Drug validation types

Netherlands drug regulation now follow European Union rules. For example, GMP inspection is based on the 1983 European Union guidelines for GMP. Since 1 January 1995, a European procedure for registration has operated in the Netherlands. Now two types of trade licences exist a European licence and a national licence. Products with a European licence may be sold throughout the whole European Union, while the national licences are only valid for the country in which the licence was issued by means of the national registration procedure. 

Of ultimate importance are the full reports of the clinical studies in humans and their results. These data will be treated statistically for their validity. The number of studies for a specific compound or combination of compounds will vary with the type of drug being tested, as will the number of tests needed to appraise relative or absolute safety and to clearly demonstrate efficacy. The basic requirement is the proof of safety and efficacy of the product being submitted under the NDA system. A drug that does not contribute to therapy, such as a new antihistamine that does not demonstrate greater safety or efficacy, or both, compared with drugs already on the market, will have a difficult or impossible time achieving approval. 

Cabrera et al. [50] modeled a set of 163 drugs using TOPS-MODE descriptors with a linear discriminant model to predict p-glycoprotein efflux. Model accuracy was 81% for the training set and 77.5% for a validation set of 40 molecules. A "combinatorial QSAR" approach was used by de Lima et al. [51] to test multiple model types (kNN, decision tree, binary QSAR, SVM) with multiple descriptor sets from various software packages (MolconnZ, Atom Pair, VoSurf, MOE) for the prediction of p-glycoprotein substrates for a dataset of 192 molecules. Best overall performance on a test set of 51 molecules was achieved with an SVM and AP or VolSurf descriptors (81% accuracy each). 

Studies in Phase IV are all studies (other than routine surveillance) performed after drug approval and related to the approved indication. They are studies that were not considered necessary for approval but are often important for optimizing the drug s use. They may be of any type but should have valid scientific objectives. Commonly conducted studies include additional drug-drug interaction, dose-response or safety studies, and studies designed to support use under the approved indication, for instance, mortality/morbidity studies, epidemiological studies. 

In addition to screening molecules for intestinal absorption, Caco-2 cells have also been used to study mechanisms of drug transport. For many compounds, intestinal permeation involves a transporter to either aid or limit transepithelial transport. The value of Caco-2 cells in this type of studies is due to the fact that these cells express various membrane transporters relevant to drug absorption.1719-23,28,30 However, when interpreting results of studies that involve carrier-mediated transport, discretion, and scaling factors may be required because of the difference in expression level of transporters between in vitro and in vivo systems.12 Another important consideration in carrier-mediated transport studies is that some transport systems in Caco-2 cells may achieve maximal expression level at different days in culture.17,21,38,74 Thus, validation of Caco-2 cells for mechanistic studies should include the identification of the time for optimal expression of transporters as well as the qualitative evaluation of the transporters to establish that they are representative of the native intestinal transporters. 

Methods used to determine the performance characteristics of finished products fall into Category III. Dissolution tests (excluding measurement) and drug release tests are examples of these types of methods. Precision is the only parameter required for these methods according to the regulatory guidances, although all validation parameters may be determined based on the intent of the method. 

In Table 1, the typical validation parameters required for the different types of analytical procedures are listed. For all these analytical procedures CE might be an appropriate analytical technique. In fact numerous validated CE methods for pharmaceutical analysis have been described in literature during the last decade.In Table 2, an overview is listed of the ICH validation parameters included in several reported CE validation studies. Since chiral purity determination is an important application area of CE methods, this test is listed separately as a specific analytical procedure. In addition, the determination of drug counterions has been included as a separate application. This overview illustrates that in general the required validation parameters are addressed in reported CE validation studies. It should be noted, however, that the validation parameters included in Table 2 are not necessarily evaluated exactly according ICH requirements in the reported references. Many pharmaceutical companies apply a phase-related validation approach in which the depth of validation depends on the clinical phase of development of the product involved. 

Hydrophobie filters do not come directly into contact with the product, and therefore the standard baeterial retention test alone is generally sufficient validation. However, as hydrophilie filters are in direet contact with the product, additional validation is necessary for eaeh produet type to demonstrate that the filters selected for product sterilization do not affeet the safety, identity, strength, quality, or purity of the drug produet. Qualifieation of hydrophilie filters is also neeessary to demonstrate that the speeifie produet type in eonjunetion with a baeterial ehallenge does not affect the filter effieaey. Validation of filters by means of baeterial retention tests requires special equipment and is often arranged between the filter manufacturer and the BPS operator. 

Many of the Supreme Court s holdings on the validity of a search are not usually affected in appHcabiHty by the type of contraband, other than the type of suspicion that it may arouse. Thus, rules that apply to the seizure of drugs should equally apply to the seizure of explosives or weapons, or any other illegal item. 

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