Critical quality attribute

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. 

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]. 

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. 

In the case of compounds that exhibit low solubility in gastric fluids, the rate of dissolution may limit the availability of the compound in vivo. The dissolution rate can be improved by increasing the surface area of the compound. In this case, the API physical property (either surface area or particle size distribution) will likely be a critical quality attribute, as it could directly impact the safety, identity, strength, purity and quality (SISPQ) of the drug product.1 2... 

Applying the closure to syringes, ampoules, and other containers usually differs in methodology from the approaches used for vials, but the objective is identical to secure the container s contents fully assuring the product s critical quality attributes (especially sterility) are maintained throughout its shelf life. 

Retrospective validation may be conducted for a well-established proeess used without significant changes to [drug product] quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approaeh may be used where 1. Critical quality attributes and critical process parameters have been identified... 

Critical quality attributes may include items, such as potency, the nature and quantity of product-related substances, product-related impurities, and process-related impurities. Such attributes can be assessed by multiple analytical procedures, each yielding different results. In the course of product development, it is not tmusual for the analytical technology to evolve in parallel with the product. Therefore, it is important to confirm that data generated during development correlate with those generated at the time the marketing application is filed. 

Metrics for scalability require a specification of the critical quality attributes and a good understanding of the chemistry and the associated processes. One can then probe the limits of acceptability of these critical attributes, and by so doing will discover the scalability limits of the process. As a process is scaled up, one needs to ensure that it is operationally simple and that there are no unacceptable environmental, safety, and health risks. 

A process that is not greatly affected by variations in process temperature, mixing, minor variations in rates of addition, and so on would be considered robust if these excursions did not adversely affect product quality. The main difference between robustness and controllability is that a capable or controlled process will stay within the desired parameters whereas a robust process may experience excursions outside the control parameters, but these excursions will not affect the critical quality attributes. 

For the process chemist, particle size affects the filtration, isolation, and drying kinetics of the API, and PSD is one of the most critical quality attributes that formulation scientists require. Particle size affects the manufacturability of the drug product in terms of flow characteristics, interactions with excipients, and bioavailability. 

The basic concepts of stability data evaluation are the same for single- vs. multifactor studies and for full- vs. reduced-design studies. Data evaluation from the formal stability studies and, as appropriate, supporting data should be used to determine the critical quality attributes likely to influence the quality and performance of the drug substance or product. Each attribute should be assessed separately and an overall assessment made of the findings for the purpose of proposing a retest period or shelf life. The retest period or shelf life proposed should not exceed that predicted for any single attribute. 

Definition of the API in terms of its critical quality attributes. Among the attributes that should be considered are chemical purity qualitative and quantitative impurity profiles physical characteristics such as particle size, bulk and tap density polymorphic forms moisture and solvent content homogeneity and microbial quality (if the product is susceptible to microbial contamination). 

Identification of process parameters that could affect the critical quality attributes of the API. Critical Parameters should be determined by scientific judgment and typically should be based on knowledge derived from research, scale-up batches, or manufacturing experiences. 

When prospectively validating a process, data from laboratory-and/or pilot-scale batches should identify critical quality attributes and specifications, critical steps, control ranges, and in-process tests. Scale-up batches could be used to generate data to confirm or refine earlier work, and production-scale batches should provide data showing consistency of the process. 

Critical quality attributes and critical process parameters have been identified and documented ... 

A major change should be defined as one that would likely significantly affect the critical quality attributes of the API. For example, a change in solvent used for the final crystallization could significantly affect the impurity profile, physical attributes, and other critical quality attributes of the API. Such changes should be justified by additional testing, and if appropriate, revalidation. 

Appropriate tests should be conducted on reprocessed batches to ensure that reprocessing does not adversely affect the quality or purity of the API or intermediate. These tests should include, as appropriate, purity, physical attributes, and impurity profiles, in all cases, the significance of the nonconformance and its impact on the critical quality attributes of the API or intermediate should determine how much analytical data is sufficient to justify the reprocessing. 

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]. 

A solid understanding of a product s critical quality attributes and what aspects of the manufacturing process control them is necessary to fully gain the benefits of PAT [94]. Furthermore, the inherent complexity of protein-based biopharma-ceutical products makes it difficult to use PAT to assess product characteristics critical to safety, efficacy, and stability. In addition, it is difficult, compared with... 

Stability is a critical quality attribute therefore, the stability program plays an important role when developing new pharmaceutical products. This applies in particular to pharmaceutical products that are to be marketed in several strengths and package types. Multiple strengths and package types combined with multiple... 

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