Elemental Impurities Regulations View from a CRO

White Paper Elemental Impurities Regulations View from a CRO Author: Alan Cross, Technical Specialist November 2016 1 www.rssl.com

Abstract Regulatory control of elemental impurities in pharmaceutical products has long been discussed, with both the European Pharmacopeia (EP) and the United States Pharmacopeia (USP) having planned on issuing specific chapters relating to contamination from elemental substances. New regulations have been postponed several times, most recently to take into consideration the guidance from The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). With this document now in place the relevant pharmacopeias are almost certainly finalised as to their respective approaches to the implementation of these regulations. What is the impact on pharmaceutical companies? The changes to the pharmacopeias have meant that a simple general wet chemistry test for assessing elemental contamination has been replaced with a requirement to assess a risk of likelihood of contamination and use of spectroscopic techniques to quantify the level of contaminants in drug products if a potential risk is identified. With emphasis on the use of spectroscopic techniques such as Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES), this will mean that there is a greater requirement for validation of these techniques for specific materials. Contract Research Organisations (CRO s) can provide a valuable support role to pharmaceutical companies to assist in their analytical needs, from development projects, through to QC and batch release, due diligence and safety testing, often to ensure raw materials and products conform to regulatory obligations set out in the pharmacopoeias. In this white paper, an overview will be given on how the regulations have evolved through the pharmacopeias, how the ICH has impacted these regulations, how these could be implemented by manufacturers and the role of CROs in this process. Contents Introduction 2 ICH Guidance 4 ICH and the Pharmacopeias 5 Control of Elemental Impurities 7 Role of a Contract Laboratory 8 Conclusion 8 2

Introduction The control of elemental impurities has long existed within the pharmacopeias. Mainly by use of a wet chemistry test using the comparison of a colour change of the product compared to a reference standard. This method has several problems, it is nonspecific, prone to low recoveries and is very subjective, the colour change is quite subtle and is very reliant on the operator and is also troublesome if a coloured test solution is obtained. Studies carried out have also shown that some elements give poor recoveries, (as low as 2% for Hg), most likely due to the high temperatures used in the preparation of the samples. A visual comparison of the heavy metals test, the left hand tube is the sample, the right hand tube is the blank and the middle tube is a 10 ppm lead standard. Average % Recoveries 120 100 80 60 40 20 0 Pb As Se Sn Sb Cd Pd Pt Ag Bi Mb Ru In Hg Elements Ref.:Lewen, N et al, J.Pharm & Biomed.Anal. 35 (2004) 739-752 USP 231 ICP-MS Relative recoveries of the heavy metals elements by ICP-MS and the heavy metals test from the USP. As a result of these limitations it has long been mooted in the pharmacopeias that these methods should be replaced by more specific instrumental techniques, thus allowing specific analysis of individual elements, in a quantitative manner, enabling sensible scrutiny of the potential toxicity of the materials from the presence of toxic metal components. These changes were worked on independently by the USP and EP, with the USP concentrating on the toxic elements such as mercury and lead, based on the potential to cause harm, whereas the EP focussed more on catalytic residues, such as palladium and platinum, as these were more likely to be present, if less toxic than the heavy metals. The ICH was also at this time carrying out a study into the toxicology and control of elemental impurities in drug materials, this was finalised in December 2014. By this point the USP and EP had their own proposed regulatory changes. On the basis of work of the ICH, and after much discussion and date changes, both pharmacopeias agreed to essentially harmonise to the ICH guidance. 3

ICH Guidance The initial proposal for elemental impurities control was released in 2009. In this concept paper it was accepted that the wet chemistry heavy metals test was not suitable and that often the levels set in regulations for elemental contaminants were based more on detectability than toxicology. As such it was proposed that new guidance be set out based on robust toxicological studies as well as practical testing considerations. The guidance from these discussions was eventually finalised in December 2014 with the publication of the ICH Q3D guidelines. The guidance issued by the ICH includes 24 elements, grouped into 4 categories based on their relative toxicity, likelihood of occurrence and route of administration, the elements in this table have also been assigned exposure limits based on the toxicology and the route of administration. These values are given as permissible daily exposure limits (PDE, in µg), but also usefully the permitted concentration in drug products are included (as µg/g), using the assumption that the maximum dosage will be 10 g per day. The purpose of the guidance is to assist manufacturers to adequately establish the risk of contamination in the final products and therefore posing a risk to patient safety. Each element listed has a specific toxicological profile, dependent on its class and route of administration, this information is used to highlight when an element is or is not required to be considered as part of the risk assessment, allowing the process to simplified. If an element has been used in the manufacture of, or added to the pharmaceutical product, then it must be included as part of the risk assessment. If an element is not intentionally added then its inclusion as part of the assessment is based on the toxicity of the material, the likelihood of being present and the route of administration. This information is set out in the guidance document (Table 1). Table 1: ICH Elements and Limits Element Class Oral Parenteral Inhalation R/A PDE 10g Dose (µg/g) R/A PDE 10g Dose (µg/g) R/A PDE 10g Dose (µg/g) Cd 1 Y 5 0.5 Y 2 0.2 Y 2 0.2 Pb 1 Y 5 0.5 Y 5 0.5 Y 5 0.5 As 1 Y 15 1.5 Y 15 1.5 Y 2 0.2 Hg 1 Y 30 3 Y 3 0.3 Y 1 0.1 Co 2A Y 50 5 Y 5 0.5 Y 3 0.3 V 2A Y 100 10 Y 10 1 Y 1 0.1 Ni 2A Y 200 20 Y 20 2 Y 5 0.5 Tl 2B N 8 0.8 N 8 0.8 N 8 0.8 Au 2B N 100 10 N 100 10 N 1 0.1 Pd 2B N 100 10 N 10 1 N 1 0.1 Ir 2B N 100 10 N 10 1 N 1 0.1 Os 2B N 100 10 N 10 1 N 1 0.1 Rh 2B N 100 10 N 10 1 N 1 0.1 Ru 2B N 100 10 N 10 1 N 1 0.1 Se 2B N 150 15 N 80 8 N 130 13 Ag 2B N 150 15 N 10 1 N 7 0.7 Pt 2B N 100 10 N 10 1 N 1 0.1 Li 3 N 550 55 Y 250 25 Y 25 2.5 Sb 3 N 1200 120 Y 90 9 Y 20 2 Ba 3 N 1400 140 N 700 70 Y 300 30 Mo 3 N 3000 300 N 1500 150 Y 10 1 Cu 3 N 3000 300 Y 300 30 Y 30 3 Sn 3 N 6000 600 N 600 60 Y 60 6 Cr 3 N 11000 1100 N 1100 110 Y 3 0.3 R/A Risk Assessment, these are elements that need to be considered as part of the risk assessment 4

ICH and the Pharmacopeias Independently the European and US Pharmacopeias started to introduce elemental impurities regulations, with very different approaches, which in turn lead to very different proposals for what elements needed to be controlled and at what concentrations they needed to be controlled at. EP Regulations: The starting point for elemental impurities changes in the EP can be traced back to a draft document tabled by the Committee for Medicinal Products for Human Use (CHMP) in 1998, this eventually appeared into the European regulations in September 2008, with immediate effect for new materials and a proposed time-scale of 5 years for implementation against existing materials. These regulations focussed on residue materials which were likely to be present in the drug products through addition of catalysts (such as platinum or palladium) or in the form of wear metals through contact with processing equipment during manufacturing, such as copper from pipework or stainless steel elements like vanadium and molybdenum from the processing equipment. See Table 2 for the original proposed elements. With a desire to harmonise to the ICH guidelines, implementation of the elemental impurities regulations within the EP were delayed. Once the ICH guidance was finalised the decision was to reproduce this document verbatim within the EP chapter 5.20 (Metal Catalyst or Metal Reagent Residues), with a compliance date of December 2017 for all products (3 years after issue of final ICH Q3D guidance). USP Regulations: The USP took a slightly different approach to the implementation of elemental impurities regulations, with working groups starting on the project in 2009. From these working groups a list of 15 elements were chosen based predominantly on toxicity and likelihood of being present, with four elements being compulsory for testing (arsenic, cadmium, mercury and lead) and 11 others which were optional based on processes used. The testing for these elements appeared within 2 chapters <232> Elemental Impurities Limits and <233> Elemental Impurities Procedures. These chapters set out the elements required for testing and their respective limits as well as describing preparation methodology, analytical techniques and validation parameters required for compliance. These regulations were proposed to be compulsory by December 2012, but pressure from industry as well as a desire to work with the ICH guidance meant that this date was moved several times. With the release of the ICH Q3D guidelines, and with much discussion with industry a final compliance date has been set for January 2018. Whilst the list of elements were included in the ICH list, the levels for some of the elements were not harmonised. The final issue of chapter <232> is now fully harmonised with the elements and levels set out in the ICH Q3D guidelines. Table 2: ICH, and Original EP and USP Elements and Limits Element ICH PDE EP Limits USP Limits Cd 5 x 25 Pb 5 x 5 As 15 x 1.5 Hg 30 x 15 Co 50 x x V 100 250 100 Ni 200 250 500 Tl 8 x x Au 100 x x Pd 100 100 100 Ir 100 100* 100 Os 100 100* 100 Rh 100 100* 100 Ru 100 100* 100 Element ICH PDE EP Limits USP Limits Se 150 x x Ag 150 x x Pt 100 100 100 Li 550 x x Sb 1200 x x Ba 1400 x x Mo 3000 250 100 Cu 3000 2500 1000 Sn 6000 x x Cr 11000 250 x Fe x 13000 x Zn x 13000 x Mn x 2500 x *Total for all elements in this group X Not required 5

Implementation of the ICH Guidelines With general harmonisation obtained, it is now a lot simpler for companies to start their implementation strategy whilst ensuring compliance to the regulations. The general approach now accepted for the control of elemental impurities is very much based on a risk assessment, evaluating the likelihood of contamination from the target elements from the materials and processes used in production of the final product. Elements deliberately added to the process are automatically included, as are the four Class 1 and 3 Class 2A elements (see Table 1), followed by any of the elements in Class 3 for non-oral dosage forms. As part of the risk-assessment process all aspects of the process are examined, these feed into a final assessment document, this will then allow the manufacturer to make an informed decision about the level of testing required to ensure compliance to the regulations. Risk Assessment For the risk assessment procedure, a fish-bone diagram is commonly used to ensure that all aspects of the process are considered. Manufacturing Equipment Drug Substance Elemental Impurities in Drug Product Water Container Closure System Excipients In most cases, the risk assessment will not return many causes of concern from most of the inputs. The impact of manufacturing equipment is generally minimal if the equipment and process is well controlled by standard GMP practises, and water can also be eliminated if the pharmacopeial controls currently in place for water for injection or sterilised water are utilised though the manufacturing process. The drug substance should also be sufficiently controlled though GMP procedures, but it is important to consider platinum group metals at this stage as catalyst residues of these elements may be present from the synthesis procedure. Container closure system should not pose too many issues in terms of contamination as generally the levels seen in packaging materials are usually low, and studies have shown that dry materials in contact with packaging do not demonstrate strong transfer of contaminants, though aqueous preparations do need to be considered more thoroughly as this route of transfer from the packaging is a lot more pronounced. One of the main potential routes of elemental contamination into a drug product is via the excipients. These materials come from a wide variety of sources, and can also be categorised into different levels of risk, for example a manufactured excipient such as povidone would be unlikely to contain contamination of metals such as cadmium or mercury, whereas a plant derived material such as sucrose would have a slightly increased risk of having these elements present as the plant can take these elements up during growth, which can then be transferred into the final product. Mined excipients, such as talc and titanium dioxide are generally of the greatest concern as these materials are often found alongside many other minerals in the ground which may contain the elements of concern. The level of this potential contamination may also vary greatly not only between suppliers or from site to site but also within a single mine, with the level of contamination also varying over time. Once all the routes of contamination and the elements likely to be present have been assessed, then a full understanding of likely problems will be obtained. Using this information from the risk assessment, elements of concern can be identified by assessing the route of administration and the approximate levels likely to be in the material. If these levels fall well below the relevant thresholds, then it is likely they can be eliminated from any further control. If after the process is complete and elements of concern have been identified for an individual product, then it must then be decided how these risks will be assessed and controlled. 6

Control of Elemental Impurities If there is a risk that toxic elements may be present in a drug product, then it will be necessary to plan adequate controls of these. In many cases this will require some analytical testing of the materials. When making a decision on the testing there are several considerations: Raw material or final product testing? Testing raw material allows for rejection of batches before they end up in the final product, but the component of risk can be diluted into the final product. Will a threshold study be sufficient? i.e. testing 6 pilot batches or 3 full scale batches at 30% of specification to demonstrate minimal risk. If a threshold study is not sufficient, or the results are non-conforming then will the testing be batch release or skip testing or due diligence control with occasional batches tested? Once the approach has been decided upon, then it will be necessary to develop an analytical method to carry out this testing, this process will generally require a feasibility and method development step followed by a validation step. Method Development and Validation One of the key steps of developing a suitable method for elemental impurities testing is the preparation of the samples. The USP <233> chapter usefully sets out three distinct preparation techniques, direct analysis, dissolution and digestion. Direct analysis is unfortunately rarely applicable as aqueous solutions with minimal matrix are uncommon. Dissolution, either in aqueous or organic solvents. This can be carried out but consideration must be given to the matrix, particularly for ICP-MS as dissolved solid content of >0.2% can be problematic. The use of organic solvents for ICP techniques also requires special instrument conditions for successful analysis. It is also important to note that the presence of carbon, either from undigested sample or from the matrix can cause a significant enhancement of signal, especially for arsenic and selenium, therefore careful matrix matching may be required. Digestion, the use of closed vessels (to minimise volatile analyte loss) and concentrated acids and heat causes destruction the matrix and releases the analytes of interest into solution. This digestion can either take place on a low temperature block digestion system, or in a microwave providing higher temperatures and increased pressures to destroy the matrix. For this technique the choice of acids is important, generally nitric acid is the main reagent used, sometimes with the addition of peroxide for more complex organic materials. Addition of hydrochloric acid is useful for the stabilisation of mercury, but this can cause problems with the analysis of arsenic generating signal enhancement though an argon chloride interference. Sometimes, particularly for inorganic materials, the use of hydrofluoric acid will be required. This again can be problematic as it reacts with glass, so will require special digestion vessels and, depending on the concentration used, modifications to instrumentation to allow these samples to be analysed. Once a sufficient digestion technique has been developed then the samples can be analysed. Typically this will be carried out using ICP-MS as it allows for low detection limits to be reached, thus allowing the required specifications to be obtained. These limits which may be challenging for ICP- OES to obtain under routine conditions, but use of ICP-OES may be useful where higher limits are set or a particular interference is encountered when using ICP-MS. When a suitable preparation technique has been established and some feasibility has been carried out to ensure the analytical technique is applicable and the digestion approach is optimised, then the method must be validated to demonstrate that it is fit for purpose. The ICH guidelines and the USP both allow for two different types of validations to take place, namely Limit and Quantitative (see Table 3). A limit test will will only show whether a sample is above or below specification. Quantitative validation allows for a numerical result to generated which may be more useful for monitoring and data gathering as part of a risk based approach to elemental impurity control. Table 3: ICH Validation Parameters Required Test Limit Quantitative Accuracy N Y Precision (inc. Intermediate precision) N Y Specificity Y Y Detection limit Y Y Quantitation limit N Y Linearity N Y Range N Y The decision on the extent of the validation will ultimately come down to the needs of the manufacturer and the extent of the testing. A limit test may be sufficient for a threshold study, but a full validation may provide more robustness if it is to be used for batch release testing. 7

Role of a Contract Laboratory Some manufacturers may have capability to perform metals analysis in-house, but often this is not the case. Investment in the appropriate equipment can be expensive, not only in terms of the cost of the analytical equipment, but also the preparation capability, infrastructure such as gases and extraction, as well as analyst training and qualification of the instrumentation. The use of an accredited contract analysis laboratory is often a highly effective way of carrying out validations and routine elemental analysis. Using a contract laboratory avoids the high overheads involved in the purchase, running and maintenance of analysis equipment. It also avoids unexpected costs and constraints, such as the requirement for qualification of the instrument, training and operation, as well as ensuring that the correct quality systems are adhered to. Once all of these factors have been considered, use of a CRO can be more desirable than performing validations in-house. A contract laboratory is also able to utilise previous experience to ensure efficient progress of a validation, and perform effective analysis of routine samples if a regular testing program is required. All work carried out by a contract laboratory is also documented under GMP principles and as such is auditable by not only the customer, but also the regulatory bodies such as the MHRA and FDA. Conclusion The road to agreement on elemental impurities regulation has been a long and winding one, but it does seem that there is now a clear view to the final destination. The work of the ICH and the relevant local regulators has led to a final procedure which has made the testing requirement less onerous on the manufacturer. With adequate risk assessment procedures the process of compliance is much simplified and reduces the reliance on analysis. Where the risk assessment does not allow for the elimination of testing, validated methodologies are critical and by collaboration with a contract laborarory, much of the burden of testing can be reduced. RSSL is an established expert in this field, working with our clients to develop and validate methods specific and sensitive enough to determine levels of elemental impurities present in raw materials, APIs and finished products. Extensive analytical capabilities ensure the method is not only suitable for regulatory submission, but also for routine testing as part of quality control procedures or compliance with existing pharmacopeial tests. To find out more about our elemental impurities service, please contact us on: +44 (0)118 918 4076, email enquiries@rssl.com, or visit www.rssl.com 8

About the author Alan Cross Technical Specialist, Metals Laboratory Alan has 16 years industry experience, having graduated in 1999 from the University of Exeter with a Bachelor s Degree in Chemistry. He has worked across a variety of sectors including environmental, food, pharmaceutical and catalysis focusing mainly on analytical chemistry. During this time he covered a wide range of instrumental and wet chemistry techniques. Alan s main area of expertise is metals analysis covering ICP-MS, ICP-OES, AA and the related sample preparation such as microwave digestion and ash samples. About Reading Scientific Services Ltd (RSSL) With over 20 years of experience RSSL is firmly established as a trusted partner in the provision of analytical, investigational, consultancy and training services to clients in the pharmaceutical, biopharmaceutical and healthcare sectors. Our chemical, physical, biochemical, biological and microbiological services are wide ranging, and provide support through your full drug product lifecycle. RSSL is routinely inspected by the MHRA, FDA and UKAS which ensures that our analytical services meet the needs of industry. Find out more about our expertise Tel: +44 (0)118 918 4076 Email: enquiries@rssl.com Web: www.rssl.com The Reading Science Centre Whiteknights Campus Pepper Lane, Reading Berkshire RG6 6LA United Kingdom 2016 RSSL. All rights reserved. 9