Information & Training. | Product & Process Validation.
What is Cleaning Validation?Cleaning validation is an activity that is focused on ensuring that process equipment, test equipment and facilities are suitable for use in manufacturing and can assure the safety and integrity of the output of a process.
Approach to Cleaning Validation.Products, raw materials, ingredients (e.g. APIs), can be contaminated by other products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates). In many cases, the same equipment may be used for processing different products. To avoid contamination of product, adequate cleaning procedures are essential. Cleaning procedures must strictly follow carefully established and validated methods of execution.
Normally only cleaning procedures for product contact surfaces of process equipment need to be validated. Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, mixing shaft, fans of ovens, heating elements etc..
Cleaning procedures for product changeover in the case of marketed products should be fully validated. Cleaning procedures for products and processes which are very similar, do not need to be individually validated. Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.
It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation program which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria.
At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.
Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures as the materials may behave differently.
It is usually not considered acceptable to “test until clean”. This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of “test until clean” should not be required. The practice of “test until clean” is not considered to replace the need to validate cleaning procedures.
Products which simulate the physicochemical properties of the substance to be removed may be used instead of the substances themselves, where such substances are either toxic or hazardous.
Regulatory expectations related to Cleaning Validation:European and Australian GMP’s (Good Manufacturing Practices).
“Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products”.
“Contamination of a starting material or of a product by another material or product must be avoided……. The significance of this risk varies with the type of contaminant and of product being contaminated. Amongst the most hazardous contaminants are highly sensitizing materials, biological preparations containing living organisms, certain hormones, cytotoxics, and other highly active materials”.
US FDA cGMP’s. – FDA 21 CFR 211.67 (a) “Equipment and 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 beyond the official or other established requirements”
WHO (World Health Organization), “It is of critical importance that particular attention is paid to the validation of analytical test methods, automated systems and cleaning procedures”.
The objective of a cleaning validation is to assure the quality, safety and integrity of product. This is achieved by minimizing the potential for contaminants entering a manufacturing process and minimizing the potential for product contamination.
What are the various cleaning mechanisms widely applied?
Cleaning by some mechanical force. the objective is to physically displace any undesired residues. This normally relates to the use of water (possibly pressurized) plus scrubbing. In real life situation, more than one cleaning mechanisms is usually applied.
Solubility involves the dissolution of one chemical (the contaminant) in a liquid solvent. For example, salts may be soluble in water, and certain organic actives may be soluble in acetone or methanol. This is normally one of the primary cleaning mechanisms to be considered during a design phase.
Wetting involves the displacement of one fluid from a solid surface by another fluid. Wetting can be improved by the addition of surfactants. Wetting improves penetration of the cleaning solution into cracks and crevices, which are usually difficult-to clean locations.
Breaking up an insoluble liquid residue into smaller droplets and then suspending those droplets throughout the water.
Emulsion = Mechanical energy + Surfactants / Polymers.
– Emulsions are thermodynamically unstable (say, 5 to 10 minutes).
– Redeposition of the cleaned residue back onto the equipment surfaces.
– Agitation should be continued till the time to discharge the cleaning solution to the drain.
Dispersion is similar to emulsification, except that it involves the wetting and de-aggregation of solid particles and then the subsequent suspension of those particles in water. This approach tends to be more important in dry product manufacturing.
This involves the cleavage of various organic bonds, such as carbon-carbon bonds, by the action of a strong oxidizing agent. Large non-polar molecule into a smaller more polar molecule.
This involves the cleavage of certain bonds in an organic molecule. The resultant hydrolyzed residues must either be water soluble or solubilized at the pH of the cleaning solution.
Mechanisms that may kill organisms but leave behind nonviable microbial residues.
Information & Training.
Product and Process Validation.
- The Validation Master Plan. Performing a Gap Analysis. Validation in the Design Process. Etc..
- How to ensure Validation efforts are aligned with potential Risks.
- How to ensure that Validation activity is appropriately documented, reviewed and aligned with requirements.
- Information & Training presentation >>>
FDA – Guide to inspections validation of cleaning processes.