Fast-to-Clinic, Fast-to-Market in Biotech Innovation: Optimizing Chemistry Manufacturing & Controls (CMC) Excellence for Clinical and Commercial Success

In the emerging world of biotech innovation, the fast-to-clinic/market strategy has emerged as a critical “mantra” for biotech, investors, and CDMOs. This approach addresses the escalating costs and complexities of research and development by streamlining the path from concept to clinical trials and, ultimately, to market. The article delves into the intricacies of implementing a fast-to-clinic/market strategy, underlining the empowering role of strategic decision-making in preclinical and commercial stages. The plan advocates for a phase-appropriate approach, where the development decision is tailored to each phase of the product’s lifecycle. This ensures that resources are allocated efficiently, risks are managed effectively, and the product can move through the development pipeline accelerated without compromising quality or regulatory compliance. The article also discusses the role of CDMOs in facilitating rapid product development and the essential factors biotech companies must consider when selecting a partner for outsourcing. These factors include the CDMO’s expertise in navigating regulatory landscapes, technological capabilities, and ability to scale processes efficiently. Moreover, the article stresses the importance of agility and flexibility in the fast-to-clinic/market approach. Biotech companies are encouraged to adopt adaptable strategies that respond to the fast-evolving regulatory and market landscapes.

Transforming Molecules into Medicines: Role of CDMOS in Phase-Appropriate Technology Transfers in Advancing Pharmaceutical Innovation

CDMOs are emerging as critical drivers of innovation within the pharmaceutical and biotech industries. As the pharmaceutical industry continues to evolve, we can expect to see CDMOs play an increasingly important role in drug development and manufacturing. Many companies within these sectors are now leveraging the expertise of CDMOs through technology transfers to foster innovation and enhance the development of new drug products. In the extensive field of drug development, technology transfer plays a crucial role at multiple stages, ranging from preclinical phases to commercialization. By working closely with drug developers, CDMOs can ensure that technologies are transferred seamlessly between phases of drug development, allowing for a more efficient and cost-effective development process. CDMOs also bring a wealth of experience in various areas of drug development, including process development, analytical testing, quality control, and manufacturing. This expertise, combined with a focus on innovation, can help drug developers to overcome technical challenges and optimize their drug development programs. CDMOs can provide drug developers with various manufacturing capabilities, from small-scale clinical trials to large-scale commercial production. This flexibility allows drug developers to focus on their core competencies while relying on CDMOs to provide the necessary infrastructure and support for drug manufacturing. The critical role of CDMOs in advancing pharmaceutical innovation in phase-appropriate technology transfer where there will be a lot of effort and patience with strong technical expertise is required. This article explores the various types of Technology transfer from preclinical to commercial stages and successful strategies to foster innovation.

Antibody-Drug Conjugates (ADCs): Navigating Four Pillars of Safety, Development, Supply Chain and Manufacturing Excellence

Antibody-drug conjugates (ADCs) are pioneering biologics that merge antibodies’ specificity with small molecules’ potency. With a handful of FDA-approved ADCs in the market and many under development, ADCs are poised to revolutionize therapeutics. This paper examines the complexities of ADC production, emphasizing the importance of process characterization and the pivotal role of supply chain characteristics, safety requirements, and Contract Manufacturing Organizations (CMOs) with proficiency. The swift transition of antibody-drug conjugate (ADC) programs from early to advanced clinical stages underscores the urgency for quick and efficient commercial launch preparation. This article delves into strategies to hasten commercial readiness, supply chain strategy, the significance of partnering with adept contract development and manufacturing organizations (CDMOs), and the challenges of ADC production.

The ABC of ADCs (Antibody-Drug Conjugates): A Comprehensive Review of Technical, Regulatory, and Clinical Challenges

Over the past several decades, there has been a significant surge in the development of Antibody-Drug Conjugates (ADCs). Designing an ideal ADC presents a multifaceted challenge, requiring the precise orchestration of various elements such as antigens, antibodies, linkers, and payloads. While ADCs aim to target tumor cells specifically, several antigens can also be found in regular tissues, potentially compromising the specificity of ADCs in therapeutic applications. The complexity extends to antibody selection, necessitating effective targeting of the desired antigen and ensuring compatibility with linkers for effective payload delivery. Additionally, the linker and payload combination are critical for the ADC’s therapeutic efficiency, balancing stability in circulation and timely payload release upon target binding. ADC doses must be safe for normal tissues while ensuring the released payloads are effective. The success of ADCs is attributed to their unmatched efficacy compared to traditional chemotherapy agents. The current research article aims to provide a technical review of Antibody-Drug Conjugates (ADCs) for cancer therapies. A brief discussion on the basics of ADCs, regulatory approach, overview, and technical complexities for quantification is presented. This review also summarizes recently approved ADCs and introduces the concepts of antibodies, linkers, and payloads. The article also outlines cancer-specific ADCs currently in late-stage clinical trials for cancer treatment.

Drug-Excipient Interactions: Case Studies and Overview of Drug Degradation Pathways

The objective of the current research article is to provide a comprehensive review of excipients impact on the stability of the drug product and their implications during the product development. Recent developments in the understanding of the degradation pathways further impact methodologies used in the pharmaceutical industry for potential stability assessment. The formation of drug excipient adducts was very common based on the sensitive chemical moieties in the drugs and the excipients. The formation of the impurities was not limited to drug related impurities but there were several possibilities of the drug-excipient adduct formations as well as excipient impurities reaction with Active Pharmaceutical Ingredients. Identification of drug degradation in presence of excipients/excipient impurities requires extensive knowledge and adequate analytical characterization data. Systematic literature review and understanding about the drug formulation process, give you a smooth platform in establishing the finished product in the drug market. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes in solid, semisolid and parenteral dosage forms.

Forced Degradation Studies on Sodium Picosulfate and Separation of 15 Process Related Impurities/Degradants by HPLC

A selective, precise and stability-indicating, high performance liquid chromatographic method was developed for the analysis of active ingredient sodium Picosulfate and forced degradation behavior was studied. The current article describes forced degradation behavior of the Sodium Picosulfate drug substance in detail by analyzing 15 process related/degradants in a single HPLC method under ICH recommended stressed conditions. Mobile phase comprised of 0.01 M of Disodium hydrogen phosphate and 0.01 M of potassium phosphate monobasic buffer and 1 mL of triethyl amine in 1000 mL water adjusted to pH 7.5 with 10% phosphoric acid. Acetonitrile was used as Mobile Phase B. The separation was achieved on a gradient method. The reversed phase chromatography was performed in Hypersil BDS C18 5.0 μm, 4.6 × 250 mm column maintained at temperature 35°C. Injection volume was 60 μL. Milli-Q water used as diluent. The mobile phase was pumped at 0.9 mL/min-1. The eluted compounds were monitored at 220 nm. Secondary wavelength of the 263 nm was studied to check any further degradants during the forced degradation studies. New additional degradants Sodium Picosulfate Benzyl alcohol Impurity and N oxide degradations were discussed and studied during the forced degradation to understand the chemical stability of the drug substance.

Drug-Excipient Interaction of Methylphenidate with Glycerin in Methylphenidate Oral Solution and Identification of its Transesterification Products by UPLC-MS/MS

Reactions between active drug substances and excipients are of interest in the drug formulation process should be checked for the interactions during the storage conditions. Some excipients react with certain chemical groups in drug substances which will form new impurities in the finished product formulations. In the present paper transesterification reaction of methylphenidate with glycerin to form different structural isomeric products was described. These impurities identified in forced degradation studies, excipient compatibility studies and stability analysis of the finished product. Stability samples were analyzed and observed that about ~0.6% of the Methylphenidate content was transformed into methylphenidate-glycerin isomers within 3 Months at 40°C/75% RH and 18 Months at 25°C/60% RH conditions. Analysis of two lots of marketed preparations having expiry dates in 2012 and 2013 showed content of the Methylphenidate esters corresponding to ~0.6% of the declared Methylphenidate content. The samples of this impurity were investigated by HPLC, UPLC-MS/MS to generate the mechanism of the impurity formation.

Simultaneous Determination of Atorvastatin and Glimepiride by LC-MS/MS in Human Plasma and Its Application to a Pharmacokinetic Study

The aim of the proposed research work was to develop and validate a simple, selective high sensitive and high-throughput assay for the simultaneous estimation of Atorvastatin and Glimepiride in human plasma using liquid chromatography tandem mass spectrometry (LC-MS/MS). Atorvastatin–Glimepiride combines a competitive inhibitor of HMG-CoA reductase and a sulfonylurea anti-diabetic drug. The purpose of this study was to develop single method for Atorvastatin and Glimepiride in plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) that would result into a simultaneous estimation of Atorvastatin and Glimepiride avoiding acid –lactone inter conversions right from sample collections to analysis on the LC-MS/MS. Sample collection procedure optimized for Atorvastatin holds good for Glimepiride, hence resulting into a simultaneous estimation of Atorvastatin and Glimepiride. Liquid-liquid extraction and liquid chromatography coupled to positive ion mode tandem mass spectrometry was used to develop the method and was validated according to US FDA guidelines. The calibration curves for two analytes were linear (R2 ≥ 0.9950, n = 4) over the concentration range of 0.2 - 30 ng/mL for Atorvastatin and 1 - 250 ng/mL for Glimepiride. Mean extraction recoveries 80.34 ± 9.43 for Atorvastatin and 88.19 ± 7.13 for Glimepiride. Intra- and inter-run mean percent accuracy was between 85% - 115% and percent imprecision was ≤15%. Stability studies revealed that Atorvastatin and Glimepiride were stable in plasma during bench top (10.5 h at room temperature), in Injector (47.5 h), at the end of three successive freeze and thaw cycles and long term at -65℃ ± 15℃ for 114 days. The method was successfully applied to the study of pharmacokinetics of Atorvastatin and Glimepiride in healthy volunteers. Simultaneous estimation of Atorvastatin and Glimepiride is cost effective, reduces analysis cycle time, enables effective utilization of resources and reduces bleeding burden on human volunteers.

Development of Better-Quality Assay Method for the Citric Acid and Sodium Citrate in Ophthalmic/Oral Solutions and Their Application to Deformulation Studies

There were several techniques determined for the analysis of citrate and citric acid mixtures in the pharmaceutical dosage forms. Titration methods, photometric and ion chromatographic methods were used for their determination. These methods will restrict too many factors where the accurate quantification of citrate and citric acid is extremely challenging. Citric acid is the natural flavor used as a preservative for many pharmaceutical applications. Deformulation techniques used for the manufacturing of generic drugs require authentic data for their regulatory submissions. Simple accurate and reproducible validated method developed for the determination of citric acid and sodium citrate by titration followed by HPLC analysis. Free citric acid was determined by the titration method and total citric acid was determined by HPLC analysis. After subtracting the free citric acid from total citric acid content, citric acid present in the sodium citrate content was determined. Sodium citrate content was determined by applying sodium correction factor to the subtracted value of the citric acid. The results met all the validation parameters and the method was successfully measured the amount of citric acid and sodium citrate in the marketed ophthalmic/oral solutions.

Studies on the Stability of Corticosteroids: Degradation of Clobetasol Propionate, Desonide and Hydrocortisone in Topical Formulations by HPLC and UPLC-MS/MS

Corticosteroids are the most widely used class of anti-inflammatory medications in the pharmaceutical industry. There are several pharmaceutical dosage forms available using different corticosteroids. Topical steroids of varying potencies are available in creams, ointments, solutions and other vehicles. Chemical instability and drug degradation are the key quality concerns for these topical dosage forms. Nature of the dosage forms, excipient quality, product composition, and process optimization are some of the common factors which affect the stability of corticosteroids. This article describes drug degradation behavior of three different corticosteroids in different topical dosage forms. Drug degradation patterns of Hydrocortisone, Clobetasol propionate and Desonide formulations observed in stability studies of respective finished drug products under ICH recommended storage conditions were investigated. HPLC, UPLC-MS/MS methods were developed for the separation and characterization of impurities. The structural elucidation of the unknown impurities observed for these steroids and mechanistic consideration of potential degradation pathways has been discussed. Detailed discussion on the analytical methodologies is included as well.

A Stability Indicating UPLC Method for Finasteride and Its Related Impurities

The objective of the present research work is to develop a gradient, reversed-phase liquid chromatographic (RP-UPLC) method for the determination of Finasteride in pharmaceutical bulk drugs for assay and its related impurities. The chromatographic separation was achieved on a Waters ACQUITY UPLC BEH Phenyl Column (150 mm × 2.1 mm, 1.7 μm), The gradient LC method employs solutions A and B as mobile phase. The solution A Contains 2.5 mM ortho phosphoric acid (Buffer) and solution B contains a mixture of acetonitrile and water in the ratio of (90:10 v/v). The flow rate was 0.22 ml/min and the detection wavelength was 210 nm. In the developed UPLC method, the resolution between Finasteride and its potential impurities, namely Imp-1, Imp-2, Imp-3 and Imp-4 was found to be greater than 2.0. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. Considerable degradation was found to occur in alkaline medium and oxidative stress conditions. Degradation product formed during oxidative hydrolysis was found to be Imp-1. The stress samples were assayed against a qualified reference standard and the mass balance was found close to 99.5%. The developed RP-UPLC method was validated with respect to linearity, accuracy, precision and robustness. The limit of quantification of Imp-1, Imp-2, Imp-3 and Imp-4 were 0.06, 0.06, 0.05 and 0.036% (of analyte concentration, i.e. 0.5 mg/ml) with 1μl injection volume. The developed method was found to be linear in the range of 2.5 - 15 μg/mL with correlation coefficient of 0.999 for assay procedures and found to be linear in the range of 0.05 - 3 μg/mL with correlation coefficient of 0.999 for related impurities.