ICH Q4B Annex 13 on Powder Density and Annex 14 on Bacterial Endotoxin Testing Out for Comment

FDA has made available for comment the Step 2 drafts of ICH Q4B Annex 13 covering the bulk density and tapped density of powders and Annex 14 on bacterial endotoxin testing.  The drafts were cleared for release by the ICH Steering Committee meeting in June.

Annex 13 recognizes the interchangeability in the bulk density pharmacopeial chapters that have been developed for implementation in the three ICH regions, subject to specific conditions noted in the annex for three of the methods included in the chapters involving bulk density, tapped density and powder compressibility.

The effective dates of the compendial texts on bulk and tapped density that will be granted interchangeable status by Annex 13 are: ● July 2010 for the European Pharmacopeia (Ph. Eur. 2.9.34) ● October 2010 for USP’s General Chapter <616> and ● March 2011 for the Japanese Pharmacopeia (JP 3.01).

The new JP text is provided in its English version as an appendix to the Annex 13 draft. The annex indicates that the introductory paragraph in the JP version is not fully harmonized.

The Annex 14 Step 2 draft provides that the chapters on bacterial endotoxin testing procedures contained in the three pharmacopeias are interchangeable subject to a restriction on which assay must be used to make a final determination in case of differing results among the approved methods.  The draft also states that the pharmacopeial procedures should be calibrated to the WHO international standard for endotoxins.

The effective dates of the interchangeable pharmacopeial texts on bacterial endotoxin testing are: ● January 2010 for the EP (Ph. Eur. 2.6.14) ● October 2010 for USP’s General Chapter <85> and ● March 2011 for the JP (4.01).

As with Annex 13, the English version of the new JP text is appended to Annex 14.  The draft indicates that the full JP text is harmonized.

Two other Q4B annexes – Annex 11 on capillary electrophoresis and Annex 12 on analytical sieving – reached Step 4 (ready for regional adoption) at ICH’s Estonia meeting.

Q4B is the umbrella guideline covering the “Evaluation and Recommendation of Pharmacopeial Text for Use in the ICH Regions.” The clearance process for the annexes basically involves the Q4B EWG working through the Pharmacopeial Discussion Group (PDG) to assess the general method chapters in the regional pharmacopeias, outline issues that need consideration and address them.

The respective Q4B annex is then developed, which recognizes the analytical procedures as interchangeable, subject to the particular conditions outlined. The annexes also contain a section on “considerations for implementation” that addresses the impact of the different regulatory mechanisms in the U.S., EU and Japan.

As such, the ICH process is helpful not only in reducing testing complexity and redundancy through general chapter harmonization and the allowance for interchangeability, but in clarifying how the testing requirements and their enforcement vary in the three regions.

ICH Initiatives on Heavy Metals (Q3D) and Drug Substances (Q11) Also Advancing

In addition to the progress on the Q4B annexes, ICH also advanced its quality initiatives on heavy metals (Q3D) and drug substances (Q11) at the June Tallinn meeting.

The decision to add Q3D to the Q3 impurities guideline series reflected the concerns of the regulatory community regarding heavy metals and the desirability of a harmonized approach to the criteria and methodologies needed to control them (IPQ Nov./Dec. 2008 Report, pp. 37-39).

Endorsed by the ICH Steering Committee at its meeting in St. Louis in October 2009, the Q3D EWG met for the first time in Tallinn to begin work on the guideline.  Q3D will provide qualitative and quantitative limits on metal impurities in drug products and ingredients.

The Q11 EWG, formed in June 2008, continued to refine its draft of the drug substance guideline at Tallinn.

At DIA’s annual meeting in Washington, D.C. in mid-June, ICH Q11 rapporteur Brian Withers (Abbott U.K.) provided an update on the EWG’s discussions and the current status of the guideline’s structure and content (IPQ “In the News” July 9).

Q11 is intended to be a high-level guidance clarifying and harmonizing the regulatory expectations relevant to manufacture as well as design and development. “That is important,” Withers commented, “because Q8 did not get into the manufacturing” of the drug product, whereas with Q11, “we are moving into that area.  And that has its own set of issues.”

The scope of Q11 stretches across small and large molecule drug substances as defined in Q6A and Q6B, which has involved the EWG in identifying the similarities and differences and how they should be addressed from a guidance point of view, the rapporteur explained.

How the Q11 guideline should address the issues around defining starting materials was among the concerns receiving particular attention by the EWG at its June meeting.  The EWG debated how best to balance regulatory transparency with industry flexibility in addressing starting materials in the guideline (see the IPQ “In the News” July 9 companion  to the Q11 structure and content story referenced above).

[Editor’s Note:  An analysis of the objectives for the ongoing ICH quality initiatives is included in the IPQ May 2010 Report, which addresses the impact of the ICH Q8-10/QbD paradigm on the CMC review and inspection processes.]



Q4B Annex 13 draft

Q4B Annex 14 draft