Production Of Active Pharmaceutical Ingredients Research Articles

Abstracts from The Aerosol Society Drug Delivery to the Lungs 22Edinburgh International Conference CentreEdinburgh, Scotland, UKDecember 7–9, 2011

Summary Background: In bronchial challenge testing lung deposition of the stimulus may be poorly controlled due to incorrect use of nebulisers. Furthermore, the need for freshly prepared solutions burdens personnel and budget. In this study we aim to develop a dry powder alternative with higher reproducibility, better stability and lower costs than the current nebulisation test. Methods: Different pharmacological stimuli in the solid state were characterised on physico-chemical properties to determine the optimal conditions for processing and storage and were tested on their potential for dry powder inhalation. Adenosine and methacholine were micronised and dispersed with the Twincer ™ dry powder inhaler (DPI). Laser diffraction technique was applied to measure particle size distributions in the aerosol clouds. Results: Adenosine allows processing under ambient conditions. It was mixed with a lactose carrier in various mass ratios to produce adhesive mixtures and nucleus agglomerates. With three formulations, almost the entire dose range could be delivered with the Twincer ™ DPI. However, the process of preparing nucleus agglomerates might not be suitable for upscaling. Currently, spherical pellets are investigated as a more robust alternative. Methacholine is very hygroscopic and should therefore not be exposed to a high relative humidity. The methacholine particles leaving the Twincer ™ had an appropriate particle size distribution for inhalation. However, inhaler retention was high and should be reduced by controlling processing and storage conditions. Conclusions: Dry powder adenosine and methacholine seem promising alternatives for nebulisation. Methacholine must be handled under dry conditions. The highest doses of adenosine require further fine tuning.

Development and Application of Laboratory Tools To Predict Particle Properties upon Scale-Up in Agitated Filter-Dryers

Agitated filter-dryers (AFDs) are commonly used for performing both filtration and drying operations in the manufacture of active pharmaceutical ingredients (APIs) and intermediates. Successful scale-up from the laboratory to manufacturing AFD equipment requires that physical properties specifications such as particle size be consistently met in addition to chemical purity specifications. Depending on the API–solvent system and equipment operational parameters, undesired attrition or agglomeration may occur, so an improved understanding of these phenomena upon scale-up is of key importance. In this paper, we describe recent advances in laboratory methods, based on material characterization methods common to drug product formulation development, to better assess the risk of agglomeration and attrition potential upon scale-up. These methods provide data to evaluate solid behavior, in both wet and dry states, associated with processing in an AFD. For agglomeration prediction, the application of mixer torque ...

Safety and technological hygiene in production of active pharmaceutical ingredients

Practical implementation of the principles of safety and technolog ical hygiene is carried out with proper organization of production design and operation of equipment under specific operating conditions. To solve biosafety issues at the stage of production design the features of technological hygiene require consideration, where a subject of production is personnel and the environment. Production of active pharmaceutical ingredients using the biotechnology and based on it pharmaceutical production have a significant impact on actions on safety and personnel hygiene, and actions to protect the environment. To ensure the product quality, personnel safety and environmental protection two basic types of actions are required - correct design of the production and proper design and operation of equipment. A methodology and principles of project activities, design and operation of equipment of technologies of active pharmaceutical ingredients for the production of immunobiological drugs were developed. An essential element of the design, production and operation of the equipment is compliance with Good Manufacturing Practices (GMR) when using clean premises

Sonofragmentation of molecular crystals

Developing processes for the production of active pharmaceutical ingredients (APIs) with a specific crystal size or polymorph distribution is critical for improved drug delivery by aerosolization, injection or ingestion, for control of bioavailability, and for economy of preparation. The use of ultrasound for the crystallization of APIs has attracted substantial recent attention due to (1) its influence on particle size and size distribution, (2) reduction of metastable zone-width, induction time, and supersaturation levels required for nucleation, (3) improved reproducibility of crystallization, (4) control of polymorphism, and (5) reduction or elimination of the need for seed crystals or other foreign materials. Possible mechanisms for the breakage of molecular crystals under high-intensity ultrasound were investigated, using acetylsalicylic acid (aspirin) crystals as a model compound for active pharmaceutical ingredients (APIs). Surprisingly, kinetics experiments rule out particle-particle collisions as a viable mechanism for sonofragmentation. Two other possible mechanisms — particle-horn or particle-wall collisions — were dismissed based on decoupling experiments. Direct particleshockwave interactions are therefore indicated as the primary mechanism of sonofragmentation of molecular crystals.

The challenge of improved secretory production of active pharmaceutical ingredients in Saccharomyces cerevisiae: A case study on human insulin analogs

The yeast Saccharomyces cerevisiae has widely been used as a host for the production of heterologous proteins. Great attention has been put on improved secretory production of active pharmaceutical ingredients, and the secretory pathway of this eukaryotic host has been the playground of diverse strain engineering studies, aiming at enhanced cellular capacities for folding and trafficking of the target proteins. However, the cellular quality assessment for secretory proteins remains mostly unpredictable, and different target proteins often do not picture similar secretion yields, underlining the dependency of efficient secretion on the physicochemical properties of the protein of interest. In this study, two human insulin analog precursors (IAPs) with minor differences in their amino acid sequences were used as model secretory proteins. No differences between cells expressing these two proteins were found in the IAP transcript levels, gene copy numbers, or intra-cellularly accumulated proteins, yet a more than sevenfold difference in their secretion yields was found. Physiological characterization of cells expressing these proteins in batch processes revealed no significant difference in their specific growth rate, but an altered overflow metabolism. Global transcriptome analysis carried out in chemostat experiments pinpointed distinct steps during the protein maturation pathway to be differentially regulated and indicated an increased degradation of the IAP with the low secretion yield. In silico protein structure modeling of the IAPs suggested a difference in conformational stability, induced by the amino acid substitution, which most likely resulted in disparity in trafficking through the secretory pathway and thus a large difference in secretion yields.

Compact Crystallization, Filtration, and Drying for the Production of Active Pharmaceutical Ingredients

With the growing problem of drug shortages worldwide, a solution could be a centralized compact pharmaceutical manufacturing platform that produces API and finished drug product. In this paper, the development of a combined crystallization, hybrid filtration-drying-dissolution apparatus to be used in such a compact platform is discussed. Experiments were conducted to evaluate each unit operation. Crystallization experiments using a conventional stirred tank and the newly designed scraped surface crystallizer demonstrated the advantages of the new design in terms of crystallization rates, yields and the ease of automation. Postcrystallization operations were operated stepwise using the custom hybrid device that delivered satisfactory results for each operation, e.g. after filtration, Fluoxetine HCl was dried in less than 20 min, with 99% yield after dissolution in the liquid excipient.

Active pharmaceutical ingredients for antiretroviral treatment in low- and middle-income countries: a survey.

Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President's Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent.

Production of antiretroviral drugs in middle- and low-income countries.

This review outlines the main issues concerning the production of antiretroviral (ARV) drugs in middle- and low-income countries and the relevant political, legal and technical requirements for supporting such production. The requirements for efficient local production, including the manufacture of generic and branded products and public demand, have been considered from economic, market and socio-political perspectives. A steady and consistent government policy is crucial to success. Additional crucial factors in establishing local production are adequate infrastructure, qualified human resources in technical and managerial areas, and production-distribution logistics systems. The creation or strengthening of a national drug regulatory agency is a basic requirement. Production of ARVs relies on the structure of the international market for active pharmaceutical ingredients (APIs), which are highly monopolized for inclusion in branded or patented drugs, or are concentrated in a few Asian generic companies. Countries seeking to begin local production must develop strategies to overcome the various barriers. For instance, sub-Saharan African countries may benefit from developing multilateral health agreements with neighbouring countries. Such agreements are recommended and should be complemented by technology transfers, especially for the manufacture of APIs. Achieving a production level that is sustainable in the long term is crucial to maintaining patients' access to ARVs.

Patents and profits: A disparity of manufacturing margins in the tenofovir value chain.

Registered in 2001, tenofovir disoproxil fumarate (TDF) has quickly become a mainstay of first line regimens for the treatment of HIV. Initially only available in developed countries at a cost of US$5 000 per person per year (ppy), Gilead's Access Programme (GAP) has extended the use of the product to 2.4 million patients in low and middle income countries. The programme has two components: distribution of the branded product at reduced prices and licensing partnerships with generic manufacturers. The licensing partnerships now supply 75% of the market by volume, at a treatment cost of US$57 ppy (1% of the branded cost). From Gilead's perspective, GAP must be considered a huge success. It has enabled the company to maintain high prices in developed countries whilst reducing its input costs and deflecting criticism of its failure to provide essential medicines for the poor, hence risking the possibility of compulsory licensing. Over the period 2001 to 2011, TDF in its various forms has generated for Gilead more than US$31 billion revenue at a gross margin of 80%, equivalent to a gross profit of US$25 billion. Analysis of the TDF value chain, from preparation of the active pharmaceutical ingredient (API) to sale of the formulated product, shows that manufacturing margins are highly skewed in favour of the originator, with the latter's profit being US$3.2 billion vs. US$4 million for API manufacturers and US$39 million for formulators (2011). The data argues for a more rational approach to drug pricing including possible regulation in developed countries and more sustainable margins for the generic producers.

En route to full implementation: driving the green chemistry agenda in the pharmaceutical industry

What is the relationship between the Green Chemistry initiative and the pharmaceutical industry? The intention is to shed some light on this issue by providing an historical overview spanning a period of about 20 years – from the start of the movement towards greener processes and manufacture in the early 1990s until today where greenness and sustainability are widely embraced throughout society. To understand and appreciate the approach to the green paradigm from a pharmaceutical business point of view, it is essential to paint the broader picture explaining the landscape in which this industry operates and its particular challenges. Looking at the special features that apply to chemical production of drug molecules for commercial use – in relative terms a low volume undertaking (from kg scale through to 10s or sometimes 100s of tons per annum) – the situation is vastly different compared to conventional bulk manufacture (for instance of commodity chemicals). After an initial lag phase, the drug industry has now caught up and is very eager to fully adopt green principles and to gather evidence on how it is performing. As an example, it is a well documented fact that more than half the mass constituting a process stream in the chemical manufacture of active pharmaceutical ingredients (APIs) stems from the solvent(s) utilized; 80–90% if water is included. In a multi-step synthesis on an average composed of 8–10 discrete chemical transformations which typically runs at a process mass intensity (PMI) factor of 100–200 kg kg−1 API, about 50–100 kg can be referred purely to the contribution from solvents; hence, the potential for improvements is huge. Thus, leaving the historic priorities behind in favor of drivers for change such as external pressure, goodwill, legislation, and company policies is a good strategy to ensure a rapid movement into a greener future, albeit without ignoring the existence of blockers that mainly relate to insufficient scientific and technological capabilities. From a chemical process point of view, there are several reasons to have an optimistic view about the prospects of a flourishing green agenda going forward as shown in a number of recent case studies.

NMR spectrometry isotopic fingerprinting: A tool for the manufacturer for tracking Active Pharmaceutical Ingredients from starting materials to final medicines

In the frame of increasingly stringent quality assessment required by the regulators, the pharmaceutical industry has to face increasingly sophisticated counterfeiting practices. Counterfeits based on deliberate copying of processes or on the infringement of current patents for generic medicines are not straightforward to detect, unless the molecular probe is the active molecule itself. In this context, impurity profiling is limited. A tool based on the determination of intramolecular isotopic profiles has been developed to provide manufacturers of APIs (Active Pharmaceutical Ingredients) with a new solution to meet this double requirement. Stable isotope analyses by NMR gives direct access to site-specific isotope content at natural abundance. In this report, it is shown how both 2H and 13C NMR spectrometry can provide complementary and valuable information that could be applied to link APIs to their manufacturing source. Isotopic 13C NMR offers additional benefits over 2H NMR in using robust adiabatic polarization transfer methods, leading to a tremendous reduction in experimental time. Two approaches are illustrated. Firstly, the use of 2H and single pulse 13C NMR spectra obtained on 20 commercial ibuprofen samples from different origins show that this combined strategy leads to (i) a unique intramolecular isotope identification and (ii) a preliminary classification of the samples according to the synthetic pathways of the main industrial processes. An approach employing polarization transfer methods applied to 11 commercial naproxen samples, for which 2H and single pulse 13C NMR spectra are not exploitable and/or are not accessible in reasonable time. The relative and partial intramolecular 13C distribution obtained on naproxen by applying this methodology is sufficiently informative to allow the same conclusions as for ibuprofen. The additional benefits that these approaches should bring to API manufacturers are discussed.

Continuous Processing in the Manufacture of Active Pharmaceutical Ingredients and Finished Dosage Forms: An Industry Perspective

Continuous manufacturing as a way of producing fine chemicals, active pharmaceutical ingredients, and finished dosage forms is gaining widespread attention. Although potential benefits over traditional batch-wise production have been discussed at many occasions and appear evident, continuous processes are only slowly being implemented. The American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable has defined “continuous processing” as one of its research priorities(1) and performed a survey of its members’ opinions, the status of implementation, and perceived hurdles blocking implementation of continuous manufacturing processes. Here we discuss the most important results of this survey and their relation to present trends in this industry to “go green”.

Use of Enzymes in the Manufacture of Active Pharmaceutical Ingredients—A Science and Safety-Based Approach To Ensure Patient Safety and Drug Quality

A significant number of marketed pharmaceuticals contain active pharmaceutical ingredients that are manufactured in part using biocatalysis as a key enabling technology. The utilization of biocatalysis is growing due to significant advances in technologies for enzyme discovery, supply, and improvement, as well as an increased focus on applications for chiral drugs and green chemistry. Nevertheless, there still remains a lack of clarity around quality and regulatory expectations when using biotransformations in research and manufacturing, and this lack of clarity can be a barrier to the uptake and adoption of biocatalysis. This commentary will explore and offer some rational, coherent, and achievable strategies for the use of biocatalysis in the manufacture of small molecule active pharmaceutical ingredients (APIs) based on a scientific, risk-based approach to drug quality and patient safety. We also seek to invite other interested parties to contact us with their views to add to the topics discussed here ...

Heating-Induced Phase Transition of Bupropion Hydrobromide Polymorphs

Crystal phase transition and isothermal crystallization kinetics of bupropion hydrobromide is studied by thermal analysis, X-ray powder diffractometry, and scanning electron microscopy. As well known, bupropion hydrobromide has two stable polymorphic forms, form I and form II, during the production. Here it is found that form II will convert into form I with thermal treatment. Avrami exponent n is evaluated to be around 2.0 in the range 170°C-190°C, which indicates that the phase transition is a process of one-dimensional nucleation growth. This viewpoint is also confirmed by microscope morphology study. In addition, phase-transition active energy is calculated to be 239.4 kJ/mol, which means that a high energy barrier needs to be overcome to start up the phase transition.

Sonofragmentation and sonocrystallization

Developing processes for the production of active pharmaceutical ingredients (APIs) with a specific crystal size or polymorph distribution is critical for improved drug delivery by aerosolization, injection or ingestion, for control of bioavailability, and for economy of preparation. The use of ultrasound for the crystallization of APIs has attracted substantial recent attention due to (1) its influence on particle size and size distribution, (2) reduction of metastable zone-width, induction time, and supersaturation levels required for nucleation, (3) improved reproducibility of crystallization, (4) control of polymorphism, and (5) reduction or elimination of the need for seed crystals or other foreign materials. Possible mechanisms for the breakage of molecular crystals under high-intensity ultrasound were investigated using acetylsalicylic acid (aspirin) crystals as a model compound for active pharmaceutical ingredients. Surprisingly, kinetics experiments ruled out particle-particle collisions as a viable mechanism for sonofragmentation. Two other possiblemechanisms (particle-horn and particle- wall collisions) were dismissed on the basis of decoupling experiments. Direct particle-shockwave interactions are therefore indicated as the primary mechanism of sonofragmentation of molecular crystals.

Data Driven Modelling and Control of Batch Processes in the Pharmaceutical Industry

Regulatory changes in the pharmaceutical industry have recast the role of chemical engineering in the development of processes for the large-scale manufacture of Active Pharmaceutical Ingredients. Health authorities' expectations have increased regarding proven demonstration of adequate process performance, process robustness, and quality control across development and manufacturing scales. These expectations have substantially increased the demands of experimental data collection, process monitoring, and multivariate process understanding. To address these requirements, innovative implementation of established and emerging automation, modeling, data management, and process monitoring techniques have been increasingly added to the repertoire of process development tools in particular, those carried out in agitated stirred tanks. This article will introduce the application of these techniques across the range of process development (from early to late phase) challenges. In particular, this article describes the implementation of Data Exploration Analysis to results obtained with automated parallel experimentation for batch reaction characterization and automated batch crystallization processes integrated to population balance modeling. Collectively these examples of new strategies for the automation of experimental batch processes, data analysis, and modeling provide an overview of recent trends in pharmaceutical chemical process development.

Interdependence of Drug Substance Physical Properties and Corresponding Quality Control Strategy

In quality by design (QbD) paradigm, specifications on active pharmaceutical ingredients (APIs) are a critical component of the overall control strategy to ensure drug product quality. In establishing appropriate specifications for highly correlated API properties, multivariate specifications were advocated recently (Duchesne C, MacGregor JF. 2004. J Qual Technol 36:78-94). In this text, we reviewed several scenarios where API properties are of varying degrees of intercorrelation, and discussed the corresponding control strategies. One scenario was further analyzed, in which high degree of property intercorrelation could afford a single univariate specification and, thereby, simplify the control strategy. In the case study provided, we first mapped the potential design space of the API physical properties, and subsequently compared the effectiveness of univariate and multivariate control strategies. On the basis of the comparison, a single univariate control scheme was proposed and boundary was defined. Finally, width of the design space for API physical properties was assessed, and the effectiveness of the API manufacturing process control was preliminarily evaluated.

Crystal structure of isotibolone: a major degradation product of tibolone

Isotibolone is frequently found as an impurity in tibolone, a drug used for hormone reposition of post-menopause women, due to some inadequate tibolone synthesis or as a result of degradation during drug storage. The presence of isotibolone impurities should be detected and quantified in active pharmaceutical ingredient products of tibolone before its use in the manufacturing of medicaments. The X-ray powder diffraction technique offers the possibility of quantifying isotibolone amounts at different stages of drug production and storage, from the chemical synthesis to the final formulation. In the course of a study involving the quantitative analysis of isotibolone by X-ray powder diffraction, the authors determined the structure of the title compound using a recently developed approach (A. Gomez and S. Kycia, J. Appl. Crystallogr. 2011, 44, 708–713). The structure is monoclinic, space group P21 (4), with unit cell parameters a = 6.80704(7) Å, b = 20.73858(18) Å, c = 6.44900(6) Å, β = 76.4302(5)°, V = 884.980(15) Å3 and two molecules per unit cell (Z = 2). The molecules are hydrogen bonded in the ab plane forming layers that are held together in the crystal by van der Waals interactions along the c-axis.

Towards the sustainable and continuous in-vitro production of active pharmaceutical ingredients from medicinal plants

Towards the sustainable and continuous in-vitro production of active pharmaceutical ingredients from medicinal plants

LONZA TO BUY ARCH CHEMICALS

TO HELP SHIFT its business away from the volatile active pharmaceutical ingredient (API) area, Lonza plans to acquire Arch Chemicals in a $1.4 billion cash deal. Although it will still have a leading position in custom manufacturing, the Swiss company will benefit from a new 15% share of the $10 billion-peryear antimicrobial market. The deal offers a “unique opportunity” and “marks the next step of Lonza building a world-class life science company,” Lonza CEO Stefan Borgas said in a conference call with analysts. The combined company will have about $4.3 billion in annual sales, with 43% in microbial control products, 35% in custom API manufacturing, and 22% in life sciences and nutrition products. Custom manufacturing, especially for biologics, currently accounts for more than half of Lonza’s sales, whereas microbial control is about 14% of sales. Acquiring Arch will help strengthen and balance Lonza’s portfolio in many ways, Borgas said, and Lonza can improve Arch’s ...