Quality by Test (QbT) and Quality by Design (QbD)

Productivity and quality are a unity that sustains the continuity of a product's business. Quality is a symbol of the level of gratification with a product; a high-quality product will produce a high level of gratification. Conversely, low-quality products will usually result in customer disappointment, usually marked by the number of customer complaints. Specifically for medicinal products, quality is also associated with compliance with the requirements set by the regulator. Good-quality products will automatically meet the requirements set by the regulator, while low-quality products cannot meet the requirements set by the regulator, so they must be withdrawn or even face the possibility of the factory being closed, which can certainly damage the company's reputation.

The development of the pharmaceutical industry is based on innovation and manufacturing. It’s understandable that the pharmaceutical industry is a business field that is fully regulated by government regulations. These regulations continue to develop, adjusting to the latest science and technology and helping the needs of the community. Thus, every industry must always make improvements and continuous improvement in order to remain able to meet the requirements set by the government and meet the needs of increasingly intelligent customers.

Quality by Test was the only way to guarantee the quality of drug products before the FDA launched the current Good Manufacturing Practice. In a quality by test (QbT) system, product quality is ensured by following a sequence of steps, including raw material testing, fixed drug product manufacturing process, and end product testing. It is only when all the specifications of the FDA or other standards are complied with that the materials can be used for manufacturing or come into the market. If not, they need to be reprocessed. Root causes for failure are usually not well understood due to the poor process understanding and uncertainty about how characteristics of substances impact the target product profile. As a result, the manufacturers have to restart the procedure until the root causes of failure are understood and addressed, or the FDA approves supplements to revise the acceptance criteria to pass the previously failed batches. This causes poor cost-efficiency and product variation, which may lead to poor drug safety.

The concept of product quality must be considered from the beginning of a product's development. Quality by Design (QbD) is a systematic approach to development that starts from the goal, understanding of the product, understanding of the process, and controlling the process that is carried out based on scientific means and quality risk management. The concept of quality by design (QbD) has been recently adopted in the pharmaceutical industry through several initiatives, e.g., ICH Q81, Q92, and Q103, and the new regulatory documents, Process Analytical Technology (PAT) and FDA's cGMP.

Thus, the goal of pharmaceutical development is to design quality products and manufacturing processes that consistently deliver the desired product performance. Information and knowledge can be obtained from pharmaceutical development studies and manufacturing experience that provide scientific understanding to support the construction of design space, specifications, and manufacturing controls. Information from pharmaceutical development studies can be the basis for quality risk management. This is important to realize that quality cannot be tested into a product, but quality must be built by design. Change in the formulation and manufacturing process during the development and management of the life cycle must be seen as an opportunity to gain additional knowledge and further support the formation design room. Likewise, the inclusion of relevant knowledge gained from experiments that gave unexpected results can also be useful.

ALSO READ: Interview Questions and Answers for Formulation Scientist

The general aim to switch from the quality by testing (QbT) paradigm previously implemented in the pharmaceutical industry to a development can be based on scientific studies, risk-based cost-effective approaches, and ensuring patient safety and product quality during the development and production of preparations related to the substance of active drug compounds, excipients, production, and packaging. The following is a comparison between QbT and QbD:

The goals of pharmaceutical QbD may include the following:

1. To achieve meaningful product quality specifications that are based on clinical performance
2. To increase process capability and reduce product variability and defects by enhancing product and process design, understanding, and control
3. To increase product development and manufacturing efficiencies
4. To enhance root cause analysis and postapproval change management

QbD consists of the following parameters:

Quality Target Product Profile (QTPP): It is a prospective summary of quality characteristics of a drug product to be achieved, taking into account dosage strength and container closure system of the drug product, together with the attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) and drug product quality criteria (e.g., sterility, purity, stability, and drug release) appropriate for the intended marketed product.

Critical Quality Attributes (CQAs): including physical, chemical, biological, or microbiological properties or characteristics of an output material, including a finished drug product. Potential drug product CQAs derived from the QTPP and/or prior knowledge are used to guide the product and process development, and they should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Critical Material Attributes (CMAs): including physical, chemical, biological, or microbiological properties or characteristics of an input material. CMAs should be within an appropriate limit, range, or distribution to ensure the desired quality of that drug substance, excipient, or in-process material.

Critical Process Parameters (CPPs): parameters monitored before or in process that influence the appearance, impurity, and yield of the final product significantly.

During the QbD process, product design and understanding include the identification of CMAs, which are different from CQAs. CQAs are for output materials, while CMAs are for input materials, including drug substances, excipients, and in-process materials. The CQA of an intermediate may become a CMA of the same intermediate for a downstream manufacturing step. While process design and understanding include the identification of CPPs and a thorough understanding of scale-up principles, linking CMAs and CPPs to CQAs is of special importance. From the viewpoint of QbD, CMAs and CPPs can vary within the established design space without significant influence on CQAs, and as a result, the quality of the final product will meet the QTPP.

The concept of QbD has two components: the science underlying the design and the science of manufacturing. Upon understanding the elements of QbD and the steps for QbD implementation, it is important to be familiar with the commonly used tools in QbD, including risk assessment, design of experiment (DoE), and process analytical technology (PAT).

The purpose of risk assessment prior to development studies is to identify potentially high-risk formulation and process variables that could impact the quality of the drug product. It helps to prioritize which studies need to be conducted and is often driven by knowledge gaps or uncertainty. ICH Q9 (4) provides a nonexhaustive list of common risk assessment tools as follows: Basic risk management facilitation methods (flowcharts, check sheets, etc.), Fault tree analysis, Risk ranking and filtering, Preliminary hazard analysis, hazard analysis and critical control points, failure mode effects analysis, failure mode, effects, and criticality analysis, hazard operability analysis, and supporting statistical tools. It might be appropriate to adapt these tools for use in specific areas pertaining to drug substance and drug product quality.

DoE is an excellent tool that allows pharmaceutical scientists to systematically manipulate factors according to a prespecified design. The DoE also reveals relationships between input factors and output responses. When DoE is applied to formulation or process development, input variables include the material attributes (e.g., particle size) of raw material or excipients and process parameters (e.g., press speed or spray rate), while outputs are the critical quality attributes of the in-process materials or final drug product (e.g., blend uniformity, particle size or particle size distribution of the granules, tablet assay, content uniformity, or drug release). DoE can help identify optimal conditions, CMAs, CPPs, and, ultimately, the design space.

The application of PAT may be part of the control strategy. PAT can provide continuous monitoring of CPPs, CMAs, or CQAs to make go/no-go decisions and to demonstrate that the process is maintained in the design space. In-process testing, CMAs, or CQAs can also be measured online or in-line with PAT. Both of these applications of PAT are more effective at detecting failures than end-product testing alone. In a more robust process, PAT can enable active control of CMAs and/or CPPs and timely adjustment of the operating parameters if a variation in the environment or input materials that would adversely impact the drug product quality is detected.

Conclusion

Product testing alone is not sufficient to assure that a process consistently produces a product with predetermined specifications. Adequate process design; knowledge and control of factors that produce process variability, and successful validation studies, in conjunction with product testing, provide assurance that the process will produce a product with the required quality characteristics.

ALSO READ: Critical Quality Attributes (CQAs) in Pharmaceutical Development