The new requirements of the "Guidelines on the formalised risk assessment for excipients"

The most important document so far as concerns "GMP for excipients" was published in the Official Journal of the European Union this year on 21 March. It has the somewhat ponderous title "Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use" (document classification: 2015/C 95/02). We reported on this in our news "EU Commission issues two final Guidelines: GMP for Excipients and GDP for APIs".

During the longer than two years period after the publication of the draft of these guidelines the fundamental principles for ascertaining the appropriate good manufacturing practice formulated in the draft were the main guides and the pharmaceutical industry had time to adapt to these requirements. But the now valid final guidelines differ considerably from the draft document. This means the companies concerned are now faced with additional requirements and they face the challenge to implement these requirements for medicinal products being in the process of development immediately and for medicinal products already authorised until 21 March 2016.

The following summary lists the newly formulated additional requirements from the final document that were not already included in the guideline draft.

Determination of appropriate GMP based on type and use of excipient

The manufacturing authorisation holder should take into consideration the following:

• potential for any impurities carried over from other processes, in absence of dedicated equipment and/or facilities; 
• cold chain management, if appropriate; 
• supply chain complexity; 
• stability of excipient; 
• packaging integrity evidence; 
• known fraudulent adulterations related to the use and function of each single excipient; 
• other factors identified or known to be relevant to assuring patient safety for each excipient; 
• qualification program of suppliers; 
• change management and deviation management system; 
• environmental controls and storage conditions.

Confirmation of application of appropriate GMP

Once the appropriate GMP for the excipient and the risk profile of the excipient manufacturer have been determined, ongoing risk review should be performed through mechanisms such as:

• monitoring and trend analysis of excipient quality; 
• observed organisational, procedural or technical/process changes at the excipient manufacturer; 
• questionnaires; 
• based on the outcome of the risk review, the established control strategy should be reviewed and revised if needed.

The requirements for ascertaining and ensuring the appropriate GMP laid down in the new guidelines are rather challenging as a whole. The initial expense is enormous since the "GMP made-to-measure" has to be defined not only for each single excipient but also for each pharmaceutical form (if the same excipient is used in different pharmaceutical forms). The pharmaceutical companies concerned must now extent their risk profiles for excipients already drawn up according to the new requirements. Additionally, the appropriate GMP and the required two risk profiles (for the excipient and the manufacturer of the excipient) must be drawn up for all authorised products in less than one year (!).

The new guidelines are also part of the EU GMP-Guideline Part III (Eudralex - Volume 4). They can be found there in the respective national language of the EU member states.