Process reproducibility

Complex nutrients, such as yeast extract, are variable in composition and consequently it is difficult to maintain process reproducibility within the narrow window required to produce a product of consistent quality. 

FIGURE 4-22 Typical response of polypyrrole detector to carbonate (S , 1 x 10-4M S2,2.5x lO M S3, 5 x 10 m) based on the doping-undoping process. (Reproduced with permission from reference 74.)... 

Figure 9.6 Visual representation of the platinum oxide growth mechanism, (a) Interaction of H2O molecules with the Pt electrode occurring in the 0.27 V < < 0.85 V range, (b) Discharge of 5 ML of H2O molecules and formation of 5 ML of chemisorbed oxygen (Ochem)- (c) Discharge of the second ML of H2O molecules the process is accompanied by the development of repulsive interactions between (Pt-Pt) -Ofi m surface species that stimulate an interfacial place exchange of Ochem and Pt surface atoms, (d) Quasi-3D surface PtO lattice, comprising Pt and moieties, that forms through the place-exchange process. (Reproduced with permission...

Figure 2. Linear shrinkage versus temperature at l°C/min heating rate for silica gels prepared by three different methods a) two-step acid hydrolysis, b) two-step base hydrolysis, c) colloidal process. (Reproduced with permission from Ref. 4. Copyright 1984 Wiley- Interscience.)...

Figure 2 Schematic of BP Chemicals Avada process (reproduced from BP Frontiers, August 2002).

Figure 12 Orientation ratios RMD (open symbols) and RTD (filled symbols) as a function of the TD draw ratio of PET films drawn for a sequential (circles) and simultaneous (triangles) process. Reproduced with permission from Gohil and Salem [70]. Reprinted with permission of John Wiley Sons, Inc.

The "Blaue Turm" process. (Reproduced from www.dml-2.de/ (accessed May 8, 2007). Copyright by DM2 Verwertunstec, chnologien. With permission.)... 

Fig. 1. The pathogenesis of metastasis. To produce metastases, tumor cells in a primary neoplasms must complete a series of sequential and selective steps, each of which can be rate limiting because a failure or an insufficiency at any of the steps aborts the process. Reproduced with permission from Fidler, Cancer Research (F5).

Schematic representation of the DLR (dry powder spraying) CCM manufacturing process. (Reproduced from Wagner, N., Kaz, T., and Friedrich, K. A. Electmchimica Acta 2008 53 7475-7482. With permission from Elsevier.)...

Figure 10.3 Simplified flow sheet of the heterogeneous Esterfip-H based process (Reproduced with permission of Elsevier from ref. [56]).

Fig. 6. Equilibrium extraction model involved in the ARMES process. (Reproduced from [188] with permission of AIChE)...

Review the process reproducibility and the batch records for process variations. 

The formal validation is often completed after the PAI, where three-batch process validation will be conducted in accordance with the protocol approved during the preapproval inspection. The primary objective of the formal process validation exercise is to establish process reproducibility and consistency. Such validation must be completed before entering the market. The formal validation studies continue through packaging and labeling operations (in whole or in part), so that machinability and stability of the finished product can be established and documented in the primary container-closure system. 

Now I would like to turn to some of the issues of operations within the manufacturing process itself and speak to certain process controls that are expected. In a chemical synthesis sequence, as I mentioned above, intermediates will need to be fully characterized. That characterization will then lead to a set of specifications for the intermediate, that is, its level of purity, its form, etc. Test procedures that demonstrate that the intermediate meets specifications must be established. Some intermediates are deemed to be more important than others and are given specific designation, such as pivotal, key, and final intermediates. In those cases, it is necessary to demonstrate that the specific and appropriate structure is obtained from the chemical reaction and that the yield of the intermediate is documented and meets the expected yield to demonstrate process reproducibility and control. Purity of the substance is to be appropriately documented. And, finally, in reactions which produce pivotal, key, and final intermediates, side products or undesirable impurities are identified and their concentrations measured and reduced by appropriate purification procedures so that the intermediate meets in-process specifications. Thus, those important intermediates become focuses of the process to demonstrate that the process is "under control" and functioning in a reproducible and expected manner. All of these activities ultimately are designed to lead to the production of the actual active ingredient which is referred to then as a "bulk pharmaceutical agent." That final product will need to be completely characterized which then will document that it meets a set of specifications ("Final Product Specifications") for qualification as suitable for pharmaceutical use. 

Fig. 29. Schematic representation of a synthetic protease [73], Four a-helical peptides bearing a specific catalytic group are linked together. The correct folding of 80 brings the catalytic groups into a relationship that enables them to catalyze hydrolytic processes. (Reproduced with the permission of Ref. 73)...

Figure 8. The point defect balancing act in silicon processing. (Reproduced with permission from reference 118. Copyright 1988 Noyes Publications.)...

Fig. 16 SEM image of the cross section of a theophylline-imprinted membrane asymmetric structure of imprinted membrane prepared by the wet phase inversion process. Reproduced with permission from [217]...

The design of the validation testing and the composition of the protocol reflect the circumstances under which the study is conducted. For retrospective validation the test may be statistical analysis of batch release data, such as assay, pH, physical appearance, residual moisture, reconstitution time, and constituted solution appearance. This retrospective process validation would be intended to demonstrate that the product is of consistent quality. A critical review of the processing conditions in a retrospective validation may consist of a test comparing actual processing conditions during lyophilization with ideal parameters. This not only shows adherence to the defined processing conditions, but also demonstrates process reproducibility. 

Figure 8.63 Variable temperature H NMR spectra of the Ir—H and N—H regions in 8.50 showing the proton exchange process. (Reproduced with permission from The Royal Society of Chemistry).

Figure 1.34 A schematic representation of a transcription process. Reproduced from G Thomas, Chemistry for Pharmacists and the Life Sciences, 1996, by permission of Prentice-Hall, a Pearson Education Company...

Any change in material, product components, equipment, environment, methodology, or assays that could affect product quality or process reproducibility should be documented. It should be guaranteed that, after the alterations, the process results in a product that meets the specifications previously approved. All changes that might affect product quality or process reproducibility require revalidation and therefore should be subject to permission by the regulatory agencies (WHO, 1996 EC, 2001). 

Fig. 14 UV-Vis spectral changes for Mn5j observed using controlled potential electrolysis at potential of process III (—700 mV). Electrolyte = DMF containing 0.1M TBABF4. Electrolysis time was 30 min for each redox process. Reproduced with permission from [14]...

Figure 20. Lurgi Multi-Purpose Gasification (MPG) process. (Reproduced by permission of Luigi)...

---