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

Randi Hernandez

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 

. 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.

	FDA’s take on manufacturing efficiency

	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.”

	
	Vendors recognize the benefits of better process control

	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.

 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 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 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.

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

	When referring to this article, please cite it as R. Hernandez, “Boosting Bioproduction Workflows with Automation Technologies,” 

Articles

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.


Boosting Bioproduction Workflows with Automation Technologies

	Richard D. Braatz, PhD, Edwin R. Gilliland professor of chemical engineering at Massachusetts Institute of Technology, recently spoke to 

 about where the industry is in terms of end-to-end continuous processes for biologics medications, batch vs. continuous flow, mathematical models to design processes and bioprocessing plants, the importance of testing critical quality attributes (CQAs) within end-to-end bioprocessing loops, and the benefits of using chemically defined media within bioreactors.

	To hear more about these and other closely related topics, attend Braatz’s upcoming presentation, 

“Continuous Manufacturing of (Bio)Pharmaceuticals,”

 to be held on Wednesday, May 17, from 4:00–5:30 pm as part of the Drug Manufacturing track at CPhI North America 2017. To learn more about this particular track and CPhI North America 2017, visit 

http://schedule.cphinorthamerica.com/track/drug-manufacturing

 Who (company, individual, or academic institution) has designed the ‘most feasible’ model of end-to-end continuous processing for biopharmaceuticals to date?

 The most feasible model was published by Genzyme (a Sanofi company) in late 2015 by Rahul Godawat, Konstantin Konstantinov, Mahsa Rohani, and Veena Warikoo: 

"End-to-End Integrated Fully Continuous Production of Recombinant Monoclonal Antibodies."

http://www.axcellahealth.com/about-us/veena-warikoo

), Konstantin went on to Codiak BioSciences, Mahsa went on to Amgen, and Rahul went on to ‎Alexion Pharmaceuticals.

 Are there any pharma companies close to mastering end-to-end continuous processing for biologics? If so, who, and what product is under investigation?

 End-to-end continuous processing technology for biologics is too new to be ‘mastered’ by anyone yet, but Genzyme demonstrated feasibility and promise in the aforementioned paper. The paper serves as a strong starting point for companies interested in future development of the technology, which is needed for its application to future products.

 How do plant design changes influence material attributes during continuous processing?

 Material attributes are more tightly controlled in a continuous process, and yield can be improved for those biologics that have a propensity to degrade during manufacturing. If designing appropriately, continuous processing reduces biologic degradation by reducing the amount of time that the biologic spends in the manufacturing process.

 Could a mathematical model of a plant for continuous manufacturing of a small-molecule drug be replicated for a large-molecule drug?

 The process operations in large-molecule (also referred to as biologic) manufacturing have very small overlap with the process operations in small-molecule manufacturing, so very few of the individual process models are transferable from a small-molecule drug to a large-molecule drug. The overall approach and strategies for the generation of mathematical models of the individual processes and the overall plant, as well as the systematic design of control strategies to ensure product quality, are the same.

 Is it possible that there could be too many measurements to test quality in an end-to-end bioprocessing loop (i.e., there are so many measurement points that it disrupts the process flow)?

 I have never encountered a measurement device that did not have value at some point during process development or manufacturing, even when not used in the control strategy. In particular, extra measurements are valuable for the fast detection of faulty behavior in a manufacturing system. A simple example is that a redundant measurement device is useful in detecting whether a measurement device needs maintenance or otherwise becomes faulty.

	There are practical reasons to limit the number of measurements, especially at a manufacturing site. Some measurement devices are so expensive that their use in manufacturing would significantly increase the cost of making the drug while providing minimal increased assurance of product quality. Also, many advanced measurement devices, especially recently developed, are not reliable enough to be effective in a manufacturing environment. Substantial R&D would be needed to make the sensor reliable enough for manufacturing operations. Based on these considerations, an effective strategy is to heavily instrument measurements during process research and development to build understanding and mathematical models, which are then used to determine which subset of the measurements are sufficient to ensure that the product CQAs are achieved in a manufacturing facility.

 Have you seen instances where the quality of the starting materials has dictated the CQAs at other points along a processing line?

 I have seen many instances where the quality of the starting materials has dictated the CQAs at other points along a pharmaceutical manufacturing line. I have also seen many instances when analyzing biologic data collected for manufacturing processes at MIT and at companies in which a seemingly small shift in the operation of the bioreactor had a very strong effect on the quality attributes of material leaving the chromatography train. For this reason, it is important to have traceability of material as it moves through manufacturing, irrespective of where the process is batch, continuous, or semi-continuous.

	A well-known example where CQAs can be affected by the quality and/or characteristics of the starting materials is by variations in biologically defined media fed to the bioreactor. This observation has driven interest in the use of chemically derived media, in which all constituents are precisely defined.

Richard D. Braatz, PhD, will discuss using mathematical models to design a continuous drug manufacturing plant and the differences between batch and continuous operations for biologics.

MIT Professor to Present on Continuous Manufacturing for Biologics at CPhI North America 2017

 on March 7, 2017 presents a study that tested PhRMA’s long-standing argument that high prices for drugs fund research and development in the pharmaceutical industry.

	The researchers, who included famed drug pricing critic Peter Bach, combed through pricing data from 15 drug companies that manufactured the 20 top-selling drugs globally in 2015. They compared the prices of these drugs in the United States versus the list prices charged for the medications in Denmark, Ireland, the United Kingdom, and Canada, and calculated “excess revenue” in the US based on the amount of total US revenue that resulted from US premium pricing. The researchers then compared the excess money to the R&D spend for each company. Information on drug pricing in the US came from average sales price (ASP) files for physician-administered drugs from Truven Health’s Redbook, and pricing on the wholesale acquisition costs of retail drugs came from the same source.

	Although the authors did not account for rebates in Denmark, Ireland, the United Kingdom, and Canada, saying that the magnitude of such discounts is not published, they did include rebate estimations in the calculation of US drug prices. Bach 

. said this provided a “conservative assumption that serves to lessen our estimate of the premium companies earn through charging higher prices to US patients…”

	The researchers concluded that the US spends an average of 66% of its excess revenue on global R&D (approximately $76 billion of the $116 billion in excess funds). Some companies spent a larger portion of their excess revenue on R&D (Novartis, AstraZeneca, Bristol Myers-Squibb), while others produced excess revenue that was more than double their R&D spend (Amgen, Biogen, Pfizer, and Teva). In fact, according to researcher estimates, “three companies covered or nearly covered their research spending through premium pricing of just their top-selling product: AbbVie with Humira, Biogen with Tecfidera, and Teva with Copaxone.”

	The point of the research was to illustrate that in the US, premium prices for drugs produce billions of dollars more in revenue than is necessary to fund R&D operations at pharma companies. If premium prices were lowered to just meet R&D expenditures, the researchers pointed out, patients, business, and taxpayers could have saved $40 billion in 2015. The conclusions are in direct opposition with PhRMA’s explanation that drugs are priced to allow for innovation in the industry and are required to fund R&D operations.

	In essence-as President Trump has implied in his comments on pharma-the US funds a chunk of the world’s pharmaceutical research. Meanwhile, other countries pay lower prices for drugs that come out of this research. According to Brian Henry, a spokesperson for pharmacy benefit manager Express Scripts, the findings of the study are not surprising. “The takeaways are consistent with what we have been saying: drug makers set drug prices, and, more and more, those prices are set higher and higher-basically orphan drug pricing for non-orphan drugs,” Henry told 

 in an email. “Our job is to bring down the cost of those medications to put them within reach of those who need them.”


	Experts on the the economic analysis of innovation say the piece in 

 is flawed, and say that while the piece identifies a correlation between the share of revenue coming from the US and innovation spending, it does not offer any explanation about whether higher US prices cause greater investments in innovation. Darius N. Lakdawalla, PhD, quintiles chair in pharmaceutical development and regulatory innovation at the University of Southern California, told 

 that the study suffers from poor empirical research design, and that a variety of other factors that influence a firm's revenue could potentially invalidate the study's findings. 

	"For instance, smaller, less-diversified companies are probably more likely to sell their products in the US, because they lack the resources to access other markets. And, they are also likely to have smaller R&D budgets," Lakdawalla notes. "This set of facts would lead to the correlation found in the Bach piece, but it does not imply anything about whether higher prices cause higher innovation spending." He added that the best way to conduct these types of studies is to look at the impact of a shift in US prices or revenue that is unrelated to any other factors that influence R&D spend. “For example, prior studies have used policy changes like Medicare Part D’s implementation, or demographic shifts like the aging of the US Baby Boom cohort-these events shifted prices and/or revenues and allow us to study the implications of higher prices or revenues.”

	Lakdawalla adds, "I also think there is some confusion about the economic issues here. Innovation investment is driven by expectations of future revenues, not necessarily by current revenues...'More money today' does not necessarily translate into more innovation spending today. Rather, the mechanism works through expectations about the future policy and market environment, and how these are likely to influence the revenues that can be earned when a pipeline drug is eventually launched."

	According to PhRMA spokesperson Holly Campbell, the study "advances a misleading narrative by understating how the competitive marketplace for medicines in the United States helps control costs and provides patients with access to innovative treatments and cures faster than in many parts of the world. In the United States, generic utilization rates are nearly 90 percent, competition occurs among brand name medicines and large, powerful purchasers negotiate aggressively." Campbell also told 

 that price differences between the US and other countries are often due to price controls that effectively restrict access to medicines for patients overseas.

*Article updated to include comments from Darius N. Lakdawalla
	*Article updated again on 3/9/17 to include comments from PhRMA

A blog posted on Health Affairs on March 7, 2017 presents a study that tested PhRMA’s long-standing argument that high prices for drugs fund research and development in the pharmaceutical industry.

Study Dismantles PhRMA’s Long-Standing Argument on Drug Pricing

	In a landmark decision, the United States FDA and the European Commission 

 on March 2, 2017 that they will recognize each other’s inspection assessments at pharmaceutical manufacturing facilities. The Mutual Recognition Agreement amends the 1998 agreement on good manufacturing practices and comes three years after initial discussions began.

	According to an FDA press release, FDA has already observed 14 audits of drug investigators across the EU through the EU’s Joint Audit Programme, including an audit of a Swedish inspectorate by Norway and the United Kingdom. FDA plans to observe more audits throughout 2017. “The enhanced cooperation with US regulatory authorities will improve the EU’s ability to identify and address problems at factories before they become a public health risk,” a 

 from the European Commission noted. “It will also reduce the administrative burdens and costs facing pharmaceutical manufacturers, including smaller producers.” The prevailing idea behind the agreement is that each agency would then be able to reallocate its inspection resources to other areas of need.

	Inspections will be officially recognized beginning in November 2017. The agreement follows a 2012 initiative-the Food and Drug Administration Safety and Innovation Act-which allowed FDA to accept the inspections of foreign regulatory authorities if they were determined to be in alignment with US policies and requirements. Within the text of the agreement, the agencies note that inspection requirements can be considered “equivalent” even if the actual procedures within each agency are not identical.

	Any new controls or changes to existing GMP requirements will be discussed by both parties in the spirit of cooperation and information exchange, the text of the agreement explained. For now, the agreement will cover pharmaceuticals made for humans (except for vaccine and plasma-derived products), but by 2019 the committee will make a decision about the inclusion of veterinary products. By 2020, the committee will announce a decision about whether it plans to include vaccines and blood-based products within the product coverage of the agreement.

The Mutual Recognition Agreement will allow FDA and EU inspectors to recognize each other’s work and avoid the duplication of drug inspections.

EU and US Pledge to Recognize Each Other’s GMP Inspections

	FDA issued a complete response letter to Amphastar for its intranasal Naloxone (naloxone hydrochloride 2mg/0.5mL nasal spray) on Feb. 21, 2017, citing issues with device evaluation, user human factors study, and other factors that the company did not identify, Amphastar said in a press release.

	Amphastar will still offer naloxone in pre-filled syringes for the treatment of opioid overdose. Amphastar's naloxone serves as a competitor to Kaléo Pharmaceuticals' Evzio, which has recently received some negative press because of a nearly 600% price increase. Amphastar has also gotten some heat for doubling the price of its own version in 2015. In June 2016, Senators Susan Collins (R-Maine), and Claire McCaskill (D-Missouri) 

 to Amphastar’s CEO, asking the company to provide a justification for price hikes.

 is currently already on the market and goes by the trade name Narcan. Approved in 2015, it became commercially available in the early part of 2016.

The regulatory agency rejected the medication, citing various issues related to device use.

Amphastar Receives Complete Response Letter for Intranasal Opioid Overdose Med

, Momenta announced on Feb. 16, 2017 that Momenta/Sandoz’s fill/finish contract manufacturer, Pfizer, received a warning letter for the manufacture of the 40 mg of Glatopa (glatiramer acetate injection), Momenta’s generic version of the drug Copaxone. Pfizer said in the statement that the warning letter does not affect the production or shipment of the 20 mg version of the drug, which is already approved by FDA. The 40-mg version of the drug is still being evaluated by FDA.

	The Momenta release stated, “under FDA policy, an approval of the application is dependent on the satisfactory resolution of the compliance observations at the Pfizer facility used to make the final product, and Momenta expects that an approval in the first quarter of 2017 is unlikely.”

	Although there are multiple contenders vying to make generic Copaxone, the 20-mg version made by Momenta is currently the only dosage and version that has been approved.

	Pfizer said the plant that received a warning letter was in McPherson, Kansas. The plant was a former Hospira plant that had received Form 483s in the past. In an email to this publication, Pfizer said, "We responded to the questions raised during the inspection of our manufacturing site in May 2016 and submitted a corrective and preventive action plan to the FDA at that time. Since the inspection, the McPherson site has been diligently implementing commitments made to the FDA. We will continue to identify assessments and potential corrective actions to ensure the FDA’s observations are addressed."

	The Pfizer spokesperson continued, "We also have conducted an assessment and concluded that the issues cited in the Warning Letter do not have any impact on products that are currently on the market that were manufactured at the McPherson site."	 	Meanwhile, on Feb. 16, 2017, a day before Momenta formally recognized the warning letter, Pfizer CentreOne 

 it has expanded its fill/finish capabilities to its Kalamazoo, MI site. The site will now handle sterile injectables.

Momenta’s fill/finish contract manufacturer, Pfizer, was cited in the letter.