MPJE Chapter 1.

What is Durham Humphrey Amendment? What year is this?

(1) Established 2 classes of drugs — Rx and OTC (2) Authorized "verbal Rx" and "Rx refill" - 1951

PMDA mandates storage, handling, and record keeping requirements of drug samples. Explain more details of this law. (Who and How do they request the drug sample? Who can't order drug sample? What would be the exception of this?)

(1) These include obtaining *written requests for samples* from practitioners* and *requiring signatures of practitioners upon receipt*. (Record of (A) Request by MD and (B) Receipt + signature.) (2) Samples may ONLY be provided to ... [practitioners] or, [upon request of a licensed practitioner, to an institutional pharmacy] or [to pharmacies of other healthcare facilities]. (3) Community pharmacies *should NOT process* Rx drug samples, except for prescription drugs that may be ordered by a pharmacist. The *only exception* to this would be a *community pharmacy that is part of a healthcare entity* such as a community pharmacy owned by a hospital. (4) In Florida, a *Complimentary Drug Distributor Permit* from the *Division of Drugs*, *Devices and Cosmetics (DDDC) of the Department of Business and Professional Regulation (DBPR)* is required to hold, distribute, and dispose of prescription drug samples.

What are the pharmacy services at LTCF? Who needs to present at LTCF? (Hint: like regular pharmacist? or consultant pharmacist?) How often drug review needs to be done at this place by Rph? and Who requires this? What drugs have what limited day supply by LTCF? How many refills or PRN orders can be renewed?

- (1) Medication Regimen Reviews Consultant pharmacist CMS regulation require a consultant pharmacist to perform Medication Regimen Review for LTCF every 30 days. (2) PRN orders for psychotropic drugs PRN orders for psychotropic drugs MUST be limited to 14 days unless the practitioner documents the rationale for extending an order beyond 14days. PRN orders for psychotropic drugs CANNOT be renewed unless the attending physician evaluates the resident for appropriateness of that drug.

Describe the difference of samples and starter packs or such.

- "Starter packs" or "Initial dose packs" or "stock samples" are human Rx drugs that are generally distributed w/o charge by manufacturers or distributors to pharmacies to be place in stock and sold at retail. Although starter packs are generally given w/o charge to the pharmacy, they are NOT intended to be a free sample to the consumer, not are they labeled as such. Starter packs are subject to regulation as Rx drugs in the same manner as stock shipments of Rx drugs. Starter packs are subject to regulation as Rx drugs in the same manner as stock shipments of rx drugs. "Starter packs are NOT drug sample."

What is Prescription Drug Marketing Act? What year?

- (1) PDMA "bans the re-importation of prescription drugs and insulin products" produced in US (except by the manufacturer). (2) Bans the sale, trade, or purchase of Rx drug samples. (3) Mandates the storage, handling, and record-keeping requirements for Rx drugs samples. (4) Prohibits, w/ certain exceptions, the resale of Rx drugs purchased by hospital or healthcare facilities - 1987

What is Kefauver-Harris Amendments? What year?

- (1) Required new drugs to be proven "*safe and effective*" for their claimed use. (Safe + effectiveness) (2) Increased safety requirements for drugs and established "*Good Manufacturing Practices (GMPs)*" for manufacturing of drugs. (Stricter rules for safety and manufacturing (GMPs (3) Gave *FDA jurisdiction over Rx drug advertising*. (FDA has power to control their advertising) - 1962

What year was FDCA established? What was the reason? What did the Congress do d/t that reason?

- 1938 - Sulfanilamide elixir in 1937. - Congress passed the 1st legislation that required new drugs to be proven" *safe* prior to marketing" They created FDA to control food, drug, medical device, and cosmetic safety.

When did outsourcing facilities (503B facilities) law passed? How many facilities are there in US?

- 2013 - about 70 in the entire country

When breaches of confidential information happens, 몇명에 따라 무슨 조치를 취해야되는지 서술하라

- <500 individuals = (1) maintain log of these breaches (2) notify HHS annually (3) notify individual w/in 60 days >= 500 individuals = (1) Secretary of HHS + local media w/in 60 days (2) notify individual w/in 60 days.

What are the Orange book code (rating) for bioequivalnce? Products with actual/potential bioequivalence problems, but for which adequate scientific evidence has established bioequivalence for those products are given rating of what?

- A= pharmaceutically equivalent & therapeutically equivalent B= NOT pharmaceutically equivalent & therapeutically equivalent AA - conventional dosage forms AN - solutions and powders for aerosolization AO - injectable oil solutions AP - injectable aq solutions AT - topical products - AB

What is Tamper resistant prescription? What features are there for tamper resistant prescription?

- CMS requires that *ALL written prescriptions* meet certain tamper-resistant requirements to prevent unauthorized copying and to prevent counterfeiting (with some exceptions). - (1) 1 or more industry recognized features designed to prevent *unauthorized copying of a completed or blank prescription form*. (2) 1 or more industry recognized features designed to prevent *the erasure or modification of information* written on prescription pad by the prescriber; and (3) 1 or more industry recognized features designed to prevent the use of *counterfeit prescription forms*.

What agency controls safety of medication by the FDCA 1938?

- FDA

What does FL state requires outsourcing facilities to obtain?

- FL requires "Special Sterile compounding permit" FL requires Out-of-state outsourcing facilities to obtain "Non-resident Sterile Compouding Outsourcing Facility Permit"

How are 503 B inspected? Is there fee? What do they need to do for registration type of thing"? What do they need to do if there is ADE? Can they bulk produce? If not when can they?

- Inspected by FDA - based risk based inspection schedule. - Annual fee - Register to secretary of HHS. Then they need to report every 6 mo = regarding the drug sold in previous 6 mo - Report ADE w/in 15 days and need to f/u investigate and reporting similar to current drug manufactures. - Nope - They can bulk produce 1. 503B bulk list = clinical need bulk list 2. FDA shortage list

Explain bit more detail about PDMA reimportation prohibition Is importation generally allowed in US? or prohibited? If so, what would be the exception of this? (Hint: specific act created this exception) Who needs to allow for importation? with what reason? Is this state level? or federal level?

- More explanation: this prohibition is on the re-importation of drugs produced in the US and then exported. This is different than the importation of drugs manufactured in another country. - Importation of drugs is generally prohibited. — However, the Medicine Equity and Drug Safety (MEDS) Act of 2000 and the Medicine Prescription Drug Improvement and Modernization Act of 2003 both have provisions that allow importation of drugs under specific conditions. —> One of those condition is that the *Secretary of Health and Human Services (HHS) must certify to Congress* that such imports do *NOT threaten the Heath and safety* of American public and provide *cost savings*. (FL state allows but TX does NOT allow) - Both, by 9/24/2020. Federal level is listed above. FDA finalized new rules on importation on Sep 24, 2020, which permit states to serve as sponsors to import drug from Canada under certain conditions. A few states (including FL NOT TX) have passed laws to allow drug importation from Canada, but as of the date of publication of this book, no state plan has been approved by HHS.

Which medicine can be mailed by "Delivery by Mail - US postal service" ? Can CS be mailed to other facilities or practitioner's office? Can ALL Drugs which include CS be delivered by Common Carriers like UPS or FedEx? and which one can be delivered b/w non-CS vs CS?

- Non-CS and CS with certain condition 1. The Rx container must be labeled in compliance with prescription labeling rules. 2. The Outer Wrapper or container (봉투) MUST be free of marking that would indicate the nature of contents 3. No marking of any kind may be placed on the package to indicate the nature of contents. (2 번 3 번 뜻은 뭐가들었는지 적혀서도안되고, 뭐가 들었는지 보여도안됨, 약국 에서 왔다는것도 적혀있음안됨) - Yes. to other DEA registrants. - Yes they can deliver, and CS and non-CS both can be delivered. Plus they are not subject to this postal regulation.

specific prescription and non-prescription drug. These include... ?

- OC, conjugated estrogen, norethindrone, medroxyprogesterone (women hormonal drugs) - hormone replacement therapy products that rely solely upon the activity 1 or more progestogen and estrogen substance. - Prednisone tabs no more than 105 per package (21x5) - Methylprednisolone tabs no more than 84mg per package (21x4) - Betamethasone tabs no more than 12.6mg per package - SL NTG, and SL/chewable isosorbide mononitrate (nitrate PO drugs) - ASA/APAP effervescent tabs/granules - K supplements in unit-dose packaging - Na-F not more than 264mg of Na-F per package - Sucrose preparation in soln glycerol and water - Anhydrous cholestyramine and colestipol packets - Erythromycin ethylsuccinate granules for PO susp and PO susp in package containing not more than 8g of erythromycin - Erythromycin ethylsuccinate tabs in packages containing no more than 16g - Mebendazole tablets containing no more than 600mg per package - Pancrelipase preparation - Preparation in aerosol containers intended for inhalation

How does pharmaceutically equivalent and therapeutic equivalence differ?

- PE is drug products in identical dosage forms and route(s) of administration that contain identical amounts of the identical active drug ingredient. TE is approved drug products that are pharmaceutical equivalents for which *bioequivalence has been demonstrated* and they can be expected to have the *same clinical effect* and safety profile when administered to patients under the conditions specified in the labeling. (짧게말해서, PE 는 물리적으로 같은거 TE 는 몸안에서 먹히는게 같은거)

Who can only provide a blanket request for all future prescription? Who can only request a non-child-resistant container on an individual prescription? What does prescriber need to write down for this request?

- Patient - Prescriber - no need to write down. it is not per the law.

What FDA book has biological product? What does biosimilar/biosimilarity mean? Which word needs to present to substitute?

- Purple book - Biological product is (1) *highly similar to the reference product*, (2) NOT withstanding minor differences in clinically inactive components and (3) there are no clinically meaningful differences b/w the biological product and the reference product in terms of *safety, purity, and potency* of the product. - Interchangeable.

Can pharmacist order sample drugs

- Samples may only be provided to practitioners. Community pharmacies should NOT process Rx drug samples. EXCEPT for Rx drugs that may be ordered by a pharmacist. The ONLY exception to this would be a community pharmacy that is part of a healthcare entity such as community pharmacy owned by a hospital. Conclusion: rph can order samples, but community pharmacy is NOT allowed to store them. So nope. (Unless the community pharmacy is owned by a hospital (institution)) Based on my understanding - Class C and D in TX pharmacy

What type of requirements are there for Center for Medicare and Medicaid Service (CMS)?

- Tamper Resistant Prescription Pharmacy services at LTCF.

The Drug Quality and Security Act (DQSA) — explain brief about what this is. What year?

- These amendments to the FDCA addressed 2 primary topics Large scale compounding by pharmacies and establishment of a frame work for a uniform track-and-trace system for prescription drugs throughout the supply chain to prevent counterfeit drugs. (1) DCQA (Drug Compounding Quality Act) (2) DSCSA (Drug supply chain security act) (Track and Trace) - 2013

Explains bit more about prohibition of resale Rx purchased by hospital or healthcare facilities.

- This is intended to prevent diversion of drugs d/t price diversion b/c hospital generally receive lower prices for drugs that community pharmacies.

What does transaction data include? (State big 2 components) What does transaction information have?

- Transaction History and Transaction statement — Transaction information includes the products (1) name, (2) strength (3) dosage form (4) NDC (5) container size (6) # of container (7) date of transaction (8) name and address of the person (a) from whom ownership is being transferred and (b) to whom ownership is being transferred (9) Unique product identifier (or serial numerical identifier (SNI))

Does hazardous warning and requirements apply to FDA approved Rx drugs? Where or what products can we see these in pharmacy then? Who administers and enforces the regulation which requires employers (including pharmacies) that deal with hazardous materials to meet Hazard Communication Standard? The standard requires chemical manufacturers and importers to classify the hazard of chemicals they produce or import and to prepare appropriate labels and what sheet? Which form of drugs are exempted from these requirements but which are NOT exempted? Pharmacy MUST have what with this law? (Hint: we need list of? and what needs to be provided to employees who treat these products?)

- no. not for Rx or FDA regulated drugs. - store product like bleach, cleaning fluids, antifreeze etc. - OSHA (Occupational Safety Health Administration) - SDS (Safety Data Sheet) - Solid oral dosage form But not solid form such as liquid products used in compounding needs this requirement. - Work place MUST ensure ALL such products are appropriately labeled AND have *SDS* AND must include training for ALL workers on hazards of chemicals, ....

Explain FDA with key points

- primary federal law dealing with food, drug, cosmetic, and medical device safety today (with many amendments)

Does Medical oxygen require Rx? What is special about medical O2 in FL? (Hint: well does pharmacy dispense this?)

- yes - Can be dispensed by Medical oxygen retail (Business) establishment licensed by the *Florida Department of Business and Professional Regulation (DBPR)* pursuant to a *valid prescription*. (It is Florida specific and one of the few drugs in Florida that can be dispensed by a business that does NOT have a pharmacy permit).

DCQA (Drug Compounding Quality Act) 1. Which sterile compounding pharmacy can produce non-specific Rx or w/o medication order? (503A vs. 503B) 2. Who regulates this sterile compounding pharmacy? and also what are they subject under? 3. Compounding pharmacies that are NOT registered with FDA as an "outsourcing facility" are often referred to as ...? 4. Who regulates this sterile compounding pharmacy? What are they subject under? 5. What are their limitation of sterile compounding??

1. 503B 2. FDA - under subject to FDA's current Good Manufacturing Practices (cGMP) 3. 503A 4. State. USP-707 5. Can only compound products pursuant to an individual prescription or medication order.

DCQA (Drug Compounding Quality Act) 1. Outsourcing facilities MUST have what profession? 2. What do they need to register as?

1. Licensed pharmacist 2. Register as an outsourcing facility in FDA (not for 503A)

Federal Hazardous Substances Act requires what information on the label of hazardous and toxic substances?

1. Name/address of mfr, packer, distributor, seller 2. Common/usual/chemical Name of each hazardous ingredient 3. The signal word "Danger" for products that are corrosive, extremely flammable, or highly toxic 4. Signal word "Caution" or "warning" for ALL other hazardous products 5. An affirmative statement of principal hazard or hazards that the product presents (ex. "Flammable", "Harmful if Swallowed", "Causes Burns," " Vapor Harmful" 6. Precautionary Statement telling users what the MUST do or what actions they must avoid to protect themselves 7. Where it is appropriate, instruciton for first adi treatment if the prodcut injures someone. 8. The word "Poison" for a product that is highly toxic in addition to the signal word "Danger" 9. If a product requires special care in handling or storage instruction for consumers to follow to protect themselves. 10. "Keep out of the reach of children" if a hazardous product such as plant does not have a package, it still must have hang tag that contains the required precautionary information. That information MUST also be printed in any literature that accompanies the product and that contain instruction for use.

When is child-resistant containers exempted? (specific drugs are in different slide)

1. Requested by Patient and Prescriber 2. Bulk containers NOT intended for household use. 3. Drugs distributed to institutionalized patients. 4. 1 package size of OTC drugs designed for the elderly 5. specific prescription and non-prescription drug. These include... (different slide)

- How was DCQA established? (Hint: there was specific outbreak) - What are the outsourcing facility under this act? Also, if they are producing non-patient specific drug, where do they need to register to? - If outsourcing facilities that meet the Act's requirements, what are they exempted from? [Previous written question: What are these facilities exempted from? But they need to still follow certain rule. (Hint: requirement is something that is required to manufacture)] - What way can't they produce? List exception as well.

DCQA (Drug Compounding Quality Act) — Fungal meningitis outbreak from compounding center. — Outsourcing facility (503A facilities = hospital sterile compounding pharmacy) Outsourcing facilities (503B facilities = outpatient sterile compounding pharmacy): establishes Section 503B in the FDCA that allows facilities that are compounding sterile pharmaceuticals that are *NOT based on patient specific Rx* to register w/ the FDA as an "outsourcing facility" — Outsourcing facilities that meet the Act's requirements are exempt from the (1) new drug provision (2) adequate directions for use and (3) drug track and trace provision. [Previous answer: Outsourcing facilities exempt from premarket approval requirements for new drugs & drug trace and trace provision. (But they are still bound to GMP)] — Cannot bulk produce compounding unless specific situation, or if it is in 503B bulk list (clinical needs), or FDA shortage list

- What is DSCSA in short? (Hint: What do they do? like purpose?) - What does DSCSA do to make everything uniform? - What drugs are under this rule? - What does manufacture require to have to supply their product? (Hint: this is something like for documentation) - What does Pharmacy need to do on their end? (Hint: once we receive products, what do we need to do with product?) - If pharmacy wants to distribute (distributing is defined as providing a drug to anyone other than the consumer/patient as compared to dispensing), what do they need to have? what else do they need to pass to obtain this authority? - What is the exception from having this?

DSCSA (Drug Supply Chain Security Act) — This is *Track and Trace system* act. — Provides uniform national framework for electronic track and trace system for Rx drugs. — This applies to Rx drugs for human use in finished dosage form, but certain products are exempted. — Mfr is required to provide "transaction data" — Pharmacies must investigate and properly handle suspect and illegitimate products. — Pharmacies that are distributing must have a wholesale distribution license and must pass DSCSA transaction data w/ that distribution. — Only exception to having a distribution license and passing transactions are there = will discuss this in other slide

DQSA 2013 Explain questions below — What event created DCSA? (no need to know detail) — What about outsourcing facilities? (There are 2 diff types) — How are production from these 2 outsourcing facilities regulated?

Drug Compounding Quality Act (DCQA) — Passed in response to an outbreak of fungal meningitis in over 20 states in fall of 2012, which was traced to a contaminated inj. Steroid produced by the New England Compounding Center. This outbreak resulted in the death of over 60 patients and over 750 cases of injection. — Outsourcing facilities, often referred to as *503B facilities*, are permitted to compound sterile products *without receiving patient-specific prescriptions or medication orders*. They are primarily regulated by FDA and are subject to *FDA's current GMP* (cGMPs). (Basically they are bulk producing Sterile Compounding Facilities) — Compounding pharmacy that is NOT contracted w/ FDA as an "outsourcing facility" are often referred as [*503A facilities or 503A pharmacy*] and may *ONLY compound products pursuant to an individual Rx or medication order*. —> 503A facilities are permitted to limited anticipatory compounding, are primarily regulated by the states, and are subject to "*USP chapter 797 quality standards*" for sterile compounding. **Outsourcing facilities are NOT except from good manufacturing practices** — 503A=USP797 (sterile compounding) and GMP (503A is but more for USP797 with state level) 503B=cGMP (with federal level)

The difference b/w Rx and OTC drug in regards to use or direction.

Rx - Adequate Drug *information* needs to be inserted (ex. Package insert) OTC - Adequate Drug *directions* for *safe and effective use*

For DSCSA, what does mfr required to provide for what actions? And what happens if this goes to pharmacy? Lastly, if this is sent to different places, what needs to be done? Again if prescription drug was dispensed and sold to the patient, where would the last resort this transaction data be?

— "Transaction data" for each product sold, and pharmacies are required to receive transaction data and pass this information along if they further distribute the product. — Pharmacy

Prohibited Acts Under the FDCA - what are main points?

— (1) Adulteration, (2) Misbranding, (3) Adulteration and Misbranding as applied to pharmacies. (Basically adulteration and misbranded, but there is pharmacy level that we need to focus on)

DQSA 2013 Explain this — Outsourcing facilities must ... (HINT: who do they need for operation? Which website gives what information regarding this facility? Where to report and how often? How is inspection done and is there fee? If any ADE occurs, what to do? Once product is done, what needs to be done?)

— (1) Have a *licensed Rph* who provides direct oversight over drugs compounded. (2) Register as an outsourcing facility. The FDA websites provides a list of names of each outsourcing facility, along with the state where the facility is located, whether the facility compounds from bulk drug substances, and whether drugs compounded from bulk are sterile or non-sterile; (This is for 503B. There are only 70 outsourcing facilities) (3) *report to the Secretary HHS* *upon registering and q6mo* thereafter, the *drugs sold in the previous 6mo*. (4) Be inspected by FDA according to a [risk-based inspection schedule] and [pay annual fees to support it]; (5) *Report serious ADE experiences w/in 15 days* and *conduct a f/u investigation* and reporting *similar to current drug manufactures* (6) Label products w/ a statement identifying them as a compounded drug and other specified information about the drug.

FDCA prohibition Act — Explain Misbranded (just put big 3 then we will go over detail in other cards) ((non-pharmacy level))

— (1) Labeling needs to match, = if not misbranded (both OTC and Rx) (2) Rx drug and mfr's labeling fails to contain the following (in other card) (3) OTC drug and fails to contain the following (in other card) (4) it is a drug liable to deterioration unless it is packaged or labeled accordingly. (5) container is made, formed, filled as to be misleading. (6) drug is an exact imitation of another drug or offered for sale under the name of another drug. (7) dangerous to health if used recommended dosage (8) packaged or labeled in violation of Poison Prevention Packaging Act.

What are there for Additional OTC requirements

— (1) Tamper-evident packaging (2) Repackaging of OTC products (will be explained later)

What would be the exceptions of distributing pharmacies to have wholesale distribution license or passing DSCSA transaction data w/ that distribution?

— (1) when the distribution is b/w 2 entities that are affiliated or under common ownership (2) when a dispenser is providing product to another dispenser on a patient specific basis. (3) when a dispenser is distributing under emergency medical reasons (4) when a dispenser is distributing "minimal quantities" to a licensed practitioner for office use.

FDCA prohibition Act — OTC drug requirement? (non-pharmacy level)

— (A) a principal display panel, including a statement of identify of the product. (B) name and address of the mfr, packer or distributor (C) net quantity of contents (D) Caution and Warning needed to protect user. (E) adequate directions for safe and effective use (for layperson) (F) content and format of OTC product labeling "Drug Facts" panel format Drug fact format: (1) active ingredient (2) purpose (3) use(s)—indication (4) warnings (5) directions (6) other information (7) inactive ingredients (alphabetical order) (8) Questions? (Optional) followed by phone #

FDCA prohibition Act — What are the requirements for Rx drug mfr labeling? (non-pharmacy level)

— (A) name and address of mfr, packer, or distributor (B) brand and/or generic name of drug or drug product (C) net quantity (weight, quantity, or dosage units) (D) the weight of active ingredient per dosage unit (E) the federal legend "Rx only" (F) if not taken PO, the specific route of administration (ex. IM inj) (G) special storage instruction, if appropriate (H) mfr's control number (lot number) (I) exp date (J) adequate information for use. For rx drug —> this is the package insert and medication guide or patient package insert if required. (This involves BBW)

Who does outsourcing pharmacy need to be registered with?

— 503A doesn't need to be registered w/ FDA, but they are regulated by States. (USP797) 503B needs to be registered with FDA

For OTC products, Explain Repackaging of OTC products

— A pharmacist that *repackages OTC products* would be subject to *cGMP requirements* and would have to meet all additional requirements, *including tamper-evident packaging*, if offered for sale to the public. Tips: if a patient wishes to purchase an OTC drug in a smaller package size than what is commercially available a pharmacist *cannot break open a commercial OTC product* and sell the lesser quantity by placing in a vial and labeling it. *The only way* this can be done is if the *patient has a prescription for the smaller quantity*, and the OTC drug is filled as a prescription as discussed below.

FDCA and Federal law — Advertising and Promotion of Rx drugs — if rph cannot advertise rx drug price, why? — What would be the exemption of this? — when would this exemption be not possible?

— Advertising of prescription drug prices (including by pharmacists) — the *advertising of prescription drug prices* is considered "reminder advertising under FDA regulations" (Remember, we can only tell price and drug name/dose etc. no more clinical information can be given) — However, such advertising is exempt from FDA advertising regulations provided that the following conditions are met: (1) The only purpose of the advertising is [*to provide information on price*], NOT information on the drug's *safety, efficacy, or indications* for use. (2) The advertising contains the [proprietary name of the drug (brand name)] (if any), [the generic name of the drug], [the drug's strength], [the dosage form], and [the price charged for a specific quantity of the drug]. (3) The advertising may include other information, such as [the availability of professional or other types of services] as long as it is not misleading. (4) The drug price stated in the advertising shall include [all charges to the consumer]; mailing and delivery fees, if any, may be stated separately — Controlled substances. (CANNOT be advertised at ALL)

FD&C Warning requirements for OTC drugs for minor sore throats

— Any OTC product label that states "For the temporary relief of minor sore throats" must include this warning: "Warning — Severe or persistent sore throat or sore throat accompanied by high fever, HA, N/V may be serious. Consult physician promptly. Do NOT use more than 2 days or administer to children under 3 years of age unless directed by physicians"

FDA Drug and Device recall classification ! List it out and explain

— Class I: reasonable probability product will cause either "serious ADE" on Heath or death Class II — may cause temporary or medically "reversible ADE" on health or where probability of serious ADE is remote. Class III — "Not likely to cause ADE" health consequences.

What falls under adulteration and mibranded both?

— Drug Strength.

FDCA prohibition Act — Explain Adulteration (non-pharmacy level)

— Drug is adulterated if.. (A) contains filthy, putrid (부패하다), decomposed substance (B) prepared in insanitary condition (contaminated condition) (C) against cGMPs (D) mfr did not meet inspection, or refuse to permit entry or inspection (E) container is poisonous or deleterious substance that can contaminate the drug (F) claim to meet USP standard (strength/quality) but it's not (G) not in USP but strength/quality differs from labeling (H) mixed or packed w/ any substance that reduce its strength or quality. Main point (1) Anything related change of quality or strength of drug. (Ex. Container, substance that's in drug, claimed strength and USP strength does not meet strength or quality) (2) mfr needs to meet cGMP and needs proof of inspection (3) pharmacy needs to be clean and not contaminated. (Ex. Do not contain any filthy, putrid substances and pharmacy itself needs to be cleaned)

What is DSCSA? What do they provide to do for their convenience and reduce error? Which drugs are applied to DSCSA and which are exempt?

— Drug supply chain security act. — Track and trace — Provides for a *uniform national framework for an electronic track-and-trace system* for Rx drugs as they move through the supply chain, and sets national standards for states to license drug wholesaler distributor. — This applies to *Rx drugs for human use in finished dosage form* Exempted drugs includes ... blood and blood components, radioactive drugs, imaging drugs, certain IV products for fluid replacement, dialysis solutions, medical gases, *compounded drugs*, medical convenience kits containing drugs (ex. first aid kits), certain combination products, sterile water, and products for irrigation.

Special Warning requirement for OTC products in FDCA — list the drugs.

— FD&C yellow No.5 (tartrazine) and No.6 Aspartame Sulfites Oil - [Mineral oil, Wintergreen oil] Salicylates OTC pain reliever Sodium phosphate Preparation - [Isoproterenol inhalation preparation, potassium salt preparation] Syrup Ipecac Phenacetin (acetophenetidin) Alcohol warning OTC drugs for minor sore throats ("temporary relief of minor sore throats) OTC vaginal contraceptives & spermicide use containing nonoxynol 9 OTC product Iron containing in Solid Oral dosage form.

Who regulates REMS?

— FDA

FDCA and Federal law — Advertising and Promotion of Prescription Drugs — what entity controls advertisement and promotion of Rx drugs? — what entity controls advertisement and promotion of OTC drugs? — is advertising of Rx drug prices able to be done by pharmacist?

— FDA — OTC drug advertising is regulated by the Federal Trade Commission (FTC) — nope

FD&C Warning requirements for Alcohol Warning

— Internal analgesics and antipyretics, including APAP, ASA, IBU, Naproxen, Ketoprofen, etc., are required to have a warning for persons consuming 3 or more alcoholic beverages per day and to consult with MD before taking.

FD&C Warning requirements for Isoproterenol inhalation preparation, and potassium salt preparation for oral ingestion

— Isoproterenol inhalation preparation: requires warning not to exceed dose prescribed and to contact physician if difficulty in breathing persists. Potassium salt preparation for PO ingestion: Requires warning regarding nonspecific small bowel lesions consisting of stenosis, with or w/o ulceration, associated with the administration of enteric coated thiazide with potassium salts.

FD&C Warning requirements for Sodium phosphate

— Limit the amount of sodium phosphate oral solution to not more than 90mL per OTC container. Also requires specific warnings.

For OTC products, Explain Tamper-evident packaging (focus on exception)

— Mfr and packagers of OTC drugs for sale at retail MUST package product in tamper-evident package. Exception Dermatological, dentifrice, insulin, or *lozenge* products

FD&C Warning requirements for mineral oil, wintergreen oil, and salicylates

— Mineral oil: requires warning to only be taken at bedtime and not be used in infants unless under advice of a physician. Label also cannot encourage use during pregnancy. Wintergreen oil: any drug containing more than 5% methyl salicylate (often used as flavoring agent) must include warning that any use other than directed may be dangerous and that the article should be kept out of reach of children. Salicylates: ASA and other salicylate drugs must have special warnings for use in children, including warning regarding Reye's syndrome. Retail containers of 1 1/4 grain (81mg) (pediatric) ASA cannot be sold in containers holding more than 36 tablets.

Adulteration and misbranded applied to pharmacies - Expired drug - Dispensing w/o Rph authorization? - Misfiling a Rx w/ wrong drug, strength, or direction? - Wrong strength - REMS drugs dispense w/o meeting the requirement? - Advertising or promotion of compounded drug that is false or misleading?

— Misbranded. (1) dispensing Rx w/o authorization causes the drug to be misbranded. (Even if the drug is correctly labeled) = Rx needs to be verified before dispensed. (2) misfiling a rx w/ wrong drug, strength, or direction (3) REMS drug dispensed w/o meeting the requirement (4) advertising or promotion of a compounded drug that is false or misleading. Adulteration (1) expired drug (strength cannot be assured = falls below quality) (2) wrong strength Misbranded + Adulteration (1) expired drug (strength cannot be assured = falls below quality + BUD date does not match to its exp date.) (2) Wrong strength = falls below quality + strength does not match.

FD&C Warning requirements for Phenacetin (acetophenetidin)

— Must contain warning about possible kidney damage when taken in large amounts or for a long period of time.

FD&C Warning requirements for yellow no.5 (tartrazine) and no.6

— Must disclose presence and provide warning in Precaution section: may cause allergic reaction in certain susceptible persons

DQSA 2013 Explain this. — What are the condition that Outsourcing facilities can bulk produce?

— Outsourcing facilities may NOT compound a drug product that includes a bulk drug substance unless (1) The *bulk drug substance appears on a list* of identifying bulk drug substances for which there is a *clinical need* (the 503B bulks list); or (2) The drug product compounded from such bulk drug substance appears on *FDA's drug shortage list* at the time of compounding, distribution and dispensing.

Under DSCSA, if pharmacy identifies illegitimate product, what should pharmacies do?

— Pharmacies must *notify FDA* using *Form FDA 3911* and *notify trading partners w/in 24 hours*. Pharmacies should also work w/ the mfr to prevent an illegitimate product from reaching patients.

For DSCSA, should pharmacies investigate and properly handle what?

— Pharmacies must investigate and properly handle *suspect and illegitimate* products

What act is related to adulterated or misbranded product prohibition?

— Prohibited Acts Under the FDCA

What is REMS and why is REMS needed? What can REMS include?

— REMS are strategies to manage a known or potential serious risk associated with a drug, drug class, or biological product. FDA requires a REMS if FDA binds that it is necessary to ensure that the benefits of the drug, drug class, or biological product outweigh the risks of the product. — A REMS can include a [*MedGuide, a patient package insert*, a communication plan, elements to assure safe use, and an implementation system]. It must also include a [timetable (시간표) for assessment of REMS].

What is patient package insert? (Hint: who supplies it, and for whom?) When is this needed? When is this necessary? And How often? What happen providing PPI is failed to do so?

— Supplied by the mfr and written for a layperson. — required to be given to patients when rx for certain products are dispensed. Currently required for ... (1) PO contraceptives (2) Estrogen containing products. — Hospitalized or institutionalized patients. PPI must be provided to a patient prior to the first administration of the drug and q 30 d thereafter. — Misbranded.

For DSCSA, what is suspect product? What is illegitimate products? Pharmacies must investigate these products. Then what woud be the process.

— Suspect products are products that one has *reason to believe are potentially* [counterfeit, diverted, stolen, subject to a fraudulent transaction, intentionally adulterated, or appear otherwise unfit for distribution such that they would result in serious adverse Heath consequences or death to humans]. — Illegitimate products are products for which *credible evidence shows* that the products are [counterfeit, diverted, stolen, subject of a fraudulent transaction, intentionally adulterated, or appear otherwise unfit for distribution such that they would result in serious adverse Heath consequences or death to humans]. — Pharmacies must investigate any suspect or illegitimate products. As part of the investigation, a pharmacy must verify the product identifier of at *least 3 products or 10% of the suspect product*, whichever is greater, or all of the packages if there are fewer than 3. Pharmacies must also verify any illegitimate product in response to a notification of illegitimate product from FDA or trading partner. (This law or requirement was scheduled to be effective on Nov. 2020, but FDA delayed to 2023.)

FD&C Warning requirements for OTC drugs for vaginal contraceptive and spermicide use containing nonoxynol 9 as the active ingredient

— These are subject to several warning requirements, including "Sexually transmitted diseases (STDs) alert: this product does NOT protect against HIV/AIDS or other STDs and may increase the risk of getting HIV from an infected partner."

How is Transaction history composed? What is Transaction Statement?

— Transaction Hx is a paper or electronic statement that includes *prior transaction information for each prior transaction back to the mfr*. — Transaction Statement is a paper or electronic statement by the *seller that the seller is authorized (licensed), received the product from an authorized (licensed) person, received the transaction information and transaction hx from the prior owner if required, did not knowingly ship a suspect or illegitimate product, has systems and processes to comply with verification requirements, and did not knowingly provide false transaction information* (Basically the statement from the seller sent complete nonfraudulent product to the buyer)

When does repackaging OTC's cGMP requirement is exempt?

— When an OTC product is prescribed an *filled as a prescription*, the OTC labeling requirements do NOT have to be followed. The prescription drug labeling requirements would apply and would include the prescriber's directions for use. If an OTC drug is filled as a prescription, any instructions for refills would apply as would BUD (valid for 1 year).

FDCA and Federal law — Advertising and Promotion of Rx drugs — Can pharmacy advertise their compounding products? If not why? Or if so what would be the exemption?

— Yes. They may advertise that they provide compounding services, including that they compound specific products. However, if a pharmacy makes *any therapeutic claims* (FDA approved indication) regarding those products, they would be subject to FDA's rules on advertising, which are complex and beyond the scope of this book. -> basically, only tell the basic info, NOT the clinical information.

What is distribution?

— distribution is defined as providing a drug to anyone other than consumer/patient, as compared to dispensing, which is providing a drug to the patient/ consumer.

FD&C Warning requirements for Aspartame

— must contain warning in precaution section of labeling to the following effect: Phenylketonurics: contains phenylalanine __mg per (dosage unit)

FD&C Warning requirements for Sulfites

— prescription drugs containing sulfites (often used as preservative must contain an allergy warning in the "warning" section of the labeling

What is Medication Guides and Patient package insert difference? When do we need to provide MedGuide? Who provides it and what must be obtained?

— similar but MedGuide is not a requirement for institutional settings. — FDA requires Medication Guides for drugs when... ‣ Patient labeling could prevent serious ADE. ‣ Product has serious risk relative to benefits. ‣ Patient adherence to direction is crucial. — Mfr. Mfr must obtain FDA approval before distributing MedGuide and are responsible for ensuring that a sufficient # of MedGuide are provided to pharmacies. Many mfrs include the MedGuide at the bottom of the package insert, but most pharmacy computer system also print MedGuide for the products that need the at the time of dispensing.

From DSCSA, pharmacies that are distributing must have what?

— they must have *wholesale distribution license* and *must pass DSCSA transaction data* with that distribution. There would be exception.

What does SNI (serial numerical identifier) or unique product identifier provide?

— this idendifies an individual bottle or unit of sale.

NDC number indications? Is NDC required to include on the drug's label? Can other medical products (other than Rx drugs) bear NDC?

— ‣ First 4-5 digits = labeler code. (Or mfr) ‣ Next 3-4 digits = specific drug, strength, dosage form. ‣ Last 1-2 digits = package size — no. But Suggested by FDA. — NDC numbers should NOT appear on non-drug prodcuts. If a dietary supplement or medical device has an NDC number on its label, it would be misbranded. Medical devices have unique device identifiers (UDIs) instead of NDC numbers. Any product implies it is an FDA-approved drug when it is not would also be misbranded.

How many meds are out there for needs of MedGuide? What top meds are necessary with MedGuides?

— ≥1000 products — ‣ Accutane (isotretinoin) ‣ Antidepressants in children and teenagers ‣ Coumadin (warfarin sodium) ‣ Epogen (epoetin alfa) ‣ Forteo (teriparatide rDNA origin) ‣ Lotronex (alosetron HCl) — IBS ‣ Lindane shampoo and lotion ‣ Nolvadex (tamoxifen) ‣ NSAIDs ‣ Remicade (Infiliximab) ‣ Trizivar (abacavir sulfate, lamivudine, zidovudine) ‣ Opioid analgesics and cough products ‣ BDZs

DQSA 2013 explain this — If outsourcing facilities meet the Act's requirements, what are they exempted from?

—> Outsourcing facilities that meet the Act's requirements are exempt from [(1)the premarket approval requirements (FDCA Section 505), (2) adequate directions for use requirements (FDCA Section 502(F)(1) and (3) drug track and trace provision (FDCA Section 582).] **Outsourcing facilities are NOT except from good manufacturing practices**

FD&C Warning requirements for OTC pain relievers

‣ APAP • Must have "acetaminophen" prominently displayed • Must warn about liver toxicity • Must warn not to use with other products containing acetaminophen and to talk to a MD or pharmacist before taking with Warfarin. ‣ NSAIDs • Must include term "NSAID" prominently on label • Must contain "stomach bleeding" warning.

FD&C Warning requirements for OTC Products Containing Iron in Solid Oral Dosage Form

‣ Must provide the following warning: "Accidental over dose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a MD or poison control center immediately". ‣ This warning requirement also applies to dietary supplements containing iron through 21 CFR101.17(e). ‣ Optional: FDA previously had a rule that required unit-dose packaging for iron-containing dietary supplements and drug products that contain 30mg or more of iron per dosage unit, but that rule was eliminated based on a court case in 2003 that concluded FDA did NOT have the authority to pass such a rule

Under REMS — Elements to assure safe use may include...?

‣ Special training, experience, or certification of healthcare practitioners prescribing the drugs; ‣ Special certification for pharmacies, practitioners, or healthcare settings that dispense the drug; ‣ Dispensing drugs to patients only in certain healthcare settings such as hospitals ‣ Dispensing drugs to patients with evidence or other documentation of safe use conditions, such as laboratory test results; ‣ Monitoring patients using the drug; or ‣ Enrolling each patient using the drug in a registry

FD&C Warning requirements for Ipecac syrup

‣ The following statement (boxed and in red letters) must appear: "For emergency use to cause vomiting in poisoning. Before using, call physician, the poison prevention center, or hospital emergency room immediately for advice." ‣ The following warning must appear: "Warning: Keep out of reach of children. Do NOT use in unconscious persons." ‣ The dosage of the medication must appear. The usual dosage is 1 tbsp (15mL) in individuals over 1 year of age. ‣ May only be sold in 1 oz (30mL) containers.

Where can we find the list of REMS drugs?

◦ A complete list of products w/ approved REMS can be found on FDA's website and may include an entire drug class, such as the Opioid Analgesics REMS. (Followings are 2 most extensive REMS — but make sure to review other common REMS drugs)