Grant Playter

A discussion with Laks Pernenkil, principal and practice leader, US Life Sciences Product & Supply Operations, Deloitte, who highlights the findings of Deloitte’s 

 report and emphasizes the impact that digitalization is having on data generation and data integrity.

Laks Pernenkil, PhD, is a principal in Deloitte’s Life Sciences Product, Supply, Manufacturing and Quality Operations practice based in McLean, Va. He has more than 15 years of consulting and technical operations experience in pharmaceutical, biologics and medical device sectors. At Deloitte, his experience includes smart/digital manufacturing and plant floor operations, plant engineering, facilities management, material sourcing, distribution, performance improvement, operational excellence, and market entry operations strategy.

Videos

Laks Pernenkil, principal and practice leader, US Life Sciences Product & Supply Operations, Deloitte, discusses the impact that digitalization is having on data generation and data integrity in bio/pharma manufacturing.

The Era of Digital Data in Bio/Pharma Manufacturing

Podcast, Shawn Liu, the president and CEO of Avirmax, relates his experience in entering the cell and gene therapy (CGT) manufacturing space and how he began his own startup cell and gene therapy CDMO. He discusses the challenges of establishing his company’s own CGT manufacturing facility and points out the pitfalls and what to avoid when starting up a business in this space.

Shengjiang (Shawn) Liu is president and CEO of Avirmax. He has 40 years of experience in virology and 28 years’ experience in biotechnology. He has entrepreneurial experience in life sciences and in biologics and business development. He has a strong research background and earned his PhD with a focus in Biochemistry from Kansas State University.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

Podcasts

In this episode of the Drug Solutions Podcast, Shawn Liu, the president and CEO of Avirmax, relates his experience in entering the cell and gene therapy manufacturing space and how he began his own startup cell and gene therapy CDMO.

Drug Solutions Podcast: Starting Up in the CGT Manufacturing Space

In an industry where product recalls and patient litigation can fundamentally undermine profit, adventitious agent testing is crucial in making certain that biologics products are free from contaminants. Consequently, 

® spoke with Kerstin Brack, PhD, scientific director of Global Biosafety at Charles River Laboratories, to update readers on the state of the industry. Topics of discussion include novel innovations in adventitious agent testing, key ongoing challenges, and what the future of the space may look like.

 What are some novel technologies/processes in the adventitious agent testing field? What makes them unique relative to existing procedures?

 Traditional test methods, which are used for adventitious agent testing, require the replication of an infectious agent either in culture media, cell cultures, or animals. After a suitable incubation period, the test system is checked for signs of an infection. Such endpoints could be the formation of bacterial colonies, cell death, or disease symptoms in animals. These assays are lengthy and usually take two to four weeks, or even longer, from initiation to read-out.

A major limitation of these assays is that false negative results are obtained when the used test system is not suitable to support the growth of a contaminant present in the tested sample. Conversely, in case of a positive result, further analyses are required to identify the causative agent. In addition to these unspecific screening assays with a broad detection range, polymerase chain reactions (PCRs) are also an important part of the testing strategy which allow the sensitive detection of nucleic acid molecules of specified adventitious agents within one day. However, prior knowledge of the target is needed, and contaminants will not be detected if primers and probes do not bind to their target sequences. If a positive result is obtained, follow-up investigations are needed to determine if the nucleic acid is associated with an infectious agent or if it is non-infectious.

New advanced detection methods have been developed in the past two decades which are suitable to overcome some of the limitations of the traditional testing methods. Most important to mention is next-generation sequencing (NGS) which allows the sensitive detection and simultaneous identification of contaminants within days by unbiased amplification of all present nucleic acid molecules in a sample and high-throughput sequencing. After data processing and bioinformatic analysis, a database is used to map and identify the detected sequences. This technology has the potential to replace the animal- and cell-based adventitious virus tests as well as PCR tests and microbial detection assays. Other examples for novel technologies are rapid sterility tests, which have a reduced incubation period from two weeks to less than one week by using endpoints such as adenosine triphosphate (ATP)-dependent bioluminescence or carbon dioxide-induced pH shift of culture media. These surrogate markers for microbial growth allow an earlier read out and faster time to result compared to the traditional culture methods. In addition, rapid microbiological methods often require less sample volume and have the advantage of being automated and adapted to high-throughput testing of samples.

Other examples for novel technologies are rapid sterility tests, which have a reduced incubation period from two weeks to less than one week by using endpoints such as adenosine triphosphate (ATP)-dependent bioluminescence or carbon dioxide-induced pH shift of culture media. These surrogate markers for microbial growth allow an earlier read out and faster time to result compared to the traditional culture methods. Rapid microbiological methods often require less sample volume and have the advantage [of being] automated and adapted to high-throughput testing of samples.

 What are the biggest challenges in adventitious agent testing? What solutions, if any, are in the works to resolve them?

 It is a big challenge that traditional test methods have their limitations, as mentioned above, and therefore there is still a risk that adventitious agents are not detected. Furthermore, sample matrices can be toxic for the cells used as detector cells in the 

 adventitious virus tests. The cells die after they were exposed to the sample, and an evaluation of the test is not possible. As a consequence, such cytotoxic samples must often be diluted for testing, which lowers the sensitivity of the method. Using NGS for adventitious virus testing can be an alternative for toxic samples matrices. Similarly, live virus vaccine harvests contain the infectious vaccine virus which must be neutralized by specific antibodies prior to adventitious virus tests in cell cultures or animals. If antibodies are not available, NGS is an alternative for adventitious virus detection. The traditional adventitious agent tests are tedious. The 

adventitious virus test, which is routinely used for adventitious virus detection, takes 14 or 28 days, respectively. These timelines are not tolerable for the production of cell therapy products with a short shelf life of only a few days.

 Would you characterize adventitious agent testing as a field that has frequent change, or are the technologies/processes relatively constant year-over-year? Why?

 Although new analytical test methods for adventitious agent testing have advantages, it takes time for these newer methods to be accepted by the industry and regulating agencies and to be implemented into corresponding guidelines. The current revision of the ICH [International Council for Harmonisation] Q5A guideline (1), 14 years after the last changes in 1999, was driven by the necessity to provide guidance to ensure viral safety of new advanced modalities and new manufacturing processes. Furthermore, next-generation sequencing and broad-range molecular virus detection methods are available today and can be used to supplement or replace traditional virus detection methods. Their integration into the testing strategies also supports the efforts to reduce animal testing in the manufacture of biological products. Thus, multiple significant changes in the field have accumulated and made it necessary to revise the underlying guideline.

 Which production stage is most at risk of contamination?

 The fermentation phase offers the chance for adventitious agents to enter the manufacturing process, for example via contaminated raw materials. The unprocessed fermenter harvest represents the most relevant process intermediate for adventitious agent testing in batch production. At this stage, potentially present adventitious agents had the chance to accumulate during the fermentation process and are not yet removed or inactivated by the following downstream process. Therefore, unprocessed bulk harvest samples offer the highest probability to detect adventitious agents, if present.

 Cell therapies are a bit of a different beast in terms of viral
testing. What unique challenges exist in this space?

 Viral testing is of major importance for cell therapy production processes for several reasons. Human cells are susceptible to human virus infections. Additionally, biological raw materials are frequently used for production. On the other hand, there are generally no process steps that are capable of inactivating or eliminating adventitious agents. At the same time, cell therapies often have a reduced shelf life, and test results are required in a short time. Therefore, lengthy traditional test methods are not suitable for viral safety testing of cell therapies, and rapid molecular and microbiological methods are used to address the identified contamination risks.

For cell therapy products, it is therefore critical to ensure the virus safety of the product by testing the used raw materials and starting materials after a thorough risk assessment of the manufacturing process. That said, another challenge is the limited availability of sample material for testing because of small production lots.

 Do you have any predictions for how the industry will handle virology testing 10 years from now?

 There are published data available which demonstrate that NGS is suitable to replace the traditional 

 adventitious virus tests (2). Together with the current efforts to reduce the use of animals for testing, it can be expected that in the coming years animal-based adventitious virus tests will only be used in well-justified exceptional cases.

 Do you have any final thoughts on this topic that you’d like to share with our readers?

Technologies for adventitious agent detection will further evolve towards more sensitive and rapid methods with broad detection ranges. Applications based on artificial intelligence and machine learning have the potential to revolutionize this field. However, the development of new technologies takes time. They must be validated thoroughly to demonstrate their suitability before they are accepted by the industry and regulating agencies and are implemented into testing strategies for adventitious agent control in biomanufacturing.

Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

2. Beurdeley-Fehlbaum, P; Pennington, M; Hégerlé, N.; et al., Evaluation of a Viral Transcriptome Next Generation Sequencing Assay as an Alternative to Animal Assays for Viral Safety Testing of Cell Substrates.

, 41 5383-5391. https://doi.org/10.1016/j.vaccine.2023.07.019

Grant Playter was formerly the associate editor for 

Articles

With advancements in analytical technologies, such as next-generation sequencing, the industry is transitioning towards next-gen technologies for adventitious agent testing.

A Look at Next-Gen Technologies in Adventitious Agent Testing

The Centers for Medicare & Medicaid Services (CMS) announced the first 10 drugs whose prices will be directly negotiated with drug companies on Aug. 29, 2023. According to an agency press release, these negotiations will occur during 2023 and 2024, with any negotiated prices coming effective at the start of 2026.

The most commonly treated conditions in the list include diabetes, heart disease, blood clots, arthritis, and psoriasis. According to a 

 released by the agency, the full list of drugs is:

Eliquis (apixaban), intended for prevention and treatment of blood clots.

Jardiance (empagliflozin), intended for treatment of diabetes and heart disease.

Xarelto (rivaroxaban),  intended for prevention and treatment of blood clots, as well as reduction of risk for patients with coronary or peripheral artery disease.

Januvia (sitagliptin), intended for treatment of diabetes.

Farxiga (dapagliflozin), intended for treatment of diabetes, heart disease, and chronic kidney disease.

Entresto (sacubitril/valsartan), intended for treatment of heart failure.

Enbrel (etanercept), intended for treatment of rheumatoid arthritis, psoriasis, and psoriatic arthritis.

Imbruvica (ibrutinib), intended for treatment of blood cancers.

Stelara (ustekinumab), intended for treatment of psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis

Fiasp and Novolog (insulin aspart), as well as various derivatives, intended for treatment of diabetes.


Of that list, apixaban affected the greatest number of Medicare patients from June 2022 to May 2023, with approximately 3.7 million patients; it also had the highest bill, approximately $16.4 billion, of the selected medicines. Ibrutinib had the smallest patient population in that timeframe, at approximately 20,000, while insulin aspart and its derivatives had the lowest price tag of approximately $2.5 billion. In total, the selected drugs comprised approximately 8.2 million patients at a price tag of $50.5 billion, according to the fact sheet.

According to the press release, CMS encourages the public to submit input on the medicines selected for negotiation. CMS also plans to host a series of patient-focused listening sessions this fall as part to provide an opportunity for patients, beneficiaries, caregivers, consumer and patient organizations, and other interested parties to share input relevant to drugs selected for the first cycle of negotiations.

The Centers for Medicare & Medicaid Services (CMS) has announced the first 10 drugs covered under Medicare Part D selected for negotiation. 

White House Sets Medicare Price Negotiation Targets

Bristol Myers Squibb announced FDA approval of Reblozyl (luspatercept-aamt) as a first-line treatment for anemia without previous erythropoiesis stimulating agent use (ESA-naïve) on Aug. 28, 2023. The drug is indicated for adult patients with low-to-intermediate-risk myelodysplastic syndromes (MDS) who may require regular red blood cell (RBC) transfusions.

According to a company press release, FDA approval was based on interim results from the Phase III COMMANDS trial. In the trial, 58.6% of patients treated with luspatercept-aamt achieved the primary endpoints of concurrent RBC transfusion independence of at least 12 weeks and mean hemoglobin increase of at least 1.5 grams per deciliter within the first 24 weeks. This was deemed to be superior efficacy to epoetin alfa, an ESA which had a 31.2% efficacy rate, regardless of ring sideroblast status.

“Today's expanded approval of [luspatercept-aamt] marks an important milestone in our commitment to MDS patients with anemia by providing a durable and more effective treatment option, with more convenient and less frequent administration,” said Wendy Short-Bartie, senior vice-president and general manager, U.S. Hematology and Cell Therapy, Bristol Myers Squibb, in the release. “We remain dedicated to addressing hard-to-treat diseases with significant burden to patients and look forward to bringing this important option earlier in the treatment process.”

“The majority of patients with MDS experience chronic anemia and require RBC transfusions,” said Tracey Iraca, executive director, MDS Foundation, in the release. “The approval of [luspatercept-aamt] in the first-line treatment of anemia for patients with lower-risk MDS represents a crucial step in making transfusion independence possible for more patients.”

Bristol Myers Squibb’s Reblozyl (luspatercept-aamt) is approved as a first-line treatment for anemia in adults with lower-risk myelodysplastic syndromes.

FDA Approves Bristol Myers Squibb Anemia Treatment

Supreme Court case caught the interest of many members of the pharma industry due to its broad implications for the future of patent law in the industry. Following the court ruling in favor of Sanofi, 

 spoke with Kisuk Lee, principal at Harness IP, a law firm specializing in intellectual property law, on the Court’s decision and its implications for the life sciences industry.

 This is actually a huge-stakes case because this case discusses one of the most important requirements—patent protection. Basically, there are four major requirements: patent eligibility, novelty, non-obviousness, and written description, which includes enablement. The patent enablement requirement essentially states that the patent specification must provide descriptions that enables the claimed invention. In other words, the patent specification must describe how to make and use the claimed invention. In this case the issue was, how much information is enough to enable full scope of the claimed invention?

 case, Amgen’s patent is directed to an antibody which is really broad. It simply claims an antibody binding to a certain antigen to treat a certain disease. The antibody itself is not structurally defined—just any antibody binding to antigen X, that’s the breadth of Amgen’s patent claim. Additionally, the original Amgen specification provided about 28 specific antibody examples, sequence information, and very detailed descriptions about how to make and use the invention.

But the problem is that the claimed invention was rather broad. So that was the issue, whether the information included in Amgen’s patent specification was enough to enable the full scope of Amgen’s broadest claim. The Supreme Court’s view was ultimately that the claim was too broad, resulting in a ruling that says the original patent specification should provide description enabling full scope of the claimed invention. This is a high burden.

In the past, the Amgen patent claim was definitely patentable and there was no issue about enabling disclosure. Typically, in the pharma world, the most important part is finding the target protein, which leads to treatment of certain diseases. If we want to treat brain cancer, then the most important part is to identify the key protein involved in this disease. That correlation, the inhibiting protein X thereby treating brain cancer, that’s the most important part of the discovery.

But according to the Supreme Court ruling, you cannot get that broad protection because you only identified one or two specific antibodies, enabling the claimed invention. So now the outcome is you cannot get that broad protection and only an extremely limited, narrow scope of protection even if you discovered a breakthrough scientific principle, such as inhibiting the hypothetical antigen X for treating brain cancer.

 How will this impact pharma researchers going forward?

 This is a huge burden for innovators. Amgen’s patent had a more than 400-page specification with many examples, yet that was not enough. Most patent applications are less than 100 pages; how far will they get?

Typically, patent filing is a high, heavy burden on universities and research institutes, who don’t have enough money and resources to support it. In a university setting, researchers typically try to identify the key antigen and then publish a paper, that’s it. Then they file a patent application. As a result, they only work on one or two antibodies, and they don’t have the capability of producing 30 or 40 different antibodies.

In the past, we saw a lot of mega-million licensing deals from university to industry because a university identified the breakthrough and under that protection could screen antibodies binding to antigen X to develop new treatments. But now the university can only test a specific antibody and minor variations of that discovered antibody. That’s it. This is really bad for the innovator side, especially for universities and research institutes.

On the other hand, this is great news for mid-sized and small pharma companies. Now, if Big Pharma or a university already identified the basic scientific principle, there’s only one or two antibody examples. These entities can just try to screen other antibodies that bind to the same target—that is not a patent infringement of the innovator-side patent. And they can also obtain separate patent protection because the originator’s patent only covers a narrow scope.

I always use this analogy: if your discovery is US territory, in the past you were able to get a full US territory patent but now can only get a California patent. Now, other researchers and companies can get a New York patent, an Illinois patent, a Florida patent. Basically, a floodgate opens for competitors.

[The latter scenario] is good for other researchers, and that [scenario] actually promotes competition, which may be good news for the general public because the public will get more treatments from different sources. Typically, innovations are patent only, and then patent protection, and we are just waiting for patent expiration. [After that] the generic comes in, and we make the generic version. So, generally speaking, patients have to wait until patents actually expire. But now the competitors can probably file new patent applications not covered by the originators. That may be good news for the general public, as it could lower drug prices as well.

 What kind of knock-on effects do you think this ruling might have for patent laws and any other pending enablement claims? What sort of effects are we seeing?

 So, unfortunately, [the ruling] will affect all patents, patent applications, and patent applications to be filed. As it concerns already issued patents, in the past the patent office allowed a broad genus claim. Just like the Amgen patent, there are so many patents out there with really broad claims. That means the competitors might challenge the validity of those patents so that they can file new applications and freely exercise their own antibody. I think we will see more invalidation challenges on the generic side from small- or medium-sized companies.

Regarding pending applications, we’ll see more enablement rejections from the patent office. Because the standard is higher, many of the already filed applications don’t meet that higher standard. As a result, we’ll see more enablement rejections from the patent office.

Lastly, the applications to be filed. This is actually the most important part now as the burden for the patent applicant is really high, and [they] need to provide enabling disclosure for the full scope of the claimed invention. In the past, I advised clients that if you already synthesized 30 different antibodies or 30 different compounds falling within the scope, you don’t need to disclose everything—just provide 10 representative examples in the patent specification and keep 20 as a trade secret. You don’t need to disclose all your information.

But now it’s different. We probably need to disclose everything, yet we may not get really broad protection. That means a lot of cost and preparation [will be required] because [a company] needs to provide data and new examples; the company needs to prepare this information, and then a law firm has to write a 400–600-page patent application, which could cost double, triple, quadruple, I don’t know, but it’ll definitely be more expensive than the previous applications cost.

Additionally, if the innovator side discovered this breakthrough discovery, but only has 10 antibodies? That’s not enough to cover the entire scope. So, what’s the solution? [They will] need to file additional patent applications. To return to the prior analogy, one might initially file patent applications for the west coast, for example, California and Washington. Meanwhile, they will also need to screen new antibodies binding to that target and then file a New York application, and [following that] an east coast application or Midwest application.

[Innovators will] have to file more applications to cover a broad scope. That’s a higher cost because of filing costs, preparation costs, prosecution costs, and maintenance costs. I think it’s really bad news for innovators. Universities in particular don’t have money—their antibody budget is quite limited—so I don’t think university research institutes can file five or six different patent applications for one discovery. That’s really a sad outcome for those small players.

 What do you think companies should be doing now, other than just spending more money and filing more of these enablement requirements?

 Unfortunately, there’s not much wiggle room. The Supreme Court ruling is quite simple. You need to provide enabling disclosure for the full scope. So, planning ahead may be useful. Now we know that it is useless to file an application with a US territory claim with only one or two examples. If you have only California examples and just start with California territory, and if the claim is covering California only and [the innovator] has three or four examples falling within the scope, then that’s fine. That may be a good approach because [the innovator] can later file applications for other areas.

If [an innovator] were to use the past approach of just filing the hypothetical US territory claim and then seeing what happens? Then they cannot file a follow-on application directed to New York or Midwest because they have already disclosed the full scope. The really important requirement for patent protection is novelty and non-obviousness. Once their US territory is disclosed in the original specification, then it would be supremely difficult to file an application later covering New York or Florida. If, however, [the innovator] focuses on one area, such as the west coast application, first, then the Midwest application is new, and the east coast application is new, because the earlier publication is limited to the west coast. Planning ahead, identifying the patentable scope, and just filing an application covering that patent scope—then later filing multiple applications covering other
areas—may be a strategy.

 Do you think this will affect how research is done in pharma? Are certain types of molecules going to be prioritized and or certain types of research?

 Generally speaking, the pharma industry’s two big areas are the traditional small-molecule drugs and biologics. Small molecules will be okay, in my opinion, because the broad invention is typically defined by a structure. When researchers discover a new molecule, they have to provide a generic, that is, the chemical structure scaffold and then possible substitution. In most cases, chemical inventions, such as small-molecule drug inventions, are defined by structure.

But the biologics industry is different. Innovators need to identify a pathway as well as the certain messenger molecules involved in that pathway. Then they have to show what happens when that pathway is inhibited to demonstrate how that kind of modulation is necessary for biologic inventions. Thus, functional language and broad coverage is necessary. That was actually the problem with Amgen—there’s no other way to cover their idea with structured terms. Someone can provide a thousand different antibodies for this discovery, which means the biologics area is really affected by this Supreme Court decision.

Exploring the state of pharma patents following the Supreme Court’s Amgen v. Sanofi decision.