Critical quality

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. 

While quality was formerly achieved by inspection of final products, it is accomplished now by prevention through controlling critical steps in the production processes along the agri-food chain. Hazard analysis critical control points (HACCP) represent a typical example of such a preventive approach. Although this concept was developed primarily to assure food safety, the basic principle is also applicable to assuring non-safety quality attributes such as color, flavor, and nutritional value. " This section translates the HACCP principles into a critical quality control point (CQP) concept that can be part of a system to assure food quality. 

To measure the scalability of a process, one needs to define the critical quality attributes and to understand the chemistry and processes involved in order to find the limits of acceptability of these critical attributes, and thus, the limits of the scalability of a process. For a chemical process to be functional at large scale it should also be operationally simple, safe and straightforward. 

The literature lists numerous examples of polymorphism i.e., the existence of several crystal forms of a given chemical that exhibit different physical properties [7]. The conversion of one polymorph to another may cause a significant change in the physical properties of the drug and in critical quality attributes of drug products. 

The most important objective in developing a freeze-dried product is to assure that critical quality attributes are met initially and throughout the shelf life... 

Sterility, freedom from pyrogens, and acceptably low level of extraneous particulate matter are critical quality attributes of all injectable products. Additional critical quality attributes depend on the clinical use of the product. For example, for IV, IM, and SC routes, isotonicity and physiological pH (7.4) are always desirable in order to minimize potential irritation upon injection. Other factors may preclude this, however. If the required dose of drug must be administered in a small volume, it may not be feasible to formulate an isotonic solution. Likewise, solubility or stability considerations may preclude formulation at physiological pH. This explains why formulation pH for injectable drugs varies from about pH 2 to about pH 11. 

Figure 3.65 Sound velocity in hydrogen mixture against wRd2, at atmospheric pressure. Critical quality Xc = 0.375. (From Clinch and Karplus, 1964. Reprinted with permission of NASA Science and Technical Information, Linthicum Heights, MD.)... 

Figure 5.75 CISE experimental data on critical quality, Xcnl. LB = boiling length. (From Bertoletti et al., 1965. Copyright 1965 by CISE, Milan, Italy. Reprinted with permission.)...

Figure 5.82 Critical quality versus boiling length, data from B W. (From GE Report, 1973. Copyright 1973 by General Electric Co., San Jose, CA. Reprinted with permission.)...

Rosenvold K, Lrerke H N, Jensen S K, Karlsson A, Lundstrom K and Andersen FI J (2002), Manipulation of critical quality indicators and attributes in pork through vitamin E supplementation level, muscle glycogen reducing finishing feeding and pre-slaughter stress , Meat Sci, 62, 485 196. 

ASO acid solnble oils CQA critical quality attribute... 

To measure the scalability of a process it is necessary to understand the chemistry and reaction kinetics involved and then to determine their impact on well-defined critical quality attributes desired of the product in order to find the optimum processing window within which there is certainty that the product will be of acceptable quality. However, these data are not readily available for many pharmaceutical chemistry reactions, so a subjective measure of a the scalability, robustness, and greenness of many processes has been developed by Pfizer based on operator knowledge and experience to assist development teams both in the laboratory and in pilot plants to develop greener processes [28]. 

ISO 9001 2000 quality manuals, together with 20 standard operating procedures, provide explicit instruction,s on how to achieve the standard for anyone responsible for writing and executing quality manuals and applicable procedures. Included herein is the ready-to-use template on a CD-ROM that one can immediately use as his own without reinventing the wheel, thus saving time and money without missing any critical quality elements. 

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. 

Process validation of an API should include an SOP to reassess a process whenever there are significant changes in the process, equipment, facilities, reactants, process materials, systems, and so on that may affect the critical quality attributes and specifications of the API. Such changes should be documented and approved in accordance with the scope of the change control SOP. The change control SOP should consist of the following elements ... 

Monitoring programs for critical quality attributes and operating conditions, including calibration of critical instruments... 

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. 

The critical qualities of the product and its packing discussed in this book are collected here ... 

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