Case study – Microbiological excursion during a phase I PQ

of a WFI system

Walid El Azab Technical Service Manager

STERIS Life Science

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

Agenda

2

Agenda

Water for injection production system – before the change

3

Microbial specification

Alert: 2 CFU/200mL Action: 20 CFU/200mL

Technical specification

2.5 bars in the loop Water t°> 80°C 1 m/s sub-loop 23m3/h return loop

Qualification and validation of a new sub-loop with three points of use (PU)

4

Phase 1 PQ Phase 2 PQ Phase 3 PQ

Routine production Q. production

IQ/OQ

Validation strategy and planning

5

Dec Jan Feb 51 52 01 02 03 04 05 06 07

02/01- 15/01

Activity

Q. production

11/02 21/01 – 03/02

Release Q. status

05/02

23/01

12/02

Phase I PQ

Phase II PQ

23/01 Media fill start

OQ

IQ 20/12 – 27/12

26/12 – 01/01

End construction 25/12

Start production Start Release

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

Agenda

6

Agenda

First investigation root cause analysis and action plan

7 Source image : http://www.ashleycecil.com/wp-content/uploads/2012/12/W4W-sketch-1.2007-2.jpg

Deviation PQI – intermediate

results confirm Gram-

What is the solution? When can we restart?

What is the impact on the

production planning?

QC

It seems to be P. aeruginosa – do

not survive at 80°C water

Ok let’s do it and continue to

sample

Then sanitize the system overnight

Will you identify the root cause

@?

Other non-conformity?

Assess the impact on the PQI.

06/01 (Day 4 – sampling): PU8 : 50 CFU/200mL PU1 : 20 CFU/200mL

PLG

Restart phase I PQ – n°2 : microbial results after hot water (80°) sanitization

8

10

PU9

70

PU2

Day 2

Results per point of use (2nd phase I PQ) Position of the non-conformity

Samples at start or return loop were conform

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

Agenda

9

Cross functional investigation team

10

Investigation team

QA PROD MTN PLG ENG QC SME

1. Daily follow-up 2. Weekly steering 3. Shopfloor investigation

Material Method Man

Equipment Environment Measure

WFI Gram - contamination

A B C

D E F

Investigation tools : fishbone

Phase I PQ – n°2 : microbial results after hot water (80°) sanitization

11

80

30

19

25

15

10

1570

10 15

24

120

PU15 PU3 PU2

70 180

PU13 PU9

Day 2 Day 3

Day 6

Day 4 Day 5

Samples at start and return loop were conform

Results per point of use (per day) Position of the non-conformity

Is it a "real" biofilm or not?

12

Testing confirmed: Gram coloration : Gram – Identification : Pseudomonas aeruginosa Pseudomonas picketti

Consider as objectionable organism

Investigation on material

13

A

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!

Investigation on method (1/2)

14

B

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

=

Investigation on method (2/2)

15

B

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

Investigation on manpower

16

C

Some readings: Human erros models and managements; James reason People are people; Rony Lardner and Dave Nicholls

Human error is not the main root cause :

“poorly design processes will ultimately lead to errors”

Investigation on equipment

17

D

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

Cross-functional investigation team avoid false root cause identification

18

Material Man Method

Equipment Environment Measure

WFI Gram - contamination

A B C

D

Materials availability

Non-sterile materials used

Valves design Unclear SOPs

Different WOW

Knowledge transfer

SOP req.

PU access

Summary of findings

Short and long term corrective/preventive actions

19

Material

Man

Method

A

B

C

Equipment

Environment

Measure

D

E

F

• Design sampling instruction methods and check list • Knowledge transfer task force • Qualification and requalification requirement

• Purchase new valves

• Purchase more material and develop visual lean tools for material management

Actions list

• SOP/protocol qualification and re-training

Validation planning and production starting - impact and rational

20

Dec Jan Feb Mar 51 52 01 02 03 04 05 06 07 08 09 10

26/12 – 01/01

Phase II PQ 22/01 – 04/02

Activity

06/03

12/02

Media fill start

07/03

14/02 05/02 23/01

Q. production

11/02 Phase I PQ

Release Q. status

05/03

25/12 End construction

13/02 – 26/02

20/12 – 27/12 OQ

21/01 – 03/02

IQ

02/01- 15/01

27/02

Start production Start Release Start production

Start Release *

Initial planning Impacted planning

Start of MFT Start of commercial batches (Final sterilization or not) Sufficient data and control for market product release

Demonstrate sufficient data for product/ patient impact analysis

Effectiveness checks should be used to confirm the efficacy of corrective or preventive actions put in place

21

KPI identification

KPI (%) improvement after 6 month of the CAPA implementation

1. Quality performance: a. No deviation related to water system b. No deviation related to project

100% 50%

a. Human hours (productivity not impacted by water related deviation)

70%

1. Maintenance performance: a. Corrective maintenance frequency b. Maintenance intervention (numbers)

60% 80%

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

80% 70% 100%

55%

Agenda

Case study – Microbiological excursion

Return from experience

Agenda

22

Combination of cleaning approaches have shown effectiveness against biofilm

23

Fluorescently labeled P. aeruginosa exposed to 5% concentration at 60⁰C: Before exposure biocide (3min) alkaline detergent (6min)

Source : STERIS Technical tip 410-200-3088

P. Aeruginosa

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

Good sampling practice

24

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)

Proactively reduce a biofilm generation is a continuous process

25

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)

26

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. 167-193 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). What is an "Objectionable Organism"?, 2012, American Pharmaceutical Review 15(6):36-48. • Sutton, S and L Jimenez. (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, 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, 65 392-403

• 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: http://www.fda.gov/ICECI/Inspections/ucm424098.htm

• Food and Drug Administration (FDA) warning letter, Accessed on May 25, 2015 at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/ucm432949.htm

• Parenteral Drug Associations (2014) PDA 9th 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.

Factor influencing biofilm generation

29

Biofilm is generally composed of multiple microorganism encased in matrix extracellular polymetric susbstance (EPS):

Conceptual drawing: Biofilm generation

Factor influencing biofilm generation Biofilm generation

Micro-organism found in pharmceutical water system

30

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):85-93