The Role of the DMF in the FDA Approval Process DMF Workshop

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The Role of the DMF in the FDA Approval Process

• DMF Workshop
• Marriott Crystal City Gateway, Arlington, VA
• March 25-27, 2002

John B. Dubeck 1001 G St, NW, Washington,
DC 202.434.4125 Dubeck_at_khlaw.com www.khlaw.com
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History

• The need for a confidential means to share data
  with FDA became apparent immediately after
  passage of FFDCA
• The oldest DMF now bears 77 and was submitted
  on Jul 18, 1939 for desoxycoritcosterone acetate.
  No Type designation was assigned. Many of the
  early DMFs were for antibiotics which were
  subject to a generic clearance process

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History (continued)

• 63 DMFs are recorded as being submitted as of Jan
  1, 1940
• Many were antibiotics
• The first DMF designated as a Type III was filed
  on Nov 4, 1947 and has the distinction of now
  being designated as DMF 1.
• The first DMF designated as a Type IV was filed
  on Jan 1, 1950

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What is a DMF?

• Voluntary action to allow FDA access to data
  needed to complete reviews of Applications when
  the Applicant is unable to provide the
  information to FDA directly
• No minimum data requirements
• Most useful if data is tailored to complement
  filing obligations of Applicants

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What is a DMF?

• A designated place in an FDA filing system that
  serves three purposes
• Holds information FDA needs to review a
  customers application that you are unwilling to
  disclose to your customer
• Requires timely amendment to reflect changes
• Requires holders of LOAs to be notified of
  amendments

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Drug Components The Legal Basis for FDA Authority

• A drug includes . . .
• (A) articles recognized in the official United
  States Pharmacopoeia, official Homoeopathic
  Pharmacopoeia of the United States, or official
  National Formulary, or any supplement to any of
  them and
• (B) articles intended for use in the diagnosis,
  cure, mitigation, treatment, or prevention of
  disease in man or other animals and
• (C) articles (other than food) intended to affect
  the structure or any function of the body of man
  or other animals and
• (D) articles intended for use as a component of
  any article specified in clause (A), (B), or (C).
  
• FDC Act 201(g)(1)

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Drug Components The Legal Basis for FDA Authority

• A drug is a New Drug if it is not generally
  recognized as safe and generally recognized as
  effective for use under the conditions
  prescribed, recommended or suggested in its
  labeling and has been used to a material extent
  or for a material time.
• FDC Act 201(p)(1) and (2)
• The introduction or delivery into interstate
  commerce of an article in violation of section
  505 is prohibited.
• FDC Act 301(d)

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Drug Components The Legal Basis for FDA Authority

• No person shall introduce or deliver for
  introduction into interstate commerce any new
  drug, unless an approval of an application is
  effective
• FDC Act 505(a)
• as part of the application (B) a full list of
  articles used as components of such drug (D)
  full description of the manufacture, processing
  and packing of the drug
• FDC Act 505(b)(1) (j)(2)(A)(vi)

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Drug Components The Legal Basis for FDA Authority

• FDA shall approve application if none of the
  grounds for denying approval apply
• FDC Act 505(c)(1)(A)
• If the methods used in the manufacture,
  processing, and packing of are inadequate to
  preserve its identity, strength, pauality, and
  purity issue an order refusing to approve
• FDC Act 505(d)(3)

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Approval Required for New Drug Products

• Need to prove safety and efficacy of
  investigational product
• Establish that production product will
  consistently have the same performance as the
  drug product that was the subject of the pivotal
  clinical studies
• Document Same

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What is a Drug or Biologic Application?

• Nothing can be proved safe or effective unless
  you know what it is
• Components must be well characterized
• Packaging must protect from change
• Documentation is contained in the Chemistry,
  Manufacturing and Control Section of an
  Application

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Road Map to API Commercialization

• API Approval Process
• DMF Approval Process
• New Opportunities for Learning
• FDA Inspections
• Pre-Approval Inspections (PAIs)
• CGMP Inspections

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API Approval Process

• Approval of samples by customer
• Customer files (A)NDA
• API manufacturer scales-up, prepares DMF
• FDA reviews file (A)NDA, DMF
• If DMF satisfactory, FDA conducts inspections of
  API and drug product manufacturer
• If both inspections passed, (A)NDA approved, drug
  product can be distributed

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Content of an API DMF

• Physical and Chemical Characteristics
• Stability
• Name and Address of Manufacturer
• Manufacture of the Drug Substance
• Process Controls
• Drug Substance Controls
• Solid-State Drug Substance Forms Relationship to
  Bioavailability

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Development Phases of a Drug

• Stability Batch
• Establish Specs
• Critical Processing Parameters

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Development phases of a Drug

• Full Scale Process Qualification
• Transfer Document
• Validation Protocol

• Submission of DMF

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DMF Holders and FDA

• Although the DMF holder has final say on content,
  FDA guidelines reflect a interest in broad
  disclosure
• FDA can request additional data during review of
  drug application DMF holder must weigh the
  consequences of excessive disclosure (commercial
  disputes subsequent changes in the materials)
  and of losing a drug customer

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DMF Holders and FDA (cont.)

• Usually a speedy approval is in the best
  interests of all
• FDA can exploit desire for speedy approval to
  ratchet up data demands
• FDA does sometimes withdrew claims of deficiency
  in DMF when challenged
• The more details in a DMF, the more times
  Applicants (and FDA) will need to be approached
  for approval of changes

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Notification requirements

• 21 C.F.R. 314.70, Supplements and Other Changes
  to an Approved Application
• The applicant shall notify FDA about each change
  in each condition established in an approved
  application beyond the variations already
  provided for in the application. The notice is
  required to describe the change fully.
• Notifications may be made in accordance with
  314.70 or pursuant to FDA guidance providing for
  a less burdensome notification of the change

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Notification requirements

• Applicants must report changes from the
  procedures described in their applications to FDA
  either in annual reports or supplements
• Procedures that were never included in the DMF
  are not part of the Application and may be
  changed without reporting to FDA
• cGMP still applies changes must be appropriately
  validated
• Notification to customer becomes a matter of
  prudence (or contract)

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Notification requirements

• Guidance Documents Rule 
• Changes to an Approved Application for Specified
  Biotechnology and Specified Synthetic Biological
  Products (Issued 7/1997)
• Changes to an Approved NDA or ANDA (Issued
  11/1999)
• Changes to an Approved NDA or ANDA Questions and
  Answers (Issued 1/2001)

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Notification requirements

• Guidance Documents Rule
• BACPAC I Intermediates in Drug Substance
  Synthesis Bulk Actives Postapproval Changes
  Chemistry, Manufacturing, and Controls
  Documentation (Issued 2/2001) 
• Container Closure Systems for Packaging Human
  Drugs and Biologics (Issued 5/1999)
• http//www.fda.gov/cder/guidance/index.htm

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Notification Requirements

• BACPAC I
• Scope is limited to well-characterized drug
  substances for which impurities can be monitored
  at the levels recommended
• Communications among the parties involved
  regarding the change is important so that the
  applicant can determine the appropriate filing
  mechanism p. 3 (emphasis added)

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Notification Requirements

• BACPAC I
• Two types of notification responsibilities
• Test Documentation
• Filing Documentation
• DMF holders responsibility is to provide FDA
  with appropriate test documentation and notify
  its customer accordingly

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Notification Requirements

• BACPAC I
• Changes are assessed by evaluating whether
  postchange material is equivalent to prechange
  material
• Impurity profile
• Physical properties
• Other relevant factors
• If equivalence is not documented, a Prior
  Approval Supp. is required

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Notification Requirements

• BACPAC I
• Specific guidance is provided re
• Site Changes
• Scale Changes
• Equipment Changes
• Specification Changes for raw materials (solvents
  and reagents), starting materials, or
  intermediates in a synthetic process

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Notification Requirements

• BACPAC I
• Requires submission of cGMP data and information
  that otherwise would be reviewed only during an
  inspection
• Validation data for in-process tests on
  intermediates
• Change control protocols
• Vendor qualifications
• Sources of raw materials

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Notification Requirements

• BACPAC I
• In exchange for freedom from FDA preapproval,
  additional documentation is expected
• Increased transparency of process puts large
  (Applicants) and small (DMF holders) companies on
  more equal ground

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