Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

s, based in Gujarat, India for current good manufacturing practice (cGMP) compliance problems that inspectors found during an inspection of the company’s facility in Indrad in early April 2019. In what is becoming a familiar theme, the warning letter mentions that these problems had previously been found in a previous inspection of the facility in April 2017.

	According to FDA, the company failed to follow written procedures for production and process control. One major problem was the fact that written process validation protocol was not followed. Official protocol required that three consecutive batches of any alternative API used in manufacturing meet specific quality specifications.  

	Instead, the warning letter states, operators and technicians opted for an undocumented approach.  After the first of three process validation batches failed dissolution tests, the letter says, they tested a fourth batch (which also wound up failing dissolution tests).  That fourth batch had never been specified in the company’s validation protocol. After out-of-specification (OOS) investigations were launched, all four batches were rejected. 

	The company developed an “interim” protocol to support use of the alternate API, FDA’s letter said, even though it had data showing that the process cold not produce material of adequate quality.  As a result, a number of out-of-spec Losartan potassium tablets (both USP 50- and 100-mg) were shipped to the United States (where they were later recalled for unacceptably high levels of nitrosamine impurities).

	In its previous response to an FDA 483 triggered by a facility inspection, the company had even stated that the change in API had no impact on the product’s manufacturing and quality, the letter stated.  Torrent had not investigated the root causes of the batch failures, or provided justification for changing the API it used in the manufacturing process, according to FDA. 

	After outlining the specific examples of noncompliance, the letter then defined the philosophy behind process validation and process qualification studies. FDA has asked for a detailed summary of the company’s validation program, and how it will ensure a state of control throughout the product lifecycle. FDA also requested clarification of how the company will perform monitoring of variation within and between different batches of product to demonstrate control, and also asked for a timeline for performing process performance qualification of each of its products. 

Lack of insight into reasons for out-of-specification (OOS) results

	The agency found multiple instances where initial OOS results were invalidated without sufficient investigation.  Between January 2017 and March 2019, FDA’s letter stated, the facility had invalidated between 60 and 70% of initial OOS test results and had not followed up to find root cause. In its response to FDA last Spring, the company stated that OOS results had fallen from 77% to 41% between January 2017 to March 2019.

	Pointing out the connection between OOS investigations and CAPA, FDA noted that the company had been criticized for these deficiencies previously, in inspections at its Indrad facility in April 2017 and at its Dahej plant in March 2019.

	“Repeated failures at multiple sites demonstrate that executive management oversight and control over the manufacture of drugs is inadequate,” the letter said, emphasizing the fact that senior managers bear the final responsibility for ensuring cGMP compliance. It asked for:

		an independent, third-party review of all invalidated OOS (including in-process and release/stability testing) results for products currently in the US market.

		a report explaining whether laboratory error was at the root of the problem, or, if that was not the cause, a full review of production including batch manufacturing records, variability of raw materials, process capability, deviation, complaint, and batch failure histories.

		 Summaries of potential root causes for each investigation, and a comprehensive review and remediation plan for systems used to investigate OOS results.

	FDA’s letter states that it may withhold approval of any new drugs that the company may have under review at the agency, and refuse to allow products made at the facility to be sold in the US, it asked for a written response within 15 days.

FDA Warning Letter to Torrent Pharmaceuticals

Articles

Emphasizing the need for senior management to take cGMP compliance seriously, the agency pointed to “improvisational” validation procedures, lack of compliance with written procedures, as well as  inadequate process control, root cause analysis, and corrective and preventive action (CAPA) in its warning letter.

FDA cites repeated, fundamental cGMP issues in its warning letter to Torrent Pharmaceuticals

	As ranitidine recalls continue, global regulators are assessing levels of contamination by the carcinogen, N-nitrosodimethylamine (NDMA) in the drug and its potential impact on patients, since the drug has been widely prescribed for over thirty years. A histamine-2 blocker (H-2), ranitidine blocks excess acid secretion in the stomach and is prescribed to treat problems ranging from acid reflux and heartburn to ulcers. 

 that test methods that it had previously recommended for assessing NDMA levels in angiotensin II receptor blockers (ARBs) such as valsartan, would not work well for ranitidine.  The Agency now recommends that companies use a Liquid Chromatography- High Resolution Mass Spectrometry (LC-HRMS) protocol, designed to run at lower temperatures than the previous method, to test samples of ranitidine. The agency also asked ranitidine manufacturers to run their own lab tests on product to assess NDMA levels, and to send product samples, ostensibly for comparative testing, to FDA.

sent to FDA on Sept. 13, 2019 by Valisure, a Connecticut-based online pharmacy, that found problems with test methods and suggested that the ranitidine molecule itself is so unstable that it can generate NDMA within the human body. The company is collaborating on an epidemiological study with Memorial Sloan Kettering Cancer Center in New York City to explore these issues.

	As noted in the petition, where FDA had established a safe daily intake limit of 96 ng for NDMA, Valisure testing, using ISO-certified methods, found levels of NDMA in excess of 3 million ng per tablet when ranitidine was tested at conditions mimicking those in the human body.  

	FDA and EMA have addressed potential manufacturing-related causes of contamination in messages to manufacturers.  However, Valisure’s tests, and past studies published by Stanford University, suggest that the ranitidine molecule is inherently unstable and can release NDMA within the human body and when exposed to high temperatures, specific chemicals, and other conditions.

 on the name-brand ranitidine product, Zantac, performed by its developer GlaxoSmithKline in 1987 used methods that would have been unable to determine the connection between ranitidine and NDMA concentrations, according to the petition. 

	“Our concern is that potential problems are being minimized. Testing suggests that there are several conditions by which the [nitrosamine] impurities can form, in the lab, in the stomach, and elsewhere in the human body,” Valisure CEO David Light told 

Problems with high-temperature lab testing

	Originally, Valisure had equipped its QC lab with FDA-recommended gas chromatography/mass spectrometry (GC-MS) analytical systems after NDMA and other nitrosamine contamination had been detected in valsartan and other sartans in the supply chain, says Light. 

	However, the company found that, at oven temperatures of 130 °C, ranitidine can react with itself, generating extremely high levels of NDMA, according to its petition. As a result, Light said, Valisure changed its analytical testing protocol so that it runs at 37 °C, the average temperature of the human body. As the petition explains, the lower-temperature method was validated to a lower limit of detection of 100 ng and used for a variety of biologically relevant conditions of the human body.  

	FDA has contested Valisure’s results.  In its October 2 statement, the agency noted that scientists at its labs and at those of other global regulatory agencies had found much lower levels of NDMA using the LC-HRMS method than Valisure had found. FDA’s new method runs at lower temperatures than the GC-MS method used to test for NDMA in sartans. However, FDA noted, even early and limited testing has detected “unacceptable levels” of NDMA in the samples. Previously, the agency had described these levels as “low.”

Tests simulating conditions in the stomach

	Besides using the customized GC-MS method, Valisure tested ranitidine tablets in conditions designed to simulate those in the human stomach and intestine using standard “Simulated Gastric Fluid” (“SGF” 50 mM potassium chloride, 85 mM hydrochloric acid adjusted to pH 1.2 with 1.25 g pepsin per liter) and “Simulated Intestinal Fluid” (“SIF” 50 mM potassium chloride, 50 mM potassium phosphate monobasic adjusted to pH 6.8 with hydrochloric acid and sodium hydroxide) methods. These tests were performed in 100-mL reaction volumes with one 150-mg tablet of ranitidine for each test, the petition states, and results suggested that significant amounts of NDMA are formed under simulated gastric conditions when nitrite is present.

	Work by Stanford researchers in 2016 suggested that the ranitidine molecule itself might be unstable.  In this 

, healthy individuals who took 150-mg Zantac tablets were tested 24 hours later, and their urine was found to contain 400 times more NDMA (i.e., over 40,000 nanograms of the compound) than it had before testing (1). As the petition stated, these results are alarming given NDMA’s role as a potential causative agent for bladder cancer. 

	“The Stanford research found less than 1% in urine, suggesting that the remainder of contaminant could remain in the human body, which could potentially mean millions of nanograms of exposure,” says Light.  

	Valisure also used molecular modeling to test biological mechanisms that might generate NMDA, Light says. “We didn’t have real insight into the biological causes but, using open-source tools we developed computational models that found that the enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH-1) can bend ranitidine and break it down to form NDMA. 

	The petition noted that few epidemiological studies have been conducted on ranitidine, and that 

studies performed by Glaxo Research Group in 1987

 would have been unable to track NDMA formation since they used a nitrogen oxide assay, typically used in food studies, to determine the presence of nitrosamines (2). The method is less accurate and specific than chromatography, but also required discarding gastric samples that contained ranitidine. “Without ranitidine being present in any samples taken, the degradation products of ranitidine, like NDMA, could not reasonably be detected,” the petition stated.

	Light stands by the findings cited in Valisure's citizen’s petition, noting ranitidine’s instability at high temperatures and the fact that both the nitrite “N” and dimethylamine “DMA” are present on the molecule. Citing results of studies run in other industries that show how the molecule can degrade after exposure, not only to heat, but to chlorine and ozone, Light raises the possibility that the contaminants could form during temperature excursions, when product is transported. He also cites 

, where regulators have found NDMA contamination levels as high as 334 times the acceptable limits. “The ability to form millions of nanograms of NDMA support findings from Stanford University that suspect this high exposure in the human body,” Light said in an official response to FDA’s announcement on October 2.

	Fundamentally, Light says, “NDMA contamination is simply a byproduct of the instability of the ranitidine molecule. The significantly more serious problem is ranitidine's potential to form millions of nanograms of NDMA, a known carcinogen, in the human body. “

	On Sept. 13, 2019, both the European Medicines Agency (EMA) and FDA launched renewed efforts to understand the root cause of the contamination. Rantidine represents the third group of drugs to be affected by trace levels of NDMA and other nitrosamine contaminants. First was contamination in angiotensin II receptor blockers (ARBs), notably valsartan but other sartans as well, and the APIs used to manufacture them. The news triggered voluntary product recalls in more than 23 countries, global regulatory reviews, and investigations into the root causes of contamination. In April 2019, low levels of NDMA were found in some batches of pioglitazone, a treatment for diabetes. 

	Valisure had sent a petition to FDA in June 2019, noting that its testing had detected unsafe levels of the carcinogenic contaminant dimethylformamide (DMF) in valsartan and other sartans, and asked the agency to clarify acceptable limits.  Currently, FDA has set the permissible exposure limit at 8,800,000 nanograms, according to the petition, which is 9,166,667% higher than the acceptable intake limit of NDMA. “This disparity lacks a rational basis and is of significant concern, particularly because of Valisure’s recent findings that high levels of DMF exist in certain on-market lots of valsartan medication,” the petition noted.

 have notified manufacturers and those planning to submit abbreviated new drug applications (ANDAs) for potentially at risk therapies, to be cautious about sourcing raw materials, and, in particular to watch out for materials that may have been recycled. 

	As FDA spokesman Charlie Kohler notes, FDA continues to study the problem with other global regulatory agencies, and is posting 

 via a dedicated web page. The agency is also updating a 

 with information on nitrosamine issues in sartans, says Kohler.

	At this point, Kohler says, FDA has no plans to update guidance on toxicology of mutagenic compounds, as spelled out in the agency’s March 2018  

Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceutical to Limit Potential Carcinogenic Risk

,” which aims to clarify ICH’s M-7 requirements and lays out risk assessments that manufacturers can use to evaluate the presence of genotoxic impurities. 

	“This is an internationally-harmonized guidance that both regulators and industry have agreed to. To implement the risk assessment for any genotoxic impurity, there has to be recognition that it can occur in the manufacture of the product.  The guidance lays out the conditions under which these risks can occur, and the steps that manufacturers should take to test for these potential impurities,” says Kohler. The recommendations in this guidance are for manufacturers of drug substances and drug products and do not create a separate standard for innovator drug products as compared to generic or OTC drug products, especially in the context of “cohort of concern” impurities such as nitrosamines, he says.

	The petition has brought publicity to a small, relatively new startup and raised some questions of why a pharmacy would get involved in testing and quality issues that are normally considered the manufacturer’s responsibility.  As Light explains, Valisure’s business model is quite different from that of the typical online, or even bricks-and-mortar pharmacy, which does not typically re-test medications for safety and quality. Valisure performs quality control tests on medications before distributing them, to validate their quality.  The company initially found the contamination during routine testing of products that it was going to distribute.

	Although it stands outside the world of current good manufacturing practices, Valisure had its analytical laboratory inspected by FDA in 2018. Because it is not a manufacturer, Light says, "the citizen's petition was the only effective option that we had to notify FDA of our findings."

	Light first had the idea for the company, which officially launched in August 2018, when a friend began to have trouble with side effects from generic anticonvulsant medications.  Variability can be a problem with some generic formulations. "We looked at medical studies of antiepileptic medications and saw that the risk of having a seizure can increase two-fold when anticonvulsant prescriptions are refilled with generics that have been produced by different manufacturers," Light says. 

	 “We saw that nobody is checking at the end of the distribution chain,” Light says. The company invested in spectroscopic equipment, focusing on Raman, and laser analytics, developed some proprietary technology and algorithms, filed patents, and then applied for and received ISO 17025 accreditation. 

	Valisure puts every batch of medication it distributes through dissolution profile testing and analysis (destructive analytical methods are used on samples from each batch). If it passes, it is dispensed with a certificate of analysis, says Light.

	The company is seeing increasing interest in its model from physicians who would like to have the option of prescribing validated generics.  “Getting prior authorization for patients to get name-brand drugs is time consuming and difficult. The validated generic option offers a way around this, to ensure quality and assure patients that they are receiving a high quality medication that just happens to be generic,” says Light.

	Having the ability to verify the quality of a generic or OTC drug would also be a benefit if US Congress decides to permit the re-importation of pharmaceuticals, e.g., from Canada, Light says. 

	In March, Valisure launched a partnership with the pharmacy benefit manager Capital Rx, which offers access to Valisure’s pharmacy to its customers.  Valisure is also involved in discussions with Civica Rx, which focuses on novel strategies for addressing drug shortages and high drug prices, on potential partnerships, Light says.

	We can expect to learn much more about ranitidine’s chemistry, toxicology, and health impacts, as regulators and the industry explore the potential root causes of ranitidine contamination from every possible angle. “These cases may well be the tip of the iceberg," says Light. "But at the very least they point out cracks in a very complex, global system and supply chain.” 

	In general, Light says, the pharmaceutical industry has a good system in place for safety and quality, but it still depends on self-reporting, which can be problematic. “Consider the aviation industry and the Boeing 737 Max. An exploding plane is very visible, but the impacts of any safety issues with medications are not always so clear,” he says.

	1. Zeng, T. and Mitch, W.A. (2016). Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine. 

 Vol. 37, p. 625-634
	2. Thomas, J.M., et al. (1987). Effects of one year's treatment with ranitidine and of truncal vagotomy on gastric contents. 

The root cause of NDMA contamination may go well beyond manufacturing problems, to the molecule itself.

Problems With Ranitidine May Transcend Manufacturing Issues

	In news that should be welcome to biosimilars and generic pharmaceutical developers, FDA is planning to update its citizen’s petition process, and has asked for industry comments. The process was designed to facilitate the public’s ability to communicate issues of concern directly with FDA.  Over the years, however, the process has been misused, as a way to block competition and innovation, rather than communicate important information to regulators. 

 has found that, between 2011 and 2015, name-brand pharmaceutical companies filed 92% of all the 505(q) citizen’s petitions sent to FDA, and FDA approved only 8% of them. (1) 

	Before he left the agency, former FDA Commissioner Scott Gottlieb noted that the petition process had become a way of gaming the drug approval process and delaying generic competitors from entering the market.  In an official press statement (2) issued on Oct. 2, 2018, Gottlieb said that the agency would be revising guidance on citizen’s petitions. “While the record shows that citizen petitions have rarely delayed specific generic drug approvals, there’s no doubt that the process requirements associated with 505(q) petitions can add to resource burdens on the generic drug review process and the FDA’s regulatory decision making. This increased burden on the FDA can take resources away from the daily work of application review,” he said.  He noted that, in the future, FDA intends to refer petitions that seek to block new market entries directly to the United States Federal Trade Commission. “We hope that this increased transparency will reduce gratuitous hurdles to generic drug development and approval,” he said, noting that the Agency would include a response to any petitions received within the 150-day application-review timeline that the agency has set as a new goal. 

	On Sept.19, 2019, FDA released a revised 

 for public comment (3), publishing it in the 

 (4). The agency’s goal was to describe factors that FDA will consider in determining whether the petition is serious or whether its primary purpose is to delay a competitor’s application (3). “With this guidance, the Agency is addressing ‘gaming’ by brand-name drug companies that may try to delay generic and biosimilar drug approvals, including discouraging petitions submitted with the primary purpose of delaying approval of applications, said FDA spokesman Charlie Kohler. 

	The guidance lays out factors that FDA will consider in determining whether a petition is submitted with the primary purpose of delaying the approval of an application, Kohler explains. If the Agency determines that a petitioner has submitted a petition to delay the approval of an application, he says, FDA may note this determination in the petition response, which will be available to the public through the citizen petition docket. The guidance states that FDA also intends to refer these matters to the Federal Trade Commission, and to highlight these determinations in its annual report to Congress, he says.

	The guidance also explains that FDA intends to treat petitions as being subject to the 150-day timeline established under section 505(q). This will apply only if the abbreviated new drug application (ANDA), 505(b)(2) new drug application (NDA), or 351(k) application targeted by the petition is pending when the agency receives the petition and the pending application has a user-fee goal date on or before the 150-day timeframe for final agency action on the petition, Kohler explains. This policy aligns the timeline to review and respond to petitions with the timeline for review of the applications themselves, consistent with user fee goal dates. This approach ensures that scientific and regulatory issues raised in a petition are considered prior to ANDA, 505(b)(2) NDA, or 351(k) approval, he says. 

	The petition process made headlines during the past few months when the online pharmacy Valisure petitioned FDA to alert regulators to the fact that testing had revealed presence of nitrosamine and 

greatly in excess of established safe limits. LINK TO NEWS STORY ON RANITIDINE

	“Citizens petitions offer a powerful way to gain attention for serious problems,” said Valisure CEO David Light. 

	Kohler explained that the petition process allows any “interested person” to petition FDA to issue, amend, or revoke a regulation or order, or to take or refrain from taking any other form of administrative action, as specified by 21 CFR 10.25(a).  Thus, citizen petitions can be submitted on safety and/or quality issues, he said. 

	As an alternative to the citizen’s petition, in order to report quality issues, manufacturers would  typically have to contact FDA’s Office of Regulatory Affairs (ORA) directly and file a Field Alert Report (FAR) outlining the product, manufacturer, defect, lots impacted, expiry, and the firm’s investigation into the root cause of the defect, Kohler said.  ORA field coordinator information can be found via the following link  

https://www.fda.gov/safety/industry-guidance-recalls/ora-recall-coordinators

	The FAR regulations were established to speed the identification of quality defects in distributed drug products that may present a potential safety threat. Under these regulations, new or abbreviated new drug application (NDA and ANDA) applicants must submit information about distributed drug products regulated by FDA’s Center for Drug Evaluation and Research (CDER) or by FDA’s Center for Biologics Evaluation and Research (CBER). 

	As Kohler explains, an NDA or ANDA applicant must submit a FAR to FDA within three working days of receiving the following: 

		Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article. 

		Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specification established for it in the application.

	Manufacturers may also provide such information to the agency by contacting the CDER Office of Communications, Division of Drug Information, Kohler said, or by contacting the CDER Office of Pharmaceutical Quality or the CDER Office of Compliance, Office of Manufacturing Quality. 

	If there is a consumer report of an adverse event or serious problem, FDA may be contacted at the following website: 

https://www.fda.gov/safety/reporting-serious-problems-fda/how-consumers-can-report-adverse-event-or-serious-problem-fda

	Between 2008 and 2015, Kohler said, CDER received 683 Citizen Petitions, of which 175 were subject to section 505(q). This represents approximately 26% of all citizen petitions received by CDER during this time period. More information can be found in HYPERLINK “

Annual Reports to Congress on Delays in Approvals of Applications Related to Citizen Petitions and Petitions for Stay of Agency Action by Fiscal Year

https://digitalcommons.wcl.american.edu/cgi/viewcontent.cgi?article=1956&context=aulr

 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/citizen-petitions-and-petitions-stay-action-subject-section-505q-federal-food-drug-and-cosmetic-act-0

https://www.federalregister.gov/documents/2019/09/19/2019-20312/citizen-petitions-and-petitions-for-stay-of-action-subject-to-the-federal-food-drug-and-cosmetic-act

https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-new-agency-actions-further-deter-gaming-generic-drug

The agency seeks comments on a draft guidance designed to make the process conform to its original intent as a communication tool, rather than a roadblock to competition and innovation. 

Revamping the Citizen’s Petition Process for FDA

 (EMA and FDA) responded to reports that trace levels of nitrosodimethylamine (NDMA) had been found in the histamine-2 (H2) blocker rantidine, which is used to block excess acid secretion in the stomach, to treat conditions ranging from acid reflux and ulcers to heartburn and acid indigestion. Contamination may affect both prescription and over-the-counter forms of the drug.

European Commission has asked EMA to begin a review

 throughout the European Union, to determine whether patients using the medication are at risk. The 

Committee for Medicinal Products for Human Use

) will issue formal guidance to help manufacturers avoid presence of nitrosamines in products and to respond quickly should contamination be found. “We will continue to work with our partners to address the presence of nitrosamines and reassure patients about the quality of their medicines,” said EMA Executive Director Guido Rasi, quoted in a press release that was issued on September 16, 2019. Rasi noted that “It is of paramount importance that we learn from our experience with sartans and take a proactive approach for other classes of medicines.” 

	Rantidine represents the third group of drugs to be affected by trace nitrosamine contamination. However, in this case, not only prescription but also over-the-counter medications (OTC) may be at risk. 

	In 2018, traces of nitrosodimethylamine (NDMA) and other nitrosamines, classified as probable human carcinogens, were found in a number of prescription blood-pressure medications. The cases involved angiotensin II receptor blockers (ARBs), notably valsartan but other sartans as well, and the APIs used to manufacture them.) The news triggered voluntary product recalls in more than 23 countries, global regulatory reviews, and investigations into the root causes of contamination.

	In April 2019, low levels of NDMA were found in some batches of the diabetes treatment, pioglitazone, manufactured by Hetero Labs in India, prompting EMA to issue manufacturer alerts to ensure the use of proper materials and adequate testing. 

	Both FDA and EMA are working to determine whether the low levels of NDMA found in rantidine pose a risk to patients. As with ARBs, FDA advises patients and healthcare givers to continue with existing rantidine treatments, according to a 

, director of the FDA’s Center for Drug Evaluation and Research, issued on September 13, 2019. “Although NDMA may cause harm in large amounts, the levels that FDA is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods,” said Woodcock in the announcement. However, for OTC treatment, both FDA and EMA suggest that alternatives be considered. FDA has asked that consumers and healthcare providers report any adverse reactions to rantidine to FDA’s MedWatch program, by 

	Beware use of reclaimed solvents and catalysts

	After the ARB contamination was found, FDA issued 

to name-brand and generic pharmaceutical companies planning to apply for approval for an ARB drug product, and to companies that hold drug master files for ARB APIs. FDA’s advice emphasized the importance of complying with ICH M7, “Assessment and Control of DNA-Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.” FDA had 

finalized guidance on complying with ICH M7 

in March 2018. The agency also underscored the fact that nitrosamines can form during API and finished drug manufacturing under specific conditions and in the presence of certain raw materials or starting materials.

	FDA pinpointed the use of recovered solvents and catalysts in the manufacturing process as requiring special precautions and testing.  Recovered solvents and catalysts may pose a risk, the regulators wrote in the general advice document, because amines may be present and quenched during the recycling process to destroy any residual azides, but these materials may not be completely removed during recovery.  

	In addition, commingled solvents can pose a manufacturing risk, the regulators warned. Finally, raw material contamination can be very difficult to detect, and basic compendial identity and purity tests will not detect trace levels of the genotocix impurities.

released a number of recommended analytical procedures

, including the LGL, Swissmedic and CVUA/Karlsruhe methods involving the use of mass spectrometry (MS), liquid and gas chromatography (LC and GC). FDA approved use of a 

to test for the contaminants. Both regulatory agencies have pledged to work together to collaborate with other regulators to prevent risks to patients and the global supply chain. However, they emphasize the responsibility that manufacturers have to test and ensure the quality of starting materials and final products. 

EMA plans to issue new guidance, as US and European regulators respond to reports of nitrosamine contamination in H2 blockers, including Zantac, that contain rantidine.


Regulators Tackle Nitrosamine Contamination in Prescription and OTC Ulcer and Heartburn Medications

Generic pharmaceuticals now account for more than 90% of all prescriptions issued in the United States. However, the generic pharmaceuticals’ pipeline flow is anything but smooth. A report issued on Aug. 7, 2019 by the US Government Accountability Office (GAO) (1) traces part of the problem to issues with FDA review. A New Prior Knowledge” concept that would make crucial process and product information available has been proposed by the National Institute for Pharmaceutical Technology and Education.

, September 2019
	September 2019
	Pages: 24–26

	When referring to this article, please cite it as A. Shanley, “Generics: Getting Beyond ‘File First, Figure it Out Later’," 

Pharmaceutical Technology Regulatory Sourcebook

A GAO report analyzes some of the reasons why so few generics are approved the first time around. NIPTE has proposed a program that would address these issues. 

Generics: Getting Beyond “File First, Figure it Out Later”

	Early adopters of continuous manufacturing approaches shared their plans and some of their experiences at the 11th annual Charles Jarowski Symposium in Industrial Pharmacy on May 6, 2019, at St. John’s University in New York City. Takeda Pharmaceuticals, which acquired Shire Pharma’s continuous manufacturing expertise when it bought the company, has continued continuous research and piloting efforts begun by Shire in 2016, according to Jim Bonner, Takeda’s director of small-molecule drug product, who spoke in the program (1). The company, along with Thermo Fisher’s Patheon, is exploring the use of continuous manufacturing for encapsulation as well as tableting, focusing on the continuous direct encapsulation of Vyvanse (lisdexamfetamine dimesylate), a treatment for attention deficit/hyperactivity disorder that was approved in 2007. Configuring encapsulation equipment for continuous manufacturing has been challenging, he noted.

	The company has completed trial runs using near-infrared (NIR) and Raman spectroscopy, which involved scanning 30 different blends three times, then using product of least squares-based chemometric methods on reference gravimetric rather than high-performance liquid chromatography assay data. Extensive design of experiments work has also been done, and the company is anticipating approval of the continuous process by 2020.  As Bonner pointed out, these efforts have underscored the need for more robust and economic process analytial technology options and simplified model maintenance. In addition, he believes that FDA should be shown that loss-in-weight feedback data are more accurate than data provided by NIR models. 

	Andrew Farrington, principal scientist for oral formulation sciences at Merck in West Point, PA, discussed the company’s pilot project, designed to build upon existing expertise in real-time release testing, raw materials monitoring, and quality by design (2). The pilot applies continuous-to-direct compression and film coating using tablet transmission NIR and tablet weighing instead of content uniformity, and hardness and disintegration instead of dissolution. The goals are to produce nearly one billion tablets per year with less than 90-day lead times from formulation to patient in a two-floor installation that is roughly one-third the size of traditional tableting facilities. 

	The company engaged early in discussions with regulators and is now working on both a continuous product development line, capable of manufacturing 5–20 kg/h of product, and a commercial line, with capacity of 10–90 kg/h. The advantages of the small-scale unit, he said, included a single point of control, facilitating remote equipment operation and potentially allowing operators to be removed from the processing environment.  The company has developed a predictive model based on material attributes for continuous feeding and has also tested twin screw granulation.  Although the company is optimistic about the role that continuous processes will play in the future, Farrington asserted that a mix of batch and continuous will be better for the industry’s assets and supply chains.

	1. J. Bonner, “Continuous Manufacturing Challenges to Commercialization” a presentation made at the 11th annual Charles I. Jarowski Symposium in Industrial Pharmacy, May 6, 2019.

	2. A. Farrington, “Challenges with Continuous Manufacturing: Integrated Development Strategy for Continuous Manufacturing of Oral Drug Products,” a presentation made at the 11th annual Charles I. Jarowski Symposium in Industrial Pharmacy, May 6, 2019.

	When referring to this article, please cite it as A. Shanley, "Industry Experiences in Continuous Manufacturing for Encapsulation and Tableting," 

Early adopters of continuous manufacturing approaches shared their plans and some of their experiences at the 11th annual Charles Jarowski Symposium in Industrial Pharmacy.