Trends, challenges and priorities

A collaboration of suppliers and manufacturers is finalizing an industry best practice guide to single use standardization, detailing the benefits to both suppliers and end users of standardizing single use designs across networks. Currently, biomanufacturers often design single-use systems (SUS) based on the needs and practices of local sites. Often, companies do not have a standard approach resulting in different systems being used across plants and sites within the same biomanufacturer. This has resulted in a proliferation of customized designs for SUS, with current estimates indicating that ~85% of designs are customized. The best practice guide aims to facilitate the creation of a SUS environment in which internal corporate design standards are developed to provide simplified, de-risked, supply chains which facilitate accurate forecasting, dual sourcing, the commoditization of components and the adoption of lean and agile working practices. This will benefit suppliers, integrators and biomanufacturers, improve the performance and reputation of the SUS supply chains and underpin product-to-patient strategies across the industry.

Applying the power of human performance documentation for successful outcomes

• Do your colleagues struggle with a never-ending cycle of document revisions while, with every document update, the rate of process deviations stays steady?
• Does your organization use a ‘one-size-fits-all’ approach to document design where training relies on reading and understanding text to meet a compliance requirement?
• Do you know what training method works for operators, so they perform the process competently while keeping deviations to a minimum?

This paper reimagines how documents are to be used in the biopharmaceutical industry. Instead of a reactive approach to audit findings and deviations with frequent SOP updates that can result in many longwinded documents and past-due training, we describe how documents should be written and designed based on how they are to be used, and that different documents serve different purposes when training and working. This paper is in the final draft stages and should be published in Q4 2021

A team of biomanufacturers and industry experts on sterilization modalities are working on an industry aligned tool with an accompanying guidance document to demonstrate equivalency between gamma and x-ray treated single use (SUS) components. The guidance will also support identification of where further in-depth risk assessments may be required to accept the change in sterilization technology by leveraging the BPSA risk assessment, available historical data and building on existing material assessments where appropriate.

Once equivalency has been established, any process or product specific assessment can be dramatically reduced or even demonstrated as not needed. Essentially, the work by this team aims to reduce the requirement for each company to perform a full FMEA type risk assessment on every product subject to the change from Gamma to Gamma and/or X-Ray.

This workstream is producing a paper to make suggestions to regulatory authorities and propose minimum filing requirements with the following features:

• One clear and consistent approach, based around a number of change scenarios to establish an industry-harmonized, science-based approach to the safe management of making and moving operational cell banks for commercial products
• Application of scientific-based criteria to the characterization and comparability approach for changes to cell banks. The relative risk for a product should determine the amount of data that is reasonable for comparability.

LER

The low recovery of endotoxin in undiluted drug products and in-process samples has been a topic of great concern with the FDA. The paper compares recovery of different endotoxins sourced from reference standard endotoxin (RSE) and control standard endotoxin (CSE) which use purified lipopolysaccharide, as well as naturally occurring endotoxins (NOE). By assessing spiked sample recoveries for endotoxin masking using various vendor reagents in sample buffer preparations, this study was designed to evaluate the “classic” excipient buffer combinations that are known to affect the endotoxin recovery with the traditional USP LAL reagents. Another factor in this study was to evaluate how NOEs sourced/prepared from different microorganism species and if the growth preparation method in a high or low nutrient affects the endotoxin recovery of NOEs.

The industry is facing a need to increase facility throughput and to maximize asset utilization. The multi-product facility workstream’s first priority is to identify and create best practices in change over and cleaning in multi-product facilities and ensure they are science, risk and data based, provide technological improvements and standardized processes to maintain compliance from a validation standpoint, but will also limit revalidation impact. Following on from the team’s initial 2023 publication, Droplets vs dryness and the requirement for equipment post-cleaning, the workstream are therefore currently scoping their next three papers around the cleaning processes including:

Empty column and packing equipment cleaning – this paper will aim deliver clear justification as to why performing a cleaning validation of the column and column packing equipment is not needed and that the “in process checks” built into the column cleaning process of packing and unpacking already support this. This will also ensure the current practice is aligned with the proposed approach.

Best practices for CIP skids and circuits – this paper will aim be to provide a recommendation/best practice for companies to use as reference. The paper will also provide an overview on the complications for different types of equipment.

Cleaning standardization and re-use of non-product contact SUS components – this paper will aim to identify opportunities to reuse certain non-contact items. The paper will also provide clarification of what can be aligned and what may not be able to be aligned due to facility and regulatory differences. The paper will also provide recommendations on standardization to support harmonization within multiple sites to allow for technical transfer; ultimately allowing for future sustainability.

While the current focus of the workstream is tactical, addressing change over and cleaning challenges, in parallel, the workstream is considering future, strategic focused topics to further develop the multi-product facility program.

Protein A Resin Reuse Sub team

The multi-product facility workstream also includes a sub-team that is currently developing a risk assessment to understand the steps required to reuse protein A resin across multiple products within clinical manufacturing. The team have also formed a collaboration with a research team in The Science Foundation Ireland Research Centre for Pharmaceuticals, to support future protein A resin reuse practical activities that will provide research data that will be used to support a review of a proof of concept in support to use in a xoxicology/ development/ pilot plant setting.

The workstream has continued with its national and regional model of activities.

In 2021, the Brazil sub-team concluded its activities with the definition of the impact of the changes to the regulations on post-approval changes and stability requirements on internal processes so that full value is realized across our member organizations.

The Colombia sub-team through its relationships with the medicines agency (INVIMA) and local industry groups (AFIDRO and ANDI ) has contributed to the decision from INVIMA to revise their post-approval change regulation, which will in the same a-way as it did to Brazil, save years to the implementation of post-approval changes in one of the other big markets in South America.

During 2021, the Russia sub-team revised the paper on the implementation of the Russian Pharmacopeia, so that it fits more with the change in the regulatory environment of the region. It has also continued to share knowledge and experience of the new EAEU (Eurasian Economic Union) regulatory framework. Key learnings will be captured in a poster that can be shared internally in our member organizations to ensure that their learnings are available to all.

The China sub-team after its review of the 45 new regulations last year, is sharing insights and best practices for their implementation. Key learnings will be captured in a poster that can be shared internally in our member organizations to ensure that their learnings are available to all.

The South Korea team shared with the rest of industry and regulatory agencies the challenges associated with post-approval changes in the country and the region, through a presentation at the PDA Asia Pac conference in Oct 2021.

A new team was created in 2021 to promote the implementation of ICH Q12 and Post-Approval Change Management Protocols in the LATAM countries. The team is in ideation phase.

• Driving predictable raw material performance
• Optimizing the raw material testing regime to reduce duplication and speed to raw material release.
• Enhancing raw material flexibility to support dual sourcing.

To this end manufacturers and suppliers are working to define a five-year plan and jointly leading a series of workstreams and initiatives to tackle immediate challenges including Media Fingerprinting and Raw Material Equivalence.

Media Fingerprinting – the team will be writing best practice guidance to achieve a simpler, more accurate ID testing for media and other non-compendial materials making it easier to qualify across suppliers
Nitrosamines – the team plans to publish lessons learnt from live benchmarking discussions considering the implications of the recent FDA and EMEA guidelines and plans for implementation
Raw Materials Change Notification – the team are finishing a guidance paper which identifies the relevant change areas, for raw materials and the type of changes which the biopharmaceutical industry needs to be informed about. It will include the required information, in terms of supporting data and documentation, to support notification of changes.
Raw Material Equivalence – the team is working in conjunction with the Regulatory Governance team to develop an industry proposal for the registration of raw materials. The proposal will be tested against viral filters

Overseen and supported by the Single-Use Technology Expert Committee and Single-Use Systems (SUS) Joint Leadership team who, in partnership with the Leadership Team in BioPhorum Drug Substance and BioPhorum Supply Partner, set strategic direction for the program, the workstreams within the SUS Program are focused on robust supply chains, validation, qualification and application of single use technologies across the biomanufacturing value chain.

A new five year rolling plan for the single-use systems (SUS) program is currently being developed and two of the active workstreams are currently included in the BioPhorum Drug Substance  program: Interchangeable Parts and Introduction of X-Ray Risk Assessment. A sub team of the Design Harmonization workstream team are also finalizing an industry best practice guide to single-use standardization.