The ICH-Q3D Heavy Metal Regulation - Pittcon Conference...Harmonisation (ICH) has been working on...
Transcript of The ICH-Q3D Heavy Metal Regulation - Pittcon Conference...Harmonisation (ICH) has been working on...
The ICH-Q3D Heavy Metal Regulation
White Paper
In recent years, the presence of metal impurities has become a major issue in the drug-making industry, and thus, the need for its effective removal. The time pressure associated for drug candidates to quickly reach the market has greatly increased the number of metal-catalysed reactions progressing from lead optimization to early scale-up.
For almost two years now, the International Conference on Harmonisation (ICH) has been working on its Q3D guidelines for metal elemental impurities in new drugs and new formulations containing known ingredients. After many revisions and improvements, the final version or the Q3D guidelines was finally accepted and signed off by the ICH Steering Committee in December 2014, hence requiring that the entire manufacturing industry and supply chain follow these regulations. The implementation phase was in January 2016.
Learn more on what do drug manufacturers need to do and how we can help you.
Water(Water / Air / Facilities)
Packaging(Container
Closure System)
Manufacturing(Equipment / Process)
Elemental Impurities
In Drug Product
Excipients(Mined vs Synthetic)
Drug Substance(Metal Catalysts)
1 http ://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf
Hydrogen Helium
Lithium Beryllium Boron Carbon Nitrogen Oxygen Fluorine Neon
Sodium Magnesium Aluminum Silicon Phosphorus Sulfur Chlorine Argon
Potassium Calcium Scandium Titanium Vanadium Chromium Manganese Iron Cobalt Nickel Copper Zinc Gallium Germanium Arsenic Selenium Bromine Krypton
Rubidium Strontium Yttrium Zirconium Niobium Molybdenum Technetium Ruthenium Rhodium Palladium Silver Cadmium Indium Tin Antimony Tellurium Iodine Xenon
Cesium Barium Lanthanides
Cerium Praseodymium Neodymium Promethium Samarium Europium Gadolinium Terbium Dysprosium Holmium Erbium Thulium Ytterbium Lutetium
Hafnium Tantalum Tungsten Rhenium Osmium Iridium Platinum Gold Mercury Thallium Lead Bismuth Polonium Astatine Radon
Francium Radium Actinides
Thorium Protactinium Uranium Neptunium Plutonium Americium Curium Berkelium Californium Einsteinium Fermium Mendelevium Nobelium Lawrencium
Rutherfordium Dubnium Seaborgium Bohrium Hassium Meitnerium Darmstadtium Roentgenium Copernicium
*Lanthanides
**Actinides
1 (IA) 18 (VIIIA)
2 (IIA)
-259.14-252.87
2.2-1,1
H1.00791
0.089
3 (IIIB) 4 (IVB) 5 (VB) 6 (VIB) 7 (VIIB) 8 (VIII) 9 (VIII) 10 (VIII) 11 (IB) 12 (IIB)
13 (IIIA) 14 (IVA) 15 (VA) 16 (VIA) 17 (VIIA)
180.541347
1.01
Li6.9413
0.534
97.81882.9
1.01
Na22.99011
0.971
63.357740.9
1
K39.09819
0.86
12782970
1.52
Be9.01224
1.85
648.81090
1.22
Mg24.30512
1.738
8391484
1.02
Ca40.07820
1.55
38.896880.9
1
Rb85.46837
1.532
28.40678.4
0.91
Cs
Fr
132.9155
1.873
276770.9
1
223.0287
7691384
1.02
Sr87.6238
2.54
7251640
1.02
Ba137.3356
3.5
7001140
1.02
Ra226.0388
5.0
15412831
1.23
Sc44.95621
2.99
15223338
1.13
Y88.90639
4.47
**89-103
16603287
1.33,4
Ti47.8822
4.54
18524377
1.24
Zr91.22440
6.51
22274602
1.24
Hf178.4972
13.3
Rf261.11104
18903380
1.52,3,4,5
V50.94223
6.11
24684742
1.23,5
Nb92.90641
8.57
29965425
1.35
Ta180.9573
16.6
18572672
1.62,3,6
Cr51.99624
7.19
26174612
1.32,3,4,5,6
Mo95.9442
10.2
34105660
1.42,3,4,5,6
W183.8474
19.3
7993426
1.13,4
Ce140.1258
6.66
9313512
1.13,4
Pr140.9159
6.77
10213068
1.13
Nd144.2460
7.00
11682460
1.13
Pm146.9261
7.26
17504790
1.14
Th232.0490
11.7
1600
1.14,5
Pa231.0491
15.4
11323818
1.23,4,5,6
U238.0392
19.0
6403902
1.23,4,5,6
Np237.0593
20.2
6413232
1.23,4,5,6
Pu244.0694
19.8
10771791
1.12,3
Sm150.3662
7.52
31805627
1.52,4,7
186.2175
21.0
8221597
1.02,3
Eu151.9663
5.24
9942607
1.23,4,5,6
A m243.0695
13.7
21724877
1.47
Tc
Re
98.90643
11.5
12441962
1.62,3,4,6,7
Mn54.93825
7.43
15352750
1.62,3,6
Fe55.84526
7.86
23103900
1.43,4,8
Ru101.0744
12.4
30455027
1.52,3,4,6,8
Os190.2376
22.6
14952870
1.62,3
Co58.93327
8.9
19663697
1.51,2,3,4
Rh102.9145
12.4
24304430
1.61,2,3,4,6
Ir192.2277
22.4
13133266
1.13
Gd157.2564
7.90
1340
1.23,4
Cm247.0796
13.51.23,4
Bk247.0797
141.23,4
Cf251.0898
1.23
Es252.0899
1.23
Fm257.18100
1.23
Md258.01101
2,3
No259.10102
3
Lr262.11103
13563123
1.13,4
Tb158.9365
8.23
14122562
1.13
Dy162.5066
8.55
14742695
1.13
Ho164.9367
8.80
14972900
1.13
Er167.2668
9.07
15451947
1.12,3
Tm168.9369
9.32
8191094
1.12,3
Yb173.0470
6.97
16633395
1.13
Lu174.9771
9.84
14532732
1.82,3
Ni58.69328
8.90
10832567
1.81,2
Cu63.54629
8.96
419.69071.7
2
Zn65.3930
7.13
15523140
1.42,4
Pd106.4246
12.0
10642807
1.41,3
Au196.9779
19.3
17723827
1.42,4
Pt195.0878
21.4
961.92212
1.41,2
Ag107.8747
10.5
320.97651.5
2
Cd112.4148
8.65
-38.841356.6
1.51,2
Hg200.5980
13.5
303.51457
1.41,3
Tl204.3881
11.85
271.31560
1.73,5
Bi208.9883
9.75
2549621.8
2,4,6
Po209.9884
9.32
3023372.0
-1,1,3,5,7
At209.9985
11.3
-71-61.8Rn
222.0286
9.73
156.52080
1.53
In114.8249
7.31
232.02270
1.72,4
Sn118.7150
7.31
29.782403
1.83
Ga69.72331
5.904
630.71750
1.8-3,3,5
Sb121.7651
6.69
937.42830
2.04
Ge72.6132
5.32
449.59902.0
-2,4,6
Te127.6052
6.24
660.372467
1.53
Al26.98213
2.699
20792550
2.03
B10.8115
2.34
33674827
2.5-4,2,4
C12.0116
2.25
14102355
1.74
Si28.08614
2.33
113.5184.4
2.2-1,1,3,5,7
I126.9053
4.93
-111.9-107.1Xe
131.2954
5.85
8176132.2
-3,3,5
As74.92233
5.73
217684.9
2.5-2,4,6
Se78.9634
4.79
-7.258.78
2.7-1,1,3,5,7
Br79.90435
3.12
-156.6-152.3Kr83.8036
3.71
44.12802.1
-3,3,5
P30.97415
1.82
-209.86-195.8
3.1-3,2,3,4,5
N14.0077
1.25
-218.4-182.96
3.5-2,-1
O15.9998
1.43
112.8444.67
2.4-2,2,4,6
S32.06616
2.07
-219.62-188.14
4.1-1
F18.9989
1.69
-100.98-34.6
2.8-1,1,3,5,7
Cl35.45317
3.21
<-272.2-268.93He
4.00262
0.17
-248.67-246.05Ne20.1810
0.90
-189.2-185.7Ar
39.94818
1.78
Db262.11105
Sg266.12106
Bh264.12107
Hs269.13108
Mt268.14109
Ds271.15110
Rg272.15111
Cn285112
9213457
1.13
La138.9157
6.145
Lanthanum
*57-71
10503200
1.03
Ac227.0389
10.1
Actinium
Ununquadium
Uuq289114
Ununhexium
Uuh289116
Ununoctium
Uuo293118
Ununtrium Ununpentium Ununseptium
Uus293117
Uup291115
Uuo287113
327.51740
1.62,4
207.282
11.4
Pb
NewNew
NewNew
SiliCycle Inc. Worldwide Headquarters2500, Parc-Technologique Blvd Quebec City (Quebec) G1P 4S6 CANADATel. : 1 418 874.0054 Toll Free : 1 877 745.4292 (North America only) Fax : 1 418 874.0355 www.SiliCycle.com [email protected]
Search by metalScavenger
SiliaMetS Thiol (Si-Thiol) PN : R51030B
SiliaMetS DMT (Si-DMT) PN : R79030B
SiliaBond Amine (Si-WAX) PN : R52030B
SiliaMetS AMPA (Si-AMPA) PN : R85130B
SiliaMetS Cysteine (Si-Cys) PN : R80530B
SiliaMetS DEAM (Si-DEAM) PN : R54430B
SiliaMetS Diamine (Si-DIA) PN : R49030B
SiliaMetS Imidazole (Si-IMI) PN : R79230B
SiliaMetS TAAcOH (Si-TAAcOH) PN : R69030B
SiliaMetS TAAcONa (Si-TAAcONa) PN : R69230B
SiliaMetS Thiourea (Si-THU) PN : R69530B
SiliaMetS Triamine (Si-TRI) PN : R48030B
Structure SHSi
NH
Si N
NN
SH
SH
NH2SiNSi P
PHO
HO
OH
OH
O
ONH
SiONa
SH
O
Si
NOH
OH
NH
SiNH2 NSi
N NSiN
N
OH (ONa)
OH (ONa)
OH (ONa)OH (ONa)
O
O
O
O
NH
Si NH
S
NH
SiHN
NH2
Loading mmol/g ≥ 1.20 ≥ 0.50 ≥ 1.20 ≥ 0.80 ≥ 0.30 ≥ 0.85 ≥ 1.28 ≥ 0.96 ≥ 0.41 ≥ 0.41 ≥ 1.07 ≥ 1.11
Met
als t
o be
scav
enge
d
AgAlCaCdCeCoCrCsCuFeHgIrLaLiMgMnNiOsPbPd (II)Pd (0)PtRh (I)Rh (II)Rh (III)Ru (II)ScSnTiWZn
A newcomer ? Our kits have been designed for maximum flexibility
PNK30730B Universal
Metal Scavengers Kit
K34530B Novel
Scavengers Kit
K34630B Palladium
Metal Scavengers Kit
Com
posi
tion
Si-Cysteine Si-DMT Si-Imidazole Si-TAAcOH Si-TAAcONa Si-Thiol Si-Thiourea Si-Triamine
Si-AMPA Si-DEAM Si-DMT Si-Guanidine Si-Thiol
Si-DMT Si-Diamine Si-Thiol Si-Thiourea Si-Triamine
PNK34730B
Tin Metal Scavengers Kit
K35230B Electrophile
Scavengers Kit
K32630B Nucleophile
Scavengers Kit
Com
posi
tion
Si-Cysteine Si-DEAM Si-DMT Si-TAAcOH Si-TAAcONa Si-Thiourea Si-Thiol
Si-Amine Si-Carboxylic Acid Si-DMAP Si-Diamine Si-Piperazine Si-TMA Acetate Si-Tosyl Chloride Si-Triamine
Si-Carbonate Si-DEAM Si-Diol Si-Guanidine Si-Isocyanate Si-Maleimide Si-Propylsulfonic Acid Si-Tosic Acid
Remember : All Kits are available in 5 g, 10 g, 25 g, 50 g, 100 g, and up to 1 kg formats Kits can easily be customized for any specific needs, contact us for more information.
SiliCycle offers an unparalleled range of Metal and Organic Scavengers, SiliaMetS®and SiliaBond®, to significantly facilitate any purification processes.
Typical procedure to be followed • Use 4-8 molar equivalent of Scavenger
• At room temperature up to 50°C
• Optimal pH range is from 2 to 10
• Typical solvents are THF, DMF, Ethyl Acetate, MeOH, PhMe, Ethers & Chlorinated solvents
• Stir one hour (1h) at moderate agitation (or more followed by ICP analysis)
TIP : Solution’s color might be a good indication of the scavenging progressDon’t forget to optimize via temperature, solvents, times, etc.
Could need some help ?Having a problem scavenging a product ?
Take advantage of SiliCycle’s expertise in scavenging. Our experienced R&D team can find the optimal conditions for you!
Our scavenging screening services are innovative as they provide an on-hand solution to quickly develop the most efficient metal or organic scavenging process for both time and cost savings.
Confidentiality is assured, as in most cases the solution involves working with API and other patented materials, and easy technology transfers are guaranteed.
Our team comprises passion driven scientists with various university levels in various specialities :
• Analytical, Inorganic, Organic & Organometallic Chemistry
• Biology & Biochemistry
• Catalysis
• Chemical Engineering
• Mesostructured Material
• Physical & Petrochemistry
22%
22% B.Sc.
Ph.D.
M.Sc.
R&DServices
Why are Potentially Genotoxic Impurities (PGI) Scavengers so important ?Genotoxic compounds induce genetic mutations and/or chromosomal rearrangements and can therefore act as carcinogenic compounds.
Whatever the nature of the impurity you might encounter, you can rely on our family of genotoxic Scavengers in order to eliminate tedious post-reaction purifications.
Search by chemicalScavenger
SiliaBond Amine (Si-WAX) PN : R52030B
SiliaBond Carbonate (Si-CO3) PN : R66030B
SiliaBond Carboxylic Acid (Si-WCX) PN : R70030B
SiliaMetS DEAM (Si-DEAM) PN : R54430B
SiliaMetS Diamine (Si-DIA) PN : R49030B
SiliaBond Diol (Si-Diol) PN : R35030B
SiliaBond DMAP (Si-DMAP) PN : R75530B
SiliaBond Guanidine (Si-GUA) PN : R68230B
SiliaBond Isocyanate (Si-ISO) PN : R50030B
SiliaBond Maleimide (Si-MAL) PN : R71030B
SiliaBond Piperazine (Si-PPZ) PN : R60030B
SiliaBond Propylsulfonic Acid (Si-SCX-2) PN : R51230B Tosic Acid (Si-SCX) PN : R60530B
SiliaBond TMA Acetate (Si-SAX2) PN : R66430B
SiliaBond Tosyl Chloride (Si-TsCl) PN : R44030B
SiliaMetS Triamine (Si-TRI) PN : R48030B
Structure NH2Si N+Si(CO3
2-)0.5 OHSi
OSi
NOH
OH
NH
SiNH2 OSi OH
OH NSi
N
NH
Si NH
N NSi C O NSi
O
O
NSi
NH
SSiOH
O
O
SiS OH
O
O
N+SiC3HC00-
SiS Cl
O
ONH
SiHN
NH2
Loading mmol/g ≥ 1.20 ≥ 0.46 ≥ 0.92 ≥ 0.85 ≥ 1.28 ≥ 0.97 ≥ 0.53 ≥ 0.80 ≥ 1.16 ≥ 0.64 ≥ 0.83 SCX-2 : ≥ 0.63 | SCX : ≥ 0.54 ≥ 0.71 ≥ 0.88 ≥ 1.11
Elec
trop
hile
s & N
ucle
ophi
les
to b
e sc
aven
ged
AcidAcid chlorideAcidic phenol
AlcoholAldehydeAlkoxideAmine
AnhydrideAniline
Boronic acid Carboxylic acid Chloroformate
HydrazineIsocyanate
KetoneOrganometallic
Sulfonyl chlorideThiol / Thiolate
ELECTROPHILE SCAVENGER : | NUCLEOPHILE SCAVENGER : | IONIC BONDING : | CATCH & RELEASE:
http ://www.silicycle.com/products/metal-scavengers
http ://www.silicycle.com/products/functionalized-silica-gels/siliabond-scavengers
Give our scavengers a try with SiliCycle MiniBlock® for mistake-proof parallel screeningsThe SiliCycle MiniBlock® platform offers full internal «flow-through» parallel processing of chemical reactions. The MiniBlock is unique in that reactions do not have to be removed from the apparatus for full processing but instead are run, partially purified and isolated in semi-crude form within the platform using a vertical flow design that is completely intuitive. Which is ideal for scavengers screening.
With our extensive experience in many niche areas, you are assured of a partner who is a leader in your domain.
BEST SCAVENGER : | GOOD SCAVENGER :
(COVALENT BONDING) (COVALENT BONDING)POS-001 v.1.2 02/15
© 2015, SiliCycle Inc.
Choosing your metal & organic scavenging solution
Why Silica outperforms Polymer-based resins ?• No Swelling
• Faster Kinetics
• Solvent Independent
• Easy to Use
• Mechanically Stable
• Thermally Stable
• Easily Scalable
• Flexible Formats
• Controlled Loading
SCX-2
SCX
Representation of the classification
The ICH-Q3D Heavy Metal Regulation2 3www.SiliCycle.com | [email protected]
White PaperICH StepsThe guideline proposed by the ICH and other regulatory agencies can be summarized in four steps :
1. Identify potential sources of elemental impurities
2. Determine the possibility of occurrences of elemental impurities in a final drug
3. Evaluate the concentration of elemental impurities according to the established potential daily exposure (PDE)
4. Control by developing a plan to reduce or limit elemental impurities in a final drug
Which metals need to be evaluated ?Henceforth, twenty-four (24) metals have been indicted and associated with great health risk and are presented in the USP’s Chapter <232>. Inside this new chapter, metals that should be evaluated are subdivided in four groups :
How SiliCycle can help you ?What SiliCycle has to offer is a turnkey solution for rapid, reliable, removal of metal contaminants.
Taking advantage of SiliCycle’s strong expertise in the field of grafting technology is your solution for metal removal.
With over 20 years of research and development on this type of technology, we are today one of the world’s leader in the industry of functionalized silicas, to purify APIs from metallic residues. We can provide you with the broadest portfolio of multi-functional scavengers (for the removal of ligands and metals), in the widest range of available formats for laboratory to plant scale purifications.
We call it the 6S Solution !
• Safe : very stable material
• Simple : no extra apparatus required, no extra solvent, no complicated calculations, no extra work-up…
• Strength : extreme affinity toward targeted metal
• Selectivity : very specific for the metal, high API recovery
• Speed : quick, one-step process
• Scalable : easily scalable technology from R&D to production scales
We are available to work with your team, step by step : from discovery, through development and all the way up to your manufacturing processeses.
If you would like more information on how we can help you with your metal removal challenges, please contact us at [email protected]
You also might be interested by our scavenging solution poster (PN : POS-001).
Call us to get yours : 1 877 745.4292 (North America only) +1 418 874.0054 (Worldwide)
Potential sources of elemental impuritiesPotential sources of elemental impurities during a drug manufacturing process are very broad. It could come from an intentionally added element during synthesis or from potentially contaminated water, excipient, equipment or containers, as shown below 1. Indeed, reaction mixtures often hold up broken-down catalyst poducts (metals, ligands, agglomerates) and unreacted by-products. Moreover, the API itself might tightly-bind some metallic residue, through various binding sites in diverse oxidation states.
The classificationClassifications
Class 1
« The Big Four »
Highly toxic across all administration routes. It will be necessary to demonstrate compliance for the removal of these metals in all drugs.
• Arsenic (As)• Cadmium (Cd)• Lead (Pb)• Mercury (Hg)
Class 2Generally considered as route-dependant toxicants, this class is divided in two groups which are related to their abundance likelihood in drugs.
Class 2A
Relatively high possibility to be present.
• Cobalt (Co)• Nickel (Ni)• Vanadium (V)
Class 2B
Reduced possibility of occurrence in the drug product.
• Gold (Au)• Iridium (Ir)• Osmium (Os)• Palladium (Pd)• Platinum (Pt)• Rhodium (Rh)• Ruthenium (Ru)• Selenium (Se)• Silver (Ag)• Thallium (Tl)
Class 3
Relatively low toxicity by oral administration but need to be considered for inhalation and parenteral routes.
• Antimony (Sb)• Barium (Ba)• Chromium (Cr)• Copper (Cu)• Lithium (Li)• Molybdenum (Mo)• Tin (Sn)
Class 4
Other elements for which a PDE has not yet been established.
• Aluminum (Al)• Boron (B)• Calcium (Ca)• Iron (Fe)• Magnesium (Mg)• Manganese (Mn)• Potassium (K)• Sodium (Na)• Tungsten (W)• Zinc (Zn)
Class 1 Class 2A
Class 2B
Class 3 Class 4 Others
As a recognized industry leader in the development, manufacturing and commercialization of innovative silica gel products, and with multi-ton manufacturing capability, SiliCycle® is your partner of choice for all your METAL REMOVAL, CATALYSIS, SYNTHESIS, and PURIFICATION requirements.
METAL & ORGANICSCAVENGING
SAMPLE PREPARATION
DESICCANTS & OTHERBULK ABSORBENTS
HIGH PRESSURECHROMATOGRAPHY
R&D SERVICES
CONSUMABLES EQUIPMENTS
LOW PRESSURECHROMATOGRAPHY
CATALYSIS& SYNTHESIS
ACIDS, BASES& REAGENTS
Removal of:• Metals• Electrophiles & Nucleophiles• Potential Genotoxic Impurities (PGI)
• SPE & Well Plates• Micro-SPE Tips• QuEChERS• SPE Hardware & Manifold
• Desiccant• Activated Alumina• Molecular Sieve
• Bulk Sorbents• HPLC & UPLC Columns• SEC & SFC Columns• Guard Cartridges & Accessories
• Scavenging Screening• Method Development & Optimization• Impurities Determination• Custom Column Packing
• Vials & Caps• Syringe Filters• Membrane Filters
• Parallel Synthesis Synthesizer - MiniBlock & MiniBlock XT
• TLC Scanner• Vacuum Manifold
• Bulk Silica Gels (Irregular & Spherical)• Bonded Phases• TLC Plates• Prepacked Flash Cartridges
• Couplings (Suzuki, Stille, Heck, ...)• Debenzylation & Hydrogenation• Oxidation• And Many More Reactions
• Acids & Bases• Amide Couplings• Reductive Aminations• Other Reactions
R-XR-Pd-X R’-M
MXR-Pd-R’
Pd
R-R’
T : 1 418.874.0054 F : 1 418.874.0355Toll Free : 1 877.SILICYCLE (North America only)[email protected]
CONTACT INFORMATION:
Printed in Quebec, Canada, © SiliCycle Inc.SiliCycle Inc - Worldwide Headquarters2500, Parc-Technologique BlvdQuebec City (Quebec) G1P 4S6CANADA
SiliCycle EuropeEuropean [email protected]
SiliCycle ChinaChinese [email protected]
SiliCycle IndiaIndian [email protected]
WP-001 V1.3 02/17