Instrumentos Cualitativos

Figure 2 (Continued) Stan- dard cleaning procedure for carbon bed steaming in place.

condition of the water system as part of a change- control procedure.

This functional design basis is easily included for new construction, but it is not so simple to obtain or develop with existing water systems. Still, some descrip- tion of the construction and design of the system must be committed to paper for an existing water system. This is important for future reference, especially to individuals who may not have been involved with the validation, but who may have to redesign and revalidate it at a later date. It is especially useful to someone who may have to explain the design and validation during an inspection some years later. It is difficult to defend a report or procedure without a clear statement of the design basis and functional goals.

There are, regretfully, no meaningful design or construction standards presently used for water production in the drug industry. All too often, the infor- mation and recommendations forthcoming from equipment suppliers are relied on. These are necessarily limited to their own expertise and are not always objec- tive. General engineering consultants may be experienced in accepted engineering practices, but these may not sufficiently apply to the particular requirements of specific pharmaceutical situations. Long-accepted design concepts suitable for process and potable waters may not suffice when extended, even by the use of sanitary components, to pharmaceutical water applications. The different design requirements dedicated to the critical needs of pharmaceutical water systems may necessitate Table 1 Submittal Documents

Document Preparation Input

Process and instrumentation drawing Design Design, operations

Instrument loop diagrams Supplier Design, operations

Equipment data sheets Supplier Design, operations

Instrument data sheets Supplier Design, operations

Control panel face layout Supplier Design, operations

Control screen presentations Supplier Design, operations

Sequence of operation Supplier Design, operations

Pipe-routing plans Supplier Design, operations

Pipe isometrics Supplier Design, operations

Skid pipe arrangement Supplier Design, operations

Junction box wiring Supplier Design, operations

Terminal layout Supplier Design, operations

Electrical conduit routing Supplier Design, operations

Construction plan Supplier Design, operations

Inst/equip/valve tag numbers Operations Design, supplier, validation

Instrument list Supplier Design, operations

Equipment tag numbers Operations Design, supplier, validation

Valve tag numbers Operations Design, supplier, validation

Pressure test procedure Supplier Design, operations

Flushing/cleaning procedure Supplier Design, operations

Passivation procedure Supplier Design, operations

Sanitization/sterilization procedures Supplier Design, operations, validation

Software documentation Supplier Design, operations

Source: From Ref. 2.

Table 2 Basis of Design Documentation

Document Preparation Input

Raw water sample Operations Design

Product water quality Operations Design, validation

Facility operation Operations Design, construction

Quantity Operations Design

Diversity Operations Design

Pressure/temperature Operations Design

Microbial control Design Operations, validation

Purification technology Design Operations, validation

Monitoring requirements Validation Corporate, design

Documentation for validation Validation Corporate, design

Design codes and standards Corporate Validation, operations, design

Current good manufacturing practices Validation Design, operations

Mechanical space limitations Operations Design, construction

Budget Operations Design, construction

Schedule Corporate Design, construction, validation

Environmental Operations Design, corporate

Control philosophy Operations Design, validation, corporate

a new approach. This design will reflect some engineering principles in its functionality, safety, and code require- ments. However, it should not be the sole burden or responsibility of the engineering department. The critical considerations of operational suitability, microbial control, and adherence to regulatory needs should first be set forth. The engineering design should then be formulated to meet these needs. Therefore, DQ should, from the first, include the participation of all appropriate groups such as engineering design, production opera- tions, quality assurance, analytical services, and others. The need for a team approach is necessitated by the complexity of the undertaking. Materials selection, equip- ment suitability, operational controls, construction techniques, cleaning and sanitization procedures, compo- nent compatibility, preventive maintenance, sterilization programs, and sampling and regulatory requirements, all are involved. It is essential that an adequate address to all these considerations are “designed in” the desig- nation of the system.

Where an insufficiency of guidance from other disciplines is involved, “add-ons” usually result in an effort to correct an inadequate system design.

The DQ document will list the activities necessary to the consistent production of the stipulated grade of water. It will contain a full description of the system, specifying its acceptable operating ranges and limits. It will supply full schematics of the electrical, mechanical, and water flows for subsequent verification of their proper installation. It will identify the specific purifi- cation units, the various control devices, and the safety and alarm systems. It will also provide for the calibration of critical instruments and set the microbial action and alert limits, which will specify sampling plans and ports for chemical and microbial testing, stipulate sanitizing methods, and define procedures for the analysis and plotting of data.

Artiss (5,6) states, “the basic design package should include the following:

1. Flow schematics for the proposed water system showing all of the instrumentation, controls and valves necessary to operate, monitor, and sterilized the system. All major valves and components should be numbered for reference.

2. A complete description of the features and function of the system. This is of critical importance to enable production and quality assurance personnel, who may be unfamiliar with engineering terminology, to fully understand the manner in which the system is to be designed, built, operated, monitored, and sterilized.

3. Detailed specifications for the equipment to be used for water treatment and pretreatment.

4. Detailed specifications for all other system com- ponents such as storage tanks, heat exchangers, pumps, valves, and piping components.

5. Detailed specifications for sanitary system controls and a description of their operation.

6. Specifications for construction techniques to be employed where quality is of critical importance. These techniques should be suitable for exacting sanitary applications.

7. Procedures for cleaning the system, both after construction and on a routine basis.

8. Preliminary SOPs for operating, sampling, and ster- ilization. These procedures will be cross referenced to the valve and component numbers on the system schematics.

9. Preliminary SOPs for filter replacement, integrity testing, and maintenance.

10. Preliminary sampling procedures to monitor both water quality and the operation of the equipment. 11. Preliminary system certification procedures. 12. Preliminary preventive maintenance procedures.

The design package should be as complete as possible to enable all disciplines involved to understand what the final system will entail.

Validation Plan

As stated earlier, the functional definition is often included as part of a Validation (Master) Plan. This document is not a requirement of the FDA (it is an EMEA expectation), but it has become almost an industry standard. It is a good idea to include such a document as part of the validation, as it sets the overall goals and limits that will be followed during the validation, and can be referred to throughout the project, but especially much later, well after the study has been completed. As a reference document, the plan permits a reviewer immediately to understand the scope of the validation, and so avoid misconceptions.

The validation plan should contain all the infor- mation relevant to the water system. It will be a repository for the basic design information, drawings, specifications, procedures, and protocols. It will state the reasons for equipment selection, for cleaning and saniti- zation frequencies, and for component replacements and renewals. It will contain the records for equipment modification and of procedural alterations. It will have the equipment and filter logs and any recertification data. In short, it will constitute the major reference file for the entire water production system. As such, it will serve internal investigatory purposes, and form the basis for outside regulatory reviews.

The validation plan is used to set the limits of the validation, to define the scope of the project, the systems included and not included in the qualifications, and what the project will attempt to prove. For example, if the project includes the use of deionized water to feed a clean-steam generator, the validation plan would define which components would be involved in the preparation of such a water; what general quality attributes each purification unit would be expected to achieve; and the length of time the system will undergo sampling at what frequency. Issues involving choices should be addressed in the validation plan, including the reasons for the choices. It must be made apparent why the selected decisions are appropriate. The validation plan must be consistent with the company QC policies, and should be included in the SOPs.

Such a validation plan will be much appreciated when reviewing the validation at a later date, such as in response to an out-of-tolerance condition, in a quality audit setting, or when performing a revalidation. Installation Qualification

The IQ protocol will consist of a system description followed by a procedures section. Before the operational

characteristics of the system can be investigated, the proper installation and assembly of the various items of equipment require verification. This follows a careful check that each piece of equipment ordered and received is identical with that stipulated in the system design. As sagely advised by Artiss (5,6), “Consideration should be given to conducting an inspection of the equipment before it is shipped from the supplier. Features of oper- ational function and compliance with specifications can be verified and any deviations can be corrected without incurring the cost and time delay of reshipment.”

The IQ ascertains that all the unit components are installed as per specifications and according to the design drawings. It is also required that the support systems such as instrument calibration programs, preventive maintenance procedures, and operating SOPs are addressed. It provides verification in that the established specifications have been complied with during construc- tion and installation. Included in this operation is a review of P&ID and isometric representations, verifica- tion of materials of construction, examination and documentation of welds, inspections for dead-legs and for pipe slopes, verification of stainless steel passivation, and any other pertinent information. The IQ confirms the “as-built” drawings, and ensures the suitability of the completed system. The absence of leaks, which may provide pathways for invading organisms, can be ensured by vacuum testing, or by the use of pressurized air or water.

As stated in the FDA guidelines (3): “This phase of validation includes examination of equipment design; determination of calibrations, maintenance, and adjust- ment requirements; and identifying critical equipment features that could affect the process and product. Infor- mation obtained from these studies should be used to establish written procedures covering equipment cali- bration, maintenance, monitoring, and control.”

The first step in the IQ document should be a general statement covering the why and how of the water purification system. This will constitute the system description. It will center on the major design criteria and operational parameters. A detailed descrip- tion of the water purification system has already been provided in the equipment design section. It would be well to repeat at this stage, detailing the succession of purification unit processes (e.g., pretreatments, principal purification devices, storage vessels, control units) that will affect the product water quality. This should be accompanied by an exposition of the operational par- ameters necessary to the major design criteria. The feedwater sources should be identified along with factors for which variations would affect the operation of the system. If ion-exchange-treated water is to be used as feedwater for stills, its bacterial endotoxin content control must be considered in the system’s description.

This is to be followed by a procedure section, the setting for a protocol on how to proceed in performing what is specifically required. The protocol should define the procedures to be performed, the documents to be assembled, and the items to be checked and verified. The plan should be approved before the qualification work begins. Subsequent changes should be quantified, recorded, and approved in the final report.

The IQ execution is usually in the form of checklists that verify components or details critical to the validated condition of the equipment. Confirmation of design items such as materials of construction, surface finishes, weld mapping and inspection documents, major equipment inventories (pumps, filters, UV lights, control valves, and such), process instrument lists, utility connections (including drains), and other such equipment, define the system as installed.

In developing these IQ check sheets, individual components must first be identified, as in the system description or in a comprehensive equipment listing. Vital characteristics, necessary to the proper operation of the components, are included, along with the specific criteria that must be met. Spaces must be provided for each item to be verified, by date and initials of the individual performing the checks.

This documentation should concentrate on the process and the components that are critical for process control. Focusing the checklists on these will help in limiting the scope of work required in the validation. The report should provide information on the items that affect the operation of the system, especially the com- ponents that change the performance of the equipment if they were to be replaced or adjusted. Information should be gathered that would be useful in evaluating changes to the operations such as design and capacities of steam traps, surface areas of heat exchangers, or communication setting on input/output boards. Items that are not critical to process operation need not be addressed. When in doubt, the process should be reexamined. If the item does not have a critical effect, it is safe to eliminate it. Record the decisions, because they may be questioned in later audits.

There must be stated criteria that describe the expected acceptable condition and sufficient space for comments and observations. The raw data gathered as part of the verification must be included as part of the final report, along with a description of the procedures used.

These checklists should be prepared with the intent that they will be taken into the field and completed as the work is performed. If raw data are recorded on separate sheets, these must be included with the completed checklists.

P&IDs are ideal documents to provide a clear description of where critical instrumentation and major system components are located. As-built construction drawings showing actual measured piping layouts, filter locations, drafting stations, dead-legs, pipe slope, etc., are necessary as verification of how these critical items are installed. Initialing the drawings along with the date that a component is verified is a common practice. Any notes or comments on the verification should be recorded right on the drawing, or attached and referenced.

Areas that are often overlooked during IQ are items that are generally contracted to service groups. Cleaning and passivation documents, especially procedures, types and concentrations of acids and neutralizers, and the pH results of the various rinses are often neglected. Request these items beforehand and make sure they are signed and dated by the technicians performing the work. This is also important for documents such as weld certifications,

for which quality procedures are sometimes lax. Make sure the welders document welds as they are made, not at the end of the day or at end of project. The purpose of the inspections and verification is to ensure careful, precise welds.

The actual construction techniques used for system installation should be carefully monitored to ensure compliance with the written specifications.

The IQ protocol should be well-documented relative to its flow of logic. This can prove critical to change control, serving as a basis on which subsequent changes to the water purification system can be explained and justified.

Instruments and Controls

One category of items that falls between the IQ and the OQ are instrumentation and control systems. These two groups contain issues that could be included in either or both.

The first step in qualifying instruments and controls is to make a list of all system instruments. This must be available for inclusion as part of the IQ document. Such a comprehensive list should be available as part of the P&ID. At this point, classification determinations must be made for each instrument as to whether it is critical or non-critical to the process.

Critical instrumentation (needed for direct process control and monitoring or recording) will require peri- odic calibration under CFR21, Section 211.68 and 211.160 of the GMPs. These calibrations must be traceable to a recognized standards organization, such as the NIST. Critical instruments include such items as temperature controlling RTDs, tank level sensors, chart recorders that provide documents for batch records, resistivity meters and controls, and flow meters used to control resin bed regeneration. Procedures must be available for the cali- bration of these instruments, which include the method of calibration, the range and accuracy of the instruments, and an appropriate schedule for performing these cali- brations. Records of these calibrations must be kept to comply with the GMPs. Instrument identification numbers and a sticker indicating date of calibration and the date of next calibration must be clearly visible on all critical instruments.

Non-critical instruments such as instrument air regulator gauges, or redundant pressure or temperature instruments, do not need rigorous calibration schedules. However, non-critical instruments must still be identified and logged into a calibration program. There must be a clear identification on such an instrument that it is not used for process control.

Instruments and controls require careful installa- tion and identification. Generally, on new systems, the instruments should be left uninstalled until most of the heavy construction has been completed. Wiring, instrument air lines and supplies, and transmitters can be checked and verified for proper installation, but instrument calibration and tuning of controls should be left for the end of the construction process. Some compa- nies like to postpone the installations and include these functions in the OQ procedures for this reason.

Calibration of instrumentation can be performed either at the end of the IQ process, and recorded as part of

the IQ, or at the beginning of OQ. Either way, before operational testing is begun, all system instruments must be verified as calibrated.

When completed, this information is included not only as part of the qualification package, but also as part