After a long wait for the new elemental impurities guidelines, the bio/pharma industry must now look ahead to implementation and take action.
After a long wait for the new elemental impurities guidelines from the United States Pharmacopeial Convention (USP) and International Conference on Harmonization (ICH), the bio/pharma industry must now look ahead to implementation. Representatives of contract testing laboratories shared observations on the industry’s approach to the new guidelines, insights and advice on implementing risk assessment, and strategies for new testing programs for elemental impurities with the editors of Pharmaceutical Technology.
Discussion participants are Michelle Cree, principal scientist, strategy and business manager–elemental analysis, Catalent Pharma; Thomas Devadder, team leader, QC AAS/ICP/Particles/TGA - Laboratory Services, SGS Life Science Services, Mike Murphy, elemental impurity analysis expert, Intertek Pharmaceutical Services; Nikki Schopp, team leader, analytical laboratory services, SGS Life Science Services; Terry Schuck, manager pharmaceutical raw materials, method establishment and development, Eurofins Lancaster Laboratories.
Bio/pharma gets readyPharmTech: How are drug companies responding to the requirements of the new elemental impurities guidelines and the pending deadlines? Is there a sense of urgency?
Murphy (Intertek): Many of the pharmaceutical companies we work with have been proactive in seeking validated methodology for their products rather than wait for the official implementation deadline. I believe there will be an increased sense of urgency going forward as companies getting started in the process have much to do to prepare for full implementation of the USP or ICH guidances. The risk assessment process must be performed for excipients, active ingredients, and finished products and will involve development and validation of final methods. Each step of the process may take longer to complete than anticipated.
Schopp (SGS): There was a sense of urgency in the past two to three years to get validated methods in place. In the past year, many companies have put this type of development/validation work on hold. This is most likely due to the changes in specifications and the uncertainty of who is responsible for the testing. Some clients already have validated methods that would now be considered outdated in relation to the specifications that are currently published.
Devadder (SGS): Pharmaceutical companies are reacting very differently to the new elemental impurities guidelines. Responses range from ‘we’ll look at this when capacity is available’ to ‘this should have been done yesterday!’. The pressure will increase in accordance with the range of their product portfolios and the number of ingredients in a particular finished-drug product. Collecting data from suppliers and testing for elemental impurities can be a challenging task.
Schuck (Eurofins): Many drug companies have been seeking help understanding the new guidelines and how the changes will impact the release of their products. Since the testing techniques described in US Pharmacopeia <233> ‘Elemental Impurities--Procedures’ require expensive instrumentation that requires trained analysts to maintain and operate, most drug companies are evaluating service providers with the capacity and experience to manage their projects.
Cree (Catalent): It appears that some companies are following the changes closely and have established teams to work on risk assessments and control strategy, recognizing the complexity of the guidelines. Others have taken a more reserved approach, preferring to wait for further harmonization between the ICH Q3D Guideline for Elemental Impurities and USP <232> ‘Elemental Impurities--Limits’. USP has harmonized permissible daily exposure limits with ICH in the second supplement to USP 38-National Formulary 33 and has encouraged early adoption in General Notice 5.60.30, official April 1, 2015.
PharmTech: Do drug companies have sufficient knowledge about the new guidelines and deadlines? What are some common misconceptions?
Schuck (Eurofins): Not in all cases. A common misconception is that USP <233> is a testing method and can be used as a direct replacement for USP <231> ‘Heavy Metals’. However, USP <233> is a performance-based general chapter, which outlines the testing approach and defines verification requirements and specifications. USP <232> needs to be used in conjunction with USP <233> to set drug-product specifications based on dose and route of administration, then a unique method needs to be developed and validated per material.
Devadder (SGS): From my point of view, most drug companies are aware of what needs to be done regarding the new regulations.
Schopp (SGS): The drug companies know the guidelines and deadlines, but do not fully understand them. It is important to know how to apply the limits according to the amount of API being used in the final product in conjunction with the dosage.
Cree (Catalent): Uncertainty exists around implementation of the guidelines, in part based on assessment and quantification of risk associated with specific types of excipients, manufacturing processes, and container-closure systems. Implementation of instrumental methods and focus on compliance of drug product eliminates requirements for elemental-impurity testing in USP and European Pharmacopoeia (Ph. Eur.) monographs for APIs or excipients. Since excipient and API suppliers are not required to test for elemental impurities, manufacturers must consider impact to compliance strategy.
Murphy (Intertek): The implementation dates can be confusing. USP <232> and USP <233> are currently effective; however, USP <231>, the original ‘Heavy Metals’ methodology, is still available for use until Jan. 1, 2018. While USP <232> and USP <233> will be broadly available for use on Jan. 1, 2018, any USP monograph that specifically references these chapters will certainly require their use. Over the next three years, new or revised monographs may reference the two new chapters, and so one must be careful to apply the correct chapters. On the other hand, ICH Q3D will have a two-stage implementation, with the date of June 2016 for new drug applications and December 2018 for existing products.
Assessing riskPharmTech: ICH Q3D promotes a risk-based approach to assessing the potential presence of impurities. How can drug owners develop effective risk-assessment programs? What role can contract-service providers play in this process?
Devadder (SGS): A scientific approach to potential routes of administration into the drug product should be the first step in building up a solid risk assessment. Vendor certificates of the excipients or APIs will also contribute to the risk assessment. Whenever an uncertainty in the data exists, a validated screening method of a contract service laboratory will provide the required information to bridge any gaps in the risk assessment.
Cree (Catalent): Application of ICH Q3D for elemental impurities presents a significant challenge due to requirements for thorough risk assessment of potential sources of elemental impurities and a control strategy to limit elemental impurities in finished drug products. Drug owners must focus on establishing a clear understanding of all aspects of drug substance, excipient, and drug product manufacturing in collaboration with outsourcing partners. Outsourcing partners can provide guidance on assessment of drug-specific manufacturing processes and evaluation criteria.
Schuck (Eurofins): Drug owners need to perform sufficient research to understand all aspects of the manufacturing process. Materials used to develop drug products (including excipients, raw materials, and APIs) need to be assessed for the potential presence of impurities. In addition, the manufacturing process and the potential for exposure to metals need to be understood. Laboratory screens for a large list of metals can be used as an initial assessment to help establish the risk and scope of the program.
Murphy (Intertek): Although companies may be familiar with a risk-based approach in relation to internal toxicology studies, application of this approach to assessment of potential elemental impurities may be novel for some. The new guidelines stress assessment of actual toxicological risk to the patient rather than merely testing as low as possible for every element. Contract-service providers can facilitate the process through the design of tailored analytical programs--based on wide experience and in-depth knowledge of the guidelines--that can provide either the screening data to aid risk assessment, if this does not already exist, or develop and validate methods tailored to the clients’ specific products.
Schopp (SGS): It is clear that arsenic, cadmium, lead, and mercury must be tested. It is important to understand the drug-substance/drug-product manufacturing process and test any catalyst used in the process. It is also important to evaluate environmental contaminants and possible equipment contamination. There is more responsibility on drug companies rather than the manufacturers of the APIs and excipients, as the final drug product is what is introduced to the public.
Establishing testing processesPharmTech: What new testing procedures or instruments are needed to assess elemental impurity contamination in drug substances, excipients, drug product manufacturing, and container closures?
Schopp (SGS): Inductively coupled plasma-optical emission spectroscopy (ICP–OES) [also called inductively coupled plasma-atomic emission spectroscopy (ICP–AES)] and inductively coupled plasma-mass spectroscopy (ICP–MS) are the main instruments being used to evaluate elemental impurities.
Devadder (SGS): Single-element techniques, such as atomic absorption spectroscopy (AAS), or multi-element techniques like ICP–OES/MS, can be used for the determination of elemental impurities. To reduce the carbon background in the sample, an acid digestion will become the necessary sample preparation step. Evidently, ICP–MS will provide the required selectivity and sensitivity to determine the lowest concentrations of elemental impurities. But even existing AAS systems can provide risk-assessment solutions when testing for a few, specific impurities.
Cree (Catalent): USP <233> describes two techniques commonly used for determination of inorganic elemental content: ICP–AES and ICP–MS. Either technique may be used to determine elemental impurity content. Choice of technique is determined by solution concentration, with ICP-MS exhibiting superior sensitivity. Use of alternative procedures is permitted provided they meet the validation requirements described in USP <233>.
Murphy (Intertek): Modern inorganic analytical instrumentation, be ICP–OES or ICP–MS are capable of performing elemental impurity testing in accordance with USP and ICH guidelines. The decision to use either type of instrumentation depends on variables such as the sample matrix and required limit of quantitation. Many companies may not have such instrumentation on site and therefore a cGMP contract laboratory that has appropriate experience will be required to perform the testing. Sample preparation will be critical to the success of the elemental analyses. For example, it may be possible to dissolve an API in an organic solvent but typically organic compounds interfere with the analysis of trace metals via ICP approaches. Most sample preparations will require a modern microwave digestion system for sample preparation.
Schuck (Eurofins): Due to the possibility of solubility issues, the use of microwave digestion has been found useful to facilitate complete digestion for many drug products, excipients, and drug substances. To achieve the sensitivity requirement to meet many of the specification limits outlined in the guidelines, ICP–MS or ICP–OES are most frequently used during the development of methods. The ICP–MS should be equipped to analyze either aqueous or organic solutions and have various gas modes to resolve interference issues. The testing facility needs to be constructed, managed, and maintained specifically to establish a clean environment for the analysis of trace metals.
PharmTech: When should test processes be developed? How should the tests be validated?
Schuck (Eurofins): Test methods should be developed as soon as the risk assessment is complete, the elements of interest have been determined, and specifications can be calculated based on drug-product dosage and the route of administration to the patient. Based on the specification and the material solubility, digest procedures and instrument test methods can be completed and validated using the guidelines in USP <233>.
Cree (Catalent): Development of test processes should be an integral component of product development and risk assessment. In early-phase work, screening studies can provide valuable information that can be used to develop robust risk assessments. Historical testing of excipients and APIs will provide insight into variability. Once a control strategy is determined, it should be supported with fully validated methods that are included in submitted regulatory dossiers.
Schopp (SGS): In our experience, it proves best to test the final product at different stages of drug method development. Manufacturing changes, including purification, have shown significant differences to the ICP method.
Devadder (SGS): Method development for every individual substance used for the production of a drug product can easily overburden capacities and budgets. To reduce the number of methods that have to be developed, a definition of worst-case sample categories can be a good approach. This procedure has to be validated according to Ph. Eur. 2.4.20 ‘Heavy Metals’/USP <233>. Spiking experiments can show the applicability of the method to the individual sample material.
Murphy (Intertek): The choice of appropriate validation procedures will become a more pressing issue as the USP and ICH guidelines become fully implemented. The validation procedures employed in USP <233> are slightly different from what one might find in ICH Q2 (R1), Validation of Analytical Procedures, for analytical method validation. This is problematic if a company is marketing products both in Europe and in the United States. Companies have sometimes opted to perform both, in the sense of following the USP <233> requirements and then perform additional experimentation to satisfy the typical ICH guideline expectations. This decision, including what level of validation is required, will need to be made by each company on a case-by-case basis.
Take action nowPharmTech: What action should drug owners take now to ensure their products comply with the new guidelines?
Murphy (Intertek): The number one thing a manufacturer can do today is to start their risk-assessment program. This will require information gathering from their suppliers as well as coordination of regulatory limits for their particular applications. It is possible that this could be more complex than anticipated and so starting sooner rather than later is recommended.
Schuck (Eurofins): Drug owners will need to perform a proper risk assessment of the potential sources of elemental impurity contamination, whether the sources are naturally occurring, added as a catalyst, or introduced from equipment during the manufacturing process. While the limits do not necessarily apply to excipients and drug substances, the levels of impurities should be known and assessed relative to their contribution in the drug product.
Schopp (SGS): There is some ambiguity in who is responsible for testing. Should each individual ingredient be tested or just the final drug product? The most cost-effective way is to test the final product. However, if the same APIs and excipients are used in a variety of products, testing each component individually will help decide which batches can be used to make the drug product using the summation technique.
Cree (Catalent): It is critical to begin developing a compliance strategy. Application of ICH Q3D presents a challenge with regard to assessment and quantification of risk associated with specific types of excipients, manufacturing processes, and container-closure systems. Since excipient and API suppliers will not be required to test for elemental impurities, manufacturers may wish to work with suppliers collaboratively to re-examine quality agreements, supplier quality history, and need to augment supply-chain control.
Researching contract lab servicesPharmTech: What questions should drug owners ask testing laboratories when investigating elemental impurities testing programs?
Schuck (Eurofins): Drug owners need to ensure that testing laboratories have the equipment, facilities, capacity, and experience to manage a trace-metals program. Experienced analysts and proven systems are needed to properly develop methods that will demonstrate accuracy, precision, and range for a variety of sample matrixes. When assessing a testing laboratory, the laboratory needs to demonstrate a clear understanding of how to manage a risk-assessment program and have the ability to develop cost-effective methods that will meet the requirements of the new guidelines.
Schopp (SGS): What type of instrumentation does the lab have available? Does the lab have both ICP–MS and ICP–OES available? Do they have microwaving capabilities? What is their experience in overcoming interferences and difficult matrices? What are their instruments’ limit of quantitation capabilities?
Devadder (SGS): Which techniques are available? What is your experience in validation of elemental impurities procedures? Is a validated screening procedure already implemented? Is the service provider able to handle high sample throughput? Are backup instruments available?
Cree (Catalent): It is important to ensure the testing laboratory has experience with development and validation of atomic spectrometric methods. Qualification of a contract laboratory should include an analytical review by a qualified analytical expert. Additionally, verify that the laboratory is compliant with cGMPs and that all instrumentation is fully validated.
b>Murphy (Intertek): Drug owners should be certain their contract laboratories are following cGMP guidelines. They should also inquire if the contract laboratory has an established strategic approach to elemental impurity analysis, which could include options for semi-quantitative screening, method development and validation (as either a limit test or a quantitative test as required), and routine analysis. Expertise in sample preparation is also necessary to meet the challenges of difficult samples that have poor solubility, enabling very low levels of detection.
Once assured of the general capabilities of the contract laboratory, drug owners should inquire as to the experience the laboratory has with trace elemental impurities not only in excipients and APIs but also in final drug products (capsules, tablets, etc.), which can be quite different than handling a pure excipient or API.
Article DetailsPharmaceutical Technology Outsourcing Resources Supplement
Vol. 39, No. 17
Citation: When referring to this article, please cite it as "Moving On to Implementation for Elemental Impurities Testing," Pharmaceutical Technology Outsourcing Resources Supplement 39 (17) 2015.