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Laboratory managers should not over - delegate primary lab functions to


underlings or maintain a lax quality control environment. FDA inspectors are
focussing attention on labs having good laboratory practice (GLP) violations
that could have been avoided if the manager had played a more active role in
the lab¶s day - to - day operations. For example, inspectors increasingly are
encountering managers who are unaware of testing being done at their labs
or who cannot locate samples of the dosage form under analysis, one FDAer
told WDL. Comprehensive management of laboratory operations is a ³major
component´ of good lab practices, that source added.

Senior management bears ultimate responsibility for authorization of


resources, the establishment of time frames and the overall correction of
objectionable conditions, the FDAer noted, and so should be kept informed.
Finally, because many labs are using new software programs for data
management and for the generation of stability reports, inspectors warn that
such software must be independently verified.
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FDA inspectors continue to crack down on drug makers' practice of averaging


quality control test results to nudge an otherwise out - of - specification batch
into acceptable limits.In the face of increasing evidence that FDA and some
firms are approaching GMP compliance from two distinct mathematical
schools of thought, inspectors warn against, for example, grouping together
validation and quality control test data on multiple batches to achieve pre -
established acceptance criteria limits.

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 batch that deviated from established formulation due to equipment


malfunction or calculation error may catch inspectors' eyes if no validation
data accompany release of that lot. For example a batch exceeding limits for
non - active ingredients by 2% may not be released without stability
monitoring. Meanwhile, filling operations continue to be an inspection focal
point. Some critical fill - related safeguards include :
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! Filter validation for aseptically - filled products.
! Filling equipment validation must demonstrate that alarms respond
as required when challenged for high and low volume fills.
! Routine and non - routine equipment maintenance must be documented.

In addition, investigation of out -of - specification results should include


identification of any organisms recovered as well as a thorough evaluation of
end product quality. Firms should also be prepared to present documentation
detailing preventative actions taken to prevent recurrence of the particular
problem.

Finally, impurities evaluations should include : determination of the source of


impurities ; a validated analytical method to evaluate impurity level ; a
determination of the solubility of the impurities ; and evaluation of impurity
levels in finished lots on the market. These violations were noted in a Jan. 22
warning letter (*) to Bristol - Myers Squibb at the company's facility located in
New Brunswick, N.J.

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.

That review should be described in a firm's standard operating procedures


and the results of each analysis should be documented. FDAers stressed.

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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Drug makers using multiple contract labs should be careful to avoid an


inspection pitfall known as "selective reporting". A common scenario is this "
Two labs test the pH on samples from the same drug lot, but arrive at two
different results, one within specifications, the other out of specification.
Quality Control staff may be tempted to keep the "good news" and toss out
the bad, but an FDA compliance officer cautioned against doing so.
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Since the odds are equal that either lab's results are correct, it must not be
assumed that the in - spec results are the accurate ones, that source warned.
Instead, firms must conduct a thorough investigation of both sets of results to
pinpoint the reason for the discrepancy. Failure to do so and to document
those efforts could spur FDA inspectors to suspect a firm of selectively
reporting only favorable results.

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 :

1. Whether the pH meter was calibrated in accordance with SOPs ?


2. Whether the probe was in good working order ?
3. Whether the calibration solutions were current and appropriate ?
4. Whether the solutions bracketed the specification range ?
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After compiling that information for both labs, quality control should compare
the two sets of results side - by - side. Key analysts also should be in
interviewed to eliminate any contamination or mishandling of samples. If
either seems probable, the result should be invalidated, with the above data
as justification. In such case, the source told WDL resampling "would be
indicated" and the retest results substituted for the originals.

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When a drug makers product lot fails to meet specifications, an immediate


and thorough investigation must follow to avoid a warning letter. The
foremost consideration is to assure that the lot does not slip past quality
control and get released for sale. FDA stresses that batch records must be
thoroughly reviewed as part of such an investigation to assure that analytical
data support all lots waiting for release.

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.

The "double sample size exemption" in regulations covering sterile drug


sample sizes has for some time caused consternation among drug makers
and FDA inspectors alike. The exemption says companies do not have to
keep twice the amount of reserve samples to perform sterility and pyrogen
tests. But the FDAer said firms should not take the latitude offered by that
rule too far.

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.

FDA employs a host of criteria to assess a microbe's safety risk, including


number and species of the organism, plus the drug's dosage form, intended
use, route of administration and target patient population. But the adjective
"objectionable" has other, less obvious facets, as well, such as a
microorganism's ability to :

! Reduce drug stability.


! React with, or damage integrity of, container / closure systems.
! Interfere with analytical methods or active ingredient bio-availability.

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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Investigation into contamination of a drug is not unlike the work of a very


astute detective, as no stone, however, remote a contaminant source, should
be left unturned, according to FDA. When devising a master investigation
plan, analysts should assure that their lists include seven broad areas : water,
raw materials, equipment, operators, facilities, processing and laboratories.
All are equally important, FDAers said.

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.

Lab equipment often serves as a micro - organism inroad, a phenomenon the


FDA source blamed on inadequate cleaning of equipment parts, including
components such as lids, domes, valves, seals and dead pockets.

In addition, lab managers should routinely check equipment parts and


material that are particularly vulnerable to deterioration. These components
typically include seals, gaskets, plastic, Teflon and glass.

Another trouble spot is equipment involved in product transfer, such as


hoses, pumps and brushes. The source cautioned firms not to overlook the
inadvertent addition of a substance, or cleaning agents as possible sources.

A general facilities review should emphasize trafficked areas of isolation and


segregation areas. Lab checks should focus on glassware. Finally, lab
operators must be furnished with hair covers, boots, gloves and masks.
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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 :

a. Approval, rejection or recall


b. Unexplained discrepancies.
c. Field alert reports
d. Other outcomes that may indicate needed changes.
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However, where multiple problems occurred in any of the above categories,
the number of batches selected for review should ³fully represent´ each type
of problem. In addition, FDA¶s rule is at least one batch per product, so
grouping products based on similar processes is prohibited. Differing
processes and / or specifications may result in varying manufacturing
outcomes, the FDAer explained.
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Pending release of a drug lot for distribution, an attendant validated
manufacturing process is as critical as release testing. The release of a
product lot without the required process validation data is almost certain to
attract inspectors' attention. For parenterals in particular, concurrent process
validation studies must encompass all "critical processing parameters",
including bulk holding times. For example, data are considered incomplete
without established holding times for non - sterile bulks before filtration.
Bioburden as well as endotoxin tests also must be done on non - sterile
bulks. Inspectors say that such tests must occur during concurrent
validation.
FDAers increasingly have stressed calibration of lab equipment.For example,
spectrophotometer calibration must include an evaluation of accuracy in the
ultraviolet range. Other examples of incomplete calibration include
autoinjector calibration sans linearity and accuracy assessments and lack of
records that show specific temperatures during polarimeter calibration.
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Such process validation lapses were noted in a Jan. 27 warning letter sent to
Wyeth - Ayerst. In the warning, FDA alleged that holding times for non -
sterile bulks prior to sterile filtration were lacking for :
Amikacin Ephedrine Naloxone
Aminocaproic Furosemide Neostigmine
Atropine Gentamicin Phenobarbital
Chlorppromazine Hep-Lock Phenylephrine
Cyanocobalamin Heparin Phenytoin
Diazepam Hydromorphone Procainamide
Digoxin Isoproterenol Prochlorperazine
Diphenhydramine Lidocaine / epinephrine Reglan
Dopamine Lidocaine Robaxin - V
Dopram Meperidine SMX - TMP
Dopram - V Metronidazole Sodium chloride
Duramorph Morphine PCA Thiamine
Water for injection
The letter also claimed that process validation data were incomplete for
diazepam injection and atracurium besylate. FDA also charged that Wyeth -
Ayerst had released lots of bacteriostatic NaCl injection since 1994 without
process validation data.
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Documentation to prove validation of manufacturing procedures is critical to


GMP compliance, particularly for drug makers performing retrospective
validation. Firms that do not provide documentation may face a warning
letter.

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.

Regarding the documentation of validation, an FDAer told WDL Luitpold "may


feel" that it did, indeed, have all proper paperwork in place, and that the
matter is "not at all black or white". It can be difficult, the FDAer said, to
distinguish whether a firm has performed validation and failed to document it,
or simply never performed validation.
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The retrospective validation issue is less vague. All companies that perform
retrospectives must have written procedures in place, which are followed
scrupulously, the FDAer said. Luitpold, he said, clearly did not have such
procedures in place when the agency inspector examined the company's
facility.

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Consistent follow - up in batch failure investigation can make the difference


between compliance with good manufacturing practices (GMPs) and failure to
meet those standards. In particular, once a given drug batch has failed to
meet release specifications due to excessive impurities, for example quality
control managers must test other batches that "could have been similarly
affected", FDA stresses.

Additionally, drug firms must conduct a thorough failure investigation


including an assessment of causes behind out - of - specification results,
documentation supporting that conclusion and descriptions of corrective
actions. And, as recent warning letters bear out, the agency is interested in
the investigative procedure itself - written procedures must be available for
FDA review.
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The "consistent follow - up" theme applies to crude materials, as well as
finished drugs. Crude materials and recovered solvents must be tested and
the results documented to assure that they fall within validated process
control specifications. Quality Control managers should be prepared to
present written evidence that both crude materials and recovered solvents
produced in - specification finished products. FDA stressed.

Incidentally, in - process requirements for recovered solvents and crude


materials must be derived from process validation studies. Another area
where attention to detail plays a key role is with validation of production
procedures and process controls. Retrospective validation must be based
not only on finished product testing results, but must identify processing
parameters like time, temperature and equipment settings.

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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 :

1. No audit trail to track the number of templates accessed in calculations.


2. Inadequate password protection.
3. Automatic deletion of data files after a hard copy is generated.
4. No requirement to identify the user / analyst.
5. No time / date stamping of spreadsheet hard copies.

Though electronic record - keeping is a hot spot for Good Manufacturing


Practice (GMP) inspectors, it is not their only current priority. FDA continues
to stress that drug makers must conduct thorough investigations of any and
all batch failures, for instance. A crucial aspect of batch failure follow - up is
retesting, which must not only determine assignable cause, but also must
have documentation invalidating the out of specification results.
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Inadequate sanitation practices are another GMP issue being stressed by
inspectors. Contaminants found in drugs or process areas range from the
microbial to the mundane, and can include items like insect debris, sunflower
seeds and even fragments of latex gloves. Firms must assure that cleaning
procedures are capable of removing all identified contaminants. The
deviations discussed above and others were cited in a Nov. 26 warning letter
to Purepac (*). A firm official says over 50% of its corrections pre - dated the
letter.

TOP 10 REASONS FOR FDA RECA LLS IN THE RECENT YEARS

1. Deviations from current GMPs 6. Label mix - ups


2. Subpotency 7. Stability data do not support an
expiration date.
3. Dissolution failure 8. Product lacks stability
4. Pyrogen test failure 9. Content uniformity requirement
failure
5. Presence of foreign substance(s) 10. pH failure
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Though regular calibration of equipment is a critical inspection flash point
and an area in which the inspectors have noted increasing violations drug
plant workers need not calibrate all plant equipment, FDAers stress. Good
Manufacturing Practice (GMP) regulations are silent as to which specific
pieces of machinery are critical for calibration / maintenance purposes. An
FDAer in the compliance office said "the need for calibrating a given a piece
of equipment depends on its function."
What functions will inspectors focus on ? One type of equipment likely to
receive attention during a GMP inspection is that devoted to measuring
materials. The FDAer said that particular guideline is "self - evident". For
other types of equipment, the answer is less clear - cut. For example, relevant
GMP standards are interpreted by a 1978 preamble, requiring calibration for
any piece of equipment affecting "product quality".
To avoid arousing inspector suspicions, drug makers should keep clear,
detailed records outlining their calibration schedule for all pieces of
equipment. FDA expects firms to calibrate and / or otherwise maintain their
equipment according to an established schedule, the FDAer stressed. That
source suggested that companies tend towards inclusiveness in determining
which equipment to include in their calibration schedule.
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He also warned that plant records must show that a company is adhering to
its own schedule for calibration and maintenance. Specifically, records
should tell an inspector when a piece of equipment was last calibrated or
maintained, the results and any action taken, and the date of the next
scheduled check. While firms may label equipment with calibration dates at
their own discretion, the FDAer cautioned that such a tag alone "should not
be assumed to satisfy regulatory demands" ; documentation is required.

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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Any equipment involved in the manufacturing, processing, packaging or


holding of a drug, whether it is automatic, electronic or mechanical, must be
calibrated and inspected routinely to avoid violations like :
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! Failure to calibrate thermocoupler used to monitor temperatures of
depyrogenation ovens and autoclaves.
! Failure to periodically monitor chamber and surface of lyophilizers to
detect presence of oil and thermal fluid.
! Failure to calibrate thermometers and hygrometers used to monitor
temperature and humidity, particularly in filling areas.

Regular cleaning, sanitizing and maintaining equipment to prevent


contamination or malfunction should encompass such components as the air
vent filters used on the formulated bulk container, autoclaves and
depyrogenation oven, as well as nitrogen gas filters used on lyophilizers.
Moreover, records outlining the cleaning procedures (and their validation)
must be readily available for inspectors' review.

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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1. Placing sterile siliconized stoppers inside a filling machine hopper.


2. Failing to perform integrity tests, air velocity and smoke studies for the
filters supplying air to the filling areas.
3. Performing inoculation of subculture flasks and fermenters in an
uncontrolled environment.

Finally, quality control must conduct a thorough evaluation before approving


changes to specifications such as moisture. The above violations were noted
in a FDA warning letter sent to the Swiss Serum and Vaccine Institute Berne
at its facility in that city.
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1. The master coating formula contains a general statement allowing for
additional quantities of coating solution due to volume loss as a result of the
solvents in the materials. However, there is no specified limit to what can be
added. There is also no documentation to indicate that even after additional
solution is incorporated that each of the five coating pans receives only the
indicated total quantity of solution of ««««. kg which is reflected in the
formula.

2. 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.

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.

5. «.the master production record for«capsules fails to include coating


parameters such as spray rates, on/off cycles, tip size and distance from bead
bed.

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.

! 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.
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7. 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.

8. The master coating formula contains a general statement allowing for


additional quantities of coating solution due to volume loss as a result of the
solvents in the materials. However, there is no specified limit to what can be
added. There is also no documentation to indicate that even after additional
solution is incorporated that each of the five coating pans receives only the
indicated total quantity of solution of ««««. kg which is reflected in the
formula.

9. 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.

10. Manufacturing process validation protocols / SOP are inadequate, they :


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! Do not indicate the number of drug batches per product to be validated.
! Do not include installation qualification studies for equipment used to
manufacture tablets and capsules.
! Lack a description of the equipment to be used for manufacturing and
sampling.
! Do not describe the sample collection method.
! Lack a description of length and duration of the study.
! Lack criteria for a successful study.
! Lack a statement of situations in which the manufacturing process would
be revalidated.
! Fail to include the worst case operating conditions for finished product
dissolution and content uniformity.
! Fail to specify the operating speed ranges of the tableting and
encapsulation equipment.
! Fail to address different speeds of tableting and encapsulation
equipments.

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 :

1. 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.
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2. 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.

3. There is no evaluation of the effect if any, of the optional step of adding


water and of variable drying times.

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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16. «..documentation was not available to show that current manufacturing


processes are validated for «.. products which include 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.

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.

21. There was no documentation available regarding specifications for


processing parameters that affect the manufacturing process.

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:

a) Impurity profiles on the active ingredient were not addressed.


b) There were no parameters for particle size distribution of the final blends.
c) Mixing speeds were not monitored.
d) Sample sizes were too large to provide adequate information with respect
to blend uniformity.
e) The length of time bulk powder can be held in drums/totes prior to
compression or filling was not evaluated during validation studies.

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 :

! Do not indicate the number of drug batches per product to be validated.


! Do not include installation qualification studies for equipment used to
manufacture tablets and capsules.
! Lack a description of the equipment to be used for manufacturing and
sampling.
! Do not describe the sample collection method.
! Lack a description of length and duration of the study.
! Lack criteria for a successful study.
! Lack a statement of situations in which the manufacturing process would
be revalidated.
! Fail to include the worst case operating conditions for finished product
dissolution and content uniformity.
! Fail to specify the operating speed ranges of the tableting and
encapsulation equipment.
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! Fail to address different speeds of tableting and encapsulation
equipments,

3. Tablet compression is not validated.

! There is no statistical characterization of the hardness, thickness or tablet


weight of any strength of ««««. Tablet. A study was developed during
this inspection.
! Process capability studies have not been performed and process control
limits established for hardness, thickness or tablet weight. Compression
is monitored every «««.. minutes against release specifications. There
was no upper control and lower control limits (alert limits) for these
parameters.
! There are no procedures established to adjust compression force or
compression rate i.e. consecutive samples trending towards the upper
release specifications.

4. 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,
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! A tablet contained a piece of latex glove. While the amount of latex
contamination could not be identified, the batch was visually inspected
and released.

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.

8. No time frames / limitations have been established for production equipment


from end of use to start of cleaning.

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.

17. «.no trend analysis is performed on any complaints.

18. «.SOP for Compression operating procedure start-up « is inadequate , in


that it does not include any procedures to ensure that ,upon restart, there are
no partial tablets or residues left in the machine. Firm received 3 complaints,
from 3diferent pharmacies, regarding large tablets for lot «.the largest tablet
returned was found to contain 128.6% of « the USP limit for this product is
107%.

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´.

21. ««SOP for compression operating procedure start-up ««« is inadequate,


in that it does not include any procedures to ensure that , upon re-start, there
are no partial tablets or residues left in the machine. Firm received 3
complaints, from 3 different pharmacies, regarding large tablets for lot «..
The largest tablet returned was found to contain 128.6% of ««The USP limit
for this product is 107%.

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 :

! Firm's Quality Assurance Manager stated that approximately once per


month a discrepancy is found between package inserts used and those
remaining. This means that parts of a lot of product must have the caps
removed, the inner seals broken and the product checked for the insert.
No records are kept of these operations.

! 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.

32. 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.
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33. 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. `````````

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.

40. Traceability to the labels used during labeling operation is difficult.

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 :

! There is no impurity profile for bulk drug substance.


! Raw data does not support the particle size of the drug substance
specified by the firm and submitted to FDA.
! 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.
! 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.
! There is no evaluation of the effect if any, of the optional step of adding
water and of variable drying times.

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.

53. 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.

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.

64. 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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65. There is no written definition of the more than ««««. tablet defects which
production and in - process quality control inspectors monitor throughout
each batch.

66. There is no documented training of production or in - process quality control


inspectors in the various tablet defects.

67. There is no record of the in - process tablet defects found by production


operators during their checks every «««.. minutes throughout
compression.

68. Raw materials are stored in a "high - bay pallet" warehouse in building ««..

! There are no heat map studies to support monitored locations.


! There has been no temperature / humidity monitoring since ««..

69. Currently the most recent scale / balance calibration documentation is


inadequate in that there is incomplete information to confirm that the
equipment was checked for linearity throughout its operational range.
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70. All in-process measurement equipment is not identified in the batch records.
For example, the balance used to weigh the sample used for the loss on
drying determination for lot «««««. is not identified.
71. In some cases, manufacturing procedures lack sufficient detail. For example :
a. Step ««««. of the encapsulation batch record requires that the
temperature and relative humidity be recorded. There is no instruction
relative to the frequency of these checks during the encapsulation process
and whether any remedial action is required if significant temperature or
humidity deviations are observed.
b. Step ««««« of the encapsulation batch record states that if capsule
weights are outside the upper or lower limits then the affected capsules
must be quarantined and evaluated individually for acceptable weight. The
procedure for this evaluation is not identified.
72. Equipment cleaning 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".

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

2. Cleaning validation for ««««. is incomplete in that no conclusion /


evaluation / final report was prepared. Cleaning SOP «««. referred to in the
cleaning validation protocol and the protocol itself, fails to specify the
cleaning solutions used and to mention the use of alcohol. 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.
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3. 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.

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.

5. The firm fails to meet commitment made in NDA / ANDA applications as


follows :

! In spite of the firm¶s commitment to perform in-process blend uniformity


testing, only a composite of the blend is tested.

! 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.
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! 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.
6. 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,
! 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´.
7. 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.
8. 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.
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9. The master coating formula contains a general statement allowing for
additional quantities of coating solution due to volume loss as a result of the
solvents in the materials. However, there is no specified limit to what can be
added. There is also no documentation to indicate that even after additional
solution is incorporated that each of the five coating pans receives only the
indicated total quantity of solution of ««««. kg which is reflected in the
formula.

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.

11. Manufacturing process validation protocols / SOP are inadequate, they :

! Do not indicate the number of drug batches per product to be validated.


! Do not include installation qualification studies for equipment used to
manufacture tablets and capsules.
! Lack a description of the equipment to be used for manufacturing and
sampling.
! Do not describe the sample collection method.
! Lack a description of length and duration of the study.
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! Lack criteria for a successful study.
! Lack a statement of situations in which the manufacturing process would
be revalidated.
! Fail to include the worst case operating conditions for finished product
dissolution and content uniformity.
! Fail to specify the operating speed ranges of the tableting and
encapsulation equipment.
! Fail to address different speeds of tableting and encapsulation
equipments,
12. Tablet compression is not validated.
! There is no statistical characterization of the hardness, thickness or tablet
weight of any strength of ««««. Tablet. A study was developed during
this inspection.
! Process capability studies have not been performed and process control
limits established for hardness, thickness or tablet weight. Compression
is monitored every «««.. minutes against release specifications. There
was no upper control and lower control limits (alert limits) for these
parameters.
! There are no procedures established to adjust compression force or
compression rate i.e. consecutive samples trending towards the upper
release specifications.
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13. 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,

! During the cleaning validation of ««« capsules, 63% from spiked


samples was recovered.
! During the cleaning validation of «««« capsules, 89% from spiked
samples was recovered.

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,

! A tablet contained a piece of latex glove. While the amount of latex


contamination could not be identified, the batch was visually inspected
and released.
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15. 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.

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 :

! 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.
! The vendor version installed was designated «« yet after modifications
resulting from installation / operation qualification no new revision number
was given.

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.

26. The Validity Assessment Report was inadequate in that :

! The auditors failed to adequately support some of their conclusive


statements. For example, the drug substance «««« was erroneously
described by the auditors as having changed from unmilled to milled : the
process validation was evaluated as satisfactory without noticing that the
protocol was approved after the validation lots were completed.

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.

31. The returned goods procedure is inadequate in that :

a. The log of all materials received in the warehouse (³docklog´) is not


audited against the ³returns log´ to assure all returns are captured.
b. The returns log is not audited against the ultimate disposition of the
return.
c. There is no traceability of materials identified to be destroyed and a
specific destruction order.

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.

40. 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.

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 :

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.

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.

44. «.no trend analysis is performed on any complaints.


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45. «.SOP for Compression operating procedure start-up « is inadequate , in
that it does not include any procedures to ensure that ,upon restart, there are
no partial tablets or residues left in the machine. Firm received 3 complaints,
from 3diferent pharmacies, regarding large tablets for lot «.the largest tablet
returned was found to contain 128.6% of « the USP limit for this product is
107%

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´.

48. ««SOP for compression operating procedure start-up «««is inadequate ,


in that it does not include any procedures to ensure that , upon re-start, there
are no partial tablets or residues left in the machine. Firm received 3
complaints, from 3 different pharmacies, regarding large tablets for lot «..
The largest tablet returned was found to contain 128.6% of ««The USP limit
for this product is 107%.
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49. ««.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.

50. There are no SOP's or records to cover reworking of packaged tablets and
capsules. For example :

a. Firm's Quality Assurance Manager stated that approximately once per


month a discrepancy is found between package inserts used and those
remaining. This means that parts of a lot of product must have the caps
removed, the inner seals broken and the product checked for the insert.
No records are kept of these operations.
b. 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.

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).

57. 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.

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.

67. Traceability to the labels used during labeling operation is difficult.

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.

93. There is no documented training of production or in - process quality control


inspectors in the various tablet defects.

94. There is no record of the in - process tablet defects found by production


operators during their checks every «««.. minutes throughout
compression.

95. Raw materials are stored in a "high - bay pallet" warehouse in building ««..

1. There are no heat map studies to support monitored locations.


2. There has been no temperature / humidity monitoring since ««..

96. Currently the most recent scale / balance calibration documentation is


inadequate in that there is incomplete information to confirm that the
equipment was checked for linearity throughout its operational range.
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97. All in - process measurement equipment is not identified in the batch records.
For example, the balance used to weigh the sample used for the loss on
drying determination for lot «««««. is not identified.

98. In some cases, manufacturing procedures lack sufficient detail. For example :

a. Step ««««. of the encapsulation batch record requires that the


temperature and relative humidity be recorded. There is no instruction
relative to the frequency of these checks during the encapsulation process
and whether any remedial action is required if significant temperature or
humidity deviations are observed.
b. Step ««««« of the encapsulation batch record states that if capsule
weights are outside the upper or lower limits then the affected capsules
must be quarantined and evaluated individually for acceptable weight. The
procedure for this evaluation is not identified.

99. Equipment cleaning 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.
i   
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.
i   
107. During validation of the twin shell V blender the sampling procedure was not
specified.

108. 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.
i   

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.
i   

110. «Current written procedures do not assure that equipment is consistently


cleaned the same as it was during cleaning validation studies. For example
! The minimum hot city water rinse used to clean filling line« during
validation studies was « written procedure allows a minimum hot water
rinse of «
! The data collection sheet show that holding tanks were manually
scrubbed with a scotch bright sponge after compounding. Written
procedure does not require scrubbing of tanks. The procedure states
scrubbing may be done when ³deemed necessary´.
! The data collection sheet for this validation study show that compounding
and holding tanks were manually scrubbed using soft sponges and/or
stainless sponges after compounding of « the compounding tanks were
scrubbed for up to « minutes.written procedure states only that manual
scrubbing may be required. It does not require the scrubbing and does
not specify what to use or how. Long to scrub the tank.
x 
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

2. Cleaning validation for ««««. is incomplete in that no conclusion /


evaluation / final report was prepared. Cleaning SOP «««. referred to in the
cleaning validation protocol and the protocol itself, fails to specify the
cleaning solutions used and to mention the use of alcohol. 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.
x 
3. 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.

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.

5. Manufacturing process validation protocols / SOP are inadequate, they :

! Do not indicate the number of drug batches per product to be validated.


! Do not include installation qualification studies for equipment used to
manufacture tablets and capsules.
! Lack a description of the equipment to be used for manufacturing and
sampling.
! Do not describe the sample collection method.
! Lack a description of length and duration of the study.
x 
! Lack criteria for a successful study.
! Lack a statement of situations in which the manufacturing process would
be revalidated.
! Fail to include the worst case operating conditions for finished product
dissolution and content uniformity.
! Fail to specify the operating speed ranges of the tableting and
encapsulation equipment.
! Fail to address different speeds of tableting and encapsulation
equipments,

6. Some cleaning validation studies conducted on various tableted products are


incomplete. For example :

! 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.
x 
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

8. Cleaning validation for ««««. is incomplete in that no conclusion /


evaluation / final report was prepared. Cleaning SOP «««. referred to in the
cleaning validation protocol and the protocol itself, fails to specify the
cleaning solutions used and to mention the use of alcohol. 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.
x 
9. The Validity Assessment Report was inadequate in that :

! The auditors failed to adequately support some of their conclusive


statements. For example, the drug substance «««« was erroneously
described by the auditors as having changed from unmilled to milled : the
process validation was evaluated as satisfactory without noticing that the
protocol was approved after the validation lots were completed.

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 :

a. The log of all materials received in the warehouse (³docklog´) is not


audited against the ³returns log´ to assure all returns are captured.
b. The returns log is not audited against the ultimate disposition of the
return.
c. There is no traceability of materials identified to be destroyed and a
specific destruction order.

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.

26. There were no written methods for cleaning of active ingredients


/intermediates from the processing equipment. Cleaning methods in use were
not validated, as evidenced by repeated boil outs and failure of residue limits.
Residues have not been identified.

27. The cleaning validation protocol does not address time frames for cleaning.

28. Cleaning procedures for equipment used in the manufacture of product ««


have not been validated in that cleaning and testing must be repeated many
times before a negative result is obtained.
x 
29. The firm fails to meet commitment made in NDA / ANDA applications as
follows :

! In spite of the firm¶s commitment to perform in-process blend uniformity


testing, only a composite of the blend is tested.
! 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.
! 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.

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.

b. The HPLC testing of rinse samples detected an unknown, ³extra´ peak at


retention time of «««. There is no established limit for unknown HPLC
peaks during cleaning effectiveness studies. There was no investigation to
determine the identity of this peak, or its potential significance in product
or degradant residue testing,.

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 :

- The auditors failed to adequately support some of their conclusive


statements. For example, the drug substance «««« was erroneously
described by the auditors as having changed from unmilled to milled : the
process validation was evaluated as satisfactory without noticing that the
protocol was approved after the validation lots were completed.

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,

a. During the cleaning validation of ««« capsules, 63% from spiked


samples was recovered.
b. During the cleaning validation of «««« capsules, 89% from spiked
samples was recovered.

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.

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. «..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 :

- The dissolution testing machine was observed to be sitting on a bench top


that was vibrating. The dissolution test apparatus could be felt to be
vibrating when a hand was placed on the dissolution tank surface. The
vibration was being caused by two continuously operating bench top
stability chambers located on the same lab bench.

25. The HPLC methodology for the determination of «««««« is inadequate


because this method establishes the use of a working standard preparation of
double the expected sample concentration.

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 :

a. Your firm limits for chromatographic purity specifically is too permissible.


Your firm allows an RSD limit for the system suitability of not more than
(NMT) ««««« (which is too high).
b. A theoretical value of «««« (borderline) was reported at the beginning
of a chromatographic run. The theoretical value for the last injection of
the run was about ««««« indicating the degradation of the initial
system suitability conditions.
c. The equipment did not remain suitable during the whole chromatographic
run.
d. There are no studies that indicate stability for samples prepared for «««.
hours prior to the analysis determination.

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.

37. 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

38. SOP ««.. ³Repeat Analysis for Confirmation of Unexpected Results´ :

a. Does not establish a time limit for the investigation.


b. Uses re - sampling for rejecting analytical results.
c. Utilizes an ³outlier´ test for invalidating / rejecting content uniformity tests
(a statically based test)
d. Uses re - sampling to assume a sampling or preparation error.
x   
39. Regarding the firm¶s laboratory training :

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.

48. There is no assurance raw material samples of active components represent


each shipment of each lot.

- 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.

50. There is no knowledge, identification, or specifications established for


residual solvents or organic volatile impurities present in the active drug
substance «««.. In addition, «««««. raw material has not been qualified
from a microbiological perspective, total microbial limits have not been
established and potentially objectionable organisms have not been identified.

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.

a. Unwritten laboratory procedures, which had not received quality unit


approval, were used to invalidate out-of-specification disintegration results
for ««««««.. In laboratory investigation reports, analyst error was
inappropriately assigned.
x   
b. Lot «««« failed to meet assay specifications at the 24 month / 30 C
stability testing interval (expiration). Records show that at 18 months this
lot already showed a downward trend in assay, however, no further action
or monitoring was undertaken to insure this lot¶s potency through its
expiration date.
c. Hold times for «««««. were changed in the system via a memo from
the Pharmaceutical Technology group, bypassing the Quality unit decision
making responsibilities regarding specifications that affect drug quality.
d. The decision to recall «««« lot «««««, that had failed at a contract
laboratory was delayed more than two months until retest as well as
resample results were evaluated.
58. Complete independent analyses are usually not performed for the ³retest´
samples. Retest aliquots of injection products are usually all taken from the
same new vial or syringe or the same fresh pooled composite. For tests with
HPLC chromatographic methods, all of the samples are analyzed in the same
chromatographic run versus the same fresh standard solutions.
59. At least seven Laboratory Investigation Reports reviewed during the
inspection indicate the corrective action plan to instruct analysts to follow
procedures more carefully, all analysts involved had been certified to conduct
the analyses where analyst error was found to be the most probable cause for
the OOS results.
x   
60. Linearity, accuracy and selectivity degradation studies were done for assay
method validation. The chromatograms show tailing effect, but a tailing
factor calculation is not included in the firm¶s method validation protocol.

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.

63. FT - IR calibration procedures are inadequate to insure that the instrument is


properly operating and capable of generating accurate data. The firm¶s wave
number specification between ««««. and «««« is ««««« cm. The
National Institute of Standards specifications for this region is › 2 cm. There
is no historical data to justify the firm¶s procedure of calibrating analytical
instrumentation once or twice a year. The frequency of instrument calibration
and maintenance, and the procedures used to calibrate some instruments are
insufficient to insure that the equipment is functioning properly.
For example : HPLC detectors, pumps and injectors.
x   
64. Complaint «««« of yellowish colour in ««««, was investigated using
only Method «««. which uses a GC. Small broad peaks are noted in the
chromatograms of the complaint and retention samples. However, no
corroboration of those peaks was conducted nor other techniques were used
to determine the yellow contaminant in the complaint sample. No other
packaging presentations that used the same bulk or batch production
records, packaging records and laboratory records were investigated. Not all
the retain samples were inspected. Your firm¶s investigation was closed
stating that no strange peak was observed in the chromatograms.

65. There is no system for tracking out-of-specification microbiological test


results. For example, the firm uses «««.. biochemical test kits for
identification of gram negative bacteria. The test results are recorded on
cards, however, there is no system for tracking this data to assure that all
positive test results are followed up and that investigations are conducted in
a timely manner.

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:

a. No statement of equivalency was received from metal cap Supplier /


manufacturers that the metal caps used by firm in place of the HDPE caps
were > plastic caps as required in firm's protocol««

b. The Specification Document reveals that specifications for the metal caps
backing liner are not the same as plastic caps.

75. ««.Rayon USP was specified as a filler in bottles of «« tablets and


capsules .According to the specification sheet , (from manufacturer), the type
of rayon supplied did not meet USP specifications for absorbency nor
titanium dioxide content.

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 :

a. No lots were placed on stability when a manufacturing change occurred


and a heat tunnel was placed into use to aid in sealing ««««« plastic
cap inner seals that had repeatedly failed the normal sealing process.

b. Two lots of 50 mg capsules in 50 count bottles ; three lots of 100 mg


tablets in 500 count bottles and 6 lots of 100 mg capsules in 50 count
bottles all with the packaging change from plastic to metal caps were
manufactured and only one lot of each type was placed on accelerated
stability.

c. Approximately ««««.. lots have been manufactured with the packaging


change of substituting rayon for cotton as a filler. Only one lot of each
strength and bottle count was placed on accelerated temperature stability.
x   
78. Products with metal closures were released for distribution bearing 5 year
expiration dates before the 3 month accelerated stability studies had been
completed on the single lot placed on accelerated stability for each product
configuration and no room temperature data had been generated.
   
1. 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 :

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 to
demonstrate that the 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 a documentation to support the use of pour plate method rather


than the multiple tube method as described in the USP for products tested.
   
2. «. The samples for microbial testing ate prepared and examined on 2nd shift
where :

a. There are no formal training procedures for employees working in the


microbiology lab.
b. There has been no documented training of the employee who
independently works on the 2nd shift.
c. There is no system for the evaluation of employee (s) working in the 2nd
shift.

3. Failure to assure micro-organism reduction of atleast 10-6 in the bio-burden


challenge for the terminal sterilization process during validation when the
verification of the inoculating source showed only to contain micro-organism
at 10-4.

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.

7. ««.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 bio-burden testing.
   
8. «..Quality control unit does not maintain complete written record of
investigations, root causes and conclusions following unexpected processing
discrepancies or failures. For example :

a. Complete investigations were not conducted when non-sterile bulk


exceeds microbial limits of « CFU/ml.

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.

12. There is no system for tracking out-of-specification microbiological test


results. For example, the firm uses «««.. biochemical test kits for
identification of gram negative bacteria. The test results are recorded on
cards, however, there is no system for tracking this data to assure that all
positive test results are followed up and that investigations are conducted in
a timely manner.
   
13. The firm¶s Airborne and Surface Bioburden Monitoring of the production area
is deficient in that :

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).

c. The firm¶s corrective action for bioburden testing is inadequate, for


example :

1. There is no adequate documentation of the firm¶s corrective action when


microbial limits are exceeded.
2. The firm failed to adequately identify the micro-organism isolated during
microbial testing for future reference.

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.

18. Investigations into WFI contamination, which were found to be incomplete.


For example, there is no data to support the conclusion of the investigation,
which states that the ³most likely source of the micro-organisms is the saline
rinse´. There was no testing of saline solutions used on this test date.

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.

23. «««environmental monitoring of aseptic filling operations does not occur


during dynamic conditions.
   
24. ««The system in place which provides for supervisory review of sterility test
media sterilization cycles, does not assure that actual cycles are reviewed for
compliance with required cycles foe various media in various containers. Ex,
a batch of TSB was incorrectly autoclaved for 25 minutes instead of the
required 30 minutes, and the error was not detected through the normal
review process but was found during an investigation into an initial sterility
test failure.

25. Media Fills :

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)

29. 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.
   
30. SOP, µEnvironmental Monitoring Program¶ specifies warning and action limits
for sampling plates used to monitor the bioburden on the floors,walls and
machinery surfaces in the manufacturing areas. Validation studies have not
been performed to establish action and warning limits.

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.

32. ««.Review of the endotoxin reduction validation studies for ««products


revealed no control was conducted to determine the amount of endotoxins
that can be recoverd from receivers after seeding the tank with pyrogens.
   
33. The firm¶s current environmental monitoring report is inadequate. The report
does not trend the amounts or types of organisms found at each test location,
but reports monthly averages of organisms detected. The data is not trended
on a monthly basis but is reported annually.

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.

2. «..Quality control unit does not maintain complete written record of


investigations, root causes and conclusions following unexpected processing
discrepancies or failures. For example :

a. Complete investigations were not conducted when non-sterile bulk


exceeds microbial limits of « CFU/ml.

3. There is no system for tracking out-of-specification microbiological test


results. For example, the firm uses «««.. biochemical test kits for
identification of gram negative bacteria. The test results are recorded on
cards, however, there is no system for tracking this data to assure that all
positive test results are followed up and that investigations are conducted in
a timely manner.
   
4. The firm¶s corrective action for bioburden testing is inadequate, for example :

a. There is no adequate documentation of the firm¶s corrective action when


microbial limits are exceeded.

b. The firm failed to adequately identify the micro-organism isolated during


microbial testing for future reference.

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

1. ««.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 bio-burden testing.

2. 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.
   
3. 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)

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.

5. «««environmental monitoring of aseptic filling operations does not occur


during dynamic conditions.

6. SOP, µEnvironmental Monitoring Program¶ specifies warning and action limits


for sampling plates used to monitor the bioburden on the floors,walls and
machinery surfaces in the manufacturing areas. Validation studies have not
been performed to establish action and warning limits.

7. The firm¶s current environmental monitoring report is inadequate. The report


does not trend the amounts or types of organisms found at each test location,
but reports monthly averages of organisms detected. The data is not trended
on a monthly basis but is reported annually.
   
D. Environment :

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:««

4. 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.

5. Investigations into WFI contamination, which were found to be incomplete.


For example, there is no data to support the conclusion of the investigation,
which states that the ³most likely source of the micro-organisms is the saline
rinse´. There was no testing of saline solutions used on this test date.
   
6. Media Fills :

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.

7. ««.Review of the endotoxin reduction validation studies for ««products


revealed no control was conducted to determine the amount of endotoxins
that can be recoverd from receivers after seeding the tank with pyrogens.

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.

4. ««««.. Preventive maintenance checks performed mid-year for in-place


testing of HEPA filters in air supply units and area exhaust systems were
done incorrectly in that the zero reading of the installed magnahelic gauge
was not checked, and a reading was not obtained after the ³zero´ step to
compare to the initial reading.
 
5. 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 ««

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 :

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.

8. 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.

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.

c. The ultraviolet sanitizers (bulbs) are to be changed annually and the


sleeves are to be cleaned semi - annually. There is no record of the semi-
annual cleaning of the sleeves, nor is there any record of the microbial kill
effectiveness of the ultraviolet light sanitizers.

d. There is no record of the maintenance of the heat exchanger.

e. There is no documentation of a daily review of the system to assure the


integrity of the «««« gasket - clamp joints used to connect the stainless
steel piping from the water storage tank to the heat exchanger.

f. There is no record of the examination of welds, stainless steel piping, tank


and housings for internal contamination and passivity during the last
annual maintenance program. There is no passivation program for the
system.
 
g. There is no record of the maintenance of the «««« micron filter at the
air compressor for air used to operate the throttling valve, the divert valve
and the steam supply valve. The SOP requires annual changing of this
filter but there is no regular maintenance program for this filter.
13. ««Written preventative maintenance procedures not developed for the firm¶s
WFI systems. Leakage which moistened pipe insulation was blamed for
sample contamination during a water system investigation. In addition,
weekly sanitization sheets document that diaphragm«««.. has been leaking
since «««..

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.

19. Written procedures which describe the monitoring of pressure differentials


are not complete. The procedures do not describe the instruments used and
do not include instructions for the calculations needed to determine the
differentials between adjacent rooms. In addition, the calculations are not
recorded and the daily readings are not reviewed by anyone other than the
person recording the readings.

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 :

a. Process water in - line conductivity meter.


b. Process water ultraviolet treatment system.
c. Air filters / air handling system.

35. You do not have a formal procedure for the calibration of your «««««.
electronic label counter with ««««. Bar code reader.

36. .«there was no formalized installation/operational qualification of the air


handling /dust collection system installed««

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.