Bulk Drug Substance Research Articles

Advanced stability-indicating RP-HPLC method for the quantification of lurasidone hydrochloride in bulk and PLGA-based in situ implant formulation

The aims of the present investigation was to develop and validate stability-indicating RP-HPLC method for the estimation of Lurasidone hydrochloride (LURA-H) followed by its drug product, LURA-H encapsulated poly-D,L lactic-glycolic acid (PLGA) based in-situ depot forming implant (LURA-H-PLGA-ISI). The LURA-H-PLGA-ISI formulation was developed by simple mixing method. According to international conference on harmonization guidelines, RP-HPLC method was developed and validated using Waters 2695 and discovery C18, 5μ, 250×4.6 mm ID column. Force degradation studied were performed by various degradation techniques. The chromatographic separations of LURA-H as well as LURA-H-PLGA-ISI with good resolutions have been achieved using the mobile phase 0.1% orthophosphoric acid and acetonitrile (50:50). The linearity in the range of 25-150 μg/mL of developed method. LOD and LOQ limits for LURA-H were found to be 0.07µg/mL and 0.22 µg/mL, respectively. The % RSD was found to be <2% showing the precision of developed method. The accuracy of developed method was demonstrated which is close to 100±2%. Little modifications in the chromatographic conditions indicated robustness of the developed method. Further, solution stability of LURA-H and LURA-H-PLGA-ISI was stable at room temperature. Furthermore, force degradation studies demonstrated LURA-H was unaffected and stable under thermal, photodegradation and neutral (hydrolytic) stress conditions. AGREE and GAPI assessment demonstrated the developed method is environmentally sustainable. The developed method is simple, robust, precise, accurate and sensitive which can be utilized for the regular analysis of LURA-H in quality control laboratories of bulk drug substance and PLGA containing formulations of LURA-H.

RP-HPLC Method Development and Validation for Determination of Sorafenib in Bulk Drug Substance and Pharmaceutical Dosage Forms

RP-HPLC Method Development and Validation for Determination of Sorafenib in Bulk Drug Substance and Pharmaceutical Dosage Forms

Optimization of Methodologies to Study Freeze/Thaw Processes in Drug Substance Bottles.

Biological drug substance (DS) is often frozen to enhance storage stability, prolong shelf life, and increase flexibility during manufacturing. However, the freezing and thawing (F/T) of bulk DS at the manufacturing scale can impact product quality as a result of various critical conditions, including cryo-concentration during freezing, which are influenced, among other things, by product-independent process parameters (e.g., container type, fill level, F/T equipment, and protocols). In this article, we report the optimization of two major methodologies to study product-independent process parameters in DS bottles at the manufacturing scale, namely the recording of temperature profiles and liquid sampling after thawing to quantify the concentration gradients in the solution. We report experimentally justified measuring positions for temperature recordings, especially for the selection of the last point to freeze position, and highlight the implementation of camera-assisted inspection to determine the last point to thaw and the actual thawing time. In particular, we provide, for the first time, a detailed description of the technical implementation of these two measuring set-ups. Based on the reported case studies, we recommend choosing relevant measuring positions as a result of initial equipment characterization, resulting in a resource-conscious study set-up.

In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase

It is recognized as a promising therapeutic strategy for cocaine use disorder to develop an efficient enzyme which can rapidly convert cocaine to physiologically inactive metabolites. We have designed and discovered a series of highly efficient cocaine hydrolases, including CocH5-Fc(M6) which is the currently known as the most efficient cocaine hydrolase with both the highest catalytic activity against (−)-cocaine and the longest biological half-life in rats. In the present study, we characterized the time courses of protein appearance, pH, structural integrity, and catalytic activity against cocaine in vitro and in vivo of a CocH5-Fc(M6) bulk drug substance produced in a bioreactor for its in vitro and in vivo stability after long-time storage under various temperatures (− 80, − 20, 4, 25, or 37 °C). Specifically, all the tested properties of the CocH5-Fc(M6) protein did not significantly change after the protein was stored at any of four temperatures including − 80, − 20, 4, and 25 °C for ~ 18 months. In comparison, at 37 °C, the protein was less stable, with a half-life of ~ 82 days for cocaine hydrolysis activity. Additionally, the in vivo studies further confirmed the linear elimination PK profile of CocH5-Fc(M6) with an elimination half-life of ~ 9 days. All the in vitro and in vivo data on the efficacy and stability of CocH5-Fc(M6) have consistently demonstrated that CocH5-Fc(M6) has the desired in vitro and in vivo stability as a promising therapeutic candidate for treatment of cocaine use disorder.

Development of a Reversed-Phase UPLC Method for Assay of Fipronil Including Determination of Its Related Substances in Bulk Batches of Fipronil Drug Substance.

Fipronil is a commonly used pesticide in the agricultural and animal health industries for the protection of crops and control of fleas, ticks, and chewing lice. It is difficult to obtain reproducible retention time and relative retention time (RRT) for a common hydrolytic degradation product of fipronil with the current European Pharmacopeia (EP) monograph for assay and estimation of related substances of fipronil. This situation causes misidentification, mislabeling, and/or false out-of-specification results for this hydrolytic degradation product of fipronil in bulk commercial batches during batch release and/or in the stability samples during the shelf life of a released batch. This study aimed to develop a reversed-phase ultra performance liquid chromatography (UPLC) method for assay and identification of fipronil including identification and estimation of its related substances in bulk drug substance batches of fipronil and provide consistent retention time of the hydrolytic degradation product. Fipronil and its related substances were separated by gradient elution on a Halo C18 column (50 mm × 2.1 mm id, 2.0 µm particle size) maintained at 40°C with 0.1% H3PO4 in H2O as mobile phase-A and acetonitrile-methanol (50 + 50, v/v) as mobile phase-B. Fipronil and its related substances were detected and quantified at 280 nm with a quantitation limit of 0.05% of the target (analytical) concentration. The UPLC method was able to separate all analytes of interest by gradient elution with a total run time of 7 min (approximately 40% faster than EP). In this paper, we report the development and validation of a fast, stability-indicating reversed-phase UPLC method for assay and estimation of related substances of fipronil in stability samples and bulk batches of fipronil. The new UPLC method is approximately 40% faster than the current Ph. Eur. monograph for fipronil assay and the new method provides reproducible retention of a common hydrolytic degradation product of fipronil.

A modular and multi-functional purification strategy that enables a common framework for manufacturing scale integrated and continuous biomanufacturing.

Biopharmaceutical manufacture is transitioning from batch to integrated and continuous biomanufacturing (ICB). The common framework for most ICB, potentially enables a global biomanufacturing ecosystem utilizing modular and multi-function manufacturing equipment. Integrating unit operation hardware and software from multiple suppliers, complex supply chains enabled by multiple customized single-use flow paths, and large volume buffer production/storage make this ICB vision difficult to achieve with commercially available manufacturing equipment. Thus, we developed SymphonX™, a downstream processing skid with advanced buffer management capabilities, a single disposable generic flow path design that provides plug-and-play flexibility across all downstream unit operations and a single interface to reduce operational risk. Designed for multi-product and multi-process cGMP facilities, SymphonX™ can perform stand-alone batch processing or ICB. This study utilized an Apollo™ X CHO-DG44 mAb-expressing cell line in a steady-state perfusion bioreactor, harvesting product continuously with a cell retention device and connected SymphonX™ purification skids. The downstream process used the same chemistry (resins, buffer composition, membrane composition) as our historical batch processing platform, with SymphonX™ in-line conditioning and buffer concentrates. We used surge vessels between unit operations, single-column chromatography (protein A, cation and anion exchange) and two-tank batch virus inactivation. After the first polishing step (cation exchange), we continuously pooled product for 6 days. These 6 day pools were processed in batch-mode from anion exchange to bulk drug substance. This manufacturing scale proof-of-concept ICB produced 0.54 kg/day of drug substance with consistent product quality attributes and demonstrated successful bioburden control for unit-operations undergoing continuous operation.

Analytical quality by design aided stability indicating a robust ultra‐performance liquid chromatographic technique for the quantification of sonidegib and its organic impurities in bulk drug substance

AbstractA simple quality by design aided stability indicating method was developed for quantification of sonidegib (SONI) and its process related impurities using on ultra‐performance liquid chromatography in bulk drug substance. AutoChrom and Design‐Expert software were used to predict physicochemical properties, draw Ionization graphs, and generate analytical target profile. SONI was subjected to forced degradation conditions, such as oxidative, acid hydrolysis, base hydrolysis, hydrolytic, thermal, and photolytic hydrolysis. All degradation products and process contaminants were separated using an Acquity Ethylene Bridged Hybrid C18 column in gradient elution mode with a mobile phase containing 0.02 M ammonium acetate buffer and acetonitrile: methanol (80:20 v/v). The predicted physicochemical properties are accurate and they facilitated for selection of robust conditions in development of chromatographic method with minimal trials. The developed method can be used for quantification of drug and its process related impurities in bulk drugs.

A dual-function chromogenic and fluorogenic benzofurazan probe for plazomicin and its innovative utility for development of two microwell assays with high throughput for analysis of drug substance and pharmaceutical formulations.

Plazomicin (PLZ) is a novel aminoglycoside which has been recently approved by The US Food and Drug Administration for the treatment of complicated urinary tract infections including acute pyelonephritis, caused by certain Enterobacteriaceae, in adult patients with limited or no options for alternative treatment. This study focuses on the development of microwell-based photometric and fluorometric assays for the quantitative determination of PLZ in its bulk drug substance and commercial pharmaceutical formulations (Zemedri® injections). Both assays utilize the dual-function chromogenic and fluorogenic properties of the 4-fluoro-7-nitrobenzofurazan (NBD-F) probe. The reaction between PLZ and NBD-F, conducted in a borate buffer at pH 8, resulted in the formation of a colored and fluorescent reaction product. The product exhibited maximum light absorption at 473 nm and emitted fluorescence at 541 nm when excited at 473 nm. Factors influencing the reaction between PLZ and NBD-F were thoroughly investigated, and optimal conditions were determined. Under the optimized reaction conditions, calibration curves were generated to establish the relationship between absorbance and fluorescence intensities of the reaction product with the corresponding PLZ concentrations. The absorbance-concentration relation was linear in a PLZ concentration range of 20-800 μg mL-1 with a limit of quantitation of 25 μg mL-1, while the fluorescence-concentration relation was linear in the concentration range of 0.05-1.5 μg mL-1 with a limit of quantitation of 0.08 μg mL-1. Both assays underwent validation and were successfully applied to the quantitation of PLZ in its bulk drug substance and pharmaceutical formulations (injections) with satisfactory accuracy and precision. The eco-friendliness/greenness assessment of the assays demonstrated that both assays comply with the requirements of green analytical chemistry approaches. Furthermore, the proposed microwell assay plates allowed for the simultaneous handling of numerous samples with micro-volumes, enabling high-throughput analysis. In conclusion, this study represents the first evaluation of NBD-F as a dual-function probe for the microwell-based photometric and fluorometric determination of PLZ. The developed assays serve as valuable analytical tools for the quality control of PLZ's bulk drug substance and pharmaceutical formulations.

Determination of Clorsulon and its related substances in commercial bulk drug substance batches by a rapid ion-pair UPLC method

Clorsulon is a potent anthelmintic agent and is widely used for the treatment and control of parasites including adult liver flukes in cattle and sheep. A rapid ion-paired reversed phase ultraperformance liquid chromatography (IP-UPLC) method has been developed and validated for determination of Clorsulon and its related substances in bulk drug substance batches of Clorsulon with a short octadecyl column. Analytes were eluted by a gradient elution on a Acquity UPLC® BEH C18 column (50 mm × 2.1 mm i.d., 1.7 µm particle size). Column temperature was maintained at 55 °C and all analytes were monitored by UV detection at 268 nm. Mobile phase-A constitutes 3 mM tetrabutylammonium hydroxide in H2O and mobile phase-B constitutes acetonitrile/methanol (50/50, v/v), respectively. All analytes of interest were adequately separated within 5 min. The analytes were quantitated against an external reference standard of Clorsulon. The chemical structures of degradation products of Clorsulon were proposed based on two-dimensional UPLC-MS data. The IP-UPLC method has been successfully validated and demonstrated to be accurate, sensitive, robust, and specific.

RP-HPLC Method Development and Validation for Determination of Abemaciclib in Bulk Drug Substance and Pharmaceutical Dosage Forms

A simple, economic, rapid and precise method for the quantification of Abemaciclib in bulk drug substance and pharmaceutical dosage forms was developed and validated using RP-HPLC. The chromatographic separation was achieved using Ascentis® C-18 HPLC column (250mm x 4.6mm i.d., particle size 5µ) with mobile phase containing 0.5% TFA: methanol: acetonitrile (35:45:20 v/v/v) with flow rate of 1.2mL/ min was used and effluents were monitored at 295nm. The retention time of Abemaciclib were found to be 3.72 min. The linearity was in the range of 6-42μg/mL. The limit of detection and limit of quantification were found to be 0.6 and 1.8 µg/mL, respectively. The % recoveries were found to be in the range of 99.65±0.77.&#x0D; Keywords: Abemaciclib, Estimation, Bulk drug substance, Pharmaceutical dosage forms

Electrochemically-selective electrode for quantification of dorzolamide in bulk drug substance and dosage form

Three smart carbon paste electrodes were fabricated to quantify dorzolamide hydrochloride DRZ, including conventional carbon paste I, modified carbon paste embedding Silica II, and modified carbon paste embedding β-cyclodextrin III. This study is based on the insertion of DRZ with phosphomolybdic acid to create an electroactive moiety dorzolamide-phosphomolybdate ion exchanger using a solvent mediator dibutyl phthalate. The three constructed carbon paste electrodes displayed Nernstian responses and linear concentration ranges with lower detection limits. The vital performance of the created electrodes was verified in relation to various parameters. The electrodes enhance the selective determination of DRZ in the presence of inorganic ions, a co-formulated drug in the dosage form timolol maleate, and the excipient benzalkonium chloride. The modified carbon paste electrode including Silica was utilized to detect DRZ in ophthalmic eye drop form utilizing the direct calibration curve and potentiometric titration methods. Satisfactory findings were achieved by comparing them to other reported methods.

An Experimental and Computational Approach to Development of Mixing Processes for Miscible Liquids in Unbaffled Tanks.

Mixing of liquids is a critical unit operation in the biopharmaceutical drug product manufacturing. It commonly consists of mixing miscible liquids to dilute bulk drug substance (DS) or pool multiple lots of drug substance. In the past, at-scale mixing studies have been conducted to determine the mixing parameters, namely mixing speed, and mixing time. At-scale studies have historically been utilized to overcome the challenges associated with geometric dissimilarity of mixing systems found when scaling up. In addition, such studies are quite costly, as they often use actual DS to overcome a lack of representativeness associated with simple salt trace models often employed. As a result, there is a significant need for alternative cost-effective methods that can predict mixing parameters with close agreement to actual experiments and operations. At-scale mixing experiments were conducted using full-sized tanks and surrogate solutions. Several computational fluid dynamic (CFD) simulation methods were conducted and compared with the experiments to determine the most reliable computational techniques. The experiments demonstrate that surrogate solutions can be used reliably to determine mixing parameters in at-scale studies instead of the valuable drug products. Studying different CFD methods also showed that transient simulations that use a large eddy simulation (LES) viscous modeland a sliding mesh can correctly predict the mixing parameters. Results of this study establish a practical and reliable methodology to perform mixing studies for miscible liquids with different kinematic viscosities. The methods discussed herein greatly reduce the routine mixing study costs in the biopharmaceutical industry and increase efficiency and accuracy of the results, allowing proactive scale-up of mixing operations.

The polymorph landscape of dabigatran etexilate mesylate: Taking the challenge to bring a metastable polymorph to market

Dabigatran etexilate mesylate is polymorphic and can exist in different crystalline forms. Two polymorphs have been encountered during the development of this drug substance, namely anhydrous form I and anhydrous form II. Additionally, a hemihydrate was observed, if larger amounts of water were present during crystallization in the salt formation step. Finally, a high temperature form III can be obtained by heating anhydrous form I above 150 °C. All three at room-temperature accessible forms were characterized by means of microscopy, X-ray powder diffraction, thermal analysis, IR- and Raman spectroscopy. In addition, solubility parameters (equilibrium solubility and intrinsic dissolution rate, heat of solution) were collected on all three forms. The crystal structure of all three at room-temperature accessible forms could be obtained using electron diffraction. Anhydrous form I has a monoclinic crystal lattice (C2/c), anhydrous form II a triclinic one (P1¯), and the hemihydrate crystallizes also in a monoclinic space group (P2/c). From the obtained data there is clear evidence that anhydrous form II is thermodynamically more stable than anhydrous form I. Form I and form II are monotropically related to each other indicating that they may coexist over a wide temperature range. The hemihydrate is a completely independent crystalline modification of dabigatran etexilate mesylate. It is another thermodynamically stable form and structurally not related to the two anhydrous forms. The hemihydrate melts at ca. 125 °C, there is no conversion to either anhydrous form I or form II upon dehydration. The high temperature form III is enantiotropically related to form I and only stable above the phase transition temperature at ca. 150 °C and its melting point at ca. 183 °C. The energy difference between anhydrous form I and form II was found to be only 2.5 – 3.0 J/g. Both forms have very similar aqueous solubility characteristics. Although anhydrous form II is the thermodynamically more stable form, anhydrous form I was chosen for development. The selection of form I for development was mainly based on the superior bulk processing properties of anhydrous form I in drug substance synthesis and further drug product processing as well as its slightly better chemically stability in pivotal long term stability studies. Anhydrous form I, although meta stable, is still stable enough that conversion to the more stable form II can occur only to a limited extent during drug substance synthesis and drug product manufacturing. From long term stability data on both bulk drug substance as well as drug product, there is no indication that form I transforms to form II during storage. Even under stress conditions where form I was stored up to 4 weeks at 70 °C, no conversion to form II was observed.

Determination of Firocoxib and Its Related Substances in Bulk Drug Substance Batches of Firocoxib by a High-Speed Reversed-Phase HPLC Method With a Short Fused-Core Biphenyl Column.

Firocoxib is a nonsteroidal anti-inflammatory drug. It provides control of postoperative pain and inflammation associated with soft tissue and orthopedic surgery in dogs, and control of pain and inflammation associated with osteoarthritis in horses. A high-speed stability-indicating reversed-phase high-performance liquid chromatography method was developed to determine firocoxib and its related substances in bulk batches of firocoxib drug substance. Firocoxib was dissolved in neat acetonitrile (ACN) and analyzed on a short HALO (fused-core) biphenyl column (30 × 4.6mm i.d., 2.7-μm particle size) at flow rate of 2.5mL/min. Column temperature was maintained at 50°C. Mobile phase A is composed of 0.1% of H3PO4 in water and mobile phase B is composed of ACN. Analytes were detected with UV detection at 240nm and quantitated against an external reference standard. Firocoxib and its related compounds were adequately separated within 4min by a gradient elution. The method was validated for specificity, linearity, accuracy, precision and robustness according to method validation guidelines described in The International Conference on Harmonization. The validation data demonstrated that this method is sensitive, accurate, robust, specific and stability-indicating.

Multisite Qualification of an Automated Incubator and Colony Counter for Environmental and Bioburden Applications in Pharmaceutical Microbiology.

Traditional microbiological techniques have been used for well over a century as the basis for contamination testing of pharmaceutical products and processes. With more recent focus on faster product release and concerns around the integrity of the test data, new technologies have been implemented to detect and enumerate organisms faster and provide paperless processes to minimize data integrity issues. Manual colony counting technologies, where incubation is performed in a standard incubator, and the plate is manually transferred to the colony counter for a single read at the end of incubation, have been used for many years to reduce the potential for human error; however, they pose validation challenges due to poor counting accuracy. Colony counters that automatically perform both the incubation and enumeration functions (multiple enumeration calculations through the incubation phase) have recently been implemented for quality control (QC) laboratory analytical processes, supporting a cGMP environment. This article summarizes the findings of eight companies demonstrating the qualification of an automated colony counter technology to perform the majority of microbial tests required for QC, environmental monitoring, and bioburden for in-process, bulk drug substance, and water system testing. Comparable analytical performance and time to result data generated during individual studies at all companies allows the system to be qualified and implemented for cGMP processes while reducing data integrity risks.

Accomplishing Scalability by Using Plate‐Based Freeze and Thaw Technologies

AbstractControlling the freezing behavior of bulk drug substance opens doors to process reproducibility and consistent quality of the final drug product by maintaining uniform conditions for the biopharmaceuticals during freezing, and consequently for frozen storage and shipment. This simplifies the commercial bulk production, particularly when manufacturing different drug substances at different sensitivities and temperature set points and enables scalability. The leverage of the ice front growth speed had a significant impact on controllability and, as a result, on the protein quality.

The use of a transient transfected expression system to deliver high quality bispecific T-cell engager drug product, NVG-111, to the clinic for a fraction of the cost and time associated with the development and use of a producer cell line.

e14506 Background: Bispecific antibodies provide an opportunity to treat a diverse range of disorders because of their ability to simultaneously attenuate several different pathways precisely and effectively, thus overcoming many of the limitations of monoclonal antibodies. The adaptability of bispecifics has facilitated the generation of compelling preclinical data covering a range of malignant and non-malignant disorders. Proof-of-concept early phase clinical trials with bispecific antibodies, including bispecific T-cell engagers (TCE) have been hindered by manufacturing challenges, including a heavy burden in terms of time, quality and costs associated with generating a stable producer cell line. We took a more agile approach, using transient transfection to manufacture a ROR1×CD3 bispecific TCE drug product (DP [NVG-111]) for a first in human, Phase I/II clinical trial. Methods: A HEK293T cell line was expanded into 10-layer cell factories. The cells were transfected with a ROR1xCD3 scFv bispecific antibody (NVG-111) plasmid and incubated. Post incubation, the supernatant containing NVG-111 was clarified by filtration and subjected to solvent/detergent viral inactivation. This was followed by a concentration/buffer exchange step and subsequent DNA reduction using an endonuclease. NVG-111 was captured using a bind/elute Protein A column and the eluate polished on a multimodal anion exchange column in flow through mode to remove residual impurities. The eluate was formulated and concentrated to the target protein concentration, viral and sterile filtered and QC tested. The bulk drug substance was 0.2 µm filtered into Din 2R vials and the DP stored at ≤-65°C pending release. Results: The transient transfection approach resulted in the rapid tech transfer and GMP manufacture of clinical NVG-111 DP. Two batches of DP were manufactured producing 1,971 vials of NVG-111, sufficient to support the Phase I/II clinical trial in patients with advanced Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma (Clinical Trial.gov NCT04763083). Both batches met the approved specifications for identity, potency, purity/impurities, strength and safety. The exercise took less than 7 months from contract signature to DP in the freezer and cost ̃50% of the more traditional producer cell line approach. Conclusions: We established a novel GMP process in 7 months, using transient transfection to manufacture NVG-111 for Phase I/II trials. The process costed less than the more conventional manufacturing approach of using a producer cell line. The strategy offers a rapid, and very efficient way of reaching a first in human study without a trade-off between time, quality and cost.

Viscosity Reduction and Stability Enhancement of Monoclonal Antibody Formulations Using Derivatives of Amino Acids

Monoclonal antibodies are complex molecules that often require high concentration formulations to meet clinical requirement and bulk drug substance storage. Stability is a common concern in both high and low concentration formulations, however, high concentration formulations are further complicated by an increase in viscosity, leading to manufacturing and administration challenges. To manage stability and viscosity, drug developers typically use salt, amino acids, sugars, polyols, and surfactant. It is possible that excipients control some of the product quality attributes (CQAs), at the cost of several others. In this paper, we have evaluated several amino acid derivatives and identified bis acetyl lysine and propionyl serine to be efficient and superior to commonly used parenteral excipients for minimizing antibody solution viscosity, as well as mitigating physical and chemical degradation by controlling protein-protein interactions and deamidation.

Simultaneous Determination of Prasugrel and its Process Related Impurities and Degradation Products in Bulk Drug Substances by RPLC-UV

Aims: This study aims to determine the quantitative prasugrel (PG) and its all possible process-related impurities. Background: To the best of our knowledge, very few analytical methods are available in the literature for monitoring process related impurities and degradation products of PG in bulk drug substance/ active pharmaceutical ingredient (API). Objective: The objective of this study is the separation of Prasugrel and its all possible process-related impurities viz., desacetyl prasugrel-tautomeric forms, intermediates including desacetyl impurity existing in its keto-enol form and positional tautomer impurities with degradation products. Method: A simple and robust HPLC-UV method having Zorbax XDB C18 column (15 cm x 4.6 mm) 3.5μm particle size column was used. Result: Prasugrel and its process related impurities were separated as well as analyzed in pharmaceutical samples' biological matrices. Conclusion: RP-LC method was developed for quantitative determination of PG and related substantial impurities were found to be highly specific, sensitive and precise. The major oxidative degradant was identified as PG desacetyl IMPs (keto-enol and positional tautomer) and hydroxyl IMP.

Streamlined life cycle assessment of single use technologies in biopharmaceutical manufacture

The rapid growth of biologics as the preferred modality in several therapeutic areas has led to changes in the environmental profile of pharmaceutical manufacturing for some companies. The increased use of single use technologies (SUT) in biologics manufacturing has been accompanied by a greater public awareness of plastics waste, but the full life cycle environmental impacts of SUT have had limited study. Therefore, a segment of American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable member companies undertook a streamlined cradle-to-gate life cycle assessment on a biological bulk drug substance (BDS) manufacturing process utilizing SUT at the 2000 L scale. The goal of this study was to highlight where pharmaceutical companies, and biologics producers in particular, can reduce the environmental impact of their drug substance manufacturing. The results have shown that the largest contribution to the life cycle environmental impact for SUT was found to be the electricity used to operate the plant. Interestingly, across all impact categories, the contribution to the environmental footprint from end-of-life due to the use of plastic SUT was extremely small. Although not quantified in this study, these findings and others suggest operational changes that increase process efficiency and decrease time in plant are among the best strategies for reducing the life cycle environmental impact of biologics manufacturing.