Attention Heightens on Creating an Independent Regulatory Pathway for Introducing Novel Excipients

Drawing increasing attention in the global industry/regulator dialogue is the need for excipients that are fit-for-purpose in meeting the complex challenges of formulating, manufacturing, and delivering the new generation of medicines and making them as safe, efficacious, and patient- and distribution-friendly as possible.

In focus are: ● the limitations in the current excipient portfolio ● what is needed in excipient development to fill the shortcomings, and ● how the current regulatory processes could be altered to better foster that development.

Responding to strong stakeholder input in recent years that an independent regulatory process for the submission and review of toxicological and quality data on novel excipients would spur their development, FDA released a proposal for a pilot review program in the Federal Register in early December 2019.

The agency requested that stakeholders provide information and comments that would assist in determining whether the pilot program should be established. The informative FDA notice included an explanation of the background, what a pilot program might look like, and the questions on which stakeholder input would be particularly helpful. By the end of the comment period in early February, twenty-six different companies and organizations had responded. 

The story is divided into five parts, which are being released serially:  

PART I focuses on FDA’s excipient review proposal and how the respondents addressed the pressing questions for which the agency sought answers. [CLICK HERE.]

PART II explores the relevant discussions that took place at a workshop at Health Canada (HC) in Ottawa in late September, cosponsored by the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) and the Canadian Society for Pharmaceutical Sciences (CSPS). In focus are presentations given by two industry experts who have been heavily engaged on behalf of IPEC and the IQ Consortium in the dialogue with regulators on the novel excipient issues.[CLICK HERE.]

PART III continues with a review of the insights provided by an HC expert at the workshop about the formulation challenges and potential patient benefits of bringing more biologics into subcutaneous systems. [CLICK HERE.]

PART IV reviews the efforts that USP is now making to support novel/fit-for-purpose excipient development and usage involving excipient performance, naming, quality, biological safety, and monograph development. Reviewed are the discussions that took place at USP’s excipient stakeholders forum in November around the results of an influential survey USP conducted during 2019 to help assess the need for improved excipients and the impact of the current regulatory constraints on their development. [CLICK HERE.]

PART V shifts attention onto how to better understand the risks that excipients pose across the selection, manufacturing, supply chain, and product formulation/processing continuum.  In focus is a collaboration between PDA and the IPEC Federation, which resulted at the end of 2019 in a report on the “formalized risk assessment of excipients.” The report draws on and fleshes out key aspects of the FDA and international regulatory guidance on the issues. Understanding better the risks is another strong catalyst for having more fit-for-purpose excipient options available for managing them. [CLICK HERE.]

[Editor’s Note: IPQ has closely tracked the global industry/regulator dialogue on novel excipients as it evolved over the past decade, and a chronological listing of the related stories is provided immediately below.]


The following is a chronological listing of the headline and first paragraph of IPQ stories since 2010 that shed light on the increasing focus being placed on having excipients developed and accessible that are fit for purpose in meeting the evolving manufacturing and medicinal product needs. Click the headline for access to the full story.

Excipient Master File System Advocated for EU (2010)

An excipient master file (EMF) system in the EU would facilitate the review process, spur excipient R&D and harmonize with other regulatory systems, advocates are saying.

IQ Consortium Creates Foundation to Address Pharma Lab Data Disconnects as Momentum Builds in Second Year (2012)

The “International Consortium on Innovation and Quality in Pharmaceutical Development” (IQ Consortium) is putting in place a separate foundation to focus on developing a common format for generating, storing, retrieving, transmitting, analyzing and archiving pharmaceutical analytical lab data and the reports generated from that data.

EC Releases Outcome of Late-2011 Variations Consultation (2013)

The European Commission (EC) has released the outcome of the proposed changes to its variations rules in early February.  The proposed changes as described “were not considered sufficiently clear and clarification has been requested” by the 40 stakeholders, the EC summarized.

Interactions Between OGD’s Inactive Ingredients Database Working Group and IPEC on IID Content and Functionality Bearing Fruit (2013)

The cooperative effort between FDA’s Inactive Ingredients Database (IID) Working Group and the International Pharmaceutical Excipients Council (IPEC) to improve the IID’s content and functionality is beginning to bear fruit and will gain further momentum from the extra resources that will become available to the Office of Generic Drugs (OGD) to support projects that meet the Generic Drug User Fee Act (GDUFA) goals of creating a more efficient review process.

IPEC and IQ Consortium Team Up to Push for an Independent Pathway for New Excipient Review (2014)

A call to action is reverberating through the pharmaceutical community for the establishment of a viable regulatory pathway for new or modified excipients, which would empower industry to develop more quality-by-design-based formulations.

Novel Excipient Enables Successful MannKind Inhaled Insulin Formulation; Formulation/Device Inhalation Technology Offers Platform Potential (2015)

The development, testing, and use of a novel excipient as part of its formulation enabled MannKind to develop a viable inhaled insulin product after other firms’ insulin inhalation projects had not been successful.

Relationship with Excipient Providers Drawing Increasing Pharma Attention, BMS Exec Stresses; IPEC Urges Regulatory Pathway for New Excipients in GDUFA/PDUFA Comments (2015)

An important component in the ability of pharmaceutical innovators to bring their new products to market in the eclipsed timelines in which they need to function will be their relationship with excipient providers, a top manufacturing executive from Bristol-Myers Squibb (BMS) stressed to participants at the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas)/ExcipientFest conference.

IPEC Continues to Urge Family Approach in Dialogue with FDA on Improving Inactive Ingredient Database (2015)

IPEC-Americas and the Generic Pharmaceutical Association (GPhA) are continuing their advocacy of FDA incorporating a family approach in the toxicology assessment of excipients as they work with the agency on further improving the inactive ingredient database (IID) to support better drug development and more efficient FDA reviews.

Excipient Regulatory Approaches Globally Differ Widely in Registration, GMP, DMF, and Application Submission Expectations (2016)

An analysis of the way excipients are handled by regulators around the world reveals significant differences in the registration/licensing and GMP requirements as well as both the form and content of what needs to be submitted to support drug applications. 

Continuous Manufacturing is Driving More Focus on Excipient Fitness for Purpose (2017)

The deployment of continuous manufacturing (CM) is prompting the pharmaceutical industry to understand better the characteristics of the excipients they are using and work more closely with suppliers to assure that the materials are fit for purpose. CM is also prompting a harder look at how to open up the clearance pathway for new/modified excipients.

Global Excipient and Drug Manufacturers Weigh Implications of China’s New Excipient Dossier and “Bundling Review” Requirements (2017)

Global excipient and pharmaceutical manufacturers are weighing the complexities and consequences of the new “bundling review” requirement put in place by the China Food and Drug Administration (CFDA) in August 2016, which calls for excipient dossiers to be received, reviewed and approved as part of new drug applications. 

Novel Excipients, DMFs, and Atypical Actives Among Pressing Issues on IPEC-Americas’ Front Burner (2018)

Novel excipients, drug master files (DMFs), and atypical actives are among the pressing issues on which the International Pharmaceutical Excipients Council (IPEC) is actively engaged with the major regulatory agencies and standards organizations around the world.

Diverging Regional Excipient Regulations Are Creating Problems for Excipient Manufacture, Distribution and Use Globally (2018)

A review of the way excipients are regulated by agencies around the world reveals that regional regulations continue to proliferate and the differences are creating problems for the manufacture, distribution and use of excipients globally. 

IPEC Digesting Implications of China’s Ending of Separate Excipient Approval Process (2018)

The International Pharmaceutical Excipients Council (IPEC) is working with its members and China’s Center for Drug Evaluation [CDE] to digest and manage the implications of the decision in China to switch from a separate approval process for pharmaceutical excipients to submission and review of an excipient dossier together with a drug application.

The Processing and Formulation Complexities of Therapeutic Biologics Compel Heightened Focus on Excipient Needs (2019)

The processing and formulation complexities of the new generation of therapeutic biologics are compelling industry and regulators to take a hard look at the risks and requirements of the raw materials and excipients involved.

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