Formulated drug products

The first linkage between a microscope and an IR spectrophotometer was reported in 1949 [15]. Today, every manufacturer of IR spectrophotometers offers an optical/IR microscope sampling accessory. The use of optical and IR microscopy is a natural course of action for any solid state investigation. Optical microscopy provides significant information about a sample, such as its crystalline or amorphous nature, particle morphology, and size. Interfacing the microscope to an IR spectrophotometer ultimately provides unequivocal identification of one particular crystallite. Hence, we have the tremendous benefit of IR microscopy for the identification of particulate contamination in bulk or formulated drug products. 

For the two pronounced phases of drug manufacturing, the technical differences for the use of process analytics between the chemical and pharmaceutical industries are more pronounced in the manufacturing of the formulated drug product than in the chemical synthesis and purification of the API. 

Note that product in this context covers both API, which is the subject of this chapter, and the formulated drug product itself. It is likely that the major applications of the PAT approach will be in secondary manufacturing, and indeed successful examples have already been published [40 2]. The FDA is also careful to qualify that the word analytical is meant in its broadest sense and covers chemical, physical, microbiological, mathematical and risk analysis conducted in an integrated manner. Although this chapter is primarily concerned with the first... 

D Chen, DL Cole, GS Srivatsa. Determination of free and encapsulated oligonucleotides in liposome formulated drug product. J Pharm Biomed Anal 22 791-801, 2000. 

This second edition updates and expands on coverage of the topics in the first edition. It should appeal to chemists and biochemists in pharmaceutics and biotechnology responsible for analysis of pharmaceuticals. As in the first edition, this book focuses on analysis of bulk and formulated drug products, and not on analysis of drugs in biological fluids. 

The API Assay, the Assay of Impurities and Product Stability. The central independent analytical research and quality control unit is responsible for the analytical release of both the API and the formulated drug product for the drug development programs. The central independent QC unit provides all the analytical data needed to build the analytical specification for the IND. It is recognized by those involved that the IND is a relatively raw document compared with the later NDA, which is built on data from a more developed process situation, using more refined analytical techniques. 

DTIC itself, not the formulated drug product, was used and only solutions exposed to fluorescent radiation were studied. In spite of these results, the photostabilization has not been generally implemented in clinical practice. 

The first set of requirements that closures for lyophilized product containers must meet are those described for stoppers used in containers for parenteral drugs. They must serve as a barrier to microbial contamination, be compatible with the formulated drug product, and not leach out toxic materials. They must be tested in the prescribed manner for seal integrity and product capability. The reader is referred to sections in the United States, European, and Japanese pharmacopoeias for appropriate test methods for evaluating extractables. 

Consider, as a typical example, the closure systems that are proposed for a given product. To pass the regulatory demands, these systems will need to be tested for extractable and leachable substances that would end up as contaminants in the hnal product. Extractables arise from individual components of the packaging systems under appropriate solvent and temperature conditions. Leachables are compounds that migrate from the container/closure system of the formulated drug product under normal conditions of use or during stability studies. 

Further, the marketing application demonstrates that the API is adequately stable, when stored under defined conditions, to assure that its quality is maintained at least until it is used in the manufacture of the formulated drug product to be marketed. 

Eckers, C. Laures, A.M. Giles, K. Major, H. Pringle, S. Evaluating the utihty of ion mobility separation in combination with high-pressure liquid chromatography/mass spectrometry to facihtate detection of trace impurities in formulated drug products. Rapid Commun. Mass Spectrom. 2007, 21,1255-1263. 

ApphcabUity to both drug substances and formulated drug products. 

The emphasis of this chapter is on the chemical development of small molecule active pharmaceutical ingredients (API) that is, a single chemical entity, natural product, or combination of chemicals, which forms the active constituent of a formulated drug product. Biopharmaceuticals, proteins and oligosaccharides are not discussed, although many of the same principles will apply. 

The formulation (drug product) also contains the macrocyclic calcium complex CaNaButrol (Figure 21) which is approved as additive in Gadovist (57). 

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