Batch Manufacturing Research Articles

Process modelling, design and technoeconomic Liquid–Liquid Extraction (LLE) optimisation for comparative evaluation of batch vs. continuous pharmaceutical manufacturing of atropine

Continuous Pharmaceutical Manufacturing (CPM) can revolutionise industrial efficiency via potential operational and economic benefits over currently dominant batch methods. Process modelling and optimisation are valuable towards rapid design space evaluation and elucidation of optimal process design configurations, without expensive and time-consuming experimental campaigns. This paper pursues total cost minimisation via nonlinear optimisation of different separation design options for atropine, a product of great societal importance. The study considers a demonstrated continuous flow synthesis, presents reaction kinetic parameter estimation towards reactor design, and illustrates a comparative analysis of the subsequent batch vs. continuous liquid–liquid extraction (LLE) for product purification, using published partition coefficient data and UNIFAC-modelled ternary liquid–liquid equilibria. Original optimisation results show that toluene is the best continuous LLE solvent, attaining the lowest total costs at both plant capacities considered and the greatest total cost savings with respect to the batch LLE design for varying solvent recovery, at acceptable material efficiencies.

Development of a Commercial Process To Prepare AMG 232 Using a Green Ozonolysis-Pinnick Tandem Transformation.

A robust process to manufacture AMG 232 was developed to deliver drug substance of high purity. Highlights of the commercial process development efforts include the following: (i) use of a novel bench-stable Vilsmeier reagent, methoxymethylene- N, N-dimethyliminium methyl sulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a new crystalline and stable isopropyl calcium sulfinate reagent ensuring robust preparation of a sulfone intermediate; (iii) development of a safe ozonolysis process conducted in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization of a salt rejecting impurities effectively. The new process was demonstrated to afford the drug substance (99.9 LC area %) in 49.8% overall yield from starting material DLAC (1).

Preclinical Development of CTX120, an Allogeneic CAR-T Cell Targeting Bcma

Autologous CAR-T cells targeting BCMA have induced robust and durable responses in patients with relapsed/refractory multiple myeloma. However, autologous cell therapies face several challenges which will likely limit the number of patients that will have access to these therapies. These limitations include manufacturing failure rates, wait time and supply constraints in addition to other factors such as reimbursement. Allogeneic CAR-T cells can potentially overcome these access challenges, and may have several other advantages over autologous therapies. Allogeneic CAR-T cells are derived from robust healthy donor T cells through a batch manufacturing process, which may result in a highly consistent product with greater potency and enable better safety management. Here we show further development and preclinical data for CTX120, an allogeneic “off the shelf” CAR-T cell targeting BCMA. CTX120 is produced using the CRISPR/Cas9 system to eliminate TCR and MHC class I, coupled with specific insertion of the CAR at the TRAC locus. CTX120 shows consistent and high percent CAR expression from this controlled insertion and exhibits target-specific cytotoxicity and cytokine secretion in response to BCMA positive cell lines. CTX120 CAR-T cells retain their cytotoxic capacity over multiple in vitro re-challenges, demonstrating durable potency and lack of exhaustion. In mouse models of multiple myeloma, CTX120 showed typical CAR-T persistence and eliminated tumors completely, resulting in long-term survival as compared to untreated animals. These data support the ongoing development of CTX120 for treatment of patients with multiple myeloma and further demonstrate the potential for our CRISPR/Cas9 engineered allogeneic CAR-T platform to generate potent CAR-T cells targeting different tumor antigens. DisclosuresDar:CRISPR Therapeutics: Employment, Equity Ownership. Henderson:CRISPR Therapeutics: Employment, Equity Ownership. Padalia:CRISPR Therapeutics: Employment, Equity Ownership. Porras:CRISPR Therapeutics: Employment, Equity Ownership. Mu:CRISPR Therapeutics: Employment, Equity Ownership. Kyungah:CRISPR Therapeutics: Employment, Equity Ownership. Police:CRISPR Therapeutics: Employment, Equity Ownership. Kalaitzidis:CRISPR Therapeutics: Employment, Equity Ownership. Terrett:CRISPR Therapeutics: Employment, Equity Ownership. Sagert:CRISPR Therapeutics: Employment, Equity Ownership.

Integrated production, statistical process control, and maintenance policy for unreliable manufacturing systems

The objective of this paper is to develop an integrated approach for the joint control of production, maintenance and quality for batch manufacturing systems. We consider such systems that are subject to degradation which is at the origin of the production of defective units. The quality control of lots produced is performed using an ‘x-bar’ control chart. This graphical tool will allow estimating the quality of the batch being produced and possibly undertake perfect preventive or corrective maintenance actions on the production system. A buffer stock is built to maintain continuity of supply during maintenance actions. The incurred total cost includes setup cost, inventory costs, the cost of unused products, maintenance costs and quality costs. Decision variables include the buffer stock size, the sample size, the sampling interval, the surveillance and the control limits of the control chart. Numerical experiments and sensitivity analyses are provided to evaluate the effectiveness of the proposed control policy and the robustness of the solving approach.

Development of near infrared spectroscopic calibration models for in-line determination of low drug concentration, bulk density, and relative specific void volume within a feed frame

This study describes the development of a near infrared (NIR) calibration model for real time determination of drug concentration, powder density, and porosity or relative specific void volume (RSVV) of 3.00%w/w acetaminophen blends within a feed frame. The NIR calibration model was developed from 1.50 to 4.50%w/w of acetaminophen, using a high variability of major excipients (from 12.92 to 81.95%w/w) which facilitates the prediction of powder density and RSVV based on near infrared calibration spectra. The model using second derivative as spectral preprocessing explained the changes related to acetaminophen concentration in the first latent variable. The second latent variable was related to changes in concentration of microcrystalline cellulose and lactose in the powder blends. NIR calibrations were also developed based on the bulk density and RSVV of the powder blends using the same design as the API model, due to the physical properties of the particles and their effects on the NIR spectra. The RSVV was predicted for the independent set blends with an RSEP(%) below 4% with a significantly low bias (0.04 cm3/g) from reference values of 1.33 to 1.58 cm3/g. The bulk density model also exhibited excellent predictions with RSEP(%) below 2.6% and significantly low bias (0.01 g/cm3) from reference values of 0.45 to 0.51 g/cm3. The excellent results obtained show the potential of near infrared spectroscopic measurements within the feed frame for a Process Analytical Technology method to control the critical properties such as tablet mass, hardness and dissolution in batch and continuous manufacturing processes.

Natural Products Extraction of the Future—Sustainable Manufacturing Solutions for Societal Needs

The production of plant-based extracts is significantly influenced by traditional techniques and the natural variability of feedstock. For that reason, the discussion of innovative approaches to improve the manufacturing of established products and the development of new products within the regulatory framework is essential to adapt to shifting quality standards. This perspective of members of the DECHEMA/ProcessNet working group on plant-based extracts outlines extraction business models and the regulatory framework regarding the extraction of traditional herbal medicines as complex extracts. Consequently, modern approaches to innovative process design methods like QbD (Quality by Design) and quality control in the form of PAT (Process Analytical Technology) are necessary. Further, the benefit of standardized laboratory equipment combined with physico-chemical predictive process modelling and innovative modular, flexible batch or continuous manufacturing technologies which are fully automated by advanced process control methods are described. A significant reduction of the cost of goods, i.e., by a factor of 4–10, and decreased investments of about 1–5 mil. € show the potential for new products which are in line with market requirements.

Production as a Service: A Digital Manufacturing Framework for Optimizing Utilization

In current practice, product developers with customized small batch production needs come across the problem of finding capable and flexible manufacturers, whereas manufacturers face underutilization due to inconsistent demand. This paper presents a Production as a Service (PaaS) framework to connect users (consumers or product developers) who have customized small batch manufacturing needs with manufacturers who have existing underutilized resources. PaaS is a cloud-based, centralized framework based on a service-oriented architecture that abstracts the manufacturing steps of a product as individual (production) service requests. Using PaaS, the user is able to reach many capable manufacturers at once and receive quotations for the production request. On the other end, PaaS reduces the effort required to find new customers and enables the manufacturers to easily submit quotations to increase the utilization of their resources. The functionalities and concepts defined in this paper are illustrated through case studies. Note to Practitioners-In order to transition product fabrication from the design phase to manufacturing, there is a need for identifying capable manufacturers with available resources that could be paired with user requirements. We propose Production as a Service (PaaS) in this paper and present initial implementations of the front-end and back-end components with a customizable optimization algorithm. Proposed abstractions and data structures make PaaS a unique, efficient, and intellectual property preserving framework. The current implementation of the framework has been tested with new designs. The PaaS framework has the potential to scale over a large network of manufacturers to effectively coordinate geo-distributed manufacturers for custom manufacturing needs.

Abstract 205: Cryopreserved Cardiac Tissue Graft (MyCardia) Improved Cardiac Function in Rats With Heart Failure

Introduction: There are currently 2M patients with NYHA Class II-IV heart failure of ischemic etiology in the United States. Cell-based therapies hold tremendous potential to provide therapeutic benefit for treating degenerative diseases such as chronic heart failure (CHF). Therapeutic adoption of engineered grafts will require ease of use and demonstration of cost-effectiveness. Here we describe for the first time the ability to cryopreserve an engineered tissue (MyCardia™) and demonstrate functional recovery in a rat model of CHF. Methods: MyCardia grafts were cultured with human dermal fibroblasts (hNDF) and human iPSC derived cardiomyocytes (hiPSC-CMs) (FCDI) into a bioabsorbable mesh (Novus Scientific). Grafts were cryopreserved at -196C for 2-4weeks, thawed, reconstituted and implanted into rats with CHF. Myocardial infarction (MI) were generated in immune competent rats by ligating the left coronary artery. Three weeks after MI, rats received graft implants via median sternotomy. Echocardiography was performed at 3 and 7 weeks post graft implantation. In addition, terminal hemodynamics were performed. Results: MyCardia maintained spontaneous and synchronous contractions pre-freeze (65±10bpm) and post thaw (60±10bpm). Grafts were maintained to 40 days post thaw with no deterioration in composition or beat rate. MyCardia reversed maladaptive left ventricular (LV) remodeling by decreasing (p<0.05) LV volume systole/diastole, LV diameter systole/diastole with trending improvement in EF and FS from 3 and 7 weeks post implantation as compared to CHF controls. Grafts decreased LV end diastolic pressure, 24±6 mmHg vs. 18±3mmHg and showed trending improvements in LV dP/dt(-) and dP/dt(+) as compared to controls. In addition, MyCardia results in 36% reduction in LV EDP operating volume as demonstrated by a leftward shift of the diastolic pressure-volume relationship. Conclusion: MyCardia can be cryopreserved, reconstituted and implanted in rats with CHF. Treated rats demonstrated reversal of maladaptive LV remodeling and continued functional improvement from 3 to 7 weeks post treatment. We anticipate that the ability to cryopreserve will allow long-term storage after large batch manufacture, providing cost and utility advantages.

Technoeconomic Modeling of Plant-Based Griffithsin Manufacturing.

Griffithsin is a marine algal lectin that exhibits broad-spectrum antiviral activity by binding oligomannose glycans on viral envelope glycoproteins, including those found in HIV-1, HSV-2, SARS, HCV and other enveloped viruses. An efficient, scalable and cost-effective manufacturing process for Griffithsin is essential for the adoption of this drug in human antiviral prophylaxis and therapy, particularly in cost-sensitive indications such as topical microbicides for HIV-1 prevention. The production of certain classes of recombinant biologics in plants can offer scalability, cost and environmental impact advantages over traditional biomanufacturing platforms. Previously, we showed the technical viability of producing recombinant Griffithsin in plants. In this study, we conducted a technoeconomic analysis (TEA) of plant-produced Griffithsin manufactured at commercial launch volumes for use in HIV microbicides. Data derived from multiple non-sequential manufacturing batches conducted at pilot scale and existing facility designs were used to build a technoeconomic model using SuperPro Designer® modeling software. With an assumed commercial launch volume of 20 kg Griffithsin/year for 6.7 million doses of Griffithsin microbicide at 3 mg/dose, a transient vector expression yield of 0.52 g Griffithsin/kg leaf biomass, recovery efficiency of 70%, and purity of >99%, we calculated a manufacturing cost for the drug substance of $0.32/dose and estimated a bulk product cost of $0.38/dose assuming a 20% net fee for a contract manufacturing organization (CMO). This is the first report modeling the manufacturing economics of Griffithsin. The process analyzed is readily scalable and subject to efficiency improvements and could provide the needed market volumes of the lectin within an acceptable range of costs, even for cost-constrained products such as microbicides. The manufacturing process was also assessed for environmental, health and safety impact and found to have a highly favorable environmental output index with negligible risks to health and safety. The results of this study help validate the plant-based manufacturing platform and should assist in selecting preferred indications for Griffithsin as a novel drug.

Current state of the art in continuous bioprocessing.

There is an upsurge of interest in continuous bioprocessing, but currently continuous downstream bioprocessing has not been implemented to generate clinical material. This review focusses on the current state of the art of continuous downstream processing, highlighting the key advantages over traditional batch manufacturing. This allows the identification of scenarios where continuous downstream processing may be critical for commercial manufacturing success.

A study concerning the critical path method for optimizing the design and crafting of a welded structure

The paper includes a study on optimum batch calculation in designing the technology of execution of a welded structure within a company with mechanical profile, this being one of its main objects of activity. Because of the duration of different operations in the technological itinerary is not equal or in a multiple report, loading of machinery and workers cannot be done in a uniform manner, the production process being interrupted most often, narrow places and stocks large unfinished production, which is why we tried to determine an optimum manufacturing batch that would no longer allow these drawbacks. The solution of these problems is differentiated, considering the particularities of the manufactured product, the technological process, based on the economic analysis, aiming at the adoption of an optimal variant. The method provides the possibility to determine the influence of the size of the batch of parts on the duration of its production cycle.

Application of expectation maximization and Kalman smoothing for prognosis of lumen maintenance life for light emitting diodes

Light emitting diodes (LED) have found widespread use for lighting and displays in recent times due to their high efficiency, favorable form factor, impact resistance, robustness, reliability and prolonged lifetime. The extended times to failure of LEDs make the problem of lumen maintenance life prediction for LED light sources using traditional reliability-based failure data collection and analysis methods quite challenging. Therefore, one has to resort to using prognostic approaches such as Kalman or particle filters applied to real time degradation data to make inferences on the remaining useful life (RUL) of such devices. The standard prognostic approach for predicting lumen maintenance life relies on an underlying degradation model with predetermined parameters from previous stress tests. However, these model parameters may vary quite a bit from device to device and for different manufacturing batch lots, thereby leading to large prediction errors. To address this issue, it would be better to learn the model parameters from the current measurement data directly. This study aims to achieve this by estimating the parameter values using the Expectation Maximization (EM) algorithm. Kalman smoothing is then applied to the identified parameter values for predicting the lumen maintenance life of the LED. The accuracy of the EM – Kalman smoothing approach was tested and compared with the standard nonlinear least square (NLS) approach prescribed by the TM-21 standard as well as the standard particle filter approach (without EM). Our results show that the EM method can give better, if not, similar RUL prediction accuracy with respect to the NLS and standard particle filter (PF) algorithms. Moreover, the accuracy of RUL prediction using our proposed algorithm is insensitive to the choice of the initial model parameter values, which paves way for this algorithm to be used in practice for automated predictive analytics of degrading electromechanical systems.

Method Development and Validation of an Inline Process Analytical Technology Method for Blend Monitoring in the Tablet Feed Frame Using Raman Spectroscopy.

Inline process analytical technology sensors are the key elements to enable continuous manufacturing. They facilitate real-time monitoring of critical quality attributes of both intermediate materials and finished products. The aim of this study was to demonstrate method development and validation for inline and offline calibration strategies to determine the blend content during tablet compression via Raman spectroscopy. An inline principal component regression model was developed from Raman spectra collected in the feed frame. At the same time, an offline study was conducted over a small amount of the calibration blends using an in-house moving powder setup to simulate the environment of the feed frame. The model developed offline was able to predict the active ingredient content after a bias correction and used only a fraction of the material. The offline method can serve as a simple method to facilitate calibration development when the time and access to the press is limited. The study takes into consideration, the necessary components of method development and offers perspectives on the validation of an inline process analytics method. Method testing and validation was performed for the inline process analytical technology method. The established Raman method was demonstrated as suitable for the determination of bulk assay of the active ingredient in powders inside the feed frame for use during batch and continuous manufacturing processes.

Proactive Automation of a Batch Manufacturer in a Smart Grid Environment

Proactive Automation of a Batch Manufacturer in a Smart Grid Environment

Regulatory requirements for the approval of Anti-Cancer drug (Mercaptopurine) in Myanmar as per ACTD

South East Asian pharmaceutical market is growing rapidly. In Asian country, The regulatory environment is similar among all countries. But still requirements and process of registration is varying among countries of Asian region. Although ACTD is harmonized for all ten countries but still every country differ in some of the local requirements such as administrative, technical, clinical and non clinical documents. Among this country Myanmar systematically regulate the manufacture, import, export, storage, distribution and sale of drugs. Aim of the present study is To discuss emerging challenges and requirements posed by compulsory licensing for drugs in diseases such as cancer. In this article we have observed documents requires for registration of Mercaptopurine drug belonging to anti – cancer category in Myanmar. Documents like batch manufacturing record, process validation records, stability study which include long term and accelerated stability studies as per zone specification of Myanmar, packing requirements for anti – cancer drug and certificate for product permission required for registration, which has covered all aspects from manufacturing to its packing and registration. This article will give the easy understanding on the drug registration requirements for anti – cancer drug such as Mercaptopurine in Myanmar.

Determination of the dried product resistance variability and its influence on the product temperature in pharmaceutical freeze-drying

During the primary drying step of the freeze-drying process, mass transfer resistance strongly affects the product temperature, and consequently the final product quality. The main objective of this study was to evaluate the variability of the mass transfer resistance resulting from the dried product layer (Rp) in a manufacturing batch of vials, and its potential effect on the product temperature, from data obtained in a pilot scale freeze-dryer. Sublimation experiments were run at −25 °C and 10 Pa using two different freezing protocols: with spontaneous or controlled ice nucleation. Five repetitions of each condition were performed. Global (pressure rise test) and local (gravimetric) methods were applied as complementary approaches to estimate Rp. The global method allowed to assess variability of the evolution of Rp with the dried layer thickness between different experiments whereas the local method informed about Rp variability at a fixed time within the vial batch. A product temperature variability of approximately ±4.4 °C was defined for a product dried layer thickness of 5 mm. The present approach can be used to estimate the risk of failure of the process due to mass transfer variability when designing freeze-drying cycle.

Modeling the effects of material properties on tablet compaction: A building block for controlling both batch and continuous pharmaceutical manufacturing processes

As the pharmaceutical industry modernizes its manufacturing practices and incorporates more efficient processing approaches, it is important to reevaluate which process design elements affect product quality and the means to study these systems. The purpose of this work is to provide insight on a methodology to correlate the effect of raw material properties to equipment and process performance using both data-driven and semi-empirical models. In this work, lubricated blends of pharmaceutically-relevant materials were made using varying levels of magnesium stearate, ranging from 0.25 to 1.5%. Materials characterization (e.g., compressibility, permeability, density, particle size) was performed for all materials and blends. The blends were compressed using a two by three experimental design, varying tablet fill cam depth and tablet thickness, respectively. Tablet properties (e.g., weight, tensile strength, and thickness) were collected for all tablets. Using the collected tablet property results, models coefficients for the semi-empirical Kuentz and Leuenberger equation, which relates the tablet tensile strength to changes in porosity, were regressed. Empirical models were then developed to correlate the values of the Kuentz and Leuenberger equation coefficients to the blend material properties. The empirical models were then used in conjunction with the Kuentz and Leuenberger equation to evaluate the compression design and operational space, accounting for material properties. This proof of concept work aimed at developing correlations between raw material properties and unit operation models can aid process development, especially in design space characterization and robustness analysis.

Control of three different continuous pharmaceutical manufacturing processes: Use of soft sensors

One major advantage of continuous pharmaceutical manufacturing over traditional batch manufacturing is the possibility of enhanced in-process control, reducing out-of-specification and waste material by appropriate discharge strategies. The decision on material discharge can be based on the measurement of active pharmaceutical ingredient (API) concentration at specific locations in the production line via process analytic technology (PAT), e.g. near-infrared (NIR) spectrometers. The implementation of the PAT instruments is associated with monetary investment and the long term operation requires techniques avoiding sensor drifts. Therefore, our paper proposes a soft sensor approach for predicting the API concentration from the feeder data. In addition, this information can be used to detect sensor drift, or serve as a replacement/supplement of specific PAT equipment. The paper presents the experimental determination of the residence time distribution of selected unit operations in three different continuous processing lines (hot melt extrusion, direct compaction, wet granulation). The mathematical models describing the soft sensor are developed and parameterized. Finally, the suggested soft sensor approach is validated on the three mentioned, different continuous processing lines, demonstrating its versatility.

Stockout risk of production-inventory systems with compound Poisson demands

Production-inventory systems with continuous production or continuous manufacturing have been implemented in a variety of manufacturing contexts. Most recently, the Commissioner of the FDA has called on drug and biological product manufacturers to begin switching from batch manufacturing processes to continuous production. Motivated by prevailing applications and the emerging and promising landscape in the healthcare and pharmaceutical industries, this paper studies a continuous-review production-inventory system with a constant production rate and compound Poisson demands, in which the cost of the system is assessed via inventory holding, stockout penalty and production costs. For any initial inventory, we derive a closed-form expression for the expected discounted cost function until stockout occurrence. We systemically quantify the stockout risk on four different dimensions (i.e., time, volume, frequency and percentage) and derive explicit expressions for each type of risk metric. The objective is to derive the production rate that minimizes the expected discounted system cost subject to a given risk tolerance level on stockouts. With the aid of the derived explicit forms of stockout risk and the cost function, we develop a computationally-efficient algorithm for the optimal solution. Extensive numerical studies are conducted to illustrate our results with rich insights. Numerically, we show that it is outrageously costly to reduce stockout risk, especially when this risk is relatively low; the value of risk is more sensitive to the stockout risk level if the demand distribution has a higher volatility.

Micro-hydromechanical deep drawing of metal cups with hydraulic pressure effects

Micro-metal products have recently enjoyed high demand. In addition, metal microforming has drawn increasing attention due to its net-forming capability, batch manufacturing potential, high product quality, and relatively low equipment cost. Micro-hydromechanical deep drawing (MHDD), a typical microforming method, has been developed to take advantage of hydraulic force. With reduced dimensions, the hydraulic pressure development changes; accordingly, the lubrication condition changes from the macroscale to the microscale. A Voronoi-based finite element model is proposed in this paper to consider the change in lubrication in MHDD according to open and closed lubricant pocket theory. Simulation results agree with experimental results concerning drawing force. Changes in friction significantly affect the drawing process and the drawn cups. Moreover, defined wrinkle indexes have been shown to have a complex relationship with hydraulic pressure. High hydraulic pressure can increase the maximum drawing ratio (drawn cup height), whereas the surface finish represented by the wear is not linearly dependent on the hydraulic pressure due to the wrinkles.