Documenti di Didattica
Documenti di Professioni
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For instance, 30 vials of injectable that fail USP weight variation standards
averaged in with 60 passing vials cannot support batch release. Also, failing
results must be incalidated according to a firm's own release limits, not
prevailing USP limits. The cumulative average results of all retested samples
must meet a firm's internal standards.
A Squibb representative told WDL that all matters raised in the warning letter
were "addressed and resolved quickly". She said that the particular problems
in question focussed on "paperwork" and that product quality was never in
question.
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Drug labs are getting low marks from inspectors lately for errors ranging from
failure to follow through on consumer complaints to failure to conduct certain
tests often enough. A thorough investigatory follow - up is in order when
customers complain about a product. The single exception to this general
maxim is when a complaint centers on an isolated incident, for instance, a
problem involving the presence of particulates. In all other cases, the
following procedures should not be overlooked :
1. Evaluation of retention samples.
2. Review of other batches of the same drug products.
3. Review of other drugs that may have been associated with the failure.
4. Review of production and control records, such as environmental
monitoring.
Though the agency stresses the need for written procedures, existence of
such for production tests like stability testing does not guarantee that a
facility will pass muster with inspectors. For example, firms can et a citation
tests are not performed with sufficient frequency, even if a company follows
its written procedures. It is not enough to test for stability only at release and
again six months after a product's expiration date, FDAers said. Inspectors
want to see stability tests done at release, at a drug's expiration date and
annually thereafter.
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Firms also are expected to continually re - evaluate their procedures. For
instance, at least annually, quality control should evaluate production, control
and distribution records to assess the need for changes to product
specifications or control procedures.
Connaught was cited for such GMP deviations, among others, in a Nov. 20
warning letter regarding its Swift water, Penn., facility. Commenting on FDA's
requirement for specific action limits for visual inspection of filled containers,
a Connaught spokesman told WDL such limits are "based on experience".
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Quality control must confirm three threshold points : that the solution tested
in both labs was identical ; that both sued the correct method ; and that
neither made any technical errors. Certain variables should be reviewed to
determine which result should be considered reliable. These include the
following :
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Release approval must be based on supporting data, not log book review. If a
failed lot gets released, failure investigation is key. If a lot fails in uniformity,
the cause for any unusual "peaks" in active ingredients must be identified and
toxicity determined. Any "strange substances" sources must be found.
Searle, of San Juan, Puerto Rico was warned by FDA regarding such
problems but could not be reached for comment.
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FDA rules do not require that sterile drug makers keep on hand twice the
amount of reserve samples required to perform sterility and pyrogen testing.
However, they do have to maintain a "sufficient quantity" of samples to
perform one such test upon demand. And for many firms, that likely will
mean maintaining twice the supplies necessary for other tests, said a
compliance officer with FDA's Marketing and Product Quality Division.
Sample size for sterile drugs is limited to an amount that can accommodate a
single sterility and pyrogen test, for several reasons. First, once a container /
closure for a sterile drug is validated, product sterility can be expected to
remain stable over time. Second, maintaining twice the sample size needed to
run sterility tests in addition to samples for other tests, often is not justified
by benefits of keeping the extra units.
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Moreover, sterility testing, by its very nature, does not yield iron - clad results,
the FDAer told WDL. For example, such tests are not likely to detect low
levels of contaminated units within a given lot. Therefore, when sterility
failure is suspected for a distributed lot, reserve sample testing is not as
useful in confirming the problem as is a thorough investigation of that lot's
production and control records. A related inspection area that is increasingly
dogging firms both here and overseas is aseptic processing, including anti -
contamination measures for "critical surfaces".
The source stressed that it is every bit as important for firms to validate
sterilization of all processes or surfaces that contact sterile drugs or
container / closures, as it must validate processes for the drug itself.
Microbiological monitoring of surfaces should yield zero colony forming
units.
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Drug makers must keep all drugs, not only those purporting to be sterile, free
of microbes. The term "non - sterile drug" is merely a term of art when it
comes to preventing intrusion by what the agency calls "objectionable micro
organisms", an FDAer stressed.
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Adherence to written procedures designed to eradicate microbial
contamination of a drug is not peculiar to sterile drugs. But less clear to
many drug makers is exactly which microorganisms the agency considers
"objectionable". The term's primary meaning, the FDAer explained, is
decidedly simple " organisms that can reduce drug safety.
The above factors will be most clear for new drugs, for which they likely will
have been addressed within the review process and reduced to end - product
specifications. The favored method for keeping dangerous microbes in check
is setting production time limits, the FDAer told WDL. He emphasized that
drug companies should set such limits for "completion of each phase of
production" for all products made.
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One particular contamination "hot spot",according to the source, is where a
bulk topical or liquid drug must be held for several months pending fill. In
such cases, firms should set a "holding time limit" to discourage microbial
build - up.
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Within those major categories, there are various bases to cover, depending
on where the contaminant is discovered, said an FDA compliance specialist.
For instance, in the case of contaminated raw materials, drug firm
investigators should focus on foreign matter that might have come from the
supplier, such as pencils or pieces of metal.
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Investigation of raw material storage areas should include a check of the
outsides of storage containers, bags and skids. Finally, a raw material
investigation must cover sampling areas and sampling scoops, as well as
processing areas where weighing, screening and transfer pneumatic systems
are found.
The number of batches set aside for annual review must tell the full story in
terms of any discrepancies, recalls or other problems associated with a given
drug. FDA rules call for annual batch review to assess the need for
specification or process change.
But the question of how many batches are enough to satisfy the
³representative number of batches´ part of the rule has caused confusion
among drug companies and agency inspectors alike. Firms have a better
chance of meeting regulatory expectations if they strive to review batch
groups large enough to ³exhibit the varying manufacturing experiences´ of a
given drug, an FDAer said. For instance, batches earmarked for review
should represent any and all of the following events that occurred in
production :
For example, at an inspection in Shirley, N.Y, FDAers said that company did
not document validation of seven unnamed drugs. That failure, along with
lack of written procedures for the retrospective approach used to validate
older drug, were among charges the agency made to the company.
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FDA's regulation of drug firms' software, the scope of that regulation and the
level of validation for software changes remain nebulous and hotly debated
issues. However, uncertainty in this nascent area is not holding FDA back
from issuing warning letters from practices it dislikes. In fact, compliance
experts at the agency have indicated that inspector observations of common
problems may be the basis for future software regulation.
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Among issues now receiving inspector scrutiny are controls to ensure the
integrity of all calculated data generated by lab software. Quality Control
should review all laboratory computer systems to check for lapses, such as :
The source also warned firms not to confuse the use of calibration tags with a
GMP requirement that major equipment be identified with a distinctive
number or code recorded in batch records. The latter is intended to aid in
documenting which pieces of equipment were used to make which drug
batches. Finally, the FDAer said a firm should be able to justify its decision
not to include a piece of equipment in its calibration / maintenance program.
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Residue limits for any fumigating agents used in production areas must be
set, as well. Inspectors continue to insist on separate or well - defined areas
to prevent contamination during aseptic processing or other equally effective
anti - contaminant control systems. For example, the following practices will
likely draw a warning letter.
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3. There were no particle size specifications for the drug substance nor for the
granulation after milling.
4. The firm has not adequately validated the manufacturing process for their
««« tablets. For example,
! According to the coating validation logs for both validation batches, actual
coating parameters such as spray rate, spray pressure, and temperature
differed from the parameters indicated in the current master coating
formula used to manufacture these batches.
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! Samples for validation of the compression operation were analysed for
dissolution and content uniformity from a single sample taken only at the
beginning of the compression run.
6. The firm has not adequately validated the manufacturing process for their
««« tablets. For example,
! According to the coating validation logs for both validation batches, actual
coating parameters such as spray rate, spray pressure, and temperature
differed from the parameters indicated in the current master coating
formula used to manufacture these batches.
11. «.the procedures to be followed when handling light sensitive material are
not specified in the production formulation for ««
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12. ««before approval, the manufacturing directions for the compression blend
process under NDA supplement «.were changed significantly, and therefore
result in the pivotal/bio-batches. The blending steps used in the commercial
scale-up/validation batches differ from that used in NDA
13. NDA «««. No specific terms and / or instructions are stated in the written
procedures for different manufacturing steps of ««««.. For example, it is
not specified in the Master Batch Record or in the batch production records
the order in which drug ingredients are added. The ««««. Monograph
does not specify those critical process parameters such as «««« time,
initial equipment settling etc. Also the sampling size and sampling frequency
are not specified.
14. The manufacturing process for «««. tablets is not validated in that :
15. Review of the batch records for «« tablets disclosed the following
deficiencies for the granulation phase :
! The batch records do not specify how the granulating solution was added.
! The records do not specify whether the process reached the granulation
endpoint.
! There is no temperature range for the gelatin solution added during the
granulation process.
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17. In the film coating area we could not verify that each of the guns in the pans
are spraying the correct amount and pattern of film coating solutions.
18. In regard to the calibration of the sprayers for the controlled film coating
equipment (the coating pans), there is no documentation available to show
that the current method of using «« and not the actual processing film
coating solutions, for calibrations, will give accurate results for all types of
coating solutions used during manufacturing. The purpose of this calibration
is to assure that the spray rates of the different film coating solutions are
accurate and the reported total amounts sprayed are accurate.
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19. A report, dated ««,stated: "when two coating pans were tested using the
same target specification range for total amount of coating solution sprayed ,
there was a significant difference in the amount of coating solution applied
per an which also reflected in the average weight gain per tablet." Personnel
stated, corrective action to this observation would involve calibrating the
sprayer with the actual processing film coating solutions, which is not
currently being done.
20. Personnel stated the frequency that the firm coating operation is stopped for
cleaning or replacement of the nozzles due to spray problems during batch
production is not known, since it is not documented.
22. The first three validation batches used a sample size of «« for uniformity of
blend analysis. The use of 1 to 2 gram sample size does not approximate the
120 mg tablet weight of this product. These samples did not reveal the
subpotency problem in the uniformity of the granulation at the end of the run
in the ribbon blender scrapings which was identified in the second set of
validation batches.
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23. The validation data for the twin shell V blender used to blend active ingredient
blends did not include the rotational speed at which the blender was run
during the studies.
24. The visual inspection of stability and retention samples for color is subjective.
To date, no standards are used in the visual examination for color.
25. «..ANDA field alerts are not routinely filed concerning any significant
chemical, physical or other changes, deterioration, or failure to meet
specifications in distributed drug product. For example, «.capsules, failed
dissolution testing at the ninth month stability station, a field alert was never
filed.
26. Available records indicate that the total blend volumes, based on blend
densities, had not been calculated and compared to the working capacity of
the blender, until the current inspection. Bulk and tap densities on the (initial)
blend were not measured, and samples weren't obtained and/or saved. When
bulk and tap densities were measured on a final blend sample during this
inspection, and calculations performed, the data indicated that the blend
volumes is approximately «.. of the blender's working capacity, per site
change NDA supplement, your firm uses a different type of blender than the
innovator's.
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27. Blending validation studies for «.tablets appear deficient:
28. Before approval, the manufacturing directions for the compression blend
process under NDA Supplement «««. were changed significantly, and
therefore result in the pivotal / bio - batch not to be entirely
representative of the current product / process. The blending steps used in
the commercial scale - up / validation batches differs from that used in
NDA pilot / bio - batches. Concerns with blend uniformity variability
observed with development and pilot batches gave way to a "design of
experiment" that resulted in the said pre - mix and mixing parameter changes.
The changes in the manufacturing directions were not included in an
addendum to this NDA supplement.
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29. There is insufficient data to provide a high degree of assurance that the blend
process is under control and fully validated. After encountering notable
variability in blend uniformity test results during development and pilot
batches, an experimental design study was done to identify factors
contributing to this variability. The conclusions drawn from that study were
not appropriately transferred to the scale - up / validation batches and
justified. The rational used for assigning parameters was contradictory.
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1. The validation studies performed on the fluid bed drying process for «««.
granulation did not include the equipment settings used on the validation
batches. There is no assurance that the settings used on current batches are
identical to those used on the validation batches.
2. Manufacturing process validation protocols / SOP are inadequate, they :
5. The firm has not adequately validated the manufacturing process for their
««« tablets. For example,
! According to the coating validation logs for both validation batches, actual
coating parameters such as spray rate, spray pressure, and temperature
differed from the parameters indicated in the current master coating
formula used to manufacture these batches.
! Samples for validation of the compression operation were analysed for
dissolution and content uniformity from a single sample taken only at the
beginning of the compression run.
6. The tablet compression process has not been validated. The tablet
compression study determining the hardness, thickness and friability of the
product was done at «.tablets per minute. The commercial production rate is
««««« tablets per minute.
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7. The problem of a foreign capsule being found in this batch occurred during
inspection. Inspection records for this batch do not document that the batch
was reinspected after finding the foreign capsule.
9. The Batch Manufacturing Record (BMR) for «« tablets, shows that the time
between removal of the ³dried granulation´ from the drying oven until the
next processing step was from «««««.. until ««««. (13 days). The SOP
in effect at that time, titled : ³Manufacturing Phase Time Limits´ defined the
maximum time limits between Granulation and Blending to be ««««..
According to the procedure, if the time limits are ³exceeded, the batch must
be evaluated by Quality Assurance before proceeding to the next step in the
process´. The above referenced BMR contains no documentation that the
batch was evaluated subsequent to the extended storage time.
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10. Capsule validation batch ««« failed mix homogeneity and content
uniformity requirements and was rejected. No assignable cause could be
identified. Drum samples were performed on three additional lots. Two lots
exhibited values above acceptable criteria. Additional samples, taken from
the same locations were assayed in duplicate resulting in values of
«««««. The validation effort was accepted without investigation or
explanation of the out - of ± specification results.
11. Investigations are not initiated when capsule batches fail in - process testing
requirements for weight variation. The impact of these failures on similar
batches is not evaluated. For example, batch ««««.., was sorted prior to
packaging as an underweight capsule (less than 50%) was found during
visual inspection. The sorting process rejected over 3,400 capsules that were
less than 90 % filled. No investigation was conducted to determine the cause
of the underweight capsules.
12. The method validation for the manufacturing process of topical products is
lacking in that in - process sampling of products is not performed in a manner
to verify that there are no ³dead spots´ in the kettles used for manufacturing.
Three of the twelve samples are taken directly from the tank while the
remaining nine are taken as product is removed from the kettle from the
bottom orifice of the kettle.
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13. The mixing speeds indicated in the manufacturing records do no coincide
with the firm¶s ³Kettle Mixing Speed Guidelines´. Mixing speeds in the batch
records are specified as ³slow, medium, and medium - high´. The kettles
monitor mixing speeds in RPMs.
14. Review of the batch records for «« tablets disclosed the following
deficiencies for the granulation phase :
! The batch records do not specify how the granulating solution was added.
! The records do not specify whether the process reached the granulation
endpoint.
! There is no temperature range for the gelatin solution added during the
granulation process.
15. Failure to follow Change Control Procedure for ««««. Systems and
Software Version Control, to provide adequate revision controls over «««..
programs, and the various source codes used in manufacturing process
control systems, in that :
! Several software changes were reportedly made but not properly
documented. For example, several changes to status prompt messages,
and changes to pan speed and spray rate deviation settings.
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! The vendor version installed was designated «««.., yet after
modifications resulting from installation / operation qualification no new
revision number was given.
16. Failure to conduct periodic reviews of the various computer control systems
for performance, changes and configuration control in deviation of ««««
per SOP. This SOP requires documented annual reviews of all system for
changes and the need for requalification. Yet, according to personnel
interviewed, it was totally overlooked and never put into practice.
19. «.the procedures to be followed when handling light sensitive material are
not specified in the production formulation for«.
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20. «. SOP « was not followed by the Compression department supervisor for
tablet press selection in that the tablet press validation guide was not
reviewed in order to ³verify that the type of compression process of the
product to be compressed has been validated on the tablet press selected´.
22. ««.Lot ««, filling "Down time" log states : "no «.H2O" and describes that
filling was subsequently suspended for more than 7 hours . No
documentation was maintained to explain this event, the management of the
fill line during the event , or impact of the event on the product being filled.
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23. There are no SOP's or records to cover reworking of packaged tablets and
capsules. For example :
! There are no SOP's to cover the reuse of inner seals and the procedures to
use to assure they can be reused / resealed properly when checking for
missing inserts in product.
24. Splices in roll labels are not checked either at the time of receipt or use to
assure that the labels before and after the splices are the same. In addition,
receiving procedures for incoming labels require that only one label per
receiving lot be checked for "Incorrect, illegible, missing copy, UPC or
design".
25. Labeled cartons are not examined for identity and conformity to the labelling
specified in the master or batch production records at the time the cartons are
issued for a finished product batch.
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26. There is no physical separation between the labeling lines in the off - line
labeling room. The spatial separation is not clearly defined. The staging
areas for each line are not identified.
27. There was no validation for the capping machine used to apply plastic caps to
the bottles containing tablets and capsules. No torque specifications have
been developed for the caps and seals used by firm on its products.
28. There was a lack of validation and specifications for the speed of the fan and
the heat of the heat gun used to "activate" the inner seals on caps used in the
packaging of ««««.. capsules.
29. Batch Production and Control records do not include complete information
relating to a batch. For instance, in - process laboratory results (control
records) such as individual values for weights (as well as hardness,
thickness, etc.) are not maintained with the batch record in the case of both
tablet and capsule products. In addition, while samples are taken at the
beginning, middle and end of production plus generally one or more random
tests, none of these random test results are included in batch records (neither
in summary sheet reports nor as individual values).
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30. Ineffective training of production assembly personnel, the actual practices of
hairnetting, gowning, hand washing, glove usage and shoe covering by
production assembly operators was inconsistent from work area to work area
and also between operators within the same work area.
31. The manufacturing process for «««.. tablets has not been validated with
respect to critical control points. A process change, to a constant increased
tablet weight, was made as the previous manufacturing process failed to
consistently meet pre - determined assay release specifications. There is a
lack of data to support this process change, as investigations into previous
failing batches lack an attributable cause.
34. Your firm's investigation into the "incorrect capsule length" as presented in
the "Memo To : Batch Manufacturing Record", dated «««« is incomplete
and inaccurate. There is no reference as to when or how the problem of the
unlocked capsules was determined. The memorandum of investigation also
does not document the fact that three different ««««. encapsulators were
used to "re-close" the batch
35. Firm has no written procedures to identify all instruments used during the
manufacturing process. During the manufacturing process portable
instruments that require calibration or certification are used at different
stages and there is no traceability of the instrument used to the batch.
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36. A large number of the production personnel could not read or understand
English, yet they were following SOP's and signing batch records that were
written in English.
37. Although you maintain a calibration log of the «««« electronic label
counter, it is inadequate in that the reference control roll that you use
consists of a known quantity of "stranger" labels ; however, the log does not
show the accuracy of the instrument by comparing the quantity of label read
by the instrument against the known quantity, and also, it does not show
whether the instrument detected the "stranger" label. Furthermore, it does
not contain an acceptance criteria. For example, a label operator stated that
when a low quantity is read by the instrument, the test is repeated until a
satisfactory reading is obtained.
38. No formally written and approved SOPs mandate the evaluation of individual
in - process hardness values or follow - up of out - of - specification results.
In addition, hardness testing is not performed frequently enough to ensure
adequate in - process control. While QA tests 10 tablets for hardness one
every two hours (at minimum) and apparently also reviews individual results,
production evaluates only an average of ten results hourly.
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39. Failure to count mylar labels received from the vendor or confirm vendor
counts or assure the count meets on receipt specifications. For example,
label specifications for «««««.. are "label count per roll cannot exceed
0.5% discrepancy" from vendor count. There is no documentation that partial
rolls of labels are counted by a vendor.
41. Two Raw Material Inventory Cards for ««««.. were not accurate. These
inventories were not closed out in a timely manner which resulted in a delay
to the start of an investigation into a ««««« discrepancy for lot ««««..
42. A reject level has not been established beyond which a lot of product would
not be released. It is the firm's policy to release lots of drug product,
irrespective of the reject rate, as long as the "defect" may be inspected for
and based on this inspection "acceptable" units are released. The following
lots of product were released although inspection reports recorded the cited
reject levels : 25.54%, 18.11%, 15.70%, 11.25% and 39.37%.
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43. The manufacturing process for «««. tablets is not validated in that :
44. Batch records are formatted so that operators record a single date for the wet
granulation mixing and drying steps, despite this process taking place over a
two day period.
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45. There are no records showing bottles being blown out before filling.
46. Although access to batch formula screen editing is assigned based on user
profile levels, these are hard coded by individual parameter and were not fully
verified during validation testing. There is no assurance these were all coded
correctly. For instance, during a particular test of «««.. an error was found
which permitted Level 2 (operators) access to edit formulas on screen. No
record was made available showing correction and re-verification of the
loaded software for this.
47. The validation of the (film coating) process control computer software
consisted of limited functional testing, with no formal code structure testing,
such as code coverage analysis and / or systematic unit testing made
available. These functional tests failed to thoroughly, rigorously and
consistently challenge the system / software in that sufficient valid testing of
all input / output values, data structure, process variables, and control flow
logic was not done. No complete and meaningful testing techniques
(boundary value analysis, combination inputs, special case analysis, etc.)
were employed for critical process parameter and / or control variables.
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48. The operational qualification of the «««. system were similarly inadequate
in that it consisted of limited functional testing, which failed to thoroughly
and rigorously challenge the system and address worst case conditions as
follows :
! Test cases did not check all reasonable «««.. conditions that can cause
errors.
! Boundary value analysis was not done at values just above and below the
process parameters ranges, and did not include special condition values
in all cases.
! The test protocol and test cases were not based on performance
specification and crossed referenced to a formal requirement specification
document.
! Test case failure or deviations were not adequately explained and followed
up with corrective actions, retesting, and / or reassessment of equipment
performance specifications.
! Test cases were not realistically based on the performance specifications
of each piece of equipment.
49. Granulation room ««. has many high (30 feet) flat surfaces that are not
cleanable between products to prevent cross - examination. The walls, ceiling
and high ledges are cleaned only «««.. times per year.
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50. Blending studies did not evaluate particle distribution throughout the blend.
A composite sample from one lot was used for particle distribution studies.
51. The Tableting Portion of the Batch Production Record does not document the
following :
! The actual weights of samples of finished tablets collected as the process
validation samples.
! That the process validation samples were collected with the tableting
press operating at parameters which yielded tablets at high and low
hardness.
! The actual weights of the full and partial containers of finished tablets.
! The actual weight of accountable loss at the end of the tableting operation.
The theoretical tablet weight was used to calculate the yield for the
compression stage.
52. The Investigation Report concerning the broken and dented capsules does
not :
1. Include any investigation into the two lots of empty capsules that were
used to encapsulate this batch.
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2. Address any corrective action taken or planned to prevent a recurrence.
3. The potential for this problem effecting other batches or products.
54. In the film coating area we could not verify that each of the guns in the pans
are spraying the correct amount and pattern of film coating solutions.
55. According to personnel, film coating pan gauges are accurate for the
measurement of «««« This could not be verified for all coating pan gauges
used to manufacture products because there is no testing performed or
documentation to show the accuracy of these gauges.
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56. In regard to the calibration of the sprayers for the controlled film coating
equipment (the coating pans), there is no documentation available to show
that the current method of using ««« and not the actual processing film
coating solutions, for calibration, will give accurate results for all types of
coating solutions used during manufacturing. The purpose of this calibration
is to assure that the spray rates of the different film coating solutions are
accurate and the reported total amounts sprayed are accurate.
57. A report, dated ««««, stated : "when two coating pans were tested using
the same target specification range for total amount of coating solution
sprayed, there was a significant difference in the amount of coating solution
applied per pan which was also reflected in the average weight gain per
tablet". Personnel stated, corrective action to this observation would involve
calibrating the sprayer with the actual processing film coating solutions,
which is not currently being done.
58. Personnel stated the frequency that the film coating operation is stopped for
cleaning or replacement of the nozzles due to spray problems during batch
production is not known, since it is not documented.
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59. According to personnel and what we observed during a walk through in the
manufacturing area ; personnel perform a 100% visual inspection. Batch
production records do not contain documentation showing that this 100%
inspection is being performed. The only visual inspection sampling
documented on the batch production records are the results of sample sizes.
60. There is no time limit restriction specified in the CIP cleaning procedures for
Liquid Manufacturing and Storage Tanks to assure that the procedure will
effectively remove product residues.
61. The multiple computer systems which influence production are not validated.
These computers control among other things the disposition (quarantine,
release, reject) of all raw materials, weighing of all raw materials to master
record specifications and tolerances, printing of labels for all raw materials
for each batch, calculating yields at various stages of production, and printing
various portions of batch records for each lot.
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62. The first three validation batches used a sample size of «««.. for uniformity
of blend analysis. The use of 1 to 2 gram sample size does not approximate
the 120 mg. Tablet weight of this product. These samples did not reveal the
sub-potency problem in the uniformity of the granulation at the end of the run
in the ribbon blender scrapings which was identified in the second set of
validation batches.
63. The validation blend uniformity test results for batch «««. Also documented
a problem with sub-potency at the end of the run which initiated a procedure
to discard the tailings from the blender for the other two validation batches.
However, the blender tailings were included in the granulation for batch
««««. Which was packaged and commercially distributed.
68. Raw materials are stored in a "high - bay pallet" warehouse in building ««..
a. The tablet press cleaning procedure states that isopropyl alcohol should
be used to wipe down the entire machine and that a suitable cleaning
agent should be used to flush / clean the punch chambers. The grade of
alcohol, cleaning agent, and method of wiping is not specified.
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b. The Cleaning Procedure states that the cleaning solutions are prepared
according to their directions. Different directions are found on the product
labels depending on disinfection level required.
73. The cleaning procedure for the «««.. tablet press was not found in the
equipment use folder / log adjacent to the press. There is no explanation as
to why this procedure was not available and no assurance that the press was
adequately cleaned during the time period when the cleaning procedure was
not available.
74. The computer system used for logging and tracking incoming raw materials in
the shipping / receiving area lacks adequate security measures to prevent
unauthorized changes to raw materials records.
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75. No documentation exists for review and approval for use of equipment used
in the processing of «««« tablets to insure that the equipment is operating
within established limits and tolerances. e.g., tablet press, coating pan,
oscillator, mill equipment.
76. Failure to evaluate and validate the impact on the final blend that the tote bin
conveyer system has in terms of homogeneity. After blending, the bins are
transported to the «««.. floor and attached to a duct - shoot fixture to
convey the blended material to the compression rooms. These fixtures have
motorized systems that (vibrate) the bins every ««. minutes to aid in
(sending) the blend down to the compression machine hopper. There is no
documented study that measures the effect (or non - effect) this has or if it
regresses or improves blend uniformity.
77. Environmental conditions, i.e. temperature, humidity, that could affect the
processing of tablets were not assessed during production / validation runs
for «««««. batches. No monitoring of room conditions took place during
production of these batches.
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78. One of the drying ovens has a 3 x 10 tray configuration and the other a 2 x 10
tray configuration. Samples are pulled from one top / middle / bottom tray
and assayed for dryness. There has been no testing or validation to
determine if there is a variance in drying through out these ovens.
79. The validation data for the twin shell V blender used to blend active ingredient
blends did not include the rotational speed at which the blender was run
during the studies.
80. During validation of the twin shell V blender the sampling procedure was not
specified.
81. Despite considerable experience with blend uniformity problems in
development and pilot batches, lesser testing and monitoring controls were
established for the scale - up / validation batches. For example, no blend
uniformity testing at the pre - mix step, no additional blend distribution
testing, and the same number of tote bin sampling points were taken. From a
practical viewpoint, taking into account the batch size increased from
development to scale - up, the testing and sampling is insufficient for
validation purposes. Five sample points were taken in both pilot and
development batches, which used ««««« bin size. Meanwhile, in the
larger bin used in the scale - up batches, five sample points (top, middle and
bottom) were again taken.
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82. In spite of the experimental effort, one of the three blend validation batches
failed blend uniformity acceptance criteria, and the investigation did not
provide conclusive scientific proof of the assumed most probable cause. The
results of two of the five blend samples (the two middle points) were out - of -
specification in individual point average (average of replicate injections).
These original results were confirmed in a series of tests, which included
reinjecting the same sample vial, re-pipeting, and re-centrifuging of the stock
solution. Also, an inconclusive study was done to reportedly analyze
variability of replicate sample, so two additional samples from each sample
point were retested. That study, although it did show some variability of
replicates, also showed low overall results. More importantly, it confirmed
the two middle sample points were at the lowest range. The study was not
conclusive in identifying what caused the variability, and inexplicably
cancelled.
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1. The cleaning validation protocol for the ««« fails to provide for :
! Additional cleaning
! Microbiological testing of swab samples
! Testing for residues of the cleaning solution
! The title of the individual /s responsible for performing and approving the
validation study
! The criteria for a successful study
! An indication of when revalidation will be required
! A description of the type of analytical equipment used
! That samples are collected using gauze squares instead of cotton swabs
4. Cleaning validation studies for some equipment including the dryer and tablet
presses allow for all of the swab samples collected to be combined into one
combined sample and analyzed as such. For example, individual swab sites
for the dryer were identified prior to cleaning validation and all the swabs
were combined into one sample.
10. Current master coating formulas lack adequate coating instruction in that
parameters such as number of guns, distance of guns from tablet bed and
distance between the guns are not specified.
14. Products manufactured which were found to contain foreign materials were
reprocessed and/or visually inspected. There is no assurance that these
corrective actions were capable of removing all identified contaminant. For
example,
! According to the coating validation logs for both validation batches, actual
coating parameters such as spray rate, spray pressure, and temperature
differed from the parameters indicated in the current master coating
formula used to manufacture these batches.
! Samples for validation of the compression operation were analysed for
dissolution and content uniformity from a single sample taken only at the
beginning of the compression run.
16. The tablet compression process has not been validated. The tablet
compression study determining the hardness, thickness and friability of the
product was done at «.tablets per minute. The commercial production
rate is ««««« tablets per minute.
17. The validation data for the twin shell V blender used to blend bulk active
ingredients did not include the rotational speed at which the blender was run
during the studies.
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18. Validation - The firm failed to follow their validation protocol in several areas.
Examples include :
! Protocol calls for 10 x 50 g (500g) samples from final blend. Actual sample
size was recorded as 550g and does not reflect individual subsamples.
! The batch record does not reflect that sample was collected for angle of
repose and density. Laboratory records reflect these analyses were
performed.
19. There were no particle size specifications for the drug substance nor for the
granulation after milling.
20. The investigation into the acquisition and release of aluminium stearate of the
wrong grade obtained from an unapproved source failed to identify that the
wrong grade of material was ordered from the vendor. Further, the
evaluations of other materials to identify other sourcing / grade problems was
not documented and SOPs for the purchasing of raw materials did not include
a requirement to reference testing standards.
21. Product performance was not evaluated with respect to the use of
alternatively sourced excipient in the production of «« tablets. Subsequent
batches had marginal dissolution results which were attributed to the use of
this raw material.
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22. Preservative effectiveness testing is not performed as part of the stability
program. In addition, the finished product release specifications are
inadequate, in that, there is no quantitative testing performed for
determination of«« levels.
23. Failure to follow Change Control Procedure for «« Systems and Software
Version Control to provide adequate revision controls over «««.. programs,
and the various source codes used in manufacturing process control
systems, in that :
24. Failure to conduct periodic reviews of the various computer control systems
for peformance, changes, and configuration control in deviation of ««««
per SOP. This SOP requires documented annual reviews of all system for
changes and the need for requalification. Yet, according to personnel
interviewed, it was totally overlooked and never put into practice.
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25. The problem of a foreign capsule being found in this batch occurred during
inspection. Inspection records for this batch do not document that the batch
was reinspected after finding the foreign capsule.
27. The Agency was not notified in accordance with NDA field alert reporting
requirements when information concerning physical change in the distributed
drug product or failure of the distributed batches to meet the assay
specifications established in the application were confirmed.
28. Firm has no data to show worst case conditions for the cleaning validation of
the Fluid Bed Dryer performed for ««««. process verification. Swabbing
was performed on general contact areas without taking into consideration
areas such as edges and crevices of windows and sampling ports of the bowl
of the Fluid Bed Dryer.
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29. Protocol «««««.., Validation of the Cleaning Procedures lists an
acceptance criteria for tested materials recovered, shall not exceed ««««.
mcg / cm2. There is no data to justify this limit.
30. No time frames / limitations have been established for production equipment
from end of use to start of cleaning.
32. The training of employees is deficient in that employees do not always notify
their supervisors about defects or problems. For example, a malfunctioning
meter on a UV light located on the water system was not fixed for six weeks
because the supervisor was not notified, and a second malfunctioning meter
was not fixed for five weeks.
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33. Training records for employees often fail to provide necessary information,
e.g. length of session(s) and the specific topic(s) which were covered. Some
records list only one or more SOP numbers as subject matter ; and there is
typically no record of the length of the training session.
34. The ³Guidelines For Defect Classification´ in SOP ««««. indicates that
³Foreign matter such as metal particles, black specks´ are to be classified as
³Critical Defects´ and therefore have an Acceptable Quality Level (AQL) of
0%. This procedure contains no provisions for the continued retesting lots
which fail the assigned limits of AQL.
35. The Batch Manufacturing Record (BMR) for «« tablets, shows that the time
between removal of the ³dried granulation´ from the drying oven until the
next processing step was from «««««.. until ««««. (13 days). The SOP
in effect at that time, titled : ³Manufacturing Phase Time Limits´ defined the
maximum time limits between Granulation and Blending to be ««««..
According to the procedure, if the time limits are ³exceeded, the batch must
be evaluated by Quality Assurance before proceeding to the next step in the
process´. The above referenced BMR contains no documentation that the
batch was evaluated subsequent to the extended storage time.
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36. The current protocol for validating the manufacturing for ««« does not
state the process parameters that would be covered by the validation. For
example, it does not require a comparison between bio - availability batches
and validation batches.
37. Capsule validation batch ««« failed mix homogeneity and content
uniformity requirements and was rejected. No assignable cause could be
identified. Drum samples were performed on three additional lots. Two lots
exhibited values above acceptable criteria. Additional samples, taken from
the same locations were assayed in duplicate resulting in values of
«««««. The validation effort was accepted without investigation or
explanation of the out - of - specification results.
38. Investigations are not initiated when capsule batches fail in - process testing
requirements for weight variation. The impact of these failures on similar
batches is not evaluated. For example, batch ««««.., was sorted prior to
packaging as an underweight capsule (less than 50%) was found during
visual inspection. The sorting process rejected over 3,400 capsules that were
less than 90 % filled. No investigation was conducted to determine the cause
of the underweight capsules.
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39. The method validation for the manufacturing process of topical products is
lacking in that in - process sampling of products is not performed in a manner
to verify that there are no ³dead spots´ in the kettles used for manufacturing.
Three of the twelve samples are taken directly from the tank while the
remaining nine are taken as product is removed from the kettle from the
bottom orifice of the kettle.
41. Review of the batch records for «« tablets disclosed the following
deficiencies for the granulation phase :
a. The batch records do not specify how the granulating solution was added.
b. The records do not specify whether the process reached the granulation
endpoint.
c. There is no temperature range for the gelatin solution added during the
granulation process.
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42. Failure to follow Change Control Procedure for ««««. Systems and
Software Version Control, to provide adequate revision controls over «««..
programs, and the various source codes used in manufacturing process
control systems, in that :
43. Failure to conduct periodic reviews of the various computer control systems
for performance, changes and configuration control in deviation of ««««
per SOP. This SOP requires documented annual reviews of all system for
changes and the need for requalification. Yet, according to personnel
interviewed, it was totally overlooked and never put into practice.
46. «.the procedures to be followed when handling light sensitive material are
not specified in the production formulation for«.
47. «.SOP « was not followed by the Compression department supervisor for
tablet press selection in that the tablet press validation guide was not
reviewed in order to ³verify that the type of compression process of the
product to be compressed has been validated on the tablet press selected´.
50. There are no SOP's or records to cover reworking of packaged tablets and
capsules. For example :
51. Splices in roll labels are not checked either at the time of receipt or use to
assure that the labels before and after the splices are the same. In addition,
receiving procedures for incoming labels require that only one label per
receiving lot be checked for "Incorrect, illegible, missing copy, UPC or
design".
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52. Labeled cartons are not examined for identity and conformity to the labelling
specified in the master or batch production records at the time the cartons are
issued for a finished product batch.
53. There is no physical separation between the labeling lines in the off - line
labeling room. The spatial separation is not clearly defined. The staging
areas for each line are not identified.
54. There was no validation for the capping machine used to apply plastic caps to
the bottles containing tablets and capsules. No torque specifications have
been developed for the caps and seals used by firm on its products.
55. There was a lack of validation and specifications for the speed of the fan and
the heat of the heat gun used to "activate" the inner seals on caps used in the
packaging of ««««.. capsules.
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56. Batch Production and Control records do not include complete information
relating to a batch. For instance, in - process laboratory results (control
records) such as individual values for weights (as well as hardness,
thickness, etc.) are not maintained with the batch record in the case of both
tablet and capsule products. In addition, while samples are taken at the
beginning, middle and end of production plus generally one or more random
tests, none of these random test results are included in batch records (neither
in summary sheet reports nor as individual values).
58. The manufacturing process for «««.. tablets has not been validated with
respect to critical control points. A process change, to a constant increased
tablet weight, was made as the previous manufacturing process failed to
consistently meet pre - determined assay release specifications. There is a
lack of data to support this process change, as investigations into previous
failing batches lack an attributable cause.
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59. There are no written procedures assigning responsibility for cleaning
equipment, and describing in sufficient detail the cleaning schedules, the
methods to be used, how the equipment is to be disassembled for cleaning,
removal of previous batch identification, and protection of cleaned equipment
prior to use.
60. NDA «««. No specific terms and / or instructions are stated in the written
procedures for different manufacturing steps of ««««.. For example, it is
not specified in the Master Batch Record or in the batch production records
the order in which drug ingredients are added. The ««««. Monograph
does not specify those critical process parameters such as «««« time,
initial equipment settling etc. Also the sampling size and sampling frequency
are not specified. `````````
61. Your firm's investigation into the "incorrect capsule length" as presented in
the "Memo To : Batch Manufacturing Record", dated «««« is incomplete
and inaccurate. There is no reference as to when or how the problem of the
unlocked capsules was determined. The memorandum of investigation also
does not document the fact that three different ««««. encapsulators were
used to "re-close" the batch.
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62. Firm has no written procedures to identify all instruments used during the
manufacturing process. During the manufacturing process portable
instruments that require calibration or certification are used at different
stages and thereis no traceability of the instrument used to the batch.
63. A large number of the production personnel could not read or understand
English, yet they were following SOP's and signing batch records that were
written in English.
64. Although you maintain a calibration log of the «««« electronic label
counter, it is inadequate in that the reference control roll that you use
consists of a known quantity of "stranger" labels ; however, the log does not
show the accuracy of the instrument by comparing the quantity of label read
by the instrument against the known quantity, and also, it does not show
whether the instrument detected the "stranger" label. Furthermore, it does
not contain an acceptance criteria. For example, a label operator stated that
when a low quantity is read by the instrument, the test is repeated until a
satisfactory reading is obtained.
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65. No formally written and approved SOPs mandate the evaluation of individual
in - process hardness values or follow - up of out - of - specification results.
In addition, hardness testing is not performed frequently enough to ensure
adequate in - process control. While QA tests 10 tablets for hardness one
every two hours (at minimum) and apparently also reviews individual results,
production evaluates only an average of ten results hourly.
66. Failure to count mylar labels received from the vendor or confirm vendor
counts or assure the count meets on receipt specifications. For example,
label specifications for «««««.. are "label count per roll cannot exceed
0.5% discrepancy" from vendor count. There is no documentation that partial
rolls of labels are counted by a vendor.
68. Two Raw Material Inventory Cards for ««««.. were not accurate. These
inventories were not closed out in a timely manner which resulted in a delay
to the start of an investigation into a ««««« discrepancy for lot ««««..
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69. A reject level has not been established beyond which a lot of product would
not be released. It is the firm's policy to release lots of drug product,
irrespective of the reject rate, as long as the "defect" may be inspected for
and based on this inspection "acceptable" units are released. The following
lots of product were released although inspection reports recorded the cited
reject levels : 25.54%, 18.11%, 15.70%, 11.25% and 39.37%.
70. The manufacturing process for «««. tablets is not validated in that :
1. There is no impurity profile for bulk drug substance.
2. Raw data does not support the particle size of the drug substance
specified by the firm and submitted to FDA.
3. There is no data justifying mixing times during granulations ; no
characterization or evaluation of granules formed, no limits on mixing time
including the effects if any of the over mixing, nor is there justification of
blend times.
4. Particle size specifications for the drug substance were developed based
on only the sizes common to the two suppliers of the drug substances
(mesh size 50, 100, 400). There is no report addressing differences in
particle size in the mix - range (mesh size 140, 270 and 325) nor their
relationship to drug substance used in the biobatch.
5. There is no evaluation of the effect if any, of the optional step of adding
water and of variable drying times.
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71. Batch records are formatted so that operators record a single date for the wet
granulation mixing and drying steps, despite this process taking place over a
two day period.
72. There are no records showing bottles being blown out before filling.
73. Although access to batch formula screen editing is assigned based on user
profile levels, these are hard coded by individual parameter and were not fully
verified during validation testing. There is no assurance these were all coded
correctly. For instance, during a particular test of «««.. an error was found
which permitted Level 2 (operators) access to edit formulas on screen. No
record was made available showing correction and re-verification of the
loaded software for this.
74. The validation of the (film coating) process control computer software
consisted of limited functional testing, with no formal code structure testing,
such as code coverage analysis and / or systematic unit testing made
available. These functional tests failed to thoroughly, rigorously and
consistently challenge the system / software in that sufficient valid testing of
all input / output values, data structure, process variables, and control flow
logic was not done. No complete and meaningful testing techniques
(boundary value analysis, combination inputs, special case analysis, etc.)
were employed for critical process parameter and / or control variables.
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75. The operational qualification of the «««. system were similarly inadequate
in that it consisted of limited functional testing, which failed to thoroughly
and rigorously challenge the system and address worst case conditions as
follows :
1. Test cases did not check all reasonable «««.. conditions that can cause
errors.
2. Boundary value analysis was not done at values just above and below the
process parameters ranges, and did not include special condition values
in all cases.
3. The test protocol and test cases were not based on performance
specification and crossed referenced to a formal requirement specification
document.
4. Test case failure or deviations were not adequately explained and followed
up with corrective actions, retesting, and / or reassessment of equipment
performance specifications.
5. Test cases were not realistically based on the performance specifications
of each piece of equipment.
76. Granulation room ««. Has many high (30 feet) flat surfaces that are not
cleanable between products to prevent cross - examination. The walls, ceiling
and high ledges are cleaned only «««.. times per year.
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77. Blending studies did not evaluate particle distribution throughout the blend.
A composite sample from one lot was used for particle distribution studies.
78. The Tableting Portion of the Batch Production Record does not document the
following :
1. The actual weights of samples of finished tablets collected as the process
validation samples.
2. That the process validation samples were collected with the tableting
press operating at parameters which yielded tablets at high and low
hardness.
3. The actual weights of the full and partial containers of finished tablets.
4. The actual weight of accountable loss at the end of the tableting operation.
The theoretical tablet weight was used to calculate the yield for the
compression stage.
79. The Investigation Report concerning the broken and dented capsules does
not :
1. Include any investigation into the two lots of empty capsules which were
used to encapsulate this batch.
2. Address any corrective action taken or planned to prevent a recurrence.
3. The potential for this problem effecting other batches or products.
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80. Documentation was not available to show that current manufacturing
processes are validated for «««. products which includes validation
documentation for equipment processing parameters for all stages of
manufacturing. This includes lack of validation documentation for the film
coating processes and manufacturing of different types and batch sizes of
coating solutions.
81. In the film coating area we could not verify that each of the guns in the pans
are spraying the correct amount and pattern of film coating solutions.
82. According to personnel, film coating pan gauges are accurate for the
measurement of «««« This could not be verified for all coating pan gauges
used to manufacture products because there is no testing performed or
documentation to show the accuracy of these gauges.
83. In regard to the calibration of the sprayers for the controlled film coating
equipment (the coating pans), there is no documentation available to show
that the current method of using ««« and not the actual processing film
coating solutions, for calibration, will give accurate results for all types of
coating solutions used during manufacturing. The purpose of this calibration
is to assure that the spray rates of the different film coating solutions are
accurate and the reported total amounts sprayed are accurate.
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84. A report, dated ««««, stated : "when two coating pans were tested using
the same target specification range for total amount of coating solution
sprayed, there was a significant difference in the amount of coating solution
applied per pan which was also reflected in the average weight gain per
tablet". Personnel stated, corrective action to this observation would involve
calibrating the sprayer with the actual processing film coating solutions,
which is not currently being done.
85. Personnel stated the frequency that the film coating operation is stopped for
cleaning or replacement of the nozzles due to spray problems during batch
production is not known, since it is not documented.
86. According to personnel and what we observed during a walk through in the
manufacturing area ; personnel perform a 100% visual inspection. Batch
production records do not contain documentation showing that this 100%
inspection is being performed. The only visual inspection sampling
documented on the batch production records are the results of sample sizes.
87. There is no time limit restriction specified in the CIP cleaning procedures for
Liquid Manufacturing and Storage Tanks to assure that the procedure will
effectively remove product residues.
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88. The multiple computer systems which influence production are not validated.
These computers control among other things the disposition (quarantine,
release, reject) of all raw materials, weighing of all raw materials to master
record specifications and tolerances, printing of labels for all raw materials
for each batch, calculating yields at various stages of production, and printing
various portions of batch records for each lot.
89. The first three validation batches used a sample size of «««.. for uniformity
of blend analysis. The use of 1 to 2 gram sample size does not approximate
the 120 mg. Tablet weight of this product. These samples did not reveal the
sub-potency problem in the uniformity of the granulation at the end of the run
in the ribbon blender scrapings which was identified in the second set of
validation batches.
90. The validation blend uniformity test results for batch «««. Also documented
a problem with sub-potency at the end of the run which initiated a procedure
to discard the tailings from the blender for the other two validation batches.
However, the blender tailings were included in the granulation for batch
««««. Which was packaged and commercially distributed.
91. Equipment used in determining component and in - process material weight and
adherence to specifications is not identified in Batch Production Records for all
lots reviewed. For example, the following equipment is used and is not specified
: scales and balances, hardness tester, moisture analyzers and calipers.
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92. There is no written definition of the more than ««««. tablet defects which
production and in - process quality control inspectors monitor throughout
each batch.
95. Raw materials are stored in a "high - bay pallet" warehouse in building ««..
98. In some cases, manufacturing procedures lack sufficient detail. For example :
a. The tablet press cleaning procedure states that isopropyl alcohol should
be used to wipe down the entire machine and that a suitable cleaning agent
should be used to flush / clean the punch chambers. The grade of alcohol,
cleaning agent, and method of wiping is not specified
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b. The Cleaning Procedure states that the cleaning solutions are prepared
according to their directions. Different directions are found on the product
labels depending on disinfection level required.
c. Non - specific / subjective terms are used in equipment cleaning
procedures. These include : 'frequent use" ; "infrequent use" ; "when
applicable" ; "thorough(ly)" ;"suitable" ; "areas of concentration" ; "if
appropriate" ; "hot tap water" ; "hot potable water" ; "high pressure
washer" ; and "or equivalent".
100. The cleaning procedure for the «««.. tablet press was not found in the
equipment use folder / log adjacent to the press. There is no explanation as
to why this procedure was not available and no assurance that the press was
adequately cleaned during the time period when the cleaning procedure was
not available.
101. The computer system used for logging and tracking incoming raw materials in
the shipping / receiving area lacks adequate security measures to prevent
unauthorized changes to raw materials records.
102. No documentation exists for review and approval for use of equipment used
in the processing of «««« tablets to insure that the equipment is operating
within established limits and tolerances. e.g., tablet press, coating pan,
oscillator, mill equipment.
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103. Failure to evaluate and validate the impact on the final blend that the tote bin
conveyer system has in terms of homogeneity. After blending, the bins are
transported to the «««.. floor and attached to a duct - shoot fixture to
convey the blended material to the compression rooms. These fixtures have
motorized systems that (vibrate) the bins every ««. minutes to aid in
(sending) the blend down to the compression machine hopper. There is no
documented study that measures the effect (or non - effect) this has or if it
regresses or improves blend uniformity.
104. Environmental conditions, i.e. temperature, humidity, that could affect the
processing of tablets were not assessed during production / validation runs
for «««««. batches. No monitoring of room conditions took place during
production of these batches.
105. One of the drying ovens has a 3 x 10 tray configuration and the other a 2 x 10
tray configuration. Samples are pulled from one top / middle / bottom tray
and assayed for dryness. There has been no testing or validation to
determine if there is a variance in drying through out these ovens.
106. The validation data for the twin shell V blender used to blend active ingredient
blends did not include the rotational speed at which the blender was run
during the studies.
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107. During validation of the twin shell V blender the sampling procedure was not
specified.
109. In spite of the experimental effort, one of the three blend validation batches
failed blend uniformity acceptance criteria, and the investigation did not
provide conclusive scientific proof of the assumed most probable cause. The
results of two of the five blend samples (the two middle points) were out - of -
specification in individual point average (average of replicate injections).
These original results were confirmed in a series of tests, which included
reinjecting the same sample vial, re-pipeting, and re-centrifuging of the stock
solution. Also, an inconclusive study was done to reportedly analyze
variability of replicate sample, so two additional samples from each sample
point were retested. That study, although it did show some variability of
replicates, also showed low overall results. More importantly, it confirmed
the two middle sample points were at the lowest range. The study was not
conclusive in identifying what caused the variability, and inexplicably
cancelled.
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! Additional cleaning
! Microbiological testing of swab samples
! Testing for residues of the cleaning solution
! The title of the individual /s responsible for performing and approving the
validation study
! The criteria for a successful study
! An indication of when revalidation will be required
! A description of the type of analytical equipment used
! That samples are collected using gauze squares instead of cotton swabs
4. Cleaning validation studies for some equipment including the dryer and tablet
presses allow for all of the swab samples collected to be combined into one
combined sample and analyzed as such. For example, individual swab sites
for the dryer were identified prior to cleaning validation and all the swabs
were combined into one sample.
! The HPLC testing of rinse and swab samples detected small amounts of
residual .««. after cleaning in several pieces of manufacturing
equipment. No calculation was performed to determine whether the
cumulative effect of «««. exceeded the limit of 2 ppm.
! The cleaning validation study performed on «.. has no written conclusion
or signatures of review and approval by senior management.
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7. The cleaning validation protocol for the ««« fails to provide for :
! Additional cleaning
! Microbiological testing of swab samples
! Testing for residues of the cleaning solution
! The title of the individual /s responsible for performing and approving the
validation study
! The criteria for a successful study
! An indication of when revalidation will be required
! A description of the type of analytical equipment used
! That samples are collected using gauze squares instead of cotton swabs
10. The Agency was not notified in accordance with NDA field alert reporting
requirements when information concerning physical change in the distributed
drug product or failure of the distributed batches to meet the assay
specifications established in the application were confirmed.
11. Firm has no data to show worst case conditions for the cleaning validation of
the Fluid Bed Dryer performed for ««««. process verification. Swabbing
was performed on general contact areas without taking into consideration
areas such as edges and crevices of windows and sampling ports of the bowl
of the Fluid Bed Dryer.
x
12. The returned goods procedure is inadequate in that :
13. Training records for employees often fail to provide necessary information,
e.g. length of session(s) and the specific topic(s) which were covered. Some
records list only one or more SOP numbers as subject matter ; and there is
typically no record of the length of the training session.
14. The ³Guidelines For Defect Classification´ in SOP ««««. indicates that
³Foreign matter such as metal particles, black specks´ are to be classified as
³Critical Defects´ and therefore have an Acceptable Quality Level (AQL) of
0%. This procedure contains no provisions for the continued retesting lots
which fail the assigned limits of AQL.
x
15. Protocol «««««.., Validation of the Cleaning Procedures lists an
acceptance criteria for tested materials recovered, shall not exceed ««««.
mcg / cm2. There is no data to justify this limit.
16. The validation data for the twin shell V blender used to blend bulk active
ingredients did not include the rotational speed at which the blender was run
during the studies.
17. The exact locations for swab samples taken during cleaning validation
studies are not identified. Additionally, procedures allow for a second set of
swab samples to be taken if necessary with no assurance that the same swab
locations are not swabbed again.
18. The tablet compression process has not been validated. The tablet
compression study determining the hardness, thickness and friability of the
product was done at «.tablets per minute. The commercial production rate is
««««« tablets per minute.
19. The tablet compression process has not been validated. The tablet
compression study determining the hardness, thickness and friability of the
product was done at «.tablets per minute. The commercial production rate is
««««« tablets per minute.
x
20. Validation - The firm failed to follow their validation protocol in several areas.
Examples include :
! Protocol calls for 10 x 50 g (500g) samples from final blend. Actual sample
size was recorded as 550g and does not reflect individual subsamples.
! The batch record does not reflect that sample was collected for angle of
repose and density. Laboratory records reflect these analyses were
performed.
21. There were no particle size specifications for the drug substance nor for the
granulation after milling.
22. The investigation into the acquisition and release of aluminium stearate of the
wrong grade obtained from an unapproved source failed to identify that the
wrong grade of material was ordered from the vendor. Further, the
evaluations of other materials to identify other sourcing / grade problems was
not documented and SOPs for the purchasing of raw materials did not include
a requirement to reference testing standards.
23. Product performance was not evaluated with respect to the use of
alternatively sourced excipient in the production of «« tablets. Subsequent
batches had marginal dissolution results which were attributed to the use of
this raw material.
x
24. Cleaning validation studies for some equipment including the dryer and tablet
presses allow for all of the swab samples collected to be combined into one
combined sample and analyzed as such. For example, individual swab sites
for the dryer were identified prior to cleaning validation and all the swabs
were combined into one sample.
25. Equipment cleaning validation consisted of only testing purified water rinses
for pH and conductivity. It was not tested for chemical cleaning agents or
product.
27. The cleaning validation protocol does not address time frames for cleaning.
30. The validation of fill room «««.. found that the velocities at the HEPA filter
face did not meet specifications in the Class 100 area. The velocities were
later corrected, but air flow patterns and laminarity tests were not repeated
after the filters were adjusted.
31. Air velocities within the Class 100 area of the fill rooms are not taken at work
height, that is the height at which the vials are filled and stoppered. The
velocities, which are checked semi - annually, are taken six inches from the
face of the HEPA filters.
x
32. The firm¶s procedure : ..« entitled, ³Failure Investigation Policy´ is deficient
in that it does not address critical system failures. For example :
a. The WFI System lost circulation and temperature [twice] for the same
reoccurring reason. On « two WFI drops reached alert levels yet there is
documented ³verbal´ release of the system even though maintenance was
still working on the system. There is no documentation of flushing of the
system before its release on ««
b. 2 leaking valves were replaced
33. «««.. The entire water system has not been validated. For example, water
from the Reverse Osmosis (RO) storage tank is stored in a Feed Tank and
pumped to the still. The water is ambient and static in the feed tank, booster
pump and a portion of pipe leading to the still. This static portion of the water
system from the RO storage tank to the still has never been validated.
34. Failure to follow Change Control Procedure for ««««. Systems and
Software Version Control, to provide adequate revision controls over «««..
programs, and the various source codes used in manufacturing process
control systems, in that :
x
a. Several software changes were reportedly made but not properly
documented. For example, several changes to status prompt messages,
and changes to pan speed and spray rate deviation settings.
b. The vendor version installed was designated «««.., yet after
modifications resulting from installation / operation qualification no new
revision number was given.
35. Failure to conduct periodic reviews of the various computer control systems
for performance, changes and configuration control in deviation of ««««
per SOP. This SOP requires documented annual reviews of all system for
changes and the need for requalification. Yet, according to personnel
interviewed, it was totally overlooked and never put into practice.
36. There is inadequate data to demonstrate that autoclave cycles for this
terminally sterilized product have been validated. Three maximum load
validation studies were conducted for the purpose of determining the
autoclave¶s cold spots for the placement of controlling thermocouples during
routine production. During validation studies, one out of three cycles (for
each size) resulted in high F0 valued in areas of the autoclave, which were
subsequently deemed as the autoclave¶s ³cold spots´. Controlling
thermocouples have since been placed in only one of the two areas of the
autoclave found cold during the three cycles.
x
37. «.failure to accurately record all down time resulting from process alarms
and system breakdown. The only means of documenting the corrective
actions to processing problems is a downtime log, but this log is not being
filled out consistently and is not formally audited and verified by the quality
assurance unit.
38. «.SOP «.. entitled; "Internal auditing" was used to perform the audits
conducted «(2 years). It is deficient in that it does not include auditing all
systems such as computer validations, change control systems and water
systems.
x
1. Some cleaning validation studies conducted on various tableted products are
incomplete. For example :
a. The HPLC testing of rinse and swab samples detected small amounts of
residual .««. after cleaning in several pieces of manufacturing
equipment. No calculation was performed to determine whether the
cumulative effect of «««. exceeded the limit of 2 ppm.
2. There is no established limit for unknown HPLC peaks found during cleaning
effectiveness studies. In addition, no attempt has been made to identify these
unknown HPLC peaks.
x
3. The cleaning validation protocol for the ««« fails to provide for :
a. Additional cleaning
b. Microbiological testing of swab samples
c. Testing for residues of the cleaning solution
d. The criteria for a successful study
e. A description of the type of analytical equipment used
f. That samples are collected using gauze squares instead of cotton swabs
4. The firm did not challenge the analytical method for analyzing cleaning
validation samples to show that contaminants can be recovered and that
testing of unclean equipment yields unacceptable results.
5. The exact locations for swab samples taken during cleaning validation
studies are not identified. Additionally, procedures allow for a second set of
swab samples to be taken if necessary with no assurance that the same swab
locations are not swabbed again.
6. Cleaning validation studies for some equipment including the dryer and tablet
resses allow for all of the individual swab samples collected to be combined
into one combined sample and analyzed as such.
x
7. Protocol «««««.., Validation of the Cleaning Procedures lists an
acceptance criteria for tested materials recovered, shall not exceed ««««.
mcg / cm2. There is no data to justify this limit.
8. The firm fails to meet commitment made in NDA / ANDA applications as
follows :
a. In spite of the firm¶s commitment to perform in-process blend uniformity
testing, only a composite of the blend is tested.
b. In spite of the firm¶s commitment to perform in-process blend uniformity
testing from the top, middle and bottom of the left and right of the blender,
the first four lots sampled after the validation lots were sampled only from
the drums.
c. The required in-process test for potency on the bulk syrup prior to filling
was not performed on two lots. The ANDA commits to performing this test
on all lots.
9. There were no particle size specifications for the drug substance nor for the
granulation after milling.
10. Process validation studies for products using the fluid bed dryer have no
specifications established for Loss On Drying (LOD), particle sizing, and bulk
density testing of granulation.
x
11. The Validity Assessment Report was inadequate in that :
12. The Agency was not notified in accordance with NDA field alert reporting
requirements when information concerning physical change in the distributed
drug product or failure of the distributed batches to meet the assay
specifications established in the application were confirmed.
13. The current protocol for validating the manufacturing for ««« does not
state the process parameters that would be covered by the validation. For
example, it does not require a comparison between bio - availability batches
and validation batches.
14. The firm lacks SOPs which specify the manner in which production blend
samples are to be withdrawn (by technical services or Quality Assurance) and
subsequently handled in the laboratory, such that the sampling and testing is
consistent with commitments made in specific ANDA. For example,
x
! Blend samples for «««« are received in the laboratory in individual
bottles which represent a composite of the top, middle and bottom from
individual drums. The contents of these bottles are pooled in the Quality
Control Laboratory, according ³to practice´. The composite is analyzed, to
obtain a result which is titled, ³in-process Blend Sample Data´.
15. There is no assurance that the sampling method employed for cleaning
validation of equipment could detect low level of residuals. A non-
quantitative method «««. transfer resulted in low recoveries of spiked
sampled via HPLC. There is no minimum requirement for the percent
recovered from spiked samples to assure adequate cleaning. For example,
16. Process validation studies for products using the fluid bed dryer have no
specifications established for Loss On Drying (LOD), particle sizing, and bulk
density testing of granulation.
x
17. The firm fails to meet commitment made in NDA / ANDA applications as
follows :
a. In spite of the firm¶s commitment to perform in-process blend uniformity
testing, only a composite of the blend is tested.
b. In spite of the firm¶s commitment to perform in-process blend uniformity
testing from the top, middle and bottom of the left and right of the blender,
the first four lots sampled after the validation lots were sampled only from
the drums.
c. The required in-process test for potency on the bulk syrup prior to filling
was not performed on two lots. The ANDA commits to performing this test
on all lots.
18. SOPs for sampling after cleaning do not specify the method that should be
used , nor do sampling records specify where the sample was taken.
19. ««.firm has not addressed the following :
a. Analytical methodology for determination of drug or other chemical
residues .
b. Length of time which may elapse between use of equipment and the
subsequent cleaning operation.
c. Cleaning solvents are not specified in the SOPs.
x
20. The investigation into the acquisition and release of aluminium stearate of the
wrong grade obtained from an unapproved source failed to identify that the
wrong grade of material was ordered from the vendor. Further, the
evaluations of other materials to identify other sourcing / grade problems was
not documented and SOPs for the purchasing of raw materials did not include
a requirement to reference testing standards.
21. Product performance was not evaluated with respect to the use of
alternatively sourced excipient in the production of «« tablets. Subsequent
batches had marginal dissolution results which were attributed to the use of
this raw material.
23. «..SOP «.permits out of specification data to be averaged with data within
specification for product release. There are no procedures in the SOP that
address rejecting or recalling a lot when out of specification results cannot be
validated.
x
24. Some laboratory equipment is being used with control settings or under
adverse environmental conditions and / or ranges not established during
validation. For example :
26. Batch ««««.. did not meet the assay specifications during the stability
studies at ««««. months. This lot has ««« months of expiration period.
The assay failure was using the official methodology, however, this failure
was disregarded because passing results was obtained in a retest using non -
approved methodology. In addition, this lot has registered OOS results at the
«««« month intervals. No action has been taken with this lot which does
not meet product specifications and is still within the expiration period.
x
27. No documentation was provided regarding the stability incubator which
reportedly failed during stability studies of «««« No documentation was
available for the installation and calibration of this incubator nor was a record
available documenting the cause for the equipment malfunction / failure.
28. The visual inspection of stability and retention samples for colour is
subjective. To date, no standards are used in the visual examination for
colour.
29. «The firm lacks the controls necessary to ensure the accuracy and reliability
of analytical data generated by the laboratory. Although more than «.. of the
³out of specification´ laboratory investigations were attributed to (analyst
error) there was no documentation that any retraining was conducted.
None of the investigation reports reviewed listed retraining the analyst as the
corrective action to prevent recurrence.
30. « There is no traceability to show how the «..%Match acceptance level was
established for IR standard Vs test article. For example :
- There is no SOP or statement stating which IR computer library reference
standard chart to use during IR testing of drug raw materials. On atleast
one occasion one of the IR computer libraries matched below the «
%comparability accept/reject level while a second of the libraries was
above the«..%level and the raw material was passed based on the second
library level.
x
31. System Suitability Aspects :
32. The infrared identification tests performed are questionable. The comparison
between standard and sample maxima wavelengths could not be completely
performed because the wavelengths data in the standard spectrum were
illegible. Specifically, we would not match the maxima of ««««. standard
spectrum with the complaint sample spectrum.
x
33. SOP «permits out of specification data to be averaged with data that is within
specification for product release. There are no procedures in he SOP that
address rejecting or recalling a lot when out of specification results cannot be
validated.
34. The laboratory investigation for the ««««. That initially failed at ««««..
months concluded that the ³UV spectrophotometric determination used
seems to be unsuitable for the «««. Test´. However, this test was the same
that your laboratory has been using routinely during several years for the
««««« determination. The problem resides within your laboratory
personnel that cannot reproduce the method. There is no proper
investigation done that proves that the method is inappropriate because it did
not identify the potential source of error of the method, for example : traces of
««««.. that stay in the ««««. or the effect of the shift of maximum of
absorbance, caused by changes in «««. of final sample preparation.
35. The investigation into the acquisition and release of aluminium stearate of the
wrong grade obtained from an unapproved source failed to identify that the
wrong grade of material was ordered from the vendor. Further, the
evaluations of other materials to identify other sourcing / grade problems was
not documented and SOPs for the purchasing of raw materials did not include
a requirement to reference testing standards.
x
36. Product performance was not evaluated with respect to the use of
alternatively sourced excipient in the production of «« tablets. Subsequent
batches had marginal dissolution results which were attributed to the use of
this raw material.
a. Analysts are only required to read the Firm¶s SOP¶s and sign a document
to that effect.
b. Firm records show that analysts covered more than 20 SOP¶s the same
day.
c. Firm records show that analysts received this training once they are hired,
but not thereafter.
d. Training is not provided on a continuing basis and with sufficient
frequency.
40. Purity Thin Layer Chromatography (TLC) testing methods have not been
adequately validated. Method validation protocols do not contain quantitative
acceptance criteria for studies such as specificity, detectability,
reproducibility, and ruggedness. For example :
a. For drug substance purity testing of «««« in the lab ruggedness results
for ³known´ unknown were not comparable between the methods
development laboratory and the quality control laboratory.
b. Results are not reported bearing quantitation limits in mind, i.e., faint
spots seen on plates are reported as 0.0% as opposed to less than a
standard spot or detection limit.
x
c. Acceptance criteria do not specify that all impurity spots are separated
from each other and that Rf / RRf values clearly identify one impurity from
another.
41. Raw data for in - process TLC analyses such as reaction completion, purity,
etc. are non - existent or undocumented. For example, standards spotted and
compared to samples are not noted in any record and documentation of TLC
results (e.g. photographs do not exist). In addition, methods used for reaction
completion - purity testing of ««««. have not been validated according to
the firm¶s In - Process Laboratory Methods Validation Protocol. The protocol
calls for sensitivity and linearity checks covering the expected by - product
range.
42. Validation - The firm failed to follow their validation protocol in several areas.
Examples include :
a. Protocol calls for 10 x 50 g (500g) samples from final blend. Actual sample
size was recorded as 550g and does not reflect individual subsamples.
b. The batch record does not reflect that sample was collected for angle of
repose and density. Laboratory records reflect these analyses were
performed.
x
43. Deficiencies involving all High Performance Liquid Chromatography (HPLC)
equipment and Computer Software System «««« include :
a. Failure to have a written program or schedule to make back - ups of
product specific assay methods on all HPLC equipment.
b. There is no data available to assure that all the instrument / software
systems have been certified or validated to assure proper performance
and integrity of data.
c. There is no established program for securing the programmed methods or
data entry in all systems to assure they are not intentionally or
inadvertently altered.
44. Laboratory personnel do not record the position of samples and standards in
the run until after they are loaded in the HPLC. The position of samples and
standards in the HPLC is retrospectively recorded from memory.
45. Continued and repeated failure to maintain all chromatogram printouts and
test reports. Chromatographic printouts (GC & HPLC) were discarded and not
made part of stability and finish product analytical reports without valid
scientific justification for voiding and discarding test results. There was no
system in place to verify and assure test data is not discarded and voided
chromatograms are adequately investigated.
x
46. There are no procedures or guidelines to direct analysts on how to handle
suspicious or invalid analytical results. The only written instructions was a
memo from the lab supervisor dated«««« on which the recording of the
reason for voiding chromatograms was required. However, no guidance is
given as to what situations the analysts are authorized to void test results and
what steps must be taken to conduct an adequate cause identification
investigation.
47. Your in-house and contract laboratories failed to consistently follow system
suitability requirements of USP when conducting stability assays and data
elements of the method validation. HPLC charts and analyst notebooks show
standard preparation ««««.. was not injected enough times to obtain
replicate chromatograms to find out if results meet the «««. RSD limit.
- Identify testing is not done on raw material taken from actual containers.
USP identity, microbiological and Loss on Drying (LOD) assays are
conducted on ³side´ samples that are received in various packaged forms
from the supplier. The supplier packages and mails the ³side´ samples
separate from bulk containers.
x
49. No alarm system is available in the stability chambers, in order to detect and
notify the responsible person(s) of any changes occurring in the already set
conditions of temperature and humidity. At the present time, the conditions
are recorded, and visually observed, and any change is detected only if you
visually inspect the conditions.
51. The change from the former USP titration method to the (Firm¶s) HPLC
method was not by supplement, but rather placed in an annual report. The
(Firm¶s) method was listed as an ³alternate´ method but it is the only method
currently approved.
52. The microbial purity test procedures conducted on finished product, raw
material and in - line samples are not validated in that preparatory testing has
not been conducted utilizing the media manufactured by an outside facility.
Additionally, the procedures are inadequate in that :
x
a. There is no growth promotion testing conducted on the media to
demonstrate that the media can support microbial growth.
b. There has been no testing conducted to support the shelf life of media that
is prepared in - house and stored for an undocumented amount of time.
c. The use of peptone water is not described as a diluent in the procedure
nor has its use been documented during validation procedures.
d. There is no documentation to support the use of the pour plate method
rather than the multiple - tube method as described in the USP for
products tested.
53. The samples for microbial testing are prepared and examined on second shift
where :
a.There are no formal training procedures for employees working the in
microbiology lab.
b. There has been no documented training of the employee who
independently works on the second shift.
c. There is no system for the evaluation of employee(s) working on the
second shift.
54. For validation of the analytical method for ««««.. the firm did not perform a
forced degradation study for the placebo.
x
55. The usual laboratory practice was to retest only test lots with out-of-
specification test results and not to retest lots with ³passing´ test results. In
most cases, the ³passing´ lots were not retested even when there was a
substantial discrepancy between the original and retest results for the
retested lots.
56. There is no statistical basis or scientific rationale for the sampling plan used
to perform the physical examination (color / clarity) of stability samples.
Current written procedures do not describe sample size or acceptance criteria
for this test. In addition, the test for colour is subjective. No standards are
used to aid in the visual examination for color.
57. The Quality Unit has not consistently been responsible for the approval or
rejection of specifications and procedures in place in that the unit has been
bypassed.
61. Failure to assure that the required humidity and temperature of the Stability
Samples Storage Room is adequately distributed throughout the room.
62. The procedure for rejection of analytical data and reassay of samples is
inadequate, in that there is no information explaining in detail how the
retesting is conducted. There is also no information explaining at what point
testing should end and the product be evaluated.
66. Laboratory notebooks for the Related Substances testing for stability trials of
««««.. validation batches failed to accurately reflect the testing conditions
and results. For example :
a. Retention factor values for all spots for each injection were not recorded.
x
b. In cases in which multiple samples were injected on the same plate there
was no indication as to which injection was used to establish the standard
gradient.
67. The finished dosage form of ««««. was out of specification for individual
and total impurities. There is inadequate documentation to justify invalidating
the original and two retest out of specification related substance results and
accepting the one within specification test. Evaluation of the first set of
chromatograms did not show excessive baseline noise, and there is no
documentation of contamination as suggested in the retest analysis. The test
values obtained on a new HPLC column with freshly prepared mobile phase
indicate the product exceed specifications for individual and total impurities.
68. HPLC mobile phase buffers are stored at room temperature in large quantities
and used for at least one month. There are no SOPs for preparing and using
the mobile phases for one month or more, nor are there procedures to check
the pH of buffers prior to using. Stability studies were not conducted to
insure that the buffers were adequate for use after storage. Analytical data
acquired for several products that were analyzed using the buffers after
storage indicates some may be unstable and incapable of producing accurate
and reliable results.
x
69. Analytical notebook and chromatographic data from the contract laboratory
was not thoroughly reviewed by responsible individuals in the firm for
accuracy, completeness, and compliance with USP and cGMP specifications.
The notebook data lacks the date analytical work was initiated, reference
standard purity, and the factors and calculations used for quantitation.
70. Quality Control chemistry and stability laboratory investigations are
inadequate. The investigation report does not include the corrective actions
necessary to prevent similar recurrences. The reports do not indicate if
similar out of specification results were reviewed, and if other lots are
affected.
71. ««capsules were packaged using a new cap inner seal which had to be heat
activated and no lots were placed on stability. These products were given 5
year expiration dates.
72. ««.Firm has not performed validation studies to determine if the use of
metal caps provides adequate protection against foreseeable external factors
during storage of the «products.
73. «..there was lack of a standard operating procedure to test, examine and
release metal caps. Lots of metal caps received before this date were released
using an SOP for plastic caps.
x
74. ««metal caps and liners used by firm may not be equivalent to plastic caps
previously used on the tablets & capsules. For example:
b. The Specification Document reveals that specifications for the metal caps
backing liner are not the same as plastic caps.
76. There is no established limit for unknown HPLC peaks found during cleaning
effectiveness studies. In addition, no attempt has been made to identify these
unknown HPLC peaks.
x
77. (Firm) is not following its Stability Testing Program SOP «««.. which
requires the smallest and the largest package size from each of the first three
batches be placed on both accelerated and room temperature stability studies
when packaging changes, formulation changes and / or change(s) in the
manufacturing process occur. For example :
b. There has been no testing conducted to support the shelf life of media to
demonstrate that the media that is prepared in-house and stored for an
undocumented amount of time.
4. The firm lacks validation of temperature at which plates are incubated for total
viable count for bacterial content of purified water. Incubation temperature
is«degrees C for a period of«.. hours. No comparison is made between the
firm¶s temperature and time of incubation and a lower temperature and longer
time of incubation to determine if the firm¶s method is capable of maximizing
detection of bacteria.
5. Failure to validate the (process) with maximum load during bio-burden study
to assure sterility with the sterilizer at this load. Although you demonstrated
proper levels of heat are achieved with your heat penetration / heat
distribution study this does not measure the microbial resistance with the
product.
6. «.The «..filter sterilization validation data for ««injection shows that the
validation did not simulate ³worst case´ production conditions regarding the
size of microrganisms in the drug product. The validation report number....
reported that the control filter (..micron) retained the challenge organism was
not small enough to challenge the sterlizing filter¶s («micron)porosity.
b. Sterility media fills are conducted to monitor the aseptic fill process. The
firm¶s procedure allows a «..% sterility failure rate , without investigation
to determine root cause. Examples of events that were not investigated
include:««
9. The ««««. filter sterilization validation data for «««« Injection shows
that the validation did not simulate ³worst case´ production conditions
regarding the size of micro - organisms in the drug product. The Validation
Report Number «««. Reported that the control filter (««««.. micron)
retained the challenge organism suggesting that the organism was not small
enough to challenge the sterilizing filter¶s (««« micron) porosity.
10. Use - point water samples from the compounding tank and accessories wash
rooms are not representative of the water used for cleaning. Tubing is
attached to the water drop for cleaning, whereas a sterile hose is used to
collect samples for microbial analysis and bioburden testing.
11. The firm¶s practice of spraying the sterile fill area with «««.. after a failing
environmental result has not been validated to show that it controls microbial
growth and that it does not leave a residue which would contaminate the
product being produced.
a. The firm lacked a documented schedule and frequency for the monitoring
and testing of the controlled environment.
b. The firm failed to identify the location and specific areas in which
microbial sampling is performed, e.g. the ««««.. room (location) and
next to the ««««« (specific area).
14. The sampling protocol for fluid bed dryer microbiological evaluation did not
include sampling of the fluid addition nozzle or the compressed air pathway.
15. The firm has not established microbial content specifications for all drug
substances used in the manufacture of their sterile small volume parenteral
products. Where specifications exist the firm is not rejecting raw material lots
found to contain potentially hazardous organisms. For example :
a. There has been no qualification of the microbial content of the active drug
substances used to manufacture the sterile injectable drug product. There
are no microbial specifications for the active drug substances.
b. The following lots of raw material were tested for microbial content, found
to contain potentially hazardous microbial organisms but were released for
use in production, based on data such as back challenge testing.
16. The ³Identification of Bacteria´ flowchart depicts that the catalase test is to be
the first test performed if gram positive cocci (GPC) bacteria are being
identified. Also, it shows that the oxidation / fermentation test is to be
performed if the MSA test is negative. However, the catalase and oxidation /
fermentatio tests were not performed in the testing of MSA (-) GPC micro-
organisms in at least 17 lots of product.
17. Failure to take remedial action or investigate the presence of mold,
Aspergillus versicolor and Aspergillus niger, found in the pure steam
generator water sampled dated «««««. The water for the steam generator
is supplied by the WFI system. The steam supply goes directly into the
««««.. sterilizer where it comes into direct contact with clean room
equipment and product container components, i.e., rubber stoppers for vials.
There is no evaluation of the effect the molds may have had on the steam
supply and rubber components.
19. The firm lacks validation of temperature at which plates are incubated for total
viable count for bacteria content of purified water. Incubation temperature is
««««« degrees C for a period of «««« hours. No comparison is made
between the firm¶s temperature and time of incubation and a lower
temperature and longer time of incubation to determine if the firm¶s method is
capable of maximizing detection of bacteria.
20. The sampling / monitoring of factory ««« endotoxin reduced water was
inadequate in that samples are not taken from the flexible hose at the points
of use. The flexible hose is used to charge water during the manufacture of
APIs.
21. The flow of raw materials, in - process granulation, and bulk tablets was
inadequate to prevent microbial contamination of «««.. tablet lots. For
example, one conclusion drawn by the microbiology laboratory regarding
contamination was that the loading dock, which gives access to the oven
drying room, is a main port of entry for mold spores into the building.
Further, the firm does not perform routine microbiological monitoring of the
facility.
22. Preparatory testing for the microbiology methods used for bioburden
detection during cleaning validation (swabs and rinse samples) did not
include an evaluation of «««« which is the test method used during these
cleaning (bioburden) studies.
a. The last media fills on line «««« are inconclusive because they were
filled in amber ampules which is inappropriate for detecting turbidity
(contamination).
b. Media fills have not simulated product fill times. Media fills have lasted «
hours, product fills run .. to .. hours. (cumulative stoppage time associated
with fill weight checks during routine production; manual stoppering is
done only when needed during media fill and for the maximum no. of times
that occur during routine production)
c. Media fills do not validate the allowed hold-time of bulk from compounding
to filling, nor is there bioburden data to support this hold time.
26. Investigation into the positive media fill of ««« was incomplete in that it did
not identify from what portion of the fill the positive vials were collected nor
evaluate people, room, or other product.
27. A review of reverse osmosis water system documents showed the frequency
for sanitizing system and what events would necessiate sanitizing system had
not been identified. The procedure for ³Evaluating bacterial growth in
deionized water system´ does not identify the microbial testing
system«..beyond calling it purchased bacterial samples.
28. Sterile filter validation for«« did not include an evaluation of bioburden
inherent to this ophthalmic solution nor an evaluation of the effects of the
product on the bioburden (i.e. size of organisms)
31. ««The purified water system used in the manufacturing of Rx, OTC and
nutritional products has not been validated . for example:
a) The firm uses the compendial microbial limit test for total plate count ,
total yeast and mold and Pseudomonas. The USP states that the
compendial microbial limit tests is not designed for the testing of
ingredient waters.
b) Chlorine, a common additive to municipal water systems, is not inactivated
by the firm or the contract laboratory with a dechlorinating agent (i.e.
sodium thiosulphate) prior to testing. Results generated by the contract
laboratory are not a true representation of actual microbial levels within
the city water.
34. «.. On ««, the filling of ««« was affected by a plant-wide power failure.
Bioburden monitoring was not performed until the next day
35. «.. Failure to validate the LAL gel clot test method for endotoxins in that
inhibition and enhancement has not been done on drug substance raw
material to demonstrate that the substance does not of itself inhibit or
enhance the reaction or otherwise interfere with the test.
A. Microbial Limit Test :
1. There is a documentation to support the use of pour plate method rather than
the multiple tube method as described in the USP for products tested.
5. The firm has not established microbial content specifications for all drug
substances used in the manufacture of their sterile small volume parenteral
products. Where specifications exist the firm is not rejecting raw material lots
found to contain potentially hazardous organisms. For example :
a. There has been no qualification of the microbial content of the active drug
substances used to manufacture the sterile injectable drug product. There
are no microbial specifications for the active drug substances.
b. The following lots of raw material were tested for microbial content, found
to contain potentially hazardous microbial organisms but were released for
use in production, based on data such as back challenge testing.
6. The ³Identification of Bacteria´ flowchart depicts that the catalase test is to be
the first test performed if gram positive cocci (GPC) bacteria are being
identified. Also, it shows that the oxidation / fermentation test is to be
performed if the MSA test is negative. However, the catalase and oxidation /
fermentatio tests were not performed in the testing of MSA (-) GPC micro-
organisms in at least 17 lots of product.
7. ««The purified water system used in the manufacturing of Rx, OTC and
nutritional products has not been validated . for example:
a. The firm uses the compendial microbial limit test for total plate count ,
total yeast and mold and Pseudomonas. The USP states that the
compendial microbial limit tests is not designed for the testing of
ingredient waters.
b. Chlorine, a common additive to municipal water systems, is not inactivated
by the firm or the contract laboratory with a dechlorinating agent (i.e.
sodium thiosulphate) prior to testing. Results generated by the contract
laboratory are not a true representation of actual microbial levels within
the city water.
8. Process validations performed on all products included Bioburden History
Data to evaluate the longest number of days each solution was held in
temporary storage with acceptable bioburden values. However, the historical
storage times were not considered when establishing the maximum
recommended days to store.
B. Water:
Water
C. Air :
1. The firm¶s practice of spraying the sterile fill area with «««.. after a failing
environmental result has not been validated to show that it controls microbial
growth and that it does not leave a residue which would contaminate the
product being produced.
2. The firm¶s Airborne and Surface Bioburden Monitoring of the production area
is deficient in that :
- The firm lacked a documented schedule and frequency for the monitoring
and testing of the controlled environment.
3. The flow of raw materials, in - process granulation, and bulk tablets was
inadequate to prevent microbial contamination of «««.. tablet lots. For
example, one conclusion drawn by the microbiology laboratory regarding
contamination was that the loading dock, which gives access to the oven drying
room, is a main port of entry for mold spores into the building. Further, the firm
does not perform routine microbiological monitoring of the facility.
4. Preparatory testing for the microbiology methods used for bioburden
detection during cleaning validation (swabs and rinse samples) did not
include an evaluation of «««« which is the test method used during these
cleaning (bioburden) studies.
1. The sampling protocol for fluid bed dryer microbiological evaluation did not
include sampling of the fluid addition nozzle or the compressed air pathway.
E. Sterile :
1. Failure to validate the (process) with maximum load during bio-burden study
to assure sterility with the sterilizer at this load. Although you demonstrated
proper levels of heat are achieved with your heat penetration / heat
distribution study this does not measure the microbial resistance with the
product.
2. «.The «..filter sterilization validation data for ««injection shows that the
validation did not simulate ³worst case´ production conditions regarding the
size of microrganisms in the drug product. The validation report number....
reported that the control filter (..micron) retained the challenge organism was
not small enough to challenge the sterlizing filter¶s («micron)porosity.
3. Sterility media fills are conducted to monitor the aseptic fill process. The
firm¶s procedure allows a «..% sterility failure rate , without investigation to
determine root cause. Examples of events that were not investigated
include:««
a. The last media fills on line «««« are inconclusive because they were
filled in amber ampules which is inappropriate for detecting turbidity
(contamination).
b. Media fills have not simulated product fill times. Media fills have lasted «
hours, product fills run .. to .. hours. (cumulative stoppage time associated
with fill weight checks during routine production; manual stoppering is
done only when needed during media fill and for the maximum no. of times
that occur during routine production)
c. Media fills do not validate the allowed hold-time of bulk from compounding
to filling, nor is there bioburden data to support this hold time.
8. «.. On ««, the filling of ««« was affected by a plant-wide power failure.
Bioburden monitoring was not performed until the next day
9. «..Failure to validate the LAL gel clot test method for endotoxins in that
inhibition and enhancement has not been done on drug substance raw
material to demonstrate that the substance does not of itself inhibit or
enhance the reaction or otherwise interfere with the test.
1. Procedure for documenting and tracking, repair and maintenance requests for
manufacturing equipment do not insure the appropriate prioritization or
completion of requesting repair work.
2. The validation of fill room «««.. found that the velocities at the HEPA filter
face did not meet specifications in the Class 100 area. The velocities were
later corrected, but air flow patterns and laminarity tests were not repeated
after the filters were adjusted.
3. Air velocities within the Class 100 area of the fill rooms are not taken at work
height, that is the height at which the vials are filled and stoppered. The
velocities, which are checked semi - annually, are taken six inches from the
face of the HEPA filters.
a. The WFI System lost circulation and temperature [twice] for the same
reoccurring reason. On « two WFI drops reached alert levels yet there is
documented ³verbal´ release of the system even though maintenance was
still working on the system. There is no documentation of flushing of the
system before its release on ««
c. The WFI system dropped below 65 degrees for 5 hours due to controlled
air line leaks causing improper operation of a blocking valve on ««««..
6. «««.. The entire water system has not been validated. For example, water
from the Reverse Osmosis (RO) storage tank is stored in a Feed Tank and
pumped to the still. The water is ambient and static in the feed tank, booster
pump and a portion of pipe leading to the still. This static portion of the water
system from the RO storage tank to the still has never been validated.
7. Failure to follow Change Control Procedure for ««««. Systems and
Software Version Control, to provide adequate revision controls over «««..
programs, and the various source codes used in manufacturing process
control systems, in that :
9. «There are no differential pressure specifications for the sterility test clean
rooms, gowning room and general microbiology laboratory. There are no
procedures for monitoring these differential pressures.
10. «.the water for injection and distilled water storage and distribution systems
are continuously monitored for pressure , water level, temperature and
resistivity at «locations. Each location has a set point, alert and action limit.
The computer which monitors and controls the water system has not been
requalified in 6 years.
11. «..no alarm system is available in the stability chambers, in order to detect
and notify the responsible person/s of any changes occurring in the already
set conditions of temperature and humidity. At the present time, the
conditions are recorded, and visually observed , and any change is detected
only of you visually inspect the conditions.
12. The firm¶s USP Purified water system has not been maintained in accordance
with the firm¶s Standard Operating Procedure - Periodic Maintenance and
Service of the Production Water System. For example :
a. The procedure requires the semi - annual integrity testing and changing of
the «««« micron sterilizing filter. There is no documentation of this
maintenance and the filter is only changed annually. There is no
documentation of any examination of this filter.
b. The sterile vent filter is required to be integrity tested semi - annually and
changed annually. There is no record of the semi - annual integrity testing
of this filter. Management stated that this filter is integrity tested and
changed annually. During the annual maintenance, this filter failed
integrity testing.
14. Purified water used to flush the system after sanitization was not heated to
minimize microbial contamination.
15. There is inadequate data to demonstrate that autoclave cycles for this
terminally sterilized product have been validated. Three maximum load
validation studies were conducted for the purpose of determining the
autoclave¶s cold spots for the placement of controlling thermocouples during
routine production. During validation studies, one out of three cycles (for
each size) resulted in high F0 valued in areas of the autoclave which were
subsequently deemed as the autoclave¶s ³cold spots´. Controlling
thermocouples have since been placed in only one of the two areas of the
autoclave found cold during the three cycles.
16. During heat sanitization of the USP Purified water loop there is no assurance
of temperature throughout the loop (purported to be 180 F). The water
temperature is only monitored within the storage tank and following a heat
exchanger. There is no monitoring of the water temperature within the
production loop prior to its return to the storage tank.
17. Preventive maintenance checks performed mid - year for in - place leak
testing of HEPA terminal filters and in - place leak testing of laminar flow units
were done incorrectly in that the initial (installation) static pressure drop from
the checklist or the history notes file was not obtained and compared to the
current static pressure drop across the HEPA filter.
18. Failure to maintain a change history and have an accurate current description
and / or schematic for all components of the water system. Water for
Injection and Pretreatment. For example :
a. There is no history of the development of the pretreatment system prior to
««««.
b. The change history does not include the ««««. still.
c. There is no current equipment list for all major components of the system.
d. The water system drawing dated ««««« incorrectly shows a sample
site in the WFI loop at clean room line number ««««« and a sample
port at the portable tank connection.
e. There is no documentation of the location of the city water points of use in
the facility.
f. Current drawings do not specifically identify components of the system
equipment currently in use.
20. The firm does not maintain a written description or an accurate pictorial
description of the Water for Injection manufacturing system. SOP «««««,
entitled, ³Water for Injection, Production, Maintenance and Testing´ serves as
the description and schematic of the system. There is no narrative describing
the system, and the schematic lacks a true representation of the piping
configuration, drainage ports, sampling ports, switch valves, pumps and
heaters.
21. The pump used to deliver WFI to the vial washer and stopper washer comes
into direct contact with the water during pumping. After use the pump is
disassembled and allowed to air dry. There is no documentation to show that
pump head is periodically cleaned and sanitized nor is there any validation
documentation to show that air drying the pump head parts does not
introduce unwanted material into the washer systems.
22. The drawing of the process system was incomplete and failed to illustrate
specific valves and drops in the piping between the feed tank and the spray
dryer.
23. The training of employees is deficient in that employees do not always notify
their supervisors about defects or problems. For example, a malfunctioning
meter on a UV light located on the water system was not fixed for six weeks
because the supervisor was not notified, and a second malfunctioning meter
was not fixed for five weeks.
24. The entire water system has not been validated. For example, water from the
Reverse Osmosis (RO) storage tank is stored in Feed Tank and pumped to the
still. The water is ambient and static in the feed tank, booster pump and a
portion of pipe leading to the still. This static portion of the water system
from the RO storage tank to the still has never been validated.
25. The firm¶s validation of Deionized Water System (DI) is inadequate in that the
firm has no validation specifications or frequency of replacement prior / after
validation of the DI system for the filter, RO filter and UV light bulb.
26. ««There¶s no sanitation schedule for the Reverse Osmosis (RO) units of the
water pretreatment system. The operating manual recommends the system to
be sanitized.
27. The firm¶s maintenance procedure for the sterilizers is deficient in that :
a. There is no preventive maintenance procedure for the sterilizer air
microbial filters used during the vacuum pressure relieve.
b. Safety pressure / vacuum mechanical gauges for both sterilizers are not
calibrated nor are they used as a safety factor to ensure that computer
pressure / vacuum readouts are accurate.
c. The firm failed to conduct boiler chlorine and orthophosphate tests as
required by the firm¶s SOP «««
d. The sterilizer¶s steam / water pipes retainers used to trap pipes debris
during operations are not maintained. The firm has not established a
formal cleaning maintenance schedule to assure that the accumulation of
debris in the retainers will not compromise the quality of the water used
for the production of steam during the sterilization cycle.
e. The firm did not conduct quality steam studies to assure that clean steam
will be used during sterilization.
f. The firm¶s sterilization cycle used during the months of «««« is
inadequate in that conductivity and potassium upper and bottom
parameters were not met.
28. A change in the location of the electronic «««. washer counters was made
as a corrective action. However, there is no documentation demonstrating
the validation of these relocated counters used for the syringe accountability.
In addition, the SOP for critical system change requests (CSCR) was not
followed, in that a CSCR was not issued and reviewed.
29. Air Velocity is not determined at critical filling sites with a frequency that
assures the maintenance of a 90 feet / minute 20% speed during the filling
operation. An outside contractor performs air velocity measurements semi -
annually at filter faces. The firm performs these measurements at critical
sites when media fills are conducted, which may be semi - annually. There is
no routine air velocity monitoring program.
30. Technical Procedure ««««.., entitled : ³Protocol for the Deionized Water
System Use, Monitor, and Maintenance´ is deficient because it does not
include the checking of the DI water system¶s four pressure gauges located
on the inlet / outlet lines.
31. The parameters used for validation lots, «««««. used to validate ««.«..
Machine does not match the parameters specified in the validation protocol.
32. There is no reference in the equipment Use and Maintenance Log for tableting
machine «««« concerning the problem of finding ³metal particles´ and
³brass fragments´ in the tablets from lot ««««. which was tableted using
this piece of equipment. This batch was ultimately destroyed for ³metal
contamination´ of tablets.
33. There is no evidence that the following processes have been validated :
a. Plant cleaning procedures (Plant - wide including vessel and water system)
b. Process water system
c. Process steam system
d. Air system
e. Process water in - line conductivity meter and ultraviolet treatment system,
including the respective automatic monitoring, alarm, and shut - down
capabilities.
34. There is no evidence that the following equipment has been qualified :
35. You do not have a formal procedure for the calibration of your «««««.
electronic label counter with ««««. Bar code reader.
37. «.failure to accurately record all down time resulting from process alarms
and system breakdown. The only means of documenting the corrective
actions to processing problems is a downtime log, but this log is not being
filled out consistently and is not formally audited and verified by the quality
assurance unit.