»GMP Notebook By Efrem H. Zaret, PhD [back to contents]
Revised GMP Legislation in the EU
A new directive requires that all manufacturers operate an effective quality management system.
It is clear that the US pharmaceutical industry is not working alone: The pharmaceutical industry is a worldwide enterprise and is particularly strong in Europe. In the last 10 years, the industry there has grown, and Europe now represents 25% of the world pharmaceutical market.1 The EU will soon represent more than 500,000,000 people.
On October 8, 2003, the EU published Commission Directive 2003/94/EC, which describes the “… principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use.” The publication confirms that all medicinal products manufactured or imported into the EU are to be manufactured in accordance with the GMPs. This includes medicinal products to be exported from the EU.
The EU GMPs were published in 1991 in Commission Directive 91/356/EEC. The new directive indicates that most provisions of 91/356/EEC must be modified for clarity, and also indicates that the 1991 directive is repealed. EU member states are required to promulgate and adopt the regulations in the directive as new laws by April 30, 2004. However, member states need to comply with the new directive as a minimum and may adopt more stringent regulations.
Effective Quality Management
Under the new directive, all manufacturers must operate an effective quality management system. This requires that implementation of a pharmaceutical quality assurance system involve active management participation. The manufacturer must establish principles and guidelines of good manufacturing practice with respect to quality management, personnel, premises and equipment, documentation, production, quality control, contracting out, complaints, product recall and self-inspection. For products made within the EU, the manufacturer needs to ensure that its manufacturing operations are in compliance with GMPs and manufacturing authorization.
For approved products and investigational medicinal products (clinical trial materials) imported into the EU, importers must ensure that the products have been manufactured according to GMP standards that are at least equivalent to the EU GMPs. For approved products, importers must ensure that the manufacturer has been approved by the product’s marketing authorization. For clinical trial materials, the manufacturer has to have been accepted by the competent national health authority of the country where the clinical trial will run.
Manufacturers must have enough competent and qualified personnel to meet the objectives of the quality system, which must be supported by the managerial and supervisory staff, including the qualified person responsible for system implementation. The qualified person is licensed and responsible for the release of each product batch, and also certifies that the batch meets specifications and was manufactured in compliance with the EU GMPs. For product that is imported into the EU, the qualified person must verify the compliance of the foreign manufacturing site.
Responsibilities must be defined in job descriptions approved according to the manufacturer’s procedures. Staff organization, including reporting relationships, must be available on an organization chart, which must also be approved. The directive requires that staff must be given sufficient authority to carry out their responsibilities. Mandated staff training should cover the theory and application of good manufacturing practice and quality assurance as appropriate. The training must include procedures that address health, hygiene practices and clothing of personnel. Training effectiveness must be verified.
Facility Layout and Operation
The manufacturing plant must be “laid out, designed, constructed, adapted and maintained to suit the intended operation.” Facility operation should minimize the risk of error and permit effective maintenance and cleaning to minimize the risk of cross contamination and “any adverse effect on the quality of the product.” All premises and equipment critical to product quality must be appropriately qualified and validated.
Documentation requirements are presented in detail. The documentation should:
1) Form the core of a system based on:
a) Specifications;
b) Manufacturing formulae;
c) Processing instructions;
d) Packaging instructions;
e) Procedures and records that cover the various operations.
2) Be clear, error free and up-to-date.
3) Be based on pre-established procedures kept available with specific batch documentation.
4) Allow the history of manufacture of each batch to be traced.
5) Allow any changes introduced during the development of a clinical trial material to be traced.
6) Be retained for one year after the expiration date or at least five years after certification, whichever is longer, if it describes a marketed pharmaceutical product.
7) Be retained for at least five years after the completion of the clinical trial or formal discontinuation of the last trial in which the batch was used if it describes a clinical trial material.
8) Be readily available in legible form if stored by validated electronic, photographic or other data processing systems.
9) Be protected against loss or damage of data by duplication or back-up and transfered onto another storage system. Audit trails must also be maintained. Production operations are to be carried out according to the pre-established instructions and procedures and in conformance to GMPs. The manufacturer must provide adequate and sufficient resources for in-process controls; any deviations and product defects must be documented and investigated. Critical phases of manufacturing must be validated and regularly revalidated, and any new procedure or important modification of an existing procedure must be validated.
For clinical trial materials, particular care is required after blinding to prevent mix-ups. The manufacturing process for clinical trial materials should be validated completely, if appropriate, taking into account the development stage of the clinical material. Critical steps such as sterilization must be validated, and all steps in the design and development of the manufacturing process must be fully documented.
Quality Control
Someone with the requisite qualifications, independent of production, must be in charge of quality control. Quality control laboratories must be appropriately staffed and equipped to test and examine starting materials, packaging materials, in-process and finished products. Contract laboratories may be used. It is not mandatory to analyze products imported from third countries.
Manufacturers must conduct repeated self-inspections as part of a quality assurance system. Self-inspections should monitor the implementation and conduct of the GMPs and propose corrective actions if needed. The self-inspections and the corrective actions taken must be recorded.
A written contract must describe any manufacturing operation or support performed by contractors. The contract should contain provisions that:
• Define the responsibility of each party;
• Define observance of GMPs by the contractor;
• Define how the qualified person responsible for batch certification is to perform his duties;
• Define conditions under which the contractor may subcontract work; and
• Require the contractor to comply with principles and guidelines of GMP and to allow inspections by regulators.
Evaluating Finished Products
Before release for sale, distribution or clinical trial, finished products must be evaluated to ensure that the manufacturing process conforms to the documentation. The review should consider the in-process control results and product conformance to specifications.
Samples of finished product must be retained for at least one year after the expiration date. Unless a longer retention period is specified by the country of manufacture, starting materials other than solvents, gases and water must be retained for at least two years after the release of the product. These must be available to regulators. In special cases, the marketing approval may include other sample and product retention requirements.
For clinical trial materials, each batch of bulk-formulated product and key-packaging components for finished batches should be retained for at least two years after completion or formal discontinuation of the last trial in which the batch was used, whichever is longer. Labeling of clinical trial materials must ensure patient protection, the proper use of clinical material, and allow traceability and identification of the product and the trial.
Reviewing Complaints
Manufacturers must have a system for recording and reviewing complaints combined with a system for recalling, “promptly and at any time,” any product in the distribution chain. The manufacturer must record and investigate all complaints regarding a product defect. They must also notify regulators of any defect that could result in a recall or abnormal restriction of supply.
For clinical trial materials, the manufacturer and the trial sponsor must have a system of recording and reviewing complaints coupled with a recall procedure for any materials that have entered the distribution network. Manufacturers must notify regulators and provide the location of all trial sites. Trial sponsors must provide procedures for rapidly identifying blinded products to allow for prompt recall if necessary. The sponsor must ensure that the identity of the blinded product is disclosed only as much as is necessary.
The new directive provides high-level regulation of good manufacturing practices for pharmaceuticals in the EU. The details of the GMPs are provided in Volume IV of the Rules Governing Medicinal Products in the European Union. They can be found on the Internet at http: //pharmacos.eudra.org/F2/eudralex/ index.htm. Two sections, sterile products and investigational medicinal products, have been revised this year. Even for those not manufacturing or importing products for the EU, Annex 16 of the GMPs requires special attention, as it covers the responsibilities of the qualified person, a concept not found in the FDA’s GMPs.
Efrem Zaret, PhD consults in GMP compliance and training, quality assurance and control, clinical supplies logistics, regulatory affairs, and product and package development. Reach him at 908-753-8566 or
[email protected].