The ICH Q2 (R1) and FDA guideline for Method Validation gives a clear vision about the expectation of an agency towards any Method Validation. These are expected for the agencies, but there are some expectations from the companies too!
Once the expectation of agency is of course a critical and satisfaction of FDA reviewer is we look forward. However, we forgot that we have more expectation towards the company on long term.
Poorly validated method can lead to following a loss of revenue in the company due to following reasons:
- Unable to release the product in time, which eventually affects the revenue.
- Loss of time working on the product due to Out of specification (OOS) /Out of Trends (OOT) / Atypical results.
- Possible recalling the Products due to failure to meet the specification.
- Repetitive problems in testing leading to CAPA (Corrective Action and Preventive Action) which may lead to revalidate the Method and possibility of informing the agency.
- Repetitive problem due to lack of good methods, can lead to FDA scrutiny during PIA inspection or GMP audit.
No matter how big or small the firm is, we all look forward for profit and we all have time limit towards method development as well as validation. How many of you might have heard from the company management that “You have 10 days to finish the Method and submit to agency”. I bet very few.
In today’s world, it is common to push for the result without compromising quality. Hence, the Analytical department has to be creative and smart to develop and validate the test method, which are robust and rugged.
I know it is easy for me to say, I worked in the analytical division for 20 years and I totally agree the challenge anyone can face to come up with error proof robust and rugged method. It is practically impossible for someone to develop this method within the speculated time frame is something to ponder over again and again. The Method has a life cycle and as we test more and more the errors as well as challenges are manifested.
However, following parameters can be implemented to reduce the error and come up with robust as well as least OOS/OOS. Let me focus here on Related Compound, since I have been in the thick of the OOS/OOT as well as Atypical results due to the presence of unknown impurity.
- FDA guidelines for ANDA impurities clearly mention about the reporting limit, identification limit as well as Qualification limit based on Total Daily Dosage (TDD). These guidelines are very crucial for the industry to come up with a justification of impurity to start with.
- During method development, there are system suitability criteria for the QC release, however, to avoid any future problems, additional in house system suitability should be considered based on the complexity of the test and impurities. For example, if the liquid suspension contains Hydrocodone and Glycerin, sorbitol in the product, it can lead to several ketal impurities. These ketals are sometimes separated and some time not separated based on the columns. Lot to lot columns can give the difference in separation. If the ketals peaks are not separated, can leads to a single peaks instead of a cluster of peaks and the limit of impurity fails above identification limit. Hence it is prudent to treat the hydrocodone with Gycerine or Sorbitol to form a clear cluster and set up the resolution. This can avoid any future OOT or OOS results.
- If the impurities are closely related, over a period time, from lot-to-lot column can merge these impurities to give single peak. Early evaluation of different vendors of columns should be considered.
- f the impurities are closely related and there may be a possibility of close elution or merging, if it is gradient method, a slight modification of gradient to separate further should be considered and should be a part of the method. System suitability should go alone with this method, so that the integrity of the method should not be affected.
- Most of the time, especially QL and DL are one of the difficult task to achieve, especially when we need to go below reporting limit of 0.1%. The method should be evaluated carefully to achieve this limit.
- Forced degradation plays an important role to understand the possible impurity generation over a period of shelf life. A careful evaluation of forced degradation is a must. Also, if possible, mass balance should be done. Any impurity which does not have chromospheres should be documented.
- Evaluation of unknown impurity over a range of wavelength is a good practice using a PDA (Photodiode array detector). In my practice, I have noticed one product failed due to high signal around (0.6%) to unknown impurities, upon synthesis of these unknown impurities by Preparative HPLC and comparing leading to 0.04% from 0.6%.
- Stability of the sample is also very critical which need to be evaluated in the solution.
- Changes in pH and composition of mobile phase should be evaluated for closely related impurity.
- Based on the forced degradation impurity, if there is a potential impurity shows up which cannot be evaluated, it is prudent to run the Reference Listed Drug (RLD) ahead of time. This will help you to assess the impurity can be qualified for in future.
- For complicated impurity methods, it is prudent to have gradient methods, although it comes with its own problem, but it is an excellent tool for separation too.
- If possible, start with LC-MS compatible mobile phase, so that in case if the impurity develops, it is much easier to evaluate using MS attached.
All these steps may not a recipe for success but each method should be evaluated case by case. However, a pro active perspective on Method Validation can manage the risk.