This document discusses various types of documentation required in the pharmaceutical industry, including master formula records (MFR), drug master files (DMF), and generic drug development. It defines MFRs as approved master documents that describe the full manufacturing process for a specific batch size. It provides details on the content required for MFRs based on guidelines from WHO, Health Canada, and the US CFR. It also discusses the purpose and types of DMFs submitted to the FDA, including Type 1 for manufacturing facilities, Type 2 for drug substances/products, and others. Finally, it briefly mentions the Hatch-Waxman Act as it relates to generic drug development.

1. DOCUMENTATION IN
PHARMACEUTICAL INDUSTRY
Presented by
Navaneethakrishnan P
Department of Pharmaceutics
Karpagam College of Pharmacy
Coimbatore -32
Department Of Pharmaceutics, KCP, CBE-32 1

2. CONTENT
• MASTER FORMULA RECORD (MFR)
• DRUG MASTER FILE (DMF)
• GENERIC DRUG DEVELOPMENT
• HATCH-WAXMANN ACT
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3. MFR - INTRODUCTION
Introduction
• In the 1997 WHO guidance document: “WHO/VSQ/97.01:
A WHO guide to good manufacturing practice (GMP)
requirements. Standard operating procedures and master formulae
• WHO identifies manufacturing instructions as “Master Formula Other
terms used in GMP guidelines and regulations are “Manufacturing
Formula”, “Master Production and Control Record”
• An approved master document that describes “The full process of
manufacturing for the batch of product with at least cross-reference
to the support operations for a batch of a specific product”
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4. Definition
The following are the extracted definitions from several guidelines:
• WHO GMP Guidelines: A formally authorized master formula should
exist for each product and batch size to be manufactured.
• Health Canada GMP guidelines: “MASTER FORMULA (formula-type)
– A document or set of documents specifying the raw materials with
their quantities and the packaging materials, together with a detailed
description of the procedures and precautions required to produce a
specified quantity of a finished product as well as the processing
instructions, including the in-process controls.”
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5. US CFR.
• To assure uniformity from batch to batch, master production and
control records for each drug product, including each batch size there
of, shall be prepared, dated, and signed (full signature, handwritten)
by one person and independently checked, dated, and signed by a
second person. The preparation of master production and control
records shall be described in a written procedure and such written
procedure shall be followed.
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6. Required Content of Master Formula:
MASTER FORMULA RECORD as per WHO
MASTER FORMULA - PRODUCTION
MASTER FORMULA FOR PACKAGING
MASTER PRODUCTION AND CONTROL
RECORDS REQUIRED BY THE USA
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7. MASTER FORMULA (PRODUCTION) as per WHO
The master formula should include:
 Name of the product, with a product reference code relating to its
specification.
 A description of the dosage form, strength of the product and batch
size
 A list of all starting materials to be used with the amount of each.
 A statement of the expected final yield with the acceptable limits,
and of relevant intermediate yields, where applicable.
 A statement of the processing location and the principal equipment
to be used
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8. Cont....
 The methods, or reference to the methods, to be used for preparing
and operating the critical equipment, e.g. cleaning (especially after a
change in product), assembling, calibrating, sterilizing.
 Detailed step-wise processing instructions (e.g. checks on materials,
pretreatments, sequence for adding materials, mixing times,
temperatures).
 The instructions for any inprocess controls with their limits.
 The requirements for storage of the products, including the
container, the labeling, and any special storage conditions.
 Any special precautions to be observed.
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9. MASTER FORMULA - PACKAGING
 The name of the product
 A description of its pharmaceutical form, strength and, where
applicable, method of application.
 The pack size expressed in terms of the number, weight or volume.
 A complete list of all the packaging materials required for a standard
batch size, including quantities, sizes and types, with the code or
reference number relating to the specifications for each packaging
material.
 Special precautions to be observed, including a careful examination
of the packaging area and equipment in order to ascertain the line
clearance before and after packaging operations;
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10. MF and corresponding Batch Records
 Master Formula give the complete production instructions for a
specific batch and batch size of cell banks, virus seed lots,
intermediates, final bulks, final formulated bulks or final container
product.
 The batch production record (BPR) is the approved copy of the
master document with filled in data entries, signatures, dates,
production locations, operators, and lot number, records of all
supporting data (autoclave records, cleaning records, equipment
identification and calibration dates, in-process test results, and QC
results)
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11. FORMATS of MF
 Generally MF should be a single documents of that provide step by
step production instruction raw material equipment's used location
production data etc.,
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12. Issuing of MF
 Master formulae are almost stored in the computer
 The official signed form is a paper copy
 When a production order is made , QA is responsible to generate a copy usually
adds the lot number and stamps each page of the reproduced MF
 The MF should make a reference to in process tests, QC tests, production
parameter that are computer recorded, environmental monitoring autoclave run
charts etc.,
 The batch records include the all production records and support records.
 Master formula once approved and signed should remain under the control of
QA.
 Copies don’t stored in production area.
 When revision are made (if any change) then a new version is assigned a revision
number, the approval signature and effective dates are added, the previous is
achieved.
 MF, copies are distributed to relevant department and in a production run
should be distributed along with stamped by QA.12
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13. Example of MF
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14. Example of MF
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15. DRUG MASTER FILE (DMF)
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16. DRUG MASTER FILE (DMF)
INTRODUCTION:
 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.
 The submission of a DMF is not required by law or FDA regulation.
 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.
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17. SUBMISSION OF DMF
• Each DMF submission should contain a transmittal letter,
administrative information about the submission, and the specific
information to be included in the DMF as described in this section.
• The DMF must be in the English language. Whenever a submission
contains information in another language, an accurate certified
English translation must also be included.
• Each page of each copy of the DMF should be dated and
consecutively numbered. An updated table of contents should be
included with each submission.
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18. SUBMISSION OF DMF
Transmittal Letters
Original Submissions
Identification of submission: Original, the type of DMF as classified in Section III, and its subject.
Identification of the applications, if known, that the DMF is intended to support, including the name and
address of each sponsor, applicant, or holder, and all relevant document numbers.
Signature of the holder or the authorized representative.
Typewritten name and title of the signer.
Amendments
Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the amendment.
A description of the purpose of submission, e.g., update, revised formula, or revised process.
Signature of the holder or the authorized representative.
Typewritten name and title of the signer.
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19. TYPE 1
• Manufacturing Site, Facilities, Operating Procedures, and Personnel
TYPE 2
• Drug Substance, Drug Substance Intermediate, and Material Used in Their
Preparation, or Drug Product
TYPE 3
• Packaging Material
TYPE 4
• Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
TYPE 5
• FDA Accepted Reference Informatio
Types of DMF
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20. TYPE 1 : Manufacturing Site, Facilities, Operating Procedures, and Personnel
• A Type I DMF is recommended for a person outside of the United States to
assist FDA in conducting on site inspections of their manufacturing
facilities.
• The DMF should describe the manufacturing site, equipment capabilities,
and operational layout.
• A Type I DMF is normally not needed to describe domestic facilities, except
in special cases, such as when a person is not registered and not routinely
inspected.
• The description of the site should include acreage, actual site address, and
a map showing its location with respect to the nearest city. An aerial
photograph and a diagram of the site may be helpful.
• A diagram of major production and processing areas is helpful for
understanding the operational layout.
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21. TYPE 2 : Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product
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
1) Drug Substance Intermediates, Drug Substances, and Material Used in Their
Preparation
• Summarize all significant steps in the manufacturing and controls of the drug
intermediate or substance. Detailed guidance on what should be included in a
Type II DMF for drug substances and intermediates may be found in the following
guidelines:
• Guideline for Submitting Supporting Documentation in Drug Applications for the
Manufacture of Drug Substances.
• Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section
of an Application.
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22. TYPE 2 : Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product
2) Drug Product
• Manufacturing procedures and controls for finished dosage forms should
ordinarily be submitted in an IND, NDA, ANDA, or Export Application. If this
information cannot be submitted in an IND, NDA, ANDA, or Export
Application, it should be submitted in a DMF.
• When a Type II DMF is submitted for a drug product, the applicant/sponsor
should follow the guidance provided in the following guidelines:
• Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls
Section of an Application.
• Guideline for Submitting Documentation for the Manufacture and Controls for Drug
Products
• Guideline for Submitting Samples and Analytical Data for Methods Validation
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23. TYPE 3 : Packaging Material
• Each packaging material should be identified by the intended use,
components, composition, and controls for its release.
• The names of the suppliers or fabricators of the components used in
preparing the packaging material and the acceptance specifications
should also be given.
• Data supporting the acceptability of the packaging material for its
intended use should also be submitted as outlined in the "Guideline
for Submitting Documentation for Packaging for Human Drugs and
Biologics."
• Toxicological data on these materials would be included under this
type of DMF, if not otherwise available by cross reference to another
document.
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24. TYPE 4 : Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
• Each additive should be identified and characterized by its method of
manufacture, release specifications, and testing methods.
• Toxicological data on these materials would be included under this type of
DMF, if not otherwise available by cross reference to another document.
• Usually, the official compendia and FDA regulations for color additives,
direct food additives, indirect food additives, and food substances, may be
used as sources for release tests, specifications, and safety.
• Guidelines suggested for a Type II DMF may be helpful for preparing a Type
IV DMF.
• The DMF should include any other supporting information and data that
are not available by cross reference to another document.
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25. TYPE 5: FDA Accepted Reference Information
• FDA discourages the use of Type V DMF's for miscellaneous
information, duplicate information, or information that should be
included in one of the other types of DMF's.
• If any holder wishes to submit information and supporting data in a
DMF that is not covered by Types I through IV, a holder must first
submit a letter of intent to the Drug Master File Staff
• FDA will then contact the holder to discuss the proposed submission.
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26. Format, Assembly, and Delivery of DMF
An original and duplicate are to be submitted for all DMF
submissions.
• Drug Master File holders and their agents/representatives should retain a
complete reference copy that is identical to, and maintained in the same
chronological order as, their submissions to FDA.
The original and duplicate copies must be collated, fully assembled,
and individually jacketed.
• Each volume of a DMF should, in general, be no more than 2 inches thick. For
multivolume submissions, number each volume.
For example, for a 3 volume submission, the volumes would be numbered 1
of 3, 2 of 3, and 3 of 3.
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27. Cont…
U.S. standard paper size (8-1/2 by 11 inches) is
preferred.
• Paper length should not be less than 10 inches
not more than 12 inches. However, it may
occasionally be necessary to use individual
pages larger than standard paper size to present
a floor plan, synthesis diagram, batch formula,
or manufacturing instructions.
• Those pages should be folded and mounted to
allow the page to be opened for review without
disassembling the jacket and refolded without
damage when the volume is shelved.
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28. Cont…
Delivery to FDA
Drug Master File submissions and
correspondence should be addressed as
follows:
• Drug Master File Staff
Food and Drug Administration
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
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29. Generic Drug Development
A Generic drug is a pharmaceutical drug that has the same chemical
substance as the drug that was originally developed, patented and
innovated.
Generic drugs are allowed for sale after the expiry of the patent of the
original drugs. Because the active chemical substance is the same, the
medical profile of generics is believed to be equivalent in performance.
The generic drug has the same active pharmaceutical ingredient (API) as
the original, but it may differ in characteristics such as manufacturing
process, formulation, excipients, color, taste, and packaging.
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30. cont.,
According to WHO,
“A generic drug is a pharmaceutical product, usually intended to be
interchangeable with an innovator product that is manufactured without a
license from the innovator company and marketed after the expiry date of the
patent or other exclusive rights”
The English dictionary defines the word GENERIC as:
“Not protected by trademark registration; Nonproprietary or any product, as a
food, drug, or cosmetic that can be sold without a brand name”
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31. cont.,
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Example for Generic drug and Branded drug

32. cont.,
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Difference between Generic drug and Branded drug

33. Approval for Generic Drugs
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The expiry of patent drug for innovator, it can be manufactured and
marketed by any pharmaceutical company.
Before marketing the drug, generic manufacturers need to obtain permission
from relevant drug regulatory authorities.
1. Any drug manufactured should follow good manufacturing
practices guidelines, the enforcement of which is the responsibility of drug
regulators.
2. There is a requirement for in-vitro dissolution and in-vivo bio-
availability and bio-equivalence (BA-BE) testing of new brand (i.e generic
manufacturer) which compares the release of active pharmaceutical
ingredient (API) on certain dissolution and liberation characteristics and
pharmacokinetic parameters (Cmax, Tmax, and area-under-the-curve) with
those from reference standard.

34. Hatch Waxman Act
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The Hatch-Waxman Amendments is also known as the "Drug Price
Competition and Patent Term Restoration Act of 1984”.
This act allow the approval pathway for generic drug products, within
short period of time.
In simple words “Hatch-Waxman act is the amendment to Federal,
Food, Drug and Cosmetics act which established the modern system of
approval of generics through Abbreviated New Drug Applications
(ANDAs)”

35. Cont.,
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Significant of Hatch-Waxman act:
1. Prior to the Hatch and Waxman act the generic drug manufacturer had to do the
entire clinical trials. After the passage of Hatch and Waxman act the generic drug
manufacturer had to only prove bioequivalence of generic drug to the innovator
drug by showing that the generic drug is 80-125% bioequivalent to the innovator
drug.
2. The time and cost involved for getting the generic drug into the market was
significantly reduced.
3. Low cost quality, safe and effective generic drugs were available to the patients.
4. Since 1984, over 10,000 generic drugs have entered the market, and generics
accounted for close to 50 percent of prescriptions filled (as on august 1, 2003).
5. Billions of dollars in health care costs are being saved annually.

36. Cont.,
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A true Hatch-Waxman system has three components, which work
together to bring generic pharmaceuticals to market quickly, all the
while encouraging innovation:
1. The first component lightens the burden of regulatory review for
generic products, by creating an Abbreviated New Drug Application
(ANDA) for generic producers to file with the U.S. Food and Drug
Administration (FDA).
• It allows generic firms to begin testing, but not to undertake
commercial activities, before the expiration of the innovator's
patent.

37. Cont.,
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2. The second component,
• Patent Term Restoration (PTR) restores some of the effective
patent life that is lost in the increasingly complex clinical trial and
FDA review process for innovative pharmaceutical products.
• Pharmaceutical inventions receive the same standard term of 20
years from the date that the patent application is filed, as do all
other patented products, but, after completion of clinical research
and regulatory approval, the effective patent life for a new
pharmaceutical product is approximately 11 years.
• PTR creates the possibility of patent term extensions to
compensate innovators for a portion of the patent exclusivity
period that is lost due to lengthy FDA regulatory review periods
upto 14 years

38. Cont.,
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3. The third component,
• The creation of finite periods of protection for commercially
valuable and confidential data in the clinical dossier, known as
DATA EXCLUSIVITY.
• Prior to Hatch-Waxman, the clinical dossier for an innovative
product was treated as permanently proprietary information.
• Data Exclusivity represents a benefit provided to the generic
industry, which is now allowed to rely on the results of the clinical
data after the expiration of a period that should be no less than
five years.

39. Reference
1. Guide to Master Formulae WHO/FWC/IVB/QSS/VQR 2011 World Health Organization Pg.No1-14 & 49
(https://www.who.int/immunization_standards/vaccine_quality/guide_to_master_formulae_final_2012.pdf)
2. Drug Master Files Guidelines, Center for Drug Evaluation and Research Food and Drug Administration,
Department of Health and Human Services September 1989
(https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122886.htm)
3.Puneet Dhamija et.al, 2015 Only generics (drugs/names): Is India ready? Indian Journal Endocrinology
Metabolism (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566332/)
4. Overview on Hatch Waxman act, The Innovative Pharmaceutical association South Africa (IPASA)
(http://ipasa.co.za/Downloads/Intellectual%20Property%20&%20Innovation/Hatch-Waxman_overview.doc)
5. HATCH-WAXMAN ACT, Regulatory one (http://www.regulatoryone.com/2011/12/hatch-waxman-act.html)
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40. Department Of Pharmaceutics, KCP, CBE-32 40