Introduction to Dosage Forms Design PDF

Official Business PHR106 Dosage Forms, Drug Delivery System, and Medical Devices Introduction to Dosage Form Design Charliemaign Stanley S. Cruz, RPh, MSc. Official...

Official Business PHR106 Dosage Forms, Drug Delivery System, and Medical Devices Introduction to Dosage Form Design Charliemaign Stanley S. Cruz, RPh, MSc. Official Business DRUGS A drug is an agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in humans or in other animals (Food, Drug, and Cosmetic Act, 1938). Diagnosis Mitigation Treatment Cure Prevention Official Business NEW DRUG AND POTENTIAL NEW DRUG A new drug is any substance derived from plant or animal sources, as by- products of microbial growth or growth through chemical synthesis, molecular modification, or biotechnology. A potential new drug substance has established: Chemical and physical characterization including the stability of the drug entity.. Basic pharmacology, MOA, toxicology, pharmacokinetics and other highly specific information (e.g., effects on fetus, nursing baby, etc.). Most effective routes of administration, appropriate dosage forms and strengths. Must be released from the dosage form in the proper quantity. Must possess attractive features like flavor, odor, color, and texture. Can be effectively packaged with clear and complete labels following regulations. Official Business PHARMACEUTICAL PRODUCTS A pharmaceutical product when properly administered and taken in sufficient quantity, at specific intervals and duration will achieve the desired therapeutic outcomes. The efficacy of a pharmaceutical product may be evaluated against the patient’s expression of disappointment in the rate of progress or complains or side effects and other issues surrounding the effectiveness of the medication. Official Business PHARMACISTS A pharmacist is a vital member of the health care team equipped with intimate knowledge of drug actions, pharmacotherapeutics, formulation and dosage form design, available pharmaceutical products, and drug information sources. Pharmacist serves as a patient advisor on drugs and encourages their safe and proper use through patient counselling. Official Business THE HERITAGE OF PHARMACY Apothecary is a person who prepares and sells drugs or compounds for medicinal purposes; a druggist or pharmacist. This is one of the earliest trades or profession. The Art of Apothecary is associated with the mysterious. The practitioners were believed to have a connection with the world of spirit combined with priestly functions. Pharmacy was derived from pharmakon connoting a charm or drug used for good or evil. Official Business EARLY DRUGS Sumerian Clay Tablet dates back 3000 BC and is the world’s oldest written prescription. Examples of prescriptions: Pulverized seed of carpenter plant, Gum resin of markhazi and thyme dissolved in beer Powdered roots of “moon plant” and white pear dissolved in beer Official Business EARLY DRUGS Ebers Papyrus (discovered and partly translated by Georg Ebers) It is a scroll of about 60 feet long and a food wide that dates back from the 16th century BC and is the most famous surviving artifact containing pharmaceuticals. It is preserved at the University of Leipzig and contains 800 formula or prescriptions and mentioned more than 700 drugs from botanical, mineral, or animal sources. It mentions different vehicles like beer, wine, milk, and honey. It also mentions dosage forms like gargles, pill, ointment, troches, plasters, and enemas. Official Business EARLY SCIENTISTS Scientist Contribution Father of Medicine Hippocrates Rationalized medicine, systematized medical knowledge, and put the practice of medicine on a high ethical plane. A botanist and physician Dioscorides Wrote De Materia Medica containing naturally occuring medicinal materials. A pharmacist and physician Claudius Galen Introduce Galenic Pharmacy or preparations of vegetable drugs by mixing or melting individual ingredients (e.g., Galen’s cerate – cold cream) Created a decree to regulate Pharmacy practice in his kingdom resulting to Emperor Frederick II separation of pharmacy and medicine. Elevated the pharmacy practice by instilling quality to products. Official Business EARLY SCIENTISTS Scientist Contribution Paracelsus A Swiss physician and chemist Transformed pharmacy from botanical to a chemical science leading to preparation of medicinal agents for specific diseases. Karl Wilhelm Scheele A Swiss pharmacist Discovered several plant acids (citric, lactic, oxalic, tartaric acids); identified glycerin; discovered oxygen with Joseph Priestley. Friedrich Serturner A German pharmacist He isolated morphine from opium. Joseph Caventou French pharmacists Joseph Pelletier Isolated quinine and cinchonine form cinchona; isolated strychnine and Pierre Robiquet brucine from Nux vomica (Caventou and Pelletier) Isolated caffeine (Pelletier and Robiquet) Isolated codeine from opium (Robiquet) Official Business EARLY RESEARCHES Paclitaxel an agent with antitumor activity isolated from the Pacific Yew Tree (Taxus baccata). Vincaleukoblastine is an antineoplastic drug from Vinca rosea. Digoxin is a cardiac glycoside isolated from Digitalis lanata. Official Business EARLY RESEARCHES Extraction and isolation of active constituents from crude botanical drugs led to the development of dosage forms of uniform strength with single therapeutic agents and then to manufacturing quality pharmaceutical products. Philadephia College of Pharmacy (est 1821) is America’s first school of Pharmacy. The Royal College of Apothecaries (est 1441) is the oldest Pharmacy college. Official Business PHARMACOPEIA Pharmacopeia comes from the Greek word pharmakon meaning drug, and poiein meaning make any recipe or formula or other standards required to make or prepare a drug. Lititz Pharmacopeia is the first American pharmacopeia used by the Military Hospital of the US Army. It is a 32-page booklet containing 84 internal and 16 external drugs and preparation. Pharmacopeia of Massachusetts Medical Society has 272 pages containing monographs of 536 drugs and preparation. Official Business USP and NF Lyman Spalding is a NY physician who submitted a plan to create a national pharmacopeia. He is regarded as the Father of USP. USP was first published on Dec. 15, 1820, in English and Latin with 272 pages containing 217 drugs that were mostly taken from the Massachusetts Pharmacopeia (precursor of USP). USP Objectives are: To select medicinal substances which is the most fully established and most understood. To form from them preparations and compositions. To distinguished articles by convenient and definite names. USP is revised every 5 years while maintaining the use of periodic supplements. Official Business USP and NF USP members: 8 elected members of the board of trustees 2 representing the medical sciences 2 representing pharmaceutical sciences 1 public member 3 members to serve without restriction on their affiliation Official Business USP and NF The evolution of pharmaceutical practice as reflected in USP Creation of elegant pharmaceutical preparations from crude botanical materials Industrial revolution affected pharmaceutical manufacturing, which adapted new machineries from other industries: Mixers from baking industry Centrifugal machines from laundry industry Sugarcoating pans from the candy industry Pharmacist was relying heavily on commercial sources for drug supply. Knowledge of chemical structures of isolated active constituents arose methods of synthetically duplicating the same structures. Official Business USP and NF The evolution of pharmaceutical practice as reflected in USP Synthesis of salicylic acid from phenol started the synthesis of analgesic compounds including acetylsalicylic acid (Aspirin). Synthesis of barbiturates – self-producing derivatives of barbituric acid. Discovery of arsphenamine by Paul Erlich and Sahachiro Hata. Agent for syphilis Introduced the era of chemotherapy – an era in which diseases of humans became curable. Official Business USP and NF National Formulary of Unofficial Preparations contains many popular drugs and formula not included in the USP (restricted to drugs of established therapeutic merit). National Formulary together with USP designated as establishing legal standards for medicinal and pharmaceutical substances as signed by US President Theodore Roosevelt. It required that products must conform to the physical and chemical standards in the compendium monograph – it made NF an official compendia. It mainly serve pharmacists by providing uniform names of drugs and preparations and working directions for the small-scale manufacture. Official Business USP and NF Unified USP/NF was created when the USP convention, Inc. purchased NF and then provided the mechanism for a single national compendium. Editions are revised annually in hard copy and as online (now online only) with twice-yearly supplements and update notices on the USP web site. Official Business USP and NF USP contains monographs for drugs substances, dietary supplements, dosage forms, and compounded preparations. NF contains monographs for pharmaceutical excipients. NOTE: The term “product” refers to manufactured drugs and the term “preparations” refers to compounded drugs. USP/NF is used by pharmacists, physicians, dentists, veterinarians, nureses, producers, and suppliers of bulk chemicals for us in drug production, large and small manufacutrers, drug procurement officers, public and private health agencies, drug regulatory and enforcement agencies, etc. USP has no enforcement powers, but it provides “standards” and not regulations or laws. Official Business USP and NF USP/NF Chapters: General Chapters numbered 1000 – informational USP Chapter - Pharmaceutical Compounding for Non-sterile Preparations Guidance on applying GMP for the preparation of non-sterile compounded formulations for dispensing and/or administration to humans or animals. USP Chapter Pharmaceutical Compounding – Sterile Preparation Guidance (both environmental and practice) to prevent harm, including death, to patients that could result from non-sterility, excessive bacterial endotoxins, variations in intended strength, unintended chemical and physical contaminants, and ingredients of inappropriate quality. Official Business USP and NF USP/NF Chapters: USP Chapter Hazardous Drugs – Handling in Health Care Settings Promote patient safety, worker safety, and environmental protection and can apply to all health care personnel who handle hazardous preparations and all entities that store, prepare, transport, or administer hazardous drugs. USP Chapter Pharmaceutical Calculations in Pharmacy Practice Assist pharmacists and support personnel in performing required calculations for the compounding and dispensing of medications. USP Chapter Quality Assurance in Pharmaceutical Compounding Discusses training, SOPs, documentation, verification, analytical/chemical testing, physical testing, microbiological testing, cleaning/disinfecting/safety, packaging outsourcing, responsibilities, etc. Official Business USP and NF USP/NF adopts standards for drug substances, pharmaceutical ingredients, and dosage forms reflecting the best in the current practices of medicines and pharmacy and provide suitable tests and assay procedures for demonstrating compliance. A drug with a name recognized in USP/NF must comply with compendial identity standards or be deemed adulterated, misbranded, or both. Adulterated drugs must comply for strength, quality, and purity. Misbranded drugs must comply for packaging and labeling. Official Business USP and NF USP/NF consist information including: Official name (generic / non-proprietary name) of the drug substance Graphic or structural formula Empirical formula Molecular weight Established chemical names Chemical Abstracts Service (CAS) registry number – a unique ID of each compound in CAS computer information retrieval system State of chemical purity Caution on its toxic nature Packaging and storage recommendations Chemical and physical tests prescribed method of assay Official Business USP and NF Official Business DRUG REGULATION AND CONTROL Official Business DRUG REGULATION AND CONTROL Food and Drug Act of 1906 First federal law in the US to regulate drug products manufactured domestically. It requires drugs marketed interstate to comply with their claimed standards for strength, purity, and quality. Sherley Amendment in 1912 – therapeutic benefits were regulated specifically prohibiting false claims of therapeutics effects, declaring them as “misbranded”. Official Business DRUG REGULATION AND CONTROL Federal Food, Drug, and Cosmetic Act of 1938 This act is due to sulfanilamide (known before as a wonder drug). It was prepared as an elixir using diethylene glycol – a highly toxic agent used in antifreeze solutions with more than 100 persons died of diethylene glycol poisoning. This act was administered and enforced by the FDA. It prohibits the distribution and use of any new drug without filing the New Drug Application (NDA) and approval of the FDA. The FDA is in-charge of reviewing the filed data on the ingredients, methods of assay, and quality standards, formulation and manufacturing processes, preclinical studies (pharmacology and toxicology), and clinical trials on human subjects. It requires the products to be safe and effective for the condition for which it is intended. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Durham-Humphrey Amendment of 1951 This established a legal distinction between prescription and non-prescription or OTC drugs. Prescription drugs (or legend drugs) must bear the symbol “Rx only” or the legend “Caution: Federal Law Prohibits Dispensing Without Prescription.” This is applicable for: New drug substances May not be refilled without the express consent of the prescriber Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Kefauver-Harris Amendments of 1962 This is due to the tragedy of a new synthetic drug – thalidomide. This amendment ensures greater degree of safety for approved drugs. The drug was meant as a sedative and tranquilizer and was available OTC in Europe. When given during pregnancy, it produced birth defects, most notably phocomelia. The severely afflicted died of malformation of the heart or GIT. Investigational New Drug (IND) application is filed with the FDA. The drug is evaluated for safety and effectiveness through human clinical trials. Once it passes, an NDA is filed for approval for marketing. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Comprehensive Drug Abuse Prevention and Control Act of 1970 This is administered by the Drug Enforcement Agency (DEA) in the Department of Justice. This created five “schedules” for the classification and control of drug substances that are subject to abuse. 5 Schedules: Schedule I: drugs with no accepted medical use or other substances with a high potential for abuse (e.g., heroin, lysergic acid diethylamide, mescaline, peyote, marijuana, etc.). Schedule II: drugs with accepted medical uses and a high potential for abuse that may lead to severe psychological or physical dependence (e.g., morphine, cocaine, methamphetamine, amobarbital, etc.). Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Schedule III: drugs with accepted medical uses and a potential for abuse less than those listed in I and II; may lead to moderate psychological or physical dependence (e.g., specific amounts of codeine, hydrocodone, etc.). Schedule IV: drugs with accepted medical uses and low potential for abuse than those in III; may lead to limited psychological or physical dependence (e.g., specified amounts of difenoxin, diazepam, oxazepam, etc.). Schedule V: drugs with accepted medical uses and low potential for abuse than those in IV; may lead to limited psychological or physical dependence (e.g., specific amounts of dihydrocodeine, diphenoxylate, etc.). Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 FDA Pregnancy and Lactation Labeling These categories A, B, C, D, and X are removed from all human prescription drug and biologic product labeling. It should include: Summary of the risks during pregnancy and lactation. Discussion of data supporting the summary. Information to help health care providers in making prescribing decisions and counselling women about the use of drugs during pregnancy and lactation. Information about pregnancy testing, contraception, and infertility for females and males of reproductive potential. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Medication Exposures During Pregnancy and Lactation Assessment of drug’s teratogenic potential: the stage of pregnancy and the amount of medication taken Patient needs to be counseled about potential adverse effects on her fetus or infant. Black Box Warnings It is used to call attention to one of the following: A serious ADR The risk of a serious ADR can be prevented or reduced by careful use FDA has approved the drug with restrictions to prescribing or distribution Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Drug Listing Act of 1972 This provided the FDA a compiled list of marketed drugs. Manufacturer, repacker, or distributor must register with the FDA and submit appropriate information, exempt are hospitals and clinics, research and teaching institutions. It is provided with National Drug Code (NDC) that must appear on all drug labeling. The first 4 numbers – identify the manufacturer or distributor The last 6 numbers – identify the drug formulation (product code) and the trade package size and type (package code). It maybe 3:3 or 4:2 configuration (e.g., 0777-3333-22). Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Orphan Drug Act of 1983 Orpha drugs are intended for treatment of rare diseases or conditions like those affecting fewer than 200,000 people or more but the company is unlikely to recover its R&D cost. It is provided with tax credits and designated years of marketing exclusivity as incentives. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Drug Price Competition and Patent Term Restoration Act of 1984 Abbreviated as New Drug Application (ANDA) is filed for generic copies of approved new drug where animal and human studies are not required. Extension of patent life is equal to the time required for FDA review of NDA plus half the time spent in the testing phase (max 5 years) and not to exceed the usual 20-year patent term. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Prescription Drug Marketing Act of 1987 and Prescription Drug Amendments of 1992 Reduces the risks of adulterated, misbranded, repackaged, or mislabeled drugs entering the marketplace through “secondary sources”. It prohibits the following: Reimportation Sales of drug samples Distribution of samples, except to licensed prescribers and pharmacies with written requests Wholesale distribution Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Prescription Drug User Fee Act of 1992 It allowed the FDA to accept user fees from drug and biologic companies to review new drug and biologic applications within certain time frames. It follows a more rapid application review process. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Dietary Supplement Health and Education Act (DSHEA) of 1994 and the Dietary Supplement and Nonprescription Drug Consumer Protection Act of 2006. Regulated the labeling claims of products such as vitamins, minerals, amino acids, and botanicals (no NDA and not evaluated for safety and efficacy by FDA). These forbids manufacturers to make any advertising or labeling claims that indicate that the use can prevent or cure a specific disease. A disclaimer MUST appear on the product: “This product is not intended to diagnose, treat, cure, or prevent any disease.” Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 It permits claim of benefit related to a nutrient deficiency disease, or how an ingredient affect the body’s structure or function, or how it affects the person’s general well-being – must be submitted first to FDA as truthful and not misleading. Examples: ginseng, gingko, saw palmetto, St. John’s wort, and Echinacea USP/NF has standards for these type of products and if they meet the them, the product can place a logo of the USP/NF on the label signifying compliance. Allowed the FDA to implement GMPs similar to pharmaceutical products ensuring that DS comply with quality standards, declared amounts, proper packaging, QC records, and a system of identification and reporting of serious ADEs. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 The FDA and the Food and Drug Administration Modernization Act of 1997 and the FDA Amendments Act of 2007 The FDA was established to administer and enforce the Federal Food, Drug, and Cosmetic Act with a mission to protect the public health against risk associated with production, distribution, and sale of food and food additives, human drugs and biologicals, radiologic and medical devices, animal drugs and feeds, and cosmetics. The modernization was done to streamline FDA policies and to codify many agency’s newer regulations. It also expanded patient access to investigational treatments for AIDS, cancer, Alzheimer disease and others. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 It provided faster new drug approvals by using sponsor’s fees to hire additional internal reviewers and authorized use of external reviewers. It provided incentives for investigations of drugs for children and added a provision to track clinical trial data with the National Institute of Health (NIH). Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 The Biologics Price Competition and Innovation Act (BPCI) of 2009 This is also called the biosimilar statute. It established a shortened or accelerated approval pathway for biologic drugs that are highly similar or interchangeable with FDA-licensed biological products. It provides 12 years of data exclusivity, prohibiting the FDA from allowing another manufacturer to rely on the agency’s prior findings of safety, purity, and potency from the innovator product. It prohibits any product from being granted more than one period of data exclusivity. If modified product, it will be considered as a new product and entitled to 12 years of data exclusivity. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 H.R 3204 Drug Quality and Security Act (DQSA) of 2013 It incorporates and brings up to date court decision regarding Food and Drug Modernization Act of 1997. It resulted from the tragedy with fungal meningitis in 2012 affecting 14,000 patients among which 64 deaths and hundreds were sickened. It traced fungal contamination in 3 lots of compounded methylprednisolone suspension for epidural steroid injections. Compounded products from new drug requirements labeled, tracked, traced under the direct supervision of a licensed pharmacist in a registered outsourcing facility are exempted. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Globalization and the FDA FDA has established foreign operation offices in receptive supplier countries and has increased inspections of foreign supplier facilities. FDA is working to develop internationally accepted quality and safety standards through coalition with foreign counterpart agencies. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Drug Product Recall Drug products may be recalled if they present a threat or a potential threat to consumer safety. The manufacturer is legally bound to report serious unlabeled ADRs to the FDA. The practitioner has a responsibility to report a problem with any drug product or medical device. A product recall may be voluntary (from the manufacturer) or initiated by the FDA. Official Business FEDERAL FOOD, DRUG, AND COSMETIC ACT OF 1938 Drug Product Recall Class I – reasonable probability that use or exposure to a violative product will cause serious adverse health consequences or death. Class II – use or exposure may cause temporary or medically reversible adverse health consequences, probability of serious adverse health consequences is remote. Class III – use or exposure is not likely to cause adverse health consequences. The depth depends on the nature of the product, the urgency of the situation, and depth to which the product has been distributed. Official Business DRUG DEVELOPMENT AND NEW DRUG APPLICATION Official Business DRUG DEVELOPMENT Drug company commonly acts as drug sponsors once they obtain a new drug approval for marketing. The drug must demonstrate that the new drug or drug product is safe and effective for its proposed use. During World War II There was rapid production of drugs and pharmaceutical products. Primarily due to undependability of overseas shipping, unavailability of drugs. There was an increased need for drugs especially those with lifesaving capabilities. Official Business NEW DRUG APPLICATION PROCESS Official Business SOURCES OF NEW DRUGS Sources: Natural sources Synthesized in the laboratory Created through processes of biotechnology Chemical or engineered biologic material resulting from the research that is more targeted - directed toward the physiologic or metabolic process or biomolecular target of a disease. Official Business SOURCES OF NEW DRUGS Natural Sources – Plants Originated from successful conversion of botanic folklore remedies to wonder drugs. Semisynthetic drugs - active plant constituents isolated from plants but chemically modified through molecular modification. Example: Dioscorea (Mexican yams) – rich steroid structure from which cortisone and estrogens are produced. Natural Sources – Animals Hormonal substances from endocrine glands of cattle, sheep, and swine used daily as replacement therapy (e.g., thyroid extract, insulin, pituitary hormone). The urine of pregnant mares is a rich source of estrogen. These pharmaceutical products are used in biologic products like serums, antitoxins, and vaccines. Official Business SOURCES OF NEW DRUGS Genetic Engineering involves the submicroscopic manipulation of the DNA double helix. It can produce any of the following: Recombinant DNA It can produce almost any protein. Gene splicing is a common techniques used where lower organism are induced to produce proteins of higher organisms. Common examples are human insulin, human growth hormone, hepatitis B vaccine, epoetin alfa, and interferon. Monoclonal Antibody (mAb) Production It can be conducted in higher organisms like in humans. It exploits the ability of the cells with the potential to produce a desired antibody. Common example is the home pregnancy test – the mAb binds to human chorionic gonadotropic or hCG-synthesized in placenta. Muromonab is the first FDA approved therapeutic drug used for transplant reduction. Official Business SOURCES OF NEW DRUGS Human Gene Therapy It is used to prevent, treat, cure, diagnose, or mitigate human diseases caused by genetic disorder through modification of the genetic material of living cells. The process transfers new genetic material to the cells with a genetic disease allowing the material to incorporate itself and alter the genetic code of the patient. Official Business SOURCES OF NEW DRUGS Goal Drug A drug that will produce the specific desired effect, administered by the most desired route (orally) at minimal dosage and dosing frequency, have optimal onset and duration of activity, and exhibits no side effect. It should be eliminated from the body efficiently, completely, and without residual effect. It should also be easily produced at low cost, pharmaceutically elegant, and physically and chemically stable. Official Business SOURCES OF NEW DRUGS Methods of Drug Delivery 1. Random or untargeted screening 2. High-throughput screening 3. Molecular modification – chemical alteration of a known and previously characterized organic compound (lead compound). Mechanism-based drug design – interferes with the known or suspected biochemical pathway or mechanism of a disease process. Molecular graphics – use of computer graphics to represent and manipulate the structure of the drug to fit the simulated structure of the receptor site. Official Business SOURCES OF NEW DRUGS Lead Compound is a prototype chemical that has a fundamental desired biologic or pharmacologic activity. Prodrug is a pharmacologically inactive molecule that requires metabolic transformation after administration to produce the active compound. The design of a prodrug considers the following: Solubility Absorption Biostability Prolonged release Official Business SOURCES OF NEW DRUGS New Drug (FDA) A new drug is also called New Molecular Entity (NME) and is an active ingredient that has never been marketed in the US in any form. A NME can be: A change in formulation or method of manufacture A combination of two or more old drugs A change in usual proportions of drugs A proposed new use, new dosage schedule or regimen, new route of administration, new dosage form. Official Business DRUG NOMENCLATURE These are several ways on how to name drug molecules. These names are used in pharmacopeia and other official documents to refer to a particular drug. Empirical Formula – indicates the number and relationship of the atoms in the molecule (e.g., C16H19N3O5S·3H2O) Chemical Name – it reveals every part of the compound’s molecular structure, it describes only a single compound (e.g., 2S,5R,6R)-6-[[(2R)-2- amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid). Official Business DRUG NOMENCLATURE Systematic Name / Shortened Name - it is less descriptive chemically but is understood to refer to a single chemical compound. It serves as the chemical’s non-proprietary name or generic name (e.g., amoxicillin). Code numbers – it comes in the form of an identifying prefix letter or letters that identify the drug sponsor followed by a number that identifies the test compound (e.g., SQ 14225). Official Business DRUG NOMENCLATURE Nonproprietary Name – it is applied by the drug sponsor to United States Adopted Name (USAN) Council when the results of testing indicate that a compound shows sufficient promise of becoming a drug. USAN Council is sponsored by the AMA, USP Convention, and the APhA. Guidelines for nonproprietary name: It should be useful to health care practitioners particularly in its safety for use in the routine processes of prescribing, dispensing, and administering drugs. It should be a single word, preferably with no more than four syllables, should be free from conflict with other nonproprietary names, should be neither confusing nor misleading. It is distinctive terminology should be used for specific drugs or drug groups. Official Business DRUG NOMENCLATURE Salt Nomenclature – a drug product and compounded preparations containing a slat of an acid or base use the name of an active moiety and the strength of the product or preparation. Active Moiety – is a molecule or ion, excluding those appended portions of the molecule that cause the drug to be a salt or other noncovalent derivative of the molecule. This is responsible for the physiologic or pharmacologic action of the drug substance. Official Business DRUG NOMENCLATURE Naming drug products and preparations: The general format is [DRUG][DOSAGE FORM], e.g., Paracetamol Tablet. [ROUTE] is omitted when obvious e.g., glycerin suppository (no route), levocetirizine HCl oral solution (with route since solutions are not always oral). For those that require some step in preparation prior to administration, the general format is [DRUG][DOSAGE FORM] for [ROUTE][DOSAGE FORM] e.g., Aspirin Effervescent Tablets for Oral Solution “Vaginal Inserts” instead of “vaginal tablets” is the latest convention for this dosage. The term “suppositories” always refer to solids for rectal administration. Official Business NEW DRUG APPLICATION PROCESS Official Business BIOLOGIC CHARACTERIZATION Pharmacology is the science concerned with drugs including its sources, chemistry, appearances, actions, and uses. Subareas: Pharmacodynamics – deals with the biochemical and physiologic effects of the drugs and their MoA (drug’s effect to the body). Pharmacokinetics – deals with the ADME of the drugs (reaction of the body to the drug). Clinical pharmacology – applies pharmacologic principles to the study of the effects and actions of drugs in humans. Official Business BIOLOGIC CHARACTERIZATION In Pharmacology, Biochemical processes are studied to understand the role of specific enzyme system in the healthy and disease states leading to the design of drugs affecting these enzymes towards positive results. Drugs work in the body by binding to cellular components called receptor sites. Structure-Activity Relationship (SAR) investigates on the selectivity and specificity of drugs related to specific sites on or within the cells which are receptive only to specific chemical structure and configuration. Official Business BIOLOGIC CHARACTERIZATION In Pharmacology, There is a relationship between the quantity of drug molecules available for interaction and the capacity of the receptor site (the more drug molecules the better chances of binding). It is possible for two drugs in a biologic system to compete for the same binding sites which may result to inhibition of the drug that did not bind, and the observed effects comes from the drug that was bound to the receptor. It is also possible for certain cells (carriers) within the body to have the capacity to bind a drug molecule without eliciting any drug effect. Official Business BIOLOGIC CHARACTERIZATION In Pharmacology, testing is important to: Determine the compound’s selectivity and activity against enzymes, then determine whether the compound is an agonist (activates the enzymes) or antagonist (deactivates the enzyme). Perform tests on isolated animal tissue to define the compound’s activity and selectivity. Perform tests on whole animal models to evaluate the pharmacologic effects on specific organ system. Perform tests on animal models of human disease for which the compound is a drug candidate. Official Business BIOLOGIC CHARACTERIZATION In Pharmacology, animal testing is: Usually performed on small animals like rodents (rats and mice) or rabbits because of the cost, availability, small amount of drug required, ease of administration, and experience in these species. For the final pharmacologic and toxicologic studies: two animal species are used –a rodent and non-rodent (commonly a dog). Official Business BIOLOGIC CHARACTERIZATION Drug Metabolism is the biotransformation of drugs from a nonpolar form into a more polar derivative in order to facilitate easier elimination of the compound. Drug metabolism is primarily performed by the liver but may also occur in other organs such as the lungs, kidneys, or skin. Drugs administered orally and passes through the liver and is exposed to the metabolic enzymes undergoes first-pass effect – a significant decrease in availability since most of the drugs are already metabolized or inactivated. Metabolism is responsible for producing drug metabolites that are active or not. It can also convert prodrugs to active compounds. Official Business BIOLOGIC CHARACTERIZATION Toxicology deals with the adverse or undesired effects of the drugs. It is important to study a drug’s toxicity to determine: Toxicity with short- or long-term use Specific organ toxicity Mode, site, and degree toxicity Dose-response relationships Gender, reproduction or teratogenic toxicities Carcinogenic and genotoxic potential Official Business BIOLOGIC CHARACTERIZATION In toxicology, Acute or Short-term toxicity studies are done to determine toxic effects or a test compound when administered in a single dose and/or in multiple does over a short period, usually a single day. Subacute or Subchronic studies are for drugs administered on a single doe un humans for a minimum of 2 weeks daily at 3 or more dosage levels to 2 animal species. Chronic toxicity studies are for drugs given for a week or more in humans, tested for 90 to 180 days in animals. For drugs used for chronic illness, 1 year or longer must be undertaken. Official Business BIOLOGIC CHARACTERIZATION In toxicology, Carcinogenicity studies are done with a high dose that should only be high enough to elicit signs of minimal toxicity without altering the animal’s normal life span by effects other than carcinogenicity. Long-term studies (18-24 months) with surviving animals, they are sacrificed and studied for causes like tumor incidence, type and site, and necropsy findings are evaluated. Reproduction studies are done to possibly reveal any effect of an active ingredient on mammalian reproduction – fertility and mating behavior, early development, multigenerational effects, and teratology. Genotoxicity or Mutagenicity studies are done to determine if the test molecule can affect gene mutation or cause chromosome or DNA damage. Official Business PREFORMULATION STUDIES Drug solubility refers to a molecule possessing some aqueous solubility for systemic absorption and therapeutic responses. Partition Coefficient is a measure of a drug’s distribution in a lipophilic- hydrophilic phase system and indicates its ability to penetrate biologic multiphase systems. Dissolution Rate is the speed at which a drug substance dissolves in a medium, can provide an indication of the drug’s absorption potential. Physical Form refers to either the crystal or amorphous forms and/or the particle size of a powdered drug that can affect the dissolution rate, thus the affecting the rate and extent of absorption. Official Business PREFORMULATION STUDIES Stability is a drug’s ability to resist physical or chemical change over a period of time. It may depend on the following: Type of crystal structure Addition of antioxidant stabilizing agents Protection against moisture in formulation, processing, and packaging Temperature and relative humidity Official Business PREFORMULATION STUDIES The initial formulation and clinical trial materials, Initial product is formulate using the information gained during the pre-formulation studies to consider the dose/s, dosage form, and route of administration desired for clinical studies and for proposed marketed product. Initial formulations will include: Phase 1 – capsules are used to contain active ingredients without excipients (non-active). Phase 2 – the excipients are added; the final dosage form is selected and developed for Phase 3 trials and submitted to FDA for marketing approval. Clinical trial materials (CTM) – dosage formulation used in clinical evaluation of a new drug, proposed new drug, placebos, drug products to be used for comparison. Official Business NEW DRUG APPLICATION PROCESS Official Business INVESTIGATIONAL NEW DRUG APPLICATION An investigational new drug application (IND) must be made before the drug may be given to human subjects. To protect the rights and safety of the subjects. To ensure the investigational plan is sound and is designed to achieve the objectives. After submission, the drug sponsor must delay the use to human subjects for not less than 30 days. Clinical hold is an order issued by the FDA to delay the start of a clinical investigation or to suspend an ongoing study. If human subjects will be exposed to unreasonable and significant risk of illness of inquiry. The qualifying credentials of the clinical investigators are questionable. IND is considered incomplete, inaccurate, or misleading. Official Business INVESTIGATIONAL NEW DRUG APPLICATION Clinical Protocol must be submitted to ensure the appropriate design and conduct of the investigation. For any changes, an amendment must be approved for the proposed changes. Common consideration in protocols: Clinical protocols must include women in adequate numbers. Pregnant women should not be included. Women with life-threatening disease (e.g., AIDS) are not automatically exclude. Elderly can be included if drugs have significant use to them. Children will be included for testing drugs for pediatric use. Official Business INVESTIGATIONAL NEW DRUG APPLICATION Internal Review Board (IRB) is the approving body for IND application. It is a body of professional and public members that review and approve any study involving human subjects in the institutions they have. It assess the proposed clinical protocol includes measures for subject protection. All investigators must qualify as experts by training and experience and must receive from the sponsor the investigator’s brochure. The study must have defined criteria for subject inclusion-exclusion; the sponsor must certify that all participants has been given informed consent. Any serious, unexpected, life-threatening, or fata ADR must be reported promptly to the sponsor and FDA. Official Business INVESTIGATIONAL NEW DRUG APPLICATION Pre-IND Meetings are held for FDA to advise the sponsor on scientific, technical, or formatting concerns in the IND. FDA Review of an IND Application is done primarily for the purpose of: Protecting the safety and rights of human subjects and ensure the study evaluates the drug’s safety and efficacy. Upon submission of an IND, it is forwarded to either the Center for Drug Evaluation and Research (CDER), or the Center for Biologics Evaluation and Research (CBEER). Official Business INVESTIGATIONAL NEW DRUG APPLICATION Pre-IND Meetings are held for FDA to advise the sponsor on scientific, technical, or formatting concerns in the IND. FDA Review of an IND Application is done primarily for the purpose of: Protecting the safety and rights of human subjects and ensure the study evaluates the drug’s safety and efficacy. Upon submission of an IND, it is forwarded to either the Center for Drug Evaluation and Research (CDER), or the Center for Biologics Evaluation and Research (CBEER). Official Business INVESTIGATIONAL NEW DRUG APPLICATION FDA Drug Classification System aids CDER in determining if a priority (P) or standard (S) shall be given to an application within 14 days of submission. Priority (P) review is given for proposed drug product that provides a significant improvement compared to the marketed product or if it provides safe and effective therapy when no alternate therapy exists. Official Business NEW DRUG APPLICATION PROCESS Official Business CLINICAL TRIALS Phase 1 – this is the initial introduction of an investigational drug into humans and is primarily for the purpose of assessing safety. This includes human subjects of 20 to 100 healthy volunteers. The initial dose is low, usually 1/10 of the highest no effect dose observed in animal studies then will progress to greater doses to new subjects until effects are observed. At this phase, investigators determine human pharmacology, SAR, side effects with increasing doses, and early evidences of effectiveness. Data on ADME, toxic effects and changes in physiologic processes are collected. Official Business CLINICAL TRIALS Phase 2 – evaluates the effectiveness in patients with the condition the drug is intended while assessing side effects and risks that may be revealed for the first time. Phase 2a – additional data on pharmacokinetics are collected; determine dose- response and dose ranging. Phase 2b – determination of minimal effective dose and safety margin. the drug product is refined with the final formulation developed for use drug in late Phase 2 and Phase 3 trial. If the safety margin is considered good, end-of-Phase 2 meeting will be conducted with FDA. Official Business CLINICAL TRIALS Phase 3 – this includes several hundred to several thousand patients in controlled and uncontrolled trials to determine the usefulness of the drug in more patients. Phase 3a – multiple dosage strengths may be evaluated. This phase evaluates the overall benefit-risk relationship. An NDA can be filed after sufficient information are gathered. Phase 3b – gathering of supplementary information that support: Labelling requests Provide information on patient’s QoL issues Reveal product advantages over competing drugs Possible additional indications Provide prospective post-marketing studies Official Business CLINICAL TRIALS Official Business CLINICAL TRIALS Clinical Study Controls and Designs Phase 2 and 3 are controlled studies where effects of the investigational drug are compared with another agent. The second (comparison) agent may be: Placebo control (no effect; empty capsule, water, or drug vehicle) Active drug (positive control; standard or comparator agent) Controlled study designs can be: Single-blind – patient is unaware of the agent administered Double-blind – both patient and clinician are unaware of the agent administered Open-label – both patient and clinician are aware of the agent administered Official Business CLINICAL TRIALS Parallel Designs Note: All clinical materials used for blinded studies should be indistinguishable from one another. Other factors to be considered for the design: Scheme and duration of the treatment period Baseline data should be gathered Random assignment of treatment groups Cross-over Designs Official Business DRUG DOSAGE AND TERMINOLOGY Dose is an amount of drug enough to achieve the optimum therapeutic effect with safety but at the lowest possible amount. Most products are formulated to contain a drug’s usual dose within a single unit or a specified volume of a liquid dosage form. A drug is manufactured often into more than one dosage form and in more than a single strength. Official Business DRUG DOSAGE AND TERMINOLOGY Dosage Regimen (schedule) is the recommended timeframe when a drug is recommended to be taken or administered. This is determined during the clinical investigation and is based largely on a drug’s inherent duration of action, its pharmacokinetic profile, and the characteristic of the dosage form (immediate or modified release - MR). Official Business DRUG DOSAGE AND TERMINOLOGY Initial, Priming, or Loading Dose is the dose required to attain the desired concentration in the blood or tissues; after which may be maintained through regularly scheduled maintenance doses. Prophylactic Dose is the amount administered to protect a patient from contracting a specific illness. Therapeutic Dose is the amount administered to a patient after exposure or contraction of illness. Official Business DRUG DOSAGE AND TERMINOLOGY Minimum Effective Concentration (MEC) is lowest concentration that can be expected to produce a drug’s desired effect in a patient. This is represented by the average blood serum concentration that corresponds to the presentation of a drug’s effect. Minimum Toxic Concentration (MTC) is a concentration that will produce a dose-related toxic effects in an average individual. Therapeutic Window is the serum drug concentration between MEC and MTC. The larger the window, the safer the drug. Official Business DRUG DOSAGE AND TERMINOLOGY Median Effective Dose is the amount of the drug that will produce the desired intensity of effect in 50% of the individuals tested. Median Toxic Dose is the amount of the drug that will produce the desired intensity of effect in 50% of the individuals tested. Therapeutic Index is the ratio between a drug’s median toxic and effective dose. The larger the TI, the safer the drug. 𝑀𝑒𝑑𝑖𝑎𝑛 𝑇𝑜𝑥𝑖𝑐 𝐷𝑜𝑠𝑒 (𝑇𝐷50) 𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝐼𝑛𝑑𝑒𝑥 𝑇𝐼 = 𝑀𝑒𝑑𝑖𝑎𝑛 𝐸𝑓𝑓𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑜𝑠𝑒 (𝐸𝐷 50) Official Business DRUG DOSAGE AND TERMINOLOGY Age is an important patient parameter in dosing especially in the treatment of neonatal, pediatric, and geriatric patients. Pediatric doses are based on body weight or body surface area (BSA) or pediatric clinical trials. Infants are patients with immature hepatic and renal function; reduced capacity to detoxify and eliminate drugs. Elderly are patients with diminished physiologic functions; decline in renal and hepatic function. May exhibit different drug response due to altered sensitivity of the drug receptors or due to age-related alterations in tissues or organs. Official Business DRUG DOSAGE AND TERMINOLOGY Pharmacogenetics is another patient parameter in dosing due to differences among racial and ethnic groups in the metabolism, clinical effectiveness, and ADRs of drugs. Genetic polymorphisms of enzymes affect the clearance from the blood. These polymorphism in the genetic make-up may influence a drug’s action by altering its pharmacokinetic profile or pharmacodynamic properties. Official Business DRUG DOSAGE AND TERMINOLOGY Body Weight is usually used as a general basis for dosing calculations. The usual doses are generally suitable for a 70 Kg (~150 lb) individual. Body weight is considered more dependable than age as a determinant of a drug dosage (mg/Kg) for your pediatric patients. Body Surface Area (BSA) is commonly determined using a nomogram, a graphical representation of the correlation between several number of physiologic processes and BSA. Official Business DRUG DOSAGE AND TERMINOLOGY Sex can influence pharmacokinetic profile leading to differences that are important for drugs with narrow therapeutic index. The menstrual cycle and menopausal status of women may have an effect on the pharmacokinetics of a drug. Sex may be a factor leading to drug interaction potential of concomitant estrogen or oral contraceptive use. Caution must be provided to female patients when taking drugs especially during pregnancy and lactation states. Official Business DRUG DOSAGE AND TERMINOLOGY Pathologic States may lead to different alteration in drug’s response as the condition may exhibit effects on the metabolic processes of the body. Tolerance is the ability to endure the influence of a drug, particularly during continued use. It can be developed to a specific drug and to its chemical congeners. Due to tolerance, the dose over time of the drug is increased. Official Business DRUG DOSAGE AND TERMINOLOGY Concomitant Drug Therapy may result into drug-drug interactions which are due to chemical or physical interaction between drugs or to an alteration of the ADME of one of the drugs. Some of the DDIs are also caused by interactions to social agents including alcohol and tobacco. Time and Conditions of Administration may influence the dosage like with orally administered drugs and their relation to meals as there can also be drug-food interactions that can take place. Official Business DRUG DOSAGE AND TERMINOLOGY Dosage Form and Route of Administration have significant influence in the effectivity of a particular dose. For parenteral routes, a lower dose of the same drug is required to achieve the same blood levels or clinical effects that can be exhibited by an orally administered drug with a higher dose. An orally administered drug would require a higher dosing as it will undergo several metabolic biotransformation before it reaches the bloodstream to illicit the intended effect. Official Business DRUG DOSAGE AND TERMINOLOGY Treatment IND A treatment protocol permitting the use of investigational new drug in the treatment of patients who are not enrolled in the clinical study but who have a serious or immediately life-threatening disease for which there is no alternative therapy. The drug should be under Phase 2 or Phase 3 clinical trial. Group C treatment IND is when the IND is distributed to oncologists for the treatment of cancer under protocols outside the controlled clinical trial. Emergency use IND is when the use of the IND for treatment arises from emergency situations. Official Business DRUG DOSAGE AND TERMINOLOGY IND for Orphan Drug FDA approves support grants to conduct clinical trials on safety and effectiveness of orphan drugs. These grants are awarded for Phase 2 and Phase 3 clinical studies with a provision of a 7-year period of exclusive marketing rights after regulatory approval. Official Business DRUG DOSAGE AND TERMINOLOGY Withdrawal or Termination of IND Sponsors may withdraw an IND at any time, ending all clinical investigations. All clinical supplies must be returned or destroyed. FDA, IRB, and all investigators must be advised of the withdrawal. Inactive state is when no subject entered for 2 years or more; or investigations remain on clinical hold for 1 year or more. Termination is when clinical investigations are stopped with reasons for safety, efficacy, or regulatory compliance. Official Business NEW DRUG APPLICATION PROCESS Official Business NEW DRUG APPLICATION The purpose is to gain permission to market the drug in the US (country). General Contents of an NDA Submission: 3 copies of NDA Archival copy – maintained by the FDA as reference document Review copy – used by the FDA review divison Field copy – used by the FDA district office and fields inspectors in an on-sire pre- approval inspection Application Form Chemical, Nonproprietary name, code, and proprietary names, dosage form, strength and route. Statement to market as prescription or an over-the-counter (OTC) Official Business NEW DRUG APPLICATION General Contents of an NDA Submission: Detailed summary of all aspects of the application Detailed technical sections on the CMCs (chemistry, manufacturing, controls) for the drugs substance Detailed technical sections for nonclinical pharmacology and toxicology Detailed technical sections for human pharmacokinetics and bioavailability Detailed technical section for clinical data Statement regarding compliance to IRB and informed consent form Statistical methods and analysis of the clinical data Samples of the drug substance, drug product, reference standard, finished market package Clinical case report forms for archival copy Official Business NEW DRUG APPLICATION Drug Product Labeling follows a specific labeling requirements which differ from prescription drugs, nonprescription drugs, and animal drugs. To ensure appropriate and safe use of the approved product Product labeling includes labels on immediate container, package inserts, company literature, advertising, and promotional materials. Package Insert should contain: Highlights of prescribing information section, containing a summary of the critical or most frequently used drug information. Full prescribing information section Boxed warning (if there is any) Official Business NEW DRUG APPLICATION FDA Review and Action Letters The completed NDA is reviewed by the FDA to decide whether to allow or disallow marketing or to require additional data before rendering a judgment. FDA must respond within 180 days upon receipt of the application (review clock). Recommendation from outside advisory committee: Approval – meaning the drug has met standards of safety and efficacy and can be marketed for sale. Complete response, letting a company know that the review period for a drug is complete and that the application is not yet ready for approval – deficiencies/recommendation. Official Business NEW DRUG APPLICATION PROCESS Official Business PHASE 4 STUDIES AND POSTMARKETING SURVEILLANCE Phase 4 Studies or Post-marketing Surveillance These studies contribute to understanding the drug’s mechanism or scope of action, indicate possible new therapeutic uses, demonstrate the need for additional dosage strengths, dosage forms, and route. It may reveal additional side effects, serious and unexpected adverse effects, and/or drug interactions. The sponsor is required to report adverse drug experience both serious and unexpected, within 15 days of receipt of information. Adverse events that are not serious or unexpected are reported quarterly for 3 years and annually thereafter. A confirmed incident of mislabeled, contaminated, or deteriorated product in distribution, the sponsor must file an NDA field alert report within 3 working days upon receipt of information. Official Business SUPPLEMENTAL, ABBREVIATED, AND OTHER APPLICATIONS Supplemental NDA is done when a sponsor of an approved NDA makes changes in the application: Change in the method of synthesis of the drug substance Use of different facility to manufacture the drug substance Change in the formulation, analytical standards, method of manufacture, or in-process controls of the drug product. Use of different facility or contractor to manufacture, process, or package the drug product. Change in the container and closure system for a drug product Extension of the expiration date based on new stability data Labeling change that does not add to or strengthen a previously approve label statement Official Business SUPPLEMENTAL, ABBREVIATED, AND OTHER APPLICATIONS Abbreviated NDA are NDA were nonclinical laboratory studies and clinical investigations may be omitted, except those pertaining to the drug’s bioavailability. This is usually filed for duplicates (generic copies) of products with approved full NDA. It can be filed by competing companies following the expiration of patent term protection of the innovator drug. Official Business SUPPLEMENTAL, ABBREVIATED, AND OTHER APPLICATIONS Biological License Application (BLA) This is submitted to CBER for the manufacture of biologics such as blood products, vaccines, and toxins. Animal Drug Application There are specific regulations pertaining to the approval for the marketing and labeling of drugs intended for animal use. Medical Devices There are regulations on the manufacture and licensing of all medical devices, from surgical gloves and catheters to cardiac pacemakers and pulmonary bypass blood glass monitors. Official Business INTERNATION COUNCIL FOR HARMONIZATION International Council for Harmonization (ICH) Established to harmonize the technical requirements for pharmaceuticals for human use. It brings together regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of pharmaceutical product development. It began in the 1980s with the European Union then in 1989, Europe, Japan, and the United States of America began creating the plans for harmonization. It is comprised of the following bodies: ICH Assembly, ICH Management Committee, MedDRA Management Committee, and ICH Secretariat. ICH topics are divided into 4 categories: Q: Quality Guidelines, S: Safety Guideline, E: Efficacy Guideline, and M: Multidisciplinary Guidelines.