Drug validation

Env sequences both temporally and between patients. Two drugs that target HIV-1 entry, enfuvirtide and maraviroc, are now licensed for treatment of HIV-1 infection. The efficacy of these drugs validates entry as a point of intervention in viral hfe cycles and, in the context of HIV treatment, contributes to the growing armamentarium of antivirals which, in multidrug combinations, can effectively inhibit viral replication and prevent disease progression. 

International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use. Validation of Analytical Procedures Methodology. ICH-Q2B, Geneva (1996) (CPMP/ICH/281/95), Internet http //www.nihs.go.jp/drug/validation/q2bwww.html. 

GB905 844 (Sterling Drug valid from 1959 USA-prior. 1958). 

Watanabe E, Sudo R, Takahashi M, and Hayashi M. Evaluation of Absorbability of Poorly Water-soluble Drugs Validity of the Use of Additives. Biol Pharm Bull 2000 23 838-843. 

Design No. Score Pharm. Prot. Drug Valid. Low MW All... 

An improved high-resolution mass spectrometry-based multiresidue method for veterinary drugs in various food matrices was reported by Kaufmann et al. (111). Their new method covers more than 100 different veterinary drugs. Validated matrices included muscle, kidney, liver, fish, and honey. A 15-cm-long Kinetex Cl8 column was applied in this study (111). 

Ideally, the results should be validated somehow. One of the best methods for doing this is to make predictions for compounds known to be active that were not included in the training set. It is also desirable to eliminate compounds that are statistical outliers in the training set. Unfortunately, some studies, such as drug activity prediction, may not have enough known active compounds to make this step feasible. In this case, the estimated error in prediction should be increased accordingly. 

STANDARD PROCEDURES FOR VALIDATION OF DRUG QUALITY CONTROL METHODS... 

Center for Drug Evaluation Research, Reviewer Guidance Validation of Chromatographic Methods, November 1994. 

Process validation should be extended to those steps determined to be critical to the quality and purity of the enantiopure drug. Establishing impurity profiles is an important aspect of process validation. One should consider chemical purity, enantiomeric excess by quantitative assays for impurity profiles, physical characteristics such as particle size, polymorphic forms, moisture and solvent content, and homogeneity. In principle, the SMB process validation should provide conclusive evidence that the levels of contaminants (chemical impurities, enantioenrichment of unwanted enantiomer) is reduced as processing proceeds during the purification process. 

In order to illustrate the critical process parameters of SMB process validation, we will consider the separation of the racemic drug as described in Process design. The study represents the effect of the influence of feed concentration, number of plates and retention factor on the second eluting enantiomer. The simulation of the process for different values of feed concentration is performed and the variations of the extract and raffinate purities are shown in Fig. 10.10. 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

Some internationally harmonized guidelines regarding specifications and tests, impurities and validation of analytical methods have particular relevance to the development of chiral drugs and are discussed below. In addition, the impact of work on the common technical document is considered. 

Guidance on specifications is divided into universal tests/criteria which are considered generally applicable to all new substances/products and specific tests/criteria which may need to be addressed on a case-by-case basis when they have an impact on the quality for batch control. Tests are expected to follow the ICH guideline on analytical validation (Section 13.5.4). Identification of the drug substance is included in the universal category, and such a test must be able discriminate between compounds of closely related structure which are likely to be present. It is acknowledged here that optically active substances may need specific identification testing or performance of a chiral assay in addition to this requirement. 

Determination of the drug substance is expected to be enantioselective, and this may be achieved by including a chiral assay in the specification or an achiral assay together with appropriate methods of controlling the enantiomeric impurity. For a drug product where racemization does not occur during manufacture or storage, an achiral assay may suffice. If racemization does happen, then a chiral assay should be used or an achiral method combined with a validated procedure to control the presence of the other enantiomer. 

The guideline states that the objective of validation is to demonstrate that an analytical method is fit for its purpose and summarizes the characteristics required of tests for identification, control of impurities and assay procedures (Table 13-2). As such, it applies to chiral drug substances as to any other active ingredients. Requirements for other analytical procedures may be added in due course. 

The receptor compartment is defined as the aqueous volume containing the receptor and cellular system. It is assumed that free diffusion leads to ready access to this compartment (i.e., that the concentration within this compartment is the free concentration of drug at the receptor). However, there are factors that can cause differences between the experimentally accessible liquid compartment and the actual receptor compartment. One obvious potential problem is limited solubility of the drug being added to the medium. The assumption is made tacitly that the dissolved drug in the stock solution, when added to the medium bathing the pharmacological preparation, will stay in solution. There are cases where this may not be a valid assumption. 

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