FDA Provisions

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FDA Provisions

• GUIDELINE FOR DRUG MASTER FILES

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GUIDELINE FOR DRUG MASTER FILES

• This guideline is intended to provide DMF holders
  with procedures acceptable to the agency for
  preparing and submitting a DMF
• The guideline discusses
• types of DMF's,
• the information needed in each type,
• the format of submissions to a DMF,
• the administrative procedures governing review of
  DMF's, and
• the obligations of the DMF holder.

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GUIDELINE FOR DRUG MASTER FILES

• DMF's are generally created to allow a party
  other than the holder of the DMF to reference
  material without disclosing to that party the
  contents of the file.
• Open part
• Closed part

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Definitions

• Agency means the FDA
• Agent or representative means any person who is
  appointed by a DMF holder to serve as the contact
  for the holder
• Applicant means any person who submits an
  application or abbreviated application or an
  amendment or supplement to them to obtain FDA
  approval of a new drug or an antibiotic drug and
  any other person who owns an approved application
• Holder means a person who owns a DMF
• Letter of authorization means a written statement
  by the holder or designated agent or
  representative permitting FDA to refer to
  information in the DMF in support of another
  persons submission

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Generic Drug

• A generic drug is identical, or bioequivalent to
  a brand name drug in dosage form, safety,
  strength, route of administration, quality,
  performance characteristics and intended use. 
• A generic is similar in its therapeutic
  properties to a branded formulation and comes
  into the market when the latter goes off patent.

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Generic Market

• The opening up of the generics market presents
  attractive opportunities for Indian bulk drug
  manufacturers
• The advantage of targeting the US market is the
  price realisation for generics. The price is much
  higher compared to what companies would get in
  the domestic market.
• Indian manufacturers have filed a higher number
  of Drug Master Files (DMF) with the US FDA in
  recent times

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DMF (Drug Master File)

• A Drug Master File (DMF) is a submission to the
  Food and Drug Administration (FDA) that may be
  used to provide confidential detailed information
  about facilities, processes, or articles used in
  the manufacturing, processing, packaging, and
  storing of one or more human drugs
• A DMF filing is required for companies to supply
  bulk drugs to the US market

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DMF (Drug Master File)

• Technical contents of a DMF are reviewed in
  connection with the review of an IND, NDA, ANDA,
  or an Export Application.
• The information contained in the DMF may be used
  to support an Investigational New Drug
  Application (IND), a New Drug Application (NDA),
  an Abbreviated New Drug Application (ANDA),
  another DMF, an Export Application, or amendments
  and supplements to any of these
• A DMF is NOT a substitute for an IND, NDA, ANDA,
  or Export Application

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DMF filings

• About 10 Indian companies have made more than 10
  DMF filings up to the second quarter of 2003

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DMF filings
Cipla 53
Ranbaxy 48
Dr Reddys 44
Wockhardt 32
IPCA 19
Unichem 19
Neuland 16
Cadila 15
Lupin 14
Shasun 12
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Types of DMF filings

• Type I Manufacturing Site, Facilities, Operating
  Procedures, and Personnel (Plant information)
• Type II Drug Substance, Drug Substance
  Intermediate, and Material Used in Their
  Preparation, or Drug Product
• Type III Packaging Material
• Type IV Excipient, Colorant, Flavor, Essence, or
  Material Used in Their Preparation
• Type V FDA Accepted Reference Information (other
  clinical toxicological and sterile manufacturing
  information)

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Abbreviations

• A Active
• I Inactive
• N Not an assigned number
• P DMF Pending Filing Review

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Submissions to the Drug Master Files

• Each DMF submission should contain a
• transmittal letter
• administrative information about the submission
• the specific information to be included in the
  DMF (technical information)
• The DMF must be in the English language

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Transmittal Letters

• Original Submissions
• Amendments
• Administrative Information
• Original Submissions
• Amendments

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Type II Drug substance, drug substance
intermediate, and Material Used in Their
Preparation, or Drug Product

• A Type II DMF should, in general, be limited to a
  single drug intermediate, drug substance, drug
  product, or type of material used in their
  preparation.
• Summary of all significant steps in the
  manufacturing and controls of the drug
  intermediate or substance.

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Content of a DMF

• Company profile
• Letter of submission/transmittal
• Batch formula
• BPR
• Key RM/FP/Intermediates
• Quality data
• Stability data
• Specifications and test methods
• Analytical method validation

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General information and suggestions

• Stability- Stability study design, data,
  interpretation, and other information should be
  submitted, when applicable
• Format, assembly, and delivery
• An original and duplicate are to be submitted for
  all DMF submissions
• The original and duplicate copies must be
  collated, fully assembled, and individually
  jacketed

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Letter of Authorisation to the FDA

• The DMF will be reviewed only when it is
  referenced in an application
• Before FDA can review DMF information in support
  of an application, the DMF holder must submit in
  duplicate to the DMF a letter of authorization
  permitting FDA to reference the DMF.

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Drug Master File Review

• A DMF IS NEVER APPROVED OR DISAPPROVED
• The agency will review information in a DMF only
  when an IND sponsor, an applicant for an NDA,
  ANDA, or Export Application, or another DMF
  holder incorporates material in the DMF by
  reference.
• If FDA reviewers find deficiencies in the
  information provided in a DMF, a letter
  describing the deficiencies is sent to the DMF
  holder. At the same time, FDA will notify the
  person who relies on the information in the
  deficient DMF that additional information is
  needed in the supporting DMF.

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Environmental Assessment

• Type II, Type III, and Type IV DMF's should
  contain a commitment by the firm that its
  facilities will be operated in compliance with
  applicable environmental laws