Avoid an FDA Warning Letter in
the Laboratory Environment
The FDA’s emphasis on laboratory audits in recent years has focused on companies con- firming that laboratory data is not fraudulent. With the rise in evidence that justifies the
FDA’s fraudulent data concerns — especially interna-
tionally — the failure of companies to provide estab-
lished historical information and ensure compliance
on the validation of their analytical methods and
procedures increases the risk of receiving an FDA
warning letter. Today, more than ever, the key point
is simply to be vigilant regarding all FDA require-
ments and regulations, and not focus solely on the
data integrity concern. The FDA also looks for evi-
dence of qualification and validation of the suitabili-
ty of a company’s analytical equipment, and certifica-
tion that staff are qualified and properly trained.
During a data integrity audit, the emphasis is
on providing evidence that analytical results are
accurate, verifiable, and not fraudulent. Firms need
to show that they have the appropriate controls in
place, and that procedures and controls are sustainable. A firm can interpret the audit process as
having to prove that there is no fault caused by its
actions. Scrutiny by the FDA and other regulatory
bodies can be unnerving, uncomfortable, and creates
an environment that presents a significant risk to a
To reduce a company’s risk and to handle a successful FDA laboratory audit, it is important to start
by ensuring that historical laboratory information is
up-to-date regarding analytical methods validation,
equipment qualification, and personnel qualifications.
Any automated equipment should have software
controls such as audit trails to assure data integrity.
An established calibration program, a written stability
program, and laboratory procedures should be in
place, up to date, and appropriate to the particular
laboratory setting. This includes information from
contract testing laboratories, which must also ensure
that the methods used in the facilities and the controls used for manufacturing, processing, packing, or
holding are operated or administered in conformity
with Current Good Manufacturing Practice (CGMP).
Pharmaceutical companies should understand that,
while data integrity concerns are currently given high
visibility by the FDA, ensuring compliance with 21
CFR Subpart I — Laboratory Controls and other
CGMP requirements is mandatory to eliminate the
risk of receiving an FDA warning letter.
Observations in warning letters
Many past and current warning letters contain references of a lack of compliance with the elements
described by 21 CFR Subpart I — Laboratory
Controls requirements. Some observations state that
laboratory records did not include complete data
derived from all tests necessary to confirm compliance with established specification and standards. In
some cases, the analytical testing documentation for
raw materials did not include sample solution preparations, sample weight, the method number used, the
initials of the analyst who performed the test, and the
date of the analysis.
Another observation noted in warning letters may
relate to a firm’s failure to calibrate instruments and
recording devices at suitable intervals in accordance
with an established written program covering specific
directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event
accuracy or precision limits are not met.
Compliance based on science
Common observations in warning letters point
to a firm’s failure to establish laboratory controls
that include scientifically sound and appropriate
specifications, sampling plans, and test procedures.
Observations may note that assay methods used to
test finished drug products for release have not been
validated, or that the firm failed to establish finished
product specifications for several drug products.
Another common observation in warning letters
deals with a firm’s failure to investigate and document
out-of-specification results. For example, a firm failed
to investigate unknown peaks found on a chromatograph during the HPLC testing for related compounds
of an API USP batch, and a firm’s investigation of the
data from the Empower software identified instances
where additional testing was performed but not properly documented in laboratory records.
Test and document all procedures
Common observations in warning letters may include:
• A firm’s failure to establish and follow an adequate
written testing program to assess the stability