{"operation":"document","citation":"14-0248","title":"R&S Compliance group, LLC. — Hazardous Materials Safety Interpretation","source_type":"guidance","agency":"Pipeline and Hazardous Materials Safety Administration","status":"guidance","official":true,"published_on":"2015-06-18","effective_on":null,"summary":"14-0248 response to R&S Compliance group, LLC. concerning 172.101, 173.22, 173.50, 173.56.","machine_formats":{"json":"https://regulus.evalyn.ai/document/phmsa-interpretation-14-0248.json","markdown":"https://regulus.evalyn.ai/document/phmsa-interpretation-14-0248.md"},"app_url":"https://regulus.evalyn.ai/document/phmsa-interpretation-14-0248","source_url":"https://www.phmsa.dot.gov/sites/phmsa.dot.gov/files/legacy/interpretations/Interpretation%20Files/2015/140248.pdf","body":"<<<PAGE 1>>>\n\nS. Departmen\nf Transportatio\nWashington. DC 20590\n1200 New Jersey Avenue SE\nPipeline and Hazardou:\nAdminist titty\nJUN 18 2015\nMr. David Rivers\nR&S Compliance Group, LLC.\n2707 W. Price Ave.\nTampa, FL 33611\nReference No. 14-0248\nDear Mr. Rivers:\nThis is in response to your December 30, 2014 letter requesting clarification of the\nHazardous Materials Regulations (HMR; 49 CFR Parts 171-180) applicable to new\nexplosives. You state your company receives a nitroglycerin and lactose mixture classified\nas \"UN 3319, Nitroglycerin Mixture, Desensitized, Solid, N.O.S., 4.1\" transported under\napproval EX2000120151. You further state that this raw material is used in the production\nof a pharmaceutical product. Various machines that come in contact with the raw material\nare cleaned and the cleaning process results in effluent waste material containing a methanol\nand water mixture with contaminate of nitroglycerin. You present in-house test data from\ntests run on several lots of effluent waste showing trace concentrations of nitroglycerin\nbetween 0.00616- 0.01220 mg/ml. You ask several questions regarding the need for\nclassification of both effluent waste material and tablet nitroglycerin. Your questions are\nparaphrased and answered as follows:\nQ1. In order for § 173.56 to apply, does the resulting effluent material resulting from the\nalteration process (testing and cleaning) of the originally classified explosive mixture need\nto meet the definition of a Class 1 material in § 173.50(a) first? Or does § 173.56 apply first\nbecause the original ingredient that was altered was subject to § 173.56 and therefore all\nproducts or by-products of the initial classified explosive, regardless of the characteristics,\nor if the product meets the definition of Class 1 per § 173.50(a), require formal testing,\nclassification and approval per § 107.705?\nAl. Per § 173.56(a) a new explosive is an explosive produced by a person who has not\npreviously produced that explosive, or has previously produced that explosive but has made\na change in the formulation, design, or process so as to alter any of the properties of the\nexplosive. Any product containing an energetic ingredient (e.g., Nitroglycerin) is therefore\nsubject to the requirements of § 173.56, and any modification of such product previously\napproved is also subject to the same requirements to determine if the modifications meet the\ndefinition of a new explosive. However, if the modification results in a new material that\nmay be classified in a hazard class or division other than Class 1 under a proper shipping\nname specifically listed in the Hazardous Materials Table (HMT) in § 172.101 (e.g.\nUN1204), the modified material would not be subject to the provisions of §173.56 unless\nthe proper shipping name has a special provision requiring approval under § 173.56.\n\n<<<PAGE 2>>>\n\nQ2. It the latter is true, does the final pharmaceutical product, nitroglycerin tablets, require\nthe same approval to transport to pharmacies as the tablet is a result of an alteration of an\ninitially classified explosive?\nA2. The nitroglycerin tablets would require approval in accordance with § 173.56(b).\nQ3. Would the resulting effluent material, containing residual amounts of what would be a\nclassified explosive in other forms or concentrations, be properly described for\ntransportation by other characteristics? In this case UN1204 Nitroglycerin solution in\nalcohol.\nA3. In accordance with § 173.22, it is the shipper's responsibility to properly classify a\nhazardous material. This Office generally does not perform this function. However, if the\neffluent waste can be appropriately described by an existing HMT entry for a hazard class or\ndivision other than Class 1 it may be oftered for transport under that entry. In your scenario,\nif the nitroglycerin solution in alcohol and water contains not more than 1 percent\nnitroglycerin in alcohol with no other energetic ingredients, the effluent would most\nappropriately be offered as UN1204.\nI trust this information is helpful. If you have further questions, please do not hesitate to\ncontact this office.\nSincerely,\nDuane A. Pfund\nInternational Standards Coordinator\nStandards and Rulemaking Division\n\n<<<PAGE 3>>>\n\nWebb\n17356\nGoodall, Shante CTR (PHMSA)\nNew seposines\nFrom:\nBetts, Charles (PHMSA)\n14-0248\nSent:\nWednesday, December 31, 2014 12:05 PM\nTo:\nGoodall, Shante CTR (PHMSA)\nCc:\nSubject:\nDodd, Alice (PHMSA); Foster, Glenn (PHMSA); Fink, William (PHMSA)\nFw: Request for Interpretation\nAttachments:\nRequest for interp less than 2 nitro.pdf; STM-AR-CV-0159 Nitroglycerin Cleaning\nVerification Method.pdf; STM-AR-FP-0164 Nitroglycerin Sublingual Tablets 0 3 mg 0 4\nmg 06 mg.paf\nShante -\nPlease log and assign for response. Thanks\nFrom: Fink, William (PHMSA)\nSent: Wednesday, December 31, 2014 09:08 AM Eastern Standard Time\nTo: Betts, Charles (PHMSA); INFOCNTR (PHMSA)\nSubject: FW: Request for Interpretation\nCc: Singh, Harpreet (PHMSA)\nCharles,\nR&S is requesting a letter of interp.\nBill Fink\nFrom: Alston, Barbara CTR (PHMSA)\nSent: Tuesday, December 30, 2014 4:43 PM\nTo: Fink, William (PHMSA); Herrera, Jacqueline (PHMSA)\nSubject: FW: Request for Interpretation\nGood Afternoon Team,\nI spoke with Mr. Rivers on the phone and he has sent information pertaining to his questions/request, please see\nattachments. Many thanks, Barbara\nFrom: David Rivers [mailto:david@rscompliance.com]\nTo: Alston, Barbara CTR (PHMSA)\nSent: Tuesday, December 30, 2014 4:17 PM\nSubject: Request for Interpretation\nBarbara,\nThank you for speaking with me today. The attached is a scenario requesting an interpretation as to the applicability of\n173.56, \"New Explosive\" of an effluent waste from a pharmaceutical manufacturing and cleaning process. The narrative\ndemonstrates the specifics of our situation. If needed, I also attached testing procedures that we use that ultimately\ncreates the \"by-product\" we are trying to ensure we classify for transportation appropriately given the raw material\nNitroglycerin.\nYour help is greatly appreciated. Happy New Year!\nDavid O. Rivers, M.S.\n1\n\n<<<PAGE 4>>>\n\n2707 W. Price Ave., Tampa, FL 33611\nCompliance Group, LIC\nPhone: (813) 433-4979\nDecember 30, 2014\nUS Department of Transportation\nPHMSA - Energetic Materials\nAttn: Division of Approvals and Permit, PHH30\n1200 New Jersey Ave. SE, East Building 2nd Floor\nWashington, DC 20590-0001\nR&S Compliance Group, Ile would like to request a letter of interpretation as to the intent of the definition\nof a \"New Explosive\" described in 173.56. This section requires that a classification and new EX\nApproval be granted for the transportation of a classified explosive if the original classified explosive is\naltered \"...as to change the formulation, design or process so as to alter the properties of the explosive.\"\nSpecifically, we receive a Nitroglycerin and Lactose Mixture classified as;\n\"Nitroglycerin Mixture, Desensitized, Solid, NOS with more than 2 percent but not more than 10 percent\nnitroglycerin, by mass\", transported under Approval EX2000120151 and reclassified by the Associate\nAdministrator as hazard class 4.1, UN3319.\nThis raw material is used in the production of a pharmaceutical product, a Nitroglycerin Tablet. Each LOT\nof final product, the table themselves, must be tested for quality control according to Good Manufacturing\nPractices (GMP) and Food and Drug Administration (FDA) requirements. The machine used to extract the\nactive ingredient from the raw material received, Nitroglycerin, also must be cleaned. Other machines\nwhich have contact surfaces that come in contact with the pharmaceutical mixture during the blending,\nmixing and tablet formation process must be washed. This testing and cleaning process results in effluent\nwaste material containing a Methanol and Water Mixture with contaminates of Nitroglycerin.\nThe in-house lab ran a test on this effluent waste material from several lots of effluent waste and found the\nfollowing concentrations of trace Nitroglycerin per volume. (In house test procedures attached)\nApproximate Conc. of Nitroglycerin per container\nContainer 1\n0.01220\nmg/mL\nContainer 2\n0.00068\nmg/mL\nContainer 3\n0.00194\nmg/mL\nContainer 4\n0.00616\nmg/mL\n*Results are \"Grab\" samples from 55 gallon drums of effluent and not meant to meet the testing criteria prescribed in 173.52,\n173.57 and 173.58\nR&S Compliance Group, LLC\n\n<<<PAGE 5>>>\n\nROSS\n2707 W. Price Ave., Tampa, FL 33611 Phone: (813) 433-4979\nCompliance Group, LIC\nOur question is if the requirements to seek proper classification and EX Approval from the Associate\nAdministrator per 173.56 apply to the effluent waste from laboratory testing and/or cleaning processes by\ndetermining if these activities meets the definition of \"altering\" an existing explosive when the resulting\neffluent material to be transported, (transportation for disposal in this case), does not meet the definition of\na Class 1 explosive ,173.50(a).\n#1\nIn order for 173.56 to apply, does the final effluent material resulting from the alteration processes (testing\nand cleaning) of the original classified explosive mixture (Nitroglycerin Mixture, Desensitized, Solid,\nNOS) need to meet the definition of a CLASS 1 material (173.50(a) FIRST? \"an explosive means\n..designed to function by explosion...\",?\nIf the resulting effluent material did in fact meet the explosive definition, we would agree an approval\nwould we required as a New Explosive defined in 173.56. But what the resulting materials does not meet\nthe definition of an explosive 173.50(a), would further examination of this effluent mixture and written\ndetermination be required from the Associate Administrator to state that the material does not need an\napproval?\n#2\nOr, does 173.56 apply simply because the original ingredient that was altered was subject to 173.56 before\ninitially offered for transportation, therefore, all products or by-products of the initial classified explosive\n(in this case, Nitroglycerin Mixture, Desensitized, Solid, NOS, EX2000120151), regardless of the resulting\ncharacteristics or meeting the definition of Class 1 set forth in 173.50 (a), require formal testing,\nclassification and approval per 107.705.\nIf the latter, #2, is true, does the final pharmaceutical product, the common Nitroglycerin tablet for heart\npatients require the same approval to transport to pharmacies as the tablet is the result of an alteration of an\ninitially classified explosive?\nOr, does this resulting effluent material, even though it contains residual amounts of what otherwise would\nbe a classified explosive in other forms or concentrations, simply need to be properly described for\ntransportation to meet the definition of its characteristics, 173.22(a), not requiring an EX Approval, and in\nthis case by 173.120(a)(2) as a flammable liquid such as;\nUN1204, Nitroglycerian Solution in Alcohol with not more than 1 percent nitroglycerin\n*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\nthe original Nitroglycerin product received and used, even though the description has the word \"Nitroglycerin\" within the name. This description would be\nselected by shippers where appropriate as required by \"Shipper's Responsibility\"\nR&S Compliance Group, LLC\n\n<<<PAGE 6>>>\n\nR8U\n2707 W. Price Ave., Tampa, FL 33611 Phone: (813) 433-4979\nCompliance Group, LIC\nWe understand that there is not a threshold of an explosive concentration that PHMSA has established for\nan \"altered\" explosive, clarified according to interpretation #09-0058 which would need an EX Approval\nif, as stated in paragraph three, ...\n\"new compositions containing any amount of explosive material...\".\nThis sentence refers to an \"explosive\" material presumably \"explosive\" by definition, 173.50(a).\nHowever, does the above described effluent waste, scenario, and furthermore the final pharmaceutical\nproduct, meet the intent or definition of a \"New Explosive\", subject to 173.56 simply because of\n\"alteration\" though a sampling and cleaning process and eventual formation and packaging or a\npharmaceutical tablet involving previously \"Classified Explosive\" requiring an EX Approval for initial\ntransport, where the \"Process\" is not intended to produce an a different \"explosive\", by definition, from the\noriginal \"explosive\" when the final effluent mixture does not exhibit characteristics of a CLASS 1 material,\nby definition?\nYour attention and interest to our request is appreciated. Please feel free to contact me with any questions\nyou may have.\nResiss\nCHMM, CSP, CET, CDGP\nDavid O. Rivers, M.S.\nPh: 813-433-4979\nR&S Compliance Group, lIc.\nFx: 813-436-5392\nwww.rscompliance.com\ndavid@rscompliance.com\nR&S Compliance Group, LLC\n\n<<<PAGE 7>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage 1 of 32\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nTest Method #: STM-AR-FP-0164\nmg\nEffective Date:\nMAR 1 4 2014\nSupersedes: 05/16/13\nPrepared by:\nDate:\n03/1/14\nReviewed by:\nDsl\nDate:\n03/1|/1L\nReviewed by:\nDate:\n03/11/14\nApproved by:\nEthe Bodes\n03/12/14\nDate:\n13/2/14€\n03/15/14\nI.\nPURPOSE\nThe purpose of this procedure is to describe the test methods used for analysis of\nNitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6 mg and Intermediate products.\nTESTS\nA. Description\nB. Identification\nC. Assay\nD. Blend Uniformity\n. Uniformity of Dosage Units\nF.\nDegradation Products\nG. Dissolution\nH. Water Content\nI.\nDisintegration\nII.\nAPPLICABILITY\nThis method applies to Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6 mg and\nIntermediate products. This method applies to Analytical Research Department.\nIII.\nPROCEDURE\nEHS Safety Statements\n1. Material Safety Data Sheets for all chemicals involved should be read prior to starting\nany chemical handling. All recommendations of work practices and Personal Protective\nEquipment (PPE) should be followed.\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 8>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n2 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nmg\nTest Method #:STM-AR-FP-0164\n2. All solutions and prepared samples must be properly labeled, including hazard\ninformation, if they are to be stored longer than a single work shift.\n3. All waste, including rinsings, should be labeled appropriately and handled per Watson\nWaste Management Policy, SOP GN-0026 and Risk Management Procedure RM-0018\n(located on the Portal). If a hazardous material was used in a filter media, the filter\nmedia is considered hazardous material and must be disposed of appropriately.\n4. All glassware should be inspected prior to use. Defective glassware should not be used.\n5. Thick walled glassware should be used when vacuum degassing media and mobile\nphases.\n6. Waste receptacles should be verified to have enough space to hold the volume of waste\nto be generated.\n7. Flammable solvents should be dispensed inside of a chemical fume hood. Flammable\nsolutions should be covered if stored outside of the hood.\n8. Appropriate PPE should be worn based on the requirements of Risk Management\nProcedure RM-0009 (located on the Portal) and the MSDS.\n9. When weighing powdered laboratory chemicals and products, excess materials should\nnot be placed into the regular trash receptacles. Excess products should be placed inside\na non-hazardous waste receptacle and excess chemical powders should be disposed of\nappropriately based on hazards present.\n10. All PPE should be inspected prior to donning. PPE should be rechecked often for\ndamage and replaced as needed.\n11. Concentrated acids and bases should be handled with care and dispensed inside a\nchemical fume hood with appropriate PPE.\n12. Incompatible waste streams should be segregated and collected separately for disposal.\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 9>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n3 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nTest Method #:STM-AR-FP-0164\nmg\nA. Description\nVisually inspect the sample and compare with the description given in the respective\nAnalytical research in-process and finished product specifications.\nRefer to the specification item number given in Section VI\nB. Identification\n1. HPLC\nThe major peak in the assay sample chromatogram corresponds to that of the\nretention time for the Nitroglycerin peak in the Standard chromatogram.\n2. Thin-Layer Chromatographic Identification Test\n2.1. Apparatus\nA chromatographic chamber made of inert, transparent material with flat\nbottom or twin trough, a tightly fitted lid and a size suitable for the plate is\nused. The chamber is lined on at least one wall with filter paper. Sufficient\nmobile phase is added to the chamber that, after impregnation of the filter\npaper, a depth appropriate to the dimensions of the plate used is available. The\nchamber is closed and allowed to equilibrate.\n2.2. Reagents\n• Acetone, ACS grade or better\n• Ethyl acetate, ACS grade or better\nToluene, ACS grade or better\n• Glacial acetic acid, ACS grade or better\n• Methanol, HPLC grade or better\n•\nDiphenylamine, ACS grade or better\n• Nitroglycerin standard\n2.3. Reagent Preparation\n2.3.1. Mobile Phase\nMixture of toluene, ethyl acetate and glacial acetic acid in a ratio 16:4:1.\nScale up or down as needed.\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 10>>>\n\n....\n-\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n4 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nTest Method #:STM-AR-FP-0164\n2.3.2. Spray Solution\nPrepare a mixture of diphenylamine in methanol (1 in 100). Scale up or\ndown as needed.\n2.4. Standard Preparation\nPrepare a solution of 1 mg of nitroglycerin in 1 mL of acetone.\n2.5. Sample Preparation\nTransfer the amount of finely powdered Sublingual Tablets, equivalent to\nabout 1 mg ot nitroglycerin, to a centrifuge tube, add 1 mL of acetone, cover\nwith parafilm shake by mechanical means for 30 minutes, and Centrifuge at\n3000 rpm for 10 minutes, use supernatant for analysis.\n2.6. Procedure\nOn a line parallel to and about 2 cm from the edge of a suitable thin-layer\nchromatographic plate coated with 0.25 mm layer of silica gel mixture:\n1. Apply 10 uL of the test and standard solutions with an interval of at least 10\nmm between the centers of spots. The application spots must be at 5 mm\nabove the level of the mobile phase.\n2. Allow the spots to dry\n3. Place the plate in the chamber, ensuring the spots are above the surface of\nthe mobile phase\n4. Develop the chromatogram in a solvent system, until the solvent front has\nmoved about three-fourth of the length of the plate.\n5. Remove the plate from chamber, mark the solvent front and allow the\nsolvent to evaporate.\n2.7. Detection\nSpray with a solution of diphenylamine in methanol (1 in 100) and irradiate the\nplate with short (254 nm) and long (365 nm) UV light for about 10 minutes.\nDetermine the chromatographic retardation factor (Rr) for the principal spots.\nThe Rf of the principal spot obtained from the test solution corresponds to the\nobtained from the standard solution.\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 11>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage 1 of 6\nTest Method: STM-AR-CV-0159\nTitle: Nitroglycerin Cleaning Verification Method\nEffective Date:\nSEP 2 9 2011\nSupersedes: 07/22/11\nPrepared by:\nDate:\n09/29/11\nReviewed by:\nDate:\n09/24/11\nApproved by:\nDate:\n09/29/11\nI.\nPURPOSE\nin manufacturing equipment.\nThe purpose of this procedure is to describe the residue test method for monitoring Nitroglycerin\nII. APPLICABILITY\nThis STM applies to cleaning swabs for Nitroglycerin. This method applies to both Analytical\nResearch and Quality Control Departments.\nIlL.\nPROCEDURE\nA. Instrumentation\nHigh Performance Liquid Chromatography system consisting of a pump, an injector, a UV\nletector and a data processing system capable of integrating the areas under the curve of the peaki\nof interest.\nColumn:\nMobile Phase:\nAlltech, Alltima C18, 5 um, 4.6 mm × 150 mm PN# 88052\nInjection Volume:\nUSP Water: Methanol (60:40)\n50 pL\nlow rate\nun time\n1.2 mL/min\nNot less than 20 min\nWavelength:\n220 (8) nm\n25°C\n10 min to 14 min\nB. Reagents\n1. Water, USP\n2. Methanol, HPLC grade or equivalent\n3. Nitroglycerin standard\nC. Reagent Preparation\n1 Mobile Phase: USP Water: Methanol (60:40)\nMix 600 mL of USP water with 400 ml of Methanol and mix well. This preparation may be\nscaled up or down as needed\nEffective Date: 29 Sep 2011 11:24:09 GMT -06:00\nUSERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION\nPrinted by: Production Activity Control (svs-aumas-001\nDate/Time: 24 Dec 20111:03:16 PM GMT -06:00\n\n<<<PAGE 12>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage 2 of 6\nSTM#: STM-AR-CV-0159\nTitle: Nitroglycerin Cleaning Verification Method\nEffective Date: SEP 2 9 2011\nSupersedes: 07/22/11\n2 Diluent: USP Water: Methanol = 50:50\nMix 500 mL of USP water with 500 mL of Methanol and mix well. This preparation may be\nscaled up or down as needed\nD. Standard Preparation:\n1. Stock Solution:\nAccurately weigh and transfer approximately 63.3 mg of Diluted Nitroglycerin Standard\n(equivalent to 0.6 mg of Nitroglycerin) into a 50 ml, volumetric flask, dissolve and dilute to\nvolume with Methanol. The concentration of Nitroglycerin stock Solution is approximately\n0.012 mg/mL.\n2. Working Standard Solution\nPipette 5.0 mL of the stock solution into a 50 mL volumetric flask, dilute to volume with\ndiluent, and mix well. Scale up or down as needed.\nThe stock and working standard solutions are stable for 5 days at room temperatures.\nConcentration of Nitroglycerin working standard is about 0.0012 mg/mL.\nE. Swab Sample Preparation:\nSwab samples are collected and submitted in 50-mL plastic centrifuge tubes. Pipette 5.0 mL of the\ndiluent into each of the sample tubes and mix the contents for at least 2 minutes using a vortex\nmixer. Transfer about 1.5 mL of the resulting solution into an HPLC vial. Swab samples and\nsolutions are stable for 3 days.\nF. Blank Swab Preparation:\nA Blank Swab is prepared and submitted in a 50 mL plastic centrifuge tubes. Treat the same way\nas a Sample Swab.\nG. HPLC Procedure:\nSiA, dad ip system according to te Make at neated mie \" dumentien Pection\nSystem Suitability Test. Calculate the reproducibility (%RSD) for six Nitroglycerin Working\nStandard injections and perform the system suitability calculations. Calculate the reproducibility\n(ORSD is ≤ 5.0 %), the number of theoretical plates (N≥ 3000), and the tailing factor (T≤ 2.0). If\nthe system is suitable, proceed with the samples analysis. Bracket the samples with the Working\nStandard Solution.\nEffective Date: 29 Sep 2011 11:24:09 GMT -06:00\nVersion: 2.0\nUSERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION.\nPrinted by: Production Activity Control (svs-qumas-001)\nDate/Time: 24 Dec 20111:03:16 PM GMT -06:00\n\n<<<PAGE 13>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage 3 of 6\nSTM#:\nSTM-AR-CV-0159\nTitle: Nitroglycerin Cleaning Verification Method\nEffective Date: SEP 2 9 2011\nSupersedes: 07/22/11\nH. Calculations\nNote: Label mobile phase, detergent and swab peaks in the sample chromatograms according\nto the table below (Refer to Validation Report ARVR-11-0068)\nPeak\nPeak RT (min)\nRRI\nMobile Phase Peak 1\n0.766\n0.06\nDetergent Peak\n0.872\n0.07\nMobile Phase Peak 2\n1.274\n0.11\nSwab Peak 1\n2.21\n20.18\nMobile Phase Peak 3\n3.368\n0.28\nSwab Peak 2\n4.485\n0.37.\nSwab Peak 3\n6.232\n0.52\nSwab Peak 4\n8.674\n0.72\nNitroglycerin\n12.084\n1.00\nSwab Peak 5\n13.39\n1.11\n:\nCalculate the quantity (Q) of Nitroglycerin or unknown ug /swab using the following equation:\nug Nitroglycerin /Swab\n=\nAu\n—X—\nWS XPFXO.1\nAs\n0.661\nWhere\nPF\n=\nPotency of Nitroglycerin Reference Standard. Use as % (e.g. 0.948%\nis entered as 0.948)\nAs\n=\nAverage area of the Nitroglycerin peaks in chromatograms for the\nbracketing Working Standard Solutions.\nAul\n=\nPeak response of Nitroglycerin in the sample chromatogram.\nWs\n=\nWeight of Diluted Nitroglycerin Reference Standard in mg.\n0.661\n=\nCorrection factor based on the ferrous plate recovery study, expressed\nin decimals.\n0.1\n=\nDilution factor including standard, Sample dilutions and conversion of\nDiluted Nitroglycerin into Nitroglycerin\nVersion: 2.0\nEffective Date: 29 SeD 2011 11:24:09 GMT -06:00\nUSERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION.\nPrinted by: Production Activity Control (svs-qumas-001)\nDate/Time: 24 Dec 20111:03:16 PM GMT -06:00\n\n<<<PAGE 14>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage 4 of 6\nSTM#:\nSTM-AR-CV-0159\nTitle: Nitroglycerin Cleaning Verification Method\nEffective Date: SEP 2 9 2011\nSupersedes: 07/22/11\nIV. REFERENCES\nCurrent USP\nCurrent SOP # AR-0051, How to write a Standard Test Method.\nCleaning Validation Request letter for Nitroglycerin (From Technical Service Department), received\non 06/09/20011.\nV. HISTORY\nNew, Effective date: 07/22/11\nRevision 1, effective date:\nSEP 2 9 2011\nLinearity range in the summary chart of page 6 updated to: 0.0001213 mg/mL to 0.002425 mg/mL\nVI. SPECIFICATION\nCleaning verification criteria: NMT 5.77 ug of Nitroglycerin/ Swab\nVersion: 2.0\nEffective Date: 29 Sep 2011 11:24:09 GMT -06:00\nUSERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION\nPrinted by: Production Activity Control (svs-qumas-001)\nDate/Time: 24 Dec 20111:03:16 PM GMT -06:00\n\n<<<PAGE 15>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage 5 of 6\nSTM#:\nSTM-AR-CV-0159\nTitle: Nitroglycerin Cleaning Verification Method\nEffective Date: SEP 2 9 2011\nSupersedes: 07/22/11\nFigure 1. Chromatogram of Nitroglycerin Working Standard Solution\nSAMPLE INFORMATION\nSample Name:\nVial:\nSample Type:\nStandard\nSTD 1-7\nAcqured By:\n43\nAcq. Method Set:\nDate Acquired:\n7/11/2011 7:39:09 PM EDT\natatkow!\nCV LC 17\n: 50000 ul\nPercering tad: 6\n-\nSanta et Nama: 37i0 tirely std stab 1C17\nToc. Chl. Desor.: DAD AUCh 1 Sample 220, Bw\nhennel Name\nA1100 DAD AU Ch1\n00G-\nAuto-Scaled Chromatográm\nMobile-Phase Peak 1 - 0.758\nMohile Phase Pook-2--1-272\nPeak 32-8:369\n2,000-\nNilroglycering =12:070--\nboblle Phale\n5:00\n2it\n400\naco\nMinte\n10/20\n72.00\n1400\nChannel Name A1100 DAD AU CAT\nSampleName: STD 17\nSimpletere\nName\n2 | STO 1-7\nMolio Prace Feast 2589:\nSID 1-7\nDategent Fak\n0759: 469\nSTD 1.7\nSTD 17\nSieb Poak1\nMobile Ptoe Feak2! 15744\nQ.670|\n400|\n_ 1.6\n1272 3012\nMotle Place Fears 35400\n2210\n1572\n157.0\nB5S\n24\nSID 17\nSuch Pa*2\n4550\nSTD 1-7\nSian Rackt\nE410\nB.870\nVersion: 2.0\nEffective Date: 29 Sep 2011 11:24:09 GMT -06:00\n201 1.2 G-DUMENTS ARE REne r. Production it or sums 0 CUMENT Rate me: 34 De 2011, 03-16 PM MIT-06.00\nPrinted bv: Production Activity Control (svs-qumas-001)\n\n<<<PAGE 16>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage 6 of 6\nSTM#:\nSTM-AR-CV-0159\nTitle: Nitroglycerin Cleaning Verification Method\nEffective Date: SEP 2 9 2011\nSupersedes: 07/22/11\nSummary Chart\nType of Swab:\nTexwipe TX714 A\nMaximum Allowable Limit:\nNMT 5.77 Mg / Swab\nArea to be Swabbed:\n100 cm?\nTarget Ingredient:\nNitroglycerin\nLimit of Detection:\n0.00006063 mg/mL\nLimit of Quantitation:\n0.0001213 mg/mL\nLinearity:\n0.0001213 mg/mL to 0.002425 mg/mL\nSpecificity:\nNo Interference\nPlate Recovery:\nFrom Ferrous Plates: 66.1 %\nSwabbing Solution:\nMethanol\nSwab Stability:\nStable for 3 days\nSwab Stability in Solution:\nStable for 3 days\nSwab Sampling Technique:\nAs per SOP # AR-0063 Section: 8.6.1\nVersion: 2.0\nEffective Date: 29 Sep 2011 11:24:09 GMT -06:00\nUSERS OF PRINTED DOCUMENTS ARE RESPONSIBLE FOR ENSURING THAT THE PRINTED DOCUMENT REPRESENTS THE MOST CURRENT VERSION.\nPrinted bv: Production Activity Control (svs-aumas-001)\nDate/Time: 24 Dec 20111:03:16 PM GMT -06:00\n\n<<<PAGE 17>>>\n\n...-.\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n5 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nmg\nTest Method #:STM-AR-FP-0164\nC. Assay\n1. Instrument\nAn HPLC system consisting of an autosampler, pump, a column, an adjustable\nwavelength UV Detector and an integrator capable of integrating the peaks of\ninterest.\nHPLC Parameters:\nColumn:\nPN# 00G-4252-E0\nPhenomenex, Luna C18 (2), 5 um, 4.6 mm x 250 mm\nMobile Phase:\nMethanol/Water=50/50\nRun time:\nInjection Volume: 20 uL\nFlow rate:\nnot less than 19 minutes\nWavelength:\n1.0 mL/min\n220 (8) nm, ref: off\nColumn\nTemperature:\nRt window:\n25 °C\n13.5 minutes to 17.5 minutes\n2. Reagents\n:\nDiluted Nitroglycerin Reference Standard\nMethanol, HPLC grade or equivalent\nUSP Water\n3. Reagent Preparation\n3.1. Mobile Phase Preparation: Methanol/Water=50/50\nMix 1000 mL of Water with 1000 mL of Methanol and sonicate to degas for 5\nminutes. This preparation may be scaled up or down as needed.\nMobile Phase was demonstrated to be stable for at least 6 weeks at room\ntemperature conditions\n3.2. Diluent\nUse assay Mobile Phase: Methanol/Water=50/50\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 18>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n6 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nmg\nTest Method #:STM-AR-FP-0164\n4. Standard Preparation\n4.1. Working standard solution\nAccurately weigh about 158 mg of Diluted Nitroglycerin standard equivalent\ndo 15 re. or ito lycene dilent and mix wel 10 is pegition may be\nscaled up or down as needed.\n4.2. Stability of Standard Solution\nThe standard solution has been proved to be stable for 15 days at room\ntemperature conditions.\n4.3. Standard Concentration calculation\nThe working solution contains approximately 0.075 mg/mL of Nitroglycerin |\nand is calculated using the following equation:\nCstd =-\nWstd× P\n20 mLx100\nCstd\nWhere,\nConcentration of Nitroglycerin standard in mg/mL.\nW std\n=\nP\n=\nDiluted Nitroglycerin Standard weight, mg\nPotency of the Diluted Nitroglycerin Reference Standard in %.\n100% =\nConversion from Diluted Nitroglycerin to Nitroglycerin\n5. Sample Preparation\n5.1. Stock Sample Solution\nWeigh the amount of tablets listed in the table below. Transfer into the proper\nvolumetric flask. Add a stir bar and 80% of the flask volume of diluent. Stir\nthe sample for 1 hour (tablets should completely disintegrate). Remove the stir\nbar and rinse it inside the flask with diluent, complete to volume with diluent\nand mix well. Transfer about 10 mL into a centrifuge tube, cover with paratilm\nand centrifuge the sample at 3000 rpm for 10 minutes. (Concentration is about\n0.3 mg/mL).\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 19>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n7 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nTest Method #:STM-AR-FP-0164\nmg\nStrength\n#of Tablets\nVolumetric Flask\nin mL\n0.3 mg\n20\n20\n0.4 mg\n20\n25\n0.6 mg\n25\n50\n5.2. Working Sample Solution\nDilute 6.0 ml, of the centrifuged supernatant stock solution into a 25 ml.\nvolumetric flask and dilute to volume with diluent, mix well. Transfer an\naliquot into HPLC vial to analyze. (Concentration is in range 0.072 to 0.077\nmg/mL).\n5.3. Stability of Sample Solution\nleast 3 days at room temperature conditions\nThe Stock and working assay sample solutions were proved to be stable for at\n6. Procedure\n6.1. Refer to SOP AR-0049 \"High Performance Liquid Chromatographic\nAnalysis\"\n6.2. System Suitability Criteria\nMake five replicate injections of the Working Assay Standard-1 solution.\nCalculate the reproducibility (% RSD) of the five consecutive injections,\ntheoretical plates (N) and the tailing factor (T) for the Nitroglycerin peak. The\nsystem is suitable if: RSD ≤ 2.0%, N≥ 3000 and T ≤ 2.5.\nInject the Working Assay Standard Solution-2 twice. Compare the potency\n(%) of Standard-2 relative to Standard-1:\n6.3. Standard Comparison Calculation\nStd Comp. (%) = -\nAstd2xWstd1\nAstdl× Wsta2\n-x 100\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 20>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n8 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6 | Test Method #:STM-AR-FP-0164\nAstal\nWhere,\n=\nPeak area of Standard-1 (Average of five injections)\nAsta2\n= Peak Area of Standard-2 (Average of two injections)\nWstal\n=\nStandard-1 weight, mg\nWstd2\n= Standard-2 weight, mg\nStandard-1 is suitable for use if Standard comparison (%) value is within the\nrange 100.0 ‡ 2.0%.\n6.4. Sample Analysis\nInject working sample solutions bracketed by working standard -1.\n6.5. Factors to be used in Empower\nFactor\nDescription\nCustom Field in\nStandard\nConcentration\nStandard Concentration\nEmpower Set up\nin mg/mL\nComponent Editor Table/\n20 (for 0.3mg and\nSTANDARDS ONLY\n0.4mg) or 25 (for\nNumber of Tablets for\nanalysis\nSample Weight\n0.6mg)\n83.3333 (for 0.3mg),\n104.1667 (for\nDilution volume in mi\nDilution\n0.4mg) or 208.3333\n(for 0.6 mg)\n0.3, 0.4 or 0.6\nNitroglycerin Strength\nComponent Editor Table/\nin mg\nSTANDARDS &\nUNKNOWNS (under LC)\n7. Calculations\n7.1. Peak identification\nFollow table below for possible peaks observed in the assay sample\nchromatograms based on the specificity study during the method validation\n(Reference: 2492p9)\nIsers of printed documents are responsible for ensuring that the printed document represents the most current revisior\nJocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 201‹\n\n<<<PAGE 21>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n9 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nmg\nTest Method #:STM-AR-FP-0164\nComponent name\nPeak\nRetention Time\nPlacebo\n2-Mononitroglycerin\nNo peak observed\n(minutes)\nRRT\nNA\nPeak observed\nNA\n2.964\n1-Mononitroglycerin\nPeak observed\n0.20\n3.120\n0.21\n1,2-Dinitroglycerin\n1,3-Dinitrolgycerin\nPeak observed\nPeak observed\n5.240\n0.36\n5.838\nMobile Phase (Diluent)\nPeak observed\n0.40\nNitroglycerin\nPeak observed\n6.154\n0.42\n14.673\nNA\n7.2. Assay Calculation\nFrom the HPLC analysis, obtain the peak area of the sample (Asp) and\nStandard-1 (Asta). The percentage of Nitroglycerin per tablet is calculated from\nthe equation:\n% LC =-\nAsplxCstdxVF×25mL\nAstd × LCx#tablets × 6.0mL\n- × 100%\nWhere,\nCstd\n=\nAspl\n=\nNitroglycerin Standard-1 concentration, mg /mL\nAstd\nPeak area of the sample.\n=\nLC\n=\nAverage Area of Bracketing standard-1.\n#tablets =\nLabel claim in mg\nnumber of tablets used in the analysis\nVFstock =\nVolume of the Stock Solution in mI\nD. Blend Uniformity\n1. Instrument, Reagent, Reagent Preparation, Standard Preparation and\nProcedure\nRefer to Assay section III. C.1, III. C.2, III. C.3, III.C.4 & III.C.6.\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 22>>>\n\n-...\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n10 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nmg\nTest Method #:STM-AR-FP-0164\n2. Sample Preparation\nSamples of one to six dosage units are provided from various blenders and drum\nlocations. Perform the following for each sample:\nTap the vial several times on the bench top. Weigh accurately the vial containing\nthe sample (with the cap included in the initial weight) and record the weight (G).\nQuantitatively transfer the content of the vial to a volumetric flask (follow table\nbelow according strength and dosage units provided as a reference only).\nNOTE: Ensure to wash the vial and the inside portion of the cap with diluent\nAdd a stir bar into the volumetric flask and diluent up to 70% of the flask volume\nand stir for 1 hour. Remove the stir bar and rinse it inside the flask with diluent.\ncomplete to volume with diluent and mix well. Transfer an aliquot into a centrifuge\nTube, cover with pot of superman it it vial to anal pm for 10 minute.\nThe Nitroglycerin concentration in the prepared Blend Uniformity Samples should\nbe within the range of 0.045 mg/mL to 0.1125 mg/ml\nDosage Units\nStrengths\nVFstock\nin mg\nin mL\n0.3\n5\n1 dosage unit\n0.4\n5\n0.6\n0.3\n10\n2 dosage units\n0.4\n10\n0.6\n0.3\n20\n10\n3 dosage units\n0.4\n0.6\n20\n25\nRinse the empty sample vials and caps with acetone and:\n-Dry the rinsed caps at room temperature for at least 2 hours or until needed\n-Dry the rinsed vials (without the cap) in the oven at 105°C for about 30 minutes,\nensuring that they are completely dry\nWeigh the empty vial (with the cap) and record its weight (T). Finally calculate the\nweight of the sample (N) = (G-T).\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 23>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n11 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nTest Method #:STM-AR-FP-0164\nmg\n3. Procedure\n3.1. Factors to be used in Empower\nFactor\nDescription\nCustom Field in\nStandard\nStandard Concentration\nEmpower Set up\nConcentration\nComponent Editor Table/\nWeight\nin mg/mL\nSTANDARDS ONLY\nSample Weight in mg\nVolumetric\nSample Weight\nVolume\nFlask\nDilution Factor in mL\nDilution\nTheoretical potency\nTheoretical potency in\nComponent Editor Table/\ndecimals (Not as in\nSTANDARDS &\npercentage)\nUNKNOWNS (under LC)\n4. Calculations\nThe percentage of Nitroglycerin is calculated using the equation below:\n%LC=-\nAspl Cstd xVF × 100%\nAstd\nWs×%Th\n-x100%\nWhere\nAspl\nAstd\n= Peak area response of the sample.\n=\nAverage area response of the bracketing standard.\nCstd\n=\nConcentration of Nitroglycerin standard in mg/mL\nWs\n=\nSample weight in mg\n%Th\n=\nTheoretical percentage of the active in the blend.\n= Volume of the Volumetric Flask in mL\nE. Uniformity of Dosage Units (Content Uniformity)\n1. Instrument, Reagent, Reagent Preparation, Standard Preparation and\nProcedure\nRefer to Assay section III.C.1, III. C.2, III. C.3, III. C.4 & III.C.6.\nUsers of printed documents are responsible for ensuring that the printed document represents the most current revision.\nDocument No.: STM-AR-FP-0164 Rev 10 Effective Date: March 14, 2014\n\n<<<PAGE 24>>>\n\nWatson Laboratories, Inc.-Florida\nSTANDARD TEST METHOD\nPage\n12 of 32:\nTitle: Nitroglycerin Sublingual Tablets, 0.3 mg, 0.4 mg & 0.6\nTest Method #:STM-AR-FP-0164\nmg\n2. Sample Preparation\nWeigh ten tablets individually. Transfer into separate volumetric flasks (VF)\nfollow table below). Add a stir bar and 70 % of the flask volume of diluent and sti\nfor 1 hour. Remove the stir bar and rinse it inside the flask with diluent, complete t\nvolume with diluent and mix well. Transfer an aliquot into a centrifuge tube, cover\nwith parafilm and centrifuge the sample at 3000 rpm for 10 minutes. Transfer an\nStrength\nVF\nin mL\n0.3 mg\n5\n0.4 mg\n5\n0.6 mg\n10\nConcentration of Nitroglycerin is from 0.06 mg/mL to 0.08 mg/mL\n3. Procedure\n3.1. Factors to be used in Empower\nFactor\nDescription\nCustom Field in\nStandard\nStandard Concentration\nEmpower Set up\nConcentration\nComponent Editor Table/\n1\nin mg/mL\nSTANDARDS ONLY\nNumber of Tablets for\nSample Weight\n5 (for 0.3mg and\na","truncated":true,"body_characters":74399}