Aproximaciones al concepto de resiliencia comunitaria

Maynard & Associates, Ewing, New Jersey, U.S.A.

INTRODUCTION

This chapter will review the utilities used in clinical trial and production facilities, whether these facilities are finished drug, APIs, whether the products are bio- logical, solids, liquids, creams, ointment or sterile products. It is important to understand the methods needed to first determine what types of utilities are critical to the processes and second those on the fringe or outside the domain of qualification. This effort will focus on the critical utilities but provide guidance on the noncritical utilities.

This chapter will assist the pharmaceutical engin- eer, clinical trial scientist, quality assurance professional, qualification engineer, etc., and the management team at the facility in determining which system needs to be addressed and how these systems will be commissioned, qualified and in some cases validated. It will suggest a team approach that is established to advance the project to its swift and successful conclusion.

Further, the decisions that need to be made in first ascertaining which utilities need to be commissioned or qualified and how this commissioning/qualification of utilities is to be accomplished are best made with a cross- functional team that will be assembled to address the project. This is sometimes termed a risk assessment. This team may be augmented by outside contractors or consultants and will be discussed later in the chapter.

The chapter will first establish some definitions that are important to the process and then use these definitions throughout the document to explain the why and how of the qualification of utilities.

TERMS USED IN THIS CHAPTER

Noncritical (No Impact). Utility that has no impact on process or product quality (i.e., water—source for clea- ning/sanitizing of non-product contact surfaces; steam— used for heating of vessels).

Noncritical Point of Use. No direct impact on quality of product/process for which it is being used.

Support (Indirect Impact). Utility that supports a Direct Impact utility but does not have a direct impact on the quality of a product.

Critical (Direct Impact). Utility that is in direct contact with the product or that could have a direct impact on the quality of the product.

Critical Point of Use. Direct impact on quality of product/process for which it is being used (i.e., water— used for cleaning of surfaces with direct contact to product, used in formulation processes, used in supply to pure steam generator; steam—used in sterilization processes).

Critical Process Parameter. A process parameter that is controlled within a predetermined range to ensure product meets its CQA.

Critical Quality Attributes. A set of measured charac- teristics inherent in the product that describes the products acceptability for use.

Commissioning. A well-planned, documented, and managed engineering approach of inspection and testing of equipment and systems to ensure they are installed according to specifications and are ready for operation in a safe and functional environment that meets established design requirements or qualification when required (1).

Installation Qualification. Documented evidence that the equipment, system or utility meets all critical installa- tion requirements (2,3).

Operational Qualification. Documented evidence that the equipment, system or utility operates as intended throughout all required ranges.

Performance Qualification. Documented evidence that the equipment, system or utility perform as intended and meets all preestablished acceptance criteria.

Sampling Plan. Written procedure describing the physical location of sample points, the frequency of samples taken to ensure system is in control, and the equipment to be used in taking the sample.

PLANNING ACTIVITIES FOR THE CRITICAL UTILITY The first step is to list all of the utilities at the facility or site and determine the criticality of the system. This can be accomplished by performing impact assessment that presents the risks to product posed by the utility. It can also be determined by following a series of questions that continue to refine the analysis until it is clear which path needs to be followed—no commissioning, commis- sioning only or commissioning and qualification required. Abbreviations used in this chapter: APIs, active pharmaceutical ingre-

dients; ASME, American Society of Mechanical Engineers; CPP, critical process parameter; CQA, critical quality attribute; GMP, good manufacturing practice; I/O, input/output; IQ, installation qualification; ISO, International Organization for Standardization; NF/EP, National Formulary/European Pharmacopoeia; NLT, no less than; NMT, no more than; OQ, operational qualification; P&ID, process and instrumentation drawings; PLC, programmable logic controller; PQ, performance qualification; SOPs, standard operating procedures; USP, United States Pharmacopeia; WFI, water for injection.

An example of the questions that can be used to determine if a system needs commissioning and/or qualification is as follows:

Is the utility supporting GMP activity? If “No” then there is probably no need to even Commission the system, but if “Yes” then it needs more clarification as in the next question.

Does the utility or direct output come in direct contact or primary packaging contact? If “Yes” then the system must be Commissioned and Qualified. If “No” then it needs more clarification as in the next question. Is the direct output of the utility used in the environment

surrounding an exposed product? If “Yes” then the system must be Commissioned and Qualified. If “No” then it needs more clarification as in the next question.

Is the utility or output used in final cleaning steps (equipment with direct product contact or the primary packaging components)? If “Yes” then the system must be Commissioned and Qualified. If “No” then it needs more clarification as in the next question.

Are the utility and its direct output used within a sterilization or sanitation process? (4) If “Yes” then the system must be Commissioned and Qualified. If “No” then it needs more clarification as in the next question.

Does the operation or control of the utility have a direct impact on the CQA of the product or the CPP of the production systems? If “Yes” then the system must be Commissioned and Qualified. If “No” then the system needs only to be commissioned.

The second step in any qualification or validation process is to develop a plan of what is to be accomplished. This can be a complex qualification plan that addresses many different utilities in multiple areas of the site or could be a specific qualification strategy or plan that addresses only one specific utility. Each of the plans will include how the system will be commissioned or quali- fied, who will perform the effort, what type of protocol is to be used and what approval signatures are required. If the commissioning documents are to be leveraged into the qualification, the copies of those documents must be integrated into the qualification documents prior to the approval of the qualification protocol.

The plans should be developed by a cross-functional team consisting of Engineering, Operations, Quality Control, Quality Assurance and the Commissioning or Qualification personnel. Each of these participants will have their own roles and responsibilities that are import- ant to the outcome of the project. This group allows all GMP functions to participate early in the project and help assure a satisfactory outcome to the testing.

The protocols will include the system limits, the physical parameters and attributes to be tested, the acceptance criteria to be met and the signatories required to approve or certify the qualification and validation actions. The reports will include the synopsis of the testing and verify the acceptance criteria have been met. Third step is the actual commissioning, qualifica- tion and validation of the individual utility. These activities will verify the design, installation and operation of the equipment or systems. As part of the qualification and validation activities, the CPPs that have been

established for the utility will be verified to ensure the ongoing control and certification of the systems in the daily activities of the facility. Prior to performing any validation testing the sampling routines for the utility must be established in order to ensure the validation activities will be the same as those used in routine operation. Note: one of the most frequent comments by regulatory agencies occurs when the validation sampling does not accurately reflect the routine use of that particu- lar point of use, including flushing times and methods of use (i.e., if a hose is used between the point of use, then the sampling should be from the hose and not directly from the point of use). The validation will test the Critical points of use of the system and set in place the routine monitoring of these points.

SYSTEMS TO BE DISCUSSED IN THIS CHAPTER

The utilities in typical facilities include gases (compressed air, nitrogen, oxygen, and carbon dioxide); liquids (process water and solvents); steam (process and clean); house vacuum; electrical and drains (process and waste). There may be other utilities encountered within the facility and the same or similar validation processes can be adapted to the other systems.

Gases

The most common gases used in pharmaceutical industry are compressed air used for instruments or product contact, and nitrogen used for providing an inert gas in the vial, ampoule or WFI tanks and used for creating an inert pressure pad in processes where solvents are present.

The validation of each of these is similar in that the equipment used to generate, store and distribute the gas must be first Commissioned and then qualified. Once the IQ and OQ Summary Reports for the equipment have been approved, then the distribution system can undergo Qualification to ensure the delivery of the gas to the acceptance criteria established that verifies the specifications for the gas. It is noted that instrument air need only be tested through the OQ, as it does not come into product contact.

Some of the instruments used to gather compressed gas samples include SAS Microbiological Air Sampler, Mattson Garvin Compressed Gas Sampler—Model P-320, and SMA Compressed Air Sampler.

Liquids

The most prevalent liquid utilities used are process waters (e.g., soft, deionized, USP purified, WFI) that are used in cleaning operations and product batching, and water used in the heating and cooling processes that are not in product contact and thus does not require anything more than commissioning of the system.

The validation of each of these is similar in that the equipment used to generate and store the water must be first Commissioned and then Qualified (5). Once the IQ and OQ Summary Reports for the equipment have been approved, then the distribution system can undergo qualification to ensure the delivery of the water to the acceptance criteria established that verifies the specifi- cations for the water. USP Purified Water and the WFI need to have an extensive testing of all points of use over

a one-month period to ensure the quality of water is delivered routinely. The points of use tested during the PQ will typically be those used for routine sampling. In addition, an extended Qualification is executed wherein the distribution system is monitored over a one-year period (including the 30-day period included in the initial PQ) to ascertain any seasonal differences that impact the quality of the water.

Steam

Typically there are three types of steam used in our industry—plant steam that typically has boiler chemicals entrained; chemical free steam, which is without boiler additives; and pure steam that, when condensed, meets the water requirements of USP purified water. Plant steam and chemical free steam distribution system vali- dations are typically completed at the end of the OQ. Each of the systems must be of appropriate design (including steam trap location), be properly maintained and operated using approved procedures.

Pure steam is typically produced by specially built steam generators or from the first effect of a multiple effect still. The feed water is typically purified water or WFI or from other sources of known chemical quality as specified by the vendor of the generator. The steam contact surfaces, including the generator and distribution system, must be corrosion-resistant material (316 L stain- less steel is the most common material used).

A properly designed and constructed steam gener- ation and distribution system that is operated and maintained correctly will negate the concern expressed by some regulatory agencies. The three physical attri- butes of noncondensable gases (dryness, fraction and superheat) appear to have been concerns in older installa- tions, including hospitals wherein the systems may not have been properly designed, installed or maintained. However, those pharmaceutical facilities that use pure steam for product sterilization purposes should consider the performing of these tests as they may be required by regulatory agencies. These steam quality tests are detailed in U.K. Department of Health and Social Security document, Health and Technical Memorandum 2010 part 3 (6) and in ISO 11134, “Sterilization of Healthcare Products—Requirements for Validation and Routine Control—Industrial Moist Heat Sterilization” (7,8). The steam quality limits are also included in the European standard EN 285 (9).

The qualification of each of these is similar in that the equipment used to generate the steam must be first Commissioned and then Qualified (Note: Plant steam does not require more than an IQ) to ensure the equip- ment operates properly. Pure steam will undergo extensive PQ testing beyond the OQ to show the quality of steam is maintained over an extended period of time, typically one month.

House Vacuum

House vacuum systems are used for many services, but the distribution systems that come into contact with the product or the primary container require attention. These systems will require that the equipment used to generate the vacuum must be first Commissioned and then Quali- fied. Once the IQ and OQ Summary Reports for the

equipment have been approved, then the reservoir tank and distribution system can undergo Qualification. Electrical

The electrical systems are often overlooked in the veri- fication/certification of the facility and utilities. These systems require similar commissioning and qualification activities are performed to ensure the continued deliver- ance of the power to operate the other utilities and the facility processes. Each of the electrical systems in the facility has specific requirements that will include both quality and quantity attributes that are established by the requirements of the facility. These attributes will include frequency, phase and voltage requirements as well as sufficient capacity to enable the full load required to operate the facility. Other systems may include battery backup, standby generator capacity, clean lines for computer operation, and voltage surge protection.

The electrical system to be tested requires complete documentation including monitoring system identifi- cation, electrical schematics that include all pertinent information including wire size, circuit identification, switching equipment and backup systems. There should be written instructions on operation and maintenance of the systems as well as emergency procedures that will come into effect in case of natural or man-made disasters. The qualification will consist of monitoring the systems to ensure voltage, phase and load conditions can be maintained while the plant is being started and main- tained during production usage. The portions of the facility that does not have backup or emergency power generation systems will need to be tested after the loss of supplied electrical power to ensure the facility can come back on line safely, both from a temporary loss of power and from a sustained loss of power. Procedures should be put in place to cover these situations, as typically there will be a need to have a sequential restart to a facility to ensure the safe operation of the plant and systems.

In areas that are subject to “brown out” or reduced voltage conditions, the electrical supplies to primary process equipment will need to be verified that the equipment can operate in this reduced energy level and continue to meet all performance attributes established.

All alarm monitoring and display systems as well as where there is emergency power equipment, the production facility should be tested using both the primary and secondary power systems. The switchover capability and operation of the equipment must be tested to ensure the smooth transition between the power sources and to verify the operation of the equipment on the backup power system. Computer equipment must be fully tested to ensure no loss of data during a transition from one power source to another.

All protection equipments (overload, safety switches, voltage stabilizers, line suppressors) should be tested for both normal operation and peak-load or worst- case conditions.

Drains

The drains in facilities are often overlooked and some- times are the source of unanticipated problems (i.e., contamination, backflow, means of causing flooding from external storm sewer systems) and as such require

full understanding of there design and connections. For this discussion consider only the drains to process and sanitary. The sanitary drains remove various wastes from the areas whereas process drains remove process specific fluids. The design and construction of the facility will need to be verified to ensure there is not an inter- connection between the two systems. A simple dye test where dye is placed into the process drain and shown that it does not appear in the sanitary waste exit from the facility will verify the systems are not interconnected. There is a need for complete IQ and OQ of drains in process areas to ensure that all drain points are inter- connected and drain to process waste.

The specific qualification will be similar to other distribution systems and the drawings, material of construction, pipe size, valves, leak testing, safety features, etc., must be verified. Hard connections between water/steam systems must be avoided and an air break must be verified to ensure there is no back siphoning. The use of check valves between process systems should be tested to ensure the systems remain separated. Where solvents are used the drainage system will be verified to be explosion proof and properly vented. TESTING

Common Steps in Commissioning, Qualification and Validation of Utilities

All of the utility systems during the various stages will have a common series of evaluations and tests that ensure the installed equipment and systems meet the required specifications and design elements that assist in ensuring the long-term operation of the utility. These will include the verification of the materials of construction to the