The regulatory requirements of pharmaceutical primary packaging: a guarantee for drug safety

Pharmaceutical packaging must comply with strict regulatory requirements and, in general, ensure that it:

adequately contains and protects the contents from external agents;
does not alter or contaminate the drug inside them;
is secure and robust enough not to be tampered with;
ensures easy access to the content.

The various drug regulatory bodies also outline guidelines to ensure that the packaging accurately protects the contents and meets safety standards. These help simplify the packaging process and ensure consistency between different manufacturers.

Beyond the requirements to be fulfilled by law, it is essential that packaging manufacturers adopt a company quality management system which formally documents the procedures, responsibilities and objectives for achieving customer satisfaction.

Pharmaceutical packaging regulators

There is no single institution worldwide for the regulation of medicines and their packaging. The supervision of these processes is entrusted to several international bodies, which draw up various guidelines containing the requirements for products to be manufactured in full compliance.

EMA (European Medicines Agency, European Union)
FDA (Food and Drug Agency, USA)
MHRA (Medicines and Healthcare products Regulatory Agency, UK)
PMDA (Pharmaceuticals and Medical Devices Agency, Japan)
CDSCO (Central Drug Standards Control Organisation, India)

Each country then has its own competent regulatory authority at national level, such as AIFA for Italy, with the power to supervise the marketing of products in their respective territory, as well as to monitor compliance with the various regulations.

Beyond individual statutes, the general trend among the various bodies is to collaborate with the aim of increasingly harmonising processes, including packaging, in order to simplify the approval mechanisms of the major pharmaceutical markets.

To this end, the International Conference of Drug Regulatory Authorities (ICDRA) (1) was established among the member states of the WHO , which provides an opportunity to discuss ways to strengthen collaboration in the field. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (also known as ICH) (2), on the other hand, brings together the main drug regulatory authorities in Europe, Japan, the USA and other international organisations to discuss common technical and scientific aspects.

World Pharmacopoeias

As with regulatory institutions, there are also various regulations governing medicines and their packaging. At national level, many states have drawn up their own 'Pharmacopoeia', i.e. a regulatory text describing the quality requirements of substances for pharmaceutical use and their packaging for their country.

As far as primary packaging is concerned, indications are usually given on the materials to be used and the parameters to be respected, to ensure full compatibility between the different substances, as well as physical-mechanical specifications to ensure the protection of the contained drugs.

The World Health Organisation has some 60 pharmacopoeias (3) and, among them, we should mention:

The European Pharmacopoeia (Ph.Eur.): founded in 1964, it is a code compiled by the European Directorate for the Quality of Medicines (EDQM), which aims to harmonise the texts of the main official pharmacopoeias of the European states and identifies common recognised standards on the quality of medicines and packaging.
The United States Pharmacopeia (USP): published by the United States Pharmacopeial Convention, it describes the quality standards for drugs and packaging for the United States, with guidance on materials and methods of analysis. The USP is published together with the National Formulary in a single volume known as USP-NF.
The Japanese Pharmacopoeia (JP): issued by the Pharmaceuticals and Medical Devices Agency, defines the specifications, criteria and standard test methods required to adequately guarantee the quality of medicines in Japan.

Good Manufacturing Practices

Good Manufacturing Practices (GMP), is a guide, drawn up by the World Health Organisation, that brings together all the measures to be applied to ensure that medicines are manufactured and controlled to appropriate quality standards.

Chapter V of the GMP (4) includes a section on the production of packaging systems, with chapters on the materials used and production operations. In particular:

the selection, qualification and approval of packaging material suppliers must be carried out with the same care as for raw material suppliers;
packaging materials must be released for use only by authorised personnel following an approved and documented procedure;
expired or obsolete primary packaging material must be destroyed and the disposal must be recorded;
Access to production areas must be allowed only to authorised personnel and production must be under the supervision of competent personnel;
for each batch there must be a Batch Packaging Record based on the relevant parts of the packaging instructions
checks on yield and reconciliation of quantities must be carried out to ensure that there are no discrepancies. Any discrepancies found must be investigated prior to release.

To date, more than 100 countries have incorporated GMP provisions (5) into their national laws, and many more countries have adopted its provisions and approach in defining their national GMP requirements.

Since the application of GMP is mandatory by law, packaging companies involve their employees in training sessions on the required requirements and procedures in order to ensure the highest quality standards in business and production processes.

ISO Standards

ISO Standards are a series of technical standards, defined by the non-governmental body 'International Organization for Standardization' and recognised internationally, created with the aim of establishing levels of homogeneity for the realisation, management and provision of products or services in a given sector.

For pharmaceutical packaging manufacturers, the reference standard is UNI EN ISO 15378: 2017. This standard integrates GMP (Good Manufacturing Practices) requirements into the design, production and distribution process of primary packaging materials for medicines.

GMP ISO 15378:2017 (6) requirements applicable to primary packaging materials include:

The design, production, quality control, labelling, handling, storage and distribution of primary packaging materials must minimise any risk to their quality.
Production, testing and storage facilities must be hygienic and controlled to prevent contamination.
Production processes must be clearly defined, and controlled to ensure consistency and conformity to specifications. Any changes to the process must be evaluated from the point of view of patient safety and product quality.
Operators should be trained to perform production and quality control of primary packaging materials according to clear, documented and approved SOPs and work instructions.
Records of production and quality control activities throughout the process are necessary to demonstrate that all required steps have been performed correctly and that the specified quality attributes of the primary packaging materials have been met.
Production, labelling, testing and distribution records should be stored and made accessible in a format that can trace the complete history of a batch and a system must be available to recall it from storage and/or distribution.
It is necessary to assess complaints, investigate the causes of quality defects and take appropriate measures with respect to defective products and to prevent their recurrence.

Medical Devices

'Medical device' means any instrument, apparatus (...) material or other article intended to be used for one or more specific medical purposes. This category includes drug administration and dispensing accessories , such as syringes, scoops and spoons.

In Europe, medical devices can be marketed in all member states after obtaining the CE mark from a certification body. In addition, Regulation (EU) 2017/745 (7) was recently introduced, which regulates the conditions under which medical devices are manufactured and placed on the market, with the aim of ensuring the safety and protection of patients during the use of such products.

The Regulation contains a detailed list of safety requirements and orders the devices into different classes (I, IIA, IIB, III), depending on their intended use and the risks associated with said use. Before placing a device on the market, the manufacturer is obliged to subject it to a conformity assessment and the drawing up of a Declaration of Conformity by a certified body.

Finally, the manufacturer also has a number of post-marketing obligations, such as ensuring traceability of the product throughout its life cycle and monitoring its proper functioning in order to identify any problems and introduce corrective actions immediately.

In conclusion, regulations in the pharmaceutical industry are constantly being updated, and it is essential for operators in the sector to know the requirements in order to ensure product compliance and quality. It is only through close cooperation between packaging material manufacturers and regulatory authorities that safe and effective packaging systems can be maintained.

(1) https://www.who.int/teams/regulation-prequalification/regulation-and-safety/regulatory-convergence-networks/icdra

(2) https://www.ema.europa.eu/en/human-regulatory-overview/research-and-development/scientific-guidelines/ich-guidelines

(3) https://cdn.who.int/media/docs/default-source/medicines/norms-and-standards/index-of-pharmacopoeias.pdf?sfvrsn=ef1100af_13&download=true

(4) https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf

(5) https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/gmp

(6) https://www.iso.org/obp/ui/es/#iso:std:iso:15378:ed-4:v1:en

(7) https://eur-lex.europa.eu/legal-content/IT/TXT/?uri=CELEX%3A32017R0745

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