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