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EU GMP revision comments focus on cross-contamination

Published on 03/12/13 at 08:22am
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Earlier this year the EU Commission published draft versions of four chapters in its Good Manufacturing Practice (GMP) guide, and comments on the updates have now been published on its website

Many of the comments relate to the revisions to Chapter 3 Premises and Equipment, and particularly new guidance on cross-contamination, toxicological evaluations and the use of shared facilities, which is linked closely to a number of elements appearing in Chapter 5 Production.

The European Federation of Pharmaceutical Industries & Associations (EFPIA) for example, welcomed the changes in principle but pointed to potential problems on the cross-contamination topic in light of draft proposals on exposure limits, for use in risk identification in the manufacture of different medicinal products in shared facilities, that was published by the Commission towards the end of last year.

This asks for toxicological assessments to underpin a risk-based approach to cross-contamination control in shared facilities, and specifically calculations of permitted daily exposure (PDE) data based on NOEL (no observed effect level) or LOEL (lowest observed effect level). EFPIA is concerned that this type of data may not be available for some drugs, for example, investigational medicinal products (IMPs).

Contract manufacturer Fujifilm Diosynth Biotechnologies (FDB) echoed those concerns, saying the cross-contamination proposals could prove overly restrictive for sites manufacturing multiple IMPs and interfere with the conduct of early-stage clinical trials, while French industry body LEEM suggested a distinction should be made between shared facilities and shared equipment.

"One could probably manufacture certain products within the same facilities, as long as the equipment for such product is dedicated and the conditions for cross contamination can be shown to be non-existent," said LEEM. 

The International Society of Pharmaceutical Engineers (ISPE) said mechanisms and routes of cross contamination are not clearly identified in the guidance, "which makes establishing whether particular controls are appropriate in a particular case difficult". The organisation would like to see generic cross-contamination routes identified in the guideline.

EFPIA said that the complexity of the topic means it would be useful to have a practical workshop for regulators and industry, timed to take place before the guidance and Chapter 3 and 5 revisions are finalised.

Meanwhile, several commentators asked for less stringent wording on allowing non-medicinal products to be made in pharma facilities, pointing out that only allowing this in ‘exceptional circumstances’ does not reflect current practice where companies may also make food supplements, medical devices or cosmetics using the same equipment employed for production of medicines. 

For example, the APIC asked specifically whether it would be acceptable for over-the-counter (OTC) medicines to be manufactured in equipment used for medicinal products.

The other major change in Chapter 5 was the addition of supply chain security measures, and particularly increased control of the sources of active pharmaceutical ingredients (APIs) and other starting materials. 

The proposal states that "where possible starting materials should be purchased directly from the manufacturer of the starting material", but several commentators asked for the language to be softened to allow purchase from a suitably qualified or approved distributor. 

The International Pharmaceutical Excipients Council (IPEC) Europe also asked for flexibility on the requirement for finished product manufacturers to audit sites making starting materials, noting that it would be useful if this could be performed by ‘appropriately-trained’ third-parties.

The change would allow the use of third-party audit of sites in accordance with standards set by certification bodies, including the recently-formed EXCiPACT approach for excipients.

The main change to Chapter 6 Quality Control relate to new requirements on the transfer of analytical methods as well as new regulations about the handling of out-of-specification results.

There were multiple requests for removal of a reference to ‘anomalous’ results as being superfluous, as out-of-specification (OOS) and out-of-trend (OOT) is sufficient to cover all eventualities, but the majority of the comment related to relatively minor tweaks and wording changes.

Finally, the Commission's update to Chapter 8 Complaints and Product Recall introduced changes such as a greater emphasis on quality management systems when evaluating quality defects that could lead to product recalls, as well as new guidance on when defects need to be reported to the regulator. 

Some respondents asked for wider use of a risk-assessment approach to gauge whether or not competent authorities should be informed of quality defects or other issues such as counterfeiting, for example if the defect is severe, the product in question is a life-saving drug or the defect/recall could lead to shortages.

EFPIA has also suggested that regulators need not be informed if defective product is destined to be destroyed, although it said notification should occur if it is to be reworked. 

The EU Commission is scheduled to finalise the revisions to the chapters next year. It already revised Chapters 1 and 7  of the GMP Guide last year, with the changes to those coming into force on 31 January, 2013.

Phil Taylor

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