Control of Parenterals
Container-/Closure-Integrity Testing & Visual Inspection Systems
Im Auftrag der ECA Academy

Control of Parenterals Container-/Closure-Integrity Testing & Visual Inspection Systems Im Auftrag der ECA Academy

Vienna, Austria

Seminar Nr. 16874


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Rückfragen unter:
Tel.: 06221 / 84 44 0 E-Mail:


Dr Martin Becker,  Siegfried Hameln
Klaus Boje, Boehringer Ingelheim
Dr Helmut Gaus, Winsol, previously  Boehringer Ingelheim
Christoph Herdlitschka, Wilco
Felix Krumbein, Roche
Christof Langer, OSConsulting
Dr Tobias Posset, Roche
Dr Bernd Renger, Immediate Past Chair of the European QP Association


Container/Closure Integrity Testing of Parenterals:
Different products and different container types require different testing methods: this event aims at giving an overview of the different CCI testing systems which are applied during production and as part of the quality control system. Apart from technical aspects the regulatory requirements on CCI testing will be highlighted as well as the applicability of inline and offline testing.

Visual  Inspection Systems:
Main topic of this course is the detection of defetcs like particles in injectables and their evaluation during batch release. Besides the current regulatory requirements with regards to particulate matter, routine 100% inspection of injectables will be addressed. Manual inspection as well as automated inspection systems will be covered, including validation, training, defect categories, AQL testing, trending and batch release considerations.


Container/Closure Integrity Testing of Parenterals:
An intact container closure system, which is the sum of packaging components that protect the dosage form, is the pre-requisite for a safe and sterile drug product. The CC system protects the product from microbial contamination and also from exposure to gases or water vapour or the loss of solvent. Container Closure integrity testing is therefore a regulatory requirement and it is part of the whole life cycle of a sterile drug product.

Initially this testing was performed as part of the initial development of the packaging system and the system’s suitability verified in stability studies including on-going stability.
Over the years, the expectation was raised to perform batch by batch verification with latest trends to 100% inline or offline testing wherever possible.

We will discuss and answer questions like:
  • What are the current and upcoming GMP and compendial requirements in the US / EU / RoW?
  • Will container closure integrity testing change to
  • 100% inline testing?
  • How do we have to define tight?
  • Which testing technologies are available and suitable?
  • Is blue dye testing still a standard? And how does modern blue dye testing look like?
  • CCI testing of prefilled syringes
  • CCI testing of lyo & liquid vials
  •  CCI testing of ampoules
Visual Inspection Systems:
In most cases particles found in parenteral medicines will lead to a quarantined product or even to the recall of the product – as we have seen in the last years in the cases of several pharmaceutical companies. Responsible staff in charge will have to start root cause analysis to find the source of the particles and will have to do an evaluation of batches already shipped.

There is still confusion within the global pharmaceutical industry with regard to the requirements for testing for visible particles. After the USP chapters <790> and <1790> were published, things have become much clearer, at least for the US. But still, lots of questions arise, e.g. concerning re-testing, detection capabilities and revalidation of inspection systems.

Furthermore there has been a recognisable trend towards automated inspection machines throughout the last years. The challenge for pharmaceutical companies is to find a suitable machine for their products and to determine reasonable inspection parameters during qualification and validation. But also during routine process there are questions arising like re-testing and the usage of test-sets, doing AQL-Testing as well as the adjustment of parameters of the vision systems.

We will address those topics during the conference and discuss and answer questions on
  • The latest compendial requirements concerning particulate matter
  • Training in the manual visual inspection
  • Qualification and operation of an automated inspection System
  • Trending and monitoring of visual inspection data
  • Correct AQL testing as part of the batch release
  • Re-inspection of defect fractions
  • Root cause analysis in case of particulate matter


All participants receive the current version of ECA’s Best Practice Paper on “Visual Inspection” for free.



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 complete overview of the different aspects of leak testing to do CCIT in the pharmaceutical production. The systems presented can be used for the CCIT of Vials, Ampoules, Syringes, BFS, IV Bags, Blisters etc.
  • Leak, Leak rate and the relevant physical units
  • Leak Test Methods
    • Pressure change methods (vacuum, pressure and LFC)
    • Head Space Analysis using TDLAS
    • Helium Leak Test and other Mass Spectroscopy Systems
    • High Voltage Leak Detection (HVLD)
    • Force Sensing Technology
  • Capabilities and examples of the different Methods
  • How to select the right method
  • How to generate positive controls
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
Case Study: 100% inline testing of Lyo Vials
  • System setup
  • Validation
  •  Routine operation
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
Integrity testing of Prefilled Syringes
  • Sampling plan
  • He-leak testing
  • Limitations of the He-leakage test
  • Cross Validation with mCCI

Regulatory Requirements for the Visual Inspection of Parenterals
  • Compendial Requirements
    • 100% visual inspection & AQL testing
    • PharmEur, USP, JP - similarities and differences
  • News from the Annex 1 revison
  • GMP Expectations
    • Manual inspection
    • Automated Inspection
  • Risk Management Considerations
Fundamentals of Visual Inspection – Theory and practical aspects
  • Probabalistic nature of visual inspection
  • Defect categorisation
  • Test kits for training, qualification and Routine
  • Qualification and training of personnel
  • Standardisation of working conditions in the manual inspection
  • Usage of the Knapp and the modified Knapp test
  • AQL testing in the process of visual inspection
Automated Visual Inspection – from setup to routine use
  • Limitations of automated inspection
  • Setting up a qualification strategy for automated systems
  • Cross validation during the PQ phase of an automated System
  • Importance of particle detection rates
  • System-Suitability, Requalification and revalidation
  • Inspection of eject fractions
  • The Roche Inspection systems: manual, semi-automated and fully automated inspection
Requirements, composition, and handling of test sets
  • Definition of defect categories
  • Set up and composition of a test set
  • Test-Sets and their use for Training, Qualification and Routine
  • Handling and release of test sets
  • Documentation
Particulate Matter: Origins and Root Cause Analysis
  • External sources (packaging material, filter, abrasion..)
  • Internal sources (product and inherent particles)
  • Potential risks for patients
  • Route cause detection and particle identification
  • Avoidance and depletion of particles
Reinspection of Defect Fractions in Visual Inspection
Different scenarios will be covered such as:
  • Re-inspection or additional inspection of “grey-channel” 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)
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”


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