Particular about particulates Gaelle Davies Lead QP Porton Biopharma Limited Presented at Pharmaceutical and Healthcare Sciences Society QP Forum Conference in association with PQG 07 November 2019 (Slide deck updated Aug 2020) Breacon, UK
Particular about particulates
Gaelle DaviesLead QP Porton Biopharma Limited
Presented at Pharmaceutical and Healthcare Sciences SocietyQP Forum Conference in association with PQG07 November 2019 (Slide deck updated Aug 2020)Breacon, UK
Overview• Issue with particulates in Erwinase
• Investigation
• Impact on PBL
• Implementation of new stopper
• Current situation
2Particular about particulates
Erwinase
• Erwinase is aseptically filled into 3mL glass vial, stoppered and freeze dried
• Manual 100% visual inspection (20 000 vials)
• Inspection conditions controlled (e.g., time, background, light intensity)
• Defects sorted into categories according to attribute (e.g., defective vial,
particulates)
• Visual inspection data compared with action and alert limits
• Following completion of the inspection, independent QA AQL
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Erwinase batch 174 (manufactured 2015)
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• Particulates action limit exceeded
• 15 % defects after 1st inspection
• Black marks on the stopper
• 3 x 100% visual inspections
• 28% of vials affected by the defect
• Industry expectation <1% particulates
Defect examples
5Particular about particulates
• Vials opened• Moveable defects
• Stopper marks
• Unable to confirm visually
Investigation observations• Analysis: “Subvisible accumulations of stainless steel particulates”
• Erwinase batches affected with varying degrees of severity
• Defects all visibly similar (consistent with analysis on batch 174)
• Defects adhered to the stopper (under silicone oil but not embedded)
• FMEA of PBL processes (receipt of materials, filling, freeze drying, capping)
• Improvement areas identified - metal to metal friction originating from the
equipment but…
• FMEA and PBL investigation did not explain the levels of particulates seen
on the stoppers
6Particular about particulates
Stopper manufacturer• PBL investigation concluded particulate matter in Erwinase drug product
likely due to incoming ‘ready to use’ stoppers
• Raised complaints and sent samples, held teleconferences: manufacturer
investigation did not support the complaint
• Unwilling to perform thorough RCA
• After 18 months, confirmation that a sample containing the typical defect
contamination originated from the manufacturer
• Visits to stopper manufacturing site eventually agreed
• Declined use of alternate supplier site for supply
7Particular about particulates
Impact on PBL• Multiple inspections of batches, failed AQLs, high reject rates, loss of product to
patient
• Robustness/application of the inspection method
• Inspection for more than 5s on each background?
• Defects identified particulate material or stopper marks?
• Discussions on size of defects seen (cannot unsee)
• Regulatory discussions: BSV, regulatory discretion
• Involvement of third party expert in particulates and VI to optimise the process
• Multiple investigations
• Gap between stopper manufacturer specification and pharma’s “essentially free”
from particulates
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Detection of particulates
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Measures implementedPBL:
• Increased incoming stopper inspection: 1 in every 4 bags tested
(destructive)
• Multiple ordering, use best batch of stoppers (lowest particulate profile)
• Plan to implement FMEA actions
• Multiple 100% inspections on drug product
• Precautionary instruction to use filter
• Regulatory discretion for batch release
10 Particular about particulates
Measures implemented Stopper manufacturer:
• Upgraded workshops, new wall coverings and optimised ventilation in the
compression area (not specifically in response)
• Introduction of camera aided inspection of stoppers
• Increased the sensitivity of the camera aided inspection when above action
failed to detect
All measures were ineffective
11 Particular about particulates
Implementation of new stopper• Identified supplier, performed machinability, compatibility trials, process
simulations
• Erwinase short supply, lengthy manufacturing process, life saving drug,
could not put 3 batches on stability, wait for data and release
• MHRA and FDA involved with the process: Type 2 variation, PACMP
submission
• Manufacture of 3 PPQ batches with concurrent release protocol
• Release on 1 month stability (accelerated and real time)
• First batch manufactured with new stopper, level particulates typical for the
process
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2020 updates follow
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Transition to new stopper
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Status up to CAMR 201
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• 13 batches manufactured with the new stopper
• All showed low level of particulate defects
• Confident and well trained VI team
• VI process is fully revised, aligned with industry and effective
• Adjustment of the VI criteria with help of consultant :
• Patient focussed critical, major, minor classifications with associated AQL levels
• Introduced opening of vials to confirm validity of visual assessment
• Allows for clear classification between genuine particulates and marks
• Established a library of all VI defects
• New microscope for assessing defects
But…..CAMR 202: detection of elevated levels of fibres.
• Inspection identified the presence of cellulose fibres
• Paused manufacture of subsequent batch
• Assessed each potential route of fibres to the product
• Identified wipes used throughout the process were not optimal, may be
leaving fibres in the process
• Potential for material deposited on the filling equipment (one off event)
• Filled CAMR 203 when confident
• CAMR 203 has a very low level of particulates (0.2%), demonstrating the
investigation was effective in addressing the issue promptly.
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