ExcipientFest Americas May 5-6, 2010

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1 ExcipientFest Americas May 5-6, 2010 New Tests for Identifying Harmfl and Potentially Deadly Adlterants in Pharmacetical Ingredients: The Role of USP-NF in Setting Revised Standards Catherine Sheehan, M.S. Director, Excipients United States Pharmacopeia Otline USP overview USP Standards Setting Process -Accelerated Revisions (Revision Blletin) History of adlteration with diethylene glycol FDA reqest to USP to strengthen USP-NF monographs FDA/USP/Stakeholder collaboration in development of new tests Conclsions How stakeholders can get involved in USP References 2 1

2 USP s Fonding 3 USP Overview Nonprofit international pblic health organization Private, independent, and self-fnded Global activities and impact Establishes qality standards (USP, NF, FCC) Expert volnteers are scientific decision-makers ISO-9001 and ISO Locations Rockville, MD (headqarters) Basel, Switzerland Hyderabad, India Shanghai, China Sao Palo, Brazil 2

3 USP Mission Statement USP mission is to improve pblic health of people arond the world throgh pblic standards and related programs that help ensre the qality, safety and benefit of medicines and foods USP s Legal Recognition Federal Law Federal Food, Drg & Cosmetic Act (FD&C Act)- USP and NF standards enforceable by FDA FD&C Act - SEC [21 U.S.C. 321] Section 201(g)(1) recognized in an official US compendim: United States Pharmacopeia, Homoeopathic Pharmacopoeia, or National Formlary intended to provide diagnosis, cre, mitigation, treatment, or prevention of disease intended to affect the strctre or any fnction of the body intended for se as a COMPONENT of any article meeting the above criteria Excipients are components of the drg 3

4 USP s Legal Recognition FD&C Act SEC [21 USC 351] Adlterated Drgs and Devices Section 501(b) - A drg or device shall be deemed adlterated -if it prports to be or is represented as a drg the name of which is recognized in an official compendim, and its strengthdiffers from, or its qality or prity falls below, the standard set forth in sch compendim USP s Legal Recognition BUT, Section 501(b) says that: A drg will not be deemed adlterated for failing to meet the compendialstandard of strength, qality, or prity if the difference from the standards is plainly stated on the label. To avoid being adlterated, drgs mst comply with compendial standards for strength, qality, or prity, nless labeled to show all differences. However, Section 501(b) & 502(e)(3)(B) also says Drg with name recognized in USP mst comply with compendial identity standards, or be deemed adlterated, misbranded, or both. Cannot label away from identity! USP does not enforce its standards FDA enforces USP standards 4

5 USP Standards Setting Process Monograph is received/development initiated Scientific Liaison performs technical review and drafts the monograph Monograph is pblished for pblic review and comment Scientific Liaison reviews comments; sbmits comments to Expert Committee Not approved Expert Committee ballots Approved Monograph is pblished in official pblication (USP-NF, FCC) Expert Committees Staff Liaison R X Indstry Other Pharmacopeias Government 5

6 Pharmacopeial Form Yor voice in standards development Working arm of the Concil of Experts Bimonthly jornal with Proposed revisions to USP-NF standards for yor comments Official revisions to standards Updates on international harmonization Stimli articles Web Postings 6

7 History of adlteration with Diethylene Glycol Contry Year Incident USA 1937 Elixir slfanilamide 107 deaths Reslted in the implementation of the1938 Amendment to the FFD&C Act Soth Africa 1969 Sedative formlated with DEG 7 deaths Italy 1985 DEG in wines from Astria no known deaths India 1986 Medicinal glycerin laced with DEG 14 deaths Nigeria 1990 Acetaminophen syrp containing DEG 40 deaths (some sorces say 200 deaths) Bangladesh Acetaminophen syrp containing DEG 339 deaths Haiti 1995/6 Cogh medicine containing DEG 85 deaths Panama 2006 Cogh and anti-allergy syrp containing DEG 46 deaths (116 or 365 according to other sorces)ef10 May 6, Hall A #2, Film, Catherine Sheehan (USP).wmv USA 2006/7 Toothpaste containing DEG no deaths Panama 2007 Toothpaste containing DEG no deaths reported Nigeria 2008/9 Teething formla contaminated with DEG from propylene glycol 84 deaths Bangladesh 2009 Paracetamol syrp to children adlterated with diethylene glycol. Twenty-for children reported dead Glycerin and Diethylene Glycol Diethylene glycol (DEG), a known nephrotoxinand hepatotoxin, is sed as an indstrial solvent and antifreeze. Glycerin, DEG, and ethylene glycol (EG) share many physical properties, inclding a natral sweet taste, color and viscosity. Inexpensive! This facilitates the adlteration of glycerin or other inactive ingredients with less expensive, more toxic DEG. Diethylene Glycol ( Antifreeze ) POISON! Ethylene Glycol ( Antifreeze ) POISON! 7

8 The Problem: Even to the Trained Professional Ethylene Glycol ( Antifreeze ) POISON! Propylene Glycol Edible and GRAS Light colored Slightly viscos liqid at room temp. Sweet taste Glycerin (Glycerol) Edible and GRAS Light colored Slightly viscos liqid at room temp. Sweet taste Diethylene Glycol ( Antifreeze ) POISON! Light colored Slightly viscos liqid at room temp. Sweet taste Albins D Sa, Ph.D., FDA, 2008 ASM Kansas Light colored Slightly viscos liqid at room temp. Sweet taste USP Response to Haiti incident for USP Glycerin Monograph In the late 1990s, in response to the Haiti incident, USP revised the Glycerin monograph to inclde: Identification section: Addition of Identification Test B. Glycerin Identification by retention time Imprities section: Addition of the Limit of DEG and Related Componds Test A capillary gas-chromatographic (GC) method with flame ionization detection (FID) NMT 0.1% DEG 8

9 Reqest for USP-NF Monograph (April 2007) Reqest from FDA: USP to strengthen the USP Glycerin Identification section to inclde the identification and qantitation of DEG in glycerin. Rationale: GMPs allow the se of Identification testing alone, by dosage form manfactrers, for raw material(s) qalification manfactrers cold therefore not deviate from the DEG limit since this wold be an aspect of identity. Challenge: Complex isse relating to reqirement that contaminant/adlterant be considered part of an article s Identification FDA s May 2007 Gidance Regarding DEG Contamination of Glycerin Reiterates (d)(2) reqirement for specific ID testing when not performing fll USP testing Recommends intimate knowledge of the spply chain Testing has to be capable of detecting DEG Applies to all recipients of Glycerin USP, not only those who formlate or compond Traceability 18 9

10 21 CFR Part CGMP Reqirements for Drg Manfactrers (relating to Glycerin) Control of Components (Sbpart E) 21 C.F.R (d)(l) At least one test shall be condcted to verify the identity of each component of a drg prodct. Specific identity tests, if they exist, shall be sed. 21 C.F.R (d)(l) reqires that manfactrers of drg prodcts detect and qantify any DEG present both at the time of manfactre and pon receipt at the point of transfer to another party. manfactrers cannot deviate from the DEG limit since this is an aspect of identity. Cannot label away from identity! In contrast, if DEG detection and qantification is solely part of a prity (imprity) test, a manfactrer need not inclde as part of its identity testing (the only test reqired to accept the material) 21 C.F.R (d)(l) and (2) 21 C.F.R (d)(l) places brden on drg manfactrers to prevent the se of adlterated ingredients Representative samples Appropriate testing or examination Appropriate written specifications Verification of identity ID testing of excipients mst be specific (or mst perform additional tests that spport neqivocal ID) 21 C.F.R (d)(2) Allows se of CoA data for conformance to other specifications provided data is verified periodically for accracy Use of the vendor CoA applies only if ongoing verification of data and the absence of adlteration exists provided that at least one specific identity test is condcted on sch component by the manfactrer 20 10

11 FDA/USP/Stakeholder collaboration in method development -Glycerin Jn 07: USP Lab tested the TLC method referenced in the FDA 2007 Glycerin gidance docment, Kenyon et al. pblished in the Jornal of AOAC International Jornal : Iodine and potassim permanganate staining, the lowest detected DEG levels were 1% and 0.5% level, respectively Modified method : chloroform, acetone, and 5 M ammonim hydroxide (10:80:10, v/v/v): the 0.1% and 0.05% DEG spots clearly visible in Standard preparations bt extremely difficlt to detect the same levels of DEG in spiked Glycerin samples with any degree of certainty The USP lab conclsions: Spot intensity dependent on staining and exposre time -can lead to false conclsions, DEG and EG not separated The method was not sitable as a compendia test USP concentrated on existing USP Glycerin GC imprities method improvement 21 Glycerin Activities contd. Jn 08 Stakeholders reqest a collaborative stdy on GC method limit USP worked closely with indstry grops and FDA to establish a limit that wold provide adeqate protection from adlteration provide indstry with a compendial standard that cold be met with common analytical technology Sep 08 Shared reslts of TLC stdy with FDA and Stakeholders 2 web meetings (Sept 18 and 19, 2008), posted on the USP Hot Topics web page 2008 USP Annal Science Meeting (Sept 24, 2008) Nov 08 PNP Stakeholder Form (21 Nov 08). Annonced the proposed limit to be not more than 0.10% each for DEG and EG. Feb. 09 Revision blletin posted on USP website, Feb. 4, 2009, Official May 1,

12 A Typical Chromatogram of a Standard Soltion (2 mg/mlof glycerin, mg/mleach of EG and DEG and 0.10 mg/mlof internal standard) Ethylene glycol 2,2,2- Trichloroethanol Diethylene glycol Glycerin Parameter Settings Detector FID Colmn 0.53-mm x30-mfsedsilica, 3.0-µm G43 stationary phase having an inverted cp or spiralliner Injection port 220 C Temperatre solvent peaks Detector 250 C Temperatre Colmn 100 C Temperatre CarrierGas: Helim at 4.5 ml/min Injection Type flowratio at 10:1 Oven Temperatre Program Injection Volme Hold at 100 C for 4 mintes 50 C/min to 120 C Hold at 120 C for 10 mintes 50 C/min to 220 C Hold at 220 C for 6 mintes 1µL USP Lab. Reslts for EG and DEG in Glycerin Accracy and Method Precision Recovery of EG and DEG from Glycerin calclated against the Standard soltion (2 mg/ml of Glycerin, mg/ml each of EG and DEG, and 0.10 mg/ml of internal standard). Ethylene Glycol Diethylene Glycol Sample ID % Recovery Spiked test soltion %RSD (n=6) % Recovery 97.2 Spiked test soltion Spiked test soltion Spiked test soltion Spiked test soltion Spiked test soltion %RSD (n=6) 0.3 a % Recovery = (Conc. Fond/ Conc. Added) x 100- average of two injections Acceptance criteria 90.0%-110.0% 12

13 FDA Second Letter Jan 14, 2009 FDA letter reqested a revision to both Sorbitol Soltion and Propylene Glycol consistent with the pdate to the USP Glycerin Monograph Inclde a Limit test for Diethylene Glycol (DEG) contamination in the Identification section Both SorbitolSoltion and Propylene Glycol were categorized by FDA as "high-priority" monographs for this type of revision. USP-NF Articles Identified as High-Priority for Adlteration with DEG and EG by FDA Maltitol Soltion (1) (H) Sorbitol Soltion (1) (H) Sorbitol sorbitan soltion (1) (H) Noncrystallizing sorbitol soltion (1) (H) Propylene glycol (2) (H) Propylene glycol dilarate (4) (M) Polyethylene glycol (3) (M) Lactitol (1) (L) Maltitol (1) (L) Sorbitol (1) (L) Polyethylene glycol monomethyl ether (4) (L) Diethylene glycol monoethyl ether (4) (L) Diethylene glycol stearates (4) (L) 1- Sgar alcohols 2- Propane diols and triols 3- Polyols (polyethylene glycol) 4- Derivatives of categories 1-3 The risk levels for ndetectable contamination are categorized as H high M medim L low 13

14 Comments from CDER Office of Compliance on the USP List Highest risk ingredients aqeos soltions or liqids that can be readily spiked with DEG or EG similar physical properties in terms of viscosity may be sweet tasting and ths make their way into soltions, syrps and elixirs at relatively high levels of se IIG search for ingredients deemed high-risk, revealed that they are in fact sed at very large amonts sch that toxic levels are readily achieved. The ingredients synthesized from DEG already have a limit test, and are only sed in non-oral applications per a USP labeling reqirement. USP-NF Articles Identified as High-Priority for Adlteration with DEG and EG Maltitol Soltion (1) (H) USP-NF Monograph Sorbitol Soltion (1) (H) Sorbitol sorbitan soltion (1) (H) Noncrystallizing sorbitol soltion (1) (H) Propylene glycol (2) (H) Propylene glycol dilarate (4) (M) Polyethylene glycol (3) (M) Lactitol (1) (L) Maltitol (1) (L) Sorbitol (1) (L) No DEG or EG test No DEG or EG test No DEG or EG test No DEG or EG test No DEG or EG test No DEG or EG test Crrent test Limit of ethylene glycol and diethylene glycol (MW 450 or less; MW 450 or above bt <1000) 0.25% of combined ethylene glycol and diethylene glycol. No DEG or EG test Related componds test -NMT1.5%. No DEG or EG test No DEG or EG test Polyethylene glycol monomethyl ether (4) (L) Limit of ethylene glycol and diethylene glycol < % of combined ethylene glycol and diethylene glycol. Limit of ethylene glycol and diethylene glycol 600 or above bt < % of combined ethylene glycol and diethylene glycol. Diethylene glycol monoethylether (4) (L) Limit of free diethylene glycol NMT 1 µg per g Limit of 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, and diethylene glycol NMT 50, 160, 620, 150 µg per g Diethylene glycol stearates(4) (L) Limit of free diethylene glycol NMT 8.0% 1-Sgar alcohols 2-Propane diols and triols 3-Polyols (polyethylene glycol) 4-Derivatives of categories 1-3 The risk levels for ndetectable contamination are categorized as H high M medim L -low 14

15 High-Priority Monographs A total of five excipientmonographs were categorized as high-priority for pdate of Identification test: SorbitolSoltion SorbitolSorbitan Soltion NoncrystallizingSorbitol Soltion MaltitolSoltion Propylene Glycol Monographs were prioritized as high (H) medim (M) low (L) Except for Propylene Glycol, the other for excipients are traditionally called sgar alcohols or polyols. 29 USP/Stakeholder DEG and EG Method Development Sgar Alcohol monographs USP evalated a total of 4 methods as part of their collaborative efforts with stakeholders for the following sgar alcohol monographs SorbitolSoltion SorbitolSorbitan Soltion NoncrystallizingSorbitol Soltion MaltitolSoltion Concrrently, indstry sbmitted a GC method to detect EG in a reqest for revision to USP-NF sgar alcohol monographs. This reqest arose becase Residal Solvents <467> does not have a test method for EG. The manfactrer sbmitting the reqest for revision indicated that 30 EG is a process imprity. 15

16 USP/Stakeholder DEG and EG Method Development The USP Lab did observe the presence of an EG peak in the chromatograms obtained sing manfactrer provided samples for the for sgar alcohols at levels arond PPM. While FDA s original reqest to USP did not inclde controlling EG in the Identification test, qestions arose abot also inclding a test for EG, given its toxicity levels, which appear to be even greater than DEG toxicity levels. At a May 8, 2009 meeting FDA agreed to the inclsion of EG in the Identification Test. 31 Method Development for EG and DEG in sgar alcohols TLC method was reviewed by the lab and by sgar alcohol manfactrers. (Method I - nsitable) Method nsitable for these type of sgar alcohols The HPLC Assay in the crrent Sorbitol Soltion monograph was fond nsitable for detection of EG and DEG in sorbitol containing sgar alcohols (Method II -nsitable) A GC method provided by a sponsor company exhibited carry over and interference of the sample matrix peaks with DEG. (Method III - nsitable) A modified method III developed by the USP lab introdced a new sample soltion sing a mixtre of acetone: water (96:4, v/v) as dilent. GC method was validated for specificity, accracy, method precision, and LOD. (Method IV) 16

17 Method Development for EG and DEG in sgar alcohols (sponsor company method III) Chromatograms of a Standard soltion obtained sing the sponsor company s GC method Figre 1 DEG Figre 2 IS Interference of the matrix peak with DEG pa pa DEG EG IS EG Mintes Mintes Figre 1. A chromatogram of a Standard soltion prior to injection of a Sample soltion Figre 2. A chromatogram of a Standard soltion after injection of a Sample soltion USP Lab Reslts for EG and DEG in Sorbitolsoltion (Method IV, Acetone: Water Mixtre (96:4,v/v) ) A chromatogram of a Sample soltion (80 mg/ml sorbitol soltion) pa Ethylene Glycol Propylene Glycol Sorbitol peak pa Mintes A chromatogram of a Spiked sample soltion containing 0.10% each of EG and DEG Ethylene Glycol Propylene Glycol Diethylene Glycol Sorbitol peak Mintes solvent peak 17

18 USP Lab Reslts for EG and DEG in sgar alcohols (Method IV, Acetone: Water Mixtre (96:4,v/v)) A chromatogram of a Standard soltion (0.08mg/mL each of EG and DEG) Signal to Noise 1216:1 pa Ethylene Glycol Signal to Noise 814:1 Diethylene Glycol LOD Signal to Noise 3:1 EG: mg/ml (0.001%) DEG: mg/ml (0.001%), Mintes solvent peak Reslts for EG and DEG in Sgar alcohols Final GC Method Conditions: Colmn: DB-1701, 15-m x 0.32-mm, 0.25-µm fsed silica Detector: 300º (FID) Injector: 240º Constant flow: 3.0 ml/min Injection volme: 1 µl Split ratio: 10:1 Oven program: 70º for 2 mintes, increase to 300º at a rate of 50º /min, for 5 mintes Liner: Agilent low pressre, deactivated split liner with glass wool Solvent: 96: 4 v/v (acetone and water) Internal Standard: None Rn time: 13 min 18

19 USP/Stakeholder DEG and EG Method Development: Propylene Glycol A capillary gas-chromatographic (GC) method with flame ionization detection (FID) originally developed for detection of EG and DEG in glycerin was validated for detection of both analytesin propylene glycol De to EG and DEG exhibiting higher area cont responses in the presence of propylene glycol, an internal standard was sed to avoid false positives (2,2,2-trichloroethanol) The method was validated for specificity, accracy, method precision, and LOD 19

20 Propylene Glycol Analytical Research and Development Laboratory Reslts A chromatogram of a Sample soltion (50 mg/mlpropylene glycol and 0.1 mg/mlof internal standard in methanol) mvolts Solvent FID Test Soln 1 13Feb-Rep1 Propylene Glycol Fll Scale Instrment Conditions Colmn:DB-624, 30-m x 0.53-mm Helim flow: 4.5 ml/min FID detector: 250º Injector: 220º Injection volme: 1μL, Split: 10:1 Oven: 100 o for 4 min, ramp to 120 o at 50 o per min, hold 10 min, ramp to 220 o at 50 o per min, hold 220 o for 6 mintes Mintes mvolts Solvent FID Test Soln 1 16Feb-Rep1 Propylene Glycol 2,2,2-Trichloroethanol Scaled to baseline mvolts Mintes Propylene Glycol Analytical Research and Development Laboratory Reslts A chromatogram of a Spiked sample soltion (50 mg/mlpropylene glycol, mg/mleach of EG and DEG and 0.1 mg/mlof internal standard in methanol) mvolts Solvent FID Spiked 1 16Feb-Rep1 Signal to Noise ~360:1 Ethylene Glycol 2,2,2-Trichloroethanol Signal to Noise ~170:1 Diethylene Glycol LOD EG: mg/ml (0.006%) DEG:0.009 mg/ml (0.018%), mvolts Mintes 20

21 USP Lab. Reslts for EG and DEG in Propylene Glycol Accracy and Method Precision Recovery of EG and DEG from Propylene Glycol calclated against the Standard soltion (2 mg/ml of propylene glycol, mg/ml each of EG and DEG, and 0.10 mg/ml of internal standard). Ethylene Glycol Diethylene Glycol Sample ID % Recovery Spiked test soltion %RSD (n=6) % Recovery Spiked test soltion Spiked test soltion Spiked test soltion Spiked test soltion Spiked test soltion %RSD (n=6) 1.4 a % Recovery = (Conc. Fond/ Conc. Added) x 100- average of two injections Acceptance criteria 90.0%-110.0% Monographs OFFICIAL via Revision Blletin Glycerin Official date May 1, 2009 Sorbitol Soltion Sorbitol sorbitan soltion Noncrystallizing sorbitol soltion Propylene glycol Official date Febrary 1, 2010 (same DEG and EG limits) Qestions: Bob Lafaver, M.S., RHL@sp.org Kevin Moore, Ph.D., (harmonization Propylene Glycol and Glycerin), KTM@sp.org 21

22 USP/Stakeholder DEG and EG Method Development: Maltitol Soltion Maltitol Soltion USP lab developed and validated a capillary GC method with FID Sitable solvent for sample preparation was identified to achieve recoveries for both analytes in the range of 90.0% % Dilent: Acetone: Water (96:4,v/v) 1,3-btanediol sed as Internal standard Revisions Blletins Maltitol Soltion Targeted Revision Blletin Posting: April 30, 2010 Targeted Revision Blletin Official date Posting: Agst 1, 2010 (same DEG and EG limits) Official Monograph and Reference standard information posted on the USP website nder the Hot Topics links: ion.html 22

23 Look for Revision Blletins and otherinformation nder Hot Topics Conclsions GC procedre developed for the Identification test and official via Revision Blletin is : Simple and easy-to-operate Employs a basic GC instrment with direct injection GC rn time is short Sample preparation is qick and easy Robst and rgged A limit that wold provide adeqate protection from adlteration Provide indstry with a compendial standard that cold be met with common analytical technology Close collaboration among USP, FDA, and USP s Stakeholders in the RB development process reslted in these critical RBs that promote pblic health 46 23

24 Call for Candidates: Concil of Experts EA007S Science, Innovation, Passion, Commitment: Yo Set the Standard Inflence Drg Qality Utilize Yor Expertise Advance Yor Profession Improve Pblic Health Visit the USP Web site to apply or to recommend a candidate: > Deadlines: December 18, 2009: Chair applications May 15, 2010: Expert Committee Member applications Starting in Jly 2010: Expert Panel recritment 24

25 References A.S. Kenyon, S. Xiaoye, W. Yan, N.W. Har, Simple, at-site detection of diethylene glycol/ethylene glycol contamination of glycerin-based raw materials by thin layer chromatography, J. AOAC Int. 81 (1998) Screening method for EG and DEG, G Holloway, Ragine Maheswaran, Alan Leeks, Sanford Bradby, Samir Wahab, J. of Pharmacetical and Biomedical analysis, 51 (2010) Development of New CompendialIdentification Tests for Determination of the Limit of Diethylene Glycol and Ethylene Glycol in Sgar Alcohols, Hong Wang et al., ExcipientFest Poster exhibition, May Thank Yo! 25