Welcome

Open Forum: Beyond-Use Date (BUD) Provisions

in General Chapters <795> and <797>

Tuesday, September 15, 2020

Objectives

–Engage a wide range of stakeholders on their perspectives

regarding the beyond-use dates (BUDs) in the compounding
chapters <795> Pharmaceutical Compounding – Nonsterile
Preparations and <797> Pharmaceutical Compounding – Sterile
Preparations

–Perspectives gathered will provide additional insights to the

Compounding Expert Committee as it reviews the BUD provisions
in the compounding chapters
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Agenda

11:00 am ET Welcome, Purpose and Goals, Agenda Review and Protocols

11:05 am Opening Remarks and Introduction of Panelists

11:15 am BUDs in <795> Pharmaceutical Compounding – Nonsterile Preparations

1:00 pm Lunch Break

2:00 pm BUDs in <797> Pharmaceutical Compounding – Sterile Preparations

3:45 pm Wrap up and Adjourn

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Introductions and Opening Remarks

 Abby Dilley – Moderator (RESOLVE)

 Tenille Davis – Civic Center
 Mason Hines – Moderator (RESOLVE)
 Krystal Stefanyk – NC BOP
 Brian Serumaga – USP
 Thomas Kupiec – ARL Bio Pharma
 Brenda Jensen – CMP EC Chair 2020 –
2025  Ashley Duty – Children’s Mercy

 Robert Shrewsbury – CMP EC Vice chair  Rich Moon - NCPA

2020 - 2025
 John Metcalfe – FDA CDER
 Gigi Davidson – CMP EC Chair 2015 -
2020

 Connie Sullivan – CMP EC Vice chair 2015

- 2020
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Overview of BUD Changes in
Revised/Remanded General Chapter
<795> Pharmaceutical Compounding –
Nonsterile Preparations
Revised/Remanded <795> Text

Section 10. Establishing Beyond-Use Dates

 Terminology
– Expiration Date = applies to conventionally manufactured drug products
– BUD = applies to Compounded Nonsterile Preparations calculated in terms of hours, days, or
months

 Parameters to consider
– Chemical and physical stability
– Compatibility of container-closure system
– Degradation of container-closure system
– Potential for microbial proliferation

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Expert Committee Rationale and Evaluation
Stability-Indicating Assays
 A strength (potency) over time test determines the amount of active ingredient in a preparation,
however, it may not be able to separate the active ingredient from its degradation products and
impurities for quantitation depending on the analytical methods used for the test.
 A stability-indicating method quantitates the active ingredient and its degradation products or
related impurities
– Can show a change in the concentration of the active ingredient with increasing storage time
 A photodiode array (PDA) detector scan is commonly used in conjunction with an HPLC assay to
determine potency
– Peak purity evaluation should be performed during validation as part of specificity testing of
force-degradation samples
– Peak purity helps ensure the method can separate degradation products and determine the
strength of active ingredient

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 <795> BUD Provisions

Current official text (2011) Remanded/revised text (2019)

• Water containing oral formulations = 14 days • Non-preserved aqueous (Aw > 0.6) = 14 days
• Water-containing topical/dermal and mucosal • Preserved aqueous (Aw > 0.6) = 35 days
liquids and semisolid = 30 days
• Nonaqueous dosage forms (Aw ≤ 0.6) = 90
• Nonaqueous formulations = 6 months days
• Solid dosage forms = 180 days

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Water Activity
<1112> Table 1. Water Activities Required to Support the Growth of Representative Microorganisms

Bacteria Water Activity (aW) Molds and Yeast Water Activity (aW)

Pseudomonas aeruginosa 0.97 Rhyzopus nigricans 0.93

Bacillus cereus 0.95 Mucor plumbeus 0.92

Clostridium botulinum, Type A 0.95 Rhodotorula mucilaginosa 0.92

Escherichia coli 0.95 Saccharomyces cerevisiae 0.90

Clostridium perfringens 0.95 Paecilomyces variotti 0.84

Lactobacillus viridescens 0.95 Penicillium chrysogenum 0.83

Salmonella spp. 0.95 Aspergillus fumigatus 0.82

Enterobacter aerogenes 0.94 Penicillium glabrum 0.81

Bacillus subtilis 0.90 Aspergillus avus 0.78

Micrococcus lysodekticus 0.93 Aspergillus niger 0.77

Staphylococcus aureus 0.86 Zygosachharomyces rouxii 0.62

(osmophilic yeast)

Halobacterium halobium 0.75 Xeromyces bisporus 0.61

(halophilic bacterium) (xerophilic fungi)
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Water Activity
<1112> Table 2. Microbial Limit Testing Strategy for Representative Pharmaceutical and OTC Drug Products Based
on Water Activity
Greatest Potential
Products Water Activity Contaminants Testing Recommended

Nasal inhalant TAMC TCYMC, absence of S.

0.97 Gram-negative bacteria aureus and P. aeruginosa

Hair shampoo TAMC, TCYMC, absence of S.

0.97 Gram-negative bacteria aureus and P. aeruginosa

Antacid TAMC, TCYMC, absence of E.

0.97 Gram-negative bacteria coli and Salmonella spp.

Topical cream 0.97 TAMC, TCYMC, absence of S.

Gram-positive bacteria aureus and P. aeruginosa

Oral liquid 0.90 Gram-positive bacteria and TAMC and TCYMC

fungi

Oral suspension 0.87 Fungi TAMC and TCYMC

Topical ointment 0.55 None Reduced testing

Lip balm 0.36 None Reduced testing

Vaginal and rectal 0.30 None Reduced testing

suppositories

Compressed tablets 0.36 None Reduced testing

Liquid- Filled capsule 0.30 None Reduced testing 10

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Water Activity
<1112> Application of Water Activity Determination to Nonsterile
Pharmaceutical Products
 Determination of water activity of nonsterile pharmaceutical dosage forms aids to:
– optimize product formulations to improve antimicrobial effectiveness of preservative systems,
– reduce the degradation of active pharmaceutical ingredients within product formulations
susceptible to chemical hydrolysis,
– reduce the susceptibility of formulations (especially liquids, ointments, lotions, and creams) to
microbial contamination, and
– provide a tool for the rationale for reducing the frequency of microbial limit testing and
screening for objectionable microorganisms for product release and stability testing using
methods contained in the general test chapter Microbial Enumeration Tests <61> and Tests
for Specified Microorganisms <62>.

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Revised/Remanded <795> Text

Section 10. Establishing Beyond-Use Dates

 In the Presence of CNSP-Specific Stability Information
– BUD may be extended up to maximum of 180 days
– Stability-indicating assay for the specific API, CNSP, and container–closure that will be used
– Should first be tested for antimicrobial effectiveness at the end of the proposed BUD
 Shorter BUDs May be Required
– If ingredients have an earlier expiration date
– If components have an earlier expiration date or BUD
– If ingredients are known to be susceptible to decomposition

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<795> BUD Provisions

 Currently official text (2011)

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<795> BUD Provisions

 Revised/Remanded Text (2019)

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Expert Committee Rationale and Evaluation
Framework for BUDs
 Previous characterization with “nonaqueous” or “water-containing” subject to frequent queries
– Water activity added to incorporate consideration for susceptibility to microbial proliferation

 BUDs in Table 3 are assigned based on consideration of stability, compatibility, and microbial
proliferation
– Nonaqueous dosage forms (e.g., suppositories, ointments, fixed oils, or waxes) will have a
BUD of 90 days
• Fixed oils and fatty acid bases are not inherently inert and inactive
 Study for Doxycyline Compounded Oral Suspension, Veterinary formulated steviol glycoside, acesulfame
potassium, and a fixed oil based showed evidence of degradation
» Strength < 90% starting at 30 days when stored at room temperature
» Significant color change starting at day 45 when stored at cold temperature
» Increase in impurity (6-epidoxycycline) during storage

– Solid dosage forms assigned a default BUD of 180 days

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Overview of BUD Changes in
Revised/Remanded General Chapter
<797> Pharmaceutical Compounding –
Sterile Preparations
Purpose of Revision

 To address public comments received in the second public comment period between June and
September 2018
– Incorporate feedback and discussion from:
• Roundtables
• Discussion Forums
• Expert Consultants

 To clarify topics that are frequently queried and misconstrued

 To align revisions to:

– <795> Pharmaceutical Compounding – Nonsterile Preparations
– <800> Hazardous Drugs – Handling in Healthcare Settings

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 <797> BUD Framework
Categories of CSPs

CSP Microbial
Contamination Risk Levels Category Category
1 CSPs 2 CSPs

High-Risk May be prepared in

a PEC located in an Must be prepared
unclassified in a cleanroom
Medium-Risk segregated suite
compounding area

Low Risk Assigned a BUD of

Assigned a BUD of
≤ 12 hours at
> 12 hours at
controlled room
controlled room
Low-Risk with 12 temperature or ≤ 24
temperature or > 24
hours when
Hour BUD refrigerated
hours if refrigerated

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Revised/Remanded <797> Text
Establishing Beyond-Use Dates

Stability factors Sterility factors

– Chemical and physical properties – Environment in which the CSP is
prepared
– Compatibility of the container-closure
system • Cleanroom suite or SCA
– Aseptic preparation and sterilization
method
– Components
• Sterile or nonsterile starting ingredients
– Sterility Testing
– Storage conditions (e.g., packaging and
temperature)

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Other Factors

 Personnel Training & Evaluation

 Garb Requirements

 Facilities and Engineering Controls 2019

2018
 Environmental Monitoring
2015
 Cleaning and Disinfecting

 Packaging and Transport

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Revised/Remanded <797> Text
Category 1 CSP BUDs

Storage Conditions
Controlled Room Refrigerator
Temperature (2°–8°)
(20°–25°)

BUD ≤ 12 hours ≤ 24 hours

Currently official <797>

Low-Risk Level CSP in SCA 12 hours

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Revised/Remanded <797> Text
Category 2 CSP BUDs
Preparation
Storage Conditions
Characteristics
Sterility
Controlled Room
Sterilization Testing Refrigerator Freezer
Temperature
Method Performed (2°–8°) (−25° to −10°)
(20°–25°)
& Passed
Prepared from one or Prepared from one or Prepared from one or
Aseptically
more nonsterile more nonsterile more nonsterile
prepared No
starting component(s): starting component(s): starting component(s):
CSPs
1 day 4 days 45 days
Currently official <797>
High-Risk Level CSPs 1 day 3 days 45 days

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Revised/Remanded <797> Text
Category 2 CSP BUDs
Preparation
Storage Conditions
Characteristics
Sterility
Controlled Room
Sterilization Testing Refrigerator Freezer
Temperature
Method Performed (2°–8°) (−25° to −10°)
(20°–25°)
& Passed
Aseptically Prepared from only Prepared from only Prepared from only
prepared No sterile starting sterile starting sterile starting
CSPs components: 4 days components: 10 days components: 45 days

Currently official <797>

Medium-Risk Level CSPs 30 hours 9 days 45 days
Low-Risk Level CSPs 48 hours 14 days 45 days
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Revised/Remanded <797> Text
Category 2 CSP BUDs
Preparation Characteristics Storage Conditions

Sterility Controlled Room

Sterilization Testing Refrigerator Freezer
Temperature
Method Performed & (2°–8°) (−25° to −10°)
Passed (20°–25°)

Prepared from one or Prepared from one or Prepared from one or

more nonsterile starting more nonsterile starting more nonsterile starting
component(s): 1 day component(s): 4 days component(s): 45 days
Aseptically No
prepared
CSPs Prepared from only sterile Prepared from only sterile Prepared from only sterile
starting components: 4 starting components: 10 starting components: 45
days days days
Yes 30 days 45 days 60 days
Terminally No 14 days 28 days 45 days
sterilized
CSPs Yes 45 days 60 days 90 days 25
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