Stability Testing related News – Vol.4

◆ GDUFA: FDA’s new Guidance on Self-Identification of Generic Drug Manufacturers (05-Oct-16 ECA)

The GDUFA (Generic Drug User Fee Amendments) is a legislative package which came into force in 2012 and entitles the US-American FDA to collect fees from generic drug manufacturers, who strive for a marketing authorisation for the American market. An annual fee has to be paid after the successful registration.

The core of the document is the obligation to “Self-Identify” for those companies that have to submit essential site-related information to the FDA. The details of this self-identification are set in a Guidance for Industry entitled “Self-Identification of Generic Drug Facilities, Sites, and Organizations” published on 22 September 2016 by the FDA in the finalised form.

The Guidance describes the following elements:

  1. Which types of generic facilities, sites, and organizations are required to self-identify?
  2. What information is requested?
  3. What technical standards are to be used for electronically submitting the requested information?
  4. What is the penalty for failing to self-identify?

Hereinafter, you will find a short summary of these four topics:

  1. Companies that manufacture finished generic medicinal products for human use or the APIs for them, or both are required to self-identify as well as companies that package the finished generic drug into the primary container and label it. Besides, sites that – pursuant to a contract with the applicant (generic drug manufacturer) – repack/redistribute the finished drug from a primary container into a different primary container are also required to submit a self-identification as well as sites that perform bioequivalence/bioavailability studies. Last but not least, the obligation to self-identify also concerns sites that are listed in the application dossier as contract laboratories for the sampling and performing of analytical testing.
  1. Essential data are: the D-U-N-S number (a unique nine-digit sequence specific for each site / each distinct physical location of an entity), the “Facility Establishment Identifier, FEI” (an identifier used by the FDA for the planning and tracking of inspections) and general information with regard to the facility (company owner, type of business operation, contact data, information about the manufacture of non generic drugs).
  1. The HLS standard (Health Level Seven Structured Product Labeling) requested for generic applications (ANDAs) has to be also used for the submission of self-identification information. A detailed description of this standard can be found in the Guidance “Providing Regulatory Submissions in Electronic Format – Drug Establishment Registration and Drug Listing”.
  1. Companies that fail to self-identify do not have to expect an explicit penalty. However, such a failure leads to two drawbacks: first, the likelihood of a site inspection by the FDA prior to approval is higher. The second drawback which is much more serious is that all the APIs or finished drugs from a manufacturer who hasn’t self-identified are deemed misbranded. For the FDA, such products are not allowed for importation in the USA.

To the satisfaction of the FDA, the regulations set in the GDUFA and the provisions laid down in the new Guidance represent a major contribution to an enhanced transparency in particular of complex supply chains.


◆ APIC updates its Guidance on Cleaning Validation with regard to the PDE Concept (02-Nov-16 ECA)

The revision of the APIC “Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredients Plants” dated May 2014 has been brought.

The original 55-page document is still divided into 13 chapters:

  • Foreword
  • Objective
  • Scope
  • Acceptance criteria
  • Levels of Cleaning
  • Control of Cleaning Process
  • Bracketing and Worst Case Rating
  • Determination of the Amount or Residue
  • Cleaning Validation Protocol
  • Validation Questions
  • References
  • Glossary
  • Copyright and Disclaimer

The main changes were made to Chapter 4 on Acceptance Criteria so that the guideline is now 57 pages long. The document frequently uses the term PDE beside the criterion ADE so far mentioned. Both terms ADE/PDE i.e. ADE or PDE can be found. Whereby, it is stated in the document that the guidance preferably refers to ADE in the calculations examples as it enables a better comparison to the examples listed in the ISPE document Risk MaPP. A new element in Chapter 4 is the calculation formula for PDE with explanation of the respective abbreviations. The glossary has been updated accordingly. Moreover, editorial changes have been made to the document.

Conclusion: The revision of the APIC “Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredients Plants” in its current version from September 2016 has now introduced the PDE concept consequently. The content changes are only marginal though, as the PDE concept supplements only the previous ADE concept.

You can find the revised document on the APIC-Website (dated September 2016).


◆ FDA’s Quality Metrics Initiative starts with voluntary Phase (30-Nov-16 ECA)

The U.S. Food and Drug Administration (FDA) published a revised version of its Quality Metrics Guidance (“Submission of Quality Metrics Data”). The goal of a final guidance will be the collection of quality metrics data from pharmaceutical companies to foster the agency’s aim of a risk based inspection planning. A first draft guidance was published in 2015, leading to a lot of responses from industry.

What’s new in the revised draft?

  • The program will begin with a voluntary phase that will run into 2018. After this rather short period, the program should become mandatory.
  • The scope will be narrowed with three different primary metrics instead of four, allowing more flexibility and a reduction in reporting burden: lot acceptance rate (LAR), a product quality complaint rate (PQCR) and an invalidated out-of-specification rate (IOOSR) plus three optional metrics.
  • Both product reports and site reports would be possible
  • Modifications to the quality metrics data definitions with clarifying examples

In its Federal Register Notice Docket No. FDA-2015-D-2537, “Submission of Quality Metrics Data; Draft Guidance for Industry; Availability; Request for Comments”,  the FDA states that it “recognizes that a voluntary phase of the program would give participants an opportunity to demonstrate transparency and a willingness to proactively engage with the Agency in pursuit of the goals described in the revised draft guidance.”

Additionally the FDA plans to release a new version of the Technical Conformance Guide it issued last June to support the revised draft guidance.


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