API Manufacturing Research Articles

Prozomix and Ginkgo Bioworks collaborate on next-gen enzyme development for sustainable API manufacturing

Prozomix and Ginkgo Bioworks collaborate on next-gen enzyme development for sustainable API manufacturing

Towards continuous flow manufacturing of active pharmaceutical ingredients in Africa: a perspective

Building start-of-the-art, sustainable and competitive local API manufacturing in Africa using continuous flow technology.

A strategic approach towards mass balance investigations in pharmaceutical drug substance release testing: A peculiar out of specification case study encountered during API manufacture

Mass balance in drug substances release testing is a critical quality attribute in pharmaceutical manufacturing that continues to challenge modern analytical characterization. This specific perspective of mass balance is lacking in literature, and the following work addresses the knowledge gap related to this topic by examining an in-depth case study and detailing the systematic investigation into mass imbalance observed during release testing of a small molecule API. The process followed a logical stepwise progression beginning with most probable causes and expanded to more obscure causes that require a deeper examination of the API in question until the undetected impurity in question was finally identified. The discovered impurity was eventually found to be formed from a unique side reaction that led to the formation of API-related oligomer impurities, which had eluded conventional small molecule release testing strategies. Ultimately, the characterization gap was traced back to deficiency in the LC results of the developed API purity methods. More importantly, this gap provides an ideal opportunity to highlight common oversights and pitfalls encountered in early phase pharmaceutical development especially as it relates to the method development of truly representative chromatography methods in the API characterization. The work reflects on the key lessons learned from the highlighted pitfalls that were encountered in this case study and offers strategic insights to guide and to improve the development workflow for drug substance characterization strategies.

Identifying the Risk of Formation of Nitrosamines and Other Potentially Mutagenic Impurities during API Manufacture Using In Silico Risk Assessment

Identifying the Risk of Formation of Nitrosamines and Other Potentially Mutagenic Impurities during API Manufacture Using In Silico Risk Assessment

Identifying the Risk of Formation of Nitrosamines and Other Potentially Mutagenic Impurities during API Manufacture Using In Silico Risk Assessment

Identifying the Risk of Formation of Nitrosamines and Other Potentially Mutagenic Impurities during API Manufacture Using <i>In Silico</i> Risk Assessment

Alleviating Effect of Supply Chain Finance on Financing Constraints of SMEs—— Empirical Analysis Based on 74 Manufacturing Samples

Based on the relevant literature, this paper makes an empirical study of the data of SMEs in the API manufacturing industry in China by using the cash-cash flow sensitivity model. By analyzing the experimental results, it is concluded that financing constraints generally plague SMEs in the API manufacturing industry. Supply chain finance can alleviate the financing constraints of manufacturing SMEs to a certain extent. This paper aims to enrich the research results in the field of supply chain finance, which has a specific guiding significance for developing supply chain finance theory and practice.

Improving the Manufacturability of Cohesive and Poorly Compactable API for Direct Compression of Mini-tablets at High Drug Loading via Particle Engineering.

To utilize a particle engineering strategy to improve the manufacturability of a cohesive and poorly compactable API at high drug loading for direct compression of mini-tablets. A high-shear mixer was used for wet milling during the API manufacturing process to obtain target particle size distributions. The targeted particles were characterized and formulated into blends by mixing with excipients. The formulated blends were compressed directly into mini-tablets using a compaction simulator. The tablet hardness, weight variation, and friability of the mini-tablets were characterized and compared with mini-tablets prepared with hammer milled APIs. Compared to the hammer milled APIs, the wet milled APIs, had smoother surface, narrower particle size distributions and demonstrated a better flow properties. Moreover, the mini-tablets produced with the wet milled APIs exhibited better weight uniformity, robust tablet mechanical strength and ultimately better friability. In addition, unlike the hammer milled process, the wet milling process is controllable and easy to scale up. This study successfully implemented API particle engineering through a high shear wet milling process to produce particles suitable for robust drug product manufacturing.

Continuous crystallization and its potential use in drug substance Manufacture: A review

Interest in the continuous manufacturing in the pharmaceutical industry for the production of Active Pharmaceutical Ingredients (API’s) has greatly increased in recent years. This has led to a variety of studies on continuous processing including a large number of studies in the area of continuous crystallization. While various potential crystallizer configurations exist, the vast majority of work in this area has focused around the Mixed Suspension Mixed Product Removal (MSMPR) crystallizer. In this review, MSMPR crystallizers will be described along with their use in continuous API manufacture.

Process intensification of atorvastatin calcium crystallization for target polymorph development via continuous combined cooling and antisolvent crystallization using an oscillatory baffled crystallizer

In this paper, continuous crystallization of Atorvastatin calcium (ASC) using a continuous oscillatory baffled crystallizer (COBC) has been investigated. Like most API manufacturing, ASC is manufactured batchwise and the pure API is recovered via batch combined cooling and antisolvent crystallization (CCAC) process, which has the challenges of low productivity, wide crystal size distribution (CSD) and sometimes polymorphic form contamination. To overcome the limitations of the batch crystallization, continuous crystallization of ASC was studied in a NiTech (United Kingdom) DN15 COBC, manufactured by Alconbury Weston Ltd. (AWL, United Kingdom), with the aim to improve productivity and CSD of the desired polymorph. The COBC has the advantage of high heat transfer rates and improved mixing that significantly reduces the crystallization time. It also has the advantage of spatial temperature distribution and multiple addition ports to control supersaturation and hence the crystallization process. This work uses an array of process analytical technology (PAT) tools to assess key process parameters that affect the polymorphic outcome and CSD. Two parameters were found to have significant impact on the polymorph, they are ratio of solvent to antisolvent at the point of mixing of the two streams and presence of seeds. The splitting of antisolvent into two addition ports in the COBC was found to give the desired form. The CCAC of ASC in COBC was found to be -30-fold more productive than the batch CCAC process. The cycle time for generating 100 g of desired polymorphic form of ASC also significantly reduced from 22 h in batch process to 12 min in the COBC. The crystals obtained using a CCAC process in a COBC had a narrower CSD compared to that from a batch crystallization process.

Exploration of a Nitromethane-Carbonylation Strategy during Route Design of an Atropisomeric KRASG12C Inhibitor.

Route design and proof of concept synthesis was conducted on a synthetically challenging atropisomeric KRASG12C inhibitor to support clinical API manufacture. Improvements to the synthesis of a chiral piperazine fragment gave reduced step count and streamlined protecting group strategy via the formation and methanol ring opening of an N-carboxy-anhydride (NCA). The complex atropisomeric nitroquinoline was accessed via an early stage salt-resolution followed by a formal two-part nitromethane-carbonylation, avoiding a high temperature Gould-Jacobs cyclization that previously led to atropisomer racemization. The substrate scope of the formal nitromethane-carbonylation strategy was further explored for a range of ortho-substituted bromo/iodo unprotected anilines.

Articulation of Quality By Design Elements for Product Development and its Unique Applications

Quality by Design (QbD) is a methodical approach to pharmaceutical product development that begins with predefined objectives and emphasizes product and process comprehension and process control based on sound science and quality risk management. Pharmaceutical development should lead to the design a quality product and its manufacturing process to meet the QTPP and CQA parameters. To arrive at the robust product development QbD articulation is important which is missing in most of the reviews. This review articulates the QbD elements in the product development. QbD process stars with identification of QTPP and source CQA from QTPP. CMAs and CPPs are derived with risk assessment from the product ingredients and process. Their impact on the CQAs can be studies with DoE tools. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the design space and control strategy. Product process follows life cycle management approach with continuous improvement. PAT tools are utilized for the online monitoring of the processes. This review paper is dedicated to provide QbD element articulation in product development and its unique applications in the various areas of the product development such as Biotechnology, Nanotechnology products, Nasal products, Inhalation, Injectable products, Targeted drug delivery, complex Solid oral, Transdermal and topical products, Bioavailability and dissolution enhancement, Analytical processes and API manufacturing etc. Current trends in the technical application of the PAT tools are discussed.&#x0D; Keywords: Quality by Design (QbD), Quality Target Product Profile (QTPP), Critical Quality Attributes (CQA) and Design of Experiment (DoE): Product development application of QbD

The challenges in commercialisation of Probiotic API manufacturing

The concept of probiotics is well known and has developed into a high value commodity in recent times. Despite the ever-expanding number of probiotic products on our pharmacy, health food and supermarket shelves, the probiotic culture active ingredient has always been imported until now. In 2019, Probiotics Australia Pty Ltd opened Australia’s first and only Therapeutic Goods Administration/current Good Manufacturing Practice (TGA/cGMP) certified facility dedicated to the manufacture of probiotic active ingredients. This article outlines the significant export demand for Australian-made health products and the lengths to which Probiotics Australia have gone to create a facility to meet needs of the probiotics research, commercialisation and consumer market today and into the future.

Indian API industry has the tide turned?

Over the past decade or so, API industry has lost out to Generics in attracting investments due to prevailing industry structure which favoured greater returns from Generics – faster growth and better margins among others. In the past three to five years, with Generics losing sheen with normalised margins and returns, API businesses are getting back onto investor radar. With inherent chemistry and engineering complexity, API manufacturing has the potential to create businesses protected by better moats. Another pain point of the API industry was Chinese exuberance in offering APIs at irrationally low prices, which eventually destroyed value for the entire industry as a whole. A slew of recent measures and events has established parity among all players – Chinese, Indian and European, with the anticipation that it should better industry wide performance. Indian API companies are well positioned to leverage the situation and improve their standing in the API industry. Financial markets have begun to recognise some of these players like Divis Laboratories, trading at market capitalisations comparable to generic companies with 10 times higher revenue. Besides large players like Divis, a bunch of upcoming Indian API suppliers led by MSN Labs have focused on developing a large number of niche, low competition APIs for supplying to the regulated markets. Such portfolio lends towards above industry average realisations and wider customer penetration. Besides public listing, API companies have been sought after targets for adjacent players in CDMO space, chemical companies, chemical distributors for forward/backward integration and creating additional revenue streams. A bunch of private equity players have already setup or in the process of setting up platforms to consolidation API companies, as we speak. For an investor, it is the key to understand the various business models and the key factors driving the choice of targets to ensure the strategy is well designed to succeed.

The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations

This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufacturing Organizations (CMOs). The survey includes staffing (personnel), chemistry, reaction platforms, postreaction processing, analytical, regulatory, and factors that influence the adoption of continuous manufacturing. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufacturing executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chemistry, while postprocessing and analytical remain in the very early stages of development and implementation.

The Delivery of Flexibility from the Application of QbD to API Development

This paper by IQ consortium member companies will describe how the application of the ICH Q11 vision for enhanced QbD development can lead to flexibility through differentiated outcomes for elements of API manufacture, such as the control strategy and lifecycle change management. Two further articles, in addition to this introductory paper, will present a series of case histories which address such flexibility and exemplify opportunities for the further development of the ICH Q11 vision.

Synthetic peptide API manufacturing: A mini review of current perspectives for peptide manufacturing

Synthetic peptide API manufacturing: A mini review of current perspectives for peptide manufacturing

Applications of Flow Chemistry in Drug Development: Highlights of Recent Patent Literature

Flow chemistry is playing an increasingly important role in API process development and manufacture in the pharmaceutical and fine chemical industry. The current article reviews routes to approved drugs that employ at least one continuous flow step, disclosed in the patent literature during 2016 and 2017, with a further constraint that the chemistry has not been published in a journal article.

Using PAT to accelerate the transition to continuous API manufacturing.

Significant improvements can be realized by converting conventional batch processes into continuous ones. The main drivers include reduction of cost and waste, increased safety, and simpler scale-up and tech transfer activities. Re-designing the process layout offers the opportunity to incorporate a set of process analytical technologies (PAT) embraced in the Quality-by-Design (QbD) framework. These tools are used for process state estimation, providing enhanced understanding of the underlying variability in the process impacting quality and yield. This work describes a roadmap for identifying the best technology to speed-up the development of continuous processes while providing the basis for developing analytical methods for monitoring and controlling the continuous full-scale reaction. The suitability of in-line Raman, FT-infrared (FT-IR), and near-infrared (NIR) spectroscopy for real-time process monitoring was investigated in the production of 1-bromo-2-iodobenzene. The synthesis consists of three consecutive reaction steps including the formation of an unstable diazonium salt intermediate, which is critical to secure high yield and avoid formation of by-products. All spectroscopic methods were able to capture critical information related to the accumulation of the intermediate with very similar accuracy. NIR spectroscopy proved to be satisfactory in terms of performance, ease of installation, full-scale transferability, and stability to very adverse process conditions. As such, in-line NIR was selected to monitor the continuous full-scale production. The quantitative method was developed against theoretical concentration values of the intermediate since representative sampling for off-line reference analysis cannot be achieved. The rapid and reliable analytical system allowed the following: speeding up the design of the continuous process and a better understanding of the manufacturing requirements to ensure optimal yield and avoid unreacted raw materials and by-products in the continuous reactor effluent. Graphical Abstract Using PAT to accelerate the transition to continuous API manufacturing.

Continuous crystallization using a sonicated tubular system for controlling particle size in an API manufacturing process

A pH swing crystallization that was very sensitive toward scale-up and required specific equipment due to the non-Newtonian characteristics of the fluid, has been investigated using continuous crystallization (CC) as a means to improve particle size control, scalability and potentially reduce manufacturing cost. A sonicated tubular crystallizer was designed and shown to allow the pH swing crystallization to be operated robustly without blockage, to give a wide range of desired particle size. The results were compared with crystallization in a premixing semi-batch system and a simple addition semi-batch system under similar conditions. Interestingly, it was found that the sonicated tubular system was the only one of the three systems that gave the desired control for small particle size (1–7μm). Even though the productivity of the sonicated tubular crystallizer still needs to be increased to allow CC and numbering-up to become cost competitive with batch crystallization, we have demonstrated the potential of continuous tubular crystallization as a useful alternative method to conventional batch operation.

ChemInform Abstract: Industry Perspectives on Process Analytical Technology: Tools and Applications in API Manufacturing

AbstractReview: 13 refs.