This will change from 30 October 2005, when the revised EU Pharmaceuticals Directive (2004/27/EC) will require that marketing authorisation holders must use drug substances that have been manufactured in accordance with Good Manufacturing Practice (GMP). The specific requirements are described in Annex 18 of the EU GMP guidelines, and are identical to the ICH guidelines used also in US and Japan.
Qualified Persons will be expected to confirm that drug substances were manufactured according to GMP as a part of their release of the finished dosage forms.
The EMEA issued a document in March 2005, which explained how the authorities intended to monitor implementation of this Directive. They expect marketing authorisation holders to carry out, or have carried out on their behalf, regular (every 2-3 years) audits of all of their drug substance manufacturers and suppliers. The audit programmes and reports are likely to be reviewed during formal regulatory inspections and the absence of these would be reported as a GMP deficiency.
All manufacturing, packaging and labelling steps, from the introduction of the starting materials through to delivery to the dosage form manufacturer, must be carried out according to the GMP guidelines. This includes:
Other procedures, eg milling, micronising, irradiation etc
Breaking bulk and repackaging
Labelling (including simply adding an “imported by” label without opening or sampling the packs)
This will create difficulties for companies sourcing their actives from non-EU countries. They will need to know not only the site where the bulk drug substance was manufactured, but also whether other companies or sites may have carried out some production activities, repacked the bulk into smaller containers or relabelled the original one.
Marketing authorisation holders will need to make plans for the implementation of this Directive.
1.Make a list of all drug substance suppliers named in marketing authorisations.
2.Submit Variations to remove any that are no longer used.
3.Contact the remaining suppliers and ask for details of the actual manufacturer and any sub-contractors, brokers and distributors used.
4.Find out whether these companies have been inspected by any regulatory authorities, and whether inspection reports or GMP certificates can be accessed.
5.Carry out audits of all of the companies in the supply chain. This could be done by an employee of the marketing authorisation holder, or by an external consultant. However, the auditor must be responsible to the marketing authorisation holder, not the drug substance manufacturer.
6.Draw up Technical Agreements with the manufacturers to ensure that they do not change any parts of the supply chain without informing the marketing authorisation holder.
This is likely to be a considerable workload for companies that source large numbers of drug substances from non-EU suppliers. Some Marketing Authorisation holders may not have staff with sufficient time or expertise to be able to audit their drug substance suppliers.
The introduction of GMP also requires considerable changes in the way that the drug substance manufacturers work. They may be more used to working within the bulk chemical industry, and may not fully understand the need for documentation of processes and investigation of deviations. Some drug substance manufacturers consider that allowing their customers access to manufacturing plant and documentation will breach their confidentiality.
Many companies are choosing to resolve these issues by employing contract auditors who have the resource and expertise to cover all areas of the manufacturing process. The drug substance manufacturers use external consultants to ensure that their facilities, systems and procedures comply with GMP before customers visit. Their customers use them to relieve resource and also to provide “Chinese Walls” between the manufacturer and customer. The customer receives a report which confirms that the manufacturer is GMP-compliant without them having access to confidential information which could breach the Intellectual Property of the manufacturer.
So, after much discussion, the EU Directive on GMP for drug substances is finally about to arrive. Drug substance manufacturers and their customers will need to plan now to ensure that batches manufactured after October 2005 can be released by the Qualified Person.