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

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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

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• 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

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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

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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

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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

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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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