# R&S Compliance group, LLC. — Hazardous Materials Safety Interpretation

**Citation:** 14-0248  
**Type / status:** guidance / guidance  
**Agency:** Pipeline and Hazardous Materials Safety Administration  
**Effective:** Not stated  
**Published:** 2015-06-18

14-0248 response to R&S Compliance group, LLC. concerning 172.101, 173.22, 173.50, 173.56.

## Document text

<<<PAGE 1>>>

S. Departmen
f Transportatio
Washington. DC 20590
1200 New Jersey Avenue SE
Pipeline and Hazardou:
Administ titty
JUN 18 2015
Mr. David Rivers
R&S Compliance Group, LLC.
2707 W. Price Ave.
Tampa, FL 33611
Reference No. 14-0248
Dear Mr. Rivers:
This is in response to your December 30, 2014 letter requesting clarification of the
Hazardous Materials Regulations (HMR; 49 CFR Parts 171-180) applicable to new
explosives. You state your company receives a nitroglycerin and lactose mixture classified
as "UN 3319, Nitroglycerin Mixture, Desensitized, Solid, N.O.S., 4.1" transported under
approval EX2000120151. You further state that this raw material is used in the production
of a pharmaceutical product. Various machines that come in contact with the raw material
are cleaned and the cleaning process results in effluent waste material containing a methanol
and water mixture with contaminate of nitroglycerin. You present in-house test data from
tests run on several lots of effluent waste showing trace concentrations of nitroglycerin
between 0.00616- 0.01220 mg/ml. You ask several questions regarding the need for
classification of both effluent waste material and tablet nitroglycerin. Your questions are
paraphrased and answered as follows:
Q1. In order for § 173.56 to apply, does the resulting effluent material resulting from the
alteration process (testing and cleaning) of the originally classified explosive mixture need
to meet the definition of a Class 1 material in § 173.50(a) first? Or does § 173.56 apply first
because the original ingredient that was altered was subject to § 173.56 and therefore all
products or by-products of the initial classified explosive, regardless of the characteristics,
or if the product meets the definition of Class 1 per § 173.50(a), require formal testing,
classification and approval per § 107.705?
Al. Per § 173.56(a) a new explosive is an explosive produced by a person who has not
previously produced that explosive, or has previously produced that explosive but has made
a change in the formulation, design, or process so as to alter any of the properties of the
explosive. Any product containing an energetic ingredient (e.g., Nitroglycerin) is therefore
subject to the requirements of § 173.56, and any modification of such product previously
approved is also subject to the same requirements to determine if the modifications meet the
definition of a new explosive. However, if the modification results in a new material that
may be classified in a hazard class or division other than Class 1 under a proper shipping
name specifically listed in the Hazardous Materials Table (HMT) in § 172.101 (e.g.
UN1204), the modified material would not be subject to the provisions of §173.56 unless
the proper shipping name has a special provision requiring approval under § 173.56.

<<<PAGE 2>>>

Q2. It the latter is true, does the final pharmaceutical product, nitroglycerin tablets, require
the same approval to transport to pharmacies as the tablet is a result of an alteration of an
initially classified explosive?
A2. The nitroglycerin tablets would require approval in accordance with § 173.56(b).
Q3. Would the resulting effluent material, containing residual amounts of what would be a
classified explosive in other forms or concentrations, be properly described for
transportation by other characteristics? In this case UN1204 Nitroglycerin solution in
alcohol.
A3. In accordance with § 173.22, it is the shipper's responsibility to properly classify a
hazardous material. This Office generally does not perform this function. However, if the
effluent waste can be appropriately described by an existing HMT entry for a hazard class or
division other than Class 1 it may be oftered for transport under that entry. In your scenario,
if the nitroglycerin solution in alcohol and water contains not more than 1 percent
nitroglycerin in alcohol with no other energetic ingredients, the effluent would most
appropriately be offered as UN1204.
I trust this information is helpful. If you have further questions, please do not hesitate to
contact this office.
Sincerely,
Duane A. Pfund
International Standards Coordinator
Standards and Rulemaking Division

<<<PAGE 3>>>

Webb
17356
Goodall, Shante CTR (PHMSA)
New seposines
From:
Betts, Charles (PHMSA)
14-0248
Sent:
Wednesday, December 31, 2014 12:05 PM
To:
Goodall, Shante CTR (PHMSA)
Cc:
Subject:
Dodd, Alice (PHMSA); Foster, Glenn (PHMSA); Fink, William (PHMSA)
Fw: Request for Interpretation
Attachments:
Request for interp less than 2 nitro.pdf; STM-AR-CV-0159 Nitroglycerin Cleaning
Verification Method.pdf; STM-AR-FP-0164 Nitroglycerin Sublingual Tablets 0 3 mg 0 4
mg 06 mg.paf
Shante -
Please log and assign for response. Thanks
From: Fink, William (PHMSA)
Sent: Wednesday, December 31, 2014 09:08 AM Eastern Standard Time
To: Betts, Charles (PHMSA); INFOCNTR (PHMSA)
Subject: FW: Request for Interpretation
Cc: Singh, Harpreet (PHMSA)
Charles,
R&S is requesting a letter of interp.
Bill Fink
From: Alston, Barbara CTR (PHMSA)
Sent: Tuesday, December 30, 2014 4:43 PM
To: Fink, William (PHMSA); Herrera, Jacqueline (PHMSA)
Subject: FW: Request for Interpretation
Good Afternoon Team,
I spoke with Mr. Rivers on the phone and he has sent information pertaining to his questions/request, please see
attachments. Many thanks, Barbara
From: David Rivers [mailto:david@rscompliance.com]
To: Alston, Barbara CTR (PHMSA)
Sent: Tuesday, December 30, 2014 4:17 PM
Subject: Request for Interpretation
Barbara,
Thank you for speaking with me today. The attached is a scenario requesting an interpretation as to the applicability of
173.56, "New Explosive" of an effluent waste from a pharmaceutical manufacturing and cleaning process. The narrative
demonstrates the specifics of our situation. If needed, I also attached testing procedures that we use that ultimately
creates the "by-product" we are trying to ensure we classify for transportation appropriately given the raw material
Nitroglycerin.
Your help is greatly appreciated. Happy New Year!
David O. Rivers, M.S.
1

<<<PAGE 4>>>

2707 W. Price Ave., Tampa, FL 33611
Compliance Group, LIC
Phone: (813) 433-4979
December 30, 2014
US Department of Transportation
PHMSA - Energetic Materials
Attn: Division of Approvals and Permit, PHH30
1200 New Jersey Ave. SE, East Building 2nd Floor
Washington, DC 20590-0001
R&S Compliance Group, Ile would like to request a letter of interpretation as to the intent of the definition
of a "New Explosive" described in 173.56. This section requires that a classification and new EX
Approval be granted for the transportation of a classified explosive if the original classified explosive is
altered "...as to change the formulation, design or process so as to alter the properties of the explosive."
Specifically, we receive a Nitroglycerin and Lactose Mixture classified as;
"Nitroglycerin Mixture, Desensitized, Solid, NOS with more than 2 percent but not more than 10 percent
nitroglycerin, by mass", transported under Approval EX2000120151 and reclassified by the Associate
Administrator as hazard class 4.1, UN3319.
This raw material is used in the production of a pharmaceutical product, a Nitroglycerin Tablet. Each LOT
of final product, the table themselves, must be tested for quality control according to Good Manufacturing
Practices (GMP) and Food and Drug Administration (FDA) requirements. The machine used to extract the
active ingredient from the raw material received, Nitroglycerin, also must be cleaned. Other machines
which have contact surfaces that come in contact with the pharmaceutical mixture during the blending,
mixing and tablet formation process must be washed. This testing and cleaning process results in effluent
waste material containing a Methanol and Water Mixture with contaminates of Nitroglycerin.
The in-house lab ran a test on this effluent waste material from several lots of effluent waste and found the
following concentrations of trace Nitroglycerin per volume. (In house test procedures attached)
Approximate Conc. of Nitroglycerin per container
Container 1
0.01220
mg/mL
Container 2
0.00068
mg/mL
Container 3
0.00194
mg/mL
Container 4
0.00616
mg/mL
*Results are "Grab" samples from 55 gallon drums of effluent and not meant to meet the testing criteria prescribed in 173.52,
173.57 and 173.58
R&S Compliance Group, LLC

<<<PAGE 5>>>

ROSS
2707 W. Price Ave., Tampa, FL 33611 Phone: (813) 433-4979
Compliance Group, LIC
Our question is if the requirements to seek proper classification and EX Approval from the Associate
Administrator per 173.56 apply to the effluent waste from laboratory testing and/or cleaning processes by
determining if these activities meets the definition of "altering" an existing explosive when the resulting
effluent material to be transported, (transportation for disposal in this case), does not meet the definition of
a Class 1 explosive ,173.50(a).
#1
In order for 173.56 to apply, does the final effluent material resulting from the alteration processes (testing
and cleaning) of the original classified explosive mixture (Nitroglycerin Mixture, Desensitized, Solid,
NOS) need to meet the definition of a CLASS 1 material (173.50(a) FIRST? "an explosive means
..designed to function by explosion...",?
If the resulting effluent material did in fact meet the explosive definition, we would agree an approval
would we required as a New Explosive defined in 173.56. But what the resulting materials does not meet
the definition of an explosive 173.50(a), would further examination of this effluent mixture and written
determination be required from the Associate Administrator to state that the material does not need an
approval?
#2
Or, does 173.56 apply simply because the original ingredient that was altered was subject to 173.56 before
initially offered for transportation, therefore, all products or by-products of the initial classified explosive
(in this case, Nitroglycerin Mixture, Desensitized, Solid, NOS, EX2000120151), regardless of the resulting
characteristics or meeting the definition of Class 1 set forth in 173.50 (a), require formal testing,
classification and approval per 107.705.
If the latter, #2, is true, does the final pharmaceutical product, the common Nitroglycerin tablet for heart
patients require the same approval to transport to pharmacies as the tablet is the result of an alteration of an
initially classified explosive?
Or, does this resulting effluent material, even though it contains residual amounts of what otherwise would
be a classified explosive in other forms or concentrations, simply need to be properly described for
transportation to meet the definition of its characteristics, 173.22(a), not requiring an EX Approval, and in
this case by 173.120(a)(2) as a flammable liquid such as;
UN1204, Nitroglycerian Solution in Alcohol with not more than 1 percent nitroglycerin
*This above authorized name does not list a special provision requiring an EX Approval from the Associate Administrator in order to describe a product as with
the original Nitroglycerin product received and used, even though the description has the word "Nitroglycerin" within the name. This description would be
selected by shippers where appropriate as required by "Shipper's Responsibility"
R&S Compliance Group, LLC

<<<PAGE 6>>>

R8U
2707 W. Price Ave., Tampa, FL 33611 Phone: (813) 433-4979
Compliance Group, LIC
We understand that there is not a threshold of an explosive concentration that PHMSA has established for
an "altered" explosive, clarified according to interpretation #09-0058 which would need an EX Approval
if, as stated in paragraph three, ...
"new compositions containing any amount of explosive material...".
This sentence refers to an "explosive" material presumably "explosive" by definition, 173.50(a).
However, does the above described effluent waste, scenario, and furthermore the final pharmaceutical
product, meet the intent or definition of a "New Explosive", subject to 173.56 simply because of
"alteration" though a sampling and cleaning process and eventual formation and packaging or a
pharmaceutical tablet involving previously "Classified Explosive" requiring an EX Approval for initial
transport, where the "Process" is not intended to produce an a different "explosive", by definition, from the
original "explosive" when the final effluent mixture does not exhibit characteristics of a CLASS 1 material,
by definition?
Your attention and interest to our request is appreciated. Please feel free to contact me with any questions
you may have.
Resiss
CHMM, CSP, CET, CDGP
David O. Rivers, M.S.
Ph: 813-433-4979
R&S Compliance Group, lIc.
Fx: 813-436-5392
www.rscompliance.com
david@rscompliance.com
R&S Compliance Group, LLC

<<<PAGE 7>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page 1 of 32
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #: STM-AR-FP-0164
mg
Effective Date:
MAR 1 4 2014
Supersedes: 05/16/13
Prepared by:
Date:
03/1/14
Reviewed by:
Dsl
Date:
03/1|/1L
Reviewed by:
Date:
03/11/14
Approved by:
Ethe Bodes
03/12/14
Date:
13/2/14€
03/15/14
I.
PURPOSE
The purpose of this procedure is to describe the test methods used for analysis of
Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6 mg and Intermediate products.
TESTS
A. Description
B. Identification
C. Assay
D. Blend Uniformity
. Uniformity of Dosage Units
F.
Degradation Products
G. Dissolution
H. Water Content
I.
Disintegration
II.
APPLICABILITY
This method applies to Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6 mg and
Intermediate products. This method applies to Analytical Research Department.
III.
PROCEDURE
EHS Safety Statements
1. Material Safety Data Sheets for all chemicals involved should be read prior to starting
any chemical handling. All recommendations of work practices and Personal Protective
Equipment (PPE) should be followed.
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 8>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
2 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
mg
Test Method #:STM-AR-FP-0164
2. All solutions and prepared samples must be properly labeled, including hazard
information, if they are to be stored longer than a single work shift.
3. All waste, including rinsings, should be labeled appropriately and handled per Watson
Waste Management Policy, SOP GN-0026 and Risk Management Procedure RM-0018
(located on the Portal). If a hazardous material was used in a filter media, the filter
media is considered hazardous material and must be disposed of appropriately.
4. All glassware should be inspected prior to use. Defective glassware should not be used.
5. Thick walled glassware should be used when vacuum degassing media and mobile
phases.
6. Waste receptacles should be verified to have enough space to hold the volume of waste
to be generated.
7. Flammable solvents should be dispensed inside of a chemical fume hood. Flammable
solutions should be covered if stored outside of the hood.
8. Appropriate PPE should be worn based on the requirements of Risk Management
Procedure RM-0009 (located on the Portal) and the MSDS.
9. When weighing powdered laboratory chemicals and products, excess materials should
not be placed into the regular trash receptacles. Excess products should be placed inside
a non-hazardous waste receptacle and excess chemical powders should be disposed of
appropriately based on hazards present.
10. All PPE should be inspected prior to donning. PPE should be rechecked often for
damage and replaced as needed.
11. Concentrated acids and bases should be handled with care and dispensed inside a
chemical fume hood with appropriate PPE.
12. Incompatible waste streams should be segregated and collected separately for disposal.
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 9>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
3 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
A. Description
Visually inspect the sample and compare with the description given in the respective
Analytical research in-process and finished product specifications.
Refer to the specification item number given in Section VI
B. Identification
1. HPLC
The major peak in the assay sample chromatogram corresponds to that of the
retention time for the Nitroglycerin peak in the Standard chromatogram.
2. Thin-Layer Chromatographic Identification Test
2.1. Apparatus
A chromatographic chamber made of inert, transparent material with flat
bottom or twin trough, a tightly fitted lid and a size suitable for the plate is
used. The chamber is lined on at least one wall with filter paper. Sufficient
mobile phase is added to the chamber that, after impregnation of the filter
paper, a depth appropriate to the dimensions of the plate used is available. The
chamber is closed and allowed to equilibrate.
2.2. Reagents
• Acetone, ACS grade or better
• Ethyl acetate, ACS grade or better
Toluene, ACS grade or better
• Glacial acetic acid, ACS grade or better
• Methanol, HPLC grade or better
•
Diphenylamine, ACS grade or better
• Nitroglycerin standard
2.3. Reagent Preparation
2.3.1. Mobile Phase
Mixture of toluene, ethyl acetate and glacial acetic acid in a ratio 16:4:1.
Scale up or down as needed.
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 10>>>

....
-
Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
4 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
2.3.2. Spray Solution
Prepare a mixture of diphenylamine in methanol (1 in 100). Scale up or
down as needed.
2.4. Standard Preparation
Prepare a solution of 1 mg of nitroglycerin in 1 mL of acetone.
2.5. Sample Preparation
Transfer the amount of finely powdered Sublingual Tablets, equivalent to
about 1 mg ot nitroglycerin, to a centrifuge tube, add 1 mL of acetone, cover
with parafilm shake by mechanical means for 30 minutes, and Centrifuge at
3000 rpm for 10 minutes, use supernatant for analysis.
2.6. Procedure
On a line parallel to and about 2 cm from the edge of a suitable thin-layer
chromatographic plate coated with 0.25 mm layer of silica gel mixture:
1. Apply 10 uL of the test and standard solutions with an interval of at least 10
mm between the centers of spots. The application spots must be at 5 mm
above the level of the mobile phase.
2. Allow the spots to dry
3. Place the plate in the chamber, ensuring the spots are above the surface of
the mobile phase
4. Develop the chromatogram in a solvent system, until the solvent front has
moved about three-fourth of the length of the plate.
5. Remove the plate from chamber, mark the solvent front and allow the
solvent to evaporate.
2.7. Detection
Spray with a solution of diphenylamine in methanol (1 in 100) and irradiate the
plate with short (254 nm) and long (365 nm) UV light for about 10 minutes.
Determine the chromatographic retardation factor (Rr) for the principal spots.
The Rf of the principal spot obtained from the test solution corresponds to the
obtained from the standard solution.
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 11>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page 1 of 6
Test Method: STM-AR-CV-0159
Title: Nitroglycerin Cleaning Verification Method
Effective Date:
SEP 2 9 2011
Supersedes: 07/22/11
Prepared by:
Date:
09/29/11
Reviewed by:
Date:
09/24/11
Approved by:
Date:
09/29/11
I.
PURPOSE
in manufacturing equipment.
The purpose of this procedure is to describe the residue test method for monitoring Nitroglycerin
II. APPLICABILITY
This STM applies to cleaning swabs for Nitroglycerin. This method applies to both Analytical
Research and Quality Control Departments.
IlL.
PROCEDURE
A. Instrumentation
High Performance Liquid Chromatography system consisting of a pump, an injector, a UV
letector and a data processing system capable of integrating the areas under the curve of the peaki
of interest.
Column:
Mobile Phase:
Alltech, Alltima C18, 5 um, 4.6 mm × 150 mm PN# 88052
Injection Volume:
USP Water: Methanol (60:40)
50 pL
low rate
un time
1.2 mL/min
Not less than 20 min
Wavelength:
220 (8) nm
25°C
10 min to 14 min
B. Reagents
1. Water, USP
2. Methanol, HPLC grade or equivalent
3. Nitroglycerin standard
C. Reagent Preparation
1 Mobile Phase: USP Water: Methanol (60:40)
Mix 600 mL of USP water with 400 ml of Methanol and mix well. This preparation may be
scaled up or down as needed
Effective Date: 29 Sep 2011 11:24:09 GMT -06:00
USERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION
Printed by: Production Activity Control (svs-aumas-001
Date/Time: 24 Dec 20111:03:16 PM GMT -06:00

<<<PAGE 12>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page 2 of 6
STM#: STM-AR-CV-0159
Title: Nitroglycerin Cleaning Verification Method
Effective Date: SEP 2 9 2011
Supersedes: 07/22/11
2 Diluent: USP Water: Methanol = 50:50
Mix 500 mL of USP water with 500 mL of Methanol and mix well. This preparation may be
scaled up or down as needed
D. Standard Preparation:
1. Stock Solution:
Accurately weigh and transfer approximately 63.3 mg of Diluted Nitroglycerin Standard
(equivalent to 0.6 mg of Nitroglycerin) into a 50 ml, volumetric flask, dissolve and dilute to
volume with Methanol. The concentration of Nitroglycerin stock Solution is approximately
0.012 mg/mL.
2. Working Standard Solution
Pipette 5.0 mL of the stock solution into a 50 mL volumetric flask, dilute to volume with
diluent, and mix well. Scale up or down as needed.
The stock and working standard solutions are stable for 5 days at room temperatures.
Concentration of Nitroglycerin working standard is about 0.0012 mg/mL.
E. Swab Sample Preparation:
Swab samples are collected and submitted in 50-mL plastic centrifuge tubes. Pipette 5.0 mL of the
diluent into each of the sample tubes and mix the contents for at least 2 minutes using a vortex
mixer. Transfer about 1.5 mL of the resulting solution into an HPLC vial. Swab samples and
solutions are stable for 3 days.
F. Blank Swab Preparation:
A Blank Swab is prepared and submitted in a 50 mL plastic centrifuge tubes. Treat the same way
as a Sample Swab.
G. HPLC Procedure:
SiA, dad ip system according to te Make at neated mie " dumentien Pection
System Suitability Test. Calculate the reproducibility (%RSD) for six Nitroglycerin Working
Standard injections and perform the system suitability calculations. Calculate the reproducibility
(ORSD is ≤ 5.0 %), the number of theoretical plates (N≥ 3000), and the tailing factor (T≤ 2.0). If
the system is suitable, proceed with the samples analysis. Bracket the samples with the Working
Standard Solution.
Effective Date: 29 Sep 2011 11:24:09 GMT -06:00
Version: 2.0
USERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION.
Printed by: Production Activity Control (svs-qumas-001)
Date/Time: 24 Dec 20111:03:16 PM GMT -06:00

<<<PAGE 13>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page 3 of 6
STM#:
STM-AR-CV-0159
Title: Nitroglycerin Cleaning Verification Method
Effective Date: SEP 2 9 2011
Supersedes: 07/22/11
H. Calculations
Note: Label mobile phase, detergent and swab peaks in the sample chromatograms according
to the table below (Refer to Validation Report ARVR-11-0068)
Peak
Peak RT (min)
RRI
Mobile Phase Peak 1
0.766
0.06
Detergent Peak
0.872
0.07
Mobile Phase Peak 2
1.274
0.11
Swab Peak 1
2.21
20.18
Mobile Phase Peak 3
3.368
0.28
Swab Peak 2
4.485
0.37.
Swab Peak 3
6.232
0.52
Swab Peak 4
8.674
0.72
Nitroglycerin
12.084
1.00
Swab Peak 5
13.39
1.11
:
Calculate the quantity (Q) of Nitroglycerin or unknown ug /swab using the following equation:
ug Nitroglycerin /Swab
=
Au
—X—
WS XPFXO.1
As
0.661
Where
PF
=
Potency of Nitroglycerin Reference Standard. Use as % (e.g. 0.948%
is entered as 0.948)
As
=
Average area of the Nitroglycerin peaks in chromatograms for the
bracketing Working Standard Solutions.
Aul
=
Peak response of Nitroglycerin in the sample chromatogram.
Ws
=
Weight of Diluted Nitroglycerin Reference Standard in mg.
0.661
=
Correction factor based on the ferrous plate recovery study, expressed
in decimals.
0.1
=
Dilution factor including standard, Sample dilutions and conversion of
Diluted Nitroglycerin into Nitroglycerin
Version: 2.0
Effective Date: 29 SeD 2011 11:24:09 GMT -06:00
USERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION.
Printed by: Production Activity Control (svs-qumas-001)
Date/Time: 24 Dec 20111:03:16 PM GMT -06:00

<<<PAGE 14>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page 4 of 6
STM#:
STM-AR-CV-0159
Title: Nitroglycerin Cleaning Verification Method
Effective Date: SEP 2 9 2011
Supersedes: 07/22/11
IV. REFERENCES
Current USP
Current SOP # AR-0051, How to write a Standard Test Method.
Cleaning Validation Request letter for Nitroglycerin (From Technical Service Department), received
on 06/09/20011.
V. HISTORY
New, Effective date: 07/22/11
Revision 1, effective date:
SEP 2 9 2011
Linearity range in the summary chart of page 6 updated to: 0.0001213 mg/mL to 0.002425 mg/mL
VI. SPECIFICATION
Cleaning verification criteria: NMT 5.77 ug of Nitroglycerin/ Swab
Version: 2.0
Effective Date: 29 Sep 2011 11:24:09 GMT -06:00
USERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION
Printed by: Production Activity Control (svs-qumas-001)
Date/Time: 24 Dec 20111:03:16 PM GMT -06:00

<<<PAGE 15>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page 5 of 6
STM#:
STM-AR-CV-0159
Title: Nitroglycerin Cleaning Verification Method
Effective Date: SEP 2 9 2011
Supersedes: 07/22/11
Figure 1. Chromatogram of Nitroglycerin Working Standard Solution
SAMPLE INFORMATION
Sample Name:
Vial:
Sample Type:
Standard
STD 1-7
Acqured By:
43
Acq. Method Set:
Date Acquired:
7/11/2011 7:39:09 PM EDT
atatkow!
CV LC 17
: 50000 ul
Percering tad: 6
-
Santa et Nama: 37i0 tirely std stab 1C17
Toc. Chl. Desor.: DAD AUCh 1 Sample 220, Bw
hennel Name
A1100 DAD AU Ch1
00G-
Auto-Scaled Chromatográm
Mobile-Phase Peak 1 - 0.758
Mohile Phase Pook-2--1-272
Peak 32-8:369
2,000-
Nilroglycering =12:070--
boblle Phale
5:00
2it
400
aco
Minte
10/20
72.00
1400
Channel Name A1100 DAD AU CAT
SampleName: STD 17
Simpletere
Name
2 | STO 1-7
Molio Prace Feast 2589:
SID 1-7
Dategent Fak
0759: 469
STD 1.7
STD 17
Sieb Poak1
Mobile Ptoe Feak2! 15744
Q.670|
400|
_ 1.6
1272 3012
Motle Place Fears 35400
2210
1572
157.0
B5S
24
SID 17
Such Pa*2
4550
STD 1-7
Sian Rackt
E410
B.870
Version: 2.0
Effective Date: 29 Sep 2011 11:24:09 GMT -06:00
201 1.2 G-DUMENTS ARE REne r. Production it or sums 0 CUMENT Rate me: 34 De 2011, 03-16 PM MIT-06.00
Printed bv: Production Activity Control (svs-qumas-001)

<<<PAGE 16>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page 6 of 6
STM#:
STM-AR-CV-0159
Title: Nitroglycerin Cleaning Verification Method
Effective Date: SEP 2 9 2011
Supersedes: 07/22/11
Summary Chart
Type of Swab:
Texwipe TX714 A
Maximum Allowable Limit:
NMT 5.77 Mg / Swab
Area to be Swabbed:
100 cm?
Target Ingredient:
Nitroglycerin
Limit of Detection:
0.00006063 mg/mL
Limit of Quantitation:
0.0001213 mg/mL
Linearity:
0.0001213 mg/mL to 0.002425 mg/mL
Specificity:
No Interference
Plate Recovery:
From Ferrous Plates: 66.1 %
Swabbing Solution:
Methanol
Swab Stability:
Stable for 3 days
Swab Stability in Solution:
Stable for 3 days
Swab Sampling Technique:
As per SOP # AR-0063 Section: 8.6.1
Version: 2.0
Effective Date: 29 Sep 2011 11:24:09 GMT -06:00
USERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION.
Printed bv: Production Activity Control (svs-aumas-001)
Date/Time: 24 Dec 20111:03:16 PM GMT -06:00

<<<PAGE 17>>>

...-.
Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
5 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
mg
Test Method #:STM-AR-FP-0164
C. Assay
1. Instrument
An HPLC system consisting of an autosampler, pump, a column, an adjustable
wavelength UV Detector and an integrator capable of integrating the peaks of
interest.
HPLC Parameters:
Column:
PN# 00G-4252-E0
Phenomenex, Luna C18 (2), 5 um, 4.6 mm x 250 mm
Mobile Phase:
Methanol/Water=50/50
Run time:
Injection Volume: 20 uL
Flow rate:
not less than 19 minutes
Wavelength:
1.0 mL/min
220 (8) nm, ref: off
Column
Temperature:
Rt window:
25 °C
13.5 minutes to 17.5 minutes
2. Reagents
:
Diluted Nitroglycerin Reference Standard
Methanol, HPLC grade or equivalent
USP Water
3. Reagent Preparation
3.1. Mobile Phase Preparation: Methanol/Water=50/50
Mix 1000 mL of Water with 1000 mL of Methanol and sonicate to degas for 5
minutes. This preparation may be scaled up or down as needed.
Mobile Phase was demonstrated to be stable for at least 6 weeks at room
temperature conditions
3.2. Diluent
Use assay Mobile Phase: Methanol/Water=50/50
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 18>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
6 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
mg
Test Method #:STM-AR-FP-0164
4. Standard Preparation
4.1. Working standard solution
Accurately weigh about 158 mg of Diluted Nitroglycerin standard equivalent
do 15 re. or ito lycene dilent and mix wel 10 is pegition may be
scaled up or down as needed.
4.2. Stability of Standard Solution
The standard solution has been proved to be stable for 15 days at room
temperature conditions.
4.3. Standard Concentration calculation
The working solution contains approximately 0.075 mg/mL of Nitroglycerin |
and is calculated using the following equation:
Cstd =-
Wstd× P
20 mLx100
Cstd
Where,
Concentration of Nitroglycerin standard in mg/mL.
W std
=
P
=
Diluted Nitroglycerin Standard weight, mg
Potency of the Diluted Nitroglycerin Reference Standard in %.
100% =
Conversion from Diluted Nitroglycerin to Nitroglycerin
5. Sample Preparation
5.1. Stock Sample Solution
Weigh the amount of tablets listed in the table below. Transfer into the proper
volumetric flask. Add a stir bar and 80% of the flask volume of diluent. Stir
the sample for 1 hour (tablets should completely disintegrate). Remove the stir
bar and rinse it inside the flask with diluent, complete to volume with diluent
and mix well. Transfer about 10 mL into a centrifuge tube, cover with paratilm
and centrifuge the sample at 3000 rpm for 10 minutes. (Concentration is about
0.3 mg/mL).
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 19>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
7 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
Strength
#of Tablets
Volumetric Flask
in mL
0.3 mg
20
20
0.4 mg
20
25
0.6 mg
25
50
5.2. Working Sample Solution
Dilute 6.0 ml, of the centrifuged supernatant stock solution into a 25 ml.
volumetric flask and dilute to volume with diluent, mix well. Transfer an
aliquot into HPLC vial to analyze. (Concentration is in range 0.072 to 0.077
mg/mL).
5.3. Stability of Sample Solution
least 3 days at room temperature conditions
The Stock and working assay sample solutions were proved to be stable for at
6. Procedure
6.1. Refer to SOP AR-0049 "High Performance Liquid Chromatographic
Analysis"
6.2. System Suitability Criteria
Make five replicate injections of the Working Assay Standard-1 solution.
Calculate the reproducibility (% RSD) of the five consecutive injections,
theoretical plates (N) and the tailing factor (T) for the Nitroglycerin peak. The
system is suitable if: RSD ≤ 2.0%, N≥ 3000 and T ≤ 2.5.
Inject the Working Assay Standard Solution-2 twice. Compare the potency
(%) of Standard-2 relative to Standard-1:
6.3. Standard Comparison Calculation
Std Comp. (%) = -
Astd2xWstd1
Astdl× Wsta2
-x 100
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 20>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
8 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6 | Test Method #:STM-AR-FP-0164
Astal
Where,
=
Peak area of Standard-1 (Average of five injections)
Asta2
= Peak Area of Standard-2 (Average of two injections)
Wstal
=
Standard-1 weight, mg
Wstd2
= Standard-2 weight, mg
Standard-1 is suitable for use if Standard comparison (%) value is within the
range 100.0 ‡ 2.0%.
6.4. Sample Analysis
Inject working sample solutions bracketed by working standard -1.
6.5. Factors to be used in Empower
Factor
Description
Custom Field in
Standard
Concentration
Standard Concentration
Empower Set up
in mg/mL
Component Editor Table/
20 (for 0.3mg and
STANDARDS ONLY
0.4mg) or 25 (for
Number of Tablets for
analysis
Sample Weight
0.6mg)
83.3333 (for 0.3mg),
104.1667 (for
Dilution volume in mi
Dilution
0.4mg) or 208.3333
(for 0.6 mg)
0.3, 0.4 or 0.6
Nitroglycerin Strength
Component Editor Table/
in mg
STANDARDS &
UNKNOWNS (under LC)
7. Calculations
7.1. Peak identification
Follow table below for possible peaks observed in the assay sample
chromatograms based on the specificity study during the method validation
(Reference: 2492p9)
Isers of printed documents are responsible for ensuring that the printed document represents the most current revisior
Jocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 201‹

<<<PAGE 21>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
9 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
mg
Test Method #:STM-AR-FP-0164
Component name
Peak
Retention Time
Placebo
2-Mononitroglycerin
No peak observed
(minutes)
RRT
NA
Peak observed
NA
2.964
1-Mononitroglycerin
Peak observed
0.20
3.120
0.21
1,2-Dinitroglycerin
1,3-Dinitrolgycerin
Peak observed
Peak observed
5.240
0.36
5.838
Mobile Phase (Diluent)
Peak observed
0.40
Nitroglycerin
Peak observed
6.154
0.42
14.673
NA
7.2. Assay Calculation
From the HPLC analysis, obtain the peak area of the sample (Asp) and
Standard-1 (Asta). The percentage of Nitroglycerin per tablet is calculated from
the equation:
% LC =-
AsplxCstdxVF×25mL
Astd × LCx#tablets × 6.0mL
- × 100%
Where,
Cstd
=
Aspl
=
Nitroglycerin Standard-1 concentration, mg /mL
Astd
Peak area of the sample.
=
LC
=
Average Area of Bracketing standard-1.
#tablets =
Label claim in mg
number of tablets used in the analysis
VFstock =
Volume of the Stock Solution in mI
D. Blend Uniformity
1. Instrument, Reagent, Reagent Preparation, Standard Preparation and
Procedure
Refer to Assay section III. C.1, III. C.2, III. C.3, III.C.4 & III.C.6.
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 22>>>

-...
Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
10 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
mg
Test Method #:STM-AR-FP-0164
2. Sample Preparation
Samples of one to six dosage units are provided from various blenders and drum
locations. Perform the following for each sample:
Tap the vial several times on the bench top. Weigh accurately the vial containing
the sample (with the cap included in the initial weight) and record the weight (G).
Quantitatively transfer the content of the vial to a volumetric flask (follow table
below according strength and dosage units provided as a reference only).
NOTE: Ensure to wash the vial and the inside portion of the cap with diluent
Add a stir bar into the volumetric flask and diluent up to 70% of the flask volume
and stir for 1 hour. Remove the stir bar and rinse it inside the flask with diluent.
complete to volume with diluent and mix well. Transfer an aliquot into a centrifuge
Tube, cover with pot of superman it it vial to anal pm for 10 minute.
The Nitroglycerin concentration in the prepared Blend Uniformity Samples should
be within the range of 0.045 mg/mL to 0.1125 mg/ml
Dosage Units
Strengths
VFstock
in mg
in mL
0.3
5
1 dosage unit
0.4
5
0.6
0.3
10
2 dosage units
0.4
10
0.6
0.3
20
10
3 dosage units
0.4
0.6
20
25
Rinse the empty sample vials and caps with acetone and:
-Dry the rinsed caps at room temperature for at least 2 hours or until needed
-Dry the rinsed vials (without the cap) in the oven at 105°C for about 30 minutes,
ensuring that they are completely dry
Weigh the empty vial (with the cap) and record its weight (T). Finally calculate the
weight of the sample (N) = (G-T).
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 23>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
11 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
3. Procedure
3.1. Factors to be used in Empower
Factor
Description
Custom Field in
Standard
Standard Concentration
Empower Set up
Concentration
Component Editor Table/
Weight
in mg/mL
STANDARDS ONLY
Sample Weight in mg
Volumetric
Sample Weight
Volume
Flask
Dilution Factor in mL
Dilution
Theoretical potency
Theoretical potency in
Component Editor Table/
decimals (Not as in
STANDARDS &
percentage)
UNKNOWNS (under LC)
4. Calculations
The percentage of Nitroglycerin is calculated using the equation below:
%LC=-
Aspl Cstd xVF × 100%
Astd
Ws×%Th
-x100%
Where
Aspl
Astd
= Peak area response of the sample.
=
Average area response of the bracketing standard.
Cstd
=
Concentration of Nitroglycerin standard in mg/mL
Ws
=
Sample weight in mg
%Th
=
Theoretical percentage of the active in the blend.
= Volume of the Volumetric Flask in mL
E. Uniformity of Dosage Units (Content Uniformity)
1. Instrument, Reagent, Reagent Preparation, Standard Preparation and
Procedure
Refer to Assay section III.C.1, III. C.2, III. C.3, III. C.4 & III.C.6.
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 24>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
12 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
2. Sample Preparation
Weigh ten tablets individually. Transfer into separate volumetric flasks (VF)
follow table below). Add a stir bar and 70 % of the flask volume of diluent and sti
for 1 hour. Remove the stir bar and rinse it inside the flask with diluent, complete t
volume with diluent and mix well. Transfer an aliquot into a centrifuge tube, cover
with parafilm and centrifuge the sample at 3000 rpm for 10 minutes. Transfer an
Strength
VF
in mL
0.3 mg
5
0.4 mg
5
0.6 mg
10
Concentration of Nitroglycerin is from 0.06 mg/mL to 0.08 mg/mL
3. Procedure
3.1. Factors to be used in Empower
Factor
Description
Custom Field in
Standard
Standard Concentration
Empower Set up
Concentration
Component Editor Table/
1
in mg/mL
STANDARDS ONLY
Number of Tablets for
Sample Weight
5 (for 0.3mg and
analysis
Dilution volume in mL
Dilution
0.4mg) or 10 (for 0.6
mg)
0.3, 0.4 or 0.6
Nitroglycerin Strength
Component Editor Table/
in mg
STANDARDS &
UNKNOWNS (under LC)
4. Calculations:
From the HPLC analysis, obtain the peak area of the sample (Aspl) and Standard-1
(Asta). The percentage of Nitroglycerin per tablet is calculated from the equation:
Jsers of printed documents are responsible for ensuring that the printed document represents the most current revision
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 25>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
13 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
%LC=Aspİ×Cstd×VF
Astd× LC
- ×100%
Where,
Cstd
=
Standard-1 concentration, mg /mL
Aspl
=
Peak Area of the Sample.
Astd
LC
=
=
Average Area of Bracketing standard-1.
Label Claim in mg
VFstock
=
Volume of the Volumetric Flask in mL
5. Criteria: (AS PER USP Monograph)
The content of each of the 10 Sublingual Tablets is within the range of 75.0% and
outside the range of 75.0% and 135.0% and if the content of none of the
135.0% of the labeled claim. If the content of not more than 1 Sublingual Tablet is
units. The requirements are met if the content of each of the additional 20 units falls
Sublingual Tablets is outside the range of 60.0% and 150.0 %, test 20 additional
within the range of 75.0% and 135.0% of the labeled claim.
F. Degradation Products
1. Instrumental
wavelength UV Detector and an integrator capable of integrating the peaks of
An HPLC system consisting of an autosampler, pump, a column, an adjustable
interest.
HPLC Parameters:
Column:
Phenomenex, Luna C18 (2), 5 um, 4.6 mm x 250 mm PN#
Mobile Phase:
00G-4252-E0
A: 0.05M Phosphate Buffer pH 3.0/Methanol=95/5
Injection Volume:
B: 0.05M Phosphate Buffer pH 3.0/Methanol=50/50
Run time:
20 uL
Flow rate:
65 min (Refer to the gradient table below)
1.0 mL/min
Wavelength:
Column
215 (8) nm, ref: off
Temperature:
Rt window:
25 °C
45 minutes to 52 minutes
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 26>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
• Page
14 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
Gradient Table
Time (min)
Flow (ml/min)
0
Mobile Phase A
1.0
100
Mobile Phase B
7
1.0
100
0
0
40
55
1.0
0
100
56
1.0
0
100
1.0
100
65
1.0
100
0
0
2. Reagents
:
Diluted Nitroglycerin Reference Standard
Methanol, HPLC grade or equivalent
••
USP Water
85% o-Phosphoric Acid, ACS grade or equivalent
•
Potassium Phosphate Monobasic (KKH2PO4), ACS grade or better
3. Reagents Preparation
3.1. Preparation of 0.05 M Potassium Phosphate Monobasic Buffer
pH 3.00 ‡ 0.05
Accurately weigh about 13.6 g of Monobasic Potassium Phosphate and
dissolve in 2000 ml of water, mix well and adjust pH to 3.00 = 0.05 with o-
Phosphoric Acid (85%). This preparation may be scale up or down as needed.
3.2. Mobile Phase A: 0.05M Phosphate Buffer pH 3.0/ Methanol =95/5
Mix 950 mL of 0.05M Phosphate Buffer pH 3.0 with 50 mL of Methanol and
needed.
sonicate to degas for 5 minutes. This preparation may be scaled up or down as
Mobile Phase was demonstrated to be stable for at least 6 weeks at room
temperature conditions
3.3. Mobile Phase B: 0.05M Phosphate Buffer pH 3.0/ Methanol =50/50
Mix 500 mL of 0.05M Phosphate Buffer pH 3.0 with 500 mL of Methanol and
needed.
sonicate to degas for 5 minutes. This preparation may be scaled up or down as
Mobile Phase was demonstrated to be stable for at least 6 weeks at room
temperature conditions
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 27>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
15 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
3.4. Diluent: Methanol/Water=50/50
Mix 500 mL of Methanol with 500 mL of water and mix well. This preparation
may be scaled up or down as needed.
4. Impurity Standard Preparation
4.1. Working Impurity Solution
Dilute 2.0 mL of the standard solution from Section III.C.4.1 (Conc. about
0.075 mg/mL) into a 50 mL volumetric flask, dilute to volume with diluent.
Mix well. Label as the "Impurity Standard".
4.2. Stability of the Standard Solutions
The stock and the working impurity solutions were proved to be stable for 17
days at room temperature conditions
4.3. Standard Concentration calculation
Concentration of Nitroglycerin Impurity Standard is approximately 0.003
mg/mL. Calculate the Impurity Standard concentration in mg/mL as follow:
Cstd =.
Wstd × P× 2.0mL
20mL ×100 × 50m.L
Where,
Cstd =
Wstd
=
Concentration of Nitroglycerin standard in mg/mL.
P
=
Diluted Nitroglycerin Standard weight, mg
100% =
Potency of the Diluted Nitroglycerin Reference Standard in %.
Conversion from Diluted Nitroglycerin to Nitroglycerin
5. Sample Preparation
5.1. Working Impurity Sample
Use the Stock Sample Solution centrifuged supernatant prepared in Section
III.C.5.1. Transfer an aliquot into HPLC vial for analysis. (Conc. about 0.3
mg/mL).
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 28>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
• Page
16 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
5.2. Stability of the Impurity Sample Solution
The impurity sample solution was proved to be stable for 3 days at room
temperature conditions
6. Procedure
6.1. Refer to SOP AR-0049 "High Performance Liquid Chromatographic
Analysis"
6.2. System Suitability Criteria
Make at least two injections of the diluent solution and six replicate injections
of the Impurity Standard Solution. Calculate the reproducibility (% RSD) of the
six replicate injections, theoretical plates (N) and the tailing factor (T) for the
Nitroglycerin peak. The system is suitable if: RSD ≤ 5.0%, N ≥ 6000 and T ≤ 2.
6.3. Sample Analysis
Inject the sample solutions bracketed by impurity standard
6.4. Factors to be used in Empower
Factor
Description
Custom Field in
Standard
Standard Concentration
Empower Set up
Component Editor Table/
Concentration
in mg/mL
STANDARDS ONLY
0.3, 0.4 or 0.6
Nitroglycerin Label
Label Claim in the Sample
Claim in mg
set custom field
20 (for 0.3mg and
Number of Tablets for
Sample Weight
0.4mg) or 25 (for
analysis
0.6mg)
20 (for 0.3mg), 25
Dilution factor in mI
Dilution
(for 0.6 mg)
(for 0.4mg) or 50
1/RRF
The inverse of the
Under RELATIVE
Relative Response
RESONSE tab of the
Factor of each impurity
Component Table in the
Processing Method
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14. 2014

<<<PAGE 29>>>

-
Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
17 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6 | Test Method #:STM-AR-FP-0164
mg
7. Calculations
7.1 Identification and Limit of Quantitation (LOQ) of Impurities
For identification of known degradation impurities refer to the table below.
RRF, RRT and LOQ of Nitroglycerin & Degradation Impurities
Approximate RRT
Related Compound
RRF
To Nitroglycerin
Peak
LOQ
2-Mononitroglycerin
0.84
0.12
0.05%
1-Mononitroglycerin
0.86
0.14
0.05 %
1,3-Dinitroglycerin
1.21
0.49
0.05 %
1,2-Dinitroglycerin
1.04
0.57
0.05%
Nitroglycerin
1.00
1.00
0.05 %
1-Chloro-2,3-Dinitro-2,3-
propanediol
1.00
1.02
0.05%
The Limit of Quantitation of the method was proved to be about 0.000151
7.2. Identification of Placebo peaks
No placebo peak is observed in sample chromatograms
7.3. Degradation Products Calculation
From the HPLC analysis, obtain the peak area of individual
Impurity/Degradants. The amount of each Impurity/Degradant is calculated
% Impurity =-
Aspl×Cstd×VF
Astd × LCx#tablets × RRF
- × 100%
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 30>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
18 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
Where,
Cstd
=
Impurity Standard concentration, mg /mL
Aspl
Peak area of impurity in the sample.
Astd
Average Area of Bracketing standard.
LC
=
#tablets =
number of tablets used in the analysis
VFstock =
Volume of the Stock Volumetric Flask in mL
RRF
=
Relative Response Factor
of Individual Unknown impurities + Known Impurities = % Total impurities
G. Dissolution
1. Instrument
1.1. Dissolution Conditions
USP ‹711> Apparatus 2 (Paddles) operated under the following
conditions:
Volume:
Medium:
0.05 M Potassium Phosphate Buffer pH 6.5
500 mL
Temperature:
37 °C + 0.5 °C
Speed:
Filter Tips:
50 грт
10 um
1.2. Sample Collection Parameters
Dissolution VK7000 tester coupled with Vankel sampling station(s)
(VK8000) with the following parameters:
Sample volume:
5 mL
Prime time:
Purge time:
30 sec
Media replacement:
60 sec
Time intervals:
Disable
1, 3, 5, 8, and 10 minutes
1.3 HPLC Parameters:
An HPLC system consisting of an autosampler, pump, a column, an UV
Detector and an integrator capable of integrating the peaks of interest
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 31>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
19 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg; 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
Column:
Alltech, Alltima C8, 5 um, 4.6 mm x 150 mm,
Mobile Phase:
PN 88072
Injection Volume:
Water/Methanol=50/50
80 ML
low rate
Lun time
Not less than 8 min
1.0 mL/min
Temperature:
Wavelength:
35 C
220(8) nm
Rt window:
5 min to 8 min
1.4. Degassing Conditions
Degas the necessary volume of medium by sonicating for 20 minutes in ~25" of
Hg vacuum (reading on gauge) in a suitable container
2. Reagent
• Diluted Nitroglycerin Reference Standard
• Methanol, HPLC grade or equivalent
• Potassium Phosphate Monobasic (KH,PO4), ACS grade or equivalent
• USP Water
• Sodium Hydroxide Pellets, ACS or equivalent
• Hydrochloric Acid (HCI), concentrated, ACS grade
3. Reagent Preparation
3.1 Media Preparation: 0.05M Potassium Phosphate Buffer pH 6.5
Dissolve 41 g of monobasic potassium Phosphate and 3.4 g of sodium hydroxide
pellets (NaOH) by stirring in a 1000 ml of Water in a suitable container.
Completely transfer this solution into a 6 L container, dilute to volume (6 L) and
mix well. Adjust the pH with 1M sodium hydroxide or sodium hydroxide pellets
so that the final pH of the buffer is in the range 6.50 + 0.05. This preparation may
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Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
20 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6 |Test Method #:STM-AR-FP-0164
mg
3.2 Mobile Phase Preparation: Water/Methanol=50/50
Mix 1000 mL of Water and 1000 mL of Methanol, mix well and sonicate for 5
Mobile Phase was demonstrated to be stable for at least 6 weeks at room
minutes. This preparation may be scaled up or down as needed.
temperature conditions
4. Standard Preparation
4.1 Stock standard solution
Weigh about 63 mg of Diluted Nitroglycerin Reference Standard (equivalent
0.6 mg of Nitroglycerin) and transfer in a 25 ml volumetric flask. Dissolve in
Methanol with sonication. Dilute to volume with Methanol. This preparation
may be scaled up or down as needed. (Conc.: ~ 0.024 mg/mL).
4.2 Working standard solution
Pipette 5.0 mL of stock standard solution into a 100 mL volumetric flask and
dilute to volume in dissolution medium, mix well. This preparation may be scaled
up or down as needed. (Conc.: ~ 0.0012 mg/mL).
4.3. Stability of the Standard Solutions
at room temperate conditions
The stock and working standard solutions were proved to be stable for 14 days
4.4. Standard Concentration calculation
The concentration of the "Working Standard Solution" in mg /mL is calculated
using the following equation:
Cstd =-
Wstd ×5.0mL × P
25mL ×100mL×100
Where,
Cstd
= nitroglycerin Working standard concentration (mg /mL)
= Weight of Diluted Nitroglycerin Reference Standard (mg).
= Potency of the Diluted Nitroglycerin Reference Standard in %.
100% = Conversion from Diluted Nitroglycerin to Nitroglycerin
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

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STANDARD TEST METHOD
Page
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Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
5. Sample Preparation
Dissolution samples will be collected after being filtered through 10 um full flow
filter (on line). The collected dissolution samples are centrifuged at 2500 RPM for
5 minutes. Transfer samples into HPLC vials to be analyzed.
5.1. Sample Solution Stability
temperature conditions
The dissolution sample solutions were proved to be stable for 3 days at room
6. Procedure
6.1
Preparation of Dissolution VK7000 tester coupled with Vankel sampling
station(s) (VK8000)
6.1.1 Dissolution System Cleaning: Follow the procedure in SOP # AR-0040
Note: Before starting the Dissolution test, clean thoroughly the
dissolution apparatus as follow:
: Apply a cleanins cycle with Water Methank - 1/1
Apply a cleaning cycle with warm water
6.1.2 Valve Calibration: Follow the procedure in SOP # AR-0040
6.1.3 Dissolution Apparatus set-up: Follow the procedure in SOP # AR-0040
6.1.4 Dissolution Program set-up: Follow the procedure in SOP # AR-0040
6.1.5 Dissolution start-up: Follow the procedure in SOP # AR-0040. Make
sure that enough clean test tubes are placed in the fraction collector tray
6.2.
Dissolution Process
• Transfer 500 mL of dissolution media into the dissolution vessels and
allow the temperature inside the vessels to equilibrate to 37 = 0.5° C.
• Drop one tablet in each vessel
• Run the dissolution apparatus and
• Collect a sample at the specified time points
• Analyze the samples by HPLC
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

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STANDARD TEST METHOD
Page
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Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
6.3. Refer to SOP AR-0049 "High Performance Liquid Chromatographic
Analysis"
6.4. System Suitability Criteria
Inject at least once the dissolution medium. Make five replicate injections of
the standard-1 solution. Calculate the reproducibility (RSD) of the five
consecutive injections, theoretical plates (N) and the tailing factor (T) for
the Nitroglycerin peak. The system is suitable if: RSD ≤ 2.0%, N≥ 2500,
and T ≤ 2.
- 2 relative to Standard - 1
Inject the Standard Solution-2 twice. Compare the potency (%) of Standard
6.5.
Standard Comparison Calculation
Std Comp. (%) =
Astd2×Wstd1
AstdlxWstd2
-x100
Where,
Peak area of Standard-1 (Average of five injections)
Peak Area of Standard-2 (Average of two injections)
Standard-1 weight, ng
= Standard-2 weight, ing
Standard-1 is suitable for use if Standard comparison (%) value is within the
range 100.0 - 3.0%.
6.6.
Sample Analysis
Inject dissolution samples bracketed by working standard - 1. The
cumulative % RSD should be NMT 3.0 %.
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STANDARD TEST METHOD
Page
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Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
6.7. Factors to be used in Empower
Factor
Description
Custom Field in
Standard
Standard
Empower Set up
Component Editor Table/
Concentration
Concentration in
STANDARDS ONLY
500
mg/mL
Dissolution volume in
mL
Initial Volume of Media in
each vessel in the Sample
set method
5
Sample volume in mt.
Volume removed on each
transfer in the Sample set
method
0.3, 0.4 or 0.6
Nitroglycerin Strength
Dissolution Claimed
in mg
amount in the Sample set
method
7. Calculations:
Note: Mobile Phase peak can be observed in the dissolution sample chromatograms
at RRT ~ 0.47.
From the HPLC analysis, obtain the peak area of the sample (Aspl) and Standard-1
(Asta). The percentage of Nitroglycerin per tablet is calculated from the equations:
Concentration of Nitroglycerin at each time point:
Cn= Asplm) x Cstd
Astd
% Nitroglycerin Dissolved:
% Dissolved =
LC
i=l
x 100%
Where:
Astd = Average Area of Bracketing standard-1 between samples analyzed
Aspl = Area of Nitroglycerin peak in the chromato gram
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<<<PAGE 36>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
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Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
C(n) = Concentration of dissolution samples taken at the nth time point, in
mg/mL
n
=
The nth time point (n≥ 1)
LC = Label Claim in mg
→ car-sumation of cisolution sample concentration to this liste
to the (n-i)th time point. (Only applicable for n≥ 2)
H. Water Content
1. Instrument
751 GPD Metrohm Titrino or equivalent
2. Reagents
:
Water, USP
Methanol, HPLC grade or better
Hydranal Composite 5 or other suitable Karl Fisher Titrant
3. Procedure
3.1. Standardization
Standardize the Karl Fisher instrument according to SOP # AR-008520 Fill the
titration vessel with methanol until it is ¼ full. Neutralize the water in the vessel
by pressing the start button on the Titrino.
3.2. Sample Preparation
Grind at least 20 tablets using a mortar and pestle. Weigh approximately 0.5 g
of the sample and transfer to the titration vessel and return the weighing boat to
the balance. Obtain the net sample weight transferred to the titration vessel and
proceed with the titration.
4. Calculation
Calculate the % of Water from the following equation:
% Water = EP x Titer x 0.1
W spl
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 37>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
25 of 32.
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
Where:
EP
= The titration endpoint in mt
Titer = Constant equivalent to the amount of water needed to neutralize one
mL of titrant, mg/mL
Wspl = The net weight of the sample, grams
I. Disintegration
1. Instrument
1.1. Disintegration Conditions
Apparatus:
Basket-rack assembly of six open-ended transparent tubes
with a woven stainless steel wire cloth, which has a plain
square weaves of 1.8 to 2.2 mm aperture and wire diameter
Medium:
Water
of 0.57 to 0.66 mm
Volume:
37+2°C 1
700 mL
Temperature:
2. Procedure
• Transfer 700 ml of water into the disintegration vessel and allow the
temperature inside the vessels to equilibrate to 37 + 2° C.
• Drop one tablet in each the six tubes of the basket
• Run the disintegration apparatus for 2 minutes
• Annotate the time needed for the tablets to completely disintegrate
• At the end of the 2 minutes, lift the basket from the fluid, and observe that the
tablets have disintegrated completely
3. Acceptance criteria
forth for sublingual tablets
Follow USP General Chapter <701> Disintegration: 2 minutes, determined as set
IV.
REFERENCES
• Nitroglycerin Technical Package, Copperhead Chemical Company.
• Watson Florida Laboratories SOP # AR-0067, "Dissolution Media Preparation
Procedure".
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 38>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
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Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
• SOP # AR-0040, "Care and Use of VanKel Dissolution System VK7000 Tester
Coupled with VK8000 Sampling Station."
• Current USP <921> Water Determination (Karl Fisher)
V.
HISTORY
New
Effective date: 09/29/11
Revision 01, Effective date: 10/06/11
Section IIl.F.1. Updated HPLC
Proposed Change
Justification
To improve separation of the
chromatographic parameters (Water in the
Impurity and therefore the
Mobile Phase was substituted by Phosphate
chromatographic performance
Buffer pH 3.0)
Section III.F.2. Added new reagents
Due to changes in the Impurity
Section III.F.3. Updated the reagent
T
HPLC conditions
HPLC conditions
Due to changes in the Impurity
preparation
Section III.F.6. Added 2 injections of diluent
To equilibrate better the system
before the system suitability
Section III.F.7. Updated the RRT of
Due to changes in the Impurity
impurities
HPLC conditions
Section III.I. Added disintegration
Based on USP General Chapter
parameters
<701>
Chromatograms: Updated the impurity
Due to changes in the Impurity
profile chromatogram
HPLC conditions
Revision 02, Effective date: 10/06/11
Proposed Change
Section III.F.1. & III.F.3. Buffer Molarity
Justification
Typo error during the
updated to 0.05M
preparation of the revision 01
Revision 03, Effective date: 11/01/11
Section III. C.5, III. F.4 and III.G.4. Added
Proposed Change
Justification
Based on the standards stability
statement of standard stability
study during the method
Section III. C.8. Added table of possible
Based on the assay specificity
peaks observed in the assay sample
chromatograms
study during the method
validation
Section III.F.7.1. Table of degradation
Based on the impurity
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
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<<<PAGE 39>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
27 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
impurities was updated with the RRF, RRT
and LOQ values
specificity study during the
method validation
Section IIL.F.7.2. Added LOQ value in the
Based on the impurity method
text
validation
Section III.G.4.2. "mg» in the denominator
As the 100 in that formula
of the formula was removed
Section III.G.6.4. Added statement of
refers to 100%
possible peak observed in the dissolution
Based on the dissolution
sample chromatograms
method validation
specificity study during the
Revision 04, Effective date: 11/07/11
Proposed Change
Justification
Section III.F.2. HPLC grade replaced by
To be able to use ACS quality
ACS grade or equivalent for Phosphoric acid
reagent in the mobile phase
preparation
Section III.G.6.1. Additional cleaning
Corrective action of the LIR #
procedure of the dissolution baths was added
11-065
before the initiation of Nitroglycerin
dissolution to avoid cross contamination
Revision 05, Effective date: 12/14/11
Proposed Change
Justification
Section III. C.6. Added statement about assay
Based on stability validation
sample stability
studies (Report No. ARVR-11-
Section III.F.5. Added statement about
0175)
Based on stability validation
impurity sample stability
studies (Report No. ARVR-11-
Section III.G.6.2. Added statement about
Based on stability validation
dissolution sample stability
studies (Report No. ARVR-11-
0175)
Revision 06, Effective date: 12/22/11
Section VI. Name of Nitroglycerin Blends
Proposed Change
Justification
To match the master batch
Tablets to Nitroglycerin Tablets Blend
updated from Final Blend for Nitroglycerin
records updates
Spec-R199412, R199424 & R199415 for
To match the master batch
Nitroglycerin Blends were updated from
Nitroglycerin Blends: The names of
records updates
Final Blend for Nitroglycerin Tablets to
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14. 2014

<<<PAGE 40>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
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Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6 | Test Method #:STM-AR-FP-0164
mg
Nitroglycerin Tablets Blend
Spec-R199417, R199426 & R199419 for
Nitroglycerin Sublingual Tablets: Tablets
Word "embossed" was replaced
by "engraved"
description was updated
Revision 07, Effective date: 06/01/12
Proposed Change
Justification
and TESTs names were updated
Section I. PURPOSE. List of TESTS readjusted
TAo-O0SY How to Prepare standars fest
Method"
statements
Section III. PROCEDURES. Added EHS
To comply with the new revision of SOP
Method
AR-0051 How to Prepare a Standard Test
Description
Section III.A: Appearance was renamed as
AR-0051 "How to Prepare a Standard Test
To comply with the new revision of SOP
Section III.B: Identification. Content was
To harmonize all STM's Tests
Method
Section III.C. Assay. Section divided in
subsections. Added the Factors to be used in
To facilitate the understanding and comply
Empower Calculations
0051'How to Prepare a Standard Test
with the new revision of SOP AR-
Section III.D: Blend Uniformity. Section divided
To facilitate the understanding and comply
Method
in subsections. Added the Factors to be used in
Empower Calculations
0051"How to Prepare a Standard Test
with the new revision of SOP AR-
Method
Units (Content Uniformity). Section was divided
Section III.E. Renamed to Uniformity of Dosage
To facilitate the understanding and comply
in subsections. Added the Factors to be used in
0051 'How to Prepare a Standard Test
with the new revision of SOP AR-
Empower Calculations
Section III.F: Renamed to Degradation Products
Method
Section was divided in subsections. Added the
To comply with the new revision of SOP
Factors to be used in Empower Calculations
Method
AR-0051"How to Prepare a Standard Test
in subsections. Added the Factors to be used in
Section III.G: Dissolution. Section was divided
R-0051 "How to Prepare a Standard Tes
o comply with the new revision of SO
Section III.H. Water Determination was
Method
renamed to Water Content and divided in
with the new revision of SOP AR-
To facilitate the understanding and comply
subsections
0051 How to Prepare a Standard Test
Section III.I: Disintegration. Section was divided
To facilitate the understanding and comply
Method
in subsections
0051"How to Prepare a Standard Test
with the new revision of SOP AR-
Method
Revision 08, Effective date: 09/10/12
Section III. EHS Safety Statements: Removed #
Proposed Change
Justification
As this statement is repeated
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 41>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
29 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
2
Section IIT.D. 2. Sample preparation procedure
the initial and final weights of the sample vial.
was updated to include the weight of the caps in
WES/E-12/033
Corrective action of Even Reference Form
the inside portion of the cap.
Also added in the procedure statement to rinse
Revision 09, Effective date: 05/16/13
Section III. C.3.1. Added stability statement for.
Proposed Change
Justification
Mobile Phase
Stability study demonstrated and recorded
Section III.F.3.2 & III.F.3.3. Added stability
in ARVR-13-0105
Section III.G.3.2. Added stability statement for
statement for Mobile Phase
Stability study demonstrated and recorded
in ARVR-13-0105
Mobile Phase
Stability study demonstrated and recorded
in ARVR-13-0105
Revision 10, Effective date: MAR 1 4 2014
Section III.F.7.1. Added new identified
Proposed Change
degradation compound
Based on conclusions from studies
at RRT 1.02. Refer to Reports:
conducted to identify the unknown impurity
-ARVR-14-0055 "Structure Elucidation and
relative response Factor Determination of
the Peak at RRT=1.02 in Nitroglycerin
DEREK Evaluation of an identifiec
mpurity from Gad Consulting service.
Spec-R199417, R199426 & R199419
from January 31, 2014
ind 0.6mg, respectively: Included the
Nitroglycerin Sublingual Tablets, 0.3mg, 0.4m;
compound under Specification section of
Added new identified degradation
the Related Compounds. Refer to Reports
2 gradation compound 1-Chloro 2, 3-Dinitro-
listed above.
VI.
SPECIFICATION AND ANALYTICAL REPORTS
For Specification Sheets, see the list below:
Nitroglycerin Sublingual Tablets Blend, 0.3 mg, Spec - R199412
Nitroglycerin Sublingual Tablets Blend, 0.4 mg, Spec - R199424
Nitroglycerin Sublingual Tablets Blend, 0.6 mg, Spec - R199415
Nitroglycerin Sublingual Tablets, 0.3 mg, Spec - R199417
Nitroglycerin Sublingual Tablets, 0.4 mg, Spec - R199426
Nitroglycerin Sublingual Tablets, 0.6 mg, Spec - R199419
Users of printed documents are responsible for ensuring that the printed document represents the most current revision.
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<<<PAGE 42>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
30 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
Example of Nitroglycerin assay standard solution
SAMPLE
INFORMATION
Sample Type:
Sample Name:
STD 1-SS
Vial:
Standard
Acquired By:
khondoke
injection #
1
Acq. Method Set:
Date Acquired
3/25/2011 5:56:26 PM ED
Nitroglycerin Assay WLC06
Injection Volume: 20.00 ul
Date Processed:
8/26/20117:53:50 AM EDT
Run Time:
Sample Set Name: 082511_ Assay_L006
19.0 Minutes
Processing Method: Nitroglycerin Assay_1
Channel Name:
Proc. Chl. Descr.: DADAU Ch 1 Sample 220, Bw 8
A1100 DAD AU Ch1
Auto-Scaled Chromatogram
0.14
012)
0,1-7
0,0s
- Nitroglycerin - 14.117
Gos
0.02-
0.007
-0,027
4,00
8.00
Minutes
10:00
12C0
14.00
16.00
18.00
Peak Results
Name
RT
Units
Area
1 Nitroglycerin 14.117 mgin 724180
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 43>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
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Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
Example of Nitroglycerin Impurity Profile solution
Empowerz
Individual Chromatograms
SAMPLE
INFORMATION
Sample Name
Sample Type
Unknown
Profile
Date Acquired:
Acquired By
10/5/201 1 2:44:04 PM EDT
oridge
nection Youre: 20.00 l
Injection#:
Acq. Method Set: Nitrog Diss WLC05
Date Processed:
rocessing Method: Nitroglycerin RC_922411.
10/5/2011 3:57:35 PM ED
Sample Set Name: 100511_40m_gradL005
Run Time:
60.0 Minutes
Channel Name:
Proc. Chl. Descr.:
DADAU Ch 1 Sample 215, Bw 8
A1100 DADAU Ch1
0,050-
Auto-Scaled Chromatogram
17:05c
1402
0.040-
- Nitroglycerin - 48,882
0,030-
₴ 0020-
1,3-DING - 23.852
1,2-DING - 27.821
Diluent 2 - 38.612
Diluent 3 - 41.844
HeAts 423.582
3-MonoN: 5053
0010-
- Diluent 1 - 10.725
0.000-
-0.010-
0.00
'500
10.00
-15co
TIST
2200 2500 3
Minutes
30,00
3500 10
40.00
0045.00
0050.00
001500
Peak Results
Name
RT
Height Area
1 2-MonoNG
2 | 1-MORONG
6.055
6512 64582
9 Diluents
Name
RT
Height | Area
43.862
218฿
5540
3 Diluent 1
10.725
7.005
0779 66953
145
10 Nitroglycerin
18.882
4578
84878
4
1,3-DING
5130
5 1,2-DiNG
127.321
23.852
6897
91358
5617
81119
6 Diluent2
/58,612
1255
17274
7 | Diluert 3
41.844
329
7756
8 Diluent4
43.150
254
5132
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<<<PAGE 44>>>

Watson Laboratories, Inc.-Florida
STANDARD TEST METHOD
Page
32 of 32:
Title: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6
Test Method #:STM-AR-FP-0164
mg
Example of Nitroglycerin Dissolution Standard
Empowerz
Individual Chromatograms
SAMPLE
INFORMATION
Sample Name:
Sample Type:
Std
Vial:
Standard
Acquired By:
Date Acquired:
729/20113:21:30 PM EDT
Injection #:
100
Date Processed:
Acq. Method Set:
Nitrog Diss WLC17 35D
Injection Volume: 80.00 ul
rocessing Method: Nitroglycin Diss WLC2
/29/2011 4:19:10 PM EL
Sample So: Name:
7.0 Minutes
Channel Name:
Proc. Chni. Descr.: DAD AUCh 1 Sample 220, Bw 8
A1100 DAD AU Ch1
Auto-Scaled Chrom atogram
0.0307
0.025
001E™
Nitroglycerin - 5.641
₴ осою!
Diluent - 3.296
0,005
0.000
a00.0
1.00
200
3.00
Minutes
4.00
5.00
6,00
Peak Results
Name
RT Height
Area % Araa int Type US Resolution USP Tailing| USP Plate Count
1 Diluent
3.296
2382 59352
63.75 BB
2,859
633
.... 2 Nitoglerin 5641
6198|
51062
46.25 B8
6.208848et000
1.051
9482
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Document No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014

<<<PAGE 45>>>

Watson®
Document Information
Name/No: STM-AR-CV-0159
Document Details:
Title:
State:
Effective
Nitroglycerin Cleaning Verification Method
Version:
Effective: 29 Sep 2011 11:24:09 GMT -06:00
Dept.:
2.0
Analytical Research (AR)
Workflow Details:
Status:
Name:
N/A
N/A
Approval Panel:
Any Approval signatures that have been applied to this document are shown below:
Signed By : Felipe, Minda (melipe)
Decision Date: 29 Sep 2011 11:06:56 GMT. -06:00
Decision : Approved
Purpose : Revise STM
Role : Change Management
Meaning Or Signature: Document Aprong
Version: 2.0
Effective Date: 29 SeD 2011 11:24:09 GMT -06:00
201 1.25,09 GM - DOCUMENTS ARE Pried by Production ality control ss umas OCUMENT OCUMENT Eatene Dee Dee 201703.16 PM GMT -050.

## Provenance

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### Source metadata

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  "interpretationArea": "hazardous_materials",
  "representation": "full_text_from_official_pdf",
  "companies": [
    "R&S Compliance group, LLC."
  ],
  "individuals": [
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