QP Declaration of GMP Compliance of Active Substances and Supply Chain Traceability

The EMA has published a draft template for the Qualified Person's declaration of GMP compliance of the active substance used in Marketing Authorisation and Variation applications, the ‘QP declaration'. This article explains what's needed to complete this and how Somerset House Consultants experts can assist.

GMP Auditing / Compliance

GMP responsibilities of drug product manufacturers

Drug product manufacturers have three main GMP responsibilities regarding the API they use:

Verify the GMP compliance of all parties in the supply chain and that all sources are in accordance with relevant marketing authorisations.

Fully understand and control the supply chain of active substances used by them (including brokers, re-labellers and re-packagers) and take steps to shorten the supply chain wherever possible.

Clearly demonstrate that each batch of active substance has been sourced through this supply chain.

The QP declaration demonstrates compliance to the regulators.

GMP auditing of active substance manufacturers

Manufacturing Authorisation holders are expected to audit all of their active substance suppliers to ensure GMP compliance. The audits must be carried out before Marketing Authorisation applications are submitted. GMP certificates from regulatory authorities, such as MHRA, cannot replace direct audits. The auditor must be suitably trained and experienced and can be either an employee or a third party contractor, such as Somerset House Consultants. Ideally, the lead auditor should have an ISO auditing qualification. If a contract auditor is used, there must be a Technical Agreement in place with them.

MA holders must keep copies of the audit reports for inspection by the regulatory authorities.

API Supply Chain Traceability

The supply chain is the ‘family tree' for the active substance, tracing its history or supply chain from critical raw material(s) used in the manufacture of the active substance to the manufacturer of the dosage form. This therefore includes brokers, traders, repackers, relabellers, micronisers and importers, as well as the manufacturer. Many drug substances used in EU and USA are manufactured in the Far East, and the supply chains can be very long, leading to risks of degradation, contamination or counterfeiting.

Manufacturing Authorisation holders must document the supply chain and use ICH Q9 risk management procedures to reduce risk. The Qualified Person must confirm that the supply chain traceability has been established when they sign the declaration. Again, the documentation may be inspected by the regulator.

QP Declaration

QP declarations have been included in Marketing Authorisation and Variation submissions since 2007, but this is the first time the authorities have produced a template document to ensure that they contain all of the information required.

In principle, individual declarations are expected from the Qualified Person of each Manufacturing Authorisation holder that uses the active substance as a starting material and the QP of each Manufacturing Authorisation holder responsible for importation / batch certification if this is different. That is because this QP takes overall responsibility for each batch

The QP signs to confirm that the API manufacturer has been audited and found to be GMP compliant, the supply chain has been established and documented, there exists a documented risk assessment for all sites in the supply chain and the documentation is available for inspection

Since Qualified Persons must be resident in the EEA, declarations by manufacturers in third countries, including those located within MRA partners, are not acceptable

All sites concerned with part processing during API synthesis and all sites upstream of the API manufacturing sites, but before the finished product, e.g. micronisation sites, should also be included in the QP declaration.

A QP declaration is required for all submissions, whether by an EDQM CEP Certificate of Suitability, Active Substance Master File (ASMF) or full details in the dossier

How to comply with these requirements

These additional auditing and risk assessment requirements will place additional pressure on QP resources. It's important to get this right, otherwise regulatory submissions will be rejected and GMP inspectors will regard this as a ‘Critical' or ‘Major' deficiency.

Many smaller companies will not have qualified auditors amongst their staff. One option is to contract this work to specialists, who can audit the API manufacturers, establish the supply chain and carry out documented risk assessments, in full compliance with GMP and ICH Q9 requirements.

Somerset House Consultants, with ISO-qualified auditors, has considerable experience in carrying out supply chain risk assessments for companies worldwide. Our consultants can help companies complete QP declarations and supply chain risk assessments meeting all regulatory requirements.

Robert Haslam
Somerset House Consultants