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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

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.

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:

  1. Name of transferee
  2. Address of transferee
  3. Name of responsible official of transferee
  4. Effective date of transfer
  5. Signature of the transferring official
  6. 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.

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.

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.

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 4th 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 27th 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.



Name of the Guidelines

Year of Introduction


Standards for stability testing of new drugs

1980-1984 (Rev)


Guidance notes on applications for product licenses (HMSO)



Guidelines for the stability testing of drugs



Submitting documentation for the stability of Human Drugs and Biological



Requirements of the registration of drug for human use



Stability testing on active ingredients and finished products


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.



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



Zone I and II Countries

Zone III and IV Countries


Argentina, Bolivia, Chile, Canada, Mexico, Peru, Uruguay and USA

Barbados, Brazil, Costa Rica, Dominican Republic, Ecuador, Jamaica, Columia, Cuba, Panama, Paraguay, Puerto Rico, Venezuela.


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.


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 Condition


Relation for inclusion

-20° C

± 5° C


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

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.

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.

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.



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