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Arsh Chanana
Department of Pharmaceutics,
Seth G.L. Bihani S.D. College of Technical Education Sri Ganganagar.

Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. Minimizing equipment downtime significant impact on efficiency and economics of pharmaceutical production. The main purpose of cleaning validation is to provide effective and consistent cleaning in a given pharmaceutical production which can prevent cross contamination and adulteration of drug products with other active ingredients unintended compounds or microbiological contamination, leading prevention of several serious problems. So it is necessary to validate the cleaning procedures to ensure safety, efficacy and quality of the subsequent batches of drug product or API’s. Cleaning validation is also essential to meet regulatory requirements. The benefits of  “cleaning validation” are compliance of regulatory requirements and potential problems, previously unsuspected. Which could compromise the safety and efficacy of drug products.


GMP Issues
Cleaning of process equipment has been part of the good manufacturing practices (GMPs) for pharmaceutical manufacturing for many years. It included recommendations for written procedures, cleaning logs, and appropriate design of equipment to facilitate cleaning. Good cleaning practices are necessary to preserve the safety and efficacy of the manufactured drugs and drug products. Possible consequences of inadequate cleaning include cross contamination (the presence of active drug in another drug product at an unacceptable level), the presence of foreign material (e.g., a cleaning agent, solvent, or excipient from another drug product), the presence of microbial contamination (numbers and/ or species of microbes), or the presence of endotoxins (particularly in parenteral or ophthalmic products).

The presence of such contaminants in a drug product may pose safety problems depending on the level of the contaminant. Such contaminants may also affect the efficacy of a drug product; effects could include modifying the bioavailability of the APIs, the dissolution time of tablets, or the stability of the finished drug products. Needless to say, failing to follow GMPs relating to cleaning processes also renders the product ‘‘adulterated’’ and subject to regulatory action. [17]

Expectation of Validation

Validation in the pharmaceutical and medical device industry is defined as the documented act of demonstrating that a procedure, process, and activity will consistently lead to the expected results. It often includes the qualification of systems and equipment. It is a requirement for Good Manufacturing Practices and other regulatory requirements. [18]

There shell be written procedure for production and process control designed to assure that the drug product have their identity, strength, quality and purity they purport or are representedto posses.”[8]

Since a wide variety of procedures, processes, and activities need to be validated, the field of validation is divided into a number of subsections including the following:

Cleaning Validation

  • Process Validation
  • Analytical Method Validation
  • Computer System Validation

Since about 1990 the regulatory expectations are that the certain cleaning processes in pharmaceutical manufacturing be validated.  As cleaning is a process, the principles of process validation apply to the cleaning process. In 1996, the FDA proposed amendments to the GMPs which clearly defined validation of cleaning processes as a GMP requirement. The U.S. FDA took the lead in requirement of validation of cleaning processes, and other agencies also issued similar requirements.  Although the initial emphasis was on cleaning validation related to finished drug products, additional guideline documents clarified that cleaning validation should be considered for active pharmaceutical ingredients and for pharmaceutical excipients also. [17]

Applicability of Cleaning Validation
It should be noted that these cleaning validation requirements apply only to critical cleaning processes. Although GMPs require the cleaning of (and cleaning SOPs for) floors, walls, and the outside of process vessels, such processes are not considered critical cleaning processes. The processes that are critical generally include processes for cleaning product-contact surfaces of equipment or utensils. It is these product-contact surfaces that have the possibility of directly contaminating the next product made in the same equipment. In addition, the cleaning of non-product-contact surfaces that could reasonably indirectly contaminate subsequently manufactured products should also be considered for cleaning validation. For example, some companies have, either on their own or because of regulatory requirements, validated the cleaning of internal surfaces of lyophilizers used for production. On the other hand, validation of cleaning between lots of the same product is not necessarily a requirement .This is based on the fact that cross-contamination of the active is not an issue. However, other concerns such as contamination with degradation products, with cleaning agent residues, or with microorganisms may suggest that such cleaning is critical, and therefore should be validated. [17]

The concepts of "clean-hold time" and "dirty-hold time" have been part of cleaning validation since its inception. Clean hold time is generally considered to be the time between the completion of cleaning and the initiation of the subsequent manufacturing operation. Dirty hold time can begin when the clean equipment is initially soiled, but more often is defined as the time between the end of manufacturing and the beginning of the cleaning process. Intuitively, it makes sense to be concerned about both hold times. Dirty equipment is harder to clean the longer the hold time, and clean equipment has a greater chance of becoming soiled as hold time increases.

FDA requirements
Regulatory authorities have been issuing guidelines regarding cleaning frequently. A validated cleaning procedure is a must for attaining cGMP norms in a pharmaceutical manufacturing potent steroids products as well as non-steroidal products using common equipment. FDA considers the potential for cross-contamination to be significant and to pose a serious health risk to the public. [8]

Current GMP  requirements for cleaning validation

  • FDA expects firms to have written standard operating procedures (SOP) detailing the cleaning process used for various pieces of equipment.
  • If firms have a specific cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, FDA expects the written procedures to address these different scenarios.
  • If firms have one process for removing water-soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is to be followed.
  • It is required by the FDA, in the general validation procedure, that the personnel responsible for performing and approving the study should comply with the acceptance criteria and the revalidation data.
  • FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.
  • It is expected that firms conduct the validation studies in accordance with the protocols and document the result of studies.

Final validation report is to be approved by the regulatory board which states whether or not the cleaning process is valid. [9]



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