Product validation

System qualifications are quality checks. They are a part of the validation of a product. Validation is defined as, Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (5). A product that is validated is considered to be of much higher quality than one that is not validated. Automated dissolution systems need to be validated as a requirement of their use in regulated laboratories. 

TABLE 6 ICH Guidelines Affecting the Analytical Testing of Drug Substances and Drug Products Valid as of November 2005... 

Production engineer Process observations and geology Manufacturing scheduling Coordinates development within production Validation and change control management Operations... 

Inhibition enhancement validation testing is performed on each raw material and finished product as part of the validation for bacterial endotoxin analysis in accordance with the current USP and the FDA Guidelines. Limits are determined from USP monographs or the FDA Guidelines and are used in calculating the maximum valid dilution (MVD). Serial dilutions are performed of spiked and unspiked product in order to determine the dilution required to overcome inhibition or enhancement (DROIE). If the DROIE does not exceed the MVD, the test is determined to be valid. Confirmation of the DROIE is performed on three finished product or raw material lots in order to complete the product validation. Products are tested at a dilution greater than the DROIE but less than the MVD. 

Product validation, test data from three formal validation batches... 

Most discussions of product and process validation that have been published [13-15] or that have been the subject of presentations at meetings have concentrated on validation associated with the full-scale manufacture of pharmaceutical processes and how equipment processing variables affect the overall quality of the finished product. Although this is certainly an important aspect of product validation, validation of numerous earlier aspects of development are critical to the subsequent phases of the process. 

Mapping of the chamber is an effective method of quantifying any effects of location and surrounding environmental influences, such as differences in heat transfer. The result of such a study can be used to identify appropriate locations for monitoring and product sampling during actual product validation studies, as well as to demonstrate sufficient batch uniformity. 

Change control Complaints and recalls Contract manufacturers and laboratories Agents, distributors, repackers, and relabelers Specific guidance for API manufacture by cell culture or fermentation APIs for use in clinical trials (quality, equipment, facilities, control of raw materials, production, validation, change control, laboratory controls, and documentation)... 

Documentation of the IQ is important for QA so that the information will be available for future reviews by QA or the FDA inspector. There are three possible approaches that may be followed. First, the IQ information may be compiled as a stand-alone document to which other parts of the validation document would refer. The advantage of this approach is that the IQ doesn t get tied into a specific process or product validation. The second approach would have each validation document stand alone, which would mean that the IQ information on the equipment and facility would be repeated for every validation report. The third approach would combine the other two approaches namely, that the facility IQ would remain generic and the equipment IQ would be a part of the... 

Whatever dimensionality the data have, they must be easily accessible and put to use. The data are imperative for product release, setting of product specifications that are based on true process variability, investigation of out-of-specification product, validation of the process, and trend analysis of production.28 A cost-estimate of the inefficient use of data for decision-making in a typical pharmaceutical plant shows the impact of such behavior on the company s costs. For a single product the annual costs are estimated as ... 

The extent of computer technology qualifications depends on a number of factors, including the criticality and the complexity of the system, whether the qualification is to be prospective or retrospective, and whether innovative elements are incorporated. Any qualification activity must be conducted before the technology is made available in the operating environment or, in case of manufacturing systems, available for process/ product validation. The qualification must be conducted in operating environment to ensure that the production component, data, and system is not corrupted or compromised. 

Performance qualification—those activities that center on the actual product or process being considered. There are other terms, such as process qualification, process validation, product qualification, and product validation, that are sometimes used to narrow the scope of this effort. Here again, semantics have gotten in the way of more important issues. If you desire to use different terminology, go right ahead. Provided all involved understand the intent, the specific title chosen is clearly arbitrary, but the principles are the same. (See Sec. 3.1)... 

Process or Product Validation "Which Came First, the... 

To this point the discussion of process and product validation has focused on parameters and attributes. The situation is somewhat more complex with regard to product attributes, as the source of the sample used to assess the attribute can have a profound effect on the results. To understand this, one must explore the genesis of sampling practice as performed in this industry. 

Myth—Too much is made of validation in this industry. If we are GMP-compliant, following procedures and making quality products, validation can be kept to a minimum. 

The concept of validation came up in the 1970s in association with sterilization procedures and was extended to all steps of pharmaceutical manufacturing procedures. Validation means proving that any and all procedures, processes, equipment, material, operations, and systems comply with the expected performance. Well-planned and well-conducted validation studies constitute GMP principles once they guarantee a consistently safe and efficacious final product. Validation is important for companies, first for QA, and also for cost reduction, decreasing failures, rejection, reworks, recalls, and complaints. The positive aspect of validation is an increase in productivity, as a consequence of a well-controlled process. Validation is required by the regulatory agencies of many countries. 

One reason for interest in plant cell culture is that over 20,000 different chemicals are produced from plants, with about 1600 new plant chemicals added each year. Also, 25% of all prescribed drugs come from plants. These chemicals can be produced in a bioreactor through suspension culture. Advantages of plant cell suspension culture, as compared to agriculture, are that plant cell suspension culture can be carried out independently of weather conditions and political problems, it does not compete with other agricultural products for land use, and it is done in a controlled environment which minimizes contamination and provides easier product validation and assurance. 

Validation is the process by which a facility is demonstrated to be compliant with GMP and fit for the manufacture of a particular product. Validation within the pharmaceutical industry normally falls into three or four parts ... 

Jacques, G. (1991). Is the concept of new production—regenerated production valid for the Southern Ocean. Mar. Chem. 35, 273-286. 

Specifications for raw materials, packaging components, and in-process and finished product Validated analytical methods Regulatory considerations Rework procedures Transportation... 

There are several definitions of validation but, in simple terms, the word means demonstrating that a process will consistently produce the results that it is intended to. Thus, with respect to sterile products, validation would be necessary for each of the individual aspects of the manufacturing process, e.g. environmental monitoring, raw materials quality assessment, the sterilization process itself and the sterility testing procedure. Of these, it is the sterilization process that is likely to be subject to the most detailed and complex validation procedures, and these will be used to exemplify the factors to be considered. A typical validation procedure for a steam sterilization process is likely to incorporate most, or all, of the following features ... 

Profile This privately held company was founded in 1972. It is a full-service drug synthesis and chemical services company that performs a variety of laboratory, process scale-up, and manufacturing tasks including development of processes and synthesis routes for new medicinal products, validating bulk pharmaceutical processes, and authoring Drug Master Files. The company also has a pilot plant/small volume manufacturing site in North Andover, Massachusetts. 

Whereas case study 1 is a good example of work performed early in the product development life cycle, the next case study presented in this chapter is more representative of a study performed much later during the development stage (or even during process/product validation). From a DOE perspective, the only real difference between the two case studies is the number of factors being considered. As case... 

Case study 2 was performed just prior to the final process/ product validation studies. There were only three controllable... 

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