Impurity profile products

Figure 1.8. Schematic frequency distributions for some independent (reaction input or control) resp. dependent (reaction output) variables to show how non-Gaussian distributions can obtain for a large population of reactions (i.e., all batches of one product in 5 years), while approximate normal distributions are found for repeat measurements on one single batch. For example, the gray areas correspond to the process parameters for a given run, while the histograms give the distribution of repeat determinations on one (several) sample(s) from this run. Because of the huge costs associated with individual production batches, the number of data points measured under closely controlled conditions, i.e., validation runs, is miniscule. Distributions must be estimated from historical data, which typically suffers from ever-changing parameter combinations, such as reagent batches, operators, impurity profiles, etc.

The crystallization step is generally studied quite exhaustively at the laboratory scale and often at the pilot scale. The reaction chemistry should be properly understood to access effects, if any, of the synthesis step on the impurity profile. In batch cooling crystallizers attempts have been made to create optimum conditions by on-line turbidity analysis (Moscosa-Santillan et al., 2000). Physicochemical characterization of the products should be done rigorously (Tanguy and Marchal, 1996). 

HPLC is extremely useful in monitoring and optimizing industrial processes. Conventional process monitors measure only bulk properties, such as the temperature and pressure of a reactor, while HPLC permits continuous realtime monitoring of consumption of starting materials, product composition, and impurity profile. There are a number of new initiatives relevant to HPLC for process monitoring, including sample preparation, automation, miniaturization, and specialized detectors. 

Since the final product is a pharmaceutical, high purity of the product is definitely required. Furthermore, the amount of any impurities in the final product has to be rigorously regulated under ICH guidelines. Rejection of impurities related to cyclopropylacetylene (37) was difficult throughout this whole process [28]. Thus, not only the isolated yield but the impurity profile of 37 was critical. 

Figure 9.3 shows an impurity separation under conventional pressures with a 5 /mi particle, 2.1 x 150 mm column, and the same separation performed via UPLC using a 2.1 x 50 mm column with 1.7 /im particles. The run time was improved by a factor of six, with overall resolution comparable to that of the original separation on the 5 /an column. The application of UHPLC technology to impurity profile analysis can exert a significant impact on laboratory productivity by achieving a... 

Impurity testing is pivotal in pharmaceutical development for establishing drug safety and quality. In this chapter, an overview of impnrity evaluations of drug substances and products by HPLC is presented from both the laboratory and regulatory standpoints. Concepts from the development of impurity profiles to the final establishment of public specifications are described. Useful strategies in the identification and quantification of impurities and degradation products are summarized with practical examples to illustrate impurity method development. 

An output of the impurity profiling of DS and stress studies of DP is an understanding of drug chemistry, particularly with respect to which synthetic impurities are expected to continue to be present in optimized synthetic lots and what degradation products are formed in DS and DP. Significant impurities and degradation products, formed during these... 

C. Impurity Profiles for Drug Products SUMMARY AND CONCLUSION DISCLAIMER... 

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. 

Several dosage forms carry an increased risk of degradation or adjunct formation. Products such as injections and aerosols are more likely to interact with volatiles or extractables from packaging and closure systems. Tablets have the potential to form adjuncts with excipients (specifically, lactose has been shown to form adjuncts in tablets). Non-CFC propellants in aerosols have a large number of impurities that typically do not interact with drug substances, but the potential for these interactions does still exist. Creams, ointments, lotions, and other such products will each have specific interactions that should be considered while evaluating the impurity profile of a drug product. 

VIII. IMPURITY PROFILING FOR DRUG SUBSTANCES AND PHARMACEUTICAL PRODUCTS... 

A. Continuous Monitoring of Impurity Profile in Drug Product... 

Various international pharmacopoeias help assure the quality of drugs worldwide. These pharmacopoeias constantly review and revise their monographs. A different impurity profile can be anticipated if a drug s production process is changed this results in the development of new analytical methods that need to be incorporated in the pharmacopoeias. In earlier editions, color reactions were performed for identification and purity evaluation purposes. 

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