THE DESIRED STATE FOR REGULATORY AND PHARMACEUTICAL INNOVATION
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.
QUALITY BY DESIGN
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
, 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
. 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.