A warning letter was issued in December 15, 2016 by the FDA to

Mr. Andrea F. Sama, Plant Manager of Aplicare, Inc. which describes

about the violations of manufactured pharmaceuticals. According to
FDA the firm failed to follow appropriate written procedures that are
designed to prevent microbiological contamination of drug products
purporting to be sterile.

Based on their labeling, Aplicare’s Povidone-Iodine products are

“drugs” as defined under section 201(g)(1)(B) of the FD&C Act (21
U.S.C. 321(g)(1)(B)), because they are intended for the diagnosis, cure,
mitigation, treatment, or prevention of disease, and/or under section
201(g)(1)(C) of the FD&C Act (21 U.S.C. 321(g)(1)(C)) because they are
intended to affect the structure or any function of the body of a
person. Specifically, these products are intended as topical antiseptics
and antifungals.

In this letter FDA listed four major violation of the firm. Firstly,
they failed to follow appropriate written procedures that are designed
to prevent microbiological contamination of drug products purporting
to be sterile. According to FDA the firm cannot validate their process
and the claim that it achieves “sterilization” as they cannot implement
adequate microbial control for povidone-iodine drug products, which
should be sterile. The process of sterility relies on (b)(4) which is used
as a biological indicator organism as it is found to be less resistant
than organisms routinely found in the manufacturing environment,
such as Bacillus licheniformis, but they failed to characterize the anti-
microbial effects on (b)(4), which assess biological indicator organism
suitability. Further, after repeated warning about the spore-forming
microorganisms found in sterility test since at least 2012, found in
sterility test, they failed to prevent the recurrence of these
contamination incidents. They assured the FDA about the quality
control and wanted a 14 to 18 months’ time period for revalidation but
failed to give any fruitful result.
 They also failed to test numerous product lots for sterility using
USP <71> or an equivalent method and instead used a surrogate
sterility test that lacks a representative sample of the batch and is
insufficiently sensitive. Neither they have a classified area for the
manufacturing of povidone-iodine drug product that purport to be
sterile, nor they have any separate or defined areas which are
necessary to prevent contamination or mix-ups. This level of
monitoring is insufficient to protect the drug and its packaging
components during production, even to evaluate whether the
manufacturing environment is in control. For instance, the (b)
(4) samples collected in March 2015 by FDA were identified
as Bacillus species, which are spore-forming bacteria.

Lastly, the firm failed to establish and follow an adequate written

testing program designed to assess the stability characteristics of
drug products. As they failed to test the sterility of the product, there
is no assurance that the povidone-iodine drug products can meet their
specifications for sterility through their 36-month expiration period.

The study of these violations is crucial so as to know the faults

and the otherwise results of using the unapproved FDA drugs and the
improvements that can be made in the manufacturing operation that
will establish a high level of sterility assurance.