Compression of film-coated pellets - key parameters for optimal tablet quality
Combining the process of tableting with a multiple unit pellet system requires the protection of the drug release controlling coating as well as the limitation of segregation of the tableting mixture in order to provide mass and content uniformity. Limiting pellet size and fraction (ideally 50 – 60 % w/w), using concave tooling and of course applying flexible coatings at high layer thickness are best precaution to prevent damage of the drug release controlling coating.
RecordedMar 4 201555 mins
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The development and application of continuous manufacturing processes for vaccines presents both great opportunity as well as significant challenges, both technical and cultural, for the global industry. The key drivers are manufacturing capacity and flexibility, speed to market, and improved quality through the application of Quality-by-Design and Process Analytical Technology (QbD/PAT). Given the diversity of immunogens (toxoids, conjugate and subunit vaccines, live-attenuated and inactivated viruses, VLPs, etc.), and the variety of unique processes currently utilized to produce either single- or multi-component vaccines, it is unlikely that the transition to continuous processing will happen overnight. Additionally, cultural challenges are faced whenever a new mode of operation appears to some as “too different”, especially in a traditionally conservative sector like the developed-world vaccine industry. That said, market forces, global climate change, and Nature’s propensity to fill unoccupied niches with emerging infectious diseases will undoubtedly induce a first round of pioneers to explore this exciting new design space, ultimately leading to a more nimble industry and more and better opportunities for protection for the global population.
The BPOG Leachables Working Group has recently published a Best Practice Guide for Leachables. The Best Practice Guide was developed to help Biopharmaceutical and Vaccines Manufacturers to develop science-based, robust, and efficient approaches to handling the risk of leachable compounds that is associated with increasing use of Single-Use Systems in manufacturing processes. The Best Practice Guide is composed of three parts: the risk assessment model, leachable study design, and analytical methods. This article provides insight into the application of the Best Practices for Leachables Study Design by end users and will include a case study to highlight the importance of the study design.
Continuous improvement, risk mitigation and adherence to compliance rely on the successful execution of key initiatives aligned with an organization’s strategic imperatives. This article summarizes the Project and Portfolio initiatives at Shire’s Biologics manufacturing facility at Shire, Lexington, MA site. In addition to practical advice, the authors discuss the need for sound business processes, alignment with Finance and budget cycles, and play special attention to the importance of resource allocation and management.
In commercial cell culture bioprocessing, consistent high quality protein is a fundamental goal that is typically accomplished during development through product and process engineering of bioreactor parameters. The FDA’s Center for Drug Evaluation and Research (CDER)’s Office of Biotechnology Products’ upstream bioprocessing laboratory, a part of the Office of Pharmaceutical Quality’s Center of Excellence (COE) in Manufacturing Science and Innovation, studies Process Analytical Technology (PAT) for upstream bioprocessing, focusing on the production of monoclonal antibodies. These capabilities are being leveraged to study continuous bioreactor cell culture production and compatible PAT tools. Case studies are presented that illustrate collaborative laboratory research being conducted on PAT tools for upstream bioprocessing to support regulatory decision making.
Qualitative analysis of environmental monitoring data is vital for pharmaceutical quality groups. Essential to identifying evolving microbial trends are the means to effectively parse and analyze EM results. To make the best use of the tools available, they must be used with a full understanding of their value and limitations. In this paper, the pros and cons of several EM trend analysis tools will be presented to aid microbiology experts to qualitatively evaluate EM performance data.
Gloria Gadea-Lopez, Ph.D., John Maguire and Gerry Glennon
The success of manufacturing relies on the availability of all the resources –personnel, materials, equipment, work instructions - , orchestrated in such a way that the operations proceed in an efficient and predictable manner. This article describes the implementation of a finite scheduling system for biologics production, the foundational work required prior to project launch, lessons learned, and benefits achieved from this deployment.
Robert Dimitri, Hugo Guerra and Gloria Gadea-Lopez, Ph. D
Technical teams rely on the availability of meaningful data and effective tools to perform process monitoring, to conduct root cause analysis and investigations and, most of all, to obtain new insights into their operations. In this article, the authors discuss the implementation and management of a comprehensive system for data analytics at Shire –Lexington, MA site, the lessons learned, and practical advice towards the successful deployment of these key applications.
Nearinfrared has a long tradition as analytical technology in pharmaceutical industry. In this article/webinar new applications, technology and improvements in regulatory guidances will be presented which will support further growth of nearinfrared in the pharmaceutical and biopharmaceutical industry.
Recently, there has been a renewed interest in the field of continuous processing. Some key factors driving this interest are – availability of better cell retention devices, improved cell lines and culture medium capable of supporting high cell densities.
These factors have contributed mainly in reducing the batch duration for making the required quantity of product, thus reducing the medium requirement and chances of batch failures significantly. With the continuous processing being considered as ‘back-in-the-game’, the question remains: Can the current perfusion technology compete or replace the conventional and widely preferred fed-batch technology?
Two cases are discussed to compare the performance features of fed-batch and perfusion processes. In both the cases, the product output from perfusion process is significantly higher (2 to 5 folds) than that from fed-batch, due to combination of factors like higher cell density, higher cell specific productivity, lower accumulation of toxic metabolites etc. These cases demonstrate the potential of perfusion process in significantly increasing the product output. However, there are certain challenges and points to be considered before a company decides to switch to a perfusion platform. Some of these are highlighted in the article.
Dr Trevor Deeks, Principal and Consultant of Deeks Pharmaceutical Consulting Services, LLC
Single-use (SU) systems are now in common use in pharmaceutical bioprocessing, as well as in other related technologies such as the manufacture of diagnostics and other biological products, and their popularity is increasing. Some types of SU systems have been in use for many decades now. The earliest SU systems being disposable filter cartridges that do not require a stainless steel (SS) filter housing. This present article seeks to focus in particular on SU bioreactors for cell culture and bacterial fermentation for the purpose of producing therapeutic proteins, monoclonal antibodies and vaccines. SU bioreactors are of particular value in early phase (Clinical Phases 1 and 2) GMP manufacturing. In some cases their use has now stretched through into commercial processing, albeit that the scale of operation is currently limited and in general the largest commercially available SU bioreactors are around 2000L working volume (WV). However, the small footprint that they require, and the reduction in investment needed for support services and utilities, means that the scale limitations can be overcome to a significant degree by having multiple SU bioreactors operating in parallel within a facility. The harvest from multiple bioreactors can be pooled for downstream processing, or each harvest can be processed as a separate batch, based upon considerations of the risks versus the economies of pooling.
Since the introduction of disposables and gaining popularity of Single-use Technology (SUT) for biopharmaceutical manufacturing there is nevertheless an ongoing controversial discussion on the advantages and disadvantages versus a conventional stainless steel environment.
In a “classical” facility design any validation cost effort can easily be distributed to a considerable number of production runs thus contributing only to a non-decisive amount to the overall production costs. The scale for such plant is nearly unlimited as is the scale of operation. The “flexible” approach using disposables and single-use equipment offers significant advantages regarding changeover work and time thus a high throughput of different processes will definitely take profit as any cleaning and related validation and costly analytics doesn’t apply to a larger extent.
Despite the potential benefits loudly advertised by the respective industry, these potential advantages derived from single-use equipment and disposables can be significantly diminished by lack of detailed process cost analysis, missing economic analysis and cost comparison between conventional and SU technologies as well as underestimating the cost of long term dependency on consumables. Due to missing appropriate standards, there is a widely non-compatibility between the equipment and consumables of the various suppliers, resulting in a strong dependence on the consumables of a single supplier once a single-use equipment has been purchased, curiously leaving some customers with surprise that they hardly have any room for price negotiations on the required consumables.
This paper’s focus is on the very different arguments for the application of SU equipment and consumables, including advantages and limitations of SUT, understanding improvement of process robustness, contribution to lean production as well as environmental impact of disposables.
Common mammalian cell lines used for biopharmaceutical production include Chinese Hamster Ovary (CHO), NS0 and Human Embryonic Kidney (HEK) cells. Each of these cell lines has been found with over 20,000 genes coded in their genome, which can result in over 10,000 proteins expressed at the same time in these cells. These proteins can be secreted from the living host cells or released to the cell culture supernatant upon lysis of the host cells during the cell culture. Biopharmaceuticals produced using these cell lines can be co-purified with a subset of the host-cell proteins (HCPs) in the cell culture supernatant.
These co-purified HCPs are considered process-related impurities for biopharmaceuticals. The HCPs can cause potential safety risks by introducing anti-HCP response in the patients. Depending on the biological functions of the residual HCPs, other potential impacts reported include lowering the biopharmaceutical protein stability and affecting the efficacy of the biopharmaceutical protein by exacerbating the symptoms.
Daniel O. Blackwood & Jeffrey Moriarty of Pfizer, Inc.
Following a decade (or more) of concerted effort by industry, regulator, and academic groups, recent technology investments are now beginning to shape how medicines are being developed and manufactured for the global marketplace. While significant focus has highlighted the emergence of continuous manufacturing processes, three additional trends have also influenced and served as underlying drivers for these technology investments. First, the emergence of scientific advances in targeted biology has created high-value personalized medicines with smaller manufacturing volumes (doses/annum). Second, new regulatory pathways, such as the FDA’s Breakthrough Therapy designation, have accelerated the development and commercialization timelines for these new medicines. Finally, manufacturing localization has extended supply chain networks to serve globally-distributed patient populations throughout the world. Together, these drivers have served to shape the future of pharmaceutical development, manufacturing, and distribution of a variety of different dosage forms. The increasing need for product development speed and commercial supply flexibility through small-footprint, modular equipment trains will be highlighted within this paper, using an immediate-release solid oral dosage form example.
ADCs are complex compounds resulting from the coupling of cytotoxic small molecules to a monoclonal antibody. Their characterization as well as their bioanalysis (quantification in biological fluids) remains challenging. Mass spectrometry at different levels (intact, middle, peptide) can be a valuable tool, and can now be used in a regulated environment thanks to advances in both hardware and software.
Historically, quality of biological products has been ensured through testing representative samples. Shift in quality paradigm started with implementation of Good Manufacturing Practice (GMP) regulations with current focus on building quality during manufacture. Inherent variability and complexity of biological products pose challenges in implementing Quality by design (QbD) concept. This presentation discusses ways to build quality during manufacture of biological products.
The importance and value of continuous bioprocessing, both upstream and downstream has economic and sustainability advantages and due to the modular nature of continuous bioprocesses means that industry is able to adapt more rapidly to changing market demands. Continuous biopharmaceutical manufacturing in the context of other industries that have already successfully adopted continuous processing. Factor other than scientific ones, are the barriers to change from batch to continuous production. an excellent example of the manufacturing strategies of the steel industry in the 20th century, when this industrial sector incrementally switched from batch to continuous operations. biopharmaceutical industry has reached a stage that requires a change in the production paradigm. For a certain class of biopharmaceutical products upstream continuous manufacturing has always been applied: for example, unstable proteins that rapidly degrade in the culture broth. In order to obtain a high quality product, the residence time in the reactor must be minimized. This can only be achieved with continuous cultivation and preferably with perfusion reactors. a brief overview on the types of cell retention devices currently used in biopharmaceutical industry.
Furthermore, this is a universal production platform that can be extended to other classes of products, such as antibodies, which are relatively stable molecules. continuous manufacturing is as productive and with a much smaller footprint of the manufacturing plant, avoiding multiple non-value added unit operations. In essence, the investment for a continuous plant is much smaller compared to a batch-operated one.
Single-Use Process Analytical Technologies (PAT) tools have a great potential to not only increase process understanding at the seed stage but also simplify cell culture operations. By utilizing PAT, the risk from bioburden or contamination can be significantly reduced and the overall operating efficiency increased. In fact, PAT also provides a data-driven platform to integrate Process Development and Manufacturing Operations that can mitigate risks associated with technology/process transfer.
New vaccine process designs – and all the kinks that go with them – are typically hammered out in a small scale capacity, for example, prior to manufacturing for early phase human clinical trials. They are then upsized and further defined for industrial scale to supply the vast market. Single-use technologies (SUTs) have been a hot topic for several years now and their advantages well-known: easy product changeover, processing in lower classification areas, reduced CAPEX, elimination of glass, sterility assurance, to name a few. In vaccine manufacturing, SUTs are used throughout the processing stages, from cell culture all the way to filling. SUTs are quickly and conveniently designed, purchased and implemented for short-term manufacturing of clinical trial phase materials. Here a large percentage of new vaccines in Research and Development do not even make it to market.
As the final production stages are critical as they are the last stages before patient injection, the scope of thisarticle covers SU applications involving drug substance formulations, adjuvant processing, final bulk formulation and filling. The actual process itself may include some or all of the following: filtration, pumping, ingredient addition, mixing, adsorption, filling, labelling, sampling and and storage.
In this presentation only liquid formulations (“presentations”) will be discussed.
Gloria Gadea-Lopez, John Maguire, Mark Maselli & Ken Clapp
The increased interest and adoption of single use systems (SUS) or disposables require that organizations rethink their operational business processes and the design and configuration of manufacturing execution systems (MES). Drawing from their previous experience implementing MES and SUS for biologics manufacturing, the authors discuss the key areas of impact of SUS on operational technology, outline new user requirements, and propose practical solutions for successful MES implementation.
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