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Particulates in allergen extracts

Particulates in allergen extracts. Historical Perspective. Precipitates recognized for many years Early efforts (1970’s) by industry to characterize precipitates Physical descriptions Solubility properties Early efforts by industry to remove precipitates

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Particulates in allergen extracts

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  1. Particulates in allergen extracts

  2. Historical Perspective • Precipitates recognized for many years • Early 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)

  3. 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

  4. Precipitated SRW Extract

  5. Precipitated SRW Extract

  6. 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

  7. 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

  8. 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.”

  9. 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.

  10. 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

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