Product optimisation specifications development

The major objective of the product optimisation stage is to ensure that the product selected for further development (the intended commercial product) is fully optimised and complies with the design specification and critical quality parameters described in the Product Design Report (refer to Chapter 5). The key outputs from this stage of development will be... 

In conclusion, during product optimisation, excipients will be selected based on a variety of acceptance criteria. The quantities included in the formulation will be finalised, based on the performance characteristics of the excipient in the final product. At this stage it is important to fix the specifications of the excipients to ensure that the materials used, and hence the product, will be consistent throughout development. Setting specifications is discussed in a following section. 

In direct insertion techniques, reproducibility is the main obstacle in developing a reliable analytical technique. One of the many variables to take into account is sample shape. A compact sample with minimal surface area is ideal [64]. Direct mass-spectrometric characterisation in the direct insertion probe is not very quantitative, and, even under optimised conditions, mass discrimination in the analysis of polydisperse polymers and specific oligomer discrimination may occur. For nonvolatile additives that do not evaporate up to 350 °C, direct quantitative analysis by thermal desorption is not possible (e.g. Hostanox 03, MW 794). Good quantitation is also prevented by contamination of the ion source by pyrolysis products of the polymeric matrix. For polymer-based calibration standards, the homogeneity of the samples is of great importance. Hyphenated techniques such as LC-ESI-ToFMS and LC-MALDI-ToFMS have been developed for polymer analyses in which the reliable quantitative features of LC are combined with the identification power and structure analysis of MS. 

For every commercial catalyst an optimal combination of unit operation sequence exists for the manufacture of that specific catalyst and there will for each unit operation exist preferential process equipment, i.e. fluid bed calciner for calcination. The sequence of unit operations with the special selection of process equipment and all process parameters forms the know-how for manufacturing a catalyst product of large commercial value. But know-how does not mean that you always know why the desired properties are obtained due to the insufficient scientific characterisation of the catalyst material as described above under 2.1. Even small adjustments of the process can change strength, pore size distribution, bulk density, crystallite size etc. of the product and, thus, harm the performance in the industrial reactor. It has normally been costly and time-consuming to reach the final recipe and, therefore, all catalyst companies want to keep it secret. If a single unit operation is changed it will often influence the optimisation of most of the other unit operations, and much of the development will have to be redone. 

Specifications will be required for the pharmaceutical active ingredient, any excipients used in the formulation, packaging components, and for the finished product (at time of manufacture and over the shelf-life). In all cases, the specifications tests and limits will evolve during development, as illustrated in Table 8.4. It is clearly beneficial to have full specifications in place for the start of the Phase III pivotal clinical studies, when the product and process should have been optimised, to ensure that there is equivalence between the product used in Phase III and the commercial product. 

The primary objective of the process design and optimisation stages of product development is to ensure that manufacturing operations supporting Phase III studies, and ultimately commercial manufacture, are carried out under optimal conditions. The product should consistently comply with specifications. 

At later development stages, when process optimisation has been completed and clinical batches are being manufactured under replicated conditions, the regulatory authorities will expect more process validation. The actual process used and results obtained must be documented so that it can be duplicated. Normally, the product must meet predetermined product specifications and acceptance criteria on three occasions. The benefit of validating the process successfully is to reduce the amount of product testing. 

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