Room B Seminars

Counterfeiting pharmaceuticals can be a highly lucrative business as a fraudulent manufacturer avoids the costs of product development, commercialisation and rigor of regulatory conformance. At best, such criminal activity robs the legitimate pharmaceutical of hard earned revenue. Such activity is, however, highly dangerous as products with no proven efficacy or therapeutic effect, which may or may not contain an active may be supplied to vulnerable patients. Without regulatory oversight, fake pharmaceutical products may comprise toxic and/or degraded actives, excipients and auxiliaries as well as contaminants. According to the WHO, falsified medicines have caused fatalities, life changing disabilities, undermined vaccination programs, and contributed to antimicrobial resistance. If not curtailed counterfeiting will undermine confidence in the healthcare industry as a whole.

This presentation will highlight the key collaboration required between the pharmaceutical manufacturer and an expert pharmaceutical forensic partner to investigate these fraudulent products whilst demonstrating not only how counterfeited products can be identified but also how to potentially pinpoint their source or develop anti-counterfeiting measures.

Throughout the manufacturing process of a pharmaceutical product or medical device, there are any number of opportunities for microbial contamination to occur due to environmental factors, operator error, or sterility failures among others. Manufacturers therefore must rely on robust process validation and environmental monitoring to reduce the risk of contamination and identify when it does occur.

Traditional identification techniques have utilised time consuming and labour intensive methods such as selective medium subculturing, Gram staining, biochemical testing or morphological identification. Recently, however, rapid methods have been developed which have the ability to reduce turnaround time and provide greater testing accuracy.

Despite the issues inherent in adoption of new methods, rapid methods are an expanding area of microbiology and are now considered viable alternatives to more traditional methods. This seminar will focus on the validation of one rapid method in particular, MALDI-ToF (Matrix Assisted Laser Desorption Ionization-Time of Flight), which utilises mass spectrometry to identify microorganisms by measuring their unique protein fingerprints.

This presentation will compare the standards and systems in use in Europe with those in the USA.

Extractable and Leachables studies will show an ever expanding number of organic and inorganic species migrating from the pharmaceutical packaging. In all the potential techniques used to provide either an extractables or leachables profile, the question that need to be addressed in the limit one must investigate to measure and understand the risk the packaging poses on the pharmaceutical product.  Applying an appropriate safety concern threshold and calculating an analytical evaluation threshold is vital in producing a scientifically robust study. It is therefore important to understand what safety concern threshold should be used, how best to calculate the analytical evaluation threshold and what other factors should be taken into consideration.

The current (2008) version of Annex 1 of the EU GMPs consists of 127 paragraphs spread over 16 pages. The draft of the new Annex 1 has been published by the European Commission and it is open to consultation up to 30 March 2018. With exactly 50 pages the new document has more than doubled. In this presentation I will give an overview of additional requirements, as well as changes to existing requirements.

Both the USP and EP implemented changes to the requirements for elemental impurities testing during the winter of 2017/2018. The changes were implemented based on the publication of ICH Q3D regulations in December 2014.

These changes have now been in place for around 100 days so are still in the early stages of being part of the regulations, but this major change has still had a significant impact on the nature of pharmacopeial testing.

The removal of the use of the wet chemistry heavy metals test, to be replaced by specific elemental testing has been the most significant change to the pharmacopeias. Elemental testing that was historically included in monographs has, for the time being, been retained. Compliance with the regulations can seem a burdensome, but through a risk assessment process this burden can potentially be reduced.

In this presentation, a brief background of these regulations will be discussed, along with the impact of the changes on the nature of control of elemental impurities within the pharmacopeias and how this new approach is starting to become incorporated into pharmaceutical control as well as covering some examples of elemental testing that has been retained within the monographs.

The utility of mini-tablet dosage forms for paediatric administration is becoming more commonplace. However, the manufacture of these dosage forms is not without its challenges and this presentation explores some of the solutions and strategies put in place to address these issues. Furthermore, a range of finished dosage form presentations are discussed and case studies on clinical supply formulations and commercial product are used to illustrate the performance and opportunities for these types of dosage forms.

How do world class firms set the culture, communication strategy and management style to ensure GMP is followed even when Supervisors are not watching? How can we use studies of human behaviour to reduce the risk of error, non-compliance and poor decision making? How can we simplify the whole process of GMP compliance.

GSK Vaccines Global Regulatory Affairs executes over 1000 submissions each year with a team of more than 400 experts. Obtaining and providing end-to-end demand visibility is more than ever a critical success factor for on time delivery and optimal use of critical resources.
In this case study we will share an innovative approach based on the Binocs Cloud platform for resource planning (discover-binocs.com). We’ll shortly demonstrate the platform, discuss our implementation approach and share our KPI improvements.

Given the growth of the Biopharma sector and the number of Biosimilars making it to market one aspect of these products that still causes concerns is the risk of protein immunogenicity. There are several factors that play a role in immunogenicity, a key factor is the presence of aggregates, which when found in products can increase the risk of an immune response. Aggregates can be formed under a number of conditions and at various stages of the production, shipment or during delivery to the patient. Therefore, understanding and characterizing these macromolecules is an important aspect of bioanalytical analysis and patient safety.

This presentation will aim to provide a "how-to-guide" to aid your macromolecule characterisation efforts, and illustrate why it is critical to have a good understanding of the techniques when interpreting the results.

The inherently complex nature of a globular proteins mean that an overreliance on in silico modelling is a highly risky, yet surprisingly common, approach to take during early formulation development activities. Light scattering is highly sensitive to changes in the apparent size of a molecule; making it ideally placed for proteins and other macromolecule analysis. Experiments can be designed in such a way that allow for the development of robust formulations that are resistant to common causes of batch failure; such as agglomeration and sensitivity to temperature changes.

Set up in 1976, INTEROR is a privately owned company producing fine chemicals in France for pharmaceutical industries, offering Starting Materials and GMP intermediates.

INTEROR assists its customers from early stage projects to industrial scaling-up thanks to its efficient R&D, QC, QA Teams.

We combine our long-standing experience in chemistry with expertise in a number of core technologies and propose multi-step synthesis, custom synthesis, toll manufacturing.

We daily perform:

• Low to high-pressure catalytic hydrogenations,
• Chemical reductions (with LAH, NaBH4, …),
• Grignard reactions (in large scale from in-house made of Grignard reactants and with recycling of THF) ,
• Bromination with liquid bromine, through diazotation and Sand-Meyer reactions, with HBr, with NBS,
• Chlorination in large scale with chlorinating agents (SOCl2, POCl3, PCl3) ,
• Chiral separation,
• Boc, Cbz protections … in stainless steel and/or glass-lined reactors from 1500L to 8000L.

Catalog products are Piperidines, Piperidones, Piperidinols, Piperidinamines, Quinuclidines, Chloroalkylamines,… Brominated compounds and its derivatives for pharmaceutical industry.

The plant is inspected by FDA, ANSM, is classified “SEVESO 3 high threshold” with authorizations to handle hazardous substances.

Total capacity is 160m3 reactors with 136 employees. Turnover is 25-30 M€.

INTEROR is a member of the Responsible Care, is awarded the silver medal by ECOVADIS.

INTEROR offers reactivity and flexibility along with efficiency, ethic, confidentiality.

Topics:

Risk Management, GMP, Pharmaceutical Safety

Abstract:

Pyrogens are any group of substances that cause a rise in temperature in an animal or human; these substances can induce shock, fever or death. Due to the effect pyrogens can have on the body, testing for them is compulsory within the pharmaceutical industry to avoid their potential life-threatening effects.

Inadequate testing places patients at risk, therefore understanding the benefits and limitations of available test methods is a critical part of all pharmaceutical product development and manufacturing.

There are currently three approved methods for the testing of pyrogenicity; the rabbit pyrogen test (RPT), the bacterial endotoxin test (BET) and the monocyte activation test (MAT). The most common type of pyrogen are endotoxins, which can be specifically tested for using BET. There are multiple method options to be used depending on the type of product in question.

Determining which method is best suited to your pharmaceutical product can be complicated and is dependent on a number of factors including composition, presentation, and potential market.

Despite the limitations of some of the existing test methods and issues that may arise during the validation stage of this process, pyrogen testing is crucial to ensuring pharmaceutical product quality and patient safety and its importance as a quality control tool should never be overlooked.

Learning Points:

Importance of in vitro safety testing methods

Overview of pyrogen detection methods

Benefits and limitations of each method

The current sophisticated technologies provide powerful new approaches for identification and quantification of E&L compounds. A brief review of the capabilities of a conventional analytical laboratory will be discussed here, a challenging “case of study” concerning  the primary packaging of an ophthalmic solution being presented. While the pivotal role of pharmaceutical packaging to guarantee product integrity is perfectly understandable, nowadays accomplishment of marketing needs or regulatory requirements  is becoming more and more complex. This makes the E&L study more difficult  due to the numerosity of possible sources and the substantial differences in the chemical nature of the potential contaminants. In fact, not only plastics and elastomeric materials can be contaminants but also inks, adhesives, secondary packaging could be sources of extractables and leachables. Given the potential toxicological risk of these compounds, their identification and quantitative evaluation is crucial to minimize patient safety concerns about exposure to E&L. Often, only a combination of different analytical techniques, including LC-DAD, LC-HRMS (Orbitrap or QTOF), GC-MS or GC-HRMS (Orbitrap or QTOF) can lead to the identification of unknown organic contaminants thus avoiding expensive and long toxicological evaluations. The final confirmation that the identification is correct could come from a “preparative” LC approach finalized to isolate analytes for NMR investigation. This presentation describes the application of all these procedures for the identification of a substance present in a commercial ophthalmic solution. The complementarity of the mentioned techniques allowed to identify the unknown contaminant as 2-hydroxy-2-methylpropiophenone, an analyte present in adhesive labels.

Informazione del mercato

A Workshop Presented by Chemistry Today -TKS Publisher

Traditional manufacturing methods for pharmaceuticals utilizing standard batch-type reactors are currently being challenged globally by more innovative and enabling concepts involving continuous flow processing. This is motivated by the potential of this technology to improve control over quality, reduce costs, enhance sustainability and significantly reduce the timelines currently involved across the drug manufacturing supply chain. Although still at an early stage of development and implementation, continuous chemical processing is seen as key enabling technology for the future of the pharmaceutical manufacturing sector and is therefore strongly supported by regulatory bodies. Case studies will be presented to support the importance of this technology.

Organic synthesis has traditionally been performed in batch that means in round-bottomed flasks, test tubes or closed vessels; however, continuous flow processes have gained lately much attention from synthetic organic chemists. Application of these systems for the preparation of fine chemicals, such as natural products or active pharmaceutical ingredients (APIs) is becoming very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semi-batch reactors, it is evident that interest is arising towards continuous flow manufacturing of APIs.

Recently, the safe manufacturing of organic intermediates and APIs under continuous flow conditions has been deeply examined in different reviews, where some positive features have been highlighted; for example, some synthetic steps that were not permitted for safety reasons (e.g. use of potentially toxic or explosive intermediates, reactions run under high pressures or above the boiling point of the solvent) could be performed under flow conditions with minimum risk. For these reasons, flow chemistry can be seen as a novel technology that opens the way for new synthetic routes of valuable molecules.

Aim of the presentation will be to highlight very recent advances concerning the continuous flow multistep synthesis of organic molecules, which found application as APIs. Without claiming to be complete, a general overview of different approaches, technologies and synthetic strategies will be given, hoping to contribute to a gap-closure between academic research and pharmaceutical manufacturing.

Our purpose is to illustrate some of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the stereoselective synthesis of chiral drugs.

Lead discovery relies on the design and synthesis of new bioactive compounds that have the potential to become efficacious drugs. The process consists in the iterative generation of structure−ac=vity and structure-property relationship data resulting from the evaluation of hit analogues designed to improve potency, selectivity, in vivo efficacy and safety. Using traditional approaches, a significant time delay may occur from compound design to results, leading to slow and expensive hit-to-lead explorations. While the advent of computational tools and high-throughput screening has enabled the design, testing, and analysis of large number of compounds, the synthesis of compound collections is not as efficient and often represents an ongoing bottleneck in the process of drug discovery. In this context, flow chemistry and automation are considered valuable tools to solve limitations of chemical synthesis in terms of compound throughput, quality and scalability, and have shown great potential in uncovering and developing novel leads and drug candidates. In this communication, we report case studies where the use of automated flow-based systems was extremely helpful to expedite lead discovery and optimization. In particular, flow synthesizers, automation, process analytical technologies, and computational chemistry were integrated in a prototype system that contributes to the shortening of medicinal chemistry discovery cycles and to the process optimization of lead candidates and important biomarkers for druggable targets.

Corning Incorporated is the world leader in specialty glass and ceramics. Drawing on more than 160 years of materials science and process engineering knowledge, Corning creates and makes keystone components that enable high-technology systems for consumer electronics, mobile emissions control, telecommunications and life sciences.

In last 18 years, Corning has brought to the chemical process industry with a powerful process intensification platform: Corning® Advanced-Flow™ Reactor (AFR) and their application technologies, which cover from “fast” lab-scale flow process development to “seamless” scale-up of flow process to commercial production.

Transferring chemical synthesis from traditional batch technology to continuous flow bring significant advantages in the reduction of cost, and in the management of safety that are usually associated with process scale-up. In the pharmaceuticals and fine and specialty chemicals industries products quality and requirement become today crucial parameters. With traditional batch technology, it is often not possible to maintain optimum product quality when scaling up a process in a short period of time. However, seamless scale-up can be achieved via straight-forward methodology due to the consistent performance of Corning AFR: 1000x improvement in heat transfer, 10-100x enhancements in multiphase mixing, x/1000 reduction in chemical holdup comparing with conventional stirred batch reactors.

Scaling up processes using Corning AFRs is faster than with traditional batch process and the time to market is drastically reduced. In addition, this technology reduces development and production costs.

Corning® Advanced-Flow™ Reactors have been successfully applied in a variety of flow-chemistry process developments. This talk will present the product and several cases of applications that have been seamless transferred from lab scale directly to industrial productions and the benefit for the pharmaceutical process.

In modern world, supply chain management is crucial to guarantee a stable supply of APIs into the market. India first and now China were markets of choice to source intermediates and starting materials which have high volumes and low prices.

With the increased need of compliance from both quality and EHS (from Clients, Health Authorities as well as Governments), what was easy to produce and sell a very low cost is now becoming difficult to achieve. On the other hands, insourcing these basic molecules are often not productive nor economically convenient with big impact on product costs and plant flexibility.

Approaches that would include minimal investments and impact on capacity, same quality with minimal if none regulatory changes and, last but not least, cost containment are key for succeeding in a supply chain risk management solution, even if combining all of these benefits could be seen as impossible.

Flow chemistry could fit perfectly this approach and Angelini Fine Chemicals has taken big effort to step into this with a cGMP advanced intermediate. After an initial R&D approach, easy scalability at industrial plant with minimal investment, it has been possible to insource 100% of production volumes (instead of 40% as classical batch reactions), with negligible impact from Regulatory point of view and improvement into quality and cost associated. A full business case will be described in our presentation.

Flamma is developing a pilot-process for the preparation of an API’s intermediate using a continuous technology.

The continuous process involves a pyrolysis step using high temperatures in the absence of oxygen, in particular it is a pyrolytic syn elimination reaction, which proceeds through a six membered transition state.

The realization of the continuous plant has been developed in-house and consists of a tube-reactor inserted in an oven. The reaction occurs in gas phase. The starting material is continuously loaded as pure material, carried over the tube by nitrogen flow being volatilized and converted due to the high temperature.

The optimization of continuous process is underway and involves both the chemistry and the equipment. The targets are to improve conversion and quality, assuring the reproducibility of the performance and maximizing the productivity, in view of the future industrialization of the process for a production of an API.

Gli approcci della tossicologica regolatoria sono fondamentali per alcuni aspetti riguardanti la qualità degli API. Sempre più cruciale è studiare attraverso i criteri della tossicologia tradizionale, nonché utilizzando gli approcci più moderni di predizione “in silico”, il tema dell’esposizione accidentale del paziente a sostanze presenti non intenzionalmente (PDE, E&L, impurezze) e, in altra ottica, l’esposizione professionale durante i processi produttivi (OEL/OEB).