Container Closure Integrity Testing (CCIT) is an assay that evaluates the adequacy of container closure systems to maintain a sterile barrier against potential contaminants, Microorganisms, Reactive gases etc. which are the potential substances that can break the integrity of container.

Container closure must maintain quality of the product throughout their shelf-life which it has contain e.g. sterile final pharmaceutical, biological, and vaccine products.

The quality of the Container is exactly well defined in the European Commission EudraLex- The Rules Governing Medicinal Products in the European Union Annex 1- Manufacture of Sterile Medicinal Products (Annexure).

It states that “Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. glass or plastic ampoules should be subject to 100% integrity testing. Samples of other containers should be checked for integrity according to appropriate procedures.” Further, it mentions “Containers should provide adequate protection against deterioration or contamination of the intermediate or API that may occur during transportation and recommended storage.”

Following various standards exist to deal with the quality and testing of Container and packaging.

  • USP (1207) Sterile Product Packaging-Integrity Evaluation
  • USP(1207.1) Package Integrity and Test Method Selection
  • USP (1207.2) Package Integrity Leak Test Technologies
  • USP (1207.3) Package Seal Quality Test Methods

Following are the some of the Code of Federal Regulations (CFR) that states the conditions for the use of Containers and Closures for any medicine or drug packaging:

Code of Federal Regulations (CFR): 21CFR211.94 Drug Product Containers and Closures – also state that

    1. Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.
    2. Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.
    3. Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. Such depyrogenation processes shall be validated.
    4. Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.

Compositional requirements, test procedures and acceptance criteria on materials for containers is also defined European Pharmacopeia Section 3.

Pharmaceutical Packaging

The packaging is the most important part of the pharmaceutical and chemical industries as it protects medicines / drugs or any chemicals from external factors such as heat, moisture, oxygen, UV-light and contamination by other chemicals or microorganisms. This packaging must not release any chemicals to pharmaceuticals which may alter the composition or efficiency of the medicine or drug.

So it is imperative that Packaging material must adhere to the various pharmacopeia standards and test protocols.

US Pharmacopeia defines detailed requirements for packaging material in the standard protocol USP 661 and to approve the plastic packaging for use with FDA, the packaging material must conform to this standards criteria.

Two sections of USP 661:

  • USP 661.1 – deals with plastic materials of construction
  • USP 661.2 – focuses on the suitability/safety of the complete packaging system

As per this standard, a plastic material of construction is considered to be well characterized for its intended use if it meets with following characteristics:

  • identity
  • biological reactivity
  • general physicochemical properties
  • composition (i.e., additives likely to be present)
  • extractable elements (where applicable)

Testing for Packaging Material includes:

  • Identification and characterization tests
  • Infrared Spectroscopy (IR)
  • Differential Scanning Calorimetry (DSC)
  • Determined concomitantly with reference standards per plastic type
  • Physicochemical tests
  • Extraction with water, alcohol, and hexane
  • Heavy Metals assessment on water extraction
  • Nonvolatile Residue (NVR) on all extractions
  • Residue on Ignition (ROI) following certain NVR results
  • UV Absorbance
  • Acidity/Alkalinity using indicators
  • Total Organic Carbon (TOC)
  • Buffering Capacity for liquid containers
  • Biological testing per USP 〈87〉 for high risk applications (inhalation, parenteral, ophthalmic)
  • Additional tests unique to PET and PETG
  • Material-specific tests for plastic additives and/or related substances
  • Spectral Transmission if light protection is necessary (identical to the spectral transmission requirement in USP 〈671〉 for light-resistant plastic packaging systems)
  • Chemical Suitability Assessment, dependent on risk assessment
    • Extractables per USP 1663
    • Leachables per USP 1664

Additionally, USP 〈665〉 (formerly drafted as 661.3) emphasizes analysis of organic extractables in plastic manufacturing materials and components used in the conversion of raw starting materials into active pharmaceutical ingredients (APIs), drug substances, and drug products. The chapter applies to pharmaceutical and biopharmaceutical manufacturing. It includes risk assessment and extraction procedures, along with general guidelines for chemical testing of the extracts.

Testing includes:

  • Nonvolatile Residue (NVR)
  • UV Absorbance
  • Organic extractables profiling (USP 1663)

This testing encompasses all polymeric materials involved in solution transfer and transport, mixing and reacting, storage, and processing including:

  • Tubing and connectors
  • Tank liners and mixing bags
  • Raw material containers
  • Filters and chromatography columns
  • USP <671> Container Permeation Testing

The Container Permeation test provides moisture permeability of container utilized for medicine / drugs being packaged.

These standards and testing ensures that polymer raw material is well-characterized and suitable for its intended use.  The pharmaceutical industry has to assess all the parameters before packaging of their products and Our Chromak Research Team can help you choose and carry out the most appropriate test plan for your particular container system because they have years of experience in USP container qualification testing.

The Chromak Research Team is ISO 17025:2017 certified laboratory with cGMP, FDA-registered services according to the standards and we have years of practical experience to develop test plans specific to the product-package system in question to ensure all regulatory requirements are met.