OR WAIT null SECS
As cost pressures mount as a result of multiple biologics being developed for the same indication, manufacturers can harness process efficiencies to maintain the value of legacy products.
As patents for branded drugs slowly run their course, and biosimilar manufacturers pop up one by one, manufacturers of legacy products face some serious obstacles to maintaining market share. Pharma is increasingly being pushed to find new ways to gain market advantage for products that are not first-in-class biologics.
One route to combat competition is the “Amgen approach”; Amgen has chosen to fiercely defend its intellectual property through a series of high-stakes lawsuits that deal with the interpretation of the information exchange requirements of the Biologics Price Competition and Innovation Act (BPCIA). This approach can be seen in the cases Amgen v. Apotex and Amgen v. Sandoz. In fact, Amgen’s aggressive legal tactics prompted Sanofi and Regeneron to file a “declaratory judgement of non-infringement” for their investigational atopic dermatitis monoclonal antibody (mAb) Dupixent (dupilumab) in March 2017 (1). Sanofi and Regeneron made this move in advance of any action by Amgen, as Dupixent is an IL-4 inhibitor, and the companies were aware that Amgen has attempted in the past to gain approval for a drug with this specific mechanism of action. Some could say that Amgen is using aggressive legal tactics as a tool to protect its legacy products and consequently, its revenue stream.
Other tactics that reference-product sponsors use to extend the commercial value of their legacy products include filing patents that cover new formulations of a drug (a practice known as evergreening), but these new formulations have to either prove to have an improved therapeutic outcome, an improved safety profile, or a positive effect on patient adherence (2). In addition, pharma companies can bundle their medications with others in combination to preserve some patent juice.
While the aforementioned strategies are well known in the industry, it could benefit manufacturers to revisit how their drugs are made--not necessarily how they are patented--to determine ways to maintain the profitability of older products. One of these new industry approaches centers on improving manufacturing efficiency of legacy products.
Because manufacturing processes are embedded in the product approval process, significant post-approval manufacturing changes must be approved by FDA. A recent example of such a change is Janssen’s HIV drug Prezista, which was the first candidate to be handled by the Center for Drug Evaluation and Research’s (CDER’s) Emerging Technology Team (ETT), a group that was formed to handle inquiries regarding emerging technology in pharmaceutical and biotechnology manufacturing. The manufacture of Prezista (a small-molecule drug) was converted from a batch process to a fully continuous method in April 2016 following the approval of the conversion by FDA.
According to N. Sarah Arden, PhD, from the Office of Biotechnology Products within CDER’s Office of Pharmaceutical Quality (OPQ), who spoke at BioNJ Manufacturing Breakfast on March 30, 2017, the Prezista conversion process reduced the manufacturing footprint for the drug from seven to two rooms, and reduced the production from two weeks to one day. Doug Hausner, PhD, associate director in the Department of Chemical and Biochemical Engineering at Rutgers University, said at the BioNJ meeting that the changeover only took three months to complete. It should be noted, however, that because Prezista is a small-molecule medication, this turnaround time for implementation may not be applicable to biologics.
The ETT encourages pharmaceutical manufacturers to apply to the program so that the agency can assess the approaches taken by manufacturers to improve drug product quality, safety, and efficacy. Although Arden said the focus of the team--which has already convened approximately 15 times since the group’s inception--is on continuous manufacturing, 3D printing, novel aseptic filling, and new container/closure systems, new approaches to automation could be eligible for agency review, should they result in material changes to product quality (3). FDA wrote in the ETT draft guidance document, “The planned submission should include one or more elements subject to quality assessment for which the Agency has limited review or inspection experience, where the technology has the potential to modernize the pharmaceutical manufacturing body of knowledge to support more robust, predictable, or cost-effective processes. Examples of such elements include an innovative or novel: 1. product manufacturing technology, such as the dosage form; 2. manufacturing process (e.g., design, scale-up, and/or commercial scale); and/or 3. testing technology” (4).
Arden said during the meeting that the connected unit operations that make up continuous lines are “highly reliant on automation software for control and monitoring.” This automation software--and efforts to optimize the manufacture of legacy biologics by exploiting improvements in automation--may be the golden ticket for legacy biologics to remain profitable, even in processes that are only partially continuous (i.e., perfusion upstream). The improvements in manufacturing control and coordination due to enhanced automation could, in fact, help speed up overall production and drive improved operational performance.
Incorporating more automation solutions for the manufacture of biologics, then, may help reference-product sponsors gain a competitive advantage over biosimilar market entrants. Older products, which may not immediately be feasible candidates for a totally continuous overhaul--and may not be eligible for extended patent protection--may benefit from improvements in process control. Automation could help keep yields consistent, reduce batch release time, and allow manufacturers and contract manufacturing organizations alike to increase capacity. “Repeatability, time to market, data trending, and reduced deviations from manual variability [are] a few of the key improvements [of automation] to biologics manufacturing,” notes Mike Smith, US sales manager at Zenith Technologies.
It does not appear that incorporating increased automation would warrant a post-approval change application to FDA, as the products themselves would not likely change per batch, but the data collection techniques informing engineers about their manufacture would change. But a change that effectively increases process robustness--including one that influences drug production rate--may, however, constitute a change that would need to be submitted to FDA for approval. It should be noted that while some changes require approval by FDA, others that don’t necessarily require a formal approval should still be reported to the agency.
Manufacturers have to prove, with validation data, that procedural changes do not influence the potency, sensitivity, specificity, or purity of a drug, according to an FDA guidance covering changes to an approved application for certain biotechnology and synthetic biological products (5). Although batch data (and other data) are not considered an “established condition” that could require notification to FDA, alterations to established conditions--which could include changes to process parameters and their ranges--usually require manufacturers to alert the agency (6). Thus, if a production rate is improved as a result of increased automation and the inclusion of sensors, would contact with agency officials be warranted?
FDA was careful not to say too much about which technological innovations would or would not be eligible for agency review: “The criteria for determining an emerging technology are based on the type of CMC [chemistry, manufacturing, and controls] change the company requests and/or the company’s proposal to the ETT,” FDA’s Sau (Larry) Lee, PhD, deputy director and ETT chair in the Office of Testing and Research/OPQ, told this publication on behalf of the ETT team. “There are rapidly evolving technological areas, so decisions are made on a case-specific basis after evaluating the information regarding the proposed technology.”
Notes Smith, “Automation has been a part of pharmaceutical/biotechnology manufacturing for many years; CMC documentation can be leveraged in many cases.” He says that most automation improvements are reserved for new equipment, new facilities, or expansions, not conversions. He points out that FDA validation is already a part of these initiatives.
Automation could also be crucial to facilitate end-to-end continuous manufacturing configurations for biologics. When this publication asked FDA specific questions on how to best implement continuous manufacturing principles, FDA’s Lee said, “Pre-specifying approaches or providing proscriptive recommendations to manufacturers, or appearing to, may not be helpful in this evolving technological area where the actual practitioners bring extensive expertise. Regardless of participation in the [ETT] program, it is ultimately the role of the manufacturer to develop technology based on scientific and engineering principles and practices.”
Many vendors in the bioprocessing space have been working to inject more automation into their processes, either by partnering with companies that specialize in automation or by purchasing these companies outright. The following are a few examples of recent deals in this space.
Thermo Fisher Scientific. Players in the bioprocessing space have been investing in improved automation solutions, data integration, and manufacturing execution systems (MES) to optimize and shorten production cycles. In February 2017, Thermo Fisher Life Science’s Solutions Segment acquired Finesse Solutions, which develops scalable control automation systems and software for the manufacture of biologics. Finesse had been Thermo’s “technology partner” since 2013 (7).
The acquisition is especially beneficial for Thermo because of a patent that Finesse owns covering an aseptic peripheral sensor carrier and methods for installing a sterilized peripheral in a bioprocessing vessel or component. Currently, many types of sensors can’t be used in single-use bioreactors because they are incompatible with sterilization procedures (such as gamma exposure). The setup described by Finesse in its patent application allows the packaged sensors and carriers to be sterilized together, rather than separately (8).
According to the patent, Finesse’s invention helps prevent “many of the negative effects that sensors endure during gamma sterilization” and will allow the insertion of more sensors upstream (7). Finesse wrote in the patent, “To date, one major issue has been the lack of robust, single-use sensors that can be readily and reliably integrated into the single-use bioprocess vessel (e.g., including but not limited to a bioreactor or mixer). By robust, we mean accurate; gamma, beta, or x-ray radiation stable; and capable of being used for real-time sensing (real time within the speeds or time responses required for bioprocessing), e.g., providing samples at 1 Hz (or fractions of a Hz to a few Hz) for biological process monitoring and/or control for at least 21 days without significant drift in any 24-hour period” (8).
Finesse also wrote that use of their aseptic carrier ports/sensors will drive more thorough data collection for each batch produced, and “will increase the number [of] measurement points to enable better process control as well as more detailed batch records with automated software- (rather than operator-) driven process alarming, loop correcting, and deviation reporting in the manufacturing execution system layer, and subsequently, in automatically generated electronic batch records” (8).
GE Healthcare. GE Healthcare invested a “meaningful stake” into Zenith Technologies in 2017. GE had prior experience with Zenith; the companies have been considered partners in automation integration since 2016. As Jan Makela, general manager, bioprocess, GE Healthcare Life Sciences told BioPharm International, “Automation enables fewer manual operations in the biomanufacturing process and provides real-time data to customers to evaluate their operations more quickly, including batch data and investigations … This greater efficiency can help reduce the non-productive time between production” (9). GE plans to further develop the breadth of Zenith’s automation and connectivity capabilities, and will incorporate the automation into some of its existing client’s systems via upgrades, as well as offer Zenith’s support to future clients.
“There is a need to increase automation in order to reduce manufacturing costs and increase time to market,” asserts Zenith’s Smith. “There is a manufacturing need for facilities to operate equipment for multi-product campaign runs, which involves flexible code design solutions. MES solutions, also, allow for electronic batch record implementation, decreases in batch release timing, reductions in manufacturing errors, reductions in deviations, and improvements in multi-batch and continuous manufacturing.” Smith notes that the use of single-use manufacturing technology also facilitates pre-engineered automation solutions.
Sartorius Stedim Biotech. Sartorius just launched a “revamp” of its BIOSTAT STR bioreactors, adding upgraded hardware and software to the bioreactors. The improved design features advanced single-use sensors that were incorporated into the brand’s Flexsafe STR disposable bioreactor bags. The bags are optimized to save time in terms of cleaning, sterilization, and set-up, and they are designed to reduce instances of cross-contamination. According to a company press release, “The new bioreactor range provides greater flexibility in bioprocess control and data acquisition as software connectivity has been upgraded to allow integrated control by either BioPAT MFCS software or commonly used third-party industrial distributed control systems, such as Emerson DeltaV or Siemens SIMATIC PCS7” (10).
The geometry of the BIOSTAT STR bioreactors is the same as that of the company’s ambr 250 mini-bioreactor, so time required for process transfer and scale-up is reduced from months to weeks. The company says that this “direct linear scalability” helps lower costs.
1. C. Hroncich, “Sanofi and Regeneron File Suit Against Amgen in Patent Case,” BioPharmInternational.com, accessed May 1, 2017.
2. W.M. Spruill and M.L. Cunningham, BioPharm Int. 18 (3) (March 2005).
3. FDA, Guidance for Industry: CMC Postapproval Manufacturing Changes to Be Documented in Annual Reports (CDER, Rockville, MD, March 2014).
4. FDA, Draft Guidance for Industry: Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base (Rockville, MD, December 2015).
5. FDA, Guidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (Rockville, MD, July 1997).
6. FDA, Draft Guidance for Industry: Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products (Rockville, MD, May 2015).
7. Thermo Fisher Scientific, “Thermo Fisher Scientific Completes Acquisition of Finesse Solutions, Inc.,” Press Release, Feb. 14, 2017.
8. Selker et al. (Finesse Solutions, Inc.), “Aseptic Connectors for Bio-processing Containers,” US patent 9,335,000, May 10, 2016.
9. R. Hernandez, “GE Healthcare: The Next Cell and Gene Therapy Manufacturing Giant?,” BioPharmInternational.com, accessed May 1, 2017.
10. Sartorius Stedim Biotech, “Sartorius Stedim Biotech Introduces New BIOSTAT STR Bioreactor Range,” accessed May 1, 2017.
Vol. 41, No. 6
When referring to this article, please cite it as R. Hernandez, “Boosting Bioproduction Workflows with Automation Technologies,” Pharmaceutical Technology 41 (6) 2017.