M E M O R A N D U M
Department of Health and Human Services
Public Health Service
United States Food and Drug Administration
Center for Biologics Evaluation and Research 
To: Administrative File of STN 125512/0
      Qiao Bobo, PhD, Lead Inspector, CBER/OCBQ/DMPQ/MRBII
From: Alexey Khrenov, PhD, Senior Staff Fellow, LH/DHRR/OBRR
Through: Tim Lee, PhD, Acting Chief, LH/DHRR/OBRR
Subject: Review of responses from Baxter to FDA 483 Observations cited by Alexey Khrenov during the pre-license inspection (PLI) that took place ---(b)(4)---------------
RECOMMENDED ACTION:
The responses received from Baxter to FDA 483 Observations cited by Alexey Khrenov during the pre-license inspection (PLI) that took place ----(b)(4)-------- were found to be acceptable.
SUMMARY:
The PLI of the Baxter facility at ---(b)(4)------ was conducted as part of the review for Biologics License Application (BLA), under STN 125512/0, for Antihemophilic Factor (Recombinant), Porcine Sequence (development name OBI-1, proposed trade name OBIZUR). The purpose of this review is to evaluate information received from Baxter in response to observations in Form FDA 483 cited by Alexey Khrenov (Observations 4, 7, 8, 9c, 9d, 9e and 10) during the PLI. Please note that reviews of the responses to Observations 1, 2, 3, 5, 6, 9a, and 9b cited by DMPQ reviewers Qiao Bobo and Jie He are in a separate memo.
The following is the timeline of information received from Baxter:
March 28, 2014 – The response to Form FDA 483 observations was received as part of amendment 125512/0.12, outlining the plan and timeline to address the observations.
June 9, 2014 – Teleconference with Baxter was held to discuss the timeline to provide the final response to Form FDA 483 observations and supporting documentation.
June 27, 2014 - The final response to Form FDA 483 observations was received as part of amendment 125512/0.24, describing the steps taken to address the observations and providing the supporting documentation.
REVIEW OF RESPONSES:
This memo addresses Form FDA 483 observations (bold) followed by the reviewer’s evaluation of the responses from Baxter (plain). The observations are numbered according to the numbering on the FDA Form 483. DHRR reviewer’s comments are in italics.
Observation 4: The SOP for the Qualified Building Management System (QBMS) MF-18-003FAC is not adequate to discriminate between alarms associated with routine operations and actual equipment malfunction, and is not followed. The excessive number of alarms hinders the response in a timely manner. For example, the logs of the QBMS alarms associated with the cell bank freezer show that the action alarm has not been acknowledged for more than a month.
Baxter acknowledged that improvements are required to ensure that timely actions are taken in response to alarms, noting that there were no adverse impact to the cell bank in case of the alarm mentioned.
To address this observation, Baxter revised SOP MF-18-003FAC “Qualified Building Management System Alarm Management and Response” to clearly define the criticality of alarms and instructions for response from equipment owners and users. The revised SOP became effective on April 15, 2014. Per the updated SOP, the Quality department routinely reviews daily alarm reports to ensure all alarms were acknowledged accurately and in a timely manner. Baxter provided a copy of the revised SOP.
Baxter also created a team to review the system and alarm management program, identify and review changes, and implement changes to the Qualified Building Management System. Baxter created a project plan “Review and Implementation of Alarm Management at Baxter (b)(4)-- Site” which was approved on ---(b)(4)----. The objectives of the project are:
* Review of Alarm Management System regarding response to alarms and responsibilities
* Review and update Alarm Management SOP to meet the compliance commitment
* Perform formal Project Risk Assessment for Alarm Management
* Reassess all alarms in system for criticality
* Review of all alarm set points and delays
Baxter Quality Assurance reviewed all the alarm reports from January 28, 2012 to 16 February 2015, which covered the manufacture of lots ----(b)(4)---------------, to ensure all equipment alarms were properly acknowledged. After the review of all alarm reports, Baxter identified some alarm acknowledgements did not have correct comment descriptions or were not acknowledged in a timely manner. Event #343316 was initiated in the ---(b)(4)---- system on May 21, 2014 to properly document an investigation and to properly conduct a corrective action plan to resolve the findings. Baxter provided the internal memo regarding this issue.
* DHRR reviewers find the response to this observation to be adequate.
Observation 7: The SOP 115859 is deficient, as it does not provide safe way to dispose of the wrappers from the tube connectors -----(b)(4)----------------- in the biological safety cabinet in ---(b)(4)---. Specifically, operator was observed disposing of wrappers by throwing them on the floor. The wrappers on the floor created a potential safety hazard for the other operators in the room.
Baxter agreed that the SOPs do not specify how to handle the disposal or removal of wrappers and similar waste from the Biological Safety Cabinet and recognized that this is not a desirable practice.
In order to address this observation by May 2, 2014, Baxter performed an evaluation of all OBI-1 process steps that require the usage of a biosafety cabinet. Baxter determined that SOP 115859 is not the correct document to be changed, but rather SOP MF-09-018-MFG “Operation of the -----(b)(4)------------- Biological Safety Cabinets”, which governs the procedures for using biosafety cabinets for OBI-1 manufacturing steps performed in Rooms ---(b)(4)---.
On May 23, 2014, MEMO-14-007 (provided by Baxter) was written to document the evaluation that had taken place earlier and the specific changes to MF-09-018-MFG (new version provided by Baxter), which became effective on May 23, 2014.
The revision of MF-09-018 MFG includes the following:
-------------------------------------------(b)(4)----------------------------------------------------------------------------------------------
--------------------------------------------------------------------------------------------- ------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------- -----------------(b)(4)--------------------------------------------------------------------.
--------- -------------------------------------(b)(4)------------------------------------------------------------------------------------------------------.
-------------------------(b)(4)--------------------------------------------
According to the memo, -------------------------------(b)(4)------------------------------------------------------------------------------------------------------ was moved from the biosafety cabinet to reduce clutter during ---(b)(4)----- step.
* DHRR reviewers find the response to this observation to be adequate.
Observation 8: The SOP MF-16-001SC “Shipment of OBI-1 -------------(b)(4)-------------------------------------------- instructs Material Management to obtain access to the (b)(4) from manufacturing, but does not describe the procedure for the release of (b)(4) from storage in the manufacturing area and its ------------(b)(4)-------------- to the -----(b)(4)-------------. Response to Observation 8:
Baxter agreed that the procedure for removing the (b)(4) from the Manufacturing (b)(4)-- and transport of the (b)(4)- to the designated location to hand off to the Materials Management group needs to be documented in an SOP.
Baxter revised procedure MF-16-001SC “Shipment of OBI-1 ------(b)(4)-------------------------------- (provided), adding section 7.11 to incorporate the current procedural steps and controls performed by Manufacturing and Materials Management for the expeditious transfer of (b)(4) from storage in the manufacturing area to the warehouse area. These changes were reviewed, approved and the SOP became effective on April 7, 2014.
* DHRR reviewers find the response to this observation to be adequate.
Observation 9: Equipment use logs are not adequately maintained. Specifically, 
c) Log book for -------(b)(4)----------------- did not contain the record of preventive maintenance for 2011 (actually performed).
d) Log book for -------(b)(4)----------------- did not contain the record of preventive maintenance for 2012 (actually performed).
e) Log book for -------(b)(4)----------------- did not contain the record of preventive maintenance for 2013 (actually performed).
Baxter acknowledged that the equipment logbook and/or equipment use record entries at Baxter (b)(4) have been inconsistent. The lack of consistent documentation of QC logbooks had been acknowledged per -------(b)(4)-----------------.
Several factors have been identified as potential contributors to the inconsistency, primarily: 1) site procedures are not consistent (e.g., QC uses logbooks, Manufacturing uses Equipment Use Log forms) and lack clarity, and 2) periodic reviews of entries are not performed in a timely manner and required only -------(b)(4)-----------. In order to improve the documentation of equipment cleaning, use and maintenance in Manufacturing, the use of logbooks was discontinued, and forms (“Equipment Usage Record”, form MF-99-011MFG) were implemented. These forms, as well as the procedures, will be improved overall, as well as to include QC Laboratory instruments.
In order to address the 483 observation #9, Baxter revised MF-09-017MFG “Equipment Usage Records” which became effective on April, 2014. The revision of MF-09-017MFG includes the following:
* 5.2 Includes QC department under Responsibilities.
* 6.2.1 Specifies activities in the description section of form MF-99-011MFG, includes, but not limited to, cleaning, use, calibration, qualification, preventative and non-routine maintenance activities.
* 6.2.3 through 6.2.11 provides examples for specific Equipment Usage Records entries.
Baxter provided revised MF-09-017MFG, form MF-99-011MFG, and the training record for the QC laboratory staff confirming that all staff took training for MF-09-017MFG on April 28-30, 2014.
* DHRR reviewers find the response to this observation to be adequate.
Observation 10: The personnel in microbiology testing laboratory and QC testing laboratory are required to wear separate lab coats in these two labs, but there is no procedure in effect. The lab coat rack sections are not physically separated; therefore, the coats may come in contact with each other and be easily switched.
Baxter acknowledged that the system for storage of laboratory coats requires improvement.
In order to address the 483 observation #10, a procedure MF-19-001QC “Gowning Procedure for the Quality Control Laboratory” (provided) was made effective on May 19, 2014 and a dedicated and segregated closed storage unit was installed to separate lab coats for each area (for a picture of the new unit, refer to MF-19-001QC Attachment 3: Storage of Laboratory Coats in ----(b)(4)-----------------. In addition, the Analytical lab coats and Microbiology lab coats are now ----(b)(4)---------- (refer to Attachments 1 and 2 of MF-19-001QC). Baxter stated that these images are laminated and posted next to the entry door to each laboratory.
* DHRR reviewers find the response to this observation to be adequate.
