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Rosa MottaRosa MottaCompliance OfficerCompliance Officer

Residual Solvents: Residual Solvents: FDA/ Regulatory Perspective FDA/ Regulatory Perspective

PDA/USP Residual Solvents PDA/USP Residual Solvents ConferenceConference

January 18 January 18 --19, 2007 19, 2007

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OutlineOutline

Laws and regulations governing the Laws and regulations governing the compliance requirements of USP chapterscompliance requirements of USP chaptersCompliance Policy Guides pertaining to the Compliance Policy Guides pertaining to the compliance requirements of USP chapters compliance requirements of USP chapters ApplicabilityApplicabilityBasis and IntentBasis and IntentSpecific requirements Specific requirements

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The USPThe USP--FDA ConnectionFDA Connectionhttp://http://www.fda.gov/opacom/laws/fdcact/fdctoc.htmwww.fda.gov/opacom/laws/fdcact/fdctoc.htm

Federal Food, Drug, and Cosmetic ActFederal Food, Drug, and Cosmetic Act

Chapter II Chapter II -- Definitions:Definitions:

201(g)(1)(A) 201(g)(1)(A) -- The term “drug” means The term “drug” means (A)(A) articles articles recognized in the official United States Pharmacopeia, recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any States, or official National Formulary, or any supplement to any of themsupplement to any of them. . . . . . 201(j) 201(j) -- The term “official compendium” means the The term “official compendium” means the official United States Pharmacopeia, official official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, Homeopathic Pharmacopeia of the United States, official National Formulary, or any supplement to any official National Formulary, or any supplement to any of them.of them.

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FDA LawsFDA Lawshttp://www.fda.gov/opacom/laws/fdcact/fdctoc.htmhttp://www.fda.gov/opacom/laws/fdcact/fdctoc.htm

Federal Food, Drug, and Cosmetic ActFederal Food, Drug, and Cosmetic ActChapter V Chapter V -- Adulteration sections:Adulteration sections:A drug or device shall be deemed to be adulteratedA drug or device shall be deemed to be adulterated----501 (b) If it purports to be or is represented as a drug the nam501 (b) If it purports to be or is represented as a drug the name e

of which is recognized in an official compendium, and its of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, thestrength differs from, or its quality or purity falls below, thestandards set forth in such compendium. standards set forth in such compendium. Such determination Such determination as to strength, quality, or purity shall be made in accordance was to strength, quality, or purity shall be made in accordance with ith the tests or methods of assay set forth in such compendium, the tests or methods of assay set forth in such compendium, except that whenever tests or methods of assay have not been except that whenever tests or methods of assay have not been prescribed in such compendium, or such tests or methods of prescribed in such compendium, or such tests or methods of assay as are prescribed are, in the judgment of the Secretary, assay as are prescribed are, in the judgment of the Secretary, insufficient for the making of such determination, the Secretaryinsufficient for the making of such determination, the Secretaryshall bring such fact to the attention of the appropriate body shall bring such fact to the attention of the appropriate body charged with the revision of such compendium… charged with the revision of such compendium…

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FDA LawsFDA Lawshttp://www.fda.gov/opacom/laws/fdcact/fdctoc.htmhttp://www.fda.gov/opacom/laws/fdcact/fdctoc.htm

Federal Food, Drug, and Cosmetic ActFederal Food, Drug, and Cosmetic ActChapter V Chapter V -- Adulteration sections:Adulteration sections:A drug or device shall be deemed to be adulteratedA drug or device shall be deemed to be adulterated----501 (a)(2)(B)501 (a)(2)(B)

If it is a drug and the methods used in, or the facilities If it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, or controls used for, its manufacture, processing, packing, or holding do not conform to or are not packing, or holding do not conform to or are not operated or administered in conformity with current operated or administered in conformity with current good manufacturing practice to assure that such drug good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and meets the requirements of this Act as to safety and has the identity and strength, and meets the quality has the identity and strength, and meets the quality and purity characteristics, which it purports or is and purity characteristics, which it purports or is represented to possessrepresented to possess. . .. . .

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FDA RegulationsFDA Regulationshttp://www.fda.gov/cder/dmpqhttp://www.fda.gov/cder/dmpq

21 Code of Federal Regulations21 Code of Federal Regulations

Parts 210 and 211 Parts 210 and 211 -- CURRENT GOOD MANUFACTURING CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALSPRACTICE FOR FINISHED PHARMACEUTICALS

21 CFR 211. 194 (a) (2)21 CFR 211. 194 (a) (2) -- A statement of each method used in the testing of the A statement of each method used in the testing of the sample. The statement shall indicate the location of data that esample. The statement shall indicate the location of data that establish that the stablish that the methods used in the testing of the sample meet proper standards methods used in the testing of the sample meet proper standards of accuracy and of accuracy and reliability as applied to the product tested. (If the method empreliability as applied to the product tested. (If the method employed is in the loyed is in the current revision of the United States Pharmacopeia, National Forcurrent revision of the United States Pharmacopeia, National Formulary, AOAC mulary, AOAC INTERNATIONAL, Book of Methods, or in other recognized standard INTERNATIONAL, Book of Methods, or in other recognized standard references, references, or is detailed in an approved new drug application and the referor is detailed in an approved new drug application and the referenced method is enced method is not modified, a statement indicating the method and reference winot modified, a statement indicating the method and reference will suffice). The ll suffice). The suitability of all testing methods used shall be verified under suitability of all testing methods used shall be verified under actual conditions of actual conditions of use.use.

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FDA PolicyFDA PolicyCompliance Policy GuidesCompliance Policy Guides

http://www.fda.gov/ora/compliance_refhttp://www.fda.gov/ora/compliance_ref

Sub Chapter 420 Sub Chapter 420 -- Compendial /Test Requirements Compendial /Test Requirements

Sec. 420.100Sec. 420.100 -- Adulteration of Drugs Under Section 501(b) and 501(c) of the AcAdulteration of Drugs Under Section 501(b) and 501(c) of the Act. t. *Direct Reference Seizure Authority for Adulterated Drugs Under *Direct Reference Seizure Authority for Adulterated Drugs Under Section 501(b)* Section 501(b)* (CPG 7132a.03) (CPG 7132a.03)

Any official drug which, when tested by compendial methods, failAny official drug which, when tested by compendial methods, fails to conform to s to conform to compendial standards for quality, strength, or purity, is adultecompendial standards for quality, strength, or purity, is adulterated unless the rated unless the differences from such standards are plainly stated on the drug'sdifferences from such standards are plainly stated on the drug's label. label.

Sec. 420.200Sec. 420.200 -- Compendium Revisions and Deletions (CPG 7132.02)Compendium Revisions and Deletions (CPG 7132.02)

All official articles shipped prior to the date that the currentAll official articles shipped prior to the date that the current USP/NF became USP/NF became official should be in compliance with the official compendia in official should be in compliance with the official compendia in effect at the time of effect at the time of shipment. shipment.

Sec. 420.300Sec. 420.300 -- Changes in Compendial Specifications and NDA Supplements (CPG Changes in Compendial Specifications and NDA Supplements (CPG 7132c.04) 7132c.04)

Any change in the Any change in the compendialcompendial specifications for an NDA drug will not normally specifications for an NDA drug will not normally require the submission of an NDA supplement unless there is a rerequire the submission of an NDA supplement unless there is a relaxation of the laxation of the acceptance criteria or deletion of a test. acceptance criteria or deletion of a test.

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FDA PolicyFDA PolicyCompliance Policy GuidesCompliance Policy Guideshttp://www.fda.gov/ora/compliance_refhttp://www.fda.gov/ora/compliance_ref

Sub Chapter 420 Sub Chapter 420 -- Compendial /Test RequirementsCompendial /Test Requirements

Sec. 420.500Sec. 420.500 -- Interference with Compendial Tests (CPG 7132a.01) Interference with Compendial Tests (CPG 7132a.01)

A compendial drug product containing an added substance which inA compendial drug product containing an added substance which interferes with theterferes with thecompendial assay of the product would be adulterated under 501(compendial assay of the product would be adulterated under 501(b) of the Act. b) of the Act.

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Applicability of <467>Applicability of <467>

Processes that use or produce residual solvents Processes that use or produce residual solvents All Official ArticlesAll Official Articles

May be used as guidance for nonMay be used as guidance for non--official official articles.articles.

Manufacturers of official excipients, officialManufacturers of official excipients, officialactive pharmaceutical ingredients (API), and official active pharmaceutical ingredients (API), and official drug products.drug products.

Note: For the purpose of this presentation whenever excipients, Note: For the purpose of this presentation whenever excipients, API or API or drug products are mentioned it refers to official excipients, drug products are mentioned it refers to official excipients, official active pharmaceutical ingredients (API), and official official active pharmaceutical ingredients (API), and official drug products. Drug substance = API Official = drug products. Drug substance = API Official = CompendialCompendial

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Basis and Intent of the Basis and Intent of the ChapterChapter

Residual solvents do not provide therapeutic Residual solvents do not provide therapeutic benefitbenefitShould be removed to the extent possibleShould be removed to the extent possibleResidual solvents are classified in 3 main Residual solvents are classified in 3 main categories based on toxicity data categories based on toxicity data Have some degree of assurance that drug products Have some degree of assurance that drug products contain acceptable levels of residual solvents contain acceptable levels of residual solvents May exceed recommended levels but only in May exceed recommended levels but only in “exceptional circumstances”“exceptional circumstances”Harmonize with Guidance for Industry ICH Q3C Harmonize with Guidance for Industry ICH Q3C Impurities: Residual Solvents Impurities: Residual Solvents

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Specific Specific RequirementsRequirements

Class I Residual Solvents:Class I Residual Solvents:

Should be avoided in all drugs Should be avoided in all drugs Their use should be justifiedTheir use should be justifiedLevels in drug products should be below the levels Levels in drug products should be below the levels in Table 1in Table 1Excipient, API, and drug product manufacturers are Excipient, API, and drug product manufacturers are expected to identify and quantify using expected to identify and quantify using appropriately validated proceduresappropriately validated proceduresExcipient and API manufacturers may report the Excipient and API manufacturers may report the levels to drug manufacturers. Drug product levels to drug manufacturers. Drug product manufacturers are expected to test incoming manufacturers are expected to test incoming components components

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Specific Specific RequirementsRequirements

Class II Residual Solvents:Class II Residual Solvents:Should be limited in all drugs. Should be limited in all drugs. ExcipientExcipient and API manufacturers are expected to and API manufacturers are expected to identify, quantify, and may report levels over Option 1 identify, quantify, and may report levels over Option 1 (Table 2) to drug product manufacturers. Drug product (Table 2) to drug product manufacturers. Drug product manufacturers are expected to test incoming manufacturers are expected to test incoming components components Drug product manufacturers may use Option 1, Option Drug product manufacturers may use Option 1, Option 2, and the drug product manufacturing process to 2, and the drug product manufacturing process to determine compliance with the levels in Table 2 determine compliance with the levels in Table 2 Drug product manufacturers should take all necessary Drug product manufacturers should take all necessary steps to reduce the levels to meet Table 2steps to reduce the levels to meet Table 2ExcipientExcipient, API, and drug product manufacturers are , API, and drug product manufacturers are expected to identify and quantify using appropriately expected to identify and quantify using appropriately validated proceduresvalidated procedures

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Specific Specific RequirementsRequirements

Class III Residual Solvents:Class III Residual Solvents:Deemed safe to use for all drugs Deemed safe to use for all drugs Levels of 50mg/day (5000ppm or 0.5% under Levels of 50mg/day (5000ppm or 0.5% under Option 1) are acceptable Option 1) are acceptable Excipient and API manufacturers are expected to Excipient and API manufacturers are expected to identify, quantify, and may report levels over Option identify, quantify, and may report levels over Option 1 to drug product manufacturers. Drug product 1 to drug product manufacturers. Drug product manufacturers are expected to test incoming manufacturers are expected to test incoming components components Excipient, API, and drug product manufacturers are Excipient, API, and drug product manufacturers are expected to identify and quantify levels over expected to identify and quantify levels over 50mg/day, 5000ppm, or 0.5% under Option 1 using 50mg/day, 5000ppm, or 0.5% under Option 1 using appropriately validated proceduresappropriately validated procedures

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Rosa MottaRosa MottaCompliance Officer

Division of Manufacturingand Product Quality, HFD-320

Center for Drug Evaluation and Research

Phone: 301-827-8941 Fax: 301-827-8908

E-mail: rosa.motta@fda.hhs.gov