Quality attributes product acceptability

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. 

Risk assessment starts with risk identification, a systematic use of available information to identify hazards (i.e., events or other conditions that have the potential to cause harm). Information can be from a variety of sources including stakeholders, historical data, information from the literature, and mathematical or scientific analyses. Risk analysis is then conducted to estimate the degree of risk associated with the identified hazards. This is estimated based on the likelihood of occurrence and resultant severity of harm. In some risk management tools, the ability to detect the hazard may also be considered. If the hazard is readily detectable, this may be considered a factor in the overall risk assessment. Risk evaluation determines if the risk is acceptable based on specified criteria. In a quality system environment, criteria would include impact on the overall performance of the quality system and the quality attributes of the finished product. The value of the risk assessment depends on how robust the data used in the assessment process is judged to be. The risk assessment process should take into account assumptions and reasonable sources of uncertainty. Risk assessment activities should be documented. 

Samples are to be taken during and/or after each critical manufacturing step. All control parameters for the manufacturing process have to be monitored and recorded. Each sample analysis will be performed in duplicate using validated or accepted pharmacopeia methods. The sample results will be used to confirm in-process and final product quality attributes as defined by the preestablished specifications. Conformance with specifications will justify the appropriateness of the critical parameters used during the process validation. 

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]. 

Installation and operational qualification work includes verification of temperature, pressure, and flow rates, instrument calibration, and thorough flushing of the entire system to remove oil, metal particles, and other contaminants. The type of testing and acceptance limits listed in the validation protocol may vary from firm to firm however, compressed air with product contact should be tested for such quality attributes as hydrocarbons, water vapor, and microbial content (typically less than 0.1 CFU/cu. ft.)... 

The primary objective of method validation is to provide a high degree of assurance that the specified method consistently provides accurate test results that evaluate a product against its defined specification and quality attributes (Chapter 12). The regulations require that validation data be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability. All analytical procedures require some form of validation, regardless of whether the method is used for stability, in-process analysis, release, or acceptance. Most of the discussions focus on the validation of HPLC methods using assay and purity determinations nevertheless, fundamentals of the approach can be applied to most method validation activities. 

Color of foods is often the first of many quality attributes judged by the consumer and is, therefore, extremely important in overall product acceptance. The importance of color in green vegetables is demonstrated by USDA quality standards where as much as 60% of the total quality score is assigned to color. The decreasing market share of canned relative to frozen green vegetables can be attributed to the dramatic color difference between the two products (1). 

Retrospective validation could be conducted for a well-established process that has been used without significant changes (e.g., changes in raw materials, equipment, systems, facilities, or in the production process) that affect the critical quality attributes of the API. This validation approach should be used only when there is sufficient history on past API batches to demonstrate the process consistently produces acceptable products, and where ... 

Performance parameters reflect the outcome of a given step and indicate that the process gave the desired result [14] or quality attribute. They are uncontrolled performance variables [15] without a control action [35]. Their natural variation is defined by operating history specifically, their variability is characterized from known historical data or estimated based on similar process performance [35]. Similarly, output variables reflect the step outcome and indicate performance was acceptable in terms of performance attributes for the step (e.g., titer and yield) or properties of the product stream (e.g., product homogeneity, purity, contaminant levels, and chromatography peak shape) [3,14]. Still another term used is critical Ys (analogous to dependent variables), defined as product and process output variables that relate to critical quality attributes (CQAs), which are measurable outputs of each process step that are used to provide evidence that the step performed correctly [37]. 

Process validation starts with the identification of product quality attributes and justification of acceptance criteria, followed by a review of the risk analysis, execution of process development runs, and compilation of clinical material manufacturing data to set specifications considering process variability [11]. There is a greater focus on process validation for downstream steps rather than for upstream steps because downstream steps are associated with virus removal. Process validation is just one approach used to control virus contamination, however others include cell bank characterization, in-process testing, inactivation procedures, control of raw materials, containment, and postmarket surveillance [6]. 

After a product or a process has been appropriately evaluated in terms of its usefulness and adequacy in the manufacturing operation the evaluation of the resulting product in terms of its acceptability to the consumer remains to be done. This also should be done with the aid of statistical methods, since there is at present in many cases no substitute for the subjective evaluation of a quality attribute of a food product. Where they exist, objective methods are usually used in conjunction with subjective methods in an effort to correlate them, with a view to the ultimate use of the objective method as a simple and inexpensive index of the quality of the product in question. In terms of research, however, in many cases this may not be done because no objective methods of evaluation exist. A good example concerns the evaluation of the flavor of a food product where, with practically no exceptions, subjective evaluation must be used. 

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