4 BioPharm International eBook December 2019 www.biopharminternational.com
• Poorly maintained equipment
and facilities
• Inadequate maintenance and
monitoring of water systems
• Insufficient cleaning validation
processes
• Inadequate—or the lack of—
written procedures for stabil-
ity testing, release testing, and
other quality testing steps
• Inadequate controls over data
and computer systems
• Failure to explain discrepancies
in drug batches
• Failure to have an adequate
quality control unit.
A recent warning letter illustrates
how an inadequate response to vio-
lations can create additional prob-
lems for a drug company. Mylan
Laboratories received a warning
letter for failing to have adequate
written procedures for the receipt,
identification, testing, and han-
dling of raw materials. Specifically,
the citation addressed the compa-
ny's failure to identify nitrosamine
impurities in solvents used to manu-
facture valsartan API. The company
also was cited for inadequate pro-
cesses for testing and handling of
these solvents and the subsequent
steps the company took to remedy
the problem. In addition, FDA noted
that Mylan's cleaning methods for
non-dedicated equipment were not
adequate to prevent contamination
or carry-over to other drugs manu-
factured on that equipment (3).
Another letter, to Greenbrier
International—the Dollar Tree dis-
count stores—illustrates two points:
quality issues by contractors can
result in warning letters to the drug
license holder, and drug license
holders must pay close attention to
regulatory enforcement activity.
In a January 2019 inspection,
FDA noted that Greenbriar "used
contract manufacturers and suppli-
ers with histories of significant drug
CGMP [current good manufactur-
ing practice] violations." Some sup-
pliers were placed on import alert,
and Greenbriar was sent copies of
the warning letters when issued.
In addition, FDA noted that
Greenbriar required suppliers to use
a testing laboratory, Bureau Veritas
(BVS), to test products it distributes.
BVS representatives told FDA that
BVS's test methods "were not suit-
able for drug CGMP purposes and
that its test results were not suitable
to make release decisions of drug
products for distribution into the
US supply chain."
FDA reminded Greenbrier that
the company was "responsible for
ensuring that the drugs you distrib-
ute are not adulterated, including
ensuring that all drug manufactur-
ers supplying Greenbrier with drugs
have had release testing conducted
in accordance with CGMP require-
ments" (4).
IN THIS ISSUE
T he latest insta llments of t he
Pharmacopoeia Compliance Series
emphasize the need for drug com-
panies to establish formal processes
to monitor global and national
pharmacopoeia changes to stay
i n for med, a nd potent ia l ly get
involved with defining changes in
compendial guidelines. Likewise,
the quality teams at drug compa-
nies and contract service providers
should closely monitor regulatory
enforcement activity. FDA's online
compliance information and Data
Dashboard are useful references.
Links to other regulatory sources
can be found in this ebook on
pages 38–43.
REFERENCES
1. FDA, Novel Drug Approvals for 2019,
www.fda.gov, accessed Dec. 11, 2019.
2. FDA, FDA Data Dashboard, accessed
Dec. 11, 2019.
3. FDA, Mylan Laboratories Limited - Unit
8, Warning Letter, Nov. 5, 2019.
4. FDA, Greenbrier International, Inc dba
Dollar Tree, Warning Letter, Nov. 6,
2019.
BP
Regulatory Sourcebook Enforcement Update
Draft Guidance Proposes Approval Pathway for Insulin Biosimilars
FDA is seeking comment on a draft guidance, Clinical
Immunogenicit y C onsiderations for Biosimilar and
Interchangeable Insulin Products, that is designed to
clarify what data and information may–or may not–be
needed to support a demonstration of biosimilarity or
interchangeability for a proposed insulin product (1).
In the draft guidance, the agency recommends that,
under certain circumstances where the agency expects the
risk of clinical impact from immunogenicity to be minimal,
a comparative clinical immunogenicity study would not
be necessary for approval of certain proposed biosimilar
and interchangeable insulin products. However, for some
products, a comparative clinical immunogenicity study may
be needed to address uncertainty regarding immunogenicity,
such as were there are differences in certain impurities
or novel excipients the agency noted. Applications for the
proposed products must include data and information
sufficient to demonstrate biosimilarity or interchangeability.
Public comments on the draft guidance will be accepted
via this link until Jan. 28, 2020.
Reference
1. FDA, "Statement on Efforts to Help Make Development of
Biosimilar and Interchangeable Insulin Products More Efficient,"
Press Release, Nov. 25, 2019.
