Accelerated Predictive Stability Study of a Pediatric Drug Product for a Supplemental New Drug Application.

In this paper, we report two Accelerated Stability Assessment Program (ASAP) studies for a pediatric drug product. Whereas the first study using a generic design failed to establish a predictive model, the second one was successful after troubleshooting the first study and customizing the study conditions. This work highlighted important lessons learned from designing an ASAP study for formulations containing excipients that could undergo phase change at high humidity levels. The stability predictions by the second ASAP model were consistent with available long-term stability data of the drug product under various storage conditions in two different packaging configurations. The ASAP model was part of the justifications accepted by the health authority to submit a stability package with reduced long-term stability data from the primary stability batches for a Supplemental New Drug Application (sNDA).

Characterization of Freezing Processes in Drug Substance Bottles by Ice Core Sampling.

Freezing of biological drug substance (DS) is a critical unit operation that may impact product quality, potentially leading to protein aggregation and sub-visible particle formation. Cryo-concentration has been identified as a critical parameter to impact protein stability during freezing and should therefore be minimized. The macroscopic cryo-concentration, in the following only referred to as cryo-concentration, is majorly influenced by the freezing rate, which is in turn impacted by product independent process parameters such as the DS container, its size and fill level, and the freezing equipment. (At-scale) process characterization studies are crucial to understand and optimize freezing processes. However, evaluating cryo-concentration requires sampling of the frozen bulk, which is typically performed by cutting the ice block into pieces for subsequent analysis. Also, the large amount of product requirement for these studies is a major limitation. In this study, we report the development of a simple methodology for experimental characterization of frozen DS in bottles at relevant scale using a surrogate solution. The novel ice core sampling technique identifies the axial ice core in the center to be indicative for cryo-concentration, which was measured by osmolality, and concentrations of histidine and polysorbate 80 (PS80), whereas osmolality revealed to be a sensitive read-out. Finally, we exemplify the suitability of the method to study cryo-concentration in DS bottles by comparing cryo-concentrations from different freezing protocols (-80°C vs -40°C). Prolonged stress times during freezing correlated to a higher extent of cryo-concentration quantified by osmolality in the axial center of a 2 L DS bottle.

Research on defect detection of bottle cap interior based on low-angle and large divergence angle vision system.

During the machine vision inspection of the inner section of bottle caps within pharmaceutical packaging, the unique conca bottom and convex side walls often create obstructions to the illumination. Consequently, this results in challenges such as irregular background and diminished feature contrast in the image, ultimately leading to the misidentification of defects. As a solution, a vision system characterized by a Low-Angle and Large Divergence Angle (LALDA) is presented in this paper. Using the large divergence angle of LED, combined with low-angle illumination, a uniform image of the side wall region with bright-field characteristics and a uniform image of inner circle region at the bottom with dark-field characteristics are obtained, thus solving the problems of light being obscured and brightness overexposure of the background. Based on the imaging characteristics of LALDA, a multi-channel segmentation (MCS) algorithm is designed. The HSV color space has been transformed, and the image is automatically segmented into multiple sub-regions by mutual calculation of different channels. Further, image homogenization and enhancement are used to eliminate fluctuations in the background and to enhance the contrast of defects. In addition, a variety of defect extraction methods are designed based on the imaging characteristics of different sub-regions, which can avoid the problem of over-segmentation in detection. In this paper, the LALDA is applied to the defect detection inside the cap of capsule medicine bottle, the detection speed is better than 400 pcs/min and the detection accuracy is better than 95%, which can meet the actual production line capacity and detection requirements.

Field testing of user-friendly perennial malaria chemoprevention packaging in Benin, Côte d'Ivoire and Mozambique.

BACKGROUND: Perennial malaria chemoprevention (PMC) aims to protect children at risk from severe malaria by the administration of anti-malarial drugs to children of defined ages throughout the year. Sulfadoxine-pyrimethamine (SP) has been widely used for chemoprevention in Africa and a child-friendly dispersible tablet formulation has recently become available. METHODS: This qualitative non-interventional observational study was conducted in Benin, Côte d'Ivoire, and Mozambique between February and June 2022. Prototype blister packs, dispensing boxes and job aids designed to support dispersible SP deployment for PMC were evaluated using focus group discussions (FGD) and semi-structured in-depth individual interviews (IDI) with health authorities, health personnel, community health workers (CHWs) and caregivers. The aim was to evaluate knowledge and perceptions of malaria and chemoprevention, test understanding of the tools and identify gaps in understanding, satisfaction, user-friendliness and acceptability, and assess the potential role of CHWs in PMC implementation. Interviews were transcribed and imported to ATLAS.ti for encoding and categorization. Thematic content analysis used deductive and inductive coding with cross-referencing of findings between countries and participants to enrich data interpretation. Continuous comparison across the IDI and FGD permitted iterative, collaborative development of materials. RESULTS: Overall, 106 participants completed IDIs and 70 contributed to FGDs. Malaria was widely recognised as the most common disease affecting children, and PMC was viewed as a positive intervention to support child health. The role of CHWs was perceived differently by the target groups, with caregivers appreciating their trusted status in the community, whereas health authorities preferred clinic-based deployment of PMC by health professionals. Empirical testing of the prototype blister packs, dispensing boxes and job aids highlighted the context-specific expectations of respondents, such as familiar situations and equipment, and identified areas of confusion or low acceptance. A key finding was the need for a clear product identity reflecting malaria. CONCLUSION: Simple modifications profoundly affected the perception of PMC and influenced acceptability. Iterative quantitative investigation resulted in PMC-specific materials suited to the local context and socio-cultural norms of the target population with the aim of increasing access to chemoprevention in children most at risk of severe malaria.

Minitablets current use and future opportunities - An APV course on manufacturing, packaging, characterization and use of minitablets.

Recently, APV organized in collaboration with Fette Compacting GmbH a course on current use and future opportunities of minitablets. The course including a workshop was attended by 30 participants and focused on the manufacturing, packaging, characterization and medical use of minitablets. It took place at the Headquarter of Fette Compacting GmbH in Schwarzenbek. This article provides an overview on the topics presented and discussed during the course.

Machine vision model for detection of foreign substances at the bottom of empty large volume parenteral.

Empty large volume parenteral (LVP) bottle has irregular shape and narrow opening, and its detection accuracy of the foreign substances at the bottom is higher than that of ordinary packaging bottles. The current traditional detection method for the bottom of LVP bottles is to directly use manual visual inspection, which involves high labor intensity and is prone to visual fatigue and quality fluctuations, resulting in limited applicability for the detection of the bottom of LVP bottles. A geometric constraint-based detection model (GCBDM) has been proposed, which combines the imaging model and the shape characteristics of the bottle to construct a constraint model of the imaging parameters, according to the detection accuracy and the field of view. Then, the imaging model is designed and optimized for the detection. Further, the generalized GCBDM has been adopted to different bottle bottom detection scenarios, such as cough syrup and capsule medicine bottles by changing the target parameters of the model. The GCBDM, on the one hand, can avoid the information at the bottom being blocked by the narrow opening in the imaging optical path. On the other hand, by calculating the maximum position deviation between the center of visual inspection and the center of the bottom, it can provide the basis for the accuracy design of the transmission mechanism in the inspection, thus further ensuring the stability of the detection.

Carboplatin desensitization - simplified 4-step 2-bag method.

INTRODUCTION: Our cancer program adopted a method for carboplatin desensitization (4-step 2-bag method) that administers the same intensity of drug exposure with a simplified approach to product management in comparison to a published protocol (4-step 4-bag method). METHODS: The intensity of carboplatin administration for 1:1,000, 1:100, 1:10, and 1:1 dilutions and concomitant fluid administration were compared for the 4-step 2-bag (bags A, B) and 4-step 4-bag (bags 1, 2, 3, 4) methods. Pharmacy preparation of bags A and B is described. A succinct overview of the desensitization procedure is provided. Important considerations germane to pharmacy practice are presented. Chart review of patients who underwent carboplatin desensitization with the 4-step 2-bag method between 7/13/2021 and 11/22/2023 was performed to demonstrate institutional use. RESULTS: The 4-step 2-bag method delivers similar rates of drug intensity from start of desensitization to completion of the planned dose as the previously published 4-step 4-bag method. Accuracy of regimen-based dose administration is assured by infusion of bag B contents irrespective of infusion interruptions or rate changes necessitated by patient tolerance. Bag A provides the 1:1000 dilution in a pharmaceutically elegant manner using administration rates and volumes compatible with clinical practice. CONCLUSION: The 4-step 2-bag method for carboplatin desensitization administers controlled drug titration corresponding to 1:1000, 1:100, 1:10, and 1:1 dilutions for dose administration using two compounded admixture bags. Inaugural clinical use of the 4-step 2-bag method for carboplatin desensitization at our healthcare facility has proceeded with expected patient tolerance.

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.

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.

Container Closure Integrity of a Glass Prefillable Syringe in Deep Frozen Storage Conditions.

Development of novel pharmaceutical drug modalities has created a need for frozen storage and transportation. Accurate and easy assessment of container closure integrity (CCI) in frozen conditions remains a challenge. Thus, container closure systems (CCS) suitable for low temperatures have been primarily restricted to vials despite the growing popularity of prefillable syringes (PFS) for parenteral administration. A new dye ingress test method, suitable for testing at low temperatures, was developed and applied to PFS across a range of deep-frozen temperatures. The method is versatile and can easily be extended to other common CCS formats over a wide range of temperatures including storage on dry ice (-80 °C). This new method was paired with an orthogonal technique, laser-based CO2 headspace gas analysis, to evaluate the CCI of a glass PFS at temperatures from -50 °C to -80 °C. Both test methods showed comparable results and consistent CCI failure below a temperature of -70 °C. The primary mode of failure was the plunger-to-barrel interface, likely attributable to dimensional changes and loss of elasticity. This study demonstrates the temperature dependent CCI behavior of glass PFS and underscores the importance of thorough characterization of package integrity for deep frozen drug products.

Freeze Drying and Vial Breakage: Misconceptions, Root Causes and Mitigation Strategies for the Pharmaceutical Industry.

Vial breakage during or following freeze drying (lyophilization) is a well-known and documented phenomenon in the pharmaceutical industry. However, the underlying mechanism and probable root causes are not well characterized. Mostly, the phenomenon is attributed to the presence of crystallizing excipients, such as mannitol in the formulation, while other potential factors are often underestimated or not well studied. In this work we document a systematic multipronged approach to characterize and identify potential root cause(s) of vial breakage during lyophilization. Factors associated with formulation, product configuration, primary container and production process stress conditions were identified and their impact on vial breakage was studied in both lab and manufacturing scale conditions. Studies included: 1) strain gauge and lyophilization analysis for stress on glass vials with different formulation conditions and fill volumes, 2) manufacturing fill-finish process risk assessment (ex. loading and frictive force impact on the vials), and 3) glass vial design and ruggedness (ex. glass compression resistance or burst strength testing). Importantly, no single factor could be independently related to the extent of vial breakage observed during production. However, a combination of formulation, fill volume, and vial weakening processes encountered during at-scale production, such as vial handling, shelf loading and unloading, were identified to be the most probable root causes for the low levels of vial breakage observed. The work sheds light on an often-encountered problem in the pharmaceutical industry and the results presented in this paper argue against the simplistic root-cause explanations reported in literature. The work also provides insight into the possibility of implementing mitigative approaches to minimize or eliminate vial breakage associated with lyophilized drug products.

Development of a generic approach for monitoring leachable compounds in hospital pharmacy-prepared prefilled plastic packaging by ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry with postcolumn infusion.

Prefilled plastic packaging is time- and cost-effective in hospital pharmacy because it prevents waste, preparation errors, dosage errors, microbial contamination and accidents. This packaging mostly includes prefilled syringes (PFS), intravenous (IV) bags and vials intended for long-term storage that can be used for immediate treatment. There is a rising availability in the market for prefilled drug products due to their practical approach. Leachable compounds could be evaluated in hospital pharmacy-prepared prefilled drug solutions. The Pharmacy Department at the Lausanne University Hospital has developed an innovative, highly sensitive, and generic method by postcolumn infusion based on ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) for the analysis of plastic additives in hospital pharmacies. The postcolumn infusion solution was developed with 2% ammonium hydroxide in methanol on a representative set of 30 candidate compounds with different physical-chemical properties, such as log P and molecular structure, to represent the most important categories of additives. The LODs obtained for all compounds ranged from 0.03 to 7.91 ng/mL with linearity up to 250 ng/mL. Through this screening method, plastic additives can be rapidly identified due to the combined use of retention time, exact mass (including isotopic pattern) and MS/MS spectra. In addition, the users can screen for vast categories of plastic additives, including plasticizers, epoxy monomers, antioxidants, UV stabilizers, and others. The screening is facilitated by assessments of a complex in-house-built database for extractable and leachable trace assessment (DELTA), containing 205 compounds for unambiguous identification. Relative response factors were established for all analytes to obtain a semiquantitation of compounds. Moreover, the database also contains valuable estimative toxicology information, which was obtained through calculating their permissible dose exposure threshold; thus, estimative toxicology assessment can be performed for identified compounds in prefilled drug products. This method and the database were applied to a hospital pharmacy-prepared prefilled vancomycin syringe for paediatric use. Ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) was used to prepare the samples for leachable analysis. As a result, 17 plastic additives were formally identified, and their concentrations were estimated. A toxicology assessment was performed by comparing their concentrations with their theoretical PDE thresholds. In conclusion, the prefilled drug solution released a negligible amount of known leachables that appeared to be safe for use in neonates and children.

Stopper Movement and Headspace (Air Bubble Size) Limitations for 2.25 mL Prefilled Syringe.

The sterile barrier is one of the most important aspects of the container closure integrity (CCI) for a prefilled syringe (PFS or syringe). This crucial barrier enables the protection of the syringe contents from contamination. The plunger stopper (stopper) is naturally in a stationary position that is controlled by the static friction between the plunger stopper and the syringe barrel wall. When an applied force is greater than the static friction, which is commonly known as the break-loose force, the plunger stopper will move. In such conditions, the stopper movement can further be increased if an air bubble (AB) is introduced between the liquid fill in the syringe and the stopper during the stoppering process. This additional movement can occur when the pressure differential between the gaseous headspace inside the syringe and the external atmosphere is large enough that the force exerted on the stopper exceeds the break-loose force of the syringe. This can occur during altitude or temperature changes incurred during aerial or mountainous transport. This article, therefore, discusses the relationship between stopper movement and initial headspace (air bubble size/ABS) in a 2.25 mL Type I glass syringe using theoretical and empirical approaches. The results showed the maximum initial headspace needed to enable CCI at specified altitudes and plunger stopper movements for the syringe-plunger stopper combination used in the study. Empirical data also indicated that CCI can be maintained for this syringe-plunger stopper combination with up to 9.0 mm initial headspace at altitudes up to 17,000 feet.

Assessment on compatibility and safety of labels for pharmaceutical packaging.

Although the secondary packing materials do not directly contact the finished drug products, compound migration may still happen between them. To ensure drug quality and safety, extractables and leachables of the packing materials should be analyzed. In this study, 2,6-di-tert-butyl-4-methylphenol (BHT) was first found in the labels for pharmaceutical packaging. For the identification of the compound, a strategy combining high performance liquid chromatography (HPLC), ultra-performance liquid chromatography-quadrupole time-of-flight mass (UPLC-Q-TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy was utilized. Afterwards, a effective and sensitive HPLC method for quantification of BHT was developed and validated. Finally, a toxicological risk assessment of BHT was performed to ensure the safety of drugs.

Stability of Opened Durvalumab (IMFINZI) Vials. The Beginning of the End of Costly Product Wastage?

Durvalumab is a monoclonal antibody approved for the treatment of lung, urothelial and biliary tract cancers. Durvalumab is supplied in vials as a solution containing no preservatives. Monographs recommend single use of durvalumab vials, and that any leftovers be discarded within 24 h. Thus, significant portions of unused product from opened vials are wasted on a daily basis, generating considerable financial losses. The objective of the present study was to assess the physicochemical and microbiological stability of durvalumab vials kept at 4 °C or room temperature, at 7 and 14 days after opening. Following pH and osmolality measurements, turbidity and submicronic aggregation of durvalumab solution were evaluated by spectrophotometry and dynamic light scattering, respectively. Moreover, steric exclusion high performance liquid chromatography (SE-HPLC), ion exchange HPLC (IEX-HPLC) and peptide mapping HPLC were used to respectively assess aggregation/fragmentation, charge distribution and primary structure of durvalumab. Microbiological stability of durvalumab was evaluated by incubation of vial leftovers on blood agar. All experiments showed physicochemical and microbiological stability of durvalumab vial leftovers for at least 14 days when aseptically handled and kept at either 4 °C or at room temperature. These results suggest the possible extension of utilization of durvalumab vial leftovers well beyond 24 h.

Measurement of Solution Composition as an Alternative to Titration for Evaluating the Hydrolytic Resistance of Glass.

The measurement of solution composition is proposed as an alternative to titration to determine titration volume, which is the figure of merit for evaluating the hydrolytic resistance of glass containers for pharmaceutical packaging. In the new method, instead of titrating the sample and blank solutions, their compositions are measured by inductively coupled plasma mass spectrometry, and these compositions are converted to titration volume using a set of coefficients and a simple equation. The coefficients were derived using the well-developed thermodynamic data and models for dilute aqueous solutions, which make it possible to calculate the pH from the solution composition and then simulate a titration as a series of pH calculations as titrant is progressively added to the solution. In this article, we explain how a titration can be simulated, describe how the set of coefficients was derived, and provide experimental evidence that the titration volume from the new method is equivalent to that from titration. Since the new method is more difficult and expensive, it is not meant as a replacement for titration in the standard and pharmacopeial methods. Its value lies in enabling previously impossible hydrolytic resistance studies, supplying additional information about the composition of the hydrolytic solution that reveals important aspects of glass corrosion, and providing insights about titration that point to possible improvements in the standard titration procedures.

Assessment of Functional and Physical Performances of Pre-filled Syringes in Deep Cold Storage Conditions.

The recent emergence of new drug technologies such as messenger ribonucleic acid-based vaccines developed to fight the outbreak of the COVID-19 global pandemic has driven increased demand for delivery solutions capable of withstanding deep cold storage conditions down to -50°C, and even down to -80°C. Although significant data exist for deep cold storage in vials, little evidence is available for pre-filled syringes. Because pre-filled syringes serve as both the storage container and the delivery mechanism, there are additional risks to performance that must be evaluated, such as plunger gliding performance, syringe lubrication, silicone layer stability, and container closure integrity (CCI). In the present study, a comprehensive assessment of functional and physical performances of pre-filled syringes (PFS filled with water) was performed after one or multiple freeze/thaw (F/T) cycles between ambient temperature and various temperature cycles including -40°C, -50°C or -80°C for both 'staked needle' and 'luer lock' configurations. The experiments were guided by historical normative methods such as ISO 11040-4 and USP <1207> and combined with headspace gas analysis for barrel-stopper tightness testing. In addition, they were complemented with a novel approach, namely in situ real-time optical imagery, to track plunger stopper movement during the F/T cycle. The findings indicated that there is no significant impact on the functional performances from F/T down to -80°C, whereas no CCI risk was found after F/T down to -50°C.

Leakage Dynamics of Glass Bottles on Container Closure Integrity Testing: Influence of Different Laser-Drilled Microhole Geometries.

Container closure integrity testing (CCIT) is a critical step in ensuring package integrity and providing feedback on package designs. In practical applications, CCIT methods, namely physical and probabilistic methods, must be appropriately selected and validated to ensure their suitability for the intended use. However, the industry still lacks practical recommendations regarding the choice of CCIT methods and artificial leaks to set the acceptance criteria. The main reason is the lack of correlation between testing methods. Artificially introduced leak microholes are the only way to determine the sensitivity of a CCIT method and to implement the method correlation. However, the type of artificial leakage is a key factor because in most studies, leakage is described and valued using a single parameter, such as size. This can significantly affect the credibility of the relevant test results, especially in the case of microbial invasion, where the difference in test conditions and samples will severely affect the probability of microbial invasion. Therefore, it is vital to conduct a systematic study on the influence of leakage conditions on CCIT methods. In this study, the influence of the shapes of artificial leaks on the two kinds of testing methods was systematically studied based on a laser-drilled microhole-a highly potential and non-exogenous artificial leak manufacturing method that can fabricate different leakage geometries. The reason for the influence of the shape of an artificial leak on the CCIT is that the deterministic method takes defects as an idealized model and ignores the influence of the leak shape, wall thickness, and other factors on leakage and pollution risks. However, these factors seriously affect the dynamic process of leakage and microbial invasion. The pressure decay method is used to test the leakage flow rate of conical and straight holes. Microbial challenge tests are then used to verify the impact of leakage shapes on the pollution risk. The results of the tests indicated that the probability of microbial invasion in the conical holes is much higher than that in straight holes with the same flow test results and that the wall thickness can also affect microbial invasion. Thus, it can be proven that the risk of leakage and invasion or the sensitivity of different methods cannot only be compared through the leak diameter. Numerous influencing factors, including leakage geometry (e.g., shape and thickness), must be considered in practical applications.

Container Closure Integrity of Vial Primary Packaging Systems under Frozen Storage Conditions: A Case Study.

As the complexities of the pharmaceuticals needed to prevail over serious diseases continue to grow, the need for technologies to enable their efficient storage and delivery are as essential as ever. Lately, drugs such as vaccines, proteins, and stem cells are increasingly requiring frozen storage to maintain their efficacies before use. Notably, the advent of cellular therapy products has invariably elevated the need for cryopreservation and frozen storage of cellular starting materials, intermediates, and/or final product. The container closure integrity (CCI)-which is a major requirement for aseptic or sterile packaging systems-at these extremely low temperatures has not been fully understood. For vial-based systems particularly, the commonly used rubber stoppers are expected to lose their elastic properties below their glass transition temperatures, suggesting a potential temporary loss of sealability under frozen storage conditions and posing a risk to CCI. The measurement of the CCI at these conditions such as -80°C is therefore critical; a process that can be very challenging. Previous works had explored the use of Oxygen Headspace Analysis to measure CCI at low temperatures. Here, we present the evaluation of the CCI of rubber-stoppered aluminosilicate glass vials (Valor®) and plastic vials (Crystal Zenith®) using the helium leak CCI test method at -80°C, with correlation to residual seal force (RSF). The results and their implications are then discussed with regard to the suitability of certain packaging components as frozen storage container closure systems.

Observation and Mitigation of Lamellar Silica Particles Formed in Pharmaceutical Products Packaged in Glass Vials.

A new type of lamellae-like particles was observed in protein based liquid therapeutic protein drug product (DP) packaged in standard (STD) and delamination controlled (DC) Type IB glass vials stored at 2-8°C as early as two weeks after manufacture. These particles were determined to be remarkably different from lamellae in not only in their chemical composition, but in the mechanism by which these are formed. The lamellae-like particles were an ultra-thin (< 200 nm) film, appeared curled, sheet-like, folded with no defined edges identified as lamellar silica composed of silica and polysorbate 80 (PS 80). It was also observed that the lamellar silica particles, when formed in a given drug product lot, not only were observed in a small percentage of vials, but also remained at low (≤ 5) numbers in affected vials, often decreasing in number over time. This is in contrast to the large number of commonly reported glass lamellae (hundreds per vial) observed in vials prone to delamination with a glass vial interior showing a delaminated inner surface. In this case study, evidence from low Si leachable levels in solution and various surface analytical techniques supported the conclusion that there was neither delamination nor early signs of glass delamination like reaction zones occurring in those impacted vials, regardless. A mechanism for particle formation was hypothesized and experimentally confirmed. Lamellar silica particles are composed of an admixture of condensed silica and PS 80 deposited on the interior walls of glass vials, which form and may be released into solution over time. The root cause was determined to be conditions present during preparation of the vials for drug product filling, specifically the vial washing and depyrogenation steps. These conditions are known to make glass vials prone to delamination; in this case study, they resulted in interactions between the glass and PS 80 present in the formulation. Incomplete drying of the glass vials during depyrogenation in closed ovens was confirmed as the contributing factors that led to lamellar silica particle formation via the studies of silicate spiked into the DC Type IB glass vials filled with the mAb DP in which lamellar silica particles were observed. Prevention of lamellar silica particles formation was successfully achieved through optimization of the duration and pressure of air blow during the vial washing and drying process in a depyrogenation oven. This was evidenced by the lack of appearance of the lamellar silica particles over 48 months for the DP lots filled post optimization. Additionally, the formation of lamellar silica was also mitigated by changing the vial washing process from a closed oven process to a tunnel process, which allowed for improved air flow and hence better drying of the vial primary container.