The document discusses guidelines for controlling elemental impurities in active pharmaceutical ingredients (APIs) according to new regulatory requirements. It provides an overview of: 1) Background guidelines from various regulatory agencies on limiting elemental impurities. 2) Reasons for the new requirements to replace heavy metal testing, including difficulties with reproducibility and safety of current methods. 3) Classification of elemental impurities based on toxicity and permissible intake limits set by the ICH. It also outlines procedures for method development, validation, and implementation of elemental impurity testing and control as defined in USP general chapters 232 and 233.

1. Implementation of Elemental
Impurities in APIs
Dr. A. Amsavel

2. Content
• Introduction
• Guidelines on elemental impurities
• Background for new requirement
• Standard / Limit
• Procedure & instrument
• Method development & validation
• Implementation

3. General Notices USP 38—NF 33
• General chapters <232> was published June 1, 2012, in the Second
Supplement to USP 35 to effect from Feb 1, 2013 and deferred.
• As per USP37 Sup-2, General Notices provision becomes official
from January 1, 2018.
– Elemental impurities has to be controlled in official drug products
according to the principles defined and requirements standard specified
in Elemental Impurities—Limits <232>, Also see <232> for information
related to drug substances and excipients.
• But It is expected for drug substances and excipients.

4. USP on Elemental Impurities
 USP General Chapter <231> Background and issues
 Toxicology considerations
 Chapter <232> - Elements and Limits
 Chapter <233> - Procedures
 Implementation Plans

5. Guidelines
1. Guideline On The Specification Limits For Residues Of Metal
Catalysts Or Metal Reagents ; EMEA/CHMP/SWP/4446/2000;
21 February 2008
2. ICH Guideline- Q3D on Elemental Impurities (Step-4;
16 December 2014)
3. CDER adopted ICH: Q3D Elemental Impurities-Guidance for
Industry; September 2015
4. EMA adopted ICH :EMA/CHMP/ICH/353369/2013- 25 August
2015

6. Why this new requirement
Presently, there is a test for Heavy metals; then why
regulatory/ standard setting agencies are insist for
revision
Is this change required?
• As a professional in Industry
• As consumer

7. Disadvantages of Heavy metal test:
Presently Heavy metal test is being followed, but there are disadvantages :
• Difficulties in reproducibility
– Colour of solution is subjective,
– standards change with time;
– recovery issues
• Difficulties with reagents – safety issues
–All procedures generate H2S (including Thioacetamide) and H2S more toxic than
cyanide
–Thioacetamide is not allowed in several countries
• Non-discriminatory screening test
–Not element specific
–Sensitivity varies by element
–Only a few elements respond at required sensitivities

8. Disadvantage of Heavy Metals test

9. Key Elements under heavy metals
• As, Cd, Pb, Hg are clasifed as key /major
elements under heavy metals
• Heavy metals are classified based on toxicity
• ICH classified as class-1, 2 & 3

10. Toxicology
• Approach to elemental impurity control that is
both health based and risk based
• Control metals that are toxic
• Setting limits that are toxicologically relevant
• At all times during a drug product’s shelf life
• Risk-based approach -what is to be tested and
when to test

11. Dose Levels and Toxicity
–NOEL: No-Observed Effect Level
–NOAEL: No-Observed-Adverse Effect Level
–LOAEL: Lowest-Observed-Adverse Effect Level
–MTD : Maximum Tolerated Dose
–LD50: Lethal Dose to 50% of population
Increasingdose
Safe
Less safe

12. Reference Dose (RfD)
(toxic level)
• An estimate of the daily dose of a chemical that
will avoid toxic effects other than cancer
• NOAEL or LOAEL is adjusted by uncertainty
factors (UF) to allow for differences in sensitivity
to chemicals
–Human data UF = 10
–Animal data UF: –100 (NOAEL)
–1000 (LOAEL)
–1000 (NOAEL, less data)

13. PDE Calculation
RfD = NOAEL/UF
Eg. NOAEL is 10 μg/kg/day based on human data
UF=10:
RfD = 10μg/kg/day (NOAEL)/10 (UF) = 1μg /kg/day
RfD is used to calculate Permissible Daily Exposure
(PDE)
(RfD X Weight) = PDE
PDE Example: 50 kg person and RfD = 1 μg/kg/day:
PDE = 1 μg/kg/day X 50 kg = 50 μg/day

14. PDE Calculation
What if only LOAEL or limited NOAEL is available
RfD = NOAEL/UF
Eg.: NOAEL = 10 μg/kg/day based on animal data
UF=1000:
RfD = 10 μg/kg/day (NOAEL)/1000(UF) = 0.01 μg/kg/day
RfD is used to calculate Permissible Daily Exposure (PDE)
(RfD X Weight) = PDE
PDE Example: 50 kg person and RfD = 0.1 μg/kg/day:
PDE = 0.1 μg/kg/day X 50 kg = 0.5 μg/day

15. Elemental Impurities-Limits <232>
• Implementation of Chapters <232> and <223>
• Omission of Chapter <231> Heavy Metals
• Elemental Impurities:
– Scope and application
– Elemental Impurities
• Implementation :
– Drug Product Analysis Option
– Summation Option
– Individual Component Option

16. General Notices USP 37—NF 32 Suppl- 2
• “Elemental impurities to be controlled in official drug
products according to the principles defined and
requirements standard”.
Scope:
• This General Chapter specifies limits for the amounts of
elemental impurities in drug products.
• The limits presented in this chapter do not apply to excipients
and drug substances, except where specified in this chapter or
in the individual monographs. However, elemental impurity
levels present in drug substances and excipients must be
known and reported.

17. General Chapter <232> Basics
• Applies to drug products
– Drug substances
– Excipients
• Does not apply to dietary supplements
• Does not apply to veterinary products
• Does not apply to Dialysates and Total Parenteral
Nutritions (TPN)
• Does not apply to vaccines
• Speciation is not addressed in this Chapter
• Procedures are specified in <233>

18. Elemental Impurities compliance
Options available for determination of drug product:
• Drug Product Analysis Option
• Summation Option
• Individual Component Approach for LVP
Drug Product Analysis Option is Generally Applicable / well acceptable
Determination & Calculation:
–The results obtained from the analysis of a typical dosage
unit scaled to a maximum daily dose.
–Daily Dose PDE > measured value (μg/g) x maximum daily
dose (g/day)

19. Source of Elemental Impurities
• Environmental contaminants
• Catalysts
They may be:
– Naturally occurring – minerals , Hyflo
– Added intentionally - Catalyst
– Introduced inadvertently
–Through interactions with processing equipment
–Through non-GMP routes - Reagents , early stage material
• Elemental Impurities are
– known to be present,
– have been added, or
– have the potential for introduction,
– A risk-based control strategy may assure compliance.
– compliance with the limits is required for all drug products at all
times.

20. Default Concentration Limits for Drug
Substances
Element
Concentration
Limits (mg/g) for
Oral Drug
Products with a
Maximum Daily
Dose of £10 g/day
Concentration Limits
(mg/g) for Parenteral
Drug Products with a
Maximum Daily Dose of
£10 g/day
Concentration
Limits (mg/g) for
Inhalational
Maximum Daily
Dose of £10 g/day
Cadmium 2.5 0.25 0.15
Lead 0.5 0.5 0.5
Inorganic arsenic0.15 0.15 0.15
Inorganic mercury1.5 0.15 0.15
Iridium 10 1.0 0.15
Osmium 10 1.0 0.15
Palladium 10 1.0 0.15
Platinum 10 1.0 0.15
Rhodium 10 1.0 0.15
Ruthenium •10• (ERR 1-Oct-2012)•1.0• (ERR 1-Oct-2012)•0.15• (ERR 1-Oct-2012)
Chromium —a —a 2.5
Molybdenum 10 1.0 •1.0• (ERR 1-Oct-2012)
Nickel 50 5.0 0.15
Vanadium •10• (ERR 1-Oct-2012)•1.0• (ERR 1-Oct-2012)•3.0• (ERR 1-Oct-2012)
Copper 100 10 •10• (ERR 1-Feb-2013)

21. Classification as per ICH Q3D
• Class 1: The elements, As, Cd, Hg, & Pb, are human toxicants; testing
should only be applied when the risk assessment identifies
• Class 2: Elements in this class are generally considered as human
toxicants are route-dependent;
– Class 2A elements have relatively high probability of occurrence in
the drug product. Elements are: Co, Ni and V.
– Class 2B elements have a reduced probability of occurrence in the
drug product related to their low abundance and low potential
– they may be intentionally added during the manufacture.
Elements : Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl.
• Class 3: The elements in this class have relatively low toxicities. The
elements in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn.
• Asses if high PDEs, generally > 500 μg/day.

22. Elements to be Considered in the
Risk Assessment-ICH
Element Class
If
intentionally
added (all
routes)
Oral Parenteral Inhalation
Cd 1 yes yes yes yes
Pb 1 yes yes yes yes
As 1 yes yes yes yes
Hg 1 yes yes yes yes
Co 2A yes yes yes yes
V 2A yes yes yes yes
Ni 2A yes yes yes yes
Tl 2B yes no no no
Au 2B yes no no no
Pd 2B yes no no no
Ir 2B yes no no no
Os 2B yes no no no
Rh 2B yes no no no
Ru 2B yes no no no
Se 2B yes no no no
Ag 2B yes no no no
Pt 2B yes no no no
Li 3 yes no yes yes
Sb 3 yes no yes yes
Ba 3 yes no no yes
Mo 3 yes no no yes
Cu 3 yes no yes yes
Sn 3 yes no no yes
Cr 3 yes no no yes
If not intentionally added

23. Limits as per ICH
Element Class2 Oral PDE μg/day Parenteral PDE, μg/day Inhalation PDE,μg/day
Cd 1 5 2 2
Pb 1 5 5 5
As 1 15 15 2
Hg 1 30 3 1
Co 2A 50 5 3
V 2A 100 10 1
Ni 2A 200 20 5
Tl 2B 8 8 8
Au 2B 100 100 1
Pd 2B 100 10 1
Ir 2B 100 10 1
Os 2B 100 10 1
Rh 2B 100 10 1
Ru 2B 100 10 1
Se 2B 150 80 130
Ag 2B 150 10 7
Pt 2B 100 10 1
Li 3 550 250 25
Sb 3 1200 90 20
Ba 3 1400 700 300
Mo 3 3000 1500 10
Cu 3 3000 300 30
Sn 3 6000 600 60
Cr 3 11000 1100 3

24. Calculation
–The results obtained from the analysis shall be calculated to
maximum daily dose.
–Daily Dose PDE > measured value (μg/g) x max. daily dose
(g/day)
Example
1. 500 mg Tablet used Once a day dosing . Measured content of arsenic of
0.75 μg/g of tablet contents
1.5 μg/day (PDE limit) > 0.75 μg/g x 0.5 g/day x 1 (0.375 μg/day)
2. 1g Tablet used thrice a day dosing . Measured content of lead 2μg/g of
tablet contents
Is Tablet meet the requirement or fails

25. Compendial Procedures
• Procedure 1: Can be used for elemental impurities
generally amendable to detection by ICP-AES/OES
• Procedure 2: Can be used for elemental
impurities generally amendable to detection by
ICP-MS.
• Verification: Meets Procedure Validation
Requirements

26. Implementation of Elemental Impurities
 Why <231> cannot be validated
 Choosing the appropriate instrument
 Qualifying the lab
 Determining which elements need to be validated
 Setting specifications
 Method development
 Method validation

27. Elemental Impurities - Procedures <233>
Definitions
Compendial Procedures
–Procedure 1: ICP-OES
–Procedure 2: ICP-MS
Validation
–Limit Procedures
–Quantitative Procedures
Calculations and Reporting

28. Analysis of Metal Residues as per EP 2.4.20
• Describes general approach for determination of metal
catalyst or metal reagent residues in substances for
pharmaceutical use.
• System suitability needs to be demonstrated
• Validation required for non-monograph procedures
• Sample preparation, detection limit technique,
instrument parameters is responsibility of the user
• Allows AAS, XRF, ICP-AES, ICP-MS

29. Analysis of Metal Residues as per EP 2.4.20
• Sample Preparation
– Aqueous of dilute nitric acid solutions
– Hydrogen peroxide, hydrochloric acid, sulfuric acid, perchloric
acid, hydrofluoric acid
– Dilute bases
– Organic solvents
– Digestions
• Hot-plate
• Microwave-assisted digestions
• Can be open-vessel if supported by spiking studies
• Acceptance criterion for preparation of sample solution: a clear
solution is obtained.

30. Analysis of Metal Residues as per EP 2.4.20
Measurement
–Acceptance criteria for measurement system: measured
concentration of standard solution does not differ from actual
concentration by NMT 20%
Quantitative Validation
–Specificity
–Range
–Accuracy – Recovery
–Repeatability
–Intermediate Precision
–Limit of Quantification
–Limit of Detection (Limit test only)

31. Elemental Impurities – Procedure USP <233>
Sample Preparation:
• Neat or dilute as per analysis range
• Direct aqueous solution – Sample is soluble in dilute acids and
bases
• Direct organic solution – Sample is soluble in an organic solvents
• Indirect solution/Closed vessel digestion – Digestion is required
using concentrated acids
• Incomplete digestion: should dissolve majority of sample
– Supported by spiking – if after filtration or centrifuge, recoveries are
within limits set in USP <233>
– Prepare appropriate ref (SRM) to matrix, values should be within COA
• Leachate extraction can be justified
• Total metal extraction is preferred

32. Instrument for Elemental analysis
• ICP-AES
• ICP-OES
• ICP-MS

33. ICP-OES and ICP-AES
Advantages
–Dynamic range: 10^6-10^8
–Ability to analyze multiple elements at one time
–Ability to perform a scan
–Able to analyze samples with high dissolved solids without
significant signal suppression
–Precision: RSD < 5%
Disadvantages
–Higher detection limits
–Spectral interferences
–Consumes 2 – 5 mL of sample preparation

34. Elemental Impurities – Procedure
Procedure I: ICP-AES, ICP-OES and Procedure II: ICP-MS
–Standardization solution 1: 1.5J of the Target elements in a Matched
matrix
–Standardization solution 2: 0.5J of the Target elements in a Matched
matrix
–Prepare a matrix matched blank
–Sample solution: Prepare/dilute the sample to obtain a final
concentration of Target elements at 1.5J.
J = The concentration (w/w) of the element t at the Target limit, appropriately diluted
to the working range of the instrument.
Note: Dilutions will be required if sample concentration exceeds 1.5J.
Analyze in accordance with manufacturer’s suggestions
–System suitability requirements – Tuning the instrument
–Suggested wavelengths

35. Elemental Impurities – Procedure
Procedure I: ICP-AES, ICP-OES and Procedure II: ICP-MS
Analysis:
• Standardization standard solution 1, Standardization standard
solution 2, and Blank
• Evaluate system suitability (after tuning)
Note: Confirm the standards prepared correctly? & background of the
instrument clean enough for use
• If system suitability has been met – Analyze the Sample
solution(s)
• –Drift: Analyze standardization solution 1 (1.5J) after Sample
solutions
• Suitability criteria: NMT 20% drift for each Target element

36. Method Development
Sample preparation used should yield a clear solution if at all possible
• If solubility of sample is known, dissolve & dilute to get desired level
• If solubility is unknown:
• –Dissolve in dilute acid solution (1 – 5%) / Dissolve in organic solvent
– Ensure solvent is not contaminated with elements of interest
• Digest the sample in an open-vessel / Hot block or microwave
– Needs to be supported by spiking studies to address possible loss of volatile
elements
• Digest samples in a closed-vessel microwave
– Digestion tubes may need to be pre-screened prior to use
– Keep acid concentration low in sample prep, if possible.
• suggest <5% for nitric, hydrochloric and <2% for hydrofluoric
• Dissolve in dilute base solution (<10%)
– Stability of metals needs to be established
– Bases may not be appropriate for all elements

37. Method Development
Prepare sample at a dilution to the desired level
– Example: Specification is 0.5 μg/g for Pb – Limit Test
• Instrument detection limit is 0.1 μg/L
• Detection limit of 0.25 μg/g is needed
• A maximum dilution factor of 2500x will be required
– Example: Specification is 0.5 μg/g for Pb –
Quantitative Method Validation
• Instrument detection limit is 0.1 μg/L
• Detection limit of 0.125 μg/g is needed (based on 50% spike at
0.25 μg/g)
• A maximum dilution factor of 1250x will be required

38. Method Development
• Prepare a sample, replicates, spike, spiked replications; use individual
sample portions for each preparation
– Spike the matrix spike and matrix spiked replicates at the specifications prior
to sample preparation
– If spiking for a wide range of specifications (ex. 0.5 μg/g – 100 μg/g)
• Prepare sample to obtain detection limits low enough for 0.5 μg/g
• Dilute this sample preparation to bring the 100 μg/g spike within the linear range of the
standards
• Spike recoveries need to be:
– Limit test: 85 – 115% and RSD < 20% between sample and spike preparations
– Quantitative method validation: 70 – 150% and RSD < 20% between sample
and spike preparations
• LOQ satisfied by meeting the Accuracy requirements
• Internal standard responses should not be suppressed or enhanced
– Recoveries of 50 -125% are suggested, but may vary based on specific method
– May need to evaluate sample preparation and use an alternative prep or
technique

39. Method Development
Decide on a limit test or a quantitative method validation, if
not specified in monograph
Limit test
– Applicable when the elements of interest are not detected
or trend at levels well below the specification
– Raw materials where catalysts are not used in
manufacturing
Quantitative method validation
– Applicable when elements of interest trend above the limit of
quantitation, especially when they are close to the specification
– Data needs to be trended
• Draft a method validation protocol for review by all
parties involved

40. Method Validation
• Limit Procedures
– Detectability
– Precision (Repeatability)
– Specificity
• Quantitative Procedures
– Accuracy
– Precision
– Repeatability
– Ruggedness (Intermediate Precision)
– Specificity
– Limit of Quantitation, Range, and Linearity—satisfied by
meeting Accuracy requirement

41. Method Validation
Limit Procedures
Detectability
• Spiked sample solution 1: Prepare sample:
– Spike at the target concentration (100%) for each target element
– Spike prior to sample preparation
– Analyze in triplicate
• Spiked sample solution 2: Prepare sample:
– Spike at the 80% of target concentration for each target element
– Spike prior to sample preparation
• Standard solution: Prepare working standard for the target element(s) at target
concentrations
– Analyze in triplicate
• Unspiked sample solution: Prepare an unspiked sample aliquot
Acceptance criteria: average of triplicate measurements of Spiked sample solution 1 is
within ±15% of the average of triplicate measurements of Standard solution

42. Method Validation
Limit Procedures
• Precision (Repeatability)
Sample solution (spiked) Prepare:
– Six independent sample preparations
– Spike each at the target concentration (100%) for each
target element
– Spike prior to sample preparation
Acceptance criteria: RSD NMT 20% for each Target element
• Specificity:
– Unequivocally assess each Target element in the presence
of components that may be expected to be present,
including other Target elements, and matrix components

43. Method Validation
• Limit Procedures
• Specificity (example ICP-OES, ICP-AES)
– Spectral interferences may be caused by background emission
from continuous or recombination phenomena, stray light or
overlap of spectral lines from another element or unresolved
overlap of molecular band spectra. "subarray" on the CID
detector.
– A metals screen/scan analysis performed on this material
demonstrated that the sample does/does not contain
appreciable concentrations of any element that are likely to
cause interferences on the analytes of interest. Discuss specific
elements with the potential to cause interference and how they
will be monitored or addressed.

44. Method Validation
Quantitative Procedures
• Accuracy
– Standard solution: Prepare working standard for the elements of
interest at target concentrations ranging from 50% to 200% of J
– Test solution: Prepare sample:
• Use the method developed
• Spike at target concentrations of 50% to 200% of J for each target
element
• Prepare three replicates at each concentration
• Spike prior to sample preparation
– Acceptance criteria: 70% - 150% for the mean of three replicate
preparations at each concentration

45. Method Validation
Quantitative Procedures
Precision (Repeatability)
• Test solution: Prepare sample:
– Six independent sample preparations
– Spike at target concentrations (J) for each target element
– Spike prior to sample preparation
• Acceptance criteria: RSD NMT 20% for each Target element
Precision (Ruggedness)
• Perform Repeatability analysis over three independent events using
the following events or combinations thereof:
– on different days, or
– with different instrumentation, or
– with different analysts
• Acceptance criteria: RSD NMT 25% (N=12) for each Target element

46. Method Validation
Quantitative Procedures
• Specificity (refer to slide for limit test)
• Limit of Quantitation, Range, and Linearity
–Demonstrated by meeting the Accuracy
requirements (at 0.5 J)

47. Establishing In-house Lab
Purchase appropriate instrumentation
Purchase apparatus to assist in sample digestion
• Hot block with polypropylene disposable digestion vessels : 50 mL /
15 mL – limited sample size available
• Microwave system with digestion vessels : 50 mL /15 mL
– Quartz – most appropriate for screen
– Teflon – resistant to hydrofluoric acid
– Borosilicate – disposable, may not be clean enough for trace levels
Purchase
– High Purity Acids (nitric, hydrochloric, hydrofluoric, sulfuric, perchloric)
– Hydrofluoric, Perchloric
–Bases
– Ammonium hydroxide , Sodium hydroxide ., CFA-C, TMAH

48. Preparedness for implementation
• Standards (NIST traceable)
– Single element for spiking at varying specifications
– Multi-element
– Custom multi-element for specification levels
– Single element standards for internal standards
– Second source standards for verification
• Plastic bottles or vials for sample preparation
• Gases : Argon, hydrogen, helium gases
• Highest purity – Ultrapure grade , Low krypton content
– Use stainless steel gas lines, avoid aluminum and copper

49. Preparedness for Contract Lab
Audit the lab for cGMP compliance/FDA / appropriate approvals;
• Each material shall require its own validation
• System suitability can be established with daily tune for ICP-OES,
• ICP-OES and ICP-MS have a wide dynamic range, single standard
analysis at 0.5J and 1.5J are sufficient, do not need to analyze 5
standards
• Not all elements listed in the chapters will need to be validated for
every material
– As, Cd, Pb, Hg needs to be validated, at a minimum
– If catalysts are not used validation is not required
– Strongly suggest incorporating ICH Class 2A elements in minimum
evaluation, as well

50. Preparedness for Contract Lab
• Audit the contract lab for suitability of resources and compliance
• Provide all information related to product
• Solubility , handling & storage
• Set specifications, work appropriate dilution/ concentration
• Ensure to full metals scan at time of method development, so that
• Communicate which elements require method validation based on
risk assessment
• Submit samples in plastic bag/containers to avoid metal
contaminant ion
• Ensure sufficient samples for development & method validation
• Prepare or review and approve method validation protocol and
Review and approve the report.

51. Summary
Heavy Metals <231> must be replaced
USP chapters <232> and <233>,
Elemental Impurities – Limits <232>
–Toxicological basis for limits
–Options to determine compliance
–Limits (aligned to ICH- Q3D)
Elemental Impurities – Procedures <233>
–Two compendial procedure
–Limit Test and Quantitative procedures
– Sample preparation
– Method development
– Method validation
Working with contract Lab

52. Q&A
1. What are the elements need to be shown in
the analysis
1. Big Four
2. Catalysts used in the process
3. All the elements present in <232>
4. Elements present as per the process only
5. Elements present in the drug product as per the
process

53. Q&A
2) In the manufacturing process, there are no
catalysts used and there is no possibility of any
elemental impurity present.
What are the elements to be shown in the analysis?
1. Big Four
2. All the elements present in <232>
3. Elements present in the drug product as per the process
4. No element is required

54. Q&A
3) What is the preferred way to determine the
elemental impurities in the drug product.
1. Analysis of drug product
2. Individual components of product
3. Both
4. None

55. Answer
• Q-1
– Ans: (1), (2), (5)
• Q-2
– Ans: (1), (3)
• Q-3
– Ans: (1)