EQUIPMENT DESIGN CONSIDERATIONS FOR CLEANING VALIDATION -Koshy George Manager, Global Technical Operations Merck & Co. Note: These slides and the content of this presentation represent the work and opinions of the author and do not constitute official positions of Merck & Co., any of its affiliates, or any other organization.

Agenda • Points to Consider • General requirements for equipment design. design • Group project (2 groups) • Presentation of Group Project • Discussion

Regulatory Agency Challenge • Prove that you can clean production equipment adequately, such that residues from the production of one product will not carry over and cross-contaminate the next product. product

Cleanability of Process Equipment • Is it an after-thought? after thought? • Is the cleaning team involved in the planning and design of new equipment? • Any thought or considerations given for th requirements the i t off cleaning l i validation lid ti during the design phase?

Points to Consider • Product contact surfaces shall not be reactive,, additive, or absorptive. • Surfaces shall be hard and smooth, and shall not shed h d particles. i l • Surfaces shall withstand the repeated use of cleaning and sanitizing agents agents. • Equipment shall be designed so as to prevent dead e ends ds o or spots, in which c p products oducts cou could d accumulate and be hidden from the operator’s view.

Points to Consider • All parts of the equipment shall be easily dismantled to permit visual inspection (use of borescope where necessary) necessary). • Valves shall be of a sanitary type. • All connections ti tto utilities tiliti shall h ll b be fitt fitted d with a back flow prevention valve. • Vessels and containers shall be drainable.

Points to Consider • Valves and instrumentation shall be installed flush with product contact surfaces. surfaces • Small parts, screws, and bearings, if unavoidable shall be fixed in such a way unavoidable, as to prevent their accidental fall into the product. product

Points to Consider • Anyy substances required q for operation, p , such as lubricants and coolants, shall not come into contact with the product. • The Th engine i shall h ll b be llocated d or d designed i d so as to prevent accidental dripping of these substances into the product product. • The engine, the electric and electronic parts, should be hermetically encased to allow for easy cleaning and to prevent safety concerns during cleaning.

What does it take to Clean? Cleaning requires both physical and chemical processes. • • • •

T ime A ction C hemistryy / Concentration T emperature

Understanding the Cleaning Process • CIP & COP Systems must repeatably control TACT • Each factor in TACT will have an impact on the cleaning performance. • Changing Ch i one parameter t can d dramatically ti ll affect another.

Preferred Cleaning Methods COP – Clean out of Place ((semi-automated / automated)) • Used for non CIP’able process equipment • Remove process components from process for cleaning • Process components immersed in bath of turbulent cleaning solutions CIP – Clean-in-Place (automated) ( ) • Process equipment is cleaned without disassembly by circulation of cleaning solutions along the process flow path. path • Typically automated.

What can be cleaned by COP Process components include: • Pump parts • Sanitary S it h hoses • Fittings, clamps, gaskets • Filter housings • Filler needles • Manual diaphragm valves

Typical COP Cleaning Squence • • • • • • •

Pre-rinse Pre rinse Detergent Wash P t Rinse Post Ri Acid Wash (optional) Post Rinse Post Rinse Final Rinse (prove purity)

CIP • Definition – Internally cleaning a piece of equipment without relocation or disassembly.

• Why –R Remove process soils il – Product and lot segregation – Bioburden removal and control

• How – Contact is essential – Flow cleaning agents over process surfaces • That remove process residues • Biologics: typically aqueous cleaning solutions

• Perform according to validated parameters – Document D t consistent i t t execution ti

TYPICAL CIP CYCLE SEQUENCE • CIP agent preparation precedes each cleaning step – CIP skid or local

• Cleaning requires fluid contact with target surfaces • Typical steps include – – – – –

Water pre-rinse Caustic wash Mid-rinse Acid wash Post-wash rinses remove cleaning chemicals • Final rinse water with same compendial quality water or p better as used for process – Rinsate validated to meet acceptance criteria – In biotech most often purified water or WFI

The CIP System CIP Supply Pi i Piping Valves T-Panels Sprayballs

CIP Skid Tanks Pumps Valves Instruments Eductor Heater

Target T k Tanks Filters Lines Skids

CIP Return Pi i Piping Valves T-Panels Pumps

• •

CIP System y Design g

Prepare, distribute and remove cleaning solutions May be local, portable, or centrally located

– Local – no separate CIP system – Portable P t bl CIP systems t are connected t d tto target t t systems t only l during d i cleaning – Centrally located systems are hard-piped to target systems • Serve multiple targets often in several rooms

•

C Components off CIP systems iinclude l d – – – – –

•

Vessel(s) Equipment to transfer and dilute chemical agents for cleaning CIP supply pumps Return pumps are often required Vent filters, instrumentation, air supply for blowdown

CIP systems in a variety of flavors: – One tank: Batch water directly to tank used for chem make up and recirculation – Two tank: • • • •

One tank dedicated to pure water Chemical agent mixed in other vessel Useful with limited water supply flow Clean tank always source of water for final rinses

– Many other variants

CIP circulation • Average: Inflow = Outflow – Outlet valve and p piping p g sized to balance flow

• “No accumulation” in target vessel – Desirable but not mandatory – Prevents formation of ring around the vessel – Subsurface of stagnant pool may not clean as well

• Return to CIP system – Gravity G it iis simple i l • Requires elevation • May require large bottom outlet valve/piping that is difficult to flood

– Return R t pump • Size piping approximately the same as supply • Select pump that tolerates running dry – liquid ring centrifugal

– Local circulation around process tank • Use process tank for CIP reservoir with minimal fill

Circulation from a CIP system • CIP system components – – – – –

•

Cleaning agent dosing CIP system tank Controls: CIP temp, agent concentration CIP supply pump and supply piping CIP return piping - pump, eductor or gravity

Advantages – Minimize pool in target vessel – Flexibility to do line and tank CIP

•

Issues/Challenges – Hydraulic balance of supply & return flow • Avoid air binding return pump.

– Supply and return piping design – apply same principles as process system • Adequate to support flows • Line size filled • Avoid dead areas during any circuit

– Facilityy g geometry y

•

Potential Issues – Soil returns to CIP tank – Bio-containment

Local Circulation •

C Circulate ffrom process tank

Chemical make up

– Local – OR– CIP skid supplies cleaning solutions

•

Advantages

AI

Cleaning Agents

– Reduced piping • No N return lilines • If dosed locally no supply • Reduced supply complexity if dosed remotely.

– No soil return to system – Biocontainment

•

Air/Vent

Local circulation – Avoid static pool by minimizing circulating volume – CIP instrumentation with each unit

•

WFI

Issues / Challenges – Minimize volume to avoid static pool in process tank – Line only CIPs, once through if CIP supply skid • No line only CIP ‘s with local make-up

– CIP instrumentation duplicated on each unit op

AI F I Drain

Transfer Panel X

X X

X

What is the best design for CIP? • •

It depends … Fully y automated cycle y is preferable p – CIP is a many step process – Continuous monitoring – Document consistent performance • Show performance of each cycle within validated range

•

Choosing among

local recirculation, central one tank system, portable systems… – Considerations • IIs it worth th running i lines li tto/from /f CIP system? t ?D Desirability i bilit off placing l i CIP equipment in mechanical areas? • What is cleaned? – Tanks, lines…

• Are CIP skids used for other purposes – Filter flush

• Biohazard containment • Water – – – –

quality q y supply flow rate reducing number of compendial water drops use of different water quality for initial steps vs. final rinse steps

Process System CIP • Flowing CIP agents must contact all process surfaces – Circulate solutions by pumping – Lines Li – filled fill d with ith flowing fl i CIP solution l ti – Vessels – sheet flow covers vessel interior surfaces

• Critical parameters for cleaning and rinse steps – Flow Fl performance f • Flow and pressure

– Contact time – Temperature – Composition • Chemical make-up • Final rinse quality

• Control system – Automated control for consistency • Often 80% or more of automation code is for CIP

– Verifies performance according to critical parameters • Monitors, controls, and alarms

– Sequences steps and paths

Two ways to apply Cleaning S l i Solutions Once Through g • Cleaning solution is introduced into process from CIP system and not recirculated. • Solutions exit process directly to drain or may return to CIP system for routing to drain. Single Use Recirculated • Solutions are introduced into process from CIP system and returned to CIP tank to be supplied to process once g again. • Solutions are dumped to drain after cleaning step is completed. • Return pump or other means used to return solutions solutions.

Once-Through CIP Design A li i Application • No possibility of cross contamination • Used where return of solutions may contaminate the CIP system, system ie: toxic drugs. • High Hi h water t and d chemical h i l usage

Single Use Recirculated CIP A li i Application • Used where cross contamination between process equipment and CIP is unlikely; ie: soluble non-toxic non toxic soils • Reduced water and chemical usage over once through design

Two Methods of Construction for CIP system • Fixed Place • Portable

Fixed Place CIP Systems • Systems are designed to be housed in one permanent location • One to several tanks mayy be included • May be located in utility (non-process) area • Utilities connections are only required in one location vs portable CIP • Permanent e a e t supp supply ya and d return etu p piping p g manifolds a o ds utilized p time over p portable systems y • Reduced setup

Portable CIP Systems • Portable systems y are designed g to allow the CIP system y to be brought to the cleaning application. • One to two tanks max due to size considerations. • Eliminates the need for permanent piping • Will require utility connections at each location where system will be used • Overall fluid volumes are reduced by not having to fill long supply and return lines • Requires time for setup at each point of use • Cleaning performance equal to fixed place designs

Typical CIP Cleaning Sequence Step Step Time Temp % chem GPM Description (min) (oC) conc. conc 1

Pre-Rinse

2

21

none

43

2

Detergent D t t Wash

20

71

2%

43

3

Rinse

2

71

none

43

4

Acid wash

15

71

2%

43

5

Final Rinseprove purity

5

80

none

43

6

Airblow to drain

4

none none

N/A

Process System CIP Paths Circulated Path

Circulated vs vs. Once Through •

X

X X

Circulated paths: – Increase contact time with a volume of solution – Conserve water and cleaning solutions – Reduce waste volume – Circulated final rinse • Simplifies sample collection • Ensures representative sample

•

Once through (Straight to drain)

Once-

– Initial rinses where soil load is heavy Through oug CIP Supply • Sweep loose soils away • Avoids

Path X

– soiling CIP lines – obstructing sprayballs.

– Post P t cleaning l i rinses i • Rapid dilution of cleaning agent solutions

– Straight to drain → High water use • Duration often longer than expected – Solutes diffusion from branches – Dissolution and diffusion from surface

– When used for final rinse • Sample represents only moment when taken

Drain

X X X

X

Process System CIP Circuit

CIP Supply y

•

– Same hygienic criteria as process lines – Slope to drain (or vessel) – Size for maximum flow

2"

HS

Vent Filter

Vent Filter

314

1"

HS

1-1/2"

VENT/ PROCESS AIR

1"

310

2"

1"

HS 110

1"

HS 120

1"

HS 113

•

3/4" I3

I1

V

Process system CIP design is often the same whether h th circulation i l ti iis local or returned to CIP system.

I2

•

Local Circu L ulation

Process Solution

Tank

CIP Return

2"

– V Vessell b bottom tt valve l -Adequate size to balance supply & return flows.

HS 004

X

TI 021

Bag

TE

TIT

021

021

PRODUCT

O

2"

CIP Return

HS 200

PRODUCT

1-1/2" HS 021

2" 2"

Drain

MIN

To CIP System

HS 001

3/4 4"

PRODUCT

CIP Supply & Return Lines

3/4"

CONTAINED DRAIN 2"

2" HS 022

2"

2"

DRAIN

CIP - Vessel

sually impractical to flood a ssel

Unlike lines Clean with CIP fluids sheeting down sidewalls and head Rounded corners essential

1

• • •

Ensure proper position with positioning device or mark. S Several l ttypes Monitor function

Cover internal tank Î surfaces

–

•

Complete coverage of vessel internals A id stagnant pooll iin tank Avoid k Static spray balls Dynamic spray balls or nozzles

Spray devices –

itical concerns

pray devices

•

Bottom outlet – –

•

2 CIP Return

Low point drainage Flush mount bottom valve

Disc type vortex breaker – –

Prevent air entrainment Improve solution flow

Î

Spray Devices • Fixed devices provide 5-7 feet of coverage from the device – Flow typically ≥ 2.5 GPM / foot (31 lpm/ meter) tank circumference – Example: p tank diameter = 3 feet,, • Sprayball flow = π x 3 ft x 2.5 gpm/ ft ≥ 24 GPM

• Spray device design criteria

Fixed Sprayball

– Provide adequate flow for operation – Must be self-draining – MOC compatible with cleaning agents • SS with finish equal to the tank

– Commonly solution directed to upper 25 25-30% 30% of tank • Coverage of lower surfaces by sheeting

Drain hole

Static Spray Ball Advantages

Disadvantages

No moving parts, low aintenance Sanitary design Allows for directed flow aths Low cost

•Relatively low velocity streams are not adequate for heavy soils •Cleaning relies mostly on erosion rather than on direct impingement

Principles of Operation – Dynamic S Spray Device D i Provide impact at surface to be cleaned Rotated by water flow or external electric or air driven motor Typically 60 psi or higher water pressure d li delivers an iimpingement i t ttype cleaning l i Shadow, baffles, ports are all concerns that still need to be taken into consideration

Dynamic Spray Devices

Advantages Direct high mpingement of the quid stream q Designed and ecommended for ery heavy soils or ery large tanks

Disadvantages •Potential for jamming and frequent maintenance on the mechanical device •Some have very high pressure requirements for proper operation •Generally require removal from tank during processing •Require proof of rotation •High cost

Require 100% coverage of tank internals • Shadowing – Dip tubes, baffles, agitator shafts may shadow portions of the tank. – May require multiple spray balls • Larger diameter vessels often require 2 or more sprayballs

– Run agitators at slow speed during CIP • Pitched blades cleaned by spray ball • Flat blade turbine (Rushton) impellers also require cleaning from below

• Baffles ff – 3 or 4 baffles often most effectively covered by equal number of sprayballs – Particularly true of larger vessels due to oblique angle of sprayball streams

• Factory F t acceptance t test t t with ith allll

Vessel Design Features Smooth surface to aid soil removal – Typically 15-20 microinch roughness after EP – Avoid sharp coners

Appurtenances selected and installed for drainability – bottom agitator pads – drain valves

Minimize number of shell nozzles Dished manway covers with minimum projection. Seals must be as close to vessel i.d. as possible – Hatchwayy O-rings g – Instrument ports: Instruments and plugs

Tank Nozzle Design for CIP Minimize L/D (2:1 target ratio) to ensure coverage from sprayballs

•Recommended minimum nozzle size: 1” L/A> 2 L/A ≤ 2 ASME, BPE 2007 Not Recommended Acceptable • Prefer nozzles flush with interior of vessel L/A (Length / Annular width) ≤ 2 for nozzles with dip tubes, splash tubes, or other inserted lines.

Vessel Sidewall

Avoid nozzles that extend om the vessel wall below pray devices (e.g. ygienic ferrules). These may not be cleanable Recommended minimum ope is 5° ASME, BPE Instrument Port 007 (e.g. Ingold fitting) susceptible to leakage around O-

Hygienic Ferrule Difficult to clean below level of spray ball

Bolted Hygienic yg Fitting (e.g. NA Connect)

Simple Rules of CIP Piping • CIP runs in Process lines. Process does not run in CIP lines. • CIP Piping must be completely drainable. • Overlap in two CIP circuits must be fully cleaned in both circuits.

• If L/D > 2, it is advisable to clean thru the branch & valve.

Line Cleaning Mechanism

Turbulent flow is essential

– Mass transfer of turbulent flow vs laminar flow is >1000X

Turbulence does not mechanically remove small particles adhered to the surface. – Soils are removed from surface as solvent and dirt “react” react – Solvent moves to and reaction products move from Velocity the surface by diffusion and convection Velocity Diffusion Diffusion –CIP Turbulent flow greatly reduces the boundary layer

Solution

Avg Velocity

CIP Solution

Avg Velocity

Biofilm – not mechanically removed b turbulence by b l Biofilm bacterium is ~ 0.5µm dia while the viscous sublayer for water is 25 µ for water moving at 8.6ft/sec. Biofilm Contamination Issues in Pharmaceutical Fluid Fluid-Handling Handling Tubing Jim Fleming and Dave Kemkes , Pharmaceutical Engineering, Sept/Oct 1999. Vol 19 No 5 Describes mechanisms of biofilm formation and effect of passivation. Good description of thickness of viscous layer (much thicker than microorganism thickness) where flow turbulence

Cleaning Process Lines • 1 1"

1"

„ Single step increase Î ½ flow velocity

•

3/4"

• Often

2"

MIN

2"

– Line from CIP header – Pump speed established on sprayball sp ayba route oute

Spray balls

2 • Flow initially• 1 established through g sprayball route • Sequentially clean line routes • Product transfer “in”

1. Line size • Avoid transitioning more than 1 standard tube size on route.

Target flow velocity 5 feet/secÎ 2. Boundary with adjacent system • Routes clean through boundary

What is the 5 Feet per Second R l ? Rule? Process piping systems must be designed for CIP flow rates allowing turbulent flow to contact all internal surfaces surfaces. Turbulent flow ensures all entrapped gases are removed from the cleaning area. If you don’t d ’t wett the th surface f then th you are not cleaning it!

5 ft/sec (1.5 m/sec) may be b needed to lood lines

TURBULENT FLOW PROVIDES GOOD MASS TRANSFER AT 1/2 FT/SEC IN A 1” DIAMETER TUBE 1

5 FT/SEC TO ENTRAIN GAS POCKETS FROM TEES.

5 FT/SEC MAY ALSO BE REQUIRED TO FLOOD VERTICAL DOWNWARD SECTIONS (1/2 FT/SEC)

(5 FT/SEC)

• Ã

5 Feet per second Cleaning Chart

ube Diameter (inches)

Flow Rate Needed to Achieve 5 FPS (GPM)

5

1.7

75

4.8

0

9.4

5

24

0

43

5

70

0

102

0

180

Velocity Calculations Formula to calculate the velocity “V” V in ft/sec through a given size of tubing in ft. V= 0 0.409 409 x GPM / tube id2 Formula to calculate the flow rate for a specific velocity “V” in ft/sec for a given size of tubing tubing. GPM = tube id2 x V / 0.409

Ported Valve vs Machined Block V l Valve

Potential deadlegs reduced or eliminated in block design

Vent and Filter Cleaning

Vent CIP supply from CIP header –

HS

830

If vent CIP is required

Remove filter elements for CIP Filter housings

HS

– –

COP dome Or - don’t clean dome at all (outside process boundary)

1"

1. CIP spools

HS 110

E

E

2. CIP Cap I3

V

•CIP Flow 3. Clean through g housing g

3. Clean through housing –

1"

1"

Replace with CIP spool Clean housing out of place (COP)

2. Replace dome with CIP cap

314

310

1. Remove • •

Vent Filter

HS 810

HS

Vent Filter

Easier with In-line filter flow up

FILTER HOUSINGS In-Line •

Orientation – Preferred orientation with the base downward. – Always orient base of a filter downward. downward – Low point drains must be provided both sides of filter

•

In-line style – Allows All di directt CIP flflow th through hh housing i • If process orientation and connected lines permit

– Cleaning and drainage of drain valve or port must be considered – particularly for liquid filters filters.

•

Tee-style – Easier to pipe and use – Dome becomes p potential dead space p if cleaned by CIP flow through process path • Remediate by CIP cap • Pipe route through gauge port

•

Decision of how to clean – Design for process and SIP as well as CIP

Drain

Tee

Machined block Tandem valves

•Tandem Valve Assembly

Route to drain from addition port may be eliminated. T d Tandem valve l assembly bl att esterilizable addition port

Machined block

– No dead leg in machined block – Enable reduction of number of routes directly to drain – Disadvantages Di d t

•Condensate Drain Valve

•Machined Block Valve

•To D

• Often more costly • Often longer lead • Requires earlier detailed design design.

•T To Drain

– CIP Dead leg between process valve and condensate drain – CIP path required to flush across weir of condensate drain valve

•CIP Dead Leg

•Condensate Drain Valve

Dead Legs Dead-Legs A dead-leg dead leg is an area in your process that is not in your direct path of flow Reduce or eliminate dead dead-legs legs in your piping design / layout H How d do you measure a d dead-leg? dl ? Length:Diameter