Container Closure System

3.4 Container-Closure System:

3.2.P.2.4 The suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).

The properties of the container-closure systems should be defined by the characteristics of the FPP and the conditions prevailing in the intended market (e.g. climatic zone IVb).

Stability testing of primary batches of the FPP is conducted on samples packaged in the container-closure system selected for marketing in order to confirm compatibility and product stability to support PDs for marketing authorization.

When the container-closure system is a critical factor for FPP stability, batch or supplier variations need to be minimized through tight specifications and extended sampling plans for QC testing.

To facilitate the visual identification of spuriously or falsely-labelled, falsified or counterfeit (SFFC) medicines (including by the public) the description needs to be completely detailed in the product information. Details may include information on the container-closure system, such as “round, white opaque, highdensity polyethylene (HDPE) bottles fitted with white opaque, polypropylene continuous thread closures with induction sealing liner”, or “a blister package comprising clear transparent polyvinyl chloride (PVC) film with a backing of aluminium foil coated with heat-seal lacquer”.

Primary packing materials, particularly plastics, should comply with relevant pharmacopoeial and food contact regulations.

Testing requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration and possibly, the manufacturing process. The pharmacopoeias provide standards that are required for packaging materials; examples include the following:

– glass containers (17, 18);
– plastic containers (19, 20);
– rubber/elastomeric closures (21, 22).

Table 1 outlines the general recommendations for the various dosage forms for once-only studies to establish the suitability of the container-closure system contact materials.

Table 1
Studies to establish the suitability of the container-closure system contact materials


Solid Oral Products

Oral Liquid and Topical Products 

Sterile Products (Including Ophthalmic Preparations) 

Description of any additional treatments a 



× (sterilization and depyrogenation of the components) 

Extraction studies 




Interaction studies  (migration/sorption)




Moisture permeability 

× (uptake) 

× (usually loss) 

× (usually loss)

Light transmission 

× b 



× Information should usually be submitted.
- Information does not need to be submitted.
a E.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.
b Not required if product has been shown to be photostable.

The suitability of the container-closure system used for the storage, transportation (shipping) and use of any intermediate or in-process products (e.g. premixes, bulk FPP) should also be discussed.


There are certain situations in which pharmaceutical dosage forms are developed in association with specific devices. The device might be critical to enabling delivery of the medicine or it might be included in order to facilitate administration.

Where the device is critical to drug delivery and fully integrated with the product formulation, this product formulation–device combination should be considered as the primary product for the purposes of regulatory submission. Examples of such products include metered dose inhalers (MDIs), dry powder inhalers, intranasal sprays and ready-made intravenous infusions. For these products the data necessary to support a regulatory submission would include:

■ Physical and chemical stability data for the product formulation–
device combination in its primary pack in order to support the
claimed shelf-life and storage conditions;

■ Relevant data on extractables and leachables;

■ For multidose products, demonstration of accurate dose delivery over
the shelf-life of the product under the registered storage conditions;

■ For multidose products with a dose-counting mechanism, stability
data to demonstrate reliable performance of that mechanism over the
shelf-life of the product under the registered storage conditions;

■ Specification control and secure sourcing of all device components;

■ Relevant information on any secondary device associated with the
FPP, such as a spacer device sometimes associated with inhaled
products such as MDIs and nebulizers. This device enables dose
delivery in situations where the patient cannot easily use the primary
product to inhale the dose, particularly where administration to
children is involved. The device acts as a temporary reservoir for
the dose which can then be inhaled more easily by the patient.
There will be some variability inherent to a spacer device but,
nevertheless, an acceptable accuracy of dose delivery when using
this device needs to be demonstrated.

Alternatively, the co-developed device may be intended to facilitate measurement of the prescribed dose prior to administration; this is particularly important for paediatric products where flexibility of dose may also be a requirement. Examples include spoons, cups, syringes or droppers for oral 
delivery and droppers for nasal or aural delivery. A device is required to be included with the container-closure system for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules), whenever the package provides for multiple doses.

In accordance with the Ph. Int. (3) general chapter Liquid preparations for oral use:

“Each dose from a multidose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable dropper.”

In these cases the following data would be required to support a regulatory submission:

■ For a device accompanying a multidose container, the results
of a study demonstrating the reproducibility of the device (e.g.
consistent delivery of the intended volume), generally at the lowest
intended dose;

■ Specifications for the device materials, including specific identification
testing of the material which will be in contact with the FPP.

When the intention is to submit a PD in CTD format a sample of the device should usually be provided with Module 1 of the PD.

Pharmaceutical Development of Multi source (generic) Finished Pharmaceutical Products – points to consider, (Annex 3, WHO Technical Report Series 970, 2012)

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