Regulatory Compliance: Mutual Recognition Agreements and Other FDA Activities for Monitoring the US Drug Product Supply Chain

The FDA Safety and Innovation Act was passed by congress in 2012, and the FDA has been working to implement this act ever since. The act authorizes the FDA to establish mutual recognition agreements (MRAs), which are agreements between two or more countries to recognize a specific process or procedure of the other country. 

A 1998 MRA signed by the US and European Union (US-EU MRA) included a pharmaceutical annex providing for recognition of each other’s GMP inspections, but the annex was never fully implemented. However, in 2017, the US and EU adopted an amended sectoral annex to the 1998 US-EU MRA¹. This amended sectoral annex allows the FDA and the EU inspectorates to use inspection reports and other related information obtained during drug manufacturing facility inspections, whether conducted by the FDA or by an EU inspectorate, to help determine whether a facility is manufacturing high-quality drug products. Then, if necessary, the FDA or EU can require further inspections or take other actions to protect the public. 

Strengthening the use of each other’s drug inspection expertise and resources will result in greater efficiencies for both regulatory systems and provide a more practical means to oversee the large number of drug manufacturing facilities outside of the US and EU. 

Prior to the 2017 amended sectoral annex, the FDA and EU would sometimes both inspect the same facilities in the same year, even if the facilities had a strong record of compliance. Going forward, such duplicate inspections should be the exception. By utilizing each other’s inspection reports and related information, the FDA and EU will be able to reallocate resources towards inspection of drug manufacturing facilities with potentially higher public health risks across the globe. This will benefit patients and reduce adverse public health outcomes. 

How does the FDA know when another inspectorate is capable of conducting drug manufacturing facility inspections that meet US requirements?

• The MRA text defines a capable inspectorate as one that: 
• has the legal and regulatory authority to conduct inspections against a standard for GMP; 
• manages conflicts of interest in an ethical manner; 
• evaluates risks and mitigates them; 
• maintains appropriate oversight of manufacturing facilities within its territory; 
• receives adequate resources and uses them; 
• employs trained and qualified inspectors with the skills and knowledge to identify manufacturing practices that may lead to patient harm; and 
• possesses the tools necessary to take action to protect the public from harm due to poor-quality drugs or medicinal products. 

“Capable” does not require that the inspectorate maintain procedures for conducting inspections and overseeing manufacturing facilities that are identical to the FDA’s procedures. 

The FDA’s capability assessment begins with observing the EU’s internal audit of an EU country to ensure that the inspectorate is functioning properly and does not deviate in any significant way from EU law and guidance. These audits include observations of drug manufacturing facility inspections conducted by the audited inspectorates and utilize the 78 indicators based on the Pharmaceutical Inspection Cooperation Scheme (PIC/S) compliance assessment program with an EU addendum. PIC/S is an internationally recognized cooperative arrangement between 49 regulatory authorities, including the FDA, and its goal is to harmonize inspection procedures worldwide and develop common standards in the field of good manufacturing practices. 

After observing an audit of a country’s drug inspectorate, the FDA conducts an independent and comprehensive assessment. This assessment includes a review of the country’s conflict-of-interest policies, specific legislation related to GMP, samples of inspection reports, inspector training records, inventory of drug manufacturing facilities, surveillance programs, and numerous standard operating procedures. 

The FDA evaluates pharmaceutical inspectors’ credentials as part of the capability assessment of each EU country and believes it is important for the authorities to employ trained and qualified inspectors with the skills and knowledge to identify manufacturing practices that may lead to patient harm. The annex also includes maintenance provisions to ensure that each capable country continues to meet FDA requirements. 

Both the FDA and the EU reserve the right to inspect at any time and in any country. However, this is expected to be the exception rather than the rule since, following positive capability assessments, the FDA will recognize the EU inspectorates as capable and recognize their drug manufacturing facility inspections as meeting FDA requirements. 

Other FDA activities for monitoring the nation’s drug product supply chain 

MedWatch reporting program. Since the early 1970s, the FDA has operated a voluntary program specifically directed to healthcare professionals for the reporting of observed or suspected defects and problems associated with finished drug products in the pharmaceutical supply chain, though the name of the program has changed over the years. From 1988 to 1993, the program was called the Drug Quality Reporting System (DQRS), and the form used for reporting was DQRS Form 3318. 

In June 1993, the FDA introduced the MedWatch reporting program to simplify reporting to the FDA by consolidating several FDA reporting programs involving drugs, biologics, devices, and medical foods through a single reporting form (FDA 3500/3500A) (Attachment Part VI B) and a toll-free telephone/fax number. The MedWatch program plays a vital role in the post-marketing phase of regulating all pharmaceutical products and has a twofold purpose: 1) to rapidly identify significant health hazards associated with the manufacturing and packaging of pharmaceuticals, and 2) to establish a central reporting system for capturing and identifying drug-quality problem areas or trends that may require regulatory action. 

Although the MedWatch form replaced the DQRS Form 3318, it did not replace the DQRS system or the offices in the FDA’s Center for Drug Evaluation and Research (CDER) that are responsible for evaluating and processing drug quality problems reported to FDA. FDA Form 3500 is used for voluntary reporting by both healthcare professionals and consumers and is the subject of the DQRS program. 

NDA field alert reports (FARs). The new drug application (NDA) and abbreviated new drug application (ANDA) field alert reporting requirements—21 CFR 314.81(b)(1)(i) and (ii)—became effective on May 23, 1985². The regulation requires holders of NDAs and ANDAs to “submit certain information about distributed drug products” to the jurisdictional FDA district offices within three working days. The three-working-day period begins when the applicant becomes aware of a reported problem through either a complaint or internal testing. It does not begin the day the applicant confirms or invalidates a problem. FARs may be reported via telephone or other means of rapid communication with a prompt written follow-up. The FAR and its mailing cover should be plainly marked: “NDA-Field Alert Report.” Form FDA 3331 (References Part VI A) provides a standardized form for applicants to report. 

FARs, in contrast to the “post marketing reporting of adverse drug experiences” covered by 21 CFR 314.80, contain a variety of drug-quality issues and are of interest to both field and CDER offices. 

Quality defect problems reported in FARs involve violative issues and concerns that pose a potential health hazard to the public. These problems include, but are not limited to, matters concerning dissolution failures, impurity levels, mislabeling, and sub- or super-potency of distributed drug products and articles. If the applicant holder can invalidate the problem (for example, by demonstrating that the problem was due to an analytical laboratory error) within three working days, a FAR is not required. For guidance on investigating out-of-specification test results, see “Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production”³. If the applicant holder determines that further investigation is required, or if a corrective action is initiated (such as a formulation revision or labeling change), a FAR must be submitted. 

Criteria for when a FAR must be submitted by the NDA/ANDA holder include but are not limited to: 

• any incident that causes the drug product or its labeling to be mistaken for or applied to another article; 
• bacterial contamination; 
• significant chemical, physical, or other changes; 
• product deterioration; and 
• failure of one or more distributed batches of drug products to meet the specification established in the application. 

Foreign NDA/ANDA holders must follow the same FAR reporting criteria required for domestic sites for drug products manufactured overseas according to the specifications of an NDA/ANDA and/or distributed in foreign markets. Per 21 CFR 314.50(a)(5), foreign application holders are required to have a US office or agent who is responsible for reporting to the FDA⁴. The US agent shall follow the same guidelines for FAR submission, reporting within three working days to the jurisdictional district office where a problem occurred. In the case of an involved foreign facility, the US agent shall submit the FAR to the district office where the US agent is located. Drug quality sampling and testing (DQST) compliance program. 

The goal of the DQST compliance program is to protect the public health by sampling and testing domestic and imported drug products to minimize exposure to noncompliant and/or poor-quality drug products. This is accomplished by targeting products (finished dosage forms, APIs, and excipients) for sampling based on risk-based selection criteria and a risk-based model. This program, in combination with other quality-assurance compliance programs, is an integral part of the FDA’s overall post-marketing surveillance strategy. 

In previous years, survey samples were typically collected directly from manufacturers, distributors, and wholesalers and were primarily prescription drug products subject to approved NDAs/ANDAs. Due to the increasing consumer risk caused by globalization of pharmaceutical products, the types of domestic and international products sampled under this program have expanded to include: 

• prescription and over-the-counter (OTC) drug products, excipients, and APIs manufactured or repackaged by domestic and international manufacturers; 
• drug products available at pharmacy retailers (including compounded drugs); 
• drug products that have approved NDAs or ANDAs; 
• • unapproved drug products; 
• APIs considered at risk for economically motivated adulteration; 
• APIs and excipients considered at risk for melamine and melamine-analog adulteration; and 
• OTC drug products at risk for diethylene glycol adulteration; 
• vitamin APIs considered at risk for adulteration. 

The FDA sample selection includes recommendations from the CDER, the FDA’s Office of Regulatory Affairs, and FDA district offices based on their intelligence and reported consumer complaints. The goal is to target those products posing the greatest potential public health risk in terms of quality. 

The FDA does publish sampling and testing results for drug products included in the DQST compliance program, and the majority of independently tested products meet their specifications. Between 2003 and 2013, the FDA tested nearly 4,000 samples and found that just 1.1 percent of the drug products analyzed deviated from acceptable standards. 

Minimizing risks from FDA inspections 

The FDA has established a process for assessing when another inspectorate is capable of conducting drug manufacturing facility inspections that meet US requirements, has signed MRAs with EU countries found capable, and plans to sign more in the future. This reduces the number of on-site current good manufacturing practice (cGMP) inspections FDA personnel must perform, though the agency does retain the right to perform on-site cGMP inspections if deemed necessary. 

The FDA monitors the quality of drug products in the US supply chain using the MedWatch program, the NDA/ANDA reporting program, and the DQST program. The agency may perform on-site cGMP inspections in MRA countries when information from these programs indicates a drug product quality problem. Foreign manufacturers should consider the risks associated with an FDA on-site directed cGMP inspection, which could result in discontinuation of the MRA and/or the inability of the manufacturer to market drug products in the US. Manufacturers can reduce these risks by having their manufacturing sites and quality systems periodically inspected by a third-party expert qualified in cGMP for drug products and FDA expectations. 

For more information on the US-EU MRA, refer to the FDA’s Mutual Recognition Agreement landing page⁵. For further MRA-specific inquiries, email FDAMRA@ fda.hhs.gov or contact a reputable consulting firm that specializes in FDA compliance. 

References 

1. https://tinyurl.com/US-EU-MRA-annex 

2. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?fr=314.81 

3. https://www.fda.gov/downloads/drugs/guidances/ ucm070287.pdf 

4. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?fr=314.50 

5. https://www.fda.gov/internationalprograms/agree ments/ucm598735.htm