[Stability Testing related News – vol.58]

◆  Draft revision of ICH Q9 Quality Risk Management Guideline published (23-Feb-22 ECA)

Since 2005 at the latest, the topic of quality risk management has dominated almost the entire GMP sector. At that time, the corresponding ICH Q9 guideline was published as “Step 4”. Now the draft of a planned revision has been published. What could be in store?

With 33 pages, the draft is significantly more extensive than the previous version with 19 pages. However, this is also due to the fact that each line is numbered for better commenting and the line spacing has thus become larger. But there are some new passages as well. This is partly reflected in the table of contents, which contains new elements in the form of subchapters 5.1 Formalities in quality risk management and 5.2 Risk-based decision making and II.9 Quality risk management as part of supply chain control/management. Likewise new in the table of contents is the title of Annex II with Quality Risk Management as Part of an Integrated Quality System, as well as the new subchapter II.9 Quality Risk Management as Part of Supply Chain Control/Supervision.

The most extensive changes are also pointed out in the introduction. For example, the issue of “subjectivity” is addressed in the context of risk management activities and the resulting decisions. Furthermore, appropriate risk-based decision making during the product life cycle and formality aspects related to quality risk management are addressed in the introduction. Basically, the introduction already summarizes the formality aspects described quite extensively in chapter 5: little formalism for low risks, more formalism for higher and more complex risks. The introduction concludes with the statement that quality risk management should not be used to justify decisions that run counter to official guidelines and/or regulations.

The risk management process itself undergoes a minor change: risk identification becomes hazard identification. The remaining terms remain unchanged.

Under point 4.1 Responsibilities, a new section has been added on the subject of subjectivity. Possible causes for subjective decisions and also “prevention strategies” are briefly addressed, as well as the hint that subjectivity in the quality risk management process should be addressed in the team.

Formalities in quality risk management are described very extensively in point 5.1 on almost 2 DIN A4 pages. As already briefly mentioned in the introduction, the degree of formality should depend on the degree of risk and can vary. So it is not about formal vs non-formal, but about smooth transitions. Criteria to be considered for the degree of formality are:

• Uncertainty
• Importance
• Complexity

Furthermore, examples of criteria that characterize a higher or lower degree of formality are listed.

The new chapter 5.2 on risk-based decision making comprises about 1.5 A4 pages. Almost 1 page of this covers approaches to risk-based decision making. It describes 3 scenarios regarding highly structured, medium structured and standardized structuring (e.g. via an SOP).
Newly included is the topic of supply chain complexity with regard to drug shortages. This is already included in 5 lines in Chapter 6 (Integrating Quality Risk Management into Industry and Regulatory Processes), but is also covered in the new section of the same chapter on the role of quality risk management in relation to product availability risks. Problem areas that are addressed are:

• Manufacturing process variations and control status
• Manufacturing premises
• Overview of outsourced activities and suppliers

In Chapter 7, two more definitions were added (Hazard Identification and Risk-Based Decision Making), and definitions, coming from the original version, were removed. References were updated (updated citations and new citations). Annex I on Quality Risk Management Methods and Tools also reiterates the potential variability in formalities.

In Annex II, with a new title, Quality Risk Management as Part of an Integrated Quality System contains a new subchapter II.9 Quality Risk Management as Part of Supply Chain Management/Control. The problem areas already mentioned above are addressed once again

• Manufacturing process variations and control status
• Manufacturing premises
• Overview of outsourced activities and suppliers

Conclusion: The planned changes to ICH Guideline Q9 Risk Management are set in a measured manner. Especially the topics subjectivity, formalities in quality risk management and risk based decision making are new aspects. Quality risk management as part of supply chain control/management is also planned as an innovation. On the ICH webpage a slide deck about the revision of ICH Q9 is available.

◆  Final Annex 21 published (23-Feb-22 ECA)

The final version of Annex 21 to the EU-GMP Guidelines (“Importation of medicinal products”) has been published in EudraLex Vol. 4. The draft was already published for comments in March 2020. Approximately 200 comments were received from 17 stakeholder organisations. The new Annex will come into operation on 21 August 2022.

What is the purpose of this new Annex?
The Union legislation addresses all actors in the supply chain and sets out their roles to ensure the integrity of the supply chain of medicinal products. The importation of medicinal products is subject to GMP requirements in the light of Article 40(3) of Directive 2001/83/EC. In addition to the requirements contained in the main chapters and annexes of the EU-GMP Guidelines, it has become necessary to summarise and publish specific requirements explaining the application of GMP principles to the import of medicinal products. This Annex 21 to the EU-GMP Guidelines now sets out the principles and requirements applicable to a Manufacturing and Import Authorisation (MIA) holder importing medicinal products (human and veterinary) across EU/EEA borders. Requirements from other parts of the EU GMP Guidance on activities around import activities continue to apply and are not repeated in full in the new Annex 21.

What has changed from the draft?
Besides editorial changes and adaptations to Annex 16, there were a few important additions and clarifications:

• Explicitly included are now Investigational Medicinal Products (IMPs). Advanced Therapeutic Medicinal Products (ATMPs) and medicinal products that do not have a marketing authorisation in the EU/EEA and are directly re-exported were not included.
• “Fiscal transactions” (where the product physically remains in the EU but changes ownership to a third country or vice versa) remain explicitly excluded.
• The complete batch documentation must be available to the MIA holder responsible for QP certification or batch confirmation at the time of certification or batch confirmation. In the draft, this was still stated as “should have access”.
• For QP certification or batch confirmation, a packing list, freight documentation or a customs import declaration, is now also required. The certification of a batch can therefore only take place after physical importation and customs clearance.

◆ FDA Warning Letters in Fiscal Year 2021: Deficient Stability Tests Reason for most frequent Complaints (30-Mar-22 ECA)

A look at the FDA’s Warning Letters sent in the period October 2020 to September 2021 (fiscal year 2021) shows a particularly high proportion of complaints relating to Section 211.166 Stability Testing (Subpart I – Laboratory Controls) of the Code of Federal Regulations (CFR). In 12 of a total of 27 Warning Letters issued, deficiencies are described in relation to the requirements for stability testing of medicinal products laid down in 211.166.

Other deficiencies reported in the Warning Letters relate to the following 21 CFR sections:

211.84 (Subpart E – Control of Components and Drug Product Containers and Closures) Testing and approval or rejection of
components, drug product containers, and closures (cited in 10 Warning Letters)
211.22 (Subpart B Organization and Personnel) Responsibilities of quality control unit (cited in 9 Warning Letters)
211.165 (Subpart I – Laboratory Controls) Testing and release for distribution (cited in 8 Warning Letters)
211.67 (Subpart D – Equipment) Equipment cleaning and maintenance (cited in 7 Warning Letters)
211.100 (Subpart F – Production and process Controls) Written procedures; deviations (cited in 7 Warning Letters)
211.192 (Subpart J – Records and Reports) Production record review (cited in 7 Warning Letters)
211.160 (Subpart I – Laboratory Controls) General requirements (cited in 5 Warning Letters)
211.68 (Subpart D – Equipment) Automatic, mechanical, and electronic equipment (cited in 4 Warning Letters)
211.188 (Subpart J – Records and Reports) Batch production and control records (cited in 2 Warning Letters)
211.198 (Subpart J – Records and Reports) Complaint files (cited in 2 Warning Letters)

In reviewing the quality control areas of the inspected companies, FDA inspectors found essentially the following deviations from the regulations for GMP-compliant stability testing of active pharmaceutical ingredients and finished medicinal products:

• Inappropriate stability studies due to
  – lack of stability testing of the active ingredient
  – missing microbiological tests
  – lack of quantitative content determinations
  – lack of testing for degradation products
  – unsuitable test methods (e.g. only visual tests, odour, pH-value)
• Shelf-life data of the products are based on stability studies that are no longer up to date (different production site, different active ingredient suppliers)
• Stability tests were not carried out in the usual market packaging
• A compilation of all current stability studies could not be provided
• No long-term stability study with the active ingredient from a new supplier available for the production-scale validation batches
• No detailed description of the stability testing programme

The lack of testing of the active ingredient for physicochemical as well as microbiological stability was the most frequently criticised. Among the 12 addressees of the Warning Letters are nine manufacturers of OTC products (OTC; over-the-counter; non-prescription medicines), two manufacturers of solid (tablets) and one manufacturer of semi-solid dosage forms (ointments).