Recently, 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.

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

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

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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Since their discovery, gene therapies have been praised for their ability to effectively deliver cures for debilitating diseases and conditions, many of which have no other alternative treatment options available. The number of gene therapy clinical trials continues to climb both in the US and worldwide. With frequent reports of successes in many of these gene therapy clinical trials, the US market may soon see the additional gene therapy drug products on the market. While gene therapies are not a new concept, the ability to bring gene therapies to the brink of widespread commercialization is due in large part to enhanced vector design and improved CMC strategies. A variety of viral vectors have demonstrated in many recent trials that therapeutic genes can be delivered safely, with researchers reporting remarkable evidence of efficacy.

While significant advancements have been made, gene therapies still present many manufacturing challenges, including the variability and complexity inherent in the components used to generate the final product (e.g., cell source and raw material quality), the potential for agent contamination, the need for aseptic processing, and low batch yields.

Earlier days of gene therapy development and the sometimes-dashed hopes of both developers and regulators taught us that very early phase product understanding and characterization is critical. This white paper discusses early-phase requirements for gene therapy products and the unique challenges they present. At several points, the white paper will also discuss longer-range challenges and approaches that will ultimately affect the outcome of the development process and the eventual marketability of the product.

Gene Therapy Products and How They Are Used

Gene therapies are quite different than traditional small-molecule drugs or even other biologics. They work by delivering altered genetic material or, less commonly, by adjusting the sequence of the human genome. Gene therapy products consist of genetically modified nucleic acids, or viruses. They often achieve their targeted effects by transferring genetic material that is then transcribed or translated inside a cell, resulting in a new RNA and protein. As mentioned above, a therapeutic is also considered a gene therapy when it directly modifies the human genome—for instance, by modifying its sequence.

How are gene therapy products used? Often, gene therapy vectors are administered directly to the patient, modifying the patient’s cells to achieve the desired outcome. In fact, this delivery is often accomplished using a virus to carry the genetic cargo into the targeted cells.

CMC Section of a Gene Therapy IND

As gene therapy developers move into the formal development process, they must consider regulatory requirements and proactively set the stage for successful later-phase development. This often means working well beyond IND requirements. The CMC section of a gene therapy IND is designed to help regulators assess whether the developer has provided sufficient information to assure the proper identification (i.e., identity testing), quality, purity, and strength of the investigational drug product.
Required Raw Material Information
All the components used in the manufacturing of a gene therapy product, including raw materials, must be considered. A raw material may refer to any component or element used in the manufacture of a gene therapy product or active ingredient. This includes any material that comes in contact with an active ingredient or…continue reading.

Opportunities and Challenges in Biosimilar Development

A biosimilar biotherapeutic product is similar (but not identical) in terms of quality, safety, and efficacy to an already licensed reference product. Unlike generic small molecules, it is difficult to standardize such inherently complex products based on complicated manufacturing processes. Table 1 describes the main differences between biosimilar and generic drug molecules.
Table 1: Major difference between biosimilars and generic drugs

The global biosimilar market is growing rapidly as patents on blockbuster biologic drugs expire (Table 2) and other healthcare sectors focus on reduction of costs. Biologics are among the highest-cost treatments on the global market today, which implies the need for low-cost alternatives. In emerging markets, biosimilars already offer more affordable prices, which are not only attractive, but indispensable to economies where expensive treatments are not financially feasible (1). Interchangeability of biosimilars could have a big impact on drug budgets around the world. However, concerns remain about the effect that could have on patients in terms of safety and efficacy.
Table 2: Patent status of some innovator biologics (3)

Developing and manufacturing biosimilars is challenging, so well-established biopharmaceutical companies are investing in these important medicines. As Table 3 shows, Continue Reading Article

Two famous pharmaceutical industry quotes encapsulate industry thinking and the push for progress in recent years. Upon launching Pharmaceutical cGMPs for the 21st Century – a Risk-Based Approach, Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER), shared the following vision: “A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drugs without extensive regulatory oversight.”

Gerry Migliaccio, former head of global quality at Pfizer, once notoriously stated, “We produce six sigma products with three sigma processes.” Gerry was referring to the fact that the pharmaceutical industry’s over-reliance on compliance-based inspection to achieve quality is a very ineffective way to do business and that most other industries, even those in heavily regulated environments such as nuclear and aviation, moved away from this way of working many years ago.

Before exploring FDA action to achieve the outlined vision and address the great challenge shared by Mr. Migliaccio, it is important to recognize some of the primary pharmaceutical quality issues the industry and regulatory community have been wrestling with in recent years:

• Treatment of all products equally, resulting in a disproportionate amount of regulatory attention devoted to low-risk products, diverting needed resources for high-risk products.
• Unacceptably high levels of product recall and defect reporting that is too frequently rooted in defects in product and process design.
• Shortages of critical drugs in recent years are also often the result of ineffective product and process design and the lack of effective quality management systems.
• Inspections are not well connected to knowledge gained from product review and applications.
• Because current FDA practice “locks in” a process before it is fully optimized, post-approval supplement submission levels are substantially higher and are a burden to both the FDA and industry.
• Product review is often conducted based on pre-marketing data from exhibit or clinical batches. There may be significant differences between these data and the conditions of commercial production.

So, within an environment of increased drug product complexity, the need for greater numbers of different specialty drugs to treat smaller patient populations, and more complex drug product supply chains, the industry and the regulatory community still:

• Do not understand their products and processes to the degree necessary
• Are hampered by a compliance-based regulatory framework that does not allow easy adjustment of processes based on the ongoing accumulation of product and process understanding
• Operate within the framework of all products, regardless of risk, essentially being treated equally

To move toward a system that ultimately regulates quality rather than compliance, the FDA and other regulatory bodies around the world are working to move to a system that considers drug product risk in a strategic manner. As other heavily regulated industries have already recognized, all products and situations should not be treated equally. Rather, regulatory resources need to be more heavily focused on the greatest areas of risk.

To achieve a risk-based construct, CDER’s new Office of Pharmaceutical Quality (OPQ) formulated the New Inspection Protocol Project (NIPP) incorporating five priorities: regulatory science, globalization, safety and quality, smart regulation, and stewardship.

NIPP will strive to differ from regulatory and inspection practices that have been in place for decades by using informatics, internal analysis, and other digital tools to prepare for and steer inspections. By utilizing data and predictive analytics, NIPP will allow the development of algorithms to reveal product quality challenges and facilitate inspections that concentrate on high-risk, inconsistent processes and products. A key aim of the NIPP is to focus attention and resources on high-risk processes and products so that, ultimately, quality improvements can be identified and made more quickly.

Organizationally, the NIPP consists of three subgroups: Pre-approval Inspection Protocol(s) subgroup, the Surveillance Inspection Protocol(s) subgroup, and the For Cause Inspection Protocol(s) subgroup. These subgroups will mine regulatory data to improve the FDA’s understanding of processes and approaches that produce quality products.

The FDA is using informatics as the cornerstone of NIPP. A database will evaluate the history of a given pharmaceutical manufacturing site for the following eight facility risk factors:

1. Process
2. Research
3. Analytical Methods
4. Sterility/Microbiology
5. Inspections
6. APIs and Excipients
7. Chemistry Manufacturing and Controls (CMC), and
8. Policy/Enforcement Actions

An algorithm will calculate the findings from the historical data and integrate them with product and facility risk factors to calculate a site ranking. Ultimately, higher-risk pharmaceutical manufacturing inspection sites will be identified and given priority resources.

To increase regulatory efficiency, based on the knowledge garnered from the NIPP inspections, the FDA can make more informed decisions on frequency of inspections, prioritization of inspections, and more effective pre-inspection planning so that time on site is optimized as fully as possible and hours are reduced as much as possible.

In the end, NIPP’s and OPQ’s goals are to strive for inspections that determine quality and more closely scrutinize risk-intensive products and operations, rather than inspecting for adherence to SOPs and other such regulatory criteria that may or may not lead to higher-quality products that reduce patient risk.

Interested in Process Validation in the Era of Expedited Approval Drugs? Download the White Paper from BioTechLogic