Drugs and devices are "adulterated," as that term is
used in the Food, Drug, and Cosmetic Act, if the drugs and devices
are contaminated, impure, or diluted; deliver too much or too
little of the active ingredient; or do not conform to mandatory
specifications. A product can also be deemed
"adulterated"—even in the absence of any such
defects—if the manner in which the product was manufactured
did not conform to the "Good Manufacturing Practice" or
"Quality System" regulations (collectively known as the
GMP regulations). Manufacturers therefore must not only avoid
product defects but must also proactively undertake thorough
measures designed to prevent defects. To enforce the adulteration,
GMP, and other laws, the Food and Drug Administration
("FDA") conducts thousands of establishment inspections
each year, issues thousands of "FDA-Form 483"
observations alleging the adulteration of medical products, and
issues hundreds of Warning Letters.
An analysis of recent Warning Letters and inspectional observation
data reveals that, more than ever, most allegedly
"adulterated" products work as intended and conform to
all release specifications. Most Warning Letters, including most of
those that focus on GMP issues, are not reactions to product
failures. Rather, the bulk of the warnings reflect instead the
FDA's increasing focus on the processes and procedures that are
intended to prevent defects. For manufacturers, this means that
there is no substitute for thoroughness and diligence, and that the
process of manufacturing is as important as the results.
Although this Commentary focuses on medical products,
food providers should note that enforcement of food GMP regulations
is moving in the same direction. The FDA currently examines whether
food processors—particularly processors of higher risk
foods—are taking proactive steps to avoid contamination.
Further, the FDA has recently released extensive proposed changes
to the food GMP regulations. The new regulations, when finalized,
will require almost all food processors to adopt stringent
preventive controls.
Trends in Inspection Observations
If an FDA inspector notes any regulatory violations during an
establishment inspection, the FDA will issue an "FDA-Form
483." This form sets out the inspector's observations.
Although the FDA does not publish most 483s,1 the FDA
does publish extensive summary statistics. This data set shows that
the FDA cites inadequacies in the procedures for avoiding product
defects far more often than actual product failures or responses to
product failures.
This trend is most pronounced in the 483s issued to device
manufacturers. The four most common observations are: failure to
establish procedures for corrective and preventive action; failure
to establish procedures for handling complaints; failure to
develop, maintain, or implement adverse event reporting procedures;
and failure to establish procedures to determine whether incoming
materials and services conform to specifications. In all, 15 of the
25 most commonly cited violations involve a lack of established
procedures (which could mean either that the written procedures are
lacking or that a firm's employees fail to follow them). To be
sure, the FDA also cites device manufacturers for inadequate
documentation, failure to validate processes and designs, not
investigating product failures, and other violations. But the
FDA's emphasis on written procedures is striking.
The observations relating to drug facilities are more
heterogeneous. Failure to establish written procedures is a
persistent issue, and four of the seven most common violations fall
into this category. Other common observations include: the
responsibilities of the quality control unit are either not written
or are not fully followed, the manufacturer failed to fully
investigate out-of-specification batches (including both released
and rejected batches), and laboratory controls are not
validated.
For biologic facilities,2 the FDA cites inadequate
procedures three times as often as any other observation. Failure
to investigate out-of-specification products is the second most
common violation, and the next four each relate to inadequate
documentation.
Warning Letters, and How to Avoid Them
A Warning Letter, although technically informal, signals that
the FDA is prepared to begin a court proceeding unless violations
are quickly corrected. Most Warning Letters demand that the
recipient set out, within 15 working days, "specific steps
[the] firm has taken to correct the noted violations, as well as an
explanation of how [the] firm plans to prevent these violations, or
similar violations, from occurring again." Warning Letters are
public. After only a short delay, and with minimal redactions, the
FDA posts all Warning Letters to its web site—and from there
it is often not long before the letters come to the attention of
the media, investors, and plaintiffs' lawyers.
A review of recent Warning Letters shows that there is no simple
method for avoiding them. Rather, manufacturers should commit
themselves to the hard work of bringing their processes into
compliance before the FDA arrives. It is also crucial to provide a
thorough response if an inspection reveals GMP issues, and to give
serious attention to complaints from patients and medical
practitioners.
Releasing a contaminated or out-of-specification product into the
marketplace increases the likelihood of an inspection and often
results in a Warning Letter. A handful of Warning Letters directly
cite such problems as grounds for issuing the Letter. More
frequently, the FDA will cite the underlying GMP violation, noting
the eventual product defect as an example of the importance of
maintaining or following appropriate procedures.
It is more common still for the FDA to issue a Warning Letter on
GMP issues where there is no known problem with the released
products, and there have been no complaints. As the FDA wrote in
one Warning Letter, "the lack of current customer complaints
alone is neither a verification of a robust quality system nor that
you have appropriate process controls in place." Indeed, only
a minority of recent Warning Letters indicate that the finished
product failed to perform or is known to be out of specification.
Even in the absence of an actual product defect, the FDA is
unwilling to tolerate unreliable processes that could
result in defects.
Since Warning Letters, at least those that focus on GMP issues,
are seldom issued immediately following an inspection, a firm can
take steps to prevent a bad inspection from developing into a
Warning Letter. In almost every instance, the FDA first provides
its criticisms through 483 observations and in-person meetings, and
solicits the firm's responses. While the FDA can and does issue
Warning Letters regardless of the response, more commonly the FDA
does not issue one unless the FDA perceives both a serious GMP
issue and a failure to respond properly.
Providing a thorough response to the 483 is critical.
Most GMP-related Warning Letters note that the manufacturer did
respond, but conclude that the response is inadequate. The FDA
typically demands an investigation of the cause of the observed GMP
violations, a proposed solution, implementation of the solution
(including retraining relevant employees), an investigation into
released lots that may have been affected, and documentation
demonstrating all actions were completed.
Another recurring cause of Warning Letters is poor handling of
complaints. Manufacturers are required to collect complaints,
evaluate them, and report certain adverse events to the FDA. The
FDA has issued numerous Warning Letters to companies that do not
implement (or do not have) written complaint handling procedures.
This issue is more common with small or foreign companies that may
not be fully conversant with FDA requirements. A problem that trips
up large and small companies alike, however, is a failure to
properly investigate complaints. If complaints indicate that a
product is defective or dangerous, the FDA will expect an
investigation that determines the root cause of the observed
problems and leads to corrective actions.
Of course, many Warning Letters do not relate, or at least do not
primarily relate, to GMP problems. Some letters are aimed at
companies that make no apparent effort to comply with their
regulatory obligations. Some of these companies may not believe
that their products are subject to regulation. Others know but do
not appear to care. Warning Letters to these companies indicate
that everything is amiss: no registration, no product approvals, no
written procedures, no adverse event reporting, etc. Established
companies are unlikely to receive such letters.
The FDA issues other letters in response to allegedly
impermissible advertising claims. The FDA sometimes issues
"cyber" Warning Letters without an establishment
inspection, relying solely on company web sites or other marketing
materials. Some recipients of advertising-focused letters are
fly-by-night operations that make extravagant claims about dubious
products. But the FDA (and in particular the Office of Prescription
Drug Promotion) also warns legitimate companies that, the FDA
believes, make claims that outstrip their product approvals, or
cross the blurry lines separating dietary supplements or cosmetics
from drugs.
Viewing the body of recent Warning Letters as a whole, there is no
one GMP regulation, nor even a discrete set of regulations, that
can be said to command the FDA's focus. Rather, the FDA will
scrutinize the entire manufacturing process.
Current and Future Enforcement of Food GMPs
When the FDA inspects food facilities, the most common negative
observation, by a considerable margin, is that the facility did not
adequately control pests. Other insanitary conditions likewise draw
inspection observations and Warning Letters. But the FDA also
focuses on failures to take proactive steps to maintain sanitary
conditions. For example, design flaws hindering the cleaning of a
facility are cited (slightly) more often than actual failures to
maintain a facility in a sanitary condition. Many fisheries, which
are subject to stringent "HACCP" regulations3
in addition to the general GMP requirements, receive warnings for
failing to take mandatory proactive steps. Eight of the 15
regulations most cited in 483s to food establishments pertain only
to fisheries. These regulations mandate establishing a plan for
sufficient monitoring of sanitation conditions, implementing the
plan, recordkeeping, and verification of various aspects of the
HACCP plan.
The FDA's focus on preventive steps will only increase when
the Food Safety Modernization Act ("FSMA") is fully
implemented. The FDA views this 2011 law as a "sweeping
reform" that will "ensure the U.S. food supply is safe by
shifting the focus from responding to contamination to preventing
it."
Among many other provisions, FSMA requires most food manufacturers
to implement "hazard analysis and risk-based preventive
controls" similar to the HACCP obligations that currently
apply to only a subset of the industry. On January 4, 2013, the FDA
released draft regulations that will implement this mandate and
will overhaul and modernize the GMP regulations pertaining to
environmental pathogens, food allergens, mandatory employee
training, and sanitation of food contact surfaces. These
regulations are not binding at present, nor are they in their final
form. But when they go into effect, the FDA's focus on
preventive steps will be redoubled.
Conclusion
There are no quick fixes for avoiding 483 observations and Warning Letters. Product failures may encourage the FDA to increase the frequency of inspection of a facility. But avoiding product failures will not prevent inspections, and even without product failures, the FDA will demand full compliance with GMP requirements.
1.Form 483s are public; the FDA posts selected 483s to the FDA web site, and generally 483s can be obtained from the FDA through FOIA (Freedom of Information Act) requests. But the FDA does not post the vast majority of the 483s.
2.In this dataset, "biologic" facilities are largely facilities that handle blood products.
3.Hazard Analysis Critical Control Points. The HACCP regulations pertaining to processors of fish or fishery products are collected at 21 C.F.R. Part 123.
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