Allergenic Extracts

1
Allergenic Extracts Precipitates

• Jennifer Bridgewater, M.P.H.
• CBER, DBPAP

2
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 lt 50 glycerin (100-1000 AU/BAU/ml)
• Venoms freeze dried, HSA based diluent
• Unstandardized (n 600 - 800)
• Glycerinated and/or aqueous

3
Historical Perspective

• Precipitates recognized for many years
• Early efforts (1970s) 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)

4
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

5
Physical Characteristics of Precipitates

• Examples of terms used by industry to describe
  precipitate appearance
• crystalline
• flaky
• cloudy
• powdery
• tarry
• fibrous
• clumpy

6
Physical Characteristics of Precipitates

• Examples 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

7
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

8
Current Industry Efforts to Characterize
Precipitates

• Potency testing of precipitated SRW extracts
• Compare potency of precipitated final container
  extract to initial (release) potency value
• Protein Nitrogen Units (PNU), pH, phenol testing
  of precipitated extracts
• Compare PNU, PH, and phenol values of
  precipitated final container extract to initial
  (release) value

9
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
10
Precipitate Potency Data - SRW
Lot (110 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

11
Current Knowledge

• Aqueous extracts precipitate more than their
  glycerinated counterparts
• Aqueous SRW commonly precipitates
• Precipitates 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

12
Knowledge Gaps

• Physicochemical composition of precipitates
• Long 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?

13
Knowledge Gaps

• Administration 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

14
Current Research Areas

• Physicochemical composition of precipitates
• Potency 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

15
Current Regulatory Position

• No shipment of final containers exhibiting
  precipitates
• Development of in-house quality control programs
  (identify and describe precipitates)
• Validation of any re-processing procedures
  performed on precipitated extracts
• Modification of labeling to address precipitates
• Submit Biological Product Deviation Reports on
  precipitated lots to CBER

16
Summary

• Precipitates occur in allergenic extracts
• Aqueous extracts precipitate more than
  glycerinated extracts
• Almost all precipitated extracts unstandardized
• Knowledge gaps on precipitated extracts exist
• Collaborating with industry to fill knowledge
  gaps
• Prudent regulatory approach

17
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