Controlling Particulates in Particulate Products. April 30, 2017 Carl Burke

Transcription

1 Controlling Particulates in Particulate Products April 30, 2017 Carl Burke

2 Reactions to Particles Granulomas Inflammation Infection Embolism Zero defects is a desired but not a pragmatic goal Particles are always present 2

3 FDA Biologics Recalls for Particulates Class I recalls - reasonable probability that use or exposure will cause serious adverse health consequences or death Blood filter devices contained fiber-like particulate matter consistent with filter material in the fluid path below the filter Vaccine has potential for a limited number of vials to contain glass particles Metallic particles partially embedded in the glass on the interior surface of the vial for an immune globulin infusion Visible particles were observed in an immune globulin infusion 3

4 FDA Pharmaceutical Recalls for Particulates Class I recalls - reasonable probability that the use of or exposure will cause serious adverse health consequences or death Small, dark particulate matter (iron oxide) in oxacillin injection Potential presence of particulate matter identified as glass in amikacin sulfate injection Particulate matter in bupivacaine injection Particulate matter in magnesium sulfate injection Particulate matter in sodium bicarbonate injection Visible particulate matter (microbial growth) in dextrose for injection Particulate matter in sodium chloride solution Glass particulate in preparations compounded with bupivacaine Potential contamination with glass particulate matter in amikacin sulfate injection 4

5 Environmental Particle Levels Cleanroom Classification ISO 5 Class 100 Grade A/B* ISO 6 Class 1000 ISO 7 Class 10,000 Grade C* ISO 8 Class 100,000 Grade D* ISO 9 Room Air * At rest Maximum Number of Particles ( 0.5 µm/m 3 ) 3,520 35, ,000 3,520,000 35,200,000

6 Particle Types Particle Type* Description Action Required Inherent Components of the formulated Characterized and monitor product over the shelf life Intrinsic Materials from the process or Control and minimize packaging Extrinsic Foreign sources Eliminate * As defined in USP <1787> Measurement of Subvisible Particulate Matter

7 Sources of Particulates for Biologics Particle Type Area Sources Inherent Cell debris and aggregation Stress during the process Source cell banks Intrinsic Extrinsic Process and equipment components and raw materials Manufacturing environment Cleaning validation Disposables (tubing, bags, filters) Primary container components Media and buffers Facility environmental control Operators/operations

8 Technically Unavoidable Particles Particles due to normal wear of equipment materials or routinely used gaskets, seals and filters Packaging component particles Color variation inherent to the product, due to heat or traces of lubricants Intrinsic components carried through from raw materials International Pharmaceutical Excipients Council

9 Particle Types in APIs Technically unavoidable particles (intrinsic) Atypical particles (extrinsic) Active Pharmaceutical Ingredients Committee 9

10 Challenges & Characteristics 10

11 Challenges with Particulate Products Control of particles in the final product when the product is particulate in nature Detection of particles in the presence of other particles Industry is gaining experience and guidances not yet established, so expectations based on existing products (e.g., clear parenterals) 11

12 Particulate Products Pharmaceutical suspensions Lowly aqueous soluble or lipophilic substances Lipidic suspensions Particulate suspensions Biological suspensions Alum adsorbed vaccines Live viral and bacterial vaccines Viral or bacterial vectors (for gene therapy) Lipidic suspensions (nucleic acid delivery) Cell-based therapeutics

13 Example Allogeneic Cell Therapy Process Harvest Cell Expansion Cell Bank Formulation Filling Inspection Cryogenic Freezing Restricted Time Window Combined Drug Substance and Drug Product straight-through process through filling Limited time once formulated for fill and inspection due to cell viability considerations Final sterilization/filtration not possible aseptic and closed processing 13

14 Cell-based Therapeutics Are Varied Cell requirements (dose) will depend on the application Types of cells can be different Autologous or allogeneic Pluripotent stem cells or non-differentiating cells Delivery Injection or implantation Device None (direct implantation or injection) Encapsulated in a unit with a porous membrane Specialized surgical application Ability to be inspected in its primary container

15 Comparison to Other Particulate Products (Submicron) Subvisible Visible um Protein Solutions (~0.01 um)* Inspection can be fully automated Clear solution Terminal filtration possible Lipidic Suspensions (0.1-5 um) Blood (~7-20 um) Cells (~20 um) Larger volumes of administration facilitate particle detection Exposed to less process steps and contact surfaces Vaccines (~0.1 um visible) * Not necessarily particulate but a common platform for comparison 15

16 Comparison to Other Particulate Products (Submicron) Subvisible Visible um Protein Solutions (~0.01 um)* Lipidic Suspensions (0.1-5 um) Terminal and intermediate filtrations possible Blood (~7-20 um) Cells (~20 um) Can filter some components late in the process Some inspected as lyophilates (different inspection process) Can leverage experience with large lots of particulate suspensions (alum) and previous experience Vaccines (~0.1 um visible) * Not necessarily particulate but a common platform often used to compare 16

17 Comparison to Other Particulate Products (Submicron) Subvisible Visible um Protein Solutions (~0.01 um)* Lipidic Suspensions (0.1-5 um) Blood (~7-20 um) Cells (~20 um) Limited time for inspection (nutrient conditions must be maintained) Re-inspection not possible Smaller batch sizes and limited lots to develop specs May be smaller volumes that limit detection Vaccines (~0.1 um visible) * Not necessarily particulate but a common platform often used to compare 17

18 Characteristics of Cell Therapy Products Translucent rather than transparent Terminal sterilization not possible Closed/aseptic process desired (like some vaccines) Material limitations lot sizes smaller Process time limiting due to cell viability cannot be re-inspected (unlike vaccines or other suspensions) Many disposables used in the process (bags, tubing, filters) Novel processes limited operational history and manufacturing experience 18

19 Guidances 19

20 Pharmacopeial Particulate Guidances (partial) (Submicron) Not applicable to suspensions, emulsions or gels Many guidances and standards exist, but not for cell therapy Subvisible USP <729> Globule Size Distribution in Lipid Injectable Emulsions USP <789> Particulate Matter in Ophthalmic Solutions USP <788> Particulate Matter in Injections PhEur Particulate contamination sub-visible particles JP XVII 6.07 Insoluble Particulate Matter Test for Injections USP <787> Subvisible Particulate Matter in Therapeutic Protein Injections USP <1> Injections and Implanted Drug Products (Parenterals) Product Quality Tests Visible um Exceptions for lyophilates, suspensions and highlycolored liquids USP <790> Visible Particulates in Injections PhEur Particulate contamination: visible particles JP XVII 6.06 Foreign Insoluble Matter Test for Injections 20

21 USP <788> Sub-visible Particles in Injections (Submicron) Subvisible Visible um 6000 / container 600 / container Difficult to apply to products that are particulate in nature, especially in or above these ranges Harmonized with: Ph. Eur Particulate contamination sub-visible particles JP 6.07 Insoluble Particulate Matter Test for Injections 21

22 USP <790> Visible Particulates in Injections Inspected units must be free from visible particulates when examined without magnification against a black background and against a white background. After 100% manufacturing inspection: Sample and inspect the batch using ANSI/ASQ Z1.4 (or ISO ). General Inspection Level II, single sampling plans for normal inspection with an AQL of 0.65%. Alternative sampling plans with equivalent or better protection are acceptable. Not more than the specified number of units contains visible particulates. 22

23 Other Particulate Guidances (partial) (Submicron) Subvisible FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Processes Visible um Visual Inspection Reference Guide American National Red Cross Canadian Blood Services Visual Assessment Guide APIC Guidance on Insoluble Matter and Foreign Particles in APIs IPEC Technically Unavoidable Particulate Profile Guide 23

24 Inspection & Acceptable Quality Limits 24

25 General Process for Visual Inspection Product Manufacture 100% Inspection Lot Rejection Perform AQL Test Lot Release AQL Passed No Yes Nonconformance Process Yes Time Exceeded No Lot Disposition

26 Cell Therapy Process for Visual Inspection Product Manufacture 100% Inspection Lot Rejection Perform AQL Test Lot Release No AQL Passed Yes Lot Rejection Yes Time Exceeded No Lot Disposition

27 Visible Particle Sizes (Submicron) Subvisible Probability of detection increases with particle size Less that 5% for a single 50 μm particle (threshold of human vision) Approximately 40% for a 100 μm particle Greater than 95% for particles 200 μm and larger Probability of Detection Visible um Automated detection of visible particles will also increase with increasing particle size RE Madsen et al., Pharmacopeial Forum 35(5), 2009 and reference cited therein 27

28 Challenges for Automated Inspection for Visual Particles in Cell Therapeutics Turbidity difficult to detect particles in the presence of other particulates (cells) and obscuration Small volume particles more difficult to detect in small volumes Lack of mobility - Narrow diameter of vial prevents much fluid motion with swirling making detection difficult Validation robust validation will require many, many lots (given the smaller lots sizes for CTs)

29 Semi-Automated Approach for Inspection of Cell Therapeutics Automated Filling and Capping Automated Cosmetic Inspection Scratches Crimps Fill volume Stopper Manual Visual Inspection Particles Cryogenic Freezing of Entire Batch Time constrained

30 Acceptable Quality Limit (AQL) An AQL is defined as: Level of acceptable nonconformance Defined as the quality level that is the worst tolerable in ISO It is: A measure of the integrity of the inspection process It is not: An indicator of the quality of the product lot itself A desired quality level 30

31 Determining AQL Criteria ISO2859 standard 1 Select inspection level Select lot size 2 3 Read code letter 5 Select AQL Read sample size 4 6 Read accept/reject criteria 31

32 Alternative AQL 0.65 Sampling Plans Lot size General Inspection Level III Sample Size - Minimum Acceptable Observations General Inspection Level II General Inspection Level I Special Inspection Level S-4 Special Inspection Level S , USP <790> For destructive tests (e.g., lyophilates, translucent containers) Some sampling plans are too restrictive for particulate products with limited manufacturing experience and inability to re-inspect since no observations allowed

33 Using existing guidances for all aspects of unestablished platforms USP <790> is just looking where the lamp is lighting

34 Considerations for an Inspection Strategy for Cell Therapeutics Cell-based therapeutics have the capability for 100% inspection of the total contents in the original container Unlike lyophilates or translucent/amber vials Special (reduced) sampling plans applicable to products that are clear when reconstituted or removed from container Not the case with some cell therapeutics May be applicable to others if placed in a device or implant Not all cell therapeutics are the same (amounts, delivery, process) Repeated or expanded AQL testing may be destructive due to time limitations Inability to repeat 100% inspection Balance AQL sampling size with additional time required for the AQL inspection

35 AQL Sampling and Acceptance Levels Lot size AQL Sampling under General Inspection Level II Minimum Acceptable Observations (AQL expressed as % nonconforming items) AQL 1.0 AQL 0.65 AQL , ,001-35, USP <790> Major defects (intrinsic, inherent) but not critical (extrinsic) particles Failure of AQL testing would trigger another 100% inspection for other types of products but would result in failure for a CT lot (due to inability to re-inspect) May select higher AQL for novel processes, especially entirely new sources of product contact and raw materials

36 Potential AQL Strategy for Visible Particulates for Cell Therapeutics Action Limit Specification AQL 1 (may be > 0.65) New process & equipment Limited process experience Manual inspection Small batch sizes Scale up process & equipment Limited process experience Semi-automated inspection Larger batch sizes AQL 2 AQL 3 Experience at manufacturing scale with many lots Phase 1/2 Phase 3 Launch Commercial 36

37 Visual Particulates Observed during Process Development of a Cell Therapeutic Increased particle control comes with better understanding of the process and improvements in operations, equipment and supplies Cellulosic Synthetic Other Synthetic Cellulosic Other Inherent

38 Control of Particles in Particulate Products Although still being at low levels and frequency of occurrence, the probability of the presence of visible particles is considered to be higher than for clear solutions after inspection Thus, a strategy for visual particulate inspection should be coupled with measures for mitigation, control and characterization to ensure an appropriate quality level. 38

39 Particle Control for Cell Therapeutics Subvisible Particulates Not readily detectable in the final product due to presence of much larger cells Visible Particulates Difficult to detect due to presence of cells/opaqueness, low volume and vial dimensions Characterize the process without cells to assess baseline particle load Establish training and control sets Perform 100% visual inspection Perform AQL inspection Use a predominantly closed process and facility environmental control to minimize particle intrusions Monitor and control particle loads on incoming raw materials and supplies Establish vendor procedures for a consistent quality approach

40 Particle Control for Cell Therapeutics Process Inspection Product Raw Materials, Components & Suppliers Process Operations Inspection Practice & Particle Characterization Observation before Administration Risk based on Administration Characteristics Materials control with supplier procedures & monitoring Filtration wherever possible Closed process and environmental controls Automation Non-cell runs to establish baseline particle levels Training and reference sets Increased visual inspection time Limited batch sizes and brief inspection window minimize inspector fatigue Trend data & re-evaluate AQL with experience Check at the point of device loading and administration Impact of device configuration and interaction Sensitivity of site of administration to particles Ability to monitor during administration or in vivo

41 Questions and Contact Information Carl Burke Janssen Research & Development Slide 41 #AAPSMeetings

42 Acknowledgements Ian Harris Fran Meacle Ken Vincent Don Powers Meredith Rice Tony Mastrobattista Katey Mader Natalie Tong Allen Callaway Jean Xu Julie Zhu Slide 42 #AAPSMeetings