GDP for APIs - New ECA/PQG Guide
The new "Guidance on interpretation and implementation" of the ECA Foundation and the Pharmaceutical Quality Group of the Chartered Quality Institute
Medicinal products are subject to special regulations for storage and transport. Good Distribution Practice (GDP) is the part of quality assurance that ensures that the quality of medicinal products is maintained at all stages of the supply chain. The topic of GDP therefore affects all partners in the distribution chain.
The introduction to the "Guidelines of 5 November 2013 on Good Distribution Practice for medicinal products for human use (2013/C 343/01)" states that compliance with these guidelines "will ensure control of the distribution chain and consequently maintain the quality and the integrity of medicinal products".
However, GDP is not limited to pharmaceuticals. Rather, GDP starts earlier, namely with the transport of the active pharmaceutical ingredients (APIs) used for production. Since September 2015, the "Guidelines of 19 March 2015 on the principles of Good Distribution Practice for active pharmaceutical ingredients of medicinal products for human use (2015/C 95/01)" have been in force. These guidelines define requirements for the storage and transport of active pharmaceutical ingredients, which have to be implemented by manufacturers, distributors and pharmaceutical companies. A central concern that prompted the EU Commission to publish this document was the fight against counterfeit medicines and active ingredients. These guidelines are intended to ensure comprehensive and seamless control of the supply chain.
In June 2020 the "Good Distribution for Active Substances Guidance on interpretation and implementation" was published as a joint publication of the ECA Foundation and the Pharmaceutical Quality Group (PQG) of the Chartered Quality Institute. The monograph is based on the text of the EU GDP Guidelines for active substances for medicinal products for human use, but its principles are applicable to all areas of the global distribution network.
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Guidelines and supplementary documents
Even before the EU GDP guidelines, guides and supplementary documents containing recommendations for the distribution of active substances were published.
The WHO Guideline on "Good trade and distribution practices for pharmaceutical starting materials" was released in 2003, with a new version last published in 2016. This WHO guideline contains general principles to ensure good practice in the supply chain for pharmaceutical starting materials and is applicable to both active ingredients and excipients. It describes the requirements for the quality system, organization and personnel. Further chapters deal with documentation, storage and transport, returned goods and recalls.
In recent years, guidelines and supplementary documents have also been published by other organizations that deal with the topic of GDP for active substances, amongst which are:
- APIC: GDP for APIs "How to do" Document,
- IPEC Guideline: Good Distribution Practices Guide for Pharmaceutical Excipients,
- PIC/S Expert Circle on APIs: Questions & Answers document regarding Distribution Activities for Active Pharmaceutical Ingredients (APIs) (PS INF 20 2011),
- PIC/S: Guideline on the Principles of Good Distribution Practice of Active Substances for Medicinal Products for Human Use (PI 047-1).
EU GDP Guidelines
The "Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use (2015/C 95/01)" are divided into an introduction, eight chapters and an annex:
- Introduction: The introduction points out that the text is based on the same principles as the guidelines of 5 November 2013 on Good Distribution Practice for medicinal products for human use. The regulations are intended to serve as independent guidance for Good Distribution Practice and are aimed at importers and distributors of active substances for medicinal products for human use. They complement the rules the provisions on distribution in the EudraLex guidelines (Volume 4, Part II) and also apply to distributors of active substances manufactured by themselves.
- Chapter 1 - Scope: It is first clarified that the guidelines apply to the distribution of active substances within the scope of Article 1(3a) of Directive 2001/83/EC intended for medicinal products for human use. An active substance within the scope of the guideline is "any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis." It is further specified that the "distribution of active substances shall comprise all activities consisting of procuring, importing, holding, supplying or exporting active substances, apart from brokering."
- Chapter 2 - Quality system: The requirements in this respect are quite extensive. For example, distributors must, as part of their quality system, operate a complete deviation management system with a CAPA system based on risk analysis, as well as a change management system.
- Chapter 3 - Personnel: Among other things, it is required that personnel be trained in accordance with a written training program and then undergo continuing training.
- Chapter 4 - Documentation: This chapter is divided into general documentation requirements and detailed regulations on "procedures" and "records". All distribution activities that influence the quality of the active ingredients must be recorded in writing. For a complete traceability of the supply chain, records must be kept of every purchase and sale.
- Chapter 5 - Premises and Equipment: This specifies that premises and equipment must be suitable for the proper storage, protection against contamination and distribution of active substances.
- Chapter 6 - Operations: This chapter is divided into "Orders", "Receipt", "Storage", "Delivery to customers" and "Transfer of information". It is of particular importance that active substances should always be stored or transported under the conditions specified by the manufacturer so that their quality is not impaired. Where necessary, these operations must be carried out under controlled temperature or humidity.
- Chapter 7 - Returns, complaints and recalls: This chapter details the procedures for returns, complaints and recalls. In particular, this includes specific documentation requirements and the requirement that these procedures be performed only by appropriately trained and authorised personnel.
- Chapter 8 - Self-inspections: Distributors should conduct selfinspections according to an approved schedule and keep records of them.
- Annex: The Appendix contains a detailed glossary of terms used in the guidelines.
The "Good Distribution for Active Substances Guidance on interpretation and implementation"The EU GDP guidelines and the resulting requirements are quite comprehensive and detailed and the involved partners have to face some challenges. Although the guidelines are primarily aimed at wholesalers and manufacturers, they are of fundamental importance for all service providers involved in the supply chain (e.g. warehouses, transport and distribution companies). It is not surprising that there are always uncertainties in view of the relatively complex regulations. The question often arises as to how exactly the individual requirements are to be implemented in business practice.
Against this background, the ECA Foundation together with the Pharmaceutical Quality Group (PQG) of the Chartered Quality Institute published a guide on interpretation and implementation ("Good Distribution Practice Guidance on Interpretation and Implementation") in 2018. The chapters are built around the structure and text of the EU GDP Guidelines of 2013. The document is the result of a joint project of the PQG and the ECA Foundation with its European GDP Association, in which individual chapters on the interpretation of the EU GDP Guidelines were initially created.
In June 2020, the "Good Distribution for Active Substances Guidance on interpretation and implementation" was published as a further document that deals specifically with GDP for active substances and is intended to provide companies with assistance and concrete recommendations for action in implementing the requirements.
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The structure of the document is based on the text of the "Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use (2015/C 95/01)". The individual chapters and subchapters are commented on in detail, with explanations given for the respective purpose or the rationale behind the individual regulations. In addition, the advantages and risks associated with the respective regulation are pointed out. Furthermore, a detailed description is given of how the requirements can be implemented in practice. For better understanding, the original text of the guideline is printed in a different color. The explanations are supplemented by some diagrams and flow charts as well as references to other directives and guidelines.
The work can be purchased as a book in DIN A 5 format via the website www.pqg.org. For members of the European GDP Association it is available as an interactive PDF document in the members' area at www.good-distribution-practice-group.org.
Dr. Markus Funk
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas GDP and analytics.
Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use (2013/C 343/01).
Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use (2015/C 95/01).
WHO Technical Report Series, No. 917, 2003: Good trade and distribution practices for pharmaceutical starting materials.
WHO Technical Report Series No. 996, 2016: Good trade and distribution practices for pharmaceutical starting materials.
APIC: Good Distribution Practices for Active Pharmaceutical Ingredients "How to do" Document.
PIC/S Expert Circle on APIs: Questions & Answers document regarding Distribution Activities for Active Pharmaceutical Ingredients (APIs) (PS INF 20 2011).
ECA Foundation/The Pharmaceutical Quality Group of the Chartered Quality Institute: Pharmaceutical Quality Group Monograph No. 13 - Good Distribution for Active Substances Guidance on interpretation and implementation.