Quality control Compound purity

Subpart F, Drug Compounding Controls. This explains the written procedures for the compounding of drug products that must be performed in order to assure that the finished products have the identity, strength, quality, and purity they purport or are represented to possess. It also discusses some of the final quality control procedures, including, but not limited to, the following (as appropriate) ... 

Fig. 13.3 The quality of commercial compounds. In general, quality control by the compound brokers has improved significantly over the past decade. Sample identity and purity is now less of an issue, but still bears watching. The graph shown above summarizes the historical data gathered over a period oftime over which vendor performance was monitored. In recent years, more than 90% of preferred vendors have provided accurate and highly pure samples.

The last filtering step involves experimental quality control, which validates whether a given compound is soluble to 2 mM in buffer solution, has a consistent NMR spectrum with its structure, has 95% or greater purity, and is both stable and soluble for 24 h in buffer solution. In addition, a water-LOGSY spectrum is taken and compounds with positive results are considered to have... 

Improvements in separation techniques, quality control, and availability of rare-earth compounds in various chemical forms, ie, mixed oxides, metals, and alloys of various purity, morphology, and reactivity, have made these materials an essential part of everyday life. 

At Evotec, all compounds delivered are quality control (QC) checked by LC-MS. This is a major effort, but it is of the utmost importance to collect the initial purity data and to eliminate those fragments with unconfirmed structures (typically this is 5 % of the compounds... 

The amount by which a given optical isomer rotates the plane-polarized light is a characteristic signature of that compound or substance. When measured under a set of standard conditions this quantity is termed the specific rotation, alpha, and written in square brackets [ ]. It can be used as a measure of the purity or authenticity of an essential oil in analysis and quality control procedures. This is discussed further in Chapter 5. 

However, this assertion is based on the assumption that the compounds intended to be made were actually made in sufficient quantities and to adequate levels of purity. The yields in many Combinatorial Chemistry synthesis vary significantly and the purity may also be problematic. The additional steps required to purify and measure the quantity generated are not usually necessary to establish whether the major product shows any significant biological activity. It is therefore not surprising that many companies perform quality control checks on a subset oftheir samples. This prohibits accurate decisions on the overlap of libraries. 

After the final cleavage from the beads, the solutions containing the discrete library individuals are submitted to a work-up procedure and then the pure individuals are tested against one or a few selected targets. The results of the assays will, hopefully, create useful information that will allow further research to be focused on active structures. However, these results must be coupled with quality control, that is, the complete analytical characterization of the library. This allows the purity of each positive compound to be determined to check if the observed activity is due to the presence of impurities (false positives) and to locate the wells where the expected library individuals are absent (false negatives). Moreover, the analysis of the whole library will determine if a final purification of the compounds is required. 

The synthesis of an SP pool library is more analytically challenging than the same library prepared as a discrete collection. The presence of many compounds in the same pool disturbs the qualitative and quantitative determination of purity and yields in all the synthetic steps, during the final quality control, and when necessary, during the off-bead purification of the pool. Several reviews (23-25) have dealt with the analytical chemistry aspects related to pool SP libraries here we will review the analytical steps required for the synthesis, characterization, and purification of an SP pool library, while the structure determination of active components from a pool will be dealt with in the next three sections. 

In addition to quality control over compound collections, the issue of purity of synthetic libraries derived using combinatorial chemistry quickly came under the microscope. In the early to mid-1990s, combichem became a household word throughout the pharmaceutical industry and was believed to be a key technology that would revolutionize drug discovery. The basis of... 

LC/MS emerged as the method of choice for the quality control assessment to support parallel synthesis because the technique, unlike flow injection mass spectrometry, provides the added measure of purity (and quantity) of the compound under investigation. In addition, universal-like HPLC gradients (e.g., 10% to 90% acetonitrile in water in 5 minutes) have been found to satisfy the separation requirements for the vast majority of combinatorial and parallel synthesis libraries. Fast HPLC/MS has been found to serve as good surrogate to conventional HPLC for assessing library quantity and purity [34-37]. Fast HPLC/MS is simple in concept. It involves the use of short columns (typically 4.6 mm i.d. x 30 mm in length) operated at elevated flow rates (typically 3-5mL/min). 

Yan B, Fang L, Irving M, Zhang S, Boldi AM, Woolard F, Johnson CR, Kshirsagar T, Figliozzi CM, Krueger CA, and Collins N. Quality Control in Combinatorial Chemistry Determination of the Quantity, Purity, and Quantitative Purity of Compounds in Combinatorial Libraries. / Com Chem 2003 5 547-559. 

Out of 719 compounds assayed, those that inhibited the ATPase activity [29] of Hsp90 by greater than 50% were selected for IC50 determination. A total of 13 compounds with IC50 < 100 pM (1.8% hit rate) and seven with IC50 < 10 pM (1.0% hit rate) were identified. More than 40% of the purchased compounds that were hits failed on quality control checks (QC) of purity and/or stability. Although many of these QC failures had similar chemotypes to validated hits, they were not considered further. 

In the case of Tc pharmaceuticals, chemistry and safety have been compounded into kits, which have overcome the limitations set by radioactive decay and the risk of bacterial contamination. Kits are manufactured in advance in accordance with GMP requirements for the manufacture of sterile medicinal products, have a long shelf life, and facilitate ad hoc labeling whenever there is a demand in nuclear medicine. Kits provide safety and ease of preparation of highly complex molecules by using aseptic techniques for labeling. Consequently, quality control requirements for kit preparations rely merely on testing the radiochemical purity of a " Tc pharmaceutical to demonstrate stability in compliance with the purity requirements stated in the pharmacopeia. 

In the past, CMCs were poorly-defined compounds, with relatively heterogeneous DPs. Their viscosity was unreliable, to the extent that they could modify the viscosity of a wine. The CMCs currently on the market have much more clearly-defined characteristics, and quality control is more effective, resulting in purer products. Minimum purity is 99.5%, with a sodium content between 7 and 8.9%. Viscosity varies from 25,000-50,000 mPa at 25°C, depending on the type of CMC selected, and cannot, therefore, alter the viscosity of the finished beverage. 

Yan, B. et al. Quality control in combinatorial chemistry Determination of the quantity, purity, and quantitative purity of compounds in combinatorial libraries. J. Comb. Chem. 2003, 5, 547-559. 

Compound purity is a real issue for stfucture-activity correlations, which become more and more important in discovering drugs. For this reason alone, purity is something to invest in because quality saves time. The label on the bottle should say something meaningful about the compound inside. If the compound is more than 90 % pure, it should also be the right compound The combination of H NMR and LC-MS is now an accepted standard in quality control for compound libraries. Also of note is the current trend for many... 

Infrared spectra are now widely used in the examination of pharmaceuticals. The sixteenth revision of The Pharmacopoeia of the United States (U.S.P.) and the eleventh edition of the National Formulary (N.F.) have presented identification tests which used infrared spectroscopy, whereas no infrared tests were used in U.S.P. XV or N.F. X. Infrared spectra have attained acceptance in legal considerations and are now given in patent applications as characteristics of antibiotics of unknown structure. In the pharmaceutical industry there are many applications for quantitative infrared analyses in research and development work, pharmacy research, and in various phases of pharmaceutical production. For example, infrared data are used to characterize reaction conditions and yields, to assay the purity of intermediate products, to examine such problems as the stability of a drug in the material in which it is suspended, and to maintain quality control in the chemical production of bulk drugs. A recent review (Papendick et al, 1969) has given many references to fractionation and isolation methods for pharmaceutical analysis, such as the various types of chromatography, electrophoresis, countercurrent distribution, and extraction. The authors presented many references to infrared analyses for a wide variety of compounds (Table 16.1). 

Unlike mass spectroscopy, gel electrophoresis does not provide a quantitative value for the amount of given protein. However, it provides a low cost and relatively rapid method for the analysis of multiple proteins in a specimen, especially when implemented as a capillary electrophoresis system. Therefore, it has been used for the separation of enzymes (e.g., creatinine phosphokinase), mucopolysaccharides, plasma, serum, cerebrospinal fluid, urine, and other bodily fluids [13]. It is also used for quality control applications for the manufacturing of biological compounds to verify the purity or to examine the manufacturing yield [14]. 

With respect to organic compounds, those that are precursors to pharmaceuticals have attracted increasing interest from the viewpoint of their thermal properties, and TA techniques are used frequently in quality control procedures for such compounds. A wide variety of common and less common pharmaceuticals have also been investigated using a variety of thermal methods - mainly BSC and mainly in the context of purity determination. There is also potential for using TA techniques to identify pharmaceutical activity and for shelf-life determinations. 

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