The late 1990s and early 2000s witnessed a slew of enforcement actions by FDA that included multiple Form 483 observations,
warning letters, and consent decrees resulting from facility inspections. The following years witnessed FDA's launching of
multiple initiatives in an attempt to inspire the industry to achieve higher standards of quality and compliance. Among these
initiatives are the Pharmaceutical cGMPs for the 21st Century, process analytical technology (PAT), quality by design (QbD), and harmonization of international standards and guidelines.
As a result of these efforts, new standards and guidelines have been published and numerous conferences held regarding quality
systems, product quality, and regulatory compliance. However, after more than 10 years since the launch of these initiatives,
manufacturing innovation and product quality do not appear to have improved to the extent originally envisioned. As recent
years have clearly demonstrated, the industry is still struggling to attain the aspirations of cGMPs for the 21st Century. The industry is now in the midst of a new cycle of enforcement actions including consent decrees. So the question remains:
have we, as an industry, learned from the mistakes of the past? Have we improved quality and compliance to the level expected,
and if not, why?
There is no doubt that FDA has a role to play as it tries to foster positive change in our industry and, at times, has had
to step up enforcement when confronted with quality and/or compliance issues. With this as background, we will attempt to
explain the main drivers and potential causes of our limited success as an industry to meet the lofty goals defined earlier.
Understanding these causes can hopefully lead to solutions. One thing is clear: the current state of quality is far from optimal.
There must be change to address the challenges of the 21st century and remain competitive. In simple terms, the barometer
of quality and compliance is skewed and is in dire need of calibration.
QUALITY IMPROVEMENT INITIATIVES
PAT, QbD, Quality, and cGMPs for the 21st Century are meant to provide increased understanding, control, and reliability of manufacturing processes, as well as consistently
high product quality and regulatory flexibility. The initiatives themselves are not poor ideas. Rather, it is more likely
they have not been as broadly or successfully implemented because they have been misinterpreted or incorrectly applied by
both regulatory authorities and industry, only partially implemented because of competing demands on operations and staff,
or not implemented at all. The magnitude of change these initiatives would introduce may have been underestimated and companies
may not have been prepared to effectively manage, integrate, or sustain that change. Perhaps more time and a careful re-examination
of the applications of these initiatives is what is needed for us to better understand and apply these approaches.
POTENTIAL CAUSES AND DRIVERS
The recent challenges the industry has faced regarding quality and compliance may be the result of multiple, converging factors
that have caught many companies in a cycle that is difficult to break. Some of the contributing factors appear to include
Lack of an effective and sustainable quality culture
While there has been considerable focus recently on the importance of attaining an effective and sustainable quality culture,
as well as management's role in leading this, the industry has not been successful in accomplishing this goal. Possibly this
is because the industry's attitude has been that quality and compliance are costly, do not produce profit, and require excessive
time, money, and valuable resources to attain. This mindset results in a reactive approach where "fire-fighting" is sometimes
all too common, but even when put out, all too frequently fires re-occur because effective measures have not been pro-actively
implemented to prevent their re-occurrence. This behavior—particularly when seen as acceptable to management—then becomes
the culture of the organization, and a major barrier to attaining a high and consistent level of quality and compliance.
Lack of effective quality management systems
Advances in technology have resulted in some paperless operations and the capability to communicate quickly. These systems
when not used effectively, however, can lead to inefficiencies and unnecessary complexity that impede proper system functioning.
Standard operating procedures (SOPs) and batch records are sometimes so complex that they are difficult to follow, leading
to human errors and deviations. The blame frequently falls on lack of effective training. The root cause, however, may be
documents that are too complex. Fueling the complexity, multiple changes (e.g., addition of steps, changes to instructions)
are introduced to documents, particularly batch records.
Deviation, investigation, and corrective and preventive actions (CAPA) management
These actions are crucial elements of the quality system that are the frequent focus of regulatory authorities. These systems,
when not developed, implemented, and managed effectively, can lead to unnecessary 483s, warning letters, and occasionally,
consent decrees. They are sometimes overly long, needlessly complex, and frequently do not provide the level of information
needed to identify and resolve the root cause of the occurrence. Long scientific explanations may be written, but the primary
questions are not answered. The effect of the deviation on product quality may also not be properly assessed. CAPAs may be
generated without identification of the proper root cause, becoming exercises in futility. Ineffective management of these
systems can result in a company getting caught in a cycle of repeated deviations and CAPAs that can result in further deviations,
significantly increasing the compliance risk/exposure of the organization.
Outdated manufacturing processes and methods
There seems to be some hesitation from industry to update/improve outdated manufacturing processes and methods that pose quality
risks, such as product contamination, excessive process variability, and lack of consistent product quality. Regulatory authorities
approved these processes and methods several decades ago, and there is the perception that change is not needed because they
have been "working fine as-is." Additionally, there is cost and time associated with having major changes approved. However,
outdated processes and methods can lead to serious agency action because they may not be sufficiently in control under today's
standards. It might take time to happen, but a process that is not designed appropriately to mitigate quality risks will almost
certainly experience a major quality event in the future. When a quality failure happens, regulators will demand the changes
and the associated time and cost to accomplish these improvements will be much higher.
The recent economic crisis has not been helpful at maintaining investment in quality and compliance. There has been more pressure
than ever to send batches out the door. Trained personnel have been laid off. Manufacturing campaigns tend to be smaller and
there are more product changeovers. Training is frequently the first quality element to experience cuts because of economic
pressure. The industry is having to do more with less, leading to increased pressures on systems and personnel.
The pharmaceutical industry is not producing the blockbuster drugs of the past. Stakeholders are more demanding as healthcare
costs continue to skyrocket. Patients are becoming more involved and demanding about their health. Additionally, there have
been several R&D disappointments in recent years that have led to dried pipelines, decreased company profitability, and lowered
employee morale—each a major challenge to innovation and growth. Situations like this have led to a slew of industry mergers
and acquisitions designed to foster increased profitability and growth but at the same time have significantly altered the
landscape of the industry, producing new challenges.