2018 BPI West Attendees Hungry for Process Validation & Regulatory Strategies for Fast-track and Breakthrough Therapies

Process Validation for Expedited Approval Drugs

BioTechLogic’s Tracy TreDenick delivered a very well-received presentation at this year’s BPI West discussing process validation and regulatory strategies for expedited approval drugs.

BioTechLogic has done numerous projects supporting clients working to bring therapeutics with accelerated approval status to market. Given the complexity and the challenge of these programs, it’s little surprise that the talk was of such great interest.

Highlights of the presentation included discussion of:

  • Overview of FDA’s Expedited Pathway Designations
  • Look at 2012-2017 Breakthrough Therapy (BT) designation by therapy
  • Expedited vs traditional development program timelines
  • Common challenges for Breakthrough Therapy products
  • Regulatory
  • Common process development challenges for BT Products
  • Common analytical challenges for BT products
  • Common manufacturing challenges for BT products
  • Keys to a successful regulatory strategy
  • Understanding scientifically complete CMC sections
  • Process validation
  • Keys for successful validation

Review full presentation deck below:

Article: Why Data Integrity Is More Important Than Ever


We are thrilled that our contributed article, “Why Data Integrity Is More Important Than Ever,” was published in the January/February 2018 issue of Pharmaceutical Manufacturing magazine.

Read Article

Access full January/February 2018 issue of Pharmaceutical Manufacturing

Cellular Therapeutics – Exploring Challenges within the Regulatory Framework

This presentation explores the progress that has been made and the challenges ahead as cellular therapeutics strive to mature in the marketplace.

Cell Therapies Come of Age: Overcoming Challenges Within the Regulatory Framework

Cell Therapies Come of Age

By Tracy TreDenick, Head of Regulatory and Quality Assurance, BioTechLogic

While the field of stem cell therapy has been in development for decades, most notably with the first successful bone marrow transplant in 1968, regenerative medicine is now experiencing rapid progress fueled by scientific and technology advancements. Although cellular therapeutics benefits greatly from embryonic stem cells, debates over the ethics of this type of research has led to the discovery of a more sustainable alternative, somatic stem cell research.

This said, many of the emerging cell therapies are scientifically and medically complex with many learnings and understandings still to come. As if core scientific and medical complexities were not enough, the industry, medical community and regulators are grappling with the challenge of conforming the regulatory framework to support the commercialization of cellular therapies, for instance cellular therapy classification, quicker approval pathways, and CMC challenges.

Cell Therapies:  A Drug or not a Drug?

Within the cell therapy arena, regulators, the medical community and industry alike are often confronted with an unsettling question. What is this, really? Should a given cell therapy be regulated as human cells, tissues, and cellular and tissue-based products (HCT/Ps), or should the cell therapy be regulated as a drug with the FDA oversight and regulatory approval process that accompanies that designation?

As cell therapies have become more common and indications have expanded, it’s becoming increasingly common to be trapped in “no man’s land” trying to answer this question, creating tension and confusion for the range of stakeholders involved in the decision-making process. Today, the dispute primarily centers around somatic stem cells that are harvested and prepared for transplantation through minor surgical procedures at stem cell clinics and other medical service providers.

Mesenchymal stem cells (MSCs) are collected from a patient’s own bone marrow or fat tissue, or from donor tissue not altered or manipulated and can form fat, bone or cartilage, making them useful for repairing bones and joints, minimizing inflammation caused by conditions such as rheumatoid arthritis, and promote the repair of a range of tissues. Hundreds of stem cell clinics now perform procedures with MSCs that are regulated as HCT/Ps under Public Health Service Act (PHSA) section 361. Procedures falling under section 361 classification are subject to regulations similar to that of other surgical procedures that are primarily aimed at avoiding contamination, infection and the spread of infectious disease.

HCT/Ps that require “manipulation” or alteration are governed by PHSA section 351. These products/procedures are considered to be indistinguishable from drugs and must undergo a rigorous regulatory approval process before being administered to patients. Some of the lines that separate section 351 products from those of section 361 are clearly drawn. For example, cells and tissues used homologously, meaning they perform the same function in the recipient as they do in the donor — such as the transplantation of bone marrow to restore healthy blood-cell production, are regulated under section 361. And therapies that employ a patient’s own stem cells (autologous) are more likely to fall under section 361 than those that use allogeneic cells (from a donor).

So back to the question at hand: A drug or not a drug? Broadly, the FDA considers a product to be a drug if “more than minimal manipulation” is required for its effectiveness. Ambiguities can arise, however, because merely separating stem cells from their neighboring cells always entails some degree of manipulation.

The question of minimal manipulation was… click to continue reading article.


Oligonucleotides: Opportunities, Pipeline and Challenges At Long Last, Nucleic Acid Therapeutics Are Coming of Age

BioTechLogic Perspectives on Oligonucleotide Therapies

Oligonucleotides: Opportunities, Pipeline and Challenges At Long Last, Nucleic Acid Therapeutics Are Coming of AgeRecently, I sat down with Tracy TreDenick, BioTechLogic’s Head of Regulatory and Quality Assurance, to learn more about her insights and experiences from the extensive oligonucleotide therapeutics work BioTechLogic has done.

Q: Briefly describe the types of work you have done within the oligonucleotide space?

A: BioTechLogic has done a great deal of working with oligonucleotide products in recent years, including process validation work for drug substance, drug product and an oligo adjuvant.

Just some of BioTechLogic’s oligonucleotide work has included:

  • CMO on-site support
  • Equipment qualification protocols
  • Commercial-ready batch records
  • Support validation protocols and studies
  • Process validation
  • Manufacturing support
  • Technical support
  • Facility validation reports
  • Microbial monitoring strategies
  • Commercialization plans
  • Formulation development reports
  • Process control strategies
  • Chromatography column troubleshooting
  • Multiproduct facility CV site policies and strategies

Q: What are the most common challenges you have confronted while working on oligonucleotide products, and how has BioTechLogic addressed these challenges?

A: One of the most common challenges is the environmental classifications for manufacturing this kind of product because in many situations, the product is not a finished product or an API, but an adjuvant. There are guidelines for drug products, and ICH Q7 for APIs, but not specific guidelines for adjuvants. BioTechLogic has had to evaluate the environmental requirements based on the needs of the product.

Another challenge is balancing the U.S. FDA filing requirements (macro-molecule) to the EU’s “centralized procedure” which is used for biologics. For the most part, this challenge has been addressed by applying the most stringent of the two requirements, allowing the given product to be filed both in the United States and in the European Union (EU).

Q: Share your views on the oligonucleotide product regulatory debate, including the likely issues that will surface on the regulatory landscape as these products mature.

A: The U.S. technical/regulatory experts for oligonucleotides say these are just macro-molecules, a type of large “small molecule,” as opposed to a biologic. A biologic is typically difficult to characterize using analytical procedures, while small molecules are far easier to characterize. There is some debate about impurities and quality assurance when manufacturing oligonucleotide products; however, via improved analytical instrumental technologies and new approaches, the industry has made a lot of ground here. But typically, the difference in regulatory environment amounts to what type of manufacturing support validation that you have to do for a biologic as opposed to a small molecule, and there is generally more complex work for a biologic.

Oligonucleotides: Opportunities, Pipeline and Challenges At Long Last, Nucleic Acid Therapeutics Are Coming of Age

101 Overview: CRISPR-CAS9

This inforgraphic is a wonderful overview for those familiarizing themselves with work going on within the genetic engineering space – hope you find it helpful. The website that created this infographic, www.Futurism.com, while not dedicated to life sciences, publishes quite interesting content within a range of up and coming areas.

CRISPR-CAS9 Infographic

Stem Cell Manufacturing: Stem Cell–Based Products Aren’t Rolling Off Assembly Lines Yet

Stem Cell Manufacturing: It’s All about Scale

According to one forecast, the stem cell market will grow at an annual rate of 9.2% and attain a value of almost $16 billion by 2025. This prediction, from a 2017 study by Grand View Research, may not justify any career- or life-altering decisions—not by itself. It does correlate, however, with figures showing consistent growth in the volume of published research. Because these market research results and bibliometric figures support each other, their common implication—high year-on-year growth in the stem cell market—seems reasonably certain.

Much of the stem cell market’s growth comes from the development and manufacture of stem cell therapeutic products. In this segment, the challenge is—and always will be—manufacturing at scales commensurate with profitability.

“Stem cell processes involve many complex, open-process steps that are still largely unintegrated and manual,” notes Aaron Dulgar-Tulloch, Ph.D., director of cell therapy R&D at GE Healthcare. “This in turn contributes to high variability and operational costs, which increase risk and drive up cost of goods.”

Stem cell therapies, in particular, face the extraordinary challenge of producing from undifferentiated cells a product that is completely matured into the desired therapeutic cell lineage.

GE Healthcare’s involvement in stem cell production dates from the industry’s earliest days. In January 2016, GE Healthcare contributed to a $40 million investment in the Toronto-based Centre for Commercialization of Regenerative Medicine (CCRM). Later that year, in April, GE Ventures teamed with the Mayo Clinic to launch Vitruvian Networks, which provides software for producers of cell-based therapies. A few months later, in August, GE Healthcare acquired the Biosafe Group, whose specialty was cell and cord blood bioprocessing.

In April 2017, GE Healthcare acquired Asymptote, a cryogenic processing company, and announced a partnership with the Cellular Biomedicine Group to develop chimeric antigen receptor T cell (CAR-T) and stem cell production technologies. In October 2017, the company opened its first 3D printing laboratory in Uppsala, Sweden. Thus, GE Healthcare thus covers quite a few bases in the cell therapy marketplace, in addition to maintaining its eminence in traditional bioprocessing.

With the increasing number of cell and gene therapies moving into mid- to late-stage clinical trials, observes Dr. Dulgar-Tulloch, “companies are challenged to improve their manufacturing process to minimize impact on their clinical development timeline and help ensure cost- and time-effectiveness.” Continue reading article

On the Cusp of a Biomedical Revolution – Best of CRISPR 2017 Articles

Best of CRISPR 2017

One can hardly pick up a science journal or biotech magazine without reading about another CRISPR-related advance. In the past six months, we have seen major advances in editing disease-causing genes in human embryos. New tools include RNA-editing CRISPR systems and ultra-precise base editors. In the latter, a modified Cas protein pinpoints and tweaks a specific nucleotide, rather than completely cleaving the double helix. In this timely supplement, GEN has compiled a selection of topical features on novel applications of CRISPR/Cas9 that neatly capture the incredible excitement and potential of this technology. Kicking things off is Malorye Branca’s excellent feature exploring clinical applications of CRISPR therapies entitled: “A Dose of CRISPR: Can Gene-Editing Cut It in the Clinic?” (This originally appeared as a cover story in GEN’s sister magazine, Clinical OMICs.)

Other articles from GEN in this supplement cover a broad range of issues, including enhancing and scaling up fundamental CRISPR genome-editing technology, and a range of new applications from engineering the pig genome for safer organ transplantation to various novel strategies in gene therapy.

Best of CRISPR 2017 Articles Include:

  • A Dose of CRISPR: Can Gene Editing Cut It in the Clinic?
  • Genome Engineering: CRISPR Proving More User-Friendly
  • Using CRISPR to Improve Disease Modeling
  • Gifted Scientists Rapidly Advance CRISPR Operations
  • Genome Editing Explores New Depths
  • Applications of Novel CRISPR Tools

Read Best of CRISPR 2017 articles

Comprehensive Regenerative Medicine Policy Framework Announced by FDA

FDA announces comprehensive regenerative medicine policy framework

On November 16, 2017 the U.S. Food and Drug Administration announced a comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies.

The framework – outlined in a suite of four guidance documents – builds upon the FDA’s existing risk-based regulatory approach to more clearly describe what products are regulated as drugs, devices, and/or biological products. Further, two of the guidance documents propose an efficient, science-based process for helping to ensure the safety and effectiveness of these therapies, while supporting development in this area. The suite of guidance documents also defines a risk-based framework for how the FDA intends to focus its enforcement actions against those products that raise potential significant safety concerns. This modern framework is intended to balance the agency’s commitment to safety with mechanisms to drive further advances in regenerative medicine so innovators can bring new, effective therapies to patients as quickly and safely as possible. The policy also delivers on important provisions of the 21st Century Cures Act.

“We’re at the beginning of a paradigm change in medicine with the promise of being able to facilitate regeneration of parts of the human body, where cells and tissues can be engineered to grow healthy, functional organs to replace diseased ones; new genes can be introduced into the body to combat disease; and adult stem cells can generate replacements for cells that are lost to injury or disease. This is no longer the stuff of science fiction. This is the practical promise of modern applications of regenerative medicine,” said FDA Commissioner Scott Gottlieb, M.D.

“But this field is dynamic and complex. As such, it has presented unique challenges to researchers, health care providers, and the FDA as we seek to provide a clear pathway for those developing new therapies in this promising field, while making sure that the FDA meets its obligation to ensure the safety and efficacy of the medical products that patients rely upon. Alongside all the promise, we’ve also seen products marketed that are dangerous and have harmed people. With the policy framework the FDA is announcing today, we’re adopting a risk-based and science-based approach that builds upon existing regulations to support innovative product development while clarifying the FDA’s authorities and enforcement priorities. This will protect patients from products that pose potential significant risks, while accelerating access to safe and effective new therapies.”

The framework includes two final guidance documents and two draft guidance documents. Read more

Top 10 U.S. Biopharma Clusters

Top 10 U.S. Biopharma Clusters
Bruce Booth, D.Phil., a partner at Atlas Venture, astutely observed earlier this year that two key resources fueling the growth of biopharma were until recently somewhat geographically spread among the 10 or so regions of the nation where the industry began to arise a generation ago.

“In recent years, this has changed—Boston and San Francisco are now the preeminent biotech clusters.  And their gravity in the ecosystem is only getting stronger,” Dr. Booth concluded in a March 21 post on his Life Sci VC blog. “Beyond having great science and the right ‘pixie dust’ in the local environment, two fundamentally important ingredients to the success of any cluster are capital and talent—and both are aggregating into the two key clusters.”

So it’s no surprise that Boston/Cambridge, MA, and the San Francisco Bay Area again top this year’s GEN List of the nation’s top 10 biopharma clusters, as they did last year and in 2015. Yet that’s not to say the other eight clusters rounding out the list are the proverbial chopped liver; they too have significant assets that make them attractive to biopharma researchers, executives, and investors, often drawing upon heritages that include the presence of big pharmas or home-grown biotech giants.

And while the regions making the list this year will be very familiar to biopharma industry watchers, the regions just below the top 10 also continue to build clusters that may someday propel them to future GEN lists. Highest among those remains Denver at No. 11, which ranked higher on two criteria—ninth in lab space (4 million square feet) and 10th in jobs (27,666, according to JLL).

GEN ranks regions based on five criteria:

  • NIH funding—Taken from the publicly available NIH RePORT database, for the current federal fiscal year, from its start on October 1, 2016, through May 23, 2017.
  • Venture Capital (VC) funding—Taken from 2016 and Q1 2017 figures furnished by the publicly available MoneyTree Report.
  • Patents—Based on the number of patents containing the word “biotechnology” awarded since 1976 in namesake cities and suburbs where key companies are located.
  • Lab space—Based on total-size-of-market figures, in millions of square feet, furnished by the commercial real estate brokerage JLL in its U.S. Life Sciences Outlook report for 2016.
  • Jobs—Based on JLL’s report. While job numbers are ranked this year compared with last year’s Top 10 US Clusters list, less weight had to be given to job totals in regions where GEN has found widespread discrepancies in job figures. However, workforce size was factored in when deciding the ultimate position of a region.

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Process Validation in the Age of Expedited Drugs CTA