Trends, challenges and priorities

The Covid-19 pandemic has upended many facets of the biopharmaceutical industry and greatly impacted the regulatory environment, but not BioPhorum’s regulatory governance vision that has been in place for the last three years. The principle of one product, one standard, one file, one approval, which seemed utopian three years ago, has been realized through the authorization of Covid-19 vaccines and therapies. The team is very aware that the realization of their vision is not something that is going to happen overnight for all products, but sees the opportunities arising from the Covid-19 pandemic for closer relationships between agencies and harmonization of regulatory requirements.

Progressing the regulatory vision

In 2021, the team gained further knowledge and understanding of the emergency use authorization processes and discovered the possibilities for sustaining different products post Covid-19. Examples include the use of post-approval change management protocols (PACMPs) that have been included in some of the Covid-19 vaccines and therapies for global use; PACMPs are described in the Chinese Health Questionnaire 12 (CHQ12) as one of the tools available for the simplification of post-approval changes.

Driving harmonization

BioPhorum Regulatory continues to focus on the implementation of our vision. One element of BioPhorum Regulatory is to support workstreams to implement and design regulatory technical changes. We encourage workstreams to collaborate with standards organizations, other industry groups and regulatory agencies to promote BioPhorum’s changes to global industry standards.

We have embarked on a new path since the start of 2021, by creating our own deliverables through the support we offer to cross-phorum initiatives on the global implementation of in-line monitoring and real-time release (ILM/RTR) and raw materials. Additional pieces of work delivered this year include the review and feedback to agencies or standards organizations on multiple guidance or draft monographs. The team has embarked on the transformative journey to ‘one standard’ through an initiative aimed at pharmacopeial harmonization.

Our work is always very cognoscente of the global aspect of our members products and work with the FDA, EMA, JDA requirements and other organizations that provide a global regulatory view. We promote and encourage harmonization through cross-phorum initiatives.

In 2021 we have facilitated training within BioPhorum, to ensure the businesses are is aware of the necessary processes and armed with knowledge of the regulatory and standards environment in which they operate in, this will impact innovation and drive opportunities. We are working on the raw materials cross-phorum initiative to promote the use of regulatory tools to build in our members regulatory files to support flexibility of supply, which has been an important issue for years, but came to the forefront of concerns during the pandemic. Through the proposal for change, we encourage members to demonstrate the understanding of raw materials in their regulatory applications and provide evidence of enhanced quality to national health agencies. We use quality by design tools and ICH Q12 guidelines published in 2020 to ease the delays prior to implementation due to regulatory review and approval.

We are supporting the global implementation of ILM/RTR, which is a significant change for manufacturing processes that are likely to be reflected in the registration pathways. There is currently limited information, guidance, or standards for the implementation of ILM/RTR for biologics, specifically from a regulatory point of view. We are working in conjunction with the ILM/RTR team to understand the changes needed in technology, point of analysis, infrastructure, and controls to define how these are reflected and presented to regulatory agencies, in regulatory submissions, and during regulatory inspections so that processes and products are accepted by regulatory agencies.

BioPhorum Regulatory encourages dialogue with standards organizations and regulatory agencies and drives alignment across industry viewpoints and regulatory expectations. This is exemplified by the team’s recent comment on an USP protocol for the collection of additional data for the addition of a new method to detect endotoxins in parenteral drugs.

Regulatory deliverables November 2021 to November 2022

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Milestones

Review of implementation of the reference for Covid-19 viral control strategy in the biological manufacturing industry – industry position on the FDA guidance

In 2020 the industry came together to review the FDA guidelines with regards to the impact of COVID-19 on the GMP aspects of biomanufacturing and published their position. 6 months after publication the team regathered to review the document in the light of the current state of the industry. The main blind spot that the team identified is that of the diffulcuties of sourcing raw materials. The tight situation from before the pandemic has evolved into a crisis, with raw materials being diverted to the manufacture of the COVID-19 vaccines and therapies, the exponential increase in demand of biologocs and their raw materials and sourcing difficulties. Following the review, the team started its collaboration with the Raw Materials teams mainly in DS to develop the regulatory solution to the crisis.

Industry proposal for the simplified registration of complex and innovative raw materials in Europe

The situation of Europe with regards to ther registrationof non-compendial innovative and complex raw materials is different from many other countries. In these other countries, the information relating to the raw materials are shared between the suppliers and the regulatory agency using a platform that is typically called a DMF platform (Drug Master File). On this platform, the raw material suppliers provide the agency with the information reauired to assess the adequacy of their materials for the manufacture of medicines. When this process is availalble, exchange of proprietary information for example, withregards to the development, manufacture, analysis and control of the raw materials is done between the supplier and the regualtory agency. When the process is not available, as in Europe, communication of the relevant information with regards to the raw materials si expected to come from the end user, which is not appropriate when the information is proprietary. The team therefore developed and documented a simplified process (that avoids multiple non-value adding activities and a potential bridge of confidential information), which also will lead to regulatory dossiers of higher quality. The paper will be shortly avaiable on the BioPhorum website for implementation. The next deliverable for the team is the actual implementation of the changes in their organizations.

Industry proposal for the registration process of complex and innovative raw materials to enable flexibility of supply

This is the regulatory solution to the raw material crisis, that came from a survey of our member organizations that revealed that almost 90% register raw materials through either supplier and part ID or brand name or a high level description based on historic information. Only a few use the regulatory tools avaialble through Quality by Design and ICH Q12 for the simplification of product vlifecycle management, essential to allow flexibility of material supply. The team developed a process that allows in a scientific, rigourous and systematic way yhe identificqtion of critical material attributes – what is a must in a raw material to achieve product and process robustness and quality. From there, the critical attributes need to be controlled, but others are more flexible. Simplifying the situtation, a viral filter part number XXX from supplier YYY is appropriate, but a filter that is compatible with the product, allows material to be produced and viruses to be removed in a pre-defined acceptable manner are also most probably acceptable; however if filter part number XXX from manufacturer YYY has been registered, a change of supplier comes with regulatory burden, and significant delay to implementation. The paper is complete from the process side of things, it is illustrated through the example of a viral filter and this section needs to be completed before publication, which is anticipated to be towards the end of the year.

Training material on the desired ILM/RTR future state – for internal and external audience

The team is working with the cross-phorum ILM / RTR global implementation initiative on the regulatory aspects of the proposed change. Their first deliverable is the provision of training material defining the future regulatory enviromnent for ILM /RTR. This is intended to be used with both internal key stakeholders (to inform on changes that need to take place to allow for ILM /RTR in our registration dossiers and quality systeams) and external ones (to inform regulators and standard agencies mainly of the intended future state, collect feedback and refine their recommendations). The team is starting with ‘the control strategy – evolution or revolution for the implementation of ILM /RTR?’

Recommendations for pre-submission meetings for ILM/RTR Submissions

Once the regulatory environment has been defined, the team will move on to implementation for pre-subission meetings when applicants meet with reguators to define in advance of filing their development strategy and get guidance or endorsement to ensure that the dossier will meet regualtory expectations, for a higher chance of regulatory success.

How to present the strategy in a harmonized manner - Recommendations for the submission of ILM/RTR dossier

Once the regulatory environment has been defined, the team will move on to implementation in the regulatory dossiers

Publication and implementation of industry proposal for the registration of alternative to compendial methods

When an analytical is not compendial, accaptance by regukators is one of the key risks for a successful acceptance. The regulatory team has summarized its thoughts and recommendations on the topic in a poster. The poster will be shortly published on the BioPhorum website and will become part of the BioPhorum toolkit for the seelction, development and successful implementation of new technologies developed by TRM.

Harmonized pharmacopeial monograph in EP, USP and JP for endotoxins Factor C recombinant

Recombinant factor C endotoxin testing in parenterals is considered by the team as a superior method to the historic one that used the blood of horseshoe crabs to detect the presence of endotoxins. The new method is more ethical (the recombinant factor C is synthetised), more sensitive, more specific and cheaper. Data have been gathered during the long years of implementation of the emthod as non compendial and summarized to be presented to the different pharmacopeias – USP, EP, JP, ChP for example. All pharmacopeias have accepted the data set and have either published a mongraph (EP) or are in the process of (JP and ChP), with the exception of the USP. USP requires additional data,that industry has been asked to provide (however the data does not exist) or that they are willing to obtain through the performance of a protocol. BioPhorum was invited to provide feedback on the protocol, which the team has done and will continue to work with USP for the delivery of the mongraph. USP is holding an open Forum on the topic in November that the team will be attending.

Publication of rationale for regulatory agencies to lead Pharmacopeial harmonization

As the biologics industry develops, its standards multiply. One of the enforcable standards is the pharmacopeias, that contain the rules associated with medicines , some of their raw materials as well as testing methods. USP, EP and JP are the pharmacopeais for the US, Europe and Japan for example. When a new standards (or monigraph) is being worked on by a pharmacopeai, the work takes place in isolation of the other pharmacopeais. It is only when the monographs are published that harmonozation with the other standards is considered, which makes the process to harmonization complex, lengthy and not always successful. Industry ahs been working with pahrlacopeias for years to encourage harmonization from the start, it has also collaborated with the WHO for the establishement of an international pharmacopeia. However inone of these initiatives have been to date successful, with our member organizations still having to test the same attribute of their products using muktiple standards for the different markets supplied. . The novel approach that the team is working on is to work directly with the regulatory agencies – allowing them to encourage harmonization. This is based ona couple of examples – the COVID-19 for emergency authorization only had one set of standards to meet (no different tests reauired for different markets) and the US FDA has published its acceptance of other pharmacopeais stating that the agency will accept a monograph published in the EP, BP or JP (reference: MAPP 5310.7) If the other agencies had the same approach, then only one set of mongraphs will be ultimately needed and used.

For internal use: spreadsheet of external partners and collaborations for a ‘one industry voice’ approach to regulatory and quality alignment

As the team is implementing its vision of regualtory harmonization, it is exploring which partners in the regualoty environment can accelerate the implementation of BioPhorum recommendations to industry standards. The examples above demonstrate how the team lisiases with regulatory agencies and pharmacopeais, but for more novel technologies and ways of working, this is typically done through industry standard organizations. Similarly other industry groups may be more advanced in their reflection on a related topic or with their relationship with regulatory agencies and therefore would be valuable partners to increase speed of change implementation. This is the aim of the spreadhseet: collect in one document these opportunities – which group is working on what topic, where they are, what would the potential benefits to partner with them and the state of our current interactions.

Industry feedback on USP endotoxin protocol

This is the BioPhorum feedback on the USP designed protocol for the gathering of additional data, currently required before the publication of a US monograph comprising of the Recombinant factor C method for testing of endotoxins. The protocol proposed was however not considered adequate, as the USP is proposing to use both the horsehoe crab and the recombinant factir C methods on matrixes that are different from those intended for the test (testing samples are not appropriate) and the protocol is designed to demonstrate equivalency between the two methods; however the synthetic method is more sensitive which will biaise the equivalency analysis. This will be shortly published on the BioPhorum website.

Industry feedback on draft monographs for bioreactivity

BioPhorum feedback was gathered on behalf of the raw materials and single-use sytems teams in DS, the Fill Finish and Med Tech Phorums on the new draft versions of USP 87, 88 and 1031. USP’s vision of less animal testing was commended and is fully aligned with that of the BioPhorum teams, however the approach described in the new monographs is vague and does not allow for clear decision making by both the suppliers of plastic materials and end users. This will be shortly published on the BioPhorum website.