Dr Emma Modrate, business development manager at Bodycote Health Sciences" pharmaceutical lab in Edinburgh, looks at steps being taken to address the current shortage of acetonitrile
Acetonitrile is produced in relatively low volumes as a by-product of the production of the monomer acrylonitrile, which is used to make its polymer, polyacrylonitrile, a raw material in the manufacture of plastics.
Global demand for acrylonitrile has reduced significantly due to the slow- down in consumer spending in sectors that use plastics, such as the car industry. Combined with global plant changes and outages, this has led to a worldwide acetonitrile shortage and supplies are now very limited.
Acetonitrile is widely used in the manufacture and analysis of drug substances and drug products. In testing laboratories, acetonitrile is commonly used in the preparation of samples and for HPLC analysis. The result is that products using acetonitrile in their analysis for batch release may encounter long delays and a possible increase in costs.
It is therefore vital that steps are taken to redevelop methods using alternative solvents or at least to reduce the volume of acetonitrile used. This may not take long for some products, as it may simply mean replacing acetonitrile with another solvent and running the analysis to demonstrate equivalence.
For HPLC separations, methanol is a potential substitute for acetonitrile. However, the change may result in a different and possibly poorer separation, so it will not be suitable for all methods. If the change is successful, then the method can be validated. The validation required may be limited, if the change is limited to the solvent used for the chromatographic separation. A change to a different solvent for sample preparation may require more extensive validation.
If no change in solvent is possible for the chromatographic method, an alternative may be to reduce the dimensions of the column used in the separation - up to a 75% cut in acetonitrile usage may be achievable in some cases.
Again, following this change some validation may be necessary. The MHRA has also recognised the severity of the shortage and issued guidelines with regard to variations in product licenses needed as a result of a change of solvent within a method.
The implementation of any changes to methods must be carried out in a way as set out by the MHRA and other relevant European agencies and for contract labs clear instructions from the customers must be given to confirm that a change to the method can occur. Even though licence holders are responsible for changes to their licence, MHRA inspectors will expect labs to show due diligence with respect to requests to change solvents and evidence of this may be requested. As a result, labs need to be aware of that:
- The change should only occur on the basis that the customer has submitted the variation and the appropriate validation work has been undertaken
- Methods should be validated; the labs will have to confirm this or carry out the work
Technical agreements should be clear in that the contract giver will inform the labs of any changes to the methods and specifications.
A minor change in test method for an active substance or finished product is likely to fall into one of two main categories of variation as outlined below. There is already clear guidance for industry, as conditions and supporting data requirements are clearly defined by the variation guidelines.
This includes validation and results showing that the current and proposed analytical methods are equivalent: Changes to the test procedure of the active substance/finished product, where the method of analysis is unchanged (e.g. change in column length or solvent but not a different type of column or method).
For active substances, this is Type IA notification, change code 13a. For finished products, it is a Type IA notification, change code 38a. Type IA notifications have a 14-day validation timescale and as they are only notifications; if timings are crucial, a company may implement the change without waiting for the MHRA Acknowledgement of a Valid Notification.
More significant method changes may need to be submitted as Type IB variations, which involve a 30-day assessment timescale. However, the MHRA is advising applicants that urgent assessment may be requested for variations resulting from the acetonitrile shortage. Further information is provided on the MHRA website.