Note: Although this FDA-483 is an
accurate representation of the original FDA-483 issued to the firm, it is not an exact
copy. Slight modifications to the original FDA-483 have been made to accommodate its
conversion to the HTML format. A scanned copy of the original FDA-483 is available in PDF format on this website. |
DEPARTMENT
OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION |
DISTRICT
OFFICE ADDRESS AND PHONE NUMBER
555 Winderley Place, Suite 200
Maitland, FL 32751
(407) 475-4700 Fax:(407) 475-4768
|
DATE(S)
OF INSPECTION 03/06/2006 -
04/18/2006* |
FEI
NUMBER 3003194604 |
NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED
TO: Thomas
P. Rice, Chief Executive Officer & Director |
FIRM
NAME
Andrx Pharmaceuticals, Inc.
|
STREET
ADDRESS
4955 Orange Dr |
CITY,
STATE AND ZIP CODE
Fort Lauderdale, FL 33314-3902
|
TYPE
OF ESTABLISHMENT INSPECTED
Pharmaceutical Manufacturer
|
This document lists
observations made by the FDA representative(s) during the inspection
of your facility. They are inspectional observations, and do not
represent a final Agency determination regarding your compliance.
If you have an objection regarding an observation, or have implemented,
or plan to implement, corrective action in response to an observation,
you may discuss the objection or action with the FDA representative(s)
during the inspection or submit this information to FDA at the address
above. If you have any questions, please contact FDA at the phone
number and address above. |
DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:
QUALITY SYSTEM |
OBSERVATION 1
The quality control unit lacks authority to review production records
to assure that no errors have occurred and fully investigate errors
that have occurred.
Specifically,
- The Quality Control Unit failed to adequately review Ketoprofen
Validation Protocol and Report No. 002PV005 and, as a result,
it released and distributed between March and July 2005 six batches
of Ketoprofen ER capsules (lot #'s: 520E017, 520F0368, 520E018,
F520F0840, F520F1030, and F520F1031) that were manufactured with
a process that showed significant variability and was not adequately
validated.
- The Quality Control Unit failed to ensure that Phase I Laboratory
Investigations were adequately investigated, documented, and trended
after they were removed from the [REDACTION] system in
September 2005 and transferred to a manual logbook.
|
PRODUCTION, LABORATORY AND EQUIPMENT/FACILITIES
SYSTEMS
|
OBSERVATION 2 Control procedures are not established
which validate the performance of those manufacturing processes
that may be responsible for causing variability in the characteristics
of in-process material and the drug product.
Specifically,
On 2/25/05, the QCU approved Doc. No. 0002PV05 titled "Process
Validation Protocol- Manufacture of Ketoprofen [REDACTION]
using [REDACTION] readings documented from the
[REDACTION] to evaluate the accuracy of scale reading versus
[REDACTION] reading for the sustained release coating process
as the difference in the [REDACTION] readings was identified
as the cause for the shift in dissolution performance at the 8th
hr. Five (5) commercial batches of [REDACTION] (520E017,
520E018, 52050, 55797 and 57043) were manufactured under this validation
protocol, which resulted in three batches (52050, 55797 & 520E018,
sublot#4) that failed dissolution specifications at the 8th hr.
and a batch (57043) that deviated from the target capsule fill weight
specified in the manufacturing batch record in order to meet dissolution
specification at the 8th hr. The remaining six (6) finished product
batches (520E017, 520F0368, 520E018, F520F0840, F520F1030, and F520F1031)
of Ketoprofen ER Capsules that had acceptable dissolution results
were released by the Quality Control Unit and distributed between
March and July 2005 despite the demonstrated variability and significant
inconsistencies of the manufacturing process documented in interim
reports 002PV05-01i, 002PV05-02i, 0002PV05-03i, and the final validation
report 0002PV05 approved on 7/28/05.
|
OBSERVATION 3 The use of instruments
and apparatus not meeting established specifications was observed.
Specifically,
- In December 2005, the Quality Control Unit (QCU) determined
the need to replace the flow rate valves of all [REDACTION]
apparatuses as a result of frequent clogging, flow rate problems,
and increased bubble formation that randomly caused "erratic"
dissolution results. [REDACTION] valves were purchased
and received in January 2006; however, the QCU failed to adequately
monitor the implementation of this corrective action and, as a
result, the valves were not installed and the use of these dissolution
baths with potentially malfunctioning valves continued for dissolution
testing of all Cartia, Diltia, Taztia, Metformin, Naproxen Sodium,
and Ketoprofen drug products.
- Subsequent to the determination of performance problems with
the [REDACTION] dissolution apparatuses, the Metrology
Department, responsible for laboratory equipment maintenance and
calibration, conducted an investigation (date not documented &
investigation not tracked) to determine the root cause of the
problems in the dissolution apparatuses. The investigation concluded
that "due to a blockage on the pores caused by crystal
deposits (salts interference), air bubbles may form cause false
readings in the middle of the run that do not represent a true
absorbance reading of the sample" and recommended more
frequent maintenance schedules to prevent flow valve problems.
However, the QCU reported that the problem had been fixed in January
2006 with the replacement of the valves (that didn't take place)
and failed to implement the recommended corrective and preventive/maintenance
actions in a timely manner.
- The set-up procedures used for the [REDACTION] apparatuses
are not adequate in that according to dissolution records reviewed
from May 2005 thru March 2006 and interviews with analysts, the
flow rate of the "blank" line is checked prior to each
dissolution run to determine if the flow valve is working properly
(flow rate spec: [REDACTION]. However, your firm lacked
scientific evidence to demonstrate that an adequate flow rate
of the blank is directly correlated to an adequate flow rate to
all [REDACTION] dissolution vessels in order to conclude
that the flow valve is working properly and the flow to each vessel
is within specifications prior to the run.
|
OBSERVATION 4 There is a failure to
thoroughly review any unexplained discrepancy and the failure of
a batch or any of its components to meet any of its specifications
whether or not the batch has been thoroughly distributed.
Specifically, your firm failed to perform adequate investigations
with scientifically justifiable conclusions to incidents of out-of-specification
results or production deviations and/or failed to implement appropriate
corrective actions for the root cause determination. The deficiencies
are evidenced in the following:
Laboratory Phase II Investigations:
- The investigation report TWR #1691 for finished product testing
of Metformin HCl Extended-release Tablets, 500 mg Lot No. F571F0692
was specifically for content uniformity testing. During analytical
testing, one of the ten capsules (73.5%) failed to meet the Stage
1 established specification of [REDACTION] of label claim
and another tablet was toward the low end of the specification
range (88.0%). The root cause analysis indicated analyst error
and two additional capsules were extracted with the results replacing
the original OOS capsules. The investigation revealed that the
analyst observed a gelatin like mass of material at the bottom
of one of the flasks and a piece of undisssolved gel at the bottom
of the other flask after adding diluting solvent A. As a result,
these two flasks were stirred for an additional 60 minutes which
is longer than the procedure or the eight other flasks. The analyst
who performed the QC method transfer stressed the importance of
full tablet disintegration before adding diluting solvent A or
the material will clump. The firm concluded that based on the
physical observation of the two stock solutions in question proper
active extraction did not take place. The investigation is inadequate
in that:
- The analysts were retrained on the analytical method itself
but there was no documented training regarding continuing the
analysis knowing that he or she made an extraction error or
that there was a problem with the disintegration of these two
capsules during the analysis.
- The investigation did not address the reason why these two
capsules did not dissolve adequately. The analyst's interview
did not determine if the capsules were taking longer than normal
to disintegrate before adding diluting solvent A, or if the
capsules took longer to dissolve because he/she added diluting
solvent A without making sure the capsules had disintegrated.
The first scenario (the capsules taking longer than normal to
disintegrate) would not indicate analyst error, but a possible
process related error that would have required the investigation
to be extended outside of the laboratory e.g. investigation
of the process and historical data to determine root cause.
- The investigation report TWR #1540 for finished product testing
of Metformin HCl Extended-release (XT) Tablets, 1000 mg Lot No.
F575F0620 Sublot C was specifically for related compounds testing.
The unknown related compound in this sample was OOS. With-in specification
results were obtained upon retest of the sample and the firm concluded
that the OOS result was due to contaminated glassware. In an attachment
to this investigation, the firm states, “As part of
GLP, all analysts normally rinse flasks before using for RC test.
Both analysts are very experienced chemists and did that during
sample preparation. In spite of that all glassware was rinsed
by mobile phase before sample preparation there was still some
contamination from glassware or from sample handling. As a corrective
action, the analysts recommended to [REDACTION] flasks
with [REDACTION] additionally and to rinse by
mobile phase before using them for Metformin XT RC test.”
This statement indicates that there is no definitive assignable
cause for the OOS result since they state that the contamination
could have come from glassware or sample handling. The investigation
does not explain how glassware contamination or sample handling
may have increased the unknown related compound for this sample.
If in fact the contamination was due to sample handling then the
proposed corrective action of additional glassware cleaning would
not be appropriate. In this case, the investigation indicated
that the current glassware cleaning procedure may not be adequate
for this particular product but does not explain why. The corrective
action does not address training for all analysts on the required
glassware procedure nor does it state if this will be incorporated
into the analytical procedure for this product. Furthermore, the
investigation was inconclusive and the results were invalidated
without extending the investigation into the manufacturing area.
- The investigation report TWR #1484 for finished product testing
of Diltiazem HCl Once-A-Day Extended-Release Capsules, 240 mg
Lot No. F599F0577 was specifically for related compounds and impurities
testing. The levels of [REDACTION] and two unknown impurities
were not typical for this product. For impurities testing, the
analysts are instructed to rinse glassware before use as part
of their cGLP training. In this instance, the investigation states
that the analyst omitted to rinse the glassware. Therefore, a
new dilution from the original stock solution was made with the
impurity levels dropping to below a detectable level upon reanalysis.
The corrective action for this investigation as stated in the
TWR report was the counseling of the analyst in regard to glassware
rinsing. According to the attached training record, the analyst
was re-trained on the analytical test method STM #599, “Diltiazem
HCl Once-A-Day Extended-release Capsule, 240 mg”. This test
method does not address the rinsing of glassware for related compounds
and impurities testing. There was no documented evidence of re-training
the analyst on the proper procedure for glassware cleaning.
- The investigation report TWR #1523 was for the assay of [REDACTION]
raw material Lot No. 11140. The sample was analyzed twice with
one of the two assay results not meeting specification. A re-injection
of the original vial was made which confirmed the original OOS
result. A new aliquot from the original flask was taken and analyzed
which gave a within specification result. The firm concluded analyst
error in that the analyst did not mix the flask sufficiently or
did not mix the flask at all. However, in this case the analyst
stated the flasks were properly mixed. Furthermore, in an attached
memorandum to the TWR, the analyst involved refused to sign an
acknowledgement of analyst error. The firm could not provide scientific
justification as to what sufficient mixing would be for this analysis
or any documented evidence that the analyst did not follow procedure.
There was no further investigation into this lot of raw material.
- The investigation report TWR #1654 was for intermediate product
testing of [REDACTION] Lot No. 572256 Sublot 3. The Phase
I investigation as described on form QC-0126 does not state why
the original OOS result was invalidated, no details on how the
samples were re-analyzed and there is no assignable cause mentioned,
yet there was no Phase II investigation performed and the original
[REDACTION] investigation record was voided with product
being released as meeting specification.
- The investigation report TWR #1617 was for the assay of [REDACTION]
raw material Lot No. 11325. This lot along with three other lots
was tested for impurities by [REDACTION] with Lot 11325
failing to meet the specification of not more than [REDACTION]
for [REDACTION] impurity. The assignable cause was determined
to be equipment failure (bad injection of the sample most likely
due to an air bubble). During the investigation, the laboratory
reviewed the online [REDACTION] logbook which did not indicate
any equipment problems or malfunctions. The laboratory also reviewed
the chromatograms as part of the investigation and determined
that this lot had a different baseline than the other three lots.
However, there is no description of how the baseline was different
and how that would impact on the results. Furthermore, the firm
did not perform any type of verification of the injector system
on the [REDACTION] before making the conclusion that the
equipment did not inject properly and there was no corrective
action implemented for the [REDACTION] system. Therefore,
there is no scientific justification for invalidating the OOS
results. The other three lots tested concurrently were not re-injected.
Though [REDACTION] is not a currently marketed product,
the laboratory practices shown in this investigation were inadequate.
This is a repeat observation from the previous FDA 483, #19(B)(1).
Phase II Investigations related to Equipment Cleaning:
- SOP QC-0135, "Evaluation of Extraneous Peaks During the
Analysis of Cleaning Validation Swab Samples", establishes
the criteria to determine when an unknown peak in a cleaning swab
should be investigated. According to the SOP, if any individual
unknown peak is not more than [REDACTION] of the target
analyte peak or if the sum of the unknown peaks per swab location
is not more than [REDACTION] of the maximum allowable residue
limit of the target analyte, no further action is required. A
Technical Services Supervisor said that their rationale for the
limits stated in their SOP is based on a Consultant's article.
The article indicates that "it might be appropriate to allow
an unknown peak provided it is no more than 5-10% of the height
or area of the target residue (the active, for example) at it
residue limit" and that "Some companies will then have
an additional stipulation that the sum of all peak heights or
areas of unknown peaks be no more than 20-40% of the height or
area of the target residue at its limit." However, the article
also states that "In this case, it is expected that an investigation
has been done to identify the unknown peak, and that it still
remains unknown." The article also indicates that the amount
of the unknown peak cannot be accurately determined unless a detector
such as [REDACTION] is used because the relative absorbance
is not known.
SOP QC-0135 allows unknown peaks at percentages even higher than
the ones recommended by the Consultant on a routine basis without
first making a reasonable attempt at identifying the extraneous
peaks. The firm manufactures a wide variety of products with different
toxicities and allowable residue levels, and even uses the same
equipment used for commercial manufacture to manufacture products
that are still under development. Applying the limits stated in
SOP QC-0135 without first investigating the source of the unknown
could result in allowing higher levels of residue than would normally
be allowed had the identity of the extraneous peak been known.
In addition, since the absorptivity of the unknown peak is not
known and the actual amount of residue cannot be determined with
the detectors used by the firm, the actual amount of residue could
be even higher than the amount estimated by using the target analyte
peak.
- At least 24 cleaning swab samples containing extraneous peaks
above the limits specified in SOP QC-0135 were reported for ten
different pieces of equipment from May of 2005 through February
of 2006. The inspection disclosed the following deficiencies regarding
the investigations conducted for these unknown peaks:
- TWRs 1374, 1580, 1591, 1594, 1744, 1868, 1895, 1896, and 1964
are all related to unknown peaks in swab samples and were investigated
under TWR 1555. The conclusion of TWR 1555 states that "Based
on indirect evidence, the sponge, a general purpose scour pad
of cellulose and nylon fiber material composition is the probable
cause of the unknown peak". This conclusion was reached
for all swab samples involved in these TWRs even when the firm's
experiments failed to demonstrate that the peak was the same
in all cases and that the source of the peak was the same. The
firm conducted experiments only with the swab samples involved
in TWRs 1744, 1868, and 1896. None of the experiments demonstrated
that the source of the peak was the sponge itself. Although
the unknown peak found in swab samples from TWR 1744 was also
found in the sponge, the source was apparently an oily residue
picked up with the sponge when it was used to clean the equipment
involved in the TWR. Nevertheless, the only corrective action
performed was removal of the sponges from the manufacturing
area. An e-mail attached to TWR 1555 stated: "At this time,
we are addressing only the sponges as they build up the contaminants."
The firm conducted their product impact assessment based on
their conclusion that the unknown peak was from a by-product
of the sponge and released all lots involved because all material
used in the manufacture of the sponges is food grade.
- According to TWR 1555, no extraneous peaks have been identified
in subsequent cleaning studies after use of single-use cleaning
cloths was implemented in September 30, 2005. However, the current
inspection disclosed that three additional swab samples collected
in February of 2006 showed unknown peaks above the limit specified
by QC-0135. These instances were not reported to the FDA Investigator
and were not investigated under a TWR. Only Phase I laboratory
investigations were conducted in these cases (INV-06-0041 and
INV-06-0633).
- The firm did not make a reasonable attempt at identifying
the extraneous peaks in order to determine if the extraneous
peaks could come from residues of products manufactured prior
to the last (target) product. None of the investigations performed
included spiking samples with previous products to determine
if the source of the unknown peaks could have been previous
products manufactured in the same equipment. Review of the cleaning
SOPs involved showed that most are not specific regarding washing
and rinsing methods; however, none of the cleaning SOPs have
been revised to provide more specific instructions regarding
washing method, rinsing times or volumes, disassembly of equipment,
etc. The corrective action in all cases was to re-clean and
re-swab the equipment.
- TWR 2194 was opened on 2/3/06 to investigate a swab failure
for Diltiazem HCl ER Capsules . The TWR lists rinsing with [REDACTION]
as one of the steps used in cleaning the capsule filler as per
SOP PD-0018, "Operating and Cleaning Procedure for the [REDACTION].
However, the firm does not use any [REDACTION] to rinse
equipment. The investigation failed to uncover the fact that the
cleaning procedure is not being followed in that no [REDACTION]
is used for the final rinse.
- No investigation was conducted for several swab samples that
failed detergent or active limits; these swabs were collected
under Swab Analysis IDs 05-11-080, 06-02-091, and 06-02-038.
- CAPA 1556 was opened on 6/20/05 to investigate the source of
unknown peaks identified in TWR's 1476 and 1504 as laboratory
glassware contamination. This CAPA has not been closed; the Investigation
Extension Request approved on 2/10/06 states that "Initial
work has been processed under QCP-05-059-MTH and reported under
QCR-05-056-MTH". However, none of these documents addresses
laboratory glassware contamination; they are related to the investigation
of the source of unknown peaks in manufacturing equipment. TWRs
1476 and 1504 were closed before completion of the required follow-up
investigation to be conducted under CAPA 1556.
- TWR 2059 was opened on 11/15/05 to investigate an incident where
a foreign tablet (Metformin HCl ER Tablet, 500 mg) was found in
a [REDACTION] during the [REDACTION] stage for Metformin
HCl ER (XT) Tablets, 1000 mg, lot 62253. The investigation disclosed
that both products ran back to back in compression in room A-19
(Building 4955) on the [REDACTION] (WP-0007). TWR 2059
indicates that the most probable cause was human error in that
the SOP cleaning instructions were not properly executed. However,
the investigation did not include an examination of the compression
machine involved and other compression machines used in the facility
to determine areas where tablets could remain after a major clean
without being detected. The investigation did not include a review
of the operation/cleaning procedure to clarify instructions in
order to make sure that those areas are given special attention
when cleaning and setting up the compressing machine. Since June
of 2005, the firm has reported five additional instances of foreign
tablets or capsules found in different pieces of equipment (most
related to packaging line equipment) for building 4955 and two
for building 4001. In addition, on 2/24/06 the firm submitted
to FDA an NDA-Field Alert Report due to a complaint of a foreign
capsule of Cartia XT in a sealed bottle of Taztia XT. This event
is still under investigation.
Laboratory Phase I Investigations (At least 31 out of a
total of 99 Phase I investigations reviewed from May 2005-March
2006 were inadequate due to incomplete documentation, lack of
scientific evidence to support conclusions and/or invalidate original
results, or lack of adequate corrective/preventive actions. Some
examples include, but are not limited to:
- INV-06-0062 was conducted on 3/2/06 to investigate the dissolution
failure of Metformin HCl Extended-Release Tablets, 500 mg, Lot
# 571G0059, which showed results of 35% for Vessel #2 at 3 hrs.
(spec: [REDACTION]) in dissolution bath QC#0074.
The next time point dissolution result at 10hrs. was within specifications
for Vessel #2. The investigation documented that there was an
air bubble observed in line 2 at the end of the run that decreased
the flow rate for Vessel #2 to 3.8ml/min (spec: [REDACTION])
and concluded that it affected the results of the 3hr. time point
only. However, the investigation did not explain how the flow
rate only affected the dissolution result at the 3hr. time point
and not the subsequent time point at 10hrs. In addition, no preventive
or corrective actions were documented in the investigation report.
- INV 05-0492 was conducted on 12/22/05 to investigate the dissolution
failure of Metformin HCl Extended Release Tabs, 500mg, which showed
results of 15% in vessel #5 at 1hr. (spec: [REDACTION]).
The results were invalidated because the flow rate for that vessel
at the end of the run was found out of specifications.
The investigation lacked scientific justification to support how
the flow rate only affected the first time point at 1hr. and not
the subsequent time points at 3 & 10hrs.
- INV-05-0457 was conducted on 11/21/05 to investigate the dissolution
failure of Diltiazem HCl Extended-Release Caps, lot # F599F1189
which showed results of 8% in vessel #3 at 2hrs. (spec: [REDACTION]).
The data was invalidated because the flow rate for vessel #3 was
found out of specification at the end of the run but the investigation
lacked scientific evidence to explain how the flow rate only affected
the 2hr. time point and not the subsequent time points at 12,
18 & 24 hrs.
- INV-05-0489 was conducted on 12/16/05 to investigate the dissolution
failure of Diltiazem HCl Extended-release tablets 60mg, lot #63730,
Pan 6, which showed results of 27% for vessel #5 and 35% for vessel
#6 at 1 hr. time point (spec: [REDACTION]). It also showed
failing results of 9%, -1%, and -2% in vessels 4, 5, & 6,
respectively for the 2hr. time point (spec: [REDACTION]).
The flow rates for all vessels were confirmed to be within specifications.
Nevertheless, the dissolution data was invalidated without considering
other possible root causes, i.e. [REDACTION] malfunction.
Production TWR Investigations:
- On 3/6/06 while inspecting the production area, the batch production
record for [REDACTION] lot #66461 was reviewed. It documented
that during the preparation of the coating solution on 2/16/06,
foreign particles coming from the bulk [REDACTION] system
were observed and, as a result, the solution was discarded. On
3/7/06, the investigation report was requested at which time your
firm provided TWR #2280 dated 3/6/06 (date opened). According
to production personnel, at the time of this incident they were
advised by QA that no investigation was needed because the solution
was discarded and therefore there was no product quality impact.
However, the draft investigation documents that the pump on the
[REDACTION] system failed and this resulted in particles
being released from the pump into the [REDACTION] stream.
The determination of the impact to previous lots manufactured
using the same [REDACTION] system was not investigated
in a timely manner.
- TWR #2169, dated 10/13/05 (occurrence date), was discovered
on 1/25/06 and opened on 1/27/06 to document that during the processing
of the second half of part 2 of the [REDACTION] stage of
Lovastatin 60 mg, lot F630F1132 (60315), it was determined that
the product temperature probe was reading seven degrees higher
than actual which means that for 45 minutes of spray time the
product temperature was running between 16-18°C instead of
the specified range of [REDACTION]. The investigation report
documented that the temperature probe was adjusted on 10/12/05,
one day before the occurrence of this incident and that the most
probable cause for the product temperature probe reading 7°
higher was actually attributed to a calibration error; however,
the documentation for the calibration performed on 10/12/05 shows
that the temperature probe was reading 9 °C and 12 °C
low and was calibrated to the required parameters. The root cause
and the determination of the impact to previously manufactured
lots using the same temperature probe were not determined during
this investigation.
|
OBSERVATION 5 Written procedures for
cleaning and maintenance fail to include description in sufficient
detail of methods, equipment and materials used.
Specifically,
- Eight out of ten cleaning SOPs reviewed are not specific regarding
the washing method (scrub, sponge, cloth, rinse) the number of
rinses, or rinsing time or volume of the rinsing agent to be used
for the rinsing step: PD-0012, "Operating/Cleaning Procedure
for the [REDACTION]; PD-0018, "Operating and Cleaning
Procedure for the [REDACTION]; PD-0043, “Operating
and Cleaning Procedure for the [REDACTION]; PD-0124, "Operating
and Cleaning Procedure for the [REDACTION]"; PD-0182,
[REDACTION] Cleaning Procedure"; PD-0103, "Operation/Cleaning
Procedure for the [REDACTION]; PD-0108, "Operation
and Cleaning Procedure for the [REDACTION] with [REDACTION]
and [REDACTION]; and PD-0152, "Operation/Cleaning
Procedure for [REDACTION]. In addition, the cleaning SOPs
reviewed lack specificity in the following sections:
- Section 7.3.2.3.7 of SOP PD-0012 indicates: "If necessary,
brush the interiors and exteriors and walls with [REDACTION]
detergent." When asked when brushing is necessary, one
operator [REDACTION] said that he "thinks"
it is always necessary to brush while another operator [REDACTION]
said that it should be done for every major cleaning.
- Several sections of SOP PD-0012 indicate spraying or rinsing
parts with [REDACTION] (e.g., 7.3.2.3.5.1, 7.3.2.3.8.3,
7.3.2.3.9, 7.3.2.5.3, 7.3.2.6.5, and 7.3.2.6.6). Operator [REDACTION]
said that he can either spray the part with [REDACTION]
and wipe it with a cloth a "little bit" damp with
[REDACTION] or just wipe it with the [REDACTION]
damp cloth.
- The current version of SOP PD-0124 (version 4 dated 6/23/05)
is missing a rinse step; after washing parts with the detergent
solution, step 8.3.20 indicates wiping with [REDACTION].
According to the firm's officials, this step was inadvertently
left out when the current version was written.
- Several investigations related to cleaning swab failures that
included product, detergent or unknown residues stated that the
root cause was the failure to thoroughly rinse or clean equipment
or that the cleaning procedures were not specific enough. However,
none of the SOPs involved in these investigations have been revised
to make the rinsing and/or cleaning instructions more specific.
For instance:
- TWR 1545 was opened on 6/17/05 due to 3 swab samples ([REDACTION])
that failed the limit for [REDACTION] residues. The SOPs
that describe the cleaning procedure for the [REDACTION]
include SOP PD-0012, "Operating/Cleaning Procedure for
the [REDACTION]; SOP PD--0115, "Operating and Cleaning
Procedure for the [REDACTION] with [REDACTION];
and SOP PD-0090, "Operation/Cleaning Procedure for [REDACTION].
The TWR indicates that none of the rinse steps in the SOPs lists
a length of time or volume of rinsing agent for the rinse, and
that the SOPs do not specify the [REDACTION] concentration
for the rinse steps. According to the TWR, the interviews of
the manufacturing operators disclosed variations of the procedure
in respect to the number of rinses and rinsing agent use and/or
order, and rinsing times (between 5 minutes to one hour). The
swab analysis forms showed inconsistency in the cleaning vehicle
used; some forms indicated [REDACTION], whereas other
forms showed [REDACTION] as the cleaning vehicle. However,
the SOPs have not been revised to make the cleaning and rinsing
procedures more specific.
- The interim report for TWR 1555 indicates that no specific
rinse times or volumes are defined in SOP PD-0005 effective
3/9/05; this SOP had not been revised at the time of the inspection.
- TWR 2194 was opened on 2/3/06 to investigate a swab failure
for Diltiazem HCl ER Capsules. The TWR indicates that "one
possible root cause for the cleaning validation failure would
be that the operator did not clean the equipment properly per
SOP, although this could not be proven". The TWR also indicates
that, "in light of the cleaning validation failure, validation
personnel reviewed the cleaning procedure, and determined that
no changes were warranted at this time." However, the cleaning
procedure (PD-0018, "Operating and Cleaning Procedure for
the [REDACTION] is not specific regarding how parts should
be washed (scrubbed with brush, sponge, cloth, or just rinsed)
and rinsed (time or volume of rinsing agent). In addition, the
procedure indicates that parts should be rinsed with [REDACTION],
but the firm does not use any [REDACTION] to rinse equipment.
- TWR 2259 was opened on 2/24/06 for detergent swab failures
on the [REDACTION]. The TWR states that "...considering
the high results, it is most likely that the rinsing of the
equipment was not thorough enough. Considering this most possible
cause for the obtained results, emphasis on proper rinsing for
equipment after any major cleaning will be discussed with the
operators, as per PD-0043." However, neither the version
that was in use at the time of the cleaning failure (version
2.0, effective 11/13/02) nor the current version (version 3.0,
effective 2/24/06) of PD-0063, “Operating and Cleaning
Procedure for the [REDACTION], (this is the correct SOP
number, not PD-0043) are specific regarding how equipment parts
should be washed (with brush, sponge, cloth, etc.) or regarding
rinsing times or volume.
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OBSERVATION 6
Written procedures are not followed for the cleaning and maintenance
of equipment, including utensils, used in the manufacture, processing,
packing or holding of a drug product.
Specifically,
- The firm's Equipment Cleaning Validation Policy, TSP-0001, indicates
that [REDACTION] or other [REDACTION] used for final
rinse shall be the same quality, or better, as that used for manufacturing
or by regulation". According to this policy, [REDACTION]
should be used for the final rinse of the equipment because it
is the quality of [REDACTION] used for manufacturing. In
addition, SOP PD-0018 indicates that [REDACTION] should
be used for the final rinse of equipment. A tour of the manufacturing
area disclosed the presence of [REDACTION] points of use;
however, an interview with the Manufacturing Director [REDACTION]
and an operator [REDACTION] disclosed that [REDACTION]
is never used to rinse equipment. The incoming city water is not
treated and, although it is sampled once a week, the test performed
(microbial) is for information only.
- Operator [REDACTION] said that he executes the cleaning
procedures by memory based on his experience; he said that he
only reads the SOP when there are changes.
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OBSERVATION 7
Equipment and utensils are not cleaned at appropriate intervals
to prevent contamination that would alter the safety, identity,
strength, quality or purity of the drug product.
Specifically,
- Filters used in [REDACTION] and [REDACTION] are
cleaned using [REDACTION] but are not included in the cleaning
validation studies to confirm that the rinsing procedures are
effective in removing [REDACTION] residues.
- Report number QCR-05-051-MTH, "Analytical Test Method Report
for the Determination of [REDACTION] on [REDACTION]
Surfaces", shows that the recoveries obtained by Analyst
[REDACTION] in [REDACTION] and [REDACTION]
plates were significantly lower than the recoveries of the other
two analysts. Since the test would not meet acceptance criteria
using the recovery data obtained by Analyst [REDACTION]
in these two surfaces, the firm changed the analyst and calculated
the correction factor for residues using the data from the fourth
analyst. No investigation of Analyst [REDACTION] swabbing
technique was conducted to determine the reason of her low recoveries
and no corrective actions were implemented to make sure her swabbing
technique effectively recovers residues from equipment. However,
Analyst [REDACTION] is still swabbing equipment for cleaning
validation and verification purposes. The firm does not have any
procedure to make sure that the analysts' swabbing techniques
are adequate before the analysts are allowed to perform swabbing
for validation and verification studies.
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OBSERVATION 8
The accuracy, sensitivity, specificity, and reproducibility of
test methods have not been established and documented.
Specifically, your firm failed to perform an adequate method validation
for Taztia XT Capsules. The current approved analytical procedure
for the analysis of [REDACTION] for drug release (STM 696, 697,
698, 699, 700) requires the use of [REDACTION] as the dissolution
media. The method validation for this product was performed using
[REDACTION] as the dissolution media.
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OBSERVATION 9
Written records of investigations into unexplained discrepancies
do not include the conclusions and follow-up.
Specifically,
- The cleaning swab failure investigations reported under TWRs
1545, 1555, 2194, 2259 disclosed that the root cause was the failure
to thoroughly rinse or clean equipment or that the cleaning procedures
were not specific enough. The QC Unit failed to follow up on these
findings and none of the SOPs involved in these investigations
have been revised to make the rinsing and/or cleaning instructions
more specific.
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* DATES OF INSPECTION
03/06/2006(Mon), 03/07/2006(Tue), 03/08/2006(Wed), 03/09/2006(Thu),
03/10/2006(Fri), 03/13/2006(Mon), 03/14/2006(Tue), 03/15/2006(Wed),
03/16/2006(Thu), 03/17/2006(Fri), 03/20/2006(Mon), 03/21/2006(Tue),
03/22/2006(Wed), 03/23/2006(Thu), 03/24/2006(Fri), 03/27/2006(Mon),
03/28/2006(Tue), 03/29/2006(Wed), 03/30/2006(Thu), 04/17/2006(Mon),
04/18/2006(Tue)
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FDA EMPLOYEE'S NAME, TITLE, AND SIGNATURE:
[signature]
LCDR Ileana Barreto-Pettit, Investigator
[signature]
Jennifer M. Menendez, Investigator
[signature of Barreto-Pettit
with handwritten “for” before typed name of Investigator
Rodriguez]
Rebeca Rodriguez, Investigator
[signature of
Barreto-Pettit with handwritten “for” before typed name
of Investigator Rodriguez]
Jennifer D. Hollstrom, Analyst
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SEE
REVERSE
OF THIS
PAGE |
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DATE
ISSUED 04/18/2006 |
FORM FDA 483 (7/00) PREVIOUS EDITION OBSOLETE
INSPECTIONAL OBSERVATIONS
Reverse Text on Page: The observations of objectional conditions and practices listed
on the front of this form are reported:
- Pursuant to Section 704(b) of the Federal Food, Drug and
Cosmetic Act, or
- To assist firms inspected in complying with the Acts and
regulations enforced by the Food and Drug Administration.
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Section 704(b) of the Federal Food, Drug, and Cosmetic
Act (21 USC374(b)) provides: “Upon
completion of any such inspection of a factory, warehouse, consulting laboratory, or other
establishment, and prior to leaving the premises, the officer or employee making the
inspection shall give to the owner, operator, or agent in charge a report in writing
setting forth any conditions or practices observed by him which, in his judgement,
indicate that any food, drug, device, cosmetic in such establishment (1) consists in whole
or in part of any filthy, putrid, or decomposed substance or (2) has been prepared,
packed, or held under insanitary conditions whereby it may have become contaminated with
filth, or whereby it may have been rendered injurious to health. A copy of such report
shall be sent promptly to the Secretary.” |
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