Drug Manufacturing Process Research Articles

MicroNIR/Chemometrics Assessement of Occupational Exposure to Hydroxyurea.

Portable Near Infrared spectroscopy (NIRs) coupled to chemometrics was investigated for the first time as a novel entirely on-site approach for occupational exposure monitoring in pharmaceutical field. Due to a significant increase in the number of patients receiving chemotherapy, the development of reliable, fast, and on-site analytical methods to assess the occupational exposure of workers in the manufacture of pharmaceutical products, has become more and more required. In this work, a fast, accurate, and sensitive detection of hydroxyurea, a cytotoxic antineoplastic agent commonly used in chemotherapy, was developed. Occupational exposure to antineoplastic agents was evaluated by collecting hydroxyurea on a membrane filter during routine drug manufacturing process. Spectra were acquired in the NIR region in reflectance mode by the means of a miniaturized NIR spectrometer coupled with chemometrics. This MicroNIR instrument is a very ultra-compact portable device with a particular geometry and optical resolution designed in such a manner that the reduction in size does not compromise the performances of the spectrometer. The developed method could detect up to 50 ng of hydroxyurea directly measured on the sampling filter membrane, irrespective of complexity and variability of the matrix; thus extending the applicability of miniaturized NIR instruments in pharmaceutical and biomedical analysis.

Correction: Comparative study of impaction and sedimentation in an aerosol chamber using defined fungal spore and bacterial concentrations.

[This corrects the article DOI: 10.1371/journal.pone.0187039.].

Inspiring process innovation via an improved green manufacturing metric: iGAL

Following our goal to devise a unified green chemistry metric that inspires innovation in sustainable drug manufacturing across the pharmaceutical industry, we herein disclose joint efforts by IQ, the ACS GCI PR and academia, leading to the significantly improved ‘innovation Green Aspiration Level’ (iGAL) methodology. Backed by the statistical analysis of 64 drug manufacturing processes encompassing 703 steps across 12 companies, we find that iGAL affords an excellent proxy for molecular complexity and presents a valuable molecular weight-based ‘fixed’ goal. iGAL thereby accurately captures the impact of green process inventiveness and improvements, making it a useful innovation-driven green metric. We conclude by introducing the comprehensive, yet easy-to-use and readily adaptable Green Chemistry Innovation Scorecard web calculator, whose graphical output clearly and effectively illustrates the impact of innovation on waste reduction during drug manufacture.

Comparative study of impaction and sedimentation in an aerosol chamber using defined fungal spore and bacterial concentrations

Biocontamination control is a very significant part of the manufacturing process of sterile drugs. Sterility is frequently monitored by active or passive air sampling measurements, but there are no specific rules as to how this is to be done. This study tested air sampling methods of active impaction and passive sedimentation under standardized conditions. Aspergillus niger (A. niger) and Staphylococcus aureus (S. aureus) were selected in this experiment to examine parallels, correlations and differences between the two methods. The results show that the number of colony forming units per plate (CFU/plate) was higher for A. niger in the active method, whereas for S. aureus it was higher in the sedimentation method. A high correlation coefficient was found between the impaction and sedimentation methods for A. niger. For S. aureus, depending on the culture media used and the time for passive air sampling, a larger number of CFU/plate was found than in active air sampling. This study concludes that active and passive air sampling can be used for monitoring the air in clean rooms. For fungal spore detection, the impaction is more efficient, as it is possible to sample a higher volume of air in a shorter period of time, whereas the optimal measurement methods for S. aureus depend on a number of factors.

How to adapt to the requirements of "clinical value-oriented drug innovation" for pharmaceutical research in application process of new traditional Chinese medicine

On August 9, 2015, the State Council promulgated the "Opinions of the State Council on the reform of drug and medical device review and approval system" (Guofa 2015 No. 44), and established the "clinical value-oriented drug innovation" model to encourage the research and development of new drugs. Following that, China Food and Drug Administration (CFDA) promulgated the "Notice on several policies for drug registration review and approval" (2015 No. 230 ) on November 11, 2015, clearly specifying that CFDA would "implement one-time approval for clinical trials application of the new drugs, and no longer take a phased declaration, review and approval system; for the new drugs that apply for clinical trials, mainly review the scientific natureof the clinical protocols and the risk control of the new drugs to guarantee the safety of subjects". Accordingly, the evaluation ideas and forms of new drug registration have also been adjusted greatly. For example, issues like the rationality of the drug manufacturing process, whether the scale can reflect the stability of the process, whether the preparation process is sufficient, and whether the choice of dosage form is reasonable are no longer the focus of evaluation before clinical trials. Issues regarding whether the preparation process design is reasonable, whether the effective components can be transferred to the preparation to a maximum extent, whether the process parameters determined in small and middle pilot trials can adapt to the requirements of mass production, no longer act as the reasons for refusing the clinical trials. The corresponding risks shall be borne by the applicant as the subject of liability. The focus in registration evaluation is mainly transferred to how to ensure the consistence of quality between clinical trial samples and the samples already available on market by guaranteeing stable sources of drug raw materials and stable quality of medicines as well as control of the whole preparation process. These issues run through the whole process of new drug development, but also have different focuses in different stages. According to the "Measures on communicating about drug research and development and technical review" (2016 No. 94) (On Trial) issued by CFDA on June 2, 2016, the applicants may communicate with the drug evaluation center in different phases in the process of new drugs registration in respects of medicine material problems, technological problems, and quality control of the preparations. In this paper, the transformation of Chinese medicine research model was described mainly in the following aspects: how to control the quality of medicines from origins, technology design of the preparation and technology process research, and how to establish whole-process quality system. The paper also reflects the concept that the quality of new Chinese drugs research and development comes from design.

Validation of Contamination Control in Rapid Transfer Port Chambers for Pharmaceutical Manufacturing Processes.

There is worldwide concern with regard to the adverse effects of drug usage. However, contaminants can gain entry into a drug manufacturing process stream from several sources such as personnel, poor facility design, incoming ventilation air, machinery and other equipment for production, etc. In this validation study, we aimed to determine the impact and evaluate the contamination control in the preparation areas of the rapid transfer port (RTP) chamber during the pharmaceutical manufacturing processes. The RTP chamber is normally tested for airflow velocity, particle counts, pressure decay of leakage, and sterility. The air flow balance of the RTP chamber is affected by the airflow quantity and the height above the platform. It is relatively easy to evaluate the RTP chamber′s leakage by the pressure decay, where the system is charged with the air, closed, and the decay of pressure is measured by the time period. We conducted the determination of a vaporized H2O2 of a sufficient concentration to complete decontamination. The performance of the RTP chamber will improve safety and can be completely tested at an ISO Class 5 environment.

Statistical Approaches to Assess Biosimilarity from Analytical Data.

Protein therapeutics have unique critical quality attributes (CQAs) that define their purity, potency, and safety. The analytical methods used to assess CQAs must be able to distinguish clinically meaningful differences in comparator products, and the most important CQAs should be evaluated with the most statistical rigor. High-risk CQA measurements assess the most important attributes that directly impact the clinical mechanism of action or have known implications for safety, while the moderate- to low-risk characteristics may have a lower direct impact and thereby may have a broader range to establish similarity. Statistical equivalence testing is applied for high-risk CQA measurements to establish the degree of similarity (e.g., highly similar fingerprint, highly similar, or similar) of selected attributes. Notably, some high-risk CQAs (e.g., primary sequence or disulfide bonding) are qualitative (e.g., the same as the originator or not the same) and therefore not amenable to equivalence testing. For biosimilars, an important step is the acquisition of a sufficient number of unique originator drug product lots to measure the variability in the originator drug manufacturing process and provide sufficient statistical power for the analytical data comparisons. Together, these analytical evaluations, along with PK/PD and safety data (immunogenicity), provide the data necessary to determine if the totality of the evidence warrants a designation of biosimilarity and subsequent licensure for marketing in the USA. In this paper, a case study approach is used to provide examples of analytical similarity exercises and the appropriateness of statistical approaches for the example data.

The solvent effect on the crystal morphology of two tegafur polymorphs

Pharmaceutical compounds are mostly produced in defined crystalline forms that are usually crystallized from solutions. Polymorphs, different crystalline phases of the same pharmaceutical compound, usually have different, precisely known dissolution rates and bioavailability, but crystal size and shape can affect these properties. Therefore, the crystal shape is monitored during the drug manufacturing process and a lot of work in the area of crystal engineering has been devoted to crystal habit control [1]. The crystallization solvent can have a significant effect on the resulting crystal shape; therefore solvent effect on crystal habit needs comprehensive studies. The compound studied in this research – tegafur (5-fluoro-1-(tetrahydro-2-furyl)-uracil) – is an antitumor agent, known to exist in α, β, γ, δ and ε polymorphs [2, 3]. Single crystal X-ray diffraction (SC XRD) was used to index crystal faces of α and β tegafur crystals grown in different solvents and molecular dynamics (MD) simulation was used as a tool to estimate the crystal face growth rates in several solvents. SC XRD results indicated that {011} and {110} faces dominated in β tegafur crystals when crystallized from ethanol, methanol, butyl acetate, tetrahydrofuran, whereas α tegafur crystals had a dominant {001}, {010} and {011} faces when crystallized from these solvents. Crystals grown in acetone had a different dominant faces for both polymorphs. The interaction between the solvents and each tegafur face was different, but the order of binding energy on these surfaces remained the same and was {011} > {110} > {010} for β tegafur and {001} > {011} > {010} for α tegafur. The analysis of MD data revealed that the system's primary interactions are weak hydrogen bonds. The achieved predictions were in agreement with experimental results. This work has been supported by the European Social Fund within the project «Support for Doctoral Studies at University of Latvia».

The Evolution of quality by design (QbD) for biologics.

In recent years, regulators have recognized the need for more controls in drug manufacturing processes. Quality by design is a science- and risk-based approach to drug product development and several pilot programs are ongoing to evaluate enhanced drug development strategies. This article provides a commentary on a recent regulatory publication on the subject of design space verification.

Evidence-Based Approach and Standardization of Nutraceuticals

AbstractEvidence-based approach for the use and selection of nutraceuticals are presented as well as the need and challenges to creating a method for the standardization of these products. A systematic review was completed to analyze the impact of evidence-based and standardization of nutraceuticals. Evidence-based approach for nutraceuticals allow for the evaluation of these products. This process involves utilizing current and best evidence to provide individualized care for patients. Current Good Manufacturing Practices (cGMP) are regulations enforced by the FDA to ensure that drug manufacturing processes meet basic standards. Under these practices, design, monitoring, and control of manufacturing processes are regulated. These practices can track and provide tools to prevent contamination of products available to consumers. Using evidence-based approach for nutraceutical can provide healthcare providers and consumers with evidence that is patient specific, for a given intervention and desired outcome. The global market for nutraceuticals is growing and all manufacturers should comply with cGMP to ensure safe, quality products for consumers. The goal is to have all nutraceutical manufacturers worldwide embrace cGMP in order to provide consumers with safe, effective and high quality products.

Control the effects caused by noise parameter fluctuations to improve pharmaceutical process robustness: A case study of design space development for an ethanol precipitation process

To provide a new method to develop a design space to improve the robustness of drug manufacturing processes based on the control of noise parameter influences, the ethanol precipitation process of Danhong injection was investigated as a sample. Water content in the concentrated extract (WCCE), the concentration of ethanol (CEA), and the amount of ethanol added (AEA) are three adjustable parameters. The effects of refrigeration temperature (RT) was investigated on three levels for simulating its fluctuations. The models between parameters and process critical quality attributes (CQAs) were obtained using a simplified central composite design with determination coefficients more than 0.84. The decrease of RT led to lower active ingredient recoveries and higher DMR. The increase of CEA and the decrease of WCCE caused more precipitation. The decrease of CEA or AEA resulted in higher active ingredient recoveries. The design space was calculated using an exhaustive search-Monte Carlo method and normal operation ranges were also obtained. The results of verification experiments agreed well with prediction results. The proposed method can be used to develop a design space applicable in a larger scale manufacturing process with the negative effects caused by the fluctuations of noise parameters controlled.

Experimental Analysis of Tablet Properties for Discrete Element Modeling of an Active Coating Process

Coating of solid dosage forms is an important unit operation in the pharmaceutical industry. In recent years, numerical simulations of drug manufacturing processes have been gaining interest as process analytical technology tools. The discrete element method (DEM) in particular is suitable to model tablet-coating processes. For the development of accurate simulations, information on the material properties of the tablets is required. In this study, the mechanical parameters Young's modulus, coefficient of restitution (CoR), and coefficients of friction (CoF) of gastrointestinal therapeutic systems (GITS) and of active-coated GITS were measured experimentally. The dynamic angle of repose of these tablets in a drum coater was investigated to revise the CoF. The resulting values were used as input data in DEM simulations to compare simulation and experiment. A mean value of Young's modulus of 31.9MPa was determined by the uniaxial compression test. The CoR was found to be 0.78. For both tablet-steel and tablet-tablet friction, active-coated GITS showed a higher CoF compared with GITS. According to the values of the dynamic angle of repose, the CoF was adjusted to obtain consistent tablet motion in the simulation and in the experiment. On the basis of this experimental characterization, mechanical parameters are integrated into DEM simulation programs to perform numerical analysis of coating processes.

Scalable Technology for the Extraction of Pharmaceutics: Outcomes from a 3 year collaborative industry/academia research programme

This paper reports on some of the key outcomes of a 3 year £1.5m Technology Strategy Board (TSB) funded research programme to develop a small footprint, versatile, counter-current chromatography purification technology and methodology which can be operated at a range of scales in both batch and continuous modes and that can be inserted into existing process plant and systems. Our consortium, integrates technology providers (Dynamic Extractions) and the scientific development team (Brunel) with end user needs (GSK & Pfizer), addressing major production challenges aimed at providing flexible, low capital platform technology driving substantial cost efficiency in both drug development and drug manufacturing processes. The aims of the Technology Strategy Board's high value manufacturing programme are described and how the academic/industry community were challenged to instigate step changes in the manufacturing of high value pharmaceuticals. This paper focusses on one of the themes of the TSB research programme, “Generate a Comprehensive Applications Portfolio”. It outlines 15 applications from this portfolio that can be published in the public domain and gives four detailed case studies illustrating the range of application of the technology on the separation of (1) isomers, (2) polar compounds, (3) crude mixtures and (4) on the removal of impurities. Two of these case studies that were scaled up demonstrate between 10 and 20% lower solvent usage and were projected to have significant cost savings compared to conventional solid phase silica gel chromatography at procss scale demonstrating that the latest high performance countercurrent chromatography technology is a competitive platform technolgy for the pharmaceutical industry.

Comparison and analysis of in vitro cytotoxocity of different shengmai injections

To compare the cytotoxic response with respect to different Shengmai injections manufactured by different manufacturers and to find the main reasons that cause the differences. L929 cells were cultured with various Shengmai injections which were incubated into serum-supplemented minimum essential medium at different doses. The cellular morphology was observed by phase contrast inverted microscopy and proliferation of the cells was examined using mitochondrial function methyl thiazolyl tetrazolium (MTT) assay. Relative growth rate (RGR) was calculated. Moreover, cytotoxicity was evaluated. For Shengmai injections manufactured by 8 manufacturers, cytotoxicity was high, Class 4. The EC value of sample A was high than other samples. This result indicated that sample A is much more toxic than other samples. For the excipients of Shengmai injections, when the concentration of tween 80 is 0.5% of composition of drug products, cytotoxicity was classified as 3-4; while the concentration of tween 80 is 0.062 5% of composition of drug products, the cellular toxicity was classified as 1 (no cellular toxic response). The content of tween 80 of shengmai injection is different during different factories; some of it is higher than 0.5%. Cytotoxic results of these various injections were significantly different because of different manufacturers of drug substance and manufacturing process. As an excipient of injection, it showed cytotoxicity when the concentration is higher than 0.062 5%. The content of tween-80 and the degree of cytotoxicity in different Shengmai injections may have a positive correlation.

도축되는 한우 혈액에서 회수한 혈청의 생물학적 안전성 분석

Bovine serum contains various nutrients and growth factors that can be potentially used in biological experiments, drug manufacturing process and food industry. However, almost all the bovine blood has been wasted during slaughter process in Korea, thus there is a high demand for alternative uses of the wasted sera. In order to produce high quality and safe sera, it is necessary to screen zoonotic pathogens as well as other microbial contaminants to prevent any downstream contamination. The present research has been undertaken to assess biological safety of Hanwoo sera by determining microbiological contamination during slaughtering and handling processes. Serological tests have been performed to detect bacteria, mycoplasma and virus contamination in total of 52 Hanwoo sera. No sera were found to be contaminated with mycoplasma or virus, but only two sera were found to be contaminated with Bacillus thuringiensis. The present result shows that Hanwoo sera obtained from slaughtering process are biologically safe and have potentials to be developed as a biological reagent. Moreover, the methods employed in our study may provide basic standard for microbiological screening methods once wasted Hanwoo sera gain industrial values. (Key words : Hanwoo, Bovine serum, Zoonoses, Biological safety)

HPLC: Highly Accessible Instrument in Pharmaceutical Industry for Effective Method Development

The analytical technique of High Performance Liquid Chromatography (HPLC) is used extensively thought the pharmaceutical industry. It allows simultaneously both qualitative and quantitative information of a drug. It is used to provide information on the composition of drug related samples. The information obtained may be qualitative, indicating what compounds are present in the sample. The information obtained may be qualitative, providing the actual amount of compounds in the sample. HPLC is used in all the different stages in the creation of new drug discoveries and also used routinely in the drug manufacturing process. The HPLC techniques is highly accessible to the author’s knowledge this review represents the most exhaust description of instrumentation, method development, recent advancement, area of application. This article reviews the most recent advances in sample preparation, separation and the mass spectrometric aspects of high-throughput for method development.

A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design

Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike.

Murkiness in the Channels of Distribution of Pharmaceuticals

Pharmacy curricula are packed with important required and elective coursework. The worth and importance to the academy of these courses and the dedicated faculty members providing these courses simply cannot be overestimated. There seems to be an overabundance of necessary curricular components and precious little surplus time to cover what needs to be added. However, there is one educational segment that appears to be sorely under addressed, or frankly missing entirely from the curricula. There are significant and increasingly disturbing problems within the drug manufacturing, regulatory, payment, and access processes regarding medications in the United States and beyond. Issues that have come to light in the past years include medication counterfeits, breakdowns or total absence of quality assurance (eg, unsterile water used in processing, production line problems, employee contamination of products, drug contamination, drug batch mix-ups), fraud and abuse in pharmaceutical pricing by manufacturers (brand name and generic), expanded demand for a compromised supply chain of manufactured products. But just as important as any of these problems, is the need for leadership at all levels to impact these pressing, life-threatening problems. Are we in the Academy providing students with the awareness, knowledge, and skills that would allow them to step into these chasms and make a difference by helping to eliminate or ameliorate these major concerns? Troubles Within the Channels of Distribution The past several years have proven to be challenging when considering the problems that have surfaced within the drug manufacturing, drug promotion, drug payment, drug regulation, and drug use processes. Drug recalls. Drug recalls and manufacturers' actions regarding the recalls have been frequent news items in the past several years with totals approaching 1,800 in 2009. (1) In the guise of cost-cutting, quality control personnel with necessary expertise and other staffing levels have been gutted with unfortunate and predictable results. (2-4) Recalls of McNeil Healthcare and Johnson and Johnson Merck products have reached double digit levels. (5) A phantom recall of Motrin in 2009 by McNeil was alleged to have occurred and involved having company personnel buy up existing stocks of the drug off store shelves to avoid a formal recall. (6) These recalled brands have been among the most trusted consumer products for decades. It is bitterly ironic that the Johnson and Johnson brand and preceding company set the bar so high with their response to the 1982 Tylenol poisoning and murders. Johnson and Johnson received praise for their remarkable response to the crisis, which included issuing an immediate recall of every bottle of Tylenol, the most popular consumer branded product in the United States. US Food and Drug Administration. The FDA has been under fire for a significant period of time for lax oversight of the drug manufacturing milieu in the United States. (7) One specific concern is the source of precursor chemicals, specifically active ingredients imported from China and elsewhere. The FDA simply does not have the resources to monitor chemicals obtained outside the country. The FDA has published a strategic priority document for the next 5 years (2011-2015). (8) In the document, challenges presented by globalization include a staggering and increasing volume of imported products (for 2010; 130,000 importers at approximately 300 ports of entry), more foreign facilities providing agents for the United States (300,000 plus facilities in over 150 countries), incomplete Regulatory information about supply chains, and corporations lacking accountability. The issues facing the FDA are incredibly complex; they certainly will not diminish in the future. More and more pressure is being exerted on the FDA from all sides. At this juncture, there has not been a dramatic influx of funds to meet the expanding requirements placed on the agency. …

Influence of Dissolution Media Composition on Cefaclor Release form Capsules

In vitro dissolution testing serves as an important tool for drug manufacturing process control and quality assurance. [...]

Influence of physical factors on the accuracy of calibration models for NIR spectroscopy

The quality of pharmaceutical drugs is strongly influenced by a number of physical and chemical factors that require careful control during the production process in order to ensure that the end-product will meet the specifications. Near infrared spectroscopy has proved effective for monitoring changes in such factors and is currently the most widely used technique for controlling drug manufacturing processes. In this work, the authors determined an active pharmaceutical ingredient (API) throughout its production process. The influence of particle size, galenic form, compaction pressure and coating thickness on NIR spectra was evaluated with a view to developing effective methodologies for constructing simple, accurate calibration methods affording API quantization at different stages of a drug production process. All calibration models were constructed from data for laboratory samples alone and NIR calibration models for determining the API determination by using product weights as reference values. The proposed models were validated by application to samples obtained at three stages of a drug manufacturing process and comparison of the predicted values with HPLC reference values. The RSEP values thus obtained never exceeded 1.5%.