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`Q3D Elemental Impurities
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`Guidance for Industry
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`U. S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
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`September 2015
`ICH
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`Q3D Elemental Impurities
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`Guidance for Industry
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`Additional copies are available from:
`
`Office of Communications, Division of Drug Information
`Center for Drug Evaluation and Research
`Food and Drug Administration
`10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
`Silver Spring, MD 20993
`Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
`Email: druginfo@fda.hhs.gov
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
`
`or
`
`Office of Communication, Outreach and Development
`Center for Biologics Evaluation and Research
` Food and Drug Administration
`10903 New Hampshire Ave., Bldg. 71, Room 3128
`Silver Spring, MD 20993
`Phone: 800-835-4709 or 240-402-7800
`ocod@fda.hhs.gov
`http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
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`
`
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`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`September 2015
`ICH
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`TABLE OF CONTENTS
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`
`
`I.
`INTRODUCTION (1) ....................................................................................................... 1
`SCOPE (2).......................................................................................................................... 2
`II.
`SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES (3) ......... 2
`III.
`A. Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and
`Inhalation Routes of Administration (3.1) ................................................................................... 2
`B. Other Routes of Administration (3.2) .......................................................................................... 4
`C. Justification for Elemental Impurity Levels Higher Than an Established PDE (3.3) ............. 4
`D. Parenteral Products (3.4) .............................................................................................................. 5
`IV.
`ELEMENT CLASSIFICATION (4) ............................................................................... 5
`V.
`RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES (5) ........ 7
`A. General Principles (5.1) ................................................................................................................. 7
`B. Potential Sources of Elemental Impurities (5.2) .......................................................................... 7
`C.
`Identification of Potential Elemental Impurities (5.3) ................................................................ 8
`D. Recommendations for Elements to be Considered in the Risk Assessment (5.4) ................... 10
`E. Evaluation (5.5) ............................................................................................................................ 10
`F. Summary of Risk Assessment Process (5.6) ............................................................................... 11
`G. Special Considerations for Biotechnologically Derived Products (5.7) ................................... 12
`VI. CONTROL OF ELEMENTAL IMPURITIES (6) ...................................................... 13
`VII. CONVERTING BETWEEN PDES AND CONCENTRATION LIMITES (7) ........ 13
`VIII. SPECIATION AND OTHER CONSIDERATIONS (8) ............................................. 16
`IX. ANALYTICAL PROCEDURES (9) ............................................................................. 16
`X.
`LIFECYCLE MANAGEMENT (10) ............................................................................ 16
`GLOSSARY................................................................................................................................. 16
`REFERENCES ............................................................................................................................ 18
`APPENDIX 1: METHOD FOR ESTABLISHING EXPOSURE LIMITS ........................... 19
`APPENDIX 2: ESTABLISHED PDES FOR ELEMENTAL IMPURITIES ........................ 22
`APPENDIX 3: INDIVIDUAL SAFETY ASSESSMENTS ..................................................... 24
`APPENDIX 4: ILLUSTRATIVE EXAMPLES ....................................................................... 72
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`Q3D Elemental Impurities
`Guidance for Industry1
`
`INTRODUCTION (1)2
`
`
`
`This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
`this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
`can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
`To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title
`page of this guidance.
`
`
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`
`
`I.
`
`
`Elemental impurities in drug products may arise from several sources; they may be residual
`catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through
`interactions with processing equipment or container/closure systems or by being present in
`components of the drug product). Because elemental impurities do not provide any therapeutic
`benefit to the patient, their levels in the drug product should be controlled within acceptable limits.
`There are three parts of this guidance:
`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 application of a risk-based approach to control elemental impurities in drug products.
`An applicant is not expected to tighten the limits based on process capability, provided that the
`elemental impurities in drug products do not exceed the PDEs. The PDEs established in this
`guidance are considered to be protective of public health for all patient populations. In some
`cases, lower levels of elemental impurities may be warranted 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, for elements with high PDEs,
`other limits may have to be considered from a pharmaceutical quality perspective and other
`guidances should be consulted (e.g., ICH Q3A).
`
`1 This guidance was developed within the Quality Expert Working Group of the International Conference on
`Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
`subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been
`endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2014, and revised to correct several
`inconsistencies, December 2014. At Step 4 of the process, the final draft is recommended for adoption to the
`regulatory bodies of the European Union, Japan, and the United States.
`
`2 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering Committee at
`Step 4 of the ICH process, November 2013.
`
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`SCOPE (2)
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`SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES (3)
`
`
`
`This guidance presents a process to assess and control elemental impurities in the drug product
`using the principles of risk management as described in ICH Q9. This process provides a
`platform for developing a risk-based control strategy to limit elemental impurities in the drug
`product.
`
`In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
`Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as
`recommendations, unless specific regulatory or statutory requirements are cited. The use of the
`word should in Agency guidances means that something is suggested or recommended, but not
`required.
`
`II.
`
`The guidance applies to new finished drug products (as defined in ICH Q6A and Q6B) and new
`drug products containing existing drug substances. The drug products containing purified
`proteins and polypeptides (including proteins and polypeptides produced from recombinant or
`nonrecombinant origins), their derivatives, and products of which they are components (e.g.,
`conjugates) are within the scope of this guidance, as are drug products containing synthetically
`produced polypeptides, polynucleotides, and oligosaccharides.
`
`This guidance does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites,
`DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood
`derivatives including plasma and plasma derivatives, dialysate solutions not intended for systemic
`circulation, and elements that are intentionally included in the drug product for therapeutic benefit.
`This guidance does not apply to products based on genes (gene therapy), cells (cell therapy), and
`tissue (tissue engineering). In some regions, these products are known as advanced therapy
`medicinal products.
`
`This guidance does not apply to drug products used during clinical research stages of development.
`As the commercial process is developed, the principles contained in this guidance can be useful in
`evaluating elemental impurities that may be present in a new drug product.
`
`Application of Q3D to existing products is not expected prior to 36 months after publication of
`the guideline by ICH.
`
`III.
`
`
`A.
`
`Principles of the Safety Assessment of Elemental Impurities for Oral,
`Parenteral and Inhalation Routes of Administration (3.1)
`
`
`The method used for establishing the PDE for each elemental impurity is discussed in detail in
`Appendix 1. Elements evaluated in this guidance 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 described in ICH
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`Q3C Residual Solvents. The available information was reviewed to establish the oral, parenteral
`and inhalation PDEs. For practical purposes, the PDEs to be applied to the drug product that are
`presented in Appendix 2, Table A.2.1 have been rounded to 1 or 2 significant figures.
`
`
` 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
`iridium, osmium, rhodium, and ruthenium. The PDEs for these elements were established on the
`basis of their similarity to palladium.
`
`The factors considered in the safety assessment for establishing the PDE are listed below in
`approximate order of relevance:
`• The likely oxidation state of the element in the drug product
`• Human exposure and safety data when it provided applicable information
`• The most relevant animal study
`• Route of administration
`• The relevant endpoint(s)
`
`Standards for daily intake for some of the elemental impurities discussed in this guidance exist for
`food, water, air, and occupational exposure. Where appropriate, these standards were considered
`in the safety assessment and establishment of the PDEs.
`
`The longest duration animal study was generally used to establish the PDE. When a shorter
`duration animal study was considered the most relevant, the rationale is provided in the individual
`safety assessment.
`
`Inhalation studies using soluble salts (when available) were preferred over studies using
`particulates for inhalation safety assessment and derivation of inhalation PDEs. Depending on
`available data, inhalation PDEs were based on either local (respiratory system) or systemic
`toxicity. For PDEs established for inhalation (and oral or parenteral routes as applicable), doses
`were normalized to a 24-hour, 7-day exposure.
`
`In the absence of data and/or where data are available but not considered sufficient for a safety
`assessment for the parenteral and or inhalation route of administration, modifying factors based on
`oral bioavailability were used to derive the PDE from the oral PDE:
`
`
`• Oral bioavailability <1%: divide by a modifying factor of 100;
`• Oral bioavailability ≥ 1% and <50%: divide by a modifying factor of 10;
`• Oral bioavailability ≥50% and <90%: divide by a modifying factor of 2; and
`• Oral bioavailability ≥ 90%: divide by a modifying factor of 1.
`
`Where oral bioavailability data or occupational inhalation exposure limits were not available, a
`calculated PDE was used based on the oral PDE divided by a modifying factor of 100 (Ref. 1).
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`Other Routes of Administration (3.2)
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`B.
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`PDEs were established for oral, parenteral, and inhalation routes of administration. When PDEs
`are necessary for other routes of administration, the concepts described in this guidance may be
`used to derive PDEs. An assessment may either increase or decrease an established PDE. The
`process of derivation of the PDE for another route of administration may include the following:
`
`
`• Consider the oral PDE in Appendix 3 as a starting point in developing a route-specific PDE.
`Based on a scientific evaluation, the parenteral and inhalation PDEs may be a more
`appropriate starting point.
`• Assess if the elemental impurity is expected to have local effects when administered by the
`intended route of administration:
`o If local effects are expected, assess whether a modification to an established PDE is
`necessary.
`o Consider the doses/exposures at which these effects can be expected relative to the adverse
`effect that was used to set an established PDE.
`o If local effects are not expected, no adjustment to an established PDE is necessary.
`If data are available, evaluate the bioavailability of the element via the intended route of
`administration and compare this to the bioavailability of the element by the route with an
`established PDE:
`o When a difference is observed, a correction factor may be applied to an established PDE.
`For example, when no local effects are expected, if the oral bioavailability of an element
`is 50 percent and the bioavailability of an element by the intended route is 10 percent, a
`correction factor of 5 may be applied.
`If a PDE proposed for the new route is increased relative to an established PDE, quality
`attributes may need to be considered.
`
`•
`
`•
`
`
`
`C.
`
`Justification for Elemental Impurity Levels Higher Than an Established PDE
`(3.3)
`
`
`Levels of elemental impurities higher than an established PDE (see Table A.2.1) may be
`acceptable in certain cases. These cases could include, but are not limited to, the following
`situations:
`
`
`Intermittent dosing
`•
`• Short term dosing (i.e., 30 days or less)
`• Specific indications (e.g., life-threatening, unmet medical needs, rare diseases)
`
`Examples of justifying an increased level of an elemental impurity using a subfactor approach of a
`modifying factor (Refs. 2 and 3) are provided below. Other approaches may also be used to
`justify an increased level. Any proposed level higher than an established PDE should be justified
`on a case-by-case basis.
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`Example 1: Element X is present in an oral drug product. From the element X monograph in
`Appendix 3, a no-observed-adverse-effect level (NOAEL) of 1.1 milligram (mg)/kilogram
`(kg)/day was identified. Modifying factors F1-F5 have been established as 5, 10, 5, 1, and 1,
`respectively. Using the standard approach for modifying factors as described in Appendix 1, the
`PDE is calculated as follows:
`PDE = 1.1 mg/kg/day x 50 kg / 5 x 10 x 5 x 1 x 1 = 220 microgram (µg)/day
`Modifying factor F2 (default = 10) can be subdivided into two subfactors, one for toxicokinetics
`(TK) and one for toxicodynamics, each with a range from 1 to 3.16. Using the plasma half-life of
`5 days, the TK adjustment factor could be decreased to 1.58 for once weekly administration (~1
`half-life), and to 1 for administration once a month (~5 half-lives). Using the subfactor approach
`for F2, the proposed level for element X administered once weekly can be calculated as follows:
`Proposed level = 1.1 mg/kg/d x 50 kg / 5 x (1.6 x 3.16) x 5 x 1 x 1 = 440 µg/day
`For practical purposes, this value is rounded to 400 µg/day.
`Example 2: The TK adjustment factor approach may also be appropriate for elemental impurities
`that were not developed using the modifying factor approach. For element Z, a minimal risk level
`(MRL) of 0.02 mg/kg/day was used to derive the oral PDE. From literature sources, the plasma
`half-life was reported to be 4 days. This element is an impurity in an oral drug product
`administered once every 3 weeks (~ 5 half-lives). Using first-order kinetics, the established PDE
`of 1000 µg/day is modified as follows:
`Proposed level = 0.02 mg/kg/day x 50 kg / 1/3.16 = 3.16 mg/day
`For practical purposes, this value is rounded to 3000 µg/day.
`
`
`ELEMENT CLASSIFICATION (4)
`
`
`For parenteral drug products with maximum daily volumes up to 2 liters, the maximum daily
`volume should be used to calculate permissible concentrations from PDEs. For products whose
`daily volumes, as specified by labeling and/or established by clinical practice, may exceed 2 liters
`(e.g., saline, dextrose, total parenteral nutrition, solutions for irrigation), a 2-liter volume may be
`used to calculate permissible concentrations from PDEs. (Ref. 4)
`
`
`IV.
`
`The elements included in this guidance have been placed into three classes based on their toxicity
`(PDE) and likelihood of occurrence in the drug product. The likelihood of occurrence is derived
`from several factors including: probability of use in pharmaceutical processes, probability of
`being a co-isolated impurity with other elemental impurities in materials used in pharmaceutical
`processes, and the observed natural abundance and environmental distribution of the element.
`For the purposes of this guidance, an element with low natural abundance refers to an element with
`a reported natural abundance of < 1 atom/106 atoms of silicon (Ref. 5). The classification scheme
`is intended to focus the risk assessment on those elements that are the most toxic but also have a
`
`D.
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`Parenteral Products (3.4)
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`reasonable probability of inclusion in the drug product (see Table V.1 (5.1)). The elemental
`impurity classes are:
`
`Class 1: The elements arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) are human
`toxicants that have limited or no use in the manufacture of pharmaceuticals. Their presence in
`drug products typically comes from commonly used materials (e.g., mined excipients). Because
`of their unique nature, these four elements should be evaluated during the risk assessment, across
`all potential sources of elemental impurities and routes of administration. The outcome of the risk
`assessment will determine those components that may require additional controls, which may in
`some cases include testing for Class 1 elements. It is not expected that all components will
`require testing for Class 1 elemental impurities; testing should only be applied when the risk
`assessment identifies it as the appropriate control to ensure that the PDE will be met.
`
`Class 2: Elements in this class are generally considered as route-dependent human toxicants.
`Class 2 elements are further divided in sub-classes 2A and 2B based on their relative likelihood of
`occurrence in the drug product.
`
`
`• Class 2A elements have relatively high probability of occurrence in the drug product, thus
`should be evaluated in the risk assessment across all potential sources of elemental
`impurities and routes of administration (as indicated). The class 2A elements are: cobalt
`(Co), nickel (Ni), and vanadium (V).
`
`• Class 2B elements have a reduced probability of occurrence in the drug product related to
`their low abundance and low potential to be co-isolated with other materials. As a result,
`they can be excluded from the risk assessment unless they are intentionally added during the
`manufacture of drug substances, excipients or other components of the drug product. The
`elemental impurities in class 2B include: silver (Ag), gold (Au), iridium (Ir), osmium (Os),
`palladium (Pd), platinum (Pt), rhodium (Rh), ruthenium (Ru), selenium (Se), and thallium
`(Tl).
`
`Class 3: The elements in this class have relatively low toxicities by the oral route of administration
`(high PDEs, generally > 500 µg/day) but could warrant consideration in the risk assessment for
`inhalation and parenteral routes. For oral routes of administration, unless these elements are
`intentionally added, 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, unless the route specific PDE is above 500 µg/day. The
`elements in this class include: barium (Ba), chromium (Cr), copper (Cu), lithium (Li),
`molybdenum (Mo), antimony (Sb), and tin (Sn).
`
`Other elements: Some elemental impurities for which PDEs have not been established due to
`their low inherent toxicity and/or differences in regional regulations are not addressed in this
`guidance. If these elemental impurities are present or included in the drug product they are
`addressed by other guidances and/or regional regulations and practices that may be applicable for
`particular elements (e.g., aluminium for compromised renal function; manganese and zinc for
`patients with compromised hepatic function), or quality considerations (e.g., presence of tungsten
`impurities in therapeutic proteins) for the final drug product. Some of the elements considered
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`include: aluminium (Al), boron (B), calcium (Ca), iron (Fe), potassium (K), magnesium (Mg),
`manganese (Mn), sodium (Na), tungsten (W), and zinc (Zn).
`
`
`V.
`
`In developing controls 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 to safety considerations for patients 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 risk assessment includes but is not limited to: data generated by the applicant,
`information supplied by drug substance and/or excipient manufacturers, and/or data available in
`published literature.
`
`The applicant should document the risk assessment and control approaches in an appropriate
`manner. The level of effort and formality of the risk 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) may also be considered acceptable. Tools to assist in the risk assessment are
`described in ICH Q8 and Q9 and will not be presented in this guidance.
`
`
`A.
`
`General Principles (5.1)
`
`
`For the purposes of this guidance, the risk assessment process can be described in three steps:
`
`
`•
`
`Identify known and potential sources of elemental impurities that may find their way into the
`drug product.
`• 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.
`• 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.
`
`In many cases, the steps are considered simultaneously. The outcome of the risk assessment may
`be the result of iterations to develop a final approach to ensure the potential elemental impurities
`do not exceed the PDE.
`
`
`B.
`
`Potential Sources of Elemental Impurities (5.2)
`
`
`In considering the production of a drug product, there are broad categories of potential sources of
`elemental impurities.
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`• Residual impurities resulting from elements intentionally added (e.g., catalysts) in the
`formation of the drug substance, excipients, or other drug product components. The risk
`assessment of the drug substance should address the potential for inclusion of elemental
`impurities in the drug product.
`• Elemental impurities that are not intentionally added and are potentially present in the drug
`substance, water, or excipients used in the preparation of the drug product.
`• Elemental impurities that are potentially introduced into the drug substance and/or drug
`product from manufacturing equipment.
`• Elemental impurities that have the potential to be leached into the drug substance and drug
`product from container closure systems.
`The following diagram shows an example of typical materials, equipment, and components used in
`the production of a drug product. Each of these sources may contribute elemental impurities to
`the drug product, through any individual or any combination of the potential sources listed above.
`During the risk assessment, the potential contributions from each of these sources should be
`considered to determine the overall contribution of elemental impurities to the drug product.
`
`Manufacturing
`equipment *
`
`Drug
`Substance
`
`Elemental
`impurities
`in drug
`Product
`
`Excipients
`
`Water **
`
`Container
`Closure
`System
`
` *
`
`
` 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 Pharmacopeial Convention) water quality requirements, if
`purified water or water for injection is used in the manufacturing process(es).
`
`
`C.
`
`Identification of Potential Elemental Impurities (5.3)
`
`
`Potential elemental impurities derived from intentionally added catalysts and inorganic
`reagents: If any element listed in Table V.1 (5.1) is intentionally added, it should be considered in
`the risk assessment. For this category, the identity of the potential impurities is known and
`techniques for controlling the elemental impurities are easily characterized and defined.
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`Potential elemental impurities that may be present in drug substances and/or excipients:
`While not intentionally added, some elemental impurities may be present in some drug substances
`and/or excipients. The possibility for inclusion of these elements in the drug product should be
`reflected in the risk assessment.
`For the oral route of administration, the risk assessment should evaluate the possibility for
`inclusion of Class 1 and Class 2A elemental impurities in the drug product. For parenteral and
`inhalation routes of administration, the risk assessment should evaluate the possibility for
`inclusion of the Class 1, Class 2A, and Class 3 elemental impurities as shown in Table V.1 (5.1).
`Potential elemental impurities derived from manufacturing equipment: The contribution of
`elemental impurities from this source may be limited, and the subset of elemental impurities that
`should be considered in the risk assessment will depend on the manufacturing equipment used in
`the production of the drug product. 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 that come in contact with
`components of the drug product. The risk assessment of this source of elemental impurities is one
`that can potentially be utilized for many drug products using similar process trains and processes.
`In general, the processes used to prepare a given drug substance are considerably more aggressive
`than processes used in preparing the drug product when assessed relative to the potential to leach
`or remove elemental impurities from manufacturing equipment. Contributions of elemental
`impurities from drug product processing equipment would be expected to be lower than
`contributions observed for the drug substance. However, when this is not the case based on
`process knowledge or understanding, the applicant should consider the potential for incorporation
`of elemental impurities from the drug product manufacturing equipment in the risk assessment
`(e.g., hot melt extrusion).
`Elemental impurities leached from container closure systems: The identification of potential
`elemental impurities that may be introduced 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 risk 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 risk assessment. For liquid and
`semisolid dosage forms, there is a higher probability that elemental impurities could leach from the
`container closure system during the shelf-life of the product. Studies to understand potential
`leachables from the container closure system (after washing, sterilization, irradiation, etc.) should
`be performed. This source of elemental impurities will typically be addressed during evaluation
`of the container closure system for the drug product.
`Factors that should be considered (for liquid and semisolid dosage forms) include but are not
`limited to:
`• Hydrophilicity/hydrophobicity
`• Ionic content
`• pH
`• Temperature (cold chain vs room temperature and processing conditions)
`
`
`
`9
`
`Eton Ex. 1013
`12 of 85
`
`

`

`Contains Nonbinding Recommendations
`
`
`
`• Contact surface area
`• Container/component composition
`• Terminal sterilization
`• Packaging process
`• Component sterilization
`• Duration of storage
`
`
`D.
`
`Recommendations for Elements to be Considered in the Risk Assessment (5.4)
`
`
`The following table provides recommendations for inclusion of elemental impurities in the risk
`assessment. This table can be applied to all sources of elemental impurities in the drug product.
`
`
`Cd
`Pb
`As
`Hg
`Co
`V
`Ni
`Tl
`Au
`Pd
`Ir
`Os
`Rh
`Ru
`Se
`Ag
`Pt
`Li
`Sb
`Ba
`Mo
`Cu
`Sn
`Cr
`
`
`
`1
`1
`1
`1
`2A
`2A
`2A
`2B
`2B
`2B
`2B
`2B
`2B
`2B
`2B
`2B
`2B
`3
`3
`3
`3
`3
`3
`3
`
`Oral
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`
`Parenteral
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`yes
`yes
`no
`no
`yes
`no
`no
`
`Inhalation
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`no
`no
`no
`no
`no
`no
`no
`no
`no
`no
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`
`Table V.1 (5.1): Elements To Be Considered in the Risk A