European Commission Finally Publishes Changes to GMP Guidelines
Almost two years after the initial changes were proposed, the European Commission (EC) finally issued changes to its GMP guidelines in Chapter 1, Chapter 7 and Annex 2 of EudraLex Volume 4. The revisions, which will come into effect on January 31, 2013, are intended to ensure complete adherence to the principles of ICH Q10 Pharmaceutical Quality System including outsourced manufacturing and analysis, and biologic active pharmaceutical ingredients.
Chapter 1 is the keystone of Volume 4 and sets the tone and expectations for the other chapters and annexes. One major change in this Chapter is harmonization with terminology used in ICH Q10 where the title “Quality Management” is replaced with “Pharma Quality System (PQS).” The responsibility of Senior Management to ensure that a PQS is in place is emphasized by the requirement that a Quality Manual, explicitly describing the quality management system and management responsibilities, be established. Chapter 1 now emphasizes that GMP “applies to the lifecycle stages from the manufacture of investigational medicinal products, technology transfer, commercial manufacturing through to product discontinuation”. Although the need for proper corrective and preventive action (CAPA) had not been expressly defined in the previous version of this Chapter, the new version defines a clear requirement for this, based upon root cause analysis, following Quality Risk Management principles. For those companies who were less than rigorous in their investigations and corrective actions, these revisions will be a wake-up call to the explicit expectations of the EMA.
The Product Quality Review section in Chapter 1 has been expanded to include an emphasis on selection and monitoring of suppliers as well as supply chain traceability for starting materials. In the wake of several high profile product adulterations, we see this as a very important addition to ensure supply chain security, as we discussed in a previous blog.
The next major changes in Volume 4 are in Chapter 7, which has been renamed “Outsourced Activities” to more accurately reflect the scope of the chapter beyond contract manufacture and analysis to include other outsourced activities. The responsibilities of Contract Giver and Contract Acceptor have been revised and extended to ensure they are completely understood. The Contract Giver must control and review any outsourced activities under its Pharma Quality System. Before outsourcing any activities, the Contract Giver should carry out a comprehensive assessment of the Contract Acceptor’s GMP competency (e.g., by audits). Regrettably, this important step is sometimes delayed until after the contract has been awarded, which should not happen. Throughout the outsourcing period, the Contract Giver is responsible for monitoring and documenting the quality of the Contract Acceptor’s performance and where necessary the identification and implementation of any needed improvement. This responsibility of the Contract Giver is spelled out for the first time, requiring greater surveillance of contractors. Chapter 7 also extends and clarifies the expectations for the Contract Acceptor. It is made plain that the Contract Acceptor cannot subcontract any of the work without the Contract Giver’s prior evaluation and approval. This ensures that critical activities are not being performed by unqualified parties. Additionally, the Contract Acceptor should not introduce unauthorized changes, which may adversely affect the quality of the activities outsourced by the Contract Giver. A particularly important addition to this chapter is the requirement to permit the Contract Giver to audit the Contract Acceptor’s subcontractors, allowing for an additional layer of over-sight of the supply chain.
The required formal contract must define the responsibilities and the communication processes relating to the outsourced activities. It must contain clear definitions of the decision making authority, approval rights and batch failure remedies, as well as the responsible party for each step of the outsourced activity, including knowledge management, technology transfer, subcontracting, and the control of quality of purchased materials and final product. All records related to the outsourced activities should be kept by, or be available to, the Contract Giver.
The revisions to Annex 2 emphasize the need to apply quality risk assessments (according to ICH Q9 Quality Risk Management) to all steps in the biologic product manufacturing process, so that the appropriate amount of process control and quality analysis can be applied. This would be in line with ICH Q8 Pharmaceutical Development and is now the accepted method, ensuring that the stringency of control and GMP compliance increases as the product progresses through the supply chain. Collectively, these changes will strengthen GMP compliance, product safety and supply chain security in the European arena, and we are pleased to see them implemented. While many high functioning biopharmaceutical developers incorporated the concepts of these updated guidelines into their operations years ago, it will be important for the laggards to come up to speed quickly, or face the consequences.