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

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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

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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.

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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:

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Department

Responsible / Position

Responsibilities Process data recording; defining of process critical parameters and their acceptance criteria; defining of SOPs, equipment and other critical information; protocol drafting. Analytical data recording; defining of critical quality attributes and their acceptance criteria; defining of SOPs, specifications and other critical information; collaboration in protocol drafting. Coordinator; supervision of protocol and recorded data; statistical analysis; ensuring of compliance of documentation with current legal requirements; protocol approval and writing of reports.

PMS Production

Assistant of Synthesis Area Production

Quality Control

Quality Control Assistant

Quality Assurance

Quality Assurance Assistant

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: Installation qualification: Operational qualification: Initial Performance Qualification: DQ 040/04 and DQ 041/04 IQ 040/04 and OQ 041/04 OQ 040/04 and PQ 041/04 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.

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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.

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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 C for sanitization purposes. The loop is provided with a heat exchanger that heats the water to more than 80 C 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.

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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 electrodes-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.
3 Purified water is maintained in the loop under constant flow at 1m /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 C. 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 C. Once the temperature is reached (controlled by means of a TT-001 probe) it is distributed though the

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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 T 20C) 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. 2. 3. 4. 5. 6. Preparation of Cleaning solution Pumping at low pressure Recirculation of cleaning solution Draining Pumping at high flow 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:

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PURIFIED WATER TEST 1 2 3 4 5 6 Appearance Nitrates Conductivity TOC Total Germs Viable Bacterial Endotoxin UNITS mg / l S cm mg / l Germs / ml IU/ml
-1

SPECIFICATIONS* Clean liquid, transparent, colorless and odorless NMT 0.2 NMT 1.3 (at 25 C) NMT 0.5 NMT 100 NMT 0.25

INTERNAL SOP ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4260 ERCROS-4303 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.

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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)

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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.

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Sampling sketch

Sampling point Purifying Plant (A) a1) VHB 001 a2) VHD 003 b2) VHD 007 c2) VHD 010 c3) VHD 011 a2) SV 541 001 b2) SV 541 002 d1) SV 541 003 c1) Points of use DC-0502-00 Reactor DC-0501-00 Reactor DC-0504-00 Reactor DC-0507-00 Reactor DC-0508-00 Reactor DF-0532-02 DF-0532-03 Dissolution Tanks DF-0532-00 DF-0532-01 Dissolution Tanks JL-0512-00 Centrifuge Laboratory DF-0531-00 DF-0531-01 Dissolution Tanks JL-0511-00 Centrifuge EI-0521-00 Drier

Identification

Location

Quality

VHB 001 VHD 003 VHD 007 VHD 010 VHD 011 SV 541 001 SV 541 002 SV 541 002

Incoming feed water After 1.5 mc microfiltration unit After reverse osmosis system After electrodesionization system After UV lamp UVA After storage tank and before UV lamp After UV lamp At return hose Level 2. Intake drainage valve at DC-0502-00 reactor Level 2. Intake drainage valve at DC-0501-00 reactor Level 2. Intake drainage valve at DC-0504-00 reactor Level 2. Intake drainage valve at DC-0507-00 reactor Level 2. Intake drainage valve at DC-0508-00 reactor Level 2. Intake common drainage valve at auxiliary tanks Level 2. Intake common drainage valve at auxiliary tanks Level 1. Intake drainage valve at JL-0512-00 centrifuge Level 1. Laboratory Level 0. Intake common drainage valve at auxiliary tanks Level 0. Intake drainage valve at JL-0511-00 centrifuge Level 0. Drier room

Potable water Potable water Osmotic water Purified water Purified water Purified water Purified water Purified water

Storage and Distribution (B)

PU-5 PU-4 PU-3 PU-2 PU-1 PU-8 PU-9 PU-6 PU-11 PU-10 PU-7 PU-12

Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water

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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 TEST 1 2 3 4 5 6 Appearance Nitrates Conductivity TOC Total Germs Viable Bacterial Endotoxin UNITS mg / l S cm mg / l Germs / ml IU/ml
-1

SPECIFICATIONS* Clean, transparent, colorless and odorless liquid NMT 0.2 NMT 1.3 (at 25 C) NMT 0.5 NMT 100 NMT 0.25

INTERNAL SOP ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4260 ERCROS-4303 ERCROS-4047

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

OSMOTIC WATER TEST 1 2 3 4 5 6 Appearance Nitrates Conductivity TOC Total Germs Viable Bacterial Endotoxin UNITS mg / l S cm mg / l Germs / ml IU/ml
-1

SPECIFICATIONS* Clean, transparent, colorless and odorless liquid NMT 5 NMT 200 (at 25 C) NMT 3 NMT 100 **

INTERNAL SOP ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4260 ERCROS-4303 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.

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POTABLE WATER TEST 1 2 3 4 5 6 7 8 9 Appearance Calcium Chlorides Sulfates Nitrates Ammonium pH Total Solids Heavy metals (Pb) UNITS mg / l mg / l mg / ml mg / l mg / l pH mg / l g / l mg / l S cm-1 mg / l Germs / ml IU/ml SPECIFICATIONS* Clean, transparent, colorless and odorless liquid NMT 500 NMT 250 NMT 250 NMT 50 NMT 0.5 6.5 9.5 NMT 1000 NMT 0.25 NMT 1.3 NMT 2500 NMT 5 NMT 100 Absence ** INTERNAL SOP ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4111 ERCROS-4260 ERCROS-4303 ERCROS-4303 ERCROS-4047

10 Organic matter 11 Conductivity 12 TOC 13 Total Germs Viable 14 Escherichia coli 15 Bacterial endotoxins

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:

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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.

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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

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

First Step
Frequency Sampling Point Day 1 VHB 001 VHD 003 VHD 007 VHD 010 VHD 011 SV 541 001 SV 541 002 SV 541 002 PU-5 PU-4 PU-3 PU-2 PU-1 PU-8 PU-9 PU-6 PU-10 PU-7 PU-11 PU-12 x x x x x x x x x x x x x x x x x x x x Day 2 x x x x x x x x x x x x x x x x x x x x Day 3 x x x x x x x x x x x x x x x x x x x x Day 4 x x x x x x x x x x x x x x x x x x x x Day 5 x x x x x x x x x x x x x x x x x x x x Day 6 x x x x x x x x x x x x x x x x x x x x Day 7 x x x x x x x x x x x x x x x x x x x x Day 8 x x x x x x x x x x x x x x x x x x x x Day 9 x x x x x x x x x x x x x x x x x x x x Day 10 x x x x x x x x x x x x x x x x x x x x Day 11 x x x x x x x x x x x x x x x x x x x x Day 12 x x x x x x x x x x x x x x x x x x x x Day 13 x x x x x x x x x x x x x x x x x x x x Day 14 x x x x x x x x x x x x x x x x x x x x Day 15 x x x x x x x x x x x x x x x x x x x x

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

Second Step

Even-numbered weeks:

Sampling Point SV 541 002 PU-5 PU-4 PU-3 PU-2 PU-1 PU-8 PU-9 PU-6 PU-10 PU-7 PU-11 PU-12

Day 1 Chemical x x x x x x x x Microbiological Chemical

Day 2 Microbiological Chemical

Day 3 Microbiological Chemical

Day 4 Microbiological Chemical

Day 5 Microbiological

x x x x x x x x x x x x

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

Odd-numbered weeks:

Sampling Point SV 541 002 PU-5 PU-4 PU-3 PU-2 PU-1 PU-8 PU-9 PU-6 PU-10 PU-7 PU-11 PU-12

Day 1 Chemical Microbiological Chemical

Day 2 Microbiological Chemical

Day 3 Microbiological Chemical

Day 4 Microbiological Chemical

Day 5 Microbiological

x x x x

x x

x x

x x x x x x x

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

APPENDIX III

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

Water Purifying System

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

Points of use

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

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

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:

SUPERVISED BY:

APPROVED BY:

Date and signature

Date and signature

Date and signature

Annex B ERCROS 02/12 Validation Protocol Rev. 1 Pag. 2 / 8

TABLE 1 Starting and operating of purifying system after stoppage Step Bisulphite removing Bisulphite removing Operation Press button: Proceso despus de parada de larga duracin Send Bisulphite Solution to sewage PLC shows: CONECTAR LAS CONEXIONES DE LIMPIEZA DE PERMEADO Y RECHAZO CON DRENAJE. Connect and press ACCEPT Decalcified water loading starts High and low pressure pumping start Stop pumps PLC shows: VOLVER A CONECTAR CLAMP CIEGO EN LAS CONEXIONES DE LIMPIEZA. Connect the Clamp and press ACCEPT Opening of valves: VHB-010, VHB-011, VHD-012 and VHD-008. Close VPD-008 and open VPD-009 Starting the preosmosis and reverse osmosis for this valve Stabilize the inlet flow Starting the concentrate recirculation pump Results Manual

Performed by: Yes No Date / Sign.

Supervised by

Date / Sign.

Manual

Yes No

Date / Sign.

Date / Sign.

Bisulphite removing

Automatic

Yes No Date / Sign. Date / Sign.

Bisulphite removing Bisulphite removing Bisulphite removing Bisulphite removing

Manual

Yes No Yes No Yes No Yes No

Date / Sign.

Date / Sign.

Automatic

Date / Sign.

Date / Sign.

Automatic

Date / Sign.

Date / Sign.

Automatic

Date / Sign.

Date / Sign.

Bisulphite removing

Automatic

Yes No

Date / Sign. Bisulphite removing E-cell system regeneration E-cell system regeneration E-cell system regeneration E-cell system regeneration E-cell system regeneration Manual Manual

Date / Sign. Date / Sign.

Yes No Yes No

Date / Sign.

Date / Sign. Manual Yes No Yes No Date / Sign. Manual


Date / Sign. Date / Sign.

Date / Sign.

Manual

Date / Sign.

Yes No Yes No

Date / Sign.

Date / Sign.

Manual

Date / Sign.

Date / Sign.

Annex B ERCROS 02/12 Validation Protocol Rev. 1 Pag. 3 / 8

Step

Operation Stabilize the flow of concentrate: Inlet Pressure from 0.3 to 0.6 bars Outlet Pressure from 0.3 to 0.6 bars Adjust the flow of purge concentrate Verification of suitability of flow rates and pressures Starting the rectifier Water quality and flow (parameters shown at PLC) are suitable Press button: NORMAL OPERATION Enter Password Confirm the password for the computer and the screen Message appears: NORMAL OPERATION Operation of UV Lamp Correct Pretreatment Cycle Correct Osmosis Cycle Correct Water Cycle of Refinement Correct water return to sanitization and cleavage tank

Results

Performed by:

Supervised by

E-cell system regeneration

Manual

Yes No Date / Sign. Date / Sign.

E-cell system regeneration E-cell system regeneration E-cell system regeneration E-cell system regeneration

Manual Manual

Yes No Yes No Yes No Yes No

Date / Sign.

Date / Sign.

Date / Sign. Date / Sign.

Date / Sign. Date / Sign.

Manual

Manual

Date / Sign. Manual


Date / Sign.

Normal Start Normal Start

Yes No Yes No Yes No

Date / Sign. Date / Sign.

Date / Sign. Date / Sign.

Manual Automatic

Normal Start

Date / Sign. Automatic Manual Automatic


Date / Sign.

Normal Start Normal Start Normal Start Normal Start Normal Start Normal Start

Yes No Yes No Yes No Yes No Yes No Yes No

Date / Sign. Date / Sign.

Date / Sign. Date / Sign.

Date / Sign. Date / Sign. Date / Sign.

Date / Sign. Date / Sign. Date / Sign.

Automatic Automatic Automatic

Date / Sign.

Date / Sign.

Annex B ERCROS 02/12 Validation Protocol Rev. 1 Pag. 4 / 8

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 B ERCROS 02/12 Validation Protocol Rev. 1 Pag. 5 / 8

TABLE 2

Starting and operating of distribution and sanitization after stoppage Step Starting Operation Verify that all the points of use are closed. Verified that storage tank valve is closed. Verify that all the pumping and intaking valves are closed. Verify that purifying system is operation. Verify the availability of comprised air. Verify the availability of electric power. Turn off the general switch in the electric frame. Release emergency stop. Connect all the switches and fuses in electric frame. Verify screen is on. Press button: CONSIGNAS. Verify that operating parameters shown in the screen are correct and no alarms are shown. Press button: AUTOMATICO. Press button: MARCHA LOOP. Verify that water is entering in storage tank. Results Manual

Performed by: Yes No Date

Supervised by

Date

Starting

Manual

Yes No

Date

Date

Starting

Manual

Yes No Date Date

Starting

Manual

Yes No Yes No Yes No Yes No

Date

Date

Starting

Manual

Date

Date

Starting

Manual

Date

Date

Starting

Manual

Date Starting Manual


Date

Yes No Yes No

Date

Date

Starting

Manual

Date Starting Starting Manual Manual Yes No Yes No Date Date

Date Date Date

Starting

Manual

Yes No Date Date

Starting

Manual

Yes No Yes No Yes No

Date

Date

Starting

Manual

Date

Date

Starting

Automatic

Date

Date

Annex B ERCROS 02/12 Validation Protocol Rev. 1 Pag. 6 / 8

Step

Operation Verify the correct level of water for pumping starts. Pumping system starts. Speed of water return is regulated. UV lamp starts. Valves at points of use operate correctly. Valves at sampling points operate correctly. Verify the operating program is: AUTOMATICO Verify the system is operating. Verify that no consume is any point of use. Verify availability of cool water and steam. Verify valves at steam entrance; condenser returns; cool water entrance and cool water return are open. Start sanitization program. Confirmation. Storage tank draining. Valve in storage tank is in draining position. UV lamp starts.

Results

Performed by: Yes No Date

Supervised by

Starting

Automatic

Date

Starting

Automatic

Yes No Yes No Yes No Yes No

Date

Date

Starting Starting

Automatic Automatic

Date Date

Date Date

Starting

Automatic

Date Starting Automatic


Date

Yes No Date Date

Sanitization

Manual

Yes No Date Date Yes No Yes No Date Date

Sanitization

Manual

Date

Date

Sanitization

Manual

Sanitization

Manual

Yes No Date Date

Sanitization

Manual

Yes No Date Date

Sanitization Sanitization

Manual Automatic

Yes No Yes No

Date Date

Date Date

Sanitization

Automatic

Yes No Date Date Date

Sanitization

Automatic

Yes No

Date

Annex B ERCROS 02/12 Validation Protocol Rev. 1 Pag. 7 / 8

ETAPA Sanitization Sanitization

ACCIN Purge Heating Water is maintained hot during sanitization. Purge. Cooling. Water is at operating temperature. Water is available at every point of use.

CONFORMIDAD Automatic Automatic


REALIZADO Date Date

VERIFICADO Date Date

Yes No Yes No Yes No

Sanitization

Automatic

Date Sanitization Sanitization Sanitization Normal operation Automatic Automatic Automatic Yes No Yes No Yes No Yes No Date Date

Date Date Date

Date

Date

Automatic

Date

Date

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

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:

SUPERVISED BY:

APPROVED BY:

Date and signature

Date and signature

Date and signature

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 2 / 29

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.

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 3 / 29

Sampling sketch

Sampling point Purifying Plant VHB 001 VHD 003 VHD 007 VHD 010 VHD 011

Identification

Location

Quality

VHB 001 VHD 003 VHD 007 VHD 010 VHD 011 SV 541 001 SV 541 002 SV 541 002

Incoming feed water After 1.5 mc microfiltration unit After reverse osmosis system After electrodesionization system After UV lamp UVA After storage tank and before UV lamp After UV lamp At return hose Level 2. Intake drainage valve at DC-0502-00 reactor Level 2. Intake drainage valve at DC-0501-00 reactor Level 2. Intake drainage valve at DC-0504-00 reactor Level 2. Intake drainage valve at DC-0507-00 reactor Level 2. Intake drainage valve at DC-0508-00 reactor Level 2. Intake common drainage valve at auxiliary tanks Level 2. Intake common drainage valve at auxiliary tanks Level 1. Intake drainage valve at JL-0512-00 centrifuge Level 1. Laboratory Level 0. Intake common drainage valve at auxiliary tanks Level 0. Intake drainage valve at JL-0511-00 centrifuge Level 0. Drier room

Potable water Potable water Osmotic water Purified water Purified water Purified water Purified water Purified water

Storage and Distribution SV 541 001 SV 541 002 SV 541 003 Points of use DC-0502-00 Reactor DC-0501-00 Reactor DC-0504-00 Reactor DC-0507-00 Reactor DC-0508-00 Reactor DF-0532-02 DF-0532-03 Dissolution Tanks DF-0532-00 DF-0532-01 Dissolution Tanks JL-0512-00 Centrifuge Laboratory DF-0531-00 DF-0531-01 Dissolution Tanks JL-0511-00 Centrifuge EI-0521-00 Drier PU-5 PU-4 PU-3 PU-2 PU-1 PU-8 PU-9 PU-6 PU-11 PU-10 PU-7 PU-12 Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water Purified water

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 4 / 29

2.

SAMPLING RECORD TEMPLATE Purifying Plant

Sampling Point: Sampling Date VHB 001 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 5 / 29

Sampling Point: Sampling Date VHD 003 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 6 / 29

Sampling Point: Sampling Date VHD 007 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 7 / 29

Sampling Point: Sampling Date VHD 010 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 8 / 29

Sampling Point: Sampling Date VHD 011 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 9 / 29

Storage and Distribution

Sampling Point: Sampling Date SV 541 001 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 10 / 29

Sampling Point: Sampling Date SV 541 002 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 11 / 29

Sampling Point: Sampling Date SV 541 003 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

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

Points of use

Sampling Point: Sampling Date PU-5 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 13 / 29

Sampling Point: Sampling Date PU-4 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 14 / 29

Sampling Point: Sampling Date PU-3 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 15 / 29

Sampling Point: Sampling Date PU-2 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 16 / 29

Sampling Point: Sampling Date PU-1 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 17 / 29

Sampling Point: Sampling Date PU-8 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 18 / 29

Sampling Point: Sampling Date PU-9 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 19 / 29

Sampling Point: Sampling Date PU-6 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 20 / 29

Sampling Point: Sampling Date PU-11 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 21 / 29

Sampling Point: Sampling Date PU-10 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 22 / 29

Sampling Point: Sampling Date PU-7 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 23 / 29

Sampling Point: Sampling Date PU-12 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

Sample taken by: (Initials and signature)

Verify by: (Initials and signature)

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 24 / 29

Deviations Description Affect the validation study: Date / Sign.

Yes No

Remarks

Final result: Performed by: Verify by:

Conforms

Non conforms

Signature: Signature:

Date: Date:

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 25 / 29

3.

ANALYTICAL DATA RECORD TEMPLATE

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

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 26 / 29

POTABLE WATER

Sampling Point:

Sampling date: Analyzed by: Verify by:

Test

Specification Clean, transparent, colorless and odorless liquid NMT 500 mg / l NMT 250 mg / l NMT 250 mg / ml NMT 50 mg / l NMT 0.5 mg / l 6.5 9.5 pH NMT 1000 mg / l NMT 0.25 g / l NMT 1.3 mg / l NMT 2500S cm-1 NMT 5 mg / l NMT 100 Germs / ml Absence (informative) IU/ml

Result

Analysis Date

Appearance Calcium Chlorides Sulfates Nitrates Ammonium pH Total Solids Heavy metals (Pb) Organic matter Conductivity TOC Total Germs Viable Escherichia coli Bacterial endotoxins*

* Only to be tested at point identified as VHB 001 Remarks

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 27 / 29

OSMOTIC WATER

Sampling Point:

Sampling date: Analyzed by: Verify by:

Test

Specification Clean, transparent, colorless and odorless liquid NMT 5 mg / l NMT 200 (at 25 C) S cm-1 NMT 3 mg / l NMT 100 Germs / ml (informative) IU/ml

Result

Analysis Date

Appearance Nitrates Conductivity TOC Total Germs Viable Bacterial Endotoxin

Remarks

Annex C ERCROS 02/12 Validation Protocol Rev. 1 Pag. 28 / 29

PURIFIED WATER

Sampling Point:

Sampling date: Analyzed by: Verify by:

Test

Specification Clean, transparent, colorless and odorless liquid NMT 0.2 mg / l NMT 1.3 (at 25 C) S cm-1 NMT 0.5 mg / l NMT 100 Germs / ml NMT 0.25 IU/ml

Result

Analysis Date

Appearance Nitrates Conductivity TOC Total Germs Viable Bacterial Endotoxin

Remarks

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

Deviations Description Affect the validation study: Date / Sign.

Yes No

Remarks

Final result: Performed by: Verify by:

Conforms

Non conforms

Signature: Signature:

Date: Date:

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