Introduction regarding aggregate/particle issues in biopharmaceuticals. Yasushi Shikata Eisai Co., Ltd.

Transcription

1 Introduction regarding aggregate/particle issues in biopharmaceuticals Yasushi Shikata Eisai Co., Ltd.

2 Activities at biopharmaceutical committee of JPMA

3 Basic question regarding aggregate/particle Pharmaceutical company in Japan vs USA/EU; USA subsidiaries vs Japan head office in Japan pharmaceutical company; Individual variation Differences in: (1)regulation regarding aggregate/particle among the US, EU and Japan? (2)understanding level to Japanese regulation regarding aggregate/particle? (3)how the risks are handled at each area? Should the criteria depend on the types of biologics? mab vs vaccine product

4 JP, USP and Ph.Eur. Foreign Insoluble Matter Japan JP 6.06 Must be clear and free from readily detectable foreign insoluble matters. USA USP<1> Essentially free from particles of foreign matter that can be observed on visual inspection EU Ph.Eur Visible particles consisting of extraneous, mobile undissolved particles, unintentionally present in the solutions. Record the presence of particles Insoluble Particulate Matter ICH Q4B Annex 3 Analytical procedure (JP 6.07, Ph.Eur , USP <788>) : Interchangeable Acceptance criteria: Interchangeable (except for 100 ml)

5 What impact on visual inspection? Visible insoluble matter include materials derived from foreign matter and product. Operator s condition: eyesight level, eyestrain degree, farsightedness degree etc. Particle characteristics: particle size, shape, color, transparency, density level and particle source Observation condition: light intensity, observation time, distance for seeing, background, rotation method (manual or automatic), rotation speed etc. Container materials used Location of particle in a container (floating in liquid solution or attaching to the container wall or closure)

6 Questions on particle (1) Definition 6.06 Foreign insoluble matter test for injection Question: Just foreign? Visible and visible/invisible? Nondestructive inspection? Definition of Foreign insoluble matter for injections in Japan Pharmacopoeia (JP) 6.06 Just foreign insoluble matter Both foreign and endogenous insoluble matters Acceptable range of free from readily detectable foreign insoluble matters in Method 1 of JP 6.06 Acceptable range of free from foreign insoluble mattes that is clearly detectable in Method 2 of JP 6.06 Detectable insoluble matter Acceptable range set

7 Questions on particle (2) In-line filter Advantage and disadvantage of inline filter Utilization of inline filter to remove fibrous particle in drug product Put the filter or not? For IV, SC, IM? Risk of infection All components passing through the filter? Validation method?

8 Questions on particle (3) Test method Test method for aggregate/particulate Appropriate test method for aggregate/particle SEC, DLS, FFF, AUC, HIAC, MFI, other test methods

9 Questions on particle (4) Stability study Should stability study for drug product be designed considering worst case regarding storage condition and transportation way from the view point of robustness? Temperature freeze-thaw Storage duration Adsorption Sensitivity to agitation

10 Testing frequency in stability study etc. Testing frequency regarding insoluble particulate mattes (JP 6.07) in stability study for a registration application All time-points specified in ICH Q5C Limited time-points Not included Storage duration of drug substance used for drug product filling Recommendation by FDA draft guidance (Feb 2013) Assessment of SVP (2-10 microns) of protein product initially and over the course of shelf-life

11 Issues Questions (5) Highly concentrated product Precipitation after administration Appearance (opalescence, particle, color etc.) Concentration to prepare highly concentrated product without aggregation and/or degradation Characterization as it is without dilution Filling of high viscosity liquid in a vial at high speed Dispensation of high viscosity liquid in a syringe

12 Management of possible immunogenic factor Appearance of ADA (Anti-drug antibody) Hypersensitivity reaction, loss of efficacy, shorten the halflife, neutralization of endogenous protein Possible immunogenic factor Product origin (epitope, sugar chain derived from nonhuman, aggregate/fragment, oxidized product, denatured product etc.) Aggregate/particle (size, shape, quantity) Impurity (host cell protein, DNA, resins etc.) Leached or extracted materials from container/closure Product-excipient adducts Patient specific (dosage, administration route, patient specific immune system etc.)