CLEANING VALIDATION What is validation?

Validation is an activity which is undertaken to generate documentary evidence to establish that a process, procedure and method adapted in pharma manufacturing, cleaning and testing of pharmaceutical product yields desired and predetermined result. Cleaning procedure is very important activity in pharma manufacturing, Cleaning is done to prevent contamination from air borne dust, dirt and residue of active pharmaceutical ingredient or excipients from other products and residues of detergent and disinfectant , microbial contaminants, so as to protect product to be manufactured will be free from from cross contamination from such contaminants, there are some drugs which have very potant activity even in very low amount and dose such products when contaminated with product being manufactured can lead to very serious hazards. Cleaning Validation: It is a process of generating , gathering data which establish that cleaning activity carried out is satisfactory , and is able to remove all sorts of contaminations, residues to a predetermined and acceptable level, from actual cleaning activity carried out under supervision of qualified technical staff as per the established standard operating procedure and as per the validation master plan, the residue may be airborne particulate matter, microbe, or residue of active pharmaceutical product or residue of disinfectant and detergent used for cleaning. Objective of the procedure should be to establish documentary evidence that the procedure adapted in cleaning is able to provide desired level of cleaning consistently. Limit of the residues of previous products is calculated by keeping in consideration its pharmacological activity, mode of action, and LD 50 , batch size ect. This is also called as The Cleaning validation is performed to demonstrate the effectiveness of procedures for Cleaning to remove residue of previous product. A standard operating procedure is made in consideration of all aspects of batch size, contaminants, and residues remaining after cleaning. A Validation master plan is drafted to plan all activities in cleaning validation as sequentially done in proper order, beginning from identification of aira, machinery and sampling procedure and testing for residue. Based on this a cleaning validation protocol is prepared and followed during validation process. `This include details as cleaning procedure, sampling procedure and sample quantity , Specification with limits for residue and test procedures. Maximum carry over limit of drug reside after cleaning depends up on the various factors like LD50, therapeutic index of the drug in question, there are many other factors which must be considered, factors related to previous product are alergenic capabilities , minimum therapeutic does , daily dose limit. Equipment factors which are also required to be considered are equipments series used to manufacture the previous product which will be again be used for nex product, minimum batch size of the next product where in the left over residue might get mixed and diluted, and never the less the amount of solvent used to take swab samples for the purpose of calculation, and surface aria of the equipment cleaned. Other important factors like teratopgenesity and allergenic capabilities of drug molecule or its metabolites are also required to be considered in assigning maximum carry over limit after a cleaning procedure in pharmaceutical manufacturing process. Microbial limits : The cleaning procedure adapted must be able to remove all pathogenic microorganisms, and allow to maintain the lowest possible load that is almost lower than the limits for raw as well active ingredients of a pharmaceutical product being manufactured.

LIMIT FOR RESIDUE AFTER CLEANING Residue limit after equipment cleaning US FDA have not mentioned specification or limits or methods cleaning and for residue after cleaning of equipments and its parts, as there are lot of variations in equipment designs and drugproducts to determine if the cleaning process is validated or not. Establishing the limit for residue after cleaning of equipments should be logical, it should be practical and achievable based on knowledge of chemistry of residue and it should be verifiable. Some pharmaceutical industry representatives do mention limits for residue after cleaning of equipments as 10 PPM for analytical detection level and for biological activity level as 1/1000 of the normal therapeutic dose of the drug in the residue, and organoleptic limit as no visible residues after cleaning. The residue of the detergent used must be absent or to a very low level only detectable in minute quantity in ultra low detection methods The sensitivity of the method used for detection and estimation of residue after cleaning should be capable to achieve the detection determinations and estimation of residues to the set limits level. The drug residues may be from intermediates and byproducts may skip the regular method of detection hence complete screening of intermediates of drug products must be done, while setting up the limits. TLC screening of the residue sample do provide good method for finding out the residue after cleaning, it is of great importance in case of steroidal drug products where very micro level of steroidal drugs contamination should be avoided. RESIDUE OF DETERGENT AFTER EQUIPMENT CLEANING, IS THERE ANY LIMIT FOR RESIDUE OF DETERGENT? Detergent selection for pharmaceutical equipment cleaning Pharmaceutical manufacturer should evaluate and validate the cleaning process so that the detergents are completely washed away or removed, and with some ultra low detection methods the value of residue must be to very less. As the detergents are not the part of the process and they are added in to the equipment to facilitate cleaning of drug residue. As the detergents composition and quality are likely to change over a period of time and many manufacturers do not provide complete chemical composition so that their residue detection may not be complete after cleaning by a regular method. Therefore selection of detergent for cleaning should be done after considering these aspects. CLEANING VALIDATION ITS REQUIREMENTS AND REGULATORY ASPECTS. Validation of cleaning process in pharmaceutical manufacturing is important validation process, it is one of the important and mandatory requirement of almost all food and drugs regulatory agencies and FDAs around the world .In US. The US FDA current good manufacturing practiceregulation 1963 says that the equipment must be maintained clean and orderly the main concept behind the cleaning validation is to prevent cross contamination or adulteration of drugs. As even in a very small amount the drug contaminations are likely to produce sever untoward reactions, example penicillin and drugs regulating blood glucose, cardiac glycosides and drugs acting on heart and blood pressure regulation system if contaminated in very trace amounts may result in fatal untoward health events in patients , a drug cross-contaminated with a potent steroids or hormones has very great adverse effect on health of an individual. Many drug products were recalled in past in USA due cross contamination with actual or potential penicillin. In 1988 a drug product Cholestyramine Resin USP was recalled as bulk pharmaceutical chemical used in the product was contaminated with low level intermediates of a pesticide due to reuse of recovered solvent, since there were no adequate controls over the solvent drums, firm lacked a validated cleaning procedure for process and did not had a cleaning validation in place for the cleaning of solvent drums.

Therefore in FDA inspections special attention is always given on cleaning validation programs at all levels in process beginning from receiving of material, and in all inprocess stages till the finished product. It is required that a pharmaceutical company should not only see absence of previous product, and detergents used in cleaning the equipment in a swab test or in equipment rinse water ( also see water system validation ), rather other aspects which affect cross contamination too are important like using common equipment and arias for processing of drugs with serious health effects if cross contaminated . CLEANING VALIDATION AND SAMPLING PROCEDURES Sampling in cleaning validation: i. Direct sampling (swab test). There are two sampling methods which are most used and are accepted by regulatory agencies worldwide, they are direct sampling methods that is the sampling of surface of the equipment and rinse solutions. The advantages of direct sampling method in cleaning validation is that the surfaces of equipments and machines which are otherwise difficult for cleaning can be evaluated for their cleanness after cleaning. The effectiveness of this method should be evaluated properly the sampling adhesives in swab many time have tendency to interfere with the test, therefore in while making the validation program and cleaning validation protocol the materials used for sampling should be verified for their interference. The residues which get dried or are insoluble can be directly sampled by physical means. ii. Rinse water (Rinse solution sampling, rinse water analysis). The advantage rinse sampling is that the large aria of the surface of equipment can be sampled and evaluated. The areas which are otherwise not accessible for direct sampling can be washed with the rinse solution and the rinse sample can be analyzed for the residue after cleaning. Rinse water, rinse solution sample can be taken over from the parts of equipments which can not be disassembled. Alternative method for sampling should be adapted when the residue becomes insoluble and occlude the equipment, observing the equipment by a quality assurance personal physical is of importance in such cases. Only rinse water quality test for contamination is not acceptable by regulatory agencies rather they want the evaluation whether it meets the required limits and whether it can assure that the cleanness of equipment when it is used during cleaning validation, it should be able to test it for potential contaminates. The quality assurance procedures should be in place for direct or physical observation of residues after cleaning. CLEANING VALIDATION AND ANALYTICAL METHODS USED FOR DETECTION OF RESIDUE CLEANING VALIDATION AND ANALYTICAL METHODS The specificity and the sensitivity of the method used for detection of contaminants after cleaning process are of great importance. If the residues of previous product or the cleaning process is not detected in the analysis, which doesnt mean that it is completely absent, it may be a case where the sensitivity of the analytical method and the limits may not be able to trace them in present concentration in the sample. The poor sampling method may be a cause of the absence of residue after cleaning as well. Therefore it is advisable that the analytical method must be challenged with different combination of sampling methods which are particularly used to demonstrate that the contaminant residue can be removed from an equipment surface at the level of 50% and 90% etc .

Cleaning process evaluation and production in process quality control tests. In process quality assurance tests can be used as tools to evaluate the efficacy of cleaning process, some of the indirect test like conductivity of last wash water can be used to predict and monitor the cleaning process. There must be a correlation between the in process test used to monitor effectiveness of cleaning, and during validation these tests should document that the the equipment not cleaned completely fail the in process tests employed. good manufacturing practices.
EVALUATION OF CLEANING VALIDATION AND ITS GENERAL REQUIREMENTS Cleaning validation is very important and integral part in pharmaceutical validation, about cleaning validation all regulatory agencies around the world require that a pharmaceutical company should have a written standard operating procedure SOP for various cleaning validation of equipments and its pieces and premises. Whenever there is a one cleaning for batch changeover of same drug product and a different cleaning process for process for cleaning between different batches of the same product and use a different process for cleaning for different product FDA require a written procedure and SOP for to take care of these different product change over and same product batch change over cleaning process and its validation. If there are two different cleaning procedures one adapted for removing water soluble residues and one for non water soluble residues it is required that pharmaceutical firm should have written procedure in place for both process and provide clear direction about the events of applications of these cleaning procedures or when to use these different cleaning procedures. In case of bulk pharmaceuticals where certain equipments should be dedicated where ever there is difficulty due to product characteristics which make residue difficult to be removed from equipment parts. Similarly Fluid Bed Driers (FBD) bags are often dedicated to a particular product to avoid cross contamination, the cleaning procedure should ensure that the detergents and cleaning aid solvents and detergents are removed completely from the equipments. FDA require a pharma company should have a written general procedures for validating cleaning procedures and process that is how to validate cleaning processes. FDA require that the responsibility for performing and approving the cleaning validations and its acceptance standards or criteria and to decide re validation schedules should be delegated properly and effectively. There should be a written validation protocol in advance for any cleaning validation to be performed on any type of equipment or its pieces or equipment systems. And the issues like sampling procedures and analytical methods and their sensitivity should be addressed properly in advance. FDA requires that the cleaning validation studies should be carried out according to cleaning validation protocol and the results of the study should be documented to documented properly. FDA require that the final validation report should be approved by the management and it should state clearly that whether the cleaning validation process is acceptable and valid or not in accordance with the sportive data suggesting that the residues of are cleaned or removed to the acceptable level. EVALUATION OF CLEANING VALIDATION Evaluation of cleaning validation is also a very important step, a pharmaceutical firm should focus on the objective of the validation process. There is no point in adapting extensive sampling and testing methodology unless the objective of cleaning validation process is set clearly and the steps in cleaning process are effective, therefore effectiveness of cleaning steps is important aspect as they will be required to be effectively achieve the objective of the cleaning process and itsvalidation. During evaluation of cleaning procedure for a equipment the methods applied for cleaning like scrubbing by hand or washing with solvent are also important variables which should considered properly in protocol, as the overall effectiveness of cleaning procedure depends very much on these variables. The number of cleaning processes required for the equipment or equipment pieces should be properly determined.

Following are some important factors in evaluation of cleaning procedures and cleaning validation 1. Equipment Design 2. Written Cleaning Process Procedure and Documentation. 3.Analytical Methods 4.Sampling :a) Direct Surface Sampling b). Rinse Samples c). Routine Production . EQUIPMENT DESIGN AND CLEANING VALIDATION Equipment design is vital factor during cleaning and its validation, semi automatic or fully automatic clean in place systems are of important point of inspection by regulatory agencies, equipment with sanitary piping with out ball should be employed. Whether the equipment requires special training of operators for cleaning operations, and cleaning these systems and its valves. The operators knowledge and training is also important. The written and documented cleaning process SOP which should be properly validated for these equipments. In case of large systems like long transfer or piping the proper flow chart for the operation should be in place with piping diagram with valves and written cleaning procedures. Valves and pipings should be tagged and properly identifiable by operators during the operation and while cleaning as well. Establishing proper time period between completion of a process and its each cleaning step is also important and are examined during inspection as critical points, as in case of suspensions and topical preparations the time period may be sufficient to allow drying of residue making it difficult to clean and the efficacy of the adapted cleaning procedure may be lost. Microbial aspects of cleaning procedures and equipment are also equally important, after cleaning equipment should not allow microbial proliferation, there should be a proper standard operating procedure for cleaning and storage of equipment, after cleaning, never the less the cleaning procedure should be able to remove the all microbial contaminations if at all. good maufacturing practices Dry equipments after cleaning before storage, stagnant water over any part or inside any part of equipment after cleaning is not allowed under any circumstances. Sanitization and sterilization procedures should be adapted for equipments where ever necessary before using them for sterile manufacturing or for the process requiring higher degree of microbial control, equipment cleaning and sterilization are important factors in removing and inactivation of pyrogen .