MANUFACTURING CONTROLS

# Observations Corrective Actions

Specifically, there is no written procedure which addresses the use of video recordings in the
conduct of quality issue investigations including the documented review and retention of individual
video sessions as a component of the investigation file. Numerous cameras are employed
throughout the facility in areas for manufacturing operations for both controlled drug products and
1. other drug products. Review of the firm’s investigation files as well as discussion with personnel
responsible for the initial handling of recordings and for transfer of those recordings to quality unit
personnel when requested for investigation purposes found that the purpose of video monitoring is
both for security and for use in the conduct of quality investigations

Specifically, cleaning validation studies conducted for verification of adequate removal of residual
detergent are conducted for new products in conjunction with validation of the adequate removal
of API residue, however, the detergent removal studies are limited to newly introduced equipment.
This observation is cited also in light of a relatively large number of investigations conducted by
the firm for failing cleaning validation results for a number of products. It is noted in virtually all
cases, the investigation conclusion was that the root cause was inadequate completion of the
2. written cleaning procedure by the responsible personnel.
Yet management has decided that a single cleaning validation for detergent removal is sufficient
to cover all future products/processes using the same equipment. Quality unit management
responsible for the investigation and follow-up actions did not address evaluation of the
effectiveness of the training/retraining of employees with respect to the use of cleaning
procedures.

Specifically, responsible quality unit personnel have not insured that blend hold time studies are
conducted for product blends stored in alternative storage containers. For example, review of hold
time summary reports and batch production records found that ….. tablet blends may be stored in
either drums or large intermediate bulk containers, however, hold time studies were conducted
3.
only for drum storage. It was also found that while the hold time studies for ….. tablet blends were
conducted for a maximum of ….. days, there was no statement inserted into batch production
records to provide this shorter hold time to replace the standard instruction that blends are not to
be held for more than ….. days.

Specifically, information provided by the firm during the FDA inspection showed discrepancies in
the information as follows:
a. Two copies of the same completed form, signed by the quality unit on ….., were provided
to FDA on two different dates during the inspection. The second copy of the form
contained undated and un-initialed information that was added after it was signed.
4.
b. The addition of undated and un-initialed information was not consistent with SOP …..,
which reads in part, “Errors identified during review may be corrected if ….. Blank entries
identified during review that can be independently verified from a valid and accurate
source should be noted by stating entry was omitted, list fact related to omission and
initial and date explanation.”

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MANUFACTURING-STERILE PRODUCT CONTROLS

# Observations Corrective Actions

Specifically, the following was observed during the post-fill cleaning of SVP ….. filling equipment
and room
a. The ISO 5 rigid barrier doors around the SVP ….. filling equipment were not closed as
soon as possible after change parts were disassembled or after wiping equipment
surfaces. One rigid barrier door remained open for more than twenty minutes.
b. Operators were observed leaning their torso on the ISO 5 filling equipment platform while
disassembling change parts. For example, an operator was seen leaning on the platform
while removing ….. The platform areas where operators were leaning are not routinely
monitored for microorganisms.
c. . ….. was added to a plastic bucket and packages of wipes moistened with ….. to clean
1. the filling equipment, rigid barriers, tables, shelves, steps, and air returns. Operators
sharing the bucket did not sanitize their hands after discarding used wipes and before
reaching into the bucket for a clean wipe.
d. An operator picked up a pile of discarded wipes from the floor and placed them into the
pass-through, then without sanitizing hands reached into the shared plastic bucket
containing ….. and wipes for a clean wipe.
e. One operator using the shared bucket was observed cleaning air returns near the floor
while another operator was sanitizing tables.
f. An operator sanitized air returns near the floor in room ….. then sanitized a higher shelf
unit used to stage sterile wipes, laminated procedures, and materials used in aseptic
production.

Specifically,
a. SOP ….. “EM Data Recording, Interpretation and Corrective Action,” is deficient in that it
does not require a response to non-viable particulate alarms if the alarms are single
alarms. The alarms are only triggered if established limits are exceeded. For example, on
….., during the production of batch ….., there was no documented response or
2. investigation for the following single non-viable particulate alarms: …..
b. Operators failed to respond to non-viable particulate monitoring alarms as required by
SOP ….., which reads in part: “ If there are multiple non-consecutive alarms – notify QA-
EM Manager and EM Supervisors for instructions.” SOP ….. reads in part “Start an
investigation as soon as an alarm is noted.” There was no documented response or
investigation to multiple non-viable particulate alarms at multiple locations on …..

Specifically, controls have not been established specifically to prevent potential mix-ups of
unlabeled and unmarked stability sample vials stored in totes within the stability chambers as part
3. of ongoing stability studies. Stability samples are stored as unlabeled bright stock in totes within
stability chambers.

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PACKAGING & LABELING CONTROLS

# Observations Corrective Actions

Specifically,
a. Your firm failed to adequately qualify each of your packaging lines as part of your
relocation of packaging operations to ….. Although Installation Qualification (IQ) and
Operational Qualification (OQ) were conducted on the slat filler, bottle unscrambler,
capper, labeler system, desiccant feeder, and induction sealer for each of the packaging
lines, Performance Qualification (PQ) was limited to the evaluation of only one batch of
one drug product on only one of the packaging lines.
b. The Equipment Qualification Report associated with the packaging line qualification
erroneously indicates that no deviations were encountered during the packaging of the
1. aforementioned (PQ) batch. However, review of the Batch Production Records for lot …..
found there was an unexplained interruption in packaging operations which lasted over
….. hours. The only documentation is a note in the Bottle Fill Test Record which reads
“Machine Down.” The investigation was not documented as a formal deviation.
Consequently, the impact of this “anomaly” on the results of your (equipment)
qualification, or on resultant product quality was not considered.
c. The Change Control under which the relocation of packaging operations was to be
managed has not yet been signed as approved by the Quality Unit, however, the
Equipment Qualification report ….. was signed as completed on ….. Furthermore, over
….. batches of finished drug product have been packaged and distributed since that
time.

Specifically, the firm identified that out of ….. packaging line cleans conducted, only …..% were
completed correctly or “Right First Time (RFT)” in CAPA ….. However, CAPA ….. was cancelled
without adequate corrective action. Corrective action such as training of operators or packaging
line personnel has not been identified or implemented as corrective action to date. As a result,
2. there has been an increase in foreign items found in all ….. packaging lines. To date, only a plan
to form a team has been identified as corrective action in CAPA ….. For example, in June alone
there were ….. exceptions initiated related to foreign items in the packaging rocess/product, yet
action items have not been identified within 30 days, per SOP …..

Specifically, the firm has no written procedure which delineates a limit to how many in-process
weight check failures can occur during the filling/packing processes for their foil-pac drug products
before a formal investigation must be initiated. Since ….., the firm has received at least …..
complaints for empty or under filled ….. Cream foil-pacs, yet, the firm has never implemented a
corrective and/or preventative action (CAPA)
3.
that requires in-process foil-pac weight check failures to be formally investigated after a pre-
determined threshold is met. SOP ….. does not contain any limits around how many in-process
weight check failures can occur during a definite production period (i.e. per packaged lot, per shift,
etc.) before a formal investigation must be opened to assess filler/packaging machine stability and
excessive machine drift.

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MEDICAL DEVICE-MANUFACTURING CONTROLS

# Observations Corrective Actions

Specifically, the results and/or dates of management reviews are not documented.
a. Management Review Meetings ….. were documented to be rescheduled for the next
subsequent month. The note to file states the Management Review Meeting scheduled
for ….. will cover data for ….. A Management Review Meeting was held on ….. The
1. signed Management Review Certification Form does not state the months of ….. were
covered.
b. The monthly Site Quality Management Review Meeting was not held as scheduled. A
note to file was not present to justify the cancellation of the meeting or when the meeting
would be rescheduled.

Specifically, for Management Reviews ….., there is no objective evidence on the Management
Review Agendas or the Management Certification Forms indicating consideration was given to the
inputs listed in the Management Review & Quality Governance Procedure. The Management
Certification Forms lack “N/A” next to the input stating the input is not applicable for the meeting.
In addition, Quality Manual states which inputs at a minimum must be covered at each
Management Review Meeting. All listed minimum inputs were not indicated as being covered at
each meeting.
2. a. The current agendas do not document which inputs were considered for the meetings.
b. There is a discrepancy between the Management Review Certification Forms and the
Management Review Agendas for ….. The form indicated that all inputs were evaluated
at the meetings, however, the agendas do not reflect the inputs were evaluated.
c. REPEAT - The firm has not added Risk Management and Design Control/Transfer to the
Management Review Agenda as stated in the firm’s response to FDA 483 Inspectional
Observations dated ….. To date, Design Transfer and Risk Management have not been
considered or discussed in Management Review Meetings as evidenced by the agendas.

Specifically, Section ….. of your current Corrective and Preventive Action Procedure, does not
adequately define requirements to verify and/or validate corrective and preventive actions prior to
implementation in that it includes the words “if applicable.” Additionally, you have not verified
and/or validated actions prior to implementation. For example:
a. You did not, prior to implementation, verify/validate actions proposed under CAPA’s …..
which both covered actions to prevent product mix-ups at locations where multiple
products/lots are simultaneously handled. Further, these proposed actions were found by
3. your firm to be ineffective once implemented.
b. You did not, prior to implementation, verify/validate actions proposed under CAPA …..
covering relocation of environmental sample sites which eliminated viable surface
monitoring for the ….. Gowning Room.
c. You did not, prior to implementation, verify/validate actions proposed under CAPA …..
covering changes to your packaging and Pouch Sealing procedure, in order to ensure
against reuse of vials.

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