Process Validation can be well-defined as the gathering and assessment of data, from the process design stage thru all production processes, therefore creates scientific evidence that a process is capable of regularly delivering quality products.
The Food and Drug Administration, also known as the FDA, or any other drugs regulation company, requests that a product meets specifications but also requires a process testing adopted during manufacturing are designed where they produce similar results that meet standard of product being manufactured and they compile to regulatory aspects. All these procedures are developed through the process of validation. This is to have a high quality of drug product, process validation is measured by the collection off essential data, through the design stage and through production this in turn will give evidence that the process is capable of delivering a quality product, and is consistent in its methods, process validation involves a lot of different activities in the life cycle of the product. Every step is taken to make sure the product is correctly implemented. Testing a sample from a final product is not considered evidence that a certain product meets the required specification.
Validation of all pharmaceutical systems processes is vital and very essential, it ensures all products are manufactured correctly and the quality is of a high standard. The benefits of validation are as follows:
Ø It decreases the chances of failure
Ø It increases the production of the manufacturing facility due to minimized rework and rejection
Ø It reduces the loss of the product
Ø It helps see the risks that may arise in the production of products
Ø Non-compliance risk is minimized
Ø It requires less process control and product testing
Ø It help the risks that may come up
Ø More study and understanding of the system is made possible
Ø Ensure products are safe, of the appropriate quality and efficacy
Effective process validation contributes greatly to assuring top drug quality. The process principle of quality is to assure that the drug should be produced for its specific and intended use. Quality is so vital in this process. Also safety is so vital in this process. These are so important features in the design and the implementation of the product. (FDA C. C., 2011)
GMP validation is an component of quality guarantee program for a pharmaceutical/biotech product or process. To make sure that the products are unquestionably fit for intended purpose, the company has to determine in a documented form that the methods, activities, processes, tests, and equipments they use is of capable standard of continually producing the anticipated product. Therefore, each crucial step in the manufacturing process has to be confirmed to achieve as intended under defined conditions. The Validation Life Cycle can be defined as the implementation mechanism which can contribute pharmaceutical (and other types of medical product) manufacturers in the association and completing of validation accomplishments. A extensive body of work happens which recognises how to validate processes of many types and description. (J., 1993)
1.1 The scope of process validation
The method requires that all validation principles should be well understood early in the process.
These include the following questions:
· find the analytes that should be detected?
· Find the expected concentration levels?
· Find out what are the sample matrices?
· Find out are there interfering substances to be expected?, should they be detected and quantified?
· Are any specific legislative or regulatory requirements required?
· Will all information be qualitative or quantitative?
· Name the required detection and quantitation limits?
· Verify the concentration range?
· What is the limit of precision and accuracy that is expected?
· How vigorous should the method be?
· Name the types of equipment to be used? Are the following methods for one specific instrument or should it be use various instruments of the same type
· Will the method be used in one specified laboratory or should it be used in other laboratories at one side or around the world?
· Name the requirements that the user possess?
The method’s performance characteristics should be based on the intended use of the method. All analytical parameters that are already in use, for a specific technique do not always require validation. Validation on all these techniques is not necessary. For example, if the method is to be used for qualitative trace level analysis, there is no need to test and validate the method’s limit of quantitation, or the linearity, over the full dynamic range of the equipment. Preliminary parameters should be selected according to the analyst’s knowledge and best decision. Final parameters should be decided between the lab or analytical chemist performing the validation and the lab or individual applying the method and users of the data to be created by the method.
The scope of the method should also have diverse types of equipment and the locations where the method will be carried out. (Sharma Ajay, 2012)
2. Cleaning Validation
2.1 The introduction, definition and purpose of cleaning validation
Cleaning validation is a vital part of quality manufacturing methods in any pharma industry or work place .Proper cleaning validation can ensure that unwanted residues will not be carried over and contaminate products. Therefore, the purpose of cleaning validation is to prove that the cleaning procedure is efficient in removing product residues, and degradation products. Cross contamination is a massive risk in production and can be reduced massively in the work place (Michel and Peglow, Sep2017)It is important in the cleaning validation to discover the parts of materials that contain higher rick of contamination. It is important to standardize cleaning procedures and cleaning material verification of residues ,chemical products ,and the post cleaning microbial load (MiritelloSantoro, 21 November 2006.)
In conclusion it can be said that the overall purpose of the cleaning validation is extremely important to confirm the reproducibility and effectiveness of cleaning procedures as well as to prove that the cleaning method currently used is reliable, effective, and complies with the GMP regulations.
2.2 Current requirements of Cleaning Validation
For the safety of food, drugs and its products, cleaning is very vital to prevent forms of contamination in products. It is also examined by the application of validation. Validation monitors the correct cleaning process, to achieve high levels of hygiene and make sure these standards are of the highest mark, cleaning also provides evidence that the product is fit for purpose, and it will be required to show evidence of this for its intended use. If new equipment is to be used, then cleaning validation and cleaning assessment is required for all new products. It also specialises in methods for assessing dairy foods, and different types of beverages. Cleaning validation activity provides a strategy where a cleaning process is used to reduce the risk of contamination and risks in products, this can only be processed if the cleaning validation is completed in full, there are certain types of cleaning validation, and a consulted approach is needed and is subject to different levels of validation in different products. A cleaning validation is to prevent cross-contamination in products, cleaning validation comes up in certain situations and procedures, particularly when some materials pose the maximum risk to the API quality. Cleaning validation is examined also by making sure unwanted contamination and unwanted material in products is below the predetermined levels required. (Forsyth, Oct2015)
Cleaning Validation from Regulatory Bodies view:
WHO Cleaning validation “Documented evidence to establish that 196 cleaning procedures are removing residues to predetermined levels of 197 acceptability, taking into consideration factors such as batch size, dosing, 198 toxicology and equipment size.” (WHO, 2016)
FDA “FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid. The data should support a conclusion that residues have been reduced to an “acceptable level.” ***.” (FDA U. F.)
GMP (1963) Regulations (Part 133.4) stated “Equipment *** shall be maintained in a clean and orderly manner ***.” (FDA U. F.)
2.3 The formulation of cleaning validation programmes
The purpose of cleaning validation is to establish that the cleaning method will always give constant results that meet the standard quality specifications. The principle of GMP is that the cleaning procedure leads to the results required validation creates extra focus on achieving process improvement.
2.4 Clean in Place (CIP) and Clean out of Place Systems for Pharmaceutical industry.
Cleaning is essential process to make sure that all materials introduced into equipment during the manufacturing processes are removed. Materials such as buffers, media, storage solutions, cell debris, non API containing placebos, and any formulation or concentration of a given drug product or API. Cleaning is a crucial process for any pharmaceutical company to ensure that all contaminants such as detergents, excipients, media residues and cross-contaminants are effectively removed. It is also required by the regulatory bodies.
Cleaning processes can be classified into two commonly used categories, such as Clean in Place (CIP), and Clean out of Place (COP).
Clean in place is a process of cleaning pipes, surfaces, filters without damaging anything, and is generally used for large equipment that is too large to remove from process. CIP was discovered to help industries that needed frequent cleaning of their processes and products. People who require this method, normally relay on high levels of hygiene. CIP is a method that makes cleaning faster, and have a more modernised affect, and it also is a safer method to use, and has less risk of chemical exposure to people. CIP is used for fully automated systems, sensors, valves, heat exchangers. CIP operated systems can still be found also in use today. CIP delivers good effective cleaning, elevated temperatures are used with chemical detergents to make cleaning effectiveness easier. To ensure the CIP is effective it requires the control of a number of conditions such as, fluid flow rates, velocities, temperatures, cleaning times, and the concentration of the cleaning chemicals/detergents. Fluid velocities are usually 5 feet per second, however may vary as some of the pharmaceutical companies might use higher velocities than other. The rate of flow of either water or cleaning detergent depends on the size of the tank used, alongside the number and the property of the spray devices. There are variety of the spray devices available, although a spray ball is commonly used now days.