CaSSS CMC Strategy Forum A Practical Approach to the Analysis and Immunogenic Potential of Aggregates and Particles

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1 CaSSS CMC Strategy Forum A Practical Approach to the Analysis and Immunogenic Potential of Aggregates and Particles January 9, 2011 Renaissance Mayflower Hotel Washington, D.C. Visual Inspection of Parenterals and USP Chapter <1>: An Update Russell E. Madsen President, The Williamsburg Group, LLC Chair, USP Visual Inspection of Parenterals Expert Panel

2 USP General Chapter <1> Injections Each final container of all parenteral preparations shall be inspected to the extent possible for the presence of observable foreign and particulate matter Inspection process designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates No inspection method is specified

3 Purpose of Visual Inspection Standard Define essentially free Inspection conditions Limits for visual particulate matter Effects of particles Emboli and granulomas Route of administration Recent data suggest particulates in IM and SubQ products can have a potent immunogenic effect, generating blocking antibodies that neutralize the therapeutic effect of the drug Advisory Panel was formed in April, 2008 Russell Madsen, Chair Scott Aldrich Mary Joan Hampson-Carlin Roy Cherris Mike Groves Steve Langille John Shabushnig Deborah Shnek

4 Fed. Std. No. 142a Basis for Proposal [1] Based on Int. Fed. Std. No , Parenteral Preparations (Aug. 1, 1959) Mandatory on all Federal agencies Applicable to human sterile parenterals in final containers Clarity of solutions and limits for visual particulate matter Black/white background, ft. candles, 10 in. from source Major A, Level II, AQL 1.0 Exception for some biological products for characteristic turbidity

5 Basis for Proposal [2] PDA industry surveys 2008 PDA Survey of Visual Inspection Practices Median value for the AQL for Major defects (most often associated with particulate matter) is 0.65% 0 inconsistent with essentially free (USP), practically free (Ph. Eur.), and readily detectable (JP)

6 USP Each final container of all parenteral preparations shall be inspected to the extent possible for the presence of observable foreign and particulate matter Inspection process designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates No inspection method is specified

7 Ph. Eur. Solutions for injection, examined under suitable conditions of visibility, are clear and practically free from particles Gently swirl or invert the container... and observe for about 5 seconds in front of the white panel; repeat the procedure in front of the black panel Record the presence of any particles

8 JP Unless otherwise specified, Injections meet the requirements of the Foreign Insoluble Matter Test for Injections <6.06> Unaided eyes, light intensity of approximately 1000 lx under an incandescent lamp Clear and free from readily detectable foreign insoluble matter Method 1 for solutions, Method 2 injections with constituted solution Plastic containers, unaided eyes, light intensity approximately 8000 to 10,000 lx

9 The Proposal [1] Test applied to product that has been 100% inspected as part of the manufacturing process it is insufficient for batch release testing alone Applicable to solutions and dry sterile solids for injection, when reconstituted as directed in the labeling Other methods with the same or better sensitivity may be used as an alternative

10 The Proposal [2] Injections shall be clear and free from visible particulates when examined without magnification (except for optical correction as may be required to establish normal vision) against a black background and against a white background with illumination which at the inspection point has an intensity of between 2,000 and 3,750 lux Higher illumination intensity is recommended for examination of product in containers other than those made from clear glass

11 The Proposal [3] Prior to performing the inspection, remove any adherent labels from the container and wash and dry the outside The unit to be inspected shall be gently swirled, ensuring that no air bubbles are produced Inspect for approximately 5 seconds against each of the backgrounds The presence of any particles should be recorded

12 The Proposal [4] Batch release purposes Sample and inspect the batch using ANSI/ASQ Z1.4 General Inspection Level II, single sampling plans for normal inspection, AQL 0.65 Not more than the specified number of units contains visible particulates Product in distribution Sample and inspect 60 units Not more than one unit contains visible particulates

13 Visual Inspection Standard PF 35(5) [Sept.-Oct. 2009] Visible Particulates in Injections A History and a Proposal to Revise USP General Chapter Injections <1> Expert Panel Meeting/Webinar May 19, 2010 to discussion comments received Discussion Points Applicability of the proposed inspection technique and limits to LVPs Lyophilized and powder injections Biotechnology protein-based injections Confusion relative to the term product in distribution Differences, if any, regarding inspection for intrinsic and extrinsic visible particles

14 Visual Inspection Standard USP reached out to the FDA to discuss their current concern regarding proposed standard (Invitation was declined) Many variables to considered with regard to the product, packaging, and nature of the particulate matter making it difficult from a regulatory standpoint to establish a single standard. Recommends: Informational chapter that discusses difference between intrinsic and extrinsic particulate matter, methods of inspecting different dosage forms and characterization of the particulate matter if any is found. Feedback from Stimuli Article and May 19 th Meeting was used to revise proposal Visual Inspection Expert Panel Recommendation: Publish revised Visual Inspection Proposal In PF

15 Revised Visual Inspection Proposal [1] Significant changes from the proposal contained in Pharmacopeial Forum Vol. 35(5) [Sept. Oct. 2009] For products such as those derived from proteins, that may contain intrinsic particles or agglomerates, requirements for visible particulates are contained in the individual monograph The unit to be inspected shall be gently swirled and/or inverted

16 Revised Visual Inspection Proposal [2] Product at the manufacturing site Sample and inspect the batch using ANSI/ASQ Z1.4 General Inspection Level II, single sampling plans for normal inspection, AQL 0.65 Not more than the specified number of units contains visible particulates Reevaluation of product shipped to customers (complaint, regulatory concern, etc.) Sample and inspect 20 units Essentially free if no particles observed If one unit contains particles, sample and inspect an additional 80 units Essentially free if none of the additional 80 units contains visible particulates

17 Thank you