Note: Although this FDA-483 is an
accurate representation of the original FDA-483 issued to the firm, it is not an exact
copy. Slight modifications to the original FDA-483 have been made to accommodate its
conversion to the HTML format. A scanned copy of the original FDA-483 is available in PDF format on this website. |
DEPARTMENT
OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION |
DISTRICT
OFFICE ADDRESS AND PHONE NUMBER
10 Waterview Blvd., 3rd Floor
Parsippany, NJ 07054
(973) 526-6000 Fax:(973) 526-6069
|
DATE(S)
OF INSPECTION 05/02/2005 -
07/01/2005* |
FEI
NUMBER 3004106764 |
NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED
TO: Garth
(NMI) Boehm, Ph.D., Senior Vice President, Chief Scientific Officer
|
FIRM
NAME
Able Laboratories, Inc. |
STREET
ADDRESS
One Able Drive |
CITY,
STATE AND ZIP CODE
Cranbury, NJ 08512 |
TYPE
OF ESTABLISHMENT INSPECTED
Generic Pharmaceutical Manufacturer
|
This document lists
observations made by the FDA representative(s) during the inspection
of your facility. They are inspectional observations, and do not
represent a final Agency determination regarding your compliance.
If you have an objection regarding an observation, or have implemented,
or plan to implement, corrective action in response to an observation,
you may discuss the objection or action with the FDA representative(s)
during the inspection or submit this information to FDA at the address
above. If you have any questions, please contact FDA at the phone
number and address above. |
The observations
noted in this Form FDA-483 are not an exhaustive listing of objectionable
conditions. Under the law, your firm is responsible for conducting
internal self-audits to identify and correct any and all violations
of the quality system requirements. |
DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:
Quality System |
OBSERVATION 1
The quality control unit lacks authority to fully investigate errors
that have occurred.
The Quality Unit and Senior Management failed to assure all drug
products distributed have the safety, identity, quality, and purity
that they are represented to possess. The Quality Unit failed to:
review electronic data as part of batch release, review computer
audit trails in the Waters Empower Data Acquisition System and provide
adequate training to analytical chemists. These practices led to
the Quality Unit releasing batches of drug products which failed
to meet in-process, finished product and stability specifications.
These practices also led to the submission of erroneous data in
Annual Reports and Prior Approval Supplement # 004, for ANDA 75-838,
which requested discontinuance of Blend Uniformity testing for Propoxyphene
Napsylate and Acetaminophen 100mg/650 mg Tablets. The lack of Quality
oversight resulted in: the ceasing of manufacturing on 5/13/05
5/19/05, the ceasing of distribution of all drug products on 5/26/05
5/13/05, the recall of all batches (3,184) of drug products
and the withdrawal of at least five Abbreviated New Drug Applications.
|
OBSERVATION 2 Drug products failing to meet
established standards, specifications, and quality control criteria
are not rejected.
Samples of drug products were routinely resampled, and re-injected
or reprocessed in the [REDACTION]
System during testing in the QC Laboratory when out of specification
(OOS) results were obtained. There were no Laboratory Investigations
into OOS results or notebook documentation available to explain
the re-injection or retesting of in-process, finished product and
stability samples which did not meet specifications. The OOS results
were not reported and within specification results from reprocessed
or re-injected samples were reported on: In-Process Specification,
Product Specification and Stability Study Specification Release
Reports and Stability Summary Reports.
Examples of drug products which were released with OOS values are
listed below.
Product/Batch # |
Sample |
Original OOS Result |
Reported Results |
Acetaminophen & Codeine Phosphate Tablet, 300/30 mg
Batch 502022 |
In-Process
Blend Uniformity
Testing |
Codeine Phosphate
% RSD: 5.4
Spec: [REDACTION] |
Codeine Phosphate
% RSD: 3.8 %
Spec: RSD < = [REDACTION] |
Acetaminophen & Codeine Phosphate Tablet, 300/30 mg
Batch 407148
|
Finished Product
Testing
|
Codeine Phosphate Content Uniformity
% RSD: 8.3 %
Spec: RSD [REDACTION]
|
Codeine Phosphate
Content Uniformity
% RSD: 5.5 %
Spec: RSD < [REDACTION] |
Atenolol 25 mg Tablet
Validation Batch 408107A
|
Stability
Sample
3 mo RT
|
Dissolution , Tablet
D5 = 83.7%
D6 = 83.8%
Spec: NLT [REDACTION]
|
Dissolution , Tablet
D5 = 98.9%
D6 = 98.7%
Spec: NLT [REDACTION] |
Atenolol 25 mg Tablet
Validation Batch 408107B
|
Stability
Sample
3 mo RT
|
Dissolution Testing
Tablet D6 = 30.9%
Spec: NLT [REDACTION]
|
Dissolution Testing
Tablet D6 = 102.8%
Spec: NLT [REDACTION] |
Atenolol 25 mg Tablet
Test Batch
TB-203E
|
Stability
Sample
3 mo RT
|
Dissolution , Tablet
D5 = 83.7%
D6 = 83.8%
Spec: NLT [REDACTION]
|
Dissolution , Tablet
D5 = 98.9%
D6 = 98.7%
Spec: NLT [REDACTION] |
Bethanechol Chloride 10 mg Tablet
Validation Batch 404042A
|
Stability
Sample
9 mo RT
|
Assay
A1 = 89.6%
Spec: [REDACTION] |
Assay
A1 = 99.5%
Spec: [REDACTION] |
Diphenoxylate HCl and Atropine Sulfate Tablets
Batch 404006
|
In-Process
Blend Uniformity
Testing
|
Blender Location:
BR1 = 128.5%
ML2 = 158.3%
TL2 = 117.6%
Spec. [REDACTION]
|
Blender Location:
BR1 = 99.5%
ML2 = 101.6%
TL2 = 108.3%
Spec. [REDACTION] |
Diphenoxylate HCl and Atropine Sulfate
Tablets
Batch 403203
|
In-Process
Blend Uniformity
Testing
|
Blender Location:
TR1= 145.9%
Spec: [REDACTION] |
Blender Location:
TR1 = 96.9 %
Spec: [REDACTION] |
Diphenoxylate HCl and Atropine Sulfate
Tablet, Batch 301068A
|
Stability
Sample
21 mo RT
|
Assay
A1 = 78.4%
A2 = 78.7%
Spec: [REDACTION]
|
Assay
A1 = 90.4%
A2 = 90.8%
Spec: [REDACTION] |
Diphenoxylate HCl and Atropine Sulfate
Tablet, Batch 301068B
|
Stability
Sample
21 mo RT
|
Assay
A1 = 77.5%
A2 = 77.5%
Spec. [REDACTION]
|
Assay
A1 = 90.11%
A2 = 89.8%
Spec: [REDACTION] |
Diphenoxylate HCl and Atropine Sulfate
Tablet, Batch 301068C
|
Stability
Sample
21 mo RT
|
Assay
A1 = 75.8%
A2 = 78.4%
Spec: [REDACTION]
|
Assay
A1 = 89.41%
A2 = 90.7%
Spec: [REDACTION] |
Dytan Suspension 25mg/5ml
Batch L409001
|
Finished Product Testing |
Assay - Beginning
A2 = 89.2%
Spec: [REDACTION]
|
Assay - Beginning
A2 = 97.9%
Spec: [REDACTION] |
Methylphenidate HCl Tablets, 20 mg Extended Release
Batch 303087
|
Finished Product Testing |
Dissolution (1 Hour) Tablet: D1: 48.9%
D2: 49.0%
D3: 48.2%
Spec: [REDACTION] (1 hour)
|
Dissolution (1 Hour)
Tablet: D1: 43.4%
D2: 43.3%
D3: 42.4%
Spec: [REDACTION] (1 hour) |
Methylphenidate HCl Tablets, 5 mg
Batch 412184
|
Finished Product Testing |
Assay
A1 = 90.0%
A2 = 90.0%
Spec. [REDACTION]
|
Assay
A1 = 98.4%
A2 = 98.5%
Spec. [REDACTION] |
Nitroglycerin 0.4 mg Sublingual Tablets
Batch 502038
|
Finished Product Testing |
Assay
A1 = 75.8%
Spec. [REDACTION]
|
Assay
A1 = 101.5%
Spec: [REDACTION] |
Prochlorperazine
Suppositories, 2.5 mg
Batch 308029A
|
Stability Sample
12 mo RT
|
Unknown Impurities
0.52%
0.73%
Spec: NMT [REDACTION]
|
Highest Unknown Impurities
0.04%
Spec: NMT [REDACTION] |
Prochlorperazine
Suppositories, 5 mg
Batch 308030A
|
Stability Sample
12 mo RT
|
Unknown Impurities
0.44 %
0.56 %
Spec: NMT [REDACTION]
|
Highest Unknown Impurities
0.14%
Spec: NMT [REDACTION]
|
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 303110A
|
Stability Sample
12 mo RT
|
Dissolution
D1 = 72.8%
D5 = 73.2%
Spec: NLT [REDACTION] |
Dissolution
D1 = 98.5%
D5 = 96.9%
Spec: NLT [REDACTION] |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 104026B
Validation Batch
|
Stability Sample
6 mo RT
|
Assay - Propoxyphene
A2 = 89.9%
Spec: [REDACTION] |
Assay - Propoxyphene
A2 = 95.9%
Spec: [REDACTION] |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 201016C
|
Stability Sample
24 mo RT
|
Assay - Propoxyphene
A1 = 89.9 %
Assay - APAP
A1 = 88.7 %
Spec: [REDACTION]
|
Assay - Propoxyphene
A1 = 100.5%
Assay - APAP
A1 = 98.9 %
Spec: [REDACTION] |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 312015
|
Finished
Product Testing
|
Content Uniformity
Propoxyphene
CU5 = 117.8 %
Spec: [REDACTION]
|
Content Uniformity
Propoxyphene
CU5 = 104.2%
Spec: [REDACTION] |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 310158
|
In-Process
Blend Uniformity
Testing
|
Propoxyphene
TL1 = 238.5 %
TR1 = 80.5 %
APAP
TL1 = 218.9%
Spec: [REDACTION] |
Propoxyphene
TL1 = 103.2 %
TR1 = 104.0 %
APAP
TL1 = 105.6 %
Spec: [REDACTION] |
|
Post -Approval Reporting |
OBSERVATION 3 An annual report did
not include reports of investigations involving chemical or physical
properties which, as new information, might affect FDA's previous
conclusions about the safety or effectiveness of the drug.
- Annual Reports for ANDA’s that were submitted to FDA did
not include out of specification (OOS) results. Only passing data
points were submitted. Due to the submission of erroneous data
the following ANDA’s were withdrawn.
Annual Report submitted 8/24/04, for reporting
period 7/12/03 through 7/11/04
Product/Batch # |
ANDA |
Sample Type |
OOS Results |
Reported Result |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 303110A
|
75-838 |
Stability Sample
12 mo RT |
Dissolution Tablet
D1 = 72.8%
D5 = 73.2%
Spec: NLT [REDACTION] |
Dissolution Tablet
D1 = 98.5%
D5 = 96.9%
Spec: NLT [REDACTION] |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 201016C
|
75-838 |
Stability Sample
24 mo RT |
Assay - Propoxyphene
A1 = 89.9 %
Assay - APAP
A1 = 88.7 %
Spec: [REDACTION]
|
Assay - Propoxyphene
A1 = 100.5%
Assay - APAP
A1 = 98.9 %
Spec: [REDACTION] |
Annual Report submitted 11/6/02, for reporting
period 7/11/01 through 7/11/02
Product/Batch # |
ANDA |
Sample Type |
OOS Results |
Reported Result |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 104026B
Validation Batch |
75-838 |
Stability Sample
6 mo RT |
Assay - Propoxyphene
A2 = 89.9%
Spec: [REDACTION] |
Assay - Propoxyphene
A2 = 95.9%
Spec: [REDACTION] |
[REDACTION, approximately 7 lines]
Annual Report submitted 8/11/04, for reporting
period 7/12/03 through 7/11/04
Product/Batch # |
ANDA |
Sample Type |
OOS Results |
Reported Result |
Prochlorperazine
Suppositories, 2.5 mg
Batch 308029A
|
40-407 |
Stability Sample
Initial, 6 and 9 month RT
|
Unknown Impurities
Initial: 0.41% & 0.37%
6M: 0.28, 0.29 & 0.23%
9M: 0.32 & 0.33% Spec: NMT [REDACTION]
|
Highest Unknown Impurities
Initial: < 0.01%
6M: 0.14%
9M: 0.05%
Spec: NMT [REDACTION] |
Prochlorperazine
Suppositories, 5 mg
Batch 308030A
|
40-407 |
Stability Sample
3 & 6 month RT |
Unknown Impurities
3M: 0.32%
6M: 0.30%
Spec: NMT [REDACTION] |
Highest Unknown Impurities
3M: 0.05%
6M: 0.15%
Spec: NMT [REDACTION] |
Annual Report submitted 6/9/04, for reporting
period 5/10/03 through 4/10/04
Product/Batch # |
ANDA |
Sample Type |
OOS Results |
Reported Result |
Methylphenidate HCl Tablets, 20 mg Extended Release
Batch 303087A&B
|
76-032 |
Finished Product Testing
|
Dissolution (1 Hour)
D1: 48.9 %
D2: 49.0 %
D3: 48.2 %
Spec: [REDACTION]
|
Dissolution (1 Hour)
D1: 43.4 %
D2: 43.3 %
D3: 42.4 %
Spec: [REDACTION] |
Annual Report submitted 5/26/05, for reporting
period 3/30/04 through 3/29/05
Product/Batch # |
ANDA |
Sample Type |
OOS Results |
Reported Result |
Methylphenidate HCl Tablets, 5 mg
Batch 202005A
|
40-404 |
18 mo RT
Stability
Testing
|
Pooled Dissolution
84.5%
Spec: NLT [REDACTION]
|
Pooled Dissolution
92.2%
Spec: NLT [REDACTION] |
- Prior Approval Supplement #004 for ANDA 75-838, Propoxyphene
Napsylate and APAP Tablets, 100/650mg, was submitted on 3/16/04
to provide for the discontinuance of Blend Uniformity Testing.
This supplement was approved 9/23/04. The test data submitted
for Blend Uniformity and Content Uniformity did not contain initial
OOS results for a number of batches, only passing results were
submitted. Due to the submission of erroneous data the ANDA was
withdrawn. OOS results for these batches are listed below.
Batch # |
Sample Type |
OOS Results |
Reported Range |
309013 |
Finished Product
Content Uniformity
|
Propoxyphene: CU8 = 84.1%
Specification: [REDACTION]
|
102.3% - 108.1% |
309014 |
Finished Product
Content Uniformity
|
Propoxyphene: CU8 = 84.1%
Specification: [REDACTION]
|
101.6% - 107.5% |
309016 |
In-process Blend Uniformity |
Propoxyphene: BL1 = 110.3%
Specification: [REDACTION]
|
97.6% - 107.0% |
312015 |
Finished product
Content Uniformity
|
Propoxyphene: CU5 = 117.8%
Specification: 85% - 115%
|
102.8% - 108.2% |
312022 |
In-process Blend Uniformity |
Propoxyphene: TL2 = 110.5%
ML2 = 110.6%
Specification: [REDACTION]
|
99.0% - 107.7% |
310052 |
In-process Blend Uniformity |
Propoxyphene: TR2 = 110.2%
Specification: [REDACTION]
|
99.0% - 106.6% |
310158 |
In-process Blend Uniformity |
Propoxyphene: TR1 = 80.5%
TL1 = 238.5%
Acetaminophen: TL1 = 218.9%
Specification: [REDACTION]
|
94.7% - 105.2%
98.5% - 107.7% |
310150 |
Finished product
Content Uniformity
|
Propoxyphene: CU10 = 80.6%
Acetaminophen: CU10 = 80.1%
Specification: [REDACTION]
|
99.8% - 106.5%
97.8% - 99.9% |
312005 |
In-process Blend Uniformity |
Propoxyphene: BR1 = 110.4%
Specification: [REDACTION]
|
96.2% - 107.8% |
312007 |
In-process Blend Uniformity |
Propoxyphene: TL1 = 113.4%
Specification: [REDACTION]
|
97.6% - 106.9% |
312044 |
In-process Blend Uniformity |
Propoxyphene: TL2 = 83.7%
: ML2 = 84.0%
Specification: [REDACTION]
|
93.3% - 100.5% |
312079 |
In-process Blend Uniformity |
Propoxyphene: TL1 = 116.9%
Specification: [REDACTION]
|
95.9% - 106.5% |
|
OBSERVATION 4 An NDA-Field Alert Report
was not submitted within three working days of receipt of information
concerning a failure of one or more distributed batches of a drug
to meet the specifications established for it in the application.
Field Alerts were not routinely filed when drug products did not
meet the specifications listed in the Abbreviated New Drug Application
(ANDA). There is no SOP covering the issuance of Field Alerts. Field
Alerts (FA) were not submitted when the following batches of drug
products failed to meet stability specifications.
Product/Batch # |
ANDA |
Sample Type |
Failing Result – No F/A Submitted |
Reported Result |
Atenolol 25 mg Tablet
Validation Batch 408107A |
76-907 |
Stability
Sample
3 mo RT
|
Dissolution , Tablet
D5 = 83.7%
D6 = 83.8%
Spec: NLT [REDACTION] |
Dissolution , Tablet
D5 = 98.9%
D6 = 98.7%
Spec: NLT 85% |
Atenolol 25 mg Tablet
Validation Batch 408107B |
76-907 |
Stability
Sample
3 mo RT |
Dissolution Testing
Tablet D6 = 30.9%
Spec: NLT [REDACTION] |
Dissolution Testing Tablet D6 = 102.8%
Spec: NLT 85% |
Diphenoxylate HCl and Atropine Sulfate
Tablet, Batch 301068A |
40-395 |
Stability
Sample
21 mo RT |
Assay - Atropine
A1 = 78.4%
A2 = 78.7%
Spec: [REDACTION] |
Assay - Atropine
A1 = 90.4%
A2 = 90.8%
Spec: 80% - 120% |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 303110A |
75-838 |
Stability Sample
12 mo RT |
Dissolution Tablet
D1 = 72.8%
D5 = 73.2%
Spec: NLT [REDACTION] |
Dissolution Tablet
D1 = 98.5%
D5 = 96.9%
Spec: NLT [REDACTION] |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 104026B
Validation Batch |
75-838 |
Stability Sample
6 mo RT |
Assay - Propoxyphene
A2 = 89.9%
Spec: [REDACTION] |
Assay- Propoxyphene
A2 = 95.9%
Spec: [REDACTION] |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 201016C
|
75-838 |
Stability Sample
24 mo RT |
Assay - Propoxyphene
A1 = 89.9 %
Assay - APAP
A1 = 88.7 %
Spec: [REDACTION] |
Assay - Propoxyphene
A1 = 100.5%
Assay - APAP
A1 = 98.9 %
Spec: [REDACTION] |
Prochlorperazine
Suppositories, 2.5 mg
Batch 308029A |
40-407 |
Stability Sample Initial,
6, 9 and 12 mo RT |
Unknown Impurities
Initial:0.41% & 0.37%,
6M: 0.28, 0.29 & 0.23%
9M: 0.32 & 0.33%
12M: 0.52, 0.73%
Spec: NMT [REDACTION] |
Highest Unknown Impurities
Initial:< 0.01%,
6M: 0.14%
9M: 0.05%
12M: 0.04%
Spec: NMT [REDACTION] |
Prochlorperazine
Suppositories, 5 mg
Batch 308030A |
40-407 |
Stability Sample
3, 6, & 12 mo RT |
Unknown Impurities
3M: 0.32%
6M: 0.30%
12M: 0.44% & 0.56%
Spec: NMT [REDACTION] |
Highest Unknown Impurities
Spec: NMT 0.2%
3M: .05%
6M: 0.15%
12M: 0.14%
Spec: NMT [REDACTION] |
|
Laboratory Control System |
OBSERVATION 5 Laboratory records do
not include complete data derived from all tests, examinations and
assay necessary to assure compliance with established specifications
and standards.
The QC Laboratory notebooks and binders lacked data from all analytical
testing conducted in the QC Laboratory. Laboratory records did not
include all data such as out of specification (OOS) results, chromatograms,
sample weights, and processing methods. OOS results were substituted
with passing results by Analysts and Supervisors. The substitution
of data was performed by cutting and pasting of chromatograms, substituting
vials, changing sample weights and changing processing methods.
For Example:
Product /Batch Number |
Lack of Complete Data |
Products and batches listed in FDA-483, point # 2 |
OOS results not documented in laboratory records. Unreported
OOS results found in electronic data files. |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 303110A
|
Changed chromatogram headers by cutting and pasting, so
during review all sample injections would appear to be in
sequence, for Dissolution Testing of Tablets D1 and D5. |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
Batch 104026B
Validation Batch
|
Original Sample Weights not recorded in notebook. Sample
weights were changed by the analyst until a passing result
was obtained for Assay (A2) |
Acetaminophen & Codeine Phosphate Tablets, 300/30mg
Batch 407148
|
Processing methods changed by analyst until the processing
method resulted in a passing result. Original processing method
not recorded in laboratory notebook. |
|
OBSERVATION 6
Input to and output from the computer and records or data are not
checked for accuracy.
Audits were not conducted of the [REDACTION] System
used to run the HPLC instruments during analysis of drug products.
Sample injections, processing methods, and sample weights were not
reviewed or verified for the accuracy of reported sample results
during testing of in-process, finished product and stability samples.
|
OBSERVATION 7
Written records are not made of investigations into unexplained
discrepancies and the failure of a batch or any of its components
to meet specifications.
Laboratory investigations were not conducted when out of specification
(OOS) results were generated during in-process, finished product
and stability testing of drug products. Examples of batches where
OOS results were generated and not investigated are included in
FDA-483, point # 2. Quality Control Procedure, SOP # QC-021-06,
Acceptance/Rejection Criteria for OOS Analytical Test Results, requires
an investigation be conducted when OOS results are generated.
|
OBSERVATION 8
Employees are not given training in current good manufacturing
practices and written procedures required by current good manufacturing
practice regulations.
QC Laboratory analysts were not routinely trained in Quality Control
procedures such as SOP # QC-011-03, Laboratory Deviation Investigations
and SOP # QC-021-06, Acceptance/Rejection Criteria for OOS Analytical
Test Results. This lack of training and oversight by management
contributed to the non-reporting of OOS results in the QC Laboratory.
|
OBSERVATION 9
Written records of investigations into unexplained discrepancies
and the failure of a batch or any of its components to meet specifications
do not always include the conclusions and followup.
OOS Investigation # 04-00S-031, for Methylphenidate HCl ER Tablets
20 mg 18 month stability lot 303087A was initiated due to dissolution
failing results. The specification required the average of 24 tablets
to be within the range of [REDACTION] at the L3,
1 hour dissolution time point. The average of the 24 tablets was
reported to be 48.4% with a minimum result of 45.8% and a maximum
of 50.2%. The investigation was found to be incomplete. The investigation
concluded that the original failing results were invalid due to
an analyst technique issue. There was no documentation provided
within the investigation or within the analyst notebook to justify
invalidating the failing dissolution results. Although corrective
measures were identified in the investigation, there was no documentation
to show that the corrective measures had been completed. Additionally,
there was no review of data acquired by the same analysts for the
same tests for other lots of the same product.
|
OBSERVATION 10
The responsibilities and procedures applicable to the quality control
unit are not in writing and fully followed.
- The Laboratory Records SOP # QC-022-04 effective 6/25/04, specified
numerically ordered notebooks will be issued and a log maintained.
Notebook issuance logs showed large gaps in numbering of notebooks
issued, which were not accounted for in the log. Additionally,
the procedure for issuance of notebooks, as described by management,
which indicated a notebook request form was to be used, was not
described in the procedure available.
- SOP Method Number I-037, approved 10/18/00, General Guidelines
for sample Logging for Analytical Laboratory using [REDACTION]
software did not include procedures and responsibilities to be
followed by personnel authorized to enter samples into the [REDACTION]
database. According to management, authorized personnel included
floor inspectors and incoming inspectors. The SOP required the
use of forms to authorize addition or deletion of groups, items,
samples, and users to the [REDACTION] system.
Forms to be used to authorize the addition or deletion of groups,
items, samples, and users to the [REDACTION]
system as specified by the SOP were not used.
- There was no SOP describing the use of (SP) special samples
tested in the Analytical Laboratory. Additionally, special samples
were not listed as a group in the [REDACTION]
procedure. Special samples in the testing of Methylphenidate HCl
ER Tablets 20mg Lot # 303087A 9MRT SP 04-101 dated 4/24/04(6 tablets)
and SP04-101
(6 tablets) dated 4/26/04 were used to report L3 Dissolution results
for the stability sample #ST04-407 for the same lot. Dissolution
testing for L2 and L3 were not labeled L2 and L3 in the notebook.
|
OBSERVATION 11
Established laboratory control mechanisms are not followed.
- An Investigation was not issued prior to any retesting for
Lot 303087B, Methylphenidate HCl ER 18M stability lot, as required
by procedure SOP # QC-011-03, Laboratory Deviation Investigation.
Lot 303087B, Methylphenidate HCl ER Tablets 20 mg, 18M Dissolution
stability analysis found that the original L3 testing results
were within specification. Two months after the analysis of 24
tablets for Lot 303087B for 18M stability, 6 more tablets were
tested. The results from the final analysis of the 6 tablets were
reported as 18 M Dissolution results.
- SOP # QC-006-01 Retesting and Resampling Analytical Control
Laboratory, effective 8/27/03 was not followed for Methylphenidate
HCl ER18M stability lot 303087A:
- There was no documentation of the number of retests to be
performed as required by the SOP. The SOP required the number
of retest to be documented prior to initiating testing to establish
a definite limit beyond which no additional testing would be
permitted.
- The procedure required retests to be conducted by the original
chemist and a second chemist, where the second chemist conducts
at least 60% of the tests, or by two chemists, neither of which
being the chemist producing the original result. Retests were
not carried out by the original chemist and a second chemist.
Additionally, the test was not carried out by two chemists other
than the original chemist.
- Investigation 04-OOS-031, initiated 12/8/04 and completed
2/18/05, exceeded 30 working days. The procedure required investigations
to be completed in a brief time frame not to exceed 30 working
days from the start of the investigation.
|
Production System |
OBSERVATION 12
Control procedures are not established which validate the performance
of those manufacturing processes that may be responsible for causing
variability in the characteristics of in-process material and the
drug product.
- There is no assurance that results for in-process physical testing
are recorded accurately. For example, the Pre-Validation batch
record (TB-110) for Hydrocodone Bitartrate and Acetaminophen Tablets,
USP 5mg/325mg shows the specification for tablet thickness range
as 0.308” to 0.358”; this range was crossed out and
the correct range of [REDACTION] was handwritten
in the batch record. The in-process tablet thickness results show
all tablets were within the corrected thickness specification
of [REDACTION] during compression on 10/15/01.
The Research and Development (R&D) In-Process Data Sheet shows
the thickness of 60 tablets to be within a thickness range of
0.330” and 0.334” which corresponds to the tablet
thickness specification which was incorrectly written on the Master
Batch Record. Retains from this batch were tested on 6/10/05,
and the results show the thickness of the tablets were between
[REDACTION] , which was the correct specification
that was handwritten on the Master Batch Record.
- Manufacturing Investigations into rejected batches of drug products
did not include an evaluation of the validated manufacturing process.
For example, seven of nine batches (78%) of Methylphenidate ER
20 mg Tablets, manufactured between May 2003 and November 2004
were investigated in the laboratory, due to initial OOS results
or out of trend results. Two of the seven lab investigations,
resulted in the rejection of batches 411021 and 310004. Manufacturing
Investigations, 04-008, for batch 310004, and Manufacturing Investigation
05-001, for batch, 411021 did not include an evaluation of the
validated manufacturing process for Methylphenidate ER 20 mg Tablets.
- There is no assurance that manufacturing processes for drug
products are validated in that out of specification (OOS) results
were generated, but not reported. Several examples are listed
below.
Product Validation Batch # |
Type Sample |
Original OOS Result |
Reported Results |
Atenolol 25 mg Tablet
Validation Batch 408107A |
Stability
Sample
3 mo RT |
Dissolution , Tablet
D5 = 83.7%
D6 = 83.8%
Spec: NLT [REDACTION]
|
Dissolution , Tablet
D5 = 98.9%
D6 = 98.7%
Spec: NLT [REDACTION] |
Atenolol 25 mg Tablet
Validation Batch 408107B |
Stability
Sample
3 mo RT |
Dissolution Testing
Tablet D6 = 30.9%
Spec: NLT [REDACTION] |
Dissolution Testing
Tablet D6 = 102.8%
Spec: NLT [REDACTION] |
Propoxyphene Napsylate and APAP
Tablets, 100/650mg
104026B
Validation Batch |
Stability Sample
6 mo RT |
Assay - Propoxyphene
A2 = 89.9%
Spec: [REDACTION] |
Assay
A2 = 95.9%
Spec: [REDACTION] |
|
* DATES OF INSPECTION
05/02/2005(Mon), 05/03/2005(Tue), 05/04/2005(Wed), 05/05/2005(Thu),
05/09/2005(Mon), 05/10/2005(Tue), 05/11/2005(Wed), 05/12/2005(Thu),
05/16/2005(Mon), 05/17/2005(Tue), 05/18/2005(Wed), 05/19/2005(Thu),
05/20/2005(Fri), 05/23/2005(Mon), 05/24/2005(Tue), 05/25/2005(Wed),
05/26/2005(Thu), 05/27/2005(Fri), 05/31/2005(Tue), 06/01/2005(Wed),
06/02/2005(Thu), 06/06/2005(Mon), 06/09/2005(Thu), 06/10/2005(Fri),
06/15/2005(Wed), 06/23/2005(Thu), 06/29/2005(Wed), 06/30/2005(Thu),
07/01/2005(Fri)
|
FDA EMPLOYEE'S NAME, TITLE, AND SIGNATURE:
[pages 1-14 hand amended with investigators'
initials or signature and date "7-6-05"]
Nancy L. Rolli, Investigator
Daniel J. Grabicki, Investigator
Marea K. Harmon, Investigator
Joanne Heim, Investigator |
SEE
REVERSE
OF THIS
PAGE |
AMENDED
|
|
DATE
ISSUED 07/06/2005 |
FORM FDA 483 (7/00) PREVIOUS EDITION OBSOLETE
INSPECTIONAL OBSERVATIONS
Reverse Text on Page: The observations of objectional conditions and practices listed
on the front of this form are reported:
- Pursuant to Section 704(b) of the Federal Food, Drug and
Cosmetic Act, or
- To assist firms inspected in complying with the Acts and
regulations enforced by the Food and Drug Administration.
|
Section 704(b) of the Federal Food, Drug, and Cosmetic
Act (21 USC374(b)) provides: “Upon
completion of any such inspection of a factory, warehouse, consulting laboratory, or other
establishment, and prior to leaving the premises, the officer or employee making the
inspection shall give to the owner, operator, or agent in charge a report in writing
setting forth any conditions or practices observed by him which, in his judgement,
indicate that any food, drug, device, cosmetic in such establishment (1) consists in whole
or in part of any filthy, putrid, or decomposed substance or (2) has been prepared,
packed, or held under insanitary conditions whereby it may have become contaminated with
filth, or whereby it may have been rendered injurious to health. A copy of such report
shall be sent promptly to the Secretary.” |
Entries marked with this logo are PDF documents. You will need “Acrobat
Reader” to view it. If you do not have it installed on your computer, click on
the following link to download a free copy.
Back to Frequently Requested ORA Documents
and FDA 483s
|
|