Elemental Impurities / Metal Impurities AFFINISOL HPMCAS (Hydroxypropyl Methylcellulose Acetate Succinate)

Transcription

1 Effective: August 14, 2017 Supersedes: December 2, 2015 Elemental / Metal AFFINISOL HPMCAS (Hydroxypropyl Methylcellulose Acetate Succinate) USP general chapter <232> "Elemental impurities - Limits" and USP <233> "Elemental - Procedure" are expected to become effective on January 1, ICH Q3D Guideline: ": Guideline for Metal " was published as an EMA guideline in early 2014 (EMA/CHMP/ICH/353369/2013) with implementation dates of June 2016 for new marketing authorization applications and December 2017 for all existing products on the EU market. The Ph. Eur. implementation strategy of the ICH Q3D guideline on elemental impurities includes the following: - deletion of the test for heavy metals (2.4.8) from the individual monographs (except those of substances for veterinary use only), including cellulose ethers. The revised monographs (version 01:2017) were published in Ph. Eur. 9 th edition, with implementation date of January 2017; - adoption of some general texts, published in Supplement 9.3 with an implementation date of 1st January 2018: General chapter 5.20 Elemental impurities: reproduces parts of the Scope and the Introduction sections of the ICH Q3D guideline and refers to the guideline which can be found in full on the ICH website; General monograph on Pharmaceutical preparations (2619): refers to chapter 5.20, rendering it, and by extension the ICH Q3D guideline, legally binding for the drug products; General monograph on Substances for pharmaceutical use (2034): introduces requirements for the control of elemental impurities intentionally added during production; General method Determination of elemental impurities: provides guidance for aspects of method development such as sample preparation and method validation for the determination of elemental impurities. In addition to this recent revision, this text remains a priority on the work program of the Pharmacopoeia Discussion Group (PDG), the aim being to harmonize the respective general chapters on elemental impurities in the different regions. While USP <232>, Ph.Eur. 5.20, and ICH Q3D are not mandatory for excipients, finished drug manufacturers and authorization holders must assess all sources of elemental impurities in their finished drug product. This letter is intended to provide elemental impurity data for AFFINISOL HPMCAS Premium grade excipient products per USP <232>, Ph.Eur. 5.20, and ICHQ3D. Dow currently performs the following elemental testing on AFFINISOL HPMCAS Premium Cellulose Ether products: As, Cd, Pb, Hg per JECFA and FCC methods, as speciated, to demonstrate compliance with the Food Chemicals Codex monographs, the JECFA Food Additive Monographs and purity criteria published in the Official Journal of the European Union.

2 Heavy metals per the USP test method to demonstrate compliance with the USP, and JP Pharmacopoeia. The USP heavy metals test will give positive indication for the presence of Ag, As, Bi, Cd, Hg, Mo, Pb, Sb, and Sn. In anticipation of customer requests for Elemental Impurity data per USP <232>, Ph. Eur and ICH Q3D, Dow has completed an assessment of the manufacturing process and tested representative samples of AFFINISOL HPMCAS pharmaceutical grade excipients representing all producing plants and production lines for batches produced over a multi-year time period. Analytical results for USP <232>, Ph. Eur. 5.20, and ICH Q3D elemental impurities are summarized in Table I. All Class 1 and Class 2A elements were tested. Selenium and Cobalt were added to the USP list for testing due to the scheme in ICH Q3D. No Class 2B elements are intentionally added to the list, but some were tested due to the USP <232> requirements. Chromium and nickel are components of stainless steel. These trace impurities are from the materials of construction. The reaction vessels are stainless steel; therefore Fe is an expected elemental impurity that is regularly measured Conclusions of the manufacturing process assessment are as follows: AFFINISOL HPMCAS products are manufactured with Dow's hydroxypropyl methyl cellulose as a raw material. Cellulose pulp is the primary raw material for hydroxypropyl methylcellulose. Dow's pulp suppliers analyze for elemental impurities on a routine basis. Results are reported to Dow and monitored. Elemental impurities are not intentionally added to these products. Metal catalysts or reagents are not used in the AFFINISOL HPMCAS manufacturing process. Dow has well-defined manufacturing processes and controls for AFFINISOL HPMCAS production. NaCl is a by-product of the HPMC manufacturing process. The level is a specification item and is regularly measured. Based on the elemental impurity analysis and the above bullets point, no additional elemental impurity testing, beyond that required to meet food monograph requirements, will be conducted on AFFINISOL HPMCAS products. AFFINISOL HPMCAS products do not contain the majority of elemental impurities listed below. Based on product chemistry, raw materials, materials of construction and the manufacturing processes and controls, as well as results of recent screening tests AFFINISOL HPMCAS products are in compliance with ICH Q3D, and the pharmaceutical pharmacopoeia monographs (pharmacopoeia compliance indicated on the COAs).

3 If you have any questions or require further information, please contact us via our web site at (Answer Center, Ask a Question tab). Because use conditions and applicable laws may differ from one location to another and may change with time, Recipient is responsible for determining whether the information in this document is appropriate for recipient s use. Since Dow has no control over how this information may be ultimately used, all liability is expressly disclaimed and Dow assumes no obligation or liability therefore. No warranty, express or implied, is given nor is freedom from any patent owned by Dow or others to be inferred.

4 Table I Elemental Arsenic (inorganic) As 1 Yes No Unknown ND <233> Elemental Cadmium Cd 1 Yes No Unknown ND <233> Elemental Mercury (inorganic) Hg 1 Yes No Unknown ND <233> Elemental Lead Pb 1 Yes No Unknown ND <233> Elemental Cobalt Co 2A Yes No Unknown ND <233> Elemental

5 Elemental Nickel Ni 2A Yes No Unknown ND <233> Elemental Vanadium V 2A Yes No Unknown ND <233> Elemental Silver Ag 2B Yes No Unknown Not tested Gold Au 2B Yes No Unknown Not tested Iridium Ir 2B Yes No Unknown ND <233> Elemental Osmium Os 2B Yes No Unknown ND <233> Elemental

6 Elemental Palladium Pd 2B Yes No Unknown ND <233> Elemental Platinum Pt 2B Yes No Unknown ND <233> Elemental Rhodium Rh 2B Yes No Unknown ND <233> Elemental Ruthenium Ru 2B Yes No Unknown ND <233> Elemental Selenium Se 2B Yes No Unknown ND <233> Elemental

7 Elemental Thallium Tl 2B Yes No Unknown Not tested Barium Ba 3 Yes No Unknown Not tested Chromium Cr 3 Yes No Unknown ND <233> Elemental Copper Cu 3 Yes No Unknown ND <233> Elemental (LOD 1 ppm) Lithium Li 3 Yes No Unknown Not tested Molybdenum Mo 3 Yes No Unknown ND <233> Elemental Antimony Sb 3 Yes No Unknown Not tested

8 Elemental Tin Sn 3 Yes No Unknown Not tested Aluminum Al 4 Yes No Unknown ND <233> Elemental (LOD 3 ppm)