Industry Perspectives on Visible Particle Requirements and Practices An overview of EBE position paper. S. Mathonet on behalf of EBE

Transcription

1 Industry Perspectives on Visible Particle Requirements and Practices An overview of EBE position paper S. Mathonet on behalf of EBE CASSS CMC Strategy Forum EBE satellite session Sorrento May 5, 2014

2 2 Primary goal of the EBE position paper Problem statement: An acceptance criterion of no or free from or without visible particles is recognised as totally unrealistic Define and justify «Practically Free from Visible Particles» as acceptance criteria for products effectively free of visible particles for biotech products (focus on recombinant antibodies) As exception, define and justify acceptance criteria for products containing low level of protein particles Provide an insight into current industry practices and reach consensus on minimum requirements and best practices for visual inspection

3 3 EBE position paper layout Position Paper Layout 1. Problem statement 2. Visual Inspection at end of DP manufacturing 3. QC sample testing a. Release testing including discussion on sampling plan and size b. Stability testing including discussion on sampling plan and size c. Acceptance criteria and justification Drug Products effectively free from particle Drug Products containing low level of proteinaceous particles 4. Proteinaceous particle characterization 5. Patient safety 6. Continuous Process optimization and Conclusion Annexes Inspector certification Risk assessment and ranking of particle defects Sampling Plans Literature references

4 Focus of the presentation: Defining Practically Free from Visible Particles - Guiding Principles 4

5 Pharmaceutical development Commercial formulation and process design Fulfilling multiple TPP goals in formulation design may represent a challenge in achieving a formulation devoid of protein particles - e.g. sub-cutaneous liquid formulation with high concentration protein solutions ph, osmolality, viscosity, soluble aggregates, opalescence, coloration and sub-visible/visible particles, syringeability / Injectability when TPP includes delivery device It was however agreed in the EBE Visible Particle Sub-Group discussion that visual appearance including visible particle free formulation was a main objective for formulation design Evaluation of process holding times and processing conditions that may bring stress to the protein including formation of protein particles should be considered in process design 5

6 Visual Inspection process Fillling into container Number of repeat to be justified in Quality System Rejected Part of the batch 100% Visual Inspection AQL Visual Inspection (statistical sampling) Visual Re- (3) Inspection 100% of accepted part Batch rejection Fail (1) Accepted Part Pass Fail (2) Investigation Mode/ Re-inspection Batch rejection (1) Rare random occurrence of single source particle (2) Obvious particle reflective of systemic failure (3) As per company-specific QA procedures 6 Rejected Part of the batch QC release Visual Inspection Small sample subset (leverage AQL results when justified) Rejected Part of the batch Periodic Trending of Visual Inspection data (Reevaluate what s Normal and limits) QC Stability Visual Inspection Small sample subset Batch release Non conformance investigations Pass

7 100 % visual Inspection 100 % inspection is a unit operation after filling. It can be manual, semiautomated or fully automated. Every filled units (100%) are visually inspected for critical, major and minor defects including particles In 100% inspection, for products practically free of visible particles, any unit with visible particle defect irrespective of its nature is discarded. It applies to liquid and lyophilisate For liquid formulations, protein particles are typically sorted during 100% inspection not being differentiated from other particles Visible Particle Defect rate ((i.e. maximum visual defects in % of whole batch filled) criteria should be in place as representative of the commercial process 7

8 100 % visual Inspection Inspection conditions defined in EP (and USP draft) monographs are:- 2,000-3,750 lux- Black and white backgrounds- 5 sec viewing against each background. The threshold of visibility depends on many parameters and can range from ca. 50 to 400 μm, with different detection probability Detection of visible particles is a statistical process, in daily practice, the detection limit very much depends on: - Individual operator, - Inspection system and Inspection time - Morphology, number and refractive index of the particles, rheology and opalescence of the solutions as well as other factors. Companies may use other, non-ep methods to improve the sensitivity or ergonomics of the process i.e. use of aids such as magnifying glasses or differences in lighting conditions or observation times and swirling procedures. These conditions may have a pronounced effect on reject rates. 8

9 AQL Inspection AQL testing is done to confirm the quality of the product and to confirm the efficiency of the 100% visual inspection to remove defective product. Inspectors should be independent from those that did the initial inspection Particle in solutions are at least a major defect in most companies. Lowest Acceptable Quality Level applied across companies is 0.65%. If AQL is exceeded, 100 % inspection may be repeated as per company specific QA procedures Occasional random occurrence is an important concept for visible particle defect. - A batch may be passed if within the AQL criteria - Any AQL failure may generate 100% re-inspection of the accepted part of the batch and a repeat of AQL testing. Companies should define and justify number of repeat in their own quality systems (usually not more than 2 cycles of re-inspection) 9

10 AQL Inspection Manufacturers are expected to have calculated the capability of the commercial fill / finish process and use this capability to set alert / action limits for the whole defect rate compared to filled units (batch size) - When these alerts limits show special cause for variation in the process, additional AQL samples may be required to provide additional assurance of quality Any obvious visible defect issues with regards to nature of particles and representing a systemic failure (insect wing, rust, paint, hairs, ) will lead to an investigation/re-inspection - The investigation should evaluate aseptic processing conditions and potential for sterility breach, systematic failure may lead to batch reject 10

11 QC Release Testing Option 1: Leverage AQL testing (Real Time Release Testing) - QC Batch Release testing may take the AQL testing results into account and can determine the AQL result as sufficient and appropriate to confirm the specification of practically free from visible particles e.g. for iv/sc liquid formulations in vials or prefilled syringes - This approach requires that the AQL inspectors are trained to the same level as QC and/or Manufacturing inspectors - The competent authorities (GMP Inspectorate) may allow the AQL testing as a release test, within scope of inspection during MAA or variation review, as required - Furthermore, by describing the RTRT approach on the drug product specification, a product manufactured in a non-eu country without MRA may have relief from repeat testing on importation into the EU? 11

12 QC Release Testing Option 2 Separate QC testing - Especially if destructive method is involved such as reconstitution of a lyophilised powder, sample size considerations need to take this fact into account QC testing of a small subset of the batch (e.g. 20 units / justified sample size) and acceptance criteria based on processing capability and packaging component is sufficient Reconstitution procedure should be carefully designed - When visual inspection is required as part of QC testing for liquid formulations, similar sample size considerations apply as for lyophilisates - When the integrity of the sample is not impacted by the testing (non destructive), reuse of sample for other testing is acceptable as long as the sample handling and testing conditions are shown not to effect the product quality 12

13 QC Release Testing (prefilled pen injectors) PFS may be inspected for visible particles, prior to assembly, if container integrity during assembly is warranted, since - the pre-filled primary container for the biologics cannot be easily removed: e.g. the device assembly components lock the PFS inside - the inspection window in a device might not always be fully adequate for a visual inspection of particle and cannot be qualified for this use - disassembly may impact the container closure integrity and create other cosmetic defects such as scratching that could impair visual inspection Similar proposal is recommended for other assembled biologics/ device combination products 13

14 QC Stability Testing Different practices across companies - For Practically free from visible particles, it is acceptable to test a subset of samples (justified sample size) using EP / USP draft monographs visual inspection method and acceptance criteria justified based on product history (with e.g. random occurrence of single source particle) - Some companies do not specify Visible Particle in shelf life specification but visible particles are still monitored in stability storage with a semiquantitative assay E.g. based against a set of standard vials containing defined level of particle defect with different number of particles presence of visible particles yes/no plus particle count) - FlowImaging replacement on visual inspection - hot debate! Sensitivity (instrument based versus eye) Influence of instrument setting/sample handling Precision Characterization or QC tool? 14

15 QC Stability Testing Same stability samples (for non-destructive testing of a liquid product) may be used for all time-points tested or separate units are inspected per timepoint Using the same stability samples provide an advantage being able to monitor a possible increase / appearance of particles over stability e.g. stemming from interactions of formulation and primary packaging, protein particles etc. However, it must be confirmed that the inspection procedures and related handling (e.g. temperature differences) do not impact visual inspection results More discussion needed on stability testing in EBE Visible Particle Topic Group! 15

16 Particle Characterization during product development or non-conformance investigations Identification of the origin of the particle(s), from the environment, product, packaging components or process is required to support risk management in control strategy and drive CAPA The identification of the whole particle population in a unit or even all units present challenges Limited sample size (e.g., thickness, size, mass of a particle and/or number of particles), changes to the chemical signature (e.g., by heat impact during manufacture) and the destructive nature of certain analytical techniques ( one shot on at the goal ) add to the challenge of particle identification - A key challenge is isolation of particles, especially single particle around 150 micron. Some inherent protein particles are fragile to filtration and may permeate the filter or even return back into solution. No agreement in the EBE Visible Particle Topic group yet on inherent, intrinsic, extrinsic particle categorization 16

17 Particle Characterization during product development or non-conformance investigations A toolset of various (complementary) analytical techniques provides the best opportunity to characterize particles, particularly protein particles (Microscopic techniques, Mass spectrometry, FTIR, Raman spectroscopy, SEM-EDX) The identification of visible particles is suggested to be focused on individual investigations and not be considered for routine or QC testing - companies have succeeded however in setting a specification allowing some level of protein particles that have been characterized and assessed during clinical trials Will be addressed in case studies 17

18 Conclusion: Justification of «practically free» acceptance criteria in Clinical/Commercial filings A suitable justification for the practically free from particles could include a definition on the intent of the specification and a brief outline of the manufacturing controls in place to control for visible particles including the 100% inspection and AQL to ANSI/ASQ Z1.4 or ISO , equivalent standards or better testing A holistic approach to control might be taken from raw materials through to finished product When particles detected under the practically free from particles specification, trigger a non-conformance process, the level of nonconformance and investigation route would depend on the assessment of the particle (nature and frequency of occurrence). The product history for detection, identification and characterisation of visible particles should be documented 18

19 Acknowledgements Thanks to all EBE Visible Particle Topic group contributors - Sharon Adderley, Manufacturing Science and Technology, Analytical Science, Pfizer - Patricia W. Cash, Analytical Biotechnology, MedImmune - Stefan Esswein, NBE Analytical R&D, Abbvie - Christof Finkler, Analytical Development & Quality Control, Pharma Technical Development Biologics EU, F.Hoffmann-La Roche Ltd, Basel, Switzerland - Andrew Lennard, Regional Regulatory Affairs CMC, Amgen - Georg Kallmeyer & Hanns-Christian Mahler, Pharmaceutical Development&Supplies, Pharma Technical Development Biologics EU, F.Hoffmann-La Roche Ltd, Basel, Switzerland - Maryam Mazaheri, Analytical Biotechnology, Medimmune - Klaus Wuchner, PDMS Analytical Development, Janssen R&D 19

20 Backup Slides 20

21 Inspector Certification Effective inspector selection, training, and monitoring necessary for a reliable and consistent visual inspection program - Certification of visual acuity and technical expertise that includes the ability to detect particulates in test panels An inspector must be able to detect a predefined amount of defects (without detecting a maximum amount of false positives ) in order to be qualified. Inspector must be re-qualified in regular intervals Ideally, the same principle of training and monitoring shall be applicable to all personnel performing visual inspection for visible particles be it during manufacture as part of 100% manual inspection, AQL testing, QC release and stability testing, QA reserves/retention and product complaints Different company practice- This Annex still heavily discussed in the EBE Visible Particle Topic Group! 21

22 Inspector Certification Training Process for Inspector - Introduction to general visual inspection method Different company practices - If a defect (incl. particle) library is available a demo of typical defects should be performed - Demo of visual inspection method by trainer - Demo of sample handling and handling (e.g. agitation) method, according to predefined SOP - Introduction to defect categories as per predefined SOP - Proficiency runs using appropriate test panels (qualification defect test set) for the process and product, as many as required - Independent Performance runs with defined acceptance criterion level for particle defects Company specific 22

23 Inspector Certification Maintenance and Monitoring of Visual Inspector - A minimum of procedure review and assessment in regular intervals. - A minimum of annual inspector assessment ; compliance to SOP and ability to detect defects - Eye exams must be performed in regular intervals - Inspector must be re-qualified at regular intervals to be considered a qualified visual inspector. 23