INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
`
`REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
`
`
`
`DRAFT CONSENSUS GUIDELINE
`
`
`
`GUIDELINE FOR ELEMENTAL IMPURITIES
`
`Q3D
`
`
`
`Current Step 2b version
`
`dated 26 July 2013
`
`
`
`At Step 2 of the ICH Process, a consensus draft text or Guideline, agreed by the
`appropriate ICH Expert Working Group, is transmitted by the ICH Steering
`Committee to the regulatory authorities of the three ICH regions (the European
`Union, Japan and the USA) for internal and external consultation, according to
`national or regional procedures.
`
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`
`Q3D
`Document History
`
`Current Step 2a version
`
`Code
`
`
`History
`
`Q3D
`
`Approval by the Steering Committee under Step 2a.
`
`Code
`
`Q3D
`
`Q3D
`
`Q3D
`
`Current Step 2b version
`
`
`History
`
`Approval by the Steering Committee under Step 2b
`and release for public consultation.
`
`Post sign-off corrigendum in:
`
` Table 4.1 W and Al were removed from the list of
`included elemental impurities in Class 2B and 3
`respectively.
` Table A.2.1 the Class for Ni was changed to read 3
`instead of 2.
`
`Post sign-off minor editorial corrections including:
`removal of references to Appendix 5 (pgs i & 13);
`deletion of redundant text (pg 4); change of Option 2
`to Option 2a (pg 10); insertion of omitted text under
`Safety Limiting Toxicity (pg 35); removal of
`duplicated redundant text (pg 41); replacing
`references to “metals” in text and “metal” in Table
`A.4.7 title with “elementals” and “elements” (pg 73);
`and deletion of header Table A.4.10 (pg 75).
`
`Date
`
`6 June
`2013
`
`Date
`
`6 June
`2013
`
`14 June
`2013
`
`26 July
`2013
`
`Q3D
`
`Addition of line numbers to facilitate the provision of
`comments by stakeholders.
`
`30 September
`2013
`
`
`
`
`
`Legal notice: This document is protected by copyright and may be used, reproduced, incorporated
`into other works, adapted, modified, translated or distributed under a public license provided that
`ICH's copyright in the document is acknowledged at all times. In case of any adaption,
`modification or translation of the document, reasonable steps must be taken to clearly label,
`demarcate or otherwise identify that changes were made to or based on the original document. Any
`impression that the adaption, modification or translation of the original document is endorsed or
`sponsored by the ICH must be avoided.
`The document is provided "as is" without warranty of any kind. In no event shall the ICH or the
`authors of the original document be liable for any claim, damages or other liability arising from
`the use of the document.
`The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for
`documents where the copyright vests in a third party, permission for reproduction must be
`obtained from this copyright holder.
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`GUIDELINE FOR ELEMENTAL IMPURITIES
`
`Draft ICH Consensus Guideline
`Released for Consultation on 26 July 2013, at Step 2b of the ICH Process
`
`TABLE OF CONTENTS
`
`INTRODUCTION .................................................................................................................. 1
`
`SCOPE ................................................................................................................................. 1
`
`SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES .................................... 2
`
`1.
`
`2.
`
`3.
`
`3.1 Principles of the Safety Assessment of Elemental Impurities for Oral,
`Parenteral and Inhalation Routes of Administration .................................................. 2
`3.2 Other Routes of Administration ....................................................................................... 3
`3.3 Justification for Element Impurity Levels Higher than the PDE ............................ 3
`3.4 Parenteral Products ............................................................................................................. 4
`4. ELEMENT CLASSIFICATION ............................................................................................... 4
`
`5. ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES ............................................. 5
`
`5.1 General Principles ............................................................................................................... 5
`5.2 Potential Sources of Elemental Impurities .................................................................... 6
`5.3 Assessment – Identification of Potential Elemental Impurities ............................... 7
`5.4 Assessment – Analysis and Evaluation .......................................................................... 9
`5.5 Converting Between PDEs and Concentration Limits ................................................ 9
`5.6 Assessment Summary ....................................................................................................... 11
`5.7 Control of Elemental Impurities ..................................................................................... 12
`5.8 Periodic Verification Testing ........................................................................................... 13
`5.9 Special Considerations for Biotechnologically-Derived Products ........................... 13
`6.
`SPECIATION ...................................................................................................................... 14
`
`7. ANALYTICAL PROCEDURES ............................................................................................. 14
`
`8. LIFE-CYCLE MANAGEMENT OF THE CONTROL STRATEGY FOR ELEMENTAL
`IMPURITIES ...................................................................................................................... 14
`
`9. RECOMMENDATIONS FOR SUBMISSION OF ELEMENTAL IMPURITIES CONTROL
`STRATEGY......................................................................................................................... 14
`
`REFERENCES ............................................................................................................................ 15
`
`GLOSSARY ................................................................................................................................. 16
`
`Appendix 1: Method for Establishing Exposure Limits ................................................. 20
`
`Appendix 2: Established PDEs for Elemental Impurities ............................................. 23
`
`Appendix 3: Individual Safety Assessments .................................................................... 25
`
`Appendix 4: Illustrative Example – Calculation Options for Converting PDEs to
`Concentrations ....................................................................................................................... 69
`
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`GUIDELINE FOR ELEMENTAL IMPURITIES
`
`Q3D
`
`
`1. INTRODUCTION
`
`Elemental impurities in drug products may arise from several sources; they may be
`added intentionally in synthesis, or may be present as contaminants (e.g., through
`interactions with processing equipment or by being present in components of the drug
`product) and are consequently detectable in the drug product. Since elemental impurities
`do not provide any therapeutic benefit to the patient, element impurity levels should be
`controlled within acceptable limits in the drug product. There are three components of
`this guideline: the evaluation of the toxicity data for potential elemental impurities, the
`establishment of a Permitted Daily Exposure (PDE) for each element of toxicological
`concern, and development of controls designed to limit the inclusion of elemental
`impurities in drug products to levels at or below the PDE. It is not expected that an
`applicant tightens the limits based on process capability provided that the elemental
`impurities in drug products are held at or below the PDE. The PDEs established in this
`guideline are considered to be protective of public health for all patient populations,
`including pediatric patients. In some cases, lower levels of elemental impurities may be
`needed when levels below toxicity thresholds have been shown to have an impact on
`other quality attributes of the drug product (e.g., element catalyzed degradation of drug
`substances). In addition, in the case of high PDEs, other limits may have to be
`considered from a pharmaceutical quality perspective; other guidelines should be
`consulted.
`
`Developing a strategy to limit elemental impurities in the drug product is consistent
`with risk management processes identified in ICH Q9. The process is described in this
`guideline as a four step process to assess and control elemental impurities in the drug
`product: identify, analyse, evaluate, and control.
`
`The PDE of the elements may change if new safety data become available. The guideline
`may be updated to include other elemental impurities or other routes of administration
`as new data become available. Any interested party can make a request and submit the
`relevant safety data to be considered.
`
`2. SCOPE
`
`The PDEs in this guideline have been established based on acceptable safety limits of
`potentially toxic elemental impurities. The guideline applies to new finished drug
`products (as defined in ICH Q6A and Q6B) and new drug products employing existing
`drug substances. The drug products containing: proteins and polypeptides (produced
`from recombinant or non-recombinant cell-culture expression systems), their derivatives,
`and products of which they are components (e.g., conjugates) are in the scope of this
`guideline. In addition, drug products containing synthetically produced polypeptides,
`polynucleotides, and oligosaccharides are within scope of this guideline.
`
`This guideline does not apply to herbal products, radiopharmaceuticals, vaccines, cell
`metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood
`components, crude products of animal or plant origin, dialysate solutions not intended
`for systemic circulation or drug products containing elements that are intentionally
`included for therapeutic benefit.
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`This guideline does not apply to drug products used during clinical research stages of
`development. In the later stages of development, the principles contained in this
`guideline can be useful in evaluating elemental impurities that may be present in new
`drug product prepared by the proposed commercial process.
`
`The application of this guideline to existing marketed drug products will be addressed by
`regional regulatory processes.
`
`3. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES
`
`3.1 Principles of the Safety Assessment of Elemental Impurities for Oral,
`Parenteral and Inhalation Routes of Administration
`
`The method used for establishing the PDE for each element impurity is discussed in
`detail in Appendix 1. Elements evaluated in this guideline were assessed by reviewing
`the publicly available data contained in scientific journals, government research reports
`and studies, international regulatory standards (applicable to drug products) and
`guidance, and regulatory authority research and assessment reports. This process
`follows the principles employed in ICH Q3C: Residual Solvents. The available
`information was reviewed to establish the oral, parenteral and inhalation PDEs provided
`in the guideline.
`
`A summary safety assessment identifying the critical study for setting a PDE for each
`element is included in Appendix 3. There are insufficient data to set PDEs by any route
`of administration for osmium, rhodium, ruthenium and iridium. The PDEs for these
`elements were established on the basis of their similarity to platinum. The PDEs for
`each element included in the guideline are summarized in Appendix 2, Table A.2.1.
`
`The factors considered in the safety assessment for establishing the PDE were:
`
` The oxidation state of the element likely to be present in the drug product;
`
` Human exposure and safety data when it provided applicable information;
`
` The most relevant animal study;
`
` Route of administration;
`
` Selection of the relevant endpoints or designations (e.g., International Agency for
`Research on Cancer [IARC] classification, animal carcinogenicity, reproductive
`toxicology, target organ toxicity, etc);
`
` The longest duration animal study was generally used to establish the PDE. In
`some instances, a shorter duration animal study was considered the most
`relevant study. The rationale for using the shorter duration study is provided in
`the individual PDE assessment;
`
`
`
`
`
`In the absence of data and/or where data were available but were not considered
`sufficient for a safety assessment for the parenteral and or inhalation route of
`administration, default factors (see below) were used to derive the PDE from the
`oral PDE;
`
`In inhalation drug products, soluble salts are more relevant than particulates to
`assess elemental impurity toxicity. Therefore, inhalation studies using soluble
`salts (when available) were preferred over studies using particulates for
`inhalation assessment and derivation of inhalation PDEs.
`
`In some cases, standards for daily intake for some of the elemental impurities discussed
`in this guideline exist for food, water, air, and occupational exposure. These standards
`have developed over time with different regional processes and may use different
`modifying factors or other estimates (e.g., body weight for an individual). In some cases,
`these standards are not only safety based, rather, based on practical considerations or
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`
`
`analytical capability. Where appropriate, these standards were considered in the
`assessment and establishment of the PDEs using the approach as outlined in Appendix 1.
`
`For PDEs established for inhalation (oral or parenteral routes as applicable), doses were
`normalized to a 24 hour, 7 day exposure. If data were available for local toxicity to the
`lung, those data were considered in establishing the inhalation PDE.
`
`Where data were available but were not considered sufficient for a safety assessment for
`the parenteral route of administration, modifying factors were employed as follows:
`
`Oral bioavailability <1% divide by a modifying factor of 100
`Oral bioavailability < 50% divide by a modifying factor of 10
`Oral bioavailability between 50% and 90% divide by a modifying factor of 2
`Oral bioavailability > 90% divide by a modifying factor of 1
`
`Where inhalation and/or parenteral data were available but were not considered
`sufficient for a safety assessment or Threshold Limit Value (TLV)/Time Weighted
`Average (TWA) values were not available for the inhalation route of administration, a
`calculated PDE was used based on the oral PDE divided by a modifying factor of 100
`(Ball et al. 2007). In cases where the TLV/TWA or a nonclinical inhalation study was
`used, the dose levels were normalized to a 24 hour, 7 day week.
`
`PDEs for elements of low risk to human health as impurities in drug products were not
`established. The elements in this category include: Fe, B, Al, W, Zn, K, Ca, Na, Mn, and
`Mg.
`
`For elements not included in this guideline for which there is limited or insufficient data,
`the concepts used in this guideline can be used to determine appropriate PDEs.
`
`3.2 Other Routes of Administration
`
`PDEs were only established for oral, parenteral and inhalation routes of administration.
`Sufficient data to permit the establishment of a PDE for other routes of administration
`were generally unavailable. However, the concepts applied and described in this
`guideline can be used to determine appropriate PDEs for other routes of administration.
`Application of the parenteral PDE can provide the basis of a route-specific safety
`assessment.
`
`3.3 Justification for Element Impurity Levels Higher than the PDE
`
`Levels of elemental impurities higher than the PDE may be acceptable in certain cases.
`These cases could include, but are not limited to the following situations:
`
`
`
`
`
`
`
`less than daily dosing
`
`short term exposures (i.e., 30 days or less)
`
`specific indications (e.g., life-threatening, unmet medical needs, rare diseases)
`
`Justification for increased levels in these situations should be made on a case by case
`basis justifying the proposed level using a risk based approach. ICH Q3C and this
`guideline use modifying factors for interspecies (Factor F1) and individual (Factor F2)
`variability. These modifying factors serve as starting points in extrapolating available
`data to obtain a PDE. The sub-factor approach (WHO, 2009), may be used to justify a
`higher PDE, where data are available, using knowledge of the mode of action and
`pharmacokinetic considerations. A justification may also include but is not limited to a
`consideration of the duration of the study used to set the PDE relative to the intended
`clinical use (Factor F3), the nature and severity of the toxicity observed, and whether the
`toxicity was reversible (Factor F4).
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`
`An example of the sub-factor approach can be found elsewhere in a risk assessment for
`boron (US Environmental Protection Agency [EPA], 2004).
`
`3.4 Parenteral Products
`
`The parenteral PDEs are applied irrespective of dose volume.
`
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`
`4. ELEMENT CLASSIFICATION
`
`The elemental impurities included in this guideline have been placed into categories that
`are intended to facilitate decisions during the risk assessment.
`
` Class 1 elemental impurities, As, Cd, Hg, and Pb, are significantly toxic across all
`routes of administration. Typically they have limited or no use in the
`manufacture of pharmaceuticals but can be present as impurities in commonly
`used materials (e.g., mined excipients) and can not be readily removed from the
`material. Because of their unique nature, these four elemental impurities require
`consideration during the risk assessment across all potential sources of elemental
`impurities.
`
` Class 2 elemental impurities are toxic to a greater or lesser extent based on route
`of administration. In addition, some of the elements present in this category are
`infrequently observed as impurities in materials used to produce drug products
`and as such, unless intentionally added have a low probability of inclusion in the
`drug product and do not present a significant risk. Class 2 elemental impurities
`are further categorized to establish when they should be considered in the risk
`assessment and when their contribution can be judged to be negligible.
`
`o Class 2A: The following elemental impurities require assessment across all
`potential sources and routes of administration: V, Mo, Se, and Co due to
`their higher relative natural abundance (US Geological Survey, 2005).
`
`o Class 2B: The following elemental impurities require assessment across
`potential elemental impurity sources only if they are intentionally added
`to the processes used to generate the material under evaluation: Au, Tl,
`Pd, Pt, Ir, Os, Rh, Ag and Ru.
`
` Class 3 elemental impurities are impurities with relatively low toxicity (high
`PDEs) by the oral route administration but require consideration in the risk
`assessment for other routes of administration (e.g., inhalation and parenteral
`routes). For oral routes of administration, unless these elements are intentionally
`added as part of the process generating the material, they do not need to be
`considered during the risk assessment. For parenteral and inhalation products,
`the potential for inclusion of these elemental impurities should be evaluated
`during the risk assessment. The elemental impurities in this class include: Sb,
`Ba, Li, Cr, Cu, Sn, and Ni.
`
` Class 4 elemental impurities are elemental impurities that have been evaluated
`but for which a PDE has not been established due to their low inherent toxicity
`and/or regional regulations. If these elemental impurities are present or included
`in the drug product they are addressed following the practices defined by other
`guidelines and regional regulation. The elements in this class include: Al, B, Fe,
`Zn, K, Ca, Na, Mn, Mg, and W.
`
`The classification system is summarized in Table 4.1.
`
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`184
`
`Table 4.1: Elemental Impurity Classification
`
`
`Guideline for Elemental Impurities
`
`
`
`Class 1
`
`
`Class 2A
`
`Class 2B
`
`Class 3
`
`Class 4
`
`Included Elemental
`Impurities
`As, Pb, Cd, Hg
`
`Include in Risk
`Assessment?
`Yes
`
`V, Mo, Se, and Co
`
`Yes
`
`Ag, Au, Tl, Pd, Pt, Ir,
`Os, Rh, and Ru
`
`Yes only if intentionally
`added
`
`Sb, Ba, Li, Cr, Cu, Sn,
`Ni
`
`Dependent upon route
`of administration – see
`Class 3 description
`
`B, Fe, Zn, K, Ca, Na,
`Mn, Mg, W, Al
`
`
`No
`
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`
`5. ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES
`
`In developing the control strategy for elemental impurities in drug products, the
`principles of quality risk management, described in ICH Q9, should be considered. The
`risk assessment should be based on scientific knowledge and principles. It should link
`patient safety considerations with an understanding of the product and
`its
`manufacturing process (ICH Q8 and Q11). In the case of elemental impurities, the
`product risk assessment would therefore be focused on assessing the levels of elemental
`impurities in a drug product in relation to the PDEs presented in this guidance.
`Information for this assessment includes but is not limited to: data generated by the
`applicant,
`information supplied by drug substance, reagent and/or excipient
`manufacturers or data available in published literature.
`
`The applicant should document the assessment and control approaches in an appropriate
`manner. The level of effort and formality of the assessment should be proportional to the
`level of risk. It is neither always appropriate nor always necessary to use a formal risk
`management process (using recognized tools and/or formal procedures, e.g., standard
`operating procedures.) The use of informal risk management processes (using empirical
`tools and/or internal procedures) can also be considered acceptable. Tools to assist in the
`risk assessment are described in ICH Q9 and will not be presented in this guideline.
`
`5.1 General Principles
`
`For the purposes of this guideline, the assessment process can be described in four steps:
`identify, analyse, evaluate and control. In many cases, the steps are considered
`simultaneously. For example, the analyse and evaluate steps may be iterative steps that
`initiate adjustments to control elements. The outcome of the assessment may be the
`result of iterations to develop a final approach to ensure the potential elemental
`impurities do not exceed the PDE.
`
`Identify:
`
`Analyze:
`
`Identify known and potential sources of elemental impurities that may
`find their way into the drug product.
`
`Determine the probability of observance of a particular elemental impurity
`in the drug product.
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`Evaluate:
`
`Control:
`
`Compare the observed or predicted levels of elemental impurities with the
`established PDE.
`
`Document and implement a control strategy to limit elemental impurities
`in the drug product.
`
`5.2 Potential Sources of Elemental Impurities
`
`In considering the production of a drug product, there are several broad categories of
`potential sources of elemental impurities.
`
` Residual elemental impurities resulting from elements intentionally added to
`reactions or processes leading up to the preparation of the drug substance,
`reagents, starting materials or excipients (e.g., metal catalysts).
`
` Elemental impurities known or suspected of being present in the drug substance,
`reagents, water, starting materials or excipients used in the preparation of the
`drug product.
`
` Elemental impurities known or suspected of being introduced into the drug
`substance and/or drug product from manufacturing equipment.
`
` Elemental impurities that are known or suspected of being leached into the drug
`substance and drug product from container closure systems.
`
`The following diagram shows an example of typical materials or components used in the
`production of a drug product. Each of these materials or components may contribute
`elemental impurities to the drug product, through any individual or any combination of
`the potential sources listed above. During the assessment, the potential contributions
`from each of these materials or components should be considered to determine the
`overall contribution of elemental impurities to the drug product.
`
`237
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`243
`
`
`* The risk of inclusion of elemental impurities can be reduced through process
`understanding, equipment selection, equipment qualification and Good Manufacturing
`Practice (GMP) processes.
`
`** The risk of inclusion of elemental impurities from water can be reduced by complying
`with compendial
`(e.g., European Pharmacopoeia, Japanese Pharmacopoeia, US
`
`
`
`6
`
`Manufacturing
`equipment *
`
`Drug
`Substance
`
`Elemental
`impurities
`in drug
`Product
`
`Water **
`
`Container
`Closure
`System
`
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`Pharmacopeial Convention) water quality requirements, if purified water or water for
`injection is used in the process(es).
`
`5.3 Assessment – Identification of Potential Elemental Impurities
`
`Class 1 elemental impurities: Due to their inherent toxicity, the risk assessment
`should include an assessment of the Class 1 elemental impurities. All potential sources
`of elemental impurities should be evaluated for the potential to transfer the Class 1
`elemental impurities to the drug product.
`
`Potential elemental impurities derived from intentionally added catalysts or
`reagents: For this category, the identity of the potential impurities is known and
`techniques for controlling the elemental impurities are easily characterized and defined.
`The predominant elemental impurities that comprise this group are the Class 2 and 3
`elemental impurities. Table 5.1 shows the suggested consideration in the risk
`assessment for each of the elemental impurities covered in this guideline. As identified,
`if any (Class 1, 2, or 3) elemental impurity is added, it should be considered in the risk
`assessment.
`
`Potential elemental impurities with a relatively high abundance and/or are
`impurities in excipients or reagents: Elemental impurities known or suspected of
`being present in the drug substance, reagents, starting materials or excipients used in
`the preparation of the drug product should be considered. These elemental impurities
`are often associated with mined materials and excipients. The presence of these
`impurities can be variable, especially with respect to mined excipients, which can
`complicate the risk assessment. The variation should be considered when establishing
`the probability for inclusion in the drug product. The elemental impurities that are of
`most significant to this potential source include the Class 1 and Class 2A elemental
`impurities (see Table 4.1). For parenteral and inhalation routes of administration, the
`risk assessment should evaluate the probability for inclusion of the Class 1 and most 3
`elemental impurities as shown in Table 5.1.
`
`Potential elemental impurities derived from manufacturing equipment: The
`contribution of elemental impurities may be limited and the subset of elemental
`impurities that should be considered in the risk assessment is relatively small and is
`dependent on the equipment involved. Application of process knowledge, selection of
`equipment, equipment qualification and GMP controls ensure a low contribution from
`manufacturing equipment. The specific elemental impurities of concern should be
`assessed based on knowledge of the composition of the components of the manufacturing
`equipment. The assessment of this source of elemental impurities is one that can be
`utilized potentially for many drug products using similar process trains and processes.
`
`Elemental impurities leached from container closure systems: Identifying the
`potential elemental impurities extracted from container closure systems should be based
`on a scientific understanding of likely interactions between a particular drug product
`type and its packaging. When a review of the materials of construction demonstrates
`that the container closure system does not contain elemental impurities, no additional
`assessment needs to be performed. It is recognized that the probability of elemental
`leaching into solid dosage forms is minimal and does not require further consideration in
`the assessment. For liquid and semi-solid dosage forms there is a higher probability that
`elemental impurities could leach from the container closure system into the drug product
`during the shelf-life of the product. Studies to understand potential extractables and
`leachables from the final/actual container closure system (after washing sterilization,
`irradiation) should be performed.
`
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`7
`
` P. 11
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`UT Ex. 2043
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

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`308
`
`Guideline for Elemental Impurities
`
`Factors that should be considered (for liquid and semi-solid dosage forms) include but are
`not limited to:
`
` Hydrophilicity/hydrophobicity
`
`
`
`Ionic content
`
` pH
`
` Temperature (cold chain vs room temperature and processing conditions)
`
` Contact surface area
`
` Container/component composition
`
` Terminal sterilization
`
` Packaging process
`
` Component sterilization
`
` Migration potential
`
` Duration of storage
`
`
`
`Inclusion of metal chelating agents in the formulation (e.g., Ethylenediamine
`Tetraacetic Acid [EDTA]).
`
`Table 5.1: Recommendation for Consideration During Risk Assessment
`
`Element Class
`
`
`As
`Cd
`Hg
`Pb
`Co
`Mo
`Se
`V
`Ag
`
`Au
`Ir
`Os
`Pd
`Pt
`Rh
`Ru
`Tl
`Ba
`Cr
`Cu
`Li
`Ni
`Sb
`Sn
`
`
`
`1
`1
`1
`1
`2A
`2A
`2A
`2A
`2B
`
`2B
`2B
`2B
`2B
`2B
`2B
`2B
`2B
`3
`3
`3
`3
`3
`3
`3
`
`If intentionally
`added (across
`all routes of
`administration)
`
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`
`yes
`yes
`yes
`yes
`yes
`yes
`