Tablet process validation

[DURGA PRASAD]

Dear Community Members,
Its a ready use document of "Process Validation of Tablets."
I see lot of comments when I load any document.
If you comment on any one of the process and processes and document set up,I would like you to correct this dokument, make necessary changes as you suggest here and upload again.
Its easy to comment. For other its difficult to understand unless you put in that document.
Best Regards

[syx]

Dear Mr Prasad,
For lubrication step, we could perform 10 points to determine homogeneity of the mixture. Could we take lesser points (top-middle-bottom) for other specifications, for instance loss on drying and flowability?
Thanks in advance.

Regards,
Siswanto

[syx]

additional question:
what substance should we use in order to determine homogeneity in lubrication step? the API or the lubricant? thanks.

[DURGA PRASAD]

You can take lesser points if the batch process is very stabilized and also if you know the hygroscopicity of the final blend and Bulk density of the active substance.

Your second question is rather difficult to explain. It depends up on the blender you use and also depends up on the quantity of Lubricant that is used.

Crtitical hygroscopic substances : Omeprazole is hygroscopic, in such API's many factors will come it play like temerature and humidity of rooms when the API is exposed.

[syx]

in our lab, I recommend to use at least 10 points for homogeneity and lesser (usually: top-middle-bottom) for non-critical parameters.

regarding to my second question, I cannot give any answer too when my staff asked me. lubricant usually added in small quantity (0.5-2.0%). we commonly used API as the marker of homogeneity, so additional assay is not needed. however, the percentage of API sometime very big and could not represent the homogeneity of small portion of the lubricant in the mixture. so, IMO, in ideal condition, the homogeneity of lubrication step should be based on the lubricant itself. CMIIW.

[DURGA PRASAD]

I totally agree what you have mentioned your last post.For a moment think lika process
person and reason the factors why there is a homogenity and why it fails?

Some of the causes are:
Wrong size of blender
Change of API : This happens when u change API mnaufacturer and mesh size changes
Bulk density variation
Variation in Seeds or breaks (Loss of power)
Lubricant added.
The head space is a blender will also decide up on this.Batch size variation I qould call.

At the end of the day when API is not found equally in all samples it means that there is no blend uniformity and this is not suitable for further activities like compression or drying etc etc.

[DURGA PRASAD]

Blend uniformity Guidance document.

[DURGA PRASAD]

Powder blend uniformity is a process control (i.e.,in-process material test) that critically impacts the uniformity of dosage form. In-process sampling and testing is essential to determine blend uniformity. The sampling technique is crucial to obtain samples that adequately represent the powder mix. The standard sampling device is a thief. However, certain sampling techniques may falsely introduce significant variations. The orientation, angle, and depth of sampling thief insertion,as well as insertion force and smoothness, impact the consistency of the sampling. Potential powder segregation during powder transfer and storage, and powder properties (e.g., flowability, particle size distribution, and density, etc.) also add to the challenge of obtaining representative in-process samples. To address sampling variations, the FDA guideline recommends a stratified sampling scheme. Stratified sampling is the process of collecting a representative sample by selecting units deliberately from various identified locations within a lot or batch or from various phases or periods of a process. By stratified sampling, a sample dosage unit is obtained specifically to target locations throughout the Compression/filling operation that have a higher risk of producing failing results in the finished product tests for uniformity of content.

For the dosage unit production step, samples are collected from 20 locations throughout the compression or capsule filling operation, seven units per location.
A product is classified as “ readily pass ” if the following criteria are met:
● for all individual results (for each batch n greater than equall to 60) the RSD is less than or equall to 4.0%;
● the mean of each location is within 90% to 110% of target strength;
● all individual results are within the range of 75% to 125% of target strength.

[anilsingh]

sir,
if I am valdating the batch and getting final result of assay 91.10%,99.30% and 108.2% and my limit is 90-110% in this case what I can do I can release batches or hold the Batch what is perfect answer of this question.

Thanking
Anil singh

[DURGA PRASAD]

As per the limits 90-110% you can release the batches.It will not have any technical breach.

But you should also have some control on the active substance on the final assay.91.10% seems to be on the border case and what is the impact on the longterm stability?
If Iam in your place I would certainly release the batches whose assay values will be between 95%-110%.
Regards

[syx]

dear anil, they are the result from a single batch or three consecutive batches? if they are taken from a single batch, I think the process should be optimized. IMO, it looks like homogeneity issue.
I am agree with mr prasad that our release specification may be more strict than product specification.

[anilsingh]

dear anil, they are the result from a single batch or three consecutive batches? if they are taken from a single batch, I think the process should be optimized. IMO, it looks like homogeneity issue.
I am agree with mr prasad that our release specification may be more strict than product specification.

dear these are the result of three validation batches in these result we are not getting the consistensy of the result so what we will do in this case without consistency we can not assure that our product is validated.
regards
Anil singh

[DURGA PRASAD]

If you are talking about validation batches-- why don't you follow fundamentals of validation?
You should first fix a tight limit. The limit need not be compendial limit. It can be internal limit which is more tight.

Such deviations in validation shows that your process parameters especially your blending is not proper and what is the temperature at which product is dried? At times product degradation takes place is tray driers.

I see only one solution. Your parameters are out of control and inconsistant.You must evaluate your batch process rather evaluate on assay limits.

Fix them first. The limits automatically fall in place.

It is not easy to just copy some process parameters and play in validation.Many things will come into play including the szie of batch and size of equipment too.

Go to your bench scale and evaluate each and every thing.You will have the answere.

Regards

[syx]

blend uniformity is related to the homogeneity of all components in the blending step, while content uniformity is more related to the homogeneity of the active component(s),

for lubrication step, especially when hydrophobic material is used as the lubricant (e.g., MgSt), the end point should be determined using shear rate and hydrophobicity properties, than assay.

[sunita]

Thank you very much. Your effort and support have helped me a lot in process validation of tablet. Once again Thank you Durga sir.

[DURGA PRASAD]

Thanks for your comments.
The main man behind this is my friend, moderator and colleague Mr.Graham.
I always thank him for making it possible to meet wonderful professionals who share their expertise, help and contacts.
Regards

[imkenshin]

Sir, thank you for that helpful protocol you have posted.

Based on the critical points mentioned in the document, what are the parameters subject for computation of CpK?
Or Blend uniformity only?

Thank you.