Process validation defined

The design of the system must take into account possible variation of critical control parameters that could affect performance. The maximum performance of the process should be defined by a reasonable safety margin. In order to comply with cGMP guidelines, established validation protocols, and parameters should allow the process to achieve reproducible purity and yield under stressed conditions. This implies that the industrial SMB system must be stressed to simulate worst-case conditions for process validation. 

In the Validation Documentation Inspection Guide, US Department of Health and Human Services, Food and Drug Administration, 1993 the process validation is defined as ... 

Here, it can bee seen that system modules are not directly matched to process structures defined in the Supply Chain Planning Matrix. Also, the asymmetry between market facing parts of procurement and sales are not intuitive. However, APS extend the perspective on business applications extending the classical tasks of ERP and transactional systems to a management and planning level. With APS implemented in multiple industries and validated specifically in the process industry (Schaub/Zeier 2003) or also for Small and Medium Enterprises (SME) (Friedrich 2000), importance will further grow. 

The FDA guidance on IVIVC development and validation defines a number of circumstances where an IVIVC can be used to justify a biowaiver request in support of (1) level 3 process changes, (2) complete removal or replacement of non-release-controlling excipients, (3) level 3 changes in release-controlling excipients, (4) approval of lower strengths, and (5) approval of new strengths. Additionally, use of the IVIVC to justify biorelevant dissolution specifications is cited as the optimal approach. 

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. 

Validation of analytical methods is important both from the standpoint of good science and to satisfy regulators of the reliability of results reported in dossiers. When approaching validation of any analytical method, one must always ensure that the method is fit for purpose. The amount of resource should be appropriate to the phase of development and the degree to which the process is defined and the methods finalised. 

Samples are to be taken during and/or after each critical manufacturing step. All control parameters for the manufacturing process have to be monitored and recorded. Each sample analysis will be performed in duplicate using validated or accepted pharmacopeia methods. The sample results will be used to confirm in-process and final product quality attributes as defined by the preestablished specifications. Conformance with specifications will justify the appropriateness of the critical parameters used during the process validation. 

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

The pilot program is defined as the scale-up operations conducted subsequent to the product and its process leaving the development laboratory and prior to its acceptance by the full scale manufacturing unit. For the pilot program to be successful, elements of process validation must be included and completed during the developmental or pilot laboratory phase of the work. 

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 ... 

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],... 

Variation in raw materials is one of the major causes of product variation or deviation from specification. The API may represent the most uncontrollable component in the complete product/process validation scheme, as key physical properties such as morphology and particle size/surface area may not be completely defined this early in the sequence. Often times the synthesis of the new API (drug substance) is not finalized, and changes occur during the development of the compound. 

The design of the validation testing and the composition of the protocol reflect the circumstances under which the study is conducted. For retrospective validation the test may be statistical analysis of batch release data, such as assay, pH, physical appearance, residual moisture, reconstitution time, and constituted solution appearance. This retrospective process validation would be intended to demonstrate that the product is of consistent quality. A critical review of the processing conditions in a retrospective validation may consist of a test comparing actual processing conditions during lyophilization with ideal parameters. This not only shows adherence to the defined processing conditions, but also demonstrates process reproducibility. 

Following an experimental design approach for developing a matrix of variables is undoubtedly a preferable method for conducting experimental studies. This type of an approach to process validation may be suitable for experimental design, but becomes extremely cumbersome when reproducibility of the process and consistent product quality is to be demonstrated. In the absence of the many studies required to fulfill a complex matrix, a simpler matrix based on the edges of a defined range would be reasonable and scientifically valid. 

According to the FDA s Guidelines on General Principles of Process Validation, the term process validation, whether for APIs or drug products, is defined as establishing documented evidence, which provides a high degree of assur-... 

The World Health Organization GMP [6] concept requires that critical processes should be validated, with validation defined as the documented act of proving... 

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. 

An efficient document management and control system is essential for minimizing the costs of a process validation effort. Detailed discussion of document management is beyond the scope of this chapter however, one suggestion is offered that has proven particularly successful. Efficiency of the document review and approval process can be greatly enhanced by a policy that defines the purpose of each signature required (e.g., technical correctness, regulatory compliance, compliance with other corporate documents, and authority to pro-... 

For some time, the opinion has been divided in the EU regarding the assessment of such validation steps. In many cases it was held to be the remit of the GMP inspectorate while member states would expect to see varying degrees of validation studies presented in support of application for marketing authorization. The guideline Development Pharmaceutics and Process Validation [39] defined more clearly what the agency wants to see in the application dossier. 

At the beginning of any qualification and validation, a validation master plan (VMP) must be worked out. The FDA defines validation plan< as a validation proto-col< (guideline of principles of general process validation) [6.7]. 

The selection of the independent process parameters (which include the choice of specifications for the raw materials and intermediates) is made during development in an effort to ensure the appropriate response of the dependent parameters. The relationship between the independent and dependent variables need not be linear, and may be inverted. The key is to recognize that the selection of the independent variable influences the dependent variable. While this description is simplistic and ignores the possible influence of other variables, it accurately describes the symbiotic relationship between process and product. Without a process (as defined by the selection of the independent variables), there is no product (with its dependent product attributes). Without a product, there is no reason for the process. The PAR approach describes how one is to develop the relationship between the process and its resultant product. There is no reason to choose one over the other consideration and confirmation of both is necessary to validate a product. 

The chances of passing a PAI are greatly enhanced if the relevant development is carried out in conformance with well-defined quality principles and some applicable cGMPs. These quality principles should cover such topic as batch disposition, stability, process validation, training, deviations, management notification, documentation change, and history of development. These principles have been described in detail in Chapter 2 and by Hynes [3],... 

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 ... 

In order to develop a consistent free-volume diffusion model, there are some issues which must be addressed, namely i) how the currently available free-volume for the diffusion process is defined, ii) how this free-volume is distributed among the polymer segments and the penetrant molecules and iii) how much energy is required for the redistribution of the free-volume. Any valid free-volume diffusion model addresses these issues both from the phenomenologic and quantitative points of view such that the diffusion process is described adequately down to the microscopic level. Vrentas and Duda stated that their free-volume model addresses these three issues in a more detailed form than previous diffusion models of the same type. Moreover, it was stated that the model allows the calculation of the absolute value of the diffusion coefficient and the activation energy of diffusion mainly from parameters which have physical significance, i.e. so-called first principles . In the framework of this model the derivation of the relation for the calculation of the self-diffusion coefficient of the sol-... 

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