1. UNIT 5: Documetation
Documentation is a process that involves the systematic interaction of people, events and documents to
create the records of the organization / corporation.
It is a collection of document (a piece of written or printed matter) relating to a piece (or) events.
Documentation is an important aspect in pharmaceutical industry irrespective of the fact the manufacturing
plant is involved in production of dosage form (or) active ingredient.
Manufacturer of a drug, ultimately needs quality of his product (or) finished goods. Therefore a good
documentation is essential part of a quality control system, hence every manufacturer of drugs should have
good documentation.
Its aim is to define the specifications for all materials, method of manufacture and control, to ensure that all
personnel concerned with manufacture know the information necessary to decide whether or not to release
a batch or a drug for sale and-to provide an
audit trail that shall permit investigation of the history of any suspected defective batch.
DOCUMENT:
As discrete packages of recorded information are the tools of quality assurance.
Used to establish standard specification and processes that assures compliance with standard specifications
and processes.
Quality cannot be assured in a regulated industry without good documents and good documentation
practices.
A document system is an interdependent, interrelated set of documents, each with a defined purpose and a
consistent format.
OBJECTIVES OF DOCUMENTATION:
· To define all materials specifications.
· To define manufacture and control methods.
· To ensure all personal of manufacture and control department know what to do, and when to
do.
· To ensure that personal authorized to release a batch for sale (or) reject, it have all
information to take decision.
· To provide information during investigation, if a batch is suspected to have
defect(s).
ESSENTIAL CHARACTERISTICS:
To design an effective & efficient documentation process first identify the important characteristics of
processing event.
· The document directing the manufacturing event fulfills current regulatory commitments to
the agency; it is appropriately written, reviewed and approved.
· The directive document is appropriate for the task to be performed.
· The data is authentic; the individual responsible for performing the work has entered the
data on an appropriate data collection document.
· The data is accurate.
· The data is complete. There is no missing information, and there is no work as yet
uncompleted that will impact the occurrence of the data presented.
· The data is legible, consistently recorded and trustworthy.
· The data collected fulfills expectations (specifications).
· The data is accessible to those who need to review it, audit it or use it to perform trending
analysis.
· The original data and the original documents (manufacturing record) is retrievable for
review or audit.
2. · The original manufacturing record is secure.
Proper control of documentation also requires that responsibility for each processing step to be
assigned.
“All documentation should be legible, clean, readily identifiable, retrievable and maintained in
facilities that provide a suitable environment to minimize deterioration or damage and to prevent
loss”.
WHY DOCUMENTATION:
· There is a saying in the pharmaceutical industry: 'if it hasn't been documented, then it hasn't
happened!'
· Good documentation practice constitutes an essential part of the QA system.
· Documentation system must be proactive vehicle of communication.
“YOUR DOCUMENTATION IS AN ADVERTISEMENT FOR YOUR WORKˮ.
WHERE DOCUMENTATION ?
· Documentation during Project Design.
· Documentation during Construction Phase.
· Documentation during Commissioning and start-up.
· Documentation during Qualification and Validations.
· Documentation during Commercial Production.
· Documentation during Testing and Release.
· Documentation for Regulatory submissions.
TYPES OF DOCUMENTS:
There are three types of Documents:
· Commitment documents.
· Directive documents.
· Record documents.
· Commitment Documents : Relationship between industry and the regulatory authorities.
EX: New Drug Applications (NDAs), Drug Master Files (DMFs) etc.
· Directive Documents : Relationship between the Management and Employees.
EX: Specifications, STPs, Standard Operating Procedures (SOPs), Medicinal Product
Records (MPRs) etc.
· Record Documents : Relationship between the Employees and the Work they perform.
EX: Protocols, Batch Production Records (BPRs), Log Books, Calibration Records etc.
· Commitment Documents:
· These presents corporate goals, expectations and standard of practice.
· It describes what to do.
· Consensus of purpose, direction and authorization for projects.
· It organize the work in a manner that assures efficient and effective work flow.
· Commitments documents can also be written to establish internal commitments.
· These documents such as master plans; organize and prioritize the work in a manner that
supports good business practice as well as regulatory compliance.
· Written to lead and guide the work and workers.
· To be used as active documents that are consulted and followed routinely.
3. · Content must be consistent and rigorous in order to lead and guide the work and the
workers.
· Must describe the work as it will be done.
· Deviations from regulatory submissions can have signification impact on product quality.
· Any deviation must be documented and managed.
· New Drug Applications (NDAs):
The New Drug Application (NDA) is the vehicle in the United States through which drug
sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. The goals
of the NDA are to provide enough information to permit FDA reviewers to establish the following:
· Is the drug safe and effective in its proposed use(s) when used as directed, and do the
benefits of the drug outweigh the risks?
· Is the drug’s proposed labeling (package insert) appropriate, and what should it contain?
· Are the methods used in manufacturing (Good Manufacturing Practice, GMP) the drug and
the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength,
quality, and purity?
· Drug Master Files (DMFs):
Drug Master File or DMF is a document prepared by a pharmaceutical manufacturer and submitted solely
at its discretion to the appropriate regulatory authority in the intended drug market. There is no regulatory
requirement to file a DMF. However, the document provides the regulatory authority with confidential,
detailed information about facilities, processes, or articles used in the manufacturing, processing,
packaging, and storing of one or more human drugs.
Drug Master File (DMF) is a document containing complete information on an Active Pharmaceutical
Ingredient (API) or finished drug dosage form. It is known as European Drug Master File (EDMF) or
Active Substance Master File (ASMF) and US-Drug Master file (US-DMF) in Europe and United States
respectively.
The DMF contains factual and complete information on a drug product's chemistry, manufacture, stability,
purity, impurity profile, packaging, and the cGMP status of any human drug product.
· Directive Document:
· Working documents that establish the standards for resources, processing, products &
quality system.
· Describe how to do it……???
· Describe how to do routine work.
· Several types of directive documents.
· The different types are determined by the specific, functional purpose of the document in the
document system.
· In order to facilitate the development, production, testing and distribution of a product in a
defined manner.
· Reviewed and approved by both management and the individuals responsible for performing
the work.
· Specifications:
A document specification contains several parts: a description of the audience(s) for the document, a
detailed outline giving the structure and contents of the document, and a work plan showing who is
responsible for each part of the document and what the deadlines are for completing each task. For large
documents, there may other managerial information, such as number of pages allocated for each section,
graphics budgets, printing costs, and so forth. We do not expect you to produce this level of detail in your
document specification.
There are three purposes for document specifications:
4. In the workplace, formal document specifications serve three important functions: economy of effort, work
planning, and writing organization.
· Economy of effort:
First, document specifications are used to help you reduce the amount you have to write. When you are
requested to write a major report, quite often you will be told something like, ‟Do a draft and then come see
me with it”. After talking with your boss, you will have to revise the draft completely so that it will have in
it what the boss really wants, since he/she hadn't thought about the project carefully until reading your
draft. You can often save yourself (and your boss) much work if you write a detailed document
specification instead. A document specification is much easier to create, change, revise, and add to than a
draft is.
· Work planning:
The second major function of a document specification is work planning. This can mean either budgeting
your own time, or, in large formal reports, distributing the work among many people. Multi-author writing
is probably the most common form of workplace writing. The more you know about the specification, the
more likely you are to get only your fair share of the writing and no more. For the purposes of the class, the
document specification will serve to distribute the work between you and your partner. You should bear
three things in mind in dividing the work: even work load, respective areas of expertise, and getting things
done in the order that you need them. These points sound obvious, but achieving a fair distribution of the
work is not always easy. It involves keeping to a schedule, for one thing, and staying in close touch with
your partner, for another.
· Writing Organization:
The third major function is the organization of the report itself.
· Standard Operating Procedures (SOPs):
Standard Operating Procedures (SOPs) are issued to specifically instruct employees in areas of
responsibility, work instructions, appropriate specifications and required records
A Standard Operating Procedure (SOP) is a set of written instructions that document a routine or repetitive
activity followed by an organization. The development and use of SOPs are an integral part of a successful
quality system as it provides individuals with the information to perform a job properly, and facilitates
consistency in the quality and integrity of a product or end-result. The term “SOP” may not always be
appropriate and terms such as protocols, instructions, worksheets, and laboratory operating procedures may
also be used. For this document “SOP” will be used.
SOPs describe both technical and fundamental programmatic operational elements of an organization that
would be managed under a work plan or a Quality Assurance (QA) Project Plan [EPA Requirements for
QA Project Plans (QA/R-5) (EPA 2001a)], or Chapter 5 of the EPA Quality Manual for Environmental
Programs, (EPA Manual 5360 A) and under an organization’s Quality Management Plan [EPA
Requirements for Quality Management Plans (QA/R-2) (EPA 2001b)], or Chapter 3 of the EPA Quality
Manual. This document is designed to provide guidance in the preparation and use of an SOP within a
quality system.
Purpose:
SOPs detail the regularly recurring work processes that are to be conducted or followed within an
organization. They document the way activities are to be performed to facilitate consistent conformance to
technical and quality system requirements and to support data quality. They may describe, for example,
fundamental programmatic actions and technical actions such as analytical processes, and processes for
maintaining, calibrating, and using equipment. SOPs are intended to be specific to the organization or
facility whose activities are described and assist that organization to maintain their quality control and
quality assurance processes and ensure compliance with governmental regulations.
If not written correctly, SOPs are of limited value. In addition, the best written SOPs will fail if they are not
followed. Therefore, the use of SOPs needs to be reviewed and re-enforced by management, preferably the
direct supervisor. Current copies of the SOPs also need to be readily accessible for reference in the work
5. areas of those individuals actually performing the activity, either in hard copy or electronic format,
otherwise SOPs serve little purpose.
· Record document:
Protocol:
Protocols are written records clearly defining the objectives and methods that will be used for the validation
programs. An important part of the protocol is the description of the testing method including who will test
the system, how they will test it and what data is to be collected and reported.
Computerized system protocols often include the three distinct stages as described in PMA reports:
Installation Qualification (IQ), Operational Qualification (OQ),and Performance Qualification (PQ).
Protocol Changes are documented requirements specifying who and how changes to parameters,
thresholds, and acceptance criteria are made after approval. It is not impossible to make changes after or
during testing, but these changes must be properly implemented and approved to be validatable.
What Good Documentation requires:
APPROVAL - this applies particularly to work instructions, procedures, manufacturing formulae and
specifications.
Approval should be by the relevant technical, management and quality personnel, to ensure that documents
comply with the principles of GMP and the specific product marketing and manufacturing authorizations.
CLARITY - they should not be open to misinterpretation by the users. They should be written in a way that
makes them easy to check, particularly when they will form part of a product manufacturing history.
Good documentation design will help to minimize errors.
REGULAR REVIEW AND UPDATE - documents must be kept up-to-date with changes in regulations or
processes and should be distributed in a controlled manner to ensure that only the most recent versions are
available for use. They must also be available to those who need them, where they need them!
FORMAL PRESENTATION - controlled documents should be prepared in accordance with a written
procedure, now a days probably using a computerised documentation control system.
Records should be made at the time of each action - do not rely on memory for their completion.
Records relating to manufacturing or testing operations should be kept for at least one year after their
expiry.
If documents or data are stored electronically, the computer system must be validated to assure data
security and integrity.
Provisions must also be made to retrieve the stored data, possibly years after they have been generated.
PROTOCOL FOR DOCUMENTATION:
Protocol is a detailed plan and instructions to the employees working in pharmaceutical industry.
It is a guidebook for those involved in work.
The manufacturing records relating to manufacture of sterile products shall indicate the following details:-
(1) Serial number of the Batch Manufacturing Record.
(2) Name of the product.
(3) Reference to Master Formula Record.
(4) Batch/Lot number.
(5) Batch/Lot size.
(6) Date of commencement of manufacture and date of completion of manufacture.
(7) Date of manufacture and assigned date of expiry.
(8) Date of each step in manufacturing.
(9) Names of all ingredients with the grade given by the quality control department.
(10) Quality of all ingredients.
(11) Control reference numbers for all ingredients.
(12) Time and duration of blending, mixing, etc. whenever applicable.
(13) pH of solution whenever applicable.
(14) Filter integrity testing records.
(15) Temperature and humidity records whenever applicable.
6. (16) Records of plate-counts whenever applicable.
(17) Results of pyrogen and/or bacterial endotoxin & toxicity.
(18) Results of weight or volume of drug filled in containers.
(19) Bulk sterility in case of aseptically filled products.
(20) Leak test records.
(21) Inspection records.
(22) Sterilization records including autoclave leakage test records, load details, date, duration, temperature,
pressure, etc.
(23) Container washing records.
(24) Total number of containers filled.
(25) Total numbers of containers rejected at each stage.
(26) Theoretical yield, permissible yield, actual yield and variation thereof.
(27) Clarification for variation in yield beyond permissible yield.
(28) Reference numbers of relevant analytical reports.
(29) Details of reprocessing, if any.
(30) Name of all operators carrying out different activities.
(31) Environmental monitoring records.
(32) Specimens of printed packaging materials.
(33) Records of destruction of rejected containers printed packaging and testing.
(34) Signature of competent technical staff responsible for manufacture and testing.
In addition to the routine good manufacturing practices documentation, manufacturing records shall show
the following additional information:-
(1) Temperature and humidity in the manufacturing area.
(2) Periodic filled weights of the formulation.
(3) Records of rejections during on line check weighing.
(4) Records of rejection during spray testing.
REFERENCES:
· www.s uperiorcontrols.com/news.php?id=31 & page=4
· http://www.medicalnewstoday.com/articles/172522.php
· http://www.drugs.com/nda/acetavance_090715.html
· http://www.sciencemag.org/cgi/content/full/326/5951/370
· http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
cm122886.htm
Formulation development for global fillings
THE IMPACT OF WORLD REGULATIONS TO DEVELOP AND LAUNCH HARMONIZED
COSMETIC PRODUCTS
Business Strategy
· Since long time ago, we have been challenged:
“ How can we develop a cosmetic product that can have its inventory ready to be exchanged around
the globe.”
· Same package with all information in
· Same formula
“In other words: How to make one fit all”
Understand what is required in each country to sell cosmetics
Global Cosmetic Regulation Scenario
We have a lack of global harmonization on Cosmetics:
· USA
7. · Europe
· Asia
· Latin America
Robust R&D system is required
Latin America
· Mercosur
· CAN
· Central America
· Mexico
· Chile
· Panama
· All others
Mercosur
· Argentina, Brazil, Paraguay and Uruguay
· PreMarketing approval process
· Lists of ingredients harmonized
· In place process to update the list
· Unique requirements still present in each country
· Administrative procedures to get product registration are not harmonized
· Requirements change country by country
· Labeling requirements not harmonized
· Claims /Safety support data requirements not harmonized
CAN
· Bolivia, Colombia, Ecuador, Peru and Venezuela*
· PreMarketing Approval process
· Recognition Process in place
· Adopts List of Ingredients from Europe and USA
· Administrative procedures to get product registration are almost quite harmonized:
· Requirements quite clear
· Labeling requirements almost quite harmonized
· Claims /Safety support data requirements almost quite harmonized
Central America (RTCA)
· Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua.
· New Harmonized cosmetic regulation since early 2009
· PreMarketing approval process
· Adopts List of Ingredients from Europe and USA
· Administrative procedures to get product registration are not harmonized:
· Requirements change country by country
· Labeling not harmonized
· Claims /Safety support data requirements not harmonized
Mexico
· Pos-Marketing Surveillance process for cosmetics
· Pre-Marketing approval process for Hygienic
8. · Has list of allowed, restricted and not allowed ingredients updated on March 21, 2007
· Specific labeling requirements ( INCI translated to Spanish)
Chile and Panama
· PreMarketing approval process
· Adopts List of Ingredients from Europe and USA
· Specific labeling requirements
R&D Process
· Product Development
· R&D systems should be able to provide to the Formulator the ingredient’s regulation
around the global/region so that only approved ones can be used
· Product Safety:
· Make sure that ingredients that are not regulated are safe.
· Make sure that final formulation is safe
· Make sure claims are substantiated
Regulatory Affairs
· Make sure to update database system
· Ingredients update
· Safety test requirements
· Specific country/region product registration requirements:
· Words/expression restriction / forbidden
· Claims requirements
· Unique requirements
9.
10.
11. Harmonized Product
· Last but not least
· Define Manufacturing strategy
· This will drive the last regulatory requirements to have harmonized product:
· Same package
· Same formula
· Same label copy
· Approved in the countries according strategy
The impact of world regulation to develop and launch harmonized cosmetic products
· Time to launch harmonized product is too long impacting:
· Marketing strategy
· Supply Chain strategy
· Adding Premium costs
· Service issues
Patents are exclusive property rights in intangible creations of the human mind. They exist only as provided
in the laws of sovereign states, and can be enforced only to the extent that application has been made and a
patent granted covering the territory of an individual state. Patent rights are limited in duration, with the
global standard being 20 years from the date of application. The new product, article of manufacture or
process described in the patent application must be something that has never been previously disclosed
anywhere in the world and something that would not be obvious to a person ordinarily skilled in the field
involved. Determinations of whether these requirements have been met are made by comparing the claims
12. of the patent applicant against the body of published literature in the field, including previously issued
patents. This process is called examination, and it assures that no one is able to claim patent rights on
anything that already is existence.
Patents work differently indifferent industries. In the electronic industry patents are often shared among
competitors through pooling or cross licensing. This sharing is necessary because a given product often
contains many patented technologies. However, in the pharmaceutical, chemical and biotechnology
industries the patent normally equals the product, and protects the extensive investment in research and
clinical testing required before placing it on the market. Patent protection for chemical and pharmaceutical
products is especially important compared with other industries because the actual manufacturing process is
often easy to replicate and can be copied with a fraction of the investment of that required for the research
and clinical testing.
The extensive cost required to produce a new pharmaceutical product has meant that private sector
investment in pharmaceutical innovation has been disproportionately directed to products meeting the
needs of patients in developed countries, particularly in the United States, which combines strong patent
protection with a market free of price controls.
Until the TRIPS Agreement in 1994 many developing countries provided no patent protection for
pharmaceutical products. And, while countries that have joined the WTO have obligated themselves to
provide such protection, least developed countries are not required to meet this obligation until 2016. The
continuing lack of patent protection for pharmaceutical products makes it very difficult to establish
research-based industries in most developing countries. Most medical research in these countries takes
place in the public sector. The lack of any means of patenting these inventions and the related lack of
experience in licensing them to the private sector, suppresses the development of commercial enterprises
focused on alleviating the disease burdens common to developing countries.
The controversy over availability of patented therapies for the treatment of HIV disease has resulted
renewed interest in the compulsory licensing of pharmaceutical products. After two years of discussion, the
WTO Council recently affirmed that the TRIPS Agreement permits such compulsory licenses in health
emergencies, even in cases where the compulsory license is for an imported product. However, to date, no
compulsory licenses actually have been issued, even though the threat of compulsory licensing has been
used as a means of seeking lower prices.
One danger in compulsory licensing is that it will discourage further the commercial R & D necessary to
new drugs to fight global epidemics. Another danger is that compulsory licensing can be used to seek price
levels below what a given national market is capable of supporting, further concentrating the burden of
financing pharmaceutical innovation on developed country consumers and discouraging development of
drugs targeted at the disease burdens of countries using compulsory licenses.
There are promising developments in countries such as India and Brazil that are beginning to use patents to
develop commercial pharmaceutical industries that produce products directed at local diseases and
available at price that patients in those countries can afford. Foundations and nonprofit organizations such
as the Bill and Melinda Gates Foundation and One World Health, Inc. are supporting such efforts. These
efforts show that developing countries have the capacity to build research-intensive pharmaceutical
industries capable of operating profitably in the conditions of the local market. However, for such local
industries to take root and grow, effective patent protection must be made available, the commercialization
of publicly funded research must be encouraged, and compulsory licensing must be kept to a minimum.
Wealthy countries can assist this process by subsidizing local markets for the purchase of drugs through the
Global Fund, and by direct programs of assistance such as that recently proposed by President Bush.
Consumers in all countries can share the burden of drug development equitably by paying for medicine at a
price level consistent with their means, rather than attempting to shift the costs of drug development to
others.
REFERENCES:
1. http://www.personalcarecouncil.org
13. 2. http://ec.europa.eu/enterprise/cosmetics/
3. http://www.cirsafety .
org/
NDA
INTRODUCTION:
New Drug Application is a Critical component for drug approval process which required to submit to
USFDA before drug commercialization. The data gathered during the animal studies and human clinical
trials of an Investigational New Drug (IND) become part of the NDA. The regulation and control of new
drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new
drug has been the subject of an approved NDA before U.S. commercialization.
Goals of the NDA:
To provide enough information to permit FDA reviewer to reach the following key decisions:
· Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the
drug outweigh the risks.
· Whether the drugs proposed labeling (package insert) is appropriate, and what it should
contain.
· Whether the methods used in manufacturing the drug and the controls used to maintain the
drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.
NDA Classifications:
· New Molecular Entity
· New Salt of Previously Approved Drug (not a new molecular entity)
· New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity)
· New Combination of Two or More Drugs Already Marketed Drug Product - Duplication
(i.e., new manufacturer)
· New Indication (claim) for Already Marketed Drug (includes switch in marketing status
from prescription to OTC)
· Already Marketed Drug Product - No Previously Approved NDA.
Assembling Applications for Submission:
Assembling Applications for Submission the FDA requires drug sponsors to submit multiple copies of the
NDA The archival copy, the review copy, the field copy. In 1997 the FDA Center for Drug Evaluation and
Research (CDER) published guidelines that allow sponsors to submit NDAs electronically instead of on
paper.
The Archival Copy:
The Archival Copy Contains all sections of the NDA, including the cover letter, Form FDA-356h
(Application to Market a New Drug, Biologic, or an Antibiotic for Human Use), the administrative
sections, Comprehensive NDA index, and All technical sections. It must contain four copies of the
Labeling section. It must contain three additional copies of the CMC and Methods Validation Package in a
separate binder. The archival copy is the only copy that contains the Case Report Tabulation and Case
Report Forms.
The Review Copy:
The Review Copy Intended for reviewers in the corresponding technical disciplines. In addition to the
appropriate technical section, each review copy also includes The cover letter, Form FDA-356h,
The administrative sections, Comprehensive NDA index Individual table of contents, The Labeling
section, and The Application Summary.
The Field Copy:
14. The Field Copy required since 1993 for use by FDA inspectors during pre approval facilities inspections. It
includes the Cover letter and Form FDA-356h, the administrative sections, the comprehensive NDA index
Individual table of contents, The Labeling section, The Application Summary, and CMC and Methods
Validation Package.
NDA CONTENTS:
The NDA may have as many as 20 different sections in addition to the Form FDA-356h itself. The specific
contents of the NDA will depend on the Nature of the drug and the information available at the time of
submission. The application Form FDA-356h serves as Checklist as well as Certification that the sponsor
agrees to comply with a range of legal and regulatory requirements.
Section 1: Index
Section 2: Labeling
Section 3: Application Summary
Section 4: Chemistry, Manufacturing, and Controls (CMC)
Section 5: Nonclinical Pharmacology and Toxicology
Section 6: Human Pharmacokinetics and Bioavailability
Section 7: Microbiology
Section 8: Clinical Data
Section 9: Safety Update Reports
Section 10: Statistics
Section 11: Case Report Form Tabulations
Section 12: Case Report Forms (CRFs)
Section 13: Patent Information
Section 14: Patent Certification
Section 15: Establishment Description
Section 16: Debarment certificate
Section 17: Field copy certification
Section 18: User fee coversheet
Section 19: Financial Disclosure
Section 20: Other/ Pediatrics
Section 1: Index:
The NDA index is a comprehensive table of contents that enables the reviewers to find specific information
in this massive document quickly. The NDA index should follow immediately after the Form FDA-356h
and the administrative items. It must show the location of every section in the archival NDA by volume and
by page number. Index It should guide reviewers the data in the technical sections, the summary, and the
supporting documents each separately bound technical section should also contain a copy of the overall
NDA index in addition to its own table of contents based on the index.
Section 2: Labeling:
The labeling section must include all draft labeling that is intended for use on the product container,
Cartons or packages, the proposed package insert.
Section 3: Application Summary:
The application summary is an abbreviated version of the entire application. This overview is one of the
few elements of the application that all reviewers receive, and it should give them a clear idea of the drug
and its application. The summary usually comprises 50 to 200 pages. The draft product labeling include the
following sections
1. Description
2. Clinical Pharmacology
3. Indications and Usage
4. Contraindications
5. Warnings
6. Precautions
15. 7. Adverse Reactions
8. Drug Abuse and Dependence
9. over dosage
10. Dosage and Administration
11. How Supplied (primary and secondary packages)
For each section of the labeling, include annotations referring to information in the summary and technical
sections of the application that support the inclusion of each statement in the labeling with respect to
Animal pharmacology and/or animal toxicology, Clinical studies, Integrated Summary of Safety (ISS) and
Integrated Summary of Effectiveness (ISE) Safety (ISS) and Integrated Summary of Effectiveness (ISE)
Pharmacologic class Scientific rationale Intended use Potential clinical benefits.
Foreign marketing history: The summary must include a list of any countries in which the drug is or was
marketed, along with the dates when it was marketed, if they are known. It must also include a list of any
countries in which the drug has been withdrawn from marketing for any reason relating to safety or efficacy
or in which an application has been rejected.
Section 4: Chemistry, Manufacturing, and Controls (CMC):
The first technical section of the NDA.It includes information on the composition, Manufacturing, and
Specifications of the drug substance and the drug product. The CMC information must include Description
of the drug substance or active ingredient, Its stability, Physical and chemical characteristics, Provide the
names/designations of the drug substance, including Generic/common name Chemical name
(IUPAC/USAN/CAS) Code(s) (CAS/internal).It Provide a structural overview including Molecular
structure, Empirical formula, Molecular weight, Elemental composition. The description of the drug
substance physical and chemical characteristics should include: Appearance, including color, crystalline
form, and odor Melting/boiling point Refractive index, viscosity, and specific gravity Polymorphs,
including modifications (forms) and relative kinetic/ thermodynamic stabilities. The physical and chemical
characteristics should also include Solubility, Ionization constants, and Partition coefficients at various
pHs. Solubility in common organic solvents as well as in various aqueous mediaWater0.1 N HCl 0.02 N
HCl SGF without pepsin Water buffered to various acidic/neutral/basic pHs. It Provide a reference standard
(RS) to elucidate the drug substance chemical structure, including Preparation method, Test methods, Test
results as shown by a certificate of analysis (C.O.A).Provide proof that the reference standard was
adequately tested and characterize the spectra completely. Provide structural elucidation using a reference
standard as applicable. Measures might include X-ray (in the case of absolute configuration or
polymorphism) UV/visible spectrum, FTIR spectrum, 1H NMR/13C NMR spectrum, Low-resolution/high-resolution
mass spectrum, Elemental analysis. The CMC information must also include theNames,
addresses and functions of each site where the drug substance is manufactured or tested. The description of
the drug substance manufacturing methods must include Synthesis scheme, Synthesis description, Typical
executed manufacturing record Compilation of and analytical controls for starting materials, Reagents,
Solvents Catalysts, and Intermediates Suppliers for starting materials. The discussion of drug substance
analytical controls should include the following: Specifications Methods Rationale for
methods/specifications Method validations Batch analytical data (including impurity profiles cross-referenced
with toxicology studies)Sampling plan Provide information on drug substance stability
including: Ambient/accelerated stability data Retest dating Highly stressed (e.g., acid, base, reflux) data
Provide a listing of all inactive ingredients. For compendial (e.g., UPS/NF) inactive ingredients, reference
the appropriate current compendial monographs and provide more precise specifications as necessary. For
noncompendial ingredients that fall under 21 CFR such as D&C and FD&C dyes, reference the appropriate
section of 21 CFR and provide any additional specifications beyond the scope of the CFR.For
noncompendial items that are not regulated by 21 CFR, provide appropriate analytical specifications and
methods. Provide information on the drug product manufacturing methods: Summary and schematics of
manufacturing procedure Master batch record for proposed marketed products, including actual operating
conditions, type and size of equipment, and in process controls and tests Executed batch record. The section
on drug product packaging must include: Summary of container/closure system(s)Listing of packaging
16. components and component/resin suppliers Specifications for each packaging component DMF
authorization letters Description of the packaging process Test methods (as appropriate)Developmental
data that confirms the suitability of the packaging. This includes water vapor permeation data for plastic
containers/ closures and compatibility testing for solutions, suspensions, emulsions, etc. The drug product
stability information will differ slightly from the drug substance stability information. Unstressed/stressed
stability data Statistical analysis to establish consistency of data Expiration dating Post approval stability
commitment/protocol. For an NDA, provide a list of all drug product investigational formulations used in
clinical studies, along with the quantitative composition of each formulation. Every NDA must include an
environmental assessment (EA)The EA, also called the environmental impact analysis report, includes an
analysis of the manufacturing process and ultimate use of the drug product as well as a discussion of how
the process and the drug product may affect the environment.
Methods validation package: The final component of the CMC technical section is the methods validation
package. The package must comprise: Specifications and test methods for each component used in the drug
product Specifications and methods for the drug product Validation of test methods Names and addresses
of component suppliers Names and addresses of the suppliers of the container closure system.
Section 5: Nonclinical Pharmacology and Toxicology:
The second technical section of the NDA provides a description of all animal and in vitro studies with the
drug. Include a narrative summary of notable findings in all studies and a discussion of notable findings
across the various studies. Provide individual study reports,including Pharmacology, Toxicology, and
ADME studies. For the pharmacology studies, following data is required
1.Effects related to the therapeutic indication, such as the pharmacodynamic ED 50 in dose-ranging studies
and the mechanism of action (if known)
2.Secondary pharmacological actions in order of clinical importance as possible adverse effects or as
ancillary therapeutic effects
3. Interactions with other drugs.
The Toxicology information must include information on Acute toxicity, Multidose toxicity (including
subchronic, chronic, and carcinogenicity) Special toxicity studies, as well as Reproduction studies and
mutagenicity studies. Present toxicology data by intended route of administration in the following order: 1.
Oral 2.Intravenous 3.Intramuscular 4.Interperitoneal 5.Subcutaneous 6.Inhalation 7 Topical 8 Other in vivo
9.In vitro.
Example:
For acute toxicity studies, present the animal study data in the following order: 1. Mouse 2.Rat 3.Hamster
4.Other rodent(s) 5.Rabbit 6.Dog 7.Monkey 8.Other nonrodent mammal(s) 9 Non mammals.
Section 6: Human Pharmacokinetics and Bioavailability :
This technical section includes data from Phase I safety and tolerance studies in healthy volunteers and
ADME studies. It should include a table of PK parameters, giving the values for the major parameters
(mean and % cv) such as Peak concentration (Cmax) Area under the curve (AUC) Time to reach peak
concentration (tmax) Elimination constant (Ke) Distribution volume (Vd) Plasma and renal clearance
Urinary excretion. Drug formulation information should include a list of all formulations used in clinical
trials and in in vivo bioavailability and PK studies. The analytical methods used must be summarized in
each in vivo biopharmaceutic study. Include detailed information, such as Sensitivity Linearity Specificity
and Reproducibility of the analytical test methods used in each study. Provide dissolution data on each
strength and dosage form for which an approval is sought. Include a comparative dissolution study with the
lot in the in vivo biopharmaceutic study. Include summary of the product Dissolution performance
Dissolution method and Dissolution specifications.
This technical section must include individual study reports from five types of biopharmaceutic. Pilot or
background studies Bioavailability/bioequivalence Pharmacokinetic studies Other in vivo studies In vitro
studies .
Section 7: Microbiology :
17. Required for anti infective drug products.Antimicrobial drugs differ from other classes of drugs in that they
are designed to affect microbial physiology rather than patient physiology. In vitro and in vivo studies are
critical in establishing the new drug effectiveness, especially if the microorganism has the potential to
develop, or has developed, resistance to other antimicrobial drugs. This section requires the following
technical information and data: 1. A complete description of the biochemical basis of the drug action on
microbial physiology. 2. The drug antimicrobial spectrum. Include results of in vitro studies demonstrating
the concentrations of the drug that are required for effective use. 3. Describe any known mechanisms of
resistance to the drug and provide information or data of any known epidemiologic studies demonstrating
prevalence to resistance factors. 4. Clinical microbiology laboratory methods, such as in vitro sensitivity
discs, necessary to evaluate effective use of the drug.
Section 8: Clinical Data:
This technical section of the NDA comprises ten elements. The document largest and most complex
section. List of investigators and list of INDs and NDAs Background/overview of clinical investigations
Clinical pharmacology section Controlled clinical trials Uncontrolled clinical trials Other studies and
information section Integrated summary of effectiveness data Integrated summary of safety information
Drug abuse and over dosage information Integrated summary of benefits and risks of the drug
List of investigators and list of INDs and NDAs-- The list of investigators should include all investigators
who have used any dosage form. Alphabetize the list and note each investigator address, the type of study,
the study identifier, and its location in the NDA .Provide a list of all known INDs under which the drug, in
any dosage form, has been studied.
Background/overview of clinical investigations-- Describe the general approach and rationale used in
developing the clinical data. Explain how information about the drug derived from clinical pharmacology
studies led to critical features of the clinical studies.Support the basis for the design features of the clinical
trials, such as number of patients, duration, selection criteria, and controls
Clinical pharmacology-- Clinical pharmacology Should include ADME studies, pharmacodynamic dose
range, and dose response studies, and any other studies of the drug action. The format and order of
presentation is as follows: 1. Table of all studies grouped by study type. Provide the investigators, study
numbers, start date, and location of the report in the NDA. 2. For each group of studies, a brief synopsis of
each study 3. An overall summary of the clinical pharmacology data
Controlled clinical trials --Controlled clinical trials Provide the following material in the order presented
below: 1. A table of all studies 2. Full clinical trial reports of all controlled studies in the following
order: Completed studies Ongoing studies with interim results Incomplete or discontinued studies 3.
Full reports of dose-comparison concurrent control studies, followed by those for aoeno- treatment
concurrent control, active control studies, and historical control studies
Uncontrolled clinical trials --Uncontrolled clinical trials They may be used to provide support for
controlled studies and to provide critical safety information. This section should include a table of
all studies. Group full reports of studies according to completeness and availability of Case Report
Forms (CRFs).
Other studies and information: Include a description and analysis of any additional information that the
applicant has obtained from any source, foreign or domestic, that is relevant to evaluating the
products safety and effectiveness. It should include information on commercial marketing
experience and foreign regulatory actions, including List of countries in which the drug has been
approved Details of any rejected registrations Copies of approved labeling (package inserts) from
major regions such as Europe, Canada, Australia, New Zealand, and Japan Any other reports from
the literature not provided
Section 9: Safety Update Reports :
A pending application must be updated when new safety data becomes available that could affect any of the
following: Statements in draft labeling Contraindications Warnings Precautions Adverse events.
Safety update reports are not to be used to submit any new final reports that may impact FDA
review time unless the FDA agrees at the pre-NDA meeting that it will accept the reports in this
18. manner. Safety updates are submitted 4 months (120 days) after the initial application, following the
receipt of an approval letter and at any other time that the FDA requests such an update.
Section 10: Statistics :
This technical section includes descriptions and documentation of the statistical analyses performed to
evaluation the controlled clinical trials and other safety information. It must include copies of All
controlled clinical trial reports Integrated efficacy and safety summaries Integrated summary of
risks and benefits.
Section 11: Case Report Form Tabulations :
This section must include complete tabulations for each patient from every adequately or well-controlled
Phase II and Phase III efficacy study, and from every Phase I clinical pharmacology study. It also
must include tabulations of safety data from all clinical studies.
Section 12: Case Report Forms (CRFs) :
It is necessary to include the complete CRF for each patient who died during a clinical study and for any
patients who were dropped from the study .
The report must be submitted regardless of whether the AE is considered to be related to the study drug,
even if the patient was receiving a placebo or comparative drug. Additional CRFs must be provided
at the request of the FDA.
several other supporting items as appropriate
Item 13: Patent information
Item 14: Patent certification
Item15: Establishment description
Item 16: Debarment certification
Item 17: Field copy certification
Item 18: User fee cover sheet (Form FDA-3397)
Item19: Financial disclosure (Form FDA 3454, form FDA-3455)
Item 20:Other/pediatric use.
Once the application is submitted, the FDA has 60 days to conduct a preliminary review which will assess
whether the NDA is "sufficiently complete to permit a substantive review". If the NDA is found to be
insufficiently complete (and reasons for this can vary from a simple administrative mistake in the
application to a requirement to reconduct much of the testing), then the FDA rejects the application with
the issue of a Refuse to File letter which is sent to the applicant explaining where the application has failed
to meet requirements. Assuming that everything is found to be acceptable, the FDA will decide if the NDA
will get a standard or accelerated review and communicate the acceptance of the application and their
review choice in another communication known as the 74-day letter. A standard review implies an FDA
decision within about 10 months while a priority review should complete within 6 months.
The NDA in CTD Format :
The NDA in CTD Format ICH has developed a Common Technical Document to streamline regulatory
submissions in Europe, the U.S. and Japan. CTD is an information format that contains clinical,
nonclinical, and manufacturing technical data.The CTD format features well-defined modules, with a
highly specific structure and numbering of sections within the modules. It makes a clear distinction
between subjective information sections and objective information sections. Use of the CTD format
benefits both regulatory agencies and the pharmaceutical industry. In addition to enhancing reviews, the
CTD use of common elements facilitates communications between the agencies and the applicants and
simplifies the exchange of information between regulatory authorities. The document also provides a
common basis for continuous improvement of Good Regulatory Practices.
REFERENCES:
Douglas J. Pisano, David S. Manlus “FDA Regulatory Affairs, A guide for Prescription Drugs, Medical
Devices and Biologics-New drug Application “Second edition-Marcel Dekker, page no 69-108.
http://www.fda.gov/cder/guidance/index.htm. 31
19. Abbreviated New Drug Application (ANDA):
Definition :
“A drug product that is comparable to a brand/reference listed drug product in dosage form, strength,
route of administration, quality and performance characteristics, and intended use”
It is termed as "abbreviated" because they generally not required to include preclinical (animal) and
clinical (human) data to establish safety and effectiveness.
It is an application for generic versions of off-patent drugs to receive FDA approval with less costly or no
preclinical and clinical testing.
The intention is to minimize duplication of available information. No safety or efficacy trials are
performed. Complete chemistry, manufacturing, and controls information and information regarding the
bioavailability of solid dosage forms.
Basic Generic Drug Requirements are:--
· Same active ingredient(s)
· Same route of administration
· Same dosage form
· Same strength
· Same conditions of use
· Inactive ingredients already approved in a similar NDA
Goal of ANDA:
Provide enough information to permit FDA to make the following key decisions:
· Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the
drug outweigh the risks.
· Whether the drug's proposed labeling (package insert) is appropriate, and what it should
contain.
· Whether the methods used in manufacturing the drug and the controls used to maintain the
drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.
· To reduce the price of the drug.
· To reduce the time development.
· Increase the bioavailability of the drug in comparison to references list drug.
Abbreviated or Supplemental NDA:
· Abbreviated NDA: includes..
· Generic drug
· New combination of approved drugs
· Proportion of ingredients in combination is changed
· Supplemental NDA: includes..
· New intended use of the drug (labeling change)
· Dose, method or duration of administration is changed
· Change in manufacturing process or location
NDA vs. ANDA Review Process:
Requirements for NDA:
· Labeling
· Pharmacology and toxicology
· Chemistry
· Manufacturing
· Controls
· Microbiology
20. · Inspection
· Testing
· Animal studies
· Human studies
· Bioavailability
Requirements for ANDA:
· Labeling
· Pharmacology and toxicology
· Chemistry
· Manufacturing
· Controls
· Microbiology
· Inspection
· Testing
· Bioequivalence
NDA ANDA
Applicable for new drug Applicable for generic drug
Takes longer time ( 12-15 years) Comparatively less time taken(1-2 years)
More expenditure of money Comparatively less
Cost of drugs are more Cost of drugs are less
Nonclinical studies and clinical
investigations are essential
Nonclinical studies and clinical investigations
are nonessential except bioavailability and
bioequivalence
Format of ANDA:
Three copies of application are required, an archival copy, a review copy and a field copy. FDA will
maintain guidance documents on the format and content of applications to assist applicants in their
preparation. ANDA includes the following:
· Application form: the applicant shall submit a completed and signed
application form that contains the information. The applicant shall state whether the submission is an
abbreviated application or a supplement to an abbreviated application.
· Table of contents: the archival copy of the ANDA is required to contain a
table of contents that shows the volume number and page number of the contents of the submission.
· Basis for ANDA submission: an ANDA must refer to a listed drug.
Ordinarily, that listed drug will be the drug product selected by the agency as the reference standard for
conducting bioequivalence testing. The application shall contain:
· The name of the reference drug, including its dosage from and strength.
For an abbreviated new drug application based on the reference listed drug must be the same as the
listed drug approved in the petition.
· A statement as to whether, according to the information published in the
list, the reference listed drug is entitled to a period of marketing exclusivity.
· Conditions of use:
· A statement that the conditions of use prescribed, recommended, or suggested in the labeling
proposed for the drug product have been previously approved for the reference listed drug.
· A reference to the applicant’s annotated proposed labeling and to the currently approved labeling
for the reference listed drug.
21. · Active ingredients
· Route of administration, dosage form and strength.
· Bioequivalence
· Labeling
· Samples: need not be submitted until requested by FDA.
· Patent certification
· Financial certification or disclosure statement.
ANDA contents:
Section 1: Overall ANDA index:- The NDA index is a comprehensive table of contents that enables the
reviewers to find specific information in this massive document quickly.
Section 2: Labeling:- It must include all draft labeling that is intended for use on the product container,
cartons or packages, including the proposed package insert.
Section 3: Application summary:- Proposed annotated package insert-
· Pharmacology class, scientific rational, intended use, and potential clinical
benefits
· Foreign marketing history
· Chemistry, Manufacturing and control summary
· Nonclinical pharmacology and toxicology summary
· Human pharmacokinetics and bioavailability summary
· Microbiology summary
· Clinical data summary and results of statistical analysis
· Discussion of benefit/risk relationship
Section 4: Chemistry, manufacturing and controls:-
· Chemistry, manufacturing and control information
· Samples
· Methods validation package
Section 5: Nonclinical pharmacology and toxicology
· Provide individual study reports, including pharmacology, toxicology,
ADME studies.
· Effects related to the therapeutic indication, such as the pharmacodynamic
ED50 in dose- ranging studies and the mechanism of act ion (if know n)
· Interactions with other drugs (or cross-reference the location of the
information in any of the above subsection
Section 6: Human Pharmacokinetics and bioavailability:- includes data from Phase I safety and
tolerance studies in healthy volunteers. Element in the section tabulated summary of studies showing all in
vivo biopharmaceutics studies performed.
· Summary of analytical method used in in vivo biopharmaceutic study
· Pilot or background studies
· Bioavailibility or bioequivalence studies
· Pharmacokinetic studies
· In vitro studies
Section 7: Microbiology:- Includes for anti infective drug products. It requires the following technical
information and data:-
· A complete description of the biochemical basis of the drug action on
microbial physiology
· The drugs antimicrobial spectrum
22. · Describe any known mechanism of resistance to the drug and provide
information/data of any known epidemiologic studies demonstrating prevalence to resistance factor
· Clinical microbiology laboratory methods
Section 8: Safety data
··
Statements in draft labeling
· Contra indications
· Warnings
· Precautions
· Adverse events
Section 9: Statistical data
· All controlled clinical trial reports
· Integrated efficacy and safety summaries
· Integrated summary of risks and benefits
Section 10: Case report tabulation:- Includes complete tabulation for each patient from every adequately
are well controlled phase II and Phase III efficacy, clinical pharmacology study. It also tabulation of safety
data from all clinical studies.
Section 11: Case report forms:- Includes the complete CRF for each patient who died during a clinical
study or adverse event, regardless of whether the AE is considered to be related to the study drug, even if
the patient was receiving a placebo or comparative drug.
Bioequivalence:
A generic drug is considered to be bioequivalent to the brand name drug if:
· The rate and extent of absorption do not show a significant difference from listed drug, or
· The extent of absorption does not show a significant difference and any difference in rate is
intentional or not medically significant.
Bio equivalent Inequivalent
Resources for ANDA Submissions:- The following resources have been gathered to provide you with the
legal requirements of an ANDA application, assistance from CDER to help you meet those requirements,
and internal ANDA review principles, policies and procedures.
Guidance Documents for ANDAs:- Guidance documents represent the Agency's current thinking on a
particular subject. These documents are prepared for FDA review staff and applicants/sponsors to provide
guidelines to the processing, content, and evaluation/approval of applications and also to the design,
production, manufacturing, and testing of regulated products. They also establish policies intended to
achieve consistency in the Agency's regulatory approach and establish inspection and enforcement
procedures. Because guidances are not regulations or laws, they are not enforceable, either through
administrative actions or through the courts. An alternative approach may be used if such an approach
satisfies the requirements of the applicable statute, regulations, or both. For information on a specific
guidance document, please contact the originating office. They includes…
· Generics
23. · Generics (Draft - Distributed for comment purposes only) .
· Procedural Draft: Applications Covered by Section 505(b)(2) (Issued 10/1999,
Posted 12/7/1999). This provision permits FDA to rely, for approval of an NDA, on data
not developed by the applicant.
· Biopharmaceutics.
· Bioavailability and Bioequivalence Studies for Orally Administered Drug Products -
General Considerations (Issued 10/2000, Posted 10/27/2000). This guidance should be
useful for applicants planning to conduct bioavailability (BA) and bioequivalence (BE)
studies during the IND period for an NDA, BE studies intended for submission in an
ANDA, and BE studies conducted in the post-approval period for certain changes in both
NDAs and ANDAs.
· Drug Master Files. A Drug Master File (DMF) is a submission to the 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.
· Required Specifications for FDA's IND, NDA, and ANDA Drug Master File Binders
· Guidance for Industry: Changes to an Approved NDA or ANDA
· Refusal to Receive. (Issued 7/12/1993, Posted 11/26/99) Clarifies CDER's decisions to
refuse to receive an incomplete application.
· Inactive Ingredient Database. This database contains all inactive ingredients present in
approved drug products or conditionally approved drug products currently marketed for human use.
Laws, Regulations, Policies and Procedures:
The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established by the
Agency to protect the consumer's health, safety, and pocketbook. The Federal Food, Drug, and Cosmetic
Act is the basic food and drug law of the U.S. With numerous amendments it is the most extensive law of
its kind in the world. The law is intended to assure consumers that foods are pure and wholesome, safe to
eat, and produced under sanitary conditions; that drugs and devices are safe and effective for their intended
uses; that cosmetics are safe and made from appropriate ingredients; and that all labeling and packaging is
truthful, informative, and not deceptive.
Code of Federal Regulations (CFR):
The final regulations published in the Federal Register16 (daily published record of proposed rules, final
rules, meeting notices, etc.) are collected in the CFR. The CFR is divided into 50 titles which represent
broad areas subject to Federal regulations.
The FDA's portion of the CFR interprets the Federal Food, Drug and Cosmetic Act and related statutes.
Section 21 of the CFR contains most of the regulations pertaining to food and drugs. The regulations
document most actions of all drug sponsors that are required under Federal law. The following regulations
apply to the ANDA process:
· (21CFR Part 314) Applications for FDA Approval to Market a New Drug or and
Antibiotic Drug
· (21CFR Part 320) Bioavailability and Bioequivalence Requirements. For more
information on retention samples, please see Bioequivalence Study Retention Samples.
· Bioavailability and Bioequivalence Requirements; Abbreviated Applications;
Final Rule. (Issued and posted 12/19/2002)
· (21CFR Part 310) New Drugs
MaPPs :- CDER's Manual of Policies and Procedures (MaPPs) provide official instructions for internal
practices and procedures followed by CDER staff to help standardize the drug review process and other
activities, both internal and external. MaPPs define external activities as well.
ANDA review process:
24. Time frames for reviewing ANDA by FDA:
Within 180 days of receipt of an application for a new drug under section 505(b) of the act or an
abbreviated application for a new drug under section 505(j) of the act, FDA will review it and send the
applicant either an approval letter under 314.105 or a complete response letter under 314.110. This 180-day
period is called the "initial review cycle."
At any time before approval, an applicant may withdraw an application under 314.65 or an abbreviated
application under 314.99 and later submit it again for consideration.
The initial review cycle may be adjusted by mutual agreement between FDA and an applicant or as
provided in 314.60 and 314.96, as the result of a major amendment.
Filing of ANDA:
Within 60 days after FDA receives an application, the agency will determine whether the application may
be filed. The filing of an application means that FDA has made a threshold determination that the
application is sufficiently complete to permit a substantive review. If FDA finds that none of the reasons
for refusing to file the application apply, the agency will file the application and notify the applicant in
writing. The date of filing will be the date 60 days after the date FDA received the application. The date of
25. filing begins the 180-day period described in section 505(c) of the act. This 180-day period is called the
"filing clock."
Approval of ANDA:
FDA will approve an application and issue the applicant an approval letter on the basis of draft labeling if
the only deficiencies in the application concern editorial or similar minor deficiencies in the draft labeling.
Such approval will be conditioned upon the applicant incorporating the specified labeling changes exactly
as directed, and upon the applicant submitting to FDA a copy of the final printed labeling prior to
marketing.
Amendments to an unapproved ANDA:
· An applicant may amend an abbreviated new drug application that is submitted, but not yet
approved, to revise existing information or provide additional information. Amendments containing
bioequivalence studies must contain reports of all bioequivalence studies conducted by the applicant on
the same drug product formulation, unless the information has previously been submitted to FDA in the
abbreviated new drug application. A complete study report must be submitted for any bioequivalence
study upon which the applicant relies for approval. For all other bioequivalence studies conducted on
the same drug product formulation, the applicant must submit either a complete or summary report. If a
summary report of a bioequivalence study is submitted and FDA determines that there may be
bioequivalence issues or concerns with the product, FDA may require that the applicant submit a
complete report of the bioequivalence study to FDA.
· Submission of an amendment containing significant data or information before the end of the initial
review cycle constitutes an agreement between FDA and the applicant to extend the initial review cycle
only for the time necessary to review the significant data or information and for no more than 180 days.
· The applicant shall submit a field copy of each amendment. The applicant, other than a foreign
applicant, shall include in its submission of each such amendment to FDA a statement certifying that a
field copy of the amendment has been sent to the applicant's home FDA district office.
References:
· Richard A. Guarino- New Drug Approval process-1)The New Drug Application, Content, Format
2) Abbreviated $ Supplementary New Drug Application- Fourth edition-Marcel Dekker,inc- page no
113-183.
· Douglas J. Pisano, David S. Manlus –FDA Regulatory Affairs, A guide for Prescription Drugs,
Medical Devices and Biologics-New drug Application –Second edition-Marcel Dekker,inc- page no
69-108.
· Loyd V. Allen Jr, Nicholas G. Popovich, Howard C. Ansel’s Pharmaceutical Dosage Forms and
delivers systems- New Drug Development and Approval Process-8th edition- B.I. publication- Page no
25-65.
· http://www.fda.gov/cder/guidance/index.htm .
· http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approv
alapplications/abbreviatednewdrugapplicationandagenerics/default.htm
· http://www1.pointcross.com/source/ddg/charts/andachart.htm
· http://www.accessdata.fda.gov/script s /cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.94
Common technical document:
The common technical document was agreed in November 2000 in sandicgo USA. It provides for a
harmonized structure and format for new product applications. This is one in a series of guidance that
provide recommendations for applicants preparing the CTD for the registration of pharmaceuticals used for
human use, that is , submission to the USFDA . It will significantly reduce time resources. This applicant
have used many different approaches to organize the information, but differences in organization of each
application made regulatory agency review, more difficult and may lead to omission of critical data or
analysis. Such omission can result in a decision by regulatory agency which is not correct for a given drug.
26. So, as to overcome this “US federal drug administration ensured that the worldwide pharmaceutical
industry should follow tightly regulated strict standard document maintained in a common format from
initial project definition to product approval.
· In addition exchange of regulatory information among regulatory authorities
will be simplified.
· The FDA characterized the CTD as “ an information package of clinical, non clinical and
manufacturing, technical data in the same format and with the same content , that would be
submitted for registering new drugs in all three ICH the US, European union of Japan.
· European Union has its own requirements for the organization of technical reports in
submission and for the preparation of the summaries and tables.
· In Japan the applicants must prepare the GAIYO which organizes and presents a summary of
the technical information.
· In Europe experts reports and tabulated summaries are required and return summaries are
recommended.
· In US FDA has guidance regarding the format and content of new drug application
submission.
Guidance for industry on preparing the CTD:
It has been divided into 4 guidance document on harmonized format.
· The organization of the CTD
· The quality section
· The efficacy section
· The safety section
Human use and has been subject to consultation by the regulatory parties in accordance with the ICH process.
· General considerations for submitting marketing applications according to ICH/CTD format.
· CTD guidance’s are intended to be used together with other ICH and agency guidance’s
· The guidance suggest that controlled procedure need to be implemented, to specific address –
maintenance, storage, access restriction, technical approach, and responsibilities of personal relevant
tasks across the retention period of an electronic record.
Preparing of organizing the CTD:
· The guidance address the general organization of the information to be presented in CTD
application for new pharmaceuticals(including biotechnology derived products)
· Guidance’s also are available that discuss the quality, efficacy and safety section of the CTD
in respective modules.
· Applicants should not modify the overall origination of the CTD
However in the non clinical and clinical summarizes section of the CTD, applicants can
modify individual formats, to provide the best possible presentation of the technical
information and to facilitate the understanding evaluation of the results
Throughout the CTD, the display of information should be unambiguous and transparent to
facilitate the review of the basic data and to help a reviewer become quickly oriented to
application contents
· Text and tables should be prepared using margins’ that allow the document to be
printed on both A4 paper(EU and Japan ) 8.5×1111 paper(US)
· The left hand margin should be sufficiently large that information is not obscured
through binding.
· Font sizes for text and tables should be of a style and size that are large enough to be
easily legible, even after photocopying.
· 12. Point Font is required for narrative text
27. · Acronyms and abbreviations should be defined the first time they are used in each
module.
The Common Technical Document (CTD) is a set of specification for application dossier for she
registration of Medicines and designed to be used across Europe, Japan and the United States. It was
developed by the European Medicines Agency (EMEA, Europe), the Food and Drug Administration (FDA,
U.S.) and the Ministry of Health, Labor and Welfare (Japan). The CTD is maintained by the International
Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH).[1]
The Common Technical Document is divided into five modules:
Administrative and prescribing information
Overview and summary of modules 3 to 5
Quality (pharmaceutical documentation)
Safety (toxicology studies)
Efficacy (clinical studies)
Detailed subheadings for each Module are specified for all jurisdictions. The contents of Module 1 and
certain subheadings of other Modules will differ, based on national requirements.
After the United States, European Union and Japan, the CTD has been adopted by several other countries
including Canada and Switzerland.
The Paper CTD is destined to be replaced by its electronic counterpart, the eCTD.
Organisation of the Common Technical Document
The Common Technical Document is organized into five modules. Module 1 is region specific. Modules
2, 3, 4, and 5 are intended to be common for all regions. Conformance with this guideline should ensure
that these four modules are provided in a format acceptable to the regulatory authorities.
Module 1. Administrative Information and Prescribing Information
This module should contain documents specific to each region; for example, application forms or the
proposed label for use in the region. The content and format of this module can be specified by the relevant
regulatory authorities.
Module 2. Common Technical Document Summaries
Module 2 should begin with a general introduction to the pharmaceutical, including its
pharmacologic class, mode of action, and proposed clinical use. In general, the Introduction should not
exceed one page.
Module 2 should contain 7 sections in the following order:
CTD Table of Contents
CTD Introduction
28. Quality Overall Summary
Nonclinical Overview
Clinical Overview
Nonclinical Written and Tabulated Summaries
Clinical Summary
The organisation of these summaries is described in Guidelines for M4Q, M4S, and M4E.
M4-Q: the CTD for the registration of pharmaceuticals for human use –quality
·The quality section of the CTD provides a harmonized structure and format for presenting CMC
(chemistry, manufacturing, controls) information in a registration dossier.
·The table of contents include sections on drug substance and drug product.
·Due to the fact that many CMC topics have not yet been the subject of ICH guidelines (e.g.: drug
substance synthesis, drug product manufacture), contain the content of CTD-Q is not totally
harmonised.
·A new section on pharmaceutical development and also a new CMC summary document, the
quality overall summary has been developed.
M4-S: the CTD for registration of pharmaceuticals for human use- safety
Non –clinical summaries and organisation of module-4
· The M4S guideline will outline the structure of format of nonclinical summaries in module2
of the CTD and will provide the organisation of module 4 i.e. the non-clinical study reports.
· The non-clinical overview should present an should present an integrated and critical
assessment of the pharmacological, pharmacokinetic, and toxicological evolution of the
pharmaceutical and generally not to exceed 30 pages.
· The non-clinical written summaries (100-150 pages) are to provide more extensive summaries
and discussion of non clinical information on pharmacological, pharmacokinetics and toxicology.
M4-E: the CTD for the registration of pharmaceuticals for human use-efficacy
Module-2:clinical overview and clinical summary
Module -5:clinical study reports.
M4E describes the structure and format of the clinical data in an application, including summaries and
detailed study reports.
There are two high level clinical summaries in module 2 of the CTD:
Clinical overview: a short document that provides a critical assessment of the clinical data
Clinical summary: a longer document that focuses on data summarisation and integration.
Module 3. Quality
Information on Quality should be presented in the structured format described in Guideline M4Q.
Module 4. Nonclinical Study Reports
The nonclinical study reports should be presented in the order described in Guideline M4S.
Module 5. Clinical Study Reports
The human study reports and related information should be presented in the order described in Guideline
M4E.
Organisation of the Common Technical Document for the
Registration of Pharmaceuticals for Human Use
Module 1: Administrative Information and Prescribing Information
Table of Contents of the Submission Including Module 1
Documents Specific to Each Region (for example, application forms, prescribing information)
Module 2: Common Technical Document Summaries
Common Technical Document Table of Contents (Modules 2-5)
CTD Introduction
29. Quality Overall Summary
Nonclinical Overview
Clinical Overview
Nonclinical Written and Tabulated Summaries
Pharmacology
Pharmacokinetics
Toxicology
Clinical Summary
Biopharmaceutical Studies and Associated Analytical Methods
Clinical Pharmacology Studies
Clinical Efficacy
Clinical Safety
Literature References
Synopses of Individual Studies
Module 3: Quality
Table of Contents of Module 3
Body of Data
Literature References
Module 4: Nonclinical Study Reports
Table of Contents of Module 4
Study Reports
Literature References
Module 5: Clinical Study Reports
Table of Contents of Module 5
Tabular Listing of All Clinical Studies
Clinical Study Reports
Literature References
Reference:
·Guidance for Industry, ICH M4: Organization of the CTD" U.S. Department of Health and Human
Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center
for Biologics Evaluation and Research (CBER) August 2001
SUPAC
( SCALE - UP AND POST- APPROVAL CHANGES )
Product development aims at formulating active drug ingredient in a palatable form .
Technology transfer of a pharmaceutical product from research to the production floor (shop floor) with
simultaneous increase in production outputs is commonly known as scaleup.In simple terms the process of
increasing batch size is termed as scaleup.Scale down refers to decrease in batch size in response to
reduced market requirements. SUPAC refers to the FDA recommended testing and filling actions to be
taken by a pharmaceutical firm when it changes the manufacturing process of a drug product that has been
approved via a New Drug Application(NDA),an Abbreviated New Drug Application (ANDA),or an
Abbreviated Antibiotic Drug Application(AADA). It is designed to lower the regulatory burden associated
with alterations in batch size ,components and composition ,manufacturing site or manufacturing of a
marketed product.
A drug may experience many changes during its life cycle .These changes may have an adverse effect on
the overall safety and effectiveness of the drug or drug product .After a number of changes over a long time
period ,the product coming to market maybe completely different from the one that was approved.Hence
data submitted to regulatory authorities in support of a change must have a comparison record of the drug
or drug product to the one that was approved initially.documentation generated in support of any change to
30. the approved drug is submitted to regulatory authority for review,and based on the benefit to risk ratio ,the
drug or drug product is approved.depending upon the intensity of change ,supporting documents are
provided to the regulatory agency.
The SUPAC Guidance offer an advantage over the regulations that the documents are specific for particular
dosage forms.This approach was taken since some product types are more complicated than others,and
require more complicated controls.Two guidance have been finalized.They are :
1. Immediate release solid oral dosage forms –Scale up and post approval changes
:Chemistry,Manufacturing and controls,in vitro dissolution testing ,and invivo bioequivalence
documentation.
2. Non sterile semisolid dosage forms –Scaleup and post approval changes : :Chemistry,
Manufacturing and controls, in vitro dissolution testing ,and invivo bioequivalence documentation.
In addition ,SUPAC documents covering other dosage forms (eg, extended-release
products,transdermals,parenteral solutions)as well as a related documents for bulk active substances ,are at
various stages of development.
Modifications are divided into one of three categories, each with specific testing and documentation
requirements.
Level 1 changes: Are those that are unlikely to have any detectable impact on formulation quality or
performance ,such as change of less than 5% in the concentration of an excipient.
likely to have a significant impact on quality or performance.
SUPAC Stability Testing:
In addition to in vitro release testing ,longterm stability studies are required at all levels of change ,while
accelerated stability studies are required for levels 2 and 3.
SUPAC Testing :
The purpose of SUPAC Testing is to verify that there is no change in product quality or performance after
a modification .A key component of a level 2 or 3 change is in vitro release testing for pre and post change
formulations.
For SUPAC Submissions,the following points should also be considered :
1.In most cases, except those involving scale-up,stability data from pilot scale batches will be acceptable to
support the proposed change.
2.Where stability data show a trend towards potency loss or degradant increase under accelerated
conditions ,it is recommended that historical accelerated stability data from a representative prechange
batch be submitted for comparision.
An invitro release rate can reflect the combined effect of several physical and chemical parameters
,including solubility and particle size of the active ingredient and rheological properties of the
dosageform.In most cases,invitro release rate is a useful test assess between prechange and post change
products.
1.In vitro release testing is a useful test to assess product “sameness”under certain scaleup and post
approval changes for semisolid products.
2.The development and validation of an invitro release test are not required for approval of an
NDA,ANDA,AADA nor is the invitro release test required as a routine batch to batch quality control test.
3.In vitro release testing ,alone ,is not a surrogate test for in vivo bioavailability or bioequivalence.
4.The in vitro release rate shouldnot be used for comparing different formulations across manufacturers.
The SUPAC guidance documents defines
1)levels of change
2)recommended chemistry,manufacturing,and controls tests for each level of change.
3)In vitro dissolution tests and in vivo bioequivalence tests for each level of change.
4)documentation that should support the change for new drug applications(NDA)and abbreviated new drug
applications(ANDAs).
31. This guidance provides recommendations to sponsors of new drug applications(NDA),abbreviated
antibiotic applications(AADA’s),who intend during the post approval period,to change :1)The components
or composition:2)the site of manufacture3)The scale up/scale down of manufacture 4)the
manufacturing(process and equipment)of an immediate release oral formulations.
The purpose of this guidance is to provided recommendations to pharmaceutical Manufacturers using the
Center for Drug Evaluation and Research’s guidance for Industry: Immediate Release Solid Oral Dosage
Forms-Scale up and post approval changes: Chemistry, manufacturing and controls ,In vitro Dissolution
testing ,and in vivo Bioequivalence Documentation(SUPAC-IR) ,which is published in November 1995,
and guidance for industry.
Dissolution testing: Case A: Dissolution of Q=85%in 15min in 900milliliters of 0.1N hydrochloride using
the United States Pharmacopoeia. Apparatus 1 at 100 revolutions per minute or Apparatus 2 At 50 rpm.
Case B: Multi point dissolution profile in the application/compendial medium at 15,30,45,60,120min until
an asymptote is reached for the proposed and currently Accepted formulation.
Case C: Multi point dissolution profiles performed in water ,0.1N HCL,and USP buffer media at pH
4.5,6.5,7.5 for the proposed and currently accepted formulations. Adequate sampling should be performed
at 15,30,45,60,120 min until either 90% of drug from the drug product is dissolved or an asymptote is
reached .A surfactant maybe used with appropriate justification.
Components and composition:
It focuses on changes in excipients in the drug product Changes in the amount of drug substance are not
addressed by this guidance Changes in components or composition that have the effect of adding a new
excipient or deleting an excipient.
A.Level 1 changes.
1.Definition of level
Level 1 changes are those that are unlikely to have any detectable impacts on formulation quality and
performance.
Examples:
a.Deletion or partial deletion of an ingredient intended to affect the color or flavor of the drug product ;or
change in the ingredient of the printing ink to another approved ingredient .
b.changes in excipients ,expressed as percentage (w/w)of total formulation ,less than or equal to the
following percent ranges:
Excipient percent excipient(w/w)out of total target dosage form weight
Filler ± 10
Disintigrant-starch ±6 : other ± 2
Binder ± 1
Lubricant –calcium or magnesium stearate ± 0.5
Other ± 2
Glidant - talc ±2
other±0.2
filmcoat- ±2
These percentages are based on the assumption that the drug substance in the drug product is formulated to
100%of label /potency .The total additive effect of all excipient changes should not change by more than
10%.
2. Test documentation
a. Chemistry documentation:
Application /compendial release requirements and batch records.
Stability testing:one batch on long term stability data reported in annual report.
b.Dissolution documentation
c.Invivo Bioequivalence documentation
32. 3.Filing documentation-prior approval supplement(all information including accelerated stability
data);annual report(long term stability data).
Level 2 changes: are those that could have a significant impact on formulation quality and performance.
Tests and filing documentation for a level 2 change vary depending on three factors :therapeutic
range,solubility,permeability.
Level 3 changes:are those that are likely to have a significant impact on formulation quality and
performance.Tests and filling documentation vary depending on the 3 factors;therapeutic range
,solubility,permeability..
SITE CHANGES:
Site changes consist of changes in location of the site of manufacture for both company-owned and contract
manufacturing facilities and donot include any scaleup changes ,changes in manufacturing(including
process and/or equipment),or changes in components or composition .New manufacturing locations should
have a satisfactory current Good manufacturing practice (CGMP)inspection..
A.Level 1 changes
1.Definition of level
Level 1 changes consists of site changes with in a single facility where the same equipment ,standard
operating procedures ,environmental conditions sites are used,and where no changes are made.and controls
and personnel common to both manufacturing to the manufacturing batch records except for administrative
information and the location of the facility.common is defined as employees already working on the
campus who have suitable experience with the manufacturing process.
2.Test documentation
a)Chemistry documentation
None beyond application/compendial release requirements.
b)Dissolution documentation
None beyond application/compendial release requirements.
c)Invivo bioequivalence documentation
None
3.Filing documentation
Annual report
B.Level 2 changes
1.Definition of level
Level 2 changes consists of site changes with in a contiguous campus,or between facilities in adjacent city
blocks,where the same equipment,SOP’s,environmental conditions(eg temparature and humidity)and
controls,and personnel common to both manufacturing sites are used ,and where no changes are made to
the manufacturing sites are used ,and where no changes are made to the manufacturing batch records,except
for administrative information and the location of the facility.
2.Test documentation
a.Chemistry Documentation
Location of new site and updated batch records.None beyond application /compendial release requirements.
One batch on long term stability data reported in annual report.
b.Dissolution Documentation
None beyond application /compendial release requirements.
c.Invivo Bioequivalence documentation
None
3.Filing documentation
Changes being effected supplement :annual report(long term stability test data)
C.Level 3 changes
1.Definition of level
33. Level 3 changes consists of a change in manufacturing site to a different campus.A different campus is
defined as one that is not on the same original contiguous site or where the facilities are not in adjacent city
blocks.To qualifyas a level 3 change,The same equipment ,SOP’s ,environmental conditions ,and controls
shouldbe used in the manufacturing process at the new site ,and no changes maybe made to the
manufacturing batch records except for administrative information ,location,language translation,where
needed.
2.Test documentation
a)Chemistry documentation
Location of new site and updated batch records.
Application/compendial release requirements .
Stability:
Significant body of the data available:
One batch with three months acclerated stability data reported in supplement;one batch on longterm
stability data reported in annual report.
Significant body of the data not available:
Up to three batches with three months acclerated stability data reported in supplement;up to three batches
on long term stability data reported in annual report.
b)Dissolution documentation
CaseB:multi point dissolution profile should be performed in the application/compendial medium at
15,30,45,60,120 minutes or until an asymptote is reached.
The dissolution profile of the drug product at the current and proposed site should be similar.
c) Invivo Bioequivalence Documentation:
None
3. Filing Documentation
Changes being effected supplement;annual report(long term stability data).
CHANGES IN BATCH SIZE (SCALE- UP/SCALE DOWN) :
Post approval changes in the size of a batch from the pivotal/pilot scale batch material to larger or smaller
production batches call for submission of additional information in the application. Scale down below
100,000 dosage units is not covered by this guidance .All scale-up changes should be properly validated
and, where needed, inspected by appropriate agency personnel.
A)Level 1 changes
1. Definition of level
Change in batch size up to and including a factor of 10 times the size of the pilotbio batch where;
i) The equipment used to produce the test batches is of the same design and operating principles;
ii) The batches is manufactured in full compliance with CGMP’s.
iii) The same standard operating procedure(SOP’s)and controls, as well as the same formulation and
manufacturing procedures, are used on the test batches and on the full scale production batches
2. Test documentation
a)Chemistry documentation
Application/Compendial release requirements .Notification of change and submission of updated batch
records in annual report.
One batch on long term stability reported in annual report .
b)Dissolution documentation
None beyond application /compendial release requirements.
c)In vivo Bio equivalence
None
3.Filing Documentation
Annual report (long term stability data).
B)Level 2 changes
34. 1)Definition of level
Changes in batch size beyond a factor of ten times the size of the pilot/biobatch,where;
i)The equipment used to produce the test batches is of the same design and operating principles;
ii)The batches is manufactured in full compliance with CGMP’s.
iii)The same standard operating procedure(SOP’s)and controls, as well as the same formulation and
manufacturing procedures,are used on the test batches and on the full scale production batches.
2.Test documentation
a)Chemistry documentation
Application/compendial release requirements .Notification of change and submission of updated batch
records.
Stability testing:
One batch with three months accelerated stability data and one batch on longterm stability.
b)Dissolution documentation
Case B testing
c)In vivo Bioequivalence documentation
None.
3.Filing Documentation
Changes being effected supplement :annual report(long term stability data)
MANUFACTURING CHANGES:
Manufacturing changes may affect both equipment used in the manufacturing process and the process
itself.
A.Equipment
1.Level 1 changes
a)Definition of change
This category consists of :
1)Change from non-automated or non mechanical equipment to move ingredients:and
2)Change to alternative equipment of the same design and operating principles of the same or of a different
capacity.
b)Test documentation
i)Chemistry documentation
Application/compendial release requirements .Notification of change and submission of updated batch
records.
Stability testng:One batch on longterm stability.
b)Dissolution documentation
None beyond application/compendial release requirements.
c)In vivo Bioequivalence documentation
None.
c)Filing documentation
Annual report(Long term stability data
2.Level 2 Changes
a)Definition of level
Change in equipment to a different design and different operating principles.
b)Test documentation
i)Chemistry documentation
Application/compendial release requirements .Notification of change and submission of updated batch
records.
Stability testing
Significant body of data available:
One batch with three months accelerated stability data reported in supplement ;One batch on long term
stability data reported in annual report.
35. Significant body of data not available
Up to three batches with three months accelerated stability data reported in supplement;upto three batches
on long term stability data reported in annual report.
ii)Dissolution documentation
Case C dissolution profile.
iii)Invivo Bioequivalence documentation
None
c.Filing documentation
Prior approval supplement with justification for change ;annual report(long term stability data).
B)Process
a)Definition of level
This category includes process changes including changes such as mixing times and operating speeds
within applicaton/validation ranges.
b)Test documentation
i)Chemistry documentation
None beyond application/compendial release requirements.
ii)Dissolution documentation
None beyond application/compendial release requirements
iii)In vivo Bioequivalence documentation
None
c).Filing documentation
Annual report
2.Level 2 changes
a.Definition of level
This category includes process changes including changes such as mixing times and operating speeds
outside of application / validation ranges.
b)Test documentation
i)Chemistry documentation
Application/compendial release requirements .Notification of change and submission of updated batch
records.
Stability testing:one batch on longterm stability.
ii)Dissolution documentation
Case B dissolution profile.
iii)Invivo Bioequivalence documentation
None
c).Filing documentation
Changes being effected supplement ;annual report(long term stability data).
3.Level 3 changes
a).Definition of level
This category includes changes in the type of process used in the manufacture of the product ,such as a
change from wet granulation to direct compression of dry powder.
b)Test documentation
i)Chemistry documentation
Application/compendial release requirements .Notification of change and submission of updated batch
records.
Stability testing:
Siignificant body of data available:
One batch with three months accelerated stability data reported in supplement ;one batch on long term
stability data reported in annual report.
Significant body of data not available:
36. Up to three batches with three months accelerated stability data reported in supplement ;up to three batches
on long term stability data reported in annual report.
ii)Dissolution documentation
case B dissolution.
iii)Invivo Bioequivalence documentation
Invivo bioequivalence study .The bioequivalence study maybe waived if a suitable in vivo/invitro
correlation has been verified.
c).Filing documentation
Prior approval supplement with justification ;annual report (long term stability data).
Handling and Maintenance of Electronic documentation
Introduction of Electronic documentation:
An electronic document is any electronic media content (other than computer programs or system files) that
is intended to be used in either an electronic form or as printed output.
Originally, any computer data were considered as something internal the final data output was always on
paper. However, the development of computer networks has made it so that in most cases it is much more
convenient to distribute electronic documents than printed ones. And the improvements in electronic
display technologies mean that in most cases it is possible to view documents on screen instead of printing
them (thus saving paper and the space required to store the printed copies).
However, using electronic documents for final presentation instead of paper has created the problem of
multiple incompatible file formats. Even plain text computer files are not free from this problem e.g. under
MS-DOS, most programs could not work correctly with UNIX-style text files (see newline), and for non-
English speakers, the different code pages always have been a source of trouble.
Even more problems are connected with complex file formats of various word processors, spread sheets
and graphics software. To alleviate the problem, many software companies distribute free file viewers for
their proprietary file formats (one example is Adobe's Acrobat Reader). The other solution is the
development of standardized non-proprietary file formats (such as HTML and Open Document), and
electronic documents for specialized uses have specialized formats–the specialized electronic articles in
physics use TeX or PostScript.
GUIDELINES FOR RECORDS OF LONG-TERM OR ENDURING LEGAL VALUE STORED ON
ELECTRONIC MEDIA
Planning Process:
Access: Before you convert your information system, decide how you will provide ready access to the
records you store off-line.
Media and systems: Select appropriate media and systems for maintaining your record information.
Recommended: Magnetic tapes or cartridges are preferred for the long-term storage of electronic records.
CD-ROMs created with the ANSI 9660 standard can be used as well. The storage capacity of a magnetic
tape, however, far exceeds that of a CD-ROM.
Not Recommended: Floppy disks, removable disks and optical disks are not recommended for the long-term
storage of electronic records.
Maintenance:
Access: Maintain your records in a useable format and keep up to date all materials needed to access them,
including indexes and other documentation, until they are scheduled for disposal or for transfer to the State
Archives.
Backups: Maintain in an off-site location backup and archived copies of records and all materials required
to access them.
Labeling: Develop procedures for labeling tapes and cartridges. Each external label should carry
information unique to the tape or cartridge it identifies. At minimum, it should display the name of the
organizational unit responsible for the data, the system title, the file title, the destruction date or permanent
status of the record, and its security classification, if applicable.