Post on 24-May-2020
transcript
Slide 1 © PharmOut 2017
Update on Toxicology, PDE and Elemental Impurity Requirements for the EU
Presented by Jacob MacDonald, July 2017
Slide 2 © PharmOut 2017
Pharmaceutical Impurities – What and Why?
What has changed
Old method (USP<231>) was not accurate or reliable. Worldwide, pharmacopeias have been working on replacement methods based on
closed-vessel digestion and instrumental (ICP) analysis
Sources of Impurities
Starting materials, APIs, excipients/additives, solvents, catalysts, reaction by-products, process equipment, containers/packaging.
Why measure impurities in pharmaceuticals
Contaminants/residues – including elemental impurities – may be toxic, or may affect the performance or shelf-life of the drug product
Slide 3 © PharmOut 2017
ICH Q3D – Guideline for Elemental Impurities
• Issue Date – 16th December 2014 (ICH)
• Issue Date – September 2015 (FDA)
• Applicable to all drug products 36 months from ICH
introduction – December 2017
• Does not apply to:
Herbal products Radiopharmaceuticals Vaccines
Cell metabolites DNA products Allergenic extracts
Cells Whole blood Cellular blood components
Blood Derivatives• Plasma• Plasma derivatives
Dialysate solutions Elements deliberately included for therapeutic benefit
ATMPs
Slide 4 © PharmOut 2017
Element Classifications – ICH Q3D
Class Element Comment
Class 1 As, Cd, Hg and Pb Human toxicants that have limited or no use in the manufacture of Pharmaceuticals
Class 2 Route dependent human toxicants
Class 2A Co, Ni and V High probability of occurrence
Class 2B Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl
Reduced probability of occurrence
Class 3 Ba, Cr, Cu, Li, Mo, Sb and Sn
Low toxicities by the oral route of administration
Slide 5 © PharmOut 2017
Pharmacopeias: Different “Guidelines”
• EMEA/CHMP/SWP/4446/2000Europe
(Ph. Eur)
• USP Chapters <232> & <233>
• <231> Obsolete
USA
(USP)
• ICH Q3D (adopted by FDA)International
(ICH)
5
Slide 6 © PharmOut 2017
Low recovery for several elements due to high temperature ashing step in USP<231> (600oC ashing leads to poor recoveries and almost total loss of volatile analytes such as Hg, Sn and Sb).
Pharmacopeial Forum Stimuli Vol. 34(6) [Nov.–Dec. 2008]
Trigger for Development of a New Method:USP<231> Ashing Step Leads to Loss of Volatiles
6
Slide 7 © PharmOut 2017
<2232>
Heavy Metals Limit Test
<233><232>
Elemental
Impurities
(Limits)
Elemental
Impurities
(Procedures)
ElementalImpurities in
Dietary Supplements
Terminology changing:“Heavy Metals” “Elemental
Impurities”
To be be replaced with:
Related method <2232> applies to dietary supplements only
<232> will eventually replace other “metals” General Chapters
<251>
<231>
Lead
<211>Arsenic
<261>Mercury
Aligned (harmonised) with ICH Q3D
USP “Metals” Chapters – Current and New7
Deletion Date: Jan 2018
USP 38 and 39 include the updates
Slide 8 © PharmOut 2017
Other Relevant Standards for Elemental Impurities
Elemental Impurities
• USP <232>/<233>
• USP <2232>
• ICH Q3D
• Drug Products• Raw materials• Dietary supplements
Packaging & CCS
• USP <661.1>, <661.2>
• USP <1663>, <1664>
• Extractable metals• Leachable metals
Slide 9 © PharmOut 2017
Harmonized PDE Levels – Same for USP and ICH
Permitted daily exposure (PDE) limits in mg/day.
• Limits in the drug material analysed must be corrected for daily dosage and route of administration
• Drugs intended for inhalational or parenteral (injectable/intravenous) administration have much lower limits than drugs taken orally
ICH/USP Class Element Oral PDE (μg/day)
Parenteral PDE (μg/day)
Inhalational PDE (μg/day)
Class 1 Cd - Cadmium 5 2 2
Pb - Lead 5 5 5
As - Arsenic (inorganic)
15 15 2
Hg - Mercury (inorganic)
30 3 1
Class 2A Co - Cobalt 50 5 3
V - Vanadium 100 10 1
Ni - Nickel 200 20 5
Class 2B Tl - Thallium 8 8 8
Au - Gold 100 100 1
Pd - Palladium 100 10 1
Ir - Iridium 100 10 1
Os - Osmium 100 10 1
Rh - Rhodium 100 10 1
Ru - Ruthenium 100 10 1
Se - Selenium 150 80 130
Ag - Silver 150 10 7
Pt - Platinum 100 10 1
Class 3 Li - Lithium 550 250 25
Sb - Antimony 1200 90 20
Ba - Barium 1400 700 300
Mo - Molybdenum 3000 1500 10
Cu - Copper 3000 300 30
Sn - Tin 6000 600 60
Cr - Chromium 11000 1100 3
Slide 10 © PharmOut 2017
Elemental Impurities – Latest Method UpdatesUSP<231> USP<232>/<233>; ICH Q3D
February 2017 – final harmonization between USP & ICH
Elements, concentrations, route of administration, risk assessment
Instrumental analytical methods
AA, ICP-OES, or ICP-MS
Validation criteria
ICH Q2 (R1) & USP<1225>
By end of 2017 – Pharma companies must comply withnew Elemental Impurities methods
Appropriate sample preparation
Solubilization or closed-vessel acid digestion
Slide 11 © PharmOut 2017
What Improvements Will USP<232>/ICH Q3D Deliver
Longer list of analytes and much lower PDE limits
• List of elements that are controlled in drug products is based on patient safety, not method capability
• Limits based on toxicological risk
• Limits are modified depending on intended route of administration
Sample preparation methods ensure no loss of volatiles
• Recommended sample digestion procedures have no high temperature ashing step, and include closed-vessel microwave digestion
Quantitative and specific analytical methods
• Recommended analytical (instrumental) procedures are ICP-MS/OES
• Quantitative analysis of individual analytes
• Subjective, colorimetric test that gives total metals result is no longer acceptable
Slide 12 © PharmOut 2017
Risk Assessment – ICH Q9 Principles
RARisk Assessment Process – Science-based
Step 1
Identify known and potential sources of elemental impurities that may enter drug product
Step 2
Evaluate the presence of a particular elemental impurity in the drug product by determining the observed or predicted level of the impurity and comparing with the established PDE.
Step 3
Summarize and document the risk assessment. Identify if controls built into the process are sufficient or identify additional controls to be considered to limit elemental impurities in the drug product.
Slide 13 © PharmOut 2017
Potential Sources of Elemental Impurities
Source 1
• Residual impurities from elements intentionally added (i.e. catalysts)
• Excipients
• Other drug product components
Source 2
• Elemental impurities that are unintentionally added and are potentially present in the drug substance, water or excipients used in the preparation of the drug product.
Source 3
• Elemental impurities that are potentially introduced into the drug substance and / or drug product from manufacturing equipment.
Source 4
• Elemental impurities that have the potential to be leached into the drug substance and drug product from the container closure systems.
Slide 14 © PharmOut 2017
Which Elemental Impurities Should be Measured
The elements that should be included in the product Risk Assessment are different depending on the intended route of administration
• Class 1 and Class 2A elements must be assessed in all products
• Class 3 elements should be considered for Parenteral and/or Inhalational routes of administration
• ALL listed elements should be included if they have been added intentionally
ICH/USP Class Element Oral PDE
(μg/day)
Parenteral PDE
(μg/day)
Inhalational
PDE (μg/day)
Class 1 Cd - Cadmium 5 2 2
Pb - Lead 5 5 5
As - Arsenic
(inorganic) 15 15 2
Hg - Mercury
(inorganic) 30 3 1
Class 2A Co - Cobalt 50 5 3
V - Vanadium 100 10 1
Ni - Nickel 200 20 5
Class 2B Tl - Thallium 8 8 8
Au - Gold 100 100 1
Pd - Palladium 100 10 1
Ir - Iridium 100 10 1
Os - Osmium 100 10 1
Rh - Rhodium 100 10 1
Ru - Ruthenium 100 10 1
Se - Selenium 150 80 130
Ag - Silver 150 10 7
Pt - Platinum 100 10 1
Class 3 Li - Lithium 550 250 25
Sb - Antimony 1200 90 20
Ba - Barium 1400 700 300
Mo -
Molybdenum 3000 1500 10
Cu - Copper 3000 300 30
Sn - Tin 6000 600 60
Cr - Chromium 11000 1100 3
Elements shaded Blue should be considered in Risk Assessment.
Slide 15 © PharmOut 2017
Pharmaceutical Manufacturing EquipmentElement Class Oral PDE
µg / g drug product
ParenteralPDEµg / g drug product
E % by weight (Maximum amounts)
316L Stainless Steel
Carbon (C) - - - 0.030
Manganese (Mn) - - - 2.00
Silicon (Si) - - - 0.75
Chromium (Cr) 3 1100 110 18.00
Nickel (Ni) 2A 200 20 14.00
Molybdenum (Mo) 3 300 150 3.00
Phosphorus (P) - - - 0.045
Sulfur (S) - - - 0.030
Nitrogen (N) - - - 0.10
Iron (Fe) - - - ~62.045
Slide 16 © PharmOut 2017
Requirements for USP/ICH Analysis
Understand Your Sample/Product/Material
• Route of administration of drug product• Oral
• Parenteral
• Inhalational
• Drug product components• API
• Excipient
• Raw material
• …
Slide 17 © PharmOut 2017
PDE Calculations (2 options)
• Concentration (µg/g) = PDE (µg/day)
daily amount of drug product (g/day)
• Permitted concentration limits of elements in individual components of a product with a specified daily intake:
PDE (µg/day) ≥
K = an index for each of N components in the drug product
Ck= permitted concentration of the element impurity in component k (µg/g)
Mk = mass of component k in the maximum daily intake of the drug product (g)
∑Ck.MkK=1
N
Slide 18 © PharmOut 2017
What is the ‘J’ value?J = The concentration (wt/vol) of the element of interest at the target PDE limit, appropriately diluted to the working range of the instrument. Dilution may also be needed to bring matrix within limit of the
instrument
Calculating the “J” value from the PDE
Slide 19 © PharmOut 2017
“J” Value and Sample Dilution
Liquid samples of oral medicines (higher PDEs apply) may be able to be run directly (undiluted) on ICP-OES; parenteral and inhalational drugs have lower PDE limits, so ICP-MS will be required.
For solid samples, Dilution Factor (typically the prep dilution) may be reduced, allowing OES to be used. Or higher dilution can be applied to bring matrix level within the range tolerated by ICP-MS
19
Implications for Instrument Selection
Slide 20 © PharmOut 2017
Speciation and other considerations
• Distribution of elements among chemical species including isotopic composition, electronic or oxidation state,
• Speciation required when justifying higher or lower levels when the identified species is more or less toxic, respectively than the species detailed in ICH Q3D Appendix 3.
Slide 21 © PharmOut 2017
Speciation Analysis Application Requirements for <232>
• PDE limit for arsenic and mercury in drug products as listed in <232> (and <2232>*) is for inorganicAs/Hg
• Direct ICP-MS analysis gives result for total arsenic/ mercury (the sum of all chemical forms)
• If total arsenic or mercury result exceeds the PDE limit, a speciation analysis may be performed to check level
• If speciation analysis results for inorganic form is less than the PDE limit, the drug product is in compliance
21
Systems should have a speciation method to quantify “inorganic As or Hg” if total As or Hg level exceeds PDE limit
* 2232 monograph for Dietary Supplements only
Slide 22 © PharmOut 2017
Sample Preparation Procedures for ICP Techniques
Options (from new pharma methods)
Neat Aqueous OrganicIndirect
Digestion
Sample ready for analysis as is, undiluted
Dilution/ solubilization in an acidic solvent
Dilution/ solubilization in an organic solvent
MW digestionGlass/quartz/PFA4:1 HNO3:HCl250 ºC
Closed-vessel digestion with HNO3/HCl works for many typical solid drug products and raw materials/excipients
22
Slide 23 © PharmOut 2017
Good recoveries with new closed-vessel acid digestion used with ICP method
Pharmacopeial Forum Stimuli Vol. 34(6) [Nov.–Dec. 2008]
New (ICP) Sample Prep Preserves Volatiles
23
Slide 24 © PharmOut 2017
Which Instrument is Best for USP<232>/ICH Q3D
Any suitable technique can be used, but multi-element analysis is simplest by ICP-MS or ICP-OES. Both ICP techniques can measure all the regulated elements. ICP-MS has much lower DLs and provides speciation capability. ICP-OES has higher matrix tolerance and faster sample throughput.
Decision factors include:
• Sample type/dosage form; lower limits apply to drugs intended for inhalation/injection
• Amount of sample available and sample prep/dilution used (bigger dilution means lower DLs of ICP-MS are needed)
• Number of samples per day (OES handles extremely high numbers >1000/day)
• Budget, lab experience, existing methods…
24
Slide 25 © PharmOut 2017
ICP-OES
•Mainly oral dose medicines – PDE limits are higher
•Large sample volume available (e.g. bulk excipients); no dilution
•Very high throughput needed
ICP-MS
• All dosage forms: Parenteral, inhalational, or oral administration
• Small sample amounts available (e.g. APIs); large dilution needed
• Speciation for As/Hg
Factors in Instrument Selection for USP/ICH?Examples:
25
Slide 26 © PharmOut 2017
Elemental Impurity Instrumentation
5110 ICP-OES 7800 ICP-MS 7900 ICP-MS
26
Agilent
Thermo Fisher
iCAP™ 7600 ICP-OES Analyzer iCAP™ 7400 ICP-OES Analyzer
Slide 27 © PharmOut 2017
Assessing Your Lab’s RequirementsConsider the following:
Analytical requirements:
• Do you already use elemental impurities analysis techniques in your lab?
• Which regulation are you following: USP, ICH, EMA?
• Which matrices and elements do you currently measure?
• Is Hg and As speciation needed or of interest for you?
• Will you use a microwave digestion system for your sample preparation?
Compliance:
• Do you have already a compliance solution in place?
• Do you need automatic backup to a network drive or server?
• Do you have already a server available?
Methods:
• Do you have SOPs for your elemental impurities analysis technique?
• What level of expertise do your operator(s) have?
• Would you benefit from support to validate methods for your products?
27
Slide 28 © PharmOut 2017
Elemental Impurities – Lab Health Check
“How prepared are we?”
1. Risk Assessments – Equipment, raw materials, processes, PDEs, etc…
2. Test method / specification updates?
3. Instrument selection – high-performance ICP-MS and ICP-OES
4. Installation, commissioning, and qualification services
5. Comprehensive method setup and reporting tool
6. SOP for Pharmaceutical Analysis by ICP-MS / OES
7. ICH/USP standards kit plus consumables?
28
December 2017
Slide 29 © PharmOut 2017
Thank you for listening
Information supplied by:• Agilent, • Chemical Analysis, • ICH, and • FDA
Blog - https://www.pharmout.net/ready-impending-ich-q3d-elemental-impurities-compliance-requirements/
White Paper - https://www.pharmout.net/downloads/elemental-impurities-ICH-guidance.pdf