Process validation, definition

The traditional approach to optimize a process is schematically shown in Figure 2 its principle elements are the development of a model, model validation, definition of an objective function and an optimizing algorithn. The "model" can be (a) theoretical, (b) empirical or (c) a combination of the two. 

The following is the FDA definition for Process Validation (FDA Guidelines on General Principles of Process Validation, May 1987) ... 

Process validation entails firstly the definition of both the critical and non-critical parameters. Qnce they are defined, emphasis can be directed to designing a program to validate these parameters. Some established steps involve the evaluation of process consistency over at least three batches, via the consideration of the processing steps and yield and comparing these with predetermined specifications. Some input parameters that may be considered as critical are temperature, flow rate, and stirring speed, and they are varied and checked against output variables such as yield, purity, and crystallization rate. 

MVP is a crucial procedure to confirm that the product manufacture is adequate and is generated in a consistent manner with the same quality. Definitions of equipment, rooms, quality of raw materials, and process parameters are necessary to validate the manufacturing process. Maintaining these definitions ensures that the product has the same quality after the process validation. Changes in equipment, raw materials, or process parameters require a manufacturing process revalidation. 

Define formulation/ synthetic route o- Optimize formula- tion/ synthesis Definitive stability manufac- ture G> Manufacture process validation => Manufac- turing... 

The U.S. Food and Drug Administration (FDA) has proposed guidelines with the following definition for process validation [1] ... 

Unfortunately, there is still much confusion as to what process validation is and what constitutes process validation documentation. At the beginning of this introduction several different definitions for process validation were provided, which were taken from FDA guidelines and the CGMPs. Chapman calls process validation simply organized, documented common sense [6], Others have said that it is more than three good manufactured batches and should represent a lifetime commitment as long as the product is in production, which is pretty much analogous to the retrospective process validation concept. 

The term process validation is not defined in the Food, Drug, and Cosmetic Act (FD C) Act or in FDA s CGMP regulations. Many definitions have been offered that in general express the same idea—that a process will do what it purports to do, or that the process works and the proof is documented. A June 1978 FDA compliance program on drug process inspections [2] contained the following definition ... 

The first drafts of the May 1987 Guideline on General Principles of Process Validation [3] contained a similar definition, which has frequently been used in FDA speeches since 1978, and is still used today A documented program which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. ... 

Validation is an essential procedure that demonstrates that a manufacturing process operating under defined standard conditions is capable of consistently producing a product that meets the established product specifications. In its proposed guidelines, the U.S. Food and Drug Administration (FDA) has offered the following definition for process validation [1],... 

Since the definition of validation seems to vary from nation to nation, we will include all activities from design to final product, as well as individual validation, such as process validation [2] (product qualification in ISO). 

One approach that QA would use to assure itself that a given process (step) is under control is the effort associated with the concept of process capability. Ekvall and Juran [15] defined the concept as the measured inherent reproducibility of the product turned out by the process. The statistical definition of process capability is that all the measured values fall within a 6-sigma range (i.e., range of the minimum to maximum limits). The information is used to show that the process is under control over a period of time as well as determine whether there is any drifting or abnormal behavior from time to time. Process validation is a QA tool in this case because its data will be used as the origin for the data curve developed for the process capability concept. 

Table 1 lists 12 steps in the process validation life cycle for a new process, starting with definitions of the product and the process [5]. Each step needs to be documented, using approved validation plans and/or protocols. 

Retrospective process validation was doubly controversial in the early 1980s because FDA and the industry even disagreed on the meaning of the term. The FDA s definition indicated that retrospective meant performing the validation after the product was already in the marketplace, a practice that nobody would endorse, and would more fittingly be referred to as retroactive. Industry argued (with ultimate success) that a more useful definition of retrospective process validation is establishing documented evidence that a system does what it purports to do based on review and analysis of historic information. The term historic could mean the information was an hour old or years old. 

The validation era brought with it the need for humans involved to communicate with new terminology. The purpose of this chapter has been to identify and explain the key terminology needed to understand nonaseptic process validation. A currently popular, lucid, and accurate definition of process validation itself is well-organised, well-documented common sense. 

In order to truly understand what validation is, we must briefly explore its definition. One of the clearest definitions was developed by Ted Byers and Bud Loftus in the late 1970s, and was formally adoptedby FDA in 1987. Process validation is establishing documented evidence which produces a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics ]. 

Premises Expression system defined Process scalability Primary definition of process No validation Refinement of operational control parameters Development of scale-down process models for validation Process out-of-limit definition Finalization of process control parameters Fixed and defined process and products Pivotal process validation and characterization studies Validated production process Well-characterized product Robust process ... 

There is much confusion regarding the definition of process validation and what constitutes process validation documentation. The term validation is used here generically to cover the entire spectrum of current GMP concerns, essential most of which are facility, equipment, component, method, and process qualification. Based upon the FDA process validation guidelines, the specific term should be reserved for the final stage(s) of the product and process development sequence. The essential or key steps or stages of a successfully completed development program are shown in Table 1. 

There are no detailed recommendations for analytical procedures in the field of biotechnological production of drugs, in contrast to the recommendations made by the FDA for bioanalytical methods [16], The absence of detailed guidelines for analytical method validation in this field is surprising. It is important to validate the quantification of both substrate and product during the process, at definite time intervals, to ensure proper calculation of the kinetics of the process i.e., the coefficients of substrate conversion, and production rates must be adequately calculated. The aim of the study in pa-... 

Process development equals process validation plus process optimization. A well-developed process is, therefore, by definition a well-validated process. Once it is decided that a bulk pharmaceutical chemical (BPC) process should be validated, the question becomes How In the case of a new process, the answer is simple Do a good process development job and document it (4). 

In contrast to the OQ procedures where all parts of the plant and equipment are qualified separately, the PQ procedures qualify the entire plant with respect to the production process. The definition given for PQ is valid for retrospective validation as well as for prospective validation. While carrying out PQ processes, all necessary SOPs (e.g., for the use or cleaning of the plant) should be approved. Values of critical and noncritical process parameters recorded during PQ must be collected to evaluate the efficiency and performance of the plant. 

What is a Validation Master Plan There is no official definition however, based on the interpretation of FDA regulatory guidelines on current Good Manufacturing Practice (cGMP), Good Laboratory Practice, and process validation, a suitable definition may be described as ... 

It is important that after campaign 4 when chemistry and pharmaceutical development are ready to initiate their activities of process validations that the variables of drug substance and product are definitively fixed (point 4 in Fig. 40.4). Validation according to the definition means to provide documented evidence that the processes consistently works. It is logical for the validation processes that the analytical methods need to be validated first and all other activities subsequently. 

Validation derives from the Latin word valere meaning to have the power [8], presumably referring to the power to prevent an unexpected and undesirable occurrence. It establishes that the process used is reliable and reproducible [9]. The level of control implemented is supported by scientific knowledge of the culture and product, along with equipment capabilities [10], The U.S. Food and Drug Administration (FDA) definition of process validation (PV) is documented evidence to... 

Process validation for biopharmaceuticals is somewhat different in application from traditional pharmaceuticals because the technology is different, but the theory and principles are similar [15], Biotechnology quality control is defined by the individual production process and the product itself [16] because quality cannot be tested into the product [4]. The manner in which the biopharmaceutical is produced is part of its description thus, biopharmaceuticals are characterized by chemical structure as well as by operational definition [17]. Few doubt the need for process validation, but there is disagreement and confusion about what needs to be validated and how to perform it [18], Operational definitions of process validation have been developed to suit the philosophies of individual companies [3], Thus, there is increased interest in developing industry guidelines for the design and performance of validation studies [19],... 

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