Edited Excerpts From Actual 483 Observation Reports by Food and Drug Administration Investigators

district address
date of issue
March 15, 2016
GMP Trends Inc.

P.O. Box 8001
Boulder, Colorado 80306
c.i. issue
Issue #940
name and title of individual to whom report is issued
To: Responsible Person, Director of Quality Assurance

firm name
street address
Pharmaceutical and Related Industries

city, state and country
5600 Regulation Lane

type of establishment inspected
United States of America and Worldwide
Pharmaceutical and Medical Device
during a review of inspection reports of u.s. firms (i) (we) observed:
EDITED EXCERPTS FROM ACTUAL 483 OBSERVATION REPORTS

BY FOOD AND DRUG ADMINISTRATION INVESTIGATORS
MANUFACTURING CONTROLS
1. ..All records of production, control, distribution, and components associated with a batch of drug product are not maintained at
least one year after the expiration date.
Specifically, your firms Quality Assurance (QA) department maintains Document/Attachment Distribution

Logsheets to track records, forms and other documents as required by SOP .. During the review of a
Document/Attachment Distribution Logsheet, your QA Document Control Specialist indicated that it is part
of your firms normal practice to destroy current records that contain errors or mistakes. When asked
to provide the returned records for review, the QA Document Control Specialist stated that all returned
documents are shredded.
2. ..There are no written procedures for production and process controls designed to assure that the drug products have the
identity, strength, quality, and purity they purport or are represented to possess.
Specifically, the process validation for .. capsules was not adequate in that the encapsulation process was

not consistent and resulted in excessive rejects, low assay, and/or low yields in two out of four validation
batches. Improper set-up and operation of the Automatic Capsule Filling Machine .. was identified as
the root cause of Incident Investigations .. but adequate corrective and preventive action was not taken
to improve the performance of the encapsulation equipment to ensure a consistent and reproducible
manufacturing process.
3. ..Equipment for adequate control over air pressure, humidity, and temperature is not provided when appropriate for the
manufacture, processing, packing or holding of a drug product.
Specifically, the .. Room Monitoring System is used to monitor and control the temperature and relative

humidity in drug manufacturing suites and supporting areas. While you generated data regarding the Limit
Alarms and Technical Alarms, your Quality, Engineering and Production Departments do not evaluate this
information to identify if there are drift and/or trends in your processing controls that should be adjusted or
corrected.
4. ..Equipment for adequate control over air pressure, humidity, and temperature is not provided when appropriate for the
manufacture, processing, packing or holding of a drug product.
Specifically, there is no time requirement specified in SOP .. or any other written procedures for

acknowledging .. alarms.
a. The VP of Quality stated your facility had a technical alarm on .. The alarm was sent via email notification
to the Production Manager, Production Supervisor, Quality Assurance Supervisor, and Engineering
Manager. The alarm went unacknowledged until .. (2 days), and it was not investigated until .. There
is no temperature or humidity data recorded for your cGMP controlled vault area where DEA controlled
APIs and finished drug products were stored during this time period.
b. While touring the facility, there was a .. alarm. The Production Manager accessed a list of current
alarms after we questioned him about the auditory alarm we heard in the Compression Suite. There
were four alarms that had not been acknowledged. Each of these alarms were acknowledged by the
Production Manager at 1:27 pm on .. Approximately 54 hours had elapsed since the first alarm was
acknowledged.
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OF THIS PAGE
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GMP TRENDS INC.
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Editor
date issued
03/15/16
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2016 GMP TRENDS, INC. FAX (303) 443-3317, PHONE (303) 443-8716, e-mail: [email protected], www.gmptrends.com
Photocopying without permission is strictly prohibited. See page 3.
district address
date of issue
March 15, 2016
GMP Trends Inc.

P.O. Box 8001
c.i. issue
Issue #940

firm name
street address


MANUFACTURING-STERILE PRODUCT CONTROLS

1. ..Routine checking of mechanical equipment is not performed according to a written program designed to assure proper
performance.

Specifically, the firms water generation system has various parameters with alarm set points that
alert personnel when these parameter set points are not respected. Alarm conditions are documented
in accordance with SOP .., however, the reason for the alarm is not always documented. There is no
documentation indicating what action was taken to correct the alarm condition and no evaluation of the
impact on the water system was documented.
2. ..There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet
any of its specifications whether or not the batch has been already distributed

Specifically, investigations into non-conformances (NCRs) are inadequate. For example, multiple action
level environmental excursions were reported for all eight RO loop ports on .. The firms investigation
(NCR ..) stated the root cause is inconclusive. The investigation did not include an evaluation of water
generation system alarms, low RO tank water levels, the impact of the valve leak repaired on .., incoming
feed water quality or assess the impact on WFI quality for the same time period.
3. ..Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

Specifically, methods for the trending of various microbiological data proceduralized in SOP .. are deficient
in that the procedure does not define what constitutes a negative trend, nor delineate the interpretation of
data. For example, Environmental Monitoring .. Trend Report for .. exhibited a 00.66% contamination rate
for .. area. Discussion with management revealed there is a target expectation of .. or less contamination
rate. However, this expectation is not defined in SOP ..
4. ..Equipment and utensils are not sanitized at appropriate intervals to prevent contamination that would alter the safety, identity,
strength, quality or purity of the drug product.

Specifically, the thermal paper used in the .. non-viable particle counter is not decontaminated prior to
use within the aseptic core. The outer bag is sanitized and once inside the core the thermal paper is placed
into the equipment without being sanitized. Discussion with management confirmed that the thermal paper
is not sterile. The sanitization process to preclude the ingress of non-viable and viable particles is not
adequate.
5. ..Employees engaged in the manufacture, processing, packing and holding of a drug product lack the training required to
perform their assigned functions.

Specifically, QA Inspectors responsible for performing incoming inspection of drug product containers and
closures for minor, major and critical defects in accordance with SOP .. had inadequate training. Six of
nine QA Inspectors assigned to this job function never had training in the QA inspection of .. syringe safety
guards or plunger rods. In addition, training quizzes administered to assess the effectiveness of training
received were incorrectly given a passing score of 100%.
6. ..There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet
any of its specifications whether or not the batch has been already distributed.

Specifically, not all potential root causes are explored for the complaint defect types. For example, during
the complaint investigation process for .. the retain samples of container closure components are not
always examined for critical quality attributes which could contribute to the malfunction of the .. prefilled
syringe. Complaint data is not trended and tracked in a manner that may alert the firm of quality problems.
SEE REVERSE
OF THIS PAGE
GMP TRENDS INC.
Editor
date issued
03/15/16

Information contained in this report has been edited and reproduced from actual FD 483 inspection observations and related reports. This information is made available twice
monthly to quality minded executives by GMP TRENDS, INC. No analytical evaluation or interpretation of the contents of this report and its significance to GMP regulations
is intended.
Page 2
district address
date of issue
March 15, 2016
GMP Trends Inc.

P.O. Box 8001
c.i. issue
Issue #940

firm name
street address


LABORATORY CONTROLS
1. ..The responsibilities and procedures applicable to the quality control unit are not fully followed.

Specifically, it is noted that corrective actions proposed/initiated in response to several specific regulatory
observations cited by an FDA inspection two months prior to this current inspection were handled by change
control rather than through the CAPA system. As acknowledged in the firms CAPA procedure, it is the CAPA
system which is intended to track and evaluate over time the adequacy of corrective actions. In citing this
FDA 483 observation, regulatory issues which were not handled through the CAPA system include:

a. Failure to initiate CAPAs to evaluate the effectiveness of corrective actions which were limited to multiple
retraining sessions of the same personnel for the same issues following ten (10) Laboratory Failure
Reports and fifty-six (56) Laboratory Deviation Notices which concerned analyst errors.
b. Failure to initiate CAPAs to evaluate the identified root cause(s) and corrective actions despite ninety (90)
Laboratory Deviation Notices which led to retesting of the sample sets in each case.
2. ..The responsibilities and procedures applicable to the quality control unit are not fully followed.

Specifically, in response to our inquiry during the current inspection as to why issues were handled through
change control rather than CAPA, it was stated that if management determines at a later date that the issues
continue, they can decide to initiate a CAPA. This approach fails to recognize the cGMP role and regulatory
expectation regarding the use of a CAPA system as the mechanism for initiating corrective actions and for
conducting documented tracking and evaluation of the effectiveness of corrective actions.
3. ..The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.

Specifically, a definitive root cause for historical repeated and inconsistent system suitability failures during
.. purity analyses has not been determined. Previous investigations and CAPA did not fully address the
issue which has resulted in the exclusion of HPLC for this method. This problem resulted in the following
delays:

a. Stability testing for at least 6 lots was delayed up to 85 days from the target test date.
b. Bulk (in-Process) and initial release testing results were delayed up to 2 months for multiple lots. There
is inadequate assurance that this problem has been fully addressed and will not affect future analyses.
4. ..Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to
assure that in-process materials and drug products conform to appropriate standards of identify, strength, quality and purity.

Specifically,
a. Your firm is using the average peak area response of duplicate injections in the calculation and reporting
of assay results for .. USP. There is no evaluation of the individual assay injections.
b. There is no documentation of HPLC test injections of standards made prior to conducting the system
suitability injections.
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OF THIS PAGE
GMP TRENDS INC.
Editor
date issued
03/15/16

Contents of GMP TRENDS are protected by U.S. Copyright Law. Reproduction of any type is strictly prohibited by law. Authorization to photocopy for internal or personal
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Page 3
district address
date of issue
March 15, 2016
GMP Trends Inc.

P.O. Box 8001
c.i. issue
Issue #940

firm name
street address


MEDICAL DEVICE-MANUFACTURING CONTROLS

1. ..Complaints involving the possible failure of a device to meet specifications were not investigated where necessary.

Specifically, your firm could not provide adequate documentation for investigations associated with
post remediation complaints. Your firm identified .. categories of issues during remediation. During
remediation, mitigations were done for all known root causes. Per your firms Engineering VP, all known root
causes associated with the symptoms were identified and the associated CAPAs were closed as effective.
However, during our review of complaints, it was noted that complaints were still being received for issues
that had been identified as having been addressed, however, issues are still occurring under .. categories.
Your firm provided trend analysis documentation, however, this documentation did not include root cause
analysis associated with the post .. issues.
2. ..Procedures for corrective and preventive action have not been adequately established.

Specifically, during the review of investigation records it was noted that corrective actions were being taken
without opening a CAPA, those actions were classified as corrections as opposed to corrective actions.
Your firms CAPA procedure .. defines a correction as .. When a correction is made without opening a
CAPA, there is no CAPA Action Plan or effectiveness check done on the action(s) taken. Of the investigations
reviewed, .. investigations identified corrections taken, however, there was no documentation of a CAPA
Action Plan or effectiveness check.
3. ..Procedures for training and identifying training needs have not been adequately established.

Specifically,
a. Training requirements for employees are not documented. Compliance Associate .. decided which
work instructions (equipment) warehouse personnel should be trained in. However, no training record
was found for this equipment in the warehouse employees training file.
b. Information (quantity of labels returned to stores) recorded on your Device Labeling Record is not being
correctly captured by employee .. who performs product labeling.
c. There was no evidence provided to show that your firms Quality Policy is understood by employees who
may not be proficient in the English language.
4. ..Products that do not conform to specifications are not adequately controlled.

Specifically, your firm maintains a SOP .., Non-Conforming Materials, which states the system is intended
for documenting rejection of materials which fail to meet specifications and disposition. Review of your
firms Non-Conformance Logs revealed that your firm has never documented any non-conforming product.
However, upon review of device history records, it was discovered that these records had discrepancies that
were not identified or documented as such.
5. ..Complaints involving the possible failure of a device to meet specifications were not investigated where necessary.

Specifically, .. complaints did not have adequate documentation of an investigation. Your firm provided
trend evaluation reports with associated .. to known issues. Per SOP .., Complaint Handling, a root
cause investigation is a detailed inquiry or systematic examination to determine the underlying causes(s)
that resulted in a device failure or adverse trend. The trend evaluation reports and referenced data do not
address the requirement of the procedure as stated.
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OF THIS PAGE
GMP TRENDS INC.
date issued
Editor

INSPECTIONAL
Published by GMP TRENDS, INC. P.O. Box 8001, Bulder, Colorado 80306, PHONE (303) 443-8716, FAX (303) 443-3317
e-mail: [email protected], www.gmptrends.com 2016 GMP TRENDS , INC.
Photocopying without permission is strictly prohibited. See page 3.
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03/15/16
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district address

March 15, 2016

GMP Trends Inc.

name and title of individual to whom report is issued

To: Responsible Person, Director of Quality Assurance

Pharmaceutical and Related Industries

5600 Regulation Lane

United States of America and Worldwide

Pharmaceutical and Medical Device

during a review of inspection reports of u.s. firms (i) (we) observed: