validation protocol

Annex A ERCROS 02/12 Validation Protocol – Rev. 1 Pag. 1 / 16

Performance Qualification (PQ) Purified Water System Validation Protocol

Multipurpose Synthesis Plant (PMS)

TABLE OF CONTENTS 0- DOCUMENT HYSTORY

1- OBJECTIVE

2- DOCUMETATION

2.1 – Related Documentation

2.2 – Applicable Documentation

3- VALIDATION TEAM

4- SCOPE

5- METHODOLOGY 5.1 – System Validation 5.2 – Description of purified water system 5.3 – Quality Critical Attributes for purified water 5.4 – Qualification strategy 5.5 – Performance Qualification tests

5.5.1 Assessment of compliance with Standard Operating Procedures 5.5.2 Testing of purified water quality

6- ACCEPTANCE CRITERIA

6.1 – Acceptance criteria for compliance with SOPs 6.2 – Acceptance criteria for purified water quality 6.3 – Deviations and conclusions

7- PROTOCOL APPROVAL

Appendix I Site general plan 90-A3-1624 Rev. 12 Appendix II Sampling plan Appendix III Purifying plant and loop sampling points plans


0. DOCUMENT HYSTORY Previous document edition: Annex A ERCROS 02/12 Validation Protocol – February 2012 Changes involved: Following FDA recommendations this document is reviewed and updated in order to complete the validation study. The main considerations included are: - Identification and evaluation of the critical elements for the purified water system. - Evaluation of the quality of the water at each step in the purification process - Evaluation of the quality of the water at each point of use - Complete microbial and endotoxin concentration analysis of purified water.


1. OBJECT The aim of this study is to demonstrate the consistent and reliable performance of the purified water production system located in Multipurpose Synthesis Plant (PMS) – Building 54, which ensures that the system produces water appropriate for its intended use in a repetitive manner. This validation study is carried out after Operational Qualification step and is part of the Performance Qualification study. It should be evaluated together with initial study ERCROS PQ 013/10. In addition, this validation study is intended to assess the suitability of production, control and maintenance of the system in the quality management system. 2. DOCUMENTATION 2.1 Related Documentation

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (ICH – Q7) USP 35 monograph – Purified Water European Pharmacopoeia 7.0 monograph – Purified Water

2.2 Applicable Documentation

Operating and maintenance handbook – Volume IV. (Afarvi) ERCROS-1697 Purified Water Specification Sheet ERCROS-4104 Process water sampling SOP ERCROS-4111 Process water general testing SOP ERCROS-4303 Process water microbiological testing SOP

3. VALIDATION TEAM Validation team responsible of carried out this qualification step is consisted of responsible persons of each involved department. They are shown in following table as well as their responsibility:


Department Responsible / Position Responsibilities

PMS Production Assistant of Synthesis Area Production

Process data recording; defining of process critical parameters and their acceptance criteria; defining of SOPs, equipment and other critical information; protocol drafting.

Quality Control Quality Control Assistant

Analytical data recording; defining of critical quality attributes and their acceptance criteria; defining of SOPs, specifications and other critical information; collaboration in protocol drafting.

Quality Assurance Quality Assurance Assistant

Coordinator; supervision of protocol and recorded data; statistical analysis; ensuring of compliance of documentation with current legal requirements; protocol approval and writing of reports.

4. SCOPE Purified water production plant which supplies water to Multipurpose Synthesis Plant (PMS) located in Building 54. Refer to site general plan 90-A3-1624 Rev. 12 provided as Appendix I. This validation protocol considers the performance qualification of production, storage and distribution of the purified water produced in this plant. 5. METHODOLOGY 5.1 System Validation Performance Qualification (PQ) step is performed after the qualification of Design (DQ); Installation (IQ) and Operation of the purified water production plant. These qualification steps have been properly performed and the supported documentation is codified as described below:

- Design qualification: DQ – 040/04 and DQ – 041/04 - Installation qualification: IQ – 040/04 and OQ – 041/04 - Operational qualification: OQ – 040/04 and PQ – 041/04 - Initial Performance Qualification: PQ – 013/10

For performance requalification purposes, two different steps should be considered:

- First step: during this phase it is demonstrated that the system consistently produces the desired water quality without failure or performance deviation when operates in conformance with the stated SOPs.


During this period the system is intensively monitored. The sampling is daily after each step of purification process and at each point of use for three weeks (15 working days). The validation approach includes:

- Undertaking of chemical and microbiological testing. - Sampling the incoming feed-water daily to verify its quality. - Sampling after each step in the purification process daily. - Sampling at each point of use and at other defined sample points daily. - Demonstrate consistent production and delivery of water of the required quality

and quantity when the system is operated in accordance with SOPs. - Use and refine the SOPs for operation, maintenance and sanitization. - Verify and confirm stated alert and action levels. - Refine test-failure procedure.

After this initial step critical sampling points are confirmed as it. After this initial study and whenever no critical deviation or failure of the system occurs, the second step can address.

- Second step: during this phase it is demonstrated that when the water system is operated in accordance with stated SOPs over a long period of time. The sampling is daily from a minimum of two critical points, with at least all points of use tested weekly, for a full year worth of data. The validation approach includes:

- Demonstrate extended reliable performance. - Ensure that seasonal variations are evaluated. - The sample locations, sampling frequencies and routine monitoring.

After this validation step, final routine water monitoring program will be stated. As appendix II is included a spreadsheet in which it is shown the samples to be taken in both steps as well as it frequency.

5.2 Description of purified water system The facility consists of a purified water production plant (pretreatment; reverse osmosis and water purifying systems); a storage tank and a loop that supply purified water to the points of use. Steps of water purifying and distribution are described as follows. In addition cleaning and sanitization of the system is described too: WATER PURIFYING PLANT

- Pretreatment This step is considered as critical since the objective is to treat in the first instance the incoming potable feed water in order to avoid fluctuations of physic-chemical characteristics of water that could affect the reverse osmosis system. Consist of the following steps: a) Silex / anthracite filter

In this step particles in suspension larger than 30 microns are retained and colloidal matter is minimized. b) Duplex decalcification unit

In this step calcium and magnesium ions are retained in ion-exchange resins. c) Microfiltration 10 microns

This additional filtration ensures the protection of reverse osmosis membranes.


d) Addition of bisulphite

By means of bisulphite addition, chlorine from the water system is neutralized, which prevents reverse osmosis membranes with polyamide composition can be damaged. Bisulphite remove other oxidants dissolved in water by means of its reduction power and has a bacteriostatic effect since oxygen dissolved is minimized. This process is automatically controlled and performed. In addition, this production plant is provided with a sanitization and cleavage tank and additional microfiltration system that ensures the suitable flow conditioning and pressure and supports the cleaning and sanitization procedures.

Sanitization and cleavage tank

After previous microfiltration, water is storage in the cleavage tank. From this tank water is pumping to the reverse osmosis membranes. In addition, the tank fulfils the following functions:

- Feeding tank: whenever the water after electrodesionization system has not the desired quality, it is returned to this tank. The system automatically makes the feeding of subsequent equipment independent of flow and pressure.

- Cleaning of membranes: periodically, in order to avoid the potential blockage of

membranes, the tank pumps water at low pressure when the production has stopped.

- Sanitization: the tank is provided with an element that can heat the water at 80 ºC for sanitization purposes. The loop is provided with a heat exchanger that heats the water to more than 80 ºC in order to sanitize the complete system.

- Chemical cleaning: cleaning products are dissolved in this tank.

Microfiltration 1.5 microns

This additional filtration ensures the remove of particles in suspension and the additional protection of reverse osmosis membranes. The system is controlled by means of a redox-meter that checks the level of chlorine in water and sends the corresponding signals to the system in order to allow water recirculation again in case of its presence is too higher. The potential influence of this treatment on membranes and final quality of water justifies that system Performance Qualification includes sampling before and after this pre-treatment in order to verify the correct operation. - Reverse osmosis By means of this treatment, water is subjected to pressure and forced to pass through a semipermeable membranes across which salts or impurities cannot pass. These membranes remove 90 – 98 % of inorganic ions, non-ionic contaminants and organic molecules with a weight more than 200 (colloidal matter, bacteria, pyrogens…), which makes that this step is considered critical. The system is provided with a high pressure pump that forces the water to flow through the membrane surface. Two different and complementary steps with two membranes per step compose the system.


The potential influence of this treatment on membranes and final quality of water justifies that system Performance Qualification includes sampling before and after reverse osmosis in order to verify the correct operation. - Purifying system This step is considered as critic since by means of this treatment, water is subjected to an electro-des-ionization E-cell system in order to perform a chemical polishing of osmotic water. The application of electric power in the system removes salts dissolved in water by means of conventional ionic exchange resins. In addition, the bactericidal action is carried out by a UV lamp which treats the water after E-cell system. In order to verify the correct performance of the purifying system and final quality of water Performance Qualification includes sampling before and after electro-des-ionization E-cell system and UV-lamp. STORAGE AND DISTRIBUTION Alter purifying system, water is storage in a storage tank and distributed to every point of use in the PMS manufacturing plant by means of a loop. Purified water is maintained in the loop under constant flow at 1m3/h which avoids point of stagnant water. In addition and in order to ensure and avoid the microorganism presence the system is provided with a UV lamp which treats the water after storage tank and prior to its distribution to the points of use. In order to verify the correct control of microorganism presence and the potential contamination of storage tank, Performance Qualification includes sampling after storage tank and before and after UV-lamp. - Points of use The loop feeds every point of use in the manufacturing plant. In order to verify the correct distribution of the purified water and identify potential sources of contamination, Performance Qualification includes sampling in every point of use. In addition, to ensure the correct recirculation of water and no influence of the loop in water quality, sampling at return hose is performed too. WATER PURIFYING PLANT - Sanitization For sanitization purposes the system is provided with a heat exchanger that allows raising the loop temperature to 80 – 85 ºC. The procedure is automatically controlled once it is starting. The frequency converter that controls the feeding pump (SW-P-001) as well as opening and closing of the other valves is automatically controlled. Osmotic water is storage in the sanitization and cleavage tank and heated to 80 – 85 ºC. Once the temperature is reached (controlled by means of a TT-001 probe) it is distributed though the


purifying system and the loop and maintained under recirculation. During this procedure all the points of use should be open in order to ensure that opening valves are sanitized too. The whole sanitization procedure takes approximately 90 – 120 minutes. Once the recirculation has finished, water is cooled by means of a default cooling gradient. Once the water is at operation temperature, it is drained and the usual production cycle starts. This procedure should be performed after a planned long stoppage (holiday period), after a break whenever the repairs takes more than 24 hours and/or whenever an analytical parameter is out of specifications. In addition as part of preventive maintenance program, this procedure could be performed quarterly. - Chemical Cleaning The aim of this procedure is to remove the damaging substances and materials that cold be accumulated in the reverse osmosis membranes (colloids, metals, organic matter, biological compounds…) in order to avoid an irreversible damage. Some evidences that could appear as it or together with other/s show that membranes should be cleaned, these are for instance:

- Loosing of load (10 - 15%) - Water conductivity is increased in 15% - Nominal flow decrease (at standard Tª 20ºC) in 15% - Accumulation of salts - Accumulation of organic and inorganic materials - Biological contamination in equipments or pipes

Cleaning procedure is performed in the usual operating and acid or base solution could be used. The procedure takes the following steps:

1. Preparation of Cleaning solution 2. Pumping at low pressure 3. Recirculation of cleaning solution 4. Draining 5. Pumping at high flow 6. Removing of cleaning solution

Once the cleaning has finished, the rejected water and treated water is removed until conductivity parameter decrease and operating parameters are as usual operating. 5.3 Critical Quality Attributes (CQAs) for Purified Water According to ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, water used in the manufacture of APIs should be demonstrated to be suitable for its intended use. In this context and in our specific case, water should comply with requirements as laid down in current edition of official USP and European Pharmacopoeia monographs for purified water. The parameters established in the monograph are considered as Critical Quality Attributes. In addition, and taking into account that the product can be used in the production of sterile drug products, microbial and endotoxin content should be assessed and considered as Critical Quality Attributes. In following table are summarized the CQAs and their limits. Reference to internal code for methods of analysis is included too:


PURIFIED WATER

TEST UNITS SPECIFICATIONS* INTERNAL SOP

1 Appearance - Clean liquid, transparent,

colorless and odorless ERCROS-4111

2 Nitrates mg / l NMT 0.2 ERCROS-4111

3 Conductivity S – cm-1 NMT 1.3 (at 25 ºC) ERCROS-4111

4 TOC mg / l NMT 0.5 ERCROS-4260

5 Total Germs Viable Germs / ml NMT 100 ERCROS-4303

6 Bacterial Endotoxin IU/ml NMT 0.25 ERCROS-4047

NMT: No more than * According to official USP / European Pharmacopoeia monographs. 5.4 Qualification Strategy The qualification strategy is based on the system validation described in section 5.1. The main objective is to check and verify that the critical production steps identified in section 5.2 for purified water system fulfill their functions correctly. In a first instance, it should be ensured that incoming water is suitable for the system feeding and from this point, the following topics should be considered for assessing:

- Correct using of SOPs for operation, maintenance and sanitization. - Performance of pretreatment step. - Performance of reverse osmosis step. - Performance of storage and distribution steps. - Quality of water in points of use and return hose.

5.5 Performance Qualification Tests Two different approaches should be taken into account for qualification purposes:

1- Assessment of compliance with Standard Operating Procedures 2- Testing of purified water quality

5.5.1 Assessment of compliance with Standard Operating Procedures 5.5.1.1 Objective The aim of this test is to ensure by writing evidences that the Operating and Maintenance SOP described properly the production and distribution of purified water. In addition alarm system will be verified. In this context, whenever al alarm is detected and informed by the system, it should be recorded in appropriate section of Annex B. The cause of every alarm should be properly investigated according to ERCROS 4008 Investigation of Deviation internal SOP. The SOPs will be checked by means of verification of every item described in the corresponding check-list. Every check-list has been drawn up on the basis of the procedures and steps described in internal SOPs and taking into account the worst-case in every situation.


Worst-case:

- Production step: starting the production after a stoppage which involves a cleaning of membranes and sanitization treatment.

- Storage and distribution step: starting the system after a stoppage which involves a

sanitization treatment.

The tests should be performed by PMS Plant staff since they are usually who operates in the Water Purifying Plant and supervised by PMS Manager. 5.5.1.3 Records The following check-list should be fulfilled:

- Annex B Water Purifying; Distribution and Sanitization of the system data check-list 5.5.2 Testing of Purified Water Quality 5.5.2.1 Objective The aim of this test is to ensure by writing evidences that the purified production system produces in a consistent and repetitive way purified water of the desired quality and only this water is distributed to the loop. In addition, it will be verified that the loop has no influence in water quality and bacteriostatic level in maintained. 5.5.2.2 Methodology Taking into account the critical production steps considered in section 5.2 Description of Purified Water System, water quality will be tested as follows. The first step of this performance qualification study should be considered all the sampling point described below. After this step, critical point (defined below and remarked in bold with “*”) will be sampled during the second step during a whole year of worth data. As Appendix III is provided a sketch of the purifying plant and loop which includes sampling points and the desired quality of water in each one. A – Purifying plant: a) Water pretreatment checking:

1. Sampling of incoming feed water. (VHB 001) 2. Sampling at the end of pretreatment (VHD 003)

b) Reverse osmosis checking:

1. Sampling at the end of pretreatment (VHD 003). This sampling point is the same mentioned above.

2. Sampling at the end of reverse osmosis treatment (VHD 007) c) Purifying system checking.

1. Sampling at the end of reverse osmosis treatment (VHD 007). This sampling point is the same mentioned above.

2. Sampling after electrodeionization treatment (VHD 010) 3. Sampling after UV lamp (VHD 011)


B – Storage and distribution a) Storage tank checking:

1. Sampling before storage tank (VHD 011). This sampling point is the same mentioned above. 2. Sampling after storage tank (SV 541 001)

b) UV lamp checking:

1. Sampling after storage tank (SV 541 001). This sampling point is the same mentioned above. 2. Sampling after UV lamp (SV 541 002)

c) Points of use checking:

1. Sampling at every point of use (refer to table below)*

d) Water recirculation checking: 1. Sampling at return hose*.

In table below is summarized all considered sampling points; their location their identification and the water quality desired in each one. Sampling points marked with “*” are those considered as critical and they should be sampled in the second step of this performance qualification during a whole year of worth data.


Sampling sketch

Sampling point Identification Location Quality

Purifying Plant (A)

a1) VHB 001 VHB 001 Incoming feed water Potable water

a2) VHD 003 VHD 003 After 1.5 mc microfiltration unit Potable water

b2) VHD 007 VHD 007 After reverse osmosis system Osmotic water

c2) VHD 010 VHD 010 After electrodesionization system

Purified water

c3) VHD 011 VHD 011 After UV lamp UVA Purified water

Storage and Distribution (B)

a2) SV 541 001 SV 541 001 After storage tank and before UV lamp

Purified water

b2) SV 541 002 SV 541 002 After UV lamp Purified water

d1) SV 541 003 SV 541 002 At return hose Purified water

c1) Points of use

DC-0502-00 Reactor

PU-5 Level 2.

Intake drainage valve at DC-0502-00 reactor

Purified water

DC-0501-00 Reactor

PU-4 Level 2.


Purified water

DC-0504-00 Reactor

PU-3 Level 2.


Purified water

DC-0507-00 Reactor

PU-2 Level 2.


Purified water

DC-0508-00 Reactor

PU-1 Level 2.


Purified water

DF-0532-02 DF-0532-03

Dissolution TanksPU-8

Level 2. Intake common drainage valve

at auxiliary tanks Purified water

DF-0532-00 DF-0532-01




JL-0512-00 Centrifuge

PU-6 Level 1.

Intake drainage valve at JL-0512-00 centrifuge

Purified water

Laboratory PU-11 Level 1.

Laboratory Purified water

DF-0531-00 DF-0531-01





PU-7 Level 0.


Purified water

EI-0521-00 Drier

PU-12 Level 0.

Drier room Purified water


5.5.2.2.1 Analytical test and methods In following tables are summarized the tests performed for every quality of water and reference to internal SOPs.

PURIFIED WATER


1 Appearance - Clean, transparent, colorless

and odorless liquid ERCROS-4111

2 Nitrates mg / l NMT 0.2 ERCROS-4111

3 Conductivity S – cm-1 NMT 1.3 (at 25 ºC) ERCROS-4111

4 TOC mg / l NMT 0.5 ERCROS-4260


6 Bacterial Endotoxin IU/ml NMT 0.25 ERCROS-4047

NMT: No more than * According to official USP / European Pharmacopoeia monographs.

OSMOTIC WATER




2 Nitrates mg / l NMT 5 ERCROS-4111

3 Conductivity S – cm-1 NMT 200 (at 25 ºC) ERCROS-4111

4 TOC mg / l NMT 3 ERCROS-4260


6 Bacterial Endotoxin IU/ml - ** ERCROS-4047

NMT: No more than * According to internal established specifications. ** No specification is established for endotoxins in osmotic water. Obtained result is only for

information and it should be taken into account for checking the capacity of purified water system for endotoxins removing.


POTABLE WATER




2 Calcium mg / l NMT 500 ERCROS-4111

3 Chlorides mg / l NMT 250 ERCROS-4111

4 Sulfates mg / ml NMT 250 ERCROS-4111

5 Nitrates mg / l NMT 50 ERCROS-4111

6 Ammonium mg / l NMT 0.5 ERCROS-4111

7 pH pH 6.5 – 9.5 ERCROS-4111

8 Total Solids mg / l NMT 1000 ERCROS-4111

9 Heavy metals (Pb) μg / l NMT 0.25 ERCROS-4111

10 Organic matter mg / l NMT 1.3 ERCROS-4111

11 Conductivity S – cm-1 NMT 2500 ERCROS-4111

12 TOC mg / l NMT 5 ERCROS-4260


14 Escherichia coli - Absence ERCROS-4303

15 Bacterial endotoxins IU/ml - ** ERCROS-4047

NMT: No more than * According to internal established specifications. ** This test will be performed only at point identified as VHB 001 with the aim of knowing the

endotoxin burden of incoming water. Endotoxins test at point VHD 003 has not been considered since any treatment to remove or

minimize endotoxins content has been performed at this point. No specification is established for endotoxins in potable water. Obtained result is only for

information and it should be taken into account for checking the capacity of purified water system for endotoxins removing.

Detailed description of method of analysis to be performed for each sample is described in the corresponding internal SOPs. (Refer to section 2.2. Applicable Documentation). 5.5.2.2.2 Sampling method Sampling should be performed once the purified plant and loop are normally working. Sampling during this validation step will be daily for 15 working days. It should be recorded date and time (in sample label) of sampling in every sample. Sampling date should be recorded as follows:

Sampling point / day / month (two digits) / year (two digits) Example: sample taken at VHD 007 on July 14th, 2012, should be identified as follows:

VHD 007 / 14 / 07 /12 Two different labels are available depending on the test. Label model is as follows:


Chemical Tests Purified Water

Sampling Point / Date Analyst Initials / Signature

Microbiological Control

Purified Water Sampling Point / Date Analyst Initials / Signature

The label should be fulfilled just before sampling and stick to the bottle immediately. The sampling should be performed according to the instructions given in ERCROS-4104 Process water sampling internal SOP. A brief summary of this procedure is provided below:

Process water sampling should be carried out by Quality Control Laboratory staff. It should be taken into account the test to be performed and prepare the material needed for sampling and testing according to this. In this context, sampling material for endotoxins test should be prepared in non-pyrogenic conditions by Quality Control staff and material for microbiological analysis should be prepared and maintained in sterile conditions. For other chemical analysis is enough that the material is properly clean. The general operating procedure is as follows: 1. Check that the drain or faucet is clean. Otherwise, clean them. 2. Open the drain or the faucet and let the water run a few minutes (5 minutes). 3. Open the bottle where it will take the sample and rinse with the same water

to be taken. Pull the water. Sample for TOC and conductivity should be approximately 500 mL in non-sterile bottle and sample for total viable germ should be approximately 200 mL in sterile bottle.

4. Fill the bottle completely and cover it perfectly. Label the form unequivocally dated, internal code and plant.

5. Transfer the sample to the laboratory as soon as possible. 5.5.2.3 Records Analytical data should be recorded in Annex C of this validation study and in ERCROS 4111 Process water general testing record data sheet. 6. ACCEPTANCE CRITERIA 6.1 Acceptance criteria for compliance with SOPs Acceptance criteria for this test is that check lists provided as Annex B and Annex C are fulfilled following the tested SOP and every item is recorded as positive. The procedure is considered valid if quality water meets established specifications after tests described in section 5.5.2.


6.2 Acceptance criteria for purified water quality Acceptance criteria for this test is that every sample taken and tested as described in section 5.5.2 meets established specifications for its quality. 6.3 Deviations and conclusions Deviations occur during validation should be recorded in the deviation sheet provided at the end of the corresponding annex. Results and conclusions will be summarized in the Validation Report. 7. PROTOCOL APPROVAL

Annex A ERCROS 02/12 Validation Protocol – Rev. 1 Appendix II

APPENDIX II


- First Step

Frequency

Sampling Point Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15

VHB 001 x x x x x x x x x x x x x x x

VHD 003 x x x x x x x x x x x x x x x




SV 541 001 x x x x x x x x x x x x x x x



PU-5 x x x x x x x x x x x x x x x













- Second Step

Even-numbered weeks:

Day 1 Day 2 Day 3 Day 4 Day 5 Sampling Point Chemical Microbiological Chemical Microbiological Chemical Microbiological Chemical Microbiological Chemical Microbiological

SV 541 002 x

PU-5 x x

PU-4 x

PU-3 x x

PU-2 x

PU-1 x x

PU-8 x

PU-9 x x

PU-6 x x

PU-10 x

PU-7 x x

PU-11 x

PU-12 x x


Odd-numbered weeks:

Day 1 Day 2 Day 3 Day 4 Day 5 Sampling Point Chemical Microbiological Chemical Microbiological Chemical Microbiological Chemical Microbiological Chemical Microbiological

SV 541 002 x x

PU-5 x

PU-4 x x

PU-3 x

PU-2 x x

PU-1 x

PU-8 x x

PU-9 x

PU-6 x

PU-10 x x

PU-7 x

PU-11 x x

PU-12 x

Annex A ERCROS 02/12 Validation Protocol – Rev. 1 Appendix III

APPENDIX III


Water Purifying System


Points of use



Annex B ERCROS 02/12 Validation Protocol – Rev. 1 Pag. 1 / 8

Compliance with Standard Operating Procedures Check-list

TABLE OF CONTENTS

1- TABLE 1 – Purifying step

2- TABLE 2 – Distribution and sanitization steps

PREPARED BY:

Date and signature

SUPERVISED BY:

Date and signature

APPROVED BY:

Date and signature


TABLE 1

Starting and operating of purifying system after stoppage

Step Operation Results Performed by: Supervised by

Bisulphite removing

Press button: Proceso después de

parada de larga duración

Manual

Yes No

Date / Sign. Date / Sign.

Bisulphite removing

Send Bisulphite Solution to sewage

Manual

Yes No Date / Sign. Date / Sign.

Bisulphite removing

PLC shows: CONECTAR LAS CONEXIONES DE

LIMPIEZA DE PERMEADO Y

RECHAZO CON DRENAJE.

Automatic

Yes No


Bisulphite removing

Connect and press ACCEPT

Manual


Bisulphite removing

Decalcified water loading starts

Automatic

Yes No


Bisulphite removing

High and low pressure pumping

start

Automatic

Yes No


Bisulphite removing

Stop pumps

Automatic

Yes No


Bisulphite removing

PLC shows: VOLVER A

CONECTAR CLAMP CIEGO EN

LAS CONEXIONES DE

LIMPIEZA.

Automatic

Yes No

Date / Sign. Date / Sign. Bisulphite removing

Connect the Clamp and press ACCEPT Manual Yes

No Date / Sign. Date / Sign.

E-cell system regeneration

Opening of valves: VHB-010, VHB-011, VHD-012 and VHD-008.

Manual

Yes No

Date / Sign. Date / Sign. E-cell system regeneration

Close VPD-008 and open VPD-009

Manual



Starting the pre-osmosis and

reverse osmosis for this valve

Manual Yes No



Stabilize the inlet

flow Manual Yes



Starting the concentrate

recirculation pump

Manual

Yes No





Stabilize the flow of concentrate:

Inlet Pressure from 0.3 to 0.6 bars

Outlet Pressure from 0.3 to 0.6 bars

Manual Yes No



Adjust the flow of purge concentrate

Manual



Verification of suitability of flow

rates and pressures

Manual


E-cell system regeneration Starting the rectifier Manual Yes



Water quality and flow (parameters shown at PLC) are suitable

Manual Yes No


Normal Start Press button:

NORMAL OPERATION

Manual


Normal Start Enter Password Manual


Normal Start

Confirm the password for the computer and the

screen

Automatic

Yes No


Normal Start Message appears:

NORMAL OPERATION

Automatic

Yes No


Normal Start Operation of UV Lamp Manual Yes


Normal Start Correct Pretreatment Cycle

Automatic

Yes No


Normal Start Correct Osmosis Cycle

Automatic


Normal Start Correct Water Cycle of Refinement

Automatic


Normal Start Correct water return to sanitization and

cleavage tank

Automatic Yes



Alarms Detected: Date / Signature: Remarks: Date / Signature: Results and conclusion: Number of Positive responses: Number of Negative responses: Conclusion*: *The test is considered valid only if all the questions are positive. Performed by:

Date / Signature Supervised by:

Date / Signature


TABLE 2

Starting and operating of distribution and sanitization after stoppage


Starting

Verify that all the points of use are

closed.

Manual Yes No

Date Date

Starting Verified that storage tank valve is closed.

Manual Yes

No Date Date

Starting

Verify that all the pumping and

intaking valves are closed.

Manual Yes No

Date Date

Starting Verify that purifying system is operation.

Manual Yes

No Date Date

Starting Verify the availability

of comprised air.

Manual Yes No Date Date

Starting Verify the availability

of electric power.


Starting

Turn off the general switch in the electric

frame.

Manual Yes No

Date Date

Starting Release emergency

stop.


Starting

Connect all the switches and fuses

in electric frame.

Manual Yes No

Date Date

Starting Verify screen is on. Manual Yes

No Date Date

Starting Press button: CONSIGNAS. Manual Yes

No Date Date

Starting

Verify that operating parameters shown in

the screen are correct and no

alarms are shown.

Manual Yes No

Date Date

Starting Press button:

AUTOMATICO.


Starting Press button:

MARCHA LOOP.


Starting

Verify that water is entering in storage

tank.

Automatic Yes No

Date Date



Starting

Verify the correct level of water for pumping starts.

Automatic Yes No

Date Date

Starting Pumping system

starts.

Automatic Yes No Date Date

Starting Speed of water

return is regulated.


Starting UV lamp starts. Automatic Yes

No Date Date

Starting

Valves at points of use operate

correctly.

Automatic Yes No

Date Date

Starting

Valves at sampling points operate

correctly.

Automatic Yes No

Date Date

Sanitization

Verify the operating program is:

AUTOMATICO

Manual Yes No

Date Date

Sanitization Verify the system is

operating.


Sanitization

Verify that no consume is any

point of use.

Manual Yes No

Date Date

Sanitization

Verify availability of cool water and

steam.

Manual Yes No

Date Date

Sanitization

Verify valves at steam entrance;

condenser returns; cool water entrance

and cool water return are open.

Manual Yes No

Date Date

Sanitization Start sanitization

program.


Sanitization Confirmation. Automatic Yes

No Date Date

Sanitization

Storage tank draining.

Valve in storage tank is in draining

position.

Automatic Yes No

Date Date

Sanitization UV lamp starts. Automatic Yes

No Date Date


ETAPA ACCIÓN CONFORMIDAD REALIZADO VERIFICADO

Sanitization Purge Automatic Yes

No Date Date

Sanitization Heating Automatic Yes

No Date Date

Sanitization

Water is maintained hot during

sanitization.

Automatic Yes No

Date Date

Sanitization Purge. Automatic Yes

No Date Date

Sanitization Cooling. Automatic Yes

No Date Date

Sanitization Water is at operating

temperature.


Normal operation

Water is available at every point of use.

Automatic Yes

No Date Date


Alarms Detected: Date / Signature: Remarks: Date / Signature: Results and conclusion: Number of Positive responses: Number of Negative responses: Conclusion*: *The test is considered valid only if all the questions are positive. Performed by:

Date / Signature Supervised by:

Date / Signature

Annex C ERCROS 02/12 Validation Protocol – Rev. 1 Pag. 1 / 29

Sampling Control and Data Record

TABLE OF CONTENTS

1. Introduction

2. Sampling record template

3. Analytical data record template

PREPARED BY:

Date and signature

SUPERVISED BY:

Date and signature

APPROVED BY:

Date and signature


1. INTRODUCTION A very important part of Performance Qualification step of this purifying water system involves sampling and testing of water along the whole production and distribution. This annex covers and compiles sampling, codification of samples, acceptance criteria and obtained results. In table below is summarized considered sampling points; their location their identification and the quality desired in each one. During the first step of this qualification study, every point listed below should be sampled during 20 days. After this step and whenever no critical deviation or failure of the system occurs, only critical points (marked in bold) will be tested during a whole year of worth data.


Sampling sketch

Sampling point Identification Location Quality

Purifying Plant

VHB 001 VHB 001 Incoming feed water Potable water

VHD 003 VHD 003 After 1.5 mc microfiltration unit Potable water

VHD 007 VHD 007 After reverse osmosis system Osmotic water

VHD 010 VHD 010 After electrodesionization system

Purified water

VHD 011 VHD 011 After UV lamp UVA Purified water

Storage and Distribution

SV 541 001 SV 541 001 After storage tank and before UV lamp

Purified water

SV 541 002 SV 541 002 After UV lamp Purified water

SV 541 003 SV 541 002 At return hose Purified water

Points of use

DC-0502-00 Reactor

PU-5 Level 2.


Purified water

DC-0501-00 Reactor

PU-4 Level 2.


Purified water

DC-0504-00 Reactor

PU-3 Level 2.


Purified water

DC-0507-00 Reactor

PU-2 Level 2.


Purified water

DC-0508-00 Reactor

PU-1 Level 2.


Purified water

DF-0532-02 DF-0532-03




DF-0532-00 DF-0532-01





PU-6 Level 1.


Purified water

Laboratory PU-11 Level 1.

Laboratory Purified water

DF-0531-00 DF-0531-01





PU-7 Level 0.


Purified water

EI-0521-00 Drier

PU-12 Level 0.

Drier room Purified water


2. SAMPLING RECORD TEMPLATE

Purifying Plant

Sampling Point:

VHB 001 Sampling Date

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

VHD 003 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:




Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:




Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:




Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Storage and Distribution

Sampling Point:

SV 541 001 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:




Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:




Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Points of use

Sampling Point:

PU-5 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-4 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-3 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-2 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-1 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-8 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-9 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-6 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-11 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-10 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-7 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Sampling Point:

PU-12 Sampling Date



Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20


Deviations

Description Affect the

validation study: Date / Sign.

□Yes

□ No

Remarks

Final result: Conforms Non conforms

Performed by: Signature: Date:

Verify by: Signature: Date:


3. ANALYTICAL DATA RECORD TEMPLATE

Complete the following record data sheet per taken sample and enclose copy of raw data

record:


POTABLE WATER

Sampling Point: Sampling date:

Test Specification Result Analysis Date Analyzed

by: Verify by:

Appearance Clean, transparent,

colorless and odorless liquid

Calcium NMT 500 mg / l

Chlorides NMT 250 mg / l

Sulfates NMT 250 mg / ml

Nitrates NMT 50 mg / l

Ammonium NMT 0.5 mg / l

pH 6.5 – 9.5 pH

Total Solids NMT 1000 mg / l

Heavy metals (Pb) NMT 0.25 μg / l

Organic matter NMT 1.3 mg / l

Conductivity NMT 2500S – cm-1

TOC NMT 5 mg / l

Total Germs Viable NMT 100 Germs / ml

Escherichia coli Absence

Bacterial endotoxins*

(informative) IU/ml

* Only to be tested at point identified as VHB 001

Remarks


OSMOTIC WATER



by: Verify by:



Nitrates NMT 5 mg / l

Conductivity NMT 200 (at 25 ºC)

S – cm-1

TOC NMT 3 mg / l


Bacterial Endotoxin (informative)

IU/ml

Remarks


PURIFIED WATER



by: Verify by:



Nitrates NMT 0.2 mg / l

Conductivity NMT 1.3 (at 25 ºC)

S – cm-1

TOC NMT 0.5 mg / l


Bacterial Endotoxin NMT 0.25 IU/ml

Remarks


Deviations

Description Affect the

validation study: Date / Sign.

□Yes

□ No

Remarks

Final result: Conforms Non conforms

Performed by: Signature: Date:

Verify by: Signature: Date:

Documents

validation protocol