E3

Describe three situations that require testing or certification of Primary Engineering Controls [PEC}.

-During certification of new facilities and equipment, Minimally every 6 months , When problems with CSPs are identified or employee work practice problems are observed.

Define Compounded Sterile Preparation [CSP]

A preparation intended to be sterile that is created by combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug product or bulk drug substance.

Define drug according to the FDA definition.

A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and a substance (other than food) intended to affect the structure or any function of the body'.

Drug Discovery:

A target that a drug can act on of a disease is known. Ideas about molecular structure of the drug that can act on the target are developed and evaluated. Potential drugs are made and tested for activity and toxicity.

Describe the advantages/disadvantages of transdermal delivery of drugs.

ADVANTAGES: - Non invasive alternative to oral route, Avoid GI drug absorption problems, Avoid first pass effect, Extended therapy with a single application (which leads to improved compliance), Extended activity for drugs with short half-life, easily and rapidly identified in emergency situations, Drug therapy may be rapidly terminated by removal from skin DISADVANTAGES: Only relatively potent drugs suitable for TDDS, May cause skin irritation or contact dermatitis (API, excipients, adhesives, and enhancers).

What are the advantages and disadvantages of injection routes of administration?

ADVANTAGES: Rapid onset of action. Predictable way of action, complete bioavailability DISADVANTAGES: More expensive than products for enteral administration, most require sterility, require administration by skilled personnel, dose difficult to remove once administered

Describe the time and expense associated with new drug development and approval.

10 to 15 years & $1.2-$1.3 billion.

Drugs administered IV tend to have _______ % bioavailability because they do not require _______ and go directly into the systemic circulation

100% & absorption

The air quality in the primary engineering control [PEC] or LAFW should be at least ISP Class _______

5

The air quality in the buffer area should be at least ISP Class_____

7 .

The air quality in the ante-area should be at least ISO Class_____

8 .

What is drug absorption? Which routes require absorption for systemic effect?

Absorption - the movement of drug molecules across biological barriers (mostly layers of cells) from the site of administration to the blood stream.

What is the main disadvantage to tablets as a dosage form?

Available only in fixed doses and fixed combinations of medications.

Why are compounded sterile preparations potentially more harmful to patients?

Because we are bypassing the body's defenses.

Identify the reference used for determining drug substitutions and discuss issues regarding substitution of biologics.

Biosimilars are approved on the basis that they are equal to the reference biologic in terms of both efficacy and safety. Biosimilars are unique but not generic versions of innovator biologic, so cannot be substituted.

What are the three main steps in manufacturing compressed tablets?

Blending (API and excipients into powder blend), massing with water/binder (power blend to granules), and compression (granules into tablet).

Excipients determine what four properties of tablets?

Excipients determine the bulk of the final product in dosage forms, speed of disintegration, rate of dissolution, release of drug, stability during storage.

Which direction does the air flow in an LAFW and where is the HEPA filter located?

Horizontal airflow. HEPA filter is on the back.

Define INDA and NDA and differentiate between them [components and time of filing].

INDA: Investigational New Preclinical safety data, drug candidate's chemical structure, submitted before Drug Application & NDA New Drug Applications: proposed mechanism of action, listing of any side effects,

When should visual inspection of CSPs be performed?

Immediately before preparation is released or dispensed.

Describe the event that led to the 1938 Federal Food, Drug, and Cosmetics Act.

In 1937, a sulfanilamide elixir that contained toxic solvent diethylene glycol killed 107 people (many were children). This led to the passage of the 1938 FFDC Act.

What was the major event that led to the Drug Quality and Security Act that grants the FDA more authority regarding compounding?

In September 2012, the New England Compounding Center (NECC) was the source of contaminated injectable methylprednisolone acetate that led to >60 deaths and >750 cases of infection in 20 states.

List the dosage forms/routes that require sterility?

Injections, irrigations for internal body, ophthalmics, aqueous preparations for pulmonary inhalation, baths and soaks for live organs and tissues, implants.

What is the only intravascular route of administration?

Intravenous.

What determines the method of sterilization selected?

It is based on physical and chemical properties of ingredients and container closure system.

Post-marketing Surveillance

It is required to report adverse drug reactions at quarterly intervals for the first 3 years after approval (for example through FDA program called MedWatch).

Define orphan drug.

It is the drug that treats diseases affecting less than 200,000 people.

Why is the topically applied Lidocaine Patch 5% not considered a TDDS?

It's not for systemic absorption. It works on area right under the patch. It is a topical patch, not TDDS. It can be cut and used too.

What are three characteristics of a drug substance that relate to biologic response?

Lipid solubility, degree of ionization and molecular size.

Recognize the brand and generic names of Top 300 drugs delivered transdermally.

Methylphenidate, nicotine, estradiol, nitroglycerin, fentanyl, clonidine, donepezil, and oxybutynin.

Does USP <797> contain standards for CSP administration?

No.

Briefly describe the process and considerations for OTC drug approval.

OTC drugs must meet the same standards for safety and effectiveness as prescription drugs. OTCs manufactured and labeled in accordance with monographs published by code of federal regulations do not require premarket approval. Others require premarket approval through submission of an NDA or ANDA. Label comprehension and actual-use studies can be assessed for safety of drug. Drugs initially approved as prescription, only may be later approved as OTCs.

Very briefly describe the approval process for generic drugs [including the name of application and the requirements compared to RLD].

OTC drugs must meet the same standards for safety and effectiveness as prescription drugs. OTCs manufactured and labeled in accordance with monographs published by code of federal regulations do not require premarket approval. Others require premarket approval through submission of an NDA or ANDA. Label comprehension and actual-use studies can be assessed for safety of drug. Drugs initially approved as prescription, only may be later approved as OTCs.

Clinical Trials (Phase III)

Only begins if there is evidence of efficacy and safety. You gather more information about efficacy and safety in diverse population with different dosages and with other drugs as well. The number of subjects is from several hundred to 5000. FDA or sponsor can stop the trial at any time if there is a problem or if the drug is doing well. Sponsors must provide regular comprehensive reports to FDA and IRB on the progress of clinical trials.

Clinical Trials (Phase II)

Only beings if there is no unacceptable toxicity during phase I. Goal is to obtain preliminary data on the effectiveness of drug in treating the disease in humans. Safety, ADMET data and short-term side effects are also evaluated. Number of subjects are few dozen to 300. FDA and sponsors agree on how the large-scale studies in phase III should be conducted. Data in phase II determines dosages in phase III.

Give an example of a PEC.

PEC = primary engineering control (ISO Class 5). Horizontal laminar airflow workbench [LAFW].

What two ingredient types are often included in transdermal drug preparations/products but not topical?

Penetration enhancers and Liposomes.

In between drug administration and effect, we have three phases. Which phase is described as "the substance is prepared for absorption"?

Pharmaceutics phase.

Which one is "what the drug does to the body"?

Pharmacodynamics phase.

Which one is "what the body does to the drug"?

Pharmacokinetics phase.

Release of a drug from an oral dosage form may be intentionally delayed in order to do what three things?

Protect the drug, reduce gastric distress, and facilitate drug absorption.

What are pyrogens and what is the most common type?

Pyrogens cause fever. Most common pyrogen is endotoxin.

Define reference listed drug and generic drug.

RLD is an approved drug to which new drugs are compared for bioequivalence. A generic drug is a drug with the same bioequivalence of a brand name drug made by a chemical process.

When is sterilization required for CSPs?

Required when starting with nonsterile components or supplies.

List the quality requirements and USP compendial requirements for tablets.

Size, shape and appearance, Thickness, hardness, and friability, Uniformity of dosage units (weight variation and content uniformity), Disintegration time, Dissolution characteristics.

How does absorption rate vary by dosage form? Rank from slowest to fastest and be able to give a rationale for this order.

Slowest to fastest: Enteric-coated tablets, tablets, capsules, powders, suspensions, solutions.

What is the primary barrier to drug absorption across the skin?

Stratum corneum (keratin).

What are the three main coating techniques used for manufactured tablets?

Sugar coating, film coating and modified release coating.

Differentiate between small molecule drugs and biologics.

The active ingredients in small molecule drugs made by chemical processes are typically small molecules. The active ingredients in biologics are much larger molecules.

Clinical Trials (Phase I)

The focus is safety. Studies include limited dosing and small number of volunteers (20-80). Information such as absorption, how drug is metabolized and excreted is compared with nonclinical data.

What is bioavailability?

The rate and extent to which the active ingredient is absorbed and becomes available at the site of action.

Preclinical Studies

This stage takes 3-6 years. Studies try to figure out how to make the API on a larger scale and do safety studies in laboratory tests and animal models. Composition of API and formulations is determined. If API/formulations are not stable, they are eliminated. The ADMET properties are studied. Any long-term adverse effects are studied. Nonclinical ADMET studies determine safe starting dose, dose range, and parameters to monitor adverse effects. Different packaging and formulations are developed. All clinical trial plans have to be approved by the institutional review board at the institution where the trials will take place.

Describe the four factors affecting percutaneous absorption.

Time in contact with the skin, drug concentration and properties, nature of the carrier vehicle, and condition and properties of the skin.

What should be used to wipe down all items before placing in LAFW? Why?

Use 70% isopropyl alcohol. We wipe items down to disinfect them, so that microbial growth doesn't happen.

Describe the physical and chemical properties of drugs that are good candidates for transdermal delivery.

Vehicle, solvents, preservatives, stiffening agents, gelling agents, pH adjusters, humectants, penetration enhancers and Liposomes.

Give three examples of critical sites that must be swabbed with sterile IPA within the PEC.

Vial stopper, ampule neck, and intravenous bag septum.

Does USP <797> apply to any professionals other than pharmacists and pharmacy technicians?

Yes.

When using sterile 70% IPA you must allow it to _______ for it to be effective.

dry

Drugs administered orally can be lost in the

due to and the due to before being absorbed into systemic circulation.

Composition of a tablet depends on

the method of preparation and the desired characteristics.

TTD facilitate the passage of ______________ quantities of drug substances through the skin and into the general circulation for their_________ effects

therapeutic& systemic

For chewable tablets, it is important to counsel patients to chew thoroughly before swallowing because they do not contain a

disintegrant .

Tablets must do what before being absorbed into the bloodstream

disintegrate, deaggregation_ and dissolution

The mechanism for enteric coated tablets may be dependent on what three factors?

pH dependent, time dependent and enzyme dependent.

Evidence of actual percutaneous drug absorption may be found through what three methods?

-measurable blood levels of the drug -detectable excretion of the drug or its metabolites in the urine -clinical response of a patient to the therapy.

What does ADME stand for? Briefly define each term.

-Absorption: the movement of drug molecules across biological barriers (mostly layers of cells) from the site of administration to the blood stream. -Distribution: drug molecules move from systemic circulation to tissues and organs. -Metabolism: drug is converted from original chemical structure to another form [metabolite] that facilitates elimination. -Excretion: irreversible removal of the drug from the body.

Differentiate between a BUD and an Expiration Date.

-BUD: either the date, or hour and date, after which a CSP must not be used. The BUD is determined from the date and time that preparation of the CSP is initiated. Applies to all CSPs. -Expiration date: The time during which a product can be expected to meet the requirements of the USP-NF monograph, if one exists, or maintain expected quality provided it is kept under the specified storage conditions. Applies to all conventionally manufactured products, APIs and added substances.

Describe the environment certification and monitoring of classified areas required by USP <797>.

-Certification of the classified areas must be done initially to make sure design and air quality requirements are met. -Recertification must occur at least every 6 months and also if there are any changes to the area [e.g., construction, replacement or relocation of PEG, other changes that affect airflow]. -All compounding facilities must develop an effective microbiological air and surface monitoring program [procedures, results, and corrective actions must be documented].

Briefly describe the types of modified-release oral dosage forms and give examples of each.

-Extended-release: allows reduction in dosage frequency compared to conventional dosage forms. Tramadol ER - Ultram ER. -Delayed-release: designated to release the drug at a time other than just after administration (may be based on time or environmental conditions). Risedronate DR - Atelvia. -Repeat action: layered tablets. Ritalin LA. Carfilzomib (Kyprolis). -Targeted-release: targeted to specific areas.

All sterile products and preparations must be free of what three things?

-Free from microbial contamination and must maintain sterility -Free of pyrogen/endotoxin contamination -Free of visible particulate matter.

Describe the physical techniques for facilitating percutaneous absorption of drugs.

-Iontophoresis: non-invasive method of systemic and local drug delivery using an electric field -Sonophoresis: use of ultrasonic energy in order to enhance the topical or transdermal delivery of drugs

List physical-chemical characteristics of drugs that make them candidates for an extended-release dosage form.

-Neither very slow or very fast rates of absorption and excretion -Uniformly absorbed from GI tract -Administered in relatively small doses -Good margin of safely [therapeutic index] -Used in the treatment of chronic conditions.

What are three methods used for personnel monitoring regarding sterile compounding?

-Observation checklist, Media-fill challenge, touch testing

List the five main reasons [purposes] for coating tablets.

-Protect drug from environment.- Mask unpleasant taste or odor.- Provide ease of administration and improve adherence.- Facilitate handling and improve product mechanical integrity.- Modify drug release.

Describe the five factors affecting drug absorption.

-Rate of release of drug form product/preparation. -Membrane permeability of drug. -Surface area for drug absorption. -Blood flow to site of absorption. -Destruction/inactivation of drug.

Describe the three methods of sterilization for CSPs. Which ones are considered terminal? What size filter must be used for sterilization?

-Steam: moist-heat sterilization [steam under pressure]. [Terminal sterilization] -Dry heat: heat by autoclaving in high-temperature oven. [Terminal sterilization] -Filtration: use 0.22 um or smaller filter, otherwise it won't sterilize.

List the general counseling points for modified release solid oral dosage forms.

-Take with a glass of water - Do not chew or crush -Explain whether the dosage form may be split or halved -Ghost or residue tablets may appear in the stool [non-erodible plastic shells and osmotic tablets] -Confirm dose, onset and frequency -Store in the least humid environment available at room temperature.

Differentiate between topical and transdermal drug delivery.

-Topical: designed to deliver drug into the skin for treating skin disorders (skin is the target organ) -Transdermal: designed to deliver drug through the skin into the systemic circulation for systemic effects (skin is not the target organ but is a barrier the drug must pass through).

Define weight variation and content uniformity.

-Weight variation - weigh and assay a group of tablets and divide by number of tablets and find average per tablet... Content uniformity - Multiple capsules or tablets are selected at random and a suitable analytical method is applied to assay the individual content of the active ingredient in each capsule or tablet.

Describe appropriate packaging and storage for tablets.

-When probably stored, tablets usually remain stable for several years (tight containers, low humidity, protect from extreme temperatures). -Dispense in package like manufacturer's packaging. -Counsel patients to store in the container they receive from the pharmacy. -Other storage considerations: Light-resistant containers, desiccants (included when something is really sensitive to moisture).

What are the three general potential sources of contamination of CSPs

Compounding materials, environment and personnel (most likely to contaminate).

What are the two types of modified-release coatings for manufactured tablets?

Delayed-release [enteric coating] and extended-release.

In what skin layer is transdermally absorbed drug enters the systemic circulation.

Dermis.

What are five common excipient types found in tablets. Give one example of each.

Diluents (Lactose), Binders (Starch), Lubricants (PEG), Glidants (Talc), and disintegrants (Microcrystalline cellulose).

What special dispensing/packaging requirement is required for volatile tablets [e.g., nitroglycerin].

Dispense in the original unopened container.

Give one example [brand and generic name] of a modified-release oral dosage form on the SOP Top 300 List.

Divalproex - Depakote ER.

Define chemical penetration enhancer and list common examples

molecules that increase skin permeability/ decrease barrier resistance by interacting with the constituents of SC Examples: azone, dimethyl sulfoxide (DMSO). Polyethylene glycol, propylene glycol, and sodium lauryl sulfate.