It’s Time To ‘Get Moving’ To Meet ICH Q3D Deadline, Industry Told
Executive Summary
A pharmaceutical industry official said while it is not too late, manufacturers that have not yet started risk assessments to comply with ICH Q3D for legacy products need to get busy. Official also advised that good risk assessments should make it easier to comply and reduce the need to retest products if new metals are introduced into the manufacturing process.
Manufacturers that have yet to begin compiling risk assessments to bring existing drug products into compliance with the International Council on Harmonization’s Q3D elemental impurities guideline better get busy as the deadline to complete the assessments is fast approaching, a leading industry expert on the topic warned last week.
Nancy Lewen, an analytical chemist with Bristol-Myers Squibb Co. also gave some tips March 23 on overcoming obstacles in complying with ICH Q3D at the 3rd Annual Conference on Advancing Product Quality, sponsored by the Product Quality Research Institute and FDA in Rockville, Md. She said robust risk assessments can help manufacturers manage changes better so they don’t have to default to automatic full testing on products.
The ICH Q3D guideline for elemental impurities, published in December 2014, sets permitted dally exposure (PDE) limits for 24 elements. The guideline takes effect in January 2018 for legacy products in the US, the EU and Japan; it has been in effect since June 2016 for new drug products in the US and Europe.
“If you are in the category where you are just beginning to be aware of things and trying to figure out what to do, even though we are coming quickly to the deadline, you still have time but you need to get moving,” Lewen said.
ICH Q3D incorporates a risk-based approach to assessing the presence of elemental impurities in drug products. For example, manufacturers must quantify the risk of metals that reach the final product from container closure systems, excipients, drug substances, water and equipment.
Risk Assessments Should Tell Story
She said the risk assessments should be living documents and should “tell a story” as well as have enough information to support their conclusions. Pharmaceutical manufacturers at a recent workshop said that the more difficult task in complying with the ICH Q3D guideline is conducting the risk assessments rather than testing for elemental impurities (Also see "Pharmaceutical Manufacturers Grapple With ICH Q3D Implementation" - Pink Sheet, 13 Dec, 2016.).
The key to effective risk assessments is to “go back to the beginning and know and understand all aspects the manufacturing process,” Lewen said.
She said it is important to ask these questions in developing risk assessments:
- How is your API made? What are the raw materials and the catalysts used?
- What are your excipients? Are they naturally sourced or mined?
- What type of processing equipment is used?
- What is the quality of the water used?
Lewen said one challenge is that good information on excipients may not be available, especially if they are naturally mined or sourced. She described an example of receiving separate batches of materials sourced from different parts of a mine.
"It is not always possible to homogenize a mine so the elemental impurities may or may not be present in that mine. These materials can be very different from batch to batch depending on the location in the mine. … So keep that in mind when you are doing a risk assessment,” she said.
For manufacturers that use these excipients, it may be necessary to collect more data and possibly conduct full testing on the final product.
Lewen said vendors' ingredient changes are another challenge, and where robust risk assessments can help. “If you have a vendor that used to use palladium as a catalyst and now they have found a way to make something that they don’t have to use a catalyst at all, then you might be able to take palladium off your list. Likewise, if something gets added, you may have to add it to your list. But you don’t know until you use a risk-based approach and look at everything. Don’t just jump to test. Understand your process.”
She said risk assessments should also be able to help in managing changes in vendors. “Talk to your vendors and ask whether there are differences in how they make materials. You may or may not need to do testing. The key is to be informed about your product and that is from your risk assessment.”
Consortium’s Excipient Database Can Help
Another challenge is vendors that refuse to provide information on their excipients. To deal with this, Lewen said that manufacturers can conduct their own searches in the published literature to gauge risk. Or they can use a database on excipients being developed by the Elemental Impurities Pharma Consortium that will soon be publicly available (Also see "Drug Makers Urged To Collect Own Excipient Metals Data To Comply With ICH Q3D" - Pink Sheet, 20 Dec, 2016.). The database organizers said it will help reduce the burden of testing excipients that have already been tested.
The database is “starting to gain momentum” she said. Currently it is available only to manufacturers that donated materials to the database.
Lewen said the burden and cost of conducting these risk assessments will yield benefits down the road. She said through these risk assessments, “you will have greater knowledge about your process. … You will be able to identify potential problems before they become bigger problems.”
Having these risk assessments will also ease the process of doing tech transfers because there is a set template for analytical testing.
“At BMS we have a set process and a set template for every tech transfer. The main difference is just different materials but the validation requirements and all those things are the same so it has made our life a lot easier in the analytical laboratory,” Lewen said.
She said understanding the process and qualifying the risk also means having “significantly fewer discussions with toxicologists.”
From the editors of The Gold Sheet.