This document discusses various types of documentation required in the pharmaceutical industry. It begins by explaining that documentation provides necessary details to reduce mistakes and batch variations. There are three main types of documents - commitment documents between industry and regulators, directive documents between management and employees, and record documents between employees and their work. Key documents discussed include master formula records, drug master files, distribution records, and generic drug development requirements. The importance of documentation for regulatory compliance and quality assurance is emphasized.

1. Documentation in
Pharmaceutical
Industry
Documentation in Pharmaceutical Industry , By : Dr. Umesh Kumar Sharma and Anu Mathew
By : Dr. Umesh Kumar Sharma
And Anu Mathew,
Department of Pharmaceutics,
Mar Dioscorus College of Pharmacy,
Thiruvananthapuram, Kerala, India

2. Documentation in pharmaceutical industry
Method of preparing a written material, which describes the process in
terms of specifications, instructions etc.
The D & C Act under conditions of granting license and schedule M
require manufacturer of drugs to maintain various records.
Importance of documentation
 Provides necessary working details,
 Reduces the risk of mistake,
 Helps in decreasing batch to batch variation,
 Considered as the history of batch operations,

3. Types of documents
 Commitment document: Relationship between industry and the
regulatory authorities.
 Directive document : Relationship between management and employee.
 Record document : Relationship between the employee and the work
they perform.

4. S
P
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C
I
F
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C
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T
Y

5. Master Formula Records (MFR):
Written procedure that give the complete description of all aspects of manufacture, packing
and control with an inspection to ensure purity, identity, quality and strength of each dosage
unit through its shelf life.
Includes all the materials used in any batch manufacturing and step by step process of
manufacturing.
The master formula must include:
a) The name of the product together with product reference code relating to its
specifications.
b) The patent or proprietary name of the product along with the generic name, a
description of dosage form, strength, composition of the product and batch size.

6. c) A statement of the processing location and the principal equipment to be used.
d) Name , quantity and reference number of all starting materials to be used.
e) A statement of expected final yield with the acceptable limits and of relevant
intermediate yields, where applicable.
f) The methods or reference of the methods to be used for preparing the critical
equipment including cleaning, assembling, calibrating, sterilizing.
g) Detailed stepwise processing instructions and the time taken for each step.
Master Formula Records (MFR): cont…

7. Types of Master Formula Records (MFR):
 The master formula records gives proportion of ingredients in the
formulation.
 Master batch formula records which specify absolute amounts of specific
potent ingredients and excipients in a batch.

8. Master production and control records:
Detailed written instructions including all operations starting from dispensing
of raw materials till finishing of bulk products and packaging operation of the
particular product.
It includes batch size, date of manufacture and full signature by 1st person and
further independently checked, dated and signed by 2nd person.

9. Preparation of master formula :
Master formula can be prepared by competent technical
staff.
It should be reviewed by the head of production, QC
department and R & D department.

10. Drug Master File (DMF):
Document prepared by a pharmaceutical manufacturer and submitted solely
at its description to the appropriate regulatory authority in the intended drug
market.
There is no regulatory requirement to file a DMF.
The DMF provides confidential, detailed information about facilities, process
or articles used in the manufacturing, packaging, storing etc. to the regulatory
authority.
DMF is filed when two or more firms work in a partnership or developing or
manufacturing a drug product.

11. Drug Master File (DMF) Includes:
A) General information
1. General properties.
2. Structure.
3. Nomenclature.
B) Manufacture
1. Manufactures.
2. Description of manufacturing process and process control.
a) Flow chart of manufacturing process,
b) Synthetic route of manufacturing process,
c) Manufacturing method,

12. 3. Control of Material
1. List of materials
2. Specification and routine test of the raw material
4.Control of critical steps and intermediates
1. Critical steps,
2. Process validation,
5.Specifications and test method for the intermediates,
6.Manufacturing process development
Drug Master File (DMF) Includes: Cont …..

13. C) Characterization
1.Elucidation of structure and other characteristics-
a) Elemental analysis
b) IR spectrum of drug substance
c) NMR spectrum of drug substance
d) Mass spectrum of drug substance
e) UV spectrum of drug substance
f) X-ray diffraction
g) Thermal analysis
h) Comprehensive illustration
Drug Master File (DMF) Includes: Cont …..

14. 2) Impurities
a) Sources of potential impurities
b) Types of impurities
c) Test procedure for determining impurities
D) Control of drug substances
a) Specifications
b) Analytical procedure
c) Validation of analytical procedure
d) Batch analysis
e) Justification of specification
Drug Master File (DMF) Includes: Cont …..

15. E) Reference standards of material
F) Container closure system
G) Stability
H) Material data safety sheet
APPENDICES
1. Facilities and Equipment’s.
2. Equipment’s design and location.
3. Adventitious agents safety evaluations statement of comment.
Drug Master File (DMF) Includes: cont …..

16. Types of Drug Master File (DMF) :
Type 1: Manufacturing site, facilities, operating procedures and personnel.
Type 2: Drug substance, drug substance intermediate and material used in
their production or drug product.
Type 3: Packaging material.
Type 4: Excipient ,colorant, flavor.
Type 5: FDA accepted reference information.

17. Types of Drug Master File (DMF) : Cont…
Type 1:
Manufacturing site, facilities ,operating procedures and personnel
No longer used, once used to describe facilities.
Recommended for a person outside of the United states to assist FDA in
conducting on site inspections of their manufacturing facilities.
Should describe manufacturing site, operational layout, equipment
capabilities, processing layout.

18. Types of Drug Master File (DMF) : Cont…
Type 2:
Drug substance ,drug substance intermediate and material used in their preparation or
drug product required for drug substance – active ingredient.
A separate DMF is filed for each active ingredient.
Brief description of the manufacturing facilities, the address, a contact, phone number
and fax number.
Manufacturing procedures and control for finished dosage forms submitted in an IND,
NDA , ANDA or export application.

19. Types of Drug Master File (DMF) : Cont…
Type 3:
 Packaging material,
 Its components and composition,
 Packaging material intended for use,
 Name of the suppliers or fabrications of the components used in preparing the packaging
material.
 Acceptance specifications,
 Eg: - Products that would be classified as type 3 DMFs include bottles, seals, dispensers
etc.

20. Types of Drug Master File (DMF) : Cont…
Type 4:
Excipient, colorant, flavor, essence used in their preparation.
Each additive should be identified by this method of manufacture, release
specification and testing methods.
Toxicological data would be included.
The official compendia and FDA regulation for color additives, direct food additives
and food substances may be used as sources for release tests and safety.

21. Types of Drug Master File (DMF) : Cont…
Type 5:
 FDA accepted reference information.
 FDA discourages the use of type 5 DMFs for miscellaneous information, duplicate
information.
 To submit the data which is not covered in type 1 to type 4 DMF.
 A holder must first submit a letter of intent to the drug master file staff.
 FDA will contact the holder to discuss the proposed submission.

22. Distribution records
Written procedures shall be established and followed, describing the
distribution of drug products
Include:
1. A procedure where by the oldest approved stock of a drug product is
distributed first
2. A system by which the distribution of each lot of drug product can be
readily determined to facilitate its recall if necessary.

23. Distribution records
• Distribution records must be constructed and procedures established to
facilitate recall of defective product.
• All records should be indexed by either the manufacturing batch-lot number
of the packaging control number as a means of accountability.
It shall contains:
Name and strength of the product-
Description of dosage form-
Name and address of the consigner-
Date and qty shipped-
Lot and control number of the drug-

25. WHO guidelines for distribution records:
Written instruments and records should be available.
Procedure should be established and maintained.
The title, name and purpose of each document should be clearly stated.
All documents should be completed, approved ,signed ad dated by an appropriate
authorized persons.
In the case of temperature-sensitivity pharmaceutical products, records of
investigations and actions should be retained for at least one year after the expiry
date of the product.

26. Generic drug product development:
Product development is the set of activities beginning with the perception of
a market opportunity and ending in production, sale and delivery of a
product.
The 1st generic drug product filed and approved by FDA has several
financial incentives.
As per Hatch-Waxman Act, a 180 day exclusively is awarded to generic
manufacturer who first files.
During this 6 month period the FDA does not approve any second product
of the same generic version.

27. The following general aspects are considered:-
 Selection of a drug product for manufacture.
 Patents and exclusivity.
 Resources for ANDA submission.
Selection of a drug product for generic version
 Previous experience in the selected areas become an advantage to the manufacturer to
introduce generic products.
 The manufacturer may be already making a variety of dosage forms, including the
immediate and modified release products.
 The products such as transdermal drug product may be difficult to make and also
riskier but have a greater financial reward due to less competition from generic drug
forms.

28. Generic drug product development: Cont……
The market research data and technological advantages influences the
selection of generic drug product.
Estimated current sales volume of the innovator product.
Estimated market share for the generic product, if introduced into the
market.
The cost of acquiring the technology is important to manufacture the
product.
Lead time required to make the product and submission of ANDA to
the FDA for the approval.

29. Patents and exclusivity:
 The patent holder may obtain the exclusivity, which prevents the approval
of ANDAs.
 When period of patent or exclusivity expires other manufactures apply to
FDA to get permission for the manufacture and sale of generic versions.
 Orange book is a register in which all the approved products of innovator
and generic products are maintained.
 Orange book updated monthly is made available in the website.

30. Patents and exclusivity: Cont….
 Patents that claim the active ingredients or other ingredients.
 Drug product patents including formulation.
 Approved polymorphic form , particle size of API.
 Drugs qualified for Orphan drugs exclusivity.
 Exclusivity information for other categories with their expiry periods.

31. Hatch –Waxman act:
• The amendment to federal, food, D&C act which established the
modern system of approval of generics through abbreviated new drug
applications (ANDA).
• The Drug Price Competition and Patent Term Restoration Act
informally known as the Hatch-Waxman Act is a 1984 United States
federal law which encourages the manufacture of generic drugs by
pharmaceutical industry and established the modern system of
government generic drug regulation in the US.

32. Significant results due to Hatch-Waxman act
 Prior to the Hatch and Waxman act, the generic drug manufacturer had to
do the entire clinical trials. After the passage of this act, the generic drug
manufacturer had to only prove bioequivalence of generic drug to the
innovator by showing that the generic drug is 80-125% bioequivalent to
the innovator drug.
 The time and cost involved for getting the generic drug into the market was
significantly reduced.
 Low cost quality, safe and effective generic drugs were available to the
patients.
 Billions of dollars in health care costs are being saved annually.

33. Patent certifications:
As per Hatch and Waxman act, generic drug and 505(b) applicants include
certifications in their applications for each patent listed in the orange book for
innovator drug.
The certification must state one of the following:
 That the required patent information relating to such patent has not been
filled (para I certification).
 That such patent has expired (para II certification).
 That the patent will expire on a particular date(para III certification).

34. Patent certifications: Cont….
That such patent is invalid or will not be infringed by the drug for which
approval is being sought (para IV certification).
The certification under paragraph 1 or II permits the ANDA to be approved
immediately, if it is otherwise eligible. A certification under paragraph III
indicates that the ANDA may be approved when the patents expires.

35. 180 day exclusivity:
 The Hatch Waxman Amendments provide an incentive of 180 days of
market exclusivity to the 1st generic applicant who challenges a listed
patent by filing a paragraph IV certification and thereby runs the risk of
having to defend a patent infringement suit.
 The statue provides that the first applicant to file a substantially complete
ANDA containing a paragraph IV certification to a listed patent will be
eligible for a 180-day period of exclusivity beginning either from the date
it begins commercial marketing to the generic drug product.
180 day exclusivity could be granted to more than one applicant.
Eg.: 180 day exclusivity was granted to Ranbaxy and Watson Laboratories for
marketing generic version of Lipitor.

36. Hatch-Waxman bill:
The Hatch-Waxman bill officially as the drug price competition and patent
term restoration act , brought about the following changes:
Generic medicine no longer need to prove their safety and efficacy. Under
the bill, generic drug manufactures need only submit an ANDA to prove their
product’s bioequivalence to the original branded drug.
Generic drug are granted a 180 day period of exclusivity.
Manufacturers filling ANDAs can only do so for drugs that have not been
patented.
ANDAs can only be filled when a branded drug’s patent has expired.
Generic drugs cannot go on to market until the branded patent has expired.

37. References:
 Generic drug product development, solid oral dosage forms, Leon
Shargel and Isaderkaufer, vol.143
 FDA regulatory affairs: A guide prescription drugs and biologics by
Douglas J pisano, David Mantus.
 Wikipedia.com

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