McGuff Pharmaceuticals Inc. 12/28/10
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Department
of Health and Human Services
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Public Health Service
Food and Drug Administration |
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Los Angeles District
Compliance Branch
19701 Fairchild
Irvine, CA 92612-2506
Telephone: 949-608-4426
FAX: 949-608-4415
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Warning Letter
CERTIFIED
MAIL
RETURN RECEIPT REQUESTED
WL: 19-11
December 28, 2010
Ronald M. McGuff
President and CEO
McGuff Pharmaceuticals Inc.
2921 W Macarthur Blvd Ste 142
Santa Ana, CA 92704-7944
Dear Mr. McGuff:
During our
May 18 to June 2, 2010 inspection
of your pharmaceutical manufacturing facility, McGuff Pharmaceuticals,
Inc., located at 2921 W Macarthur Blvd Ste 142, Santa Ana, California,
investigators from the Food and Drug Administration (FDA) identified
significant violations of Current Good Manufacturing Practice (CGMP)
regulations for Finished Pharmaceuticals, Title 21, Code of Federal
Regulations, Parts 210 and 211. These violations cause your drug
product(s) to be adulterated within the meaning of section 501(a)(2)(B)
of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. §
351(a)(2)(B)] in that the methods used in, or the facilities or controls
used for, their manufacture, processing, packing, or holding do not
conform to, or are not operated or administered in conformity with, CGMP.
In addition, you distribute unapproved new and
misbranded drugs in violation of sections 505(a) and 502(f)(1) [21 U.S.C.
§§ 355(a) and 352(f)(1)] of the Act.
We have reviewed your firm’s response of
June 16, 2010, and note that it lacks sufficient
corrective actions.
Specific violations observed during the inspection
include, but are not limited to, the following:
CGMP Violations
1. Your firm has
not established appropriate written procedures designed to prevent
microbiological contamination of drug products purporting to be sterile,
including procedures for validation of all aseptic and sterilization
processes [21 C.F.R. § 211.113(b)]. For example:
a. Your firm has
failed to conduct a media fill representative of the different packaging
configurations of your drug products for the past two years. Your firm
has been using a volume of (b)(4) for
media fills; however, commercial products are available in
(b)(4) and (b)(4). In
addition, you have not established maximum aseptic fill duration.
In your response, your firm states that you have amended your Standard
Operating Procedure (SOP) (b)(4) to
“bracket” the container sizes by utilizing both the
(b)(4) and (b)(4)
volumes. Your response, however, is inadequate because you have not
provided a risk assessment that examines the effects of differences
between product fill sizes (i.e., fill speed, operating methods,
container opening size, mass) to determine if bracketing is appropriate.
b. Your firm’s
qualifications of the Getinge Model 4300 autoclave and the Grieve
CLE-500 oven are inadequate in that you have not qualified this
equipment with representative loads. Your firm’s practice is to qualify
the equipment using minimum loads as opposed to actual loads during
routine operation (e.g., Grieve CLE-500 oven was qualified to
depyrogenate glass vials using (b)(4)
tray when the actual load is a maximum of 60 trays).
In addition, your use of biological indicators and penetration
thermocouples in the qualification studies are inadequate. Your firm has
not used any penetration thermocouples during the qualification of
Getinge Model 4300 since February (b)(4),
nor have you incorporated the use of biological indicators. During the
maximum load configuration study, your firm only used a
(b)(4) penetration thermocouple and
failed to use any biological indicators.
In your response, your firm commits to evaluate the adequacy of your
current procedure, to qualify your minimum and maximum load on each of
your manufacturing operations, and to include penetration thermocouples
and biological indicators in appropriate areas and in appropriate
quantities. However, your response is inadequate because you did not
explain how you will determine the appropriate locations and quantities
for the thermocouples and the biological indicators. Since your firm is
currently manufacturing sterile drug products using unqualified
equipment, your response fails to include any additional controls to
assure the quality of your drug products while you are evaluating your
current procedures.
2. Your firm has
not conducted at least one specific identity test and has not
established the reliability of the supplier’s analyses through
appropriate validation of the supplier’s test results at appropriate
intervals [21 C.F.R. § 211.84(d)(2)].
For example, your firm accepts and relies upon the Certificate of
Analysis (COA) from your active pharmaceutical ingredient (API)
suppliers without conducting appropriate validation of the supplier’s
test results. This is of heightened concern since you have not
established endotoxin specifications, nor have you performed endotoxin
testing on APIs intended to be used in the manufacture of sterile drugs.
In your response, your firm commits to test any APIs with amended
specifications in an attempt to correct this deficiency. However, your
response fails to explain which specifications are to be amended or
which APIs are to be tested. In addition, you do not describe corrective
actions regarding products currently in the market manufactured with
APIs of questionable quality.
Please note that adequate qualification of suppliers is critical in
assuring that your sterile drug products are of the quality intended.
3. Your firm has
not thoroughly investigated the failure of a batch or any of its
components to meet its specifications whether or not the batch has
already been distributed [21 C.F.R. § 211.192]
For example, your firm failed to conduct adequate investigations into
action level excursions. Your investigations (e.g.,
(b)(4)) of growth in a media fill did
not include a review of the batch records, equipment logs, or HVAC
system by the most responsible personnel (e.g., a microbiologist
reviewed a batch record). Further, the Quality Assurance Unit did not
review and approve the investigation. Finally, your firm failed to
implement the corrective/preventative action identified in the
investigation.
In your response, your firm states that: 1) your SOP will be revised to
require a formal investigation by the Quality Assurance Unit when
environmental monitoring action levels are exceeded and 2) retrospective
investigations into previous excursions were conducted. You also commit
to re-investigate (b)(4) and that any
impact on aseptic operations will be assessed by the Quality Assurance
Unit. Your response, however, is inadequate because you have not
described how you will assess the potential impact on products that have
already been distributed.
Unapproved New Drug and Misbranding Violations
In addition to violating CGMPs, you manufacture and market unapproved
new drugs in violation of sections 505(a) and 502(f)(1) [21 U.S.C. §§
355(a) and 352(f)(1)] of the Act. Based on the information your firm
submitted to FDA’s Drug Registration and Listing System and the
information collected during the inspection of your facility, you
manufacture the following prescription drugs, including, but not limited
to:
- Ascor L 500, Ascorbic Acid
Injection, USP, 500 mg/mL in 50 mL vial (McGuff Pharmaceuticals)
- Ascorbic Acid Injection, USP,
500 mg/mL in a 50 mL vial ((b)(6))
- Ascor L NC, Ascorbic Acid
Injection, USP, Non-Corn Source (500 mg/mL in 50 mL vial) (McGuff
Pharmaceuticals)
- Magnesium Chloride Injection,
200 mg/mL, in 50 mL Multi-Dose vial (McGuff Pharmaceuticals)
- Magnesium Chloride Injection,
200 mg/mL, in 50 mL Multi-Dose vial ((b)(6))
- Vitamin B-Complex 100
Injection, 30 mL Multi-Dose vial (McGuff Pharmaceuticals)
These products are drugs within the meaning of section 201(g) of the
Act, [21 U.S.C. § 321(g)] because they are intended for use in the
diagnosis, cure, mitigation, treatment, or prevention of
diseases. Further, they are “new drugs” within the meaning of section
201(p) of the Act [21 U.S.C. § 321(p)] because they are not generally
recognized as safe and effective for their labeled uses. Under sections
301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)] a new drug
may not be introduced into or delivered for introduction into interstate
commerce unless an application approved by FDA under either section
505(b) or (j) of the Act [21 U.S.C. § 355(b) or (j)] is in effect for
the drug. Based on our information, you do not have any FDA-approved
applications on file for these drug products. The marketing of these
products, or other applicable products, without an approved application
constitutes a violation of these provisions of the Act.
Additionally, because the above products are intended for conditions
that are not amenable to self-diagnosis and treatment by individuals who
are not medical practitioners, adequate directions cannot be written for
them so that a layman can use this product safely for its intended uses.
Consequently, their labeling fails to bear adequate directions for their
intended uses, causing it to be misbranded under section 502(f)(1) of
the Act [21 U.S.C. § 352(f)(1)] Because your products lack required
approved applications, they are not exempt under 21 C.F.R. § 201.115
from the requirements of section 502(f)(1) of the Act. The introduction
or delivery for introduction into interstate commerce of these products
therefore violates sections 301(a) of the Act [21 U.S.C § 331(a)].
You should discontinue manufacturing and distributing all of your
unapproved drugs at all facilities immediately. For questions about the
regulatory status of your drugs, contact Kathleen Joyce, at
301-796-3329. For assistance in communicating with the FDA concerning
the application process for your unapproved drug(s), contact FDA's
unapproved drugs coordinator, Dr. Sally Loewke, at 301-796-0710.
To ensure that all drugs marketed in the U.S., prescription and
over-the-counter, have been shown to be safe and effective, FDA published a
Compliance Policy Guide (CPG) Section 440.100, Marketed Unapproved Drugs,
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070290.pdf. FDA
expects manufacturers of products requiring approval to submit applications
to the agency showing that their products are safe and effective. The CPG
describes the very strict criteria under which the Act permits drugs to be
marketed without approval. The CPG also outlines the Agency’s enforcement
policies aimed at efficiently and rationally bringing all drugs requiring
approved applications into the approval process.
The violations cited in this letter are not intended to be an
all-inclusive statement of violations that exist at
your facility. You are responsible for investigating and determining the
causes of the violations identified above and for preventing their
recurrence and the occurrence of other violations. It is your
responsibility to assure compliance with all requirements of federal law
and FDA regulations.
You should take prompt action to correct the violations cited in this
letter. Failure to promptly correct these violations may result in legal
action without further notice including, without limitation, seizure and
injunction. Other federal agencies may take this Warning Letter into
account when considering the award of contracts. Additionally,
FDA may withhold approval of requests for export
certificates, or approval of pending drug applications listing your
facility, until the above violations are corrected. FDA may re-inspect
to verify corrective actions have been completed.
Within fifteen working days of receipt of this letter, please notify
this office in writing of the specific steps that you have taken to
correct violations. Include an explanation of each step being taken to
prevent the recurrence of violations and copies of supporting
documentation. If you cannot complete corrective action within fifteen
working days, state the reason for the delay and the date by which you
will have completed the correction. Additionally,
your response should state if you no longer manufacture or
distribute the drug products manufactured at this facility, and provide
the date(s) and reason(s) you ceased production. For discontinued
products, you must update the Drug Listing files in accordance with 21
C.F.R. § 207.30(a)(2).
Your reply should be sent to the following address: Food and Drug
Administration, Attention: Blake Bevill, Director Compliance Branch,
19701 Fairchild, Irvine, California 92612-2445.
Sincerely,
/S/
Alonza E. Cruse
District Director