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The Basis Facts of Cleaning Validation

The Basis Facts of Cleaning Validation



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Published by: jljimenez1969 on Aug 21, 2008
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The Basic Facts of Cleaning Validation
Contributed by Robin FredricSaturday, 13 November 2004
Robin Fredric, QA-Validation Department, Novopharm Ltd, Canada. Email: leoroby@yahoo.com Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in the pharmaceutical industry. The focus of cleaning validation is those cleaned surfaces that, if inadequately cleaned, could potentially contaminate the product subsequently manufactured in that same equipment. This primarily covers product contact surfaces in the cleaned equipment. Cleaning validation is not performed only to satisfy regulatory authorities. The safety of patients is the primary objective, and product contamination presents serious liability issues for any pharmaceutical manufacturer or contract organization.The history behind cleaning validationThe unhygienic conditions in Chicagos meat- packing plants revealed in Upton Sinclairs novel, The Jungle, allowed the government  investigators and congress to enact the meat inspection law and the Pure Food and Drugs Act in 1906, the law forbade adulteration, misbranding adulteration, misbranding of foods, drinks, and drugs.Thirty years later the drug tragedy elixir of sulfanilamidewhich killed over 100 people, greatly dramatized to broaden the existing legislation. On June, 25th 1938 Franklin D. Roosevelt signed the Federal Food, Drug, and Cosmetic Act, it required manufacturers to provide scientific proof of drug safety before it could be marketed.All these events brought the current regulatory requirements for cleaning validation. Cleaning:Cleaning can be defined as removal of residues and contaminants. The residues and contaminants can be the product themselves manufactured in the equipment or residues originating from the cleaning procedure (detergents / sanitizers) or degradation products resulting from the cleaning process itself. The basic mechanisms involved in removing the residues and contaminants from the equipment are mechanical action, dissolution, detergency and chemical reaction.1.Mechanical action It refers to the removal of residues and contaminants through physical actions such as brushing, scrubbing and using pressurized water. 2.Dissolution It involves dissolving the residues with a suitable solvent. The most common and practical solvent is water being non-toxic, economical, environment friendly and does not leave any residues. Alkaline and acidic solvents are sometimes preferred as it enhances the dissolution of the material, which are difficult to remove.3.Detergency-Detergent acts in four ways as wetting agent, solubilizer, emulsifier and dispersant in removing the residues and contaminants from the equipment
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4.Chemical reaction- Oxidation and hydrolysis reaction chemically breaks the organic residues and contaminant to make them readily removable from the equipmentWhat is cleaning validation ?It is documented evidence with a high degree of assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits.Why cleaning validation ?To verify the effectiveness of cleaning procedures and to ensure no risks are associated with cross contamination of active ingredients or detergent/sanitizer.When cleaning validation ?· Initial qualification of a process/equipment· Critical change in a cleaning procedure· Critical change in formulation· Significant change in equipment· Change in a cleaning process· Change in a cleaning agent.Why we do validation for 3 times ?Once an FDA was asked why do we do it 3 times?His answer was - Because if it comes out right once it is an accident, twice coincident, three times validation.{mospagebreak title=FDA requirements for cleaning validation} Regulatory requirements: " FDA has required that the equipment to be cleaned prior to use (GMP regulation-Part 133.4) This is one of the basic GMP requirement and it is indicated in more than one section of 21CFR 211 (FDA, April 1998)" Section 211.63 relates to the equipment design, size, location, and requires that equipment used in the manufacture, processing, packaging, holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and 
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maintenance." Section 211.65 states that a) the construction of equipment which contact the in-process materials, or drug products shall not be reactive, additive or absorptive so as to alter the safety, identity, strength, quality or purity of the drug product beyond official or other establishment requirements.b) Any substances required for operation, such as lubricants or coolants, shall not come into contact with components, drug product containers, closures, in-process materials, or drug products so as to alter the safety, identity, strength, quality or purity of the drug product beyond official or other establishment requirements." Section 211.67 further requires that the equipment and the utensils shall be cleaned, maintained and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product in form of written procedure including all the parameters during cleaning." Section 211.180 and 211.182 relates to the record that should be kept for the maintenance, cleaning, sanitation and inspection of equipment.{mospagebreak title=The common elements of cleaning validation} The Common elements of Cleaning Validation · Written cleaning procedures should be established. Attention should be addressed to dedicate certain equipment to specific products, such as fluid bed dryer bags and to residue originating from the cleaning detergent or solvent themselves.· Procedure on how validation will be performed should be in place.· Who is responsible for performing and approving the study.· Acceptance criteria should be set.· Procedure dealing with the subject of when revalidation study stating issues such as sampling procedure and analytical methods.· Study should be conducted according to protocol.· Approved report should state the validity of the cleaning process.Cleaning procedureThe two common cleaning procedures are,· Manual cleaning· Automated cleaning procedures such as CIP (Cleaning In Place
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