Introduction
This document recommends sampling locations, frequencies, and testing activities associated with the commissioning and qualification of new installations or major revisions of Clean/Pure Steam Systems (e.g. the addition of new subloops or other system wide retrofitting).
This guidance defines the sampling location, frequency, and testing activities utilizing a risk based approach for supporting the commissioning and qualification for a clean/pure steam system. The recommended practices are derived from the latest edition of the ISPE Good Practices Guide “Commissioning and Qualification of Pharmaceutical Water and Steam Systems”.
Clean Steam is defined to be steam that does not contain any additives (e.g., boiler additives), 1 is used where the steam and/or condensate have direct contact with product, and the steam condensate meets USP/EP WFI requirements. In addition, clean steam that is used for sterilization applications of “porous loads” for international manufacturing also should meet the requirements of European Standard EN 285. The USP states that “Pure Steam [Clean] is prepared from suitably pre-treated source water analogously to either the pre-treatment used for Purified Water or Water for Injection”.
This guidance does not cover the additional commissioning and qualification activities associated with other aspects of system validation (e.g., drawing development, system
equipment/component installation/testing activities, cleaning/passivation, monitoring equipment, etc.). Ongoing operations (i.e. routine monitoring) after qualification activities are also outside of the scope of this guidance.
Recommendations & Rationale
The results of the commissioning and qualification demonstrate the equipment, personnel, and operating procedures are capable of consistently providing Clean Steam meeting the necessary steam quality requirements.
Regarding the quality of water feeding the clean steam generator, consider the requirements for Bacterial Endotoxin Testing (BET) validation studies in order to assure that there is no Bacterial Endotoxin being carried over in the steam during generation for those applications that have an endotoxin specification.
For example, clean steam that is strictly used for the production of ophthalmic products or non-sterile products would typically not have defined bacterial endotoxin specification requirements.
The testing of clean steam systems includes the Generation System and associated Distribution System piping starting with commissioning activities through the three phases of qualification studies that is synonymous with high-purity water systems. 1,2,3,4
Commissioning
Commissioning is defined in the ISPE Good Practice Guide as “a well planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the end-user that results in a safe functional environment that meets established design requirements and stakeholder expectations”. Sampling and monitoring of the Generation and Distribution Systems for Clean Steam Systems during commissioning are considered Good Engineering Practice. These activities help to define operational and maintenance practices and procedures that will be challenged later during qualification. 3 The sampling and testing activities include chemical testing as appropriate for the unit operation with the maximum acceptable chemical levels of the condensate meeting the applicable WFI compendial limits as determined by the associated compendial methods.
In addition, bacterial endotoxin testing, as needed, to identify bacterial endotoxin levels (if any) within the system based on the intended use of the system. Finally, the quality of the feedwater should be verified both microbiologically and chemically to ensure that the clean steam condensate will meet USP and international WFI specifications as required.4
Typically, the duration of commissioning activities may vary depending upon the complexity and size of the system. Once the entire system is operating, each unit of operation should be tested at least once during the commissioning phase. It is the ability to complete this testing of use test points at least once during this phase, which determines the total time necessary to complete commissioning sampling.
Qualification (3 Phase Approach)
Qualification is an adjunct to commissioning and serves to provide documented evidence with oversight by Quality Assurance personnel that a clean steam system will consistently produce the appropriate quality of steam to end users in accordance with regulatory expectations.
Furthermore, it is important to note that activities performed as part of qualification do not necessarily have to repeat work that was already conducted during commissioning of the clean steam system if the commissioning documentation is prepared according to established site quality documentation practices. Depending upon the quality of the initial commissioning plan, the subsequent qualification can simply serve as verification that the system will consistently produce quality product (i.e. steam). The data collected as part of the commissioning sampling phase can be used to directly justify the sampling plan developed for qualification if the acceptance criterion has been pre-approved by the appropriate Quality Assurance representative.
Phase 1 (approximately 3 Days)
Per current industry practice, the Phase 1 Qualification study lasts a minimum of three days with samples being taken at least once from each point of use and the outlet of the generation system.
The Phase 1 or “start-up” activities are to demonstrate production and delivery of clean steam meeting the necessary quality requirements. It is also very important during Phase 1 activities to finalize appropriate operating ranges for critical process parameters and to finalize Standard Operating Procedures (SOPs) for the system operation, cleaning, and maintenance.
Phase 2 (approximately 1 Week)
The Phase 2 or “system consistency/stability” activities typically last for one week following completion of Phase 1 sampling. 4 The sampling and testing frequency are nearly identical to the activities in Phase 1 with the exception of the sampling of the outlet of the generator. Current industry practice is to sample the outlet of the clean steam generator more than once during the Phase 2 testing activities such as a bracketing approach (e.g. once during the start of Phase 2 sampling and again at the end of Phase 2 sampling).
The purpose of Phase 2 is to further demonstrate stable and consistent production and delivery of clean steam of the required quality with consistent operation within the established ranges when using SOPs. The use of steam for production is permissible during the qualification phase as long as the data collected demonstrates system stability, the steam produced is of the appropriate quality and that this approach has been approved by the appropriate site Quality Assurance representative.
Phase 3 (approximately 4 weeks)
The Phase 3 or “deviations” portion of the clean steam system qualification activities generally continue for an additional four weeks. Typically, the Phase 3 sampling plan is modified from the Phase 1 and Phase 2 schedule with the sampling and testing activities consisting of sampling the outlet of the clean steam generator on a weekly basis with additional samples being taken from the use test points on a weekly basis such that each use test point is sampled at a minimum of every 2 weeks during the Phase 3 studies.
As for clean steam quality tests, prior to plant usage of the clean steam within autoclaves for “porous loads” (as defined by the site) for products marketed in Europe, there needs to be testing of the following quality attributes, with the test conditions and specifications being listed within
Health Technical Memorandum (HTM) 20108:
1) Superheat
2) Dryness Fraction
3) Noncondensible Gases
It is important to clarify that these additional steam tests may not be initially required as part of the installation of a new clean steam system or clean steam generator if the initial application of clean steam will not involve the use of autoclave sterilization. This testing may be deferred and documented within appropriate validation documentation until such time that an autoclave installation and subsequent validation is planned and connected to the clean steam system.
Risk Based Approach
A risk based approach to commissioning and qualification may be utilized to develop the sampling strategy. For example, impact assessments may be used to determine what components, equipment, or process functions of the Clean Steam System are considered critical.
A Clean Steam quality attribute may be defined as critical based upon the need to meet specific quality requirements where the quality is not enhanced further by additional downstream operating steps. For example, conductivity is a critical attribute that is measured at the outlet of a Clean Steam Generation System (e.g., condensate outlet of the clean steam generator) for verifying the results meet necessary steam quality requirements. Sampling the conductivity at this point would occur both during commissioning and qualification activities. For details regarding the design of a condensate collection apparatus for testing, refer to European Standard EN 285 – Sterilization-Steam Sterilizers – Large Sterilizers.