Guideline "ICH Q3D - Elemental Impurities" published as Step 4 Document!

On 19 December 2014, the Guideline "ICH Q3D - Elemental Impurities" was released on the ICH website - nearly one year and a half after the publication of the draft (Step 2b document) on 5 August 2013. The Expert Working Group (EWG) in charge of the guideline has taken more time to find an agreement and a consensus because of the several comments given by diverse associations on the guideline and the final determination of the "permitted daily exposure" (PDE) for the different metals.

Compared to the draft guideline from August 2013, most of the limits have changed: more stringent PDE values apply for 17 out of the 24 elements! The following table shows the PDE of these elements with regard to the different dosage forms (in brackets the value indicated in the draft guideline from August 2013):

Element

Class

Oral [µg/Day]

Parenteral [µg/Day]

Inhalation [µg/Day]

Cadmium (Cd)

  1( 1)

5 (5.0)

2 (6.0)

2 (3.4)

Mercury (Hg)

  1 (1)

30 (40)

3 (4.0)

1 (1.2)

Selenium (Se)

2B (2A)

150 (170)

80 (85)

130 (140)

Vanadium (V)

2A (2A)

100 (120)

10 (12)

1 (1.2)

Silver /Ag)

2B (2B)

150 (170)

10 (35)

(see Table 2)

Gold (Au)

2A (2A)

100 (130)

100 (130)

1 (1.3)

Iridium (Ir)

2A (2A)

100 (1000)

10 (10)

1 (1.4)

Osmium (Os)

2A (2A)

100 (1000)

10 (10)

1 (1.4)

Platinum (Pt)

2A (2A)

100 (1000)

10 (10)

1 (1.4)

Rhodium (Rh)

2A (2A)

100 (1000)

10 (10)

1 (1.4)

Ruthenium (Ru)

2A (2A)

100 (1000)

10 (10)

1 (1.4)

Thallium (Tl)

2A (2A)

8 (8.0)

8 (8,0)

8 (69)

Barium (Ba)

3 (3)

1400 (13000)

700 (13000)

300 (340)

Lithium (Li)

3 (3)

550 (780)

250 (390)

25 (25)

Nickel (Ni)

2A (3)

200 (600)

20 (60)

5 (6.0)

Antimony (Sb)

3 (3)

1200 (1200)

90 (600)

20 (22)

Tin (Sn)

3 (3)

6000 (6400)

600 (640)

60 (64)

It is remarkable that the metal nickel has now moved to a class 2A - a class with stricter requirements/ greater toxicity. Elements listed in this class require a risk assessment of the finished product as - according to the synthetic route and/ or the manufacturing process - there is a substantial likelihood of accumulation in the final product. Class 3 - the former class of nickel - contains the elements which show a relatively low toxicity for oral use. The reclassification of nickel and the associated lower limits (one third of the value set in Q3D Step 2!) means for certain products higher control efforts as nickel is frequently used as catalyst in the API synthesis and is present as supplement in metallic materials in many parts of the production equipment. The PDE for thallium has also been considerably reduced with regard to inhalation and sank from 69 to 8 µg per day! Further (partly drastic) tightening concern the elements iridium, osmium, rhenium, ruthenium, and platinum whose current PDE for oral administration is roughly one-tenth of the value indicated in Q3D Step 2. Some of these metals are also used as catalysts in chemical syntheses.

In the present guideline, some limits have been eased compared to the draft from 2013. The following 6 elements have now higher PDE values: 

Element

Class

Oral [µg/Day]

Parenteral [µg/Day]

Inhalation [µg/Day]

Arsenic (As)

1( 1)

15 (15)

15 (15)

2 (1.9)

Cobalt (Co)

2A (2A)

50 (50)

5 (5.0)

3 (2.9)

Silver (Ag)

2B (2B)

(see Table 1)

(see Table 1)

7 (6.9)

Molybdenum (Mo)

(2A)

3000 (180)

1500 (180)

10 (7.6)

Chromium (Cr)

3 (3)

11000 (11000)

1100 (1100)

3 (2.9)

Copper (Cu)

3 (3)

3000 (1300)

300 (130)

30 (13)


Only the values for lead (Pb) and Palladium (Pd) have remained the same as in the Draft Consensus Guideline.

This guideline constitutes a milestone in the risk assessment and analysis of new medicinal products that have not yet been authorised. It is partly complex and will pose a considerable challenge to the chemical and pharmaceutical industry - particularly of already authorised medicinal products. A transposition period of 3 years has been granted for the application of the requirements set in the guideline. (Last sentence in Chapter 2 Scope: "Application of Q3D to existing products is not expected prior to 36 months after publication of the guideline by ICH".).

You can find the final ICH Q3D Guideline here.

Note: You will get up-to-date information about the implementation of ICH Q3D at the "ECA Impurities Forum" from 16 to 18 June 2015.
 

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