1、BIOPHARMACEUTICAL DEVELOPMENT & REGULATION,Ron Guido Alan McEmber,Course Details,Fall 2007: W4200 Section 001 : BIOPHARMACEUTICAL DEVELOPMENT ,Course Details,Class Modules (Subject to Change)History of Regulation (incl. Regulatory Defined, Major Regulatory Bodies Worldwide) Basics of Drug Discovery
2、and Development Pharmacokinetics / Pharmacodynamics (from a Regulatory viewpoint) Non Clinical Pharm/ Tox (incl. cGMP) Standards of Approval (Rx, OTC, Biologics, Biotech) IND / CTD / CTx (inc. cGCP) NDA / MAA (US, EU, Japan, National Deep Dive US Regulatory Deep Dive EU Regulatory Clinical Program D
3、evelopment / Labeling Development and Revision Post Approval Actions (Studies, Amendments, Supplements, Variations) EU / US cGMP and Inspection CM&C and Change Control Recalls and Field Actions Product Queries OTC / Consumer Products Advertising and Promotion Agency Meetings and Communication Introd
4、uction to Regulatory Assessment and Strategy,Course Details,Method of Assessment: 3 Take Home (24-Hour) Assessments, 10 short responses per assessment. May require light research and problem solving Textbook: Drug Discovery and Development: Technology in Transition, H.P. Rang, Churchill Livingstone
5、(Elsevier) 2006 NOTE: Supplemental readings will be posted,Drug Development Terminology and Basic Concepts,from the Regulatory Perspective,For your consideration,Drug /Biotech Development requires cutting edge science, but thats not all its about Regulation is supported by science, but science and r
6、egulation often part company Industry, clinical excellence groups lead regulation Novelty lowers hurdles for approval, but often complicates review process Product is defined by its active, and the associated claims of actionProduct needs to have a meaningful clinical effectBurden of proof is on the
7、 sponsor to demonstrate the safety, necessity and/or efficacy of any component not already recognized.,Regulatory Affairs,What is it?,A Broad Scope: Regulations and Agencies,Pharmaceutical products are regulated in essentially every country of the world.These regulations are applicable to both the i
8、nvestigation and marketing of compounds.,Regulatory Affairs Defined,Regulatory Affairs is a specialized profession within the pharmaceutical/biotechnology sector. Regulatory Affairs oversees company compliance with regulations and laws pertaining to the manufacture, marketing and development of regu
9、lated products. Regulatory Affairs acts as point of contact between the company, its products and regulatory authorities Regulatory Affairs interacts with worldwide, federal, state, and local regulatory agencies (e.g., FDA (US), EMEA (EU), BfARM (Germany), TPD (Canada), etc) to assurelicensing, regi
10、stration, development, manufacturing, marketing and labeling .of pharmaceutical and medical products are conducted in compliance with all applicable rules,Regulatory Framework,Development, approval for marketing, manufacturing, and ongoing compliance of pharmaceutical/biotech products is among the m
11、ost regulated activities of any industry Regulations are complex systems of interrelated rules that govern a broad range of activities These rules are continuously undergoing amendment and supplementationTheir main function is to assure that these products are safe (do no harm) and effective ( do so
12、me good),Regulatory Framework,Why do we pay so much attention to regulation and process ?It takes 8 to 15 years to develop a new drug/biologic product. Costs up to $ 800 million. Attention to early development, successfully execution of significant clinical studies helps to reduce number of developm
13、ent failures. Regulatory affairs provides insight/guidance into this development through agency wisdom collected in guidance, previous experience, market precedence, etc. Compliance with Regulator expectations therefore equates with development success. Patient Protection is of greatest importance,D
14、evelopment Costs in Perspective,FROM: The Price of Pills; July 2003; Scientific American Magazine; by Carol EzzellForty F16 jet fighters, or $802 million. Thats how much it takes to develop a new drug, according to the first academic analysis of the process published in 12 years. That number reaches
15、 $897 million if postmarketing studies-additional clinical research that the U.S. Food and Drug Administration sometimes requires as a condition for approving a new drug-are taken into account, the reports authors announced in May. These sky-high prices (in 2000 dollars) have prompted disbelief and
16、consternation among some critics, who allege that the pharmaceutical industry is inflating the true cost of drug development to justify the escalating price tags of many therapies. The naysayers also accuse big pharma of seeking to justify its tax credits for research and development and to dissuade
17、 Congress from rolling back those benefits.,Drug Discovery,US Base Standards for Drugs / Biopharmaceutics,Drugs must be generally recognized as safe and effective Benefits of use must always outweigh potential risk,Definition of a Drug,The term “drug“ means any articles intended for use in the diagn
18、osis, cure, mitigation, treatment, or prevention of disease in man or other animals.,What is a “new” drug,The term “new drug“ means any drug the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safe
19、ty and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof (except drugs so recognized subject to the Food and Drugs Act of June 30, 1906) “Old Drug”,Chemistry and Manufacturing,Drug Substance,Drug substance (Active
20、 pharmaceutical ingredient) It is the material that is exerting the pharmacological action. Along with other ingredients (excipients, inactives) it subsequently it is used to formulate, the drug product. It can be composed of the desired active material, product-related substances, productor process
21、 related impurities (subsequently removed) It also may contain other components, including vehicles, or buffers. Biologics and biotechnology industry. Alternatively referred to as bulk concentrate, bulk intermediate, or simply bulk,Drug Product,Drug product (Dosage form; Finished product) one or mor
22、e drug substances (active pharmaceutical ingredients) usually with excipients Excipients components of a finished medicinal drug product other than the active pharmaceutical ingredient (API). Included in the formulation to facilitate manufacture, enhance stability, control release of API from the pr
23、oduct, assist in product identification, or enhance other product characteristics.,Impurity,ImpurityAn impurity is any component present in the excipient, drug substance, or drug product that is not: the desired product, a product-related substance, or excipient, (including buffer components). It ma
24、y be either process- or product-related. It may be the result of active principle degredation during holding/processing,Chemistry Manufacturing & Controls,Analytical Method Degradation Products Specifications In-process controls Methods Validation Process Validation (DP/DS) Characterization Containe
25、r / Closure System Characterization Stability,Drug Discovery & Approval,Drug Discovery,Target Profile Intended therapeutic site of action and clinical outcome Lead Identification Identified candidate compounds with potential drug activity commensurate with profile from a library of actives (hits) Le
26、ad Optimization Identification / modification of lead compounds for best action / least side effects, etc Combinatorial Chemistry generation of active compounds (hits) from a library of building blocks Structure-Activity Relationship determination of the relationship between a specific chemical stru
27、cture and a pharmacological action,Clinical Investigation,US: IND Investigational New Drug (Application)EU: CTA / CTX Clinical Trial Authorization/Clinical Trials Exemption,Marketing Approval,US NDA New Drug Application 505(b)(1), 505(b)(2) ANDA - Abbreviated New Drug Application BLA Biologic Licens
28、e Application EU MAA Marketing Authorization Application CTD Common Technical Document; common format for organization of information in marketing authorization (registration) applications. Format for CTD acceptable in three regions (US, Europe, Japan). Content requirements are not fully harmonized
29、and there are differences between the three regions.,Label,LabelThe label is the document physically attached directly to the packaging materials that are in direct contact with the excipient, drug substance, or drug product. LabelingLabeling includes the label and the documents included with, but n
30、ot attached to, the packaging materials that are in direct contact with the excipient, drug substance, or preparation (e.g., package insert).,Labeling Terminology,Primary and Secondary Container US Package Insert (PI) US Patient Package Insert (PPI) Structured Product Labeling (SPL) labeling electro
31、nically packaged “in a form“ that FDA can process, review, and archive EU SPC Summary of Product CharacteristicsBasis of information for health professionals on how to use the medicinal product safely and effectively. EPAR - European Public Assessment Report. Conclusion reached by the Committee for
32、Medicinal Products for Human Use (CHMP) at the end of the centralized evaluation process. Includes summary, list of authorized presentations, and the product information (SPC, labeling and package leaflet),Basic Concepts Clinical Pharmacology,Broad Categories of Pharmacology,Pharmacodynamics How the
33、 drug affects the bodyPharmacokinetics How the body affects the drug ADME Absorption, distribution, metabolism, excretion Clearance,Pharmacodynamic Interactions,Drug-receptor effects Increased effect: Enhancement by occupancy : diazepam and zopiclone Reduced/blocked effect: Competitive antagonism: s
34、albutamol and propranolol Enhanced therapeutic effects Alcohol and sedatives Side effects Aspirin and diclofenac (both acting on cytoprotective pathways),Pharmacokinetic Interactions: Metabolism,Phase I metabolism Phase II metabolism Many organs, systems involved,Phase I Metabolism: Functions,Tend t
35、o make drugs: More water soluble Less active Less toxic Prepares drugs for greater metabolic conversion and clearance,Phase I Metabolism: Reactions,Oxidation Cytochrome P450 (CYP) Cytoplasmic: Alcohol dehydrogenase Xanthine oxidase Monoamine oxidase Reduction CYP in liver, flora in gut Hydrolysis CY
36、P Other (e.g. cholinesterases),Phase II Metabolism: Functions,Primary : Conjugation (binding to another molecule) Bigger than the drug alone Less able to cross cell membranes Less likely to reach site of activity More likely to be removed,Phase II Metabolism: Reactions,Glucuronidation (e.g. morphine
37、) Conjugation with glucuronic acid Acetylation (e.g. isoniazid) Conjugation with acetyl co-enzyme A Conjugation with other molecules: Amino acid (e.g. glutathione, glycine) Sulphate,Clearance,Removal of drug from the body Parent drug and metabolites have individual clearance characteristics Linked t
38、o ADME characteristics of the compound,Types of Clearance,Metabolic First pass metabolism e.g. nitrates Mostly liver Other metabolic tissues Renal (urinary) Biliary (fecal) Other (expired air, sweat),Summary,Pharmacodynamic interactions: When drugs have similar (additive) or antagonistic effects (po
39、tentiation, or diminution of effect)Pharmacokinetic interactions: When drugs interfere with each others mechanisms of clearance (taking one drug in the presence of another causes either accumulation, or greatly expedited metabolism),Worked Example,What makes something a drug ?,Is this a drug ?,Ingre
40、dients Analysis,Ingredients define the “Drug” Product Carbonated Water, sucrose, glucose, sodium citrate, taurine, glucuronalactone, caffeine, inositol, niacinamide, calcium pantothenate, pyridoxine, HCL, Vitamin B12, natural and artificial flavors, colors,Ingredients Analysis - Actives,Definition o
41、f Drug Substance Carbonated Water, sucrose, glucose, sodium citrate, taurine, glucuronalactone, caffeine, inositol, niacinamide, calcium pantothenate, pyridoxine, HCL, Vitamin B12, natural and artificial flavors, colors,Ingredients Analysis,Carbonated Water, sucrose, glucose, sodium citrate, taurine
42、, glucuronalactone, caffeine, inositol, niacinamide, calcium pantothenate, pyridoxine, HCL, Vitamin B12, natural and artificial flavors, colors,Recognition of Taurine,Recent studies show that taurine supplements taken by mice on a high-fat diet prevented them from becoming overweight. Taurine is bei
43、ng tested as an anti-manic treatment for bipolar depression. Recent studies have also shown that taurine can influence (and possibly reverse) defects in nerve blood flow, motor nerve conduction velocity, and nerve sensory thresholds in experimental diabetic neuropathic rats. Taurine is often used in
44、 combination with bodybuilding supplements such as creatine and anabolic steroids, partly due to recent findings in mice that taurine alleviates muscle fatigue in strenuous workouts and raises exercise capacity. Taurine has also been shown in diabetic rats to decrease weight and decrease blood sugar
45、.,Caffeine,Recognized in OTC regulation (monograph) for relief of fatigue Sub-monograph potency,Claims Analysis,Improves Performance NOT: Relieves fatigue Increases Concentration and Reaction Speed NOT: Helps relieve adult attention deficit disorder Increases Endurance NOT: Helps relieve muscle weak
46、ness associated with X disease process Stimulates Metabolism NOT: Prevents obesity, promotes weight loss,Current FDA Analysis,FDA position: Product is a beverage containing a conditionally active, common amino acid with no known deleterious effects. No requirement to scrutinize beverages in the abse
47、nce of uncharacterized ingredients,Conclusion,Drugs have action in ameliorating disease Actives must have a recognized basis for recognition (S/E), not just scientific substantiation of action A drug is defined not only by the provision of an active substance but also by the (therapeutic, disease ameliorating) claims made in its labeling,Article Analysis,Where does the science and regulatory diverge Does anything potentially cross the line Does the Agency uphold its mission in the protection of public health Are there any ethical considerations ?,
