Validation studies: a glossary of some important terms

Validation master plan

Validation protocol

Prospective validation

Concurrent validation

Retrospective validation Qualification

Design qualification

Installation qualification Operational qualification Performance qualification

Document that serves as an overall guide for a facility's validation programme. It identifies all items/procedures, etc., that must be subjected to validation studies, describes the nature of testing in each instance and defines the responsibilities of those engaged in validation activities Document describing the specific item to be validated, the specific validation protocol to be carried out and acceptable results, as per acceptance criteria

Validation undertaken prior to commencement of routine product manufacture

Validation undertaken while routine manufacture of product is also taking place

Validation carried out by review of historical records How an individual element of an overall validation programme performs. When validation of that specific element is complete, it is 'qualified'. When all elements are (satisfactorily) completed the system is validated Auditing the design of a facility (or element of a facility, such as a cleanroom) to ensure that it is compliant with the specifications laid down and that it is, therefore, capable of meeting GMP requirements

Auditing/testing to ensure that specific items of equipment have been correctly installed in accordance with the design specifications laid down

Auditing/testing process that evaluates the system being tested to make sure that it is fully operational and will perform within operating specifications Demonstration that equipment/processes operate satisfactorily and consistently during the manufacture of actual product comprehensive, with follow-up validation studies being undertaken at appropriate time intervals (e.g. daily, weekly or monthly). It is considered judicious to validate older items of equipment with increased frequency. Such studies can forewarn the manufacturer of impending equipment failure. Some validatory studies are straightforward, e.g. validation of weighing equipment simply entails weighing of standardized weights. Autoclaves may be validated by placing external temperature probes at various points in the autoclave chamber during a routine autoclave run. Validation studies should confirm that all areas within the chamber reach the required temperature for the required time.

Periodic validation of clean room air (HEPA) filters is also an essential part of GMP. After their installation, HEPA filters are subjected to a leak test. Particle counters are also used to validate cleanroom conditions. A particle counter is a vacuum-cleaner-like machine capable of sucking air from its surroundings at constant velocity and passing it through a counting chamber. The number of particles per cubic metre of air tested can easily be determined. Furthermore, passage of the air through a 0.2 ^m filter housed in the counter will trap all airborne microorganisms. By placing the filter on the surface of a nutrient-agar-containing Petri dish, trapped microorganisms will grow as colonies, allowing determination of the microbial load per cubic metre of air.

In addition to equipment, many processes/procedures undertaken during pharmaceutical manufacture are also subject to periodic validation studies. Validation of biopharmaceutical aseptic filling procedures is amongst the most critical. The aim is to prove that the aseptic procedures devised are capable of delivering a sterile finished product, as intended.

Aseptic filling validation entails substituting a batch of final product with nutrient broth. The broth is subject to sterile filtration and aseptic processing. After sealing the final product containers, they are incubated at 30-37 °C, which encourages growth of any contaminant microorganisms. (Growth can be easily monitored by subsequently measuring the absorbance at 600 nm.) Absence of growth validates the aseptic procedures developed.

Contaminant-clearance validation studies are of special significance in biopharmaceutical manufacture. As discussed in Section 7.6.4, downstream processing must be capable of removing contaminants such as viruses, DNA and endotoxin from the product steam. Contaminant-clearance validation studies normally entail spiking the raw material (from which the product is to be purified) with a known level of the chosen contaminant and subjecting the contaminated material to the complete downstream processing protocol. This allows determination of the level of clearance of the contaminant achieved after each purification step, and the contaminant reduction factor for the overall process.

Viral clearance studies, for example, are typically undertaken by spiking the raw material with a mixture of at least three different viral species, preferably ones that represent likely product contaminants, and for which straightforward assay systems are available. Loading levels of up to 1 x 1010 viral particles are commonly used. The cumulative viral removal/inactivation observed should render the likelihood of a single viral particle remaining in a single therapeutic dose of product being greater that one in a million.

A similar strategy is adopted when undertaking DNA clearance studies. The starting material is spiked with radiolabelled DNA and then subjected to downstream processing. The level of residual DNA remaining in the product stream after each step can easily be determined by monitoring for radioactivity.

The quantity of DNA used to spike the product should ideally be somewhat in excess of the levels of DNA normally associated with the product prior to its purification. However, spiking of the product with a vast excess of DNA is counterproductive, in that it may render subsequent downstream processing unrepresentative of standard production runs.

For more comprehensive validation studies, the molecular mass profile of the DNA spike should roughly approximate to the molecular mass range of endogenous contaminant DNA in the crude product. Obviously, the true DNA clearance rate attained by downstream processing procedures (e.g. gel filtration) will depend to some extent on the molecular mass characteristics of the contaminant DNA.

Other manufacturing procedures requiring validation include cleaning, decontamination and sanitation (CDS) procedures developed for specific items of equipment/processing areas. Of particular importance is the ability of such procedures to remove bioburden. This may be assessed by monitoring levels of microbial contamination before and after application of CDS protocols to the equipment item in question.

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