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Vaccines, Blood & Biologics

Record of Telephone Conversation, August 2, 2012 - EVARREST


Submission Type: BLA    Submission ID: 125392/0    Office: OBRR


Fibrin Pad


Ethicon, Inc.

Telecon Date/Time: 02-Aug-2012 08:00 AM        Initiated by FDA? Yes

Telephone Number: ------(b)(4)------

Communication Category:

1. Inspection Related



Telecon Summary:

Teleconference to discuss DMPQ issues

FDA Participants:

Randa Melhem

Destry Sillivan

Natalya Ananyeva

Tracy Tilghman


Non-FDA Participants:

Jessica Chung

Raina Dauria


Samson Tom

Christie Bielinski







Trans-BLA Group: No


Related STNs: None

Related PMCs: None

Telecon Body:

The purpose of this teleconference was to discuss the remaining 483 items related to cleaning validation for Evarrest Fibrin Sealant Patch 483 items regarding the cleaning validation. The following includes a summation of responses under consideration.


1.      Groupings and the validation plan for each group. In certain instances you employ a (b)(4) validation approach, and in others you only perform validation on (b)(4) of a group, and claim that the equipment is equivalent or identical.


·     CLN22 - Cleaning Validation should be performed on ----(b)(4)----. You should supply the results from at least --(b)(4)-- on the other (b)(4) as soon as possible.

·    CLN45 - Please consider using a (b)(4) strategy.  Not performing at least -------(b)(4)-----------  is generally not acceptable. Please also consider that the (b)(4) are not identical considering some may have deteriorated more than others over time.

·    VAL-R-0182 - Please consider using a (b)(4) strategy.  The other --(b)(4)-- are brand new and (b)(4)is older; it is not clear how can you equate them considering the deviations you encountered in other areas of CV due to deteriorating parts.

Undergoing maintenance work is not an acceptable justification for not doing cleaning validation on a piece of equipment. If the maintenance work would significantly alter the equipment, re-validation/verification should be performed after the maintenance work to ensure that after maintenance the equipment is able to be cleaned using established cleaning cycles.

Question #1 Discussion: Ethicon stated that they followed PDA TR 49 in determining their cleaning strategy, and that form a cleaning validation perspective the aging  of equipment does not affect cleaning performance. FDA asked clarification considering several pieces of equipment failed the cleaning validation due to deteriorating parts. FDA asked whether additional runs were performed on all the (b)(4) (that were in maintenance) in CLN22 and CLN45 studies, and Ethicon stated that they have not.

FDA stated that Ethicon is not bound to adhere to PDA TR 49, and that not performing at least -(b)(4)- on each piece of equipment is not normally acceptable.  At least (b)(4) cleaning validation run should be performed for each piece of equipment, even if the equipment is identical. Ethicon stated that they acknowledged FDA’s position, and restated the expectation of (b)(4) run on every piece of equipment.  FDA stated that for any piece of equipment that had significant maintenance performed, that equipment should be subjected to re-qualification and/or re-evaluation to ensure that it is being cleaned appropriately.

Ethicon added that they will have an internal discussion, and would provide a proposal to FDA by August 10, 2012.

Regarding VAL-R-0182, Ethicon inquired if the expectations are the same for cleaning validation as for the validation of -------(b)(4)------- (i.e. for each piece of equipment). FDA stated if all equipment in the group are properly validated and they are stored under the same conditions, then it is acceptable to perform ----(b)(4)---- on a representative (worst case).


2.      Please be prepared to justify your acceptance limits for --------(b)(4)--------------. Please provide, prior to the teleconference, your actual (b)(4) test results that you check prior to CV, for comparative purposes.

Question #2 Discussion: Ethicon stated that the acceptance limits for -------------(b)(4)-------- should remain the same based on historical data, and that alert limits are implemented to flag the higher results of the data and trigger an investigation, so as to improve process capability.  FDA stated that the acceptance limits should be based on (b)(4) standards. A review of the data provided by Ethicon shows that only few pieces of equipment have a -------(b)(4)--------, and that these pieces had issues with deteriorating parts. FDA added that these pieces of equipment should not set the standard for the ---------(b)(4)-------- limits. FDA stated that they are concerned that Ethicon set a --------(b)(4)-------- for their cleaning validations instead of (b)(4) specifications, and that they validated their cleaning process to meet those specifications. For example if the cleaning process of any piece of equipment that did not meet (b)(4) for (b)(4), the process was modified: larger rinse volume, longer rinse time and/or additional rinses.

Thus Ethicon did not set their acceptance limits for both -------------(b)(4)----------- to (b)(4) specifications, and did not validate their cleaning of equipment to meet those specifications.

Ethicon stated that they understand FDA’s position that is why they set the alert limits to allow them to evaluate their process capabilities while they continue to collect data.

FDA asked if alert limits were tested after each cleaning process, which Ethicon confirmed, and added that exceeding the alert limits will trigger an investigation, and exceeding the alert limits two times in a row triggers a more thorough investigation.

FDA stated that the cleaning validation should provide assurances that the process delivers clean equipment that would not interfere with manufacturing, and that routine monitoring is not a requirement. Some companies monitor all the time, however this is not a requirement.

Ethicon stated that they have implemented a cleaning validation in (b)(4) (older facility) and have created alert limits in order to make their cleaning validation more robust moving forward. They added that for several pieces of equipment, it is hard to get the ----(b)(4)---- specifications. FDA responded that for those upstream pieces of equipment where --(b)(4)-- is used, Ethicon could set a higher acceptance limit -----(b)(4), but that should not be the standard for all pieces of equipment especially those used in downstream processing which should meet (b)(4) specifications. In addition, FDA asked if there is a way to definitively show that --(b)(4)-- is a contributing factor, and Ethicon stated that they will evaluate their cleaning process and determine where --(b)(4)-- contributes to higher (b)(4).

FDA stated that Ethicon should revaluate their acceptance limits for both --------(b)(4)--- for all their equipment to be in line with (b)(4) specifications. If there are any outliers, they should be identified, and if a higher limit is needed, it should be justified. Ethicon stated that they will have an internal discussion about the acceptance limits for cleaning validation, and submit a proposal to FDA by August 10, 2012.


2a. You have not adequately justified your acceptance limit for product --------(b)(4)----------------.  Additionally, you did not specify in your response regarding the (b)(4) samples, whether the thrombin from these samples was ----------------------(b)(4)------------------------------------------.  Please be prepared to provide further justification of your -----(b)(4)----- limit, and clarification as to which --(b)(4)-- was used to        --(b)(4)-- the (b)(4) samples.







Ethicon agreed to perform these studies as a PMC.



3.      ---------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------


2 pages redacted (b)(4)

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