Pharmaceutics Final Exam Review Part I

Final Exam Review Part I (Lectures #2 to 10) 65 MC Questions 5-6 excipient questions Pharmaceutics Exam #1 Material (25% of Final Exam)      Introduction to Drugs and Pharmacy Drug Regulation and Control Good manufacturing Practices General Considerations in Dosage Form Design Powders and Granules ________________________________________________________________________ Introduction to Drugs and Pharmacy 1) Write the name in full and then define the role of each What is NF and USP? Why was it critically important to adopt these legal documents? NF is a National Formulary. USP is a pharmacopeia. These are organized sets of monographs or books of standards. Written with high degree of clarity and specificity.  Adopt standards for drugs, pharmaceutical ingredients and dosage forms  Reflect the best current practices of medicine  Provides information on tests and assay procedures for demonstrating compliance with these standards  For individual components not combinations What is the function of the CDER? The Center for Drug Evaluation and Research.  Make drugs available to the public sooner  Balances the risks and benefits of new drug before approval  Provide clear standards for drug evaluation  Determines if studies show that drug is safe and effective before approval  High priority drugs o These are defined as drugs that offers significant medical advantage over current therapies o Cancer, contraceptive, generic Major difference between FDA of 1906 and FDA of 1938 1 Food and Drug Act of 1906: required that drugs marketed interstate comply with claimed standards for strength, purity and quality (not safety) Food and Drug Act of 1938: There is a need for SAFE administration of drugs (due to sulfanilamide tragedy) 2) Answer all parts of this question. What is the name of the agent that caused the Sulfanilamide Tragedy? Was the problem ingredient an excipient or the active agent? Name of the agent: diethylene glycol, it was the solvent used to prepare the elixir. It was an excipient used to enhance taste + solubility. (i) What was the finished preparation intended to treat? Sulfanilamide was a “wonder drug” used to treat bacterial (streptococcal) infection (ii) Could this tragedy have been prevented? How? The tragedy could have been prevented by implementing a law that required that drugs comply with standards for SAFETY, not just strength, quality, and purity. The use of a different solution such as Propylene-glycol would have prevented this tragedy from occurring. 3) Who was Frances Kelsey, and why did President Kennedy award her the Distinguished Federal Civilian Service Award? Dr. Kelsey was an FDA employee in charge of reviewing the marketing application for thalidomide in the US. She noticed that the drugs acted DIFFERENTLY in people than in animals. She investigated the effects of the drug and found that it could be harmful to fetuses. She made key observations eventually linking the general use of Thalidomide to Phocomelia and safeguarded all pregnant women from the effects of the drug. 4) In a few words define each of the following. Don’t exceed the space provided. A) Black Box Warning: Strongest labeling requirements used for high risk medications. Stresses close patient monitoring. FDA approves drugs but restrictions to prescribing and distributing to ensure safety. 2  Required that all new drugs be tested by manufacturers for safety; tests must be submitted to government via NDA process; drugs must be labeled with directions; FDA can conduct unannounced inspections B) Kefauver Harris Amendment of 1962: Thalidomide tragedy created this act. Requires drugs to be efficacious as well as safe before FDA approval for marketing C) Durham-Humphrey Amendment of 1952: No refills without a valid prescription. Determined what drugs are OTC and what are not. D) Prescription Drug Marketing Act of 1987: (Updated in 1992): This act prohibits reimportation of drugs, prohibits sales, trading, and purchasing of drugs. Functions to protect the supply of prescription agents and prevent repackaged and mislabeled drugs from entering the legitimate market. 3 5) Can a Drug Product Recall ever be initiated by the manufacturer? Discuss.. Either the FDA OR the MANUFACTURER can reveal the product presents a threat to the public so a drug product recall may be initiated by the FDA or by the manufacturer. There are 3 classes of drug recall: Class I: Exposure will cause serious adverse health consequences or even death Class II: Exposure will cause temporary or medically reversible adverse health consequence Class III: Exposure is not likely to result in adverse health consequences 4 Drug Regulation and Control 6) Name the natural plant source from which the following alkaloid drug agents were originally derived? Morphine: from Opium Poppy used for pain relief Quinine: from Cinchona Bark Digitalis: from Foxglove Belladonna: from Deadly Night Shade 7) If we have a lead compound why continue searching for the goal drug?  Is to get more of the desired features of the goal drug. Lead Compound: this compound is the closest agent to the “goal drug” possessing the fundamental desired biologic or pharmacologic activity. It may not contain all the properties of the desired compound, and so medicinal chemists often modify the lead compound. Goal Drug:     can produce a desire effect can be administered at the most desirable route (orally) can be administered at a minimal dosage frequency After exerting a necessary effect should be eliminated from the body efficiently, and without negative side effects 8) Why is the partition coefficient important in pharmaceutics? Partition Coefficient: optimal balance b/w H2O and lipid   P = conc. of drug in octanol/ conc. of drug in H2O Most drugs undergo transport by simple diffusion, whether in cytoplasm or interstitial fluid environment What is the significance of the Crystal and Amorphous drug form? Crystal form is LESS soluble; Energy required for molecule of drug to escape from crystal GREATER. Amorphous drug form: MORE SOLUBLE. How are Phase I, Phase II and Phase III Clinical Trials different? Phase l:  Drug should show promise as a useful drug: 20 to 100 patients  Usually brief study (less than 1 year) 5  Use healthy volunteers Purpose: to determine toxicology, metabolism, and pharmacologic actions, test for ADEQUATE SAFETY  Application contains: o The plan for the study o Manufacturing information o Chemical structure o Animal testing results Phase ll:  Drug is tested in hundreds of patients (~100 to 300 people)  Patients have the disease that the drug is intended to treat  Extensive pharmacologic, toxicological, and pharmacological testing  Many clinical agents do not make it to this point Purpose: to determine compounds effectiveness, many do not make it to this point Phase lll:  Several thousands of patients in many centers (~1000-3000 people)  Carried out over several years  How good is the drug in treating the disease or condition? Short term side effects? Risks?  Investigational drug will be used in several randomized, controlled studies various clinical research facilities including, o Clinical research facilities o Veterans administration University teaching hospitals Purpose: to demonstrate long-term safety and efficacy of drug product, to discover drug efficacy standards 9) Can new clinical trial material (CTM) be introduced at a phase other than Phase I? If so, with all of our concerns regarding drug regulation and control, why do you think this is allowed? Weigh the benefit versus the risk. New CTM CAN be introduced at phase other than Phase I. New formulation closer to desired commercial dosage form can be introduced DURING PHASE II or may be changed specifically for two reasons: 6  when required dosage strength is NOT supported  when medium-to-large scale is NOT feasible In Phase III, changes in dosage strength + manufacturability may occur as long. But same formulation processing, and packaging procedures is RECOMMENDED. 10) What is the major problem with dosing below the MEC and above the MTC? Minimum effective concentration (MEC): The minimum dose required to get a desired effect Minimum toxic concentration (MTC): Administering drugs above this level will produce dose related toxicities   The drug serum levels should be maintained above the MEC and below the MTC Concentrations above the MTC will cause toxic side effects  Major implication of dosing below the MEC: will not see desired effect  Major drawback of maintaining MEC over an extended period of time: resistance can occur, may have to change drug 11) What is the difference between the Prophylactic Dose and the Therapeutic Dose? Prophylactic Dose: Administered to prevent patients from contracting disease Therapeutic Dose: Administered once disease has been contracted *look up how to use nomogram **If you can only administer the drug once and it can only stay above the MEC for a limited amount of time, what could you do? You could fractionate the dose (give smaller doses at many times) could developed an extended-release (look at excipients) Just because the drug is not available at the MEC, DOESN’T MEAN that it is not exerting a beneficial effect ***Metronomic scheduling : takes extremely low concentrations of drugs for an EXTENDED PERIOD OF TIME (month or two) *this may be better --you always have some amount of drug present -concentration will be well below the MEC -but there is some conc. of drug all the time in the blood -drug is exerting physiological effects --NOT AS EFFECTIVE OVER A SHORT PERIOD OF TIME -MORE EFFECTIVE than injecting a SINGLE INJECTION -do NOT achieve MEC -toxic effects not as much with metronomic scheduling 7 Good manufacturing Practices 12) What is the difference between Batch and Batchwise control? Batch: SPECIFIC QUANTITY of a drug of uniform specified quality produced according to a SINGLE manufacturing order during the same cycle of manufacture Batchwise control: the USE of validated in-process SAMPLING & TESTING METHODS in such a way that results prove that the process has DONE WHAT IT PURPORTS TO do for the SPECIFIC BATCH concerned 13) What is the difference between Lot and Lot number? Lot: any batch or part of a batch of UNIFORM specified quality + distinctive identifying lot # Lot number: any distinctive combination of letters, numbers, or symbols from which the complete history of the manufacture, processing, packing, holding + distribution of batch/lot of product may be determined 14) What is the name of the regulatory process through which industry measures quality performance, and compares to standards? A) B) C) D) Quality control Quality Unit Quality assurance Quality control unit 15) During the Production and Process Control written documentation is required to make sure that each drug product has the correct, Identity, strength, quality, and purity 8 16) Review notes and textbook chapter on Tamper-evident packaging. Film wrapper Sealed around product and/or product container; film must be cut or torn to remove product Blister/strip pack: Individually sealed dose units; removal requires tearing or breaking individual compartment Bubble pack: Product and container sealed in plastic, usually mounted on display card; plastic must be cut or broken open to remove product Shrink seal, band: Band or wrapper SHRUNK BY HEAT or DRYING to conform to cap; must be torn to open package Foil, paper, plastic pouch: Sealed individual packet; must be torn to reach product Bottle seal: Paper or foil sealed to mouth of container under cap; must be torn or broken to reach product Tape seal: Paper or foil sealed over carton flap or bottle cap; must be torn or broken to reach product Breakable cap: Plastic or metal tearaway cap over container; must be broken to remove Sealed tube: Seal over mouth of tube; must be PUNCTURED to reach product Sealed carton: Carton flaps sealed; carton cannot be opened without damage Aerosol container:Tamperresistant by design Any person or organizational element designated by the firm to be responsible for the duties relating to quality control Provision to all concerned the evidence needed to establish confidence that the activities relating to quality are being performed adequately. IDENTITY QUALITY (Think "ISQP") Records and Reports: production information must be maintained on file for at least 1 year following expiration date of batch. Control Records must include the following: - Name and strength of product dosage form - Components and dosage units - Control procedures - Equipment used - In-process controls - Results of analysis - Calibration of instruments -Pharmaceutical excipients MUST be produced according to cGMP specifications. NO FDA approval system for pharmaceutical excipients. -All regulatory requirements must be met by phase 3 and reported to FDA. Placebos must also be prepared by this stage. 17) What are the major problems associated with the use of Plastic versus Glass containers for the packaging of finished pharmaceutical preparations? Be specific. 9 What are the advantages for plastic vs. glass? Lightness in terms of weight Plastic squeeze bottle Greater flexibility in terms of design and appearance What are the problems with plastic over glass?  Permeability of containers o Atmospheric oxygen, moisture vapors  Leaching of constituents of container to internal contents o Such as polymer additives Absorption of drug from contents to container Transmission of light through container Change in container material overtime    18) What is required for OTC labeling?  Product name  Net quantity of contents o This includes all ingredients  Must indicate pharmacologic category  Cautions and warnings to protect consumer  Sodium content (for oral products) when necessary o 5mg or more per single dose o 140mg or more in maximum dose  Storage conditions o Must include storage in safe place out of the reach of children o Lot number and expiration date 19) What are the storage temperatures as defined by USP? Cold = 8 ºC Cool: Between = 8 ºC and 15 ºC Room Temp = 22 ºC Warm: Between = 30 ºC and 40 ºC 10