Annelie Hultqvist

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. 

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

There are also other requirements that do not stem from the product quality, but concern operator safety, including European directives 98/37/EC (Machinery);

  89/336/EC (Electromagnetic compatibility);

  Underwriters Laboratories (UL) standards

  and American Society of Mechanical Engineers (ASME) codes and standards.

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

  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 Systems

Guide to Inspection of High-Purity Water Systems

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. 

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 the information will be delivered to the project manager.

The people responsible for reviewing and approving the documents. 

The number of days assigned to the review process. 

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. 

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 Validation

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

piping and instrumentation diagram (P&ID)

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. 

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. 

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. 

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.

 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. 

Articles

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.