Impurities In Drug Products Research Articles

Resolution of Historically Discordant Ames Test Negative / Rodent Carcinogenicity Positive N-nitrosamines using a Sensitive, OECD-aligned Design.

The in vitro Bacterial Reverse Mutation (Ames) Test is crucial for evaluating the mutagenicity of pharmaceutical impurities. For N-nitrosamines (NAs) historical data indicated that for certain members of this chemical class the outcomes of the Ames Test did not correlate with their associated rodent carcinogenicity outcomes. This has resulted in negative outcomes in an OECD aligned Ames Test alone (standard or enhanced) no longer being considered sufficient by regulatory authorities to assess potential carcinogenic risk of NAs if present as impurities in drug products. Consequently, extensive follow-up in vivo testing can be required to characterise the potential mutagenicity and genotoxic carcinogenicity of NA impurities (i.e., beyond that defined in the ICH M7 guideline for non-NA impurities). We previously demonstrated that the mutagenicity of alkyl-nitrosamines can be detected by the appropriately designed, OECD aligned Ames Test and identified those conditions that contributed most to assay sensitivity. This OECD aligned Ames Test design was used to assess seven NAs, i.e. (methyl(neopentyl)nitrosamine, N-methyl-N-nitroso-2-propanamine, N-nitrosodiisopropylamine, bis(2-methoxyethyl)nitrosoamine, N-nitroso-N-methyl-4-fluoroaniline, dinitrosoethambutol, (R,R)- and mononitrosocaffeidine) that were reported to be negative in historical Ames Tests but positive in rodent carcinogenicity studies. All seven of the NAs were demonstrated to be mutagenic in the OECD aligned Ames test and therefore these compounds should no longer be considered as discordant (false negatives) with respect to the correlation of the Ames Test and rodent carcinogenicity. These results confirm the sensitivity of the OECD aligned Ames Test for the detection of NA mutagenicity and provides further support of its pivotal placement within the ICH M7 framework for the assessment of mutagenic impurities in pharmaceuticals to limit potential carcinogenic risk. In addition, we present data for 1-cyclopentyl-4-nitrosopiperazine, that indicates it could serve as a suitable positive control to provide further confidence in the sensitivity of the Ames Test for the NA chemical class.

B-166 Differentiation of Aziridine Functionality from Related Functional Groups in Protonated Analytes by Using Selective Ion-Molecule Reactions

Abstract Background The development of better methods for the rapid and reliable identification of unknown compounds in mixtures is urgently needed in drug development. Aziridines, in particular, are used for drug synthesis but are potentially mutagenic and carcinogenic compounds. However, the detection and identification of these compounds pose challenges for many analytical methods, such as Nuclear Magnetic Resonance (NMR) spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), and X-ray crystallography. These techniques are time-consuming and often require large quantities of highly pure compounds. Methods Therefore, this study demonstrates that selective gas-phase ion-molecule reactions of protonated analytes with neutral tris(dimethylamino)borane (TDMAB), followed by diagnostic collision-activated dissociation (CAD), can be used to differentiate aziridines from structurally related compounds in a modified linear quadrupole ion trap (LQIT) mass spectrometer. The experiments were performed using an atmospheric pressure chemical ionization (APCI) source in positive ion detection mode. TDMAB was purchased from Sigma-Aldrich and used without purification. It was introduced into the ion trap (2 mtorr of helium buffer gas) via an external reagent mixing manifold through a syringe pump at a flow rate of 10 μL h-1 and diluted with helium before entering the ion trap through a variable leak valve. All analytes were prepared at a concentration of 1 mM in methanol. The protonated analytes were transferred into the ion trap, isolated, and allowed to react with TDMAB (MS2 experiments). Results Product ions formed upon reactions of the analyte ions with TDMAB were subjected to a collision-activated dissociation (CAD) experiment (MS3 experiments). CAD on product ions produced diagnostic fragment ions with 25- and 43 m/z-units lower m/z values than the adduct - DMA product ions. Quantum chemical calculations were employed using the Gaussian 16 program calculated at the M06-2X/6-311++G(d,p) level of theory to provide theoretical foundation and to explore the underlying mechanisms of the observed gas-phase reactions. None of the tested structurally related analytes produced a similar fragmentation pattern Conclusions The innovative approach presented in this study offers a promising avenue for enhancing efficiency and accuracy in drug development. The successful differentiation of aziridine is an alternative method in overcoming the limitation of traditional techniques. The findings from the research contributes to the advancement of analytical techniques, addressing critical issues in identifying impurities in drug products. The versatility of the methods extends beyond drug developments, making it applicable in various other fields such as in molecular diagnostics, metabolism and laboratory medicines.

Drug-Leachable Interaction Product Evaluation in Prefilled Syringe of Ganirelix Acetate Injection

The concept of extractables and leachable has introduced a new era for identifying potential impurities in drug products. Pharmaceutical packaging materials encompass a variety of polymers due to their appealing properties for storing the drug product. However, numerous chemical species may leach into the drug product from these polymers, posing significant health hazards in the public domain. Identifying such leachable is crucial for assessing safety and addressing toxicological concerns. Acrylic acids are commonly used materials for adhering needles to the barrel in pre-filled syringes. In this study, we identified acrylic acid leachable impurities in ganirelix drug products available in the market using mass spectrometry as an analytical technique. These impurities leached into the drug product during storage conditions. Characterization of the impurities was carried out through data obtained from HRMS and MS/MS analysis, revealing them as polyacrylic acid-ganirelix adduct impurities. This study offers valuable insights into identifying leachable and susceptible sites, providing a foundation for potential modifications in similar classes of drug products, thereby enhancing their safety and efficacy.

Analytical Methods and Their Significance in Pharmaceutical Process Impurities: A Review

AbstractPotential genotoxic substances in medicines are of rising concern to pharmaceutical and regulatory authorities at detectable levels due to their potential to induce human carcinogenesis. Molecule functional groups may contribute to the genotoxicity of small molecules by converting starting materials and synthetic intermediates into reactive components. It is challenging for the pharmaceutical research and development analytical community to identify these genotoxic chemicals at trace levels without using susceptible and selective analytical methods. The literature currently needs more experimental advice for analyzing some significant contaminants. Analytical methods play a vital role in the pharmaceutical industry for monitoring and controlling impurities in drug products. These methods provide critical information on the final product's quality, purity, and efficacy by identifying unwanted substances such as degradation products, residual solvents, and process contaminants. The significance of analytical methods in pharmaceutical process impurities includes ensuring quality control, regulatory compliance, process optimization, troubleshooting, and batch release. These methods help to ensure that the final product meets the required specifications, complies with regulatory requirements, and provides the safe and effective patient treatment. The study analyses the structural alarms of commonly encountered likely genotoxic contaminants and draught regulations of various regulatory authorities to restrict the number of impurities in medicinal substances and to identify their toxicity.

Modeling the Migration Behavior of Extractables from Mono- and Multilayer Polyolefin Films to Mathematically Predict the Concentration of Leachable Impurities in Pharmaceutical Drug Products. Part 1: Experimental Details and Modeling Experimental Results.

An important step in the development of a pharmaceutical drug product is to demonstrate acceptable levels of leachable impurities during the shelf-life and therapeutic use of the drug product. If the diffusion and partition coefficients are known, the concentration profile of a leachable impurity in the drug product can be predicted theoretically at a given temperature and time. With this objective in mind, kinetic experiments were performed to study the migration of low- to high-molecular-weight organic compounds from mono- and multilayer polyolefin films. Migration curves at different temperatures were generated for each compound when these films were brought in contact with aqueous solutions with varying pH or with another plastic film made from a different polyolefin material. "Best fit" migration curves and the corresponding diffusion and partition coefficients (about 300 pieces) were obtained by using numerical software developed by FABES. The results obtained show that, in general, the correlation between the calculated diffusion and partition coefficients and temperature, between 30°C and 85°C, obeys the Arrhenius and Van't Hoff equations. In this temperature range, the diffusion and partition coefficients can be used to model and predict migration of the investigated compounds from the same pharmaceutical packaging materials. A comparison of these coefficient values with other polyolefin films also provides insights into the chemistry of the mono- and multilayers and the impact it has on the migration behavior of the compounds. In a consecutive paper, an approach to overestimate the diffusion and partition coefficients to account for the variability in experimental data is explained and finally, the use of these overestimated parameters to predict the concentrations for other compounds leaching from the multilayer films into aqueous drug product formulations is discussed.

Modeling the Impact of Excipients Selection on Nitrosamine Formation towards Risk Mitigation.

Risk control for nitrosamine impurities in drug products is currently a major challenge in the industry. Nitrosamines can form during drug product manufacturing and storage through the reaction of nitrites with amine-containing APIs or impurities. The level of nitrites in excipients and the rate of reaction often control the build-up of nitrosamine. Although the variability in nitrite levels across excipient types and suppliers is well recognized, the impact of excipient selection on the level of nitrosamine formed has not been systematically studied. This gap of knowledge is addressed in the current work. We present theoretical case studies of formulations where microcrystalline cellulose (MCC), or lactose supplier, or superdisintegrant type are changed in pursuit of lower levels of nitrite. The impact of the average, maximum, and minimum levels of nitrites in each excipient on nitrosamine formation in the dosage form is calculated. The input data for this calculation are the formulation composition, nitrosamine molecular weight (MW), percentage of conversion, and nitrite levels per excipient. The percentage of conversion (based on the formulation and manufacturing variables) and nitrite levels were taken from the recent literature. We show that changing the supplier of a single excipient, or of the three most critical excipients, can reduce nitrosamine formation by up to -59% and -89%, respectively. We also show that high-risk formulations, e.g., high MW nitrosamines, high dosage weights, and high percentages of conversion (e.g., wet granulation), can often be de-risked below regulatory acceptable daily intake via careful excipient selection. Finally, we provide an open-access tool that enables users to calculate the theoretical formation of nitrosamines in their specific formulations. This calculation template can be used for (i) the preliminary screening of the risk of nitrosamine formation in drug products and (ii) the preliminary assessment of the impact of excipient selection for risk mitigation.

Validation of a HPLC method for the determination of diclofenac diethylamine and three of its impurities in a gel pharmaceutic form.

Monitoring impurities in drug products is a principal requirement of pharmaceutical regulatory authorities all over the world to ensure drug safety. For this reason, there is a great need of analytical quality control of dugs products. In this study, a simple, efficient and direct high performance liquid chromatography (HPLC) method was developed for the determination of three impurities of diclofenac. The HPLC method was developed using the mobile phase which consisted of HPLC grade mixture (Acetonitrile and 0.01M phosphoric acid adjusted to pH = 2.3) in the ratio of (25:75 v/v) respectively. The separation was performed in 15 minutes. The calibrations curve of the three impurities were linear; the correlation coefficient was 0.999 at a concentration of (0.00015 - 0.003 µg/mL). The validation of this method shows that this method meets all validation criteria. This shows the reliability of the use of this method for the routine control of diclofenac impurities. The validation of a robust HPLC method for the determination of diclofenac impurities is of great importance for the pharmaceutical industry to control its products.

Elemental impurities determination in bromhexine hydrochloride injections

Elemental impurities in drug products have no therapeutic effect and may pose toxicological concerns, therefore it is urgent to assess the safety of elements especially in parenteral exposure drug. In the present work, a high throughput inductively coupled plasma mass spectrometry (ICP-MS) method was developed for the quantitative determination of 31 elemental impurities in bromhexine hydrochloride injections from 9 manufactures. The method was successfully validated for linearity, accuracy, precision, stability, the LOD and the LOQ according to the United States Pharmacopeia (USP) < 233 > . All the elemental impurities determined were below the permitted daily exposure (PDE) limits proposed by the International Council for Harmonisation (ICH). However, significant differences were found between different manufactures’ products for some elements, particularly for Al, As, B, Ba and Zn. Besides, discussions considering potential risks of elemental contamination were also presented.

Nitroso Impurities in Drug Products: An Overview of Risk Assessment, Regulatory Milieu, and Control Strategy

Many nitrosamines have been recognized to be carcinogenic for many decades. Despite the fact that several nitrosamine precursors are frequently used in the manufacturing of pharmaceutical products, their potential presence in pharmaceutical products has previously been overlooked due to a lack of understanding on how they form during the manufacturing process. From the risk assessment, it is clear that nitrosamines or their precursors may be present in any component of the finished dosage form. As a risk mitigation strategy, components with a high potential to form nitrosamine should be avoided. In the absence of suitable alternatives, sufficient measures to maintain nitrosamines below acceptable intake levels must be applied. Excipient manufacturing pathways must be extensively studied in order to identify probable excipient components that may contribute to nitrosamine formation. The manufacturers must not solely rely on pharmacopeial specifications for APIs and excipients, rather, they should also develop and implement additional strategies to control nitrosamine impurities. The formulation can be supplemented with nitrosating inhibitors, such as vitamin C, to stop the generation of nitrosamine. The purpose of this review is to identify key risk factors with regard to nitrosamine formation in pharmaceutical dosage forms and provide an effective control strategy to contain them below acceptable daily intake limits.

Genotoxicity evaluation of nitrosamine impurities using human TK6 cells transduced with cytochrome P450s.

Many nitrosamines are recognized as mutagens and potent rodent carcinogens. Over the past few years, nitrosamine impurities have been detected in various drugs leading to drug recalls. Although nitrosamines are included in a 'cohort of concern' because of their potential human health risks, most of this concern is based on rodent cancer and bacterial mutagenicity data, and there are little data on their genotoxicity in human-based systems. In this study, we employed human lymphoblastoid TK6 cells transduced with human cytochrome P450 (CYP) 2A6 to evaluate the genotoxicity of six nitrosamines that have been identified as impurities in drug products: N-nitrosodiethylamine (NDEA), N-nitrosoethylisopropylamine (NEIPA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosomethylphenylamine (NMPA), N-nitrosodiisopropylamine (NDIPA), and N-nitrosodibutylamine (NDBA). Using flow cytometry-based assays, we found that 24-h treatment with NDEA, NEIPA, NMBA, and NMPA caused concentration-dependent increases in the phosphorylation of histone H2A.X (γH2A.X) in CYP2A6-expressing TK6 cells. Metabolism of these four nitrosamines by CYP2A6 also caused significant increases in micronucleus frequency as well as G2/M phase cell-cycle arrest. In addition, nuclear P53 activation was found in CYP2A6-expressing TK6 cells exposed to NDEA, NEIPA, and NMPA. Overall, the genotoxic potency of the six nitrosamine impurities in our test system was NMPA > NDEA ≈ NEIPA > NMBA > NDBA ≈ NDIPA. This study provides new information on the genotoxic potential of nitrosamines in human cells, complementing test results generated from traditional assays and partially addressing the issue of the relevance of nitrosamine genotoxicity for humans. The metabolically competent human cell system reported here may be a useful model for risk assessment of nitrosamine impurities found in drugs.

Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities.

The potential for N-nitrosamine impurities in pharmaceutical products presents a challenge for the quality management of medicinal products. N-Nitrosamines are considered cohort-of-concern compounds due to the potent carcinogenicity of many of the structurally simple chemicals within this structural class. In the past 2 years, a number of drug products containing certain active pharmaceutical ingredients have been withdrawn or recalled from the market due to the presence of carcinogenic low-molecular-weight N,N-dialkylnitrosamine impurities. Regulatory authorities have issued guidance to market authorization holders to review all commercial drug substances/products for the potential risk of N-nitrosamine impurities, and in cases where a significant risk of N-nitrosamine impurity is identified, analytical confirmatory testing is required. A key factor to consider prior to analytical testing is the estimation of the daily acceptable intake (AI) of the N-nitrosamine impurity. A significant proportion of N-nitrosamine drug product impurities are unique/complex structures for which the development of low-level analytical methods is challenging. Moreover, these unique/complex impurities may be less potent carcinogens compared to simple nitrosamines. In the present work, our objective was to derive AIs for a large number of complex N-nitrosamines without carcinogenicity data that were identified as potential low-level impurities. The impurities were first cataloged and grouped according to common structural features, with a total of 13 groups defined with distinct structural features. Subsequently, carcinogenicity data were reviewed for structurally related N-nitrosamines relevant to each of the 13 structural groups and group AIs were derived conservatively based on the most potent N-nitrosamine within each group. The 13 structural group AIs were used as the basis for assigning AIs to each of the structurally related complex N-nitrosamine impurities. The AIs of several N-nitrosamine groups were found to be considerably higher than those for the simple N,N-dialkylnitrosamines, which translates to commensurately higher analytical method detection limits.

Elemental Impurities in Pediatric Calcium Carbonate Preparations-High Throughput Quantification and Risk Assessment.

Calcium carbonate which is extracted from the Earth in combination with other mineral impurities, is largely used in preparations for pediatric supplements. Elemental impurities in drug products pose toxicological concerns without therapeutic benefits. Thus, it is very urgent to assess the safety of chronic exposure to elements that may be present in trace amounts. In the present study, we developed high throughput ICP-MS method for the quantitative determination of 62 elemental impurities in high matric calcium carbonate samples and validated according to USP 233. Calcium carbonate preparations which state clearly used for child (including neonates, infants, toddlers and children) from 9 manufactures and two types of raw materials (light calcium carbonate and ground calcium carbonate) were investigated in terms of the content and variability of 62 elemental impurities. According to the results, ground calcium carbonate was more suitable to be used in pediatric preparations concerning elemental impurities. Parts of elemental impurities in CaCO3 preparations which are derived from the raw materials and the preparation process, may cause potential risks for children. These results indicate that it is necessary to establish a modern instrumental analysis method to evaluate and control elemental impurities in CaCO3 raw materials and preparations.

Quality by design with design of experiments approach for development of a stability‐indicating LC method for enzalutamide and its impurities in soft gel dosage formulation

A novel ultra-performance liquid chromatographic (UPLC) method has been developed and approved for the quantitative determination of enzalutamide (ENZ) and its impurities in drug product dosage form by applying the quality by design with design of experiments approach. An efficient chromatographic separation was achieved on a Waters ACQUITY CSH C18 (100 × 2.1 mm × 1.7 μm) column in gradient elution mode. A mixture of potassium phosphate monobasic buffer and acetonitrile (10 mm, adjusted to pH 4.0 with 1% orthophosphoric acid) at a flow rate of 0.2 mL min-1 (column temperature at 40°C) under ultraviolet detection at 270 nm was used for quantitation. The peak resolution among ENZ and its impurities (Impurity-1, Impurity-2, Impurity-3, Impurity-4, Impurity-5, Impurity-6 and Impurity-7) was greater than 2.5. Regression analysis confers an R2 value (correlation coefficient) higher than 0.999 for the active substance and impurities. The detection level for ENZ impurities was at a level below 0.015% (0.12 μg/mL). The accuracy levels for different compounds were close to 100%. The inter- and intra-day precisions for ENZ and impurities were evaluated and their relative standard deviation (%) values were less than 3.5. Our results show that the UPLC-UV stability-indicating method will be an essential tool that could determine the drug product's impurities and be useful in regular quality control and stability studies of the ENZ drug product dosage form.

A simple high‐performance liquid chromatography method development for Carbidopa and Levodopa impurities: Evaluation of risk assessment before method validation by Quality by Design approach

AbstractThe current study is to develop a simple high‐performance liquid chromatography method for Carbidopa and Levodopa impurities' simultaneous determination with the combination of Entacapone in solid oral dosage forms. The estimation of impurities are critical in a combination product due to the more number of impurities. The presence of impurities in drug products affects quality and bio‐efficacy. The quality by design approach allows the assessment of various analytical parameters and their effects with the minimum number of experiments. The current high‐performance liquid chromatography method was developed using a kromasil column with gradient mobile phase. The detection was made 220 nm; the flow rate was 1.0 mL/min, and the column's temperature was 25°C. The analytical curves presented a coefficient of correlation of &gt;0.99, and detection and quantification limits were evaluated for all impurities. Excellent precision and accuracy were obtained for carbidopa and levodopa impurities. Intra‐ and interday precisions RSD were lower than 10.0, and recoveries of impurities varied between 91.2 and 108.2%. The results reveal the method's successful applicability for estimating Carbidopa and Levodopa with their process and degradation impurities from its marketed formulation.

A Risk-Based Approach to Evaluate and Control Elemental Impurities in Therapeutic Proteins

Control of elemental impurities in the drug products evolved from the generic visual testing of heavy metals as their sulfides to specific elements of toxicological concern in the final drug products by instrumental analysis. The International Council for Harmonisation (ICH) Q3D (R1) guideline for elemental impurities describes a risk-based approach to identify, assess, and control the potential elemental impurities in drug products within the established permitted daily exposures (PDE). Challenges to this approach include how to assess the risks associated with contributing sources such as utilities, manufacturing equipment, container-closure systems, and excipients. Defining at what stage of development that such assessment should be performed to identify the risk levels can be equally challenging.In this article, we report an approach to control elemental impurities of toxicological concern, compliant to the Q3D (R1) guideline, and a summary of results obtained on multiple protein therapeutic products. This approach follows the elements of Process Validation, i.e., Design, Qualification, and Continuous Verification. The design includes the selection of excipients and their suppliers that meet the Option 1 requirement of Q3D (R1). It also comprises the selection of manufacturing equipment, container-closure systems, and utilities. The qualification includes the testing of the potential sources of elemental impurities, i.e., excipients, utilities, and leachables/extractables from the manufacturing equipment and container-closure systems. The Continuous Verification comes from the testing of representative batches at the initiation of stability studies of clinical or commercial drug product batches and at the end of shelf-life expiry of the drug product, and when changes are made to the manufacturing equipment, sources of excipients and container closure systems, and any formulation changes.Our experience shows that the risk associated with the impurity levels of the ten elements of toxicological concern in the therapeutic protein drug products, parenterally administered, is well below the control threshold (30% PDE) in the drug product recommended by the ICH Guideline. Although our focus is on the injectable therapeutic proteins, this approach can be applied to the products administered via other routes as well.

Review of Elemental Impurities in Pharmaceuticals Arena

Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in the 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. The main objective of the International Conference on Harmonization (ICH) (Q3D) guideline applies to new finished drug products and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides. This guideline 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. The evaluation of the toxicity data for potential elemental impurities; the establishment of a permitted daily exposure (PDE) for each element of toxicological concern; application of a risk-based approach to control elemental impurities in drug products. Different analytical techniques for elemental impurities detection: flame atomic absorption spectrometry (FAAS), graphite furnace atomic absorption spectrometry (GFAAS), atomic fluorescence spectrometry, X-ray fluorescence spectrometry (XRF), instrumental neutron activation analysis (INAA), inductively coupled plasma-atomic emission spectroscopy (optical emission spectroscopy, ICP-OES), inductively coupled plasma mass spectrometry (ICP-MS), and microwave plasma atomic emission spectrometry (MP-AES).

Quantitative X-ray fluorescence analysis: Trace level detection of toxic elemental impurities in drug product by ED-XRF spectrometer

Inorganic impurity analysis of pharmaceutical drug products is of paramount importance at trace levels due to the availability of toxic metals. The existing techniques require extensive development and chemical treatment to evaluate the presence of class I (Pb, Cd, Hg and As) and class II (Co, V and Ni) heavy metal elements which are harmful to the environment. To overcome these issues, a cost and time effective wavelength dispersive X-ray fluorescence spectrometry (XRF) was introduced to determine the concentration of trace elements in one of the angiotensin receptor blocker (ARB) (tablet sample 300 mg) according to guidelines addressed in ICH Q3D and USP. The validation study focused on class I and class II elements are also in accordance with regulatory guidelines. Overall it includes the comprehensive characterization of analytical method which is compliant with the requirement of USP. The novelty of this work includes the application of EDXRF in routine analysis of trace elements (especially volatile Hg) present in the pharmaceutical product beyond the previously published studies for the limited number of the non-pharmaceutical regime. Apart from this it also requires minimal sample preparation and method development and is able to quantify toxic impurities which are present in the sample in less than 20 ppm concentration, with the lowest level of detection up to 0.1 ppm.

Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: An Updated Literature Review.

Elemental impurities in drug products arise from different sources and via a number of different means, including leaching of elemental entities (including the elements themselves or element-containing compounds) from the drug product's manufacturing or packaging systems. Thus, knowledge about the presence, level, and likelihood of leaching of elements in manufacturing and packaging systems is relevant to understanding how these systems contribute to a drug product's total elemental impurity burden. To that end, this manuscript updates a previous review of available literature on elemental entities in pharmaceutically relevant polymers and the presence of these elemental entities in material extracts and/or drug products. This updated review contains the information that has been published subsequent to the publication of the initial review and considers two questions: (1) What elemental entities are present in the relevant polymers and materials and at what levels are they present? (2) To what extent are these elemental entities leached from these materials under conditions relevant to the manufacturing and storage/distribution of solution drug products? The compiled recent data reaffirms the conclusions drawn from the original review: (1) Elemental entities are present in the materials used to construct packaging and manufacturing systems as these materials either contain these elemental entities as additives or are exposed to the elemental entities during their production. (2) Unless the elemental entities were parts of the materials themselves (e.g., SiO2 in glass) or intentionally added to the materials (e.g., metal stearates in polymers), their incidental amounts in the materials were generally low. (3) If elemental entities were present in materials and systems, generally only a very small fraction of the total available amount of the entity could be leached under conditions that were relevant to the packaged drug products. Thus, although sources of certain elemental impurities may be ubiquitous in the natural environment, they were not ubiquitous in materials used in pharmaceutical packaging and manufacturing systems and when they were present, they were not extensively leached under relevant conditions of use for those systems. This conclusion, supported by an ever-increasing body of literature, suggests that in general the manufacturing and packaging systems, by themselves, do not contribute sufficiently large quantities of elemental impurities that the impurities pose a meaningful threat to patient safety. Furthermore, this conclusion should be considered when standards are developed for the characterization and qualification of manufacturing systems, packaging systems, and their associated materials and components of construction.

High-resolution continuum source graphite furnace atomic absorption spectrometry for screening elemental impurities in drugs to adhere to the new international guidelines

New guidelines for the limits of elemental impurities in drug products were introduced by the International Council for Harmonization in 2014. While the guidelines define a limit for each element, the complete quantification of the 24 elements included is, in fact, unnecessary. An accurate “pass/fail” test to determine whether the threshold was exceeded or not could be valuable in this context. In this study, a screening procedure using the features of high-resolution continuum source graphite furnace atomic absorption spectrometry for the evaluation of 12 elements in three different drugs was developed. The three-dimensional absorbance spectrum including time and wavelength in the vicinity of the main line of the element allows for a pass/fail decision related to the presence or absence of the element in the sample. Additionally, the bi-dimensional absorbance-wavelength spectrum defines the elements captured in the window when additional peaks are seen in the spectrum. The analysis of the selected drugs included sample digestion, the definition of pyrolysis and atomization temperatures, determination of the limit of detection and other validation parameters for each element. The evaluation of the spectra, both three- and bi-dimensional, revealed that only three elements, Cr, Ni, and Cu, were present in the samples in amounts above the LOD and therefore “fail” in the test. Nevertheless, they were quantified, and the analysis revealed that their levels were below the permitted daily exposure, which are at least 6 times higher than the LOD of the selected elements. Operating in a routine mode, the proposed method is a good option for the evaluation of elemental impurities in drug active ingredients or drug final products.

Establishing Patient Centric Specifications for Drug Substance and Drug Product Impurities

In this paper, we remind readers of several ICH guideline documents such as ICH Q3A, Q3B, Q3C, Q3D, Q6A, Q6B, M7, and ICH S9 which are related to the drug substance and drug product impurity limit setting. In particular, ICH Q6A clearly states that “specifications should focus on those characteristics found to be useful in ensuring the safety and efficacy of the drug substance and drug product”; however, recent negotiations between health authority and applicants (company) related to proposed marketing applications show that on a global level, batch experience, even when limited, plays an overwhelming role in developing impurity acceptance criteria rather than clinical relevance. The drawback of such practice and the great need to establish patient centric specifications (PCS) are highlighted. Secondly, this paper proposes approaches on how to establish patient centric criteria for drug substance and drug product impurity limits based on the principles outlined in ICH guideline documents and scientific literature. Three case studies are presented to illustrate the challenges in establishing PCS and the divergence of regulatory acceptance to such specifications. We propose some approaches that can be considered for specification setting based on clinical relevance in the drug development, registration and post-approval phases of a product life-cycle. Lastly, we give thoughts on the future perspective of this movement and offer recommendations to foster discussions between regulatory agencies and pharmaceutical industry on getting medicinal products that are safe and effective to the patient sooner to meet unmet medical needs without supply interruption concerns.