Supporting process change control

Poisoning is caused by chemisorption of compounds in the process stream these compounds block or modify active sites on the catalyst. The poison may cause changes in the surface morphology of the catalyst, either by surface reconstruction or surface relaxation, or may modify the bond between the metal catalyst and the support. The toxicity of a poison (P) depends upon the enthalpy of adsorption for the poison, and the free energy for the adsorption process, which controls the equilibrium constant for chemisorption of the poison (KP). The fraction of sites blocked by a reversibly adsorbed poison (0P) can be calculated using a Langmuir isotherm (equation 8.4-23a) ... 

The FDA guidance on IVIVC development and validation defines a number of circumstances where an IVIVC can be used to justify a biowaiver request in support of (1) level 3 process changes, (2) complete removal or replacement of non-release-controlling excipients, (3) level 3 changes in release-controlling excipients, (4) approval of lower strengths, and (5) approval of new strengths. Additionally, use of the IVIVC to justify biorelevant dissolution specifications is cited as the optimal approach. 

Fuji and co-workers have demonstrated the use of a PPY derivative that utilizes remote stereochemistry and an interesting induced fit process to control selectivity [21]. Upon acylation of catalyst 20, a conformational change occurs, stabilizing the intermediate N-acyliminium ion 21 (Fig. 2a,b). Chemical shifts in the XH NMR and nOes observed support a Jt-Jt interaction between the electron-rich naphthyl ring and the electron-deficient pyridinium ring. This blocks the top face of the catalyst and directs attack of the alcohol from the bottom face. Catalyst 20 effects resolutions of diol-monoesters and amino alcohol derivatives such as 22 and 23 with moderate to good selectivity factors (fcrei=4.7-21, see Fig. 2c) [22]. 

Beyond the periodic evaluation of the product, process, or system it is important to assess that the other elements that contribute to the validated state are still in place. This would include an assessment of change controls, calibration, product annual reports (if applicable), process deviations (waivers, alerts, etc.), physical inspection of the equipment, and an evaluation of relevant regulatory guidance. All of these help to augment the data generated in the revalidation study and significantly support the dossier proving successful validation maintenance. 

The CRS s VMP (or corporate policy) should state during the validation process that a system will be managed under the firm s change control policy or system. For example, the subject system will be considered to be under change control upon the acceptance of the OQ summary report by the quality unit. Consider when the system in question will actually begin to be used to support GXP production. 

There are several sections of the CFR that address the control of documents. Obviously, documentation supporting each phase of the life cycle of the master production record should be maintained under change control. A change control program at these early stages will verify that appropriate departments are part of the review process and that changes are not made without sufficient data support. 

The identification of the fall off in plant output uses the same statistical process control methods as for product quality [D-4]. Usually, and certainly in the larger manufacturing units, these issues will be handled by the local plant support teams. However, sometimes output issues arise which are outside the more routine evolutionary techniques employed by the process control teams. A typical example is when the output from a process is constrained by a particular plant item. An improved piece of equipment needs to be identified and evaluated. The introduction of this equipment will usually necessitate process changes for maximum efficiency. This and similar packages of work are best done by an R D project team. 

There are no detailed specihcation documents for any of the computerized process control systems that contain sufficient information on how these systems/software were represented and developed. The only specification documents made available and referred to as the design document were the system specifications however, these documents only provide a high-level explanation of what the systems do. They lack sufficient detailed description of specihc and complete data structure, data control flow, design bases, procedural design, development standards, and so on to serve as the model for writing code and to support future changes to the code. [FDA 483, 2000]... 

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