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Product Quality Responsibilities Shared Between CMOs and Sponsor Firms Under FDA Scrutiny

FDA is putting industry on notice that relationships between sponsors and contract manufacturing organizations (CMOs) will be receiving close attention during upcoming agency inspections.

The growing agency focus on the relationship between marketing application holders and their CMOs received attention at the PDA/FDA meeting in mid-September in Washington, DC.

Among those commenting on the issue was CDER Office of Compliance Division of Manufacturing and Product Quality (DMPQ) Director Richard Friedman.

As a result of the “undoubtable trend toward outsourcing,” FDA is paying closer attention to contract relationships, Friedman stressed, and sponsors “should expect to hear questions during inspections about how their companies are making sure that their CMOs are actually being monitored.”

He pointed to quality agreements and communication/notification mechanisms as items the agency would examine closely – for example, notifications from CMOs to sponsor firms when an out-of-specification (OOS) result occurs.

In these “shared manufacturing agreements,” the DMPQ director emphasized, issues discovered at a CMO have been leading to subsequent inspections and enforcement actions at the sponsor firm.

[Also see a related story providing an inspector’s view on potential problems in contracting relationships see IPQ “In the News” story June 18 “FDA Wants to See More Transparency Between Drug Companies and Contractors on Sponsor’s Application and Contractor’s GMP Status.”]

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483 at CMO Leads to Warning Letter at Sponsor Firm

At the PDA/FDA meeting, CDER Office of Compliance (OC) Acting Deputy Director Ilisa Bernstein cited an example of a recent warning letter to a marketing application holder that addressed “significant quality concerns and issues with the product” originally discovered at a contract firm from which the sponsor was receiving product.

River’s Edge in Suwanee, Georgia received the warning letter in May, after an inspection of one of its contract manufacturers resulted in a form 483 and a subsequent inspection at River’s Edge.  All of the products the firm sells, including both prescription and over-the-counter drug products, are manufactured by CMOs.

The warning letter contained items discovered previously at the contractor as well as items specific to the operations at River’s Edge.

Lots of a lidocaine hydrocortisone product were released and distributed “even though they failed stability testing,” the letter points out.  The lots failed the firm’s initial release and shelf-life viscosity specification at the 3, 6, and 9 months time points. In response, the contract firm revised the viscosity specification.   River’s Edge also revised its viscosity spec, but did not “describe a scientific rationale for making these changes [or] discuss the impact, if any,” to product quality, according to the warning letter.

Certificates of analysis (COA) were also a concern.  River’s Edge did not check the data on each COA against the product specifications prior to distributing product, but instead simply checked “for the presence of a COA prior to accepting shipment.”

The letter stressed that there was no training in cGMPs for River’s Edge employees as “evidenced” by the inspection findings.

“We are concerned about your firm’s fundamental understanding of what is required by your [quality control department] and the regulatory expectations for a firm that enters into agreements with contract manufacturers to manufacture all drug products,”  FDA’s Atlantic District said.  “Regardless of who manufactures your products or the agreements in place, you are required to ensure that these products meet predefined specifications prior to distribution.”

At the PDA/FDA conference, DMPQ’s Friedman fielded questions about warning letters to contract manufacturers and the companies that use them.

One conference participant asked about how communications take place to CMOs and sponsors regarding warning letters either receive.

Friedman replied that FDA’s practice is to copy the CMO or the sponsor when either receives a warning letter, or to mutually notify them when compliance issues arise through other means.

In the case of River’s Edge, he noted, problems were found initially at the CMO resulting in a 483.  “Then we went back to the product owner, which we are not always doing” and informed them that “you are responsible for these products – your name is on them.”

The compliance official pointed out that the agency is seeing “more and more” situations where sponsors are “virtual owners” who need to take responsibility for assuring that the CMO “manufactures the product in a safe and effective way – every day, every dose.”  He noted that the CMO is required to ensure that its operations meet GMPs, but ultimately “the owner of the product has to take responsibility.”

Center for Devices and Radiological Health (CDRH) Office of Compliance official Steven Silverman stressed that his center has the same view.

“I just want to state that CDRH absolutely and unqualifiedly endorses the perspective that Rick just described.  This is an “integrated responsibility.”  In the case of specification developers and contract manufacturers, Silverman emphasized, “finger-pointing…is unacceptable.”

“There has to be integrity assured throughout the supply chain,” he said, “and that is going to be our expectation going forward.”

A conference attendee commented that his firm had change control, deviation and OOS agreements in place with one of its CMOs, and had “posted our quality folks on their production floor for an entire campaign,” but still felt that there were issues to be resolved.  “Short of discontinuing sale of a product, what is the expectation then on the license holder in terms of this CMO or third party oversight?”

Friedman responded that the issue is a “tough” one because ‘the person in plant’ is not the panacea. I think everybody has found that out over the years.”  He explained that ultimately it is the CMO’s responsibility to put in place a quality management system that is robust and that would “actually be able to address these issues within their site.”

“If their quality system is not compatible with yours,” the drug compliance official stressed, “then it is making a statement to you, I think, that says that this is not a company that merits being an extension of your operation. Any contract manufacturing operation that manufactures any aspect of your process, any unit operation, is an extension and a reflection of your operation. I think you have to decide whether or not you have strong enough provisions in your external supplier qualification program to disqualify someone who is not operating appropriately or at least suspend manufacture until an issue is corrected if it is a serious one.”

Agreements Within Sponsor Firms Lead to Similar Problems

The discussion turned from relationships between CMOs and sponsors to similar issues that can arise within companies regarding internal agreements and product transfer between sites.

“What is getting to be a real question with all the multi-national companies now having plants all around the world,” a conference attendee pointed out, is “who are you going to hold accountable” when product purchased from a “sister company” in another country has been audited by the corporate function but has not been audited by the plant receiving the material.

Friedman responded that communications and interactions in organizations are always a challenge, especially as organizations get bigger and are geographically diffuse.  “In those circumstances,” it may be “even more important for senior management to take the responsibility to assure that there is information sharing in the organization, and that clear roles and responsibilities are in place.”

The DMPQ director referenced ICH Q10, noting that “Q10 was written by industry and the regulators” and provides guidance for what a “good quality management system” should contain to be effective.

“I hear these things often – that regulatory affairs and production, or QA and production, or R&D and commercial” do not communicate as they should, Friedman commented.

“Whoever is doing [an audit] needs to take responsibility for showing that it is effective,” and then needs to share it within the organization to ensure everyone who needs to see it does.

“At FDA, we have the same issues,” he noted, “but the fact is that we found a way now with meager resources to assure that inspection reports are now available throughout FDA,” which demonstrates that it is possible.

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