Particulates in allergen extracts

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Particulates in allergen extracts
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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)

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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

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Precipitated SRW Extract
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Precipitated SRW Extract
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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

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Current Regulatory Position

• No shipment of final containers exhibiting
  precipitates
• Development of in-house quality control programs
  (identify and describe precipitates)
• Validation of any reprocessing procedures
  performed on precipitated extracts
• Modification of labeling to address precipitates
• Submit Biological Product Deviation Reports on
  precipitated lots to CBER
• If no approved license supplement in place for
  reprocessing or reworking of precipitated
  products, one should be submitted

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Dosage and Administration section 21 CFR 201.57
(j)

• Parenteral drug products should be inspected
  visually for particulate matter and discoloration
  whenever solution and container permit.

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Recommended additions to Description,
Warnings, and Dosage and Administration

• A statement indicating that precipitation occurs.
• A description of the typical appearance of the
  precipitant.
• A statement that precipitated extracts should not
  be used.

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Summary

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