Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Essential Aspects of Quality Assurance in Outsourcing Production and Purchase of Active Pharmaceutical Ingredients

Claudia Koritke (Abschlußjahr: 2003)

The quality of a medicinal product is not only accomplished by controlled manufacturing of the finished dosage form, but rather depends on the quality of the starting materials used. Same holds for the safety, a finished medicinal product will only be as safe as its ingredients are. Consequently, it is in the responsibility of pharmaceutical companies for quality and safety of their medicinal product to only employ starting materials of appropriate quality and purity.

Good manufacturing practice plays an important role in this context. Unlike to the legal situation in the US, GMP for APIs is not yet mandatory in the European Union; however, in the course of the review of the pharmaceutical legislation a corresponding requirement will be introduced.

Nonetheless, it is highly recommended to apply GMP in the field of APIs already now. The rules of good manufacturing practice for active pharmaceutical ingredients are laid down in the tripartite harmonised guideline ICH Q7A, released for information in November 2000.

For several reasons pharmaceutical companies decide for outsourcing the production or purchase of the API. Although not being involved in manufacturing of the active substance anymore, the responsibility for its quality stays with the finished product manufacturer.

Thus, contract manufacturers and API suppliers have to be selected carefully. Apart from specialisation and know-how with regard to the process to be outsourced, compliance with GMP and the quality management system have to be considered.
Prior to the start of production at a contract site respectively placing the first order with a certain supplier, the manufacturer's facilities need to be inspected to verify compliance with GMP. The basic principles of such customer audits are described within the scope of this thesis.

Another aspect to be taken into account is the validation of the API production process. Process validation, as required by current GMP guidelines for active pharmaceutical ingredients, shall provide evidence whether the manufacturing process at the contract site consistently delivers a product matching the specifications and quality attributes.

The various incidents of the last years emphasize the need for adequate measures of quality assurance also during distribution and trading of the APIs, regardless of whether these are purchased directly from the manufacturer or, which is common practice, traders or agents are involved.

In order to maintain the quality as certified by the API manufacturer throughout the entire distribution chain, storage, transport and distribution of APIs have to be performed in compliance with GMP as well.

The corresponding rules can be subsumed under good distribution practices. Besides the GMP requirements for storage and distribution of APIs, ICH Q7A lays down the regulations for traders, brokers and agents.

Since active pharmaceutical ingredients are used for production of medicinal products, they have to be considered as sensitive goods, which have to be treated with special care. Any risk that may come from APIs of inappropriate quality must be prevented for the protection of the patients subsequently using the medicinal product.

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