PROCESS VALIDATION: A CRITICAL TOOL IN QUALITY ASSURANCE
Abhilash Kumar, Navneet Upadhay
School of Pharmaceutical Sciences,
Solan, H.P., India
The objective of this work is to overview the process validation in various pharmaceutical processes. Quality is the most important requirement in the manufacturing process. All the drugs must be manufactured to the highest quality level. Quality cannot be guaranteed just by end product testing but we have to control carefully each critical step during the manufacturing process. Thus process validation plays an important role to control each critical step in order to maintain quality of the final product. Validation involves a series of activities that are taking place during the life cycle of products and processes. It also involves careful planning of various steps in the process and all the work should be carried out in a structured way according to standardized working procedures.
Reference Id: PHARMATUTOR-ART-1296
Introduction [1, 2, 13]
The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the quality of pharmaceuticals. The first validation activities were focused on the processes involved in making these products, but quickly spread to associated processes including environmental control, media fill, equipment sanitization and purified water production.
In a guideline,Process validation can be defined as documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.“(FDA 1987)
A properly designed system will provide a high degree of assurance that every step, process, and change has been properly evaluated before its implementation. Testing a sample of a final product is not considered sufficient evidence that every product within a batch meets the required specification.
Validation in itself does not improve processes but confirms that the processes have been properly developed and are under control. Adequate validation is beneficial to the manufacturer in many ways – It deepens the understanding of processes; decreases the risk of preventing problems, defect costs, regulatory non compliances and thus assures the smooth running of the process. In general, an entire process is validated and a particular object within that process is verified. The regulations also set out an expectation that the different parts of the production process are well defined and controlled, such that the results of that production will not substantially change over time.
Basic Principles of Quality Assurance 
Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use; this principle incorporates the understanding that the following conditions exist:
1. Quality, safety, and efficacy are designed or built into product.
2. Quality cannot be adequately assured merely by in-process and finished product inspection or testing.
3. Each step of manufacturing process is controlled to assure that the finished product meets all design characteristics and quality attributes including specifications.
Goal of Validation [1, 4]
The goal for the regulators is to ensure that quality is built into the system at every step, and not just tested for at the end, as such validation activities will commonly include training on production material and operating procedures, training of people involved and monitoring of the system whilst in production. In general, an entire process is validated; a particular object within that process is verified. The regulations also set out an expectation that the different parts of the production process are well defined and controlled, such that the results of that production will not substantially change over time. This also extends to include the development and implementation as well as the use and maintenance of computer systems. The software validation guideline states: “The software development process should be sufficiently well planned, controlled, and documented to detect and correct unexpected results from software changes.”
Why Validate? [1, 2]
Where process results cannot be fully verified during routine production by inspection and test, the process must be validated according to established procedures. When any of the conditions listed below exist, process validation is the only practical means for assuring that processes will consistently produce devices that meet their predetermined specifications:
1. Routine end-product tests have insufficient sensitivity to verify the desired safety and efficacy of the finished devices;
2. Clinical or destructive testing would be required to show that the manufacturing process has produced the desired result or product.
3. Routine end-product tests do not reveal all variations in safety and efficacy that may occur in the finished devices.
4. The process capability is unknown, or it is suspected that the process is barely capable of meeting the device specifications
Elements of Validation [4, 11]
Design Qualification (DQ) -Defines the functional and operational specification of the instrument, program, or equipment and details the rationale for choosing the supplier.
Installation Qualification (IQ) –Demonstrates that the process or equipment meets all specifications, is installed correctly, and all required components and documentation needed for continued operation are installed and in place.
Operational Qualification (OQ) –Demonstrates that all facets of the process or equipment are operating correctly.
Performance Qualification (PQ) –Demonstrates that the process or equipment performs as intended in a consistent manner over time.
Component Qualification (CQ) –is a relatively new term developed in 2005. This term refers to the manufacturing of auxiliary components to ensure that they are manufactured to the correct design criteria. This could include packaging components such as folding cartons, shipping cases, labels or even phase change material. All of these components must have some type of random inspection to ensure that the third party manufacturer's process is consistently producing components that are used in the world of GMP at drug or biologic manufacturer.
Types of Process Validation [4, 11]
The guidelines on general principles of process validation mentions four types of validation:
1. Prospective Validation
Prospective validation is conducted before a new product is released for distribution or, where the revisions may affect the product's characteristics, before a product made under a revised manufacturing process is released for distribution.
2. Concurrent validation
Concurrent validation is a subset of prospective validation and is conducted with the intention of ultimately distributing product manufactured during the validation study.Concurrent validation may be conducted on a previously validated process to confirm that the process is validated. If there have been no changes to the process and no indications that the process is not operating in a state of control, product could be released for distribution before revalidation of the process is completed. There is some risk to early release of product in that subsequent analysis of data may show that the process is not validated.
3. Retrospective Validation
Retrospective validation is the validation of a process based on accumulated historical production, testing, control, and other information for a product already in production and distribution. This type of validation makes use of historical data and information which may be found in batch records, production log books, lot records, control charts, test and inspection results, customer complaints or lack of complaints, field failure reports, service reports, and audit reports. Historical data must contain enough information to provide an in-depth picture of how the process has been operating and whether the product has consistently met its specifications. Retrospective validation may not be feasible if all the appropriate data was not collected, or appropriate data was not collected in a manner which allows adequate analysis. If historical data is determined to be adequate and representative, an analysis can be conducted to determine whether the process has been operating in a state of control and has consistently produced product which meets its predetermined specifications and quality attributes. The analysis must be documented.
As long as the process operates in a state of control and no changes have been made to the process or output product, the process does not have to be revalidated. Whether the process is operating in a state of control is determined by analyzing day-to-day process control data and any finished device testing data for conformance with specifications and for variability.
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