ICH Q3D Metal Impurities: Excipient Realities

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1 ICH Q3D Metal Impurities: Excipient Realities David R. Schoneker Vice Chair Maker & Distributor Relations IPEC Director of Global Regulatory Affairs Colorcon April 25,

2 Q3D: the beginnings Approved in 2009 by ICH SC EWG created in Spring 2010 Scope restricted to criteria and limits Methodology purview of Compendia Representatives Equal mix of Safety/Toxicologists and Quality Personnel US: FDA & PhRMA EU: EMA & EFPIA Japan: MHLW/PMDA & JPMA Interested Parties IPEC, WSMI, IGPA, KFDA, BIO, WHO 2

3 ICH Q3D EWG Process Limits to be set based on published safety and toxicology data Detailed Safety & Toxicological Assessments have been done on each of the metals of interest Each will have its own report including references to the appropriate studies Build upon EU Metal Catalysts guide Excipients within scope 3

4 Challenges Determining how we are impacted? Since it is the finished dosage form that is required to comply BUT.. Testing every dosage form is not feasible Data not yet available for all components Test methods are still unclear How do we get the data we need? Need a layered approach to looking at dosage forms and components IPEC Americas held a Q3D Workshop on April 4-5, 2012 to discuss the issues outcome report will be sent to ICH Q3D EWG 4

5 Points to Consider Materials which use mined-excipients Since many metal impurities are naturally present (for example Lead) in minedexcipients and cannot be further processed out, it is important to understand the actual levels present May have finished product which contain multiple mined excipients 5

6 IID Maximum Levels of Use in an Approved Product Max Concentration iexisting Specifications for some commonly used grades mg e a Lead, ppm Cadmium, ppm Arsenic, ppm Mercury, ppm Aluminum silicate 94 Aluminum stearate 105 Calcium carbonate Calcium silicate Calcium stearate 91.9 Calcium sulfate 443 Colloidal silicon dioxide Potassium phosphate, dibasic 30 Sodium phosphate, dibasic, anhydrous 300 Sodium phosphate, dibasic, heptahydrate 500 Anhydrous Dibasic calcium phosphate Dibasic calcium phosphate, dihydrate Dihydroxyaluminum sodium carbonate 1350 Magnesium aluminum silicate hydrate 60 Magnesium carbonate 250 Magnesium hydroxide 450 Magnesium oxide 63 Magnesium stearate Magnesium sulfate 29.8 Magnesium trisilicate Talc Titanium dioxide Tribasic calcium phosphate

7 Points to Consider Please note especially the two highlighted per dose levels TiO2 is used in some approved drug products at very high levels and actual typical levels of 1 to 9 ppm for lead have been seen in actual routine commercial batches. This may cause some issues if the lead PDE will be < 5 ug per day. Lead from TiO2 per dose, based on 10 ppm spec 1387 mg x 10 ug/1000 mg = ug <---- One dose could be 2 1/2 times higher than the 5 ug per day PDE. This only takes into consideration Pb from one excipient other excipients in the formulation could also contribute.. What if there are multiple doses prescribed? Even if the lead level in the TiO2 was only 5 ppm which is very typical of actual commercial material, the 5 ug PDE would still be exceeded by one dose. 7

8 Excipient Realities!!! Many times the metal content of certain excipients is inherent from their sources and cannot be easily purified

9 Excipient Sources Mineral-based Excipients Conversion of Ores from Mines Conversion of Waste Materials Plant-derived Excipients Grown in Soil Grown in the Ocean Synthetic Excipients Derived from Oil through synthetic processes may use metal catalysts

10 Kaolin mine near Kaznejov, Czech Republic Known at least 12 to 55 ppm Lead from periodic testing

11 Talc extraction in Trimouns Talc Mine, Midi-Pyrenees, France Known Current USP Spec <10 ppm only tested once per year

12 Typical Open Pit Mining Operation

13 Raw Material for Iron Oxide Manufacturing

14 Iron Oxides from scrap metal to oxidation tanks Known Current USP Spec <10 ppm only tested periodically

15 Cellulose Sources for MCC, Cellulose derivatives, etc. What s in that Soil the Tree is growing in?

16 Brown Seaweed used to manufacture Sodium Alginate What has been absorbed from the ocean?

17 Unknown Unknowns Most Excipients have not been routinely tested for the metals covered by ICH Q3D therefore current levels are Unknown!! CAN WE PREDICT WHAT TO EXPECT?

18 Knowns - Metal Impurities from Supplier COAs Mineral Based Excipients Item Description Supplier/Manufacturer Arsenic ppm Cadmium ppm Total Lead ppm Inorganic Mercury ppm Chromium ppm Copper ppm Nickel ppm TITANIUM DIOXIDE, USP/FCC/EP/JP TITANIUM DIOXIDE USP/EP/JP Supplier A 1.0 max 0.2 max 10.0 max 1.0 max 1.9 max 0.5 max N/A Supplier B 3.0 max 1.0 max 10.0 max 1.0 max N/A N/A N/A CALCIUM CARBONATE EP Supplier C 3 max 1 max 10 max N/A N/A N/A N/A CALCIUM CARBONATE USP - PRECIPITATED Supplier D N/A N/A 3 max 0.5 max N/A N/A N/A TALC USP/FCC/EP/JP - Supplier E 3 max N/A 10 max N/A N/A N/A N/A TALC MICRONIZED USP/EP Supplier F 4 max N/A 10 max N/A N/A N/A N/A TALC USP/EP Supplier G 3 max N/A 5 max N/A N/A N/A N/A Unknowns: The following additional Metal Impurities did not have Specifications or Results on the Suppliers COA & Specification: Manganese, Molybdenum, Palladium, Platinum, Vanadium, Osmium, Rhodium, Ruthenium, and Iridium.

19 Titanium Dioxide (TiO2) Global Supply Ore sources used to manufacture TiO2 are common to all producers Lead content in TiO2 is determined by the Ore used as starting material TiO2 used in Pharmaceuticals is generally High Purity Anatase made using Sulphate process There are limited number of HP SP Anatase producers TiO2 supply is constrained and price is under pressure as demand exceeds supply

20 Ilmenite Ore from Mine TiO2 Purified Anatase Sulphate Process USP Current Spec for Pb <10 ppm

21 Hmmm I wonder what the lead level is like Here And Here And Here

22 And Here

23 High purity Anatase SP Plants Illmenite Ore Sources

24 World's largest opencast ilmenite mine - in Sokndal, Norway

25 Ilmenite from Kragero, Norway.

26 Ilmenite from the Normanville, South Australia.

27 Ilmenite from St-Urbain, Quebec, Canada.

28 Purified Anatase (PA) Supply The Global TiO2 Shortage has put pressure on the availability of PA. As demand for Technical grades has increased so has pricing for technical grades. Technical grade pricing now exceeds that of PA. This gives producers incentive to switch to Technical grade production. Producers are on allocation New Pharma customers mean they have to shed volumes in other markets

29 Example TiO2 Supplier A Manufactures TiO2 with Ore from Ore Mine A Supplier A routinely tests for a number of Metal Impurities including Lead and Leachable Lead Experiences unplanned Excursions from typical historical levels that can be prolonged

30 Batch to Batch Variability of some Metal Impurities in TiO2 from Supplier A TITANIUM DIOXIDE, USP/FCC/EP/JP COA Results Lot Number Arsenic Cadmium Total Lead Leachable Lead Inorganic Mercury Chromium Copper Nickel 1 < 0.2 ppm < 0.2 ppm 5.1 ppm 2.4 ppm < 0.1 ppm 1.9 ppm < 0.5 ppm N/A 2 < 0.2 ppm < 0.2 ppm 5 ppm 2.5 ppm < 0.1 ppm 1.7 ppm < 0.5 ppm N/A 3 < 0.2 ppm < 0.2 ppm 5 ppm 2.6 ppm < 0.1 ppm 1.9 ppm < 0.5 ppm N/A 4 < 0.2 ppm < 0.2 ppm 5 ppm 2.8 ppm < 0.1 ppm 2.1 ppm < 0.5 ppm N/A 5 < 0.2 ppm < 0.2 ppm 7 ppm 3.7 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 6 < 0.2 ppm < 0.2 ppm 5 ppm 2.7 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 7 < 0.2 ppm < 0.2 ppm 4 ppm 1.6 ppm < 0.1 ppm 2 ppm < 0.6 ppm N/A 8 < 0.2 ppm < 0.2 ppm 5 ppm 2.7 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 9 < 0.2 ppm < 0.2 ppm 3 ppm 1.8 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 10 < 0.2 ppm < 0.2 ppm 4 ppm 2.0 ppm < 0.1 ppm 1.8 ppm < 0.5 ppm N/A 11 < 0.2 ppm < 0.2 ppm 4 ppm 1.6 ppm < 0.1 ppm 2 ppm < 0.6 ppm N/A 12 < 0.2 ppm < 0.2 ppm 3 ppm 1.9 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 13 < 0.2 ppm < 0.2 ppm 2 ppm 0.8 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 14 < 0.2 ppm < 0.2 ppm 2 ppm 0.8 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 15 < 0.2 ppm < 0.2 ppm 2 ppm 1.1 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A

31 10 Lead Content Variability in Titanium Dioxide from Supplier A Ore Mine A Lead Content, ppm ppm 3 7 ppm ppm 0 4 ppm 4 Total Leachable

32 What Metal Impurities are Bioavailable? ICH Q3D says they are setting safety-based limits, however, they are focusing just on Total metal content which makes no sense!!! Ex; Only Leachable Lead is bioavailable from TiO2 Leachable Lead level is typically much lower than the Total Lead content Sample prep and test methodology is very important to utilize data for decision making!! Using Total Lead content in Q3D PDE requirements is NOT safety-based and should be re-evaluated!!!

33 CALCIUM CARBONATE PhEur Lot Number Arsenic Cadmium Lead Inorganic Mercury Chromium Copper Nickel ppm 0.73 ppm 2 ppm N/A N/A N/A N/A ppm 0.73 ppm 2 ppm N/A N/A N/A N/A 3 < 3 ppm 0.19 ppm 2.2 ppm N/A N/A N/A N/A 4 < 3 ppm 0.17 ppm 2.4 ppm N/A N/A N/A N/A ppm 0.21 ppm 2.3 ppm N/A N/A N/A N/A ppm 0.5 ppm 2 ppm N/A N/A N/A N/A ppm 0.3 ppm 1.1 ppm N/A N/A N/A N/A ppm 0.5 ppm 4.7 ppm N/A N/A N/A N/A ppm 0.6 ppm 2.5 ppm N/A N/A N/A N/A ppm 0.63 ppm 4.5 ppm N/A N/A N/A N/A ppm 0.44 ppm 2.6 ppm N/A N/A N/A N/A ppm 0.38 ppm 7.1 ppm N/A N/A N/A N/A ppm 0.6 ppm 3 ppm N/A N/A N/A N/A ppm < 0.1 ppm 1.4 ppm N/A N/A N/A N/A Excursion

34 Common Excipients Existing Elemental Impurity Data Item Description TITANIUM DIOXIDE, USP/FCC/EP/JP HPMC 3 cp - USP/EP/JP HPMC 6 cp - USP/EP/JP PEG 400 NF/EP/JP SODIUM CITRATE - DIHYD. USP/EP/JP/FCC/JSFA POLYSORBATE 80 (VEG.) NF/EP/JP POLYVINYL ALCOHOL, USP/FCC/EP/JPE PEG 3350 NF/EP/JP Lead Limit Listed on COA Max 10 ppm NMT 20 ppm (Heavy Metals) NMT 20 ppm (Heavy Metals) < 5 ppm (Heavy Metals) Typical Lead Limit Test Method Frequency of Testing 1 to 9 ppm based on 2 year history, 2 to 5 ppm typically ICP Every Batch 0.2 to 2 ppm ICP-MS Once per year 0.2 to 2 ppm ICP-MS Once per year NMT 1 mg/kg * * < 2 mg/kg < 1 mg/kg ICP Weekly < 10 ppm (Heavy Metals) Max 1 ppm Atomic Absorption Electro-thermal Atomization (Furnace Atomization) according to Combined Compendium of Food Additives Specifications, FAO JECFA Monographs, vol 4 (2005). Statistic Basis NMT 2 ppm * AA Analysis Once per year < 5 ppm (Heavy Metals) * * *

35 Testing of Aluminum Lakes Test Results 80 Samples Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums > Method 7 Reference Metals EPA 6010B EPA 7471B Method Detection Limit Reporting / Quantitation Limit FD&C RED #40/ALLURA Cost RED AC ALUMINUM > LAKES $20, <0.191 <0.132 < low dye% <0.191 <0.132 < < <0.191 <0.132 < low dye% <0.191 <0.132 < <0.191 <0.132 < < <0.191 < medium dye% <0.191 <0.132 < <0.191 <0.132 < medium dye% <0.191 <0.132 < high dye% < <0.191 <0.132 < < <0.191 <0.132 <0.0309

36 USP ICH Efforts USP plans to implement General Chapter requirements once ICH publishes their limits which will include the lch PDE limits and some information about the use of appropriate test methods based on the matrix issues that may exist FDA appears to understand the need for a slow implementation to gain an understanding first of the impact USP had indicated last year they would like to implement these General Chapters in 2013 IPEC FELT THIS WOULD HAVE BEEN A BIG MISTAKE!!! This date has now been taken off the USP website. USP Plans to be publishing their current position and a new date in the near future

37 USP ICH Efforts No implementation date should be identified at this point since most excipient manufacturers will not have a good understanding of their true variability for some time. Therefore, all they can do is commit to the existing USP-NF specifications if they exist this results in higher levels than might be typical Many Q3D metals do not have specifications in USP-NF Suppliers may not agree to any spec on these metals ICH Q3D EWG targeting to publish a Step 2 document in June 2012 at Tokyo meeting

38 Supplier Information concerning Metal Impurities As the ICH Q3D Guideline and the USP Chapters are being finalized, many suppliers are waiting to assess their products so that they are using the appropriate test methods and detection limits which will be necessary once the limits are established Therefore, many suppliers currently have very limited information related to the actual levels of metal impurities in their excipients and food additives Routine testing for these Metal Impurities is not typically done at this time and actual levels below the current specifications are not known The IPEC Federation has published a position paper on the web which explains why users should NOT request detailed metal impurity information from their suppliers at this time

39 Supplier Realities Many suppliers who don t routinely test for metal impurities may NOT be willing or able to agree to specifications that are lower than what they are required to meet to comply with USP-NF monograph, 21 CFR or other regulatory requirements for the component In some cases, they may be willing to agree to levels based on their best understanding of typical values but it is expected that this will be the exception not the rule Remember, for many excipient companies, the pharma business is a very minor part of their sales and they will not implement a lot of additional controls without getting premium prices if they are even willing to do it at all.

40 User Realities What does this all mean to Pharma Companies? Option #1? Option #2a or 2b? Option #3? Confusion?

41 Realities for Implementation Many Excipients do sometimes contain Metal Impurities at the 1 to 10 ppm level. Typical levels Unknown at this time. Forget using Option 1 limits not realistic for many excipients Suppliers typically will not be willing to agree to tighter specifications than the historical compendial requirements for Option 2 calculations Most Suppliers may not do significant testing to determine typical levels until after the ICH Q3D requirements are published excursions may make it impossible to define typical levels Some suppliers may choose not to participate in supplying the pharmaceutical industry if too much pressure is put on them to do routine testing and agree to lower limits

42 Realities for Implementation Pharmaceutical companies will probably need to do significant testing themselves on their excipients or drug products to determine actual levels and if they comply with PDEs Think Option 3!!! Some drug products will probably need to be reformulated to meet PDE requirements Lead from TiO2 per dose, based on 10 ppm spec IID Max. of 1387 mg x 10 ug/1000 mg = ug One dose could be 2 1/2 times higher than the 5 ug per day PDE. All these efforts are going to take quite a bit of time to do properly (probably several years min.) ICH and Compendias MUST work closely with industry to only make these requirements official once the unknowns are much better understood!!

43 IPEC Proposals IPEC plans to develop a standardized mechanism for how makers and users should best share information on metal impurities Standard format will be provided that meets the key needs at this time Request will NOT allude to setting tighter specifications just information gathering Mechanism will be shared throughout the Coalition associations and with Rx-360 for broad usage Q3D Workshop many recommendations to the EWG and points to consider

44 Q3D Workshop Recommendations to EWG Categories should be added to the guideline with metals segregated according to whether they are likely to be present from the environment or may be due to use as catalysts (etc) Clarification is needed on risk assessments and testing specifically to indicate that process knowledge, understanding of your materials and so forth could be used to justify not checking for all 27 metals If the limits are to truly be safety based, the guideline limits should be focused on the amount of metal that is absorbed by the body (as opposed to total metals) Target to meet total metals (PDEs) as a first step for simplicity, however if that is not achievable Then consider what portion of the metal(s) is absorbed by the body (bioavailable)

45 Q3D Workshop Recommendations to EWG An adequate implementation timeframe (minimally 2 years) is required for new drugs and an additional 5 years after that would probably be needed for existing drugs. The ICH Q3D EWG postpone the publication of the Step 2 guideline until the November meeting so that additional data concerning actual metal impurity content and potential for bioavailability can be developed and considered by the EWG Many other points were made concerning excipient realities for consideration by EWG during the meetings in Japan in June

46 Questions?