Allergenic Extracts – Precipitates
Jennifer Bridgewater, M.P.H.CBER, DBPAP
Product Line Overview
Standardized Products (n = 19) Short Ragweed (SRW) - glycerinated and
aqueous formulations Cat, grasses, mites = glycerinated only
• Exceptions = some cat pelt extracts, intradermal tests with < 50% glycerin (100-1000 AU/BAU/ml)
Venoms = freeze dried, HSA based diluent
Unstandardized (n = 600 - 800) Glycerinated and/or aqueous
Historical PerspectivePrecipitates recognized for many yearsEarly efforts (1970’s) by industry to
characterize precipitates Physical descriptions Solubility properties
Early efforts by industry to remove precipitates Manufacturing changes (e.g., bulk “settling”
steps) Formulation changes (e.g., extraction fluids)
How Did Precipitate Issue Arise?Appearance of precipitates noted during
Team Biologics inspections of several firms (99-present)
Areas in which precipitates were observed by inspectors: bulk containers final containers retain samples customer complaint and product return files
Physical Characteristics of PrecipitatesExamples of terms used by industry to
describe precipitate appearance crystalline flaky cloudy powdery tarry fibrous clumpy
Physical Characteristics of PrecipitatesExamples of terms used by industry to
describe precipitate appearance color of precipitate ability to resuspend precipitate into solution amount of sediment/precipitate at bottom of
vial percentage of extract containing precipitate
Current Industry Efforts to Characterize Precipitates microscopic examination of precipitates
Assess physical appearance Sterility testing
Rule out microbial contamination IEF or SDS-PAGE examination of
precipitated extracts In some cases profiles are similar In some cases bands are missing or lose
definition
Current Industry Efforts to Characterize PrecipitatesPotency testing of precipitated SRW
extracts Compare potency of precipitated final container
extract to initial (release) potency valueProtein Nitrogen Units (PNU), pH, phenol
testing of precipitated extracts Compare PNU, PH, and phenol values of
precipitated final container extract to initial (release) value
Precipitate Data (Unstandardized)
Extract pH release
pH retest
Diff. PNU release
PNU retest
Percent Diff.
Penicillium 7.26 7.06 -.020 139000 136000 - 2.0%
3 Weed Mix
7.08 7.65 +0.57 67000 75000 + 12.0%
Red Maple 6.8 6.5 -0.3 134000 99000 - 26.0%
Scrub Oak 7.83 7.68 -0.15 53000 67000 + 26.0%
Precipitate Potency Data - SRW
Lot
(1:10 w/v)
Antigen E Pre
Antigen E Post
Difference
A 281.7 252.2 -29.5
B 243.3 231.8 -11.5
C 317.2 204.1 -113.1
D 294.8 334.0 +39.2
• Data in table taken from pooled data (2 sets of n = 19)
• 5% average drop in AgE value in pooled data; difference not statistically different
Current KnowledgeAqueous extracts precipitate more than their
glycerinated counterpartsAqueous SRW commonly precipitatesPrecipitates are a primary cause of
physician complaints (visual appearance) and product returns to industry
Precipitates do not appear to be caused by microbial contamination
Extraction ratio/concentration of extract and phenol may contribute to precipitation
Knowledge GapsPhysicochemical composition of
precipitatesLong term effect on potency of the extracts
all but one precipitated extracts are unstandardized, therefore knowledge limited
How precipitated extracts are treated in clinical practice Are precipitates recognized? Are precipitated extracts administered as is,
decanted and administered, or returned?
Knowledge GapsAdministration of precipitated extracts
Is there a higher risk for adverse events (AE) if a precipitate is injected?
AE reporting for allergenic extracts (MedWatch) is voluntary and passive
Limited number of AE reports submitted to FDA
AE reports = signal system Information submitted via MedWatch often
incomplete
Current Research AreasPhysicochemical composition of
precipitatesPotency and stability studies of precipitated
standardized extracts (limited to aqueous SRW)
Evaluation of pH, phenol content, and PNU of precipitated unstandardized extracts over shelf life
Current Regulatory PositionNo shipment of final containers exhibiting
precipitatesDevelopment of in-house quality control
programs (identify and describe precipitates)Validation of any re-processing procedures
performed on precipitated extractsModification of labeling to address precipitatesSubmit Biological Product Deviation Reports
on precipitated lots to CBER
SummaryPrecipitates occur in allergenic extractsAqueous extracts precipitate more than
glycerinated extractsAlmost all precipitated extracts
unstandardizedKnowledge gaps on precipitated extracts
existCollaborating with industry to fill
knowledge gapsPrudent regulatory approach
Committee Discussion Point
Please discuss future areas of investigation which may provide information in ascertaining the effect of precipitates on the administration of allergenic extracts