CIP (Clean in place)

INTRODUCTION

In a general fermentation process, occurring in a fermenter, there is a contact between micro-organisms and feed solutions to the bioreactor parts. Before going further to the next batch these fermenters need to be properly cleaned, sterilized and free of in process residues and endotoxins. A hygienic and cleaning environment is necessary for microbial growth in large production plants.

Manual cleaning of fermenter parts is not easy procedure, an automated cleaning of interior surface of vessel, pipes and associated fittings is a demand. This demand is also a necessity in many food and dairy industries but is totally different from those encountered in bioreactors.

CLEANING PROBLEMS- The configuration and features of a bioreactor cause problem in cleaning process. We all know as basic requirement of a reactor vessel there are side ports for temperature, pH and dissolved oxygen. Sensors also play major role and are a minimum requirement in a vessel. The shaft of agitator is provided with double seal and spargers are located down the vessel. For anti-foam and media additional points are there. This coupling assembly of vessel and design of cleaning process affects clean ability of vessel. Fermenters which process non-filamentous bacteria and broth of yeasts generally have cleaning problems and cleaning procedures must match to fermentation process and vessel configuration for satisfactory cleaning.

WHAT IS CIP AND ITS OPERATION- A less expensive, less labor-intensive, less chemical expose and faster process to clean interior surfaces of a reactor like pipes, valves and other utility parts without vessel disassembly is CLEAN IN PROCESS (CIP). It is an effective, repeatable and reliable procedure for biotech and pharmaceutical industries. Its procedure is as follows:

1. Pre-rinse- It is mainly for the pressure and passage test throughout the tubing, removes solid residues and visible particles present in the vessel. A non-chemical cycle that wet the reactor, tubes and piping so that nothing resist the following cycle. De-ionized water is used for this step and a turbidity sensor to detect efficacy.

2. Caustic wash- an alkali or a detergent, sodium hydroxide popularly known as caustic soda has very high pH that softens all the fats and proteins present and flush them out easily. It is used as a non-foaming formulation at higher temperatures, can be reused in other cycles making it a cost effective step.

3. Intermediate rinse- Fresh water is used to remove traces of detergent and remains. To ensure this step, sensors like level and flow transmitters, probe monitors and conductivity transmitters are used to monitor and control set points.

4. Acid wash- nitric acid or phosphoric acid are commonly used after caustic wash for scale removal and protein degradation. This step requires less heat and lower temperature unlike caustic wash and eventually stabilizes the pH environment in the reactor. Acid is good in removing calcified mineral stains and are good in brightening material of the vessel.

5. Final rinse- Again with de-ionized water chemical compounds are flushed out. This water can be reused as pre-rinse solution for next cycles making it more economical.

6. Air blow- this step removes the moisture present in tank, pipes or valves after final rinse. This step removes the need of disassembly of the utilities and valves keeping less efforts for cleaning process.

7. Sanitizing rinse- Before starting the production run, to kill unwanted microbes and to remove hypochlorite salts sanitizing is effective step and inexpensive to use. Mostly PAA (combination of hydrogen peroxide and acetic acid)- a bleach based sanitizer is used which does not cause corrosion of bioreactor.

CIP SYSTEM-

1. RECIRCULATION PUMP- For maintaining turbulence throughout the piping circuit, pressure and solution flow- velocity should be optimum and that is why supply pumps are used. According to the diameter and size of tubes and valves pressure and solution velocity is calculated.

2. HEAT EXCHANGER- From a metal plate or metal tube trough thermal conduction indirect contact of steam exchanges heat from one system to another. This type of exchange is called indirect heat. A second form of heat is via fluids which are injected at that moment called as direct heat. Shell-frame and plate-frame are few types of heat exchangers.

3. DOSING PUMP- Manual addition of chemicals might not be accurate, so pumps are

used to deliver exact amount of fluids or chemicals to meet the requirements of cycles. Acid and caustic soda are added through this pump.

4. CONTROL PANEL- These panels are used for automatic feed of water, maintain heat of the tank, flushing and circulation of solutions via instrumentation and sensors.

5. PIPING AND INSTRUMENTATION- Inflow of water, solutions and chemicals is done by pipes and valves and a proper set of system is developed for utilities to be handled.

FACTORS AFFECTING CIP-

1. Rinse activity

2. Contact time of solution

3. Solution flow rate

4. Supplied temperature and pressure

5. pH control

6. Material of tanks and its level

TYPES OF CIP

1. Single tank- It is the most basic, simple, flexible and compact type of system. Single tank is used for dual purposes, rinsing and cleaning both in one tank by recirculation typically designed to reduce cross-contamination. It is a stationary design which is portable from one place to another. It is low cost system where space occupied by tank is also minimum. For low scale procedures single tank CIP is used.

2. Separate tank- It is two-tank type of CIP system where one tank is for rinsing and other tank is for washing. These tanks can be both fixed or portable types, depends on the industry level. In this the water requirement and usage of water is comparatively less to single tank system, wash solution can also be re-used for certain number of cycles which eventually reduces solution make-up time. For low production level to pilot scale two-tank CIP systems are used.

3. Multi-tank- At most 4-5 tanks are used in this CIP unit where transport of tanks cannot be done. Hot rinse tank is used to provide hot water at specific temperature and a separate tank for cold water (PW or WHI) is also used. Wash tank is for washing and one detergent tank where acid/alkali solutions can be stored is also present. This unit is mainly used for production scale where water consumption and reuse of washing and rinse media solutions are economized.

4. Automatic, manual and skid mounted units- Thinking about small facilities manual CIP systems are beneficial as they do not require automation and manually residues can be removed. In case of medium and larger units movable and automated systems are important factors where manual operation cannot be performed. The more advanced versions include ball sprays, mounted skids and nozzle systems that gives effective cleaning.

CIP MONITORING AND CONTROL- For monitoring and control evaluation different sets of sensors are used at different set of points.

Few sensors are as follows:

1. FLOW VELOCITY SENSORS

2. CONDUCTIVITY SENSORS

3. TEMPERATURE SENSORS

4. ELECTROMAGNETIC FLOW METER

5. CALORIMETRIC FLOW SENSORS

6. HYDROSTATIC PRESSURE SENSORS

7. ULTRASONIC SENSORS

*Image source: DEMA, Journal of industrial microbiology by Yousuf Chisti, Milkon heavy engg. co.

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