CIP Cleaning in the Life Science Industry

CIP Cleaning in the

Lif Science
Life
S i
Industry
I d t
The ASME Guide for Bioprocessing Equipment (BPE 2007)
and CIP Design
Decentralized
D
t li d CIP System
S t
Design
D i with
ith
Full TACCT functionality

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Agenda
Cleaning in the Life Science Industry
ASME Guide for Bioprocessing Equipment 2007
Decentralized CIP System Design with full TACCT functionality
Pump types
Spray
S
b ll versus JJetHead
ball
tH d d
devices
i
Pressure control versus Flow control
Testing of performance

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Life Science Industry Equipment

Bio-pharma production
R&D
Drug discovery
Bench top equipment
Pilot plants

U stream
Up
t

D
Down
stream
t

API(B)

Media preparation
Cell culture

Harvest
Capture
concentration

Freezing
Lyophilizing

Sterile production
API (b)
API (c)

Mixing process and

Formulation
Fixed tanks and hard piped systems
Tank farms

Filling process
Disposable filling process
Standard filling machines

Sterile
Liquid Drug

Ointment, Creams & Liquids

Mixing process and

formulation
Fixed tanks and hard
piped systems
By Ole T. Madsen

otm@McFlusion.com

Filling process
Standard filling
g machines

Non sterile
GMP Product

API (b)

CIP Cleaning in the Life Science Industry

Solid dosage
Milling
Mills

Pre
blending

Granulatio
n

Blenders

Granulator
s

Classificati
on

Drying

Milling

Fluid Beds

Mills

Final
blending
Blenders

Agglomera
tion

Final
milling

Tableting

Tablet
coating

Packaging

Oral Drug
API production

IBC
containers

By Ole T. Madsen

Reactors

Mixers

otm@McFlusion.com

Collectors

Condensers

Filters

Inline
systems

API(c)

CIP Cleaning in the Life Science Industry

Life Science Industry and cleaning

Statement
The cleaning in the life science industry is insufficient,
lacks consistency and is still - mainly - based on
manual methods
methods.
Core issue is that the automated CIP approach is
based on the CIP process originally developed for the
dairy industry in the 1950s.
This is especially true when efficient cleaning is
needed most as e.g.
g where p
product residuals are
difficult to remove, like non-water soluble residuals
and with products residuals with sedimentation
issues
issues.
CIP = Cleaning-in-Place
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Life Science Industry and cleaning

As a result the industry is facing:
Cross-contamination issues
Cleaning failures
Cleaning validation struggles
Sterility issues
Solutions so far?
Dedicated production lines
Disposable equipment
Manual cleaning, when possible
Automated CIP however often insufficient
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Life Science Industry and cleaning

FDA enforcement and position:
Equipment
E
i
Cl
Cleaning
i and
dM
Maintenance
i
iis one off the
h
most frequent Warning Letter citations ( ~ 18%)

ECA (European Compliance Academy) analysing FDA warnings letters 21 CFR 211.67
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Applied Cleaning Methods / Procedures within the Pharmaceutical Process Areas

Product
Segment

Market share

COP
25%

CIP
25%

CIP
15%

CIP
5%

COP
25%

Rev
3%

Disp.
7%

Rev Disp.
2%
3%

COP
15%

CIP
2%

By Ole T. Madsen

Manual
40%

Biopharmaceuticals

Manual
55%

Sterile
manufacturing

Manuall
M
80%

Reversing Process Fill, Boil & Dump

83%

otm@McFlusion.com

S
Solid
dosage

Manual
15%

API c

CIP Cleaning in the Life Science Industry

Hygienic and Sanitary Design Standards

DIN EN 1672-2 Hygienic requirements of food processing equipment.
EHEDG (European Hygienic Equipment Design Group)
ASME Guide for Bioprocessing Equipment 2007
ISO 14159 Hygienic requirements of equipment for processing of
food, pharmaceutical and biotechnological products.
USDA (US Department of Agriculture)
NSF (National Sanitation Foundation)
3A (Sanitary standard and accepted practices (1950ies)
QHD (Qualified Hygienic Design) VDMA, Frankfurt, Certification)

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Life Science Industry and cleaning

This presentation will focus on describing how to
achieve efficient and reproducible CIP cleaning.
Full TACCT functionality in CIP systems
Changing the BPE guideline for utilizing full TACCT

TACCT (H. Sinners circle describing the contribution factors for removing soil from a surface of
processing equipment)
BPE (ASME guideline
id li for
f Biopharmaceutical
Bi h
i l Equipment,
E i
2007

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

ASME Guide for

Bioprocessing Equipment 2007
The American Societyy of Mechanical Engineers
g
((ASME)) p
prepared
p
the
Bioprocessing Equipment to set up guidelines for designing process
equipment (herewith also CIP system) that is applied within the biotech and
sterile segments of the pharmaceutical industry (life science).
The guidelines are based upon the 3A standard and focus on mechanical
design, such as component selection criteria, stainless steel grades, surface
finish welding procedures
finish,
procedures, sanitary (hygienic) requirements
requirements, etc
etc.
First version of the guideline was released in 1990.
Has become the Bible for most engineering firms in North America.
Differ on specifics from European Hygienic standards
standards.
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

ASME Bioprocessing Equipment 2007

Problematic sections in guideline from a cleaning
efficiency perspective:
SD-4.5

Pumps

SD-4.15.1 (3)

CIP Systems and Design (CIP variables)

SD-4.15.2

CIP Design Concepts (a), (f), (h),

SD-4.15.4
SD
4.15.4

Design Guidelines for Cleaning Process Vessels (a), (b)

SD-4.15.6

CIP Spray Devices (a), (e), (g)

SD-5.1

Spray Ball testing

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Centrifugal pumps
ASME BPE: SD-4.5 Hygienic Centrifugal Pumps

BPE is only describing single stage centrifugal pumps and positive

displacement pumps (rotary lube) as acceptable.
These pump types can basically only be controlled by flow,
flow and are
low-pressure pumps (< 60 psi).
This makes CIP processes difficult to validate, because of
substantial pressure fluctuations in the cleaning media throughout
the process equipment and therefore also flow fluctuations.
From a validations point-of-view, you need to setup and maintain an
overkill
overkill approach in order to ensure that each flow path and static
spray ball ON AVERAGE* has been supplied with cleaning media at
the right pressure/flow for a specified amount of time.

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Si l stage
Single
t
C
Centrifugal
t if
l pumps

The median lines

indicate the optimal flow
during the specified
cleaning.

Flow rates below the

lower median line will
create laminar flow in
tubes as well as
insufficient flow for the
static spray balls to
achieve coverage.

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

H Sinners
H.
Sinner s Circle for Cleaning - TACCT

Time to clean

Action (Impact)

Flow of
cleaning
liquid
Mechanical
energy /
Wall shear
Factor

Temperature
p
of cleaning liquid

Coverage of surfaces to be cleaned

Chemical concentration

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

SD-4.15.1 (3)

CIP Systems and Design (CIP variables)

(3) The
Th following
f ll i CIP variables
i bl are iimportant
t t tto success with
ith any cleaning
l
i
process:
(a) time of exposure to cleaning and rinsing solutions
((b)) temperature
p
of wash and rinse solutions
(c) chemical concentration of wash solutions
(d) CIP solution flow rates
(e) hygienic design of the equipment or system being cleaned
In order to comply with Sinners circle for cleaning (d), (e) should be
changed to:
(d) Physical impact or action of the cleaning media
(e) Coverage of all parts of the equipment to be cleaned

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

SD 4 15 2 D
SD-4.15.2
Design
i C
Concepts
t
(a) The centralized CIP system consists of a recirculation tank that
is mounted on a common frame with all requisite valves
valves, pumps
pumps,
and controls.
(b) (c) (d) (e) (f) The system will have flow control, either via pump speed/flow or
byy means of flow control valves.
(g) (h) CIP supply and return pumps shall meet guidelines for hygienic
pumps as outlined in this Standard.
(i) (j) -

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

SD-4.15.4 Design Guidelines for Cleaning Process Vessels (a), (b)

(a) Dished-head vertical vessels are cleaned with the majority of
flow directed toward the upper head and sidewall area at the
knuckle radius. Gravity then provides for a continuous solution
sheeting over the sidewall and bottom head.
(b) The guideline for cleaning flow rates for vertical process
vessels with dished heads provides sufficient coverage for typical
cleaning loads.

These guidelines apply for Spray balls cleaning only

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Spray Ball Cleaning

Static spray
p y ball coverage
g is p
partial
Hits one point
Water cascades down in streams
Leaves dry spots in even easy-to-clean
equipment
Cannot clean behind obstacles
Static spray ball impingement is low
Functions as shower head
- i.e. a soft rinse of surfaces with low impact / impingement
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Spray Ball Cleaning

Main part of tank area is dependant on gravity

gravity-driven
driven cascading flow
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Spray Ball Cleaning

Clear lack of coverage

and
d iimpingement
i
t

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Spray Ball Cleaning

Cascading Flow
Dry spots
Rivers

Force Technology
Purified water vessel

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Spray Ball Cleaning

Questionable self-cleanabilityy
unpredictable blockage of holes

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Spray Ball Cleaning

The rule of thumb is to apply static spray balls, to comply with the BPE
recommendation.
The FDA, however, does not dictate sanitary view points on CIP
cleaning. In contrary, the FDA continues with more and more emphasis
to focus on the poor cleaning efficiency of the spray ball cleaning.

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

SD-4.15.6 CIP Spray Devices (a), (e), (g)

( ) Spray
(a)
p y devices shall p
produce a uniform spray
p y coverage
g over a
particular defined area of the equipment.
(b) (c) (d) (e) The performance of the spray device should not be affected by
variations of 20% in flow rate or 20% in delivered pressure, at
the design conditions.
(f) The spray device shall be designed in such a manner as to be
easily removable if required. If removable, then a positioning device
or mark shall be incorporated into the design to allow for proper
location and cleaning of the equipment
equipment.
(g) For optimum cleanability, fixed ball-type sprays operating in the
range of 15 psi to 30 psi are suggested. Dynamic spraying/cleaning
devices may be used with the approval of the owner/user.
(h) By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Spray Ball Cleaning

+ 20% variations in operating pressure

and flow will lead to coverage failures
wording is, however, necessary to justify
use of single stage centrifugal pumps
(refer to pump flow curve)

Partly or completely insoluble residues will not be removed

due to the spray characteristics of the static spray ball.

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Spray Ball Cleaning

In short, static spray balls can be applied successfully in many applications provided that the production design is simple with
No built-in devices
devices, sensors
sensors, and agitators that create shadow areas
No hard-to-reach areas, such as dead-leg type top nozzles, etc.
The static spray ball is not capable of overcoming design challenges.
The only possible solution from a BPE point-of-view is to install more
static spray balls.

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Jet Heads

Jet head coverage is full

Water jets built up pattern
Combination of direct attack of soil through water
jets and cascading flow
Can clean behind obstacles
Can clean through indirect impingement and water
splashing back
Jet head impingement is High
Functions
F
ti
as power washer
h
- i.e. a targeted jet that rotates to cover all surfaces with force By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Jet Heads

1. Pressure is the driving force

- Pressure is converted to water jet velocity
2. The flow turns the tank cleaning machine
3. C
3
Clean-ability
ea ab y by Wall
a S
Shear
ea S
Stress
ess
4. Machine gearing makes an
indexed pattern
Water Jet

Wall Shear Stress under

Turbulent Flow Conditions
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Jet Heads

Rotating Jet Heads

By Ole T. Madsen

otm@McFlusion.com

Indexed pattern
Impingement, Attack of residue

CIP Cleaning in the Life Science Industry

Dead Legs
Dead-Legs
ASME BPE: DT Dimensions and Tolerances for Stainless Steel Automatic Welding and
Hygienic
yg
Clamp
p Tube Fittings
g and Process Components
p

Problems
Solutions
Low velocity in dead leg
High
g flow rate turbulence
Unused areas where water
Co-ordination between process
(product residues) can
and design
accumulate
Risk assessment analysis
Accumulation (stagnation) can
Small
S ll or no d
dead
d llegs only
l
lead to various types of
where it is necessary
contamination
Slow cleaning
Extended
E t d d cleaning
l
i periods
i d
No clear rules
Existing recommendations are not
always
y applicable
pp
Small or no dead legs are
expensive to design/manufacture
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Dead leg Definition

Process pipe in use

L3
L

d
L2

L1

"FDA g
guide to inspection of High
g Purity
y Water systems"
y
defines "dead leg"
g as >6*d of the
branching pipe measured from the center of the circulation pipe (L1). This represents a
constraint.
In worst case it is impossible to observe if a sampling tap is wanted on a large circulation pipe.
Therefore, the aim is to make the dead leg distance" as small as possible and maximum 3*d of
the branching pipe measured from the inner periphery of the main pipe to the valve center (L2).
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Dead legs impact on temperature

DL-FACTORS
2 = 9,4
3 = 5,6
4 = 4,0
5 = 1,5
1,6 = 0

6
1

2
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Temperature Distribution Downstream Position of Dead leg

1,2 m/s

TEMP. (C
C)

0,4 m/s

2,0 m/s

DL-FACTORS

100

TEMP 2 = 9,4

90

TEMP 3 = 5,6
56

80

TEMP 4 = 4,0

70

TEMP 5 = 1,5

60

TEMP 1,6 = 0

50
40

TEMP 1, 5, 6

30

TEMP 2

20

TEMP 3

10

TEMP 4

0
0

10

15

20

25

30

35

TIME (min)
By Ole T. Madsen

otm@McFlusion.com

40

45

50

55

60

CIP Cleaning in the Life Science Industry

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Other design factors relevant for efficient CIP Cleaning

Sterility concept sterile filter, sterile air blanket

Type of valves zero-dead leg radial diaphragm
Surface roughness
Orbital versus manual welding methods
Heat exchanger design
One or two tank CIP system
Turbulent flow in pipes (Reynolds number) go beyond 5 ft/sec

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Summary of mismatch between BPE and H. Sinners Circle

for Cleaning - TACCT

Time to clean

Action (Impact)

Flow of
cleaning
liquid
Mechanical
energy /
Wall Stress
Factor

Temperature
p
of cleaning liquid

Coverage of surfaces to be cleaned

Chemical concentration

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Summary of mismatch between BPE and H. Sinners Circle

for Cleaning - TACCT

Temperature
p
of cleaning liquid

Make it possible to CIP at

temperatures above 90 oC. Use multi-stage centrifugal
pump to avoid cavitation.
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Summary of mismatch .

Achieve coverage through JetHead technology in

stead of spray ball.
Obtain full coverage of all parts
Do it faster
Use less water
Reproducible process

Coverage of surfaces to be cleaned

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Summary of mismatch

Use pressure as controlling parameter to meet a +/3% requirement in stead of +/- 20%

Coverage of surfaces to be cleaned

Therefore use pumps with pressure control in

stead of flow control
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Summary of mismatch

Use impact through JetHeads

and higher pressure (>100 psi)Action (Impact)
Increase efficiency
Mechanical
Lower water usage
g
energy /
Wall Stress
Factor

CIP process can be monitored (PAT)

Therefore
Th
f
use sanitary
i
multi-stage
li
pumps
to deliver enough pressure
((Hilge,
g , Fristam,, ITT,, GEA,, Grundfos))
By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Summary of mismatch .

Flow of
cleaning
liquid

Action (Impact)

Increase velocity of flow and have enough

pressure available control performance
accurately
t l through
th
h pressure in
i stead
t d off flow.
fl

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

TACCT Cleaning to its full extent

Efficient CIP cleaning is achieved when the following factors and their
underlying parameters can be adjusted and controlled as part of the CIP
recipe:
Mechanical Forces; powerful flows of fluid
in combination with physical effects through nozzles
nozzles.
Chemical Reaction; dissolves residues.
90% of chemical cleaning agents are based on a alkaline formulation, using a
acid to remove the alkaline film
Temperature Reaction;
(Heat), kills micro organisms and increases solubility and thereby the removal
of residues.
Time / Duration;
the period of time in which the above points are in effect.

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Testing of Coverage and Impact Performance

p y Ball Test Riboflavin is sprayed
p y on internal
BPE SD-5.1 Spray
surfaces, and coverage is verified by visually by ultraviolet lamp
Test / verify coverage but not cleanability.
As riboflavin is 100% soluble in water it is easily removed
removed.

Add other substances like protein and chemicals to detect and

verify coverage and cleanability.

By Ole T. Madsen

otm@McFlusion.com

CIP Cleaning in the Life Science Industry

Testing of Coverage and Impact Performance

Newer methods available for verifying reproducibility of cleaning

performance are besides conductivity:
Monitor frequency and amperage on multi-stage centrifugal pumps
Acoustic monitoring of:
Rotation
Spray Loss
Spray Pressure Variations
Rotational Frequency Variations
TOC monitoring

By Ole T. Madsen

otm@McFlusion.com