Lecture #8 Flashcards
What is the United States Pharmacopeia?`
Recall that USP is part of the Official Compendia, which is the standard drug reference in the United States.
* Drug monographs within the USP have the force of law, and not following that information leaves a drug adulterated or misbranded.
USP also publishes information on the appropriate means for drug preparation and drug storage.
* While this does not have the force of law federally, many states and have adopted aspects of these chapters into their own law.
* Even in states where these do not have the force of law, they are utilized as standards for competent practice.
* You will be responsible for basic information regarding 3 USP chapters
USP <795> - nonsterile compounding
First published in 2000, this chapter sets nonsterile compounding standards to be followed by pharmacies.
* The most recent revision of the chapter was published November 1st, 2022, and took effect November 1st, 2023
* Focuses on ensuring the quality and safety of nonsterile compounding
* Requires beyond-use dates (BUDs) to be assigned to nonsterile products
USP <797> - sterile compounding
First published in 2004, this chapter sets the standards for sterile compounding.
* The most recent revision of the chapter was published November 1st, 2022, and took effect November 1st, 2023
* Covers numerous sterile compounding requirements, including personnel, training, facilities, environmental monitoring, and storage and testing of finished products.
USP <800> - hazardous substances
First published in 2016 and went into effect December 1, 2019. Could not be fully implemented until <795> and <797> were updated in November 2023.
* Discusses the handling of hazardous drugs in healthcare settings.
* Hazardous means one of the following: carcinogenic, teratogenic or developmental toxicity, reproductive toxicity, organ toxicity at low doses, genotoxicity, new drugs that mimic existing hazardous drugs
Expiration date requirements
All manufacturers must assign an expiration date to their product and include this information on the product label.
* The expiration date is the last date the product will meet the requirements of the USP monograph for strength or stability
* Expiration dates can come in two ways:
* Exact dating (January 21st, 2029)
* Month and year (January 2029)
* When dated as a month and year, assume the product is good through the last day of the month noted
Beyond use dates (BUDs)
Beyond use dates (BUDs) are required for some medications when dispensed to patients or within institutions.
* A BUD is a date after which a product should not be used. It cannot be later than an expiration date and is often sooner.
* BUDs are based on many different factors, including when a product is opened, storage, reconstitution, and stability or sterility data, to name a few.
The USP provides guidance on BUDs for compounded products, but also the following general guidance for all products:
* A BUD shall not be later than the expiration date on the manufacturer’s container, or
* 1 year from the date the drug is dispensed, whichever is earlier
Repackaging
Repackaging occurs when a location takes a drug from a manufacturer’s bottle and puts it into a new package without doing other things. Examples:
* Moving tablets from a large container into unit-dose packaging
* Taking creams from large containers into smaller containers
* Transferring contents of bulk containers into a machine for future dispensing
Repackaged products must meet all provisions of the FDCA
Importantly, taking a drug out of a stock bottle and placing into a prescription bottle for dispensing does not meet the criteria for repackaging
Repackaging guidance
Many companies (including pharamcies) engage in repackaging and may not meet all requirements of the FDCA. The FDA knows this and has provided guidance where the FDA does not intend to take action against companies for violating the FDCA. These exemptions include:
* A prescription drug product on the drug shortage list
* A drug product repackaged under direct supervision of a licensed pharmacist
* If repackaged by a pharmacy, only distributed upon receipt of a valid prescription for an individual patient
* Repackaged product is assigned a BUD as described in the repackaging guidance
Guidance in determining BUDs
Decided according to expiration date or in-use time (the time in which the product must be used once it is prepared or accessed)
1. FDA-approved product with specific in-use time: BUD established with in-use time or the expiration date on the product repackaged, whichever is sooner
2. FDA-approved product without an in-use time, or unapproved product (aka compound):
Non-aqueous formulation – no more than six months or the expiration date, whichever is sooner
Water-containing oral formulations – no more than 14 days or the expiration date, whichever is sooner
Water containing topical, mucosal, and semisolid formulations – no more than 30 days or the product expiration date, whichever is sooner
Repackaging guidance BUDs
FDA-approved sterile product with specified in-use time: BUD established with in-use time or the expiration date on the product repackaged, whichever is sooner
FDA-approved sterile product without a specified in-use time or unapproved product: BUD established by USP <797> or the expiration date of the product repackaged, whichever is sooner
Inspections
Pharmacy inspections are conducted to ensure that pharmacies are in compliance with all applicable laws and regulations. Generally, they occur in one of two ways:
1. A routine inspection (done periodically at random)
2. An inspection triggered by knowledge, suspicion, or a formal complaint of wrongdoing that may be a danger to public safety
We will review inspections conducted by the following agencies: FDA, DEA, State Board of Pharmacy
FDA inspections
Pharmacies are exempted from FDA inspection per the FDCA, unless the pharmacy manufacturers, prepares or compounds drugs or devices.
* Despite this, the FDA may inspect a pharmacy to determine if they manufacture drugs and to verify compounding is done appropriately
* FDA inspectors may request entry to a pharmacy by showing a notice of inspection (FDA form 482) and their credentials
FDA Inspections of pharmacies are rare, the FDA primarily focuses on the pharmaceutical industry and outsourcing facilities.
DEA inspections
The DEA may inspect any place where controlled substances are kept.
* They may examine records and reports related to controlled substances, inspect the premises, and inventory controlled substances without a warrant.
* When requesting inspection, a DEA inspector must: State the purpose of their inspection, Show their credentials, and Provide written notice of inspection to the pharmacy owner or pharmacist in charge
This person may refuse inspection or revoke consent at any time and require inspectors to get a warrant. Be warned: they will come back with a warrant!
DEA notice of inspection (NOI)
When requesting entry for inspection, the DEA must show an NOI or a DEA form 82. This lists out the following rights:
* You have the right to require the DEA to get an administrative inspection warrant (AIW)
* You have the right to refuse an inspection (at which point they will get an AIW)
* Anything incriminating found can be seized and used against you in prosecution
* You will get a copy of the NOI
* You may withdrawal your consent to inspection at any time
Only the owner, operator, or agent in charge may sign an NOI.
DEA warrants
There are two types of warrants utilized by the DEA, both of which may only be issued when there is probable cause for entry:
* Administrative Inspection Warrants (AIWs): provided for anything considered a valid public interest. Low bar to clear
* Search Warrants: provided if an officer can “convince a judge that a reasonable person would believe that a crime has been or will be committed on the premises to be searched or that evidence relevant to a crime exists at the premises.” Higher bar to clear
AIWs can only be served during regular business hours, search warrants can be served anytime
There are situations where a warrant is not required for entry (consent, imminent danger, emergency situations, etc.)
Board of pharmacy (BoP) inspections
The Board of Pharmacy can send board inspectors or compliance officers to your pharmacy for a routine inspection.
* In almost every state, you cannot say no to these inspections (including Indiana)
* BoP inspectors can inspect without a warrant
This is allowable because the Board of Pharmacy grants licensure and, as a result, can verify that you are following applicable laws and regulations.
Rules of thumb for inspections
- Be cooperative and friendly
- Ask for the inspector’s credentials
- Document the important details of the inspection
- Never sign anything unless it is completely understood what is being signed
It is usually the case that the person doing the inspecting is looking for someone/something besides you
Generic equivalency
Medications are frequently substituted (brand for generic, one generic for another, one brand for another). This leads to a question: who/what determines what can and cannot be substituted?
* The Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book) provides equivalency ratings for many products
* Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimiliarity or Interchangeability Evaluations (the Purple Book) provides interchangeable biological product information
The orange book information
Market Status, Active Ingredient, Proprietary Name, Application Number, Dosage Form, Route Strength, Therapeutic Equivalence (TE) Code, Reference Listed Drug (RLD), Reference Standard (RS), Applicant Holder
What is the reference listed drug (RLD)?
*The RLD is usually the original brand name product, which is utilized by the generics when submitting ANDAs
What is the reference standard (RS)?
The RS is what the product to which generic has to demonstrate equivalency
What is therapeutic equivalence?
To be therapeutically equivalent, the product must be both pharmaceutically equivalent AND bioequivalent
Pharmaceutical equivalence: active ingredient, dosage form, strength, route, labeling
Bio-equivalence: in vivo (human) results, in vitro (lab) results (kinetics, dynamics, clinical effects)
Therapeutic equivalence (TE) code
Examples: AB1, AT, BX
* First letter indicates the relevant therapeutic equivalence code (if
substitutable or not)
* Second letter indicates the dosage form (T= topical, X= insufficient data, etc)
* Drugs with a three-character code are considered therapeutically equivalent only to other drugs with the same three-character code (AB1 = AB1, AB1 ≠ AB2)
Therapeutic equivalence (TE) code A
Product is therapeutically equivalent to other equivalent products, with no concerns related to pharmaceutical equivalence or bioequivalence
* The first letter, A, represents Therapeutic Equivalence.
* The second letter can be one of many options (B, O, T, N, P, etc), and is related to the dosage form
Therapeutic equivalence (TE) code B
Product is NOT therapeutically equivalent to other equivalent products, with concerns related to pharmaceutical equivalence and/or bioequivalence
* The first letter, B, denotes that the product is not therapeutically equivalent
* The second letter can be one of many options (B, O, T, N, P, etc), and is related to the dosage form
Three-character TE codes
Nifedipine has two brand names (Adalat CC and Procardia XL)
* These brands are not bioequivalents because they have different
release mechanisms, therefore they are not therapeutic equivalents
* Adalat CC is assigned AB1 and Procardia XL is assigned AB2
