NEWS

Collaborating with USP on its Bacterial Endotoxin Test Protocol and Bioreactivity Draft Monographs

1 February 2022
Advanced Therapy Medicinal Products
BioPhorum

With a clear objective of setting standards for the industry and protecting patients worldwide, the USP is a key partner of BioPhorum. Ensuring that the industry position defined through the BioPhorum collaboration is reflected back to the USP is also one of BioPhorum’s key objectives. 

Two recent documents typify BioPhorum’s approach to this collaboration and how it provides expert feedback on consultations.

Industry feedback on Bacterial Endotoxin Test (BET) Protocol

The absence of bacterial endotoxins in parenteral products, as most biologics are, is a key attribute to ensure patient safety as they can lead to a catastrophic outcome. The compendial test described in this USP uses the lysate from the blood cells of horseshoe crabs (known as the LAL method, standing for limulus amebocyte lysate). An alternative known as the Recombinant Factor C (rFC) method that uses only synthetic reagents, as opposed to animal-sourced ones, was developed, and patented in 1997, and has been successfully implemented since 2018.

The rFC method is now a compendial method in the European and Chinese Pharmacopoeias. The Japanese Pharmacopeia allowed the rFC method as an alternative in its XVIII edition and is moving toward a compendial status in a couple of years. Also, the South Korean Agency conducted an independent study with manufacturers and found equivalency between rFC and LAL. Overall, rFC has been accepted in more than 60 countries.

The USP has been considering publication of a general method for the rFC method for several years; however, it is looking for additional insurance that the new method is as reliable as the current LAL compendial method. It therefore designed a study to collect data comparing the rFC and the lysate reagents method described in <USP85> Bacterial Endotoxins Test. It aims to compare levels of endotoxin activity arising from autochthonous Gram-negative bacteria present in pharmaceutical (deionized) water samples, which are analyzed by both the current monographed methodology and recombinant reagents.

The USP has published details of the proposed study in Bacterial Endotoxin Test (BET): A USP Comparability Study of Recombinant Reagents (Recombinant Factor C and Recombinant Cascade) to Lysate Reagents (LAL) and has asked for industry comments.

Using a select group from its Regulatory and Microbiological Teams, BioPhorum has published Industry feedback on Bacterial Endotoxin Test (BET). It contains feedback on the USP document grouped into these areas:

  • Protocol review
  • Reagents
  • Samples for study
  • Number of samples and statistical methods

It comments on issues such as the feasibility of testing the recommended matrix using four different recombinant reagents and four different lysate reagents, and that water post-deionization (low-purity) but before distillation/ultra-filtration (high-purity) is not representative of samples typically tested for bacterial endotoxins. It also questions whether industry will be able to provide known contaminated samples as these would be difficult to obtain and then compare.

BioPhorum supports the publication of a general pharmacopeial method that will enable the wider use of recombinant reagents in the BET method.

“BioPhorum has contributed to the USP’s paper by providing insightful comments on a more sustainable source and avoiding any animal-sourced material,” said Philippe Gadal, Regulatory Intelligence advisor at bioMérieux. “This will benefit patients and stakeholders alike.”

Industry feedback on USP Bioreactivity Draft Monographs

Bioreactivity is a mandatory test for plastics used in the composition of primary packaging for parenterals and implanted devices. It is typically tested in two ways – using an in vivo test where extracts from the plastic are injected into live animals (e.g., rabbits), or an in vitro test where extracts are exposed to cultured cells.

USP <87> describes in vitro tests, USP <88> in vivo tests, and USP <1031> provides the strategy for testing plastics either way or both ways depending on the risk to the patient.

USP is currently revising these three monographs to update the bioreactivity compendial tests and the decision-making process to ensure the safety of plastics used for the packaging or administration of pharmaceuticals. The USP has asked for industry comments.

Feedback on the draft monographs was provided by a team of 15 subject matter experts from BioPhorum’s Regulatory, Single-Use systems, Packaging and Medical Devices Teams and has been published in Industry Feedback on USP Bioreactivity Draft Monographs.

It contains feedback on the USP document grouped into strategy, application of the bioreactivity monographs to plastics used for manufacturing, and the use of resources.

It also comments on the potential in vitro tests that should be included in <87>, the removal of the implantation test and safety in <88>, the removal of Class I to VI from <88>, and the topics for omission or inclusion into the <1031> chapter outline.

At this point in the process, the industry’s feedback is high level as the team feels that further alignment to other industry standards, such as ISO 10993: Biological evaluation of medical devices, is required before this can be done effectively.

BioPhorum and the USP are fully aligned with the 3R principles (the ‘Replacement, Reduction and Refinement’ approach that aims for more humane animal research). The expert feedback provided in these documents aims to support the USP and, ultimately, produce documents that improve patient safety – but with adequate use of finite analytical resources, which would not be the case with divergent expectations.

Chinese Flag Fluttering In The Wind
NEWS
What’s changing in the Chinese CMC regulatory environment?
DNA pink background
NEWS
Registering innovative raw materials using QbD principles: Protein A resins
Spots On Blue Background
NEWS
BioPhorum’s input on ICH guidance on products derived from cell lines of human or animal origin
Raw Material Document
NEWS
The four steps for registering innovative and complex raw materials

Advanced Therapy Medicinal Products

Advanced Therapy Medicinal Products support the quest for better and faster development of cell, gene and RNA therapies​ through connecting therapy developers, contract manufacturing, and testing organizations to gain an understanding and respond to the challenges faced by the advanced therapeutics industry.

Development Group

Development Group accelerates and improves the development process of biopharmaceutical medicines for the benefit of the patient. Replacing isolation with collaboration by providing a “safe” space where subject matter experts can work on sharing solutions and best practice on emerging industry trends, implementation of new technologies and common issues whilst ensuring their intellectual property and confidentiality is protected.

Drug Substance

Drug Substance advances excellence in drug substance manufacturing and testing, acting as an industry voice to accelerate technology adoption, implement post-approval change more rapidly and increase confidence in maintaining compliance.

Fill Finish

Fill Finish accelerates development and acceptance of sustainable world-class filling and packaging operations for drug product which meets the future needs of patients. Through innovative solutions resulting from the sharing of expertise, we can overcome common performance challenges and deliver on quality and regulatory compliance.

Information Technology

Information Technology accelerates digital maturity across the ​global pharmaceutical manufacturing industry.

Quality

BioPhorum Quality provides a dedicated, safe space for quality professionals from biomanufacturers and contract organizations to coalesce and enhance effective collaboration to address shared industry challenges.

Regulatory-CMC

Regulatory CMC brings leaders together who have a common goal – to improve access to medicines through innovation in the Regulatory ecosystem. It provides a dedicated space for strategic leadership and a coordinated industry voice, to move from divergence to convergence.

Supply Chain to Patient

Supply Chain to Patient transforms the performance of global pharmaceutical clinical and commercial outbound supply chains through industry collaboration by creating transparent patient-centric, resilient and agile E2E supply chains, that consistently deliver high-quality medicines ensuring an uninterrupted supply to patients.

Supply Partner

Supply Partner is a trusted advisory group and collaboration that is the engine for driving change across the global industry for all things relevant to the inbound supply chain. Addressing the challenges of complexity, resilience, cost, sustainability, and innovation.

Sustainability

Sustainability enables the industry’s transition to a low carbon, circular future – supporting members to improve patient health while respecting the planet. We activate multi-disciplinary teams drawn from our network to deliver environmental sustainability improvements across the value chain.

Technology Strategy

Technology Strategy acts as one voice of the industry to define strategy, accelerate technology transformation and support technology translation and adoption. With a purpose of enabling the future state of flexible, resilient, sustainable end-to-end biomanufacturing.

DOWNLOAD
An industry perspective on understanding AAV capsid content variants
Needle On Yellow Background
EXTERNAL-RESOURCE
An intercompany perspective on practical experiences of predicting, optimizing and analyzing high concentration biologic therapeutic formulations
DOWNLOAD
The Drug Substance 2.0 Strategic Value Framework
Coloured dots on teal, next to vial
DOWNLOAD
BioPhorum’s holistic approach to container closure integrity
Magnifying glass over a tablet all coloured blue
DOWNLOAD
Digital Plant Maturity Model 3.0
Investigation Digital Workstreams
DOWNLOAD
Peer to peer practical guidance on remote inspections and audits
PODCAST
The next step in building regulatory as a capability to enable strategic innovation across the BioPhorum community
BioPhorum roundals on sugical gloves
DOWNLOAD
A visionary strategic framework for future patient-centric outbound biopharmaceutical supply chains
DNA and Earth on blue background
DOWNLOAD
A vision for the biopharmaceutical industry’s inbound supply chain
Lightbulb And Icons On Colourful Background
DOWNLOAD
BioPhorum environmental sustainability roadmap 2022
Technology Roadmap V 2.0
DOWNLOAD
BioPhorum Technology Roadmapping roadmap vision 2.0

Publications

Documents including best practices, vision statements and peer reviewed papers to help you take value back to your business.

Webinars

Discussing all aspects of the biopharmaceutical industry, from digitization and knowledge management to raw materials, supply chain, sustainability and more. Learn from the perspectives of those at the forefront of the industry.

Podcasts

BioPhorum Connect is our podcast series that keeps you up to date with the latest news and trends in the biopharmaceutical industry. From experienced professionals to thought leaders, these podcasts bring you the insights and perspectives of experts from around the world.

Tools

A variety of resources including design tools and user requirement specifications to help you improve and streamline your business processes.

Benchmarks and Surveys

Research conducted among the BioPhorum membership providing evidence to support change and identify best practice.

Browse all

Access a variety of free tools and papers and other resources designed to provide you with up-to-date information and insights to help you make informed decisions and maximize your success. Access our resources today and start making improving and streamlining your business processes.

WEBINAR
Bioreactivity testing in single-use system biomanufacturing
WEBINAR
Bioreactivity testing in single-use system biomanufacturing
WEBINAR
Bioreactivity testing in single-use system biomanufacturing
Magnifying glass over a tablet all coloured blue
DOWNLOAD
Digital Plant Maturity Model 3.0
WEBINAR
Bioreactivity testing in single-use system biomanufacturing