Critical quality parameters

The specification development process is a data-driven activity that requires a validated analytical method. The levels of data needed include assay precision, replicate process results (process precision), and real-time stability profiles. A statistical analysis of these data is critical in setting a realistic specification. Most often, aggregation and fragmentation degradation mechanisms are common to protein and peptide therapeutics. Therefore, the SE-HPLC method provides a critical quality parameter that would need to be controlled by a specification limit. 

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 addition to the design selection criteria, there are some other design specification criteria and critical quality parameters that should be emphasised. 

Table 3 shows some physicochemical properties used as international GA quality parameters, for example moisture, total ash content, volatile matter and internal energy, with reference to gums taken from Acacia Senegal species in Sudan (FAO, 1990, Larson Bromley, 1991). The physicochemical properties of GA may vary depending on the origin and age of trees, the exudation time, the storage type, and climate. The moisture content facilitates the solubility of GA carbohydrate hydrophilic and hydrophobic proteins. The total ash content is used to determine the critical levels of foreign matter, insoluble matter in... 

Because these systems can monitor multiple processes, equipment, and infrastructure and then provide quick notification of, or response to, problems or upsets, SCADA systems typically provide the first line of detection for atypical or abnormal conditions. For example, a SCADA system that is connected to sensors that measure specific water quality parameters shows measurements outside of a specific range. A real-time customized operator interface screen could display and control critical systems monitoring parameters. 

QA, quality attributes SPC/MSPC, statistical process control/multivariate statistical process control CPPs, critical process parameters. 

Ensure that vendors in-process controls include the use of statistical process control critical product parameters that are significant and may affect the final product quality... 

Confirm critical process parameters and determine their effects on product quality attributes. 

Critical Process Control Parameters. The critical process control parameters are those contollable parameters that have impact on the final product quality. Parameter operating limits and the methods of assuring control of these parameters within these limits are discussed in this section. 

For API processes, the FDA does not expect validation of all manufacturing steps, but accepts validation of critical process steps. Section XI.A of the March 1998 draft API guidance document states, Validation should embrace steps in the processing of APIs that are critical to the quality and purity of the final API. The FDA, however, does not specify what it considers critical, but wants the manufacturer to determine the critical process steps and critical process parameters. For new chemical entities, data used to identify critical processing steps and critical parameters would be derived from research or pilot scale batches. For established API processes this information could be obtained from previously manufactured production scale batches. 

Critical process steps are usually determined by analyzing process parameters (factors in a process that are controllable and measurable) and their respective outcomes. Not all process parameters affect the quality and purity of APIs namely its impurity profile and physical characteristics. For validation purposes, manufacturers should identify, control, and monitor critical process parameters that may influence the critical quality attributes of the API. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in process validation. 

Critical quality attributes and operating parameters should be documented and monitored. The program may include a combination of in-line sensors or recorders (e.g., a conductivity meter and recorder), manual documentation of operational parameters (such as carbon fdter pressure drop), and laboratory tests (e.g., total microbial counts). The frequency of sampling, the requirement for evaluating test results, and the necessity for initiating corrective action should be included. 

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