Batch Chromatography API - Blending of Batches

[validationeng]

My question is as follows...Hoping for some advice. I am working on a remediation project for an API manufacturing company in europe where part of their manufacturing process involves large scale column chromatography using silica gel.

The company at present does not test each batch post chromatography i.e. the product cut.....but runs the product cut from each column (based on known times when product comes off on the column) to a common holding tank....Maybe 2-3 columns are run a day. The holding tank where all of the 'good' product' goes post chromatography is tested each day...i.e a composite that is being topped up daily.....

Aware of the guidelines around blending potential in-spec and potential out of spec batches and the issues around that....Just wondering if there is any guidance / advice out there on this distinct area.

Thanks,

 

[v9991]

My question is as follows...Hoping for some advice. I am working on a remediation project for an API manufacturing company in europe where part of their manufacturing process involves large scale column chromatography using silica gel.

Since it is a remediation project, you might have already got an idea about the 'problem' (either 'non-compliance to regulations' or due to 'customer complaints' / 'product failure') I think rest of answer would depend upon the response/understanding of the stated problem! ( it would be relevant to understand/know the problem, to complete the response...given that, here's an attempt for way forward...)

The company at present does not test each batch post chromatography i.e. the product cut.....but runs the product cut from each column (based on known times when product comes off on the column) to a common holding tank....Maybe 2-3 columns are run a day. The holding tank where all of the 'good' product' goes post chromatography is tested each day...i.e a composite that is being topped up daily.....

What is the basis to 'not testing each lot of the batch!.
* Is there any development, scale up or validation data established?
* considering that it is continuous process, are there any inprocess controls (process parameters and material-checks); are they established to be adequate! (scientifically & performance wise., viz., validation)
* what are the quality attributes which are tested on the samples from the tank.,
* purification step, if available in the downstream, what is the efficiency of purification step to address any problems(if any) of the bulk,
* how well controlled is the purification step (control strategies, process monitoring etc)

Aware of the guidelines around blending potential in-spec and potential out of spec batches and the issues around that....Just wondering if there is any guidance / advice out there on this distinct area.

now the easy part,

h) Proposed in-process controls with acceptance criteria and the reason(s) which each in-process control is selected.

Chapter 6: Quality Control - European Commission
6.18 All the in-process controls, including those made in the production area by production personnel, should be performed according to methods approved by Quality Control and the results recorded.

Basic scientific understanding of the process and how variations impact product quality are also critical just in case if you haven't already considered following thoughts....hope this helps.


Sec. 211.110 Sampling and testing of in-process materials and drug products.
(a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

unfortunately i am unable to access the EMEA version of new PV guideline, but am sure to remember similar lines/intent outlined there as well...here's quick excerpts from FDAs

Under this regulation, even well-designed processes must include in-process control procedures to assure final product quality. In addition,
the CGMP regulations regarding sampling set forth a number of requirements for validation:
samples must represent the batch under analysis (? 211.160(b)(3)); the sampling plan must result in statistical confidence (? 211.165(c) and (d)); and the batch must meet its predetermined specifications (? 211.165(a)).

Process controls address variability to assure quality of the product. Controls can consist of material analysis and equipment monitoring at significant processing points (? 211.110(c)). Decisions regarding the type and extent of process controls can be aided by earlier risk assessments, then enhanced and improved as process experience is gained.

We recommend that a statistician or person with adequate training in statistical process control techniques develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and process capability.18


hope this helps.

 

[validationeng]

Thanks v9991,

Very much appreciate the comments...There would have been some very basic work done to come up with when the current product cuts should occur....but this was done a long time ago...and very little evidence remains to back it up.

One avenue I am exploring is getting analysis done on maybe 30 - 50 distinct chromatography runs and using those results to perhaps allow for non testing of every batch. All the inputs remain the same for chromatography in terms of amount of the material to be purified via chromatography, the solvent amounts and the product cut set points.

Just looking for a second opinion here really....If all of those30 to 50 results were statistically consistent and well within acceptance criteria and assuming all critical parameters were adhered to during normal chromatography runs, then is there logic to not have testing on every chromatography run ?.....As mentioned just looking for a 2nd viewpoint on all of this before I tease it out further myself.

 

[v9991]

given that there are very few details of product-history to review, your suggested action plan makes sense. However, that is only half the story, you also need to consider the variability(not only quantities, but the quality) of the input material, excipients/solvents etc., and also capability of process parameters, yield etc.,
You also need to ensure that traceability/identification of final finished product to the bulk batches. (more of a system control, just in case of any product problems or recall scenario) refer to one of the slide 34-39 of the continuous manufactureing ppt )
further, you may not eliminate the testing altogether, but can opt for 'skip / reduced testing'; But, i am not sure how well it will be received by the EU-agency for review & approval. (especially with the background of the remediation!!!) (& US FDA does accept the skip testing in certain instances )

 

[validationeng]

Thanks for that....food for thought, appreciate the input.