FDA Soliciting Input on Global Supply Chain Provisions in FDASIA

In a recent post from the FDA Voice Blog, Office of Compliance Director for FDA’s Center for Drug Evaluation and Research (CDER) wrote about the agency’s future activities to help combat the globalized supply chain—in particular about the Food and Drug Administration Safety and Innovation Act (FDASIA).

In addition to sharing his priorities about resolving problems regarding drug compounding, Office of Compliance Director Howard Sklamberg noted that one of his main priorities is the globalized supply chain. He noted how today, “nearly 40 percent of the drugs Americans take are imported and nearly 80 percent of the active ingredients come from overseas sources.” He also recognized that a “growing number of clinical trials that test the safety and effectiveness of potential new drugs are also moving overseas, making FDA oversight more challenging.”

He also identified that “counterfeit drugs are proliferating around the world and sometimes even entering the U.S. supply chain” and the “ever burgeoning worldwide use of the Internet continues to spawn avenues for illegal online sales of medicines of unknown safety and quality.”

Confirming other priorities of the U.S. Department of Justice and recent FDA activities, Sklamberg also noted that “poor manufacturing practices that lead to facility shut-downs often contribute to shortages of important drugs,” and another agency priority will be to “ensure that wherever drugs are made, wherever their ingredients are from, or wherever and however they are tested and sold, that they meet FDA’s strict standards of quality and that they remain in adequate supply.”

In setting out these priorities, Sklamberg recognized the new authorities Congress gave FDA under FDASIA, “including stronger authorities and funding to support the inspection of foreign manufacturing facilities. For example, FDASIA facilitates our ability to partner with and work more effectively with foreign regulatory agencies. FDASIA also gave FDA more authorities to control the drug supply chain,” Sklamberg noted.

Because FDASIA’s provisions do not “automatically translate into effective change without effective implementation and enforcement of these laws,” Sklamberg also noted that his priority will be to ensure that FDASIA is properly and timely implemented. Keeping with that promise, FDA recently released a notice for comment and notice for meeting in the Federal Register regarding “how to implement the drug supply chain provisions found in Title VII of FDASIA.

Under Title VII FDA is authorized to require that importers submit information demonstrating that their drug complies with applicable requirements of the Federal Food, Drug and Cosmetic Act before their products can enter the U.S. In addition, commercial importers must register with FDA and meet good importer practices. Comments (discussed below) are due by August 12, 2013, and should reference Docket Nos. FDA-2013-N-0683, FDA-2013-N-0684, and FDA-2013-N-0685.

At the public meeting, which will be held at FDA on July 12, 2013, from 9 a.m. to

5 p.m., the agency will discuss with stakeholders a number of important topics regarding Title VII of FDASIA.  In addition to providing a general overview of Title VII and FDA's approach to implementing these  provisions, the meeting will give interested persons an opportunity to  provide input that will assist FDA in the development of regulations  implementing two sections of Title VII, which relate to standards for  admission of imported drugs and commercial drug importers.

Specifically, FDA is seeking information on the types of information that importers should be required to provide under Title VII as a condition of admission.  FDA is also seeking information regarding registration requirements for commercial drug importers and good importer practices to be established under Title VII.

FDA acknowledged that implementation of Title VII of FDASIA is "difficult and complex, and requires not only the development of new regulations, guidances, and reports, but also major changes in FDA  information systems, processes, and policies."  Since the enactment of FDASIA in July 2012, FDA has been working diligently to implement the  provisions of Title VII and has prioritized these efforts based on  public health impact in order to maximize use of the Agency's limited  resources.

Sections 713 and 714 in Title VII of FDASIA relate to drugs  imported or offered for import and commercial drug importers. Section  713 allows FDA to require, as a condition of granting admission to a  drug imported or offered for import into the United States, that an importer electronically submit information demonstrating that the drug  complies with applicable requirements of the FD&C Act. As specified in  section 713, such information may include:

• Information demonstrating the regulatory status of the drug, such as the new drug application  number, abbreviated new drug application number, investigational new drug number, or drug master file number;
  

• facility information, such as proof of registration and the unique facility identifier;
  

• indication of compliance with current good manufacturing practice (CGMP), testing results, certifications relating to satisfactory inspections, and compliance with the country of export regulations; and
  

• any other information deemed necessary and appropriate by the Secretary to assess compliance.
  

Section 713 also allows FDA to take into account differences among importers and types of imported drugs and, based on the level of risk posed by the imported drug, provide for expedited clearance for those importers that volunteer to participate in partnership programs for highly compliant companies and pass a review of internal controls, including sourcing of foreign manufacturing inputs, and plant inspections.

Section 713 requires FDA to adopt regulations implementing section 713 not later than 18 months after the date of enactment of FDASIA.

Section 714 requires commercial drug importers to register with FDA and submit a unique identifier for the principal place of business at the time of registration. FDA is to specify a unique facility identifier system to be used by registrants.  Section 714 amends section 502(o) of the FD&C Act (21 U.S.C. 352(o)) to deem misbranded a drug imported or offered for import by a commercial importer of drugs not duly registered.

Section 714 also requires FDA, in consultation with the Secretary of the Department of Homeland Security acting through U.S. Customs and Border Protection, to issue regulations establishing good importer practices that specify the measures an importer shall take to ensure that imported drugs are in compliance with the FD&C Act and the Public Health Service Act.

Section 714 requires FDA to adopt regulations implementing section 714 not later than 36 months after the  date of enactment of FDASIA.

The public meeting is an opportunity for FDA to share information regarding Title VII and the Agency's approach to implementation, and to obtain input from stakeholders that will assist FDA in developing regulations under sections 713 and 714.

Purpose and Format of Meeting and Scope of Public Input Requested

The first part of the public meeting will consist of introductory presentations by FDA that will provide an overview to stakeholders regarding Title VII, including the new authorities granted to FDA under Title VII and their importance in ensuring drug safety, effectiveness, and quality; how Title VII relates to and will help advance FDA's larger strategic initiatives; the Agency's approach to implementation; and the progress achieved to date.

The second part of the meeting will be used to obtain input from stakeholders on issues relating to standards for admission of imported drugs, registration of commercial importers, and good importer practices that will assist FDA in the development of the regulations described previously.  Individuals will have opportunities to express their views by making presentations at the meeting and submitting written comments to the dockets for these matters (see section V of this document).

FDA is particularly interested in obtaining information and public

comment on the following topics:

Section 713: Standards for Admission of Imported Drugs

1. How should the regulations implementing section 801(r) of the  FD&C Act (21 U.S.C. 381(r)), as amended by section 713 of FDASIA, define "importer" as that term is used in 801(r)(l)?
   

2. What information should FDA require importers to submit at the time of entry that would demonstrate a drug's compliance with applicable requirements of the FD&C Act as a condition of granting admission of the drug into the United States?
   

3. What information could an importer submit to FDA at the time of entry to demonstrate compliance with applicable requirements of the FD&C Act relating to:
   

   1. homeopathic drugs intended for human use,
      

   2. articles intended for human drug compounding,
      

   3. articles intended for animal drug compounding, and
      

   4. drugs intended for research?
      

4. What facility information should FDA request from importers at the time of entry to help assess whether a drugcomplies with applicable requirements of the FD&C Act?
   

5. What information could importers submit at the time of entry to demonstrate compliance with country of export regulations in accordance with section 801(r)(2)(C) of the FD&C Act?
   

6. What information could importers submit at the time of entry to demonstrate that a drug offered for import complies with U.S. CGMP requirements?
   

7. What information could importers submit at the time of entry that would serve as evidence of satisfactory inspection, such as by a foreign government or an agency of a foreign government?
   

8. Should FDA require that importers submit certificates of analysis (COAs) to the Agency as a condition of admission under section 801(r) of the FD&C Act? If so, how could an importer demonstrate a COA's authenticity?
   

9. Section 801(r)(4)(B)(i) of the FD&C Act permits FDA, as appropriate, to consider differences among imports and types of drugs and "based on the level of risk posed by the imported drug, provide for expedited clearance for those importers that volunteer to participate in partnership programs for highly compliant companies and pass a review of internal controls, including sourcing of foreign manufacturing inputs, and plant inspections."
   

   1. What criteria should FDA use to evaluate potential participants in "voluntary partnership programs for highly compliant companies"?
      

   2. How could FDA take into account differences among importers and types of drugs to allow for expedited entry as part of a voluntary partnership program?
      

   3. What risk factors should FDA consider when determining drug admissibility under a voluntary partnership program?
      

10. What benefits and burdens may be created by requiring drug importers to electronically submit information demonstrating that a drug complies with applicable requirements of the FD&C Act as a condition of admission? How could we minimize any possible burdens? How do we strike a reasonable balance between rigor and efficiency in requiring information that is both reliable and yet can be submitted and reviewed efficiently?
    

Section 714: Registration of Commercial Importers of Drugs

1. How should the regulations implementing section 714 of FDASIA (section 801(s) of the FD&C Act) define ``commercial importer'' to ensure that the appropriate entities are required to register with FDA and meet requirements regarding good importer practices (GIP)? Should these "commercial importers" be the same entities as the "importers" required to comply with the standards for admission to be adopted under section 801(r) of the FD&C Act?
   

2. Under section 801(s)(1) of the FD&C Act, the registration regulations will apply to commercial importers of "drugs." A "drug" is defined in section 201(g)(1) of the FD&C Act (21 U.S.C. 321(g)(1)) and includes, but is not limited to, finished dosage form drug products, drugs for further processing, active pharmaceutical ingredients, and other drug components, including inactive ingredients. Should commercial importers of certain types of drugs, such as inactive ingredients, be exempt from the commercial importer registration requirements? Should the importation of drugs for certain purposes (e.g., research use) be exempt from registration?
   

3. What information should commercial importers be required to submit as part of their registration?
   

4. What benefits and burdens might be created by requiring commercial drug importers to register with FDA? How can we minimize any possible burdens (e.g., through gradual implementation, exemption of certain commercial importers, use of other alternatives)?
   

Section 714: Good Importer Practices

1. How might FDA structure the GIP regulations to avoid imposing redundant regulatory requirements on commercial importers that also are drug manufacturers and therefore would be subject to both the GIP and CGMP requirements?
   

2. Should the GIP regulations require commercial importers of drugs to establish drug safety management programs to ensure that imported drugs meet the requirements of the FD&C Act and the Public Health Service Act, as applicable? If so, what matters (e.g., procedures, personnel) should the GIP regulations require commercial importers to address in such programs?
   

3. What drug safety management programs or other measures do commercial importers currently have in place to ensure that imported drugs are manufactured in compliance with applicable FDA requirements? How do these programs and measures differ for different ``types'' of drugs?
   

4. Should the GIP regulations include qualifications and training for personnel who perform GIP activities? If so, what qualifications and training should be required?
   

5. Should the GIP regulations include a requirement for commercial importers to assess whether it is appropriate to import a particular drug from a particular foreign supplier? If so, what information on the drug and the supplier should the commercial importer be required to consider as part of this assessment?
   

6. Should commercial importers be required to conduct activities to verify that a drug that is offered for import is in compliance with applicable U.S. requirements (e.g., the CGMP regulations) and are not adulterated under section 501 of the FD&C Act (21 U.S.C. 351) or misbranded under section 502 of the FD&C Act? If so, what supplier verification activities should commercial importers be required to conduct?
   

7. Should there be different supplier verification or other GIP requirements for different ``types'' of drugs? Should there be different requirements for particular types of finished dosage form drug products that might be associated with different levels of risk (e.g., sterile injectables, drugs that require temperature controls)?  If so, what should these requirements be?
   

8. Should the GIP regulations require commercial importers to obtain a COA for each imported drug? Should such a requirement apply only to certain types of drugs or commercial importers? If commercial importers are required to obtain COAs, should the commercial importer also be required to conduct testing to verify the accuracy of the COA?
   

9. Should the GIP regulations include specific requirements for drugs imported for export in accordance with section 801(d)(3) of the FD&C Act? If so, what should these requirements be?
   

10. How should the GIP regulations reflect or incorporate the requirements concerning the standards for admission of imported drugs under section 801(r) of the FD&C Act? For example, should the GIP requirements include the adoption of procedures to ensure that the commercial importer submits the compliance information required under section 801(r) and the regulations implementing that section? If so, what procedures should commercial importers be required to follow to ensure that these requirements are met?
    

11. Should the GIP regulations require commercial importers to take corrective actions when the drugs they import or offer for import are not in compliance with applicable U.S. requirements? If so, what actions should importers be required to take?
    

12. Should the GIP regulations include a requirement for commercial importers to list the drugs they import or offer for import? If so, whatinformation should be required with listing?
    

13. What records should commercial importers be required to maintain under the GIP regulations?
    

14. What other matters, if any, should the GIP regulations address?
    

15. How should FDA take into account ``differences among importers and types of imports, including based on the level of risk posed by the imported product,'' in determining reasonable time periods for commercial importers to come into compliance with the GIP regulations under section 714(d)(3) of FDASIA? In considering such differences, how should FDA determine the level of risk posed by an imported drug?
    

16. What benefits and burdens might be created by requiring commercial importers to comply with GIP regulations? How can we minimize any possible burdens (e.g., through gradual implementation, exemption of certain commercial importers, use of other alternatives)?