IMPROVED FILL-AND-FINISH PROCESSES REDUCE THE TOTAL COST OF OWNERSHIP

Pharmaceutical companies are continuously assessing the productiveness of their filling lines to achieve higher yields with less resources, thereby ensuring high quality standards and maintaining flexibility in the fill-and-finish process. Lower cost, better quality and higher flexibility might appear to be contradictory goals.

This article focuses on possible fill-and-finish solutions based on an increased usage of pre-washed and pre-sterilised drug containers compared with traditional filling concepts that work with purchasing non-sterile, so-called ‘bulk’ containers from primary packaging suppliers.

The challenges facing pharmaceutical companies today require a fundamental rethinking of manufacturing processes. Pharma companies are increasingly outsourcing value chain steps to simplify their manufacturing processes and streamline their production footprint by forming mutually beneficial strategic partnerships with CDMOs. Multi-sourcing is becoming the new normal for key products, not only to reduce the risk of supply-chain interruptions, but also because collaboration spreads the costs and risks of developing and producing new treatments.

There are three main challenges affecting drug manufacturing and filling operations. First, reducing value chain complexity by outsourcing production steps allows pharma companies to focus on their core business. Second, detecting and eliminating areas of risk along the value chain ensures patient safety. And third, speeding up time to market maximises patent lifetimes.

When deciding on a filling strategy, all costs must be factored in and carefully balanced against each other. Profitability is best assessed by looking at the total costs of ownership, including all incurring and recurring costs, across the whole project lifetime. Deciding on a fill-andfinish concept that needs to be economical for several yearsor even decades - is becoming more challenging with new container options entering the market and the increased need for flexibility.

For fill-and-finish operations in the pharmaceutical industry, the total costs of ownership (TCO) can be calculated for RTU containers in different scenarios to help pharmaceutical companies choose the right packaging configuration for their business case. Taking into account capital expenditure and operational costs, the TCO must also incorporate a number of other important factors, such as the geographical location of the factory, the duration of the project, the types of different containers to be filled, the equipment to be used, the shift pattern and whether it will be small batch or campaign production.

There are several ways in which RTU packaging can reduce TCO, including more flexible operation, faster time to market and lower costs of non-quality (CONQ). As a supplier of pharmaceutical drug containment and delivery solutions, SCHOTT Pharma’s extensive industry knowhow can help pharma manufacturers get a clear picture of which machine and container combination enables a feasible operation throughout the project lifetime, and thereby reach a sound business decision.

In the value stream for bulk pharmaceutical containers, glass containers are produced and transported to the pharmaceutical manufacturing facility, where they are fed into the filling line, washed, dried and depyrogenated, to provide a safe and sterile container for the fill-and-finish process. This translates into a significantly higher initial capital investment when installing the filling lines and a greater cleanroom footprint requirement.

With RTU systems, the value stream is forward integrated. The glass containers are washed, dried and depyrogenated, before being nested and sterilised and supplied to the pharma facility ready to feed directly into the fill-and-finish operation. Besides the smaller area of cleanroom space required, there is no need for a washing station, a depyrogenation oven, a range of filling and capping machinery, transport belts or format parts.

A key feature, e.g. as builtinto the SCHOTT iQ platform, is the compatibility of different RTU container types with a wide range of new and existing filling equipment. The different container formats can be filled on a single line, minimising capital investment, reducing complexity and greatly increasing flexibility. The ability to switch easily between different vial formats and types is especially relevant for sequential small batch production, while for large scale production it allows the manufacturer to choose the optimum combination of vial, secondary packaging and filling line to suit the product and processes.

But capital expenditure savings are only part of the story. Although filling traditional containers is associated with lower expenses for primary packaging, RTU filling offers advantages when it comes to recurring operational expenses. Using an RTU system means there are no direct costs for washing and sterilisation, greatly reducing the inputs, such as the energy required for depyrogenation and the need for a WFI loop. The higher degree of automation of RTU fillings lines also requires fewer personnel, thus also reducing labour costs.

IMPROVED FILL-AND-FINISH PROCESSES ENSURE PATIENT SAFETY

The cost of non-quality is another factor that needs to be considered. Switching to an RTU system reduces the amount of glass-to-glass contact to which the containers are subjected during fill-andfinish operations. In traditional filling operations using bulk containers, vial transport in the depyrogenation tunnel or on turning plates causes the containers to bump into and rub up against each other, resulting in a deterioration in the cosmetic quality of the glass.

As RTU vials are nested in a tub, they can be processed without glass-to-glass contact, without any deterioration in their cosmetic quality. This not only minimises rejects arising from cosmetic defects but also significantly reduces the generation of particles and cuts the risk of breakages on the filling line.

IMPROVED FILL-AND-FINISH PROCESSES REDUCE TIME TO MARKET

Switching from bulk to RTU containers can also significantly speed up the time to market for new products thanks to the reduction in qualification and validation resources required. Traditional bulk container operations use bespoke packaging, which multiplies the qualification steps. But a standardised RTU platform, such as adaptiQ vials from SCHOTT Pharma, unifies the transfer steps to get the containers into the aseptic core (debagging, decontamination, delidding) and these need to be qualified only once. This allows the qualification effort to be refocused around the aseptic filling and closure steps. And with the adaptiQ documentation built into the DMF, less paperwork is needed for the FDA.

SCHOTT Pharma uses trusted partners to carry out efficient and highly standardised sterilisation procedures to the industry standard of EtO sterilisation. Sterilisation cycles are optimised to have minimal environmental impact, and residuals in the final RTU container are below detection limit and thus significantly lower than industry-wide accepted ISO standards.

As new drugs are commercialised, adopting RTU packaging based on fewer process steps requiring development and validation can contribute to easier scale-up and scaleout. Internationalisation of production can also be accelerated as tech transfer is made easier and expansion of the manufacturing footprint is more flexible. In cases where manufacturing is taking place in parallel across a number of facilities to supply local markets, installation of new filling lines can be accelerated, reducing the time to market.

Rather than custom designing a filling line around a specific drug prior to its launch, the pharma manufacturing company can install flexible filling capacity that can process different vial formats on the same line, allowing batch size variations to meet the changing market demand or manage a multiproduct portfolio.

This strategy can also simplify and derisk the supply chain by reducing reliance on a single large production line at one central location, while also facilitating partnerships with CMOs and CDMOs.

The SCHOTT iQ platform is available across the globe and can be used with more than 50 machine types from a broad range of global machine vendors. The online shop and stocks of Fast Track Kits for quick shipping can offer immediate supplies of small quantities direct to the customer’s door, enabling pharma companies to focus on developing best-in-class drugs and worry less about packaging components.

The key to leveraging the advantages of RTU packaging is standardisation. The customer receives high-quality, washed and sterilised containers in an industry-standard 3-inch tub, allowing them to reduce the complexity of the fill-and-finish operation and ensure that each filling line functions at optimum overall equipment effectiveness (OEE) by maximising uptime and minimising changeover times.

The adaptiQ RTU vial platform from SCHOTT Pharma enables flexibility while simplifying and speeding up processes, and thus saving costs. Implementation, validation, and ramp-up of new filling lines can be carried out in shorter time scales while enhancing the quality of the containers. When choosing the primary packaging and the corresponding fill-and-finish concept, medical safety and economic viability must be considered in parallel, and the benefits arising from wellthought decisions cannot be overstated.

MATTHEW LOWRIE, QUALITY ASSURANCE MANAGER, ALMAC CLINICAL TECHNOLOGIES, EXPLORES HOW THE EVOLVING REGULATORY GUIDANCE AROUND DATA INTEGRITY IS IMPACTING CLINICAL TRIAL APPLICATIONS AND DATA.

EU Regulation 536/2014 came into effect for new trials in January 2023, impacting supply management practices for clinical trials conducted in the EU, replacing Directive 2001/20/EC. With an aim to simplify trials and enforce consistent rules throughout Europe, these changes have a definitive impact on clinical trial planning activities.

The regulation enhances patient protections and adds increased requirements for trial oversight and data integrity. Some examples are heightened GMP standards for investigational medicines, stricter oversight of auxiliary medicines, and consistent expectations for safety reporting.

There are significant changes that require attention and consideration in how you are using, and will use, established systems for supply chain management, which is the focus of this article.

A key change raising much concern is the restrictive labelling requirements inclusive of investigational and auxiliary medicinal products, laid out in Annex 6 of the regulation. One being the expectation that the expiry date must be printed on all primary and secondary container labels. The revision allows the expiry date to be omitted from the immediate container only when the immediate container will remain with the outer container, or when the immediate container is small and has limited space for label text. In both cases, the immediate container must be provided with an outer container that has the expiry date printed on the label.

Annex VI also allows for the information on the label to be managed through alternative means, such as a central IXRS system, however some particulars cannot be omitted from labels. It never allows for the expiry date to be omitted from the outer container label. Allowances to exclude the expiry date from the immediate container label of IMP or Auxiliary MP are aligned with the specific circumstances detailed above.

This revision will make management of expiry updates significantly easier – whenever the immediate container is packaged and supplied with a labelled outer container, it will likely be possible for the sponsor to justify the omission of the expiry date from the immediate container. However, this has the potential to make expiry updates more complex because if there is outer packaging, it will need to be opened to expiry update the label on the immediate packaging.

Another requirement details that tracing, storage, return, accountability and destruction arrangements must be in place and detailed in the clinical trial application. Destructions and returns haven’t historically been an area of focus during the trial set-up phase but will now be required to be established and described upfront. What this means is you need a system or process that can address these arrangements while also maintaining the integrity and chain of custody. Your eClinical systems can be utilised to link and manage electronically these actions, often with greater accuracy and efficiency than performing the tasks manually on paper.

It is very common that IXRS includes features that facilitate and automate the accountability, reconciliation, returns and destruction processes. The benefit of including this functionality in the IRT is that the data already known about the medicinal products can be used to fuel these subsequent steps of the process. This streamlines the process, reducing data entry activities, helping to avoid mistakes, and reducing overall efforts. The technology also provides reporting and alert mechanisms to ensure the trial is on track, avoiding any end-ofstudy push to catch up on tasks and data reconciliation that should be done throughout.

Another important aspect, which should not be minimised, is the overall traceability of

Labeling (Annex VI) GMP Requirements Trail Conduct CT Application Process

• Specific requirements for all EU Coutries

• Expiry date must be printed on all primary containers

• Auxiliary Medicinal product laneling requirements

• Specific GMP Regulation and new Detailed Guidelines for IMP (replaces Annex 13)

• Emphasis on GMP of IMP

• Return / accountability and destruction arrangements- at start

• Stricter control of Auxiliary Medicies (formerly NIMPs) the supply. IXRS is commonly managing the trial supply activities electronically: drug release, supply transfers and shipments, patient assignments, accountability and returns/ destruction, amongst others. Being able to track activities, but just as critical as the view of the data. Data must be presented in a way that allows easy review at both summary and detailed levels providing endto-end traceability. This enables oversight of the data, providing assurances to the viewer that processes are occurring as expected. This is key to the prevention of large reconciliation efforts at the end of the trial and questions around why the data is being updated sometimes years after its initial entry. An electronic chain of custody solution that incorporates all IP events in a single system is the best way to comply thoroughly with GCPs and GMPs and to gain maximum efficiencies in the accountability process.

In line with these regulations, data integrity guidance from MHRA, FDA and EMA is evolving

• Emphasis on safety reporting and building

• Incorporation of GDPR into CT Regulation

• 25 year retentionn of Trial Matser File

Single application and single approval

• Substantial modification process around sponsors’ responsibilities with respect to trial data oversight. As stated in ICH E6(R2), inspectors expect to see documented evidence on how the sponsor performed oversight of the study data. We are seeing a rise in the number of findings where there was a lack of real-time data monitoring and/or data monitoring was not done in a contemporaneous manner to show continuous oversight of the trial. Inspectors are expecting to see established data monitoring processes. Planning the study’s approach to proactive data reviews and knowing what tools are available from your technology partners and how they will be used is key.

In summary, with EU Regulation 536/2014 now in force, modifications to practices around supply chain management are a necessity for clinical trials running in the EU. With upfront planning, leveraging eClinical solutions such as Almac’s IXRS, challenges can be overcome. A comprehensive end-to-end approach to clinical supply chain planning will ensure clinical trial integrity ensuring regulatory compliance.