BioPhia Consultant Ed Moore presents a training video as part of the Great Lakes Medical Jumpstart I-CORPS program discussing the regulatory paths associated with Artificial Intelligence/ Machine Learning or Software as a Medical Device (SaMD).

Software as a Medical Device (SaMD) is a relatively new area of medical devices that are now regulated by FDA (CDER).  FDA partnered with regulatory authorities from other countries/regions to create the International Medical Device Regulatory Forum (IMDRF) which is a risk-based approach to determine validation guidance, quality systems, and clinical requirements for SaMD products.

The following presentation was given March 25, 2022 at Rosalind Franklin University for the Educational Series sponsored by the Office of the Executive Vice President of Research by BioPhia consultants Edwin Moore, PhD and Robin Geller, PhD.  It describes an overview of the regulatory processes and considerations for entrepreneurs and startup companies in the medical product space.  The overview presents considerations for the different regulatory paths for medical device, pharmaceutical and biologic products.  The presentation covers regulatory pathways and requirements of CDER (drugs), CBER (vaccines, blood, and biologics) CDRH (medical devices) and the Office of Combination Prodcuts.

Medical devices product development has taken an added significance with COVID-19 as new technology is being investigated to provide new approaches to PPE and clinical diagnostics. On February 5, 2020, BioPhia consultants Marc Minkus, Rich Johnson, and Ed Moore gave a presentation at EnterpriseWorks, the incubator at University of Illinois, Champaign-Urbana.

Medical devices cover a broad range of healthcare products from relatively simple bandages to complex devices such as heart valves, oxygenators, dialysis equipment, and clinical diagnostics equipment and reagents. At a presentation to entrepreneurs, students, and University of Illinois faculty at EnterpriseWorks (UIUC incubator in Champaign, Illinois), we provide some of the current best practices that are used in the industry today for development and commercialization of these medical products. Besides meeting regulatory requirements, these best practices ensure safety and efficacy of medical devices and delivery of quality results to patients. If you are engaged in medical device product development, we would be glad to discuss your specific projects and help you apply these best practices.

The presentation can be found for download at biophia.com/news

BioPhia principle consultant, Edward Chess shares his perspective on working with the USP on Expert Committees and Expert Panels.  In this article, he shares his unique perspectives of how the USP brings together experts from many areas to develop their robust reference standards that provide quality for the pharmaceutical industry.  He also shares about the benefits both individuals and companies gain from their participation with the USP.  Please click on the link below for the full article.

How USP Panel and Expert Committee members help create better standards: A personal perspective

Risk-Based Approach to Method Transfer

Jeffrey Staecker, PhD (jstaecker@biohpia.com)      BioPhia Consulting, Inc., November 1, 2018

An article summarizing the CMC Forum “Methods on the Move: Addressing Method Transfer Challenges for the Biopharmaceutical Industry” was recently published in BioProcess International and can be found at https://bioprocessintl.com/business/cmc-forums/methods-on-the-move-addressing-method-transfer-challenges-for-the-biopharmaceutical-industry/.   The article summarizes various ideas and approaches to test method transfer.

I was fortunate to both co-chair and present at this Forum where I focused on using a “Risk-Based Approach to Method Transfer”.  My presentation can be found on the BioPhia website (BioPhia website link inserted here).  Some key principles from my presentation include:

• Method transfers can introduce changes in bias and/or precision.
• The commonly employed risk tool of FMEA (Fault Mode Effect Analysis) can be utilized in evaluating the risk of method transfer.
• The risks associated with method transfers are impacted by how “close to the edge” the process as measured by current testing is running. That is, a centered process with results far away from specifications is less at risk than a process being measured as running near a specification extreme.
• Many companies use Cpk to monitor processes which can be leveraged to predict probability of errant results from introduction of bias and/or imprecision.
• A statistical approach can be devised to ensure that only an acceptable level of bias/imprecision is introduced during method transfer.
• After transfer, appropriate SPC (statistical process control) monitoring can ensure that method at receiving site continues to operate within pre-defined limits.

An alternative to method transfer is to use the identical statistical approach for all method transfers regardless of process/method performance.  The danger of this approach is to introduce a small amount of bias or imprecisions that passes method transfer criteria but results in inappropriately passing or failing material.  I personally experienced this when a method was transferred for a process running at the high end of the specification range.  The method transfer introduced a small bias (less than 2%) that resulted in inappropriately failing drug product.

Startup Companies turning ideas into viable products

Edwin Moore, PhD (emoore@biophia.com), BioPhia Consulting, Inc., September 10, 2018

I have been mentoring startup companies in the life sciences for the last couple years.  Great ideas are coming from university research labs that may become future products.  The faculty, postdoctoral fellows and graduate students are taking on these opportunities, but most have not had experience commercializing a product.  They have many questions and unknowns to work through.  Incubators affiliated with the universities can be a phenomenal resource to educate, provide valuable resources, and offer lab and office space.  I-CORPS (https://www.nsf.gov/news/special_reports/i-corps/) is a national program offered by the National Science Foundation that provide training on customer discovery and developing the fundamentals of a business plan.  SBIR and STTR funding (https://www.sbir.gov/about/) from government agencies provides non-dilutive funding to transition applied research to commercialization through the valley of death between initial seed funding and infusion of venture capital.  Finding these resources and gaining access is catalytic to budding entrepreneurs, but not always obvious even to those that have ready access.

First-time entrepreneurs in life sciences have many questions about setting up a business, navigating regulatory requirements, understanding legal aspects, and finding funding.  Literature from experienced entrepreneurs and mentors, e.g. Leah Cannon How to Start a Life Science Company (https://leahcanscience.com/2017/10/27/how-to-start-a-life-science-company/), can answer many of the generic questions. 

Connecting with an incubator can answer specific questions if the incubator has mentors and staff experienced in life science products.  Incubators vary broadly in the quality and quantity of resources they provide.  Incubators provide space, advice, and leads on funding.  Advice may be in the form of mentors with expertise in the areas that entrepreneurs need help, as well as staff with knowledge of commercialization.  Incubators can provide lab space and equipment needed for research and development along with offices.  Some incubators are part of the university, while others affiliated with the university, and some are for-profit that take a position in the companies.  One of the first steps for budding entrepreneurs should be to explore the incubators available and the enabling resources that they provide.  In Illinois, EnterpriseWorks (http://researchpark.illinois.edu/enterpriseworks) is an excellent example of an incubator that is part of University of Illinois providing resources, space, and mentors for budding startup companies.  The Illinois Innovation Network (https://www.illinoisinnovation.com/find-services-resources) provides access to other incubators in the ecosystem for startup companies.

I-CORPS is a phenomenal program started by the NSF to teach university startup companies about customer discovery and business knowledge needed to become successful.  Startup ventures accepted into I-CORPS are provided with seven weeks of an intensive program where teams are expected to participate in training sessions and conduct 100+ customer and customer-related interviews.  A cohort of chosen teams meet at the beginning of a program for 3 days at the kick-off session, at weekly webinars during the program, and at a two-day wrap-up to receive training and critique from a teaching staff of experienced entrepreneurs. Startup teams also hear about the trials and tribulations of other teams.  The NSF provides a grant to the teams to cover expenses for customer discovery.  Besides the direct benefit to the startup team, the team PIs learn the practical aspects of product commercialization, identify customer needs, and will hopefully apply those learnings to future grants and research in their academic labs.

Participation in I-CORPS dramatically improves the probability of funding through SBIR and STTR grants.  Congress created SBIR and STTR grants believing that small company startups were a valuable source of jobs for US citizens.  Agencies of the government are required to set funds aside for these grants to help transition academic research to commercial application.  Funds from SBIR grants in phase I are expected to provide for development of the concept and then commercialize the concept in phase II.  These funds are expected to be supplemented with venture funding as the development progresses.

There are numerous competitions that startup companies can participate, some dedicated to students and others open to any startup company.  At University of Illinois, COZAD competition (https://tec.illinois.edu/programs/cozad) is available to students.  iBIO, Illinois Biotech Innovation Organization, has PROPEL (http://ibioinstitute.com/category/propel/) that supports startup companies, holding business plan competitions that result in funding awards.  Competitions not only offer opportunities for funding awards, but they are a stage for entrepreneurs to present their companies, to sharpen their skills explaining their product concepts, and develop elevator speeches and pitches that will be useful when meeting with venture capital groups and shareholders.

Many companies that reach this stage recognize the need for a CEO who has connections with industry and venture capital.  Big companies, especially big pharma, have de-risked their internal profiles in favor of finding nuggets among the small and startup companies.  Many big companies have started venture funds to fuel development of products in areas of interest.  The CEO for a startup needs to have an understanding of the industry and how to structure venture funding to advance a product concept.  Individuals with knowledge and character to lead the startup company efforts and navigate the paths of uncertainty are crucial to a company success story.

If youre a budding entrepreneur, congratulations!  Still dont know what to do next?  Start digging into available resources and examples, like I-CORP: https://hbr.org/2017/03/this-program-uses-lean-startup-techniques-to-turn-scientists-into-entrepreneurs.  There is no path to follow you have to be resourceful and figure out what is right for your concept.  If you are a faculty with great technology and a great story to tell that could become a product, thanks for your ingenuity and persistence.  Now if you want to find application for that great research, find an entrepreneur willing to give heart and soul to make it happen, support as much as you can, and then stay diligent.  If you are an industry expert, your mentorship is gravely needed to bring this great new research and product concept to fruition.  Industry mentors are woefully lacking.  I found after retirement from my career in R&D product development that mentoring startups is extremely rewarding and a fantastic way to pay forward all those lessons I was privileged to learn.

Impact of Multi-Attribute Testing in the Biopharmaceutical Industry

I was fortunate to work with Bill Paulson in writing an article Biopharma Is Working with Analytics Providers and Government Agencies to Further Multi-Attribute Method Use in QC published in IPQ (International Pharmaceutical Quality) August 7, 2017.  I refer people to that article for the specifics of MAM and in this blog I will touch upon the business and strategic impact of multi-attribute methods (MAM) given the apparent inevitable implementation of MAM.

MAM utilizes mass-spectrometry to analyze biopharmaceuticals and is on the cusp of being ready for full implementation into development and QC (see IPQ article) and seems certain to become the primary biopharmaceutical method in coming years.  MAM offers the potential to bringing biopharmaceuticals a significant step closer to small molecule drugs that are defined rather than characterized.  Below are some of the current analytical technologies that MAM has the potential to replace in product development and QC:

• SDS-PAGE and cSDS
• Existing methods for glycan analysis
• Various methods used to assay for purity
• ELISAs used for HCP quantitation
• Various identity tests
• Methods used to quantitate charge variants

The economic drivers to move forward with MAM include:

• Cost savings from reduced QC testing
• Improved quality from using a test that tells us more about our product
• The ability to retrospectively expand analysis by pulling up older data

It would be remiss to overlook a couple of hurdles MAM still needs to overcome comprehending that there are no significant technical barriers:

• Establishing a history of method and instrument robustness
• Worldwide regulatory acceptance and implementation

Additional implications of MAM implementation include:

• Smaller QC staffing/footprint
• Fewer instruments required for product development and QC testing
• A shift in needed analytical skill-sets

All industries that encounter a fundamental change in business as usual corresponding to a substantial increase in efficiency are challenged by changing business practices, finding people familiar with the innovative technology and the displacement of people and companies.  While large biopharmaceutical companies have systems in place to plan around the eventual implementation of MAM and the impact on lab footprint, changing technical needs, and cost to doing business,  how are peripheral and smaller companies situated in preparing for the changes that will come about as MAM is implemented?  Some examples of potential changes include:

• Reduced need for instruments and reagents for technologies to be replaced
• How does the contract industry that the biopharmaceutical industry is dependent on adjust to the change? Have these industries yet considered how to establish this new technology?
• When is it prudent for smaller biopharmaceutical companies to embrace MAM? The need of smaller companies and their dependence on contract companies will require an evolution of their interdependence that will be an interesting story to watch
• Maintaining older methods and the companies required to support those methods until the analytical life cycle catches up with MAM

Currently MAM is slowly being implemented by large, biopharmaceutical companies with drivers including government agencies, business leaders, and vendors heavily investing in this technology.  It seems likely that MAM will be embraced first by large biopharmaceutical companies and leading regulators followed by smaller companies and world-wide regulatory acceptance.  A seminal event in this story will be when any major regulatory group requires implementation of MAM based on safety/quality desires.

Note:  To read the full article in IPQ requires a subscription to this journal.  I recommend that people and groups look through the free IPQ online content at https://www.ipqpubs.com/ and consider subscribing to the contents.