Quality by Design (QbD)

Quality by Design (QbD):

A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. 

It is a systematic approach for formulation development to include the prior knowledge, results of studies using design of experiments and use of quality risk management. Such approach can enhance the quality of product and help the regulaors to better understand a company's strategy.

Quality by Design = Process Input (Process Parameters + Material Attributes)

 + Quality Attributes

 + Target Product Profile

Quality Target Product Profile (QTPP): It relates to quality, safety and efficacy, considering e.g., the route of administration, dosage form, bioavailability, strength, and stability. The quality target product profile forms the basis of design for the development of the product. Considerations for the quality target product profile could include: 

• Intended use in clinical setting, route of administration, dosage form, delivery systems; 
• Dosage strength(s); 
• Container closure system; 
•  
• Therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form being developed; 
• Drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for the intended marketed product. 

Critical Quality Attributes (CQA)

A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) and drug product. 

CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, drug release and stability. CQAs for other delivery systems can additionally include more product specific aspects, such as aerodynamic properties for inhaled products, sterility for parenterals, and adhesion properties for transdermal patches. For drug substances, raw materials and intermediates, the CQAs can additionally include those properties (e.g., particle size distribution, bulk density) that affect drug product CQAs. 

Potential drug product CQAs derived from the quality target product profile and/or prior knowledge are used to guide the product and process development. The list of potential CQAs can be modified when the formulation and manufacturing process are selected and as product knowledge and process understanding increase. Quality risk management can be used to prioritize the list of potential CQAs for subsequent evaluation. Relevant CQAs can be identified by an iterative process of quality risk management and experimentation that assesses the extent to which their variation can have an impact on the quality of the drug product. 

Risk Assessment: Linking Material Attributes and Process Parameters 

to Drug Product CQAs

Risk assessment is a valuable science-based process used in quality risk management (see ICH Q9) that can aid in identifying which material attributes and process parameters potentially have an effect on product CQAs. Risk assessment is typically performed early in the pharmaceutical development process and is repeated as more information becomes available and greater knowledge is obtained.

Risk assessment tools can be used to identify and rank parameters (e.g., process, equipment, input materials) with potential to have an impact on product quality, based on prior knowledge and initial experimental data. For an illustrative example, see Appendix 2. The initial list of potential parameters can be quite extensive, but can be modified and prioritized by further studies (e.g., through a combination of design of experiments, mechanistic models). The list can be refined further through experimentation to determine the significance of individual variables and potential interactions. Once the significant parameters are identified, they can be further studied (e.g., through a combination of design of experiments, mathematical models, or studies that lead to mechanistic understanding) to achieve a higher level of process 

understanding.

Design Space:

The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval (ICH Q8).

(Reference : ICH Q8-R2)