In early 2017, the United States Pharmacopeial Convention (USP), European Medicines Agency and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) finalised guidelines (ICH Q3D and USP ) containing new permitted daily exposure limits for elemental (inorganic) impurities in pharmaceuticals and dietary supplements.
On the 17th of August 2015, the Australian TGA announced that the date for ICH Q3D coming into effect in Australia will align with implementation in the EU, i.e. from June 2016 for new products containing new drug substance/s; and from December 2017 for new products containing existing drug substance/s. In Australia this guideline applies to registration applications for prescription medicines only.
With the first deadline now upon us and the second one looming what do you need to do to comply?
Implement a risk-based control strategy
Both ICH Q3D and USP recommend implementing a risk-based control strategy for elemental impurities. The ICH Q9 ‘Quality Risk Management’ guideline and Q11 ‘Development and Manufacture of Drug Substances’ guideline can be used as guidance for this process.
Applying the Quality by Design principles, you should have detailed knowledge of the product and its manufacturing process and thus be able to identify likely sources of elemental impurities in the product. It’s important to map your product pathways and identify potential sources of impurities, as shown in the diagram below (reproduced from ICH documentation).
Note that the ICH has provided some excellent training materials to support the implementation of the ICH Q3D guideline.
What are manufacturers doing?
It seems that most manufacturers in Australia are well on the way to implementating ICH Q3D. We spoke to several of our customers and most had done their risk assessment and had put control measures in place to determined that they didn’t need any.
One pharmaceutical manufacturer we spoke to said “We mapped the product pathways for all of the eight parenteral and inhalation products that we produce on site. It took one staff member about 6 months to complete this. This included gathering lots of information from suppliers and assessing the impact of the equipment used to manufacture the products. We sent product samples out for testing for elemental impurities. This confirmed our findings that there was very low risk of elemental impurities in our products and that no controls were necessary. “
For API manufacturers, like Sun Pharmaceuticals, they have received lots of requests for data from customers doing risk assessments. “We pre-empted the requests by doing a risk assessment to establish likely sources of elemental impurities in our product and sent samples out for testing”, said Peta Kane, Laboratory Quality Control and Analytical Development Manager at Sun Pharmaceuticals. “Scope of elements for inclusion and the limits used in the risk assessment were based on recommendations of ICH Q3D. Our product is only used in oral medications, so the lower limits for elemental impurities apply. As maximum elemental impurity concentration was less than 0.5% of the limit and batch to batch variability was low, we established that there was very low risk associated with our API and no controls were necessary. When customers started asking for data we were in a great position to supply it.”
As the December deadline approaches for existing products, TGA-certified independent laboratories are seeing a surge in requests for elemental impurities analysis. Samples are being submitted as part of the risk assessment process and as ongoing controls that companies are implementing. Most of the samples are tablets and capsules, which require microwave digestion prior to analysis. Labs have also seen an increase in requests for validation and verification services.
Laboratories in Australia have reported difficulty in hiring analysts with pharmaceutical ICP-MS experience in Australia – most come from the environmental monitoring industry. Pharmaceutical manufacturers considering purchasing an ICP-MS may wish to test the labour market prior to purchasing the instrument if they don’t already have analysts with the right experience – or factor in training and/or consultants to get their analysts up to speed.
Implementing ongoing testing as a control strategy
If you’ve decided to implement testing for elemental impurities as a control strategy we’ve written a white paper that provides guidance on choosing between ICP-OES and ICP-MS.
PharmOut can help you do your risk assessment, implement control strategies, and validate new equipment. contact us at one of our offices around the world for further information.