FDA Guidance Documents
When can compounding for a drug using a bulk drug substance that does not appear on the approved bulks list and that is not used to compound a drug that appears on the FDA drug shortage list be done?
1. A Category 1 substance may be eligible for inclusion on the bulks list 2. The original manufacturer are establishments that are registered with the FDA 3. The bulk drug substance is accompanied by a valid COA 4. If the bulk drug substance is the subject of an applicable USP or NF monograph 5. The drug product compounded using the bulk drug substance is compounded in compliance with all other provisions of section 503B of the FD&C Act.
How long must the records relating to adverse drug experiences reported to the FDA be kept?
10 years.
FDA recommends that outsourcing facilities maintain the records to demonstrate compliance with the essentially a copy provision (prescription or order records of a prescriber's determination of clinical difference or approved drug product that appeared on FDA's drug shortage list) for how long?
3 years
How often must an outsourcing facility register with the FDA in order to remain an outsourcing facility?
Annually
If the outsourcing facility occupies suites B and C of a building located at 1234 Maple Street, how should it register its place of business?
As 1234 Maple Street, Suites B and C
What are the dates for the registration period for an outsourcing facility?
October 1st - December 31st
How may an outsourcing facility repackage a licensed biological product without violation?
The repackaged biological products must have a written stability testing program.
How does the FDA define a *serious adverse event*?
• Death • A life-threatening adverse drug experience • Inpatient hospitalization or prolongation of existing hospitalization • A persistent or significant disability or incapacity • A congenital anomaly or birth defect
What tests are included for repackaged biological products stability testing program?
*Nondestructive Tests* Appearance Color and clarity Visible particulates *Destructive Chemical Tests* pH Subvisible particles Protein content Product-related impurities Potency Sterility testing Container-closure integrity test
If the drug product is repackaged by an outsourcing facility, the label on the immediate container must include what statements?
- "This drug product was repackaged by [name of outsourcing facility]" - "Not for resale" - "Office Use Only" if not in pursuant of a patient specific order or prescription.
If a registered outsourcing facility compounds one thousand 100 ml vials of 5 mg/ml of Drug X, what is... the strength of the active ingredient per unit? the package description? the number of individual units produced?
- 5 mg/ml - 100 ml vials - 1,000 vials
What are the 3 categories for substances nominated for the 503A or 503B bulk drug substances list?
- Category 1 -Substances Nominated for the Bulks List Currently Under Evaluation - Category 2 -Substances Nominated for the Bulks List That Raise Significant Safety Risks - Category 3 -Substances Nominated for the Bulks List Without Adequate Support
What is the BUD of a biological product that is mixed, diluted, or repackaged by a 503A or 503B compounder?
- Does not exceed the time frame to be used as specified in the approved labeling ("in-use time") - Expiration date of the biological product being mixed, diluted, or repackaged - If there is not a specified in-use time and the product is refrigerated, no longer than 24 hours (Whichever is shorter is all instances)
How is the BUD for sterile drug products repackaged by State-licensed pharmacies or Federal facilities determined according to the FDA?
- Drug product that specifies in the labeling a time within which the opened product is to be used (an "in-use" time) - Expiration date on the drug product being repackaged - In accordance with the proposed revision to USP Chapter <797> if no "in-use" time available. (Whichever is shorter in all cases.)
Each time an outsourcing facility registers with the FDA, the facility must indicate whether it intends to compound, within the next calendar year, what 2 kinds of preparations?
- Drugs that appear on FDA's drug shortage list - Compounds from bulk drug substances, (must specifically state sterile, nonsterile, or both)
What is the BUD for a prescription set of allergenic extracts for subcutaneous immunotherapy?
- Earliest expiration date of any allergenic extract or any diluent - one year from the date the prescription set is mixed or diluted.
How does the FDA define *repackaging*?
- Taking a finished drug product from the container in which it was distributed by the original manufacturer and placing it into a different container without further manipulation. - Placing the contents of multiple containers (e.g., vials) of the same finished drug product into one container, as long as the container does not include other ingredients. - Does *not* include a drug manipulated in any other way (reconstituted, diluted, mixed, or combined with another ingredient).
What kind of adverse drug events *must* an outsourcing facility report to the FDA? What kind of adverse drug events are strongly recommended by the FDA *should* an outsourcing facility report to the FDA?
- all serious, unexpected adverse drug experiences - all serious adverse drug experiences
The FDA does not recommend registering as an outsourcing facility if the only compounding activities done are what?
- repackaging - compounding non-sterile drugs - compounding animal drugs - mixing, diluting, or repackaging biological products subject to licensure
What are the four *data elements* an outsourcing facility must investigate upon reporting an adverse drug experience?
1. An identifiable patient 2. An identifiable reporter 3. A suspect drug 4. A serious adverse event
What are 2 technology systems that store drug lot information to assist in product recall management? Provide advantages and disadvantages for each.
1. Barcode scanning and photographic capturing - Advantage: Easy during preparation - Disadvantage: Hard to search and trace back 2. Manual entry onto compounding log - Advantage: Easy to search and trace back - Disadvantage: Increases dose preparation time
How long does the outsourcing facility have to report adverse drug experiences to the FDA after receipt of the information?
15 calendar days. (Any updated information or follow-up reports are also sent within 15 calendar days as well.)
Which of the following compounding scenarios is a violation? - Liquid form of Drug A, compounded drug will be prescribed to patients who can't swallow tablet (Drug A only comes as tablets) - 1 mg of Drug B because pediatric patients need lower dose (Drug B only comes in 25 mg capsules) - Drug C with no red dye because patient is allergic (Drug C only comes manufactured with red dye) - 5 mg Drug D because it is a lower price (Drug D only comes as 12 mg tablets) - 150 mg Drug E in 120 ml cherry-flavored Syrup USP because patient needs alcohol-free preparation (Drug E is only available in formulations that contain alcohol)
5 mg Drug D because it is a lower price (Drug D only comes as 12 mg tablets) The *clinical difference identified* on either a patient-specific prescription or order, or non-patient specific order, must be produced by the "change" with the compound. A lower price has no change in the patient's clinical status.
How long from the last time the drug was on the FDA shortage list does the outsourcing facility have to distribute the drug?
60 days (There may be circumstances in which a drug product is in shortage when the outsourcing facility compounds the drug, but the shortage is resolved before the outsourcing facility distributes it.)
The highest number of units of drug X for which the compounder has received such valid patient-specific prescriptions in a 30-day period between August 1, 2015, and August 1, 2016, is 500 units. However, between July 15, 2016, and August 15, 2016, the compounder receives valid patient-specific prescriptions for 750 units of compounded drug X. What is the *maximum* allowed units of drug X that the 503A compounding facility can make without exceeding the *limited quantity* for *anticipatory compounding*?
750 units
The FDA website posts the name and location of each registered outsourcing facility as well as certain publicly disclosable information related to past FDA inspections and compliance actions. How often is this information updated?
FDA intends to update the list of registered outsourcing facilities weekly.
T/F An outsourcing facility may follow 503B regulation for sterile compounds while following 503A regulation for non-sterile compounds for patient specific prescriptions.
False! *All* drug products compounded in an outsourcing facility are regulated under section 503B and subject to CGMP requirements. Subdividing the rooms of the outsourcing facility with a temporary barrier such as a curtain, or by limiting the compounding of patient-specific prescription compounding within the facility to certain periods of time are not good enough.
T/F If the outsourcing facility has not compounded any drug products during the previous six-month period of the last drug product report, there is no need to submit a report to the FDA.
False! It must submit a report to FDA indicating that it has not compounded any drug products during the period.
T/F Prescription set of allergenic extracts for subcutaneous immunotherapy do not need to be included in the outsourcing facility's drug product report.
False! The prescription set is included in a report submitted to FDA each June and December.
T/F The assignment of BUDs for sterile drug products repackaged by outsourcing facilities is the same as State-licensed pharmacies or Federal facilities.
False. The outsourcing facility assigns a BUD as described in *Current Good Manufacturing Practice*.
T/F An outsourcing facility will not see a prescription for an individual patient.
False... The facility may or may not obtain prescriptions for individual patients. If they do, they must be a licensed pharmacy.
When can a 503A compounding facility compound preparations for *office use*?
In advance of receiving a *valid prescription order* for an identified individual patient to have a supply of the drug product ready to provide to a patient when a patient-specific prescription order is presented. (This must not violate anticipatory compounding in limited quantities outlined in 503A.)
If a USP monograph does not exist and the bulk drug substance is not a component of an FDA-approved human drug product, what qualification must the drug substance have before complying with USP standards for compounding?
It must appear on a list of bulk drug substances for use in compounding developed by FDA.
What must be done if an outsourcing facility compounds a drug that is the subject of a risk evaluation and mitigation strategy (REMS)?
Must demonstrate to FDA that it will use controls comparable to the controls applicable under the REMS.
How does the FDA define an identical or nearly identical drug?
Same... active ingredient(s) route of administration dosage form dosage strength excipients
What is the exception for a drug product that is packaged in a single-dose vial that is repackaged into multiple units in terms of conflict with the approved labeling?
Statements designating the product as a single-dose or single-use product and related language (e.g., discard remaining contents) do not need to be followed.
T/F Any product that is not compounded in a particular 6 month period for the drug product report is not require to be submitted to FDA even if the outsourcing facility sent in a submission for that product previously.
That's true.
T/F FDA does not consider USP monographs for dietary supplements to be "applicable" USP or NF monographs.
That's true.
When establishing the BUD for a repackaged biological product, if the data for any test does not meet the established specifications, how is the BUD determined?
The BUD is limited to the time point at which all of the data remained within specifications, so check multiple time points!
What are examples of factors that may be the basis for concluding that preparations has been compounded regularly or in inordinate amounts and thus not qualified for 503A exemptions?
The compounded drug product amounts to *more than a small number* of prescriptions or a small percentage of the compounded drug products that a compounder prepares. The compounder routinely *substitutes* compounded drugs that are essentially copies of commercially available drugs upon receiving prescriptions for patients. The compounder *offers pre-printed prescription pads* that a prescriber can use to write a prescription for the drug product that is essentially a copy without making a determination that there is a change that will produce a significant difference for a patient. The compounded drug product is *not compounded on an as-needed basis*, but on a routine or pre-set schedule.
How often must stability testing for repackaging biological products be performed from the outsourcing facility?
The outsourcing facility would conduct these tests on *one lot annually* and whenever the formulation or the container into which the biological product is being repackaged may have changed
T/F If a licensed biological product is diluted or mixed with components other than those described in the approved labeling, or if it is removed from its original container-closure system and placed in a new container-closure system that is not described in the approved labeling for the product, these additional manufacturing steps would create a new, unlicensed biological product.
True
T/F An entity that owns or manages an outsourcing facility may compound drugs under section 503A in a separate establishment located outside the boundaries of the outsourcing facility.
True! The section 503A establishment may be located near the outsourcing facility or in the same building, provided the compounding in the outsourcing facility is *completely segregated*
T/F Each outsourcing facility at a separate geographic location or address must register separately despite being in the same health system entity.
True.
T/F FDA does not take action against an outsourcing facility if it fills orders for a compounded drug that is essentially a copy of an approved drug that has been discontinued and is no longer marketed.
True... As long as the drug has not been withdrawn because of safety or effectiveness reasons.
T/F Drug products repackaged by State-licensed pharmacies, Federal facilities, or outsourcing facilities are not eligible for the exemptions provided under 503A or 503B.
True... Repackaged drug products are generally subject to the adulteration, misbranding, and approval provisions of the FD&C Act.
How often must a 503B outsourcing facility submit a drug product report to FDA?
Upon initial registration and twice each year (in June and December).
T/F Failure to report adverse events by an entity that is registered with the FDA is a prohibited act.
Yeah, it's true.
When will the FDA consider whether a 503A compounding facility has exceeded the *limited quantity* for *anticipatory compounding*?
• Makes no more than a 30-day supply of a particular compounded drug product to fill valid prescriptions it has not yet received. • The amount of the supply of a particular compounded product is based on the number of valid prescriptions that the compounder has received for identified individual patients in a 30-day period over the past year that the compounder selected.
The drug product report must identify all sterile and non-sterile drugs compounded at the outsourcing facility during the previous six-month period and must provide what 7 pieces of information about the compounded preparations?
• The active ingredient and strength of active ingredient per unit • The source of the active ingredient • The National Drug Code (NDC) number of the source drug or bulk active ingredient, if available • The dosage form and route of administration • The package description • The number of individual units produced • The NDC number of the final product, if assigned
How does FDA determine whether a section 503A facility and an outsourcing facility are completely segregated?
• The outsourcing facility and section 503A establishment do not share any rooms. • The outsourcing facility and section 503A establishment do not share any fixed equipment or supplies for use in compounding. • The outsourcing facility and section 503A establishment have separate entrance(s) and exit(s), do not share an internal pass-through opening, and are separated by permanent physical barriers. (It should not be necessary to go through the outsourcing facility to reach any part of the section 503A establishment.)
What 3 conditions must be met in order to qualify for the exemptions of 503A compounding?
• compounding is for an identified individual patient • drugs compounded in advance of receiving prescriptions are compounded only in limited quantities • drugs are distributed pursuant to a valid patient-specific prescription.
