SEMINAR
ON

REGULATORY AFFAIRS

PRESENTED BY:

AISWARYA CHAUDHURI

M.PHARM (PHARMACEUTICS) 1ST YEAR

SCHOOL OF PHARMACEUTICAL EDUCATION AND RESEARCH (SPER)

JAMIA HAMDARD

CONTENTS

 INTRODUCTION
 MASTER FORMULA RECORD
 DRUG MASTER FILE
 DISTRIBUTION RECORD
 GENERIC DRUG PRODUCT DEVELOPMENT
 HATCH-WAXMAN ACT AND AMENDMENTS
 CONCLUSION
 REFERENCES

INTRODUCTION

Regulatory affairs is a comparatively new profession which
developed from the desire of governments to protect the public
health by controlling the safety and efficacy of the products in
areas including pharmaceuticals, veterinary medicines, medical
devices, cosmetics and complementary medicines

MASTER FORMULA
RECORD

 DEFINITION: MASTER FORMULA RECORD is a set of documents which contains
list of starting material, their quantities, methods of preparation , precautions needed
during manufacture, full description of the product, in- process control measures and their
packaging and storing conditions.

 CONTENTS OF MFR:

 Product name, its reference code and specifications

 The generic name, proprietary name , dosage form, strength, composition and batch size

 Equipment used while manufacturing and the location

 Starting material – its quantity and the reference number

 Expected final yield and also intermediate yield with acceptable limits

 In-process control measures with their acceptable limits

 Methods of cleaning, sanitization, sterilization etc.

 Labelling details, storage conditions and packaging techniques.

 WHY MFR IS PREPARED AND BY WHOM ?

 MFR is prepared to obtain every detailed information of the finished product i.e. from obtaining raw material to packaging of
finished product and to form a record or document of it so that it can be checked after regular interval of time to minimise errors
and get a safe product.

 MFR is prepared either by the qualified staff like manufacturing chemist or analytical chemist depending upon their experience.
Or

prepared from the documents obtained through batch manufacturing record of a batch size.

 MFR is prepared by production department in association with F&D.

 PROCEDURE OF PREPARATION OF MFR:

 MFR is divided into two parts: 1. Manufacturing part 2. Packaging part

 The first page of both section contains the detailed description of the product.

 The second page of manufacturing part contains the flow chart which includes the step wise movement of process and raw
material from dispensing of material to transfer of a batch to finished stores.

 The third page contains any special precautions taken during manufacturing and packing of the product. The same page contains
batch manufacturing formula.

 The fourth page contains stage wise and step wise manufacturing process and at the end of each process, the yield obtained is
mentioned with acceptable limits and also the result of in-process quality checks.

 The second page of packaging part contains complete list of all the packaging material including quantities, sizes and types.
All three pages must be authorised by three persons:

 the person who shall prepare the MFR i.e. Production officer.

 the person who shall check the MFR i.e. Production head

 the person who shall finally approve the MFR i.e. QA head.

Their designations and their names shall be mentioned below their signatures along with the date of signing the document.

BATCH MANUFACTURING FORMULA: It contains columns of-

1.Serial No.

2. Name of the ingredients

3.Reference of the specification of ingredients

4.Quantity to be added ( in mg/ml or /tablet or /capsule or /gm as the case may be)

5.Overages to be added (in %).

FIG: SAMPLE OF MASTER
FORMULA RECORD

DRUG MASTER
FILE

• DRUG MASTER FILE is defined as documents or file submitted to Food and Drug Administration (FDA)
concerning with the confidential detailed information regarding chemistry, manufacturing and controls of drug product
or a component of a drug product.

• It contains complete information regarding API, finished drug dosage form.
• There is no legal or regulatory requirement to file a DMF.

 TYPES OF DMF:
1. TYPE I: Comprises of manufacturing site, facilities, operating procedures and personnel. The FDA no longer accepts

type I DMFs as per a final rule published on 12 Jan’ 2000.
2.TYPE II: Comprises of drug substances, drug substance intermediate and materials used in their preparation.
3.TYPE III: Details of packaging materials.
4.TYPE IV: Details of excipients, colourant, favour, essence and materials required for manufacture.
5. TYPE V: FDA accepted reference information

 The information contained in DMF can be used to support the IND ( investigational new drug application), NDA ( new
drug application) and ANDA ( abbreviated new drug application) but cannot act as a substitute for IND, NDA and
ANDA.

 WHY DMF IS USED?
 To maintain confidentiality of proprietary information for the holder

 To review the information by FDA to support applications submitted by one or more applicants.

 HOW THE SYSTEM WORKS? If DMF is administratively complete,
FDA sends the filing acknowledgement to holder
and DMF is ACTIVE

DMF
Application DMF Status: Active

If DMF is not administratively complete, FDA sends
a letter
to firm identifying issues. DMF is not active until

FDA performs administrative review issues are resolved.
of submitted DMF

 REQUIREMENT OF DMF:
1. A transmittal letter

2. Administrative information about the submission

3. Special information if included in DMF.

 It must be in English language.

 FORMATING, ASSEMBLING AND DELIVERY OF DMF:
 FORMATING, ASSEMBLING: All the DMF holder should retain a copy of the DMF and it should be arranged in the same

order as submitted. Each volume is greater 2 inch thick and in case of multivolume, each volume should be numbered. If
there are four volume, then volumes are numbered as 1 of 4, 2 of 4, 3 of 4 and 4 of 4.

 DELIVERY OF DMF: DMF is submitted to –

DRUG MASTER FILE STAFF
FOOD AND DRUG ADMINISTRATION

5901-B AMMENDALE ROAD
BELTSVILLE, MD 20705-1266

 DESIGN OF DMF:
 TRANSMITTAL LETTER (COVER LETTER):

ORIGINAL SUBMISSION AMENDMENTS
1. Identification of submission – 1. Modification regarding DMF no.,

authenticity, content and objective of DMF nature and kind of DMF.
2. Recognition of application- 2. Recognition of application-

name and address of each holder Details of aims and objectives,
and other relevant documents updates and revised formula.
3. Signature of the authorised holder 3. Signature of the authorised holder.

 ADMINISTRATIVE INFORMATION:
ORIGINAL SUBMISSION AMENDMENTS

1.Name and address of the following: 1. Name of DMF
a. DMF holder 2. DMF number
b. Corporate headquarters 3. Name and address for correspondence
c. Manufacturing/processing facility 4. Affected section and /or
d. contact for FDA correspondence page no. of DMF.

ORIGINAL SUBMISSION AMENDMENTS
2. The responsibilities assigned to each person 5.Name and address of each person whose IND,

3. Statement of commitment. NDA and ANDA relies on subject of amendments.

6.Particular items and number associated with

IND, NDA, ANDA and export application.

 If the DMF is signed, it implies that the DMF is current and that the DMF holder will comply with the statements
made in it.

 AUTHORISATION TO DMF: LETTER OF AUTHORIZATION (LOA) is a written statement given by the holder or
designated agent to the FDA.

LOA contains:

 The date

 Name of DMF holder

 DMF number

 Name of person authorised to incorporate information in the DMF

 Submission date

 Section number and/or page number to be referenced
 Statement of commitment that the DMF is current
 Signature of the authorizing official
 Name and title of official authorizing ref. to DMF.

 REVIEW OF THE DMF:
Review When reviewer receives an application that references a DMF The reviewer request
DMF from CDR ( central document room) After getting DMF, the reviewing process get started

If reviewer found any deficiency in the content of DMF ,then
deficiencies are communicated to the holder.

The holder should submit the requested information to the DMF in
response to the agency’s deficiency letter along with transmittal letter

having subject matter.

DISTRIBUTION
RECORD

• DISTRIBUTION RECORD is defined as record comprises f data associated with distribution of drugs from the
manufacturer to the distributors. Such records are needed for the GMP regulations.

 OBJECTIVE:

The objective of such record is that if there occurs any adverse drug reaction or some quality defect, then such batch are
promptly withdrawn from the market by the manufacturer.

 CONTENTS OF DISTRIBUTION RECORD:
1. PRODUCT information: It provides information regarding product name, manufacturer identity, batch number, strength,

type of dosage form.

2. TRANSACTION information: It provides information regarding sales transfer, return of any product or any other
documents related to the product like quantity, invoice number, invoice date etc.

3. DISTRIBUTION information: It provides information regarding distribution of product (selling/transferring) to other
group or party. It involves the name of the person who will distribute the product and also the signature of the person.

4. RECIPIENT information: It tells about the party/person receiving the product. It involves name, address of the recipient
and signature and also the data collected.

GENERIC DRUG
PRODUCT DEVELOPMENT

 GENERIC DRUG: They are defined as the copies of brand name drugs having same dosage, use, effects, strength,
safety and efficacy and route of administration as the original drug.

 ESSENTIAL CRITERIA FOR MANUFACTURING GENERIC DRUG:
 Affordable and accessible by lowering the prices for the consumers

 Therapeutically equivalent and bioequivalent to the brand name of drug product.

 GENERIC DRUG PRODUCT DEVELOPMENT : Generic drug product development should influence the innovator
new product with improved efficacy and/or safety features.

 SELECTION OF A GENERIC DRUG PRODUCT FOR MANUFACTURE: The selection of generic drug product
for manufacture depends on the following:

 Sales and potential market share

 Patent expiration and exclusively issues.

 Availability of API

 Timing

 Technology

 Formulation

 Experience

 GENERIC DRUG APPROVAL: FDA’s office is responsible for the approval of generic drug product.

 The FDA’s office of generic drugs has a website named http://www.fda.gov/cder/odg/ that provides
information regarding flow chart presentation of ANDA review process and how FDA determines quality,
safety and efficacy of generic drug before going for marketing.

 To obtain FDA approval, the generic drug should

– contain same API as approved reference listed drug product

– contain same strength, concentration, dosage form and route of administration

– bioequivalent

– purity.

 The FDA’s approved drugs are listed in orange book – contains all approved products –both innovator
and generic. The orange book is available in internet at http://www.fda.gov/cder/ob/default.htm and is
updated monthly.

Fig: Generic drug (ANDA) review process.

HATCH-WAXMAN ACT
AND AMENDMENTS

HATCH-WAXMAN ACT is also known as “THE DRUG PRICE COMPETITION and PATENT TERM RESTORATION
ACT” enacted in 1984.

 OBJECTIVE :
 Reducing the cost of generic drug.

 Allowing early experimental use

 Motivating the manufacturer of generic drug

 Compensating the branded drugs manufacturer for the time that is lost from the patent term because of the regulatory
approval formality.

 Hatch Waxman Act created an abbreviated process which allow the manufacturer of generic drug to obtain FDA
approval. And because of this Act the drug companies demonstrate the safety and efficacy of their generic drugs.

 PROVISION OF ACT:
 Creation of section 505(j) which establishes ANDA approval process.

 Orange book

 Four types of patent certifications.

 ORANGE BOOK: It contains list of drugs approved by the FDA. For getting a drug approved by the FDA, an NDA
applicant must submit the following information:

1.Patent number and its expiry date
2.Type of products
3. Name of the patent owner.

 FOUR TYPES OF PATENT CERTIFICATIONS:
When an applicant submits ANDA to FDA, the applicant has to certify certain facts under section 505 (j)(2)(A)(vii) that:
 The patent information related to such patents has not been filed (para I)
 such patent are expired (para II )
 The patent will expire on a particular date (para III)
 such patent is invalid or not be infringed by the drug, for which approval is being sought (para-IV-patent challenge

 INCENTIVES AND PROTECTION:
 180 DAY MARKET EXCLUSIVITY: given to those applicant who first submit a complete ANDA.

such exclusivity can be shared by multiple applicants.
subject to fine.

 30-MONTH STAY OF FDA APPROVAL: such stay occurs when a NDA holder files case against ANDA for patent
violation within 45 days of receiving notice of the paragraph IV certification.

Runs from the time and date of notification and the period of stay can be lengthened or shortened by the court.

 PARA IV DEADLINES:
 NOTIFICATION LETTER: 20 DAYS- When ANDA get acceptance for filing, they must provide a notice to the NDA

patent owner within 20 days. The notice comprise of a complete fact stating the authenticity of the applicant regarding
the patent i.e. the patent is invalid or will not be violated.

 LAWSUIT 45 DAYS: After getting the notice, the NDA holder and patent owner have 45 days to initiate an action for
infringement. Within 45 days, if the matter is solved, ANDA is subjected to a 30 month stay of FDA approval .

 HATCH WAXMAN TRADE OFF:
BRAND GENERIC

 30 MONTH STAY OF FDA APPROVAL 180 DAY EXCLUSIVITY

 BENEFITS FOR THE BRANDED MANUFACTURERS:
1. orange book provides public notice of the patents

2. patents disputes are resolved prior to generic entries

3. 30 month stay of FDA approval offered

4. allow for several marketing exclusivities: a. 5 yrs. for NCE drugs

b. 3 yrs. for non-NCE drugs

c. 7 yrs. for orphan drugs

d. 6 months paediatrics.

 BENEFITS FOR THE GENERIC MANUFACTURERS:
1. 180 days market exclusivity offered to the first applicant to challenge orange book patent

2. it allows the generics to challenge the orange book patent without risk of damages

3. “SAFE HARBOR” rule provide the generics to conduct bioequivalence ans other testing relating to regulatory
approval without risk of patent infringement.

CONCLUSION

Regulatory affairs thus 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 rewarding, intellectually stimulating and highly
regarded profession within pharmaceutical companies

REFERENCES

• http://www.pharmaguideline.com
• http://pharmafranchisehelp.com
• http://www.fda.gov
• http://en.m.Wikipedia.org
• www.nalsarpro.org
• Generic Drug Product Development Solid Oral Dosage Forms; Leon

Shargel, Isadore Kanfer;10th edition;2005;1