Trends, challenges and priorities
Markets are growing and the range of new product types is expanding. To prepare for these exciting opportunities, drug product and secondary packaging processes will need to develop excellent operations and quality management systems (QMS) and develop new capabilities. New markets continue to emerge for existing medicines that will require lean supply chains and more in-region manufacturing. New product types will include non-mAbs, cell and gene therapies, and more complex devices. Also, patients and clinicians are understandably demanding more convenient modes of delivery, such as longer-lasting formats and better electronic patient information.
The industry will need to invest to realize the opportunities, adding pressure on current CAPEX and OPEX costs. Another challenge, more acute in the Covid-19 world, is the uncertainties of inbound supply where there are shortages of quality, vital, raw materials, such as vials and single use systems (SUS).
In a competitive multi-opportunity market, it is essential fill finish does not impede speed to supply clinical trials and speed to supply the market. Industry’s relentless drive for quality is matched by the expectations from health authorities that continue to expect higher standards or quality, for example in demonstrating sterility assurance and product serialization. Of course, the industry must also contribute to environmental sustainability and reduce material waste generated by its operations and products.
The costs of quality and compliance are high. It is a complex and time-consuming task to minimise the risk of harm to patient, batch loss and challenges by inspectors. Even the most experienced companies face challenges in designing processes and using equipment which will meet ever more stringent regulatory requirements. Quality and demonstrating compliance will remain the priority of BioPhorum Fill Finish. To address these challenges, drug product aseptic filling (‘fill’) and secondary packaging (‘finish’) operations are working relentlessly to continually improve the pharmaceutical quality system (PQS). BioPhorum Fill Finish has recently made progress in best practices in several key areas: sterile filtration quality risk management (SFQRM), environmental monitoring (EM), container closure integrity (CCI), visual inspection (VI) and isolator gloves management. The seminal work of the SFQRM consortium provides a risk-based approach to the sterilization of filters has been very well-received by industry and health agencies.
In these areas, major improvements with currently available technologies are also being evaluated and the barriers to adoption being cleared. For example, the Alternative and Rapid Micro Methods (ARMM) team is working to remove settle plates in grade A areas with direct-detection systems (i.e., bio-fluorescent particle counters (BFPCs) that can detect viable and non-viable particles in real-time). The Isolator of the Future team is developing best practices for automation that will reduce the need for human beings, which is the primary contamination risk. In 2022, the Phorum’s Visual Inspection team provided a user requirement specification for testing technologies and wrote a paper providing much needed clarity on misunderstandings about 100% testing.
The Phorum members are also wanting to create space to support each other with the implementation of Annex 1, a key driver for changes to filling operations.
An essential element to successfully meet challenges is the need for a single industry voice. The Phorum will utilize BioPhorum’s collaboration with the ASTM and USP and continues to form partnerships to add value for members, which include: the SFQRM consortium with the Parenteral Drug Association (PDA); the ARMM team’s partnership with thought leaders in the PEMM group and OWBA; and discussions with EDQM’s Expert Group 1 EDQM; the EM team and the team revising the PDA’s TR13; and the Phorum’s Robotic team coordination with the ISPE–DACH’s Robotics Special Interest Group. The Secondary Packaging team are also working with experts from GS1 on ePI (electronic patient information). The Lyophilization team in 2022 partnered with the University of Purdue’s Advanced Lyophilization Technology Hub to work on a paper on technology transfer best practices with case studies.
In 2022 a set of manufacturing scenarios were defined by our members, that are required to address the opportunities and challenges mentioned above. The emerging goals are shown in the figure below. In the final months of 2022, we are developing a plan to work collaboratively towards a future set of priorities. Including an ambitious workstream accelerate progress towards commercial lines of the future.
Demand for FF capacity exceeds supply, and there is demand for new more complex to make product types and flexible manufacturing. FF capacity is expensive and takes time to build. So, our work on commercial facilities of the future will accelerate availability of next generation filling and process control technology and make it simpler for members to make smart CapEx choices. Here, BioPhorum FF is also leveraging supplier expertise in the Technology Roadmap and Supply Partner Phorums.
Many of the Phorum members depend greatly for fill finish capacity on contract manufacturing companies. While several contract manufacturers are valued members of the Phorum, we continue to encourage non-members to collaborate and keep pace with views on best practices; in turn contract manufacturers could connect with their clients to eliminate variation in practices which add no value. Potential topics for collaboration include tech transfer and deviation management.
The Phorum’s ethos is very much about declaring success only when best practices are implemented. All workstreams are chartered to both deliver best practices and provide stewardship and support for wide-scale implementation. Perhaps the most important feature of the Phorums is that the work is done in positive atmosphere in which problems are discussed openly, advice shared generously. Subject matter experts find-like minded scientists and engineers to work with and learn from. Our professional facilitation is about creating this vibe of mutual trust and joy in developing robust solutions to tough problems together.
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Fill Finish deliverables November 2021 to November 2022
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Alternative and Rapid Micro Methods (ARMM)
The ARMM program is working to support the use of three ready-to-implement and high-value applications, which are pivotal to achieving the ambitions for in-line monitoring/ real time release (ILM/RTR):
- Bio-fluorescent particle counters (BFPCs) for routine direct-detection air monitoring
- Rapid sterility testing systems
- Automated colony counters
The validation strategies for the technologies have been discussed with key opinion leaders from the EMA, FDA, USP, EP and national inspectorates. In July and August respectively, best practices papers were submitted to the PDA journal describing best practices for the evaluation and validation or rapid sterility systems and automated colony counters. The methods in these papers have stood up to the scrutiny of several health authorities in post approval change submissions.
In August 2021, the BFPC team partnered with key opinion leaders accelerating progress on key empirical work and five seminal papers designed to remove barriers to BFPC adoption (a vital enabler for gloveless isolators).
Clean Room Automation Pathfinder
This is a pathfinder activity started in August 2021 to find collaborative opportunities for automation in the wider clean room environment, sample transport, co-bots, cleaning robots etc. The pathfinder will work with the TR automation pathfinder team to share learning and experiences where appropriate. This team and the Isolator of the Future team formerly know as the FF Robotics team.
Container Closure Integrity (CCI)
With more than 50 active SMEs from 25 member companies at 30 international sites, this team forms the most representative group of biopharma CCI practitioners globally. In 2021 the team provided a scientific approach to sampling and sample size selection , and provided to vendors an industry view of user requirements for optimized container closure integrity testing equipment.
An holistic approach to CCI overing product lifecycle is the primary work of the CCI team. This work will result in a guidance paper which will enable the industry to harmonize on a ‘quality built-in’ approach rather than a ‘testing into compliance’ paradigm for CCI. A thorough review process is in progress of this comprehensive paper, although the challenges of the pandemic has slowed paced, the planned publication is due in Q1 2022.
Following publication the team will turn their attention to two supplemental papers: the first covering special considerations for devices, and the second paper will cover considerations when 100% CCI testing is justified.
Enabling In-Line Monitoring and Real-Time Release (RTR) in Fill Finish – a path forward
The workstream has served as a pathfinder group to define the route to RTR with the target to accelerate product release to one to two days. The team have completed initial work on the criteria to define the RTR roadmap:
- Identification of technologies that can enable ILM/ RTR in the fill finish manufacturing process
- Development of strategies
- Provision of guidance for a QMS that supports ILM/RTR.
The Fill Finish ILM/RTR FF team is part of the cross-phorum adoption of ILM/RTR program, which focuses on the operational requirements for the implementation of ILM/RTR in a GMP environment across all manufacturing operations. The recommendations of the FF ILM/RTR will discussed and actioned in November 2021 by the FF leadership team.
Harmonized Risk-based approach to routine Environmental Monitoring (EM)
The EM team have continued to drive home adoption of the best practice guidance on routine EM risk assessments. The majority of member companies have adopted this work as their own standard and feedback indicates fewer questions from inspectors.
An open webinar in September 2021 attracted 105 participants from around the globe. The BioPhorum risk assessment is recommended in the 2020 update to the PDA TR13.
In August 2021 started dialogue with the with USP about the potential of a link in USP<1116>. In January the team started work on defining best practices for EMPQ in new facilities and then existing facilities, due to complete in Q1 2022 and end of 2022 respectively.
Isolators and Commercial Lines of the Future
The focus of this teams is developing the practical application of technology to ensure that outputs serve to further develop the route from restricted access barrier systems (RABS) to a gloveless isolator. The URS will be published in 2022 and the team will focus on collaborative work to facilitate the realization of technology in line with the URS.
In September, the Phorum leadership decided to start a pathfinder which will broaden the vision to commercial lines of the future. The objective is accelerated progress towards the next generation aseptic filling lines. A consortium project is envisioned, comprizing biomanufacturers, vendors, technology hubs, and Health Agency representatives. Phase one will start in 2022 to create a ‘theoretical designs rendered in computer simulations; then Phase two will deliver a physical prototype; and Phase three a full proof of concept. As with other BioPhorum proof of concept projects, a consortium approach will help to maximise value from capital expenditure, reduce investment and risk and foster innovative approaches.
Isolator good operating practices
Since publishing the glove management paper at the beginning of 2020 the team have been reviewing the adoption of the paper’s recommendations both internally within member companies as well as by the wider industry. A report of this adoption review will be available early 2022.
The new recommendations in the recent Annex 1 update are pertaining to isolator sterility. The team have discussed the impact of these new regulations and in particular the issues it highlights regarding the perceived fragility of vaporized hydrogen peroxide (VHP) as an effective method for decontamination. This remains a hot topic for the team and has been the subject of a number of case studies shared across the team.
Lyophilization community of practice: productively addressing today’s pain points
The Lyophilization Community of Practice continues to be productive forum for discussion and debate within the lyophilization community. In Nov 2020 the CoP delivered a paper on modelling of the primary drying phase and in May 2021 the team delivered a opinion piece advocating a better approach to aseptic process simulation for lyophilized products. In September 2021 their paper on standards for leak rates was submitted for pre-publication company legal review. And in October the BioPhorum team were pleased to start a collaboration with the University of Purdue’s Advanced Lyophilization Technology Hub on a paper on technology transfer best practices with case studies.
Pre-filled syringes: launch of community of practice
Pre-filled syringes (PFS) are of growing interest to the industry and a community of practice was launched in March 2021. The subject matter experts are sharing the unique challenges of PFS manufacturing; for example, challenges experienced with silicone particles; control and measure of air bubble size; and plunger movement.
Process Validation (PV): launch of community of practice
A community of practice was started in Spring 2022 to share know-how on process validation. After collecting topics of interest, a call series has been set up which started at the end of August working through the schedule of discussion topics. Recorded case-studies are available on request to Phorum members covering for example, overview of PV readiness and execution for a new liquid product; application of QbD principles in process validation: learning from drug substance; statistics in process validation; and, sampling plan and acceptance criteria.
Secondary Packaging – delivering an ambitious program
The Secondary Packaging Workstream’s goal is to help member companies transition from large batch manufacture to small-batch, high-value packaging runs. The workstream has organized four sub-teams, each has delivered the first part of their mission in 2021. The Electronic Product Information (ePI) complete their work with key stakeholder organizations, including GS1 HealthCare, toward a commonly accepted ePI packaging operations implementation strategy that will help shape future regulations by providing the packaging perspective on broader ePI.
The Line Clearance/Change Over sub-team completed their work best practices on the implementation of Rhythm Wheel, change over and the implementation of global OEE standards.
The team have a final draft of a tool to support a risk-based approach to line clearance.
The Serialization sub-team delivered points to consider document. This will broaden the industry knowledge of best practices and capabilities and highlight the risks of a lack of standardization. Topics included in the paper are operational (training, technical limitations, OEE and the decommissioning of serial numbers) and regulatory/strategic (primary pack serialization, print grading and non-standard requirements).
The Vision Systems sub-team developed a tool to help set limits on specifications for vision systems. The protocol covers the readability of single characters to establish a data background, showing how much of each character can be missing before it is not perceived as the correct character aimed at reducing labelling errors.
By October 2021 the team had completed their work on a vision and five+ year strategy for secondary packaging. Currently in member consultation phase and due for publication in Q2 2022.
SFQRM Community of Practice (CoP): Supporting Adoption
On completing their primary mission in establishing a framework for a risk-based approach to pre-use post-sterilization filter integrity testing (PUPSIT), in 2021 the BioPhorum SFQRM team worked as a CoP to support and drive home adoption. The CoP addressed the following key topics:
- Case study sharing of completed risk assessments that have led to effective risk mitigations
- Case study sharing of interactions with inspectors
- Filter user questionnaire for the assessment of masking risk
- Single-use systems in regard to PUPSIT
- React to other projects and studies related to filtration and continue engagement with the regulatory agencies.
In August the team completed the 2021 The PUPSIT failure survey (updating the 2017 and 2019 survey). The initial conclusions from the data comparison was presented at the 2021 PDA Pharmaceutical Manufacturing and Quality Symposium in September and a publication is due to be published in Q1 2022.
Visual Inspection (VI)
Risk-based tool for classification and investigations
The VI team are near to completing their work on an update to this common methodology guidance on the risk classification of particles . Version two provides a tool and several cases studies on a risk-based approach to classifying visible particles and a tool to help with decision-making in particulate investigations. The much-anticipated update went through a comprehensive technical review in the Summary of 2021 and the paper is now in pre-publication company legal review .
The team has completed a survey and current practices around test kits. After further scoping work, the team have started writing a ‘good practice’ paper on the development, use, and maintenance of test kits for VI will help to add clarity to an essential topic.
Taking a closer look at how technology is applied for VI across the industry, and future trends and opportunities, was another major topic for the team in 2021. The link between VI and CCI (container closure integrity) is just one of the avenues to be explored, with a possible mindset shift from a ‘silo’ mentality towards a more holistic ‘inspection’ paradigm. A survey seeking to understand the trajectory of technology in the VI space was completed in March 2021.