Pharmaceutical Packaging Materials Research Articles

Development and Validation of an ICP‐OES Method to Determine Extractable and Leachable Metals in HDPE (Plastic) Pharmaceutical Packaging Material

ABSTRACTThe safety and effectiveness of pharmaceutical medicines depend heavily on extractables and leachables. Patients may be adversely affected by contaminants that enter drug products through packing materials. As a result, regulatory organizations like the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have set standards and regulations for evaluating and managing extractables and leachables. Characterizing the packing materials, carrying out extraction experiments and checking the extracted solutions for contaminants are all parts of this research. As part of the process for approving new drugs, regulatory agencies make use of these data. In present work, an inductively coupled plasma optical emission spectroscopy (ICP‐OES) method is developed and validated for quantifying trace elements from a high‐density polyethylene (HDPE) packaging material. The approach delineated in accordance with United States Pharmacopoeia (USP) <661.1> and <661.2> for the comprehensive analysis of 16 metallic elements including aluminium, arsenic, cadmium, chromium, cobalt, lead, mercury, nickel, titanium, vanadium, zinc, zirconium, barium, manganese, calcium and tin is applicable for evaluating the efficacy of packaging materials. The method detection limits (MDLs) complied as per USP 39‐NF 34 <661.1> along with relative standard deviations (RSDs) obtained were ranging from 0.3% to 3.1% and recoveries of all elements spiked at two different trace levels in HDPE samples were within 97%–110%, providing sensitive, accurate and reproducible methodology.

Eco Friendly Pharmaceutical Packaging

Abstract: Concerns over environmental contamination have been raised by the use of nonbiodegradable and non-renewable materials such as glass, plastics, and metals in packaging applications. With the goal of lessening the environmental impact of petroleum-based packaging materials, an extensive amount of research has been conducted to find alternative packaging materials. Due to their biodegradability, studies have shown that using bio-polymer-based materials can reduce the amount of packaging waste produced, which could partially address the issue of trash disposal. This review article is mainly focused on eco-friendly biodegradable material that can replace nonbiodegradable pharmaceutical packaging material. These materials come from natural resources like proteins, carbohydrates, etc. that have negligible to no negative effects on the environment and organisms that depend on it. This article depicts how we can replace the existing non-biodegradable plastics with eco-friendly material as the use of pharmaceutical packaging material also plays a crucial role in the therapeutic performance of pharmaceutical products.

Environmental Impact of Treatment of Pharmaceutical Packaging Materials

Environmental Impact of Treatment of Pharmaceutical Packaging Materials

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.

Applicability of polypropylene/polyethylene glycol/molecular sieve composites as desiccant pharmaceutical packaging materials

Pharmaceutical oral dosage forms are vulnerable to moisture-induced damage during transport and storage. This paper investigates the applicability of polypropylene (PP), polyethylene glycol (PEG), and molecular sieve (MS) as packaging materials, focusing on their moisture-absorbing properties, to mitigate this issue. PP/PEG/MS composites were developed in this study to replace conventional desiccants. These composites absorb moisture via hydrophilic channels, physically formed by PEG and MS. The efficacy of moisture absorption is influenced by the number of these PEG channels, functioning as molecular sieves. Increasing MS content in the composites led to decreased mechanical strength, attributed to an inhomogeneous interface with the PP. In storage tests, the composites effectively reduced moisture content and water activity, particularly in multivitamin tablet packaging. These results indicate that the PP/PEG/MS combination efficiently protects the hydration of pharmaceutical products and can be used as a packaging material.

Ecofriendly pharmaceutical packaging material: A review

One of the possible dosage regimens allows pharmaceutical goods to be packaged in environmentally friendly pharmaceutical packaging materials. Proteins, carbohydrates, and other naturally occurring chemicals that do not severely disturb the ecosystem or the animals that depend on them may have given rise to them. The focus of this reviewis on environmentally friendly products, their utilization, and the advantages of categorizing them before summarizing the range and future requirements for pharmaceutical packaging. A variety of industries, including biomedical technology, integrated nutritional labeling, drug delivery, power train, bio-membranes, and industrial composting, are actively interested in utilizing bio-composite materials that are both renewable and biodegradable. Due to its distinct advantages over conventional plastics made of petrochemicals, green packaging made of biodegradable composite materials is presently generating a lot of attention in a variety of fields. They are fully biodegradable and entirely degrade into carbon dioxide, water, and humus. Therefore, enhancing the major goal of packaging is to increase both safety and quality of food while extending the product's period of storage.

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 Migration Behavior of Extractables from Mono- and Multilayer Polyolefin Films to Mathematically Predict the Concentration of Leachable Impurities in Pharmaceutical Drug Products. Part 2: Conservative Diffusion and Partition Coefficient Determinations.

In the development of a pharmaceutical drug product packaging, an important step is to demonstrate acceptable levels of leachable impurities migrating from the packaging material into the drug product during its shelf life and therapeutic use. Such migration processes can be quantified either by analytical methods (which is often challenging and labor intensive) or (in many cases) through theoretical modeling, which is a reliable, quick, and cost-effective method to forecast the level of leachable impurities in the packaged drug when the diffusion and partition coefficients are known. In the previous part, it was shown how these parameters can be determined experimentally, and subsequent theoretical fitting of the results for a series of low- and high-molecular-weight organic compounds (known leachables) in a series of polyolefin materials was performed. One of the interpretations of these results is that a theoretical calculation can be made only for organic compounds and materials whose diffusion/partition/solubility coefficients were determined experimentally and theoretical fitting was achieved. However, in practice, there will be situations in which other leachable compounds may have to be investigated. In such cases, strictly speaking, it would be necessary to perform the whole experimental and fitting procedure for the new compound before a proper theoretical modeling is possible. But this would make the theoretical calculation of a leaching process from a pharmaceutical packaging material a cumbersome and cost intensive procedure. To address this problem, the pools of diffusion and partition coefficients were used to develop an approach that allows the estimation, without any additional experimentation, of so-called "conservative" diffusion and partition coefficients for a much wider range of potential leachables in the polyolefin pharmaceutical packaging materials and aqueous solutions investigated previously.

Identification and quantification of extractables and leachables in laminated film and pouches for pharmaceutical packaging

Extractables and leachables from pharmaceutical packaging material can potentially be detrimental, which may affect the safety of the drug products. In this study, two compounds were found to be the possible extractables from the secondary packaging material. A strategy combining high performance liquid chromatography (HPLC), fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and nuclear magnetic resonance (NMR) spectroscopy was utilized for identification of the two compounds. Afterwards, a simple and sensitive HPLC method was developed and validated for the simultaneous quantification of both. The results indicated that this method was suitable for quantificating the two extractables in the pharmaceutical packaging material.

Attitudes and Considerations towards Pharmaceuticals-Related Environmental Issues among Finnish Population

A number of policy recommendations identify the general public as a key participant in environmentally sustainable pharmaceutical policies. However, research into pharmaceuticals-related environmental issues from the population perspective is scarce. We studied the awareness among Finnish adults (n = 2030) of pharmaceutical residues in Finnish waterways, their perceived environmental sources, views on pharmaceuticals-related environmental issues, and their association with background characteristics. Of the respondents, 89.5% were aware of the presence of pharmaceuticals in Finnish waterways. Wastewaters from the pharmaceutical industry were most frequently, and pharmaceuticals excreted by humans least frequently, considered a major environmental source of pharmaceuticals. The vast majority of the respondents were worried about the environmental and health impact of pharmaceutical residues and emphasized issues such as the importance of environmentally sustainable actions by pharmaceutical companies and the recyclability of the pharmaceutical packaging materials. Age, education, use of prescription medicines, and environmental attitude were associated with awareness of pharmaceutical residues, while gender, age, education level, and environmental attitude were associated most frequently with pharmaceuticals-related environmental considerations. These results indicate a need for improved communication about the environmental effects of pharmaceuticals and the significance of different pharmaceutical emission sources in order to promote a more environmentally friendly, effective pharmaceutical policy.

Methyl Esterification Combined with Gas Chromatography-Mass Spectrometry (GC-MS) for Determining the Contents of Lubricant to Evaluate the Compatibility of Chlorinated Butyl Rubber Stoppers with Liposome Injections.

A simple, sensitive, and exact methyl esterification in combination with gas chromatography-mass spectrometry (GC-MS) method was developed to determine the contents of palmitic acid and stearic acid in the chlorinated butyl rubber stoppers and liposome injections in order to evaluate the compatibility of pharmaceutical packaging materials. In this experiment, palmitic acid and stearic acid were detected in the form of methyl hexadecanoate and methyl stearate in chlorinated butyl rubber stoppers and liposome injections. The results showed good linearities in the range of 0.50–10.00 µg·mL−1 for methyl hexadecanoate and 1.00–20.00 µg·mL−1 for methyl stearate, with the limits of detection (LOD) 11.94 ng·mL−1 and 11.90 ng·mL−1, respectively. The recoveries that ranged from 95.25% to 100.29% were satisfied, and the relative standard deviation (RSD) was no more than 7.16%. The developed method was successfully applied to evaluate the compatibility of chlorinated butyl rubber stoppers with liposome injections and the safety assessment.

Design of Nanosilver-Epoxy Films for Hygienic Pharmaceutical Packaging

Nanosilver-in-epoxy lining can serve as self-disinfecting coating in pharmaceutical packaging materials and surfaces. Silver nanoparticles were synthesized using antioxidant-rich fractions of the methanolic extracts of Alchornea cordifolia. The concentration ratio of extract to silver nitrate was varied (from 2:1, 1:1 to 1:4) to obtain several batches of silver nanoparticles (A to F). The resulting silver nanoparticles were characterized using UV-visible spectroscopy, photon correlation spectroscopy, and atomic force microscopy. Antimicrobial activities of the batches of silver nanoparticles were tested in vitro using selected bacteria and fungi. Different volumes of the optimized silver nanoparticles solution were mixed with epoxy resin in different ratios, resulting in film 1 (21% v/v) and film 2 (40% v/v). Square films were cut from the coated substrate and their antimicrobial inhibition, eye irritation, and other properties tested. The optimized silver nanoparticles (batch D) were obtained by reacting the extract and silver nitrate in a 1:2 ratio, and it exhibited an excellent activity against both gram-positive and gram-negative organisms as well as fungi. It also exhibited the lowest 2-month particle size and polydispersity. Films 1 and 2 differed significantly in bioactivity (P < 0.05), with film 2 demonstrating a good level of inhibition against Escherichia coli, Staphylococcus aureus, and Salmonella typhi, but not fungi. It did not elicit any irritation using the Draize eye irritation model. Silver nanoparticle-in-epoxy matrix synthesized with the extract maintains an adequate level of antibacterial activity and finds application in protecting surfaces and packages where bacterial contamination may pose a problem.

Preparation of alcohol-based handrub in COVID-19 Alsatian cluster

AbstractAlsace, in particular Haut-Rhin, is one of the main clusters of COVID-19 in France. There has been a shortage of essential supplies in the area, especially alcohol-based hand sanitizer. In this context, and in accordance with the decree dated March 6, 2020, our hospital management team asked us to start local production of alcohol-based handrub. This was a real challenge: In one week, we had to implement the production of handrub to meet the needs of a 1,400-bed hospital. The production had to comply with the French preparation guidelines and take place on specific premises, with qualified and calibrated equipment, by qualified staff, under the supervision of a pharmacist. The other big challenge we faced was the supply of pharmaceutical raw and packaging materials. During this particular critical period, all suppliers were out of stock. Here, we describe the organizational set-up and the decisions made, e. g., to use technical-grade ethanol before the publication of the decrees dated March 13 and March 23, 2020.

Rationality Evaluation of Packaging Materials and Study on Impurity Profiling of Cilnidipine Preparations by HPLC-Q-TOF/MS

Background: The rationality of cilnidipine tablets and capsules with four different pharmaceutical packaging materials was evaluated, and the structure of photodegradation impurities was analyzed by LC-Q-TOF. Materials and Methods: The impurity profiling of commercial cilnidipine tablets and capsules was analyzed by LC-Q-TOF for the further improvement of official monograph in pharmacopoeias and the source of the impurities was investigated. The contents of photodegradation impurities were analyzed by HPLC, and remarkable difference in the formation of the photodegradation impurities in cilnidipine tablets and capsules with four different pharmaceutical packaging materials was observed. The shading effect of the four packaging materials was investigated by UV-Vis spectrophotometer and a remarkable difference was detected, which might be responsible for the difference in the formation of photodegradation products. The structures of photodegradation products were further characterized by LC-Q-TOF MS/MS. Five impurities in commercial cilnidipine tablets and capsules were separated and identified based on the high resolution MS/MS data. Results: The obtained results revealed that the impurity III was derived from the ethanol solution of cilnidipine when it was exposed to light, and the impurity II was produced when the cilnidipine powder was exposed to light directly. The concentrations for 50% reduction of impurity II and impurity III on the Chinese hamster lung cells (CHL) with CellTiter-Glo method were studied and the results indicated that the cytotoxicity of impurity II and impurity III on CHL cells was larger than cytotoxicity of cilnidipine. Conclusion: On the basis of our study, we suggested that the pharmaceutical packaging materials of cilnidipine tablets should be modified.

Method Development and Validation for Simultaneous Determination of 44Ca, 34S, 28Si and 18 Other Trace Elements in Pharmaceutical Packaging Materials’ Extractable Solutions by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS)

ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) already issued and implemented Q3D guideline in elemental impurities in final drug products. Consequently, it will be essential to monitor trace elements from packaging material to ensure the final drug product compliance. This study successfully developed a new method for simultaneous identification and quantification of 44Ca, 34S, 28Si and 18 trace elements (27Al, 51V, 52Cr, 55Mn, 56Fe, 58Ni, 59Co, 63Cu, 66Zn, 75As, 78Se, 95Mo, 111Cd, 118Sn, 121Sb, 137Ba, 201Hg and 208Pb) in pharmaceutical packaging materials’ extractable solutions by using ICP-MS in one single method without auxiliary. The method development focused on elemental mass selection, optimization of ICP-MS operational parameters and the sample/standard solutions preparation. Furthermore, the new developed analytical method (accuracy and precision, standard and sample linearity, matrix specificity and robustness of the method) was successfully validated by following US and European compendia criteria. The success of the analytical method development and validation illustrates that the trace elements analysis in pharmaceutical industry becomes feasible per the single ICP-MS method. The analysis of trace elements via this new developed ICP-MS method can provide the worthy information for risk assessment of packaging system and final drug products with relatively low operational cost.

Application of dispersive liquid–liquid microextraction based on solidification of floating organic drop for the determination of extractables from pharmaceutical packaging materials

A new method was established for the determination of the extractables from pharmaceutical packaging materials using dispersive liquid–liquid microextraction based on solidification of floating organic drop (DLLME-SFO) coupled with ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Packaging samples were filled with three kinds of buffer solutions: acid buffer (pH = 3), alkaline buffer (pH = 9) and 0.9% NaCl solution to extract as many extractables as possible, and then the extractables in buffer solutions were enriched by DLLME-SFO technique. Parameters affecting the efficiency of the extraction procedure were evaluated and optimized, including the type and volume of dispersant, extractant volume, pH and vortex-mixing time. After optimization, the values obtained for limits of detection and quantification for three kinds of common antioxidants were 0.3 and 1.0 μg/L respectively, and good linearity (R2 > 0.99) was observed in their respective concentration ranges. The recoveries ranged from 80.61% to 117.87% at three spiked levels with the relative standard deviations (RSDs) between 0.92% and 9.29% (n = 6) in all three buffer solutions. The developed method was successfully applied to the analysis of extractables from pharmaceutical packaging materials. The results indicated that the proposed procedure is a novel, sensitive, fast and repeatable method and has a great significance for evaluation of safety of pharmaceutical packaging materials.

Cyclo Olefin Polymer (COP) as Pharmaceutical Packaging Materials

Cyclo Olefin Polymer (COP) as Pharmaceutical Packaging Materials

Chemical Approaches for the Identification of PVC and PVDC in Pharmaceutical Packaging Materials

Chemical Approaches for the Identification of PVC and PVDC in Pharmaceutical Packaging Materials

Comparison of a Lyophilized Drug Product to Other Solid and Liquid Media for the Extraction of Elastomeric Oligomers from a Butyl Rubber Stopper.

Lyophilization is commonly used to extend the shelf life of pharmaceutical products that are otherwise unstable when stored as a liquid formulation. However, the ability of a lyophilized drug, or other solid medium, to leach or extract substances from a pharmaceutical packaging material is not well characterized. To provide insight into this area of uncertainty, the extraction properties of a lyophilized drug product, the lyophilized drug product reconstituted in water, and several other solid and liquid media of varying polarity were determined using a glass vial with a butyl rubber stopper as a representative pharmaceutical packaging system. The results obtained in this study show that the extracting power of a medium, whether solid or liquid, was primarily a function of polarity. Thus, the amount of each extractable observed for the lyophilized and reconstituted drug product were in trend with the other solid and liquid media, respectively. Nevertheless, it was notable that the lyophilized drug product was able to leach substances from the stopper in quantifiable amounts, whereas the reconstituted drug product contained no detectable leachables. Using a mathematical relationship, it was determined that the extraction power of the lyophilized drug product was equivalent to a 50/50 isopropanol/water solution.LAY ABSTRACT: Freeze drying is commonly used to extend the shelf life of pharmaceutical products that are otherwise unstable when stored as a liquid formulation. However, the propensity for substances to migrate from a pharmaceutical packaging material and into a solid drug formulation is not well characterized. To provide insight into this area of uncertainty, the migration of substances from a glass vial with a butyl rubber stopper and into a lyophilized drug product, the drug product reconstituted with water, as well as several solid and liquid media of varying polarity were assessed. The results obtained in this study show that the extracting power of a medium, whether solid or liquid, was primarily a function of polarity and thus could be related to one another. Furthermore, the results for the freeze-dried and reconstituted drug products were in trend with the other solid and liquid media tested, respectively, and showed that the freeze-dried drug was able to leach substances from the stopper in measureable amounts, whereas the reconstituted drug product contained no substances that had originated from the stopper.

Short-range and long-range cross-linking effects of polygenipin on gelatin-based composite materials.

Genipin is an ideal cross-linking agent in biomedical applications, which can undergo ring-opening polymerization in alkaline condition. The polygenipin can create short-range and long-range intermolecular cross-linking between protein chains. In this article, the polygenipin with different degree of polymerization was successfully prepared and used to fix gelatin composite materials. The short-range and long-range cross-linking effects of polygenipin were systematically studied. The results show that the composite materials present porous structure with tunable pore sizes in the gel state, which can be easily controlled by adjusting the degree of polymerization of polygenipin. Long-range cross-linking can increase the pore size of the gel. However, during the drying process, the composite films cross-linked by polygenipin with higher degree of polymerization shrank to smaller size to create more compact structure, resulting in the improvement of water resistance properties, thermal stability, tensile strength, and darker color for the composite films. It is interesting that the composite films can partly swell to the original gel structure when in contact with water and saturated water vapor. All the composite films have excellent barrier properties against UV light. However, the compatibility of gelatin and polygenipin is reduced when the degree of polymerization of polygenipin increases to a certain extent, which will result in the formation of phase separation structure. The obtained composite films are ideal candidates for food and pharmaceutical packaging materials. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2712-2722, 2016.