Handling of APIs and Excipients - New Guidelines in Chapter 5 of EU GMP Guide

On 17 January 2013, the European Commission published the re-revised version of draft chapter 5 - Production - of the EU GMP Guide for comment.

The chapter entitled "Production" deals with many aspects which are relevant for quality assurance and quality control too - like, for example, purchasing, controlling and processing APIs and excipients, as well as topics with regard to reduced sampling and reduced testing.

The selection, qualification, approval and maintenance of starting materials suppliers has to be documented as well as the purchase and acceptance of the starting material itself. The level of control should be proportionate to the potential risks posed by the individual materials. These are among other things:

  • Origin of the starting material
  • Manufacturing process of the starting material
  • Complexity of the supply chain
  • Use of the starting material in the pharmaceutical product.

Where possible, starting materials should be purchased directly from the manufacturer of the starting material. All the quality requirements important to the starting material have to be set in specifications or quality agreements.

With regard to APIs, there are additional requirements to the general requirements on starting materials like, for example:

  • Supply chain traceability: it should be formally assessed and periodically verified.
  • Records should be available for the traceability of each API.
  • Performance of regular and detailed audits at the manufacturers and distributors. The audit report should fully reflect what was done and seen on the audit and which deficiencies were identified, if any.

Excipients which are considered to present a particular risk to the quality of the medicinal product, should be given similar attention to those for active substances.

As before, if a material is made up of different batches, each batch must be considered as separate for sampling, testing and release. Basically, the identity of the contents of each container of starting material must be assured.

Manufacturers of medicinal products are responsible for testing all starting materials as described in the marketing authorisation dossier. However, it is explicitly accepted to utilise partial or full test analysis results from the approved starting material manufacturer (in accordance with the recommendations laid down in EU GMP Annex 8 on Sampling). 

The outsourcing of such testing must be justified and documented. The following requirements must be fulfilled:

a) A formal agreement (according to chapter 7 of EU GMP Guide) should be available with the transport conditions to ensure the maintenance of the quality characteristics of the starting materials and to ensure that test results remain applicable to the delivered material.

b) Audits should be performed regularly at the production sites carrying out the testing and sampling of the starting materials by the manufacturer of medicinal products to assure compliance with GMP and with the specifications and testing methods described in the Marketing Authorisation dossier.

c) The certificate of analysis issued by the starting material manufacturer should be signed by a designated person with appropriate qualifications and experience.

d) The medicinal product manufacturer should have a significant experience in dealing with the starting material manufacturer including assessment of batches previously received and the history of compliance before reducing in-house testing.

e) The medicinal product manufacturer should also perform full analyses regularly and compare the results with the supplier's certificate of analysis. An investigation should be performed if any deviations are observed. Any acceptance of certificate of analysis of the supplier should be stopped until these deviations are explained.

Basically, starting materials can only be used for the manufacture of medicinal products after they have been released by quality control and as long as their lifetimes haven't expired.

Please also see the complete "Chapter 5: Production". Deadline for comments is 18 July 2013.

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