Raw Material testing – Implementation of Compendial Tests

Take, for example, the average Butterworth Laboratories Ltd in-house method for chromatographic impurities, which is typically around 7 pages long and has over 2000 words.  The method will include important sections like Quality Control to ensure that it continues to operate within its validated parameters and specific instrument parameters that have been validated on the equipment in our laboratory.  Within the validated method, detailed instructions on sample and standard preparation will be provided, along with important health and safety implications of working with the various materials.  Contrast this with the average compendial method containing just 400 words, which will include system suitability, but with method conditions which are only briefly outlined with minimal instruction on sample preparation and some allowable adjustments permitted, often only mentioned in general chapters, to allow for differences in instrumentation.  Perhaps it is not surprising that the first time use of a compendial method, can be a journey into the unknown.

Of course, the Regulators and Pharmacopoeia publishers are aware of this.  The European Pharmacopeia (PhEur) chapter 5.26 requires methods used for the first time, or revisions to existing methods, to be “implemented” into the testing laboratory prior to testing samples.

It is also important for both us and our customers that we establish that the test methods will perform correctly when used on their samples using our equipment and instrumentation.  This minimises the risk of Out-of-Specification (OOS) or Non-conforming results being generated in error, which may result in excessive delays and costs for both parties.

Implementation is the process of demonstrating the test method’s suitability under actual use conditions.  The first stage of implementation considers whether there are any factors that might impact the complexity of the procedure.  There will likely be one of two outcomes to this assessment:

• No factors are critical.  The procedures may be used without any specific verification tests that demonstrate their suitability under actual conditions of use.
• Critical factors are identified. Prior to testing samples, the suitability of the method under actual conditions of use will be demonstrated using a set of verification experiments listed on the implementation form along with the acceptance criteria to be applied.

When our LIMS indicates that we have not previously performed a requested test, we inform the customer that the test is being performed for the first time, which may require some verification testing.  We offer the option of either a feasibility test or a formal verification via a protocol.  This is important as different customers have their own policies around verifying compendial methods, and we try to satisfy all of their requirements.

Formal verifications are always performed for finished drug product testing; however, the lower-cost feasibility test is the preferred option for most customers testing raw materials.

With the feasibility option selected, the technical reviewer will then consider factors that may impact the complexity of the test. These are likely to include:

• Composition of material
• Preparation
• Reagents
• Equipment
• Environment
• AQC/System suitability requirements

Their review will be documented on an internal record form to provide a scientific justification of the feasibility tests and any acceptance criteria that will be applied. The cost of any additional testing will be included in the quotation for the work.

Guidance is given in PhEur as to the performance characteristics to be considered.  In some cases, method system suitability will be sufficient.  In other cases, the testing of a reference material may be beneficial.  Once the feasibility test has passed, the sample may be tested.  It may be possible to do this as part of a chained sequence so that testing can still be performed within our standard 10-day turnaround minimising both cost and delay to the customer.

David Riches

Technical Director