European Commission Seeks to Tighten the API Supply Chain

Supply-chain integrity is a critical issue for the pharmaceutical industry. Recent proposals by the European Commission (EC) to impose stricter anticounterfeiting measures on drugs in Europe include tightening requirements relating to manufacture and related supply-chain issues for active pharmaceutical ingredients (APIs).

In March 2008, the EC issued a public consultation on proposed anticounterfeiting measures that would amend European Union legislation. A major thrust of these reforms are to address problems in packaging and related supply-chain activities. The proposal requires tamper-evident packaging on all products, use of overt and covert authentication features, strengthening product identification at an individual pack level through a harmonized coding standard, banning repackaging of drugs, and strengthening measures for liabilities and criminal penalties.

In addition to addressing problems in packaging and the supply chain from the manufacturer to end-product users, the EC also noted the problem of substandard APIs. “The risk of counterfeit or substandard active substances entering the supply chain towards a medicinal product poses additional risks to patients,” said the EC in its proposal. “For example, in the early 2000s, numberous side effects were connected with antibiotics containing gentamicin as an active substance. These effects were assumed to be related to faulty manufacture and impurities of active substances.”

Mandatory notification

The EC is considering several measures to tighten requirements for good manufacturing practices (GMPs) for APIs and inspections. One measure would require a mandatory notification procedure for manufacturers and importers of APIs. The EC proposal points out that the legal framework for APIs applies only to the manufacturing stage, and that the activities of distributors, traders, agents, and brokers, are outside the scope of EU legislation. The EC proposes to subject the manufacturing and import of APIs to a mandatory notification procedure and to enter such information into an EU database, such as by extending the EudraGMP database. The EudraGMP database contains information on all manufacturing and importation authorizations issued by competent authorities in the European Economic Area. It also contains information on GMP certificates, which member states issue following each GMP inspection.

The European Federation of Pharmaceutical Industries and Associations (EFPIA), the trade association representing European pharmaceutical manufacturers, largely agreed to the measures, but also emphasized the importance of using risk-based strategies.

“Accountabilities and roles and responsibilities for any API notification procedure needs to be clearly defined for the ‘different actors’ in the supply chain,” said EFPIA in a prepared response. “Minimum qualifications and experience for ‘qualified auditors’ for APIs should be specified.”

EFPIA emphasizes that a risk-based approach is necessary and that cooperation with and acceptance of inspection reports from other agencies should be sought to avoid duplication of effort.

Member states also weighed in on the debate. The Medicines and Healthcare products Regulatory Agency (MHRA), which regulates pharmaceutical manufacturers in the United Kingdom, pointed out that mandatory notification should not only include APIs manufactured in a given country but should also include product that is “passing through” a member state such as from one country to another. It also noted that the manufacture of atypical APIs, where the end user of the material may be unknown, needs to be addressed.

Enhancing audit and enforceability of GMPs
The EC is further recommending ways to improve audit and enforceability of GMPs. Currently, the manufacturing and importation of APIs is regulated in the EU by requiring the manufacturing authorization holder to use APIs manufactured under GMPs. Although manufacturers are required to test APIs supplied to them, such testing does not address residues or inappropriate use of toxic solvents and impurities, says the EC in its public consultation. The EC is proposing to:

• Make regular audits of API suppliers on GMP compliance by manufacturers and importers of medicinal products mandatory and require that auditors by sufficiently qualified.

• Require, where scientifically feasible, control of APIs via discriminating analytical techniques such as fingerprint technologies, and require near infrared spectroscopy as a mandatory method for identification. Such testing is meant to identify deviations of the manufacturing process and manufacturing site for each batch.

• Turn GMPs for APIs placed on the European Community market into EC Directive in order to enhance enforceability.

Although agreeing that minimum qualifications and experience should be specified for qualified auditors, EFPIA is uncertain whether more GMP audits would enhance product safety. “The key question is whether the manufacturing process has followed the registered manufacturing practice–a question of regulatory compliance more than a GMP question,” said EFPIA in a prepared response.

EFPIA also agreed that an API should undergo testing for unknown impurities using fingerprint technologies, but expressed concern over mandating specific types of testing. “The cost implications of introducing near infrared spectroscopy tests for all APIs needs further review,” said EFPIA. “…Imposing this type of testing could risk promoting reliance on receipt testing which is no substitute for good supplier management based on a risk assessment, technical agreements, change control, knowledge of products, process performance, etc.”

MHRA also pointed out that although NIR is effective for fingerprinting finished dosage forms, its potential in testing APIs has yet to be established.

As to the level of API inspections, the EFPIA concurred that there is variability as to which EC member states do routine API inspections and those who do not, again citing a need for increased cooperation with and acceptance of inspection reports from other agencies. 

Improving GMP inspections
The EC is also proposing to strengthen the inspection process. Currently, inspections by competent authorities in the European Community are restricted to cases of suspected noncompliance. “This limitation raises particular concerns with regard to the manufacturing of active substances in third countries where GMP are not equivalent to those laid down in the Community or where inspections and control mechanisms are insufficient,” said the EC in its consultation.

To address these problems, the EC is recommending that competent authorities be able to carry out announced or unannounced inspections of API manufacturers to verify GMP compliance for APIs that are sold in the European Community. This requirement would further apply to manufacturers in countries outside of the European Community that export APIs into the European Community by requiring member states, the EC, or the European Medicines Agency to inspect those facilities if noncompliance to GMPs are suspected or the country in which the APIs are exported from do not have equivalent GMPs. 

The EC is evaluating public input on its proposals and plans to offer a summary of the outcome of the public consultation.