M E M O R A N D U M
Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and Research 
TO:   Administrative File STN: 125512/0 (Antihemophilic Factor (Recombinant), Porcine Sequence)
FROM:   Qiao Bobo, Ph.D., Co-Lead Inspector, CBER/OCBQ/DMPQ/MRBII
                 Jie He, MS., Co-Lead Inspector, CBER/OCBQ/DMPQ/MRBII
cc:   Alexey Khrenov, Ph.D., CBER/OBRR/DHRR/LH
        Natalya Ananveya, Ph.D., CBER/OBRR/DHRR/LH
THROUGH:   Marion Michaelis, Chief, CBER/OCBQ/DMPQ/MRBII
APPLICANT:  Baxter Healthcare Co.
MANUFACTURING LOCATION: ---------------(b)(4)--------------------------------
SUBJECT:   Review Memo for FDA Form 483 Responses – Review of responses from Baxter Healthcare Co. to FDA 483 Observations issued by Jie He and Qiao Bobo during the pre-license inspection (PLI) that took place ---------------(b)(4)----------
RECOMMENDED ACTION: 
Baxter’s responses to FDA Form 483 Observations issued by Jie He and Qiao Bobo (Observations 1, 2, 3, 6 and 9a) during the PLI that took place ---(b)(4)----------- were found to be acceptable.
SUMMARY:
The scope of this inspection ----(b)(4)---------- conducted at Baxter ---(b)(4)------- was a pre-license inspection as part of the Biologics License Application (BLA) STN 125512/0 for Antihemophilic Factor (Recombinant), Porcine Sequence. The purpose of this review is to evaluate information received from Baxter in response to FDA Form 483 Observations issued by Jie He (Observations 1, 2, 3, 5 and 9a), Qiao Bobo (Observations 6). Please note, the response to rest of the observations (Observations 4, 7, 8 and 9b, 9c, 9d, 9e) were reviewed, accepted and signed off by the OBRR/DHRR in a separate memo.
The following is the timeline of information received from Baxter and teleconferences held with the firm affiliated with this 483 response review memo:
* March 28, 2014 – Initial information received for FDA Form 483 responses
* June 9, 2014 –– Telecon with Baxter to discuss responses received so far and what was expected in the final response package
* June 27, 2014 – Additional response to FDA Form 483
* August 12, 2014 – Additional response to FDA Form 483
REVIEW OF RESPONSES:
This memo addresses Form FDA 483 observations (bold) followed by Baxter’s response (plain) and reviewer’s evaluation of the responses (bold italic). The observations are numbered according to the numbering on the FDA Form 483.
Observation 1: The ----(b)(4)-------- bottle is used for -----------------(b)(4)------------------------------------------- storage at (b)(4) which is outside of manufacturer’s recommended low temperature limit of (b)(4). The use of this container for (b)(4) storage at (b)(4) has not been qualified.
Baxter’s Response to Observation 1:
Baxter stated that the recommended lower limit of (b)(4) for (b)(4)--------bottles with ------------------(b)(4)---------------------- from the supplier does not represent an inherent limit of acceptable performance behavior but was the range evaluated and reported by supplier (b)(4)------, and Baxter provided additional study reports on using the (b)(4) ---------- at temperatures below (b)(4). Baxter conducted qualification studies for the  (b)(4) 
Baxter proposed two action items in its initial response to the 483 observation.
Observation 1, Action #1
Create and approve a protocol to qualify the -----(b)(4)----------------bottles with ---------------------(b)(4)----------------- for use at temperatures as low as (b)(4)-----. This study would include checks for the tightness of the cap, and examination for cracks. Target Completion Date: April 30, 2014
Observation 1, Action #2
Implement Baxter Material Qualification procedure for product container/closure systems.
Baxter’s second response to Observation 1 was received on June 27 in Amendment 24 and provided updates to the proposed actions from the initial response: Action #1, the protocol ----(b)(4)-------, effective April 25, 2014) was approved to qualify the ----(b)(4)------------------- bottles with (b)(4)- closures for use at temperatures as ----(b)(4)---. Baxter plans to submit final report from this study in August 2014. Action #2, a material qualification procedure (MF-09-002QC) for the (b)(4) site was approved and became effective on May 23, 2014.
Baxter submitted a final response on August 12, 2014 to Observation 1 in Amendment 27 providing ----(b)(4)-------------------- Qualification Report” for the low temperature -----------(b)(4)----------- bottle qualification study under formal protocol ---(b)(4)------------. Bottles with various filling volumes were initially torqued at ---(b)(4)--, re-torqued after a minimum of -(b)(4)- of ----(b)(4)------, and stored at -----(b)(4)--------- total. No cracked or leaking bottle was observed in all tests. Baxter also reiterated that it has in-process testing to monitor ---------------------------------(b)(4)-------------------- upon receiving (b)(4) at the fill/finish site to provide additional assurance that any compromised bottle would be identified.
Reviewer’s comment: Baxter conducted studies for --------(b)(4)-------------------- and -------(b)(4)------------ of the (b)(4) during storage and shipping, the data provided in the final study report support the use of the bottle at below supplier’s recommended lower temperature range. Considering that the bottle contains the ----------------------------------------------------(b)(4)-----------------------------------------------------------------, I consider the response acceptable.
Observation 2: The internal audit program is inadequate. Specifically, there have been no internal audits during the last 14 months and there are no written procedures for auditor qualification and training. 
Baxter’s Response to Observation 2:
Baxter discussed the integration plan after their acquisition of the current facility and stated that they have identified that the internal audit program lacked clear requirements for auditor qualification and there was a gap in personnel to perform internal audits. Baxter described their ongoing effort including multiple site visits by senior Baxter Quality, Compliance and Regulatory Affairs personnel, along with an expert consultant conducted gap analyses for GMP compliance since August 13, 2013. A Senior Manager of Compliance was hired in August 2013 who has over 20 years of experience in the Biotech/Pharmaceutical field and has either conducted or managed audits/ auditors for the past 14 years. In addition, a Senior Quality Auditor was hired in January 2014 to conduct Internal Audits. Baxter -(b)(4)- had already initiated actions to restart the internal audit program and the 2014 Internal Audit Schedule has been created and approved on January 20, 2014. In the initial response to 483, Baxter proposed to create a new Internal Audit Procedure based on Baxter procedures, which will define the auditor training and qualifications based from their knowledge, skills and abilities. This will include the development of forms to support the documentation of the auditor qualification with a targeted completion date by April 7, 2014.
Baxter’s Final Response to Observation 2 was received on June 27, 2014 in Amendment 24. The new document, MF-20-007QA (Effective: April 4, 2014) Internal Audit Procedure, provides additional details on what the expectations are for an internal audit and internal audit deliverable timelines. In order to define the auditor’s training and qualifications, another procedure has been created; MF-20-006QA; Effective: April 20, 2014; Auditor Training, Qualification and Requalification. Two forms are tied to this procedure, MF-99-011QA, “Auditor Qualification Record” and MF-99-015QA, “Auditor Training and Evaluation Record”. Both forms have an Effective Date of 04Apr14. This procedure and forms cover the qualifications based on knowledge, skills and abilities to document that the auditor has been trained and qualified to conduct audits.
Reviewer’s comment: I reviewed the new auditing SOP that has been implemented, and auditing schedule for the 2014 for the Baxter -(b)(4)- site. The response is acceptable.
Observation 3: Deviation management procedures are not followed. Specifically,
a) There are 22 out of 51 currently open deviations in the ---(b)(4)------ system beyond the-b(4)---- closing requirement specified in SOP CQP0703018; Corrective Action Preventive Action (CAPA) Procedure (Effective date: November 11, 2013)
b) There are 154 out of 283 (54%) deviations from January 3, 2012 to November 25, 2013 not closed within –b(4)---- from initiation as specified in SOPs 045454-SOP/2.0, “Deviation Reporting and Investigations” (Effective date: from April 27, 2011 through November 11, 2013) and 113906-INS; “The Use of ---(b)(4)---- for Unplanned Events” (Effective date: from June 11, 2012 through November 11, 2013).
Baxter’s response to Observation 3:
Baxter acknowledged that the -(b)(4)- site has been in transition regarding implementing the ---(b)(4)------ system to manage all event types, as well as in depth training on how to conduct robust investigations. A cross-functional team was formed to close all the deviations open ---b(4)-------. The initial response included proposed two action items:
Observation 3, Action #1
Implement CAPA Review Board meetings. The purpose of this meeting is to review all quality events and CAPA with the focus being on overdue items as well as discussion on any higher risk events. Through the CAPA Review Board, current and future items open beyond –b(4)--- will be escalated to the Site Leadership Team for immediate review and mitigation.
Observation 3, Action #2
Create local job aides to facilitate consistent and timely execution of the investigation and CAPA process.
Baxter’s Final Response to Observation 3 was received on June 27, 2014 in amendment 24. Baxter now conducts weekly CAPA review board meetings which had been initiated on February 11, 2014, to review all quality events and CAPAs, now include on the agenda a review of closure timelines. Through the CAPA review board, meeting events open ---b(4)------------ closure requirement will be communicated to the Site Leadership Team for immediate review and mitigation, to further ensure timely completion. A May 14, 2014 CAPA review board meeting minutes was provided.
For action 2, a job aid (Job Aid MF-20-CAPAJA1) was created to ensure consistent and efficient CAPAs and became effective on April 25, 2014. This local job aid procedure supports the CAPA program SOP by providing detailed, customized instructions for the (b)(4) site.
Reviewer comment to Observation 3: Baxter (b)(4) has implemented regular CAPA review meeting and Baxter’s global SOP for deviation management that requires all deviations to be closed –b(4)-------- from initiation. Any deviation opened beyond –b(4)----- will need to be justified by the technical expert (investigator) to the QA, and be communicated to the senior management team at the (b)(4)-- facility. The CAPA review board meeting minutes provided detailed the agenda and actions from the review board, and showed the current CAPA SOP has been implemented effectively. The response is acceptable.
Observation 5: SOP 045700 “Determining the Polysorbate 80 Content in –b(4)----------------” for ---b(4)------------------------------------- has not been updated when CAPA 138037 was completed; and there is no updated SOP in effect.
Baxter’s Response to Observation 5:
An Unplanned Event 138037 was initiated to investigate the reagent concentration document error. A Change Control was initiated to provide an interim control (within the –b(4)-- system, called a temporary change control) and revision to the affected procedure 045700-SOP, “Determining the Polysorbate 80 Content in –b(4)-----------------” An evaluation was performed and documented within Unplanned Event 138037 assessing the impact to the performance of the assay. This investigation concluded that the identified errors had no impact on the assay performance and that the data generated are all valid. Therefore, the Unplanned Event was closed on December 9, 2013 with no further actions as the Change Control governed the interim control and revision of the SOP. This event occurred prior to the implementation of the Baxter -----------(b)(4)-----. At the time of this event, existing procedures allowed for interim controls (temporary change controls) to be utilized per 045451-SOP version 3.0, “Change Control”, as documented in Unplanned Event 138037. The analyst correctly performed the test in accordance with details in the interim controls until the revision of procedure 045700-SOP became effective on 06-Mar-14. With the implementation of the Baxter CAPA system, governed by CQP0703018, “Corrective Action Preventive Action (CAPA) Procedure” and the use of ----(b)(4)-------- implemented at the -(b)(4)- site on November 11, 2013, the current process requires all corrective actions to be completed prior to event closure. There is a Quality approver who is responsible for verifying that the related actions have been completed as part of the approval process. Integration and use of the Baxter procedure should mitigate this type of occurrence from happening in the future.
Reviewer’s comment: I have reviewed the current CAPA SOP CQP0703018 for the Baxter -(b)(4)-- site, and the new procedure governing closing of CAPAs requires assurance from a quality approver that all related action(s) have been completed. The response is acceptable.
Observation 6: Validation results were not reviewed in a timely manner to assess the performance of relevant testing procedures. Specifically,
a) Bioburden test (SOP No 045679-SOP; “Microbial Limits Testing”) procedure was validated in 2009-2010 to use -----------------------------------------------------------------------------(b)(4)-----------------------------------------------------------------------------------------------------------------. The bioburden testing procedure was in existence prior to the validation but the tests only required the use of ---(b)(4)--. No actions were taken until August 2013 to revise the procedure to include the use of ---(b)(4)-----.
b) Environmental monitoring performance qualification (EMPQ) was completed in 2012. The environmental monitoring program (SOP No. MF-12-002QC; “Environmental Monitoring Program”) was in existence prior to the EMPQ using different sampling locations. The gap analysis and justification for continuously using the existing environmental monitoring program was not performed until February 2014.
Baxter’s response to Observation 6:
Observation 6, Action #1:
Revise procedures CMF045220 “Analytical Methods Validation” and CMF045733 “Validation Document Process, Content and Numbering” to include the additional instruction of creating an action record associated with the change control in the TW8 Change Management System to ensure that any required changes or documented justification of existing procedures are completed. For new equipment that is only put “On Hold”, procedure CMF045733 will require that a line item will be added to the “On Hold” form for the impacted system for any required changes or documented justification of existing procedures.
Target Completion Date: April 30, 2014
Observation 6, Action #2:
Review existing final validation reports for the analytical methods, as well as process and utility performance qualifications along with related SOPs to verify that any recommendations have been implemented and to ensure alignment of analytical methods and current monitoring programs.
Target Completion Date: May 26, 2014
Reviewer comments: Baxter’s proposed changes are acceptable. The revised SOPs were submitted and I verified that changes were incorporated in the Step 7.7.3 of MF-20-006QC “Analytical Method Validation”, effective 25-Apr-14 and Step 7.2.9.4 of MF-20-001VAL “Validation Document Process, Content and Numbering”, effective April 25, 2014.
Observation 9: Equipment use logs are not adequately maintained. Specifically, a) A missing entry was observed in the sterile filter integrity tester use log for conformance batch –b(4)----.
Baxter’s Response to Observation 9a:
Baxter acknowledged that the equipment logbook and/or equipment use record entries at Baxter --(b)(4)- have been inconsistent and identified several factors 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 is not performed in a timely manner and is required only every 6 months. Baxter discontinued their current equipment log forms and implemented new (“Equipment Usage Records”) and procedures.
Baxter acknowledged that at the time of this occurrence, a logbook entry was not made for the use of the filter integrity tester, --b(4)------. This event has been captured under ---(b)(4)--- event 272767 that opened on Mar 12, 2014. The filter integrity test was performed and met specifications as documented in batch record ----(b)(4)---, “Purification of RPFVIII Final Dilution and Filtration”, for DS batch ---(b)(4)------------ Baxter’s acquisition in June 2013, logbooks were replaced by equipment usage records within manufacturing division,, governed by CMF115561, Manufacturing Equipment Usage Record. Baxter proposed action items to address the logbook issue.
For Observation 9, Action #1
Baxter revised SOP CMF115561, Manufacturing Equipment Usage Record, to add specifics for each type of entry to be made including equipment use, cleaning of equipment, calibration and preventative maintenance, non-routine maintenance and processes with a related ---(b)(4)-- event. Once the document revision is approved, training will be provided to manufacturing staff members.
Observation 9, Action #2
Train Quality Control staff members on the requirements of CMF115561 (revised per Observation 9, Action #1).
Baxter submitted its final response to this observation on June 27, 2014 in amendment 24 Baxter has revised SOP MF-09-017MFG, Equipment Usage Records (effective date April, 28, 2014) and included responsibilities for the QC department. Baxter also conducted trainings for operators for this revised SOP.
Reviewer comment to Observation 9a: I reviewed the revised SOP (MF-09-017MFG ) which specifies responsibilities for equipment use log record keeping, and Baxter --(b)(4) has conducted trainings for their manufacturing staffs on the implementation of this SOP. The response is acceptable. The responses to the rest of the Observation 9 items are reviewed by OBRR product reviewers.

