What are the GMP Requirements for Pharmaceutical Packaging Materials?

GMP (Good Manufacturing Practice) in the manufacture of primary and secondary packaging materials is crucial for ensuring the quality and suitability of container closure systems. It is an important element in guaranteeing consistent quality, safety and functionality when these materials are later used to package pharmaceutical, cosmetic or food products.

Does "GMP for packaging materials" exist?

ISO 15378 - 'Primary packaging materials for medicinal products' defines GMP principles in the development, production and quality control of primary packaging materials for medicinal products and specifies requirements for a quality management system for primary packaging material manufacturers. It combines ISO standard 9001:2008 with GMP for pharmaceutical packaging materials. It is primarily intended for suppliers of primary packaging materials, but the GMP requirements are suitable for a wide variety of (pharmaceutical) packaging materials. The standard also includes relevant GMP requirements for the distribution of primary packaging materials for medicinal products.

Other available standards are:

• The PS 9000:2016 standard (Good Manufacturing Practice relating to the manufacture of packaging materials for medicinal products) developed in the UK by the PQG (Pharmaceutical Quality Group) in collaboration with the pharmaceutical industry and its suppliers. It is based on ISO 9001:2015 and is recognised as a standard by the British Medicines and Healthcare Products Regulatory Agency (MHRA). This standard specifies GMP requirements and guidance for a quality management system (QMS) intended for suppliers of packaging materials and printed packaging materials for the pharmaceutical industry.
  
• Sterile packaging materials: The EMA Guideline for the sterilisation of medicinal products, active substances, excipients and primary containers includes GMP requirements for the selection and validation of sterilisation processes for primary packaging materials used for aseptically manufactured medicinal products. Sterile primary packaging materials, such as ready-to-use (RTU) or ready-to-sterilize (RTS) materials, are also covered by the revised Annex 1 (Manufacture of sterile medicinal products) of the EU GMP guidelines. This applies in particular to the GMP compliance evidence of the company providing the sterilisation service.
  
• Defect classification lists - these play a crucial role in the assessment of the release decision for the packaging batch (both at the supplier and at the user) and in the processing of complaints. Some of them also contain templates for supplier certificates and technical agreements. 

Printed Packaging Materials

Printed packaging materials are important information carriers for medicinal products. Incorrect or false information on cartons, labels or package leaflets is the most common reason for recalls of finished medicinal products.

According to Chapter 5 'Production' of the EU GMP Guidelines, 'printed and embossed information on packaging materials should be clear, lightfast and abrasion-resistant'.

The creation, verification and compliance with packaging specifications and print data in cooperation with the supplier therefore plays a major role in printed packaging materials. In addition, the requirements for serialisation and verification (in accordance with Delegated Regulation (EU) 2016/161) of the medicinal products concerned must be implemented. Another requirement of the EU Falsified Medicines Directive concerns tamper-evident packaging, which is intended to make potential tampering with the packaging visible.

Supplier Qualification and Audits

Supplier qualification should play a decisive role both on the part of the packaging manufacturer (with regard to the suppliers of the materials used to manufacture the packaging) and on the part of the packaging user (with regard to the packaging supplier). For use in the manufacture of medicinal products, the EU GMP Guidelines in Chapter 5, Production, require:

'The selection, qualification, approval and retention of suppliers of primary and printed packaging materials should be given as much attention as that given to suppliers of starting materials.'

Risk-based approaches to supplier qualification, supplier questionnaires and technical agreements are of great benefit here.

Extractables and Leachables

There are currently no globally uniform guidelines for extractables and leachables (E&Ls). The draft ICH Q3E guideline on the evaluation and control of E&Ls therefore attempts for the first time to create a harmonised scientific framework for the evaluation of E&Ls from packaging materials, application systems (devices) and manufacturing processes. The new ICH Q3E guideline is intended to assist both applicants and regulatory authorities by focusing on the risk management process. The guideline is therefore of considerable importance for pharmaceutical development, approval and the life cycle management of medicinal products.

Compendial Monographs

Specifications and requirements for testing primary packaging materials and material components can be found in the monographs and general texts of pharmacopoeias such as the United States Pharmacopeia (USP) and the European Pharmacopoeia (Ph. Eur.). The following list provides a selection of relevant chapters:

Glass:

• USP <660> Glass Packaging Systems
• USP <1660> Evaluation of the Inner Surface Durability of Glass Containers
• Ph. Eur. Chapter 3.2.1 Glass Containers for Pharmaceutical Use 

Plastics:

• USP <661> Plastic Packaging Systems
• USP <661.1> Plastic Materials of Construction
• USP <661.2> Plastic Packaging Systems for Pharmaceutical Use
• Ph. Eur. 3.2.2 Plastic Containers and Closures for Pharmaceutical Use
• Ph. Eur. 3.1 Materials for the manufacture of containers (e.g. 3.1.17 Cyclo-olefin copolymers (COC), 3.1.16. Cyclo-olefin polymers (COP), 3.1.3 Polyolefins, etc.)

Elastomers:

• Ph. Eur. 3.2.9. Rubber stoppers
• USP <381> Elastomeric Components
• USP <382> Elastomeric Component Functional Suitability
• USP <1382> Assessment of Elastomeric Component Functional Suitability

Silicones:

• USP <383> Cured Silicone Elastomers
• Ph. Eur. 3.1.9 Silicon Elastomer for Closures and Tubing

Container Performance and Container-Closure Integrity (CCI):

• USP <671< Containers-Performance Testing
• USP <1207> Package Integrity Evaluation-Sterile Products (including subchapters)

E&Ls:

• USP <1663> Assessment of Extractables
• USP <1664> Assessment of Leachables (including subchapters)
• Ph. Eur. Chapter 2.4.35 Extractables in Plastic Materials

Biocompatibility: USP <1031> The Biocompatibility of Pharmaceutical Packaging Systems

Supplier Qualification: USP <1083> Supplier Qualification

To date, there are still no harmonised pharmaceutical standards for metal packaging. To ensure the safety, suitability and compatibility of metal packaging systems, the USP is therefore proposing two new general chapters (<662> and <1662>) dealing with the characterisation of metal materials, components and systems used for the packaging of pharmaceutical products. 

Useful Links

• Packaging Update - Requirements on Packaging and Materials - (Part I) - GMP Journal, Issue 17
• Packaging Update - Requirements on Packaging and Materials - (Part II) - GMP Journal, Issue 18
• EudraLex Volume 4 (EU GMP) 
• EMA Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container 
• EMA Guideline on plastic immediate packaging materials 
• FDA Guidance for Industry "Container Closure Systems for Packaging Human Drugs and Biologics" 
• Supplier Qualification: Sourcing PFS Components as a Challenge for Emerging Biotechnology Companies - GMP Journal, Issue 44