Update on Toxicology, PDE and Elemental Impurity Requirements for · 2018-02-14 · Potential...

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Update on Toxicology, PDE and Elemental Impurity Requirements for the EU

Presented by Jacob MacDonald, July 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


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


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


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)

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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

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<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


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


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


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


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


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.


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.


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.


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


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

• …


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


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


“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

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Implications for Instrument Selection


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.


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

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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


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

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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


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…

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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:

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Elemental Impurity Instrumentation

5110 ICP-OES 7800 ICP-MS 7900 ICP-MS

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Agilent

Thermo Fisher

iCAP™ 7600 ICP-OES Analyzer iCAP™ 7400 ICP-OES Analyzer


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


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?

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December 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

https://www.pharmout.net/ready-impending-ich-q3d-elemental-impurities-compliance-requirements/

https://www.pharmout.net/downloads/elemental-impurities-ICH-guidance.pdf

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Update on Toxicology, PDE and Elemental Impurity Requirements for · 2018-02-14 · Potential...

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