cip cleaning in the lif s i i d tlife science industry

CIP Cleaning in the Life Science Industry

CIP Cleaning in the Lif S i I d tLife Science Industry

The ASME Guide for Bioprocessing Equipment (BPE 2007)and CIP Design

D t li d CIP S t D i ithDecentralized CIP System Design with Full TACCT functionality

By Ole T. Madsen [email protected]


AgendaAgenda

Cleaning in the Life Science Industry

ASME Guide for Bioprocessing Equipment 2007 Decentralized CIP System Design with full TACCT functionality

Pump types S b ll J tH d d i Spray ball versus JetHead devices Pressure control versus Flow control Testing of performance



Life Science Industry EquipmentLife Science Industry Equipment

R&D U t D t API(B)

Bio-pharma production

R&DDrug discovery• Bench top equipment• Pilot plants

Up stream • Media preparation• Cell culture

Down stream• Harvest• Capture• concentration

API(B)• Freezing• Lyophilizing

API (b)

Mixing process and Formulation

Filling process• Disposable filling process

Sterile production

API (b) Sterile • Fixed tanks and hard piped systems• Tank farms

• Standard filling machines

API (c)Liquid Drug

Mixing process and formulation

Filling process• Standard filling machines Non sterile

Ointment, Creams & Liquids


• Fixed tanks and hard piped systems

gGMP Product


Solid dosage

Milling• Mills

Pre blending• Blenders

Granulation• Granulator

s Classificati

onAgglomera

tion

Drying• Fluid Beds

Milling• Mills

Final blending• Blenders Final

milling Tableting Tablet coating Packaging

Oral Drug

API production

IBC containers Reactors Mixers Collectors Condensers Filters Inline

systems API (c)



Life Science Industry and cleaningLife Science Industry – and cleaning“Statement”

• The cleaning in the life science industry is insufficient, lacks consistency and is still - mainly - based on manual methodsmanual methods.

• Core issue is that the automated CIP approach is based on the CIP process originally developed for the dairy industry in the 1950’s.

• This is especially true when efficient cleaning is needed most as e.g. where product residuals are g pdifficult to remove, like non-water soluble residuals and with products residuals with sedimentation issues


issues. CIP = Cleaning-in-Place


Life Science Industry – and cleaning

As a result the industry is facing:Cross-contamination issuesCleaning failuresCleaning failuresCleaning validation strugglesSterility issues

Solutions so far?Dedicated production linesDedicated production linesDisposable equipmentManual cleaning, when possibleAutomated CIP however often insufficient


Automated CIP – however often insufficient



FDA enforcement and position:

“E i Cl i d M i ” i f h“Equipment Cleaning and Maintenance” is one of the most frequent “Warning Letter” citations ( ~ 18%)


ECA (European Compliance Academy) – analysing FDA warnings letters – 21 CFR 211.67


Market share ProductSegment

Applied Cleaning Methods / Procedures within the Pharmaceutical Process Areas

BiopharmaceuticalsManual

40%CIP 25%

Rev3%

Disp.7%

COP25%

Sterile manufacturing

SM lCIP COP

Manual55%

CIP15%

Rev2%

Disp.3%

COP25%

Solid dosageManual 80%

CIP5%

COP15%

API cManual

15%CIP2% Reversing Process – Fill, Boil & Dump

83%83%



Hygienic and Sanitary Design StandardsHygienic 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 (1950’ies)• QHD (Qualified Hygienic Design) – VDMA, Frankfurt, Certification)




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 TACCTChanging 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 id li f Bi h i l E i 2007


BPE (ASME guideline for Biopharmaceutical Equipment, 2007


ASME Guide for Bioprocessing Equipment 2007

The American Society of Mechanical Engineers (ASME) prepared the y g ( ) p pBioprocessing 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 sanitary (hygienic) requirements etcfinish, welding procedures, sanitary (hygienic) requirements, 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


Differ on specifics from European Hygienic standards.


ASME Bioprocessing Equipment 2007ASME Bioprocessing Equipment 2007Problematic sections in guideline from a cleaning efficiency perspective:efficiency perspective:

SD-4.5 PumpsSD-4.15.1 (3) CIP Systems and Design (CIP variables)SD-4.15.2 CIP Design Concepts (a), (f), (h), SD-4.15.4 Design Guidelines for Cleaning Process Vessels (a), (b)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



Centrifugal pumpsASME 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 and areThese pump types can basically only be controlled by flow, and are low-pressure pumps (< 60 psi).

This makes CIP processes difficult to validate, because of substantial pressure fluctuations in the cleaning media throughoutsubstantial 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” approach in order to ensure that each flow path and staticoverkill 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.



Si l t C t if lSingle stage Centrifugal 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 tostatic spray balls to achieve coverage.



H Sinner’s Circle for Cleaning TACCTH. Sinner s Circle for Cleaning - TACCT

Time to clean

Mechanical

Action (Impact)Flow of cleaning

liquid

Temperature

energy /Wall shear

Factor

Coverage of surfaces to be cleaned

pof cleaning liquid

Chemical concentration



SD-4.15.1 (3) CIP Systems and Design (CIP variables)

(3) Th f ll i CIP i bl i t t t ith l i(3) The following CIP variables are important to success with any cleaning process:(a) time of exposure to cleaning and rinsing solutions(b) temperature of wash and rinse solutions( ) p(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 Sinner’s circle for cleaning (d), (e) should be changed to:(d) Physical impact or action of the cleaning media(d) Physical impact or action of the cleaning media(e) Coverage of all parts of the equipment to be cleaned



SD 4 15 2 D i C tSD-4.15.2 Design Concepts

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



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(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 …



Static spray ball coverage is partial

Spray Ball Cleaning

p y g p

• Hits one point

• Water cascades down in streams• 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


i.e. a soft rinse of surfaces with low impact / impingement


Spray Ball Cleaning

Main part of tank area is dependant on gravity driven cascading flow


Main part of tank area is dependant on gravity-driven cascading flow


Spray Ball CleaningSpray Ball Cleaning

Clear lack of coverage d i i tand impingement




Cascading Flow

Dry spots Dry spots

Rivers

Purified water vessel

Force Technology ©



Spray Ball Cleaning

Questionable self-cleanability

Spray Ball Cleaning

y

unpredictable blockage of holes



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.



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

(a) Spray devices shall produce a uniform spray coverage over a ( ) p y p p y gparticular defined area of the equipment.(b) -(c) -(d)(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 equipmentlocation and cleaning of the 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) -



+ 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 removedPartly or completely insoluble residues will not be removed due to the spray characteristics of the static spray ball.



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 sensors and agitators that create shadow areas• No built-in devices, 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.static spray balls.



Jet Heads

Jet head coverage is full

• Water jets built up pattern• 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 backsplashing back

Jet head impingement is High

F ti h


• Functions as power washer - i.e. a targeted jet that rotates to cover all surfaces with force -


1. Pressure is the driving force

PJet Heads

- Pressure is converted to water jet velocity 2. The flow turns the tank cleaning machine

3. Clean-ability by Wall Shear Stress

3 C ea ab y by a S ea S ess

4. Machine gearing makes an indexed pattern

Water Jet

d dtWall Shear Stress under


Wall Shear Stress under Turbulent Flow Conditions


Jet Heads

Rotating Jet Heads


Indexed pattern Impingement, Attack of residue


Dead LegsDead-LegsASME BPE: DT – Dimensions and Tolerances for Stainless Steel Automatic Welding and

Hygienic Clamp Tube Fittings and Process Components

Problems– Low velocity in dead leg

Solutions– High flow rate turbulence

yg p g p

– Unused areas where water (product residues) can accumulate

– Accumulation (stagnation) can

g– Co-ordination between process

and design– Risk assessment analysis

S ll d d l lAccumulation (stagnation) can lead to various types of contamination

– Slow cleaningE t d d l i i d

– Small or no dead legs – only where it is necessary

– Extended cleaning periods– No clear rules– Existing recommendations are not

always applicable


y pp– Small or no dead legs are

expensive to design/manufacture


Dead leg Definition

d

D

L3

Process pipe in useL

L1L2L3

L

L

"FDA guide to inspection of High Purity Water systems" defines "dead leg" as >6*d of the g g y y gbranching 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).


Dead leg’s impact on temperature

DL-FACTORS

2 = 9,42 9,4

3 = 5,6

4 = 4,0

5 = 1,5

6

5 1,5

1,6 = 0

1

45

6

3


23


Temperature Distribution Downstream Position of Dead leg

90

1000,4 m/s 1,2 m/s 2,0 m/s DL-FACTORS

TEMP 2 = 9,4

TEMP 3 = 5 6

60

70

80

90

C)

TEMP 3 5,6

TEMP 4 = 4,0

TEMP 5 = 1,5

TEMP 1,6 = 0

30

40

50

TE

MP.

(°C

TEMP 1, 5, 6

TEMP 2

TEMP 3

0

10

20

0 5 10 15 20 25 30 35 40 45 50 55 60

TEMP 3

TEMP 4


TIME (min)


• Sterility concept – sterile filter, sterile air blanket

Other design factors relevant for efficient CIP Cleaning

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



Summary of mismatch between BPE and H. Sinner’s Circle for Cleaning - TACCT

Time to clean

Mechanical


liquid

Temperature

energy /Wall Stress

Factor


pof cleaning liquid

Chemical concentration



Summary of mismatch between BPE and H. Sinner’s Circle for Cleaning - TACCT

Temperaturepof cleaning liquid

Make it possible to CIP at temperatures above 90 oC. -Use multi-stage centrifugal pump to avoid cavitation.


pump to avoid cavitation.


Summary of mismatchSummary 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




Summary of mismatchSummary of mismatch …

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


Therefore use pumps with pressure control in stead of flow control



Summary of mismatchSummary of mismatch …

Use impact through JetHeads

Mechanical

Action (Impact)and higher pressure (>100 psi)• Increase efficiency• Lower water usage

energy /Wall Stress

Factor

g

• CIP process can be monitored (PAT)

Th f i l iTherefore use sanitary multi-stage pumps to deliver enough pressure(Hilge, Fristam, ITT, GEA, Grundfos)


( g , , , , )


Summary of mismatchSummary of mismatch ….


liquid

Increase velocity of flow – and have enough pressure available – control performance

t l th h i t d f flaccurately through pressure in stead of flow.



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

TACCT Cleaning – to its full extent

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 nozzlesin combination with physical effects through nozzles.

Chemical Reaction; dissolves residues. 90% of chemical cleaning agents are based on a alkaline formulation, using a acid to remove the alkaline filmacid 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.



Testing of Coverage and Impact Performance

BPE SD-5.1 Spray Ball Test – Riboflavin is sprayed on internal p y p ysurfaces, 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 removedAs riboflavin is 100% soluble in water it is easily removed.

Add other substances like protein and chemicals to detect and verify coverage and cleanability.



Testing of Coverage and Impact Performance

Newer methods available for verifying reproducibility of cleaningNewer methods available for verifying reproducibility of cleaning performance are – besides conductivity:

Monitor frequency and amperage on multi-stage centrifugal pumpsAcoustic monitoring of:• Rotation• Spray Loss• Spray Pressure Variations Spray Pressure Variations• Rotational Frequency Variations

TOC monitoring


cip cleaning in the lif s i i d tlife science industry

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