Sample size 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. 

Independent of existing intra-lot variability, a sample size of six dosage units is generally recognized to suffice the needs of quality control (QC). In very early development less than six specimens may be used to create data, but as soon as possible tests should be run with at least n = 6. It is advisable to create statistically valid and sound data for manufacturing prototypes even at very early phases of development, in order to be able to identify formulations/batches with unwanted dissolution behavior. In the early phases of a drug product s development, formulations may not be of acceptable stability. This means that stability phenomena may mask... 

For any new excipients, APIs or drug products (where new does not necessarily mean novel, but new to the receiving site) there are additional testing criteria, e.g. supplier audits, third-party contract laboratory audits, analytical method transfers, sample management/tracking, etc. For those key excipients, where there is on-site historical experience, it still behoves both parties to check whether the local grade/supplier used by the CMO is equivalent to that used by the supplier (Worsham, 2010). There are many examples of differences in excipient physical properties, e.g. particle size, which have been attributed to different excipient sources that could ultimately impact on the performance of those excipients in formulated products (Frattini and Simioni, 1984 Dansereau and Peck, 1987 Phadke et al., 1994 Lin and Peck, 1994). 

Validation provides confidence in the quality of products manufactured as the over quality of a particular process cannot be established due to the limited sample size. Validation leads to less troubleshooting within routine production. As a result, it reduces the number of customer complaints and drug recalls. 

Note that bracketing was not applied to the batch factor because the FDA regulation requires testing at least three batches to determine a drug product shelf life. Even so, the sampling required for the bracketing design was reduced substantially. The sample size required per time period is 12, a small number when compared to... 

After solvent development, the detection procedures can be either qualitative or quantitative. Qualitative procedures require that a drug product be identified on the chromtographic plate as having the identical Rf and at about equal magnitude to a reference sample. Semiquantitative estimations can be a visual comparison of the size and intensity of the spots versus various standard concentrations. Quantitative procedures require either densitometry or the extraction of the components of interest from the sorbent followed by spectrophotometric measurement. 

It is important in any discussion of residue limits to understand that limits for a cleaning process may be expressed in different ways. This includes the limit of the residue in the subsequently manufactured product, the limit of the residue on the cleaned equipment surfaces, and the limit of the residue in the analyzed sample. These are all related, but they are usually different numbers. For an active ingredient in the cleaning of a finished drug product, the limit in the next product is usually calculated based on application of a safety factor (usually 0.001 or lower) to the minimum daily dose of that active in the maximum daily dose of the subsequently manufactured product. The active or level of active in the subsequently manufactured product is irrelevant unless there is information about unusual deleterious interactions. This calculation is also independent of manufacturing issues such as batch size and equipment surfaces areas, and can be calculated solely on information about the dosing of the two products as follows ... 

Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and possibly, in some cases, different container closure systems. 

Numerous methods are required to characterize drug substances and drug products (Chapter 10). Specifications may include description identification assay (of composite sample) tests for organic synthetic process impurities, inorganic impurities, degradation products, residual solvents, and container extractables tests of various physicochemical properties, chiral purity, water content, content uniformity, and antioxidant and antimicrobial preservative content microbial tests dissolution/disintegration tests hardness/friability tests and tests for particle size and polymorphic form. Some of these tests may be precluded, or additional tests may be added as dictated by the chemistry of the pharmaceutical or the dosage form. 

---