The biopharmaceutical industry continues to develop advanced manufacturing processes, systems, technologies, and facilities. Regulations play a significant role in assessing and approving marketing authorizations for drug products that are submitted for approval. The industry and regulators together should form a coordinated, streamlined process that delivers much-needed medicines around the world.
The complex global nature of biopharmaceuticals sometimes means that progress is not always as smooth as it could be. One main reason is that regulatory agencies often differ in their degrees of harmonization. That has created an environment of divergence, in which countries each have unique standards, requirements, submissions, and review processes.
Some agencies make a few changes to US or European submissions. Typically, those receiving agencies take review and approval reports from more-established agencies and approve or reject submitted files based on those reports. However, other agencies require performing their own assessments.
Both situations can jeopardize compliance for the following reasons. Biomanufacturers have to manage files differently, often making a separate file for each agency (for both new drug applications and postapproval change filings throughout a product’s life span). Biomanufacturers also need to write files differently according to specific requirements of the regulatory agencies. Companies often are required to provide information that has little to do with the quality of a dossier. Those requirements vary depending on the country in which a file is to be submitted. For example, submissions can be paper or electronic, and they often include many ancillary documents: e.g., local, handwritten, signed certificates; detailed information about raw materials even when compendial; and good manufacturing practice (GMP)-related information. Requirements to accept filings for postapproval changes often differ among countries. For example, a change can be filed and approved with stability data ranging from none to half of a product’s shelf-life. That can delay all launches if a biomanufacturer has chosen a “hard” switch to a new product or cause multiple inventories of similar products if a manufacturer has chosen a “soft” switch.
Compliance risk also can be elevated if new or improved products have different timelines for patients located in different countries or regions. If an agency requires stability data for half of the shelf-life of a product, then that will delay the drug’s availability to patients. When curative or preventative therapies are life-saving, such actions can lead to problems that are much wider in scope than those related to compliance or in a supply chain.
Impact of COVID-19
The potential consequences of those issues are evident in the context of the COVID-19 pandemic. Each vaccine that is developed will have regulatory compliance issues related to different files, requirements, and approval processes.
Some regulatory agencies have proactively changed their regulations to accept a “global dossier” for COVID-19 products, allocating personnel to expedite review and working closely with industry to ensure fast-track approval. Now that several vaccines have been developed, however, will the lack of regulatory harmonization lead to some governments delaying vaccine administration because regulatory requirements are significantly different? That answer probably would be “no.” With COVID-19, that scenario is unlikely to happen — not only for the sake of public health, but also because of the broad political, economic, and social impacts of the novel coronavirus.
BioPhorum’s Harmonization Strategy
The biopharmaceutical industry’s work during this pandemic has shown that swift changes can happen when all groups in an industry work together. The approach of BioPhorum’s Regulatory Governance Team has a similar collaborative strategy and is all about harmonization — not only of what biomanufacturers write in their dossiers, but also for working with different agencies, so that their requirements are aligned with those in other countries. For example, the team is helping regulatory agencies to work to guidelines issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).
The BioPhorum team aims to move the regulatory environment for biologics away from its current state of divergence. Until recently, the team has helped agencies develop tailored regulatory solutions within each country. However, building on the fast-track processes used for COVID-19 has meant that the team can accelerate its plans to achieve a long-term ambition of global harmonization. Please visit the BioPhorum regulatory webpage for updates on this topic: https://www.biophorum.com/phorum/regulatory.
Three recent successes for the team demonstrate how well its approach to harmonization works, and all three have been documented in free-to-download technical white papers. The studies include hands-on, detailed reviews and recommendations for agencies and biomanufacturers that work toward the common goal of harmonization. Doing that one country at a time within an overall framework is crucial to developing and implementing solutions that are tailored to each country’s needs.
China: Since 2017, China has mandated that suppliers of active pharmaceutical ingredients (APIs), excipients, and packaging materials register their materials with the country’s drug master file registration platform. Many agencies ask for details of a pharmaceutical component’s quality and its effect on products. But the Chinese requirements for “high-risk” materials, such as those used in biopharmaceuticals, also ask for historical information that typically is proprietary, so many suppliers are reluctant to share it.
BioPhorum’s paper, Industry Reflection of the Registration of Raw Materials Entering the Composition or Presentation of Biopharmaceuticals in China (1), summarizes requirements for biopharmaceutical raw materials in other ICH countries and compares those requirements with those of China. It also lists all details needed for the Chinese registration of raw materials to help suppliers register their products into this vast market.
Brazil: The Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, ANVISA) was the first regulatory authority in Latin America to gain full membership in the ICH. However, the country’s stability and manufacturing data requirements typically delayed the submission of postapproval changes by months or even years. The agency asked BioPhorum to support a review of its postapproval change regulation to align that with ICH and World Health Organization (WHO) guidelines.
BioPhorum’s paper, General Recommendations for Harmonization of Local Regulations for Postapproval Submissions with WHO and ICH Guidelines (2), describes how to align national regulations with international standards. That can speed up submissions and result in a more efficient review process for the agency. The team’s work with ANVISA was so successful that the agency has published its new regulations for postapproval and stability requirements, all of which follow BioPhorum’s recommendations.
Russia: In 2020, the Russian Federal Service for Surveillance in Healthcare began adopting a new testing regimen for biological imports. The strategy changed from testing all batches to testing the first imported batches and then potentially only annual batches. Although the changes are intended to support the biopharmaceutical industry and align with procedures in other regions, some industry experts have expressed concern that some parts of the approach could have unintended consequences that might limit the supply of biological products to patients. BioPhorum’s General Recommendations for In-Country Analytical Testing of Biopharmaceuticals in the Russian Federation (3) makes a series of proposals and recommendations to mitigate those concerns and facilitate alignment among the Russian agency’s requirements and those of other prominent agencies.
BioPhorum imagines the future environment as a harmonized one in which
- there is a high level of collaboration among regulatory agencies and industry
- digitization of data is a game-changer that enables immediate decisions on product lifecycle management
- accelerated development is the norm
- new therapies are implemented quickly and successfully and demonstrate compliance with standards.
Successful global harmonization would lead to having one product, one globally accepted set of standards, one submission, and one review process. That will take many years to achieve, but it would be transformative for the industry and, most important, for patients around the world.
1 Industry Reflection of the Registration of Raw Materials Entering the Composition or Presentation of Biopharmaceuticals in China. BioPhorum Operations Group, 2020; https://www.biophorum.com/how-to-register-pharmaceutical-raw-materials-in-china.
2 General Recommendations for Harmonization of Local Regulations for Postapproval Submissions with WHO and ICH Guidelines. BioPhorum Operations Group, 2019; https://www.biophorum.com/slicing-years-off-change-implementation.
3 General Recommendations for In-Country Analytical Testing of Biopharmaceuticals in the Russian Federation. BioPhorum Operations Group, 2020; https://www.biophorum.com/russian-release-how-to-manage-the-risks-of-new-analytical-testing-in-russia.
Isabelle Lequeux is a facilitator at BioPhorum Operations Group; email@example.com.