Excipients: Final EU Guideline for formalized risk assessment ensuring appropriate GMP published

After a consultation period of about two years (the respective Draft guidelines have been published in 02/2013), the European Commission has published end of March the respective final EU GMP Excipient guideline (official title: “Guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use”). The time frame for implementation of this guideline is listed with one year i.e. by 21 March 2016 excipients used in approved and marketed medicinal products must have been evaluated according to the guideline. The “Manufacturing authorisation holders should have the risk assessment/management documentation for appropriate GMP for excipients available on site for review by GMP inspectors.” according to the guideline.

The guide consists of three different sections covering

  • Chapter 2: Determination of appropriate GMP based on type of excipient
  • Chapter 3: Determination of Excipient Manufacturer´s Risk Profile
  • Chapter 4: Confirmation of Application of Appropriate GMP

The final guideline is considerably more detailed, compared to the draft version as follows: Under Chapter 2 e.g. potential areas to be considered have been extended from 7 items to 10, with the following items have been added (bold) and/or modified:

  • (vi) potential for any impurities carried over from other processes, in absence of dedicated equipment and/or facilities
  • (vii) environmental control and storage/transportation conditions including cold chain management, if appropriate
  • (viii) supply chain complexity
  • (ix) stability of excipient
  • (x) packaging integrity evidence

The minimum high level GMP elements to be considered have been extended from 14 to 16 with the following items have been added (bold) and/or modified:

  • (ix) qualification program of suppliers
  • (xiv) change management and deviation management system
  • Any other (non-GMP) measures required to manage or control the identified risk
  • (xvi) environmental control and storage conditions

Chapter 3 of the final guideline is literally unchanged.

Under Chapter 4 e.g. the list of ongoing risk review mechanisms has been extended from 5 to 8 with the following items have been added (bold) and/or modified:

  • (iii) monitoring and trend analysis of excipient quality
  • (vi) observed organisational, procedural or technical/process changes at the excipient manufacturer
  • (viii) questionnaire.

APIs: Final EU Good Distribution Practice (GDP) Guideline published

With about the same consultation period of two years, the European Commission has published end of March also the respective final EU Good Distribution Practice (GDP) guideline for APIs. The time frame for implementation of this guideline is listed with six months i.e. by 21 September 2015.
Compared to the Draft version, also this guideline has been subject to considerable modifications with much more details and more precise phrases being contained in the final guideline. By way of example e.g. the following items are listed hereunder:

  • Chapter 1 / Scope: “the guidelines do not apply to intermediates of active substances”
  • Chapter 2 / Quality System: details of the quality system have been added with 7 new items to sub-point 2.2
  • Chapter 3 / Personnel: extended from 3 items to 4, each point with more precise and detailed wording (e.g. training records including periodical assessment of training efficiency)
  • Chapter 4 / Documentation: extended from 5 items to 9, more specific requirements concerning documentation/procedures/records compared to DRAFT version and thereby more adopted to general GMP requirements
  • Chapter 5 / Premises and Equipment: wording extended (e.g. “They should be suitably secure to prevent unauthorised access” and more precise)
  • Chapter 6 / Operations: the part ‘receipt’ was considerably extended concerning contamination, falsification and tampering evidence. Additional parts (e.g. ‘transfer of information’ have been phrased in more detail).
  • Chapter 7 / Returns, Complaints and Recalls: also more detailed and extended wording (e.g. returns “should only be returned to approved stock if all of the following conditions are met”, the number of conditions was increased from 4 to 5)
  • Chapter 8 / Self-inspections: the following sentence was added: “Regular self-inspections should be performed in accordance with an approved schedule”

Major GxP Events I & II/2015