Regulatory Affairs Professionals

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Healthcare Regulatory Affair Professional with their experience and strong motivation to excel in the Regulatory field has an ability to motivate & give support and strengthen to teams members, involved in process of product registration. Professional has taught a self-starter with the proven ability to prioritize and manage projects in a busy, fast-paced, multitasking environment, along with their experience in establishing relationship with the decision makers & coordinator. The Pharmaceutical industries are among the most highly regulated industries in the country. As India is growing very rapidly in pharmaceutical sector, there is a need of regulatory affairs professionals to cater the current needs of industries for the global competition. Regulatory affairs professionals are the link between pharmaceutical industries and worldwide regulatory agencies. They are required to be well versed in the laws, regulations, guidelines and guidance of the regulatory agencies. There is a growing need to incorporate the current requirements of pharmaceutical industries in the standard curriculum of pharmacy colleges to prepare the students with the latest developments to serve the industries. The present article discusses the regulatory education and its need, learning resources, courses available, syllabus contents and job opportunities in regulatory affairs.

INTRODUCTION:-
What is Regulatory Affairs:-
Regulatory Affair is an upcoming profession within the biomedical / health products sector, its heart is all about Collecting, Analyzing and Communicating the Risks and Benefits of health care products to regulatory agencies and public all over the world.

An organization their prime responsibilities involves preparation and presentation of registration documents to worldwide regulatory agencies. To keep a track on ever changing legislation in all countries where the companies is looking to market their product.

Regulatory Affair professional is broader than registration of products, they advise companies both strategically and technically at the highest level. Their role begins right from development of a product to making, marketing and post marketing.
They have a major contribution in company’s success both commercially and scientifically.

Roles of RA professional:-
1.                   To cater the current needs of industries for the global competition.
2.                   Are the link between pharmaceuticals industries and world wide agencies.
3.                   Well versed in laws/ regulations/ guidelines & guidance of the regulatory agencies/ document.

Need to become a RA professional:-
1.       Good background knowledge of the pharmaceuticals and medical environment
2.       A meticulous approach to work
3.       Attention to detail.
4.       Academic Qualification in Regulatory Affairs.

Areas Under Regulatory Affairs Department Supervision:-

SPECIFIC AIMS:-
*   To cater the current needs of industries for the global competition.
*   Link between pharmaceuticals industries and worldwide agencies.
*   Well versed in laws/ regulations/ guidelines & guidance of the regulatory agencies/ document.

RESEARCH PLAN:-
As the pharmaceutical industries throughout the world are moving ahead towards becoming more and more competitive, these are realizing that the real battle of survival lies in executing the work by understanding the guidelines related to various activities carried out to give an assurance that the process is under regulation. Pharmaceutical Industry, being one of the highly regulated industries, is in immense need of people than ever before who are capable of handling issues related to regulatory affairs in a comprehensive manner.

Act & Year of Establishment:

Act	Year
Opium Act	1878
Epidemic Disease Act	1897
Poison Act	1919
Dangerous Act	1930
Drug & Cosmetic Act/ Rules	1940/1948
Pharmacy Act	1948
Drug Control Act	1950
Pregnancy Act	1970
Narcotic & Psychotropic Act	1985
Drug Prices Control & Order	1995
Pregnancy Rules & Regulation	2003

List of Schedules and there Area of Function:

Schedule	Function
A	All types of forms for application (License / Renewal/ Certificate / Application).
B	Analysis Fee (Central drug laboratories & state drug laboratories).
C	Biological & special products.
C1	Other special products.
D	Application form for a registration certificate.
E	Poisonous substance list.
F1	Vaccines/Toxins/Antigens/Manuf. Of blood products from bulk finished product.
F2	Surgical dressing standard.
F3	Umbilical tapes standard.
FF	Ophthalmic preparation standard.
G	Caution: It is dangerous to take this preparation except under medical supervision.
H	Prescription Drugs (NRx/Rx-Left top corner of the label. Warning:To be sold by retail on prescription of RMP only.
I	Preparation of poison in certain cases.
J	Diseases and ailments which a drug may not purport to prevent or cure.
K	Class of drug.
L	Omitted.
M	Good manufacturing Practices.
M1	Homeopathic medicine.
M2	Cosmetic.
M3	Medical devices.
N	Minimum equipment for pharmacy running.
O	Standard for disinfectant fluid.
P	Life period of drug.
P1	Pack size of drug.
Q	List of dyes, pigments & colours used in cosmetics
R	Standard for condoms made of rubber latex for single use.
S	Standards for cosmetics.
T	GMP for Ayurvedic.
U	Manufacturing record/ R.M. Record/ Analytical record.
V	Standard for patent or proprietary medicines.
W	Omitted
X	XRx-Left top corner of the label (Warning: To be sold by retail on prescription of RMP only).
Y	Requirement and guidelines for permission to import of new drug.
Z	Omitted.

Laisening work:

Check-list for license Approval:
A)   Check-List for Grant of License:
a.   Covering Letter
b.   Challan of Rs.7500/- for each form
c.   Affidavit I & II (By proprietor, Managing Director)
d.   Proof of Ownership
e.   Rent or Lease Agreement (if Applicable)
f.   Consent letter of Technical Staff
g.   Affidavit For Brand name not Use
h.   Plan Of Premises
i.   DMHO Letter
j.   SSI Registration
k.   Pollution Certificate
l.   List of Machineries in QC and Production
m.   Validation Certificates for the above
n.   Area specification for each section
o.   Water Reports (Potable)

B)   Check-List for Loan License:
a.   Covering Letter
b.   Challan of Rs.7500/- for each form
c.   Affidavit I & II (By proprietor, Managing Director)
d.   Proof of Ownership
e.   Rent or Lease Agreement (if Applicable)
f.   Letter from the Loan licensee to Parent Organization
g.   Letter from the parent Organization
h.   Mfg. License Copy
i.   Consent letter of Technical Staff
j.   Affidavit For Brand name not Use
k.   Plan Of Premises
l.   List of Machineries in QC and Production
m.   Validation Certificates for the above

C)   Check-List for WHO GMP Certificate for Export Purpose:
a.   Covering Letter
b.   User Charges receipt for Rs.1000/- PER PRODUCT
c.   Site Master File as per WHO GMP Guidelines
d.   List of Products for which applied
e.   Copy of drug licenses with list of products approved
f.   (3 batches) Stability study data for the products applied
g.   Affidavit –IV (format enclosed)

D)   Check-List for Additional Certificate of Pharmaceutical Product CPP:
a.   Copy of WHO GMP Certificate Issued
b.   User Charges receipt for Rs.300/- PER PRODUCT
c.   List of products for which CPP required with country name

E)   Check-List for Issue of Free Sale Certificate:
a.   Covering letter with list of products for which free sale certificate required.
b.   List of products approved with copy of drugs licenses
c.   User Charges receipt for Rs.100/- per product
d.   Country for which certificate required
e.   In case of banned drugs NOC from DCGI

F)   Check-List for Issue of GMP Certificate:
a.   Covering letter
b.   User Charges receipt of Rs.300/-
c.   Self appraisal report as per Schedule M signed by the approval Technical Persons (Mfg & Anal) counter signed by area Drug Inspector
d.   Copy of Drug license

G)   Check-List for Issue of Market Certificate:
a.   Covering letter with list of products for which certificate required
b.   Copy of current drug licenses with list of first approval of product
c.   Production and marketing details of each product certified by Charted Account
d.   User charges receipt of Rs.300/-

H)   Check-List for Issue of Non-Convection Certificate:
a.   Covering letter
b.   User charges receipt of Rs.300/-
c.   Self declaration as per Affidavit – V, of the applicant stating that either he or any one of the partner or director is not convicted under Drugs and Cosmetic Act, 1940 during the specified period.

I)   Check-List for Issue of Production capacity Certificate:
a.   Covering letter
b.   Copy of current drug licenses with category of products approval
c.   Proposed production capacity and utilized capacity of the firm certified by the approved Technical Staff.
d.   User charges receipt of Rs.300/-

J)   Check-List for Issue of Validity Certificate:
a.   Covering letter
b.   User charges receipt of Rs.300/-
c.   Copy of acknowledgement in support of the submission of application for renewal

K)   Check-List for Approval of Technical Person Certificate:
a.   Covering letter
b.   Attested copies of Educational Qualifications from SSC onwards
c.   In case of female candidate; if married the details of place of working etc.., of the Spouse
d.   Experience certificate in chronological order
e.   Evidence of previous approval if any
f.   Evidence of leaving previous employment
g.   Appointment and acceptance letters
h.   Attested passport size photographs of the proposed technical staff, to Be affixed to the application.
i.   Consent of technical staff employed in the firm in the prescribed proforma.

Application Forms & Fee Structure:

A)Licenses for sale or distribution of Drugs/Licenses to sell drugs by way of retail:

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty -Six Months	Fees-Duplicate Lic
1.	Other Than Those Specified inC,C1& X	19	20	Rs.1500/-	21C	Rs.1500/+500 P.M	Rs.150.
2.	Specified in C&C1	19	21	Rs.1500/-	21C	Rs.1500/+500 P.M	Rs.150
3.	Specified in X	19C	20-F	Rs.1500/-	21C	Rs.1500/+500 P.M	Rs.150

B) Licenses to sell drugs by of whole sale:

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty -Six Months	Fees-Duplicate Lic
1.	Other Than Those Specified inC,C1& X	19	20-B	Rs.1500/-	21C	Rs.1500/+500 P.M	Rs.150.
2.	Specified in C&C1	19	21-B	Rs.1500/-	21C	Rs.1500/+500 P.M	Rs.150
3.	Specified in X	19C	20-G	Rs.1500/-	21C	Rs.1500/+500 P.M	Rs.150

C)Licenses to sell House-Hold remedy drugs (Restricted Circulation):

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty -Six Months	Fees-Duplicate Lic
1.	Other Than Those Specified inC,C1& X	19-A	20-A	Rs.1500/-	21C	Rs.1500/+500 P.M.	Rs.150/-
2.	Specified in C&C1	19-A	21-A	Rs.1500/-	21C	Rs.1500/+500 P.M.	Rs.150/-

D)Licenses to sell from motor vehicles-wholesale:

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty -Six Months	Fees-Duplicate Lic
1.	Other Than Those Specified inC,C1& X	19-AA	20BB	Rs.500/	21CC	Rs.500 +Rs.250	21-CC
2.	Specified in C&C1	19-AA	21BB	Rs.500/	21CC	Rs.500 +Rs.250	21-CC

E)Licenses to manufacture Drugs (Repacking-Limited 10 items):

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty -Six Months	Fees-Duplicate Lic
1.	Other Than Those Specified inC,C1& X	24B	25B	Rs.500+200	26B	Rs.500+250 p.m. +200	Rs.1000

F)Licenses to manufacture Drugs (Own manufacturing units-Limited 10 items):

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	Renewal Cert.	Fee Penalty -Six Months	Fees -Duplicate Lic
1.	Other Than Those Specified inC,C1& X	24	25	Rs.6000+1500	26	Rs.6000+1000 /P.M+1500/	Rs.1000

G)Licenses to manufacture Drugs (Loan License-Limited 10 items):

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty -Six Months	Fees-Duplicate Lic
1.	Other Than Those Specified inC,C1& X	24A	25A	Rs.6000+1500	26A	Rs.6000+1000/P.M+1500/	Rs.1000

H)Licenses to manufacture Drugs (Schedule X-Limited 10 items):

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty -Six Months	Fees-Duplicate Lic
1.	Other Than Those Specified inC,C1& X	24F	25F	Rs.6000+1500	26A	Rs.6000+@1000/P.M+1500/	Rs.1000

I)Licenses to manufacture Drugs (Schedule C&C1-Limited 10 items):

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty-Six Months	Fees-Duplicate Lic	Addl. item for each category fee
1.	Own Unit	27	28	Rs.6000+1500	26	Rs.6000+@1000 P.M.+1500	Rs.1000	Rs.300/ item
2.	Loan Lic.	27A	28A	Rs.6000+1500	26A	Rs.6000+@1000 per Month+1500	Rs.1000	Rs.300/ item

J)Licenses to manufacture Drugs (Schedule C, C1&X-Limited 10 items):

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty-Six Months	Fees-Duplicate Lic	Addl. item for each category fee
1.	Own Unit	27B	28B	Rs.6000+1500	26F	Rs.6000+@1000 P.M.+1500	Rs.1000	Rs.300/item

K)Licenses to manufacture Drugs (Schedule C-Limited 10 items):

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty-Six Months	Fees-Duplicate Lic	Addl. item for each category fee
1.	Own UnitLVPs, Sera, Vaccines &r- DNA	27C	28C	Rs.6000+1500	26G	Rs.6000+@1000 P.M.+1500	Rs.1000	Rs.300/item

L)Licenses to manufacture Drugs for whole human Blood Components

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty-Six Months	Fees-Duplicate Lic	Addl. item for each category fee
1.	Blood&BloodComponents	27D	28D	Rs.6000+1500	26H	Rs.6000+@1000 P.M.+1500	Rs.1000	Rs.300/item

M) Licenses to manufacture Drugs for Examination, Test or Analysis

S. No.	Category	Appl. Form	Lic. Form	Fees Grant or Renewal	Remarks
1.	All Drugs Bulk orFormulations	30.	29.	Rs.250	Not For Sale

N) Licenses to manufacture Cosmetics:

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty-Six Months	Fees-Duplicate Lic	Addl. item for each category fee
1.	Own Unit	31	32	Rs.2500+1000	33	Rs.2500+400p.m+1000	Rs.250	Rs.100 perItem. Max.3000/-
2.	Loan Lic.	31A	32A	Rs. 2500 +1000	33A	Rs.2500+400p.m+1000	Rs.250	Rs.100 perItem. Max.3000/-

O) Approval of Testing Labs.

S. No.	Category	Appl.Form	Lic. Form	Fees Grant or Renewal	RenewalCert.	Fee Penalty-Six Months	Fees-Duplicate Lic	Addl. item for each category fee
1.	SchC,C1& x	36	37	Rs.6000	38	Rs.6000+p.m1000	—	Rs.1000per category
2.	Other drugs	36	37	Rs.6000	38	Rs.6000+p.m1000	—	Rs.1000per category

P) Import Licenses

S. No.	Purpose of Import	Appl. Form	Lic. Form	Lic. Fee	Fees-Duplicate Lic.	Remarks
1.	Other Than Those Specified in schedule X	8+Forms 9 & 41	10	Rs.1000+100/product	Rs.250.	Valid – 3 yrs.Apply-3monthsIn advance
2.	Those Specified inschedule X	8A+Forms 9&41	10A	Rs.1000+100/product	Rs.250.	Valid – 3 yrs.Apply-3monthsIn advance
3.	For Examination,Test or Analysis.	12	11	Rs.100+50/product	Rs.250.	Valid – 3 yrs.Apply-3monthsIn advance
4.	Govt. Hospital / Autonomous Medical institute for treatment of a patient.	12A	11A	Rs.100+50/product	Rs.250.	Valid – 3 yrs.Apply-3monthsIn advance
5.	Small quantities of drugs for personal use. (not more than 100 doses.)	12A	12 B	Rs.100 +50/product	Rs.250.	Valid – 3yrs. Apply-3monthsIn advance
6.	Small quantities of New drugs by Govt. Hospital / Autonomous Medical institute for treatment of a patient.	12AA	11 A	Rs.100 +50 Per product	Rs.250.	Valid – 3 yrs.Apply-3monthsIn advance
7.	Application for grant of permission to import or manufacture a new drug or to under –take clinical trials.	44	45Finished formulation	Rs. 50,000 +15,000Per subsequent product	RemarksRule 122-A.No new drug shall be imported, except under, and in accordance –
8.	——– DO ——–	44	45ABulk drug	Rs.100 +50/product	With the permission granted by theDCG (I)

ICH Guidelines and Q10 Rules:

ICH Guideline Indication:

ICH	Function
Q1	Stabilities
Q1A(R2)	Stability testing of New drug substances and products
Q1B	Stability testing of Photo stability testing of New drug substances and products.
Q1C	Stability Testing For New Dosage Forms
Q1D	Bracketing and matrixing designs for Stability testing of new drug substances and products
Q1E	Evaluation For Stability Data
Q1F	Stability Data Package For Registration Applications In Climatic Zones III And IV
Q2	Analytical validation
Q2(R1)	Validation Of Analytical Procedures Text & Methodology
Q3	Impurities
Q3A(R2)	Impurities In New Drug Substances
Q3B(R2)	Impurities In New Drug Products
Q3C(R3)	PDE for Tetrahydrofuran & N-Methylpyrrolidine
Q3C(R4)	Impurities: Guideline For Residual Solvents
Q4	Pharmacopeias
Q5	Quality of Biotechnological Products
Q5A	Viral Safety Evaluation Of Biotechnology Products Derived From Cell Lines Of Human Or Animal Origin
Q5B	Analysis of the expression construct In cells used for production of R-DNA derived protein products
Q5C	Quality of biotechnological products: Stability testing of biotechnological/biological Products
Q5D	Derivation and characterisation of cell substrates Used for production of Biotechnological/biological products
Q5E	Comparability Of Biotechnological/Biological Products Subject To Changes In Their Manufacturing Process.
Q6	Specifications
Q6A	Specifications: test procedures and acceptance criteria For new drug substances and new drug products:Chemical substances.
Q6B	Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products.
Q7	Good Manufacturing Practice
Q7A	Good manufacturing practice guide for Active pharmaceutical ingredients.
Q8	Pharmaceutical Development
Q8(R2)	Pharmaceutical Development
Q9	Quality Risk Management
Q10	Pharmaceutical Quality System

Q¹⁰RulesDRA Documentation

Q1_Stabilities

Q2_{Analytical Validation}

Q3_Impurities

Q4_{Pharmacopoeias}

Q5_{Quality of Biotechnological Products}

Q6_{Specifications}

Q7_{Good Manufacturing Practices}

Q8_{Pharmaceutical Development}

Q9_{Qualty Risk Management}

Q10_{Pharmaceutical Quality Syste}

Worldwide Regulatory Authorities:

S. NO.	COUNTRY	AGENCIES
01	Australia	Therapeutic Goods Administration.
02	Azerbaijan Republic	Ministry of Health.
03	Brunei	Ministry of Health.
04	China	State Food and Drug Administration.
05	Fiji	Ministry of Health
06	Hong Kong	Department of Health
07	India	Central Drugs Standard Control Organization
08	Indonesia	Ministry of Health
09	Japan	Ministry of Health and Welfare
10	Korea	Food and Drug Administration
11	Malaysia	Ministry of Health
12	Mongolia	Ministry of Health and Social Welfare
13	New Zealand	Medicines and Medical Devices Safety Authority
14	Papua New Guinea	Department of Health
15	Philippines	Bureau of Food & Drug
16	Singapore	Ministry of Health
17	Sri Lanka	Ministry of Health
18	Taiwan	Department of Health
19	Thailand	Ministry of Public Health, Food and Drug Administration
20	Algeria	Ministry of Health and Population
21	Bahrain	Ministry of Health
22	Botswana	Ministry of Health
23	Kenya	Ministry of Health
24	Mauritius	Ministry of Health & Quality of Life
25	Morocco	Ministry of Public Health
26	Namibia	Ministry Of Health And Social Services
27	Nigeria	National Agency for Food and Drug Administration and Control
28	South Africa	Department of Health
29	Swaziland	Ministry of Health and Social Welfare
30	Tunisia	Ministry of Public Health
31	Zambia	Ministry of Public Health
32	Zimbabwe	Ministry of Health
33	Argentina	National Administration of Drugs, Foods and Medical Technology
34	Bahamas	Department of Environmental Health Services
35	Belize	Ministry of Health

S. NO.	COUNTRY	AGENCIES
36	Bolivia	Ministry of Health and Social Welfare
37	Brazil	Agency Nation ale Devigilance Sanitaria.
38	Canada	Health Protection Branch
39	Chile	Institute of Public Health
40	Colombia	Ministry of Health
41	Costa Rica	Ministry of Health
42	El Salvador	Ministry of Public Health and Social Assistance
43	Guyana	Ministry of Health
44	Honduras	Ministry of Health
45	Jamaica	Ministry of Health
46	Mexico	Ministry of Health
47	Netherlands Antilles	Department of Public Health and Environmental Protection
48	Nicaragua	Ministry of Health
49	Panama	Ministry of Health
50	Paraguay	Ministry of Public Health and Social Welfare
51	Peru	General Directorate of Pharmaceuticals, Devices and Drugs
52	Trinidad & Tobago	Bureau of Standards
53	United States	USFDA
54	Uruguay	Ministry of Public Health
55	Venezuela	Ministry of Health and Social Development
56	European Medicines Agency	European Directorate for the Quality of Medicines
57	Austria	Ministry of Labor, Health and Social Affairs
58	Belgium	Pharmaceutical Inspectorate
59	Bulgaria	National Drug Institute
60	Croatia	Ministry of Health
61	Republic of Cyprus	Ministry of Health
62	Czech Republic	State Institute for Drug Control
63	Denmark	Danish Medicines Agency,Veterinary and Food Administration
64	Estonia	State Agency of Medicines
65	Finland	National Agency for Medicines,
66	France	Ministry of Health
67	Georgia	Ministry of Health Care
68	Germany	Federal Institute for Drugs and Medical Devices
69	Greece	Ministry of Health and Welfare
70	Hungary	National Institute of Pharmacy

S. NO.	COUNTRY	AGENCIES
71	Iceland	Ministry of Health and Social Security
72	Ireland	Department of Health and Children, Medicines Board
73	Italy	Ministry of Health, National Institute of Health
74	Latvia	State Agency of Medicines
75	Lithuania	State Medicines Control Agency
76	Luxembourg	Ministry of Health
77	Lebanon	Ministry of Public Health
78	Malta	Medicines Regulatory Unit
79	Netherlands	Medicines Evaluation Board
80	Norway	Norwegian Board of Health
81	Poland	Ministry of Health and Social Security, Drug Institute
82	Romania	National Medicines Agency
83	Portugal	National Institute of Pharmacy and Medicines
84	San Marino	Ministry of Health and Social Security
85	Slovak Republic	State Institute for Drug Control
86	Slovenia	Agency for Medicinal Products
87	Spain	Spanish Drug Agency
88	Sweden	Medical Products Agency
89	Switzerland	Federal Office of Public Health, Federal Veterinary Office
90	Turkey	General Directorate of Medicines and Pharmaceutics
91	Ukraine	Ministry of Health
92	UK	Medicines and Healthcare Products Regulatory Agency
93	Bahrain	Ministry of Health
94	Egypt	Ministry of Health and Population
95	Israel	Ministry of Health
96	Jordan	Ministry of Health

Guidelines for Drug Master File:

Drug Master File:
I. INTRODUCTION
II. DEFINITIONS
III. TYPES OF DRUG MASTER FILES
IV. SUBMISSIONS TO DRUG MASTER FILES

A. Transmittal Letters

Original Submissions
Amendments

B. Administrative Information

Original Submissions
Amendments

C. Drug Master File Contents

1. Types of Drug Master Files
a.Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
b.Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product
c.Type III: Packaging Material
d.Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
e.Type V: FDA Accepted Reference Information

2. General Information and Suggestions
A. Environmental Assessment
B. Stability
C. Format, Assembly, and Delivery

V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE
A. Letter of Authorization to FDA
B. Copy to Applicant, Sponsor, or Other Holder

VI. PROCESSING AND REVIEWING POLICIES
A. Policies Related to Processing Drug Master Files
B. Drug Master File Review

VII. HOLDER OBLIGATIONS
A. Notice Required for Changes to a Drug Master File
B. Listing of Persons Authorized To Refer to a Drug Master File
C. Annual Update
D. Appointment of an Agent
E. Transfer of Ownership

IX. CLOSURE OF A DRUG MASTER FILE

I. 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. A DMF is submitted solely at the discretion of the holder. 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. It is not approved or disapproved. Technical contents of a DMF are reviewed only in connection with the review of an IND, NDA, ANDA, or an Export Application.

This guideline does not impose mandatory requirements (21 CFR 10.90(b)). It does, however, offer guidance on acceptable approaches to meeting regulatory requirements. Different approaches may be followed, but the applicant is encouraged to discuss significant variations in advance with FDA reviewers to preclude spending time and effort in preparing a submission that FDA may later determine to be unacceptable.

Drug Master Files are provided for in 21 CFR 314.420. 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.

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. When an applicant references its own material, the applicant should reference the information contained in its own IND, NDA, or ANDA directly rather than establishing a new DMF.

II. DEFINITIONS
For the purposes of this guideline, the following definitions apply:
II.1.Agency means the Food and Drug Administration.

II.2Agent or representative means any person who is appointed by a DMF holder to serve as the contact for the holder.

II.3.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 (21 CFR 314.3 (b)).

II.4.Drug product means a finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3 (b)).

II.5.Drug substance means an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient (21 CFR 314.3 (b)).

II.6.Export application means an application submitted under section 802 of the Federal Food, Drug, and Cosmetic Act to export a drug that is not approved for marketing in the United States.

II.7.Holder means a person who owns a DMF.

II.8.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 person’s submission.

II.9.Person includes individual, partnership, corporation, and association. (Section 201(e) of the Federal Food, Drug, and Cosmetic Act.)

II.10.Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization (21 CFR 312.3 (b)).

III. TYPES OF DRUG MASTER FILES
There are five types of DMF’s:
Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel
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

Each DMF should contain only one type of information and all supporting data. See Section IV.C of the guideline for more detailed descriptions of the kind of information desired in each type. Supporting information and data in a DMF can be cross referenced to any other DMF (see Part V).

IV. SUBMISSIONS TO DRUG MASTER FILES
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.

IV. A. Transmittal Letters

The following should be included:
IV. A.1. Original Submissions
a. Identification of submission: Original, the type of DMF as classified in Section III, 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.

IV. A. 2. Amendments
a. Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the amendment.
b. A description of the purpose of submission, e.g., update, revised formula, or revised process.
c. Signature of the holder or the authorized representative.
d. Typewritten name and title of the signer.

IV. B. Administrative Information
Administrative information should include the following:

IV. 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.

IV. 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 Application relies on the subject of the amendment for support.
f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on the subject of the amendment for support, if known.
g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are affected, if known.

IV. C. Drug Master File Contents

IV. C.1. Types of Drug Master Files

IV. C.1.a. Type I: 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. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique.

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.

IV. C.1.b.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.

IV. C.1.b.(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.

IV. C.1.b.(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 of and Controls for Drug Products Guideline for Submitting Samples and Analytical Data for Methods Validation

IV. C.1.c.Type III: 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.

IV. C.1.d.Type IV 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 (21 CFR Parts 70 through 82), direct food additives (21 CFR Parts 170 through 173), indirect food additives (21 CFR Parts 174 through 178), and food substances (21 CFR Parts 181 through 186) 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.

IV. C.1.e.Type V: 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 (for address, see D.5.a. of this section). FDA will then contact the holder to discuss the proposed submission.

IV. C.2. General Information and Suggestions

IV. 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. If a completed environmental assessment is needed, see 21 CFR Part 25.

IV. 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.“

IV. D. Format, Assembly, and Delivery

IV. 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.

IV. 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.

IV. 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.

IV.D.4.
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. See the page measurements shown in the following figure:

IV.D.5. Delivery to FDA

IV.D.5.a.

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

IV.D.5.b. Delivery charges to the above address must be prepaid.

V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE

V. 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. If the holder cross references its own DMF, the holder should supply in a letter of authorization the information designated by items 3, 5, 6, 7, and 8 of this section. The holder does not need to send a transmittal letter with its letter of authorization.

The letter of authorization should include the following:

The date.
Name of DMF holder.
DMF number.
Name of person(s) authorized to incorporate information in the DMF by reference.
Specific product(s) covered by the DMF.
Submission date(s) of 5, above.
Section numbers and/or page numbers to be referenced.
Statement of commitment that the DMF is current and that the DMF holder will comply with the statements made in it.
Signature of authorizing official.
Typed name and title of official authorizing reference to the DMF.

V. 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.

VI. PROCESSING AND REVIEWING POLICIES

VI. A. Policies Related to Processing Drug Master Files

VI. A.1.
Public availability of the information and data in a DMF is determined under 21 CFR Part 20, 21 CFR 314.420(e), and 21 CFR 314.430.

VI. A.2.
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.
If the submission is administratively incomplete or inadequate, it will be returned to the submitter with a letter of explanation from the Drug Master File Staff, and it will not be assigned a DMF number.

VI. B. 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. When the holder submits the requested information to the DMF in response to the agency’s deficiency letter, the holder should also send a copy of the accompanying transmittal letter to the affected persons relying on the DMF and to the FDA reviewing division that identified the deficiencies. The transmittal letter will provide notice that the deficiencies have been addressed.

VII. HOLDER OBLIGATIONS
Any change or addition, including a change in authorization related to specific customers, should be submitted in duplicate and adequately cross referenced to previous submission(s). The reference should include the date(s), volume(s), section(s), and/or page number(s) affected.

VII. A. Notice Required for Changes to a Drug Master File
A holder must notify each affected applicant or sponsor who has referenced its DMF of any pertinent change in the DMF (21 CFR 314. 420(c)). Notice should be provided well before making the change in order to permit the sponsor/applicant to supplement or amend any affected application(s) as needed.

VII. B. Listing of Persons Authorized To Refer to a Drug Master File

VII. B.1.
A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference [21 CFR 314.420(d)]. The holder should update the list in the annual update. The updated list should contain the holder’s name, DMF number, and the date of the update. The update should identify by name (or code) the information that each person is authorized to incorporate and give the location of that information by date, volume, and page number.

VII. B.2.
Any person whose authorization has been withdrawn during the previous year should be identified under a suitable caption.

VII. B.3.
If the list is unchanged on the anniversary date, the DMF holder should also submit a statement that the list is current.

VII. C. Annual Update
The holder should provide an annual report on the anniversary date of the original submission. This report should contain the required list as described in B.1., and should also identify all changes and additional information incorporated into the DMF since the previous annual report on the subject matter of the DMF. If the subject matter of the DMF is unchanged, the DMF holder should provide a statement that the subject matter of the DMF is current.

Failure to update or to assure FDA annually that previously submitted material and lists in the DMF remain current can cause delays in FDA review of a pending IND, NDA, ANDA, Export Application, or any amendment or supplement to such application; and FDA can initiate procedures for closure of the DMF (see Section IX).

VII. D. Appointment of an Agent

When an agent is appointed, the holder should submit a signed letter of appointment to the DMF giving the agent’s name, address, and scope of responsibility (administrative and/or scientific). Domestic DMF holders do not need to appoint an agent or representative, although foreign DMF holders are encouraged to engage a U.S. agent.

VII. E. Transfer of Ownership
To transfer ownership of a DMF to another party, the holder should so notify FDA and authorized persons in writing. The letter should include the following:

Name of transferee
Address of transferee
Name of responsible official of transferee
Effective date of transfer
Signature of the transferring official
Typewritten name and title of the transferring official.

The new holder should submit a letter of acceptance of the transfer and an update of the information contained in the DMF, where appropriate. Any change relating to the new ownership (e.g., plant location and methods) should be included.

VIII. MAJOR REORGANIZATIONOF A DRUG MASTER FILE
A holder who plans a major reorganization of a DMF is encouraged to submit a detailed plan of the proposed changes and request its review by the Drug Master File Staff. The staff should be given sufficient time to comment and provide suggestions before a major reorganization is undertaken.

IX. CLOSURE OF A DRUG MASTER FILE
A holder who wishes to close a DMF should submit a request to the Drug Master File Staff stating the reason for the closure. See Section IV.D.5.a for the address.

The request should include a statement that the holder’s obligations as detailed in Section VII have been fulfilled.

The Agency may close a DMF that does not contain an annual update of persons authorized to incorporate information in the DMF by reference and a list of changes made since the previous annual report. The holder will be notified of FDA’s intent to close the DMF.

Many of the guidelines referred to in the text and a current list of available guidelines may be obtained from the following.

Basic Details of Stability Studies Concept:

Stability Studies:
In our universe, no example of stability can be found; everything changes, every thing is transfer, everything evolves. We are thus living in permanent state of instability.

When we deal with the drugs and their stability, we must investigate the origin of their instability and its effects on their toxicological and therapeutic activity.

Kinetics of transformations of various molecules physical, chemical or even technological transformations.

When a drug is being manufactured, the various components have a certain internal energy and certain reactivity. It is thus possible to be define an entropy for each component, this entropy being known only to within a constant factor.

This system is not isolated; it is subjected to various possible actions from the environment.
* Physical: Temperature, pressure, humidity, radiation.
* Chemical: Action of oxygen, action of water, acids, bases

Under these various energy-carrying influences, drugs will alter more or less rapidly, which may modify their toxicology-pharmacological activity.

STABILITY STUDIES
Helps in generate information, which permits well-considered proposals to be made for the shelf life of drug substance and products, and recommended storage conditions.

Stability data are required to be submitted as a part of the dossier submitted to the regulatory agencies for licensing approval. Hence it is an unavoidable activity in the drug industry.

The application of the science of degradation kinetics of active ingredients in the medicines was initiated in 1950’s. From these studies it was realized that most drug substances were inherently unstable molecules.

Around this period, the manufacturers started developing formulations in wide range of packaging materials and started selling their products to an increasing number of countries. While doing so, it was felt that there was need for conducting standardized stability studies before marketing to assure that optimally stable molecules were manufactured, distributed and supplied to the patient.

To assist in execution of stability testing, the authorities in some countries obliged the manufacturers by drawing up stability testing guidelines. These guidelines were mainly issued in 1980’s.

The guidelines, while addressing basic issues, spelt out the stability data requirements for application dossier and broadly outline the steps for execution.

However, these individual country guidelines varied in concepts, requirements and point of emphasis which subsequently proved to be a bottleneck in the drive by various manufacturers to market and register their products in more than one country- a direct fallout of globalization.

Towards the end of 1980’s the process of the harmonization of regulatory requirements begun through bilateral meetings between the officials and experts from US, Japan and EC. This culminated in holding of a symposium under the head – “Stability testing, new trends and requirements” June 5-7darmstadt, Germany. A preliminary draft was prepared at this meeting, which was discussed on 4^th November 1993 at Brussels by an Expert working group and reported to Quality workshop of the first international conference on Harmonization held at the same place from 5-7 November 1991. Subsequently the guidelines “Stability Testing of New Drug Substances and Products” finalized on 27^th October 1993 in Orlando.

WHO in the meantime, being an observer to the ICH, felt that the ICH parent stability guideline was unfit for universal application. The reasons were
1. The guideline did not address the extreme climatic conditions found in many countries.
2. It only covered new drug substances and products and not the already established products that were in circulation in the WHO umbrella countries.

They come up with the separate “Guideline for Stability Testing of Pharmaceutical Products containing well Established Drug Substances in Conventional Dosage Forms”.

USFDA on its part has published the guidance document entitled “Expiration Dating and Stability Testing of Solid Oral Dosage Form Drugs Containing Iron” in June 1997. in 1998, it has issued a draft version of the guidance for industry under the title “Stability Testing of Drug Substances and Drug Products”. The guidance discusses stability for NDA, ANDA and IND.

SOME OF THE INDIVIDUAL COUNTRY GUIDELINES ISSUED IN 1980’s

COUNTRY	Name of the Guidelines	Year of Introduction
Japan	Standards for stability testing of new drugs	1980-1984 (Rev)
UK	Guidance notes on applications for product licenses (HMSO)	1984
Zimbabwe	Guidelines for the stability testing of drugs	1985
USFDA	Submitting documentation for the stability of Human Drugs and Biological	1987
Ethiopia	Requirements of the registration of drug for human use	1986
EC	Stability testing on active ingredients and finished products	1988

Test Conditions:
ICH guidelines take the accelerated test condition to be 15° C above the long term testing temperature. GMP WHO the difference in accelerated and long term storage is only 10° C.

GLOBAL CLIMATE ZONES

ZONE	ZONE I Moderate	ZONEII Mediterranean	Zone III Hot/Dry	Zone IV Very hot/Moist
Kinetic average temperature	21° C	25° C	30° C	30° C
Yearly average relative humidity	45% RH	60% RH	35% RH	70% RH

DISTRIBUTION OF WORLD NATIONS INTO DIFFERENT ZONES

Region	Zone I and II Countries	Zone III and IV Countries
America	Argentina, Bolivia, Chile, Canada, Mexico, Peru, Uruguay and USA	Barbados, Brazil, Costa Rica, Dominican Republic, Ecuador, Jamaica, Columia, Cuba, Panama, Paraguay, Puerto Rico, Venezuela.
Asia	Afghanistan, Armenia, Azerbaijan, China, Georgia, Iran, Israel, Japan, Kazakhstan, Korea, Lebanon, Nepal, Syria, Turkey, Uzbekistan	Hong Kong, India, Bangladesh, Iraq, Jordan, Qatar, Kuwait, Malaysia, Maldives, Myanmar, Saudi Arabia, Singapore, Srilanka, Taiwan, Thailand, UAE, Vietnam, and Yemen.
Africa	Egypt, Algeria, Tunisia, Libya, Morocco, Namibia, Rwanda, South Africa, Zambia, Zimbabwe.	Angola, Ghana, Cameroon, Kenya, Liberia, Niger, Senegal, Central African Republic.
Australian / Oceanic	Australia, New Zealand	Fiji, Society Islands, Marshould Islands, Samoa, Tonga

Recommended Stability Storage conditions for various Products in Zone I and II
Stability requirements for marketing applications / Regulatory submission;

Data from formal stability studies are to be provided on at least three batched of the substance. The batches manufactured to a minimum of scale should be by the same synthetic route and use a method of manufacture and procedure and packing that simulates the final process to be used on a production scale.

Batches will be needed to be selected to comply with current FDA site specific stability requirements. To eliminate the need to provide additional data on the first three production scale batches manufactured at the commercial site, primary stability batches would need to be made at production scale at the proposed site of commercial manufacture.

STORAGE CONDITIONS

Storage Condition	Tolerance	Relation for inclusion
-20° C	± 5° C	Freezer
5° C/Ambient RH	± 3° C	Refrigerated Storage condition
25° C/60% RH	± 2° C/ ± 5% RH	(ICH) Long Term Storage Condition
30° C/60% RH	± 2° C/ ± 5% RH	Long Term/ Intermediate Condition
40° C/75% RH	± 2° C/ ± 5% RH	Accelerated Testing Condition

MANAGING STUDIES
Incubator Management:
Environmental chambers used for the storage of stability samples should be validated for the purpose. A monitoring system should be in place which can provide a record of the temperature and humidity measurement with in the chamber.

Sampling:
Samples to be supplied for analysis at each scheduled test point on a study should be withdrawn from storage randomly. The requisite number of finished product primary containers for testing at each time point should be drawn from storage. These are calculated based on the testing to be performed and the details of samples drawn should be recorded in study records. Where additional samples are required the reason for this should be documented.

Pre-test Storage:
This refers to the condition at which samples are stored after removal from the incubator and prior to commencement of testing. It is recommended that whilst samples await test the standard pre-test storage condition should be controlled room temperature. There is no requirement to store samples protected from light unless the product is known to require light protection. Products that require a lower (or frozen) pre-test storage, should be assessed and the pre-test storage documented on a case by case basis.

Transportation:
Samples requiring transport prior or testing should wherever possible be maintained at their designated pre-test storage condition during transport. Where this is not feasible, documented evidence of the range of conditions likely to be experienced by the samples in transit should exist. Additionally, maximum allowable transit times and an acceptable range of conditions should be established before samples are transported. When transported samples exceed any of the established transport parameters their continued validity as representative logging device should be included with the sample in transit.

For samples which are normally stored frozen, transit temperatures should ensure that there is no change of state in the samples. To establish whether or not thawed in transit a visual inspection is required immediately after transport of the samples, and if they have thawed, their continued validity as representative samples needs to be documented.

Testing:

Atypical and Out of Specification Results:
All atypical results and all OOS results on samples stored within recommended storage conditions and shelf life must be investigated, evaluated and clearly documented, according to procedure. If an OOS result, obtained on samples stored under accelerated conditions or beyond shelf life, is expected (e.g. a low assay follows the trend established for other samples and conditions) no investigation is required, but the documentation must include a statement to acknowledge that the result has been assessed, is valid and acceptance.

Reporting Stability Results:
The results obtained from stability testing should be assessed and reported, including any decisions made. This should include an assessment of any trends or outlines observed, as well as a comparison against the end of life specification.

Reference should be made to the predicted effects of the product change(s) on the product stability, and to whether or not these effects have been seen in practice.

Notification of Stability Failures:
Failure in studies running in support of Clinical Trials should be notified within 24 hrs to the person responsible for the CTS The failure of post approval stability studies to meet specification either at end of life, or during storage, should be notified to FDA. For studies run in support of NDAs, the FDA should be notified using the Field Alert mechanism. In European markets the relevant licensing authority should be advised of the failure. The QA and manufacturing area should be contacted also to notify them of the failure within 24 hrs and to participate in the investigation and corrective action. All details should be documented in the relevant project of study file.

Testing scope for DRUG SUBSTANCES
• Physical-chemical properties
– Appearance
– Water content
– pH
– Color / clarity of solution
– Thermo analytical stability
» Melting point
» Polymorphism

• Chemical properties
– Assay
– Degradation products

• Microbial properties
– (Microbial purity)

Testing scope for TABLETS
• Physical-chemical properties
– Appearance
– Mean mass
– Water content
– Hardness
– Disintegration
– Dissolution

• Chemical properties
– Assay
– Degradation products