Ensuring the quality of a finished pharmaceutical product is a complex, multi-faceted undertaking. For the drug product manufacturer, quality considerations range from good manufacturing practices (GMPs) and process engineering checks to proper storage conditions and distribution mechanisms. However, the quality of any final product is only as good as all the parts that go into its making. Understanding the levels of impurities in finished products or their components — and understanding their impact with respect to safety — requires process knowledge and, in some instances, the technology to efficiently identify and quantify these impurities. Although USP does not mandate testing, USP requires compliance with its standards at all times; to conclusively demonstrate compliance with the new elemental impurities limits, these new chapters must be used.

Earlier this year, the United States Pharmacopeial Convention (USP) announced its new standards for elemental impurities — General Chapters Elemental Impurities — Limits and Elemental Impurities — Procedures. The general chapters were published June 1, 2012 in the Second Supplement to United States Pharmacopeia (35) and National Formulary (30) (USP(35)–NF(30)), which will become official on December 1, 2012. General Chapters and will not become applicable until a new General Notices provision relating to these chapters is subsequently published in USP–NF and becomes official May 1, 2014.

The implementation concludes this phase of an extended standards-setting process that began in 2008 and involved several public meetings, including one conducted by the Institute of Medicine. In 2009, USP held a workshop on the topic of elemental impurities. Since 2008, USP has also hosted several stakeholder forums and pharmacopeial education courses to gather and share user input on the topic. In addition to a 2008 stimuli article published in Pharmacopeial Forum (PF) — USP’s public comment journal — the general chapters were published twice (in 2010 and 2011) in PF for additional stakeholder feedback. The standards were developed by a USP Expert Panel reporting to the appropriate USP Expert Committee and involved analysts and toxicologists from industry, academia, government laboratories, the U.S. Food and Drug Administra-tion (FDA) and international regulatory bodies.

FDA and other public health officials have monitored the presence of elemental impurities such as arsenic, cadmium, lead and mercury in products intended for human consumption for some time. Elemental impurities can occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment). Elemental impurities also include catalysts used in manufacturing that may be present in drug products.

Because of the broad-reaching impact of these new general chapters on a large number of articles in USP–NF and the introduction of limits as well as new instrumentation methods in these chapters, it will be important for manufacturers to consider the wide range of changes they must implement in order to meet the requirements of and . As the date for required compliance draws closer, manufacturers, raw material suppliers and contract service organizations should have coordinated strategies in place to address those needs.

For context, standards apply to articles recognized in USP–NF, and are conveyed in monographs, applicable general chapters, and General Notices. General chapters may contain tests, procedures and/or specifications that apply across multiple medicines or ingredients. Until the development of General Chapters and , USP standards for elemental impurities were included in USP–NF’s General Chapter Heavy Metals, which applied to monographs for active pharmaceutical ingredients and excipients, not to those of finished drug products. USP–NF general chapters fall into two categories. Those designated as above-1000 are considered interpretive and informational. General chapters designated as below-1000 — such as and — contain tests that may apply to items recognized in USP–NF, and may also be required by the FDA to demonstrate conformance to the article’s compendia specifications. General Chapters and will be implemented through a provision in the General Notices, making them applicable to all articles in USP–NF, as was recently done with General Chapter Residual Solvents. Implementation of and will include removal of all references to General Chapter from monographs in USP–NF.

Limits for Elemental Impurities
The test methodology for detecting elemental impurities in General Chapter (visual comparison to a lead sulfide precipitate) was developed more than 100 years ago. While widely used, the methodology based on this longstanding technique is not sufficiently sensitive to detect levels of a number of impurities now known to be toxic, some at very low levels. The development of more sensitive analytical methods coupled with greater knowledge about the toxicology of elemental impurities have led to the replacement of General Chapter with the new, improved standards.

General Chapter specifies acceptable limits for 15 elemental impurities in drug products, including those for the “Big Four”: arsenic, cadmium, lead and mercury. These are considered to be the most ubiquitous of elemental impurities, and compliance with their limits specified in General Chapter is required for all drug products. In the case of arsenic and mercury, the limits have been based on toxicities of their inorganic forms, given that differing toxicities are associated with both their organic and inorganic forms. Also included on the list are 11 catalysts that must be considered if their presence is expected based on an assessment of a product’s formulation and manufacture.

Since the toxicity of an elemental impurity is related to its extent of exposure, General Chapter includes permissible daily exposure (PDE) amounts that have been determined for each of the elemental impurities of interest for three routes of administration: oral, parenteral and inhalational. The limits associated with these routes are based on chronic exposure data.
Mucosal and topical routes of administration are deemed to be the same as oral for the purpose of this standard. General Chapter also provides options for demonstrating compliance based on the measured amount of each impurity in a typical dosage unit of a drug product or the summation of the amount of each impurity present in each of the components of a drug product. If using the latter option, a manufacturer must assure that additional elemental impurities cannot be inadvertently added through the manufacturing process.

While the limits in General Chapter do not apply to excipients and drug substances, elemental impurity levels present in drug substances and excipients must be known and reported for purposes of compliance. As an aid for discussions between drug product manufacturers and the suppliers of their product components, General Chapter includes default concentration limits for drugs substances and excipients used in drug products based on a maximum daily dose of 10 grams/day.

Limits for selected elemental impurities also are being developed by the International Conference on Harmonisation (ICH) Q3D Expert Working Group. With the exception of the limit for mercury, the limits in General Chapter are consistent with those in the ICH Q3D pre-Step 2 draft — a precursor to ICH’s public comment draft known as a Step 2 document. At a future date, USP intends to revisit General Chapter relative to the final outcome of ICH Q3D deliberations. At that time USP’s relevant Expert Panel and Committee may add additional elements and limits to General Chapter based on ICH Q3D and may develop an informational chapter to incorporate elements of low toxicity.

Procedures for Elemental Impurities
As previously mentioned, a more sensitive method capable of detecting low levels of individual elemental impurities was needed to replace the legacy procedures included in General Chapter . The analytical procedures in new General Chapter apply inductively coupled plasma–atomic (optical) emission spectroscopy (ICP-AES) or inductively coupled plasma–mass spectroscopy (ICP-MS) for the detection and evaluation of elemental impurities. ICP-AES and ICP-MS are modern analytical methods that have been more commonly used in pharmaceutical research and development applications rather than quality testing in manufacturing.  Their value over techniques such as atomic absorption spectroscopy is their ability to screen for multiple elements in one analysis.  In addition to providing descriptions of the analytical procedures, General Chapter provides information on sample preparations for the two procedures.

For manufacturers of multiple drug products, several key considerations must be taken in account with regard to compliance to . Should a company decide to bring its evaluation work on elemental impurities in-house, it must determine whether it has the expertise and instrumentation needed to conduct the necessary procedures. If additional training or instrumentation is needed, is there ample time to complete the training prior to the deadline for compliance? While some manufacturers have opted to purchase the required instrumentation in preparation for compliance to the new standards, have they accounted for the time needed to master sample preparation techniques and instrumentation use for all the different test articles in their entire product portfolios? Because a finished drug product distinguishes itself in the market through properties that are different from those of its competitors’ products, a drug product can exhibit unique properties. This uniqueness can be a contributor to matrix interference when using, for example, ICP-MS for evaluation. Thus, it is crucial to build in ample time to develop and hone appropriate sample preparation techniques as well as to master the use of the instrumentation itself when dealing with differing matrices.

In addition to providing details on the use of the ICP procedures, General Chapter also provides criteria for acceptable alternative procedures. Manufacturers must be able to demonstrate that alternative procedures meet the criteria listed in General Chapter and that the alternative procedures are suitable for detecting and evaluating impurities in a specified material. Thus, a product manufacturer must calculate the time and resources needed to conduct an assessment of its portfolio for all of its products in order to be compliant.

Suppliers of raw materials are not required to meet specific PDEs since they do not know a priori how their materials will be used, in which products or at what levels.  However, they are expected to know and report to their customers the levels of the elemental impurities found in their materials. Because raw materials are manufactured in bulk quantities, and often in continuous processes, a challenge for suppliers will be to ensure that they know the levels of elemental impurities on an on-going basis. Close collaboration between raw material customers and suppliers will be important as manufacturers establish that their supply chain is in good control.  Additionally, a growing number of drug product manufacturers will likely expect their raw material suppliers to supply them with elemental impurity levels once the standards become official on December 1, 2012.

Implications for Contract Organizations
As the May 2014 date for compliance to USP’s new standards for elemental impurities draws closer, contract laboratories will have to prepare for the increased volume of work this change is likely to trigger. Much of this will come in the form of validation work needed by drug product manufacturers and raw material suppliers alike. Given that this is the first time that drug manufacturers have been required to test for elemental impurities in this manner, contract laboratories can anticipate an increase in demand from this sector.

As stated, some drug product manufacturers will opt to bring the necessary instrumentation and associated expertise in-house to meet the requirements of General Chapters and ; others will rely more heavily on contract laboratories to support and sustain their submissions to the FDA. For contract organizations to provide their customers with appropriate method validation work of high quality, it will be necessary to develop and implement the necessary strategies in a timely manner. This includes the development of sample preparation techniques, feasibility testing, drafting protocols and balancing QA requirements of both the contract laboratory and the manufacturer — not to mention conducting the validation itself.

Manufacturers of raw materials have the challenge of dealing with large amounts of materials that will need to be tested and validated. Raw materials also are prone to interference. While these reasons support the argument for raw material manufacturers to integrate the relevant technical expertise in-house, finding personnel experienced in sample preparation techniques and appropriate instrumentation procedures will be important. For those turning to contract organizations to support compliance efforts, dealing with materials in bulk will pose some challenges if proper time and resources are not allotted for the testing of large amounts of materials. For the raw material supplier that is relying on the contract laboratory to conduct testing and validation work, waiting until the last minute to complete this work could result in unwanted delays in delivering materials to customers. Thus, it will be important for raw material suppliers to develop a strategy regarding meeting compendial requirements and customer expectations well in advance of the required date.

Implementation of USP’s New Standards
USP’s modernized standards related to elemental impurities undoubtedly will present some new challenges to drug manufacturers and raw material suppliers. The newly established limits for selected elemental impurities and the introduction of new test procedures based on modern instrumentation will require a shift in industry practices needed for compliance. By laying the foundation of these general chapters in 2008 and delaying General Chapters and implementation until May 1, 2014, USP has provided manufacturers, suppliers and contract organizations with an opportunity to plan accordingly for these new requirements.