Practical guidelines for qualifying purified water systems

Purified water (PW) is used in the pharmaceutical industry as a raw material in production or to clean equipment. It is, therefore, important that the water meets the set standards and constantly provides the specified quality and quantity to ensure there is no contamination of the product or equipment. Depending on quality, raw water can be difficult to purify, and can require various processing stages to obtain PW quality. Raw water quality can also change with the seasons so conducting regular inspections, tests and samples is imperative to ensure that the installation complies with regulations and the user's requirements on a continuing basis.

Requirements for PW installations

A PW installation must meet the following requirements regarding water quality:

• Pharmacopoeias (e.g., US Pharmacopeia,¹ European Pharmacopoeia,² or Japanese Pharmacopeia³ ).

• cGMP, 21 Code of Federal Regulations.⁴

• National laws and regulations.

There are also other requirements that do not stem from the product quality, but concern operator safety, including European directives 98/37/EC (Machinery);⁵ 89/336/EC (Electromagnetic compatibility);⁶ 73/23/EC (Low voltage);⁷ PED 97/23/EC (Pressure equipment);⁸ Underwriters Laboratories (UL) standards⁹ and American Society of Mechanical Engineers (ASME) codes and standards.^10,11

User requirement specification

The prospective owner of the system creates a user requirement specification (URS). From a practical perspective, and to obtain good traceability, it is important that requirements are clear, well-structured, numbered and testable. A requirement such as 'heat exchangers must be of a high quality' becomes difficult to handle in validation because it is not a tangible statement. The requirements must also be at the right level regarding acceptance criteria (e.g., what temperature or hardness has to be reached or what materials are required?). It is also essential to avoid setting requirements unnecessarily high during start-up, testing or operation that, on closer inspection, do not need to be met. In fast-track projects where time is an important factor, changes and updates take time and it is preferable to assess the installation carefully at the start in the requirements specification. A risk analysis regarding the end product (e.g., water quality) should be performed before compiling the URS. The requirements relating to the safety of plant operators must be part of the risk analysis that occurs for CE marking of the installation, according to the machinery directive.

It is an advantage to divide the requirement specification into 'C' and 'Q' requirements with the help of the risk analysis performed. This is described in the ISPE Baseline Guide Volume 5, Commissioning & Qualification.¹² C stands for commissioning and the requirement will then be tested under a factory acceptance test (FAT) or a site acceptance test (SAT). Q stands for qualification and the requirement is tested under an installation qualification (IQ) or an operation qualification (OQ). To find and select the typical Q requirements for the system, the ISPE's Baseline Guide Volume 4, Water & Steam Systems¹³ and FDA's Guide to Inspection of High-Purity Water Systems¹⁴ can provide assistance.

The easiest way to create traceability in the project is to write the requirement specification in table format, with the requirements divided into C and Q requirements, which can then be given to the supplier as a Word document for further processing and completion of the references to design documents and tests. The supplier can then create a traceability matrix from the file, or copy the requirements to an Excel table. This avoids having to write the requirements in the matrix again, thus eliminating a possible source of errors and saving time.

Quality and project plan

A quality and project plan (QPP) is devised at the beginning of a project. The purpose of this is to establish parameters for quality control (QC), inspections, approval, project execution, organization, responsibility and authorizations. This guarantees that activities are performed according to the requirements set within the agreed framework. It is also useful to write down practical details of project execution that are not dealt with in the URS. This would define:

• How communication is performed.

• How the information will be delivered to the project manager.

• Exceptions to the agreed protocols.

• The document approval process.

• The people responsible for reviewing and approving the documents.

• The number of days assigned to the review process.

• In which form comments must be returned.

• The amount of time allocated for amendments and updates, and how the conclusions and approvals are obtained.

Comments should be specified in writing and compiled in one document clarifying who has commented on what. For fast-track projects, these approval routines are particularly important and must be established at the beginning of the project. It is also recommended that the number of approving parties is kept to a minimum. The user should specify which routine applies to change requests in the project and from when it is applicable. A well-devised QPP, which has been agreed on and signed by both parties, saves time and makes it easier to complete activities such as design, installations and tests. An interface agreement should also be issued early in the project and will clarify details regarding tie-in points, control system interfaces and media.

Design

During the design phase of the installation, the focus is on existing requirements and catering for them in the design. It is crucial to have an analysis of the incoming water to design the system correctly with the right pretreatment for the application. There is plenty of literature regarding the design of water purifying installations. Pharmaceutical Water System Design, Operation, and Validation¹⁵ is particularly useful, and Baseline Volume 4 Water & Steam Systems¹³ from ISPE is essential.

Design documents

The following design documents are consulted for a water treatment system:

• piping and instrumentation diagram (P&ID)

• functional specification (FS)

• software design specification

• hardware design specification (HDS)

• electrical schematics

• layout drawing

• component list

• instrument list

• valve list.

The documents illustrate the set installations and functions of the system. When the system is built, the design specifications will be used for the verification of the system during commissioning and qualification. At the end of the project, when all inspections and tests are performed and possible deviations are measured, it is important that the 'as built' design documents are included into the documentation of the system (Figure 1).

Figure 1 The V-model: verification of the system according to the design.

Design verification

The design is verified in relation to the user's requirements, ensuring they will be complied with. This is easily done by establishing a traceability matrix in table form from the URS (Table 1).

Table 1 A traceability matrix showing in which protocols and tests the requirements will be met.

Design approval

The design approval is an important milestone in a project as it makes it possible to progress with manufacturing and programming. To reach an approval it is necessary to review all design documents and drawings according to the requirements (Figure 2).

Figure 2 Piping and instrumentation diagram distillation unit.

Acceptance tests

With today's tight time schedules, a FAT is very useful for the new installation of a plant. The advantage is that premanufactured units are checked and tested as much as possible before they are sent to site. This is of absolute necessity, for example, in a turn-key project where lots of equipment shall be installed and commissioned in a short time frame. If the skids/units are at the factory, it is quick and efficient to make any changes to eliminate any deviations.

During FAT and SAT, typical C-defined requirements will be tested according to good engineering practice (GEP) as described in the ISPE Baseline for Commissioning and Qualification.¹² The C requirements do not have a direct impact on the product quality and it is an advantage to per-form as many of those tests as possible in the factory. To get an impression of process values, product quality and system capacity, these values can be recorded in the factory. The C requirements not tested during FAT will be performed onsite within the SAT Protocol. The FAT and SAT results will be presented in a FAT and SAT report respectively.

Installation qualification

This is performed by a number of different verifications, such as mechanical inspections, instrument calibrations and documentation verifications. It is recommended to include a review of the FAT/SAT reports at the start of the IQ to ensure that all deviations have been closed. The sequence of test performances also needs to be considered. The slope of the pipes must, for example, be measured before the distribution pipe is insulated — in the case of a hot distribution system — which often occurs before the IQ is started because the installation is ready.

Documentation verification is a test where the status must be checked according to the project schedule on the IQ precisely, otherwise the IQ test could be open until both IQ and OQ are ready and the final documentation has been copied. A good way of performing document inspections is to have a document schedule clearly indicating which documents must be completed by when in the project. When the IQ is finished and reviewed, the result is presented in the IQ report and, if no critical deviations were identified, the OQ can begin.

Operation qualification

The OQ will verify the operation of the system according to the descriptions in the FS highlighted as critical for the product. The acceptance criteria, particularly for the OQ, must be carefully evaluated — which conductivity and temperature must be complied with? Which flow? What are the actual limits? What is acceptable for the process and the product? The product requirements depend on the water quality that the system has been designed to achieve. The process engineer should also have evaluated suitable alert and action levels for the process, which form the basis for the alarms generated by the system. When all tests are performed and reviewed, the result of the OQ is presented in the OQ report. If no critical deviations were identified, the PQ can start.

General

Test procedures should be written in a way that is complete, understandable and possible to repeat. With all qualifications, it is important to collect all relevant data, make clear references to documents used, mark attachments and review performed tests regarding completeness, traceability and signatures.

Complete documentation for the water treatment system

It is fundamental that the structure of the documentation must be:

• logical

• trackable

• simple

• clear.

Simplicity and user-friendliness are key, and cannot be emphasized enough. It has to be possible to find specific sections/documents several years later and the supplier must consider whether the structure is logical. If it seems complicated it should be changed until it can be explained and defined in a logical manner. The supplier may also consider whether there are groups/departments that need different parts of the documentation. It may be advantageous to have certificates for instruments, valves and components in separate binders, and data sheets, technical specifications and manuals in others. Certificates are often stored by the quality department while technical documentation is needed by the users.

Decisions must be justified and followed to obtain consistency in the documentation. The system owner should understand the train of thought and how the tests were performed at a latter stage. Good documentation practice (GDP) must be followed. Nothing must be left incomplete and empty — unused fields in tables, for example, should be crossed-out. The execution must be followed by a review to detect whether anything is incomplete, or has not been described or referred to in a logical way.

Summary

The main focus when validating water treatment systems should be on the requirements the water must comply with. This relates to parameters that control the current water quality, such as: conductivity, total oxidizable carbon (TOC), microbiological values and the presence of contaminants, including endotoxins, nitrates and heavy metals.

A risk assessment for the system should be created based on these parameters, and the process steps and components required to produce the desired quality need to be evaluated. The design of the water purification system should then be assessed and the appropriate inspections and tests developed. A thorough knowledge of the process is required to perform optimum qualification. Good communication and a comprehensive understanding of the requirements at the planning phase will guarantee a successful project — and a water treatment system that performs well.

Annelie Hultqvist is the QA/validation manager at Christ Nishotech Water Systems Pvt. Ltd in Navi Mumbai (India). She began her career at a fermentation company in Sweden and became a validation engineer in 1998. She was a member of the team which started Christ Nordic AB in 2000 where she was responsible for quality and validation. She has worked on projects across Europe, as well as in the US .

References

1. US Pharmacopeia Edition 29, (12601 Twinbrook Parkway, Rockeville, MD, USA 20852, 2006).

2. European Pharmacopoeia Edition 5 (EDQM.226. avenue de Colmar BP 907, F-67029 Strasbourg, France, 2005).

3. Japanese Pharmacopeia Edition 14 (National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158, Japan, 2001).

4. 21 Code of Federal Regulations — Part 210 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General, 2005. www.fda.gov

5. Directive 98/37/EC of the European Parliament and of the Council of 22 June 1998 on the Approximation of the Laws of the Member States Relating to Machinery. www.europa.eu

6. Directive 89/336/EC on the Approximation of the Laws of the Member States Relating to Electromagnetic Compatibility, 2004. www.europa.eu

7. Directive 2006/95/EC of the European Parliament and of the Council of 12 December 2006 on the Harmonisation of the Laws of Member States Relating to Electrical Equipment Designed for Use Within Certain Voltage Limits. www.europa.com

8. Directive 97/23/EC of the European Parliament and of the Council of 29 May 1997 on the Approximation of the Laws of the Member States Concerning Pressure Equipment. www.europa.eu

9. UL Standards for Safety (Underwriters Laboratories Inc.) www.ul.com

10. ASME Codes and Standards. ASME Boiler and Pressure Vessel Code, (ASME, 2004) Section 8, Division 1.

11. ASME Codes and Standards. ASME Bioprocessing Equipment (ASME, 2002) p 84.

12. Baseline Guide, Volume 5, Commissioning and Qualification (ISPE, 2001) p 142.

13. Baseline Guide, Volume 4, Water and Steam Systems (ISPE, 2001) p 228.

14. Guide to Inspections of High Purity Water Systems (US FDA, 1993). www.fda.com

15. W.V. Collentro, Pharmaceutical Water System Design, Operation, and Validation (Informa Healthcare USA, 1998) p 694.