Case study Microbiological excursion during a phase I PQ of a WFI system. Walid El Azab Technical Service Manager STERIS Life Science

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1 Case study Microbiological excursion during a phase I PQ of a WFI system Walid El Azab Technical Service Manager STERIS Life Science

2 Agenda Agenda Case study Microbiological excursion Description of the change and validation strategy Output of first investigation Benefits of a cross-functional investigation team Return from experience 2

3 Water for injection production system before the change Technical specification 2.5 bars in the loop Water t > 80 C 1 m/s sub-loop 23m3/h return loop Microbial specification Alert: 2 CFU/200mL Action: 20 CFU/200mL 3

4 Qualification and validation of a new sub-loop with three points of use (PU) IQ/OQ Phase 1 PQ Phase 2 PQ Phase 3 PQ Q. production Routine production 4

5 Validation strategy and planning Activity End construction IQ OQ Dec Jan Feb /12 20/12 27/12 26/12 01/01 Phase I PQ Phase II PQ 02/01-15/01 23/01 21/01 03/02 11/02 Media fill start Q. production 23/01 05/02 Release Q. status 12/02 Start production Start Release 5

6 Agenda Agenda Case study Microbiological excursion Description of the change and validation strategy Output of first investigation Benefits of a cross-functional investigation team Return from experience 6

7 First investigation root cause analysis and action plan It Deviation seems to PQI be P. aeruginosa intermediate do results not survive confirm at 80 C Gram- water Other nonconformity? you identify Will Assess the root the cause impact on PQI. What is the Ok solution? let s do When it and can continue we restart? to sample 06/01 (Day 4 sampling): PU8 : 50 CFU/200mL PU1 : 20 CFU/200mL What is the impact on the Then production sanitize the system planning? overnight QC PLG Source image : 7

8 Restart phase I PQ n 2 : microbial results after hot water (80 ) sanitization Position of the non-conformity Results per point of use (2 nd phase I PQ) Day Samples at start or return loop were conform PU2 PU9 8

9 Agenda Agenda Case study Microbiological excursion Description of the change and validation strategy Output of first investigation Benefits of a cross-functional investigation team Return from experience 9

Shopfloor investigation QA PROD MTN PLG ENG QC SME Investigation

10 Cross functional investigation team Investigation team 1. Daily follow-up 2. Weekly steering 3. Shopfloor investigation QA PROD MTN PLG ENG QC SME Investigation tools : fishbone A B C Material Method Man WFI Gram - contamination D E F Equipment Environment Measure 10

11 Phase I PQ n 2 : microbial results after hot water (80 ) sanitization Position of the non-conformity Results per point of use (per day) Day 6 Day 5 Day 4 Day 3 Day Samples at start and return loop were conform PU2 PU3 PU9 PU13 PU15 11

12 Is it a "real" biofilm or not? Testing confirmed: Gram coloration : Gram Identification : Pseudomonas aeruginosa Pseudomonas picketti Consider as objectionable organism 12

13 A Investigation on material QC material : contamination not from the QC laboratory Sampling material : need to be sterile for each sampling PU Manual stainless steel valve O rings Stainless steel connector Silicone tube Valve visual check on shopflor! Valve 15 was closed with a stainless steel cap Valve 2 and valve 9 - presence of residual water after output valves DO NOT STOP THE INVESTIGATION AT THE FIRST FINDING! 13

14 B Investigation on method (1/2) QC method : contamination not from the QC laboratory Interviews of sampler operators : Understand their way of working Some operators were using the same sampling kits for different PU Read the SOP requirement Instructions were leading to interpretation = Shopflor visualization Some PU are very difficult to access Draining time and volume were not align between operators 14

15 B Investigation on method (2/2) Protocol training: Knowledge transfer and time between training- phase I PQ starting were inadequate: Training time varies from 2 month to 0.5 day prior the PQ phase I Training in emergency! SOP for operator qualification: There were no guidance for new operator qualification 15

16 C Investigation on manpower Human error is not the main root cause : poorly design processes will ultimately lead to errors Some readings: Human erros models and managements; James reason People are people; Rony Lardner and Dave Nicholls 16

17 D Investigation on equipment Review of the loogbook and technical intervention On field investigation : Presence of standing water in some output PU valves PU not easily accessible Swab of the contaminated valves: Presence of the same micro-organism identified 17

transfer Unclear SOPs Materials availability SOP req.

18 Cross-functional investigation team avoid false root cause identification Summary of findings A C B Material Man Method Valves design Knowledge transfer Unclear SOPs Materials availability SOP req. Different WOW Non-sterile materials used WFI Gram - contamination PU access D Equipment Environment Measure 18

19 Short and long term corrective/preventive actions Actions list A C B D Material Man Method Equipment Purchase more material and develop visual lean tools for material management SOP/protocol qualification and re-training Design sampling instruction methods and check list Knowledge transfer task force Qualification and requalification requirement Purchase new valves E F Environment Measure 19

20 Validation planning and production starting - impact and rational Activity End construction IQ OQ Dec Jan Feb Mar /12 20/12 27/12 26/12 01/01 Initial planning Impacted planning Phase I PQ Phase II PQ 02/01-15/01 22/01 04/02 21/01 03/02 11/02 13/02 26/02 05/03 Media fill start 23/01 05/02 14/02 27/02 06/03 Q. production Release Q. status 12/02 07/03 Start production Start Release Start production Demonstrate sufficient data for product/ patient impact analysis Start of MFT Start of commercial batches (Final sterilization or not) Sufficient data and control for market product release Start Release * 20

Effectiveness checks should be used to confirm the efficacy of corrective or preventive actions put in place KPI identification 1. Quality performance: a. No deviation related to water system b.

21 Effectiveness checks should be used to confirm the efficacy of corrective or preventive actions put in place KPI identification 1. Quality performance: a. No deviation related to water system b. No deviation related to project a. Human hours (productivity not impacted by water related deviation) 1. Maintenance performance: a. Corrective maintenance frequency b. Maintenance intervention (numbers) 1. Production performance: a. Planning respect (no delay due to water deviation) b. Human hours (productivity not impacted by water related deviation) c. Deviation related to water KPI (%) improvement after 6 month of the CAPA implementation 100% 50% 70% 60% 80% 80% 70% 100% 55% 21

22 Agenda Agenda Case study Microbiological excursion Return from experience 22

Combination of cleaning approaches have shown

remediation will always use a combine strategy:

the chemical action Increase the mechanical

Use of the sporicidal chemistry or thermal to

aeruginosa exposed to 5% concentration at 60⁰C:

23 Combination of cleaning approaches have shown effectiveness against biofilm Biofilm remediation will always use a combine strategy: 1. Use of alkaline cleaning chemistry: Increase the chemical action Increase the mechanical action 2. Use of the sporicidal chemistry or thermal to sterilize the system Fluorescently labeled P. aeruginosa exposed to 5% concentration at 60⁰C: Before exposure biocide (3min) alkaline detergent (6min) P. Aeruginosa Source : STERIS Technical tip

Good sampling practice Clear instruction sampling via check list Attention points staying water, rouging, visual check Through freshly autoclaved tubing Allowing outlet to be

24 Good sampling practice Clear instruction sampling via check list Attention points staying water, rouging, visual check Through freshly autoclaved tubing Allowing outlet to be flush (volume or time) Take sampling via good aseptic manipulation Testing sampling time (~2h) Testing sample : temperature holding time Sampling process holding time (~24h) 24

25 Proactively reduce a biofilm generation is a continuous process Engineering Design Good sampling method and practice Optimal cleaning/sanitization frequency and procedure Optimal disinfection/sterilization frequency and procedure Correct chemistry and disinfectant choice Routine trend analysis is also important Source : An Audit Approach to Address Microbial Contamination in Process Equipment, Chapter 15 in Contamination Control in Healthcare Product Manufacturing, Volume 1, PDA/DHI Publishing (2013) 25

26 26

27 References Paula H. Dreeszen. (2003). The key to understand and controlling bacteria growth in Automated Drinking Water Systems, Second edition. European Medicines Agency. (2002). Note for Guidance on Quality of Water for Pharmaceutical Use. European Pharmacopeia (EP) (5.1.4), Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use European Pharmacopeia (EP) (0008) Water, Purified monograph European Pharmacopeia (EP) (0169) Water For Injection monograph European Pharmacopeia (EP) (1729) highly Purified Water monograph United States Pharmacopeia (USP) <1231> WATER FOR PHARMACEUTICAL PURPOSES. The United states Pharmacopeial Convention/National Formulary, Rockville, MD. Japanese Pharmacopeia (JP) <1572> Water monograph Dolan, R and Costerton. (2002). Biofilms: Survival Mechanisms of Clinically Relevant Microorganisms, Clin. Microbiol. Rev., Vol. 15, pp Japanese Pharmacopeia (JP) <G8> Water - Quality Control of Water for Pharmaceutical Use Parenteral Drug Associations (1983) PDA Technical Report No. 4 : Design Concept for the Validation of a Water for Injection System Parenteral Drug Associations (2015) PDA Technical Report No. 69 : Bioburden and Biofilm Management in Pharmaceutical Manufacturing Operations World Health Organization (WHO) Technical Report Series No. 970, Annex 2 - Water for Pharmaceutical Use, 2012 Parenteral Drug Associations (2012) PDA survey: Business Case for Pharmaceutical Quality Note: This is not a complete listing, just a guidance to literature the speaker has found to be interesting/beneficial.

Parenteral Drug Associations (2014) PDA Technical Report No. 67 : Exclusion of Objectionable Microorganism from Nonsterile Pharmaceuticals, Medical devices and cosmetics. Sutton S..(2012).

A Review of Reported Recalls Involving Microbiological Control 2004-2011 with Emphasis on FDA Considerations of Objectionable Organisms, American Pharmaceutical Review 15(1):42-57 Tim Sandle,

European Journal of Parenteral & Pharmaceutical Sciences 2014;19(3):85-93 Tim Sandle. (2011). A Review of Cleanroom Microflora: Types, Trends, and Patterns.

28 Parenteral Drug Associations (2014) PDA Technical Report No. 67 : Exclusion of Objectionable Microorganism from Nonsterile Pharmaceuticals, Medical devices and cosmetics. Sutton S..(2012). What is an "Objectionable Organism"?, 2012, American Pharmaceutical Review 15(6): Sutton, S and L Jimenez. (2012). A Review of Reported Recalls Involving Microbiological Control with Emphasis on FDA Considerations of Objectionable Organisms, American Pharmaceutical Review 15(1):42-57 Tim Sandle, Assessment of the suitability of the R3A agar for the subculture of microorganisms isolated from pharmaceutical water systems. (2014). European Journal of Parenteral & Pharmaceutical Sciences 2014;19(3):85-93 Tim Sandle. (2011). A Review of Cleanroom Microflora: Types, Trends, and Patterns. PDA J Pharm Sci and Tech 2011, Lopolito, P. and Rivera, E. (2013) An Audit Approach to Address Microbial Contamination in Process Equipment, Volume 1, DHI/PDA, Chapter 15, Food and Drug Administration (FDA) top deficiency. Accessed on April 05, 2015 at: Food and Drug Administration (FDA) warning letter, Accessed on May 25, 2015 at: ttersandnoticeofviolationletterstopharmaceuticalcompanies/ucm htm Parenteral Drug Associations (2014) PDA 9 th Annual Global Conference on Pharmaceutical Microbiology, Sharon K. Thoma, Microbiological Inspections Regulatory Investigator Update (2014) USP chap 1111 Note: This is not a complete listing, just a guidance to literature the speaker has found to be interesting/beneficial.

29 Factor influencing biofilm generation Biofilm is generally composed of multiple microorganism encased in matrix extracellular polymetric susbstance (EPS): Factor influencing biofilm generation Biofilm generation Conceptual drawing: Biofilm generation 29

30 Micro-organism found in pharmceutical water system Gram - Gram + Ralstonia pickettii Micrococcus Luteus Pseudomonas spicies (spores) Chryseobacterium indologenes Burkholderia cepacia Pseudomonas fluorescens Maroxella species Staphylococcus maltophilia Flavimonas oryzihabitans Ochrobactrum anthropi LIST NON EXHAUSTIVE Source : Assessment of the suitability of R3A agar for the subculture of microorganism isolated from pharmaceutical water; EJPPS 2014; 19(3):

Avoid recurrent microbial contamination using trending of historical data. El Azab Walid Technical Service Manager STERIS

Avoid recurrent microbial contamination using trending of historical data El Azab Walid Technical Service Manager STERIS Agenda Factors influencing the cleaning and disinfection performance Recurring microbial