CONCEPT OF CIP (Clean In Place ) AND FACILITY CLEANING

Cleaning is much important step in pharmaceutical production and delivering high quality products to the system .

Cleaning is done by multiple step approach and all that have necessary role in production of high quality accepted product.

To minimise the times , money and inventory we discovered the concept of CIP - i.e. Clean In Place
System.

By this system we clean and sterilize all the pharmaceutical equipment on working site , without any loss and dissemble that's the advantages of CIP .

And also other method of cleaning are explained here .

1. CONCEPT OF CIP AND FACILITY CLEANING Presented by Shankar D. Maind M.Pharm ( QA ) Guided by Dr. M.C.DAMLE ( HOD Quality Assurance ) AISSMS COP, Pune 12/07/2023 1

2. INDEX INTRODUCTION CONTAMINATION TYPES OF CLEANING SITUATION CIP (CLEAN-IN-PLACE ) REGULATORY REQUIREMENTS 6) CLEANING METHODS 7) REFERANCE 2

3. INTRODUCTION Cleaning : It is generally as just as critical to have effective cleaning processes as to have consistent ,validated manufacturing processes .Several developments have caused this emphasis on the cleaning . The new generation of products (as well as those in the current "pipeline") tend to be more potent ( eg , many are potent in mg and sub-mg doses). A series of tragic contaminations occurred over the last several years that led to serious personal injury. Many individuals are sensitive to various drugs and that these sensitivities, often described as allergenicities , can be very serious. The basic reason for having good, effective, consistent cleaning procedures is to prevent the contamination of products made subsequently in the same equipment. The goal is to provide pharmaceutical products of the highest quality to our patients. 3

4. Contamination & Its Causes Defin e : The act of contaminating, or of making something impure or unsuitable by contact with something unclean, bad, etc. There are multiple causes of Contamination : Cross – Contamination with active ingredients Microbial contamination Contamination by cleaning or Sanitizing agents Contamination by miscellaneous other materials 4

5. 1). Cross-contamination with Active Ingredients : Addition of two or more API show different set of effects a) Synergetic Effect b) Antagonist effect c) Agonist d) Reverse antagonist 2). Microbiological Contamination : Microbial growth continue even after the ,cleaning of equipment from chemical product residues . The critical part is the storage of equipment in wet condition . This microbial contamination in non sterile product ,causes illness to the patient . Sevearity depends on the route of administration . 5

6. 3). Contamination by cleaning or Sanitizing Agents : To remove the stubborn residues ,its essential to use strong toxic materials for cleaning purposes . Sometimes these materials acts as a potential threat as contaminants . 4). Contamination by Miscellaneous other materials . In addition to usual and expected list of potential contaminants , there are some elements which can cause conamination . ex; paper filters , bristles from brushes ,micron filters ,gowning material , cleaning aids ,cloth and cotton fibres etc. 6

7. Types of Cleaning Situation Another factor that helps define the cleaning strategy is recognizing the type of problems faced with what is going to be manufactured next in the equipment. A useful exercise is to list some typical changeover situations and examine the potential for contamination. For example, in the manufacture of APIs there are the following types of changeovers: Switch from batch to batch for same product (campaign situation) . Switch from final step of one product to final step of different product. Switch from final step of one product to intermediate step of a different product Switch from final step of one product to initial step of a different product Switch from intermediate step of one product to final step of another product 7

8. In the manufacture of drug dosage forms, there are still other changeover situations. Some times are as follows : Changeover from one batch of a product to another batch of the same product. Changeover from one product to a different product. Changeover from one strength of a product to a different strength of the same product . 8

9. Regulatory Requirements The focus here will be on the US Food and Drug Administration (FDA). The FDA has taken the lead in requiring cleaning validation and in helping shape what is expected in a cleaning validation program. Pharmaceutical companies have always practiced cleaning, and cleaning has always been a part of Good Manufacturing Practices (GMP). A review of the cGMPs Q21 CFR Parts 210-211) shows many statements, paraphrased below, that are related to the cleaning process 211.42 : Buildings shall be of suitable size, construction, and location to facilitate cleaning 211.42 (10/v): A system shall be maintained for cleaning and disinfecting the aseptic processing room and equipment to produce aseptic conditions 211.56a) Buildings shall be maintained in a clean and sanitary condition. 211.56 b): There shall be written procedures signing responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning. 211.56 c) There shall be written procedure for the use of cleaning and sanitizing agents 211.63 Equipment shall be of the appropriate design cleaning 9

10. 211.67 a ) : Equipment and utensils should be cleaned , maintained, and sanitized at appropriate intervals . 211.67 b) : Written procedures shall be established and followed for the cleaning of equipment. These procedures shall include responsiblity for cleaning maintenance , sanitizing schedule, description of cleaning methods, protection from recontamination, inspection of instrument before use . 211.94 Containers and downs shall be clean and, where appropriate, sterilized and depyrogenated . Methods of cleasing sterilizing, and de- pyrogenating shall be written and followed . 211.105(6) : All processing lines and major equipment shall be properly identified to indicate their contents and, when appropriate, the phase of processing. 211.111: Time limits for the completion of each phase of production shall be established 211.113: Appropriate written procedures to prevent microbiological contamination shall be established and followed. 211.182: A written record of major equipment cleaning shall be included in equipment logs. 211.188 : Records shall include documentation that each significant step in the manufacture was accomplished. Clearly, these GMPs require that cleaning SOPS (Standard Operating Procedures) be in place and the cleaning processes be documented. 10

11. CLEANING METHODS Cleaning methods are usually differentiated based on the extent of disassembly required for the cleaned equipment and on the method of contacting the chemical cleaning agent with the surface to be cleaned. Knowing of the limitations of cleaning methods is important to facilitate appropriate controls to help assure a validated or validatable cleaning process. Application methods include the following: CIP (clean-in-place) Agitated immersion Static immersion (soaking) Automated parts washing Ultrasonic cleaning High pressure spraying Manual cleaning 11

12. 1. CIP-Clean in place CIP is a chemical process dependent on the type and concentration of solutions used and also on solution temperature, time in contact with the substance of deposits . The deposits are dissolved chemically, and the cleaning solution flow velocity must always be sufficient to carry away the dissolved and dislodged particles from the wet surfaces. Cleaning-in-Place Systems Cleaning-in-place (CIP) is a commonly established cleaning method in food and beverage manufacturing operations. CIP is designed to remove residual product and bio films from processing lines and equipment using turbulent cleaning fluid, without the need to dismantle the equipment. Cleaning applications can be classified into two groups based on the extent of disassembly-CIP. (clean-in-place) and COP (clean-out-of-place) 12

13. The Factors Influencing the CIP Cleaning The removal rate of deposits is affected by temperature and concentration of the cleaning solution, contact time, pressure and general flow hydrodynamics . 1. Temperature - Effective CIP cleaning can be achieved when the temperature of the cleaning solution is around 55 OC to 70 OC (Lloyd, 2008; Majoor , 2003). 2. Concentration - The concentration of caustic widely used is 1.0-wt% NaOH (Lloyd, 2008; Majoor , 2003) . 3. Pressure - The pressure used with CIP inside pipelines is typically around 4.1 x 105Nm-2 (60 psig) to 6.9 x 105 Nm-2 (100 psig); and in the case of tanks the pressure should be less than 4.1 x 105N m-2 (60 psig) 4. Flow - Because CIP relies on shear force removal of material turbulent flow conditions are preferred, generally with Re > 4000 13

14. The Clean-In-Place system was developed in 1950 The people before 1950 14

15. A process control unit. The concentrated cleaning agent storage tank is usually a plastic tank or carbon, although a drum of the cleaning agent may serve as the vessel for the concentrated cleaning agent. Alkali (1.0 wt% Sodium hydroxide ) Acid ( Nitric Acid &Phosphoric Acid ) Specially Formulated Deteregents A separate CIP wash tank (also called the recirculation tank) is used for cleaning agent dilution and serves as the reservoir of diluted cleaning agent for recirculation throughout the CIP system. The recirculation pump is usually a centrifugal pump that pumps the cleaning solution from the wash tank to the spray devices. Usually the spray device (a device not unlike a shower head, albeit one that typically sprays up rather than down) sprays the cleaning solution around the dome of a process vessel so that the cleaning solution is adequately distributed within the process vessel. 15

16. There are usually Two types of spray devices . Fixed (Stationary ) Rotating (Dynamic ) Fixed spray devices may be permanently installed in a tank, or they may be installed in place immediately before CIP cleaning is performed. Rotating spray devices are also mounted in one orientation; however, the head will rotate through a pattern providing direct impingement over a larger area Rotating spray devices are generally operated at higher pressures, up to 100 psi or greater. The higher pressure allows more mechanical energy to be inputted into the system, therefore making the cleaning process more efficient in some cases. 16

17. Spray devices are usually of either fixed (sometimes called stationary) or rotating (sometimes called dynamic) types. Fixed spray devices (usually spray balls) are mounted in one orientation, and the direction of spray does not change during the cleaning process. Fixed spray devices are simple in design, have no moving parts, are free draining, and are therefore ideal for "sanitary" applications. Fixed spray devices are generally used at lower pressures of about 15-40 psi. 17

18. CIP systems are usually designed for cleaning with aqueous cleaning solutions. The key parts of the CIP system are the spray device(s), the CIP unit, and the associated piping to carry the solution to and from the equipment to be cleaned . The CIP unit consists of one or more CIP tanks, a recirculation pump, and Chemicals utilised are as follows Alkali : 1.0wt%NaoH Acid : Nitric acid or Phosphoric Acid Specially Formulated Detergents 18

19. 7 Steps of CIP Process The Pre rinse Caustic wash Hot Water Acid wash Hot water Hot Water (At High Temp ) Sanitising Rinse 19

20. Advantages of CIP System. Designed for cleanability Automated Consistancy Water /cleaner savings Reduced Time Savings Equipment wear Ease of Validation Safety of Operation Increased efficiency . 20

21. 2 . Agitated Immersion Agitated immersion involves filing a process vessel (and associated piping) with a cleaning solution and then agitating the solution with a mechanical agitator already in place in the process vessel. The cleaning solution can be either an organic solvent or an aqueous cleaning agent. In such a system, after the cleaning step, the vessel is drained and then filled multiple times with rinse water for other rinsing solvent) to remove soil residues and the cleaning solution. During the rinsing steps, the rinse solutions are agitated just a s in the cleaning step. The effect of the agitation is to bring fresh cleaning solution in contact with the residue on the surface. This maximizes the cleaning effect . The second purpose of the agitation is to remove solubilized / emulsified/suspended soils from the equipment surfaces and carry them to the bulk cleaning solution. This prevents soil concentration gradients from forming near the equipment surfaces; such gradients can slow down the cleaning process 21

22. 3 . Static Immersion Static immersion is agitated immersion without the agitation. In static immersion, a process vessel is merely flooded with the cleaning solution (either aqueous or organic solvent). The sole cleaning effect is due to the chemical action of the cleaning solution. Even this chemical cleaning action is minimized because concentration gradients of residues solubilized , emulsified, or suspended near the equipment surfaces tend to retard the cleaning process. Depending on the nature of the residue and the cleaning agent, times for the cleaning step can take from 50 percent longer to as much as500 percent longer than with agitated immersion 22

23. 4 . Automated Parts Washing Automated parts washing is in the domain of true COP applications. Parts that are disassembled from process equipment or other small parts such as scoops that are used in the manufacturing process can be cleaned in this manner. The parts are placed in a mechanical washer and processed through cleaning, rinsing, and drying cycles. The cleaning solution and the rinse water are applied to all surfaces of the objects to be cleaned by spray jets and nozzles. Automated washers are two types . In cabinet washers, the parts are placed on racks inside the washing cabinet, and all cycle occur with the racks in a fixed position (like a home dishwasher). In tunnel washers, the parts placed on racks that travel through the tunnel washer. Cleaning, rinsing, and drying o different locations within the tunnel washer. 23

24. 5 . Ultrasonic Washer Ultrasonic washers are essentially open or covered tanks with a cleaning solution in the tank Tanks may be covered to prevent evaporation or aerosolization of the cleaning solution. The tank is equipped with ultrasonic transducers, which pass high frequency soundwaves through the cleaning solution. At the surfaces of objects placed in the ultrasonic cleaning solutions, the soundwaves cause tiny bubbles to form. As these bubbles grow, they eventually collapse upon themselves. The mechanical energy of the collapse helps dislodge any residues or particulates on the surface. This process is called cavitation . The cleaning agent solution helps to wet the residue wand then keep it suspended or emulsified. As a general rule, ultrasonics are run at temperatures below about 55°C . For example, filing needles might best be cleaned by an ultrasonic process. Following the exposure in the ultrasonic bath, the part is manually removed and rinsed by any suitable method, such as with flowing water. The advantages of ultrasonics :Excellent cleaning for delicate items Low initial capital cost Disadvantages are as follows :Significant manual processing Validation issues 24

25. 6 . High pressure Spraying A high-pressure spray application involves using a high-pressure, continuous, directed water or detergent solution to clean parts or to clean the inside of process equipment. Water pressures may be on the order of hundreds of psi. This usually involves the use of a spray "wand" of some type. In its simplest version, the spray wand is manually controlled to clean small parts . In a more sophisticated version, an automated spray wand is inserted inside process vessels, where the spray direction and orientation are robotically controlled to clean and rinse all surfaces, water alone would be effective in dislodging residues; a detergent solution is usually needed to avoid the redeposition of particles in other parts of the system . Advantages: Relatively Low capital cost , Highly effective Disadvantages • Large amount of water Variability of manual system Equipment 25

26. 7. Manual Cleaning Manual cleaning covers a variety of cleaning types. The types of manual cleaning covered are wiping, sink brushing, and equipment brushing. They all have the inherent advantage of low capital costs and the inherent disadvantage of higher variability. When done right, they can be very effective . 26

27. Referance https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-D/section-211.67 A guide on CIP by CSI ,Cleaning Resources , https://youtu.be/B1YC6SBGdTU B idswell , Edward, “Risk Based Approaches Facilitate Expedient Validations for Control of Microorganisms During Equipment Cleaning and Holding,” American Pharmaceutical Review, November/December, 2005, pp. 28-33 4) FDA Guide to the Inspections Validation of Cleaning Processes. 1997, p. 2 . Code of Federal Regulations, 21 CFR Part 211.67, Equip- ment Cleaning and Maintenance. Sheetal patil , Modern College pune , Book of Pharmaceutical Validation , PV ,Publication ,First edition ,Page No. 8.1-8.15 . Davey, K. R., Chandrakash , S. and O’Neill, B. K. (2012). A new risk analysis of Clean-In-Place milk processing. Food Control – accepted 6 June doi.org/10.1016/j.foodcont.2012.06.014 27