Standards role reversal

Good manufacturing practices within the pharmaceutical industry are becoming ever more stringent, with the influence moving from the US to the EU. Compounding this situation have been several industry changes with serious implications for manufacturers.

Ten years ago, there was a general belief in the pharmaceutical industry that US good manufacturing practice (GMP) requirements were the most stringent in the world and, thus, if US FDA expectations could be satisfied, then everyone would be happy. Now, the EU’s GMP expectations have become the most demanding and EU regulatory inspectors the most difficult to satisfy.

There are several areas within pharmaceutical GMP where EU expectations exceed those of the US, including:

• Clinical trials manufacturing – with the adoption of European directive 2001/20/EC and Annex 13, EU now has the most stringent GMP requirements for the manufacture and control of clinical supplies. Moreover, unlike the US, these GMP expectations are enforced via inspection.
• Sterile products manufacturing – the latest version of Annex 1 confirms EU’s GMP requirements as the most demanding for manufacturing sterile products. In short, if a company complies with Annex 1, it will meet global GMP expectations for sterile products, but if it complies only with US expectations, it will not satisfy EU requirements.
• Quality management systems – EU GMP inspectors have long placed greater emphasis on the quality management system than has the FDA. Unsurprisingly, US companies are frequently cited by European inspectors for failure to operate an effective quality management system. Adoption of ICH Q10 may redress this balance, but change is unlikely to be instantaneous.
• Raw material control – EU’s expectations for the control of raw materials, detailed in Annex 6 of the GMP guide, are far more stringent than those of FDA, especially in terms of requirements for assurance of identity and the development of risk-based, statistical sampling plans rather than the blanket application of n+1.
• Biopharmaceuticals manufacturing – the EU has long had detailed and demanding GMP requirements for the manufacture of human biological products in the form of Annex 2. By contrast, the FDA’s regulatory guidance for biologics and biotech products is far less detailed and onerous, being based predominantly on ICH Q7a and an ageing inspection guideline.
• Batch release – EU regulations surrounding batch release and the qualified person (QP) are without doubt the most rigorous in the world. Furthermore, criteria for batch review and assessment, as detailed in the EU GMP guide (Annex 16), exceed any similar guidance internationally.

Situation turnaround
This dramatic turnaround in roles between the two continents is due to several events. When it became clear that the FDA had neither the personnel nor the resources to continue to regulate in its traditional way, the agency developed its GMPs for the 21st century initiative, which sought to balance regulatory oversight with patient risk. Thus, the FDA became more pragmatic in its expectations.

The seemingly doomed attempt to have a Mutual Recognition Agreement between the US and the EU on GMP standards provided impetus for new GMP expectations in the EU to achieve equivalence of standards. Thus, EU implemented regulation on topics traditionally regarded as FDA requirements, notably product quality review, API manufacture and ongoing stability testing. However, in adding these US requirements to EU GMP expectations, additional demands were frequently added, increasing the level of stringency.

The EU has expanded rapidly. The arrival of new countries into the regulated pharmaceutical environment has posed challenges to regulators as they seek to communicate GMP requirements to an increasing number of countries with a variable history of regulation and GMP compliance. Not surprisingly, expansion of the EU has coincided with increased GMP regulation and guidance.

The swing in GMP stringency from FDA to EMEA has clear implications for pharmaceutical manufacturers: when preparing global quality standards: look first at EU GMP regulations and guidelines.