Regulatory affairs

Regulatory affairs is a profession developed from the intention of governments

to protect public health by controlling the safety and efficacy of products
including pharmaceuticals, veterinary medicines, medical devices, cosmetics so
that that supplied products make a worthwhile contribution to public health and
welfare.

The drug development process is a lengthy, complex and extremely costly

although necessary process. Regulatory Affairs plays a crucial role in the
pharmaceutical industry and is involved in all stages of drug development
and also after drug approval and marketing.

Regulatory Affairs is a unique combination of science and management to

achieve a commercially important goal within a drug-development
organization. 

It gives strategic and technical advice at the highest level in their

companies, right from the beginning of the development of a product,
making an important contribution both commercially and scientifically to
the success of a development program and the company as a whole.
 A regulatory affair plays a crucial role in the industry and is involved in all stages of
drug development and also after drug approval and marketing.
 Keeping track of the ever-changing legislation in all the regions in which a company
wishes to distribute its products.

 Advising on legal and scientific restraints and requirements.

 Collecting and evaluating scientific data.

 Presenting registration documents to regulatory agencies and carrying out any

subsequent negotiations necessary to obtain or maintain marketing authorization for
the products concerned.
 Giving strategic and technical advice at the highest level in their companies, making
an important contribution both commercially and scientifically to the success of a
development programme and the company as a whole.

 Helping the company avoid problems caused by badly kept records, inappropriate
scientific thinking or poor presentation of data.

 Preparation of organized and Ensure adherence and compliance with all the
applicable CGMP, ICH, GCP, GLP guidelines regulations and laws.
Documentation in Pharmaceutical industry
• Specifications describe in detail the requirements with which the products or
materials used or obtained during manufacture have to conform.
• Documents should be designed, prepared, reviewed and distributed with care.
• Documents should be approved, signed and dated by appropriate and authorised
persons.
• Documents should have unambiguous contents;
• Reproduced documents should be clear and legible.
• Documents should be regularly reviewed and kept up-to-date.
• Documents should not be handwritten; although, where documents require the
entry of data, these entries may be made in clear, legible, indelible handwriting.
• Any alteration made to the entry on a document should be signed and dated; the
alteration should permit the reading of the original information.
• The records should be made or completed at the time each action is taken and in
such a way that all significant activities concerning the manufacture of medicinal
products are traceable.
• They should be retained for at least one year after the expiry date of the finished
product.
• Data may be recorded by electronic data processing systems, photographic or other
reliable means
MASTER FORMULA
RECORD
(MFR)
 Master Formula Record

• Master formula record (MFR) is a master document for any

pharmaceutical product.

• MFR contains all information about the manufacturing process for the
product.

• MFR is prepared by the research and development team of the

company.

• MFR is used as a reference standard for preparing batch manufacturing

record (BMR) by manufacturing units.

• MFR is also called Master Manufacturing record or Master production

record.
 Definition

“A document or a set of documents specifying the starting materials with

their quantities and the packaging materials, together with a description of

the procedures and precautions required to produce a specific quantity of a

finished product as well as the processing instructions, including the in-

process control.”
• WHO GMP Guidelines: A formally authorized master formula should
exist for each product and batch size to be manufactured.
• EU and PIC GMP guidelines: “Formally authorized Manufacturing
Formula and Processing Instructions should exist for each product and
batch size to be manufactured. They are often combined in one
document.”
• Health Canada GMP guidelines: MASTER FORMULA - 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.
• US CFR. :To assure uniformity from batch to batch, master production
and control records for each drug product, including each batch size
thereof, 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.
 MFR should have following parts

1. Product Details:-
• Name, logo and address of the manufacturing process
• Dosage form name
• Brand name
• Generic name
• Product code
• Label claim of all ingredients
• Product description
• Batch size
• Pack size and packaging style
• Shelf life
• Storage conditions
• MFR number and date
• Effective batch number
• Authorization by the production and quality assurance head
 MFR should have following parts Cont’d…

2. Flow chart
• Steps of the manufacturing process to be monitored.
• Flowchart of the material movement from dispensing to the final
product to stores.

3. Equipment
Create a list of all required equipment and machines required in the
manufacturing process with their capacity.
 MFR should have following parts Cont’d…

4. Special Instructions

• Write down the precautions special instructions to follow during the

product manufacturing and packing and these should also be added in

the batch manufacturing formula.

• Batch manufacturing formula should include the following:-

✔ Name of the ingredient with test reference (As IP,BP,USP etc)

✔ Quantity to be added

✔ Overages to be added (%)

 MFR should have following parts Cont’d…

5. Calculations

• Include the calculation steps of all active material to get the 100% of

the active material.

• The calculations shall be done using water content or LOD to get 100%

potency.
 MFR should have following parts Cont’d…

6. Manufacturing Process

• Write all steps in all stages of the manufacturing process.

• All process steps like shifting, milling, mixing, lubricating,

granulation, compression and coating should be written in detail

including the process time and yield.

• Include atmospheric conditions as temperature, humidity and storage

conditions for every step.

 MFR should have following parts Cont’d…

7. Packing Process
• List of all packing materials with their quantity is written.

• Line clearance, reconciliation of printed and unprinted packing

material should be included in details.

8. Yield

• Include the theoretical, actual yield and acceptance limit of the batch

• The detail given above should be included in a general master formula

record. Other details should be added as per company requirements in

the master formula record.

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Drug Master Files
(DMF)
 DEFINATION

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.
 Important facts regarding DMFs

• It is submitted to FDA to provide confidential information

• Its submission is not required by law or regulations

• It is neither approved nor disapproved

• It is filed with FDA to support NDA, IND, ANDA another DMF or

amendments and supplements to any of these

 Types of DMF’s

Type I:  Manufacturing Site, Facilities, Operating Procedures, and Personnel (No
longer accepted by FDA)
Type II:  Drug Substance, Drug Substance Intermediate, and Material Used in
their Preparation, or Drug Product

Type III:  Packaging Material

Type IV:  Excipient, Colorant, Flavour, Essence, or Material Used in Their

Preparation

Type V:  FDA Accepted Reference Information.

 SUBMISSIONS TO DRUG MASTER FILES

• The DMF must be in the English language

• Each DMF submission should contain a transmittal letter, administrative
information about the submission, and the specific information to be include in
the DMF
• 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.
 A. Transmittal Letters
The following should be included:-
A.1. Original Submissions
a) Identification of submission: Original, the type of DMF, and its subject.
b) 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.
c) Signature of the holder or the authorized representative.
d) Typewritten name and title of the signer.

A. 2. Amendments
e) Identification of submission: Amendment, the DMF number, type of DMF, and
the subject of the amendment.
f) A description of the purpose of submission, e.g., update, revised formula, or
revised
g) process.
h) Signature of the holder or the authorized representative.
i) Typewritten name and title of the signer.
 B. Administrative Information
Administrative information should include the following:-

B.1. Original Submissions

a. Names and addresses of the following:

(1) DMF holder.
(2) Corporate headquarters.
(3) Manufacturing/processing facility.
(4) Contact for FDA correspondence.
(5) Agent(s), if any.
b. The specific responsibilities of each person listed in any of the categories in
Section a.
c. Statement of commitment.
A signed statement by the holder certifying that the DMF is current and that the
DMF holder will comply with the statements made in it.
 B. Administrative Information Cont’d...
B2. Amendments
a) Name of DMF holder.
b) DMF number.
c) Name and address for correspondence.
d) Affected section and/or page numbers of the DMF.
e) The name and address of each person whose IND, NDA, ANDA,
DMF, or Export
f) Application relies on the subject of the amendment for support.
g) The number of each IND, NDA, ANDA, DMF, and Export Application
that relies on the subject of the amendment for support, if known.
h) Particular items within the IND, NDA, ANDA, DMF, and Export
Application that are affected, if known.
 C. Drug Master File Contents
C.1. Types of Drug Master Files
Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
1. 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.
2. The DMF should describe the manufacturing site, equipment capabilities,
and operational layout.
3. 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.
4. Major equipment should be described in terms of capabilities, application,
and location.
5. A diagram of major corporate organizational elements, with key
manufacturing, quality control, and quality assurance positions highlighted,
at both the manufacturing site and corporate headquarters, is also helpful.
 C. Drug Master File Contents Cont’d...
Type II: Drug Substance, Drug Substance Intermediate, and Material Used in
Their Preparation, or Drug Product

1. Summarize all significant steps in the manufacturing and controls of the drug
intermediate or substance.
2. 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.
 C. Drug Master File Contents Cont’d...
Type III: Packaging Material

1. Each packaging material should be identified by the intended use,

components, composition, and controls for its release.
2. The names of the suppliers or fabricators of the components used in preparing
the packaging material and the acceptance specifications should also be given.
3. 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.“
4. Toxicological data on these materials would be included under this type of
DMF, if not otherwise available by cross reference to another document.
 C. Drug Master File Contents Cont’d...
Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their
Preparation

1. Each additive should be identified and characterized by its method of

manufacture, release specifications, and testing methods.
2. Toxicological data on these materials would be included under this type of
DMF, if not otherwise available by cross reference to another document.
 C. Drug Master File Contents Cont’d...
Type V: FDA Accepted Reference Information

1. 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.
2. 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 (for address, see D.5.a. of this section).
3. FDA will then contact the holder to discuss the proposed submission.
 C. Drug Master File Contents
C.2. General Information and Suggestions

C.2.A. 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.

C.2.B. Stability
Stability study design, data, interpretation, and other information should be
submitted, when applicable, as outlined in the "Guideline for Submitting
Documentation for the Stability of Human Drugs and Biologics."
 D. Format, Assembly, and Delivery
D.1. 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.

D.2. 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.

D.3. U.S. standard paper size (8-1/2 by 11 inches) is preferred.

Paper length should not be less than 10 inches nor 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.
 D. Format, Assembly, and Delivery Cont’d...
D.4. Assembly
✔ The agency's system for filing DMF's provides for assembly on the left side of
the page.
✔ The left margin should be at least three fourths of an inch to assure that text is
not obscured in the fastened area.
✔ The right margin should be at least one half of an inch. The submitter should
punch holes 8 1/2 inches apart in each page.
D.5. 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
Delivery charges to the above address must be prepaid.
 AUTHORIZATION TO REFER TO A DRUG MASTER FILE
A. Letter of Authorization to FDA
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.
The letter of authorization should include the following:
1. The date.
2. Name of DMF holder.
3. DMF number.
4. Name of person(s) authorized to incorporate information in the DMF by
reference.
5. Specific product(s) covered by the DMF.
6. Submission date(s) of 5, above.
7. Section numbers and/or page numbers to be referenced.
8. Statement of commitment that the DMF is current and that the DMF holder
will comply with the statements made in it.
9. Signature of authorizing official.
10. Typed name and title of official authorizing reference to the DMF
AUTHORIZATION TO REFER TO A DRUG MASTER FILE Cont’d...
B. Copy to Applicant, Sponsor, or Other Holder
The holder should also send a copy of the letter of authorization to the affected
applicant, sponsor, or other holder who is authorized to incorporate by reference
the specific information contained in the DMF. The applicant, sponsor, or other
holder referencing a DMF is required to include a copy of the DMF holder's letter
of authorization in the application.
 PROCESSING AND REVIEWING POLICIES
An original DMF submission will be examined on receipt to determine
whether it meets minimum requirements for format and content. If the
submission is administratively acceptable, FDA will acknowledge its receipt
and assign it a DMF number.

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. As noted, the incorporation by
reference must be accompanied by a copy of the DMF holder's letter of
authorization. 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. The general
subject of the deficiency is identified, but details of the deficiency are disclosed
only to the DMF holder.
Thank You