Brief Introduction to General Requirements of Health Regulatory Agency

UNITED STATES FOOD & DRUG ADMINISTRATION

1. History From the beginnings of civilization people have been concerned about the quality and safety of foods and medicines. Regulation of food in the United States dates from early colonial times. Federal controls over the drug supply began with inspection of imported drugs in 1848.

Cont… S.S.P.C. Year Events occurred 1820 U.S. Pharmacopoeia 1848 Drug importation act 1883 Bureau of chemistry's food adulteration studies 1907 Certified color regulations 1939 First food standards 1949 Guidance to industry on procedures for the appraisal of the toxicity of chemicals in food 1954 Radiological examination of food 1966 Child protection act 1971 National center for toxicological research 1976 Medical device amendments 1982 Tamper-resistant packing regulations 1994 Dietary supplement health and education act 2004 Food allergy labeling and consumer protection act 2005 Drug safety board

S.S.P.C. 2. What is the need?

S.S.P.C. 3. FDA Objective information. consumer Better marketing safety Post terrorism Counter review product New manufacturing and handling watch on safe Keep Monitoring new risk for Standard regulation and Enforcement correcting problem &

S.S.P.C. In short, To promote and protect the public health by helping safe and effective products reach the market in a timely way. To monitor products for continued safety after they are in use, and To help the public get the accurate, science- based information needed to improve health

S.S.P.C. 4. FDA Components CBER CDRH CDER CFSAN CVM NCTR OC ORA COSMETICS

Cont… S.S.P.C. Sr. No Component Full Form Regulates 5A CBER Center For Biologics Evaluation And Research Biological Products 5B CDRH Center For Devices And Radiological Health Safety and Effectiveness of New Medical Devices Before they are Marketed 5C CDER Center For Drug Evaluation And Research Health of by Assuring Prescription and OTC Drugs are Safe and Effective 5D CSFAN Center For Food Safety And Applied Nutrition Food Supply is Safe, Sanitary, Wholesome, and Honestly Labeled, and Cosmetic Products are Safe and Properly Labeled. 5E CVM Center For Veterinary Medicine Assure that Animal Food Products are Safe. 5F NCTR National Center For Toxicological Research Human Toxicity 5G OC Office Of The Commissioner 5H ORA Office Of Regulatory Affairs Products Comply with Appropriate Public Health Laws and Regulations.

4A. CBER S.S.P.C. CBER regulates biological products to advancing the public health through innovative regulations that ensure- the safety effectiveness and timely delivery to patients of biological products. Current authority for this responsibility resides in Section 351 of the Public Health Service Act and in specific sections of the Food Drug and Cosmetic Act. The mission of CBER is to protect and enhance the public health through the regulation of biological and related products including blood, vaccines, tissue, allergenic and biological therapeutics.

S.S.P.C. 4B. CDRH CDRH assure that new medical devices are safe and effective before they are marketed. Surgical Tools or Treat Diagnose Prevent Monitors Devices Surveillance System Product Life Cycle, Throughout the Postmarketing Including Products Emitting Radiation

S.S.P.C. 4C. CDER The FDA's Center for Drug Evaluation and Research (CDER) promotes and protects the health, by assuring that all prescription and over-the-counter drugs are safe and effective. CDER evaluates all new drugs before they are sold, and serves as a consumer guide for the more than 10,000 drugs on the market to be sure they continue to meet the highest standards.

S.S.P.C. 4D. CFSAN The Center for Food Safety and Applied Nutrition, known as CFSAN, is one of six product-oriented centers, in addition to a nationwide field force, that carry out the mission of the Food and Drug Administration (FDA). The mission of CFSAN is, promoting and protecting the public's health by ensuring that the nation's food supply is safe, sanitary, wholesome, and honestly labeled, and that cosmetic products are safe and properly labeled. Scope as follow,

S.S.P.C. Cont… The safety of substances added to food, like food and color additives. The safety of foods and ingred. developed through biotechnology. Seafood hazard analysis and critical control point (HACCP) regulations. Health risks associated with food borne chemical, and biological contaminants. Regulations and activities dealing with the proper labeling of foods and cosmetics. Policy governing the safety of dietary supplements, infant formulas, and medical foods. Food industry postmarketing surveillance and compliance. Consumer education and industry outreach. Cooperative programs with state and local governments.

Cont… Some of CFSAN's current areas of food safety concern are: S.S.P.C. Cont… Some of CFSAN's current areas of food safety concern are: biological pathogens (e.g., bacteria, viruses, parasites) naturally occurring toxins (e.g., mycotoxins, ciguatera toxin, paralytic shellfish poison) dietary supplements (e.g., ephedra) pesticide residues toxic metals (e.g., lead, mercury) decomposition and filth (e.g., insect fragments) food allergens (e.g., eggs, peanuts, wheat, milk) nutrient concerns (e.g., vitamin D overdose, pediatric iron toxicity) dietary components (e.g., fat, cholesterol) radionuclide product tampering

S.S.P.C. 4E. CVM The FDA's Center for Veterinary Medicine (CVM) evaluates the safety and effectiveness of drugs used to treat animals. Nearly 300 drugs currently on the market have been approved by the FDA for dogs, cats and horses. CVM has two top priorities: Prevent the establishment of bovine spongiform encephalopathy (BSE), "mad cow disease." & Counter the risk of antibiotic resistance in humans from animal food. CVM regulates the manufacture and distribution of food additives and drugs that will be given to animals. CVM is responsible for regulating drugs, devices, and food additives given to animals like poultry, cattle, swine, and minor animal species (other than cattle, swine, chickens, turkeys, horses, dogs, and cats).

S.S.P.C. 4F. NCTR All of the research performed at the National Center for Toxicological Research is targeted to fulfill  three strategic research goals in support of FDA's public health mission. Risk Assessment for Regulated Products Knowledge Bases that Predict Human Toxicity Methods use for FDA Standard Development and Product Risk Surveillance NCTR includes, Centre of Excellence Research Division

Cont… S.S.P.C. NCTR Centre of Excellence informatics Toxico toxicology Photo Genomics Functional Structural Hepato Metabolomics Proteomics

Biometry and Risk Assessment S.S.P.C. Cont… NCTR Research Division Biometry and Risk Assessment Biochemical Toxicology Genetic and Reproductive Toxicology Microbiology Molecular Epidemiology Neurotoxicology Systems Toxicology Veterinary Services

S.S.P.C. 4G. OC The Office of the Commissioner is made up of several components, Ethics Program Good Clinical Practice Program History Office Office of Combination Products Office of Crisis Management Office of Equal Employment Opportunity and Diversity Management Office of Financial Management Office of International Programs Office of the Ombudsman Office of Orphan Products Development Office of Pediatric Therapeutics Office of Planning Office of Policy Office of Public Affairs Office of Special Health Issues Office of Women's Health Small Business Program

S.S.P.C. 4H. ORA to ensure that FDA regulated products comply with appropriate public health laws and regulations. Compliance Strategies of ORA includes, Providing information to industry Highlighting areas of significant violations and impact on public health Prioritizing and targeting high-risk areas Cooperating with state and local public health authorities and regulators Focusing on covering products imported into the US through border coverage and foreign inspections.

S.S.P.C. 4I. COSMETICS FDA is only able to regulate cosmetics after products are released to the marketplace. Neither cosmetic products nor cosmetic ingredients (except color additives) are reviewed or approved by FDA before they are sold to the public. Includes, Animal Testing for Cosmetic Products Inspection of Cosmetics Shelf life Federal Food, Drug, and Cosmetic Act (FD&C Act) and Fair Packaging and Labeling Act (FPLA)

I. Animal Testing for Cosmetic Products S.S.P.C. I. Animal Testing for Cosmetic Products FDA does not mandate to do animal testing FDA develop validated alternatives to animal testing in assessing cosmetic safety

II. Inspection of Cosmetics S.S.P.C. II. Inspection of Cosmetics An investigator may look for the following, Use of prohibited ingredients Improper use of restricted ingredients noncompliance with requirements related to color additives Microbial contamination Failure to adhere to requirements for tamper-resistant packaging Deficiencies in labeling and packaging

S.S.P.C. III. Shelf Life No regulations or requirements under current united states law Manufacturers have the responsibility to determine shelf life for products

IV. Cosmetic Labeling The name of manufacturer, packer or distributor S.S.P.C. IV. Cosmetic Labeling The name of manufacturer, packer or distributor Place of business of the manufacturer, packer or distributor An accurate statement of the quantity of contents Any appropriate directions for safe use and Warning statements

S.S.P.C. 5. FDA Mission Statement Mission Strategic Plan FDA Standards Service Customer Regulates What Regulate Not Does Enforced By Laws

5A. MISSION STATEMENT S.S.P.C. The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and affordable. And helping the public to get the accurate, science-based information they need to use medicines and foods to improve their health.

5B. FDA STRATEGIC PLAN S.S.P.C. PLAN Management Efficient Risk Improving Health Information Through Better Patient and Improving Consumer Safety From Terrorism America Protecting Through a Stronger Regulation More Effective Workforce

I. Efficient Risk Management S.S.P.C. I. Efficient Risk Management Use science-based, efficient risk management in all agency regulatory activities, so that the agency's limited resources can provide the most health promotion and protection at the least cost for the public. The Most Public Health risk for Regulatory are at the time of, Enforcement: Targeting Limited Resources for Maximum Protection New Drug Development. Manufacturing. Imports. Foods: Foodborne Disease Remains a Major Public Health Threat

Maximum liable areas for Risk S.S.P.C. Cont… Maximum liable areas for Risk Design Process Materials Manufacturing Facilities Distribution Patient

S.S.P.C. Cont… Objective 1 -- Provide timely, high quality, cost-effective process for review of new technologies / premarket submissions. Objective 2 -- Provide high quality, cost-effective oversight of industry manufacturing, processing and distribution to reduce risk. Objective 3 -- Assure the safety of the U.S. food and cosmetics supply to protect consumers at the least cost for the public. Objective 4 -- Develop methodological strategies and analyses to evaluate options, identify the most effective and efficient risk management strategies, and optimize regulatory decision-making.

II. Improving Health Through Better Information S.S.P.C. II. Improving Health Through Better Information Empowering Consumers: Improving Health Through Better Information able consumers about the benefits and risks of FDA-regulated products. Objective 1 – Develop an FDA-wide consumer communications infrastructure. Objective 2 – Enhance the FDA's efforts to help ensure that industry communications to consumers and health care providers are truthful and not misleading, provide information about product risks and benefits, and appropriately convey the degree of scientific uncertainty associated with such product messages.

III. Improving Patient And Consumer Safety S.S.P.C. III. Improving Patient And Consumer Safety Objective 1. Enhance the ability to quickly identify risks associated with FDA- regulated products. Objective 2. Increase capacity to accurately analyze risks associated with medical products, dietary supplements, and foods. Objective 3. Take appropriate actions to communicate risks and correct problems associated with medical products, dietary supplements and foods. Objective 4. The FDA must uphold its responsibility for ensuring the safety of approximately 80 percent of the nation's food supply. Objective 5. Protect the safety and security of human drugs, biologics (vaccines, blood and blood products, gene therapy, human tissues, and cellular therapies), medical devices (including radiation-emitting and screening devices), veterinary drugs, and other FDA-regulated products.

IV. Protecting America From Terrorism S.S.P.C. IV. Protecting America From Terrorism Objective 1. Facilitate the development and availability of medical countermeasures to limit the effects of a terrorist attack on the civilian or military populations. Objective 2. Enhance the agency's emergency preparedness and response capabilities to be better able to respond in the event of a terrorist attack. Objective 3. Ensure the safety and security of FDA personnel, physical assets, and sensitive information.

V. More Effective Regulation Through a Stronger Workforce S.S.P.C. V. More Effective Regulation Through a Stronger Workforce Ensure a world-class professional workforce, effective and efficient operations, and adequate resources to accomplish the agency's mission. Objective 1 -- Ensure a high quality, diverse and motivated workforce. Objective 2 -- Increase efficiency and effectiveness of agency management. Objective 3 -- Ensure effective communication and working relationships with key external stakeholders to enhance U.S. and global health outcomes. Objective 4 -- Transition Information technology from an enabler to a strategic tool for realizing the FDA's policy goals and objectives. Objective 5 -- Provide a consolidated FDA headquarters campus to improve operations for employees.

5C. FDA CUSTOMER SERVICE STANDARDS S.S.P.C. 5C. FDA CUSTOMER SERVICE STANDARDS Customers Health professionals Regulated industry Other government agencies

I. Customers S.S.P.C. Fair, courteous and professional treatment, Information that is accurate and current, Timely responses to requests, Reasonable access to appropriate staff, Confidence that efforts are made to assure that regulated products in the marketplace are in compliance with FDA laws and regulations, Two-way communication, Opportunities for collaboration and partnerships, as appropriate, Participation in the agency's decision-making process Accurate and timely health information about regulated products

II. Health Professionals S.S.P.C. II. Health Professionals Timely information that will assist them in advancing and protecting the public health

III. Regulated Industry S.S.P.C. III. Regulated Industry Timely review of product applications, Professional treatment in resolving disputes, Fair application of laws and regulations in enforcement activities, Fair and consistent inspections and product application reviews, Respect in the agency's performance of duties and responsibilities.

5D. WHAT FDA REGULATES S.S.P.C. Biologics Product and manufacturing establishment licensing Safety of the nation's blood supply Research to establish product standards and develop improved testing methods Cosmetics Safety Labeling Drugs Product approvals OTC and prescription drug labeling Drug manufacturing standards Foods

Cont… S.S.P.C. Safety of all food products (except meat and poultry) Bottled water Medical devices Premarket approval of new devices Manufacturing and performance standards Tracking reports of device malfunctioning and serious adverse reactions Radiation-emitting electronic products Radiation safety performance standards for microwave ovens, television receivers, diagnostic X-ray equipment, cabinet x-ray systems (such as baggage x- rays at airports), laser products, Ultrasonic therapy equipment, mercury vapor lamps, and sunlamps Accrediting and inspecting mammography facilities Veterinary products

25. GMP Building and Facilities Equipment Personnel Raw materials S.S.P.C. 25. GMP Building and Facilities Equipment Personnel Raw materials Production Laboratory controls Records Labeling Complaints Other

Cont… GMP Workshop in July 2003: 5 year vision: S.S.P.C. Cont… GMP Workshop in July 2003: 5 year vision: “Develop a harmonised pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to quality risk management and science” Consequent ICH Expert Working Groups (EWG): ICH Q8, on Pharmaceutical Development, doc. approved Nov. 2005 ICH Q9, on Quality Risk Management, doc. approved Nov. 2005 ICH Q10, on Quality Systems, topic accepted 2005

Risk from Manufacturing site S.S.P.C. Concluding… Risk from Manufacturing site Product / Process Risk High Low Q10 Pharm. Quality Systems Q8 Pharmaceutical Development

5E. WHAT FDA DOES NOT REGULATE S.S.P.C. 5E. WHAT FDA DOES NOT REGULATE Advertising Alcohol Consumer Products Drugs of Abuse Health Insurance Meat and Poultry Pesticides Restaurants and Grocery Stores Water

5F. LAWS ENFORCED BY FDA S.S.P.C. Federal Food, Drug and Cosmetic Act Food and Drug Administration Modernization Act (FDAMA) Infant Formula Act of 1980 Orphan Drug Act Drug Price Competition and Patent Term Restoration Act of 1984 Medical Device Amendments of 1992 Prescription Drug User Fee Act (PDUFA) of 1992 Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994 Dietary Supplement Health and Education Act of 1994 Food and Drug Administration Modernization Act (FDAMA) of 1997 Best Pharmaceuticals for Children Act

S.S.P.C. Cont… Medical Device User Fee and Modernization Act (MDUFMA) of 2002 Animal Drug User Fee Act of 2003 PDF Minor Use and Minor Species Animal Health Act of 2004 Food Allergen Labeling and Consumer Protection Act of 2004 Federal Anti-Tampering Act Sanitary Food Transportation Act Mammography Quality Standards Act (MQSA) Bioterrorism Act of 2002 Public Health Service Act Trademark Act of 1946 Controlled Substances Import and Export Act

6. FDA Activities S.S.P.C. Broad Responsibilities Benefits Vs. Risks Safe, Wholesome and Sanitary Food Safe and Effective Medicine, Biological and Medicinal Device Safe Consumer and Medicinal Radiation Products Truthful and Informational Labels Safe Cosmetics Safe and Effective Animal Drugs Standards and Regulations Science, Regulation and Consumer Protection Keeping Watch Safe Manufacturing and Handling Monitor for New Risks Research Enforcements

7. Information for Others S.S.P.C. 7. Information for Others Consumers Patients (HIV and AIDS Activities) Health Professionals (Clinical Trials, Dietary Supplements & Drugs) Health Educators (Latest FDA medical product and health news ) State/Local Officials Industry Press Women (Guide to Pregnancy Registries Menopausal Hormone Initiative) FDA Alumni Seniors Teens (Birth control guide, Tobacco information) Kids (Food Safety Quiz, Match the pair)

S.S.P.C. 8. What is New ? DRUGS FOOD DEVICES MEDICAL MISCELLANEOUS

S.S.P.C. Cont… DRUGS Antidepressant Use in Children, Adolescents, and Adults Buying Medicines Online Celexa Cialis Counterfeit Drugs COX-2 Inhibitors (Vioxx, Bextra, Celebrex...) Foreign Rx Drugs Oxycontin Phenylpropanolamine (PPA) Protonix Viagra FOODS E. coli East Coast Outbreaks Spinach/E. coli Information Food Safety for Moms-to-Be Food Guide Pyramid Hurricane and Food Safety Bioengineered Foods Color Additives Foodborne Illness Holiday Food Safety Konjac Candy Recalls Mercury in Fish Dietary Supplements

Cont… S.S.P.C. MEDICAL DEVICES Contact Lenses and Eye Infections Decorative Contact Lenses Breast Implants Device User Fees LASIK Eye Surgery Tampons Radiation Protection Whole Body CT Scans Wireless (Cell) Phones MISCELLANEOUS Animal Cloning Antibiotic Resistance Bioterrorism Act BSE (Mad Cow Disease) Buying Medical Products Online Cosmetics Counterterrorism Flu Information Poison Ivy Halloween Safety Tips Heart Health Losing Weight Marijuana for Medical Use Quitting Smoking SARS Tattoos White Oak

9. Challenges faced by FDA S.S.P.C. 9. Challenges faced by FDA Scientific breakthroughs More sophisticated products New public health threats International commerce Consumer information

S.S.P.C. 10. Reference

SEMINAR ON…. Therapeutic Goods Administration

Home page of TGA

About TGA TGA is an unit of the Australian Government Dept. of Health & Ageing. Carries out assessment and monitoring activities over Therapeutic goods. To ensure that Australian community has an access, within a reasonable time, to advanced therapeutics.

The TGA regulates therapeutic products through: pre-market assessment; post-market monitoring and enforcement of compliance with standards; and licensing of Australian manufacturers and verifying overseas manufacturers' compliance with the same standards as their Australian counterparts.

Activities undertaken by TGA The regulation of therapeutic goods Committees Online services Consultation documents Tenders Recruitment Laboratories TGA news International activities

International activities Management and coordination of advisory and training services for regulatory matters. TGA integrates its activities with similar projects initiated by Food Standards Australia New Zealand (FSANZ) and co-ordinate TGA’s therapeutics regulation with New Zealand.

International activities International agreements WHO Collaborating Centers TGA international training information TGA retroviral medicines

Blood and tissues Blood, Blood components, Plasma derivatives, Tissue and cellular products, and Tissue cell based derivatives Regulated under the Therapeutic Goods Act 1989.

Blood and tissues Regulation of blood Regulation of tissues Consultation documents Committees Global Collaboration for Blood Safety Export of human blood, tissues, related materials International agreements

Chemicals The Office of Chemical Safety undertakes the risk assessment and provides advice on potential public health risks posed by chemicals used in community. Example includes : Cosmetics, Agricultural, Veterinary, Industrial Chemicals, Pesticides.

Chemicals Regulation of chemicals Agricultural and veterinary chemicals Environmental chemical issues Committees Cosmetic claim guidelines Consultation documents

Committees Australian drug evaluation committee (ADEC) Adverse Drug Reaction Advisory Committee (ADRAC) Complementary Medicines Evaluation Committee (CMEC) Medical Device Evaluation Committee (MDEC) Medicines Evaluation Committee (MEC)

Committees National Coordinating Committee on Therapeutic Goods (NCCTG) National Drugs and Poisons Schedule Committee (NDPSC) Therapeutic Goods Committee (TGC) Australian Influenza Advisory Committee (AIVC) Gene technology committees

Australian drug evaluation committee (ADEC) Advises the minister or the secretary on medical and scientific evaluations of drugs and on the timely availability of new therapeutic advances in Australia.

Adverse Drug Reaction Advisory Committee (ADRAC) Subcommittee of ADEC. Reviews reports of adverse reactions to medicines and vaccines.

Medical Device Evaluation Committee (MDEC) Provides independent medical and scientific advice to the Minister and TGA on the safety, quality and performance of medical devices supplied in Australia. Pre-marketing and post-marketing monitoring.

Medicines Evaluation Committee (MEC) Advices the Minister and Secretary on matters relating to the registration of Over-the-counter (OTC) medicines.

Therapeutic Goods Committee (TGC) An expert committee which advises the Minister for Health and Ageing on adoption of therapeutic standards, requirements for labeling/packaging and the manufacturing principles.

Complementary medicines Complementary medicines are also known as ‘traditional’ or ‘alternative’ medicines. Examples include vitamins, minerals, nutritional supplements and herbal, aromatherapy and homeopathic products.

Complementary medicines Regulation of complementary medicines Information for sponsors Forms Guidelines Hints, tips and other information Electronic listing facility (ELF)

Complementary Medicines Evaluation Committee (CMEC) Advise to the TGA’s office of complementary medicines on whether a new complementary substance or medicine should be permitted in the ARTG as a listed or registered product

Gene technology The Gene Technology Act 2000 introduces a national scheme for the regulation of genetically modified organisms in Australia to protect the health and safety of Australians and the Australian environment.

Gene technology Regulation of gene technology Policy principles Record of genetically modified products Consultation documents Committees

Gene technology committees Gene Technology Ministerial Council( GTMC) A commonwealth, state and territory council established by the intergovernmental Gene Technology Agreement 2001 Gene Technology Standing Committee (GTSC) Provides high level support to the Gene Technology Ministerial Council Gene Technology Technical Advisory Committee (GTTAC) A statutory advisory committee which takes the place of GMAC and provides scientific and technical advice to the Gene Technology Regulator and the Gene Technology Ministerial council.

Over-the-counter medicines Can buy OTC medicines for self-treatment from pharmacies, with selected products also available in supermarkets, health food stores and other retailers. Ex. includes cough and cold remedies anti fungal treatments sunscreens Non-prescription analgesics such as aspirin, PCM

Over-the-counter medicines Regulation of OTC medicines OTC medicines electronics lodgement system Advertising therapeutic goods Medicines labeling review Information for sponsors Forms Guidelines Hints, tips &other information

Manufacturing In most cases manufacturers of therapeutic goods must hold a license. To obtain a license to manufacture therapeutic goods, a manufacturer must demonstrate, during a factory audit, compliance with manufacturing principles which include codes of good manufacturing practice.

Manufacturing Codes of good manufacturing practice Manufacturing guidelines Manufacturing principles Online services Forms for manufacturers Australian manufacturers Overseas manufacturers International agreements

Australian Code of GMP for Medicinal Products

Australian code of GMP for medicinal products includes 9 chapters. Quality Management Personnel Premises and Equipment Documentation Production Quality control Contract Manufacture and Analysis Complaints and Product Recall Self Inspection

ANNEXES Annex 1 Manufacture of sterile medicinal products Annex 2 Manufacture of biological medicinal products for human use Annex 3 Manufacture of radiopharmaceuticals Annex 4 Manufacture of veterinary medicinal products other than immunologicals Annex 5 Manufacture of immunological veterinary medical products Annex 6 Manufacture of medicinal gases

ANNEXES Annex 7 Manufacture of herbal medicinal products Annex 8 Sampling of starting and packaging materials Annex 9 Manufacture of liquids, creams and ointments Annex 10 Manufacture of pressurized metered dose aerosol preparations for inhalation Annex 11 Computerized systems Annex 12 Use of ionizing radiation in the manufacture of medicinal products

ANNEXES Annex 13 Manufacture of investigational medicinal products Annex 14 Manufacture of products derived from human blood or human plasma Annex 15 Qualification and validation Annex 16 Qualified person and batch release Annex 17 Parametric release Annex 18 GMP guide for Active Pharmaceutical Ingredients

Guidelines on Standard of Overseas Manufacturers Intended to provide information on- What is regarded by the TGA as an acceptable form of evidence Guidance for sponsors and manufacturers on the submission of that evidence to the TGA for assessment.

Evidence of the standard of manufacture submitted will be reviewed by the Manufacturer Assessment Section (MAS) of the TGA. Current sponsors of therapeutic goods manufactured outside Australia will be requested on periodic basis to provide evidence that the standard of manufacture of those therapeutic goods continues to be acceptable.

Failure to supply this information may result in the product’s registration/listing being cancelled (Therapeutic Goods Act 1989 Subsection 30(2)(c)) Sponsors should also note that TGA reserves the right to request an audit (inspection) of any overseas facility.

References www.tga.gov.au.

Seminar on: WHO GUIDELINES (Under Global Regulatory Requirements)

INTRODUCTION The World Health Organization is the United Nations specialized agency for health. It was established on 7 April 1948. WHO is governed by 192 Member States through the World Health Assembly . All countries which are Members of the United Nations may become members of WHO The Executive Board is composed of 32 members technically qualified in the field of health. Members are elected for three-years. The Organization is headed by the Director-General, who is appointed by the Health Assembly on the nomination of the Executive Board.

Regional offices are in- Africa, America, Southeast Asia, Europe, Eastern Mediterranean, Western Pacific

WHO has four main functions: To give worldwide guidance in the field of health To set global standards for health To cooperate with governments in strengthening national health programs To develop and transfer appropriate health technology information WHO RESEARCH TOOLS INCLUDE- WHOLIS- World health organization database available on net, all publication since 1948 WHOSIS-A guide to epidemiological and statistical information available from WHO.

WHO stability guidelines “Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms” It is for the stability testing of final drug products that are well established (e.g. generics) and are in conventional dosage forms (e.g. tablets).

The storage conditions recommended by manufacturers on the basis of stability studies should guarantee the maintenance of quality, safety, and efficacy throughout the shelf-life of a product. The effect of the extremely adverse climatic conditions existing in certain countries to which they may be exported calls for special consideration. In a stability study, the effect of variations in temperature, time, humidity, light intensity and partial vapor pressure are investigated.

For reconstituted product : “in use” stability data must be submitted to support the recommended storage time and conditions. Four climatic zones can be distinguished for the purpose of worldwide stability testing, as follows: • Zone I: Temperate. • Zone II: Subtropical, with possible High Humidity. • Zone III: Hot/Dry. • Zone IV: Hot/Humid.

Design of stability studies Test samples 1) For registration purposes, test samples of products should contain fairly stable active ingredients and should be from two different production batches. 2) Should be representative of the manufacturing process. 3) Should be manufactured from different batches of API, if possible. 4) Suggested sampling schedule : - - One batch every other year for formulations considered to be stable, otherwise one batch per year; - - One batch every 3-5 years for formulations for which the stability profile has been established, unless a major change has been made

Test conditions Accelerated studies Less stable Zone 2 6 months stable

Alternative Storage condition : 1) Storage for 6 months at a temp of at least 15 °C above the expected actual storage temp & appropriate RH. 2) Storage at higher temp may also be recommended, e.g. 3 months at 45-50 °C and 75% relative humidity (RH) for zone IV. 3) Where significant changes occur in the course of accelerated studies, additional tests at intermediate conditions should be conducted, e.g. 30 ± 2 °C and 60 ± 5% RH. Real-time studies For registration purposes, the results of real time studies of at least 6 months' duration should be available at the time of registration.

Frequency of testing and evaluation of test results For accelerated studies: 0, 1, 2, 3 and, when appropriate, 6 months; For real-time studies: 0, 6 and 12 months, and then once a year. For on-going studies: For the confirmation of the provisional shelf-life: 6-months For well established products : 12 months Highly stable formulations : first 12 months and then at the end of the shelf-life. Less stable drug substances : every 3 months in the first year, every 6 months in the second year, and then annually

Analytical methods Analytical methods should be validated or verified All product characteristics likely to be affected by storage should be determined Tests for related compounds or products of decomposition should also be validated. Stability report: Provides details of the design of the study, as well as the results and conclusions

WHO Guidelines on Sampling of Pharmaceuticals

Sampling comprises of the operations designed to select a portion of a material for a defined purpose. All operations related to sampling should be performed with care, using proper equipment and tools prequalification inspection for customs clearance, deterioration, adulteration, etc.; acceptance of consignments Purpose Of sampling in-process control

Controls to be applied to the sample may be: Starting materials Pharmaceutical products Pri. and sec. packaging materials Classes and Types of Materials Intermediates  Controls to be applied to the sample may be: - checking the identity of a material;       - performing complete pharmacopoeial or analogous testing;       - performing special/specific tests.

Sampling operation and precautions - Procedure should be such that any non-uniformity of the material can be detected - Non-homogeneous portions of the material or bulk should be sampled and tested separately Compositing of the samples from the diff. portions should be avoided, since it can mask contamination For Finished drug products the sampling procedure must take account - Official and non-official tests ( for dosage forms) - Non-official tests could include testing for adulteration, counterfeiting, etc.

STORAGE AND RETENTION Container used to store a sample shouldn’t interact with the sampled material nor allow contamination, should protect from light, air, moisture, etc., as req. by the storage directions for the material sampled Samples should be stored in accordance with the storage conditions as specified for the respective API, excipient or drug product Closures and labels should be preferably of such a kind that unauthorized opening can be detected. Samples must never be returned to the bulk.

SAMPLING FOR REGULATORY PURPOSES - Additional samples for regulatory testing and verification purposes should be provided (e.g. duplicate testing and parallel testing by different regulatory laboratories and by the consignee of the product)

SAMPLING PLANS FOR STARTING MATERIALS, PACKAGING MATERIALS AND FINISHED PRODUCTS STARTING MATERIAL: The “n plan” Used only when material 1) is uniform & 2) supplied from a recognized source FORMULA : n = 1+√N Where, N is the number of sampling units According to this plan, original samples are taken from N sampling units selected at random n-plan is not statistically based and should be used only as a guiding principle.

The “r plan” Used when material 1) is non-uniform & 2) supplied from source that is not well known FORMULA : r = 1.5√N Where, N is the number of sampling units According to this plan samples are taken from each of the N sampling units of the consignment and placed in separate sample containers & tested. If the results are in agreement, r final samples are formed by appropriate pooling of the original samples. If these results are in agreement, the r samples are combined for the retention sample.

GUIDELINES ON GOOD MANUFACTURING PRACTICES (GMP): VALIDATION Focuses mainly on the overall concept of validation and is intended as a basic guide for use by GMP inspectors. It encompasses details related to :Validation; Qualification ; Calibration and verification Other aspects addressed in this guideline include the Validation Team, Validation Master Plan, Validation Protocol (VP), Validation Report (VR), types of validation, Re-validation and Change Control associated with validation.

WHO’s guidelines on- INSPECTION Inspection of….. pharmaceutical manufacturers drug distribution channels (products) Guidelines for pre-approval inspection Quality system requirements for national GMP Inspectorates -Intended to promote harmonization of pharmaceutical inspection practices among WHO Member States

Evaluation of the establishment’s compliance with GMP requirements Objectives Evaluation of the establishment’s compliance with GMP requirements Evaluation of the procedures and controls implemented in the mfg Audit of the completeness and accuracy of the mfg and testing information submitted with the application The collection of samples for the validation or verification of the analytical methods included in the application. 17

Types of Inspection Routine Inspection Concise Inspection Follow up Inspection Special Inspection Investigative Inspection

When Inspections are Required? New chemical entity Drugs of narrow therapeutic range Products previously associated with serious adverse effects, complaints, recalls Applications from manufacturers who have previously failed to comply with GMP or official quality specifications. Products that are difficult to manufacture or test, or that are of doubtful stability New applicants or manufacturers

WHO’s guidance on interchangeability of medicines Guidance on selection of comparator products for equivalence assessment of interchangeable generic products New draft: BCS classification to limit in vivo tests In vitro test methodology for BCS class I drugs

Why is bioequivalence needed ? Pharmaceutical equivalence does not necessarily mean therapeutic equivalence Multisource drug products should conform to the same standards of quality, safety and efficacy required for the reference product and must be interchangeable. Differences in excipients or manufacturing process may lead to differences in product performance. Also, in vitro dissolution does not necessarily reflect in vivo bioavailability.

What are the ways of demonstrating therapeutic equivalence ? Comparative BA ( BE ) studies Comparative pharmacodynamic studies in humans Comparative clinical trials In vitro dissolution tests

When BE Studies are not needed for Multisource product ? A) An aqueous solution for parenteral use B) A solution for oral use C) A medicinal gas D) A powder for reconstitution as a solution for oral or parenteral use E) An otic or ophthalmic solution F) A topical aqueous solution G) An inhalation product or nasal spray as an aqueous solution  For e, f and g, formulation of multisource product must be similar to reference product. Also, bioequivalence studies may be waived for compositionally similar strengths when one strength in a range has been studied.

Design of comparative BA studies Studies should be carried out in accordance with provisions of guidelines on Good Clinical Practice, Good Manufacturing Practice, Good Laboratory Practice Most common design is single-dose, randomized, two-way crossover study (non-replicated) Other designs possible, e.g. parallel design for drugs with long half-lives, steady-state studies for some non-linear drugs

Factors to consider in the design of a study Study formulation should be representative of formulation to be marketed Subjects - number - health status - age, weight, height - ethnicity - gender - special characteristics e.g. poor metabolizers - smoking - inclusion/exclusion criteria specified in protocol Randomization Blinding Sampling protocol Washout period Administration of food and beverages during study Recording of adverse events

Bioequivalence standards (acceptance ranges) The 90% confidence interval of the relative mean AUC of the test to reference product should be between 80-125%. The 90% confidence interval of the relative mean CMAX of the test to reference product should be between 80-125%. Since CMAX is recognized as being more variable than the AUC ratio, a wider acceptance range may be justifiable.   These standards must be met on log-transformed parameters calculated from the measured data   If the measured potency of the multisource formulation differs by more than 5% from that of the reference product, the parameters may be normalized for potency.  TMAX may be important for some drugs

Critical parameters to look into when evaluating dossiers with respect to BE studies Is the reference product suitable? Was the study design such that variability due to factors other than the product was reduced? Other design issues e.g. sample size, sampling protocol Assay validation adequate? Pharmacokinetic analysis appropriate? Statistical analysis appropriate? Acceptance criteria met?

Some statistical considerations A priority specification of methods - Statistical methods to be used must be specified beforehand in the protocol Number of subjects - Minimum 12 subjects. Usually 18-24 subjects sufficient. Log-transformation - AUC and CMAX should be analyzed after log-transformation - Satisfies assumption of Analysis of Variance (ANOVA model is additive rather than multiplicative) Outliers - Must be valid medical reason to drop outlier from analysis - Post hoc deletion of outlier values is generally discouraged Parametric methods are recommended for the analysis of log-transformed BE measures Non-parametric methods can be used when the log transformed data is not normal

Pharmacodynamic studies Not recommended : for oral product for systemic action due to high within-subject variability Used : If quantitative analysis of the drug and/or metabolite(s) in plasma or urine can’t be made with sufficient accuracy and sensitivity If measurements of drug concentration can’t be used as surrogate endpoints for the demonstration of efficacy and safety of the particular pharmaceutical product

Computer-assisted Drug Registration WHO Model System for Computer-assisted Drug Registration (SIAMED) Objective To improve the efficiency of drug regulatory authority (DRA) enabling them to assure that marketing authorizations are consistent with their national drug policy.

What does the model system do? - Information on companies, Summary information on inspections carried out at company premises Information on medicinal products for which an application has been received or a marketing authorization is issued, Status of applications in the evaluation process. Decisions such rejection, issuance, cancellation, renewal, and variation to marketing authorizations - Variations to valid marketing authorizations, automatically keeping history of all variations made.

PROVISIONS AND PREREQUISITES FOR A CLINICAL TRIAL Justification for the trial - Ethical principles : As per current version of Declaration of Helsinki - Supporting data for the investigational product: Pre-clinical studies Information about manufacturing procedures compilation of information on safety and efficacy based on previous Clinical data for subsequent trials - Investigator and site(s) of investigation - Regulatory requirements

THE PROTOCOL: Clinical trial should be carried out in accordance with a written protocol agreed upon and signed by the investigator and the sponsor PROTECTION OF TRIAL SUBJECTS Declaration of Helsinki: Recommendations guiding physicians in biomedical research involving human subjects It is the accepted basis for clinical trial ethics & must be fully followed and respected by all parties. Ethics committee It ensure the protection of the rights and welfare of human subjects participating in clinical trials, and to provide public reassurance, by previewing trial protocols, etc.

Confidentiality The investigator must establish secure safeguards of confidentiality of research data as described in the current revision of the International Ethical Guidelines for Biomedical Research Involving Human Subjects.

RECOMMENDED GUIDELINES FOR ORGANIZATIONS SUCH AS CONTRACT RESEARCH ORGANIZATIONS (CROs) PERFORMING BE STUDIES ON BEHALF OF SPONSORS This document provide guidelines to organizations such as CROs that are involved in the conduct of in vivo BE studies. This document provides information on: - organization and management; - clinical phase of a study; - bioanalytical phase of a study; - pharmacokinetic and statistical analysis; and study report.

ROLE OF THE DRUG REGULATORY AUTHORITY Provides the legal framework for clinical trials Have a mandate to review protocols and, where necessary, to protect the safety of subjects, to require protocol revisions and/or termination of trials. Carry out on-site inspections of the clinical trial site.

Investigational pharmaceutical products for clinical trials in humans WHO GMP: Investigational pharmaceutical products for clinical trials in humans The present guidelines supplement both the WHO guide on GMP and the guidelines on GCP. why application of the principles of GMP is necessary??? • To assure consistency between and within batches of the investigational product & thus assure the reliability of clinical trials. • To assure consistency between the investigational product & the future commercial product and therefore the relevance of the clinical trial to the efficacy and safety of the marketed product. • To protect subjects of clinical trials from poor-quality products resulting from manufacturing errors, or from starting materials and components of inadequate quality. • To document all changes in the manufacturing process.

WHO’s global guidelines – DISTRIBUTION WHO Certification Scheme for Products Moving in International Commerce SMACS new scheme for pharmaceutical starting materials: - model certificate, when inspected by national authority - WHO model for self-assessment for manufacture of pharmaceutical starting materials Good Distribution and Trading Practices for pharmaceutical starting materials (GTDP) Good Distribution Practices (GDP) (for products in prep.) Good Storage Practices (GSP)

Guidelines on the implementation of the WHO certification scheme on the QUALITY OF PHARMACEUTICAL PRODUCTS moving in international commerce The Scheme is an administrative instrument that requires each participating Member State, to attest to the competent authority of another participating Member State that: ·     -    A specific product is authorized or, if it is not authorized, the reason why that authorization has not been accorded; ·     -    The plant is subject to inspections at suitable intervals to establish that the manufacturer conforms to GMP; ·     -    All submitted product information, including labelling, is currently authorized in the certifying country.

Eligibility for participation Any Member State intending to participate in the Scheme may do so by notifying the Director-General of the WHO, in writing, of: ·         Its willingness to participate in the Scheme; ·      Any significant reservations it intends to observe relating to this participation; and ·       The name and address of its national drug regulatory authority or other competent authority.

A Member State may opt to participate solely to control the import of pharmaceutical products and active substances. This intention should be stated explicitly in its notification to the WHO A Member State intending to use the Scheme to support the export of pharmaceutical products should first satisfy itself that it possesses: An effective national licensing system GMP requirements, as recommended by WHO Effective controls to monitor the quality of pharmaceutical products A national pharmaceuticals inspectorate, Administrative capacity to issue the required certificates,

Requesting a certificate Three documents can be requested within the scope of the scheme:  a) Certificate of a Pharmaceutical Product (Product certificate)  b) Statement of Licensing Status of Pharmaceutical Product (s) c) Batch Certificate of a Pharmaceutical Product.

WHO pharmaceutical starting materials certification scheme (SMACS): guidelines on implementation

Objectives The Scheme is an administrative instrument that can be used by: 1) A Member State to attest that: — A specific starting material is authorized to be placed on the market and —The manufacturing site is subject to inspections at suitable intervals to establish that the manufacturer conforms to GMP as recommended by WHO. 2)Manufacturer to attest compliance with a quality assurance system

Contents of the GTDP( starting material) & GDP( Pharmaceutical products) - Quality management Organization and personnel Premises - Warehousing and storage - Equipment - Documentation - Repackaging and re-labelling - Complaints - Recalls - Returned goods - Handling of non-conforming materials - Dispatch and transport - Contract activities

WHO GMP Guidelines for pharmaceutical products

GMP for pharmaceutical products: MAIN PRINCIPLES The following points are covered in the recent one. Quality Assurance - Is achieved by following GMP, GCP and GLP. 2. GMP 3. Sanitation and hygiene-A high level of sanitation and hygiene should be practised 4. Qualification AND validation 5. Complaints 6. Product recalls

7. Contract production and analysis Contract giver -contract acceptor- cannot pass it on to a third party without prior approval of a contract giver. 8. Self inspection and quality audits Quality audit- is to supplement self inspection, is the assessment of a part of or complete quality system with the specific purpose of improving it. 9. Personnel 10. Training 11. Personal hygiene 12. Premises Ancillary, storage, weighing, production, quality control areas. 13.Equipment- be suitable for its intended use; facilitate thorough cleaning; minimize the risk of contamination of products and containers during production; and facilitate efficient and, if applicable, validated and reliable operation.

14. Materials 15. Documentation 16. Good practices in production Prevention of cross contamination Processing operation Packaging operation 17. Good practices in Quality control Control of starting materials, intermediates, bulk and finished products. -Test requirements- the materials have been tested for conformity with specifications for identity, strength, purity and other quality parameters. Batch record review-Production and quality control records -Stability studies-Stability should be determined prior to marketing and following any significant changes in processes, equipment, packaging materials .

WHO GMP: STARTING MATERIALS ACTIVE PHARMACEUTICAL INGREDIENTS (bulk drug substances) Explanation- the guideline gives procedures and practices that manufacturer should employ to get products having quality and purity appropriate for their use in pharmaceutical products. General consideration-these guideline are for human as well as veterinary use. Personnel- Equipment- Premises –for cytostatic substances antibiotics etc , there should be separate areas with separate AHU. Documentation-includes master formulae records, batch formulae records and SOP’s . Outdated master formulae records should be withdrawn but should be retained for reference. Batch records electronically stored should be protected by back up transfer or magnetic tape, microfilm , paper print outs etc.

6. Retention of records and reference samples- of the API, and where necessary of intermediate products, should be retained for at least 1 year beyond the expiry date of the finished product or for a specified period if there is no expiry date. 7. Production- -Processing procedures -Starting materials- Some may not be tested for compliance because of the hazards involved (e.g., phosphorus pentachloride and dimethyl sulfate). This is acceptable when a batch certificate of analysis is available from the vendor and when there is a reason based on safety or other valid considerations. -Intermediate products -Packaging 8. Quality control 9. Stability studies- expiry date do not usually need to be set for active pharmaceutical ingredient, if the stability testing does not indicate a reasonable shelf life, then the product can be labeled with an appropriate arbitrary expiry date and should be retested on or before that date. 10. Self inspection and quality audits 11. Storage 12. Complaints defects and rejected samples.

WHO good manufacturing practices: starting materials Pharmaceutical EXCIPIENTS 1. General considerations – An excipient manufacturer should be able to identify critical or key points in the process where selective intermediate sampling and testing is necessary in order to monitor process performance. 2. Self-inspection it is a review of the following areas: Non-conformance • Complaint files. • Change control documentation.

3. Quality Audits Master formula and batch production records. • Specifications for the presence of unreacted intermediates and solvent residues in the finished excipient. • Storage areas for rejected products. adequacy of measures taken to preclude contamination of materials in the process. 4. Equipment - -Use of equipment - Equipment that contains tarry or gummy residues that cannot be removed easily should be dedicated for use with these products only. Cleaning programme - Detailed cleaning procedure - Sampling plan - Analytical methods/cleaning limits 5. Materials -Starting materials –labile products - Rejected and recovered materials - Returned excipients

6. Documentation Specifications ,Batch production records , Other documents 7. Good practices in production and quality control -Change control and process validation , -Good practices in production -Prevention of cross-contamination -Control of microbial contamination -Water systems/water quality -Packaging operations -Delivery 8.Good practices in quality control -Control of starting materials -certificate of analysis from the supplier -In-process testing -Quality records and retention samples Reserve samples should be retained for 1 yr after the expiry or re-evaluation date, or for 1yr after distribution is complete. .-Stability studies

WHO GMP- HERBAL medicinal products 1.Glossary 2. General- 3. Premises- Medicinal plant materials should be stored in separate areas. The storage of plants, extracts, tinctures and other preparations may require special conditions of humidity and temperature or protection from light.

4. Production area- to avoid cross-contamination whenever dust is generated, special precautions should be taken during the sampling, weighing, mixing and processing of medicinal plants. 5. Specifications for starting materials- .The botanical name, with reference to the authors. • Details of the source of the plant • Whether the whole plant or only a part is used. • When dried plant is purchased, the drying system. • A description of the plant material based on visual and/or microscopical inspection . Assay Any treatment used to reduce fungal/microbial contamination or other infestation should be documented.

6. Qualitative and quantitative requirements Medicinal plant material: (a) the quantity of plant material must be stated; or (b) the quantity of plant material may be given as a range, corresponding to a defined quantity of constituents of known therapeutic activity. The composition of any solvent or solvent mixture used and the physical state of the extract must be indicated 7. Specifications for the finished product If the preparation contains several plant materials and a quantitative determination of each active ingredient is not feasible, the combined content of several active ingredients may be determined. 8. Processing instructions- The processing instructions should list the different operations to be performed on the plant material. 9. Quality control -Reference samples of plant materials must be available for use in comparative tests.

10. Sampling 11. Stability tests –it must be shown that, substances present are stable and that their content as a proportion of the whole remains constant. If it is not feasible to determine the stability of each active ingredient, the stability of the product should be determined

WHO GMP for STERILE pharmaceuticals products General considerations- Manufacturing operations are divided here into 2 categories: 1. Terminally sterilized 2. Aseptically sterilized at some or all stages. 2.Quality control -The sterility of the finished product is ensured by validation of the sterilization cycle in the case of terminally sterilized products, and by “media-fills” runs for aseptically processed products. Pharmacopoeial methods must be used for the validation and performance of the sterility test. 3.Sanitation –because of limited effectiveness of ultraviolet light it should not be used as a substitute for chemical disinfection.

4.Manufacture of sterile preparations – Limits for microbiological contamination Grade Air sample Settle plates Contact plates Glove print (CFU/m3) (diameter 90mm) (diameter 55mm) (5 fingers) (CFU/4 hours) (CFU/plate) (CFU/glove) A <3 <3 <3 <3 B 10 5 5 5 C 100 50 25 — D 200 100 50 — 5.Terminally sterilized products-The filling of products for terminal sterilization should generally be done in at least a grade C environment.

6.Sterilization- Dry heat Moist heat radiation Filtration The sterilization is carried out by Dry heat Moist heat radiation Filtration By gases and fumigants 7.Aseptic processing and sterilization by filtration The objective is to maintain the sterility of a product that is assembled from components, each of which has been sterilized by one of the above methods. 8.Personnel – 9.Premises -Grade B areas should be designed in such a way that all operations can be observed from outside.

A conveyor belt should not pass through a partition between a 10. Equipment – A conveyor belt should not pass through a partition between a grade A or B clean area and a processing area of lower air cleanliness, unless the belt itself is continuously sterilized . Equipment that has to be taken apart for maintenance should be resterilized after complete reassembly, wherever possible. Finishing of sterile products- Containers should be closed by appropriately validated methods. Samples should be checked for integrity according to appropriate procedures.

WHO GMP for RADIOPHARMACEUTICAL products 1. Scope : • The preparation of radiopharmaceuticals in hospital radiopharmacies. • The preparation of radiopharmaceuticals in centralized radiopharmacies. • The production of radiopharmaceuticals in nuclear centers and institutes or by industrial manufacturers. • The preparation and production of radiopharmaceuticals in positron emission tomography (PET) centers. 2.Principles-Because of their short half-lives, many radiopharmaceuticals are released and administered to patients shortly after their production, so that quality control may sometimes be retrospective. Therefore a strict adherence to GMP is mandatory. 3. Personnel- -person who has academic achievement together with a practical expertise and experience in radiopharmacy and radiation hygiene

2.can be relied on to observe the appropriate codes of practice and are not subject to any disease. 3. minimum number of personnel required should be present in clean and aseptic areas when work is in progress. 4.personnel should be trained in GMP, the safe handling of radioactive materials and radiation safety procedures. 5. Training records 4. Premises and equipment- 1.Specific disposal systems should be mandatory for radioactive effluents. 2. Sinks should be excluded from aseptic areas. Any sink installed in other clean areas should be of suitable material and be regularly sanitized. 3. Separate air-handling units should be used for radioactive and non-radioactive areas. 4.Proper HVAC

5.Production- 1.SOPs must be available for all operating procedures. 2. Specifications for starting materials. 3. Great care should be taken in cleaning, sterilizing and operating freeze-drying equipment used for the preparation of kits. 4.For the measurement of very short half-lives, national central laboratories should be contacted to calibrate the apparatus. Where this is not possible, alternative approaches, such as documented procedures, may be used. 5.If an inert gas such as nitrogen is used to fill vials, it must be filtered to remove possible microbial contamination. 6. dispensing, packaging and transportation of radiopharmaceuticals should comply with the relevant national regulations and international guidelines. 6. Labelling- -All products should be clearly identified by labels, which must remain permanently attached to the containers under all storage conditions.

-An area of the container should be left uncovered to allow inspection of the contents. -Information on batch coding must be provided to the national and/or regional authorities. 7. Production and distribution records- -Separate records for the receipt, storage, use and disposal of radioactive materials -Distribution records should be kept. -The return of radioactive products should be carried out in accordance with international and national transport regulations. 8. Quality assurance and quality control- -Quality assurance and/or quality control have the principal responsibilities same as that for any other pharmaceutical product.

WHO GMP for BIOLOGICAL products: 1. Scope: Manufacturing procedures within the scope of these guidelines include: — growth of strains of microorganisms and eukaryotic cells, — extraction of substances from biological tissues, including human, animal and plant tissues (allergens) — recombinant DNA (rDNA) techniques, — hybridoma techniques, — propagation of microorganisms in embryos or animals. 2. Principles- biological products are manufactured by methods involving biological processes and materials, such as cultivation of cells or extraction of material from living organisms. These processes display inherent variability. For this reason, in the manufacture of biological products full adherence to GMP is necessary.

3. Personnel- -The staff engaged in the manufacturing process should be separate from the staff responsible for animal care. -To ensure the manufacture of high-quality products, personnel should be trained in GMP and GLP in appropriate fields such as bacteriology, virology, biometry, chemistry, medicine, immunology and veterinary medicine. All personnel engaged in production, maintenance, testing and animal care (and inspectors) should be vaccinated with appropriate vaccines and, where appropriate, be submitted to regular testing for evidence of active tuberculosis. 4. Premises and equipment - -Products such as killed vaccines, including those made by rDNA techniques, toxoids and bacterial extracts may after inactivation be dispensed into containers on the same premises as other sterile biological products, providing that adequate decontamination measures are taken after filling, including, if appropriate, sterilization and washing.

-Spore-forming organisms shall be handled in facilities dedicated to this group of products until the inactivation process is accomplished. -Dedicated facilities and equipment shall be used for the manufacture of medicinal products derived from human blood or plasma. 5. Animal quarters and care - -Animals shall be accommodated in separate buildings with self-contained ventilation systems. -The buildings' design and construction materials shall permit maintenance in a clean and sanitary condition free from insects and vermin. -The health status of animals from which starting materials are derived and of those used for quality control and safety testing should be monitored and recorded. -Provision shall also be made for animal inoculation rooms, which shall be separate from the postmortem rooms. -There shall be facilities for the disinfection of cages, if possible by steam, and an incinerator for disposing of waste and of dead animals

6. Production – -Standard operating procedures -Specifications for starting materials - Media and cultures shall be added to fermenters and other vessels under carefully controlled conditions to avoid contamination. Care shall be taken to ensure that vessels are correctly connected when cultures are added. If possible, media should be sterilized in situ. In-line sterilizing filters for routine addition of gases, media, acids, alkalis, defoaming agents, etc. to fermenters should be used consideration should be given to the validation of sterilization methods. 7. Labelling- -All products shall be clearly identified by labels. -The information given on the label on the container and the label on the package shall be approved. -The leaflet in the package should provide instructions for the use of the product, and mention any contraindications or potential adverse reactions.

8. Lot processing records (protocols) and distribution records – The label on the package should show at least the nature and amount of any preservative or additive in the product. 8. Lot processing records (protocols) and distribution records – Processing records of regular production lots must provide a complete account of the manufacturing history of each lot of a biological preparation. 9. Quality assurance and quality control- -In-process controls very important here -Tests that are crucial for quality control but that cannot be carried out on the finished product shall be performed at an appropriate stage of production. -Special consideration needs to be given to the quality control requirements arising from production of biological products by continuous culture.

WHO Guidelines to GOOD STORAGE PRACTICES for pharmaceuticals 1.Introduction -involved in the storage, transportation and distribution of pharmaceuticals. -It is closely linked to other existing guides recommended by the WHO Expert Committee on Specifications for Pharmaceutical Preparations, such as: • Good trade and distribution practice (GTDP) of pharmaceutical starting materials. The stability testing of pharmaceutical products The cold chain, especially for vaccines and biologicals; • The International Pharmacopoeia This guidance has been prepared in close collaboration with the International pharmaceutical Federation (FIP).

2. Personnel- All personnel should receive proper training in relation to good storage practice, regulations, procedures and safety . Personnel employed in storage areas should wear suitable protective or working garments appropriate for the activities they perform. 3. Premises and facilities – -Precautions must be taken to prevent unauthorized persons from entering storage areas. -sufficient capacity -Storage areas should be designed or adapted to ensure good storage conditions. clean, and free from accumulated waste and vermin. -Receiving and dispatch bays should protect materials and products from the weather . -The materials or products, and areas concerned should be appropriately identified. - The “first expired/first out” (FEFO) principle should be followed.

Storage conditions should be in compliance with the labelling. 4. Storage requirements Storage conditions should be in compliance with the labelling. Monitoring of storage conditions -Recorded temperature monitoring data should be available for review. -All monitoring records should be kept for at least the shelf-life of the stored material or product plus 1 year. 5. Storage requirements- Documentation: written instructions and records Labelling and containers Receipt of incoming materials and pharmaceutical products Stock rotation and control-Periodic stock reconciliation should be performed by comparing the actual and recorded stocks. Control of obsolete and outdated materials and pharmaceutical Products

6.Returned goods- including recalled goods, should be handled in accordance with approved procedures and records should be maintained. All returned goods should be placed in quarantine Any stock reissued should be so identified and recorded in stock records. Pharmaceuticals returned from patients to the pharmacy should not be taken back as stock, but should be destroyed. 7. Dispatch and transport- Materials and pharmaceutical products should be transported in such a way that their integrity is maintained. The dispatch and transport of materials and pharmaceutical products should be carried out only after receipt of a delivery order. All records should be readily accessible and available on request. 8. Product recall

MISCELLANEOUS WHO action to address Substandard and Counterfeit medicines WHO provides support to countries to strengthen -pharmaceutical legislation Good Manufacturing Practices (GMP) national drug regulatory capacity and performance to promote information exchange among drug regulatory authorities – to strengthen drug procurement.

ECBS – Expert Committee on Biological Standardization The WHO Expert Committee on Biological Standardization is commissioned by WHO Its function is to- establish detailed recommendations and guidelines for the manufacturing, licensing, and control of blood products, cell regulators, vaccines and related in vitro diagnostic tests. The Expert Committee on Biological Standardization meets on an annual basis since 1947. The Expert Committee directly reports to the Executive Board, which is the executive arm of the World Health Assembly.

INTERNATIONAL PHARMACOPOEIA The desire for the unification of terminology and of the strengths and composition of drugs led on to attempts to produce an international pharmacopoeia. The work on The International Pharmacopoeia is carried out in collaboration with members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations as well as specialists from industry and other institutions. The information published in it is collated via a consultative procedure and may thus be regarded as being based on international experience. The current edition completes the list of monographs for active pharmaceutical substances. It also includes a number of important general texts, e.g. on the dissolution test, drug nomenclature, general specifications for dosage forms, and many more.

The needs of developing countries are taken into account and simple, classical physicochemical techniques are recommended that have been shown to be sound. Whenever possible, classical procedures are used in the analytical methods so that the pharmacopoeia can be applied without the need for expensive equipment. Priority is given to drugs that are widely used throughout the world. High priority is accorded to drugs that are important to WHO health programmes, and which may not appear in any other pharmacopoeias, e.g. new antimalarial drugs. Unlike other pharmacopoeias, the International Pharmacopoeia has no legal status. WHO Member States can adopt it and incorporate it into national legislation, either in part or in whole.

Essential Drugs and Medicines Policy WHO gives a list of essential drugs- Essential medicines are those that satisfy the priority health care needs of the population. They are selected in regard to public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness. Essential medicines are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality and adequate information, and at a price the individual and the community can afford.

References www.who.int/medicines

ICH TRIPARTITE GUIDELINES

CONTENTS Introduction What is ICH? Topics of ICH Quality Topics Q1A (R2): Stability testing of New Drug Substances and Products. Q1B: Photostability testing Q1C: Stability testing of new dosage forms Q1D: Bracketing and Matrixing designs Q1E: Evaluation of Stability data Q1F: Stability data package for registration in climatic zones III and IV. References Study Questions

Patient taking a pharmaceutical product expect the product to be safe and efficacious. Pharmaceutical regulatory agencies worldwide demand that the product retains its identity, quality, purity and potency for the time the product is commercially available. They also requires stability data supporting the proposed expiry date of the product. Various stability guidelines describe the type of studies & type of data needed.

Purpose of stability testing: To provide evidence of how the quality of drug substances or products varies with time under the influence of environmental factors. To establish a re-test period for the drug substances or the shelf-life for the drug products and recommended storage conditions. To ensure that the drug products retain their full efficacy until the end of their expiration date. Most important Guidelines: Food and Drug Administration (FDA) International Conference on Harmonization (ICH) European Union Guidelines (EU) Japanese Guidelines (MHW) World Health Organization (WHO) Guidelines.

Prior to 1960s there were not many controls over introduction of new drugs and also over the assurance of the quality by the manufacturer over his established drug products. Around 1970s the pharmaceutical industry started getting global but the registration of medicines remained a national responsibility. So the companies had to duplicate many time consuming and expensive test procedures, in order to market new products, internationally. All this resulted in unnecessary expenses and long delays in introducing new drugs. So a necessity to harmonize, the testing procedures and regulatory requirements of different countries was felt and the result is the birth of ICH in April 1990.

More economical use of human, animal & material resources. ICH - The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Aim: It is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration. OBJECTIVES More economical use of human, animal & material resources. Elimination of unnecessary delay in the global development & availability of new medicines. Maintaining safeguards on Quality, Safety & Efficacy, and regulatory obligations to protect the public health.

TOPICS OF ICH Quality (Q): Topics related to Manufacturing QA. Safety (S): Topics related to non- clinical pharmacology & toxicology studies. Efficacy (E): Topics related to Clinical studies in humans. Multidisciplinary (M): Topics affecting more than one discipline. Our concern is only with quality topics.

QUALITY TOPICS Consists of six subtopics:- Q1: Stability testing Q2: Analytical methods validation Q3: Impurity testing Q4: Pharmacopoeias Q5: Quality of Biotechnological products Q6: Specifications for new drug substances & products. Our concern is only Q1.

SPECIFIC GUIDELINES UNDER Q1 Q1A (R2): Stability testing of new drug substances and products. Q1B: Photostability testing. Q1C: Stability testing of new dosage forms. Q1D: Bracketing & Matrixing designs for stability testing of new drugs substances and products. Q1E: Evaluation of Stability data. Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV

STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Q1A (R2): STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS 1. INTRODUCTION 1.1 Objectives of the Guideline. 1.2 Scope of the Guideline. 1.3 General Principles.

2. GUIDELINES 2.1 DRUG SUBSTANCES 2.1.1 General 2.1.2 Stress Testing 2.1.3 Selection of Batches 2.1.4 Container Closure System 2.1.5 Specification 2.1.6 Testing Frequency 2.1.7 Storage Conditions 2.1.8 Stability Commitment 2.1.9 Evaluation 2.1.10 Statements/Labeling

Q1B: PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND DRUG PRODUCTS

CONTENTS 1. GENERAL A. PREAMBLE B. LIGHT SOURCES C. PROCEDURE (DECISION FLOW CHART) 2. DRUG SUBSTANCES A. PRESENTATION OF SAMPLES B. ANALYSIS OF SAMPLES C. JUDGEMENT OF RESULTS 3. DRUG PRODUCTS 4. ANNEX A. QUININE CHEMICAL ACTINOMETRY

1. GENERAL The light testing should be an integral part of the stress testing. A. PREAMBLE Normally, photo-stability testing is carried out on a single batch of material selected as described under Selection of Batches in the Parent Guideline. Following studies are covered such as: Tests on the drug substance Tests on the exposed drug product outside of the immediate pack; and if necessary; Tests on the drug product in the immediate pack; and if necessary Tests on the drug product in the marketing pack.

B. Light sources. (Defined in ISO 10977 (1993)) An appropriate control of temperature should be maintained to minimize the effect of localized temperature changes. Option 1: Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial daylight fluorescence lamp combining visible and ultraviolet (UV) outputs, xenon or metal halide lamp. D65 is the internationally recognized standard for outdoor daylight. ID65 is the equivalent indoor indirect daylight standard. Option 2: Same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp (having a spectral distribution from 320 to 400 nm with a maximum energy emission between 350 & 370 nm)

C. PROCEDURE An overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter to allow direct comparisons to be made between the drug substance and drug product. Samples may be exposed side-by-side with a validated chemical actinometric system to ensure that the specified light exposure is obtained. If protected samples (e.g., wrapped in aluminum foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change, these should be placed alongside the authentic sample.

DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS START FORMULATION CHANGE? YES DIRECTLY EXPOSED ACCEPTABLE CHANGE? YES NO TEST END NO IMMEDIATE PACK CHANGE? YES IMMEDIATE PACK ACCEPTABLE CHANGE? YES NO NO TEST END MARKETING PACK CHANGE? YES MARKETING PACK ACCEPTABLE CHANGE? YES TEST END NO REDESIGN PACKAGE OR REFORMULATION

2. DRUG SUBSTANCES 3. DRUG PRODUCTS Photo-stability testing should consist of two parts: 1. Forced degradation testing: To evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation. 2. Confirmatory testing: To provide information necessary for handling, packaging and labeling. A. Presentation of samples B. Analysis of samples C. Judgement of Results 3. DRUG PRODUCTS

4. ANNEX A. Quinine Chemical Actinometry Each actinometric system should be calibrated for the light source used, by 2% W/V aqueous solution of quinine monohydrochloride dihydrate. Option 1: Use 20 ml colourless ampoules. (seal hermetically). Option 2: Use 1 cm quartz cell. For both the options, prepare sample and control wrap in aluminum foil to protect completely from light, and measure their absorbance At and Ao respectively at 400 nm using a 1 cm path length. Measure the change in absorbance. The length of exposure should be sufficient to ensure a change in absorbance of at least 0.9.

STABILITY TESTING OF NEW DOSAGE FORMS Q1C: STABILITY TESTING OF NEW DOSAGE FORMS

1. GENERAL 2. NEW DOSAGE FORMS This document is an annex to the ICH parent stability guideline and addresses the recommendations on what should be submitted regarding stability of new dosage forms. 2. NEW DOSAGE FORMS Stability protocols for new dosage forms should follow the guidance in the parent stability guideline. However, a reduced stability database at submission time (e.g., 6 months accelerated and 6 months long term data from ongoing studies) may be acceptable in certain justified cases. STABILITY STUDY PROTOCOLS: Same as Q1A(R2)

Q1D: BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

CONTENTS 1. INTRODUCTION 2. GUIDELINES 1.1 OBJECTIVES OF THE GUIDELINE 1.2 BACKGROUND 1.3 SCOPE OF THE GUIDELINE 2. GUIDELINES 2.1 GENERAL 2.2 APPLICABILITY OF REDUCED DESIGNS 2.3 BRACKETING 2.4 MATRIXING 2.5 DATA EVALUATION

2. GUIDELINES 2.1 General STUDY DESIGN FULL STUDY DESIGN REDUCED STUDY BRACKETING MATRIXING

2.2 Applicability of reduced designs Reduced designs can be applied to the formal stability study of most types of drug products. For the study of drug substances, Matrixing is of limited utility and bracketing is generally not applicable. Data variability and product stability, should be considered when a matrixing design is applied. 2.3 Bracketing Bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g. strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of an intermediate levels is represented by the stability of the extremes tested. 2.3.1 Design Factors Design factors are variables (e.g., strength, container size and/or fill) to be evaluated in a study design for their effect on product stability.

2.3.1.1 Strength Bracketing can be applied to studies with multiple strengths of identical or closely related formulations. Examples include: Capsules, tablets and oral solutions of different strengths. In cases, where different excipients are used among strengths, bracketing generally should not be applied. 2.3.2.2 Container closure sizes and/or fills. Bracketing can be applied to studies of the same container closure system where either the container size or fill varies while the other remains constant. However, if a bracketing design is considered where both container size and fill vary, it should not be assumed that the largest and smallest containers represent the extremes of all packaging configurations.

2.3.2 Design considerations and Potential risks If, after starting the studies, one of the extremes is no longer expected to be marketed, study design can be maintained to support the bracketed intermediates. A commitment should be provided to carry out stability studies on the marketed extremes post-approval. Before a bracketing design is applied, its effect on the retest period or shelf life estimation should be assessed. If the stability of the extremes is shown to be different, the intermediates should be considered no more stable than the least stable extreme (i.e., the shelf life for the intermediates should not exceed that for the least stable extreme).

2.3.3 Design example:

2.4. Matrixing Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

2.4.1 Design factors (Same as in bracketing) 2.4.2 Design considerations A matrixing design should be balanced as far as possible so that each combination of factors is tested to the same extent over the intended duration of the study and through the last time point prior to submission. In a design where time points are matrixed, all selected factor combinations should be tested at the initial and final time points, while only certain fractions of the designated combinations should be tested at each intermediate time point.

2.4.3 Design examples: “One-Half Reduction” “One-Third Reduction”

2.4.4 Applicability and degree of reduction Knowledge of data variability. Expected stability of the product. Availability of the supporting data. Stability differences in the product within a factor or among factors. Number of factors combinations in the study. In general, a matrixing design is applicable if the supporting data indicate predictable product stability. If the supportive data show large variability, a matrixing design should not be applied. 2.4.5 Potential risk 2.5 Data Evaluation

EVALUATION OF STABILITY DATA Q1E: EVALUATION OF STABILITY DATA

1. INTRODUCTION 1.1 Objectives of the Guideline This guideline is intended to provide recommendations on how to use stability data generated in accordance with the principles detailed in the ICH guideline “Q1A(R)” (here after referred as the parent guideline) to propose a retest period/shelf life in a registration application. This guideline describes when and how extrapolation can be considered when proposing a retest period for a drug substance or a shelf life for a drug product that extends beyond the period covered by “available data from the stability study under the long-term storage condition” (hereafter referred to as long-term data). 1.2 Background The parent guideline states that regression analysis is an important approach to analyzing quantitative stability data for retest period or shelf life estimation and recommends that a statistical test for batch poolability be performed using a level of significance of 0.25.

1.3 Scope of the Guideline This guideline addresses the evaluation of stability data that should be submitted in registration applications for new molecular entities and associated drug products. 2. GUIDELINES 2.1 General principles 2.2 Data presentation Data for all attributes should be presented in an appropriate format (e.g., tabular, graphical, narrative) and an evaluation of such data should be included in the application. 2.3 Extrapolation Extrapolation is the practice of using a known data set to infer the information about a future data. Extrapolation to extend the retest period or shelf life beyond the period covered by long-term data can be proposed in the application, particularly if no significant change is observed at the accelerated condition.

2.4. Data evaluation for re-test period or shelf life estimation for drug substances or products Intended for Room Temperature Storage 2.4.1 No significant change at accelerated condition 2.4.1.1 Long-term and accelerated data Showing a little or no change over Time and little or no variability 2.4.1.2 Long-term or accelerated Data showing change over Time and/or variability. The drug substance or product will Remain well within the acceptance criteria for that attribute during the proposed Re-test Period or shelf life. Statistical analysis of long term data can be useful In establishing a retest Period or shelf life. A statistical analysis is normally Considered un-necessary.

2.4.2 Significant change at accelerated condition 2.4.2.1 No significant change at intermediate condition 2.4.2.2 Significant change at intermediate condition The proposed re-test period or Shelf life should not exceed the Period covered by long-term data The extent of extrapolation would depend on whether long-term data for the attribute are amenable to statistical analysis Data amenable to Statistical analysis Data not amenable to Statistical analysis The proposed re-test period or shelf life should not be more than 6 months beyond, the period covered by long-term data. The proposed re-test period or shelf life can be upto 3 months beyond the period covered by long-term data

2.5 Data evaluation for re-test period or shelf life estimation for drug substances or products intended for storage below room temperature. 2.5.1 Drug substances intended for storage in a refrigerator 2.5.2 Drug substances intended for storage in a freezer 2.5.3 Drug substances intended for storage below -20°C

2.6. General statistical approaches Regression analysis is considered as appropriate approach for evaluation of stability data for a quantitative attribute and establishing a retest period or shelf life. The relationship between an attribute and time can be represented by a linear or non-linear function on an arithmetic or logarithmic scale. An appropriate approach to retest period or shelf life estimation is to analyze a quantitative attribute (e.g., assay, degradation products) by determining the earliest time at which the 95 % confidence limit for the mean intersects the proposed acceptance criterion. Upper and lower confidence limit (95%) should be calculated and compared to acceptance criterion.

Q1F: STABILITY DATA PACKAGE FOR REGISTRATION APPLICATIONS IN CLIMATIC ZONES III AND IV

CONTENTS 1. INTRODUCTION 1.1 OBJECTIVES OF THE GUIDELINE 1.2 BACKGROUND 1.3 SCOPE OF THE GUIDELINE 2. GUIDELINES 2.1 CONTINUITY WITH THE PARENT GUIDELINE 2.2 STORAGE CONDITIONS 2.2.1 General Case 2.2.2 Aqueous-based drug products packaged in semi-permeable containers. 2.2.3 Tests at elevated temperature and/or extremes of humidity 2.3 ADDITIONAL CONSIDERATIONS

A product’s shelf life should be established according to climatic conditions in which the product is to be marketed. Climatic conditions in countries where the product is to be marketed should be carefully considered during drug development phase. So the world has been divided into four climatic zones based on prevalent annual climatic conditions. Storage conditions recommended by manufacturers on the basis of stability studies are meant to guarantee the maintenance of quality, safety and efficacy throughout the shelf-life of product. Temperature and humidity determine the storage conditions and so they greatly affect the stability of drug product.

DEFINITION AND STORAGE / TEST CONDITIONS FOR FOUR CLIMATIC ZONES Examples I Temperate Climate 21°C ± 2°C and 45% RH ± 5% RH Northern Europe, Canada II Mediterranean & Subtropical climate 25°C ± 2°C and 60% RH ± 5% RH Southern Europe Japan, US. III Hot dry climate 30°C ± 2°C and 35% RH ± 5% RH Egypt, Sudan IV Hot humid climate 75% RH ± 5% RH Central Africa, South Pacific.

2.1 Continuity with the parent guideline 2. GUIDELINES 2.1 Continuity with the parent guideline Stress testing Selection of batches Container closure system Specification Testing frequency Storage conditions for drug substance or product in a refrigerator Storage conditions for drug substance or product in a freezer Stability commitment Evaluation Statements/labeling

2.2 Storage conditions 2.2.1 General case TYPE OF STUDY STORAGE CONDITION FOR CLIMATIC ZONES III and IV MINIMUM TIME PERIOD COVERED BY DATA AT SUBMISSION LONG TERM 30°C ± 2°C/ 65% RH ± 5% RH 12 months ACCELERATED 40°C ± 2°C/ 75% 6 months No intermediate storage condition for stability studies is recommended for Climatic Zones III and IV.

2.2.2 Aqueous based drug product packaged in semi-permeable containers TYPE OF STUDY STORAGE CONDITION MINIMUM TIME PERIOD COVERED BY DATA AT SUBMISSION LONG TERM 30°C ± 2°C/35% RH ± 5% RH 12 months ACCELERATED 40°C ± 2°C/ not more than 25% RH ± 5% RH 6 months The ratio of water loss rates at a given temperature is calculated by the general formula: (100 - Reference %RH / 100 - Alternative %RH) ALTERNATIVE %RH REFERENCE %RH RATIO OF WATER LOSS RATES AT A GIVEN TEMPERATURE 65% RH 35% RH 1.9 75% RH 25% RH 3.0

2.2.3 Tests at elevated temperatures and/or extremes of humidity Special transportation and climatic conditions outside the storage conditions recommended in this guideline should be supported by the additional data. Stability testing at a high humidity condition. Eg. 25°C/80%RH, is recommended for solid dosage forms in water-vapour permeable packaging e.g., tablets in PVC/aluminium blisters, intended to be marketed in territories with extremely high humidity conditions in Zone IV. 2.3. Additional considerations. If it cannot be demonstrated that the drug substance or drug product will remain within its acceptance criteria when stored at 30°C ± 2°C/65 % RH ± 5 % RH for the duration of the proposed retest period or shelf life, the following options should be considered: (1) a reduced retest period or shelf life, (2) a more protective container closure system, or (3) additional cautionary statements in the labeling.

REFERENCES: ICH HARMONISED TRIPARTITIE GUIDELINES www.ich.org USP 2000 Encyclopedia of Pharmaceutical Technology, Vol-19: 227-235 Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C. T. Rhodes

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