Benchtop NMR Coupled with Chemometrics: A Workflow for Unveiling Hidden Drug Ingredients in Honey-Based Supplements.

Recently, benchtop nuclear magnetic resonance (NMR) spectrometers utilizing permanent magnets have emerged as versatile tools with applications across various fields, including food and pharmaceuticals. Their efficacy is further enhanced when coupled with chemometric methods. This study presents an innovative approach to leveraging a compact benchtop NMR spectrometer coupled with chemometrics for screening honey-based food supplements adulterated with active pharmaceutical ingredients. Initially, fifty samples seized by French customs were analyzed using a 60 MHz benchtop spectrometer. The investigation unveiled the presence of tadalafil in 37 samples, sildenafil in 5 samples, and a combination of flibanserin with tadalafil in 1 sample. After conducting comprehensive qualitative and quantitative characterization of the samples, we propose a chemometric workflow to provide an efficient screening of honey samples using the NMR dataset. This pipeline, utilizing partial least squares discriminant analysis (PLS-DA) models, enables the classification of samples as either adulterated or non-adulterated, as well as the identification of the presence of tadalafil or sildenafil. Additionally, PLS regression models are employed to predict the quantitative content of these adulterants. Through blind analysis, this workflow allows for the detection and quantification of adulterants in these honey supplements.

Basics of Sterile Compounding: Sterilization Methods in Sterile Product Manufacturing.

Sterilization methods to produce sterile preparations include heat, gas, radiation, and filtration. This article focuses on heat, gas, and radiation sterilization, plus a brief introduction to bright-light sterilization. Microbiology basics and microbial death kinetics, key to understanding why these sterilization methods work, will also be briefly discussed. Filtration sterilization will be covered in a separate article.

Linear solvent strength model on porous graphitic carbon stationary phase using high temperature liquid chromatographic method for allopurinol related substances analysis.

A high-performance liquid chromatography (HPLC) method was developed for the analysis of Allopurinol and its Ph.Eur. impurities using a porous graphitic carbon (PGC) stationary phase. Retention behavior of solutes was studied across a wide temperature range (30-90 °C) and various gradient times (5-20 min). Analysis of the data revealed distinct retention mechanisms between reversed-phase and PGC phases. However, it was proved that the retention of Allopurinol and its Ph.Eur. impurities on PGC stationary phase can be effectively modeled using the linear solvent strength (LSS) theory. This allows for the utilization of LSS-based method development software to optimize methods under these conditions. By using commercial chromatographic modeling software, separation of Allopurinol and Ph.Eur. impurities was optimized within a large design space. At the optimized operating conditions (pH = 2.0, tG = 6 min, T = 60 °C), all solutes were separated within 6 min with baseline resolution. Comparison between predicted and experimentally measured chromatograms further confirmed the applicability of LSS theory in developing analytical methods for PGC-based HPLC systems. The presented approach offers a general framework for method development on PGC phases.

A culture-independent nucleic acid diagnostics method for use in the detection and quantification of Burkholderia cepacia complex contamination in aqueous finished pharmaceutical products.

The Burkholderia cepacia complex (Bcc) is the number one bacterial complex associated with contaminated Finished Pharmaceutical Products (FPPs). This has resulted in multiple healthcare related infection morbidity and mortality events in conjunction with significant FPP recalls globally. Current microbiological quality control of FPPs before release for distribution depends on lengthy, laborious, non-specific, traditional culture-dependent methods which lack sensitivity. Here, we present the development of a culture-independent Bcc Nucleic Acid Diagnostic (NAD) method for detecting Bcc contaminants associated with Over-The-Counter aqueous FPPs. The culture-independent Bcc NAD method was validated to be specific for detecting Bcc at different contamination levels from spiked aqueous FPPs. The accuracy in Bcc quantitative measurements was achieved by the high degree of Bcc recovery from aqueous FPPs. The low variation observed between several repeated Bcc quantitative measurements further demonstrated the precision of Bcc quantification in FPPs. The robustness of the culture-independent Bcc NAD method was determined when its accuracy and precision were not significantly affected during testing of numerous aqueous FPP types with different ingredient matrices, antimicrobial preservative components and routes of administration. The culture-independent Bcc NAD method showed an ability to detect Bcc in spiked aqueous FPPs at a concentration of 20 Bcc CFU/mL. The rapid (≤ 4 hours from sample in to result out), robust, culture-independent Bcc NAD method presented provides rigorous test specificity, accuracy, precision, and sensitivity. This method, validated with equivalence to ISO standard ISO/TS 12869:2019, can be a valuable diagnostic tool in supporting microbiological quality control procedures to aid the pharmaceutical industry in preventing Bcc contamination of aqueous FPPs for consumer safety.

Microbiological acceptance criteria, specifications of herbal drugs and herbal drug preparations in various pharmacopoeias: a global scenario.

PURPOSE: A pharmacopoeia is a compendium of guidelines and criteria for drug quality. It was established by a national or regional entity and has legal significance. This applies to administration of drugs in a particular nation or region. METHOD: In this study, the differences and similarities of microbiological acceptance criteria, specifications for microbial enumeration of herbal drugs and herbal drug preparations in 14 national and international pharmacopeias were investigated. RESULTS: It was found that 12 pharmacopeias have given separate microbial limits for total aerobic microbial count (TAMC) and total yeast and mold count (TYMC), and a list of specified microorganisms for which acceptance criteria are defined. However, similarities were noticed in Ph.Eur, Ph. Helv and, BP. Salmonella, and Escherichia coli are the most common pathogens specified for herbal preparations in which boiling water is added prior to use and for internal use in all Pharmacopoeias because they serve as indicators of potential contamination. CONCLUSION: From this study, it can be concluded that the differences in microbial limit tests and their acceptance criteria as specified in the various pharmacopoeias need to be harmonized. It will become a more convenient option for global drug manufacturers to import/export herbal drugs, and this would also eliminate the burden of performing various analytical methods and comply with different microbial acceptance criteria set by various pharmacopoeias. The comparative data obtained from this study will be used to develop strategies for revisions of pharmacopoeias in a harmonized manner with respect to microbiological acceptance criteria, specifications for microbial enumeration of herbal drugs and herbal drug preparations.

Targeted and untargeted screening for impurities in losartan tablets marketed in Germany by means of liquid chromatography/high resolution mass spectrometry.

Technical advances in the field of quality analysis allow an increasingly deeper look into the impurity profile of drugs. The ability to detect unexpected impurities in addition to known impurities ensures the supply of high-quality drugs and can prevent recalls due to the detection of harmful unexpected impurities, as has happened recently with the N-nitrosamine and azido impurities in losartan (LOS) drug products. In the present study, the LC-MS/HRMS approach described by Backer et al. was applied to an even more complex system, being the investigation of 35 LOS drug products and combination preparations purchased in 2018 and 2022 in German pharmacies. The film-coated tablets were analysed by means of four LC-MS/HRMS method variants. For the separation a Zorbax RR StableBond C18 column (3.0 ×100 mm, particle size of 3.5 µm, pore size of 80 Å), a gradient elution and for mass spectrometric detection a qTOF mass spectrometer with electrospray ionization in positive and negative mode was used. An information-dependent acquisition method was applied for the acquisition of high-resolution mass spectrometry data. The combination of an untargeted and a targeted screening approach revealed the finding of eight impurities in total. Beside the five LOS related compounds, LOS impurity F, J, K, L, M, and related compound D from amlodipine besilate, LOS azide and an unknown derivative thereof were detected. Identification and structure elucidation, respectively, were successfully performed using in silico fragmentation. Differences in the impurity profiles of drug products from 2018 and 2022 could be observed. This study shows that broad screening approaches like this are applicable to the analysis of drug products and can be an important enhancement of the quality assurance of medicinal products.

A Novel Technique of Aseptic Manufacture of Autologous Serum Eye Drops (ASEDs) and Sterility Analysis of the Bottled Ophtioles.

PURPOSE: To introduce a novel technique of the aseptic manufacture of autologous serum eye drops (ASEDs) with a prefiltered closed system and to analyze the sterility of the produced ophtioles between 2018 and 2022. METHODS: This is a prospective single-center study conducted at the Department of Ophthalmology at a Swiss University Hospital between 2018 and 2022. For regulatory reasons, closed systems for manufacturing ASEDs are strongly recommended. We attached an upstream sterile filter (Sterivex PES0.22 µm Burlington, USA) to a commercially available closed system (COL System Modena, Italy) for manufacturing ASEDs. The goal of this novel approach was to reduce the microbiological contamination of the donated autologous blood. Using the presented manufacturing method, we are able to produce, on average, 56 ophtioles per batch, containing either 1.45 mL or 2.5 mL of autologous serum per ophtiole. For each batch of ASEDs, we performed a microbiological analysis by automated blood culture testing (BACTEC). This system examines the presence of bacteria and fungi. RESULTS: We analyzed all manufactured batches between 2018 and 2022. None of the 2297 batches and the resulting 129 060 ophtioles showed bacterial or mycotic contamination. During the analyzed period, two batches were discarded: one due to fibrin-lipid aggregations, further microbiological and histological work-up excluded any contamination; another due to false-positive HIV in serological testing. Overall, the contamination rate was 0%, and the batch discharge rate was 0.09%. CONCLUSIONS: The combination of upstream sterile filtration with a commercial closed system for manufacturing ASEDs proved to be effective in ensuring sterility without any contamination over the past 4 years. This is becoming crucial, as the demand for autologous blood products for treating ocular surface disorders, such as refractory dry eyes or nonhealing defects of the corneal epithelium, is on the rise.

Deep eutectic solvents as green and sustainable diluents in headspace gas chromatography for the determination of trace level genotoxic impurities in pharmaceuticals.

Genotoxic impurities (GTIs) are potential carcinogens that need to be controlled down to ppm or lower concentration levels in pharmaceuticals under strict regulations. The static headspace gas chromatography (HS-GC) coupled with electron capture detection (ECD) is an effective approach to monitor halogenated and nitroaromatic genotoxins. Deep eutectic solvents (DESs) possess tunable physico-chemical properties and low vapor pressure for HS-GC methods. In this study, zwitterionic and non-ionic DESs have been used for the first time to develop and validate a sensitive analytical method for the analysis of 24 genotoxins at sub-ppm concentrations. Compared to non-ionic diluents, zwitterionic DESs produced exceptional analytical performance and the betaine : 7 (1,4- butane diol) DES outperformed the betaine : 5 (1,4-butane diol) DES. Limits of detection (LOD) down to the 5-ppb concentration level were achieved in DESs. Wide linear ranges spanning over 5 orders of magnitude (0.005-100 µg g-1) were obtained for most analytes with exceptional sensitivities and high precision. The method accuracy and precision were validated using 3 commercially available drug substances and excellent recoveries were obtained. This study broadens the applicability of HS-GC in the determination of less volatile GTIs by establishing DESs as viable diluent substitutes for organic solvents in routine pharmaceutical analysis.

Quality control in SARS-CoV-2 RBD-Fc vaccine production using LC-MS to confirm strain selection and detect contaminations from other strains.

Coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing outbreak, disrupting human life worldwide. Vaccine development was prioritized to obtain a biological substance for combating the viral pathogen and lessening disease severity. In vaccine production, biological origin and relevant materials must be carefully examined for potential contaminants in conformity with good manufacturing practice. Due to fast mutation, several SARS-CoV-2 variants and sublineages have been identified. Currently, most of COVID-19 vaccines are developed based on the protein sequence of the Wuhan wild type strain. New vaccines specific for emerging SARS-CoV-2 strains are continuously needed to tackle the incessant evolution of the virus. Therefore, in vaccine development and production, a reliable method to identify the nature of subunit vaccines is required to avoid cross-contamination. In this study, liquid chromatography-mass spectrometry using quadrupole-time of flight along with tryptic digestion was developed for distinguishing protein materials derived from different SARS-CoV-2 strains. After analyzing the recombinantly produced receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, nine characteristic peptides were identified with acceptable limits of detection. They can be used together to distinguish 14 SARS-CoV-2 strains, except Kappa and Epsilon. Plant-produced RBD-Fc protein derived from Omicron strains can be easily distinguished from the others with 4-5 unique peptides. Eventually, a peptide key was developed based on the nine peptides, offering a prompt and precise flowchart to facilitate SARS-CoV-2 strain identification in COVID-19 vaccine manufacturing.

Development of a loop-mediated isothermal amplification assay for the rapid detection of Styphnolobium japonicum (L.) Schott as an adulterant of Ginkgo biloba (L.).

BACKGROUND: Species adulteration is a concern in herbal products, especially when plant substitutes of lower economic value replace valuable botanicals. Styphnolobium japonicum is well known as a potential adulterant of Ginkgo biloba, which is one of the most demanded medicinal plants due to its wide use in pharmaceuticals, food supplements, and traditional medicine. Despite bearing some resemblance to ginkgo's flavonol composition, S. japonicum lacks many of G. biloba's desired therapeutic properties. To prevent adulteration practices, it is crucial to implement rigorous quality control measures, including fast and simple diagnostic tools that can be used on-field. PURPOSE: This study aims to develop for the first time a species-specific loop-mediated isothermal amplification (LAMP) method for the fast identification of S. japonicum in ginkgo-containing products. METHODS: A set of four specific primers (SjF3, SjB3, SjFIP, and SjBIP) and loop primers (SjLF and SjLB) were designed for a LAMP based assay using the 5.8S partial sequence and the internal transcribed spacer 2 of nuclear ribosomal DNA of S. japonicum. RESULTS: The successful amplification of the LAMP assay was inspected through visual detection, with the highest intensity recorded at the optimal conditions set at 68 °C for 40 min. The primers showed high specificity and were able to accurately discriminate S. japonicum from G. biloba and 49 other species of medicinal plants. Furthermore, the proposed LAMP assay proved to be fast, selective, and highly sensitive, as demonstrated by the absolute and relative limits of detection, which were reached at 0.5 pg for S. japonicum DNA and 0.01 % S. japonicum in G. biloba, respectively. CONCLUSIONS: This novel approach allows easy identification and discrimination of S. japonicum as a potential adulterant of G. biloba, thus being a useful tool for quality control. Compared to chromatographic or PCR-based methods, the assay proved to be fast, sensitive and did not require expensive equipment, thus offering the possibly usage in field analysis.

Proceedings of the 2023 Viral Clearance Symposium, Session 8: Cell Banks, Advanced Technologies (ATMPs, NGS).

The Cell Banks, Advanced Technologies (ATMPs, NGS) session at the 2023 Viral Clearance Symposium (VCS) focused on the assurance of high virus safety profiles of advanced technology medicinal products (ATMPs) by implementation of advanced virus detection methods using rapid and sensitive technologies, such as next-generation sequencing (NGS). All presentations in this session made the need to replace in vivo testing for viruses by new technologies that have been demonstrated to be incomparably broad in their detection capabilities and can even detect unknown viruses. An evaluation of historical data collected by the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) from their members' in vivo and in vitro adventitious virus test experience as well as on using NGS was presented. The data convincingly supported the necessity to replace in vivo testing with faster, broader, more sensitive, more accurate, and more specific virus detection methods. Additionally, a collaborative study-initiated by the CAACB-with the goal to revisit traditional adventitious agent testing by using targeted NGS to replace in vivo and in vitro tests for well-known and broadly used Chinese hamster ovary (CHO) cells was presented, including the planned risk-assessment approach using prior knowledge and historical data. Overall, this session demonstrated that the use of new virus detection methods, such as NGS, represents a great opportunity to provide sufficient viral safety margins, specifically, for ATMPs, where downstream virus clearance is not possible. This path forward is also supported by the final ICH Q5A(R2) guideline.

Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening.

Plastic components are essential in the pharmaceutical industry, encompassing container closure systems, laboratory handling equipment, and single-use systems. As part of their material qualification process, studies on interactions between plastic contact materials and process solutions or drug products are conducted. The assessment of single-use systems includes their potential impact on patient safety, product quality, and process performance. This is particularly crucial in cell and gene therapy applications since interactions with the plastic contact material may result in an adverse effect on the isolated therapeutic human cells. We utilized the cell painting assay (CPA), a non-targeted method, for profiling the morphological characteristics of U2OS human osteosarcoma cells in contact with chemicals related to plastic contact materials. Specifically, we conducted a comprehensive analysis of 45 common plastic extractables, and two extracts from single-use systems. Results of the CPA are compared with a standard cytotoxicity assay, an osteogenesis differentiation assay, and in silico toxicity predictions. The findings of this feasibility study demonstrate that the device extracts and most of the tested compounds do not evoke any measurable biological changes on the cells (induction ≤ 5%) among the 579 cell features measured at concentrations ≤ 50 µM. CPA can serve as an important assay to reveal unique information not accessible through quantitative structure-activity relationship analysis and vice versa. The results highlight the need for a combination of in vitro and in silico methods in a comprehensive assessment of single-use equipment utilized in advanced therapy medicinal products manufacturing.

How to Evaluate If Microorganisms Isolated From Sterile Drug Production Environments Monitoring Are Undesirable.

This study addresses the identification of undesirable microorganisms (MOs) recovered during the environmental monitoring in manufacture of sterile medicinal products. We developed a methodology evaluation based on a decision tree; then, such approach was applied to hypothetical scenarios of uncommon MOs isolation in sterile drugs production settings. The scenarios were formulated on the basis of our field experience, in terms of both MOs selection and types of sampling site. The MOs were chosen in order to include emerging pathogens and MOs responsible for drug recall, and several sampling sites were considered for their detection (air, surfaces, and personnel). The classification of the unusual MOs revealed that most of them were undesirable, because they represented the loss of environmental control or a potential impact on the quality of the product. In some cases, the uncommon MOs were not considered as undesirable. Therefore, our results demonstrated the importance of a methodology, also in terms of recovery rate of unusual MOs and of the threshold probability for the unacceptability (e.g., 1% or 5%). The proposed methodology allowed an easy and documented evaluation for the undesirable MOs isolated from the environment of the analyzed settings for sterile drugs production.

Identification and quantification of medical device extractables and leachables via non-target analysis (NTA); Analytical uncertainty.

Leachables are substances that are leached from a medical device during its clinical use and are important due to the patient health-related effects they may have. Thus, medical devices are profiled for leachables (and/or extractables as probable leachables) to assess their potential impact on patient health and safety. This profiling is accomplished by screening extracts or leachates of the medical device for released organic substances via non-targeted analysis (NTA) employing chromatographic methods coupled with mass spectrometric detection. Chromatographic mass spectral response factors (RFs) for extractables and leachables vary significantly from compound to compound, complicating the quantitation of these compounds and the application of assessment strategies such as the Analytical Evaluation Threshold (AET). The analytical uncertainty resulting from response factor variation can be expressed in terms of an uncertainty factor (UF), which estimates the magnitude of response factor variation. This manuscript discusses the concept and impact of analytical uncertainty and provides best practice recommendations for the calculation and use of the uncertainty factor, UF.

Cell and Gene Therapies: Challenges in Designing Extractables and Leachables Studies and Conducting Safety Assessments.

Over the past decade, Cell and Gene Therapies (C>) have been an emerging therapeutic area with more than twenty C> drug products approved and over 1000 registered trials. The remarkable progress in these modalities brings new challenges for scientists who evaluate manufacturing and storage materials, including risk assessments for extractables and leachables (E&L). Establishing a business process to qualify materials for these applications is an important risk mitigation strategy in support of these assessments. Process validation verifying process performance and product quality requirements using qualified materials also ensures that leachables from the materials do not result in an impact to process and product. The authors provide an overview of available guidelines and publications relevant to E&L risk assessments that can be used to support ex vivo C> products, highlighting gaps and standardization needs in the areas of biocompatibility and extractables conditions. Finally, the authors present leachable testing strategies, relevant to the specific manufacturing and storage conditions of C> products, and safety assessment considerations for organic and inorganic chemical entities.

Evaluation of a Novel LC-MS/MS Based Analytical Method for the Risk Assessment of Nitrosamines in Pharmaceutical Products and Packaging Materials.

The detection of nitrosamine impurities, particularly small dialkyl types, which are frequently known to be potent mutagenic carcinogens, in some Sartan group active pharmaceutical ingredients (APIs) and finished drug products caused global regulatory organizations to have concerns. Accordingly, Registration Holders/Applicants, API manufacturers, and their raw material suppliers are required to check the presence of nitrosamines in their products and carry out risk assessments using the quality risk management principles specified in the ICH Q9 guide. In this context, a new LC-MS/MS method has been developed and validated for the simultaneous determination of NDMA, NDEA, NMBA, NDIPA, NEIPA, NDBA, and MeNP nitrosamine compounds in API and finished products as well as in primary packaging materials, one of the risk sources. This validated method was applied to check the nitrosamine content may occur from canister, blister, printed aluminum foil, nasal spray, and eye drop packaging materials as part of the Extractables & Leachables studies arising from interactions between the product and the primary packaging. For the determination and quality control of nitrosamines in sartan group pharmaceutical products and packaging materials, the developed LC-MS/MS analytical method offers highly reliable, fast, high accuracy, good sensitivity and simultaneous detection even at low concentrations.

A new ultrasound-assisted microextraction for elemental impurities determination in tablets by ICP-MS according to USP chapters 232 and 233.

Along with the United States Pharmacopeia (USP) chapters 232 and 233 regarding elemental impurities in pharmaceutical products, new challenges have been imposed in terms of sample preparation procedures prior to inductively coupled plasma mass spectrometry analysis, considering the matrix complexities. As so, a new microextraction procedure assisted by ultrasound using a cup-horn sonoreactor, minimal reactants, and sample was proposed and validated according to USP. The procedure was optimized with samples of milled tablets and 3 different acid mixtures (HNO3, 3HNO3:1HCl, and 9HNO3:1HF) and it was compared with microwave-assisted acid digestion. In the validation step, recoveries ranging from 85 to 120 % and RSD below 10 % were obtained for 22 analytes (except Ag and Pt) with satisfactory linearity and good sensitivity. The method was then applied for 37 samples of antidepressants, which presented trace levels of As, Ba, Cd, Co, Cr, Cu, Ni, Pb, Pd, Sn, and V.

Pilot study: External surface contamination of gemcitabine and 5-fluorouracil on drug packaging.

INTRODUCTION: Antineoplastic drugs (ADs) are commonly used pharmaceuticals for anticancer treatments. It has previously been shown that the external surface of drug vials frequently is contaminated with ADs. More than a decade ago methods to prevent occupational exposure were introduced by using plastic coverage of the glass vials or packing vials in a secondary plastic container. The aim of the pilot study was to determine contamination levels of ADs on different parts of AD packaging of two different commercially available drug vials on the Swedish market and to investigate the occurrence of cross contamination of ADs. METHODS: Packagings of gemcitabine (GEM) and 5-fluorouracil (5-FU) were tested by wipe sampling. Five ADs; GEM, 5-FU, cyclophosphamide (CP), ifosfamide and etoposide were quantified using liquid chromatography mass spectrometry. RESULTS: AD contaminations were detected in 69% and 60% of the GEM and 5-FU packaging samples. Highest levels, up to approximately 5 µg/sample, were observed on the glass vials. The protective shrink-wrap of 5-FU vials and the plastic container of GEM were contaminated with low levels of 5-FU and GEM, respectively, and furthermore the 5-FU vials with shrink-wrap were cross-contaminated with GEM. Cross-contamination of CP and GEM was detected on 5-FU vials with plastic shrink-wrap removed. CONCLUSIONS: External contamination of ADs are still present at primary drug packagings on the Swedish market. Protection of AD vials by plastic shrink-wrap or a secondary plastic container does not remove the external contamination levels completely. The presence of cross contamination of ADs on drug packagings was also observed.

Genotoxic Impurities in Critical Analysis of Product Development: Recent Advancements, Patents, and Current Challenges.

The current review intends to regulate and accurately evaluate genotoxic contaminants in drug substance and drug product method and formulation process development, validation, and degradation pathways. The Quality by Design (QbD) principles can be applied to the systematic evaluation and control of impurities enabled by the development of modern analytical techniques, including the performance of risk assessment, the screening of Critical Process Parameters (CPPs), and the identification of the most influential variables in the optimization of the evaluation and control methods. Current difficulties in removing genotoxic contaminants and the procedures for doing so have been outlined in this review, along with the steps necessary to acquire optimum techniques and the most acceptable formulations. In addition to this, division, characterization, assessment, quantification, and formation of genotoxic impurities sources and control strategy for genotoxic impurities, handling of nitrosamine assay content of drug products in different industrial methodologies and their chemometric prospects and associated recent patents are also explored.

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.