Particles in Parenterals PLUS Container/-Closure-Integrity Testing Conference

Programme

Container/Closure Integrity Testing, 10 October 2017, Vienna, Austria

Container Closure Integrity testing of sterile drug products – requirements, expectations and exaggerations

• Container Closure Integrity during Development, Qualification and Stability Testing
• Regulatory, Pharmacopoeial and GMP requirements
• System integrity versus container damages
• Patient risks – do we need batch by batch testing?
• Industrial best practices

Overview of container/closure integrity testing technologies
The presentation gives a comprehensive overview about current CCI technologies and techniques. It focuses in the first part on physical fundamentals of the different testing methods

• Pressure / Vacuum Decay
• LFC (Liquid Filled Container) leak testing
• TDLAS/ HSA (frequency modulated spectroscopy)
• High Voltage leak testing
• 3µm IR and Mass-Spectroscopy
• Force Detection

In the second part criteria or a selection matrix for test methods related to the product requirements and properties including primary container type, product properties (liquid, lyo, etc.) is presented. The main topics here are as follows.

• Inline versus sample testing
• Limits and false acceptance traps
• Leak sizes and leak rates (false friends and measurable properties?)

Modern Blue Dye Testing – still the standard CCI method?

• Regulatory requirements and subsequent test method in industry
• Critical method aspects, e.g. process monitoring
• Perspective and limits in context of product life cycle

Integrity testing of Prefilled Syringes

• Sampling plan
• He-leak testing
• Limitations of the He-leakage test
• Cross Validation with mCCI

100 % inline CCI testing of ampoules

• High Voltage inline testing: method description
• Integration in the production process
• Limits of the system
• Qualification of the system
• Validation
• Routine Operation

Case Study: 100 % inline testing of Lyo Vials

• System setup
• Validation
• Routine operation

Particles in Parenterals, 11-12 October 2017, Vienna, Austria

Regulatory Requirements for the visual inspection of parenterals

• Compendial Requirements: 100 % visual inspection & AQL testing, PharmEur, USP, JP - similarities and differences
• GMP Expectations : Manual inspection, Automated Inspection
• Risk Management Considerations

Presentation and discussion of the ECA Best Practice Paper on Visual Inspection
The best practice paper has been originally developed by the advisory board of the ECA Visual Inspection Group. Much rather than a strict requirement document, this paper is intended to be a reference for controversial issues. The first version of this paper has been published in September 2014 in Copenhagen. It has gained a broad acceptance in the industry afterwards. The current version as well as planned updates will be explained and discussed in Vienna.
FDA’s current thinking on particles and testing of parenterals

• A summary of recent recall data due to visible particulates
• The FDA’s take on AQL testing
• Training and qualification of visual inspection staff
• Automated inspection validation
• A lifecycle approach to visible particle inspection and control

Particles in Parenterals: Methods for the root cause analysis

• Isolation of single particles
• Analysis of particles using FTIR, REM-EDX, and ICP-MS
• Usage of witness-wafers
• Intrinsic particles and their origin
• What can we learn from aerospace research.
• Examples

Qualification in manual visual inspection in a multi-product environment

• Defects and defect categorisation in the manual visual inspection of vials and ampoules
• Composition and qualification of test sets
• Initial qualification of human inspectors
• Bracketing of products in the context of the qualification of human inspectors
• Requalification and continuous evaluation of the inspectors performance
• Maintaining the qualified state of the test sets

Validation of an Automated Inspection System - Alternative Ways for the 5000 Test

• General requirements: Requirements of the Pharmacopeia, Defect categorisation. Test kits for training, qualification and routine
• Manual Inspection: Training and qualification of manual operators, Standardisation of working conditions, AQL in the manual inspection
• Automated inspection: Setup of the vision system, Qualification of the machine in 3 steps, Detection verification using probabilistic models (i.e. Knapp-Test / Particle-Qualification-Kit), Detection verification using fixed detection rates (i.e. Standard-Defect-Kit), Man-machine-comparison during production run (test of 5000), Alternatives for the test of 5000
• Others: System-Suitability-Test, requalification and revalidation

Visual Inspection and Health Authority Expectations & Observations

• Observation at the AIM qualification
• Comments to the 5000 test
• Dealing with particles & complaints

Particle testing and the correlation with trending and Batch release

• Why do we Monitor (What is it all about)
• Data and Measurement
• The AQL trap
• Improvement Process Map
• Investigation and Routine Analysis,
• Release Process. “To AQL or not to AQL that is the Question”
• Product Release: “Falling off a log”

Particles in Biotech Parenteral Products

• Particles are a major challenge in the development, manufacture and analysis of Parenteral Products
• The Pharmacopeias and guidances aim towards minimizing visible particulates, yet, the requirements not easy to translate into everyday practice
• Particles can come from different sources and USP has suggested a categorization with particles being extrinsic, intrinsic or inherent, yet, clinical relevance and safety of these would not be necessarily different and identification is often not unambiguous
• This talk aims to discuss approaches and practicality and industry perspective on Visible Particles in Parenteral Products containing active ingredients derived by recombinant manufacture (biologics)

Threshold testing between inspection method development and setup of a qualification set

• Concepts for planning threshold tests
• How to design the test to be representative for routine manufacturing conditions
• Transformation of a threshold test into a qualification set
• Other good use of threshold test (results)

(Re-) inspection of parenteral products
Different scenarios will be covered such as:

• Re-inspection or additional inspection of “grey-chanel” units from (semi-) automated inspection
• Re-inspection in case of exceeding alert limits or AQL failures
• Focused re-inspection
• Inspection approaches in case of investigations due to unexpected particles (e.g., to determine frequency of occurrence of visible particles when particles are found during release/stability testing

Development of a tool for determining the criticality of particles

• Defining the appropriate AQL level for specific particles