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Pharmaceutical Manufacturing and Packing Sourcer

Success from Failure

To achieve product performance, product validation and shelf life it is important to consider the nature of primary packaging and explore appropriate plastics material selection. Indeed, the consequences of inappropriate selection can ultimately be product failure, and prove very costly, both financially and for brand reputation.

The EU Packaging Directive 94/62/EC defines packaging as “all products made of any materials of any nature to be used for the containment, protection, handling, delivery and presentation of goods, from raw materials to processed goods, from the producer to the user or the consumer” (1). Article 3.1 of the Packaging Directive gives descriptions of three packaging categories as part of the definition: primary packaging (or sales packaging); secondary packaging (or grouped packaging); and tertiary packaging (or transport packaging). Primary packaging is intended to constitute a sales unit to the final user or consumer at the point of purchase. In the pharmaceutical sector, examples of primary packaging include blister packs, pressurised meter dose inhalers (pMDIs), blow-fill-seal products, and solution bottles, and therefore may consist of plastic, aluminium, glass, and/ or elastomeric materials. Plastics-based packaging is the principal consideration of this article.

Packaging can be considered to deliver multiple functions, which include physical protection, security, convenience, barrier protection, containment or agglomeration, dose application, and information transmission. The materials used in primary packaging must be selected to achieve the appropriate functions for the application.

Material Selection Process

In an age of consumer awareness and regulatory agencies, the plastics designer, manufacturer and retailer are under pressure to assure themselves, their customers, and the general public that their product can perform throughout a prolonged life span, in a safe and trouble-free manner. The key to performance of plastics packaging is that it must remain serviceable for a reasonable life cycle, and failure must not occur in a manner that could jeopardise the product or patient safety.

The material selection process must take into account the full range of long-and short-term mechanical, physical and environmental conditions that may be experienced by the primary packaging during processing, assembly, storage, transport and service. In the course of such consideration, functional requirements and the necessary material attributes – in other words, the product design specification (PDS) – may be identified. The material attributes can be considered as essential or desirable properties, and may then be used to carry out a search to eliminate those materials which fall outside the boundaries of acceptability. There are various software database tools available to assist with such an exercise.

In order to perform plastic material selection successfully, a complete understanding of plastic material characteristics, specific material limitations and potential failure modes is required. Good material selection requires a judicious approach and careful consideration of application requirements in terms of mechanical, thermal variation, environmental, chemical and optical properties, for example. Production factors, such as feasible and efficient method of manufacture in relation to part size and geometry, need to be assessed. Figure 1 gives an overview of a fairly general materials selection process.

The success of the product relies on an appropriate combination of materials, design and processes to satisfy the service environmental demands, and it is important that the functional requirements reflect this. Figure 2 illustrates the relationship between all of these factors.

It may be that the required performance of the primary packaging is only achieved by combinations of materials, either as blends, alloys or multi-layer structures. Different components bring a range of properties to the packing; for example moisture barrier, mechanical strength, sealability, printability and so on.

Building sustainability into the selection, sourcing, design and manufacture of products can deliver important business advantages, including: reducing wall thickness; lowering costs from reduced waste; improving customer satisfaction; and increasing competitive advantage. Improving the environmental sustainability of plastics from production, through use, to disposal, is an important consideration; however, there may be limitations regarding the recycling of containers in contact with drug products.

Good Manufacturing Practices
Once the packaging is selected, the pharmaceutical sector and its primary packaging material suppliers must ensure that Good Manufacturing Practices (GMP), including a quality management system for the design, manufacture and supply of packaging, are in place. With international consensus, the International Organization for Standardization has published ISO 15378:2011 (2). Implementation of this management tool aims to improve patient safety, represent good practice and establish a bench mark that can be applied for quality improvement, training, auditing and certification. Furthermore, the application of GMP principles provides assurance that the pharmaceutical packaging materials meet the regulatory and pharmaceutical industry requirements.

GMP requires that manufacturers can demonstrate and verify the ongoing compliance of their suppliers. To control the risks to patients’ safety, pharmaceutical companies have to take into account all of the factors that affect the quality of their product. In this context, primary packaging components are a risk factor because of their direct contact with the drug product and patient.

The product enclosed in the primary package may require protection from, among other things, mechanical shock, vibration, electrostatic discharge, compression, temperature, and so on, as appropriate to the application. Additionally, barrier protection from outside influences such as oxygen, water vapour and dust may be required. Keeping the contents clean, fresh, sterile and safe for the intended shelf life is an essential target.

In addition to the requirements contained in ISO 9001:2008 (3), ISO 15378:2011 contains a list of additional specific requirements unique to the primary packaging sector, for example:

  • Batch or lot traceability
  • Environmental control, with special emphasis on components for sterile products
  • Risk management, to be implemented throughout product manufacturing
  • Validation of critical processes


Pharmaceutical validation refers to establishing documented evidence that a process or system, when operated within established parameters, can perform effectively and reproducibly to provide a medicinal product meeting its pre-determined specifications and quality attributes. In a similar way ISO 11607-1:2009 is concerned with the validation of medical packaging, specifically dealing with sterile barrier systems (4).

Packaging validation is a total process involving the identification and control of materials and processing variables that affect the ability of a packaged device to meet its acceptance requirements. This forms part of the development process, as illustrated in Figure 3.

Packaging validation must address three basic elements: requirements, assumptions; and capability assessments of materials, equipment and processes. It examines variations within a package, from package to package, and from batch to batch. Hence, the performance and processibility of the selected material(s) is of great importance.

Packaging validation entails the qualification of materials and the initial package design qualification. The principals for submitting information may be found in EMA and FDA guidance documentation (5,6). As a follow on from material selection, a materials qualification plan should be developed to analyse the material requirements with respect to safety, product performance, sorption, sterilisation compatibility, compatibility of the drug and the container, shelf-life stability, and suitability for the intended manufacturing, handling, distribution and storage methods (7). In forming material requirements, batch-to-batch variations must be considered in order to establish the minimum performance requirements.

The product design should be qualified to the product requirements before proceeding with the development project. The design should be reviewed to input requirements, and initial testing should address end-use requirements and device protection, as well as the manufacturing and distribution requirements. Design performance testing should be conducted under actual use or conditions that simulate actual use. Initial evaluation of both the material and design prior to process qualification can save a tremendous amount of effort and time. If either the material or design does not meet the requirements, process qualification is worthless.

Failure Modes

Failure is a practical problem with a product and implies that the material no longer fulfils its function. Frequently, the ability to withstand mechanical stress or strain is an important criterion in service, and consequently mechanical failure is usually a primary concern. However, failure may be attributed to many factors, for example drug degradation, extractable and leachables, container integrity, and even loss of attractive appearance or distortion.

The two main forms of mechanical failure are ductile and brittle failure. Ductile failure is, by definition, failure at high strain. It is relatively straightforward to design plastic components to avoid ductile failure. However, in practice, ductile materials often fail in a brittle manner, which becomes much more difficult to predict from a theoretical standpoint. Brittle fracture is a low energy process characterised by failure at low strain, with little or no deformation. Components can contain small, crack-like defects which can act as stress concentration features; these micro-cracks grow under load and may eventually lead to rapid failure.

When considering the design and development of a plastic product, it is imperative that a designer fully understands the fundamental limitations of plastics. A designer must be aware that:

  • Plastics are non-linear, visco-elastic materials that respond to stress as if they were a combination of elastic solids and viscous liquids
  • They physically age
  • They are temperature-dependant
  • They are susceptible to chemical attack and environmental stress cracking
  • They will, under the action of a tensile stress, eventually fail
  • The time to fail will diminish as the stress increases, the temperature increases, in the presence of certain environments, and under the action of cyclic loading
  • The moulding process can result in significant levels of residual stress in components
  • Weld lines are planes of weakness
  • Most plastics are highly notch-sensitive
  • Moulded articles rarely achieve theoretical material properties

Industry experience has shown that many designers do not consider, or are unaware of, these issues when considering the use of plastic materials.

The importance of correctly identifying the technical requirements of the product at the early stage of development/ design process is demonstrated by the frequency of product failures, as illustrated in Figure 4. Most failures are found to be due to poor identification of design risk (materials and product specification) in the initial stages of product development. The modes of failure typically experienced by plastic products primarily include; environmental stress cracking (ESC), dynamic fatigue, UV attack, notched static rupture, creep, creep rupture, chemical attack and thermal degradation.

Long-term performance and durability are therefore important considerations. In critical applications, to avoid under-designing, properties such as creep rupture strength, creep modulus and fatigue strength must be determined experimentally under worst-case scenario operational conditions; for example, maximum envisaged service temperatures, maximum stress and environmental effects. Long-term performance data is typically not made available by material suppliers.


Primary packaging is conceived to provide a sales unit to the final user or consumer at the point of purchase. In the pharmaceuticals sector, examples include blister packs, blow-fill-sealed products, solution bottles and so on.

When considering the design and development of a plastic product, it is imperative that a designer fully understands the fundamental properties (and limitations) of plastic materials. As a result, appropriate material selection is vital in order to meet the performance requirements of primary packaging during processing, assembly, storage, transport and service, as well as to ensure that the product not only achieves customer satisfaction but also avoids premature deterioration or failure. Some packaging failures can be significant, resulting in expensive recalls, initiating investigation, additional regulatory reporting, and can affect the brand image.


  1. European Parliament and Council Directive 94/62/EC of 20 December 1994 on packaging and packaging waste
  2. International Organization for Standardization 15378:2011, Primary packaging materials for medicinal products, Particular requirements for the application of ISO 9001:2008, with reference to Good Manufacturing Practice (GMP)
  3. International Organization for Standardization 9001:2008, Quality management systems, Requirements
  4. International Organization for Standardization 11607-1:2009, Packaging for terminally sterilized medical devices, Part 1: Requirements for materials, sterile barrier systems and packaging systems
  5. European Medicines Agency, Guideline on Plastic Immediate Packaging Materials, 1 December 2005
  6. Food and Drug Administration, Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry, Manufacturing, and Controls Documentation, May 1999
  7. International Conference on Harmonisation, Harmonised Tripartite Guideline, Stability Testing of New Drug Substances and Products Q1A(R2), 6 February 2003

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Michael Lock is a Principal Consultant at Smithers Rapra, where he has been supporting a variety of customers in material selection, failure diagnosis, technical review and product testing. Michael also provides general polymer support helping the company to remain at the forefront of polymer testing and consultancy. This capability is rooted in extensive previous experience, both in polymer R&D and as a technical manager for a packaging supplier in the plastics manufactuing sector.
Michael Lock
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