GCEM 1st

Practical CIP system Design

The official Journal of ISPE March/April 2003, VOL. 23 No. 2

Reprinted from PHARMACEUTICAL ENGINEERING

Training Material No. SS0107-01

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 Introduction

 CIP (clean in place / 제자리 세정 ): the process used to ensure

that process lines, vessels and reactors are free of inorganic
and organic contaminants.

 In processes in which microbiological is essential, CIP also

encompasses SIP (Steam In Place) procedures.

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 Purpose of CIP

 CIP : the term used in the biopharmacetical industry to refer to

the process cleaning process system and equipment without
major disassembly of components.
 CIP assists in SIP operations by removing chlorides and
proteins. (leaving chlorides could cause stress corrosion)
 CIP involves a specific combination of predetermined manual
and automated operations to perform the cleaning, monitor the
operation, and document the results.
 Advantages: the minimum amount of water, chemicals, utilties,
effulent / improvement of safety / reduction of human errors /
documentation for validation through minimal operator
intervention (It will maintain product quality and reduce turn-
around time between batches.)

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 Factors affecting the CIP system

 Time
 Typical biopharmaceutical production: 24 hrs per day seven days a
week (CIP : a typical 8-hrs turn around cycle)
 Temperatures
 If proteins are present, the pre-rinse should be done to remove much
proteins. (Subsequent rinses and washes should be done done at
higher temperature.)
 Solution Concentration and Type
 Solutions can be made from commercially available bases and acids
or proprietary solutions can be purchased from firms specialized in
cleaning biopharmaceutical equipment.
 The rinses and washes: ambient DIW
 The alkaline wash: 1~2% caustic concentration
 The acid wash: lower concentration of acid

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 Factors affecting the CIP system

 Surface Characteristics of Equipment

 Historically, there has been disagreement as to advantage of polishing
compared to mill finish.
 Advantage: microscopic scratches provide surfaces for protein and
other contaminant adherence.
 Disadvantage

: sub-microscopic “scratches” are too narrow for contaminants to hide

 Internal Finish
- Cleaning: chemical reaction
- The typical biopharmacetical finish: 15 Ra u-in electropolished 316 L SS
- Electropolishing: smooth the surfaces and reduce the differential
between the microscopic peaks and valleys.

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 Factors affecting the CIP system

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 Flow Rate / Turbulence

 Tanks
 Component
 Spray balls
- function: to distribute the washes and rinses to the top of the tank
to wet all surfaces by a combination of spray and falling films
to allow the chemical action to take place
- properties
: typically sized for 15-20 GPM each and a 25 psi
mulitiple spray balls at the same time
important to design all paths within a circuit for the same flow rate
(measured by a Reynolds Number)
 Lines
 Principle : the controlling elements of cleaning kinetics
 turbulence will increase fluid movement to the surface
 a velocity of 0.5 ft/sec : sufficient turbulent flow
 Recommendation
 the higher velocity: better flow for cleaning (a velocity of 5ft :valid)

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 The typical CIP system

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 The typical CIP system

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 Design for Cleaning (1)

 Piping
 The system should be completely welded.
(the possibility of accumulation of contaminants)
 Return lines should have as much slope as possible to both encourage
gravity draining and discourage air pockets from forming which would
prevent cleaning fluids from reaching the surfaces to be cleaned.
 Branches should join the return header with minimum dead legs.
(Dead legs and pocket can retain dirt or even cleaning chemicals.)
 The lines should be cleaned individually or in series.
 No permanent connections should be provided between CIP and the
process: transfer panels, hoses, or mix-proof valves should be used to
make and break connections.
 Proximity switches or sanitary pressure gauges are used to confirm
paths and prevent mis-operation and/or unsafe operation of the CIP
circuit.

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 Design for Cleaning (2)

 CIP skid
 Normally contains a tank for rinse and chemicals solutions and a tank
dedicated to WFI for the final rinse.
 Components of the CIP skid : a circulating pump, heat exchanger, and
chemical day tanks
 Provide cleaning for CIP tanks since the tanks can be the dirtiest part
of the system.

the Niro Pharma Systems CIP System Skid

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 Design for Cleaning (3)

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 Components of CIP

Tank equipment valves

Pumps

Installation material Heat exchanger

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 Design for Cleaning (4)

 Filters
 Since filters are hard to drain, it may be necessary to remove, and
possibly discard, the cartridge for cleaning and then reinstall a new one
before sterilization.

 Accumulation

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 CIP Systems
 It is preferable to use a common philosphy for all CIP systems in a
plant. This will avoid operational errors, provide consistent control
system configuration, and maintain documentation format between CIP
system and users.
 Systems use either a self-priming pump or an eductor to assist in
returning and recycling washes and possibly some rinses to minimize
chemical consumption, utilities, and effluent.
 (Fig 2 : a typical CIP system : wash, rinse ranks, supply and return
pumps, a heater, piping, instrumentation, controls)
 Eductor systems use eductors either alone or in combination with
pumps to assist with recirculation and to make up the chemical
solutions
 Pump systems have flow rates and smaller diameter piping than
eductor systems. (eductor and pump system will operate better at
colder fluid temperatures.)
 Systems can be balanced by splitting spray balls so that they are
utilized either individually, in pairs, even two of three open at any one
time to make all paths within a circuit use the same flow rate.

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 CIP Cycles : ‘5’ steps

 Draining
Washer model 1
 Rinsing

 Cleaning

Washer model 2
 Sanitizing wash

 Final rinse

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 CIP Cycles : ‘5’ steps (1)

 condition : the same sequence during normal operation

 components: valves, agitators, pumps
(to ensure each fulid successively contacts all surfaces)
 CIP cycle in each step : 5,6 rotation for 3 ~ 5 sec
 The properties of CIP cycle
- regeneration of used rinse in the cycle
- the remaining rinse can be used as the starting point for caustic

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 CIP Cycles (2)
 Pre-Rinse
: use either a fresh, clean, cool water source (DIW)
or reuses the previous final rinse
: The pre-rinse is used to remove residual process fluid and debris.

 Recirculated Alkaline Wash

: Residual rinse water could be heated and fed with caustic or other
detergent to make up the alkaline wash.
→ denature and solubilize the remaining proteins.
: If desired cleaning results are not obtained, this is the step which
normally provides the most benefit from an increase in time.
: a mixture of chemicals, detergents, chloride or other additives
→ air blows are used after chemical wash

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 CIP Cycles (3)
 Hot-Rinse
: removal of the alkalinity and additional dirt

 Recirculate Acidified Wash

: neutralization of residual base, solubilzation of remaining dirt
and removal of mineral deposit / passivate the surface

 Hot-Rinse
: residual acid and any additional dirt is removed with a hot DIW rinse.

 Final-Rinse
: A final rinse (WFI) removes traces of previous wash.
: monitoring of pH, conductivity or resistivity

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 Control
It is important that the control system be easy to monitor, control, and validate.

The main control elements are time, temperature, and flow rate.

The main function of the control system is to pulse valves and operate rotating
equipment

The CIP system status can be considered as one of three or four states.

(1) Normal : target circuit cycles valves to clean associated paths

(2) Makeup : main path in targeted circuit is open for heatup and chemical
addition
(3) Hold : drain valves are closed to prevent loss of chemicals, valves are not
cycled, and timer is paused in the CIP PLC until state is returned to normal.
(4) Abort : system fails to pre-established safe position

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 Validation

 Advantage : minimization of the possibility of human error, time and reduction of

maintenance cost, improvement of operator safety
 In order to validate a CIP system, written documentation is required to define the
procedures for cleaning each piece of equipment, circuit, and flow path.

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 Conclusion

Proper implementation of CIP seems to be a mixture of art and science.

There is nothing wrong with using empirical relationships provided they

don’t conflict with good engineering practices.

A well-designed CIP system can achieve minimum flow of velocities in both

supply and return lines without accumulating fluid in the tanks being
cleaned.

A combination of properly designed outlet connections and return pumps

can be used to achieve the desired results.

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