Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

In this episode of the Drug Solutions podcast, Felicity Thomas, European/Senior Editor, talks to David Tisi, technical director at Senopsys LLC, and Reenal Gandhi, global business development director for the Prescription Division of 

. In the first segment of the episode, David chats about some of the key challenges impacting oral dosage forms and the approaches and solutions available that are helping developers overcome these hurdles. After, Reenal details the intricacies of intranasal drug dosage forms, such as the convenience and the growth of this route of administration, challenges of development, and the possibilities of repositioning drug products.

David Tisi, technical director at Senopsys LLC

David is founding member of the scientific team at Senopsys LLC, a specialty services firm dedicated to the development of palatable drug products. He has over 15 years of experience in taste assessment and taste masking novel drug formulations for children and adults, leveraging his background in sensory science and food chemistry. David received his Masters in Food Science from Cornell University and began his career in product innovation at PepsiCo and Nestle.

Reenal Gandhi, global business development director for the Prescription Division of 

Reenal has more than 15 years’ experience within the drug delivery and pharmaceutical industries, involved in the development and commercialization of wide-ranging drug delivery solutions. Over the course of her career, Reenal has actively worked on business development related to nasal and injectable devices, such as prefilled syringes and autoinjectors. Since December 2020, Reenal has been working for Aptar Pharma, driving the assessment of new opportunities and focusing on new technologies in particular.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

Podcasts

In this episode, David Tisi and Reenal Gandhi provide expert insights into advances and innovations changing the drug dosage form landscape.

Drug Solutions Podcast: Innovations and Advances in Drug Dosage Forms

In this episode of the Drug Solutions podcast, Felicity Thomas, European/Senior Editor, chats with Sergey Vlasenko, associate vice-president, Pharma/Biopharma, Agilent, about trends impacting bio/pharmaceutical manufacturing. Sergey provides an overview of some of the key trends and then focuses on a novel modality—oligonucleotides—highlighting the specific challenges related to the manufacture of these exciting therapeutics.

Sergey Vlasenko, associate vice-president, Pharma/Biopharma, Agilent

Vlasenko joined Agilent in 2018 through its acquisition of the privately owned company ProZyme, a developer and manufacturer of glycan reagents, kits, and standards, required for biotherapeutic protein characterization. Prior to ProZyme, Vlasenko managed the R&D and marketing teams developing and commercializing innovative products for the Pharma and Biopharma industry.

In this episode, Sergey Vlasenko from Agilent chats about bio/pharmaceutical manufacturing trends, with a particular focus on oligonucleotides.

Drug Solutions Podcast: Unlocking the Latest Manufacturing Trends

Meletios Therapeutics, a French biotech company focused on the R&D of next-generation antiviral treatments, has been awarded with funding worth €1.2 million (US$1.3 million) from Bpifrance’s Deeptech development program to aid in its work.

According to a June 29, 2023 press release, the monies granted to Meletios Therapeutics will be used to validate the company’s Defective Viral Genome (DVG) platform and to develop the first candidates from this platform until they are suitable for entry into clinical phases. It was this technology that was deemed to meet the criteria set out by Bpifrance to discern whether a company can be classified as Deeptech—one that is closely linked to the world of research and that proposes a disruptive innovation compared with existing technologies.

The DVG platform, which originated from the Pasteur Institute and has been developed by Meletios Therapeutics, generates, identifies, and uses DVGs—truncated copies of a virus that have lost their pathogenic properties. In February 2022, Meletios Therapeutics obtained authorization from the Pasteur Institute to extend the exclusive license for the platform, allowing Meletios Therapeutics to apply a highly specific method of generating new DVGs to the entire family of flaviviruses, alphaviruses, and coronaviruses.

“One of our main challenges in the development of this new generation of treatments was to develop a safe, effective, and, above all, rapid method for the identification and supply of DVGs in the context of viral epidemics. Viruses are indeed capable of spreading very quickly in the population, and this is all the truer in the case of new emerging viruses whose properties are not yet fully known. Therefore, there is a real challenge to develop and make available to clinicians a rapid and effective therapeutic response to these infections,” said Catherine Martre, CEO of Meletios Therapeutics, in the press release. “We are delighted to receive this funding, which demonstrates the scientific relevance of our technology and the confidence place in us by Bpifrance. With this new financial support and its disruptive technology platform, developed together with the Pasteur Institute, […] Meletios Therapeutics is now fully equipped to enter the next phases of the development of its lead drug candidates.”

Articles

Meletios Therapeutics has been awarded with funding worth €1.2 million (US$1.3 million) from Bpifrance’s Deeptech development program.

Meletios Therapeutics’ Efforts in Antiviral Field Gains Recognition from Bpifrance

Integrated research, development, and manufacturing services company, Syngene, has acquired a multi-modal facility in Bangalore, India, from Stelis Biopharma, it was announced in a July 4, 2023 press release. The acquisition provides Syngene with an extra 20,000 L of installed biologics drug substance manufacturing capacity.

Originally built to manufacture COVID-19 vaccines, the acquired facility will now be repurposed and revalidated for the manufacture of monoclonal antibodies by Syngene. Additionally, the site, which includes a commercial-scale, high speed, fill/finish unit, has the potential for future expansion of a further 20,000 L capacity.

“This acquisition strengthens our growing position as a leading biologics contract development and manufacturing service provider and adds drug substance capacity and a drug product capability years earlier than our internal capex program,” said Jonathan Hunt, managing director and CEO of Syngene, in the press release. “We see healthy demand for high-quality biologics manufacturing capacity from sectors ranging from large pharma to emerging biotech companies.”

The transaction for the facility cost INR 702 Crores ($86 million) and has been approved by both companies’ boards of directors. Closure of the transaction is expected within 90 days, as long as the customary conditions are met.

Syngene has acquired a multi-modal biologics drug substance manufacturing facility in Bangalore, India, from Stelis Biopharma.

Syngene Adds Biologics Drug Substance Manufacturing Capacity with Facility Acquisition

Parenteral drug delivery is a common and useful option for drug developers and manufacturers when dealing with substances that have poor bioavailability, low solubility, or a narrow therapeutic index. According to research, the proportion of parenterally administered drugs in the pipeline is rising, which is mostly attributed to the growth in biologics (1).

Any drug product that is to be introduced to the patient via a parenteral route must be sterile as the patient’s natural defense system is bypassed, so any contaminant can have a severely adverse impact on the patient’s health. However, terminal sterilization methods involving heat are not always applicable or suitable, as such methods can have a negative impact on the potency/purity of thermolabile drug products. In these instances, aseptic processes are employed.

“Aseptic manufacturing is needed for dosage routes that are more targeted than oral ingestion,” specifies Waiken Wong, manager, Product Development Engineering, Woodstock Sterile Solutions. “Those entry points are more vulnerable to microbial intrusion, so maintaining sterility of those drug products through aseptic manufacturing is critically important for patient safety.”

“Sterile products need to be manufactured with considerable robustness and assurance of sterility,” continues Tim Sandle, head of GxP compliance and sterility assurance at Bio Products Laboratory (BPL) in Elstree, United Kingdom. “With the types of sterile products, aseptic processing presents the highest risk area of pharmaceutical manufacturing because the drug product in the final container cannot be subjected to any additional sterilization treatment (as any additional processing would damage the product). This designation includes many complex drug products, including ophthalmic suspensions, sterile injectables, reconstituted lyophilized powders for injection, and aqueous-based aerosols for inhalation. Therefore, considerable attention needs to be paid to the design and control of the filling and dispensing process.”

There are multiple points at which contamination can infiltrate a drug product and, hence, put the drug product’s integrity at risk. The importance of aseptic formulation and manufacturing begins with sterile filtration, points out Sandle, in which companies must ensure the filtration controls are in place to protect the filter integrity and control the filtration process within its validated state. Then, careful sterilization of containers and the maintenance of a filling environment that meets relevant regulatory requirements is critical, he adds.

“The filling environment is at a particular risk from microbial contamination, and the product needs to be protected by barrier technology (ideally through an isolator subjected to a decontamination cycle) and by the maintenance of unidirectional airflow,” Sandle says. “Any incursion into the filling zone is a considerable risk, along with any activity that disturbs ‘first air’ (such as the use of gloveports on an isolator) and, therefore, these activities need to be understood and risk assessed.”

Additionally, there is a preference within industry to work with larger batch sizes, which can lead to certain sterility complications. “An important control element is time, and this can affect everything from the validation of sterile filtration to the length of the filling period, which will require qualifying through media fills. In designing media fills (or ‘aseptic simulations’), it is important that all worst-case conditions have been evaluated, including the different types of interventions and the frequency at which they are conducted,” Sandle states.

“Companies that have a well-developed infrastructure for formulation and manufacturing can easily scale operations to meet the needs of complex drug products and larger batch sizes,” remarks Wong.

Regulatory bodies have set out numerous guidance documents on the matter of aseptic processing, to help chaperone industry toward best practices. Recently, the European Union’s good manufacturing practice (GMP) Annex 1 guidance was revised to improve clarity and extend the scope of the products included within the guidelines (2).

“When addressing any changes to regulatory guidance, the first point must be to clearly understand the intent of the changes, and more specifically what has actually been changed,” emphasizes Andy Whittard, managing director, Cherwell. “This is where easy-to-use comparisons between old and new can be informative in focusing on those elements that could have the biggest impact to manufacturers’ processes and facilities.”

For Helen Sauter, director Quality Assurance, Vetter, to ensure compliance, pharmaceutical and biotech companies, along with contract development and manufacturing organizations (CDMOs), need to view the aseptic process as a collection of interdisciplinary tasks. “Enhanced process understanding is a key element of the revised Annex 1,” she says. “Therefore, risks must be well understood, and it is important to talk to all relevant subject matter experts about the requirements, any gaps, or needs prior to a successful implementation.”

Generally speaking, there are key challenges for pharma and biotech companies described in the revised Annex 1 guidance, Sauter continues. “A major requirement is the implementation of a contamination control strategy (CCS),” she states. “The Annex 1 document says to implement a CCS across the facility, which can pose a major obstacle for some companies. Although this requirement is not new, it is now more formal and detailed, leaving less room for interpretation and expecting all companies to have their CCS in place.”

The greater focus on a broader level of risk assessment and strategy is considered critical to the Annex 1 revisions by Whittard. “The establishment of a CCS that takes a holistic approach will be the foundation from which all decisions will be driven,” he specifies.

“Overall, it is beneficial to call for multiple viewpoints, such as insights from external conferences and authorities to navigate and best interpret the regulations,” confirms Sauter. “A variety of perspectives gives a more comprehensive evaluation of what the revised Annex 1 guidance requires.”

Sandle points out that the changes to Annex 1 were extensive. “One important aspect is with harnessing the best available technologies to exclude personnel from any direct interaction with the product,” he says. “Other important sections relate to sterilization methods, cleanroom classification and control, and cleaning and disinfection.”

As a result of the revised Annex 1 guidance, CDMOs are under greater pressure to increase their inspection compliance, notes Brian Korson, director of Finishing, Grand River Aseptic Manufacturing. “New inspection equipment and technology increases inspection capabilities and quality results, while decreasing time out of refrigeration, which is a big win for pharma manufacturing,” he adds. “It is imperative that CDMOs take the steps to have the right processes and equipment in place to supply patients with safe and effective products.”

“There are several technologies available for use in development and aseptic production,” explains Stefan Kuehnhold, director Pharmaceutical Production, Langenargen Site, Vetter. “These options include the classic isolator technology, which is a closed system, as well as the restricted access barrier system (RABS). Every system has its advantages, and it is up to each company to choose the right technology for its specific purpose.”

Deciding between RABS and isolators is the first choice, according to Sandle. “Here, RABS is the minimum standard; although, within the RABS paradigm, there are ‘closed’ and ‘open’ variants (with the ‘closed’ versions being superior as the risk of surrounding room air ingress is lowered),” he says.

“Isolators are superior because they provide a complete barrier, and they can be subject to biodecontamination through an automated disinfection process,” Sandle continues. “A complexity remains in that product contact parts need to be subjected to a separate sterilization process (including filling needles and stopper bowls).”

However, both RABS and isolators have a weakness with potential air leakage—a risk that is particularly high with the gloveport gauntlets, Sandle explains. “Systems that can be fully automated and do away with gauntlets entirely (that is robotic systems) are optimal,” he affirms.

Focusing on inspection technologies, Korson reveals that there are a variety of options available that can help to support increased compliance in aseptic manufacturing. “Fully automated inspection solutions use innovative inspection algorithms to ensure high particle detection rates, plus voltage leak detection to detect very small cracks,” he says. “This technology brings a unique opportunity for throughput of up to 400 vials per minute.”

“Innovations in pharma inspection systems are helping FDA-regulated timelines while achieving high standards of quality and maintaining product stability,” Korson asserts. “Companies should decide on the most appropriate technology solutions by evaluating the latest regulatory guidelines. Staying ahead of compliance will ensure your technology investments payoff for the future.”

Rapid real-time methods have been gaining interest for some time within pharma environmental monitoring, adds Whittard. “These viable particle counters can deliver continuous monitoring and potentially speed up release of product,” he says. Recently, Cherwell launched a rapid, viable detection system—MicronView BioAerosol Monitoring System (BAMS)—which allows for rapid, real-time, continuous monitoring of airborne microbes, supporting Annex 1 requirements, Whittard explains.

For Wong, blow-fill-seal (BFS) technology stands out as an excellent platform for aseptic products. “Containers are formed, filled, and sealed within a very compact sterile environment within the BFS machine itself. This eliminates the need to maintain entire rooms and suites under sterile conditions and reduces the container componentry to just the resin needed to make the units,” he says. “BFS containers are also customizable in shape and size, and more robust when it comes to handling and use.”

The difficult nature of aseptic needs within the pharmaceutical industry, and the evolving demands that are being placed upon companies and individuals working within the field mean that improvements in understanding of the process is imperative. Attending conferences and events on aseptic processes is beneficial to companies and individuals seeking to improve their understanding of aseptic needs, notes Whittard. “These [events] not only provide the opportunity to learn from talks and presentations, but to also share and discuss good practice with fellow delegates,” he asserts. “Engaging with companies and suppliers who specialize in the pharma space is also key.”

“When considering how companies can improve their understanding of aseptic needs, it is important to address both internal and external improvements,” adds Kuehnhold. So, while externally speaking, it is beneficial to attend conferences and events, learn from representatives of industry and authorities, and exchange with suppliers or customers on specific aspects of aseptic processes, it is also important to promote cross-functional communication internally.

“Integrating a holistic understanding of GMP within the workplace culture promotes a sense of motivation to consider and adhere to aseptic requirements for the sake of the patients at the other end of the line,” Kuehnhold emphasizes. “This [integration] is done through constant communication and well-established training programs to support employees’ gaining knowledge.”

“One department alone cannot cover all aspects in the complex aseptic environment,” confirms Sauter. “Only working within interdisciplinary teams provides processes that drive quality.”

It is imperative to assure compliance across every facet of the aseptic chain, from facility design to manufacturing controls and risk management, Wong stresses. “Maintaining a strong foundation of quality-driven practices allows companies to respond quickly and nimbly to evolving guidance,” he says.

“The aseptic filling process is continually being challenged, not least because the range and scope of products that need to be filled aseptically shows no sign of slowing down,” asserts Sandle. “Spending time investing in a robust training package is important, from upper management to operators, so they are aware of microbial concerns and good aseptic practices. Each member of staff should have a basic understanding of microbiology, hygiene, cleanrooms, contamination control, aseptic techniques, product protection, and patient safety.”

Kuehnhold emphasizes that the world of injectables is niche, meaning that not many pharma and biotech companies have the deep experience that they need to get their drug products to market successfully. “The more knowledge that can be gained on best practices, the better suited a company will be to advance,” he concludes.

1. Fact.MR. Parenteral Drug Market. Market Report, March 2022.
2. EC. Annex 1 Manufacture of Sterile Medicinal Products, 

Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.

When referring to this article, please cite it as Thomas, F. Gaining a Deeper Understanding of Aseptic Needs. 

To overcome the challenges of the widening range and scope of products that require aseptic processing and the evolving regulatory landscape in this field, companies should deepen their knowledge base on best practices.

Gaining a Deeper Understanding of Aseptic Needs

Since 2020 and the United Kingdom’s exit from the European Union, Britain has been locked out of the Horizon research programme, despite agreements being in place for associate membership, as arguments over the Northern Ireland protocol persisted. However, in March 2023, after the implementation of the Windsor framework, talks between the UK and EU about the association with the programme resumed, culminating in reports of a draft deal being reached on 5 July (1).

This draft deal is reportedly now under consideration by the UK’s Prime Minister, Rishi Sunak (1). Sunak is being urged to finalise the deal to ensure the scientific community in the UK can regain the advantages of the Horizon programme, such as funding and leading multi-country research consortia.

“Outside Horizon Europe, the UK is in real danger of ceding our hard-won position in the global R&D hierarchy and becoming less attractive as a research partner and less attractive for foreign direct investment,” stressed Andy Slaughter, member of parliament for Hammersmith in a parliamentary debate on the topic of Horizon Europe (2). “As part of Horizon Europe, the UK can influence the future direction of billions of pounds worth of research investment to more closely align with UK strategic priorities.”

Cost has been a factor delaying the draft deal. Although not required to pay participation fees for the two missed years, the UK government has requested further discounts due to the fact that researchers and businesses in the country have been weakened when compared with EU counterparts from missing out on collaborative opportunities. Additionally, the UK government have pushed back on the matter of how much research funding the country will receive in return for its input into the programme (3).

Officially, talks are still ongoing with no confirmed deal struck yet—at the time of writing—so, for now, a return to a closer scientific research relationship between the UK and the EU remains just out of reach on the horizon.

1. Gallardo, C. Britain and EU Agree Draft Horizon Deal. 

, 5 July 2023.
2. UK Parliament. Research and Development Funding and Horizon Europe. Parliamentary Debate, 18 April 2023.
3. Ghosh, P. Horizon Research Deal with EU Awaits Sunak’s Signature. 

When referring to this article, please cite it as Thomas, F. The Swiss Appeal. 

The UK and EU have negotiated a new draft deal for Britain to re-join the Horizon Europe research programme.