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Quality Assurance (Unit:- 2)

Organization and personnel: Personnel responsibilities, training, hygiene and
personal records.
Premises: Design, construction and plant layout, maintenance, sanitation,
environmental control, utilities and maintenance of sterile areas, control of
contamination. Equipments and raw materials: Equipment selection, purchase specifications, maintenance, purchase specifications and maintenance of stores for raw

A system for designing, analyzing and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of new and in-process materials and processes, with the goal of ensuring final product safety.
The concept of “Quality by Design” (QbD) was defined as an approach which covers a better scientific understanding of critical process and product qualities, designing
controls and tests based on the scientific limits of understanding during the
development phase and using the knowledge obtained during the life cycle of the product to work on a constant improvement environment. QbD describes a pharmaceutical development approach referring to formulation design and development and manufacturing processes to maintain the prescribed product quality.
Guidelines and mathematical models are used to ensure the establishment and use of the knowledge on the subject in an independent and integrated way.
Benefits of QbD for:
 Good business
 Eliminate batch failures
 Minimization deviations and costly investigations
 Avoiding regulatory compliance problems
 Organizational learning is an investment in the future
 Better development decisions
 Efficient, agile, flexible system
 Increase manufacturing efficiency; reduce costs and project rejections and waste
 Build scientific knowledge base for all products
 Better interact with industry on science issues
 Ensure consistent information
 Incorporate risk management
QbD is a concept first developed by the quality pioneer Dr. Joseph M. Juran. Dr. Juran believed that quality should be designed into a product, and that most quality crises and problems relate to the way in which a product was designed in the first place. Woodcock defined a high quality drug product as a product free of contamination and reliably delivering the therapeutic benefit promised in the label to the consumer. The FDA encourage risk-based approaches and the adoption of QbD principles in drug product development, manufacturing, and regulation. FDA’s emphasis on QbD began with the recognition that increased testing does not necessarily improve product quality. Quality must be built into the product.
Over the years, pharmaceutical QbD has evolved with the issuance of ICH Q8 (R2)
(Pharmaceutical Development), ICH Q9 (Quality Risk Management), and ICH Q10 (Pharmaceutical Quality System). In addition, the ICH Q1WG on Q8, Q9, and Q10 Questions and Answers; the ICH Q8/Q9/Q10 Points to Consider document; and ICH
Q11 (Development and Manufacture of Drug Substance) have been issued, as have the conclusions of FDA-EMA’s parallel assessment of QbD elements of marketing applications. These documents provide high level directions with respect to the scope and definition of QbD as it applies to the pharmaceutical industry.

Nonetheless, many implementation details are not discussed in these guidances or documents. There is confusion among industry scientists, academicians, and regulators despite recent publications. This paper is intended to describe the objectives of pharmaceutical QbD, detail its concept and elements, and explain implementation tools and studies.
The principle of QbD has been used to advance the product and process quality
in every industry. Because of need of potent drug with safety profile, pharmaceutical industries are investing billions of money in the drug discovery and development process with endeavour to design quality product and that to with consistency in manufacturing process to deliver the intended performance of product. The information and knowledge gained from pharmaceutical studies and manufacturing provide a base for scientific understanding to support establishment of design space, specification and manufacturing control. Information from pharmaceutical development studies can be a root for quality risk management.
Life cycle management allows making changes in formulation and
manufacturing processes during development and providing additional opportunities to gain added knowledge and it further supports establishment of the design space. Design space is planned by the applicant and will undergo regulatory assessment and approval.
Working within the design space is not considered as a change. But an operation out of the design space is considered to be a change and has to face a regulatory post approval change process.
During the drug development process, the aspects like drug substances,
excipients, container closure systems, manufacturing processes and quality control tests are critical to product quality. Critical formulation attributes and process parameters are generally identified and controlled to the extent of assurance of quality which is also an important task. This scientific and knowledge rich understanding will help industry to manufacture quality products and ultimately flourish industry by means of fame as well as financial assets.
Pharmaceutical QbD is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and control based on sound science and quality risk management. The goals of pharmaceutical QbD may include the following:
 To achieve meaningful product quality specifications that is based on clinical
 To increase process capability and reduce product variability and defects by enhancing product and process design, understanding, and control.
 To increase product development and manufacturing efficiencies.
 To enhance root cause analysis and post approval change management.
 Under QbD, these goals can often be achieved by linking product quality to the desired clinical performance and then designing a robust formulation and
manufacturing process to consistently deliver the desired product quality.
Since the initiation of pharmaceutical QbD, the FDA has made significant progress in achieving the
First objective: performance-based quality specifications. Some examples of FDA policies include tablet scoring and bead sizes in capsules labeled for sprinkle. The recent FDA discussions on the assayed potency limits for narrow therapeutic index drugs and physical attributes of generic drug products reflect this trend. Nonetheless, it should be recognized that ICH documents did not explicitly acknowledge clinical performance

based specifications as a QbD goal, although this was recognized in a recent scientific paper.
The second objective of pharmaceutical QbD is to increase process capability
and reduce product variability that often leads to product defects, rejections, and recalls.
Achieving this objective requires robustly designed product and process. In addition, an improved product and process understanding can facilitate the identification and control of factors influencing the drug product quality. After regulatory approval, effort should continue to improve the process to reduce product variability, defects, rejections, and recalls.
QbD uses a systematic approach to product design and development. As such, it enhances development capability, speed, and formulation design. Furthermore, it transfers resources from a downstream corrective mode to an upstream proactive mode. It enhances the manufacturer’s ability to identify the root causes of manufacturing failures. Hence, increasing product development and manufacturing efficiencies is the third objective of pharmaceutical QbD.
The final objective of QbD is to enhance root cause analysis and post approval
change management. Without good product and process understanding, the ability to efficiently scale-up and conduct root cause analysis is limited and requires the generation of additional data sets on the proposed larger scale. FDA’s change guidances provide a framework for post approval changes. Recently, the FDA issued a guidance intended to reduce the regulatory filing requirements for specific low-risk chemistry, manufacturing, and control (CMC) post approval manufacturing changes.
In a pharmaceutical QbD approach to product development, an applicant identifies characteristics that are critical to quality from the patient’s perspective, translates them into the drug product critical quality attributes (CQAs), and establishes the relationship between formulation/manufacturing variables and CQAs to consistently deliver a drug product with such CQAs to the patient. QbD consists of the following elements:
A quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product. Product design and understanding including the identification of critical material attributes (CMAs).
Process design and understanding including the identification of critical process parameters (CPPs) and a thorough understanding of scale-up principles, linking CMAs and CPPs to CQAs. A control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process capability and continual improvement regulatory aspects to QbD. FDA Perspective In 2005 USFDA asked participating firms to submit chemistry manufacturing control (CMC) information demonstrating application of QbD as part of New Drug Application. QbD involves thorough understanding of process; a goal or objective is defined before actual start of process. Design space and real time release risk assessment are other parameters for implementation of QbD. ICH in its Q8 pharmaceutical development, Q9 quality risk assessment and Q10 pharmaceutical quality system gives stringent requirements regarding quality of product. FDA also states the importance of quality of pharmaceutical products by giving Process Analytical Technology (PAT) which is a Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance. QbD ultimately helps to implement Q8 and Q9. FDA’s view of QbD is “QbD is a systematic approach to product and process design and development”.