Transformation of Toxicology data into Specific PDE’s
Presented by Kim Li, PhD, DABT, MPH, Amgen Inc.
Followed by an industry perspective presented by Dries Cardoen, Team Leader of Study Directors - Inhalation/topical/transdermal products at Nelson Laboratories, LLC
Permitted Daily Exposure (PDE) has origin in ICH Q3C: Impurities – Guideline for Residual Solvents. This webinar will discuss the principles and methods of applying PDEs to extractactables and leachables (E&L) impurities in pharmaceutical products. We will review the regulatory advice on the DO’s and DON’Ts. Then we will review the current toxicology risk assessment practice on data gathering, literature synthesis and selection of the critical studies with robust toxicity endpoints. We will show how the toxicity endpoints are transformed into chemical-specific PDE values with modifying factors. We will highlight the importance of clinical relevance to further refine the PDE values. For a case study, we will share an extraction study of a polyolefin bag for use with a lyophilized product. We will examine the risk matrix per USP Assessment of drug product leachables associated with pharmaceutical packaging/delivery systems. The toxicology assessment of the extractables profile of the bag will illustrate the derivation of chemical-specific PDEs, as well as the refinement by taking clinical relevance into consideration.
RecordedApr 23 202092 mins
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Dr Friedrich von Wintzingerode, QC Lead iNeST, Roche and Eelo Gitz, Head product development at Sanquin Reagents
Full Title: CCAB: A universal tool to address the risk of microbial impurities in parenteral drug manufacturing including ATMPs
For parenteral drugs such as monoclonal antibodies, injectable oligonucleotides, and RNA- or DNA-based ATMPs, filtration using pore sizes ranging between 0.02 and 0.2 µm is the method of choice to reduce bioburden and ensure terminal sterilization of the drug product. While filtration efficiently removes intact microbial cells it does not remove subcellular microbial components like toxins, lipopeptide/lipoproteins, flagellin, bacterial and fungal DNA, cell wall polysaccharides, extracellular proteases or endoglycosidases. These microbial impurities can have a significant impact on product quality and patient safety when critical loads are exceeded during a contamination event. The CCAB approach described here enables a comprehensive assessment of these risks.
Lance Marquardt, Associate Director -Upstream Processing Gene Therapy, Hopewell Biologics Manufacturing at PTC Therapeutics
An overview of single use manufacturing for the production of AAV gene therapy products with comparisons to traditional monoclonal antibody production. Specific challenges of scaling up AAV production and considerations to accommodate a range of demands of differing gene therapy products will be discussed. I will review the reasons for starting and the challenges of being the inhouse manufacturing facility for a rapidly growing company. The challenges of making non-COVID products in the era of Warp Speed along with future commercial production comparing fully single use with a hybrid facility will be explored.
Eileen Martin Merck KGaA, Darmstadt, Germany, Global Director of Diversity, Equity and Inclusion
At Merck, we aim to recruit, retain and promote the best talent around the world to support our drive for innovation and growth. This includes ensuring balanced representation of women across all levels in the organization. Our leaders are committed to fostering a culture where women can thrive, because we believe gender equity helps our business and our patients.
Our global strategic diversity, equity and inclusion plan has a particular focus on gender. We aspire to increase representation of women in management and leadership positions across our healthcare, life science and electronics sectors. The leaders at Merck will track progress of women in leadership roles, along with other key metrics, including gender balance in our development courses, succession plans, and the sponsorship of women. In a world where women make up 50 percent of the population, we want to make Merck more reflective of the countries in which we do business and better reflect the customers we serve.
We believe that a diverse workforce paired with a respectful and inclusive company culture is fundamental to our ability to innovate and contribute significantly to our business success. Curious minds make Merck better.
Lizbeth Martinez, Ph. D, at Novartis Basel Switzerland and Emiliano Genorini, at Viavi Solutions
Full Title: Using PAT to accelerate and optimize the process development of solid dosage forms.
Near-infrared spectroscopy (NIRS), as one of the major PAT tools, has attracted lot of attention from the pharmaceutical industry. NIRS can analyze samples without previous pretreatment, therefore reducing or eliminating wet chemistry analysis. During development of the drug product process, each unit operation brings challenges that need to be assessed in order to prevent compromising the quality of the final product. Two examples of real PAT applications are presented in this study. The first case tackles the challenges of process development in an international environment, with different locations for manufacture and traditional analytics. Showing how PAT enables a lean evaluation of the product quality, better understanding and supports process transfer. By means of in-line monitoring of the blending process, at-line content uniformity determination on high number of tablets and by helping the troubleshooting of segregation. The second case describes in-line monitoring by NIRS for assay determination in a wet met media milling process of a nano-suspension. NIRS proved to be a versatile and valuable tool for the pharmaceutical development and manufacturing of solid dosage forms.
Presented by Dr Ravendra Singh, Research Faculty at C-SOPS at Rutgers University, NJ, USA
Full Title: Applications of industry 4.0 concepts in continuous pharmaceutical tablet manufacturing process
Currently, Industry 4.0 concepts are being applied to pharma industry to achieve Pharma 4.0 paradigm. Pharma 4.0 reduces the time and resources needed for continuous pharmaceutical manufacturing and also improves the product quality and production consistency. It has many advantages but also have bigger challenges on the applications of artificial intelligence (AI)/machine learning (ML), and advanced control systems because of different level of complexities.
Four machine learning (ML) models have been trained to predict the response of continuous pharmaceutical manufacturing process and the performance of these ML models has been compared. The investigated ML methods are long short term memory (LSTM), 1D convolution neural network (CNN), random forest (RF), and artificial neural network (ANN). The best performing ML model is then implemented into the continuous pharmaceutical tablet manufacturing process. An advanced model predictive control (MPC) system coupled with an RTD based control system has been also implemented in the continuous pharmaceutical manufacturing (CPM) pilot-plant . The CPP’s and CQA’s are controlled in real time using advanced model predictive control (MPC) system while the none-confirming products are diverted in real time in waste using RTD based control system to assure the final CQA’s of qualified tablet lots. All the relevant data generated during continuous manufacturing has been systematically collected, stored and organized in a data hub (OSI PI) and cloud system as per industry 4.0 standard.
The objective of this presentation is two-fold; first to highlight the pharma 4.0 technology and then demonstrate the development and implementation of machine learning (ML) and advanced control systems into continuous pharmaceutical tablet manufacturing process.
Presented by Dr. Zlatibor Velickovic PhD at Royal Prince Alfred Hospital and Alan Hoffmeister at Charles River Laboratories
Full Title: Validation Of Endotoxin Testing For CAR T-cell Manufacturing Quality Control & Benefits of Cartridge Technology
During manufacture of CAR T-cells there is a risk of contamination of the final product and/or materials with endotoxins. Endotoxins are lipopolysaccharide molecules produced by gram-negative bacteria that can cause toxic reactions in patients and lead to serious complications.
Endotoxins can be detected reliably by the limulus amoebocyte lysate (LAL) test. Endosafe nexgen-PTS, (Charles River) is a portable system designed to read cartridges loaded with LAL reagents and endotoxin control. Each cartridge is supplied with a predetermined spike recovery with two sample and two spiked channels enabling quick and easy endotoxin detection.
Materials used in cell manufacturing may interfere with the test and therefore validation of bacterial endotoxin testing (BET) is mandated for each cell product. We’ll present the validation approach for endotoxin testing using Endosafe nexgen-PTS designed to meet Australian regulatory requirements.
In this webinar, you will learn from our experts:
Introduction to cartridge technology and its benefits
How the Endosafe nexgen-PTS provides a rapid quantitative method for Endotoxin detection in CAR T-cell products.
Why Maximum Valid Dilution (MVD) needs to be calculated and validated for each CAR T-cell product formulation and volume of infusion.
Why it is important to perform interference testing using I/E cartridges and serial dilutions of the CAR T-cell product up to the MVD.
Robert Gronke, Ph.D., Senior Principal Scientist, at Biogen and John Cyganowski, Director of Customer Application, Merck
Following on the commercial success of Spinraza® (the first successful treatment for patients with spinal muscular atrophy), antisense oligonucleotides (ASO) are now an important part of Biogen’s drug portfolio that enables us to better treat neuromuscular diseases. Development of the ASO process employs orthogonal chromatography to achieve industry high purities while maintaining good yield along with detritylation and UF/DF steps. This purification platform process is all aqueous based on green chemistry principals that easily fits into our existing biologics manufacturing facilities. To date, we now leverage this ASO platform process to purify 13+ ASO molecules that contain different sequences, chemistries, and most recently incorporating conjugation reactions.
Having completed process characterization for our lead ASO candidate, we have achieved a greater understanding of the process, its capabilities to clear process and product related impurities and understand the mechanisms that control the chromatography. On the manufacturing side, Biogen recently completed at scale PPQ validation batches of an ASO clinical candidate. Cases studies and learnings will be presented on results from characterization studies and PPQ batches.
Jurgen Mulberg Associate Director at Bristol Myers Squibb and Audrey Brussel at PathoQuest
Full Title: Application of Next Generation Sequencing (NGS) Based Methods for Detection of Viral Contaminants in Biomanufacturing
Contamination of a biological product with viruses, potentially harmful for humans, is of concern for therapeutics derived from human and animal sources, i.e. plasma, and for protein therapeutics and vaccines produced in mammalian cells. More recent “Advanced Therapeutic Medicinal Products (ATMPs)”, such as gene and cell therapies, share the same concern. Tests for viral contaminants are performed at several stages of manufacturing. Current tests for detection of viruses are lengthy; cell culture based assays and animal experiments are required. Alternative molecular tests, such as “next generation sequencing (NGS)”, provide faster results, and can eventually replace in vivo animal studies. It is noteworthy that identification of a viral contaminant that evaded detection in classical tests, by NGS, has been demonstrated. In addition, due to the fast turnaround time, application of targeted NGS for “in process” detection of viral contaminants can be envisioned. Current efforts for development of unbiased and targeted NGS based viral safety assays will be discussed
Charlotte Masy at GSK Vaccines and Patrick Evrard at Pall Life Sciences
Single-use technologies are more and more used in critical sterile applications, e.g. close to final manufacturing steps handling Drug Product, leading to increasing concern related to integrity. In this presentation, we make a review of the regulatory environment and present key elements to consider to defined and apply a sound integrity control strategy.
The regulatory environment has significantly evolved in last years, with the publication of new guidance and standards and additional ones in preparation. Current draft of EU GMP Annex 1 illustrates the increased scrutiny of regulatory authorities on this topic.
We will position integrity tests in the more global picture around integrity strategy. Concepts such as QbD and QRM, as well as close collaboration between supplier and end-user are required to build a good strategy and enhance the integrity assurance for processes using single-use systems. A defined integrity control strategy is very important for critical applications where single use systems are used after last sterile filtration step or in a process where no sterile filtration is possible.
We will discuss the different technologies available on the market to control integrity of single-use systems and key parameters that are affecting integrity measurements, at supplier’s and at end-user’s side.
Several case studies will be shared, illustrating how integrity concerns can be practically addressed for cGMP manufacturing applications, and what are the results observed after a few years of use.
Flavien Susanne at Sanofi and Sean Bermingham at PSE Ltd
In the past decade, there has been a growing interest in the application of continuous processing in the pharmaceutical industry with 100s millions of investments and several products delivered to the market using this technology.
Continuous processing demonstrates several value propositions for the Pharmaceutical industry. Amongst them we can name, access to better chemistry, product quality enhancement, reduction of CoGs but mostly speed to market where phase 3 to launch is drastically accelerated.
Sanofi R&D is building capacities to perform future GMP clinical batches using this technology. The first investment was completed last year, and we are in the process of expansion. It is a really changing time for science at Sanofi.
Sanofi is investing in modular concept with high capability of production of API and ability of infinite reconfiguration. We are not only thinking machine; to enhance our ability to always produce best quality drugs to our patient, we are also implementing digital twin system, tracking and controlling the quality of our product at any moment of time.
We are ready to meet the challenges of tomorrow and produce the new APIs to help patients.
Steve Hammond, Independent Consultant at Steve Hammond Consulting
It is well recognized that continuous processing requires continuous monitoring, at the “heart-beat” of the process to ensure product quality and patient safety. However, the use of PAT in the optimization of equipment and the development of processes from which a product will be manufactured is also of significant value, and justifies the investment in PAT for a continuous manufacturing. The data density and timeliness can deliver immediate feedback and exquisitely detailed information on the success of processing steps. The gathered information can aid in the establishment of an effective and robust processing regime for new or existing products.
This paper will discuss the use of information rich PAT technologies to understand equipment and process steps during development. Examples of equipment characteristics and the effect on the product will be examined.
An important area for PAT in continuous manufacturing is cleaning. The equipment trains to be effective must be capable of rapid change over. PAT’s designed for rapid assessment of surface cleanliness are important. Devices that allow rapid cleaning verification will be discussed.
Oliver Steinhof, PAT Scientist at Biogen and Nicolas Langenegger, Senior Associate Scientist at Biogen
Full Title: Development of automated chemometric platform for accelerated Raman-based model optimization in biologics
The increasing use of multivariate models both as part of the control strategy in commercial (bio)pharmaceutical production as well as for process monitoring calls for an efficient strategy for model development and model life cycle management. The traditional approach to develop multivariate models based on spectroscopy involves manual data management such as selection and transfer of spectroscopic data, import into modeling software and selection/exclusion of data. That is followed by addition of reference data, alignment of time stamps and import into the modeling software. 90% of the time required to construct a multivariate model is spent on data preparation. It was decided to develop a solution to automate these steps to prepare (stage) the data required for model development, reducing the time required to prepare a typical set of batch data to about five minutes. A second tool was developed to automatically optimize data pretreatment parameters and spectral range for PLS models. Both tools allow our scientists to invest their time into more value-added activities.
Dr. S.K. Jana at Serum Institute of India Pvt. Ltd, Vikas Revankar at Merck and Piergiuseppe Nestola at Sartorius
Full Title: Vaccine Development & its Manufacturing using Integrated High Throughput Technology
The billions of doses of vaccines manufactured worldwide each year are used to vaccinate the healthy people. This is the fact which drives vaccine manufacturing to be among rigorously designed, manufactured, monitored & compliant health products. In order to produce this huge number of doses, there is a need to have a manufacturing process which strongly influence the cost effectiveness, volume, application of technologies involving ease of scale-up, flexible in nature, automated integration with different manufacturing unit operations, minimal manual intervention or hybrid for complex biologics like vaccines manufacturing. The use of integrated way of automation with different online sensors like IOTs, AI at different measurement points of processes to make manufacturing process continuous, seamless, robust with high throughput yield, higher process capability with less time or no failure is the cornerstone of a modern, advanced & powerful manufacturing system. The concept of High Throughput Manufacturing is related to time required for a product to pass through a manufacturing process converting raw materials in to finished goods involving automation, integration of several unit operations with minimal manual intervention during the manufacturing. The ability to manufacture vaccines safely and consistently must be built on the theme with consistent quality, compliance, easier regulatory authorization in order to reach the market fast as manufacturing complexity is compounded by the need for different producing strains, type of vaccines & their processes. The present talk on “Vaccine Development and its manufacturing using integrated high through put Technology” is going to address some challenges & opportunities and its full scale application to future biologics manufacturing.
Sarah Nielsen, at Janssen and Herman He, at Thermo Fisher Scientific
The Janssen real time release strategy will be presented. Multivariate statistical process modeling is used as a way to guide batch release (either via RTR or conventional testing). The RTR strategy uses spectroscopic release tests, skip lot testing and a surrogate model for dissolution. The surrogate dissolution model was developed with a dedicated pilot scale DOE and validated with commercially manufactured product. Multivariate raw material and process “health check” models ensure that the surrogate dissolution model is used appropriately. RTRT provides greater manufacturing efficiency, process monitoring and allows for additional sampling when compared to a traditional release strategy. The presentation will illustrate the commercial use of this technology for a batch manufactured product within Janssen
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Transformation of Toxicology data into Specific PDE’sKim Li, PhD, DABT, MPH, Amgen Inc and Dries Cardoen, Team Leader of Study Directors at Nelson Laboratories, LLC[[ webcastStartDate * 1000 | amDateFormat: 'MMM D YYYY h:mm a' ]]92 mins