In my plant we are installing a new chromatographic column for the production of API lots. this column is considered equivalent in performance to the old column. This is my question: how is considered the change by the Regulatory view (minor, major…). It is necessary the process validation, because this column is part of chromatographic phase in the process to manufacture API lots? How are the eventual step of validation to plan ?
Woow I finally see some one asking about chromatography.
Its a good question.
There are many changes here which effects the resolution.
What is the diameter of old vs new column?
The hieght must remain same as it has been scaled up earlier and the change is only diameter.
What is the rate of flow between old and new column --may be in liters per mini or cm/hr?
Has there been any change in the particle size of resin or chromatographic media?
Normally smaller particles sizes of chromatographic resins are used to have a good resiolutions in final purification steps.
What is the material of construction between old and new coloumn?
Are you packing in house or it comes as prepacked coloumn?
Has there been change in the cleaning and regeneration of the coloumn?
Do you have a scale down study in place?
Is there any change in pressure of the new column?
Collect all the material data sheets.
Collect list of all components.
Install the coloumn.
Perform the integrity test with a known substance or a salt --by UV method or by conductivity method.
This is how you have to start.
If you have any questions do write .We shall reply you right here.
Unless you do you will not know.
So please do not ask before you perform any thing.
Chromatography is an art. Its a skill.
Regards
Bruce Neagle
[FONT=inherit]
The real question is whether the new column is equivalent to the old column and whether it will affect the quality of your drug product. If you cannot do this then you must fully re-validate (IQ, OQ, PQ, CV, PV).[/font]
1 Like
The real pain in this you have to repeat all the things again and again.
Try to know your HETP. (Hieght equivalent to Theoritical plates)
Is that equivalent to your old column?
Try to know the capacity of the column.That is milligram of api that will bind to milligram of chromatographic resin.
Compare the data.This will set forth what you have to do next.
Best of luck.
Hi,
In my opinion, Even in case of Identical (Like to Like) column replacement for the API process the change will come under Major category. Performance qualification (If your Process Validation is in place with old column) of the column needs to be performed along with IQ & OQ.
Happy reading !
[quote=DURGA PRASAD]Woow I finally see some one asking about chromatography.
Its a good question.
There are many changes here which effects the resolution.
What is the diameter of old vs new column?
The hieght must remain same as it has been scaled up earlier and the change is only diameter.
What is the rate of flow between old and new column --may be in liters per mini or cm/hr?
Has there been any change in the particle size of resin or chromatographic media?
Normally smaller particles sizes of chromatographic resins are used to have a good resiolutions in final purification steps.
What is the material of construction between old and new coloumn?
Are you packing in house or it comes as prepacked coloumn?
Has there been change in the cleaning and regeneration of the coloumn?
Do you have a scale down study in place?
Is there any change in pressure of the new column?
Collect all the material data sheets.
Collect list of all components.
Install the coloumn.
Perform the integrity test with a known substance or a salt --by UV method or by conductivity method.
This is how you have to start.
If you have any questions do write .We shall reply you right here.
Unless you do you will not know.
So please do not ask before you perform any thing.
Chromatography is an art. Its a skill.
Regards[/quote]
Thank you for your suggestions. I will try to answer to your questions.
-
What is the diameter of old vs new column?
Øint = 3.3 m vs 2.5 m. -
What is the material of construction between old and new coloumn?
AISI 316L both new and old column.
3)What is the rate of flow between old and new column --may be in liters per mini or cm/hr?
The flow is in m3/h.
-
Has there been any change in the particle size of resin or chromatographic media?
No, it hasn’t. -
Are you packing in house or it comes as prepacked coloumn?
The packing will be in house. -
Has there been change in the cleaning and regeneration of the coloumn?
No, there will be the possibility to pack and unpack with on/off of agitator. -
Do you have a scale down study in place?
No, I don’t. -
Is there any change in pressure of the new column?
The pressure is 5 bar vs 4 bar old column. This parameter is not critical parameter but physical characteristic of the column. -
Perform the integrity test with a known substance or a salt --by UV method or by conductivity method.
The column is certified ASME 7 including hydraulic and fluid tests.
awaiting response
regards
Emanuele
[quote=gokeeffe]Bruce Neagle
[FONT=inherit]
The real question is whether the new column is equivalent to the old column and whether it will affect the quality of your drug product. If you cannot do this then you must fully re-validate (IQ, OQ, PQ, CV, PV).[/font]
[/quote]
Thank you
I hope the answers I given to Durga Prasad may be help to understand if the column is effectively equivalent.
Thats good data.
I appreciate your effort.
The only change I see that the Dia has been increased. That means the capacity is increased.The hieght remained almost same.
From 2.5m to 3.3m.
If the amount of resin increased the total API binding also increased.
There will be 2 major issues when you run this column
- You have to equilibrate this column with atleast 7 to 8 column volumes of buffer. Try to initially do little more than prescribed value.
2.The elution in increased size is a tricky business.
Even you have ASME 7 test for integrity-- when you pack the column inhouse you need to know and understand your packing consistancy and efficiency. It is always good to carry out column integrity test aftert packing.
Simple test is run 0.25M Nacl in your equilabration buffer.
2 column volumes.
Note the conductivity curve.
It should be perfect.
It should not get elongated or even get some sort of spike.
HETP here is same. You need not worry about column.
Best of Luck.
What I am interpreting from the above data is the volume is changed …so the resin qty…elution time, contact surface are of product layer definetly going to increase & we don’t have the scale down study as well :(. Again few more questions also can be asked for better interpretation
- Change in which stage ?
- Is the elution time really going to affect the process ?
- Resin replacement frequency…?
- How we are going to address (In absence of Validation) the product processing to the auditor… ?
If really it sounds technical justified to you make a assessment duly approved for the reasons why one should not perform the validation of process in this case & preserve it with the relevent docs…
I will bet on performing the validation…
Dear egizzi and others,
This message is suggested after 5 years later to egizzi’s first question.
Column process has become important to drug substance production as in mass purification measure. In addition, new process validation has been emphasized since Jan. 2011 in US FDA guidance. Now, the column (chromatography) process should be validated according to this new guidance for cGMP, as well in Europe.
However, lots of companies are still following up the old regime which one or two big-column makers, even though world widely famous companies, have persuaded with the limited and outdated scope range. Here, in order to be of help to re-definition of the column process validation, I leave this message for open discussion.
Coming back to your first questions and answers on Sep ’11, I would like to say that you have two aspects in solving your new column issue.
The one is only relevant to the column technology: that is, to verify the equivalency of the new column (larger) to the old one (smaller) on the view point of simply meaning column performance. What I mean here by “simply meaning” column performance is the work limited to confirming the function of the both columns to each other. That is, it is concerning to the least extent with regulatory issues.
The other one is of the column process validation: that is, the work, more or less, relevant with the regulation. It is of the validation of the chromatographic process with NEW column installation. Judging from your questions here, you were not seemed to mean this. Regarding some subjects, you must be concerned a little bit with the regulation, but the main issue you showed is to get the reliable installation of the new column.
Then, you mentioned clearly in your beginning question that process validation is necessary because of API to be purified with your new column. Here, there is raising a question again. It is “Has the old column been compliant in using to purify API on the process validation or not?” As the case of YES, if you had the documentation package provided with the old column, you may need only the qualification of equivalency with the new column.
So far, to be sure of your status, I would like to ask one more, “Has DESIGN SPACE been constructed in the work of the process validation of the purification process of API with the old column?”
If yes, your team must have had the process validation and the documentation of the old column. What you have to do is only the qualification/documentation according to the protocols which were implemented in the old column. Among the protocols, the following are important and essential to be qualified, but not limited to these.
HETP number (column efficiency).
Input raw material profile: qualitative and quantitative.
Equivalency of chromatogram and recovery of API across the column scales.
Equivalency of packing material.
Life time of packing material and how to determine the repacking time.
On the other hand, had you not taken the validation of the old column process, or had you not had DESIGN SPACE, you should do the WHOLE work of the column process validation as mentioned below. This shall be done together with your organization.
.
As you are probably aware, chromatographic process validation demands understanding not only the chromatography technology itself but also chromatography process based on nonlinear chromatography. QA/QC Department shall help you for the purpose of good PAT measures to be supported by the analysis team. Also you need to be aware of scaled up column instrumentation: specialty in column equipments.
Briefly speaking of the involved jobs required in the column process validation as well in constructing DESIGN SPACE, the following are listed even as partial.
Defining Critical Quality Attributes(CQA).
Listing up Critical process parameters(CPP) affecting CQA’s.
Risk analysis ( RA on the range of all CPP variables ).
Establishing Process Analysis Technology(PAT).
Planning Design of Experiments (DoE) for CPP.
Constructing Design Space (DS).
Verification of column change(scale-up, scale-down) in DS.
CAPA according to RA and DoE results.
Relevant Standard Operating Procedures.
Process Validation Audit.
Regarding the questions and answers exchange between you and DRUGA PRASAD, those should be reconsidered on the view point whether any change or any action may or not affect on CQA. Here, CQA is assumed as the purity (e.g. 99%) and confirmation of non-existence of critical impurity(ies) in API.
For an example, to the question asking about particle size change, you answered, “No, it hasn’t”. However, your answer is not enough for the process validation of the new column. For your understanding, I would like to list up some questions to be answered.
Is the resin from the same maker?
Is the particle size distribution same?
Is the pore size same?
Is the specific surface area same?
Is the chemistry of the particle surface same?
All the above concept properties can affect CQA of the product API even if the column is used in the equivalent condition with the old column. So, all the answers to the above should be documented as the results of experiments implemented according to protocols or SOP’s in DoE.
As another example, you answered that you did not have a scale down study “in-place”, but all the experiments on column scales are to be planned and done in lab. The consistent CQA shall be expected as the result in any scale-up column runs. This is the concept of QbD, essential to the new process validation guidance valid from Jan. 2011 and according to ICH Q8(R2), Q9, Q10.
If you had accumulated the technical data and provided the qualification even with the column in lab ensuring the scale-up column results based on knowledge and science, this would mean the construction of Design Space of column chromatography process. When DESIGN SPACE is constructed, any scale of column within the space will be considered to be validated. So, automatically, you can get the process validation of the new column if you have the design space with the old column.
Here, we can smoothly make you the answer to your message, “Change about Chromatographic column” left some months later after this message. That is, any column change shall bring deviations of the critical quality attribute. This implies any change which can alter CQA should be observed as major and subject to risk analysis and be re-evaluated. So, I would like to omit repeating about the column process validation because the major scheme is very similar.
As the last comment, I am wondering how many column chromatographic purification processes have been validated as cGMP equipments on the world. Being raised with your questions of the new column installation, the correspondences questions and answers let me think that the chromatography process even in the western countries might have not been so much systematically validated as demanded by the new US FDA guidance of process validation. However, the time of the well defined chromatographic process validation will come sooner or later.
I am afraid that this may be too long comment to be of help to you.
Thank you for your notice and talking.
Best regards