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Drug Development

The complete response letter: The mail no one wants to receive

Manufacturing issues can delay drug approvals and complicate relationships between drug firms and their contract suppliers

by Ann M. Thayer
May 15, 2017 | A version of this story appeared in Volume 95, Issue 20

A photo of a person's thumb and forefinger removing a letter that reads "Center for Drug Evaluation and Research" from a manila envelope.
Credit: Yang H. Ku/C&EN/Shutterstock

Everyone has felt the anxiety of waiting for a reply to an application. Will it be the fat envelope holding an acceptance or the skinny one with a rejection? For a pharmaceutical company, the unwanted package is a complete response letter (CRL) from the Food & Drug Administration laying out the reasons why a drug can’t be approved. Covering safety, efficacy, and manufacturing, the CRL describes deficiencies, possible remedies, and options for moving ahead.

In brief

Getting regulators to sign off on the processes and facilities used for making drugs is essential for any company seeking to market a new product. In 2016, however, FDA complete response letters (CRLs) explaining why a drug can’t be approved increased both in number and in their focus on manufacturing problems. The repercussions of receiving one of these letters can include delayed approval, lost business, and financial uncertainty. But a look at several companies’ experiences with CRLs shows that solutions can be found. Read on to learn how drug developers and their partners are working together to solve manufacturing problems and improve quality.

FDA’s Center for Drug Evaluation & Research issued 14 CRLs for novel drugs in 2016. The number was steep and contributed to a decline in drug approvals, John Jenkins, then-departing director of FDA’s Office of New Drugs, wrote in a blog post in January. Not only was the number of CRLs higher than in recent years, but also the primary deficiency in many cases was a failure to comply with current Good Manufacturing Practices (cGMPs) designed to control product quality.

Satisfying regulators and getting them to sign off on the facilities and procedures used for making active drug substances or formulating final products is essential before a company can market a new drug. So the last thing a drug firm wants to hear about is a manufacturing issue found during a preapproval inspection that will delay a drug launch.

The problem is complicated when the drug company has outsourced production and is counting on the contract manufacturing organization (CMO) it has hired to be in compliance. If compliance is lacking, the drug firm and its contractor must find a remedy, alone or together, to get an application back on track.

Drug companies often outsource to access specialized and hard-to-find capabilities. Small companies that lack manufacturing capabilities may rely entirely on outside suppliers. As a result, outsourcing is on the rise. Cognizant of this change, FDA is focusing on supply-chain management in a way that may alter the dynamic between drug developers and their CMOs.

“Even before companies were outsourcing, they could have gotten held up by manufacturing issues,” says Joseph W. Cormier, a regulatory attorney with the law firm Hyman, Phelps & McNamara. “But certainly as globalization has become more of a norm with respect to the drug supply chain, there has been an increasing reliance on CMOs by drug companies, and that means that the applicant must rely on a third party for quality assurance and cGMP compliance.”

Clear as mud

FDA seems to be trying to shift responsibility for compliance back to drug companies while pushing them and their CMOs to be more vigilant about quality. Agency warning letters and reports of unfavorable observations made during contractor plant inspections can trigger a CRL.

Manufacturing glitches have always occurred, but they may be more evident now, points out Cormier, who was also trained as a pharmacologist and worked for several years at FDA. With the advent of user fees, particularly for generic drugs, FDA has the money to conduct more inspections.

“Any uptick in the CRLs that deal with chemistry, manufacturing, and controls issues is really a function of increased focus by the agency on drug manufacturing, particularly of foreign firms,” he says. “Like anything, if you put more microscopes on a problem, you are going to find more issues.”

The agency doesn’t release CRLs publicly because of confidentiality concerns, and most companies disclose only limited details. “Whether and how a company discloses why it got its CRL really depends on the company,” Cormier says.

“Most publicly traded companies will disclose that information because they have U.S. Securities & Exchange Commission obligations to disclose material facts to their shareholders,” he says. “Small companies that often are privately held may be less likely to make public that they even got a CRL and, if they go that far, the ‘why’ behind it.”

To understand how much information companies make public, FDA Associate Commissioner for Public Health Strategy & Analysis Peter Lurie and other agency staffers analyzed confidential CRLs issued between August 2008 and June 2013 (BMJ 2015, DOI: 10.1136/bmj.h2758). They then compared them with public disclosures by the companies.

Of the 61 CRLs issued, 11 did not have corresponding press releases. When press releases were issued, they tended to be substantially different from the CRLs and “generally an incomplete source of reasons for FDA non-approval of applications,” the study found.

Lurie and his team acknowledged industry’s desire to protect trade secrets and confidential business information. But they also supported sharing more of the scientific and clinical content of CRLs as a way to inform drug development and public health. They made three recommendations for reducing the information gap: drug companies release CRLs, drug companies release more complete statements, or FDA makes the letters public.

Support for more openness by FDA appeared again in March in a “Blueprint for Transparency at the Food and Drug Administration” created by an academic group that was largely from Johns Hopkins University. Among the blueprint’s recommendations are adopting a 2010 FDA task force plan to disclose CRLs, albeit in a way that avoids any need for legislative changes, respects trade secrets, and makes disclosures only after critical studies and regulatory milestones are met.

And in April confirmation hearings, newly appointed FDA head Scott Gottlieb also backed increased transparency, including the release of redacted CRLs.

Out in the open

Getting hit with a CRL clearly impacts a drug firm and any suppliers it might have. Delayed approvals translate into lost sales. Stockholders and investors may react negatively, causing a company’s valuation to fall or limiting its ability to raise capital. Reputations are at stake. And a much-needed drug may be unavailable.


FDA conducts several types of inspections ...

Preapproval inspection after a firm submits an application to market a new product. It assesses readiness for commercial manufacturing and verifies data in the application.

Routine inspection of a regulated facility to check for compliance with current Good Manufacturing Practices.

“For-cause” inspection to investigate a specific problem that has come to the agency’s attention.

Compliance follow-up inspection to review corrective actions for previously identified problems and to check compliance in order to support regulatory actions.

... and communicates problems in different ways.

Complete response letters inform drug companies that their applications are not approvable. They lay out deficiencies and outline possible remedies. They are usually confidential, but FDA publishes redacted versions in an approved drug’s regulatory history.

Form 483s are issued at the end of plant inspections to point out critical observations made by FDA inspectors. They are generally confidential, but FDA may post some at its discretion, especially those frequently requested. They are available redacted under a Freedom of Information Act request.

Establishment investigation reports describe the results of plant inspections and whether any follow-up actions are required. They are available redacted under a Freedom of Information Act request.

Warning letters are delivered when serious regulatory violations are found or previously identified issues are not adequately addressed. FDA publishes these on its website.

Source: FDA

In January, the English contract manufacturer Porton Biopharma received a warning letter about repeated issues found in 2015 and 2016 with its active pharmaceutical ingredient and sterile aseptic manufacturing. Porton is the sole maker of Erwinase, an enzyme drug sold by Ireland’s Jazz Pharmaceuticals for treating acute lymphoblastic leukemia, a type of cancer that particularly affects children.

Erwinase is now on FDA’s drug shortage list. “We continue to expect that we will experience inventory and supply challenges in 2017,” Jazz Chief Executive Officer Bruce C. Cozadd said during a late-February earnings call. Jazz is working with FDA to get the product released as quickly as possible and with Porton on expanding production.

Similarly, manufacturing problems blocked Portola Pharmaceuticals’ AndexXa, an FDA-designated breakthrough biologic that reverses the effects of anticoagulants. Although FDA asked some clinical questions in the firm’s August 2016 CRL, most questions related to manufacturing and analytical testing.

Portola was disappointed and surprised to receive a CRL, CEO William Lis said in a conference call. The company was confident after a preapproval inspection in April 2016 at its contract manufacturer, CMC Biologics, yielded only “noncritical observations,” Lis said. “We were led to believe that we were in pretty good shape, or very good shape, on this front.”

On the same call, Portola R&D head John Curnutte said, “There was not a fundamental concern about our ability to make the drug.” The loose ends in analytical bookkeeping and validation that were found were tied to the rapid pace of clinical development and review for a breakthrough drug, he said.

Curnutte said Portola thought it had a “pretty good understanding with FDA” that these problems could be worked out postapproval. Apparently this wasn’t the case. After borrowing $50 million from development partners Bristol-Myers Squibb and Pfizer, Portola is now working to reapply to FDA in the second quarter.

Repeat problems

Even more odious to FDA than manufacturing problems are repeat manufacturing problems.

Momenta Pharmaceuticals felt the effects of such repeat problems and took a financial blow when it reported in February that compliance issues at a supplier might delay approval of a high-dose version of its multiple sclerosis drug, Glatopa. After the news, Momenta’s stock price dropped 20%, and it continued to fall further.

Momenta’s development partner, Sandoz, had contracted with Pfizer for filling and finishing the final product. Pfizer, in turn, had received a warning letter in regard to a sterile injectable drug facility in McPherson, Kan. The plant is one of several with cGMP violations that Pfizer acquired when it bought Hospira in 2015.

“These repeated failures at multiple sites demonstrate that your company’s oversight and control over the manufacture of drugs is inadequate,” FDA wrote in the warning letter. That the letter was also addressed to Pfizer CEO Ian Read is noteworthy, Evercore ISI stock analyst Umer Raffat said. “When FDA addresses the letter to the senior-most person, it is trying to make a statement.”

Hospira’s McPherson plant again, along with a Wockhardt active pharmaceutical ingredient plant in India, presented problems for the planned launch of a new antibiotic, solithromycin, by the biotech firm Cempra. In late 2016, a few days after Wockhardt got a warning letter, Cempra received a CRL that also noted the problems at Hospira.

Cempra was working to develop alternative suppliers, but it didn’t complete its efforts in time. A more critical blow was that the CRL called for an enormous clinical safety study. The combination of manufacturing and clinical problems has put Cempra’s future in question.

AstraZeneca bought into its manufacturing problem in 2015 when it spent $2.7 billion to acquire ZS Pharma. The deal included ZS-9, a potassium-lowering sodium zirconium cyclosilicate therapy that ZS developed and manufactures. In May 2016, AstraZeneca got a CRL outlining issues in “operational manufacturing practice and quality,” reported Leerink stock analyst Seamus Fernandez after talking with the firm.

Thinking it had adequately addressed all the issues, AstraZeneca was able to resubmit its application in less than six months. But after a reinspection five months later, FDA shot down the filing with a second CRL in March. The delays now add up to well over a year.

Back on track

Responding to and fixing manufacturing problems cited in a CRL and underlying warning letter can take time, and FDA may spend up to six months reviewing a resubmitted application. Raffat, the stock analyst, has analyzed all warning letters in the past 20 years that specifically relate to cGMP problems on finished drug products. For this set of 31 letters, he found that it takes anywhere from four months to four years to resolve the issues. The average resolution took 17 months.

Photo of drug product filling at Sanofi’s Le Trait plant.
Credit: Céline Clanet/Interlinks Image
Sanofi experienced problems in filling operations at this plant in Le Trait, France.

In some cases, success comes quickly. In late March 2016, Opko Health received a CRL related to its extended-release kidney disease drug Rayaldee. The problems were not specific to the drug but rather to the St. Petersburg, Fla., plant where it is encapsulated by Catalent, Opko’s finished-product contract manufacturer.

At the time, Opko said it had anticipated an inspection but that neither it nor Catalent were aware of any deficiencies. After the inspection, Catalent moved quickly to fix the problems, and a week later Opko was able to refile its application. FDA reviewed it ahead of schedule and approved Rayaldee in June, just three months after the CRL.

The French ophthalmic drug developer Nicox has persevered through CRL problems twice with only modest delays. In July 2016, FDA raised concerns after a cGMP inspection of a Tampa, Fla., facility run by Bausch & Lomb, the licensee of Nicox’s glaucoma drug Vyzulta. By February of this year, Bausch & Lomb had resolved the problems and resubmitted the application.

Then in October 2016, Nicox received a CRL for Zerviate, a form of the antihistamine cetirizine, that cited cGMP issues at an unidentified active pharmaceutical ingredient maker. In March of this year, after the problems were fixed, Nicox resubmitted its application. “We now await two approval decisions from FDA during the next six months for our lead programs,” CEO Michele Garufi said in April.

Two blockbuster biologic drugs were at risk for Regeneron Pharmaceuticals and its partner Sanofi: sarilumab for rheumatoid arthritis and dupilumab for atopic dermatitis. In October 2016, the companies disclosed that deficiencies were found during an earlier routine cGMP inspection of a Sanofi facility in Le Trait, France, that handles filling and finishing of both products.


Company watchers were alarmed. “Investors were unaware of this issue, and the risk it posed to Sanofi and Regeneron’s launch plans, until the companies received a CRL,” Leerink stock analyst Geoffrey C. Porges said in report to clients. After looking at a redacted inspection report, he pointed out that the list of issues was “longer and somewhat more concerning” than the company had indicated, with some carrying over from a 2014 inspection.

“It is possible that the FDA has deliberately ‘gone overboard’ in the granularity of the issues they have cited for remediation with the intention of sending a sharp wake-up call to Sanofi,” Porges wrote. In a February conference call, Regeneron CEO Leonard Schleifer agreed that “FDA has been, and should be, tough about manufacturing.”

Meanwhile, Sanofi CEO Olivier Brandicourt predicted that the problems could be resolved with little impact. Indeed, the companies reported in January that FDA deemed the Le Trait facility “acceptable.” Soon after, Regeneron resubmitted the sarilumab application. It has received a review date for later this month. FDA approved dupilumab under the name Dupixent in March, consistent with the original schedule.


Third-party manufacturing issues have been delaying New Drug Applications.

AstraZeneca ZS-9 ZS Pharma API May 2016 Refiled October 2016
AstraZeneca ZS-9 ZS Pharma API March 2017 Working to resolve
Cempra Solithromycin Wockhardt, Hospira API, final product December 2016 Pending clinical data
Momenta/Sandoz Glatopa 40 mg Hospira Final product February 2017 Working to resolve
Nicox Zerviate Not disclosed API October 2016 Refiled March 2017
Nicox/Valeant Vyzulta Bausch & Lomb Final product July 2016 Refiled February 2017
Opko Health Rayaldee Catalent Final product March 2016 Approved June 2016
Portola Pharmaceuticals AndexXa CMC Biologics API August 2016 Working to resolve
Sanofi/Regeneron Sarilumab Sanofi Final product October 2016 Refiled April 2017
Tesaro Rolapitant Not disclosed Final product January 2017 Working to resolve

API= active pharmaceutical ingredient.
Source: Company information

Exploring options

After a drug company and its manufacturing partner have invested time, effort, and money to prepare for approval and commercial launch of a new drug, fixing problems seems like an obvious choice. But when the problems are too challenging to overcome, drug firms may try to find an additional or alternative supplier.

Doing so “cuts down on the risk, but having a second supplier is an extremely expensive process,” says Paul Mason, a director at Lachman Consultants, which specializes in pharmaceutical regulatory and technology activities. If a switch isn’t well under way, duplicating the manufacturing process is time-consuming and can result in substantial changes to an application.

Portola’s problems, for example, made the company rethink its strategy for commercial production. Its application relied on a manufacturing line at CMC Biologics that had been producing materials for clinical trials. For commercial purposes, Portola was working on developing a larger line at CMC as well as a second-generation approach that Lonza, another CMO, is to have on-line this year.

However, given the resources needed to address the deficiencies at CMC and resubmit its application, Portola has suspended work on the bigger line at CMC and will launch with limited supply. Approval for the second-generation process is to come about six months after launch, CEO Lis said in February. Before that happens, Lonza’s facility will have to be inspected, and Portola will have to show, possibly through additional studies, that the new material is comparable to what CMC produces.

Comparability was the holdup with Tesaro’s application for an intravenous version of its antiemetic drug, rolapitant. The cancer drug firm had identified potential deficiencies at its original finished-dose contract manufacturer. After securing a second supplier, it included both in its March 2016 application. In January, FDA issued a CRL requesting information about comparability of the products.

Tesaro plans to “address FDA’s questions expeditiously and complete this application, which we expect to enable approval in the first half of 2017,” President Mary Lynne Hedley said.

Although some companies try to go with a second supplier, industry consolidation and quality concerns limit the number available, particularly those with specialized facilities and expertise. “The landscape for contract manufacturers has changed, and there may not be a huge choice,” Mason says. A lot of them, especially those handling sterile injectable drugs, “have come into quality issues, and many have closed due to inspection issues.”

Finding a fix

As part of its push for quality, FDA published draft guidance in November 2016 focused on the collection of quality metrics from manufacturers. These metrics may help guide the agency in deciding which plants to inspect. It also issued final guidance on contract manufacturing quality agreements.

Drawn up between a drug firm and a manufacturer, these quality agreements are put in place “to assure that there’s success with the outsourced activities and that they ultimately meet the requirements of the finished product,” Mason says. Building on existing international guidelines, FDA’s guidance details its expectations and emphasizes that the owner of the drug has ultimate responsibility.

“A lot of the risk is taken by the owner of the activities that it outsources, and that must be reflected in the quality agreement,” Mason adds. “If you only have a sole supplier, that further exacerbates the criticality of the quality agreement.”

The agreements are intended to clearly lay out the requirements, expectations, and respective roles and responsibilities for cGMP production. They should also define mechanisms for communication, including those for problems, between a drug firm and contract manufacturer. Certain aspects of drug production—specifically final release of the product—are not delegable by the owner.

Although FDA doesn’t require these agreements, agency inspectors can ask to see them during a plant inspection. Because of this, and because the guidance represents FDA’s thinking on improving quality, companies are being advised that such agreements are de facto expectations.

One might assume that drug companies would already address quality concerns in their business contracts with suppliers. But this is not always the case. For many companies, “the guidance is asking companies to put into practice what has already been industry best practice,” Cormier, the attorney, says. For others, especially some of the smaller firms, “this is a new way of thinking,” he adds.

Cormier has helped both drug firms and contract manufacturers draft and review such agreements. Well-crafted and thorough ones can be extremely useful to both sides, he says, as can the exercise of thinking them through and making decisions together. “It sets up a tone about how the interaction is going to work.”

Increased interaction and communication should make the drug sponsor and manufacturing contractor relationships closer and more collaborative. “FDA’s opinion is that when it is more impersonal, there is a greater propensity to have issues arise that the sponsor is not made aware of and get into the product unintentionally,” Cormier says.

Even with close communication, issues inevitably arise. “It’s just a fact, and not a statement on the ability or technical capabilities of one company or another,” Cormier says. But companies that do preordain how activities will be handled are likely to carry out remediation more efficiently and completely.

In owning the responsibility and risk, drug firms, even virtual ones, may become more hands-on in assessing, auditing, and reviewing suppliers’ activities. And CMOs may benefit by having a trusted partner with which to solve problems.

“Sometimes it is a little bit like convincing a couple about to get married that a prenup is probably a good idea,” Cormier says. “Things may happen or they may not happen, you don’t know. But talking about it ahead of time, when cooler heads are prevailing, usually makes events go smoother if things do go south.” 


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