Drug substances sources

Scheme 4 Decision tree for disposition of impurities in the drug substances. Source. Courtesy of Pharmquest Corporation, Mountain View, California, U.S.A.

Description of the source and preparation of any new drug substance used as a component... 

Trace amounts of bromine in sodium diclofenac, sodium (2-[(2, 6-dichlorophenyl)amino] phenyl acetate, have been determined using XRF [82], since the drug substance should not contain more than 100 ppm of organic bromine remaining after the completion of the chemical synthesis. Pellets containing the analyte were compressed over a boric acid support, which yielded stable samples for analysis, and selected XRF spectra obtained in this study are shown in Fig. 7.19. It was found that samples from the Far East contained over 4000 ppm of organic bromine, various samples from Europe contained about 500 ppm, while samples from an Italian source contained less than 10 ppm of organic bromine. 

In such cases, it is obviously advantageous to use biorelevant dissolution tests to characterize the drug substance, to compare formulations and to make a preliminary assessment of possible food effects. However, for routine quality control work, the manufacture of media containing bile components is not only rather time-consuming but may also present difficulties in terms of quality assurance and validation of the raw materials, as is the case with many chemicals obtained from natural sources. 

One of the first major pharmaceutical biotransformations was the development of the synthesis of hydrocortisone in the late 1940s by whole-cell hydroxylation (Figure 2.2). Up until then a 40-step synthetic route developed by the Noble Prize winning chemist R.B.Woodward was the only source of this important drug substance and intermediate. Nowadays, a biocatalyst exists for the selective hydroxylation of every position on the steroid nucleus. ... 

As the stability data can be affected by many factors like formulation, manufacturing, storage conditions, in-process and GMP controls, analytical methods, and process validation, the biggest challenge is to figure out the source of the variability in the stability results. At least three batches of the drug substance or product are required to establish the acceptance criteria for future production batches as a measurement... 

Impurities in drug substances and drug products continue to be a source of great concern, discussion, debate, and research. " These concerns and debates typically center on the potential safety risks associated with impurities due to contamination and the setting of acceptance criteria. However, the bulk of the work being performed in the pharmaceutical industry, with respect to impurities, is focused on the isolation, identification, qualification and quantification of impurities that are found as a result of the manufacturing process or through chemical decomposition. On the... 

The generic representation in Figure 1 illustrates the various types of impurities that may arise during the production of a dosage form. It is not all inclusive, as each dosage form has unique sources of impurities, but it includes most of the important ones. The sources of impurities increase with the increase in the number of components and the number of steps in the process. Each drug substance and excipient has its own impurity profile and the potential for interactions and reactions. 

In theory, all impurities should be eliminated. In practice, it is generally not economically feasible to totally eliminate all impurities. However, the levels of all impurities should be controlled to provide a consistent product. In most cases, only low levels of impurities should be allowed, but in rare cases, even quite high levels of impurities are tolerated. In some cases, for example, biotechnology derived products such as macrocyclic antibiotics, or extracts of a botanical source such as some dietary supplements, the drug substance or active component contains multiple compounds, all of which have biological activity. However, only organic impurities, which include residual solvents in the drug substance, are addressed in this chapter. 

Although it may not always be possible to control the sources or extraction conditions to produce only a single component, they should be arranged so as to produce, as far as possible, a consistent mixture. Impurity profiles of botanical products are often monitored by a number of anal3hical procedures to ensure product quality. Minor components that have pharmacological activity should not necessarily be viewed as impurities. In some cases, the activity of a botanical or fermentation drug substance may be attributed to a number of components. 

Table 1.2, adapted from Paesen etal.[, shows the varying amounts of some major impurities in the fermentation drug substance erythromycin from seven sources. The major components that make up the drug substance are identified. Note that the level of water also varies quite widely. 

By understanding the manufacturing process and the stability of the drug substance, whether from synthetic, natural, or recombinant sources, the chemist is able to identify, control, and measure the impurities, and so the quahty of the drug substance and reproducibility from production batch to batch are maintained. 

Stereochemical impurities present in drug substances or drug products can arise from a number of different sources. Armstrong et al. performed an extensive study in the 1990s focusing on enantiomeric impurities in chiral synthons... 

In addition, summaries of published papers/reviews of the substance in question are included. Because of its clinical emphasis, Martindale represents a valuable drug information source to pharmacists and clinicians, but also provides much relevant drug information to personnel engaged in pharmaceutical manufacturing. 

Successful scale-up of the tableting process also requires control of the raw materials used in compaction. Typically, pharmaceutical excipients vary in their physicochemical properties, which result in batch-to-batch variations. The tableting process, especially direct compression processes where there is limited raw material alteration before compaction, is susceptible to raw material variation, which may be magnified upon scale-up. Compaction science affords the ability to fingerprint raw materials, including the drug substance, to determine if the same compaction properties will be observed from batch to batch. This also allows for a rational approach for determining alternate vendor sources of the same materials. 

Evaluating changes in drug substance (particle size, manufacturing site, and manufacturing process), excipient sources, or processing conditions. 

Changes in Components (Excipients) and Composition Changes in the amount or source of drug substance are not addressed by this guidance. Changes in components or composition that have the effect of adding a new excipient or deleting an excipient are dehned at level 3 except as described below ... 

Source of a drug substance natural, synthetic, biotechnological... 

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