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Warning Letter Bulletin
The Inside Alert to FDA Enforcement Activities, Inspections & Compliance Programs
Vol. XXI, No. 7
July 2013
Inside This Issue…
FDA released the following Warning
Letters in June amd early July 2013
DRUGS
Cispharma .....................................................1
RPG Life Sciences .......................................3
DIETARY SUPPLEMENTS
Nutrient Synergy ..........................................8
MEDICAL DEVICES
Alma Lasers ................................................10
Alpha Medical Instruments ......................11
Asahi Kasai Medical ..................................12
Biomedix .....................................................13
GS Medical Packaging...............................16
KooJoo Trading Company.......................18
Lucky Board Manufacturing.....................19
Medinvents NV..........................................20
Transonic Systems .....................................20
Tytex Slovakia.............................................22
BiMo
Janet K. Tillisch, M.D. .............................23
DRUGS
Cispharma Inc.
Cranbury, NJ, July 2
New Jersey District
During its March 12-April 23, 2012, inspection of Cispharma Inc., Cranbury, NJ, FDA identified significant violations of GMP regulations covering the production of finished pharmaceuticals. After
receiving a 483 for these infractions, Cispharma dis-
patched a response letter, which, in turn and after
careful review by FDA, prompted the agency to issue
a warning letter to the company for its failure to implement a robust quality system at the facility.
According to the warning letter, FDA made
mention of the fact that many of the GMP issues
highlighted by the 2013 inspection were deficiencies
that investigators had observed during an inspection
conducted in January 2011. Further, FDA stated that
the firm’s current response lacked sufficient corrective and preventive actions (CAPAs).
The violations that investigators observed
during the inspection include the following:
Observation 1: Your firm failed to thoroughly
investigate any unexplained discrepancy or failure of a batch or any of its components to meet
any of its specifications, whether or not the
batch has already been distributed. FDA stated
that this infraction was a repeat observation from the
January 2011 inspection.
The current audit highlighted issues with the
firm’s SOP for investigations, as exemplified by:
a. A company probe into a complaint of 200mg
Phenazopyridine HCI tablets comingled into several
lots of 100mg Phenazopyridine HCI tablets (lot
009008 and 012006) was inadequate. Cispharma concluded the mix-up was probably a pharmacy error
without having investigated any other possible root
causes. Because the production schedule indicates
that the 200mg lot had been manufactured just before the 100mg lots named in the complaint, the possibility of a mix-up in the filling and packaging area
should have been investigated.
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Warning Letter Bulletin
The firm’s response indicated that Cispharma
had updated its complaint handling SOP to assign
the investigation to the "heads of the functional areas" with final responsibility being assigned to QA.
FDA found this to be inadequate because Cispharma
failed to address how QA will ensure complaint investigations are completed in the future.
b. A Cispharma investigation into an employee accident that occurred during compression of Acetaminophen tablets, lot 112011 was inadequate because
the company failed to document the specific nature
of the event and the product impact.
Cispharma had responded that it revised the
investigation into the accident. In addition, company
officials stated that several extensive cleanings were
performed after the accident occurred and the investigation had concluded. The response also indicated
that all product that was opened during the incident
was discarded. FDA again found this to be inadequate as it asserted that Cispharma failed to describe
how it ensured there was no blood or tissue remaining after extensive cleaning was completed.
FDA again found this to be inadequate
as it asserted that Cispharma failed to
describe how it ensured there was no
blood or tissue remaining after extensive cleaning was completed.
Observation 2: Your firm does not have adequate written procedures for production and
process controls designed to assure that the drug
products you manufacture have the identity,
strength, quality, and/or purity they purport or
are represented to possess. Again, this infraction
represents a repeat observation from the January
2011 inspection.
Here, FDA noted that the coating processes
for three of Cispharma’s products, Salsalate tablets,
Acetaminophen White Film Coated Caplets, and Aspirin Enteric Coated tablets, were not adequately
validated, in that the company had not demonstrated
that a uniform, quality coating is consistently
achieved. Specifically, Salsalate tablets validation
studies did not identify the equipment parameters
and coating solution characteristics that impact coating quality and assure they are properly controlled.
Surface erosion was noted in one validation during a
July 2013 — Page 2
QA check but it was not investigated. The lot was released.
Subsequently, a Cispharma customer rejected
the lot after performing their own sampling and inspection in April 2011. Chipped, peeling, and broken
tablets were found in that inspection. Referencing
this event, Cispharma informed FDA’s investigators
that the firm had subsequently performed a visual inspection of the affected tablet lot and culled out an
unspecified (redacted) number of poor quality tablets. (Note: At the time of the inspection, Cispharma did not
have any records of this inspection or disposition records of the
rejected tablets which the company reported were destroyed.)
The remaining tablets were packaged and shipped to
a different customer. During the inspection, retain
samples from two different lots associated with the
comingling complaint were both observed to have
surface erosion and faded imprints.
Similarly, the company’s Acetaminophen
White Film Coat lot 201004 exhibited coating and
hardness problems during manufacturing. According
to the quality assurance manager the lot was inspected, resulting in an unspecified (redacted) number of rejected tablets. There was no record of the
inspection, no investigation into the discarded tablets
and no record of the destruction.
Another incident involved observed during
the inspection saw FDA’s investigators examining retained samples from lots of Aspirin Enteric Coated
81mg tablets, and lots of Aspirin Enteric Coated
325mg tablets. Colored specks were observed on the
surface of the tablets. Aspirin Enteric Coated 81mg
tablets, lot 103013, exhibited sticking tablets in addition to having gray and red specks on the surface of
the tablets. Cispharma failed to investigate these
quality issues which could reasonably be related to
the coating process. Also, during production of Aspirin Enteric Coated 81mg. tablets, an excessive number of tablets were rejected during compression and
coating; however, the batch records associated with
this did not indicate any cause for the rejected tablets. No investigation was performed by the quality
assurance (QA) unit.
Without a thorough investigation to understand the root cause of coating defects (or hardness
problems) proper corrective actions to prevent recurrence cannot be implemented. FDA stated to
Cispharma that repeated instances of sorting finished
tablet lots to cull out defective tablets is indicative of
a failure by the company to assure its manufacturing
processes were in a state of control.
Warning Letter Bulletin
Final product inspection for visibly defective
product is an acceptable quality control practice but
only in conjunction with a well-designed and controlled operation. Reliance on end-product testing
alone will not offer adequate assurance that all substandard product is removed and that the portion of
the batch released and distributed will meet all product specifications throughout expiry.
Observation 3: Your firm has not established
scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity,
strength, quality, and purity. Note that this was a
repeat observation from the January 2011 inspection.
One example of this was shown by a test procedure
for the release testing of Salsalate Film Coated Yellow Tablets, 500mg, and Salsalate Caplets, 750mg,
which indicated that these products had not been
validated.
FDA also pointed to chromatographic test
methods which did not have established integration
parameters.
Cispharma responded to this citation by stating that integration parameters and processing methods would be secured so that all data is processed
with the same processing method. This response
would be evaluated at the next routine inspection of
the facility, FDA stated.
Observation 4: 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. Again, note
that this was a repeat observation from the January
2011 inspection.
FDA’s example here was that Cispharma
failed to perform identity testing on Magnesium
Stearate, NF that was used to manufacture Guaifenesin Tablets, lot 202002 in February 2012.
Cispharma had responded by saying that it
did not provide details on what specific identity tests
with acceptance criteria would be performed on all
incoming materials. The company also stated all active and inactive ingredients would be covered under
a comprehensive approval process based on vendor
qualification procedures; however, the firm did acknowledge its vendor qualification program was not
adequate and also did not provide details on how it
would improve it or when a new program would be
implemented.
July 2013 — Page 3
FDA concluded its warning letter by stating
that, based on the information the firm submitted to
FDA's Drug Registration and Listing System and the
information collected during the March-April 2012
inspection, FDA found that the firm was manufacturing the following unapproved prescription drugs:
• Salsalate Tablets, USP, 500mg oral tablets
• Salsalate Tablets, USP, 750mg oral tablets
• Phenazopyridine HCl F/C Tablets, USP,
95mg oral tablets
• Phenazopyridine HCl F/C Tablets, USP,
100mg oral tablets
• Phenazopyridine HCl F/C Tablets, USP,
200mg oral tablets
FDA advised Cispharma that the agency’s guidance
entitled "Marketed Unapproved Drugs-Compliance
Policy Guide (CPG)," explains FDA's policies aimed
at ensuring that all drugs marketed in the U.S. have
been shown to be safe and effective.
FDA concluded its warning letter to the
manufacturer by stating that the firm has a limited
period of time in which to effect changes and corrections, although, at this time, no information is available to indicate what, if any, changes or corrections
have been accomplished or implemented.
CAPA; C-H; OOS; PMA; QC/QS; Val
RPG Life Sciences Limited
Ankleshwar, Gujarat, India
Navi Mumbai, Maharashtra, India, May 28
CDER
FDA found significant GMP violations at the
finished-dosage plant of RPG Life Sciences Limited-Ankleshwar (MS-Ankleshwar), located in
Ankleshwar, Gujarat, India, and the active pharmaceutical ingredient (API) facility, RPG Life Sciences
Limited-Navi Mumbai (MS-Navi Mumbai), located in Mumbai, Maharashtra, India, following recent audits.
The finished dosage plant was audited Nov.
20-24, 2012 and the API factory was audited Jan. 2831, 2013, and each facility received a separate 483,
the warning letter stated.
Following the receipt of the response letters
from the management staff from each facility, FDA
conducted a detailed review of the responses dated
Dec. 11, 2012 and Feb. 19, 2013, and noted that they
lacked sufficient corrective actions. The agency also
acknowledged receipt of the firm's additional corre-
Warning Letter Bulletin
CODES
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AE — Adverse event reporting violations
510(k) — Failure to file 510(k)
BiMo — IRB, sponsor/monitor, CRO, clinical
investigator issues
BLA — Biologics License Application
CAPA — Corrective/preventive action
C-H — Complaint handling
Cal — Calibration
Compound — FDCA drug-compounding violations
Comp/Soft — Computer software validation
Design — Design controls
E-M — Environmental monitoring
E-Sig — 21CFR Part II, Electronic Signatures
/Records Rule
F.A.R. – Field action reporting
F-B — Lack of fair balance in promotions
Lab — Laboratory
L-B—Labeling issues
Mark — Marketing and misbranding
MDR — Medical Device Reporting violations
NDA — Lack of new drug application
O-L Use — Off-label use
OOS — Out-of-specification results
Pak — Packaging
PMA — Lack of premarket approval
QC/QS — Quality Control/Systems deviations
Stab — Stability
Ster — Sterility
Val — Validation
Web — Internet promotion irregularities
spondences dated Jan. 14, 2013; Feb. 6, 2013; March
18, 2013; and April 9, 2013.
The violations cited in FDA’s warning letter
are listed below. Note that each facility is presented
in separate listings.
MS-Ankleshwar – Finished Dosage Forms
Observation 1: The firm failed to thoroughly investigate any unexplained discrepancy or failure
of a batch or any of its components to meet any
of its specifications, whether or not the batch has
already been distributed. The investigator asserted
that the firm did not identify, report, maintain records, or investigate a number of out-of-specification
(OOS) results, such as:
a. On May 6, 2012, a 12-month stability interval assay
test for an unspecified (redacted) drug product batch
failed to meet the established specifications with
adequate results.
b. On July 16, 2011, the assay for an API batch failed
to meet the established specification with an accept-
July 2013 — Page 4
able result. This API batch was used in the manufacture of several other finished drug product batches.
c. On Jan. 26, 2011, the related substance assays for
three API raw material batches exceeded impurity
specifications. These API batches were used in the
manufacture of an unspecified finished drug product
batches.
d. On Oct. 10, 2012, the two-month stability assays
for a USP batch of tablet drug products showed a
significant unknown peak in chromatograms.
For incidents (a)-(c), the firm repeated these
assays, and selectively reported only the passing retest values in the final assay results, then disregarded
the initial OOS data without conducting investigations. In incident (d), MS-Ankleshwar disregarded
the stability OOS data, and selectively used only the
passing results from other presentations.
In response to the FDA-483, the company
conducted retrospective investigations and hypothesized the causes of the OOS results as sample dilution error, HPLC auto-sampler injection error, use of
aged sample solutions, and vial contamination, respectively. However, the agency deemed that response to be inadequate because the retrospective
investigations lacked documentation, raw data, or
scientific evidence to support presented hypotheses. As mentioned above, the firm did not retain
documents associated with the sample weights, sample preparations and sample dilutions. MSAnkleshwar also acknowledged that without raw data
it is difficult or impossible to definitively determine
the root causes and the exact actions of the analyst
when OOS results are encountered.
The firm was, at this point, instructed to
conduct a comprehensive review of the laboratory
data for all finished drug products within expiry, and
for the raw materials within retention period, with
those results to be included in a subsequent response
letter to FDA. Also, the agency mandated that a
summary report be included for all OOS results that
the firm disregarded without conducting an investigation. FDA advised the company to thoroughly investigate all OOS results, including testing of the reserve samples if necessary, and provide its conclusions in the report. The firm was ordered to describe
the corrective actions it would take against all
batches for which a non-conforming result was obtained. As the company had stated in its response
that it revised its investigation procedure and implemented specific audit trails for each laboratory instrument. Further, MS-Ankleshwar’s QC managers
Warning Letter Bulletin
were asked to review those audit trail printouts to ensure identification and investigation of OOS results. FDA stated that it would verify the effectiveness of these corrective and preventive actions during its next inspection.
Observation 2: Your firm failed to follow required laboratory control mechanisms and to record and justify any deviations from them. For an
example of this, FDA pointed to the firm’s Investigation of Out-of-Specification Results procedure establishing
sample retesting as part of an OOS investigation. This procedure required re-analysis of the original retained test solution to determine assignable
causes prior to new sample retesting during the
phase I laboratory investigation. It also required
preservation of all samples, dilutions, and related
printouts, as well as prompt initiation and documentation of OOS investigations on the specific Annexure-I form. The firm performed related substance
analyses of unspecified (redacted) tablet batches multiple times on May 10, 2012, and on May 12,
2012. The firm then repeated the analysis again on
May 13, 2012, using a new set of sample solutions,
and reported only this test result on the certificates
of analysis (COAs). Moreover, the company used
several different HPLC processing methods to process the data for these analyses. FDA asserted that the
company did not diligently investigate or document
all these tests, and discarded raw data related to sample weights and preparations, in disregard of the SOP
requirements.
The company’s response to these issues was
to conduct a retrospective investigation and then attribute the causes for the OOS to instrument communication error, lack of standard and blank injections, and peak splitting, respectively. However, the
company did not explain what caused the peak splitting. In addition, MS-Ankleshwar personnel did not
record or provide justifications for not documenting
these incidents on form Annexure-I as required by the
procedure.
Observation 3: Your firm failed to ensure that
laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards. FDA stated that the firm did not retain any
raw data related to sample weights and sample solution preparations for the HPLC assays of unspecified
(redacted) drug product tablet batches that the firm
conducted on July 18, 2012. In addition, the company did not include those results in the calculation
July 2013 — Page 5
of the final assay values. Instead, MS-Ankleshwar repeated the analysis the next day using a new set of
sample solutions, and reported the retest results on
the certificates of analysis (COAs).
MS-Ankleshwar, in its response to FDA,
conducted a retrospective investigation and concluded that the analyst realized he had recorded the
initial data incorrectly in the HPLC “trial folder” instead of the regular folder. Thus, he repeated the test
the next day using the same sample solutions. However, the QC manager stated during the
inspection that the initial injections were trial runs,
and that performing trial standard and sample analysis prior to official analysis is a standard practice in
the QC laboratory. Moreover, FDA’s review of the
final QC worksheet revealed that the firm prepared
the new retest samples on July 19, 2012, the day after
it had performed the trial injections.
FDA requested in the warning letter
that the company perform a retrospective quality review of all retests conducted related to any unexpected or
OOS results…
FDA’s investigator also observed several trial
HPLC injections were tested during the period of
Jan. 5-Nov. 16, 2012. The firm’s response acknowledged that a number of these trial injections involved
sample testing. However, plant personnel failed to
provide any evidence that the company had retained
laboratory records and raw data associated with these
sample tests. Additionally, during an audit of the data
submitted in support of unspecified (redacted) product testing, the investigator requested to review the
electronic analytical raw data to compare the values
for assay and degradation products. However, the
firm provided only the printed copies of the raw data
because the firm did not have the software program
available to view the electronic raw data.
FDA requested in the warning letter that the
company perform a retrospective quality review of all
retests conducted related to any unexpected or OOS
results, and include a summary that identifies the test
results that apply to product currently within expiration and distributed that are lacking supporting raw
data. MS-Ankleshwar also was asked to include a
corrective and preventive action (CAPA) plan to
prevent recurrence that addresses this observation
Warning Letter Bulletin
and that would ensure that all electronic analytical
raw data would be readily available for review during
the next inspection.
Observation 4: Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control
records, or other records. FDA noted that MS-
Ankleshwar had analyzed an unspecified (redacted)
API lot on Feb. 14, 2011, at 2:55 a.m., and then retested it at 2:05 p.m. using a new sample solution. The company, in this case, did not maintain any
raw data associated with the initial test.
In MS-Ankleshwar’s response, the firm stated
that the retest was performed due to data deletion of
the original analysis. The company concluded that
the analyst misused the administrator password to
delete and overwrite the actual data logged in the audit trail. The ability of analysts to alter and delete
electronic analytical data raised serious concerns with
FDA regarding laboratory controls in place at the facility.
Also during the inspection, the investigator
also identified a backdated QC worksheet in the analytical report of API raw material batches. When the
analyst performing these tasks affixed the related
substance and IR weight printouts to the Format for
Blank Sheet for Printout, he signed and dated this worksheet as July 29, 2011. A second analyst, who reviewed this worksheet, also signed and dated it as
July 29, 2011. However, the QA department did not
issue this worksheet until July 31, 2011. The analyst
acknowledged during the inspection that he backdated this worksheet on July 31, 2011.
FDA stated that MS-Ankleshwar had remarked in its response letter that the analyst incorrectly dated the worksheet as July 29, 2011, instead
of July 31, 2011, and that there was no intention to
deliberately backdate the document. However, MSAnkleshwar’s response contradicted the analyst’s
backdating admittance during the inspection. In addition, the response did not explain the reviewer’s
signature which also was dated July 29, 2011. Backdating documents is an unacceptable practice and
raises doubt about the validity of MS-Ankleshwar’s
records.
At this point, FDA mandated that the firm
conduct an investigation regarding the practice of deleting critical analytical data and backdating records. This practice is a clear breach in any quality
system, and raises serious concerns regarding the in-
July 2013 — Page 6
tegrity and reliability of the laboratory data used to
release drug products. As a corrective action, the
firm revised its Good Documentation Practices procedure
and provided training on password policy procedures
to prevent deletion and overwriting of electronic records. Because of this, FDA also mandated that the
firm provide a copy of its investigation into the matter, along with its risk assessment regarding the extent and impact of the missing data on the quality of
all finished drug products released for distribution.
MS-Navi Mumbai – APIs
Observation 1: Your firm failed to investigate
and document out-of-specification results according to a procedure. FDA pointed out that the
facility’s nine-month stability assays of three API
batches, conducted on April 2, 2012, exceeded the
related substance specification for unknown impurities. The firm failed to report and investigate these
OOS results, the letter added. The firm also subsequently repeated these analyses the next day using a
new set of sample solutions, and reported only the
passing retest results. Moreover, MS-Navi Mumbai
discarded all raw data related to the OOS results including sample weights, sample solution preparations, and sample dilutions.
In response to the FDA-483, MS-Navi
Mumbai conducted a retrospective investigation and
attributed the cause of these OOS results to syringe
contamination. However, the investigative report,
“Justification for Unprocessed Runs on Waters HPLC,”
provided to the investigator during the inspection
described the cause of these OOS results as vial or
glassware contamination. This was interpreted by
FDA to mean that the firm’s investigation lacked scientific evidence to support the company’s root cause
hypothesis.
Because of this, FDA requested that MSNavi Mumbai, in its response letter, provide a summary of OOS results for all API product batches
within expiry that the firm disregarded without adequate investigations. The firm was instructed to
thoroughly investigate the OOS results, including
testing of the reserve samples if necessary, and to
provide its conclusions. MS-Navi Mumbai also was
ordered to describe corrective actions it will take for
any non-conforming batches.
Observation 2: Your firm failed to adequately investigate all quality-related complaints. FDA as-
Warning Letter Bulletin
July 2013 — Page 7
serted several points here, with these examples highlighted:
a. The firm received three complaints from December 2011 to August 2012 regarding unspecified (redacted) particles found while testing four batches of
a distributed API. A complaint report, MC/11/13,
acknowledged that personnel observed particles in
the returned samples, yet MS-Navi Mumbai never
determined the identity and cause of the particles.
Rather, the company simply discarded the samples. MS-Navi Mumbai’s response stated that it could
not evaluate the samples because of their small quantities. However, the firm did not describe the quantity of the returned samples, nor did the company request additional sample quantities from its customer.
In response to the 483, MS-Navi Mumbai returned several batches through a testing procedure
and found no particles to be present. However, according to a company returned goods investigation
report, RG/12/006, testing personnel only visually
inspected the base material for the presence of foreign particles, and discarded the oversized material. Thus, there was no assurance that MS-Navi
Mumbai thoroughly inspected all returned materials
for the presence of foreign particles.
b. A customer rejected an API batch on Sep. 19,
2011 for exceeding the impurity limit for an unspecified impurity. As part of MS-Navi Mumbai’s investigation, personnel randomly retested the reserve samples from several other batches distributed since May
2011, and found that another batch also had exceeded the unknown and total impurity limits. MSNavi Mumbai subsequently tested the returned
batches, and confirmed that all of the drums of API
materials inspected exceeded unknown and total im-
Warning Letter Bulletin
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purity limits, and that all of the drums of another
API also exceeded unknown and total impurity limits.
Yet, company investigation did not extend to
other API batches within expiry that may have been
associated with these confirmed batch failures. The
company’s decision to exclude testing of other API
batches was based on the fact that its customers had
accepted them. However, this is not a scientifically
sound justification for not extending the investigation to other associated API batches.
Observation 3: Your firm failed to establish and
exercise adequate controls over computers to
prevent unauthorized access or changes to electronic data. Here, FDA showed where the com-
puters that control the firm’s analytical laboratory instruments, including an HPLC analyzing system,
GCs, and an FTIR, lacked control mechanisms to
prevent unauthorized access to, changes to, or omission of data files.
This resulted in the firm’s analysis of USP
batches exceeding the residual solvent limit on Feb.
29, 2012. And, the company did not report or investigate this OOS result, and deleted the related electronic records. During FDA’s audit, an analyst admitted he also deleted other uninvestigated failing
and/or OOS electronic data from the laboratory database in January 2013. MS-Navi Mumbai’s QC Senior Manager also acknowledged this laboratory-wide
electronic data deletion practice.
In another instance, during the inspection,
analysts demonstrated to FDA that they could delete
any electronic analytical data files from the laboratory
computers and external backup hard drives.
FDA took exception to this, and advised in
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Warning Letter Bulletin
the warning letter that the company employ adequate
controls to prevent improper deletion of essential
data. The firm had stated in its response that it was
procuring a centralized server and software, which
would prevent electronic data deletion. Each analyst
would have an individual user ID and password. The
company also committed to training analysts not to
delete electronic analytical data and report all laboratory incidences to managers. FDA further advised
MS-Navi Mumbai that investigators would verify the
effectiveness of these corrective actions during its
next inspection.
FDA warned the firm that it was responsible
for the accuracy and integrity of the data generated
by its personnel. The agency stated that a firm must
maintain all raw data generated during each test, including graphs, charts, and spectra from laboratory
instrumentation. These records should always be
properly identified to demonstrate that each released
batch was tested and met release specifications.
FDA’s inspection had revealed that the firm
discarded OOS laboratory records and deleted OOS
electronic analytical data. Staff at MS-Navi Mumbai
also disregarded OOS data without investigations,
and selectively reported only passing results. The lack
of reliability and integrity of data generated is a serious GMP deficiency that raises concerns with all data
generated by the company, FDA stated.
In summary, FDA commented that the
agency, based on investigative observations, was led
to question the effectiveness of MS-Navi Mumbai’s
current quality system to achieve overall compliance
with GMP at the facility. It was apparent that MSNavi Mumbai had not implemented a robust quality
system at the facility, FDA maintained. The agency
then advised that corporate management is responsible for ensuring the quality, safety, and integrity of
drugs manufactured by RPG Life Sciences Limited. FDA strongly recommended that MS-Navi
Mumbai’s corporate management immediately undertake a comprehensive evaluation of global manufacturing operations to ensure compliance with GMP
and GMP regulations.
Additionally, FDA said it highly recommended that MS-Navi Mumbai hire a third party
auditor, with experience in detecting data integrity
problems, to assist with this evaluation and the company’s overall compliance with GMP.
FDA concluded the warning letter by saying
that MS-Navi Mumbai had a responsibility to ensure
that data generated during operations is accurate and
July 2013 — Page 8
that the results reported are a true representation of
the quality of the company’s APIs and drug products.
Currently, the facilities cited in these 483s
and accompanying warning letters have not issued
any further responses to FDA’s communications.
FDA has not published any further information or
updates to these events. API, Cal; Comp/Soft;
E-Sig; OOS; QC/QS; Val
DIETARY
SUPPLEMNTS
Nutrient Synergy, Inc.
Longmont, CO, June 25
Denver District
Following review of the website,
www.nutrientsynergy.com, maintained by Nutrient Synergy, in June 2013, FDA has issued a warning letter to the proprietors of the company that
owns and operates the website, Don and Judy Stattine.
The warning letter was issued after the
agency reviewed the website as part of its campaign
aimed at curtailing and shuttering illegal online
pharmacies and stemming the tide of counterfeit and
risky pharmaceutical products that had not been approved through FDA’s protocols. While the products featured and marketed via the website do not
seem to be counterfeit or illegally formulated, FDA
nonetheless issued the letter to the company based
on its inspection of the promotional material posted
on the website.
The warning letter focused on a violation
pertinent to the FD&C Act, wherein the company’s
product, Nepretin, is promoted for conditions that
cause it to be a drug. The therapeutic claims on the
website and the product label establish that the
product is a drug because it is intended for use in the
cure, mitigation, treatment, or prevention of disease.
As explained further below, introducing or delivering
such products for introduction into interstate commerce for such uses violates the FD&C Act.
Examples of some of the website claims that
provided FDA with evidence that the company’s
product is intended for use as a drug included:
Warning Letter Bulletin
•
•
The website link for the product Nepretin,
http://www.nutrientsynergy.com/diabet
ic retinopathy.htm , references a disease.
Under the heading “Nepretin,” content
on the website alleged such things as
Nepretin being a “revolutionary treatment for diabetic retinopathy and nephropathy”; that the product was “designed to control complications of diabetes”; that “symptoms of diabetic retinopathy were dramatically slowed,
stopped, or even reversed…when Nepretin was taken orally on a daily basis”;
and that the product “may also be used
as a preventive strategy for a large percentage of the diabetic population.”
The firm’s promotional materials for
Nepretin and testimonials from customers could not be confirmed by
FDA…
Similarly, additional promotional and marketing content seemed to suggest that “Dramatic results
from clinical trial” of Nepretin had been garnered to
show the product’s efficacy against diabetic retinopathy and other complications associated with the disease. For example, the website stated that the “trial
studied the effects of Nepretin in slowing, stopping,
or reversing the symptoms of diabetic retinopathy in
human patients with Type I diabetes with low or
medium eye grades. Approximately 70% of the patients who started the study with a grade level above
one either slowed, stopped, or reversed their diabetic
retinopathy grade level during the course of the 24
months.” Likewise, the company claims that Nepretin improved the final eye grade in at least one
eye; improved glycohemoglobin and albumin excretion rates; improved systolic and diastolic blood
pressure values; and even lessened the need for total
insulin.
Examining the website further, FDA pointed
to the firm’s use of no less than 15 testimonial
statements from consumers who allegedly used Nepretin for the same conditions as referenced by the
company’s product indications. None of these testimonials could be effectively confirmed or authenticated, and as such, FDA labeled the testimonials to
be misleading or of a persuasive nature that might
July 2013 — Page 9
sway a consumer into using the product for control
of a diabetic condition that may or may not be present.
Additionally, FDA noted that, along with the
previous claims and testimonials, the company also
utilized metatags to bring consumers to its websites
through Internet searches. The metatags are “diabetes nephropathy treatment,” “diabetes retinopathy
supplements,” “diabetes nephropathy supplements,”
“diabetes retinopathy treatment,” “supplements for
diabetes,” and “treatment for diabetes.”
FDA asserts that Nutrient Synergy’s product
is not generally recognized as safe and effective for
the above referenced uses and, therefore, the product
is a “new drug” under the Act. FDA only approves a
new drug on the basis of scientific data submitted by
a drug sponsor to demonstrate that the drug is safe
and effective.
During a June 6, 2013, conference call, prior
to the issuance of the warning letter, FDA representatives from several departments and divisions, informed the company owners that their promotion of
Nepretin for conditions causes the product to be an
unapproved drug, and that distribution of the Nepretin product was a separate violation of the Act. At
that time, the company’s owners committed to contacting customers via letter to inform them that Nepretin was not intended to prevent, treat, or cure
diabetic retinopathy or nephropathy. The firm also
committed to sharing the notification letter with
FDA prior to sending it to affected customers.
In addition, FDA cited Nutrient Synergy’s
written response letter prompted by the conference
call; the letter was dated June 10, 2013. In that written response, the owners of the company indicated
that they had cancelled their agreements with both
Google and Yahoo for website placement, so that a
search of “diabetic retinopathy” would no longer
lead to Nutrient Synergy’s website. The proprietors
also indicated that they were not new customers for
the product. However, as discussed above, the website continues to take orders for this product and to
promote the product for conditions that cause the
product to be a drug.
FDA also stated that the company had not
submitted a copy of the customer notification letter
to agency officials, as was stipulated in the conference call that transpired June 6.
This publication reviewed the same website
on July 15 and found that the product Nepretin is
still being marketed against regulations, and that little
Warning Letter Bulletin
to none of the verbiage indicated by FDA’s initial
complaint has changed. In addition, the company
had not sent FDA any customer notification letter.
At time of publication deadline, no additional
information pertinent to FDA or company action
was forthcoming from either party, and the ultimate
disposition of the matter has yet to be determined.
Mark; Web
July 2013 — Page 10
•
•
DEVICES
Alma Lasers, Inc.
Buffalo Grove, IL, June 7
Chicago District
FDA conducted an inspection from Jan. 1729, 2013, of the medical device manufacturer Alma
Lasers, Inc., Buffalo Grove, IL, which serves as a
medical device complaint handling firm and servicing
center, specifically for Class II cosmetic lasers and
thermotherapy systems.
The inspection revealed that the facility receives these devices from Alma’s Israel facility,
thereby making the U.S. site the initial importer,
FDA said. As a result, the agency said in the letter
that the facility is actively engaged as a manufacturer
of the aforementioned medical device products.
During the inspection, FDA’s investigator
noted violations that, when coupled with the responses voiced in the firm’s letter addressing the 483,
compelled FDA to issue a warning letter. That letter
addressed the following:
Observation 1: Failure to report to FDA no later
than 30 calendar days after the day that your firm
received or otherwise became aware of information, from any source, that reasonably suggests
that a device that your firm markets may have
caused or contributed to a death or serious injury. This deviation from MDR regulations was
highlighted by an unspecified complaint that the
company received that described an event where the
use of the firm’s device resulted in a third degree
burn to a patient (i.e., a full thickness burn), FDA
said, noting an MDR was not even submitted.
Observation 2: Failure to adequately develop,
maintain and implement written MDR procedures. After reviewing the firm’s procedure titled,
“Adverse Events and Recall Procedure,” FDA noted
the following issues:
•
The SOP did not establish internal systems
that provided for timely and effective identification, communication, and evaluation of
events that may be subject to MDR requirements;
There were no definitions for what the firm
considered to be a reportable event under
regulations. (To facilitate the correct interpretation of reportable events and to assure the
quality of MDR submissions, the procedure
should include definitions for the terms “become aware,” “caused or contributed,” “malfunction,” “MDR reportable event,” and “serious injury,” and definitions for the terms
“reasonably known” and “reasonably suggests,” that are found respectively in federal
regulations; and
The SOP did not establish internal systems
that provided for a standardized review process or procedure for determining when an
event meets the criteria for reporting under
this part. Specifically, there were no instructions for conducting a complete investigation
of each event and evaluating the cause of the
event. Similarly, the procedure, as written, did
not specify who makes the decision for reporting events to FDA.
FDA noted the procedure did not contain instructions for how to obtain and
complete FDA’s 3500A form. Also, the
SOP did not include the address for
where to submit MDR reports.
Also, the procedure did not establish internal
systems that provided for timely transmission of
complete medical device reports. Here, FDA noted
the procedure did not contain instructions for how
to obtain and complete FDA’s 3500A form. Also,
the SOP did not include the address for where to
submit MDR reports. And, the procedure failed to
include a listing of the circumstances under which a
firm must submit initial, supplemental or follow-up
reports and the requirements for such reports.
FDA also noted that the firm’s MDR procedure did not describe how the firm would address
documentation and record-keeping requirements, including:
Warning Letter Bulletin
•
July 2013 — Page 11
Documentation of adverse event related information maintained as MDR event files;
• Information that was evaluated to determine
if an event was reportable;
• Documentation of the deliberations and decision-making processes used to determine if
a device-related death, serious injury, or malfunction was or was not reportable; and
• The systems that ensure access to information that facilitates timely follow-up and inspection by FDA.
In addition, the procedure included references to baseline reporting and annual certification,
which are no longer required.
The inspection also unearthed significant
Quality System (QS) violations, including these
items:
tions for use, which Alma Laser personnel concluded
had led to the adverse events. However, no responses were made to the clinic to inform them of
the correct instructions for use.
FDA concluded that the company’s written
response was inadequate because the response indicated the firm planned to develop a work instruction
stating when a formal response is made to the complainant, update the corresponding procedures, and
train personnel on both procedures once those were
updated. Documents were not included in the firm’s
response to confirm these corrections, nor were the
specifics of the corrections planned. The response to
the observation listed was not sufficiently explanatory and was, thus, deemed inadequate.
No additional information pertaining to this
inspection and warning letter was available at time of
deadline. CAPA; C-H; MDR
Complaints reviewed during FDA’s inspection did
not possess vital, required information to handle appropriately complaints.
FDA concluded the company’s response was
inadequate. The response indicated that the firm
planned to develop and train personnel on work instructions for reporting adverse events to FDA, include adverse event files in your internal audit program, and discuss audit findings at the firm’s management review. Documents were not included in the
firm’s response to confirm these corrections, so their
adequacy could not be determined.
The company also submitted updated work
instructions for collecting data on adverse events, but
did not include in accompanying work instructions
for addressing the skin test fluence discrepancies.
Similarly, the company’s response did not include
specific information about patients and the medical
treatment records which the clinical staff needs to attempt to obtain. Here, FDA indicated that Alma Laser’s response was not sufficiently explanatory, and
was thus deemed inadequate.
Alpha Medical Instruments, LLC
Mission Viejo, CA, June 24
Los Angeles District
Observation 3: Failure to include required information in records of complaint investigations.
Observation 4: Failure to adequately establish
procedures for receiving, reviewing, and evaluating complaints by a formally designated unit.
Alma Laser’s procedures for complaint handling,
“Customer Communication & Complaints Procedure” and “Adverse Events and Recall Procedure,”
did not address circumstances whereby a response is
made to complainants. Several adverse event complaints were reviewed by FDA, and the associated records indicated the clinic did not follow the instruc-
Alpha Medical Instruments, LLC (AMI), a
maker of angiographic balloon catheters and electrophysiology catheters, was the focus of an FDA inspection conducted Dec. 19, 2012 through Jan. 11,
2013, primarily over GMPs, but also because the
firm had no FDA clearance for its products.
FDA’s investigator also observed that AMI’s
electrophysiology catheters possessed labeling that
could be deemed as false and misleading. Labeling
affixed to the packaging states: “Manufactured in the
U.S.A. for Alpha Medical Instruments
LLC”. However, the inspection revealed these catheters were actually manufactured outside of the U.S.,
and they were improperly declared upon entry to the
United States.
The inspection and consequent warning letter
focused on two points, one for GMP shortcomings
and one for quality systems concerns. Those issues
were addressed in AMI’s response letter to FDA,
dated Jan. 25, 2013, and are as follows:
Observation 1: Failure of management with executive responsibility to review the suitability
and effectiveness of the quality system at defined
intervals, as required. FDA specified that AMI’s
management review procedure, Management Responsibility, was not being adhered to, in that the SOP requires management review meetings to be held annually. Management had not conducted a review of
Warning Letter Bulletin
the quality system since Dec. 15, 2009. Furthermore,
FDA deemed the company’s response to be inadequate. AMI personnel stated that the company had a
management review meeting on Jan. 17, 2013, but
did not provide evidence such a meeting was held.
Observation 2: Failure to perform quality audits
at defined intervals to determine whether the
quality system activities and results comply with
quality system procedures, as required by law.
AMI’s Internal Quality System Audit procedures require
audits of the quality system to be conducted at least
annually. FDA asserted that no such quality system
audit had been conducted in 2011 or 2012.
FDA found the company’s response to be
inadequate as the company had, previously, stated,
that it had established a schedule for monthly audits
to start in December 2012, and continue through
November 2013. The firm did not provide an audit
schedule or evidence these audits have begun.
No further information relative to this matter
was released by either the company or by FDA in
this matter. QC/QS; 510(k); PMA
Asahi Kasai Medical
Oita-shi, Japan, June 11
CDRH
The Japanese manufacturer of dialyzers,
plasmapehersis and leukocyte reduction filters, Asahi
Kasai Medical Co., located in Oita-shi, Japan, received an adverse inspection of its plant March 1114, 2013, in which FDA noted several deviations
from GMPs, Medical Device Reporting (MDR) rules
and corrective and preventive action (CAPA) requirements.
Asahi responded April 2, and based on what
the firm stated in its response, the agency issued a
warning letter on June 11, citing the observed violations and the assessments FDA rendered on the
company’s responses to the 483. Those observations
and assessments included:
Observation 1: Failure to report to FDA no later
than 30 calendar days after the day that your firm
received or otherwise became aware of information, from any source, that reasonably suggests
that a device that your firm markets may have
caused or contributed to a death or serious injury. FDA noted the company became aware of numerous events that were MDR reportable; however,
the company did not submit them to the agency
within the 30 calendar day time period. Specifically,
July 2013 — Page 12
company records indicated that six separate events,
ranging in dates from November 2010 to March
2012, were not reported appropriately to FDA, with
some of the reports being delinquent for up to 51
months after the company received news of the
event.
The adequacy of Asahi’s response was
deemed indeterminate at the time the warning letter
was composed because the company’s response did
not include a copy of the revised MDR procedure
for review.
Observation 2: Failure to adequately develop,
maintain and implement written MDR procedures. FDA observed that the firm’s MDR proce-
dure Procedures for Safety Control Information
Evaluation held several deficiencies. One of the deficiencies included the firm’s MDR procedure lacking
established internal systems that provided for timely
and effective identification, communication, and
evaluation of events that may be subject to MDR requirements. FDA’s determination was that there
were no definitions of what the firm considered to
be a reportable event under regulations. To facilitate
the correct interpretation of reportable events and to
assure the quality of MDR submissions, FDA stated,
the SOP should include definitions based on regulations, for the terms “become aware,” “caused or
contributed,” “malfunction,” “MDR reportable
event,” and “serious injury,” and definitions for the
terms “reasonably known” and “reasonably suggests.”
Also, the firm’s MDR procedure did not establish internal systems that provided for timely
transmission of complete medical device reports. Specifically, FDA expressed concerns that the
firm did not address these issues:
• The procedure did not contain instructions
for obtaining and completing the FDA
3500A form;
• the circumstances under which the firm must
submit initial, supplemental or follow-up reports and the requirements for such reports;
and
• the correct address for where to submit
MDR reports.
FDA highlighted another issue with Asahi’s
MDR procedure was that it did not describe how to
address documentation and record-keeping requirements, including:
• Documentation of adverse event related information maintained as MDR event files;
Warning Letter Bulletin
•
information that was evaluated to determine
if an event was reportable;
• documentation of the deliberations and decision-making processes used to determine if a
device-related death, serious injury, or malfunction was or was not reportable; and
• systems that ensure access to information
that facilitates timely follow-up and inspection by FDA.
In addition, FDA noted nonconformances
with regards to the firm’s quality system pertaining to
GMP requirements specified in Quality System (QS)
regulations. These nonconformities were noted in
the following observations from the 483 and cited in
the warning letter:
Observation 3: Failure to establish and maintain
adequate procedures for validating the device
design. Design validation shall include risk
analysis, where appropriate. FDA pointed out that
the firm implemented a new design, but the associated risk analysis for that design failed to evaluate all
of the risks.
Here, FDA reviewed Asahi’s response and
concluded that it was not adequate, stating that the
firm conducted risk assessment and revised its Risk
Assessment procedure to address the above deficiencies. However, the firm did not conduct a retrospective review of design history files for similar deficiencies. Additionally, this response did not provide a
copy of the risk assessment report and revised Risk
Assessment procedure for review.
Observation 4: Failure to adequately document
Corrective and Preventive action activities and
their results. FDA cited one of the firm’s noncon-
forming reports, wherein it was revealed that the
firm failed to document all of the elements listed in
the nonconformance report.
The adequacy of the firm’s response could
not be determined by FDA due to the fact that, although the firm revised its testing procedures, titled
“Test and Inspection Control Standard” and “Manufacturing Control Standard,” to incorporate the requirements for proper testing and segregation of
nonconforming devices, nowhere in the report were
there listed any procedures or personnel training records for review.
Observation 5: Failure to establish adequate
procedures for management review. Here, the
adequacy of the firm’s response could not be determined by FDA; the firm revised its Management
Control Standard procedure to include the require-
July 2013 — Page 13
ments for implementing management review action
items on time, but it did not provide a revised procedure and personnel training records.
In concluding the warning letter, FDA advised that a follow-up inspection would be required
to assure that all corrections and/or corrective actions undertaken by the firm are adequate.
Currently, no further information pertaining
to this warning letter is available from any companyor government-related sources. CAPA; Design;
MDR; QC/QS; Val
Biomedix, Inc.
Bloomington, IN, June 14
FDA June 14 issued a warning letter to device manufacturer Biomedix, Inc., which makes the
Select-3 Intravenous (IV) Administration Set, after
the Bloomington, IN, firm received a 483 for a variety of GMP problems unearthed during a Feb. 5March 4, 2013, audit.
The company president, Myra J. Bender, issued an initial response to the inspection, on March
21, 2013. That communication concerned the inspector’s initial observations noted on the Form FDA
483 issued to Biomedix. Additionally, in the warning
letter, FDA noted that the company issued an updated response letter dated May 16, 2013. FDA considered the collective points of those letters in its
warning letter.
The violations found during the inspection
and subsequent review included the following:
Observation 1: Failure to establish and maintain adequate procedures to control the design
of the device as required by regulations. Specifi-
cally, FDA stated that the firm had not established
and maintained procedures to control the design of
its device in order to ensure that specified design requirements are met, as required. The agency also
found the company deficient in that it had made design changes to the SELEC-3 IV Administration Set
without establishing and maintaining procedures for
the identification, documentation, validation or
where appropriate, verification, review and approval
of the changes before implementation, which, again,
is counter to regulations. Further, the company was
found to be deficient in its lack of maintaining a design history file that documents the design changes
made during the life of your SELEC-3 IV Administration Set, as required.
Warning Letter Bulletin
Although Biomedix’s response of March 21
addressed the issues here, the agency found it to be
inadequate as objective evidence of implementation
of corrective action was not submitted for review.
Observation 2: Failure to establish and maintain
adequate procedures for implementing corrective and preventive actions (CAPAs), as required. To support it assertion that the firm’s re-
sponse was inadequate, FDA cited the fact that from
Jan. 1, 2010 to Dec. 31, 2012, the firm documented
an unidentified number of scrapped components
from its SELEC-3 IV Set manufacturing process (excluding barrel tubes), that did not indicate whether
the associated data had been analyzed or investigated
to determine the root cause of the problem that necessitated the corrective action. Likewise, FDA stated
that there did not appear to be any discovery of either an existing or potential quality problems in your
manufacturing process that would explain the need
for scrapping the affected components.
Here, the adequacy of Biomedix’s response
could not be determined at the time the warning letter was composed. Biomedix stated it would further
revise CAPA SOP to include the sources of data that
will be reviewed and the frequency of such reviews
by June 28, 213. However, FDA stipulated, such a
revision should also ensure that the company’s
CAPA policy would include all of the elements included in corresponding regulations, including the
statistical methodology that would be utilized to analyze quality data where necessary; the implementation
and recording of changes in methods and procedures
needed to correct and prevent identified quality
problems; and the assurance that information related
to quality problems or nonconforming product is
disseminated to those directly responsible for assuring the quality of the product or prevention of the
problems.
Observation 3: Failure to adequately ensure that,
where the results of a process cannot be fully
verified by subsequent inspection and testing,
the process shall be validated with a high degree
of assurance and approved according to established procedures. FDA’s investigator noted that
the firm utilizes a specific sterilization method for its
SELEC-3 IV Administration Sets, but observed that
neither production personnel nor quality systems
personnel had validated the sterilization process to
determine the parameters that would consistently
achieve the desired Sterility Assurance Level without
negatively impacting the product.
July 2013 — Page 14
Biomedix also was found to produce the
SELEC-3 IV Administration Sets on semi-automated
processes that had not been validated, using specific
equipment, the names of which were redacted in the
letter.
The adequacy of the company’s response
was, once more, labeled as indeterminate. Biomedix’s
response stated that personnel had initiated the process of reviewing a validation protocol and would implement validation of the sterilization process and
equipment by June 28, 2013. The response also indicates the company’s intent to begin system dose auditing to substantiate the sterilization dosages.
Observation 4: Failure to establish and maintain
adequate procedures to control product that
does not conform to specified requirements.
FDA pointed out, in this instance, how from Jan. 2,
2012 to Dec. 21, 2012, the firm documented an unspecified amount of scrapped components from the
SELEC-3 IV Administration Set manufacturing
process; however, no evaluation of the scrapped
components was conducted to determine the need
for an investigation and notification of the persons
or organizations responsible for the nonconformance.
The company’s response was found inadequate as objective evidence of implementation of
corrective action was not submitted for review.
Observation 5: Failure to establish and maintain
process control procedures that describe any
process controls necessary to ensure conformance to specifications. The agency maintained
that the firm had not established procedures for
equipment settings to be utilized during the manufacturing of Select-3 IV Administration Sets and the settings of equipment used in the production area were
not consistent across similar pieces of equipment. The example of this was the gluers that production personnel used to apply adhesive to the barrel tube and allow for full assembly of the device
were used with inappropriate settings for the system’s use.
FDA also cited the fact that the company
was not following its own SOPs to ensure that devices conform to specifications. For example, one
such SOP stated that the conveyor speed on the assembly line should be set at a specified point. However, during the inspection, the investigator observed
the speed setting during manufacturing on Feb. 5, 7,
and 8, 2013, to be out of specified settings. According to the production supervisor, who
Warning Letter Bulletin
stated she was the only one authorized to make
changes in the conveyor speed, she was told to use
the speed specification from 2.5 years ago and has
done so ever since, despite the existence of the conflicting setting in the associated SOP.
Biomedix’s response again was ruled as inadequate as objective evidence of implementation of
corrective action was not submitted for review.
Observation 6: Failure to establish and maintain
adequate schedules for the adjustments, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met.
Maintenance activities including the date and
individual(s) performing the maintenance activities shall be documented. The SOP titled “Facility
and Equipment -Maintenance and Housekeeping”
states that all maintenance tasks must be recorded in
the Monthly Maintenance Form, and performed with
the frequency stated in the SOP. Instead, according
to Biomedix officials, maintenance activities have
been performed "as needed" and have been recorded
on a loose-leaf paper log in the production area.
FDA also took exception with the firm’s failure to calibrate as required. Calibration stickers and
documentation for three pieces of equipment of an
indeterminate designations stated that the equipment
was due for annual calibration on July 16, 2008; Aug.
9, 2011; and Jan. 29, 2003 respectively; however,
there was no documentation presented to the inspector to demonstrate this equipment was calibrated on
or since those dates.
Once more, FDA found the company’s response here to be inadequate as objective evidence
of implementation of corrective action was not
submitted for review.
Observation 7: Failure to establish and maintain
procedures to ensure that all purchased or otherwise received products or services conform to
specified requirements. The agency stated that the
company had not established requirements, including
quality requirements that must be met by vendors or
suppliers and have not documented the evaluation of
those suppliers or vendors.
The company’s response here also was
deemed inadequate as objective evidence of implementation of corrective action was not submitted for
review by FDA.
Observation 8: Failure to establish and maintain
procedures for quality audits and to conduct
such audits to assure that the quality system is in
compliance with the established quality system
July 2013 — Page 15
requirements and to determine the effectiveness
of the quality system. These quality audits shall
be conducted by individuals who do not have direct responsibility for the matters being audited.
Biomedix’s Quality Audits SOP states "A 'Quality
Audit is to be conducted on a [redacted] schedule to
review and evaluate the effectiveness of the Biomedix Quality System," however, according to Biomedix officials, no personnel had conducted a quality
audit since 2002.
As in most of the previous points of the
warning letter, FDA once more indicated that the
company’s response was inadequate as objective evidence of implementation of corrective action was
not submitted for review.
The company’s Management Responsibility SOP was deemed inadequate in
that it did not include provisions for
management review or for governing
the management review process.
Observation 9: Failure of management with executive responsibility to review the suitability of
the quality system at defined intervals and with
sufficient frequency according to established
procedures. The company’s Management Respon-
sibility SOP was deemed inadequate in that it did not
include provisions for management review or for
governing the management review process. In addition, management with executive responsibility has
not reviewed the suitability and effectiveness of your
firm’s quality system at defined intervals and with
sufficient frequency to ensure that it satisfies the
quality system regulation.
The firm’s response was once more deemed
inadequate as objective evidence of implementation
of corrective action was not submitted for review.
Observation 10. Failure to establish and maintain procedures to control all documents that are
required. Specifically, FDA stated, Biomedix did
not document the approval date or the signature of
the approving official for the company’s “Reclamation and Reprocessing of Spike Lines (SLA) and Patient side lines (PSA)” and “Biomedix Raw Material
Inventory Control” procedures. Also, another procedure specified maintenance and housekeeping requirements for the firm’s equipment and facility;
however, the procedure was not available at a loca-
Warning Letter Bulletin
tion for which it was designated, used, or otherwise
necessary. Furthermore, changes to these documents
had not been recorded as required.
Again, the adequacy of Biomedix’s response
could not be determined at the time of the issuance
of the Warning Letter. The company’s response
stated that the company was currently reviewing its
SOPs, to include document control procedures, updating or making them obsolete as appropriate, and
that this would be completed by Sep. 30,
2013. Biomedix’s response also stated that its “Biomedix Raw Material Inventory Control” memorandum would be replaced with an updated procedure
by June 28, 2013.
FDA went on in the warning letter to indicate that the inspector had observed that the Selec-3
Intravenous (IV) Administration Sets were adulterated per federal laws and guidelines because the firm
either did not have an approved application for premarket approval (PMA) in effect pursuant to regulations, or did not possess an approved application for
an investigational device exemption (IDE). FDA also
determined that the firm’s Selec-3 Intravenous (IV)
Administration Sets were also misbranded because
Biomedix had not notified the agency of its intent to
introduce the device into commercial distribution in
that a notice or other information respecting the
modification to the device was not provided to the
FDA.
Specifically, Biomedix was seen as modifying
the Selec-3 Intravenous (IV) Administration Sets
originally cleared under K901949, K925645 and
K961928, by providing customers with an ordering
system to alter the device through various options
and configurations. Further, FDA’s review of the
company’s website revealed a provision for selectable
lengths of IV tubing, an optional vented spike, and
other optional components.
These features were not part of the original
510(k). Depending on the configuration of the new
components and customization, the functionality of
the device can change beyond what was cleared under the 510(k). These combinations of features can
alter the performance of the device and require a
new 510(k) submission. For a device requiring premarket approval, the notification required by law is
deemed satisfied when a PMA is pending before the
agency.
At the conclusion of the warning letter, FDA
advised the company to take appropriate measures to
correct the shortcomings noted by the agency and its
July 2013 — Page 16
investigator. Biomedix, which has a defined period of
time in which to make such corrections, has not indicated a response here. FDA has not published any
further information regarding Biomedix or the issued
warning letter.
CAPA; Design; OOS; PMA; QC/QS; Val
GS Medical Packaging Inc.
Mississauga, Canada, June 12
CDRH
During a Jan. 28-31, 2013 inspection of GS
Medical Packaging Inc. (GSMP), a manufacturing
firm located in Mississauga, Canada, an FDA investigator noted several violations in the production area
of the plant. The company, which manufactures the
Professional's Choice Sterilization Pouch and the
Steril-Peel Sterilization Pouch, was issued a 483 by
the investigator at the conclusion of the inspection.
The five violations noted on the 483 and addressed
by the company’s Feb. 22, 2013 response letter were
as follows:
Observation 1: Failure to establish and maintain
procedures to control the design of the device in
order to ensure that specified design requirements are met. Corresponding to this citation, the
investigator had noted that no procedures for design
control had been established to govern new medical
device designs or changes to existing designs.
Upon reviewing the company’s response,
FDA deemed the response in this case to be inadequate. Although the firm had written and approved a
design control SOP, that procedure was incomplete. The SOP did not address design transfer or the
design history file. The SOP also did not define the
design and development activities and stages, lacked
specifics with regard to how or where information
would be captured (specific form title and or numbers), and did not define how often reviews would
take place. Per GSMP’s response, the procedure was
to be reviewed by management; however, documentation of this was not provided. The response did not
indicate that the company had conducted a retrospective review of all device designs and evaluated
whether or not all design control elements were present and documented.
Observation 2: Failure to establish and maintain
procedures that ensure that complaints are
evaluated to determine whether the complaints
represent an event that is required to be reported
to FDA, per regulations (governing medical de-
Warning Letter Bulletin
July 2013 — Page 17
vice reporting (MDR). Cited as the fact that the
firm did not have established procedures to ensure
that complaints were evaluated for events that are
categorized as reportable under MDR regulations,
and no such evaluation was documented in individual complaint records.
FDA again found GSMP’s response inadequate. The company had provided an SOP in response to this observation, but that SOP indicated
that an unnamed process served as a CAPA and
could be used for adverse event reports for MDR required activities. However, upon further review,
FDA determined that neither the process nor the required Non-Conforming Product form captured
whether or not a complaint should be evaluated for
MDR reportability. Further, the SOP was to be reviewed by company management, but documentation of this was not provided. The response did not
indicate that GSMP conducted a retrospective review
of all complaints and evaluated whether or not they
were MDR reportable.
acceptance activities have been defined, performed,
and documented.
The investigator noted that the company did not
have procedures for conducting appropriate testing
on finished product lots, including, how sampling
was to be conducted; the number of samples per lot;
test parameters and methods; acceptance criteria;
procedures for when failing results are obtained; and
documentation of test results.
FDA once more concluded that the company’s response was not adequate. Although GSMP
had written, approved and released, on Feb. 14,
2013, an SOP correlating to this concern, that SOP
did not address the nature of the testing. The SOP
appeared to address the purpose and operation of
the test and materials, yet did not address the specifics of the test. The Project Completion Checklist appeared to serve as a list of Acceptance Records to be
included in the Design History Record (DHR). The
company’s response did not include an earlier SOP
that was associated with the testing procedure.
Also, the “QC Checked, Skid Approved and
Release” form presented in the response lacked
documentation of which lot number was being released. Per GSMP, the SOP was to be reviewed by
management; however documentation of this was
not provided. The response did not indicate that the
firm conducted a retrospective review of all device
designs and evaluated whether or not all applicable
FDA once more deemed the company’s response to be inadequate, due to the fact that although the company had written and approved an
associated SOP on Feb. 14, 2013, that procedure did
not explicitly address what was to be included in the
DHR. The SOP addressed how to assign lot numbers and track raw materials and finished products. The end of the SOP listed documents to be
filled out by the quality inspector as well as other related documentation; however, the SOP did not indicate which records needed to be included in the
DHR.
The SOP did not call for a final release signature to release each lot for distribution. Per GSMP’s
response, the SOP was to be reviewed by management; however documentation of this was not provided. The response did not indicate that the company had ever conducted a retrospective review of all
device designs and evaluated whether or not all applicable records were present in the DHR.
Observation 3: Failure to establish and maintain
procedures for acceptance activities, including
inspections, tests, or other verification activities.
Observation 4. Failure to maintain device history
records (DHRs). Each manufacturer shall establish and maintain procedures to ensure that
DHRs for each batch, lot, or unit are maintained
to demonstrate that the device is manufactured
in accordance with the device master record and
the requirements of this part. FDA maintained
that GSMP did not have written procedures that
govern which documents and information should be
present in each DHR. Also, DHRs were observed to
not contain a final release signature of the person authorized to release each lot for distribution.
The SOP did not call for a final release
signature to release each lot for distribution. Per GSMP’s response, the SOP
was to be reviewed by management;
however documentation of this was not
provided
Observation 5: Failure to develop, maintain and
implement written MDR procedures. FDA here
provided a single example: plant personnel had expressed and acknowledged that the company did not
have an MDR procedure.
The company’s response here was deemed
inadequate. While the firm had submitted an SOP titled, “Recall of Nonconforming Product”, a review
Warning Letter Bulletin
of the document showed the SOP was not an MDR
procedure. The document simply described the
company’s process for device recalls while not providing detailed, structured steps needed to fully execute the SOP.
At time of deadline, no additional information was available from the company or FDA.
CAPA; C-H; Design; MDR; QC/QS; Val
KooJoo Trading Company
Gmpo-City, Geyongki-Do, Korea, June 24
CDER
Following an FDA inspection that ran April
22-25, 2103, KooJoo Trading Company, a company engaged in the manufacture of lancets and lancing devices, received a 483 that contained at least
four citations for observed violations.
The citations in the letter included inadequate
handling of corrective and preventive actions (CAPAs) connected with nonconformances in the devices KooJoo Trading produced. FDA pretty much
rejected the firm’s response to the following:
Observation 1: Failure to develop, conduct, control, and monitor production processes to ensure
that a device conforms to its specifications. This
observation is tied to the GMP issues noted by the
FDA investigator, who used as examples the fact that
the sterilization dose range used by the firm’s contract sterilizer for sterilizing the GP Lancets and
Safety Lancets did not meet the dose range established by KooJoo’s sterilization validation. The sterilization dose established by the sterilization validations for both products was found to be consistently
out of acceptable parameters, as records taken from
2012 and 2013 would indicate. All of the lots of the
devices affected by the out-of-specification sterilization ranges were accepted by the firm and released
for distribution by the company.
FDA found that the firm’s response was inadequate as the firm proposed changing the sterilization dose range that initially was approved by the
Korean FDA at the time the company registered the
device. However, the firm had not initiated any corrective actions related to the product distributed that
did not meet its validated radiation dose specification. Such CAPAs are mandated by regulations.
Also, KooJoo did not follow the plan that
was included in the SOP, Process Validation, for the
sterilization dose audit for the gamma sterilization of
the GP Lancets and Safety Lancets. That plan states
July 2013 — Page 18
that the sterilization dose audit shall be performed at
specific intervals if there is no non-conformity identified in a validation of lots produced, and then, in the
event a non-conformity has been identified, the audits are to be advanced on an accelerated basis. The
firm completed the sterilization validation in 2010
but had not performed the dose audit per the SOP.
No documentation of the corrective action
was available for review since the company stated
that a revalidation of the sterilization process would
be conducted and dose audits would be conducted
per procedure within six months.
Observation 2: Failure to ensure, when the results of a process cannot be fully verified by subsequent inspection and test, that the process
shall be validated with a high degree of assurance and approved according to established procedure. To illustrate this complaint, FDA showed
that the company had not validated an unspecified
production process for the GP Lancets and Safety
Lancets.
No documentation was available for review
since the firm stated that the referenced process
would be validated appropriately.
Observation 3: Failure to establish and maintain
procedures for implementing corrective and preventive action. FDA stated that KooJoo had not
identified correctly CAPAs to prevent recurrence of
nonconformances for two documented CAPA
events. One of the CAPAs, initiated on Nov. 28,
2011, was flagged for an unspecified (redacted)
shortcoming. This issue was closed on Feb. 16, 2012,
after training was provided to personnel involved in
the referenced CAPA.
Another event, similar to the Nov. 28, 2011
incident, was initiated on Nov. 17, 2012, for the lack
of proper training for personnel involved in the production process. This CAPA was closed on Jan. 25,
2013, after training was provided to the associated
personnel.
FDA found the company’s response to be
inadequate, and the agency said the letter did not
consider corrective action to include an evaluation of
the firm’s quality system to determine if other CAPAs were verified or validated to ensure that actions
were effective and did not adversely affect the finished device.
Observation 4: Failure to maintain complaint
files and establish and maintain procedures for
receiving, reviewing, and evaluating complaints
by a formally designated unit. FDA asserted that
Warning Letter Bulletin
KooJoo had not investigated complaints received on
June 10, 2011, and June 14, 2011. These two complaints were related to the same unspecified issue.
The reason for not investigating these complaints
was not documented. The complaint procedure for
this issue requires an investigation of a complaint
unless an investigation for a similar complaint was
done previously. The complaint procedure also requires documenting the reason for not investigating a
complaint. Neither of these SOP components had
been performed.
FDA concluded the warning letter with the
customary advisory for the company’s response to
the warning letter. At time of deadline, no further information had been disseminated by the agency or
the company.
CAPA; C-H; QC/QS; Val
Lucky Board Manufacturing
Panchiao, Taipei, Taiwan ROC, June 20
CDRH
Medical device maker, Lucky Board Manufacturing (LBM), had its Shenzhen, China production facility inspected by FDA from March 11-13,
2013. When the inspectors concluded the tour, they
issued a 483 to the company, for no less than five
observed violations. All of those violations exposed
GMP issues associated with FDA regulations for
quality system requirements. These issues were assessed, by FDA, to be so serious in nature that the
agency was compelled to issue a warning letter to the
company on June 20, 2013.
Among the issues were the following observations:
Observation 1: Failure to ensure, where the results of a process cannot be fully verified by subsequent inspection and test, that the process
shall be validated with a high degree of assurance and approved according to established procedure.
Observation 2: Failure to establish and maintain
procedures for implementing corrective and preventive action (CAPA) to include investigating
the cause of nonconformities relating to product,
processes, and the quality system. Here FDA
cited that the company submitted samples of products involved in a CAPA for an unspecified series of
testing. However, the most recent testing for this
CAPA, conducted in 2008, was reported incorrectly
July 2013 — Page 19
and as an out-of-specification, as was indicated by
the device’s labeling. No investigation was made to
identify the reason for the out-of-specification result.
Observation 3: Failure to establish and maintain
procedures for receiving, reviewing, and evaluating complaints by a formally designated unit.
FDA noted that the firm’s complaint handing procedure did not describe the process for evaluation of
complaints to determine if those complaints constituted events that are required to be reported to FDA
under the Medical Device Reporting regulation.
The most recent testing for this CAPA,
conducted in 2008, was reported incorrectly and as an out-of-specification, as
was indicated by the device’s labeling. No investigation was made to identify the reason for the out-ofspecification result, FDA noted...
Observation 4: Failure to develop, conduct, control, and monitor production processes to ensure
that a device conforms to its specifications. The
investigators noted that certain manufacturing process parameters were not adequately controlled within
tolerance settings and were not documented. The
firm’s procedure did not specify such parameters.
Observation 5: Failure to ensure that all inspection, measuring, and test equipment, including
mechanical, automated, or electronic inspection
and test equipment, is suitable for its intended
purposes and is capable of producing valid results. Investigators cited the company here for the
fact that it did not calibrate gauges, thermometers,
and other devices used to monitor certain manufacturing processes.
One final observation was mentioned in the
warning letter, this one focusing on the company’s
adherence to regulations pertinent to medical device
reporting (MDR).
Observation 6: Failure to develop, maintain, and
implement written medical device reporting
(MDR) procedures. Simply stated, LBM lacked a
structured MDR procedure.
Currently, neither the company nor FDA
have given any indication as to the final disposition
of the issues addressed in this warning letter.
Cal; CAPA; MDR; QC/QS; Val
Warning Letter Bulletin
Medinvents NV
Hasselt, Belgium, June 6
CDRH
During an inspection of Medinvents NV’s
production facility located in Hasselt, Belgium, conducted Jan. 21-Jan. 24, 2013, an investigator from
FDA recorded several violations centered on medical
device reporting (MDR) standards and quality system
deficiencies. On June 6, the agency issued a warning
letter to the Belgian manufacture. It was unclear if
the company had ever supplied an initial response
letter in conjunction with the 483.
The violations and points of discussion in the
warning letter included the following:
Observation 1: Failure to develop, maintain, and
implement MDR procedures. The basis of this ci-
tation was found in the fact that Medinvents was
found to have no MDR procedures in place whatsoever.
Observation 2: Failure to establish and maintain
adequate procedures to develop, conduct, control, and monitor production processes to ensure
that a device conforms to its specifications.
Observation 3: Failure to establish and maintain
procedures for finished device acceptance to ensure that each production run, lot, or batch of
finished devices meets acceptance criteria. When
the firm’s device history records (DHRs) were reviewed, the inspector revealed that the acceptance
testing performed on the finished devices was not
documented in a procedure and not listed in the device history records. The testing/inspection performed was not documented in any device history
record.
Observation 4: Failure to establish and maintain
adequate procedures to control product that
does not conform to specified requirements.
Here, FDA showed that DHRs reviewed did not
document any non-conforming products. The quality
control history documented the number of nonconformance for those lots, but there was no documentation on the disposition of the nonconforming
product. Also, the DHRs reviewed showed that
documented nonconformance did not include disposition and retesting of rework.
Observation 5: Failure to establish and maintain
adequate procedures for implementing corrective and preventive action. The records for corrective and preventive actions reviewed by FDA were
incomplete and not implemented.
July 2013 — Page 20
Observation 6: Failure to establish and maintain
adequate procedures for validating the device
design, including software validation and risk
analysis, where appropriate. FDA asserted that the
firm did not include all medical devices manufactured and sterilized. Medinvents did establish a procedure for recording and controlling load sizes for
each device type, but no evidence to support the load
sizes was documented.
At this date, no further details as to additional FDA action or the company’s response is
available. CAPA; C-H; Comp/Soft; MDR;
OOS; QC/QS; Val
Transonic Systems, Inc.
Ithaca, NY, June 19
New York District
Transonic Systems, Inc.’s (TSI), which
makes and distributes a carbon monoxide (CO)
status system that is used in conjunction with an Arteriovenous (AV) Loop Kit and other related accessories, was cited for a series of GMP and MDR violations following an audit Feb. 25-March 21, 2013.
The firm’s products are used for the measurement of cardiac output and related hemodynamic
and blood volume parameters, the letter stated.
The following is a synopsis of the warning
letter, which the company responded to on April 8,
but which FDA deemed inadequate on pretty much
all counts:
Quality Systems Violations
Observation 1: The design history file does not
demonstrate that the design was developed following FDA regulations. Specifically, FDA said the
firm’s SOPs for design controls require the use of a
phase and gate approval system. Gate 4 approval
ends the design phase of the project and certifies the
product has been designed under the firm's quality
system; the product is ready to be manufactured and
marketed; is ready for release to production and
transfers the design.
The agency cited a number of issues where
the firm either manufactured, marketed, or distributed device units prior to required approvals; failed
to document design history files (DHF) reviewed; or
provided incomplete documentation of DHR reviews. According to FDA, all of these were instances
of inadequate design controls pursuant to established
procedures and incomplete design history files.
Warning Letter Bulletin
Observation 2: Design validation did not ensure
the device conforms to defined user needs and
intended uses. FDA stated that TSI’s design verifi-
cation and validation activities for the COstatus system were executed by plant personnel under the
processes set forth by a number of software systems
and protocols. However, these activities failed to
demonstrate that the COstatus system conforms to
defined user needs and intended uses.
Observation 3: Results of the validation of the
device software were not adequately documented. FDA noted that the COstatus Acquisition
Software Validation Report was approved on March
31, 2010. This validation was executed using three
designated monitors. The validation results for these
three monitors were not maintained. The report
documents results of one system without a documented conclusion.
FDA stated that TSI’s acceptance
criteria was not established, nor
documented prior to the execution
of validation activities…
Observation 4: Acceptance criteria were not established prior to the performance of validation
activities. According to FDA, the COstatus system
verification and validation activities were executed
utilizing three designated validation components, but
despite this, the acceptance criteria were not established prior to executing these activities.
Observation 5: Corrective and preventive action
activities and/or results have not been adequately documented. Specifically, FDA stated that
TSI’s activities were inadequate due to the company’s
failure to capture all lots of products affected by
identified problems, as in the case of CAPA 0029,
which the company closed on March 13,2012, even
though the CAPA failed to address and document all
failure modes associated with leaking device components. Further, corrective actions did not demonstrate that the actions taken were fully effective. Another failing of the company was its lack of documentation of investigative activities that led to corrective activities revolving around a COstatus monitor problem; this CAPA, labeled simply 0042, involved direct customer feedback and should have
July 2013 — Page 21
been more thoroughly investigated and completely
documented, FDA said.
Observation 6: Complaints involving the possible failure of a device, labeling, and packaging
to meet any of its specifications were not reviewed, evaluated, and investigated where necessary. TSI reported to investigators that all com-
plaints received by the company are processed
through the Customer Service Department. In turn a
CRS determines whether the reported event is a
complaint that is a device related issue or service related issue. The agency showed 11 examples of COstatus related complaints where the events were determined to be service related and were not reviewed,
evaluated, and investigated as a complaint in accordance with established procedures. Additionally,
other than warranty dates, servicing dates were not
documented.
The adequacy of this area of the company’s
response could not be adequately assessed until work
instruction for Customer Feedback and Adverse
Event Reporting was completed and reviewed by
FDA. Also, FDA awaited the outcome of TSI’s quality assurance (QA) review of non-warranty and service issues for trending and complaint analysis in
conjunction with repair department personnel.
Observation 7: Records of complaint investigations do not include required information. FDA
noted during the inspection that several customer
service tickets of complaints involving COstatus AV
Loop leak issues were received between Apr. 20,
2011and Feb. 13, 2013. The complaint records
lacked complete documentation of investigation activities including the results and dates of the investigation. In addition, complaint records did not document whether or not corrective action is required.
Observation 8: Process control procedures that
describe any process controls necessary to ensure conformance to specifications have not
been adequately established. Specifically, AV
Loops had been manufactured under Engineering
Project Requests (EPRs) and the company had not
established procedures for handling those requests. It
was unclear to FDA whether products manufactured
under EPRs needed to conform to specifications
prior to release of the products for distribution. In
addition, forms utilized for EPRs lacked traceability
for which components and accessories were manufactured under EPRs.
Warning Letter Bulletin
MDR Violations
During the inspection of the facility, the
FDAers noted significant deviations relevant to
MDRs. These included:
Observation 9: Failure of your firm to adequately
develop, maintain and implement written MDR
procedures. After reviewing the firm’s procedure ti-
tled, “Customer Feedback & Adverse Event Reporting,” the inspectors noted that the SOP did not establish internal systems that provide for timely and
effective identification, communication, and evaluation of events that may be subject to MDR requirements. Serving as an example here was the fact that
the procedure did not include definitions for the
terms "remedial action” found in regulations and
"reasonably known" and "reasonably suggests," also
found respectively in federal regulations. The exclusion of these terms from the procedure posed a risk
that the firm might, in the future, make an incorrect
reportability decision when evaluating complaints
that may meet the criteria for reporting.
Also, that same SOP did not establish internal systems to provide for a standardized review
process or procedure for determining when an event
meets criteria for reporting under this part. Specifically, the procedure, as written, did not specify who
makes the decision for reporting events to FDA.
Additionally, the SOP did not establish internal systems that provide for timely transmission of
complete medical device reports. At issue were the
lack of instructions for how to obtain and complete
the corresponding FDA 3500A form; the lack of
clearly defined circumstances under which the company must submit initial, supplemental or follow-up
report and the requirements for such reports; and the
lack of a description as to how the firm would address documentation and record-keeping requirements, including the documentation of adverse event
related information maintained as MDR event files.
Similarly, the company was found deficient in identifying systems that ensure access to information that
facilitates timely follow-up and inspection by FDA.
In addition to the other noted shortcomings,
FDA cited that the SOP, titled “Medical Device Reporting and Vigilance Reporting,” included references to baseline reporting and annual certification,
which are no longer required by FDA.
In review of the firm’s response, FDA concluded that the adequacy of the response could not
be determined, as the company indicated that it
planned to revise its current MDR procedures by
July 2013 — Page 22
May 31, 2013, but had not yet supplied appropriate
documentation for this revision to FDA.
Neither FDA nor Transonic Systems, Inc.
have made any additional comments on whether the
company has performed the steps to resolve the issues in the warning letter. CAPA; C-H;
Comp/Soft; MDR; OOS; PMA; QC/QS; Val
Tytex Slovakia S.R.O.
Humenne, Slovak Republic, June 12
CDRH
An FDA inspection of medical device maker
Tytex Slovakia S.R.O., on Jan. 21-24, 2013, resulted in the issuance of a 483 for several observed
violations.
The firm, which manufactures the Safehip
AirX Textile Hip Protector devices, responded to the
citations in the 483 in a Feb. 13, 2013 response letter
furnished by Kim Remin Rasmussen, the Director of
Quality & Evaluation for the firm. Based on the response letter and seriousness of the infractions noted
by the inspector, FDA dispatched a warning letter on
June 12. The following details the points of violation
and FDA’s assessment of the company’s response
letter:
Observation 1: Failure to report to FDA no later
than 30 calendar days after the day that your firm
received or otherwise became aware of information, from any source, that reasonably suggests
that a device that it markets may have caused or
contributed to a death or serious injury. FDA’s
position was that, in the case of adverse event reporting (AER), any AER complaints must be addressed
and disposed of with strict adherence to regulations.
The inspector’s review of AER records showed that
a complaint of an unnamed nature (redacted) had
been submitted to the company. The information included for the complaint reasonably suggested that
the device may have caused or contributed to a reportable serious injury. However, an MDR report
was not submitted to FDA within 30 calendar days
of becoming aware of the reportable event.
FDA found Tytex’s response to this citation
to be inadequate because the company failed to consider if the reported injury was or may have been attributed to Tytex’s device, user error or the injury.
Observation 2: Failure to develop, maintain, and
implement written MDR procedures. FDA’s in-
spector, after reviewing the MDR procedure, noted
Warning Letter Bulletin
that the SOP did not establish internal systems that
provide for timely and effective identification, communication, and evaluation of events that may be
subject to MDR requirements. Offered as an example was the fact that the procedure omitted the definition of “malfunction,” “MDR reportable event”
and “remedial action,” as is found in regulations.
The exclusion of these terms may have led or could
lead the company to make an incorrect reportability
decision when evaluating complaints that may meet
the criteria for reporting such events.
Likewise, the procedure presented by the
firm did not establish internal systems that provided
for a standardized review process to determine when
an event meets the criteria for reporting under this
part. FDA was able to show where the procedure
did not have instructions for conducting a complete
investigation of each event and evaluating the cause
of the event.
Additionally, the procedure did not establish
internal systems that provided for timely transmission of complete medical device reports. It was revealed that the procedure did not have instructions
for how to obtain and complete the FDA 3500A
form, and did not state that the MDR reports should
be submitted to FDA’s CDRH, Medical Device Reporting division in Rockville, MD, U.S.A.
Again, FDA assessed Tytex’s response as inadequate, due to the firm’s on MDR Reporting,
which did not establish internal systems that provide
for timely transmission of complete medical device
reports. Additionally, the revised procedure failed to
address certain key aspects of MDR mandates.
Observation 3: Failure to establish and maintain
adequate procedures for finished device acceptance to ensure that each production run, lot, or
batch of finished devices meets acceptance criteria. FDA’s review of manufacturing test records
dated October 20, 2012, for the Safehip devices
showed that certain lots did not meet the company’s
design specification. The tested article was ultimately
accepted for release, although it was tested and identified as out-of-specification. Additionally, the checklist used for reviewing the final acceptance and determining release of the devices did not include the
final testing for production specification requirements.
Based on the fact that Tytex did not address
the issue of whether the firm had established an acceptable specification range used in the final acceptance testing of the device, FDA found the com-
July 2013 — Page 23
pany’s response to be not adequate. Additionally, the
response did not indicate the maximum number of
specification failures the device can have before it affects the safety of the device.
To date, neither the company nor FDA have
supplied any additional information or updates to the
warning letter or the company’s response of same.
MDR; QC/QS; Val
BiMo
Janet K Tillisch, M.D.
Fargo, ND, June 20
CBER
Janet Tillisch, M.D., who had been performing research involving investigational drugs, received a 483 following an April 9, 2013, audit, in
which the agency found various violations of clinical
subject protection rules.
The violations were discussed with Tillisch,
advising her of the need for a response to the inspectional observations. The agency received just such a
response, dated April 24, 2013. The warning letter
came June 20, citing the following:
Observation 1: You failed to fulfill the general
responsibilities of an investigator. FDA indicated
that Tillisch delegated to the Site Management Organization (SMO), the conduct of study visits and the
completion of study records for such visits, including
Case Report Forms (CRFs). There was no evidence
that researcher adequately oversaw and reviewed the
study activities the physician delegated to other research personnel. FDA said Tillisch, being the principal investigator and signer of the 1571 Form, is ultimately responsible for the study, not the SMO.
As described below, it appeared to FDA that
Tillisch failed to review study records with reasonable care, including failing to ensure that she had access to certain source documents while the studies
were ongoing. Tillisch’s lack of supervision and personal involvement resulted in the failure to ensure
that the study was conducted according to the signed
investigator statement, the investigational plan, and
applicable regulations.
FDA stated that, based on the available information, it appeared that, while the studies were
ongoing, the researcher did not have access to certain
source records— “electronic diaries” or “e-
Warning Letter Bulletin
diaries”— in which subjects recorded adverse event
information and other observations pertinent to the
subject’s case history.
As a result, FDA said Tillisch placed subjects
at risk because she did not promptly review and
evaluate adverse events to determine their seriousness and relationship to the investigational product,
and to perform any necessary medical intervention.
Also, Tillisch failed to ensure that adverse events
were recorded in CRFs as required by protocol.
Tillisch’s response letter explained that she
was issued a password to access the e-diaries. To this,
FDA requested that the researcher explain when she
received access to the e-diaries and when the ediaries were accessible to Tillisch for review.
FDA also maintained that multiple study records, including CRFs, were incomplete or missing.
Tillisch responded to this by explaining that
specific personnel managed key aspects of the clinical trials, including clinical study coordination and
recordkeeping. She further explained that the research facility abruptly closed in August 2012 and did
not provide her with documentation or information
for any of the trials the facility managed. As noted
above, while researchers may delegate certain study
tasks to individuals qualified to perform them, such
delegation requires adequate supervision. Had Tillisch, as the clinical investigator, reviewed the study
records with reasonable care, these recordkeeping
deficiencies would have been obvious to the researcher.
Observation 2:You failed to ensure that the in-
vestigation was conducted according to the
signed investigator statement, the investigational plan, and the applicable regulations in order to protect the rights, safety, and welfare of
subjects under your care. FDA cited the re-
searcher for the fact that adverse events were recorded in the subjects’ e-diaries but were not reported in the Adverse Event Log of the CRFs as required regulations.
Protocol for study processes requires that an
effort must be made to determine why subjects failed
July 2013 — Page 24
to return for the necessary visits and that information
detailing why a subject fails to return for the necessary visits or is discontinued from the study, as well
as the date of withdrawal, will be recorded on the
study outcome CRF. This requirement was not met
for two subjects.
In Tillisch’s response letter, the researcher
did not address FDA’s findings. Again, the researcher was asked to provide a written response.
Observation 3: You failed to prepare and maintain adequate and accurate case histories recording all observations and other data pertinent
to the investigation on each individual administered the investigational drug, including case report forms and supporting data.
Because Tillisch’s response letter did not address this finding, the researcher was again asked to
provide a written response. FDA also noted a number of recordkeeping deficiencies were observed during their inspection, and, since Tillisch did not address these deficiencies, the agency requested such an
address in her next communication.
Another matter FDA noted was that of multiple CRFs containing an incorrect header showing
the name and site number of another investigator.
Here, Tillisch in her response letter acknowledged
that certain CRFs had incorrect headers. She further
explained that the headers were later corrected by
Essentia Health staff during the internal review of
the study, after notification of the original managing
research center’s closure. Further, Tillisch explained
that the headers corrected by Essentia Health staff
were not dated, timed, nor initialed and the staff that
made the corrections were no longer available to be
contacted.
To date, no indication that Tillisch has responded to the warning letter is available. Also, FDA
has not provided any additional information in this
matter. The identity of the study drug was not disclosed. BiMo
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