Elemental Impurities
(USP, PhEur & ICH Q3D)
Excipient Realities and
Challenges
David R. Schoneker
Director of Global Regulatory Affairs
dschoneker@colorcon.com
KNOWN
What do we know today about the levels of metal
impurities in excipients?
3
Kaolin & Talc mines
Kaolin mine near Kaznejov, Czech
Republic
Known – at least
12 to 55 ppm Lead
from periodic testing
Talc extraction in Trimouns Talc
Mine, Midi-Pyrenees, France
Known – Current USP
Spec <10 ppm Lead – only
tested once per year
www.ipecamericas.org
Current Compendia Methodologies
• Semi quantitative, non-specific for individual metals
(use Pb limit test)
• Compendial methods & metals not harmonized
USP <231>
EP 2.4.8
JP 1.07
• 3 methods described
• 8 methods described.
• 4 methods described.
• Uses Pb ref. std +
CH3C(S)NH2-glycerinebase TS
• Use of Pb ref. std +
CH3C(S)NH2 or Na2S
Reagent
• Use of Pb ref. std. +
Na2S Reagent
• Permissible limit
expressed in ppm for Pb
• Permissible limit expressed
in ppm for Pb
www.ipecamericas.org
• Permissible limit
expressed in ppm for
Pb
Trends and Implementation plans
Global desire to control metals with known toxicological concerns in
finished drug products
 Today, there are no known metal impurity issues impacting patient safety
 HOWEVER, to enhance future monitoring,
− ICH is developing Q3D Metal Impurity Guideline,
− USP proposed General Chapters <232> Elemental Impurities - Procedures and
<233> Elemental Impurities – Methods
− PhEur is implementing 2.4.20 Determination of Metal Catalyst or Metal Reagent
Residue and 5.20 Metal Catalyst or Metal Reagent Residues
 Regulators and industry need to establish a consistent/reliable set of

expectations to ensure a “right first time” approach to implementation
Regulators and industry need to carefully plan and phase-in
implementation timelines and approaches for these new requirements in
order to allow adequate preparation by suppliers and drug
manufacturers and prevent disruption of the drug supply.
www.ipecamericas.org
Elemental Impurities
Coalition for the Rational Implementation of
the USP Elemental Impurities Requirements
Coalition for the Rational Implementation of
the USP Elemental Impurities Requirements
Industry Coalition Meetings & Activities
Other trade associations and many IPEC-Americas
member companies in the United States and
Europe
ICH Q3D Guideline
 Scope  criteria and limits
− Applies to new drug products
 Excipients outside the direct scope of the guideline
 Does not include metals intentionally part of the drug product
 Approach similar to EU Metal Catalysts & Reagents; however, EU focuses on
metals utilized in the manufacturing process (catalyst) whereas USP and ICH
have extended well beyond metals utilized in the manufacturing process.
 Limits based on published safety & toxicology data
 Compendia responsible for methodology, as appropriate
 ICH advanced the proposed guideline to Step 2 in June 2013
 Guideline received through IPEC-Americas on June 20th 2013
 Step 2b Guideline published on ICH website on August 5, 2013
 Step 2b Guideline will be published in Federal Register in next few weeks
 Public comment period will occur before the guideline goes to Step 4
www.ipecamericas.org
ICH Q3D Step 2 Guideline
 Incorporates Risk Assessment, Risk Management and Risk
Mitigation concepts
 Testing is not the default; however, where necessary
−
−
−
Methods are outside the scope of ICH Q3D
Appropriate, validated analytical methods should be used
Tests should be specific for each metal (e.g. ICP-AES/ICP-MS)
 Assessments for each metal of interest based on
−
−
Permitted daily exposure (PDE) for each metal of toxicological concern
Permitted use of defined metal impurities concentrations when daily
“drug product” dose is NMT (not more than) 10 g/day
www.ipecamericas.org
Table A.2.1: Permitted Daily Exposures for Elemental impurities1
1PDEs
reported in this table are rounded to a 2 significant figures (µg/day).
Classification as defined in Section 4
3 Insufficient data to establish an appropriate PDE; the PDE was established based on platinum PDE.
2
Element
As
Cd
Hg
Pb
Co
Mo
Se
V
Ag
Au
Ir3
Os3
Pd
Pt
Rh3
Ru3
Tl
Ba
Cr
Cu
Li
Ni
Sb
Sn
Class2
1
1
1
1
2A
2A
2A
2A
2B
2B
2B
2B
2B
2B
2B
2B
2B
3
3
3
3
2
3
3
Oral PDE
μg/day
Parenteral PDE, μg/day
Inhalation PDE, μg/day
15
5.0
40
5.0
50
180
170
120
170
130
1000
1000
100
1000
1000
1000
8.0
13000
11000
1300
780
600
1200
6400
15
6.0
4.0
5.0
5.0
180
85
12
35
130
10
10
10
10
10
10
8.0
1300
1100
130
390
60
600
640
1.9
3.4
1.2
5.0
2.9
7.6
140
1.2
6.9
1.3
1.4
1.4
1.0
1.4
1.4
1.4
69
340
2.9
13
25
6.0
22
64
USP <232> and <233>
 USP was unilaterally implementing two elemental impurity general chapters
which became official on 1 Feb 2013
− Elemental Impurities - Limits <232>
 15 elements defined, some with different limits than ICH Q3D
− Elemental Impurities - Procedures <233>
 Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES)
 Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS)
 Other methods shown to be “equivalent”
 Conformance with <232> and <233> in applicable monographs was proposed for
May 1, 2014 implementation
 Based on comments received from the Coalition and other industry groups USP
has decided to delay implementation and harmonize limits and implementation
timeline with ICH Q3D – BIG INDUSTRY SUCCESS!! - MORE LATER!!
www.ipecamericas.org
PhEur 2.4.20 & 5.20
The European Pharmacopoeia Commission adopted
 general chapter
− Metal catalysts or metal reagents residues (5.20)
− Only need to test/control when used in the mfg. process
 method
− Determination of metal catalysts or metal reagent residues (2.4.20).
General approach for determination of metal catalysts or metal reagent residues in substances for
pharmaceutical use, to be applied wherever possible. Method and measurement techniques noted
include:

Atomic Emission Spectroscopy (AES)

Atomic Absorption Spectroscopy (AAS)

X-ray Fluorescence spectroscopy (XRFS)

Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES)

Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS)
Official for pharmaceutical ingredients in September 2013 - ???
13
EU PhEur 2.4.20/5.20 or ICH Q3D?
• PhEur has stated that it will harmonize with ICH
Q3D once it moves to Step 4
• Will publish it word for word in PhEur without
change (similar to Q3C - Residual Solvents)
• However, what will happen in September 2013
with implementation of 2.4.20 and 5.20?
• EMA decided to delay the requirements and
harmonize existing drug requirements with ICH
Q3D on July 24, 2013
• New drugs – still a question???
User Realities
What does this all mean to Pharma
Companies?
PhEur
2.4.20 &
5.20?
USP <232>
& <233>?
ICH Q3D ?
Excipient
Realities?
Confusion ?
www.ipecamericas.org
Realities for Implementation
 Requirements will be on the dosage form, NOT the excipients. Excipients do
not have to “comply” to Q3D!
 Many excipients contain metal impurities at the 1 to 10 ppm level.
 Many users may try to set specifications on excipients; HOWEVER, many
suppliers may NOT be willing or able to agree to excipient specifications
below those currently required to comply with monographs or other
regulatory requirements.
 Pharmaceutical companies may find it necessary to perform significant
elemental testing of excipients and/or drug products in order to determine
actual drug product impurity levels and whether they comply with final PDE
limits
www.ipecamericas.org
Realities for Implementation
 For many excipient companies their pharmaceutical business is a minor
part of their sales. Pressures for these companies to perform routine
testing or reduce specification limits could lead to:
− Cease supporting product sales to pharmaceutical industry
− Increased pricing to cover additional costs needed to address new
requirements.
 Some drug products may require changes in excipient sourcing, and
perhaps even reformulation in order to meet PDE requirements.
 Collective implementation efforts will require time to do properly.
www.ipecamericas.org
Validated Metal Impurity Realities
Today little data exists to perform a scientific risk
assessment of metal content
 Unknown Unknowns
− Most excipients have not been routinely tested; therefore, current
metal concentrations and variability is often UNKNOWN!
− Communication between pharma industry and suppliers is critical to
best understand what is known and NOT known about metal impurity
levels in excipients and APIs
 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
www.ipecamericas.org
Validated Excipient Sources
Metal content often inherent (due to sourcing)
and cannot be “easily” reduced or removed
 Plant-derived Excipients
− Grown in soil (e.g. cellulose derivatives)
− Harvested from the ocean (e.g. alginates,
carageenan)
 Synthetic Excipients
− Derived from oil through synthetic processes –
may use metal catalysts (e.g. povidone, PEG,
silicones)
 Mineral-based Excipients
− Conversion of ores from mines (e.g. TiO2)
www.ipecamericas.org
Validated Potential Normal Variation
 Many metal impurities are naturally present (e.g. lead) in mined
excipients 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
www.ipecamericas.org
Knowns – Limited Industry data
Metal impurity examples for mineral based excipients - Supplier COAs
Total
Inorganic
Pb
ppm
Hg
ppm
0.2 max
10.0 max
3.0 max
1.0 max
Supplier C
3 max
CALCIUM CARBONATE USP PRECIPITATED
Supplier D
TALC USP/FCC/EP/JP -
Item Description
Supplier/
Manufacturer
As
ppm
Ca
ppm
Cr
ppm
Cu
ppm
Ni
ppm
TITANIUM DIOXIDE,
USP/FCC/EP/JP
Supplier A
1.0 max
1.0 max
1.9 max
0.5 max
N/A
TITANIUM DIOXIDE USP/EP/JP
Supplier B
10.0 max
1.0 max
N/A
N/A
N/A
CALCIUM CARBONATE EP
1 max
10 max
N/A
N/A
N/A
N/A
N/A
N/A
3 max
0.5 max
N/A
N/A
N/A
Supplier E
3 max
N/A
10 max
N/A
N/A
N/A
N/A
TALC MICRONIZED USP/EP
Supplier F
4 max
N/A
10 max
N/A
N/A
N/A
N/A
TALC USP/EP
Supplier G
3 max
N/A
5 max
N/A
N/A
N/A
N/A
Unknowns:
The following additional metal impurities were not specifications or reported on
the Suppliers COAs: Mn, Mo, Pd, Pt, V, Os, Rh, Ru, Ir
Coalition 2012 -2013 Activities
 Called for Data for submission to ICH Q3D EWG - developed blinded
sample study with FDA to gain some limited understanding
 Designed “Information Exchange Request” (to gather data)
 Published Pharmaceutical Technology article on Elemental/Metal
Impurities
 Filed Formal Appeal with USP Requesting Withdrawal of Elemental
Impurities General Chapters and General Notices
 Established initial FDA meeting (Nov. 20, 2012) to present concerns with
USP non-harmonized approach and timeline
 Developed Tools to help support elemental impurity assessment
 Set up several Project Teams to work on collecting data to justify the use of
acid leach methodology and to assess the technical challenges in
performing appropriate ICP-MS methodologies for EI testing
www.ipecamericas.org
Information Exchange Request
Developed standardized request letter and form templates to help facilitate
industry communication between users and makers of APIs and excipients.
Template created and designed to help pharmaceutical companies:
 gather information from suppliers pertaining to potential metals/concentrations
in both APIs and excipients used in the production of drug products.
 use information from suppliers to determine potential presence / concentration
of each metal in the assessment of a finished drug product Permitted Daily
Exposure (PDE) level.
NOTE: both API and excipient manufacturers are encouraged to utilize the Information Exchange
request template form to proactively develop their own product
documentation/information.
www.ipecamericas.org
Information Exchange Request
URGENT industry need for BASE-LINE DATA!
IDEAL WORLD….
Pro-actively completed by
suppliers and sent to users
REAL WORLD…
Few suppliers have data or
will complete and return
the form to users
Templates and request letter:
http://ipecamericas.org/content/ichq3d-information-exchange-request
Formal Appeal/Comments to USP
Oct 19, 2012
Feb 1, 2013
Submitted formal appeal to
USP requesting withdrawal
of April 2012 draft Chapter
<232> & <233>
USP published <232>
and <233> and retained
May 1, 2014
implementation date
Appeal
Denied
1/25/2013
Nov 15, 2012
March 27, 2013
USP postponed publication
of <232> and <233>
pending review of industry
appeals
Comments sent to USP
concerning the May 2014
planned implementation
timeline
http://www.usp.org/usp-nf/official-text/revision-bulletins/elemental-impurities-limits-andelemental-impurities-methods
www.ipecamericas.org
USP Advisory Committees
• USP formed an Advisory Committee with two
project teams to assess next steps for
harmonization and implementation with ICH Q3D
– Experts chosen from Coalition members, FDA and
others
– Project teams have met twice and provided feedback
to USP
– USP will harmonize <232> limits with ICH Q3D and republish in 2014 (timing not yet established)
– Implementation timing TBD
– Three options under consideration – decision by
October
Elemental Impurity Assessment Tools
 Implementation Timeline Model
 PDE calculator for component metal information
− Sample formulations for dosage forms
 Examples of industry data comparing total metals
vs extractable metals.
www.ipecamericas.org
Total Metal vs Acid Leached Metal
As, Pb and Cd in Smectite Clay Excipients
As, ppm
Pb, ppm
Cd, ppm
HCl Leach*
<233> Digestion**
HCl Leach <233> Digestion HCl Leach
<233> Digestion
Purified Bentonite NF
0.4
0.7
6.9
12.9
0.03
0.08
MAS NF Type 1A
0.3
1.5
5.5
10.8
0.02
0.09
MAS NF Type 1B
<0.1
1.4
3.8
9.2
0.01
0.08
MAS NF Type 1C
0.3
2.1
4.4
10.9
0.02
0.08
MAS NF Type 2A
1.0
1.6
8.6
15.3
0.02
0.08
* Dilute HCl extraction based on the Pb test in the MAS NF monograph; ICP-MS
** Closed vessel microwave digestion with HNO3; ICP-MS
Pb analyses using Acid leach tests vs direct biorelevant simulated gastric
fluid extraction
Magnesium Aluminum Silicate NF Type 2A (Smectite Clay)
Pb, ppm
Simulated Gastric Fluid Extraction, 2hr (SGF extraction + ICP-MS)
5.9
Monograph specification test (dilute HCl extraction + AA)
9.5
HCl Leach (dilute HCl extraction + ICP-MS)
8.6
“Total” Pb content (closed vessel microwave digestion with HNO3 + ICP-MS)
15.3
Coalition Project Teams
• One team is gathering data and drafting a white paper
concerning the need to allow for bioaccessability
related test methods (acid leach) rather than just total
dissolution
– To be submitted to ICH Q3D EWG
• New team recently started to assess the technical
methodology challenges with the use of ICP-MS
methods for EI of pharmaceutical materials – possible
USP PF Stimuli article and General Chapter – looking
for interested parties!
– Testing is proving to be much more complex than
previously thought
FDA Guidance
 FDA has developed a Guidance pertaining to ICH Q3D and USP
232/233 implementation for Drug Products Marketed in the
US. Timeline for publication not known but expected soon
 Coalition members developed a list of questions (FAQs) for the
FDA to consider during guidance development and possibly
use to post a Q&A document in the future
 Preliminary draft FAQs submitted to FDA before USP
deferment – Revision was needed since USP has delayed
implementation and since ICH Q3D Step 2 guideline published
 FDA has informed the USP Advisory Committee project team
that they used the Coalition FAQs to help them revise their
draft guidance document after the USP deferment – they claim
to have addressed many of the concerns – WE WILL SEE!!
ACTIONS
Current Industry Needs
•
Complete Information exchange requests/provide available information
– Suppliers complete initial assessment for each excipient
– Users compile information from forms to determine next steps… to be used,
as available for PDE calculator and Risk Assessment
•
•
•
•
•
•
Establish / validate equipment (ICP-AES/ICP-MS) or identify external test
facility
Develop “sample preparation” and “analysis” methodologies
Train personnel
Develop base-line elemental impurity levels for each ingredient used in a
drug product – where necessary, monitor for excursions
Collaboratively work together (drug manufacturers / ingredient suppliers) to
develop (via risk assessment) future testing / reporting strategy for each
ingredient used in a drug product.
Drug manufacturers use PDE calculator and risk assessments to assure
compliance of elemental impurity levels in finished drug product formulations
32
Your Questions/Concerns
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