GDP-compliant Storage of APIs: What needs to be considered?

Medicinal products are subject to special regulations for storage and transport. Good Distribution Practice (GDP) is the part of quality assurance that ensures that the quality of medicinal products is maintained at all stages of the supply chain.

However, GDP is not limited to pharmaceuticals. Rather, GDP starts earlier, namely with the transport and storage of the active pharmaceutical ingredients (APIs) used for production. But what general requirements actually apply to the GDP-compliant storage of APIs for medicinal products for human use or veterinary medicinal products?

Definition

The "Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use (2015/C 95/01)" gives the following definition for the term "Holding":

• "Storing active substances."

For APIs for veterinary medicinal products, there is an analogous definition in article 2(e) of the "Commission Implementing Regulation (EU) 2021/1280 of 2 August 2021 as regards measures on good distribution practice for active substances used as starting materials in veterinary medicinal products in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council":

• "'Holding’ means storing active substances used as starting materials in veterinary medicinal products."

Requirements for the Storage of APIs for Medicinal Products for Human Use

The storage of APIs for medicinal products for human use is subject to quite specific requirements. In this context, chapter 5 (Premises and Equipment) of the EU GDP Guidelines should on the one hand be mentioned. According to section 5.1, the following applies:

• Premises and equipment should be suitable and adequate to ensure proper storage and protection from contamination.
• Unauthorised access should be prevented.
• Monitoring devices should be calibrated according to an approved schedule against certified traceable standards.

On the other hand, chapter 6 (Operations), especially subchapters 6.7 to 6.12 (Storage) must be followed. There you will find the following requirements:

• Storage should be carried out under the conditions specified by the manufacturer, where necessary at controlled temperature or humidity.
• The storage conditions should be monitored and records maintained. These records should be reviewed regularly by the person responsible for the quality system.
• Specific storage conditions should be taken into account.
• The storage facilities should be clean and free from litter, dust and pests.
• Adequate precautions should be taken against spillage or breakage, attack by micro-organisms and cross contamination.
• There should be a system to ensure stock rotation.
• Electronic warehouse management systems should be validated.
• APIs beyond their expiry date should be separated from approved stock and not be supplied.
• Subcontractors must be controlled and a written contract must be concluded between the contract giver and contract acceptor. The contract acceptor should not subcontract any of the work entrusted to him under the contract without the contract giver’s written authorisation.

Requirements for the Storage of APIs for Veterinary Medicinal Products

The requirements for the storage of active substances for veterinary medicinal products are comparable to those for human medicinal products.

Article 9 (Requirements for premises and equipment) of Implementing Regulation (EU) 2021/1280 states the following:

• Premises and equipment shall be suitably located, designed, constructed and maintained to ensure appropriate operations, protection from contamination, and proper distribution.
• There shall be sufficient space, lighting and ventilation to ensure required segregation, appropriate storage conditions and cleanliness.
• Monitoring devices shall be subject to calibration against certified traceable standards, according to an approved schedule.
• Appropriate cleaning equipment and cleaning agents shall be chosen and used so as not to constitute a source of contamination.
• Premises shall be protected from the entry of birds, rodents, insects and other animals.
• A rodent and a pest control programme shall be in place.
• Segregated areas shall be provided for the storage of received, quarantined, rejected, recalled and returned active substances used as starting materials in veterinary medicinal products, including those with damaged packaging.
• Any system replacing physical segregation must be validated.
• Segregated areas and products shall be appropriately identified.

Chapter 16 (Storage) must also be taken into account. The points listed there correspond, for the most part even in the wording, to those from subchapters 6.7 to 6.12 (Storage) of the EU GDP Guidelines for APIs for medicinal products for human use.

According to chapter 17 (Outsourced activities) of the Implementing Regulation (EU) 2021/1280, also analogous to the requirements for active substances of medicinal products for human use, in the case of subcontracting of the storage activity, a written contract must be signed.