Production Of Active Pharmaceutical Ingredients Research Articles

API Supplier Change or Addition of Alterate API Supplier in Generic Drug Products: Cost, Quality and Regulatory Factors

Generic drug product (GDP) competition for market existence and profitability has become a challenging task for the manufacturers. All the generic players are putting intensive efforts to enter the market with competitive price and consistent drug product (DP) quality. The generic firms have to manage the delicate balance between the cost and quality of raw materials, especially the active pharmaceutical Ingredient (API) for market survival. Major Pharma companies have adopted the merger and acquisition strategies with API manufacturers to withstand the competition and price erosion. Still the majority firms don’t have their own API manufacturing facility. Since the finished product cost is majorily driven by API, the supplier selection plays prominent role in the generic profitability as well as quality. The supplier screening and selection includes extensive evaluation and comparison of documents, quality and cost. As part of risk mitigation strategy many generic manufactures prefer to include additional or alternate sources for API supplier. This exercise could be triggered anytime during the DP life cycle. The authors have tried to share the view on supplier change process at various stages of product lifecycle and related regulatory authority requirements and expectations. Generic products have been targeted majorly for US and Europe regions and same is being focused here. These two regulatory bodies have almost similar requirement for supplier selection and change, except difference in procedural approaches. The regulatory requirements may vary for each phase of generic product life cycle. At the development stage, the supplier change may not significantly fall into regulatory umbrella. Generally development phase comes under relatively less regulatory scruitiny than CTD submission or post approval phase. The dossier review and post approval phase have almost similar regulatory requirements. All the post approval changes shall be routed through SUPAC filing in US and VARIATION filing procedures in Europe.

Impact of API (Active Pharmaceutical Ingredient) Source Selection on Generic Drug Products

The pharmaceutical industry is emerging as a significant industrial sector with tremendous potential for providing innovative drugs to treat life-threatening diseases as well as for providing economical generic alternatives of supreme quality. Hence this sector is not only responsible to provide the much desired boost to the health of the society, especially of the developing countries, but also it is a competitive yet profitable sector from a business perspective. Currently, the primary focus of the pharmaceutical industry is to raise the bar for the quality, safety and efficacy of the drug products that are made available in the global market place. Product quality, price of raw materials [API (active pharmaceutical ingredient) and excipients] and market return competition are vital factors that determine the longevity or existence and profitability of a company in the crowded pharmaceutical market. . Hence these critical factors receive special consideration from drug product manufacturers. Active Pharmaceutical Ingredient (API) is the primary constituent of a pharmaceutical drug product that governs the final cost of the drug product as well as the commercial profit earned by the company. Most of the major generic drug manufacturing companies have their own API manufacturing facility and hence may not prefer to screen independent API suppliers as part of their generic drug development plan to procure additional API. Contradictorily, the generic drug manufacturers who do not synthesize the API themselves are dependent on external and independent API manufacturers for procurement of the API. Such generic drug manufacturing companies have to select suitable API suppliers by adapting a risk aversive approach. This article presents an informed and comprehensive discussion on the primary and alternate API supplier selection processes for generic drug products manufacturing firms. This API supplier selection process can be categorized into several stages which include preliminary assessment, documents review, samples analysis, onsite or offsite audit, results evaluation and final approval or rejection. This API selection process includes the anticipated product specific risk assessment with relation to API characteristics, specifications, analytical results, document review observations and inspection results. A generic drug product manufacturing company can choose an alternative API supplier or change the existing API supplier either during the development phase or after development of the drug product. Generic drug product manufacturing companies should rework on development activities if any API supplier change happens during the development phase. API supplier change or addition of an alternative API supplier has to be followed as per SUPAC guidance for US market and VARIATION filing procedures for European market.

Potential ecological footprints of active pharmaceutical ingredients: an examination of risk factors in low-, middle- and high-income countries.

Active pharmaceutical ingredients (APIs) can enter the natural environment during manufacture, use and/or disposal, and consequently public concern about their potential adverse impacts in the environment is growing. Despite the bulk of the human population living in Asia and Africa (mostly in low- or middle-income countries), limited work relating to research, development and regulations on APIs in the environment have so far been conducted in these regions. Also, the API manufacturing sector is gradually shifting to countries with lower production costs. This paper focuses mainly on APIs for human consumption and highlights key differences between the low-, middle- and high-income countries, covering factors such as population and demographics, manufacture, prescriptions, treatment, disposal and reuse of waste and wastewater. The striking differences in populations (both human and animal), urbanization, sewer connectivity and other factors have revealed that the environmental compartments receiving the bulk of API residues differ markedly between low- and high-income countries. High sewer connectivity in developed countries allows capture and treatment of the waste stream (point-source). However, in many low- or middle-income countries, sewerage connectivity is generally low and in some areas waste is collected predominantly in septic systems. Consequently, the diffuse-source impact, such as on groundwater from leaking septic systems or on land due to disposal of raw sewage or septage, may be of greater concern. A screening level assessment of potential burdens of APIs in urban and rural environments of countries representing low- and middle-income as well as high-income has been made. Implications for ecological risks of APIs used by humans in lower income countries are discussed.

Analytical technology aided optimization and scale‐up of impinging jet mixer for reactive crystallization process

Reactive crystallization is widely used in the manufacture of active pharmaceutical ingredients (APIs). As APIs often have low solubility, traditional stirred tank reactors and the route of process operation and control using metastable zone width are not effective. This work investigated the integration of an impinging jet mixer and a stirred tank crystallizer that can take advantage of both the reaction and crystallization characteristics, the focus being on design optimization and scale‐up using process analytical techniques based on the Fourier transform infrared spectroscopy and focused beam reflectance measurement, as well as X‐ray diffraction and particle imaging Morphologi G3. The parameters for process operation and design of the impinging jet mixer were optimized. The research was carried out with reference to the manufacture of an antibiotic, sodium cefuroxime, first in a 1L reactor, then a 10L reactor. The crystals produced showed higher crystallinity, narrower size distribution, higher stability, and purity. © 2014 American Institute of Chemical Engineers AIChE J, 61: 503–517, 2015

ChemInform Abstract: Metabolic Engineering: The Ultimate Paradigm for Continuous Pharmaceutical Manufacturing

AbstractReview: [32 refs.

Life Cycle Analysis within Pharmaceutical Process Optimization and Intensification: Case Study of Active Pharmaceutical Ingredient Production

As the demand for new drugs is rising, the pharmaceutical industry faces the quest of shortening development time, and thus, reducing the time to market. Environmental aspects typically still play a minor role within the early phase of process development. Nevertheless, it is highly promising to rethink, redesign, and optimize process strategies as early as possible in active pharmaceutical ingredient (API) process development, rather than later at the stage of already established processes. The study presented herein deals with a holistic life-cycle-based process optimization and intensification of a pharmaceutical production process targeting a low-volume, high-value API. Striving for process intensification by transfer from batch to continuous processing, as well as an alternative catalytic system, different process options are evaluated with regard to their environmental impact to identify bottlenecks and improvement potentials for further process development activities.

Redefining Solution-Mediated Transformations: Pharmaceutical Systems

Engineering the isolation of a metastable or stable crystalline phase of an active pharmaceutical ingredient (API) is of critical importance when crystallizing from solution as an uncontrolled outcome can directly affect API manufacture and performance. The theoretical framework for understanding solution-mediated crystal phase or polymorphic transformation (SMPT) was first established by Cardew & Davey.[1] The process is defined to consist of a metastable phase that dissolves and a stable phase that nucleates and grows independently from the solution. That paper also identified that in terms of a reaction pathway, SMPT could be controlled in either of two ways: by growth of the stable phase or dissolution the metastable phase. Studies concerning SMPT since then have brought the definition and those conclusions into question. Firstly, the recent case of the SMPT from FI to FIII carbamazepine and FII to FIII piractem were studied separately where data on both the solid state composition and solution concentration were collected during the transformation using powder X-ray diffraction and in situ infra-red spectroscopy, respectively. These studies, in combination with a brief review of the literature, reveal that SMPT can be controlled not only in the two ways described by Cardew & Davey but rather in 4 principal ways (Figure 1).[2] Secondly, many studies now identify that nucleation of the stable phase often occurs on the surface of the metastable phase during SMPT [3] and not independently from solution. Again when the literature is examined, this surface supported nucleation event is identified as being either epitaxial in nature or having no or inconclusive evidence of epitaxy. It is concluded that the term "independently" in the definition by Cardew & Davey be redefined to recognize that the crystallization of the stable phase during SMPT is often dependent on the surface of the metastable phase in solution.

End To End

In 2009, when Lonza made a bid to acquire Patheon, a contract manufacturer of drugs in final dosage form, industry watchers shook their heads and said, “Nope.” Such an acquisition didn’t make sense, given the fundamental differences between Lonza’s main business, the manufacture of active pharmaceutical ingredients (APIs), and Patheon’s production of finished drugs. Many viewed it as a step too far in a trend, heating up at the time, of API manufacturers adding service components to their business via acquisition. And, sure enough, the deal fell through. Last November, however, a successful deal was struck between Patheon and the Dutch chemical company DSM. The two formed a new firm, DPx, consisting of DSM Fine Chemicals, Patheon, and Banner Life Sciences, a manufacturer of over-the-counter drugs that Patheon acquired in 2012. The combination seems less surprising than when Lonza proposed its version of it four years ago. Any eyebrows raised ...

Review of quality deficiencies found in active pharmaceutical ingredient master files submitted to the WHO Prequalification of Medicines Programme.

The aim of this work was to determine the number and type of active pharmaceutical ingredient (API) quality deficiencies in API Master Files (APIMFs) as submitted to the World Health Organization (WHO) Prequalification of Medicines Programme (PQP). We conducted a retrospective review of API quality deficiencies identified following the assessment of new APIMFs for non-sterile APIs during a 6-year period from 1 January 2007 to 31 December 2012. All deficiencies were collected, classified and quantified according to the Common Technical Document (CTD) sections and subsections and as groups of commonly raised questions. There were 5446 deficiencies collected from 159 APIMF deficiency letters by CTD section, by selected CTD subsections and by selected CTD subsections and year. More than 50% of the total number of deficiencies related to the manufacturing sections of the CTD, followed by deficiencies concerning the impurities, the API specification and the stability sections of the CTD. A pattern of API deficiencies across the different CTD subsections and over time was identified. The most frequent critical deficiencies were related to how the specific manufacturing process and the key materials used, in particular the API starting material, impact the API impurities content. The number and pattern of APIMF deficiencies did not change over time. The results are compared to the findings in similar studies as reported by the United States Food and Drug Administration (USFDA), the European Directorate for the Quality of Medicines (EDQM) and the European Medicines Agency (EMA) and similarities and differences are discussed. Our findings highlight the need for greater guidance and technical assistance for API manufacturers submitting APIMFs to the PQP.

Metabolic Engineering: The Ultimate Paradigm for Continuous Pharmaceutical Manufacturing

Research and development (R&D) expenditures by pharmaceutical companies doubled over the past decade, yet candidate attrition rates and development times rose markedly during this period. Understandably, companies have begun downsizing their pipelines and diverting investments away from R&D in favor of manufacturing. It is estimated that transitioning to continuous manufacturing could enable companies to compete for a share in emerging markets. Accordingly, the model for continuous manufacturing that has emerged commences with the conversion of late-stage intermediates into the active pharmaceutical ingredient (API) in a series of continuous flow reactors, followed by continuous solid processing to form finished tablets. The use of flow reactions for API synthesis will certainly generate purer products at higher yields in shorter times compared to equivalent batch reactions. However, transitioning from batch to flow configuration simply alleviates transport limitations within the reaction milieu. As the catalogue of reactions used in flow syntheses is a subset of batch-based chemistries, molecules such as natural products will continue to evade drug prospectors. Also, it is uncertain whether flow synthesis can deliver improvements in the atom and energy economies of API production at the scales that would achieve the levels of revenue growth targeted by companies. Instead, it is argued that implementing metabolic engineering for the production of oxidized scaffolds as gateway molecules for flow-based addition of electrophiles is a more effective and scalable strategy for accessing natural product chemical space. This new paradigm for manufacturing, with metabolic engineering as its engine, would also permit rapid optimization of production variables and allow facile scale-up from gram to ton scale to meet material requirements for clinical trials, thus recasting manufacturing as a tool for discovery.

A control strategy for bioavailability enhancement by size reduction: Effect of micronization conditions on the bulk, surface and blending characteristics of an active pharmaceutical ingredient

In a Quality by Design (QbD) development environment the effect of early process parameters on downstream manufacturing parameters, and the ultimate effect on drug product quality, need to be understood. For poorly soluble drugs, size reduction is frequently employed to obtain consistent in-vivo exposures. As a result, micronization is a key early stage processing step for many active pharmaceutical ingredients (APIs).This paper demonstrates the effect of varying micronization conditions on an API for which micronization is deemed necessary to ensure consistent drug delivery after human administration. Material micronized to different extents are confirmed as different by surface area, surface energy, particle size analysis, bulk density and surface adhesion measurements.These material characteristics can be correlated with the outcomes from a key processing step, blending. The evolution of the blending process is followed using PAT techniques, so that an overall understanding of the relationship between particle properties and blend uniformity can be demonstrated.Execution of such a study during drug development can enable selection of the appropriate control strategy to ensure production of API in the desired range where consistent optimal bioavailability and downstream processability are achieved.

Development and Characterization of a Single Stage Mixed-Suspension, Mixed-Product-Removal Crystallization Process with a Novel Transfer Unit

A continuously operated single stage mixed-suspension, mixed-product-removal (MSMPR) crystallizer using intermittent withdrawal via a dip pipe with combined pressure/vacuum was successfully developed for the manufacture of active pharmaceutical ingredients. Approximately 5.8% of the total operating volume was intermittently removed at a high velocity using vacuum. The transfer line was also periodically purged with nitrogen to ensure complete removal of residual solids. In situ process analytical technologies (focused beam reflective measurement (FBRM) and process video microscopy (PVM)) were successfully applied to monitor and characterize the MSMPR crystallization process. In this study, a cooling crystallization of paracetamol from an aqueous isopropyl alcohol solution was investigated. Experimental results indicate that the crystallization system was able to operate without any clogging issues for over 10 residence times, before which the system had approached steady state. Three different start-up strategies for continuous crystallization were investigated, and the results indicate that the chord length distributions at steady state were the same for all cases. Also, starting the continuous operation from a saturated solution that was seeded with product from a previous MSMPR run offered the quickest route to steady state. To better control and scale up the crystallization process, the nucleation and crystal growth kinetics of the model compound were also determined through use of the newly developed process. The growth rates were found to be size dependent, and an exponential three-parameter model was employed to characterize the size-dependent growth. It was seen that the crystal growth rate was extremely low and increased linearly with particle size when the particle size was below 10 μm. However, the growth rate increased dramatically with particle size when the particle size was between 10 and 1000 μm. The nucleation kinetics was correlated by the semiempirical equation BTOT = 1.11 × 1015MT0.98Gavg1.12. The orders of the total nucleation rate with respect to the magma density and average growth rate were 0.98 and 1.12, respectively. Therefore, the effect of supersaturation (or residence time) and magma density on the steady state crystal size was investigated.

Regulatory status of drug master file in Taiwan 2009–2011

The drug master file submission in Taiwan commenced on 1 October 2009 and is driven by the health reimbursed pricing system. To clarify the consequences of this policy, we focused on the applications for the initiation of the policy from overseas active pharmaceutical ingredient manufacturers, which were the majority of the total applications. Indian manufacturers filed the most drug master files, representing 44% of total overseas drug master files and accounting for the largest number of multiple drug master files with the same molecules. Antibacterial, cardiovascular, and psychiatric drugs were the main therapeutic categories for the submitted molecules. The acceptance rates in the original submission and the appeal/resubmission applications for Indian drug master files were 32 and 38%, respectively, comparable with the average of overall drug master file acceptance rates (30%, 38%) under corresponding conditions. The nonaccepted applications included 12% of drug master files that failed to provide the restricted part and 24% of drug master files that did not respond to deficiencies. The main deficiencies were associated with the manufacturing process, active pharmaceutical ingredient specification, starting material, material/intermediate, and analytical method/validation.

Optimization of environmental impact reduction and economic feasibility of solvent waste recovery using a new software tool

The environmental impact reduction and operating costs savings associated with the purification and recovery of solvent waste in the manufacture of active pharmaceutical ingredients (API's) were investigated. A software toolbox has been developed that combines Aspen Plus® process simulation with SimaPro® and Ecosolvent life cycle assessment (LCA) databases. A LCA approach was used in order to consider the environmental impact beyond pharmaceutical production plant boundaries. The feasibility of a relatively small flexible equipment-skid capable of recovering multiple solvent waste streams was evaluated. Distillation and pervaporation were considered to separate binary waste solvent mixtures. Optimum distillation reflux ratio and feed stage were determined to maximize the environmental impact reductions and operating cost savings. The optimum reflux ratio was significantly higher than 1.2 times the minimum reflux ratio suggested by traditional heuristics. The emissions and cost reductions obtained were as much as 49% and 56% higher, respectively, as compared to using the conventional optimum reflux ratio. A comprehensive cash flow analysis showed that the recovery of low volume solvent waste streams is economically feasible, despite traditional thinking. Three case studies from Pfizer are presented to show how our software tool can aid in green engineering decision making.

Modeling a seeded continuous crystallizer for the production of active pharmaceutical ingredients

The approximation of a well mixed reactor is prevalent when it comes to the modeling of a crystallization process. Since temperature, concentration, and mass content vary due to inhomogeneous mixing, this approximation is a very loose one. The continuously operated seeded tubular crystallizer system developed in our group overcomes obstacles like a slow response to changes in the outer parameters and inhomogeneous mixing. Therefore the applicable well mixed assumption facilitates detailed modeling of the crystallization process by means of population balance equations (PBE) coupled with mass and energy balances. Modeled results were validated by means of experiments. The amount of aggregation events during the crystallization could be quantified and it was proven that the growth of seeded crystals is almost exclusively responsible for solid mass uptake if the reactor is operated appropriately. The performed sensitivity analysis exposed which process settings should be maintained most accurately to avoid fluctuations in the product crystals’ quality attributes and to limit undesired nucleation events.

Cross‐Linked Imidazolium Salts as Scavengers for Palladium

Five imidazolium-based materials have been synthesised and used for the first time as palladium scavengers. Radical reactions of suitable bis-vinylimidazolium salts led to a series of insoluble materials through homo-polymerisation, immobilisation with a 3-mercaptopropyl-modified silica gel or co-polymerisation with ethylene glycol dimethylacrylate. These materials were screened as palladium scavengers with a set of palladium(0) and palladium(II) compounds in different solvents and at different starting amounts of palladium. In many cases, residual amounts of palladium were lower than 5 ppm, as requested for the manufacture of active pharmaceutical ingredients and fine chemicals. The application of one of these materials as a palladium scavenger in a Suzuki coupling reaction resulted in a 29-fold abatement of the palladium content in the final product with respect to the control reaction.

ChemInform Abstract: En route to Full Implementation: Driving the Green Chemistry Agenda in the Pharmaceutical Industry

AbstractReview: 53 refs.

Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape

The American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues was held on 13–14 October 2012 at the McCormick Place in Chicago, IL, USA. The goal of the workshop was to discuss control strategies of chemical and physical changes of active pharmaceutical ingredients (API) and drug products in the drug development process. These changes can affect both the safety and efficacy of drugs; therefore, the ability to rapidly predict and assess the potential for drug product performance changes for impurity formation and the associated safety concerns are important parts of speeding the development of innovative drug therapies without compromising quality. The workshop comprised four different sessions. Each session focused on separate fundamental issues to build a comprehensive understanding of the physical and chemical processes that affect drug impurities and drug degradation products, the control of impurities, and the impact of these factors on safety and regulatory areas. Taken together, this comprehensive understanding is used to achieve a more robust development approach that enables predictability with a concomitant assurance of safety and efficacy. Innovative methodologies for development of effective stability control strategies were also presented. This article summarizes sessions 3 and 4 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues and addresses issues of safety considerations of impurities in pharmaceutical products and surveying the impurity landscape. Sessions 1 and 2 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues are summarized in Recent Trends in Product Development and Regulatory Issues on Impurities in active Pharmaceutical Ingredient (API) and Drug Products Part 1: Predicting Degradation Related Impurities and Impurity Considerations for Pharmaceutical Dosage Forms published separately.

Copper(I)/N‐Heterocyclic Carbene (NHC)‐Catalyzed Addition of Terminal Alkynes to Trifluoromethyl Ketones for Use in Continuous Reactors

AbstractA copper(I)/N‐heterocyclic carbene complex‐catalyzed addition of terminal alkynes to trifluoromethyl ketones at low loading is described. The developed process functions well using a range of terminal alkynes but functions best when an aryl trifluoromethyl ketone is used. This substrate scope is well‐suited for the production of active pharmaceutical ingredients (APIs) such as efavirenz. In this vein, we demonstrate that the described method can be translated into a flow process laying the framework for a completely continuous synthesis of efavirenz in the future.magnified image

A Process Analytical Technology (PAT) approach to control a new API manufacturing process: Development, validation and implementation

Pharmaceutical companies are progressively adopting and introducing Process Analytical Technology (PAT) and Quality-by-Design (QbD) concepts promoted by the regulatory agencies, aiming the building of the quality directly into the product by combining thorough scientific understanding and quality risk management. An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) manufacturing crystallization step during which the API and residual solvent contents need to be precisely determined to reach the predefined seeding point. An original methodology based on the QbD principles was designed to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. On this basis, Partial least squares (PLS) models were developed and optimized using chemometrics methods. The method was fully validated according to the ICH Q2(R1) guideline and using the accuracy profile approach. The dosing ranges were evaluated to 9.0-12.0% w/w for the API and 0.18-1.50% w/w for the residual methanol. As by nature the variability of the sampling method and the reference method are included in the variability obtained for the NIR method during the validation phase, a real-time process monitoring exercise was performed to prove its fit for purpose. The implementation of this in-process control (IPC) method on the industrial plant from the launch of the new API synthesis process will enable automatic control of the final crystallization step in order to ensure a predefined quality level of the API. In addition, several valuable benefits are expected including reduction of the process time, suppression of a rather difficult sampling and tedious off-line analyses.