UNIT 5: DocumetationDocumentation 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 anaudit 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. 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. 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: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 recordsA 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 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.(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.superiorcontrols.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/ ucm122886.htm

Formulation development for global fillingsTHE IMPACT OF WORLD REGULATIONS TO DEVELOP AND LAUNCH HARMONIZED COSMETIC PRODUCTSBusiness 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 ScenarioWe have a lack of global harmonization on Cosmetics:

USA Europe Asia Latin AmericaRobust 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 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

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 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 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: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/ PediatricsSection 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. Description2. Clinical Pharmacology 3. Indications and Usage4. Contraindications5. Warnings 6. Precautions7. Adverse Reactions8. Drug Abuse and Dependence9. 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 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 required1.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 effects3. 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 :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 drugList 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 controlsClinical 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 aœno- 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 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 informationItem 14: Patent certification Item15: Establishment description Item 16: Debarment certification Item 17: Field copy certificationItem 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

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 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. 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 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 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:

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 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/ approvalapplications/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.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

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 informationOverview and summary of modules 3 to 5Quality (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 DocumentThe 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 InformationThis 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 SummariesModule 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 ContentsCTD Introduction

Quality Overall SummaryNonclinical OverviewClinical OverviewNonclinical Written and Tabulated SummariesClinical 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- safetyNon –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-efficacyModule-2:clinical overview and clinical summaryModule -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 dataClinical 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 ReportsThe nonclinical study reports should be presented in the order described in Guideline M4S.Module 5. Clinical Study ReportsThe human study reports and related information should be presented in the order described in Guideline M4E.

Organisation of the Common Technical Document for theRegistration of Pharmaceuticals for Human UseModule 1: Administrative Information and Prescribing InformationTable of Contents of the Submission Including Module 1Documents Specific to Each Region (for example, application forms, prescribing information)Module 2: Common Technical Document SummariesCommon Technical Document Table of Contents (Modules 2-5) CTD IntroductionQuality Overall Summary

Nonclinical OverviewClinical OverviewNonclinical Written and Tabulated SummariesPharmacology PharmacokineticsToxicologyClinical SummaryBiopharmaceutical Studies and Associated Analytical MethodsClinical Pharmacology StudiesClinical EfficacyClinical SafetyLiterature ReferencesSynopses of Individual StudiesModule 3: QualityTable of Contents of Module 3Body of DataLiterature ReferencesModule 4: Nonclinical Study ReportsTable of Contents of Module 4Study ReportsLiterature ReferencesModule 5: Clinical Study ReportsTable of Contents of Module 5Tabular 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 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 defines1)levels of change2)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).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 levelLevel 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 weightFiller ± 10Disintigrant-starch ±6 : other ± 2Binder ± 1Lubricant –calcium or magnesium stearate ± 0.5 Other ± 2Glidant - talc ±2 other±0.2filmcoat- ±2These 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 documentationa. Chemistry documentation:Application /compendial release requirements and batch records.Stability testing:one batch on long term stability data reported in annual report.b.Dissolution documentationc.Invivo Bioequivalence documentation3.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 levelLevel 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 documentationa)Chemistry documentation None beyond application/compendial release requirements.b)Dissolution documentationNone beyond application/compendial release requirements. c)Invivo bioequivalence documentationNone3.Filing documentationAnnual reportB.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 documentationa.Chemistry DocumentationLocation 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 DocumentationNone beyond application /compendial release requirements.c.Invivo Bioequivalence documentationNone3.Filing documentationChanges being effected supplement :annual report(long term stability test data) C.Level 3 changes1.Definition of levelLevel 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 documentationa)Chemistry documentationLocation 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 documentationCaseB: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:None3. Filing DocumentationChanges 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 changes1. Definition of levelChange 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 batches2. Test documentationa)Chemistry documentationApplication/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 documentationNone beyond application /compendial release requirements.c)In vivo Bio equivalenceNone3.Filing DocumentationAnnual report (long term stability data).B)Level 2 changes1)Definition of levelChanges 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 documentationa)Chemistry documentationApplication/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 documentationCase B testingc)In vivo Bioequivalence documentationNone.3.Filing DocumentationChanges 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.Equipment1.Level 1 changesa)Definition of change This category consists of :1)Change from non-automated or non mechanical equipment to move ingredients:and2)Change to alternative equipment of the same design and operating principles of the same or of a different capacity.b)Test documentationi)Chemistry documentation Application/compendial release requirements .Notification of change and submission of updated batch records.Stability testng:One batch on longterm stability.b)Dissolution documentationNone beyond application/compendial release requirements.c)In vivo Bioequivalence documentationNone.c)Filing documentationAnnual report(Long term stability data2.Level 2 Changesa)Definition of levelChange in equipment to a different design and different operating principles.b)Test documentationi)Chemistry documentation Application/compendial release requirements .Notification of change and submission of updated batch records.Stability testingSignificant 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 availableUp 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 documentationCase C dissolution profile.iii)Invivo Bioequivalence documentationNonec.Filing documentationPrior approval supplement with justification for change ;annual report(long term stability data).B)Processa)Definition of levelThis category includes process changes including changes such as mixing times and operating speeds within applicaton/validation ranges.b)Test documentationi)Chemistry documentation None beyond application/compendial release requirements.ii)Dissolution documentationNone beyond application/compendial release requirementsiii)In vivo Bioequivalence documentationNonec).Filing documentationAnnual report2.Level 2 changesa.Definition of levelThis category includes process changes including changes such as mixing times and operating speeds outside of application / validation ranges.b)Test documentationi)Chemistry documentation Application/compendial release requirements .Notification of change and submission of updated batch records.Stability testing:one batch on longterm stability.ii)Dissolution documentationCase B dissolution profile.iii)Invivo Bioequivalence documentationNonec).Filing documentationChanges being effected supplement ;annual report(long term stability data).3.Level 3 changesa).Definition of levelThis 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 documentationi)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: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 documentationInvivo bioequivalence study .The bioequivalence study maybe waived if a suitable in vivo/invitro correlation has been verified.c).Filing documentationPrior approval supplement with justification ;annual report (long term stability data).

Handling and Maintenance of Electronic documentationIntroduction 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 MEDIAPlanning 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.Inventories: Develop procedures to maintain an accurate and up-to-date inventory of all records stored off-line. A useful inventory will contain the following information about each tape/cartridge: tape ID, file title(s); dates covered by files; date moved off-line; the recording density; type of internal labels; volume

serial number, if applicable; number of tracks; character code/software dependency; information about block size; and the number of the tape if part of a multitape set. Where applicable, it will also give the number of records for each set of data, the format of the record, and logical record length.Care and Handling of Magnetic Tapes:

Purchase and use high-quality storage tapes. Six months or less before using the tapes to record information, test them to make sure they are error free. Read a statistical sample of stored tapes annually to identify and correct any loss of data. Every three to four years (or more frequently if you read them often) rewind each tape under controlled tension. Before they tapes are ten years old, copy the old tapes onto new tapes that have been tested and verified. Maintain tapes in storage areas that are dust-free and controlled for temperature and humidity. A constant temperature between 60 and 68 degrees F., and a constant relative humidity between 35 and 45 percent are recommended. Prohibit smoking, eating and drinking in areas where tapes are stored. These same prohibitions should apply to media test or evaluation areas where there are records of long-term or enduring legal value. Minimize handling and avoid touching the tape surface or edge.

Maintenance and retention of electronic recordsWith the ever changing technology that has become a major consideration in doing business, the Bureau of Internal Revenue (BIR) recently issued Revenue Regulation (RR) 09–2009, dated December 23, 2009, for the maintenance, retention and submission of electronic records for taxpayers, in general, and the mandatory adoption of computerized accounting system (CAS) for large taxpayers.Among the salient features of the regulations are:A. General requirements in keeping electronic records. A taxpayer must maintain all records that are necessary for the determination of his correct tax liability. These records must be made available on request by the Commissioner of Internal Revenue or its authorized representatives.If a taxpayer retains records in both electronic and hardcopy formats, the taxpayer shall make available to the BIR such records in electronic format upon request of the BIR. The taxpayer may demonstrate tax compliance with traditional hardcopy documents or reproductions, whether or not such taxpayer has retained or has the capability to retain records on electronic or other storage media, but he/it shall not be relieved of the responsibility from his/its obligation to comply with the requirement to make available records in electronic format.B. Adoption of CAS for large taxpayers. All large taxpayers classified under RR 01–98 are now required to adopt CAS in maintaining their books of accounts and accounting records.C. Maintenance and location of electronic records. The taxpayer’s computer hardware or software should accommodate the extraction and conversion of retained records in accordance with existing BIR regulations.Electronic records must be kept at the taxpayer’s place of business in the Philippines or other places designated by the Commissioner of Internal Revenue. Records kept outside the Philippines and accessed electronically from the Philippines are not considered to be records in the Philippines. However, the BIR may accept a copy of such records if made available in the Philippines and submitted to the BIR in an electronically readable and usable format, and contain adequate details to support the taxpayer’s tax returns.D. Retention of hardcopy records and source documents. Taxpayers must retain hardcopy records that are created or received in the ordinary course of business, unless such hardcopy records are allowed to be retained, using alternative storage media such as microfilm, microfiche, etc.Taxpayers keeping electronic records must also retain source documents. A source document includes items such as sales invoices, cash register receipts, formal written contracts, credit card receipts, delivery

slips, deposit slips, work orders, dockets, checks, bank statements, tax returns, and could also include email and other general correspondence where relevant for tax purposes.E. Alternative Storage Media. Taxpayers may, however, convert hardcopy documents received or produced in the normal course of business and required to be retained under this regulation to microfilm, microfiche or other storage only imaging systems and may discard the original hardcopy documents, provided the conditions here under enumerated are met.However, a prior permit from the BIR is required before use of microfilm, microfiche and other storage only imaging systems.It must be noted, however, that these regulations are for BIR purposes only and do not extend to other government agencies that may require other legal format/requirements for documentation purposes. Thus, Section 9.1 of these regulations specifically provides that “the provisions of this regulation do not relieve taxpayers of the responsibility to retain hard copy records that are created or received in the ordinary course of business, as required by existing law and regulations.”Specifically, Republic Act 8792, or the Electronic Commerce Act of 2000, defines “electronic data message” and “electronic document.” As such, information shall not be denied validity or enforce ability solely on the ground that it is in the form of an electronic data message or electronic document, purporting to give rise to such legal effect. Electronic data messages or electronic documents shall have the legal effect, validity or enforce ability as any other document or legal writing. Thus, for evidentiary purposes, an electronic document shall be the functional equivalent of a written document.In any legal proceedings, therefore, nothing in the application of the rules on evidence shall deny the admissibility of an electronic data message or electronic document in evidence (a) on the sole ground that it is in electronic form; or (b) on the ground that it is not in the standard written form. But, of course, the person seeking to introduce an electronic data message or electronic document in any legal proceeding has the burden of proving its authenticity by evidence capable of supporting a finding that the electronic data message or electronic document is what the person claims it to be. The authenticity may be proved by showing the integrity of the information and communication system in which it is recorded or stored or the reliability, for example, of the manner or method in which it is communicated, generated or stored.Electronic common technical documentThe electronic Common Technical Document (eCTD) is an interface for the pharmaceutical industry to agency transfer of regulatory information. The content is based on the Common Technical Document (CTD) format.It was developed by the International Conference on Harmonisation (ICH) Multidisciplinary Group 2 Expert Working Group (ICH M2 EWG). As of January 1, 2008, the U.S. Food and Drug Administration announced that the eCTD is the preferred format for electronic submissions.[1] To date, over 98,000 eCTD sequences have been submitted to the FDA.[2] Although the agency has not released an expected target date, the FDA revealed during the 2009 DIA Annual Meeting that it is looking at draft legislation to require eCTD.[3]Pharmaceutical and Biotechnology Companies and ICH:Pharmaceutical and biotechnology are fortunate, in that a consortium of regulatory authorities and trade organizations have developed standards for documents and data that must be collected to support a company's claims of the quality, safety, and efficacy of their products.The International Conference on Harmonisation (ICH) has been working since the late 1980s to develop standards that enable companies to conduct studies once and submit the results globally. In addition, ICH has developed a standard for submissions to health authorities that enable these submissions to be delivered in a standardized electronic format for review by regulators. This standard the electronic Common Technical Document (eCTD) means that the majority of the content of a submission can be compiled once and submitted electronically to multiple health authorities where regulators can perform their reviews in a fully electronic environment. What had once been a semi-trailer truckload of paper that took up to a year to compile into three-ring binders can now be 100 percent electronically managed.

The ICH initially covered the requirements of US, European Union and Japan. The applicability of the ICH submission standards has grown exponentially with the expansion of the European Union to 28 member states, and the endorsement of the eCTD format by Canada, the World Health Authority (WHO), Switzerland, Australia, and the Association of Southeast Asian Nations (ASEAN).Pharmaceutical point of view:The eCTD has five modules1. Administrative Information and Prescribing Information2. Common Technical Document Summaries3. Quality4. Nonclinical Study Reports5. Clinical Study ReportsA full table of contents could be quite large.There are two categories of modules:Regional module: 1 (different for each region; i.e., country)Common modules: 2-5 (common to all the regions)The CTD only defines the content of the common modules. The contents of the Regional Module 1 are defined by each of the ICH regions (USA, Europe and Japan).The eCTD is a common organizational structure for the content of submissions for drug and biologic products intended for human use (see Figure 1). It is divided into five modules in the following organizational structure:

Figure.1•Module 1 is not part of the ICH eCTD standard as it has been designated to each regulatory authority to define the contents of Module 1 for the regulatory and administrative documentation it requires with the different types of applications.•Module 2 contains the summaries and overviews of Modules 3 through 5. Everything contained in Modules 3 through 5 must be summarized along with a critical analysis of the findings about the pharmaceutical or biotechnology product.•Module 3 contains the documentation about the chemistry, manufacturing, and controls content of the submission. •Module 4 contains the nonclinical (animal and in vitro) studies that have been conducted to support the company's assertions about the safety of the product. It includes the pharmacology, Pharmacokinetic, and toxicology studies and datasets that are required to be conducted during preclinical development, and phases 1 through 4 of clinical development.•Module 5 contains the clinical (human) studies that have been conducted to support the company's assertions about the efficacy of the product. It includes case report forms and datasets. The study types include bioavailability, pharmacokinetic, Pharmacodynamic, efficacy and safety studies and any post marketing studies.

Electronic Common Technical Document (eCTD)- Submission:Common Technical Document is an industry standard document in Pharmaceutical industry adopted by US, EU, Canada and Japan for regulatory submission. eCTD is an electronic version of CTD.eCTD is an interface for Pharmaceutical industry to agency transfer of regulatory information. Here eCTD is not limited to transfer of information it also considers creation, review, life cycle management and archival of electronic submission. It facilitates paperless submission to the respective authorities.Challenges Faced in Implementing eCTD • Business Process needs revision• Infrastructure needs to be updated• Personnel needs to be trained• High Investment and Maintance Cost in purchasing and adopting the system We Add Value by1. Preparation of Complete Dossier in eCTD Format.2. Conversion of CTD format to eCTD format by using our software.3. Complete support for Managing the lifecycle of eCTD.4. Consultation on Transition from paper based system to Electronic Common Technical Document (eCTD) system.Who will be beneficial from our eCTD Consultation 1. Small Companies having 5-10 submission in a year - High investment and Maintenance of system can be a costly affair.2. Pharmaceutical Companies - Looking for transition from paper based system to eCTD 3. Companies who want quick and speedy submission - Avoiding losses arriving as a result of delayed submission. Significance of Electronic DocumentationThe main benefits of electronic document management are:

Electronic document management frees your staff from the drudgery of bulk paper filing and intuitive additional tools help streamline work processes even further. Powerful filing flexibility - the same document can be filed under several references such as Name, Document Number and Date - not possible with paper documents or computer files unless copies are made. This lays the foundation for a very effective retrieval tool. Indexing a document is an easier and simpler task than giving it a complex filename and having to save it to a particular named Explorer folder. Integrating the filing of other electronic files as well as paper documents enables you to achieve one consistent and logical filing structure for ALL your documents. Paper and PC-generated files received from any source (Post, Email or Fax) are filed into one system. They can then be viewed or actioned by any user or users simultaneously across a network or web. The ability to share documents has several advantages: inter-departmental queries are resolved more effectively by reducing the time and physical effort required to communicate and move between departments. When talking to customers, questions can be answered instantly, as information such as specifications, price lists & delivery notes are available on screen without leaving one’s desk. The need to print or copy documents reduces dramatically, saving time and money. No more lost or mislaid files. A 4-drawer filing cabinet typically contains 8-10,000 pieces of paper, occupies 0.7 square metres (7.5 square feet) of precious office space, and takes around 100 valuable staff hours to fill. By the time it is full, many documents will not have been retrieved since they were first filed: as many as 1 in 10 will be missing or in the wrong place: and once full, it is a costly and inefficient chore to weed out old files – either for archiving, or for destruction. And a misfiled piece of paper is as bad as a lost piece of paper: in both cases, the information is not available.

Freeing up expensive floor space can result in large cost savings as space becomes available. More desks or new equipment can be added without having to consider larger premises.

Electronic documentation enhances accuracy and information gathering:Electronic charting has allowed this respiratory care department to improve efficiency and patient care.Advances in information technology have accelerated the growth of information-gathering systems, so much so that electronic documentation has become an element of all aspects of society.1 The accurate documentation of vital clinical information is essential when examining the effect of interventions on patient outcomes.2 Precise documentation becomes even more paramount when patient safety concerns need to be assessed. Tracking patient safety indicators, determining clinician compliance regarding the utilization of ventilator bundles, or trending the incidence of accidental extubations can be time-consuming and often is less than accurate.3 With electronic documentation, retrieving patient data is quicker and more efficient, with a reduced chance of error.4 The use of electronic charting gives the bedside clinicians another tool to use to ensure high-quality patient care. All of the professionals treating a given patient have the need to document clinical assessments and performed interventions,5 and they need to coordinate and have equal assess to all documented information. Electronic documentation allows multiple providers to document spontaneously and also to evaluate other clinician assessments. The coordination and gathering of this information can be done by the development of individual queries or databases. Compliance with performance improvement initiatives or the observation of safety indicators is an additional benefit garnered from electronic documentation.6 We examined the documentation of reporting patient safety indicators after the implementation of electronic monitoring. As medical professionals, we are continuously trying to find ways to document accurate data, but our ability to query and retrieve different pieces of that data has always been a complex process. In the past, members of the health care team spent many hours poring through traditional patient records for different points of data. At times, this data was not even recorded, and, when it was documented, each clinician had a different method of documentation. The frustration that occurred in this process could make the data collection inaccurate. Individuals would make assumptions about what other clinicians meant, and those assumptions would lead to other inaccuracies in the data collection and reporting. Although the importance of collecting exact data has really never changed, it is now looked at from a different perspective. With the creation of Medicare Bill CMS 1533-P, which dictates that when patients develop a hospital-acquired infection, payment for treatment will be minimized or absent,7 accurate documentation and data collection have an even bigger impact than in the past. The ability to collect, collate, and report this data has now become a major requirement for most respiratory care departments across the country.8 The ability of respiratory care practitioners to now collect and report data has placed them on the radar screen of hospital administration.9 The department has now become a major player in the prevention of ventilator-acquired pneumonia (VAP)—specifically, because of our ability to perform quality assurance for our department to make sure each ventilated person is assessed on a daily basis for their ability to wean. If deemed clinically stable, a spontaneous breathing trial is performed on these people each day. Our electronic charting now allows the management team to perform a query at the end of each month to make sure that the bedside therapists are assessing their patients on a daily basis. Although not each patient will have a spontaneous breathing trial every day, at least they are being assessed for their ability to wean each day. Tangible Benefits of Electronic Document Management:An electronic document management system potentially includes tangible benefits such as:•Reduced paper storage - removal of paper by converting paper documents that are stored within the business or in an archive into an electronic form•Improved retrieval time - obtaining paper from storage or an archive is typically slower than electronic retrieval of documentation. Along with the improved retrieval time comes the ability to perform searches for similar information. This is especially useful when trying to perform major changes or perhaps searching for information subject to litigation

•Saves paper, printer and toner costs - reduced need to print paper documents as electronic versions are available for use or reuse. Whilst the paperless office is still not a reality, it is anticipated that the availability of an EDMS would reduce the need for multiple paper copies of documents. If the EDMS does not have an electronic signature capability then at least one "master" paper signed document will need to be printed•Improved staff productivity - less time spent searching for documents or trying to find the current version. Faster document review and approval cycles, particularly where multiple reviewers and approvers are involved in the business process•Improved disaster recovery - EDMS contains business critical documents and has its own disaster recovery plan that allows the documents to be restored in the event of significant disruption or disaster for the businessSome of these tangible benefits, in particular productivity, may lead to a financial assessment of the benefit and allow the redeployment of resources.Intangible Benefits of Electronic Document ManagementAn electronic document management system potentially includes intangible benefits such as:•Improved security through a single secure location for documents and ensuring that the right people are able to access the right documents•Improved compliance with regulation or legislation•Central control and management of documentation•Reduced chance of "losing" documents•Enhanced competitive situation due to improved internal document processes•Improved customer service through faster access to and retrieval of important customer informationRefernces:

www.mastercontrol.com/.../speeding_time_to_market_pharmaceutical_0210.html - Cached www.mastercontrol.com/.../speeding_time_to_market_pharmaceutical_0210.html - Cached www.ema.europa.eu/pdfs/human/ich/288799een.pdf www.perfect-consultants.com/e-ctd.html - United States - Cached – Similar www.ngpharma.com/.../Optimizing-Efficiency-with-Electronic-Regulatory-Submissions/ - Cached