European Commission issues new Draft of Chapter 5 "Production" of the EU GMP Guide

Chapter 5 "Production" of the EU GMP Guide has been revised and was recently published on the European Commission's GMP-information page. The changes offer some surprises and concern the points 5.25, 5.26 and 5.27 on the qualification of suppliers of starting materials and reflect the legal obligation to produce active substances in accordance with GMP. Besides, a new point, 5.31, regarding the testing of starting materials was introduced for clarification and harmonisation. Further work on changes is ongoing and affects chapter 5.19 (cross-contamination).

The most important changes in the provisions of the revised chapter 5 are listed below.

The original point 5.25 on the subject of purchase was incorporated in point 5.26.

The new point 5.25 was extended from the original expression stated in point 5.26 (old) "approved supplier" to "manufacturer, importer or distributor". The focus is put on active substances, but this point remains a bit vague. The passage demanding that the purchase of starting materials should be controlled by written procedures and that the supply chain of each starting material should be known and be documented is completely new.

In future, not only handling, labelling and packaging should be discussed with the suppliers, but distribution as well. And now the outcome of these discussions should be documented.
5.26: Selection, qualification and approval of suppliers are to be regarded as important operations in the future. This will also include the risks involved in the starting material's supply chain. It is also new that procedures for the assessment, purchase and acceptance of starting materials, including critical packaging material should be documented as part of the quality management system.

Now the approval of suppliers of starting materials should be controlled by quality control and production.

The new draft also calls for a periodical re-auditing of suppliers of active substances and, certain excipients considered to be high risk materials used as starting materials. According to the draft, the re-audits aim at confirming the compliance with GMP requirements and at demonstrating the supply chain's functioning. Moreover, this text passage contains a footnote concerning the assessment of the supply chain. It makes recommendations on the respective record. It should include, for example, the DUNS number (number for the individual and clear identification) of the corresponding manufacturer, distributor, trader and shipper. The findings from the audits should be documented and the audit reports should be available for review by Inspectors.

In relation to each delivery the revised point 5.27 calls for the introduction of a documented verification of the supply chain's traceability.

Point 5.31 was newly introduced. Due to this, the following (initial) quotations are moved forwards by one point each. Now, 5.31 is about the minimal requirements concerning the subcontracting of the testing of starting materials by the manufacturers of the medicinal product (contract giver) to the approved starting material manufacturer (contract acceptor):

A formal agreement should be signed between the two parties. Among the respective responsibilities special attention should be paid to the distribution in order to ensure that the initial test results remain valid even after the transport (unchanged quality of the starting materials).

The contract giver should audit the contract acceptor at regular intervals, in order to assure compliance with GMP and the specifications and testing methods as described in the Marketing Authorisation.

When a designated person with appropriate qualifications and experience signs the certificate of analysis, he or she also confirms the compliance with the contract conditions.

Prior to the reduction of in-house testing, the contract giver should conduct at least three full analyses. He should also perform a full analysis at appropriate intervals in order to check the contract acceptor's reliability. Should this testing identify discrepancies then the acceptance of certificates of analysis should be discontinued until investigations are completed.

Interestingly, there are two further notes concerning 5.31, namely:

1.) The same requirements apply to packaging materials (reference to 5.40)

2.) Identity testing should be performed according to the specifications in the Marketing Authorisation

Conclusions: the proposed changes contain some explosive material. The assessment of the starting material's supply chain is new. And depending on the supplier, the implementation will perhaps not be that simple. The planned assessment of the starting materials in the quality management system will also cause irritations. What does this mean in concrete terms? It will surely also be discussed how the approval of suppliers of starting materials can be controlled by quality control and production. The availability of audit reports for review by Inspectors, which is required in the revision, almost seems to be an invitation to comment. The requirement specifications (appropriate qualifications and experience) concerning the "designated" person of the contract acceptor for the testing of starting materials leaves room for interpretation. The introduction of separate notes and footnotes is apparent. Why are they not incorporated directly into the text? The changes concerning the subcontracting of the starting materials are partly associated with the proposed changes of Chapter 7 ("Outsourced Activities") of the EU GMP Guide (see our GMP News from 17 November 2010). The announcement of changes affecting the chapter on cross-contamination remains just an announcement. Does this mean there will be a further revision of Chapter 5? Here, ISPE's new Risk-MaPP could play a role (see the following news in this newsletter).

The deadline for public consultation on the revision of Chapter 5 is on 28 February 2011. The industry should take advantage of its possibility to comment on this revision.

ECA Members will find a document with a comparison of the current version of Chapter 5 with the proposed revision in the ECA Members' Area under "GMP Regulations".

Sven Pommeranz
On behalf of the European Compliance Academy (ECA)

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