CIP Cleaning Process Steps:1.Pre-wash step involves removing heavily soiled material using hot water-once through the mode 1. Addition of the hot cleaning solution 2. Recirculation of the used cleaning solution back into the fixed equipment (recirculating mode) 3. Last rinse using hot water to get rid of any excess of cleaning solution 4. Blown down using compressed air 5.
Drying using hot air CIP Unit consists of the following, 1 to 5 tanks (a hot water, cleaning detergent, wash solution etc.), control system, pressure pumps for circulating the cleaning fluid the fixed equipment. The whole installation is installed on a stainless steel frame. (Lekkerkerker Dairy & Food)Cleaning out of place systems is a method where cleaning equipment is taken away from its operational areas, and taken to a certain place or area to be processed and cleaned.
Areas might require additional disassembly for COP and additional sanitization to achieve the necessary cleanliness. COP might mean to pull a part a plant site down, and to wash and cleanse equipment, and keep the products away from the plant ,certain parts will not be washed within the site with this process. Many different detergents are used, such as cationic, anionic ,non-ionic, alkaline etc. it depends on the surfactant found in the detergent, for different types of cleaning processes.
Non-ionic are used for the cleaning of equipment in pharmaceutical manufacturing. Non-ionic detergents also are used in cleaning glass products in pharma analysis. Other detergents such as extreme oxide are used very carefully and used on special equipment. Non-ionic detergents do not ionize when they are dissolved in water .They do not have the acidic or a basic nature, they can be cleaned easily and from the equipment surface. This detergent is very effective on oily material. These detergents are nearly always found in liquid form.
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2.5 Detergents used for cleaning of pharmaceutical equipmentNow days there is a broad spectrum of commercially available cleaning agents (detergent). However proper selection of these cleaning agents is critical prerequisites for cleaning validation The cleaning detergents commonly used can be classified into caustic, neutral, acidic, alkaline and oxidizing. Some pharmaceutical companies might only use water for injection to clean particular equipment without cleaning chemicals. Caustic detergents also known as sodium hydroxide is frequently used to clean equipment, storage tanks.
The mode of action include the degradation of fats, oils, protein deposits. To prevent redeposition, surfactants are also added among with the sodium hydroxide. Generally used as a degreaser on stainless steel and glass surfaces. An Alkaline detergents are the most popular, and use to remove a wide variety of organic soils. A neutral agents due to mild pH and enhanced compatibility are frequently used in manual cleaning applications. An Acidic agents are mainly used to remove any inorganic deposits and salts.
Commonly used for for rouge removal and passivation of stainless steel equipment. (Sterris) 2.6 Contamination control Contamination control is s generic term to control contamination in certain areas, it looks at temperatures, and surfaces to prevent contamination. Areas it convers are the environment such as dust, work surfaces, walls, and floors, and this method makes sure all these areas are non-contaminated, other areas of contamination are, pipe work, paint flaking, these would maybe have fibres and dust showing. Many organisms are potently detrimental to processes in the environment, contamination provides a massive risk to the technical processes of the production activities ,as well also to the people involved in the work and projects being carried out. There is also a protocol called the cleanroom, which would include ,clothing requirements for staff, people for example can change clothes under sterile conditions to prevent any particulates’ from entering outside areas of the environment ,contamination control is also vital for labs in the pharmaceutical and life science sector ,shops, and kitchens.
Food shops are also places where this method has to be in place correctly .product ranges are at a massive risk if these procedures are not met ,and can be very costly and expensive to companies if this is not met, example a company could lose thousands of euros if a bad batch was found contaminated ,it would be recalled .and the company would suffer and be at a loss . 2.7 Sampling methods:The sampling procedure refers to the method of collecting the residues from the surface so that they can be measured. There are a few types of sampling such as: swabs and wipes which dissolves and physically removes sample and can be used to wide variety of area; rinse which is easy, quick and can be used on large surface area; coupon-non technique dependent. Placebo which contacts the same surfaces as the product and direct surface which is rapid, non-invasive and economical, however some techniques are not widely developed. There are two general types of sampling: direct surface sampling using swabbing methods and the use of rinsing solutions.
Swabbing is more popular because it is a direct way of sampling. It gives the level of contamination per selected surface area, and even insoluble residues can be sampled by physical removal. Unfortunately many systems in production lines cannot be routinely dissembled and in this case the rinsing method has to be used. In this case a certain amount of insoluble or physically occluded residues should be taken into account. Spray Desorption Collection is for larger surfaces area’s to be sampled and compared to other swabbing techniques, providing a valuable pre-concentration advantage. Analytes coming from the sample surface are collected onto a partial part of the surface, which in a second step can be analysed. The FDA requires that all pharma manufacturing plants verify the cleaning procedures between active pharmaceutical ingredients (APIs) as residues can contaminate the subsequent products.
A residue limit is determined based on the size of the equipment in question. Equipment in use should always be examined and cleaned after its use ,the normal methods used for sampling and normally rinse and swabbing sampling, swabbing might sometimes use cotton wool to clean for example, rinse sampling is normally used for analytical testing, this method involves rinsing a certain area of a cleaned surface ,rinse sampling allows to test larger surface areas, and this is an advantage compared over swabbing. Pharmaceutical manufacturing facilities have hundreds of pieces of equipment, which can contain different materials of construction, thus high quality techniques are required .
The start of ambient ionization mass spectrometry techniques such as DESI12,13 and DART14 can allow samples to be analysed ,and often to bypass all sample preparation steps, this in turn will supply large area surface information analysis. Laser ablation products have been researched in recent times, also coming up with different analysis.Manufacturing equipment construction materials can be from aluminium stainless steel to and certain types of plastics. The material of particular interest is aluminium, which is difficult to recover active pharmaceutical ingredients (APIs) and detergent from, using swabbing techniques.
Further, while it is possible to achieve DESIMS analysis from metal surfaces, normally low signal intensities are observed due to the loss of charge to the conductive surface. (Shashank Jain, Received 17th September 2010, Accepted 16th December 2010) 2.8 Analytical techniquesVerification of cleaning processes is a massive task in pharmaceutical manufacturing in order to reduce and minimize cross-contamination of drug substance and/or drug product. Regulatory authorities require written documents on how to validate , monitor and conduct cleaning processes.
To evaluate the success of equipment cleaning, validated methods for analysing residues or contaminants from the manufacturing equipment surfaces are required. There are a few approaches used in to verify cleaning processes. The first approach employs methods designed to analyse for residues from samples collected ,such as swabs or solvent rinses of the equipment surfaces after equipment cleaning. The second approach employs automated methods executed by directly analysing the equipment surfaces after cleaning.
Ion mobility spectrometry (IMS) is an technique that separates ions according to their gas phase mobility at atmospheric pressure. IMS is very sensitive, normally it takes an analysis typically to be completed within 60 seconds , these areas of IMS should make it an perfect choice for use in cleaning verification analysis of pharma manufacturing equipment. All swab and rinse samples gathered from the equipment surfaces are successfully analysed and manufacturing equipment down-time was largely minimized due to the less work in cleaning verification analysis time (for example, the total analysis time for more than 35 samples using IMS was reduced to less than 120 minutes ,otherwise it would have taken much more work .and longer to complete the tasks if other methods were used. (A.GrangerV.PapovJ.
McCaffreyD.L.Norwood, 5 January 2010) 2.9 Validation of cleaning proceduresThe hygiene in production of surfaces at, dairies ,and beverage plants has a massive say on the quality of final products.as a result, the hygienic standard and the effect of the cleaning policy as well as the standard of cleaning and disinfection actions must be completed with the process design. Therefor validation methods will be available to get relevant information about the hygienic state of processes plants. The standard methods available all use physical testing at the surface in question. Also , the main surface area may be limited compared to the entire product contact surface.
Therefore validation of the cleaning policy is a rick and problematic in closed processes, as most of the inside in big tanks are hard to get to. The sizes of process tanks can be very big leading to small problems in cleaning as well as in physical sampling, i.e. it is hard to take a representative set of samples in tanks with a volume measured in hundreds of cubic meters. Also getting at surfaces in pipelines, pumps and valves for biofilm residue samples is scarce.
Secure test methods for viewing cleanliness are needed to validate evaluate and evaluate the cleaning process of fermentation tanks. The size of a fermentation tank can be many hundred cubic meters stopping the use of many used sampling methods since the reachable areas are hard to get to, compared to the all the tank surface. Pilot scale tanks were used to test the applicability of lots of methods for evaluation of the cleanliness of fermentation tanks. The main task of this study were to find reasoning methods to detect cleanliness in pilot scale tanks, to know which parts of the tank were hard to clean and to optimise the cleaning procedure. The main methods found to be correct for validation of the cleanliness were visual observation of a fluorescent indicator using UV-light, a contact agar method and culturing based on swabbing and swiping with non-woven cloths.
The validation of the cleaning procedure and the design of a correct cleaning system can be supported and improved using computational fluid dynamics, which via a simulation reveals the areas not easily found by the cleaning fluid. Microbial results from pilot scale studies are done to interpret the simulation results correctly. Using many methods simultaneously improves the interpretation of the cleaning of tanks.
(Satu Saloa, September 2008) 2.9.1 Validation of equipment cleaning methodsThe methods used for detecting problems in tank cleaning must be informative , practical , and harm free to the tank surface as well as to the product since residues of sampling chemicals can always stay on the surfaces.The cleaning of mainly large tanks can be validated utilising visual inspection. The visualization can be made more effective by soiling the tank with soil containing a fluorescent component, for example riboflavin or uranine, before starting the cleaning procedure.
The areas with fluorescent soil debris becomes visible by using UV-light. Though it sometimes can be difficult to see, if areas light up due to reflections in the area as intended. Mistakes are easily seen on stainless steel surfaces whereas plastic material is often fluorescent. Example an experienced observer is needed in this case to separate fluorescence soil from fluorescence of plastic surface. Normally the fouling appears as a dim white and sometimes pink coating. Jacob and Brandl (2002) also saw limitations in the visual process when they saw the efficiency of the cleaning and disinfection procedures in tanks in breweries.
They have also used UV illumination to see deposits. They also have used Fuchsine staining to see proteins and Lugol’s iodine solution to detect starch. Such methods are commercially available from, e.g. Bactoforce. (Satu Saloa, September 2008) 2.9.2 Cleaning validation protocolA lot of products have been taken back from the market due to cross-contamination with chemicals and pharmaceuticals in past years.
In the pharma industry and more times in food industry, the removal of some residues from the surfaces of production equipment is becoming a vital requirement. In a lot of production lines the same equipment is used for processing different products. proper cleaning procedures are also needed in order to avoid contamination of subsequent products. According to regulatory requirements, equipment must be clean and cleaning must be scripted 1–3. Cleaning operations should always be validated, with all steps carefully documented, for preparation and also the final report of the cleaning validation. analytical methods must be sensitive, robust and selective .
The most vital factors in measurements of effectiveness of proper cleaning are a standardized sampling procedure and a consistent recoveryA vital key to proper cleaning is also a scientifically justified analytical limit. Limits of surface contamination are usually assessed from the acceptance limits in the subsequently manufactured drug product on the main production line. For practical work a helpful document is FDA’s guidance for determining residue limits (Mirko Prosek, July 2005)
