Randi Hernandez was science editor at Pharmaceutical Technology from September 2014 to May 2017.

Randi Hernandez

	The National Institute for Bioprocessing Research and Training (NIBRT), an organization that provides training to the bioprocessing industry, released results to its 2016 survey on Jan. 11, 2017. Suppliers, manufacturers, government officials, and people from academia were relatively positive about the direction of the industry, with 69% saying they were “highly optimistic.”


	There were 101 respondents in the survey. In some cases, respondents skipped questions, so the percentages are based on the number of respondents for each question (i.e., n is not equal to 101 for all questions). Regardless of this factor, the report provides a broad overview of the state of the biopharma industry and where it may be headed in the next decade.


	Of the products that are currently available, respondents said the the top three most commercially important products are monoclonal antibodies, vaccines, and non-mAb recombinant proteins. In the next 5–10 years, however, vaccines, mAbs, antibody-drug conjugates (ADCs), gene therapies, and cell therapies will be highly important. As a result, respondents expressed concern about establishing cost-effective manufacturing solutions for these newer therapies, and one respondent commented that new devices and the aseptic manufacture of new therapies into new devices will be a priority in the coming years. One respondent added that cell-based therapies and gene therapies will transform the market, but the industry is still 10 years or more from realizing its potential in these fields. Approximately 65% of respondents said that biosimilars will have a major disruptive impact in the biopharma sector during the next five years.


	Half of the respondents noted that the scientific complexities surrounding drug discovery was the main challenge associated with bringing biopharmaceutical therapies to the market. They were least concerned with submitting products for regulatory approval in the future-approximately 2% of respondents said this was the highest challenge, which is surprising considering the complexities that are associated with demonstrating the safety and efficacy of new products. In light of the recent deaths during trials for experimental chimeric antigen receptor-based (CAR-T) therapies, and the still not finalized draft guidance documents covering stem cell-based therapies, it would seem that manufacturers would be more concerned about regulatory process hurdles for new therapies.

	Another top concern among industry veterans is process robustness of manufacturing operations. Fifty-eight percent said this was a concern, and approximately 53% said that reproducibility of a process was a key manufacturing concern.

	Other challenges that may affect the growth of the industry included cost considerations of bringing biopharmaceuticals to market and uncertainties surrounding reimbursement of therapeutics. Another noteworthy point that was considered troublesome to the industry was the lack of qualified experts working in biopharma-57% of respondents reported having problems recruiting skilled bioprocess engineers.


	Survey participants said that the area of biopharma could benefit most from innovation was cell-line development and optimization (nearly 67% noted this was a high priority). Additionally, approximately 61% identified bioanalytical capabilities as an area needing improvement, and approximately 59% thought downstream processing could be developed further. The adoption of single-use technologies was identified as having the highest impact on manufacturing (approximately 73% rated this as having the most beneficial impact on biopharma); however, issues with lack of standardization and with extractables and leachables will continue to be technical challenges of single use. Nearly 57% of participants said continuous manufacturing, when fully adopted, would be beneficial to the industry in the next five years-but nearly 64% of respondents also acknowledged that process development of continuous operations was still a major challenge. Half of respondents also said that continuous processing is still considered an “unproven technology” for biopharma and more than half said that regulatory uncertainties, technology transfer issues, and real-time monitoring will continue to prevent full adoption of continuous biomanufacturing.

Articles

Industry experts identify the future focus of the biopharma industry in a new survey.

NIBRT Summarizes Top Trends in the Biopharma Industry

	Following the successful opening of an end-to-end bioprocessing plant in Martillac, France in 2012, MilliporeSigma announced on Jan. 10, 2016 that it will open two more bioprocessing locations, one of which will be in China and the other in Boston, Massachusetts. The new locations will offer cell-line development services, process development expertise, and non-GMP clinical production services. The main difference between the new locations and the existing Martillac site is that the France location is a GMP facility that manufactures clinical-stage batches. The France site is the main biodevelopment center worldwide, according to Karen Tiano, head of media relations at MilliporeSigma.

	According to a company press release, the Boston and Shanghai sites are non-GMP. The locations will feature the full suite of MilliporeSigma technologies. The suite includes single-use, sterile connectors, single-use disposable modules for viral clearance, tangential flow filtration cassettes for filtration, and a gene-editing technology to confer viral resistance to Chinese hamster ovary (CHO) cell lines.

The locations will feature end-to-end bioprocessing centers and will be in Shanghai, China and Boston, MA.

MilliporeSigma to Open Two New Bioprocessing Centers

	Gore announced at the 2017 PepTalk meeting that it is introducing new technology for the purification of monoclonal antibodies (mAbs). The Protein A chromatography column uses an expanded polytetrafluoroethylene (ePTFE) membrane composite that is said to confer a binding capacity advantage at high flow rates and improve purification speeds.

	Unlike resin-based columns made up of porous beads, the membrane from Gore is said to allow faster processing times because the device has a higher capacity with a shorter product residence time (srt). Gore estimates the the solids retention time for its technology is 20 srt vs. 60 srt for traditional agarose beads. The company says use of the membrane technology will allow for the elimination of a downstream concentration step during purification.

	The membrane is chemically resistant and can withstand high temperatures, and therefore, several cleaning cycles.

The membrane-based Protein A purification tool was unveiled at the 2017 PepTalk Conference in San Diego, California.

Gore Releases New Fluoropolymer-Based mAb Purification Technology

	Medi-Post, a Korean-based biopharmaceutical company, announced on Jan. 10, 2017 that it has secured a patent from the United States Patent and Trademark Office protecting a method for culturing mesenchymal stem cells. The patent itself was issued on Nov. 22, 2016 and focuses on the treatment of lung disease in newborn or premature babies via cells proliferated from umbilical cord blood. The patent is being used to develop a therapy called Pneumostem, which was granted an Orphan Drug designation in 2013 by FDA (1). The patent is co-owned by Samsung Life Public Welfare Foundation and is already issued in Canada. The underlying belief about stem-cell treatments is that precursor cells will differentiate into the tissue of interest (in this case, new lung tissue) and will help heal patients through use of autologous cells.

	Despite the advances in the field of regenerative therapies, there are some regulatory sensitivities that plague the industry. Direct-to-consumer stem cell therapy clinics are increasingly popping up, and FDA is tasked to monitor each processing or “manufacturing” site in a piecemeal fashion. In the beginning of 2016, FDA issued a 

 to three stem-cell clinics selling stem-cell treatments purported to treat a variety of chronic conditions (2). Many of the violations listed in the letters were largely related to failing to follow proper cGMP procedures and failing to safeguard against potential microbiological contamination of sterile products.

	Shutting these types of clinics down one by one may prove to be a daunting task for the agency. According to an August 2016 article in 

, there are 351 businesses currently offering unapproved stem-cell treatments across 570 clinics in the United States. Separated out by state, California had the largest number of stem-cell clinics (3). The available interventions were mostly derived from autologous cells, approximately 21% of the therapies offered were from allogenic cells sourced from umbilical cord blood, amniotic material, and placental tissue (3).


	Development of Medi-Post’s Pnemostem is backed by the Translational Stem Cell & Regenerative Medicine Consortium Grant as a part of Public Health and Medicinal Technology R&D Project funded by the Ministry of Health and Welfare of Korea and the Korea Health Industry Development Institute. In Japan, conditional approval for stem-cell treatments is granted by the Pharmaceuticals and Medical Devices Agency after Phase II trials if the investigative agent is deemed effective for a very small number of subjects-in other words, companies can be exempt in some cases from conducting Phase III trials. This is alarming, considering that a recent analysis found that 70% of drugs 

	The Medi-Post product is one of many stem-cell therapies under clinical investigation, and the science behind the use of these therapies is promising. Investigators have shown that multipotency of these types of cells remains after amplification and the stem cells that are extracted are capable of turning into various types of tissue. As Medi-Post says in its patent application, “Methodologically, the umbilical cord blood extracted from the real placental tissue is an ideal source for autologous and allogeneic stem cells, and such stem cells obtained thereby can be used directly or after amplifying stage whenever and as many as required” (5).

	Support for investigative cell-therapy products in the US, however, is a little more convoluted. Although many scientists see the value of the research, they think the therapies should be held to rigorous efficacy and safety standards. FDA issued a

 in 2012 warning consumers of the dangers of stem-cell treatments (6). As yet, FDA has not finalized its drafts on guidance documents relating to the regulation of human cells, tissues, or cellular or tissue-based products (HCT/Ps). As of Sept. 27, 2016 (when the comment period closed), there were 

 in the FDA docket on these guidance drafts. A public hearing occurred in 

 to discuss the draft guidance items, and many in the scientific community communicated that the guidance documents required significant amendments.

	A piece of legislation introduced in March 2016 seeking to lower standards for the approval of cell-therapy products, the REGROW (Reliable and Effective Growth for Regenerative Health Options that Improve Wellness) Act, is opposed by prominent industry groups such as the International Society for Stem Cell Research, the International Society for Cellular Therapy, and the Alliance for Regenerative Medicine. It seeks to allow marketing of a conditionally approved cellular therapy prior to the approval by FDA. Language from the REGROW Act snuck back into the final text of the 21

 Century Cures Act prior to its final passage (7).


	1.  Medi-Post, “Medipost receives US Patent for ‘PNEUMOSTEM’ for Treating Lung Disease, 

, accessed Jan. 10, 2016.
	2. R. Hernandez, “Stem Cell Treatment Centers Receive FDA Warning for Not Following cGMP Procedures,” 

www.biopharminternational.com/stem-cell-treatment-centers-receive-fda-warning-not-following-cgmp-procedures

, accessed Jan. 10, 2016.
	3. L. Turner and P. Knoepfler, 

 19 (2), pp. 154–157 (Aug. 4, 2016).
	4. R. Hernandez, “Clinical Development Success Rates Examined in New BIO Report,” 

www.biopharminternational.com/clinical-development-success-rates-examined-new-bio-report

, accessed Jan. 10, 2016.
	5. Y.S. Chang, W.S. Park, and Y.S. Yang, "Method of treating lung diseases using cells separated or proliferated from umbilical cord blood," US patent PCT/KR2007/000535, Nov. 2015.
	6. FDA, "FDA Warns About Stem Cell Claims," FDA.gov, www.fda.gov/ForConsumers/ConsumerUpdates/ucm286155.htm, accessed Jan. 10, 2016.
	7. K. Servick, “Under 21st Century Cures legislation, stem cell advocates expect regulatory shortcuts,” 

www.sciencemag.org/news/2016/12/under-21st-century-cures-legislation-stem-cell-advocates-expect-regulatory-shortcuts-0

Language surrounding regenerative medicine and the REGROW Act appeared back into the 21st Century Cures Act right before it passed. What will this mean for the controversial testing and marketing of stem-cell therapies?

How Tightly Should Stem-Cell Therapies Be Regulated by FDA?

	Amgen announced on Jan. 9, 2017 that it will partner with Immatics in the discovery of novel immunotherapy candidates based on bispecific T-cell receptor technology. Immatics’ XPRESIDENT technology recognizes tumor-specific peptide antigens, and Amgen plans to use this information coupled with its own bispecific T-cell engager (BiTE) technology to create T-cell-based therapies specific to tumors.

	Both Immatics' TCR-bispecifics and Amgen’s antibody constructs recognize two or more binding domains. One domain is typically on the surface of a cancer cell via a T-cell antigen-specific receptor (TCR), and another is designed to recognize a T-cell activator, such as a T-cell stimulator CD3. These signals typically result in the clonal expansion of T-cells, differentiation into effector cells, cytotoxicity, and then cell death of the tumor cell.

	Amgen already has a bispecific antibody drug on the market, so it is familiar with pushing this class of drug through the regulatory process. Amgen’s Blincyto (blinatumomab) is an antibody contruct for the treatment of refractory B-cell precursor acute lymphoblastic leukemia (ALL) and it was approved in the United States under an accelerated approval pathway. Blincyto targets cell surface proteins CD19 and CD3 simultaneously, helping to bring T cells to the cancerous cells.

	Amgen will give Immatics an upfront fee of $30 million and Immatics will be eligible to receive milestone payments and royalties of more than $500 million. In 2015, Amgen entered into a similar research collaboration with Xencor for $45 million to license Xencor’s XmAb bispecific technology platform for the development of a total of six targets.

The companies will combine expertise on T-cell therapies with two or more binding domains to create novel oncology medications.

Amgen Links with Immatics to Continue Work on Bispecific T-Cell Therapies

	The Biopharmaceutical Manufacturing and Academic Resource Center (BioMARC), a nonprofit contract manufacturing service unit owned and operated by Colorado State University, announced it will work with CSSi LifeSciences to map out clinical development solutions and guidelines for cost-effective good manufacturing practices (GMP).

	So far, BioMARC has “brought a diagnostic parenteral product through clinical trial and commercial production (including PAI [preapproval inspection]), manufactured a virus vaccine for a Phase I clinical study, established several master and working cell or virus banks, developed and qualified cell-based and analytical assays for product testing and release, and established a controlled process for manufacturing a vaccine product for preclinical studies in non-human primates bridging to a Phase I study in humans,” according to a press release.

	CSSi has performed similar lifecycle management tasks for clients, and says it has helped with the development of more than 500 medical products, including biologics.

	"Our combined capabilities will provide a fully-integrated, one-stop manufacturing solution for the accelerated preclinical, manufacturing, and clinical testing of biological therapeutics, novel vaccines, and diagnostic products intended for use in humans," said Raymond Goodrich, PhD, executive director, infectious disease research center, BioMARC.
	 

The partnership will focus on providing practical information to clients on the development of biologics and vaccines.