U.S. Requirements for Dietary Supplement Ingredients and USP <2232> Elemental Impurities Is Your Company Ready for Implementation? Priscilla Zawislak NIA-West, Ojai, CA May 28, 2015 1 Outline Ø U.S. Regulatory Requirements for Ingredients in Dietary Supplements FDA and Compendial Requirements Ø USP <2232> Elemental Contaminants in Dietary Supplements Is Your Company Ready for Implementation? Background Challenges Current Industry Needs 2 1
FD&C Act - Dietary Supplement Ingredients U.S. Food Drug & Cosmetic Act, Sec. 201. [21 U.S.C. 321] Chapter 9, Subchapter II Definitions: (ff) a dietary supplement shall be deemed to be a food within the meaning of this Act..the ingredients, other than dietary ingredients under section 201(ff) [vitamin, mineral, herb or botanical, amino acid ] of the act, be lawful under the applicable food additive regulations or be generally recognized as safe (GRAS) 3 Conformance to Dietary Supplement Compendial Monographs Dietary Supplement Health and Education Act of 1994 (DSHEA), Sec. 7(a)(1)(D) A dietary supplement may be misbranded if it states conformance to a compendial monograph but does not conform. 4 2
Use of Excipients in Dietary Supplements Data widely known may be used to form a basis for a consensus among experts that use of an excipient in a dietary supplement is safe. However, the use of excipients in drugs may be short term or intermittent, leading to far less exposure than routine use in some dietary supplements. As human exposure increases, not only does the safety profile of the intended excipient become more important, but the purity specifications also become more critical. FDA Response, Comment 239, Federal Register, Vol. 72, No. 121, June 25, 2007, 21CFR Part 111 Final Rule 5 WHY is this important? There is confusion among some dietary supplement companies about whether ingredients should be food grade or excipient grade The USP is leading supplement manufacturers to believe that only USP or NF ingredients should be used Whats impacted: Customer and supplier agreements regarding product grades, specifications, quality/gmp systems and costs Expectations under the USP Verified Dietary Supplements certification Potential regulatory compliance issues for ingredients 6 3
WHAT is being done about it? Our trade associations are: Ø Communicating with FDAs Office of Food Additives and other departments in the Agency to continue support for FDAs position on the use of food additives in supplements Ø Submitting comments to FDA proposed rules and guidances under FSMA and other regulations to ensure food additives are included and/or differentiated appropriately Ø Engaging USP to clarify their position Ø Added wording to USP Convention Resolution 9: Quality Standards for Dietary Ingredients and Dietary Supplements 7 WHY is this important to USP <2232> Elemental Contaminants in Dietary Supplements? USP <2232> : Is mandatory for supplements that have compendial monographs Requires knowledge of the potential for elemental contaminants contributed by ingredients Ingredient monographs generally do not have specifications for the elements in <2232> or if they do, they are based on non-quantitative limit tests Suppliers of ingredients generally dont have data on these elements! 8 4
USP Elemental Impurities History ICH and USP have developed guidelines and general chapters related to Elemental Impurities in drug products USP also has a chapter for Elemental Contaminants in Dietary Supplements <2232> Ø Official August 1, 2013 but General Notices 5.60.30 Elemental Impurities in USP Drug Products and Dietary Supplements establishes January 1, 2018 for applicability of chapter <2232> unless specified otherwise in a monograph Ø Early adoption of <2232> is permitted Ø <233> Elemental Impurities Procedures becomes official December 1, 2015 Ø General Chapter <231> Heavy Metals will be removed from the USP 9 USP FAQs (Jan 24, 2015)* Current heavy metals limit test <231> is >100 yrs old, does not speciate elements and may not detect certain elements such as Hg at toxicologically-relevant levels <2232> Establishes limits of acceptable levels of elemental impurities (Pb, Hg, As, Cd) in dietary supplements Methodology in <233> includes procedures that use modern analytical technology As more ingredients are sourced globally these standards are expected to protect manufactures and consumers in the US As Hg Cd Pb * http://www.usp.org/usp-nf/key-issues/elemental-impurities 10 5
USP <2232> Elemental Contaminants in Dietary Supplements Applies ONLY to finished dietary supplements dosage forms labeled as conforming to USP or NF standards Does NOT set limits for dietary supplements. If applicable, limits are set in the individual monographs Focuses on the big 4: arsenic, cadmium, lead and mercury Extent of testing is determined based on a risk-based approach Takes into account the likelihood of contamination Manufacturers should consider the presence of unexpected elemental contaminants to determine compliance 11 Options for Compliance with the Limits of Elemental Contaminants Option 1 Dietary Supplement Analysis Option Option 2 Individual Component Option Option 3 Summation Option 12 6
<2232> Options 1 & 3 Option 1: Dietary Supplement Analysis Finished dosage form is analyzed according to methods in <233> or speciation procedures given in <2232> Acceptance criteria: results are not more than the PDE Option 3: Summation Finished dosage forms that are consumed in quantities >10 g/day or where the acceptance limit for any contaminant in any component of the supplement exceeds the applicable individual component limits Unless otherwise specified in the individual monograph, use the procedures in <2232> Acceptance criteria: amount of each component /daily intake is not more than the PDE 13 <2232> Options 1 & 3 Limits Element Arsenic (inorganic) 15 Cadmium 5 Lead 5 Mercury (total) 15 Methylmercury (as Hg) 2 PDE (µg/day) Methylmercury determination is not necessary when the content for total mercury is less than the limit for methylmercury 14 7
<2232> Option 2 & Limits Option 2: Individual Component Option Applicable to finished dosage forms with a max. daily intake of NMT10 g of the finished supplement product Unless othewise specified in the individual monograph use the procedures in <2232> Acceptance criteria: each component meets the limits below Element Individual Component Limits (µg/g) Arsenic (inorganic) 1.5 Cadmium 0.5 Lead 0.5 Mercury (total) 1.5 Methylmercury (as Hg) 0.2 Methylmercury determination is not necessary when the content for total mercury is less than the limit for methylmercury 15 How to Determine Which Option to Use? Appropriate control of elemental contaminants must be based on risk but also take into consideration the challenges faced by industry in implementing these requirements. How do you do this? What role will data vs information play in this? Where to find solid and appropriate data today? How do you evaluate risk? Without reliable information on components you will test everything or simply default to Option 1 Product Testing 16 8
Sources of Potential Contamination Focus is on the final product but consider the components Dietary Ingredient Active Utilities (e.g. Water) Inactive Ingredients Dietary Supplement Product Manufacturing Equipment Primary Packaging Materials 17 Sources of Potential Elemental Contaminants Solvents Water Metal Catalysts Elemental Contaminants in DS Organic Materials Mfg. Equip. Inorganic Reagents Process Aids How can data assist in classifying risk? Deliberately added metal catalysts Water monitoring Equipment construction of materials; GMP/ inspection Solvents few utilize metals deliberately in manufacture. Many are distilled 18 9
How to Evaluate & Control Potential Elemental Contaminants Dietary supplement manufacturing often involves a complex series of processes, however: Simple scientific principles can be applied to ensure that elemental contaminants in the final product are controlled to appropriate levels Application of a risk-based control strategy: Ø Ø Ø Understand the manufacturing process and key sources of elemental contaminants focusing on critical later stages Appropriate equipment selection/qualification Adoption of suitable GMPs and the selection and application of appropriate controls will typically result in the manufacture of the dietary supplement with elemental contaminant levels well below USP limits 19 Risk of Potential Elemental Contaminants in Ingredients Mined (e.g. talc) Synthesized with Metal Catalyst (e.g. mannitol) Plant Origin (e.g. cellulose derivatives) Animal Origin (e.g. lactose & gelatin) Increasing Potential Risk of Contributing Elemental Contaminants Synthesized without Metal Catalyst (e.g. colloidal SiO 2 ) 20 10
Potential Sources of Elemental Contamination from Ingredients Ø Many are from natural sources anticipate variability Ø Contaminants often inherent due to sourcing & can not be easily reduced or removed Plant-derived ingredients Synthetic ingredients Grown in soil (e.g. cellulose derivatives) Harvested from the ocean (e.g. alginates, carrageenan) Derived from oil through synthetic processes may use metal catalysts (e.g. povidone, PEG, silicones) Mineral-based ingredients Conversion of ores from mines (e.g. TiO2) 21 Hmmm I wonder what the lead level is Here and Here and Here 22 11
And Here 23 Kaolin mine near Kaznejov, Czech Republic Known at least 12 to 55 ppm Lead from periodic testing FCC lead spec NMT 10 ppm Talc extraction in Trimouns Talc Mine, Midi-Pyrenees, France Known only tested once per year FCC lead spec NMT 5 ppm 24 12
Excursions - Potential Normal Variation Many impurities are naturally present (e.g. lead) in mined raw materials and cannot be further processed out; therefore, it is important to understand the actual levels present Normal variation can be expected from excursions that occur in the raw material source 25 Elemental Contaminant Realities Today little data exists to perform a scientific risk assessment of elemental content Unknown Unknowns Specifications, where they exist, for the 4 elements have been largely based on limit tests Most ingredients have not been routinely tested using quantitative methods; therefore, current elemental concentrations and variability is often UNKNOWN! Communication between the supplement manufacturers and suppliers is critical to best understand what is known and NOT known about levels in ingredients Lack of industry data required to confirm actual vs theoretical metal impurity levels It will take a long time to develop enough data to understand normal variation needed for a science-based risk assessment 26 13
Key Analytical Challenges for Industry Analytical testing required to quantify elemental contaminants in dietary supplements down to the levels in USP <2232> Current work indicates that analytical challenges may be greater than previously anticipated by regulators and pharmacopeias. Labs are finding ICP-MS testing to be much more complex than previously thought Complexity of samples Adapting to ICP-MS analysis Existing spectroscopy labs adapting to the requirements of <233> 27 Technical Challenges ICP-MS analysis requires specialized experience: Maintenance/operation Interference interpretation & remediation Chemical incompatibilities with analytes Use of internal standards, reaction gases, correction equations, etc Sample preparation concerns: Variety of samples Aggressive microwave digestions Total digestion vs acid leach methods High dissolved solids, acid concentrations, incomplete digestions, etc No appropriate reference standards available for assessing inter-laboratory variation 28 14
Analysis by Industry and FDA Labs IPEC and FDA* labs analyzed 200+ samples of excipients. The data generated to date is encouraging BUT some caution is needed. Ø At this stage we have only cursory knowledge relating to the level of variability especially for naturally sourced materials Ø The limited number of samples tested can not as yet represent what types of excursions may be possible Ø This will only really be known after much more testing over a period of time Ø How much data is needed? * John Kauffman, Rapporteur and Regulatory Chair, ICH Q3D IWG, Lab Chief, Branch II, FDA, CDER Division of Pharmaceutical Analysis 29 Study Conclusions Data for standardized samples show high variation across laboratories Flexibility and further evaluation needed in methodology for testing labs Overall the risk of elemental contaminants in the final dietary supplement is going to be low in most cases The more data we can collect and interpret the closer we can get to achieving practical implementation differentiated and focused on actual rather than perceived risk. 30 15
What Should Your Company Do NOW? Determine which <2232> Option is appropriate for your products based on knowledge of the ingredients and finished product - Complete initial assessment for each ingredient as needed - If appropriate, develop baseline levels for each ingredient used in a dietary supplement product where necessary, monitor for excursions Establish / validate equipment (ICP-AES/ICP-MS) or identify external test facility Develop sample preparation and analysis methodologies Train personnel Collaboratively work together (supplement manufacturers / ingredient suppliers) to develop (via risk assessment) testing / reporting strategy January 1, 2018 is fast-approaching!! 31 Sharing Information between Suppliers and Customers Use information, where available, from ingredient suppliers to determine potential presence / concentration of each metal (and the potential for excursions) used in the production of dietary supplements and in the assessment of a finished dietary supplement Permitted Daily Exposure (PDE) level. 32 16
BUT Remember. Unknown is an acceptable answer from suppliers Testing for ingredients by the suppliers is not required unless otherwise specified in the ingredients compendial monograph Ingredients in dietary supplements are not subject to the limits in <2232> or <232> (drug products) So.be prepared to consider multiple options to achieve product compliance! 33 Thank You! Acknowledgements Katherine Ulman Dow Corning David Schoneker Colorcon Andrew Teasdale Astra Zeneca Helmut Rockstroh Roche John Kauffman FDA, CDER 34 17
Questions? 35 36 18