Improvement of the robustness of the purification process of the intravenous immunoglobulin product (10%) Gammagard Liquid/Kiovig

Transcription

1 Improvement of the robustness of the purification process of the intravenous immunoglobulin product (10%) Gammagard Liquid/Kiovig Baxter BioScience F. Hupet, E. Felix, J. Van Malleghem, D. Delplace, C. Carnewal, E. Foy Presenter(s), Arial 18pt Gray Title/Function/Business Plasma Product Biotechnology Meeting 2011 Session: Manufacturing Perspectives 5/16/2011 1

2 Gammagard Liquid/Kiovig - Process robustness Outline Background Methodologies and tools (macro vs. micro approach) Improvement of process robustness: examples Challenges and risks Benefits 5/16/2011 2

3 Background Gammagard Liquid/Kiovig Immune Globulin Intravenous sterile solution (Human), 10% (w/v) Vial size: grams. Launch in 2005 (US) and 2006 (EU) Manufacturing facilities: Fractionation (LA, Rieti, Vienna) Purification (Lessines - Belgium) 5/16/2011 3

4 Background Process Robustness The ability of a manufacturing process to tolerate the expected variability of raw materials, operating conditions, process equipment, environmental conditions and human factors is referred to as process robustness (PQRI White Paper) Firms have to strive for the implementation of robust manufacturing processes that reliably produce pharmaceuticals of high quality and that accommodate process changes to support continuous process improvement (FDA report Pharmaceutical cgmps for the 21th Century A Risk-Based Approach) The system for robustness begins in R&D at the design phase of the process and goes on all along the product life cycle (scale-up, commercialization, postcommercialization). The scope of this presentation is the improvement of the process robustness during the post-commercialization phase of Gammagard Liquid/Kiovig. 5/16/2011 4

5 Methodologies and tools FMEA vs. DDFP Two complementary methodologies were and are used to improve the robustness of the Gammagard Liquid/Kiovig downstream process: 1. FMEA (Failure Modes and Effects Analysis) Macroscopic approach Risk identification & reduction 2. DDFP (Developing Defect Free Process) Microscopic approach Robust process 5/16/2011 5

6 Tools and methodologies FMEA (Failure Mode and Effects Analysis) FMEA is a widely known and used methodology. It is out of scope to give a detailed overview of the FMEA methodology; yet we remind here below the main steps: Review the process; Brainstorm potential failure modes and list the effects; Assign severity, occurrence and detection rankings; Calculate RPN; Develop the action plan and implement actions; Reassess the RPN after implementation of the actions. 5/16/2011 6

7 Tools and methodologies FMEA (Failure Mode and Effects Analysis) Gained experience from our FMEA performed on the Gammagard Liquid/Kiovig process: Due to the complexity and scale of manufacturing process, it is not practical to perform an FMEA on the whole process at the same time. The first process steps to be investigated have to be selected based on: Preliminary screening of the process steps using a matrix of scoring (# of failures, compliance risk,.); Major exceptions or recurrent issues for some steps; Process step impacted by a change (FMEA requirement is incorporated into the Change Control system). 5/16/2011 7

8 Tools and methodologies FMEA The team to be setup must be cross-functional and multi-disciplinary. It is a key element for successful FMEA. The absence of one or more services in the FMEA workshop can reduce its efficiency, and result in unrepresentative scoring. When starting a new working group, it can be useful to have a facilitator (e.g. Black Belt) in order to ensure that the methodology is applied objectively ; Manufacturing Engineering Technical Services FMEA Quality in Operations IT (Automation) Quality Engineering For an effective brainstorming, bring and use the relevant documents: Process narrative, In-Process Controls, P&ID, validation reports, database of exceptions, process flow charts, R&D development reports ; 5/16/2011 8

9 Tools and methodologies FMEA The scale for severity, occurrence and detection has to be clearly defined and well understood by the team. Two considerations: Limiting the number of scores eases the discussions. The magnitude between the lowest and the highest score values helps at differentiating between high and low priority risks. Example of scale used for Gammagard Liquid/Kiovig: 5/16/2011 9

10 Tools and methodologies FMEA Dedicate as much time as possible to the brainstorming session for the identification of failure modes. Do not adopt the This can never happen attitude; For major potential failures identified, go through the whole process to see if they may also happen at other manufacturing steps; The selection of the actions must favor preventing the error (elimination, replacement, mitigation) rather than minimizing the effects of the failure (detection, mitigation); Increasing robustness in a pharmaceutical process may take some time. Make manufacturing people aware of the risk if the implementation of related actions takes a long time; Frequency of FMEA workshops is typically ~3 per year (for a manufacturing process as Gammagard Liquid/Kiovig). Complete the implementation of the actions related to the identified risks before launching a new FMEA. 5/16/

11 Tools and methodologies FMEA Some process steps may present similarities between different products (e.g. nanofiltration). For those steps, there is a lot of added value in adopting a transversal approach (FMEA for a specific process step that is common to different products). Baxter Bioscience has recently applied this transversal FMEA approach for the viral inactivation steps of its products. Gammagard Liquid Gammagard SD Hemofil-M Advate Aralast Immunate SD Subcuvia S/D Treatment FMEA with an interfacility team of experts 11

12 Tools and methodologies DDFP (Developing Defect Free Process) What has driven the launch of this initiative? Experience from on-the-floor observations reveals that: People rarely challenge the status quo: We ve always done it that way ; I was told to do it that way. By nature humans will adapt to issues rather than address them: I have no authority to change that ; It takes less effort to go around the issue than to address it ; People have a limited understanding of their job: I don t know exactly why what I m doing is important 5/16/

13 Tools and methodologies Slide not distributed. 5/16/

14 Tools and methodologies Slide not distributed. 5/16/

15 Examples of Process Robustness Improvements FMEA - Example Improvement of the robustness of the glycine dialysis buffer preparation Glycine buffer preparation (original situation in 2006 RNP=729): Manufacturing runsheets: WFI addition in buffer tank: simple check Calculation for the amount of glycine to use: simple check Addition of glycine and final addition of WFI: double check ph adjustment of the glycine buffer: simple check Automation: No defined sequence for the buffer preparation; Workflow for supervision system commands unsecured in ifix user interface. 5/16/

16 Examples of Process Robustness Improvements Improvement of the robustness of the glycine dialysis buffer preparation Current situation after implementation of robustness actions (RPN=9): Manufacturing runsheets: Fixed amount of glycine to be added (no calculations) : simple check Conductivity and ph measurements of the buffer + check of the values vs. ranges (before ph adjustement): double check ph measurement before use of buffer: simple check Automation: Well-defined sequence (see next slide); At each sub-process step, critical parameters (ph, conductivity, mixing speed ) are automatically checked by the system; if not satisfactory, the buffer preparation cannot move to the next step; «Release» of the glycine buffer when completed. 5/16/

17 Examples of Process Robustness Improvements ifix user interface for dialysis buffer Slide not distributed. 5/16/

18 Examples of Process Robustness Improvements FMEA Additional examples of robustness Integrity test for CUNO setups; Reconcialiation calculation for the S/D preparation; Securing chronological sequences of the chromatographic sub-steps; Additional back-up for some critical samples; Maximum CM elution volumes; Securing opening of bottom valve for protein tanks; Range for the protein solution volume during dialysis; Most of the robustness improvements implemented in the frame of FMEA are based on automation and batch records modifications. 5/16/

19 Examples of Process Robustness Improvements DDFP - Example CIP Station: standardization of usage and change of HAc drums Slide not distributed. 5/16/2011

20 Examples of Process Robustness Improvements CIP Station: mistake proofing Slide not distributed. 5/16/

21 Examples of Process Robustness Improvements CIP Station: standardization of usage and change of HAc drums Slide not distributed. 5/16/

22 Examples of Process Robustness Improvements DDFP Slide not distributed. 5/16/

23 Examples of Process Robustness Improvements Additional examples of topics for DDFP workshop ph adjustement of CM eluate; Recovery of protein solution after filtration steps; Preparation of PptG (from freezer to process room); Preparation of SD components; Calibration of ph-meter 5/16/

24 Challenges/risks Increasing the robustness of a process may lead in some cases to unexpected process deviations (e.g. too tight range defined for buffer preparation). You need to find the right balance between increasing robustness and over-constraining the process; All potential failure modes cannot be identified during FMEA, especially those that would arise from combined failures; FMEA may lead to the identification of «gaps» (needs to be quickly corrected and possibly reported to Regulatory Agencies); Documentation of FMEA needs to be properly done, at least for those which have high visibility (e.g. for Change Control); Outputs from DDFP have to be incorporated into existing Quality systems. 5/16/

25 Benefits FMEA & DDFP: Increased process understanding; Quality improvement & cost reduction (reduced % of lot discarded); FMEA: Catalyst for teamwork and idea exchange between functions; Provide new ideas for improvement in similar design or processes; DDFP: People development; Defined robust best manufacturing sequences; Answer the question «How can we bring continuous improvement on the shopfloor». 5/16/