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`Metal Residue: How Much is Too Much?
`
`To comply with evolving guidelines, drug makers will need analytical and regulatory support
`
`By Dr. Ulrich Reichert and Dr. Najib Sehat, Merck Millipore
`Aug 19, 2013
`
`
`
`Contamination of medicinal products with heavy metals may arise from metals deliberately added as
`catalysts or reagents. Natural occurrence in source materials or processing equipment including
`vessels, pipes or metal connections to tubes or hoses may be further causes for metal residues. The
`presence of heavy metals may exert toxicological effects and therefore should be excluded or limited
`to an acceptable threshold. For many existing substances, approved specifications are provided by
`the pharmacopoeias in various regions of the world. The following compares current requirements for
`pharmaceutical substances (APIs, excipients and process chemicals) and describe new guidelines
`such as those from USP that will take effect in 2014.
`
`Metals in medicinal products or human nutrition can be beneficial or problematic: On one hand, they
`are used directly as active substances in drug products to exert a beneficial effect, or they are
`necessary as minerals or trace elements. Many products on the market used as dietary supplements
`contain trace elements like iron, copper, zinc, selenium, manganese, chromium, molybdenum or
`other. Many of these metals are essential as parts of enzymes, vitamins or cofactors.
`Supplementation of minerals or trace elements is needed when dietary intake is deficient and may be
`beneficial for compensation of deficiencies.
`
`Metals used in drug substances still have importance in modern drug therapy. For example platin
`compounds (cisplatin, carboplatin) are administered as highly potent anticancer drugs. Aluminum is
`widely used in antacids; iron is used for treatment or prevention of iron deficiency and anemia; zinc is
`part of insulin zinc suspensions; cobalt is part of vitamin B12; gold compounds were shown to be
`efficacious as anti-rheumatoid drugs.
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`On the other hand, metals in medicinal products may also be present as impurities. Contamination
`may arise from metals deliberately added as catalysts or reagents. Natural occurrence in source
`materials (e.g., in minerals or herbals) or processing equipment like vessels, pipes or metal
`connections to tubes or hoses may be further causes for metal residues. As contaminants, these
`metals may exert toxicological effects and therefore they should be excluded or limited to an
`acceptable threshold.
`
`NO THERAPEUTIC BENEFIT
`Since there is no therapeutic benefit from metal residues in pharmaceutical products unless
`administered therapeutically, they should be removed to the extent possible to meet product
`specifications, good manufacturing practices or other quality-based criteria.
`
`For many existing substances, approved specifications are provided by the pharmacopoeias in each
`region, such as the European Pharmacopoeia, United States Pharmacopeia and the Japanese
`Pharmacopoeia. Further, the International Conference on Harmonization (ICH) has published a
`concept paper (Q3D: Impurities: Guideline for Metal Impurities) on the development of a guideline
`which would harmonize the limits of metal impurities in the three large economic areas Europe, United
`States and Japan.
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`Impurities typically arise from the manufacturing process or from degradation of the substance (Figure
`1). An impurity in a drug substance as defined by the guideline ICH Q3A(R2) is any component of the
`drug substance that is not the chemical entity defined as the drug substance. Quite similar is the
`definition for an impurity in a drug product. It is any component of the new drug product that is not the
`drug substance or an excipient in the drug product (ICH Q3B). The impurities which are already
`controlled in the drug substance need not be monitored or specified in the drug product again, unless
`they are also degradation products (ICH Q6A).
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`EMA GUIDELINES
`EMA guidelines on specification limits for residues of metal catalysts and reagents were put into place
`in 2008. The guidelines define maximum acceptable concentrations limits for metal residues arising
`from the use of metal catalysts or metal reagents in the synthesis of pharmaceutical substances. The
`objective of the guidelines is to control residues from metals added intentionally.
`
`For products that were already on the market when the new guidelines were enacted, the drug
`product manufacturer had five years to address. This transition period will end September 1, 2013.
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`According to the guideline, limits should be provided for metals which are likely to be present due to
`introduction into the manufacturing process as metal catalyst or metal reagent. What is not in the
`scope of the EMA guidelines are metals introduced through raw materials, metals arising from
`interaction with processing equipment, metals added inadvertently or by the environment and
`packaging materials. The guidelines indicate that these so-called “extraneous metal contaminants”
`are more appropriately addressed by GMP, GDP or other relevant quality provision.
`
`Thus, only process-related metal residues are in the scope of the guideline to control the sufficient
`removal of the pharmaceutical substance. Pharmaceutical companies do not need to perform
`extensive tests on metal residue findings of unknown sources to comply with the guideline. In these
`cases, companies typically rely on general information from trusted suppliers.
`
`There are four conditions for a metal to be in the scope of this guideline:
`
`1) The metal has to be used in the manufacturing process as catalyst or reagent (regardless of the
`speciation or form of the element
`2) It is likely to be present in the pharmaceutical substance
`3) It is not a deliberate component of the pharmaceutical substance
`4) It is among the metals of the guideline (see below)
`
`The term “pharmaceutical substances” is defined as a substance that is either an active
`pharmaceutical ingredient or an excipient. The guideline refers also to metals used in the synthesis of
`any of the pharmaceutical excipients used during the manufacture of the drug product, but no longer
`present in the drug product itself and includes 14 metals which are divided in three classes:
`
`Class 1 metals are considered to be metals of significant safety concern. This group includes metals
`that are known or suspect human carcinogens, or possible causative agents of other significant
`toxicity. Class 1 is further divided into three subclasses 1A, 1B, and 1C. The subclasses 1A and 1B
`cover highly toxic or carcinogenic metals. For subclass 1B a group limit is applied, the total amount of
`listed metals should not exceed the indicated limit.
`
`Class 2 metals are metals of low safety concern. This group includes metals with lower toxic potential
`to man. They are generally well tolerated up to exposures that are typically encountered with
`administration of medicinal products. They may be trace metals required for nutritional purposes or
`they are often present in food stuffs or readily available nutritional supplements.
`
`Class 3 metals represent a minimal safety concern. This group includes metals with no significant
`toxicity. Their safety profile is well established. They are generally well tolerated up to doses that are
`well beyond doses typically encountered with the administration of medicinal products. Typically they
`are ubiquitous in the environment.
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`For each of these classes, exposure and concentration limits are defined. Limits are based on toxicity
`of the metal compared to the amount typically ingested, dosage, duration of treatment, and route of
`administration — whether oral, inhaled or parenteral.
`
`The classification of impurities in three classes was already carried out with the ICH guideline on
`residual solvents (ICH Q3C). As such, the approach is known with the manufacturers of
`pharmaceutical starting materials. The classification is solely driven by the toxicological assessments
`of the specific metals. Quality aspects, for example the color or the possibility to interact on other
`components like inducing oxidation or catalysis of degradations, is not considered.
`
`EUROPEAN PHARMACOPEIA
`In 2009, the European Directorate for the Quality of Medicines and Healthcare (EDQM) established a
`working party on the topic of heavy metals. Documents were reviewed and finished for adoption by
`the commission in October 2011. General chapter 5.20 (Metal Residues) implements the text of the
`EMA guidelines into the European Pharmacopeia; a pharmacopeial text means a higher level of
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`commitment. The general method 2.4.20 on metal catalysts or reagents does not describe a discrete
`method but offers advice on the choice of method for sample preparation and measurement and
`defines validation requirements.
`
`It appears that the EDQM may implement monographs based on the EMA guideline fairly soon. The
`ICH Q3D guideline will replace the EMA guideline in chapter 5.20 in at some point. The conventional
`heavy metal test will be abolished once the ICH regulations are implemented in the Pharmacopeia.
`
`The EMA guideline seems appropriate to control the risk of elemental impurities in pharmaceutical
`substances produced by a chemical production process. The list of elements should be extended by
`metals frequently used in the production of pharmaceutical substances (e.g. lithium, boron, aluminum
`and silver). The coverage of iron and zinc is questioned since both elements pose a minimal
`toxicologic risk and Zn is even not very likely to be present. The classical heavy metal test is
`considered not to be meaningful for control of these elements and should be removed.
`
`An addendum to the general monograph “Substances for Pharmaceutical Use” (2034) is prepared,
`making the provisions of general chapter 5.20 mandatory. Substances of pharmaceutical use for
`veterinary use only will be exempted since these substances are out of the scope of the EMEA
`guideline.
`
`U.S. PHARMACOPEIA
`In January 2010, USP proposed new general chapters on elemental impurities limits and
`methods. The revisions focused on two key areas:
`
`• Update the methodology used to test for elemental impurities in drugs and dietary supplements to
`include procedures that rely on modern analytical technology
`• Setting limits for acceptable levels of metal impurities in drugs and dietary supplements
`
`The monograph on elemental impurities limits ( <232> ) applies to drug products, drug substances
`and excipients; compliance, however, is required for drug products only (Figure 2). A risk-based
`approach for testing strategy was adopted.
`
`General chapters <232> and <233> have been published on the USP website in a finalized version
`since April 2012. A new provision will be added to General Notices that will make these General
`Chapters applicable to all official articles recognized in USP and/or NF. Because the General Notices
`provision making these chapters applicable to articles in USP and NF, the date on which users will be
`required to meet the requirements of these Elemental Impurities chapters will be May 1, 2014.
`
`In the final version, there is no longer a classification. The elements included are those of the EMA
`guideline but without iron, zinc and manganese due to low toxicity. Additional elements are inorganic
`arsenic, cadmium, inorganic mercury and lead. Table 1 compares the concentration limits for
`parenteral drug products with a maximum daily dose of 10 g/day are compared.
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`In addition to the EMA guideline in which testing is required only if these metals are intentionally
`added during manufacture, the control strategy of the USP chapter <232> also comprises elemental
`impurities that may occur naturally or are introduced inadvertently (Figure 2).
`
`When elemental impurities are known to be present, have been added, or have the potential for
`introduction, assurance of compliance to specified levels will be required for the drug product. The
`conventional heavy metal test will be abolished.
`
`While the limits do not apply to excipients and drug substances but only drug products, it was noted
`that elemental impurity levels present in drug substances and excipients “must be known and
`reported.” With regard to these components, limits remain a matter of negotiation between the drug
`product manufacturer and supplier of pharmaceutical starting materials. Table 2 compares EMA and
`USP requirements.
`
`ICH GUIDELINES
`In 2009, the International Conference on Harmonization issued a plan for the establishment of a new
`guideline on metal impurities. Current status of the ongoing discussion can be summarized as
`follows:
`
`• The guideline will cover all drug products including biotech products, but will exempt herbals,
`radiopharmaceuticals and conventional vaccines
`• The guideline will cover PDE and control strategy, but will not cover testing strategy and analytical
`methods
`• The guideline will be applicable to new drug products, but will not be applied to existing products and
`clinical trials
`• The guideline will cover the general risk of contamination with metal impurities
`
`In early 2012, draft guidelines were published for commentary. The guidelines cover drug products
`and the sources of metals being catalysts and reagents, but also those added inadvertently. PDEs
`and limits were set for 27 elements, with some limits being stricter and other being less strict. New
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`limits were added for 12 elements and different conversion factors from parenteral to oral limits,
`depending on the oral bioavailability provided.
`
`OUTLOOK
`Regulations governing the presence of heavy metals in drug products are evolving. USP and ICH are
`setting strict acceptance limits for drug products, and ICH has outlined a risk-based control strategy
`for up to 27 metals.
`
`The pharmaceutical industry is expected to comply with the new USP requirements from May 2014
`on. A risk-based control strategy will be more likely applied than full testing of all elements for each
`batch. However, a risk-based approach has to be demonstrated to be appropriate. Most
`considerations at pharmaceutical industry will probably be at excipients. Performing of (inorganic)
`impurity profiles is currently not required for excipients and not a common practice at many excipients
`manufacturers. For APIs, the risk of contamination may be less due to the required full validation
`program of manufacturing process. Impurity profiles for inorganic impurities are more likely to be
`performed with APIs, predominantly for known impurities from the manufacturing process (among
`others catalysts, heavy metals, inorganic salts). Actions of excipient manufacturers to set up an
`appropriate risk-based control strategy shall be supportive to fulfill the requirements addressed to
`pharmaceutical industry.
`
`As a result of these changes, drug product manufacturers will need proper analytical and regulatory
`support to achieve compliance for the pharmaceutical substances they use. In parallel, suppliers of
`raw materials to pharmaceutical manufacturers should be able to state that metals were either not
`used as catalysts or reagents or are consistently removed. An impurity profile should be available
`showing evaluation against guideline limits.
`
`
`
`ABOUT THE AUTHORS
`Ulrich Reichert is a pharmacist and the Head of Regulatory Experts and Customer Audits at Merck
`Millipore. He has more than 10 years experience in leading analytical laboratories at Merck KGaA
`where he was responsible for release of pharmaceutical starting materials, GMP and IVD products.
`He then worked with Regulatory Services responsible for global regulatory projects within Merck
`Millipore.
`
`Najib Sehat is Director for Regulatory & Technical Services at Merck Millipore. Najib has been with
`Merck Millipore for over 13 years and has held various leading positions of increasing Regulatory
`responsibility in various Merck Chemical Divisions. He is a member of various professional
`organizations such as IPEC Europe, IFT (USA), German Chemical Association, Global Steering
`Committee of EXCiPACT and member of and deputy Board of Director for the Rx-360 Consortium.
`
`
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`References
`1 U. Reichert: Implementing the Guideline on the Specification Limits for Residues of Metal Catalysts
`or Metal Reagents (EMEA/CHMP/4446/2000, Master Thesis, University of Bonn, June 2009
`
`Metal Residue: How Much is Too Much?
`
`2 ICH Harmonized Tripartite Guideline. Q3A(R2) – Impurities in New Drug Substances, Step 4
`version, 25 October 2006
`
`3 ICH Harmonized Tripartite Guideline. Q3B(R2) – Impurities in New Drug Products, Step 4 version,
`02 June 2006
`
`4 ICH Harmonized Tripartite Guideline. Q6A – Specifications: Test Procedures and Acceptance
`Criteria for New Drug Substances and New Drug Products: Chemical Substances, Step 4 version, 06
`October 1999
`
`5 EMEA/CHMP/SWP/4446/2000, Guideline on the specification limits for residues of metal catalysts
`or metal reagents. Committee for Medicinal Products for Human Use (CHMP), London, 21 February
`2008
`
`6 ICH Harmonised Tripartite Guideline. Q3C(R5) - Impurities: Guideline for Residual Solvents, Step 4
`version, 4 February 2011
`
`7 The United States Pharmacopeial Convention: Draft <232> and <233>, Pharmacopeial Forum
`36(1), 2010
`
`8 The United States Pharmacopeia, Chapter <232> and <233>, 2nd supplement to USP 35-NF 30,
`Rockville, MD: U.S. Pharmacopeial Convention, Inc.; 2012
`
`9 M. Türck: Elemental impurities in Substances for pharmaceutical use – Current trends in
`pharmacopoeial testing. Slides to oral presentation, Bern, 24th October 2011.
`
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