:
Soil containing proteins, nucleic acids and other components of bacterial origin.
Group 2 soils may also contain components derived from in-process activities
(e.g., inorganic salts, phenol).
Group 3 Soil:
Soil containing proteins for use as bacterial growth media or in-process reagents.
Group 3 soils contain no components derived from viral or bacterial culture.
Group 4 Soil:
Soil containing small molecule organic compounds and/or inorganic salts.
Group 4 soils are typically reagent solutions, inactivation solutions and buffers.
46
Now Choose a Worst Case Soil in each
group
A worst-case process soil may be selected within each
grouping. Worst-case soil selection is based on the
difficulty to clean and, where applicable, the risk that
any carryover would present to a subsequently
manufactured product.
47
Choosing a Worst Case Soil (cont)
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Choosing a Worst Case Soil (cont)
49
Choosing a Worst Case Soil (cont)
50
Choosing a Worst Case Soil (cont)
51
Evaluate Cleanability – but how?
52
Evaluate Cleanability – but how?
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Gravimetric Last to Leave
Determination
Coupon Dissolution
Gravimetric Last to Leave Determination
Coupon Preparation
Soil Preparation
Dissolution
Evaluation
Worst Case Soil Determination
55
Gravimetric Last to Leave Determination
Coupon Preparation
Select MOC that matches your process
Properly Label Coupons
Thoroughly Clean Coupons Prior to Analysis
Drying, Desiccation, and Storage of Coupons
Tare Weight
56
Gravimetric Last to Leave Determination
Coupon Selection
MOC
In-Process Soils
Temperatures
Detergents
Size/weight
DOE: Analysis Desired Teflon 316SS
#8
316SS
#8
Viton Noryl
Silicone
57
Gravimetric Last to Leave Determination
Labeling
Should Identify MOC
Should Reference
Certificate of Manufacturing
Should have a unique
Identifier
58
Gravimetric Last to Leave Determination
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Gravimetric Last to Leave Determination
Coupon Cleaning
Sonication in 3% CP310
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Gravimetric Last to Leave Determination
Coupon Cleaning
Drying
Desiccation
Storage
61
Gravimetric Last to Leave Determination
Weighing
Tare Weight of the MOC Coupon
is the Most Important
Measurement
Make sure balance is level
Wear gloves or handle
coupons with forcepts
Make sure Coupon is dry and
free from debris
Accurately record coupon ID
Wait for mass measurement to
stabilize before recording
weight
Record out as far as possible
62
Gravimetric Last to Leave Determination
Soil Preparation
Accurately measured
(Volume, Mass, Dose)
Reproducible Application
Pipette
Dry/Desiccate/Store
Proper Handling
Document Visual
Observations
63
Gravimetric Last to Leave Determination
Dissolution (standardization)
Temperature
Turbulence
Time
64
Gravimetric Last to Leave Determination
65
Gravimetric Last to Leave Determination
66
Gravimetric Last to Leave Determination
Evaluation of Data
Dry Soil Weight Pre-Cleaning
Dry Soil Weight Post Cleaning
Percent Soil Loss
67
Second:
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Product Contact
Equipment
VS
Equipment that is
Contacted by Product
Biologically Active Material – BAM – live or inactivated vaccines
(intermediates, bulk and final product) that have a potential to engender
an immune response.
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75 t
76
Ensure your Trace Matrix contains all equipment
77
Third:
Equipment Flow
Understand the
Building 46
Equipment Cleaning
Building 37 Building 14
Building 28 Menactra
Flu Yellow Fever
Know the Cleaning Systems Utilized
Clean-in-Place (CIP): The process of cleaning a piece of equipment,
piping, or device without taking it out of line; cleaning performed
without the need to relocate the equipment being cleaned(may be
manual or automated.)
84
S
o
n
i
c
a
t
o
r
s
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Sonicators
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P
a
r
t
s
W
a
s
h
e
r
87
Parts Washer
88
Parts Washer
89
P
a
r
t
s
W
a
s
h
e
r
90
Vial Washer
91
Vial Washer
92
Clean In Place Skid (CIP)
93
CIP Flow Example
Rinse Conductivity
Sensor
To drain
To drain
94
Manual Clean
95
Manual Clean
96
Manual Clean
97
Fourth:
Required Testing
Definition of Failure
Degradation Studies
Filing Strategy
Routine Monitoring
Revalidation
105
Now – Onto Equipment Grouping
106
One Example of how to Group Equipment
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One Example of how to Group Equipment
108
One Example of how to Group Equipment
109
One Example of how to Group Equipment
110
One Example of how to Group Equipment
111
Consider Using Surrogate Small Parts
112
Finally:
Execute!