An industry first – a holistic approach to container closure integrity

17 January 2024
Fill Finish
Jane Worthington
Global Change Facilitator

Container closure systems (CCS) for parenteral products must maintain sterility and product quality throughout their shelf life until final use. Traditionally, there is a tendency to demonstrate appropriate control of the integrity of a CCS through testing, e.g., by sterility and/or container closure integrity testing (CCIT) of drug products.

A holistic approach to CCI is recommended and, in line with current regulations, a science- and risk-based approach in (bio)pharmaceutical product development and manufacture.

A holistic approach is more robust and aims to build quality into the design and processes rather than testing or inspecting the finished product, and this is why we have published BioPhorum’s holistic approach to container closure integrity.

It provides an industry perspective on ensuring CCI throughout the product lifecycle and includes discussions on development, validation, routine manufacturing, shipping and stability, and the ongoing monitoring of holistic CCI strategy. It also includes appendices on qualification activities, a process performance qualification readiness checklist, CCS assembly steps (and associated preventions and detections), and analytical considerations.

“Our industry needs to move the needle from CCIT to CCI,” said Henri Hebting, Sr Director TS/MS at Eli Lilly. “Testing has never been the sole way to assure parenteral drug products are safe to inject. It all relies on the robustness of what we do every day, whether in development, designing good CCS, or in manufacturing to execute reliable processes. This paper is an unprecedented summary of best-in-class practices our industry experts have been applying to assure we deliver safe medicines to patients.”

This paper is intended to trigger technical and scientific discussions. Key topics include:

  • Building CCI of a parenteral drug product into the overall process and assuming CCI through a holistic approach, rather than relying solely on final release/stability testing of the product
  • Taking a robust ‘quality by design’ approach with formalized risk assessments to de-risk CCI by the tailored design of critical component interfaces and confirming the robustness of design with characterization data
  • Ensuring close collaboration with primary packaging component suppliers and robust change management processes to guarantee consistent quality of parts between batches and supplier manufacturing sites over long periods.

To our knowledge, it is the first publication of an industry-wide view of a holistic approach to CCI for a parenteral product.

“This paper provides a roadmap for industry on how to assure CCI, which is long overdue,” said Michael Edey, Senior Principal Engineer at Pfizer. “Building quality into parenteral products to assure patient safety, rather than attempting to test quality in, is the basis of the paper. While regulations continue to evolve, a roadmap for biopharmaceutical companies on how to fulfill them in this complex and often misunderstood field is most welcome. This paper represents an opportunity to build knowledge across industry and provide further stimulus for engagement with all partners.”

Specific considerations and studies around a holistic approach to CCI are exemplified at different stages in the product lifecycle. The use of ‘quality by design’ principles and scientific and risk-based justifications are emphasized at each stage for a ‘new’ drug product, i.e., CCS design and development, validation, routine manufacture, stability, and shipment.

Where a high level of assurance is created by a holistic approach throughout the lifetime of a product, final testing may be reduced or even eliminated at a batch level or during routine stability testing. Nonetheless, some analytical CCIT method considerations are provided.

Industry should stop considering CCIT as a compliance endpoint and see the value of managing CCI as a risk to the safety and efficacy of drug product, which must be managed during the whole lifecycle. Our paper is a crucial part of making that happen. For more information, download the paper here and contact Jane Worthington, Global Change Facilitator, at

How to minimize the impact of CCIT on gene therapy batch yields
DNA pink background
Registering innovative raw materials using QbD principles: Protein A resins

Advanced Therapy Medicinal Products

Advanced Therapy Medicinal Products support the quest for better and faster development of cell, gene and RNA therapies​ through connecting therapy developers, contract manufacturing, and testing organizations to gain an understanding and respond to the challenges faced by the advanced therapeutics industry.

Development Group

Development Group accelerates and improves the development process of biopharmaceutical medicines for the benefit of the patient. Replacing isolation with collaboration by providing a “safe” space where subject matter experts can work on sharing solutions and best practice on emerging industry trends, implementation of new technologies and common issues whilst ensuring their intellectual property and confidentiality is protected.

Drug Substance

Drug Substance advances excellence in drug substance manufacturing and testing, acting as an industry voice to accelerate technology adoption, implement post-approval change more rapidly and increase confidence in maintaining compliance.

Fill Finish

Fill Finish accelerates development and acceptance of sustainable world-class filling and packaging operations for drug product which meets the future needs of patients. Through innovative solutions resulting from the sharing of expertise, we can overcome common performance challenges and deliver on quality and regulatory compliance.

Information Technology

Information Technology accelerates digital maturity across the ​global pharmaceutical manufacturing industry.


BioPhorum Quality provides a dedicated, safe space for quality professionals from biomanufacturers and contract organizations to coalesce and enhance effective collaboration to address shared industry challenges.


Regulatory CMC brings leaders together who have a common goal – to improve access to medicines through innovation in the Regulatory ecosystem. It provides a dedicated space for strategic leadership and a coordinated industry voice, to move from divergence to convergence.

Supply Chain to Patient

Supply Chain to Patient transforms the performance of global pharmaceutical clinical and commercial outbound supply chains through industry collaboration by creating transparent patient-centric, resilient and agile E2E supply chains, that consistently deliver high-quality medicines ensuring an uninterrupted supply to patients.

Supply Partner

Supply Partner is a trusted advisory group and collaboration that is the engine for driving change across the global industry for all things relevant to the inbound supply chain. Addressing the challenges of complexity, resilience, cost, sustainability, and innovation.


Sustainability enables the industry’s transition to a low carbon, circular future – supporting members to improve patient health while respecting the planet. We activate multi-disciplinary teams drawn from our network to deliver environmental sustainability improvements across the value chain.

Technology Strategy

Technology Strategy acts as one voice of the industry to define strategy, accelerate technology transformation and support technology translation and adoption. With a purpose of enabling the future state of flexible, resilient, sustainable end-to-end biomanufacturing.

An industry perspective on understanding AAV capsid content variants
Needle On Yellow Background
An intercompany perspective on practical experiences of predicting, optimizing and analyzing high concentration biologic therapeutic formulations
The Drug Substance 2.0 Strategic Value Framework
Coloured dots on teal, next to vial
BioPhorum’s holistic approach to container closure integrity
Magnifying glass over a tablet all coloured blue
Digital Plant Maturity Model 3.0
Inaugural BioPhorum Quality face to face – get involved
The next step in building regulatory as a capability to enable strategic innovation across the BioPhorum community
Delivering a Cell and Gene Therapy Outbound Supply Chain Pathway for the Industry
DNA and Earth on blue background
A vision for the biopharmaceutical industry’s inbound supply chain
A major milestone – a harmonized approach to product carbon footprint data
Technology Roadmap V 2.0
BioPhorum Technology Roadmapping roadmap vision 2.0


Documents including best practices, vision statements and peer reviewed papers to help you take value back to your business.


Discussing all aspects of the biopharmaceutical industry, from digitization and knowledge management to raw materials, supply chain, sustainability and more. Learn from the perspectives of those at the forefront of the industry.


BioPhorum Connect is our podcast series that keeps you up to date with the latest news and trends in the biopharmaceutical industry. From experienced professionals to thought leaders, these podcasts bring you the insights and perspectives of experts from around the world.


A variety of resources including design tools and user requirement specifications to help you improve and streamline your business processes.

Benchmarks and Surveys

Research conducted among the BioPhorum membership providing evidence to support change and identify best practice.

Browse all

Access a variety of free tools and papers and other resources designed to provide you with up-to-date information and insights to help you make informed decisions and maximize your success. Access our resources today and start making improving and streamlining your business processes.

Bioreactivity testing in single-use system biomanufacturing
Bioreactivity testing in single-use system biomanufacturing
Bioreactivity testing in single-use system biomanufacturing
Magnifying glass over a tablet all coloured blue
Digital Plant Maturity Model 3.0
Bioreactivity testing in single-use system biomanufacturing