Manufacture Of Pharmaceutical Products Research Articles

Spray Freeze-Drying as a Solution to Continuous Manufacturing of Pharmaceutical Products in Bulk

Pharmaceutical manufacturing is evolving from traditional batch processes to continuous ones. The new global competition focused on throughput and quality of drug products is certainly the driving force behind this transition which, thus, represents the new challenge of pharmaceutical manufacturing and hence of lyophilization as a downstream operation. In this direction, the present review deals with the most recent technologies, based on spray freeze-drying, that can achieve this objective. It provides a comprehensive overview of the physics behind this process and of the most recent equipment design.

Deep learning for continuous manufacturing of pharmaceutical solid dosage form

Continuous Manufacturing (CM) of pharmaceutical drug products is a new approach within the pharmaceutical industry. In the presented paper, a GMP continuous wet granulation line for production of solid dosage forms was investigated. The line was composed of the subsequent continuous unit: operations feeding – twin-screw wet-granulation – fluid-bed drying – sieving and tableting. The formulation of a commercial entity was selected for this study. Several critical process parameters were evaluated in order to probe the process and to characterize the impact on quality attributes. Seven critical process parameters have been selected after a risk analysis: API and excipient mass flows of the two feeders, liquid feed rate and rotation speed of the extruder and rotation speed, temperature and airflow of the dryer. Eight quality attributes were controlled in real time by Process Analytical Technologies (PAT): API content after blender, after dryer, in tablet press feed frame and of tablet, LOD after dryer and PSD after dryer (three PSD parameters: x10 x50 x90). The process parameter values were changed during production in order to detect the impact on the quality of the final product. The deep learning techniques have been used in order to predict the quality attribute (output) with the process parameters (input). The use of deep learning reduces the noise and simplify the data interpretation for a better process understanding. After optimization, three hidden layers neural network were selected with 6 hidden neurons. The activation function ReLU (Rectified Linear Unit) and the ADAM optimizer were used with 2500 epochs (number of learning cycle). API contents, PSD values and LOD values were estimated with an error of calibration lower than 10%. The level of error allow an adequate process monitoring by DNN and we have proven that the main critical process parameters can be identified at a higher levelof process understanding. The synergy between PAT and process data science creates a superior monitoring framework of the continuous manufacturing line and increase the knowledge of this innovative production line and the products that it makes.

Implementation of the Latest Scientific Knowledge/Technologies and Activities for International Harmonisation of the Japanese Pharmacopoeia

The Japanese Pharmacopoeia (JP) is an official document that defines the specifications, criteria, and standard test methods necessary to properly ensure the quality of medicines in Japan. To ensure the efficacy and safety of pharmaceutical products, it is essential to establish standards that ensure their quality. For this purpose, the JP aims to include all drugs that are important from the viewpoint of healthcare and medical treatment, and description of each monograph of medicine is maintained and improved so that those standards can be generally practiced. In addition, to play a key role as the official document in the field of pharmaceutical product quality, JP contents are enhanced by proactively introducing the latest scientific knowledge and technologies. As the international manufacturing of pharmaceutical products and their raw materials that are distributed in Japan is increasing, the JP has recently begun to promote the international harmonisation of pharmaceutical excipients and general tests through the Pharmacopoeial Discussion Group (PDG) and to swiftly implement the harmonised items in the JP. In addition, the JP will implement internationally harmonised concepts and specifications for pharmaceutical products, e.g., the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), to define the latest concepts of quality control for pharmaceutical products in the official document. We introduce the implementation of the latest scientific knowledge, technologies, and activities for international harmonisation of the JP.

Validation of moist and dry heat processes used for sterilization and depyrogenation during ampoules manufacturing

Pyrogens are fever-producing substances, which are metabolic products of microorganisms and most potent pyrogens are the endotoxins. Depyrogenation can be defined as the elimination of all pyrogenic substances which is an important part of the manufacture of sterile pyrogen free pharmaceutical products. This study compared between sterilization and depyrogenation using moist heat by autoclave, as well as dry heat. After incubation period (24 hours) at 55oC-60oC the color of Geobacillus stearothermophillus spores’ control vial which didn’t sterilized in autoclave changed from blue to yellow color representing the (+ve) result, while the other sterilized vials have no color change (-ve). In addition, all examined endotoxin containing ampoules showed gel formation (+ve) when examined by Limulus Amebocyte Lysate) LAL). All ampoule groups that have autoclaved for periods of 1 hour to 4 hours showed gel formation (+ve) after LAL test, while only the last group which have autoclaving periods of 5 hours (5 cycles) showed no gel formation (-ve). Sterility of vials that contained spores of Geobacillus stearothermophillus after dry heating at 250oC for 30 min showed no color change (-ve). In addition, LAL test for endotoxin containing ampoules after dry heating at 250oC for 30 min showed no gel formation representing -ve pyrogen. So, moist heat is effective in sterilization and not for depydrogenation, whereas, dry heat is effective in sterilization as well as for depyrogenation.

Studying Regional Clusters with the Use of Data Processing Systems: The Case of the Biopharmaceutical Cluster

Introduction. The dynamics of the development of the digital economy necessitates introduction of integrated information and analytical systems. This provides integration with the existing statistics for making managerial decisions in the field of public administration of cluster development in Russia. The objective of this study is to develop an information and analytical system, a database, and test it taking the case the biopharmaceutical cluster as an example. Materials and Methods. The study employed materials from the Clusters of Russia’s Regions database as well as statistical tools in accordance with the methodology proposed by the European Cluster Observatory. The tools used made it possible to calculate such factors as ‘coefficient of localization’, ‘size’ and ‘focus’; groups of Russian regions (stable, increasing, and decreasing ones) were identified depending on the state of the cluster under study. Results. Statistical databases containing the number of employees in the constituent entities of the Russian Federation for 2009–2018 have been formed and grouped in accordance with the structure of the core of the biopharmaceutical cluster. The core of the biopharmaceutical cluster includes two codes of the Russian National Classifier of Economic Activities: 24.4 – Manufacture of pharmaceutical products and 24.5 – Manufacture of soap; detergents, cleaning and polishing preparations; perfumes and cosmetic products. Regions of localization of biopharmaceutical clusters in Russia in 2009–2018 have been identified; corresponding cartograms have been developed. Discussion and Conclusion. The developed methodology enables quick monitoring of the concentration of employment in the regions and can be used to assess the effectiveness of managing the cluster development of the territory. The results of the study can be used by the authorities to substantiate the cluster industrial policy of the regions, as well as by researchers analyzing the state of the cluster structure of the regions, and by teachers implementing higher education programs in the field of Economic Geography and State and Municipal Administration.

The Challenges to be a Regulatory Affair Associate: Day-To-Day Questions on How to Reach Consensus between Manufacturers of Pharmaceutical Products and Government Regulatory Authorities

The modern pharmaceutical industry is one of the main branches in the healthcare segment and is considered to be the most highly regulated industries worldwide. The regulation is provided by a specialist, named Regulatory Affairs Manager (syn.: Regulatory Affairs Executive or Regulatory Affairs Associate), involved in authorization process of pharmaceutical products. When person graduates from University with medical, pharmaceutical or even chemical diploma, he/she never thinks about professional career as a Regulatory Affairs Manager, because this specialty is new, about 40 years old. What is a Regulatory Affairs Associate’s duty? One category-Regulatory Affairs Associate inside the manufacturing office, whose duty is to prepare registration dossier based on the process of artworks and Patient Information Leaflet preparation, prior to completing Common Technical Document (CTD) format dossier; other category (national regulatory affairs Associate)-are those who are ensuring mediation between Manufacturer and Government Regulatory Authorities. Regardless of differences of each Government requirement for dossier registration, the main task of each Regulatory Affairs Associate is to prepare Dossier for submission which will pass successful registration. For this purpose, the National Regulatory Affairs Associate should ensure that manufacturer/Marketing Authorization Holder (MAH)’s dossier is complete and in line with different documentation requirements, following the national requirements and in case such requirement don’t exist-with the guidelines of the World Health Organization (WHO) and International Council for Harmonization (ICH). On the other hand, National Regulatory Affairs Associate is working with National Regulatory Affairs officers to correct and align deficiencies in documentation in accordance with the National requirements. Each drug as a living organism (innovative drugs even have birthdays), which is subject to many changes reflected in the registration dossier: whether in its pharmaceutical part (composition, production process, stability etc.,) or pharmacological (therapeutic indications, side effects and others), as a consequence the Regulatory Affairs Manager is constantly involved in registration of an infinite number of Variations. The main goal of Regulatory structures-both governmental and private-is to ensure the safety, quality and efficacy of medicines.

Female labor in Egyptian manufacturing sector: The demand side story

This study investigated demand for female labor in Egyptian manufacturing sector. It utilized information provided in the C13 together with data from the ELMPS2012 to estimate wage rate by gender in the C13 and then estimated a labor demand function for females. Determinants included in the analysis covered firm characteristics as well as industry specific characteristics. Results indicated a positive association between female employment on one side and micro and small sized firms and firms that export on the other side. While it suggested a negative association between capital employed by the firm and female labor indicating substitutability. Moreover, results confirmed the important role played by industries in determining female labor demand. Were number of females employed by firms is higher in industries with higher share of firms that export, and in high technology industries. Accordingly, promoting female employment require more openness and integration into global markets and hence more exports specially in labor-intensive. In addition, more attention should be given to policies that encourage and promote micro-startups. Finally, more attention should be given to encouraging high technology industries like Manufacture of basic pharmaceutical products and Manufacture of computer, electronic and optical products, where the highest association with female employment was evidence.

Comparison of Limulus Amoebocyte Lysate and Recombinant Factor C Assays for Endotoxin Detection in Four Human Vaccines with Complex Matrices

Endotoxins, heat-stable lipopolysaccharides from Gram-negative bacteria, are potential contaminants that can be introduced during manufacturing of pharmaceutical products, including vaccines. Parental pharmaceutical products undergo endotoxin testing because endotoxins are pyrogenic in humans and can induce severe physiological reactions. Currently, animal-derived Limulus amoebocyte lysate (LAL) assays are widely used. Assays using recombinant factor C (rFC), a nonanimal-derived reagent, have been proposed as alternatives. Some components in the matrices of pharmaceutical products can interfere with these assays. We compared two LAL- and two rFC-based assays for endotoxin detection in four complex human vaccine matrices. We showed that the results for the rFC-based assays were at least equivalent to those for the LAL-based assays, although the rFC-based assays were found to be adequate but slightly less suitable for one of the products that contained proteases as the methods used to inactivate the proteases reduced the assay performance. Likewise, LAL was adequate but less suitable for another product that contained glucans. The rFC assays offer a number of benefits, including compliance with the principles of the 3Rs, i.e., replacement, reduction, and refinement of animal testing by safeguarding animal welfare and promoting more ethical and sustainable use of animals for testing. After they are fully validated, as per the compendial requirements, they could be considered as suitable replacement assays for the detection of endotoxin in the manufacturing processes of pharmaceutical products. In summary, we demonstrated that both LAL and rFC assays are adequate for testing and releasing four vaccine products.

Green Transformations In The Healthcare System: The Covid-19 Impact

This paper summarizes the arguments and counterarguments within the scientific discussion on the healthcare systems’ transformations towards sustainability, considering COVID-19 pandemic. The paper aims to forecast changes in the healthcare sector’s greenhouse gas emissions of the EU countries. For gaining that purpose, the authors carried out the study in the following logical sequence. Firstly, the bibliometric analysis was conducted based on 2313 publications indexed by Scopus database. The study sample consists of 1995 publications indexed by the keywords such as healthcare, green, carbon and sustainable; and 318 publications – green, carbon-free, covid, pandemic, coronavirus and health. The fields for search are titles, keywords and abstracts. The search was limited to the subject areas such as Social science; Environmental sciences; Business, Management and Accounting; Economics, Econometrics and Finance. The time framework is 2000-2020. The scientific background analysis stated the strong relationship between implementing green innovation in the healthcare system towards gaining sustainable development goals. The obtained results indicated that the COVID-19 requires the decisive green transformation in the economy. Thus, the forecast of greenhouse gas volume from the healthcare activity (human health and social work activities; human health activities; manufacture of basic pharmaceutical products and pharmaceutical preparations) until 2030 was conducted. The methodological tool of this research based on the Autoregressive Integrated Moving Average (ARIMA) model. The software EViews 11 was used to provide empirical calculation. This study involved data of the EU countries such as Hungary, Slovakia, Malta, Denmark and Portugal from 1995 to 2019. The base of data is the EU statistical service Eurostat. Based on the obtained results, the authors concluded that there are still disparities in the healthcare sectors of the EU-countries towards sustainability. Therefore, the authors highlighted the necessity to improve the EU countries’ cohesion policy, which would allow decisively and quickly cooperate to find effective solutions towards developing resilience in the healthcare sector due to implementing green strategies. The authors emphasized that this study’s obtained results could be the base for future investigations devoted to effective green solutions to minimize greenhouse gas emissions from the healthcare activity.

Whose Risk Is It Anyway?

The U.S. territory of Puerto Rico was once the fifth-largest region in the world for manufacturing of pharmaceutical products, including many of the top global producers. In 2016, the pharmaceutica...

Evaluation of NIR and Raman spectroscopies for the quality analytical control of a solid pharmaceutical formulation with three active ingredients.

The manufacture of pharmaceutical products is one of the most regulated industrial sectors due to the importance of its products on human health. These regulations require a high number of physical and chemical determinations. These last are commonly performed by using chromatographic techniques coupled to different detectors, even though the use of spectroscopic techniques is growing.This study was aimed to evaluate the performance of a NIR and Raman spectroscopy methodologies for the quantitative determination of three active ingredients (APIs) with different concentrations (6.8%w/w, 26.3%w/w and 26.3%w/w) in a solid pharmaceutical product. Calibration models and prediction results were compared in terms of precision and prediction accuracy with those obtained through HPLC reference method. Different spectral pretreatments have been used to reduce the spectral variability associated with the physical characteristics of samples. Standard Normal Variate (SNV) and 2nd derivative (2D) were used as spectral treatments to correct scattering effect in NIR spectra. The best pretreatments for Raman were a baseline correction and a normalization. Each model was developed and evaluated with full subsets cross-validation and external validation sample set. For each technique, the best model was selected based on conventional criteria (R2, RMSEPCV).Results show highly predictive models based on NIR and Raman spectroscopy with root mean square error of prediction values between 0.26%w/w and 2.60%w/w depending on the active ingredient and the analytical technique. The methodologies have been applied for an adequate determination of the uniformity of the dosing units of two commercial lots. In addition, Raman spectroscopy application allowed the detection of an inappropriate distribution of active ingredients in pharmaceutical products.

Chemical Properties and Therapeutic Potential of Citral, a Monoterpene Isolated from Lemongrass.

Citral is one of the main components of lemongrass oil present at a concentration of 65-85% approximately and is generally separated by steam refining. It is an important component in the manufacturing of scents, citrus chemicals, cosmetics, food and pharmaceutical products. This article aims at reviewing the published literature to highlight the metabolism, extraction strategies and therapeutic significance of citral for improving the scope of its application in the food and pharma industry. Apart from steam refining, there are other techniques like solvent extraction, supercritical fluid extraction and ultrasonication by which citral can be extracted and the method of extraction defines its quality. It is an unstable molecule and undergoes rapid deterioration on exposure to air. Citral is biosynthesized by the plants through the 5 carbon precursor isopentenyl diphosphate (IPP) units utilizing two diverse biochemical pathways, acetate- mevalonate (acetate- MVA) pathway or 2C-methylerythritol-4-phosphate (MEP). Orally Citral was absolutely digested in the gastrointestinal tract and its metabolism leads to the discharge of metabolites which include a number of acids and a biliary glucuronide. There is no scientific evidence about the long term bioavailability of citral in the body and it has no adverse effect on tissue related to its accumulation and delayed excretion. Citral exhibits various important therapeutic properties like antimicrobial, antioxidant, anticancer, anti-diabetic and anti-inflammatory. Citral is a potent biomolecule with various important biological activities and therapeutic implications. Strategies are required to increase the stability of citral which could increase its applications.

Pharmaceutical formulation and manufacturing using particle/powder technology for personalized medicines

Particle/powder technology is used in the manufacture of many pharmaceutical products, and research on the physical properties of particles in the nano- to micro-particle range is important in the pharmaceutical field. The concept of precision medicine will require an increasing shift in pharmaceutical manufacturing toward the design of individualized products. This perspective article focuses on particle design and powder technology for advanced formulations that will be needed in the future for individualized drug formulations and on-demand production. Nanoparticles as drug carriers in drug delivery systems will require particle designs to meet the treatment requirements of individual patients with a particular disease. In pharmaceutical manufacturing, process intensification, such as continuous manufacturing and integrated drug production from drug synthesis to final formulation, has attracted increased attention. Digital design approaches, such as artificial intelligence based on computer-aided development, also will be increasingly used. Continuous production of pharmaceutical products enables downsizing of manufacturing equipment, and on-demand manufacturing equipment has been developed. In addition, additive manufacturing, such as 3D printing, is considered to be suitable for personalized formulations, and small-scale powder handling and predictive modeling of powder characterization will be important for individual preparations.

Continuous manufacturing process monitoring of pharmaceutical solid dosage form: A case study

Continuous Manufacturing (CM) of pharmaceutical drug products is a rather new approach within the pharmaceutical industry. In the presented paper, a GMP continuous wet granulation line used for clinical production of solid dosage forms was investigated with a thorough monitoring strategy regarding process performance and robustness. The line was composed of the subsequent continuous unit operations feeding – twin-screw wet-granulation – fluid-bed drying – sieving and tableting; the formulation of a new pharmaceutical entity in development was selected for this study. In detail, a Design of Experiments (DoE) was used to evaluate the impact of the three main factors (amount of water, filling rate, and shear force in twin-screw granulator) on the tablet quality. The process was monitored via in-process control (IPC) tests (e.g. weight, hardness, disintegration, and loss-on-drying), Process Analytical Technologies (PAT), and through the analysis of the process parameters (multivariate process control). The tested formulation was very robust to the large process variation of the DoE: all IPC results were in specification, the PAT probes provided stable results for the content uniformity and no critical variations can be detected in the process parameters. An adequate monitoring strategy was presented and the robustness of the process with one formulation has been demonstrated. In summary, this continuous process in combination with smart formulation development allows the robust production of constant quality tablets. The synergy between PAT, process data science and IPC creates an adequate monitoring framework of the continuous manufacturing line.

Use of Hazard Analysis Critical Control Point (HACCP) methodology for biocontamination control: Assessing microbial risks and to determining environmental monitoring locations

Quality Risk Management has been an essential feature relating to the manufacture of pharmaceutical and healthcare products for several decades, and its centrality is embedded in key regulatory documents, such as Annex 1 to EU GMP where risk assessment needs to be part of the overall biocontamination control strategy. While the message for constructing pro-active risk assessment sis clear, where the industry lacks direction is with case studies. This paper presents one risk assessment tool, and one which is perhaps best suited to microbiological assessments of pharmaceutical processes and presents a case study for its application. The tool discussed is Hazard Analysis and Critical Control Points (HACCP) and the application is with assessing microbiological risks and then establishing locations for environmental monitoring. The case study is a sterility testing isolator. The paper first discusses what HACCP is and how it can be applied in general, before demonstrating how HACCP can be deployed as a robust tool for constructing or reviewing an environmental monitoring regime.

Catalytically sustainable, palladium-decorated graphene oxide monoliths for synthesis in flow

Continuous flow synthesis is an essential route towards high throughput manufacturing of fine chemical and pharmaceutical products. The mentioned chemistries are often catalyzed by solid-supported catalysts via packed beds which are characterized by multiple issues such as high pressure-drops, micro channeling through the bed, and leaching of the metallic catalyst into the product stream. These issues lower the overall process efficiency. Three dimensional (3D) structures, known as monoliths, with high porosity and mechanical robustness, offer the ideal properties to be used macroscopic supports for metallic catalyst particles. This approach has shown to alleviate several known issues with catalyst packed beds effectively.Herein centimeter-scale monolithic catalysts of palladium (Pd)-decorated, covalently-bonded graphene oxide (GO) layers have been prepared via a completely aqueous, one-pot system. These monolithic composite structures were designed for Suzuki cross-coupling reactions in flow. As highly engineered materials, monoliths’ properties such as oxygen content and Pd catalyst ionic species were tuned via microwave irradiation and ethanol vapor reduction treatments. The optimal monolithic catalysts showed over 5 h of operational longevity in flow, which was 300% higher than the conventional Pd on GO catalyst packed beds. As a proof of concept, the monolithic catalyst was successfully used as a model structure for nondestructive X-ray CT-scan elemental and porosity mapping in the centimeter scale.

Chitin and Chitosans: Characteristics, Eco-Friendly Processes, and Applications in Cosmetic Science.

Huge amounts of chitin and chitosans can be found in the biosphere as important constituents of the exoskeleton of many organisms and as waste by worldwide seafood companies. Presently, politicians, environmentalists, and industrialists encourage the use of these marine polysaccharides as a renewable source developed by alternative eco-friendly processes, especially in the production of regular cosmetics. The aim of this review is to outline the physicochemical and biological properties and the different bioextraction methods of chitin and chitosan sources, focusing on enzymatic deproteinization, bacteria fermentation, and enzymatic deacetylation methods. Thanks to their biodegradability, non-toxicity, biocompatibility, and bioactivity, the applications of these marine polymers are widely used in the contemporary manufacturing of biomedical and pharmaceutical products. In the end, advanced cosmetics based on chitin and chitosans are presented, analyzing different therapeutic aspects regarding skin, hair, nail, and oral care. The innovative formulations described can be considered excellent candidates for the prevention and treatment of several diseases associated with different body anatomical sectors.

Using TMAI to determine the competitive position of companies in Poland’s chemical industry

Currently, the fastest growth of the chemical industry is, besides the Asian markets, expected in the countries of Central and Eastern Europe, including Poland. However, the Polish chemical industry is facing several challenges such as high prices of raw materials, tougher environmental standards and growing competition from the rapidly growing Asian markets. It is, therefore, appropriate to define the competitive position of companies in the chemical industry in Poland. This goal was achieved through the use of the Taxonomic Measure of Attractiveness of Investment (TMAI), which belongs to a group of multidimensional comparative analysis. The assessment was made of 25 chemical companies listed on the Warsaw Stock Exchange (WSE) in Poland in terms of liquidity, debt, turnover, profitability and market efficiency. Companies were ranked in terms of their competitive position in two-time points, 2012 and 2016. Rankings were presented in two variants namely, with weighted and unweighted indicators. The research confirmed a compliance of companies’ rankings calculated in both variants of the applied method. Repeatedly high ranking positions were achieved by the majority of companies engaged in the production of mineral fertilizers. Although cosmetics companies were, in 2012, classified low, most of them recorded improvements in 2016. The opposite was observed in respect of manufacturers of pharmaceutical and medical products. The results obtained are useful in assessing the market value of companies in the chemical industry and in developing strategies for the development of the chemical industry in the light of sustainable development.

A quantitative risk analysis approach to a process sequence under uncertainty – A case study

Process plants for the manufacture of pharmaceutical products often need to be designed and built quickly to make the most of available patent life which necessitates using uncertain or unavailable data. It is common that pilot plant equipment and data are available and new data can be generated if they are important. We present a model based approach to risk analysis to aid design for pharmaceutical processes which combines systematic modelling procedures with Hammersley sampling based uncertainty analysis and sensitivity analysis used to quantify predicted performance uncertainty and to identify key uncertainty contributions. The main contribution of the paper is the demonstration of the methodology on an industrial case study where the process flowsheet was fixed and some pilot data was available. Expected performance was improved by considering the propagation of uncertainty over the whole process. The case study results indicate the importance of considering uncertainty systematically and quantitatively. The methodology showed the opportunity to improve process performance potential through considering uncertainty systematically.

Measurement of residence time distributions and material tracking on three continuous manufacturing lines

Over the recent decade, benefits of continuous manufacturing (CM) of pharmaceutical products have been acknowledged widely. In contrast to batch processes, the product is not physically separated into batches in CM, which creates a few challenges. Product release is done for batches that should have a uniform quality over time, materials need to be tracked along the line, and locations to reject product must be established. To enable these, the residence time distributions (RTDs) of all unit operations must be known. In this paper, three CM tableting lines, each employing a different granulation technique, were investigated. The RTDs of their main unit operations were characterized, utilizing different measurement techniques successfully. All of these RTD measurement techniques could have been performed in any of the lines. The differences were related to the techniques themselves. Overall, external tracer with in-line Near-Infrared detection or color tracer with video recording proved most usable techniques, with few limitations. The RTDs for full lines were calculated by convoluting the unit operation RTDs, which enables material tracking through entire lines. The lines exhibited both truly continuous and quasi-continuous unit operations. Quasi-continuous unit operations divide the material stream into lots that can be utilized for tracking and rejection.