Regulatory Challenges in the QbD Paradigm - The authors demonstrate how an integrated model is helping to achieve regulatory flexibility. This article is part of a special section on biopharmaceutical


Regulatory Challenges in the QbD Paradigm
The authors demonstrate how an integrated model is helping to achieve regulatory flexibility. This article is part of a special section on biopharmaceutical trends.

BioPharm International
Volume 25, Issue 9, pp. 44-53


In 2002, FDA launched Pharmaceutical CGMP for the 21st Century–A Risk-Based Approach , an initiative to encourage the adoption of modern and innovative manufacturing technologies (3). Another aspect of the initiative was to ensure that "the product review and the inspection program operate in a coordinated and synergistic manner." The desired state was defined as "a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight." FDA and the pharmaceutical industry are spending considerable efforts to understand how to achieve this incredible feat and to identify the necessary elements required. This section discusses some of these elements.

The desired state must be defined first in more detail. The roles of manufacturers and regulatory authorities must also be defined. Under this paradigm, manufacturers have extensive knowledge about product, process, and quality attributes and strive for continuous improvement to reach the desired end point of consistent, safe and effective, pure and potent, drug products. They share this knowledge with FDA. The agency develops the expertise to evaluate products and processes using a science- and risk-based approach through the review of submitted data in applications and performance of prelicense and preapproval facility inspections. Subsequent, postapproval changes do not need the submission of supplements if these changes are to happen within the design space of critical process parameters as established and approved in the original application. Surveillance inspections are conducted periodically using a risk-based approach to verify the changes. The desired state includes the potential for less inspectional oversight for a facility or firm that has maintained an acceptable compliance status and has reached a state of quality excellence. Therefore, in addition to the expertise that application reviewers need to develop, field investigators also must develop expertise to address the demands of the new desired state. An integrated model of review and inspection should be in place to complement and coordinate the attainment of the desired state for new pharmaceutical products. New guidance documents and compliance program guidance may need to be created.

It appears that the new desired state can be achieved or at least approached with the adoption of two main elements by the pharmaceutical industry and by FDA: QbD and effective, agile quality systems with good quality risk-management principles.


QbD is not a new concept (4). It was introduced decades ago and adopted by the automobile and food industries to enhance process design and consistency by employing effective and measurable in-process controls with less reliance on end-product testing. The intent was to allow for corrections in real time for the manufacture of quality product with less variability and with the expected attributes. Furthermore, this principle led to Six Sigma processes and lean manufacturing concepts. QbD was introduced relatively recently in the pharmaceutical industry and embraced by FDA as a means to enhance the regulatory process.

QbD is defined in the International Conference on Harmonization (ICH) Q8 guideline as "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" (5). The publication of FDA's guidance, PAT—A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance , initiated an effort that eventually evolved into QbD (6). The underlying principles of science- and risk-based process and product development and commercialization are also reflected in the contents of the quality guidelines ICH Q8 Pharmaceutical Development , ICH Q9 Quality Risk Management, and ICH Q10 Pharmaceutical Quality System as well as by the recently issued guidance on process validation from FDA (5, 7–9). The past five years have seen QbD gaining widespread adoption in the biopharmaceutical industry with several publications attempting to elucidate a path forward for its implementation and resolution of the various issues that serve as detriments to its success (10–12).

The key steps for QbD implementation include: identification of the product attributes that are of significant importance to the product's safety or efficacy (i.e., target product profile and critical quality attributes); design of the process to deliver these attributes; a robust control strategy to ensure consistent process performance; validation and filing of the process demonstrating the effectiveness of the control strategy; and finally, ongoing monitoring to ensure robust process performance over the lifecycle of the product (10, 11). Risk assessment and management, raw material management, use of statistical approaches and process analytical technology (PAT) provide a foundation to these activities.

There are many significant differences that contrast a QbD-based process and product development from traditional practices. In the traditional approach, the process defines the product, and as a result, the process needs to be performed within narrow operating ranges to get consistent product quality. In QbD, the product defines the process, so as long as the process stays within the defined design space, product quality is acceptable. Product specifications in the traditional approach are set based on process performance, and regulators expect them to be narrowed after enough process history has been established. On the other hand, in QbD, product specifications are set based on process and product knowledge and this allows them to be kept wider, resulting in greater operational flexibility. The regulatory filing in the traditional approach describes the process and presents data on product characterization. The focus is on presenting the status quo . In a QbD filing, the focus is instead on process and product knowledge. Data are presented to explain how the process affects the quality attributes (QA) of the product and how the QA affect the safety and efficacy of the product. Postapproval support through product lifecycle requires high maintenance in the traditional approach. The regulatory burden is high for process changes and, therefore, process improvements are few.

Many postapproval supplements are focused on alleviating repeat violations of the approved ranges and limits even though these violations do not necessarily affect product quality. Many postapproval supplements introduce new filling lines and manufacturing sites for similar processes. In a QbD paradigm, the regulatory burden is low because there are wider ranges and limits based on product and process understanding. Changes within these ranges and limits do not require prior approval. Resolution of nonconformances is faster because the required process knowledge already exists.

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