El Elemental I Impurity R Risk A Assessment - Case S Studies Author: Andrew Teasdale and Laura Rutter (on behalf of EFPIA) Date: 5 April 2016 * Version: Final 1 www.efpia.eu
Overview ew Using the principles outlined in ICH Q3D and training modules we will: • Present a series of risk assessments based on actual products. • Examining different routes of administration. • Through this seek to highlight there is more than one approach, illustrated through the examples shown. • Marketing application – example summary and proposed location. • Approach to products during clinical development. 2 www.efpia.eu
ICH Q Q3D Gui Guidel eline f e for E Elem emen ental Impu purities es – Practical I Implem emen entation of ICH Q Q3D • ICH Q3D recommends taking a risk based approach. • Focus is on the final product – the fishbone diagram assists by advising on the components for consideration: all potential sources of elemental impurities should be considered and evaluated for their contribution to the drug product. • The product assessment will form the basis of a specific control strategy for EIs and should be available to be presented to Regulators during an inspection upon request. • An industry position paper has been jointly authored and published in PharmTech. More Likely Sources Drug Excipients Substance Elemental Impurities in Drug Product – Lower Risk Container Manufacturing Utilities (e.g., Closure Equipment Water) System 3 www.efpia.eu
Risk P Process – General al P Principl ples • Review API, excipient and drug product • ICH Q3D advocates a 3 step process : manufacturing process to identify known and potential sources of Elemental • Identify Identify Impurities • Evaluate • Summarize Control • Collect predicted and/or observed levels of elemental impurities • Compare data with the established Evaluate Permitted Daily Exposure • Different approaches to each stage are now examined through a series of actual risk • Summarize and document the risk assessments. assessment • Identify additional control requirements, if Summarize required, to ensure PDE is met Control 4 www.efpia.eu
Industry Risk Assessment Example 1 Synthetic API – tablet 5 www.efpia.eu
Industry R Risk A Asses essment Example 1 le 1 – Oral S l Solid lid D Dos ose e Product Compound X Dose Form Tablet Strength 200/ 400 mg compound X Therapeutic Target (Why patients take this Osteoarthritis product) Dosing Regemine (Frequency & Duration of Daily, one tablet dosing) Maximum Daily Dose of Active 400mg Compound X Mass of Dosage Unit 638.6 mg Route of Administration Oral USP Monograph for Product No Site of Manufacture GMP Packing Site GMP Elements being Evaluated Class 1 Cd, Pb, AS, Hg Class 2A Co, V, Ni Class 2B Pd – Metal catalyst used in API synthesis Class 3 Sn - Hypromellose Additional metals identified by risk 6 Assessment www.efpia.eu
Component Functionality Amount per % in coated Type (Excipient) 400 mg tablet tablet Exa xample 1 1 – Oral (mg) Core Solid Dose Solid ose Drug substance API 400.00 62.64 Binder Hypromellose 2910 21.70 3.40 Plant Diluent Microcrystalline Cellulose 37.20 5.83 Plant Diluent Lactose Monohydrate 111.50 17.46 Animal Disintegrant Crospovidone 43.40 6.79 Synthetic Lubricant Magnesium stearate 6.20 0.97 Mineral Coating Film-former Hypromellose 2910 11.16 1.75 Plant Pigment Titanium dioxide 5.55 0.87 Mineral Plasticiser Triacetin 1.49 0.23 Synthetic Colorant Blue Aluminium Lake #2 0.37 0.06 Mineral Colorant Blue Aluminium Lake #1 0.03 0.005 Mineral 7 www.efpia.eu
Prod oduct ct I Infor ormation – API S Synth thes esis PRE-RSM Y Y' O O N H N H N H 2 N Xylenes, KHCO 3 , H 2 Pd H 2 O,xylenes 140°C DMF/H 2 O X X X X Y'' Alk Y'' Alk Br X Y'' i. NaOH, H 2 O N N N NBS Br Alk ii. HBr, THF API X X X cf. ICH Q3D: " For biotechnology-derived products, the risks of elemental impurities being present at levels that raise safety concerns at the drug substance stage are considered low .") 8 www.efpia.eu
Prod oduct ct I Infor ormation – drug p product m manu nufac acture Formulation and components Unit operations Formulation and components Unit operations → Stage 6: Blending API Crospovidone Lactose Stage 1: Dry Mix → Magnesium stearate Diffusion mixers (tumble) Microcrystalline Cellulose High shear wet granulator Crospovidone Stage 7: Lubrication Hypromellose → Stage 2: High Shear Wet Granulation Diffusion mixers (tumble) Hypromellose High shear wet granulator ↓ Purified water Pharmacopeial Stage 8: Compression ↓ Tablet press Stage 3: Wet Milling ↓ Screening Mills Grade → Stage 9: Film Coating Film Coat Stage 4: Fluidised Bed Drying Pan coating Direct heating, fluidised solids bed Stage 10: Packing ↓ Stage 5: Milling Screening mill Section 5.2 – Risk can be Evaluation process not just data driven reduced through process • Can be based on first principles. understanding / equipment With regards to the process described an evaluation was conducted prior to manufacture • selection / qualification and • Concluded that risk very low given lack of any extremes of pH and low residence GMP processes. times. 9 www.efpia.eu • Visual inspection / cleaning also part of GMP.
Prod oduct ct I Infor ormation – pac ackag aging Drug Substance packaging • Drug substance stored in double low density polyethylene bags individually closed with plastic tie wraps. The closed bags are stored inside a rigid outer container/drum. Drug Product packaging • X tablets are presented as blister packs formed from unplasticized polyvinyl chloride (PVC) film laminated to a polychlorotrifluoroethene (PCTFE) and sealed to push-through blister foil Risk factors: • Contact Solid to Solid – no mechanism* • Data relating to PE / PVC show very low EI risk Section 5.3 – Probability of elemental leaching into solid dosage forms is minimal and does not require further consideration in the risk assessment 10 www.efpia.eu
There are multiple ways to conduct an assessment St Step ep 1 – Id Identify fy • Review API, excipient and drug product • In this example all input materials were manufacturing process to identify known and potential sources of Elemental recorded and a specific risk assessment Identify Impurities tool used to evaluate each potential EI • Collect predicted and/or observed levels of source elemental impurities • Using a pre-defined scoring system. • Compare data with the established Evaluate Permitted Daily Exposure • This is then represented graphically • Summarize and document the risk assessment coding risk in terms of red/amber/green • Identify additional control requirements, if Summarize as well as the numerical risk factor. required, to ensure PDE is met Control 11 www.efpia.eu
Identify Typical high risks: metal catalysts/reagents, mined excipients Risks controlled by GMP: purified water, equipment compatibility 12 www.efpia.eu
Identify Evaluation process not just data driven Can be based on first principles Other factors • Any risk assessment needs to be supported by an appropriate IPEC Questionnaire overall quality system. Key aspects of this would typically include: Vendor Assurance • • Change Control • Supplier Information • Certificate of Analysis • EI risk assessment • In this example for Crospovidone the following information available: • Pharmaceutical excipient handbook suggests that a catalyst can be used in the production of crospovidone. • Supplier provided a statement to confirm that no metal catalysts are used in the manufacture of their xx grade crospovidone. 13 www.efpia.eu
Step 2 2 - Evaluate Potential No. of batches to be Elemental l impurities to include in Comments source of metal analysed analytical screening • Based on the risk analysis – impurities Environmental Intentionally and naturally added’ metals e.g. screening requirements were abundant metal elements catalysts/reagents defined. Hypromellose 3 batches Class 1: As, Cd, Sn representative of the Hg, Pb • Screening focused on Class 1 quality/supplier/grad Class 2A: V, Co, e to be used during Ni and Class 2A metals + Identified commercial manufacture metals. Microcrystalline 3 batches None cellulose • Section 5.6 - 3 production or 6 Lactose 3 batches None monohydrate pilot scale lots Magnesium 3 batches None stearate • Analysis performed using ‘fit for Crospovidone None None Addressed through detailed supplier purpose’ methodology response Coating 3 batches Class 1: As, Cd, Aluminium lakes Section 9 – The determination of EIs should be Hg, Pb are used to colour conducted using appropriate procedures suitable for the coating blue. Class 2A: V, Co, their intended purpose Ni API 3 batches Pd - catalyst 14 www.efpia.eu
Step 2 2 – Evaluate • Negligible levels of Class 1 / Class 2A metals across API and excipients tested Potential Elemental impurity concentration in µ g/g source of Batch elemental Number impurities As Pb Cd Hg V Co Ni Pd Batch 1 <0.1 <0.1 <0.1 1.8 <0.1 <0.1 1.0 <5 API Batch 2 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 1.0 <5 Batch 3 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 0.3 <5 Limit of detection ( µ g/g) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 5 Option 2a target limit µg/g 23 7.8 7.8 47 160 78 310 160 (0.64 g/day drug product) 30% Option 2a target limit 7.0 2.3 2.3 14 47 23 94 47 µg/g 15 www.efpia.eu
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