Pharmaceutical Purified Water Systems: USP Compliance and Microbial Control Guide
CLEAR & CLEAN SOLUTIONS FOR PHARMACEUTICAL PURIFIED WATER SYSTEMS
Purified water is a critical regulated ingredient like any other raw material ingredients used in the manufacturing of pharmaceutical drugs and formulations. Purified water generation, storage and distribution systems are designed specific to the facility it is catering to considering the raw water characteristics, water quality requirements, and considering water demand for manufacturing and cleaning purposes. The operations are dynamic in nature. FDA insists the purified water produced meets all current regulatory specification and cGMP norms and the purified water generation system must run in a validated environment. Water quality parameters must meet various regulatory monographs such as USP, EP, WHO, JP, IP etc. at all times. Due to the critical nature of the purified water and the influence of seasonal and source variations expected in the raw water from which it is produced, emphasise is given for the design, installation, operational and performance qualification of the water system. Due to the concern of microbial contamination of water especially pathogens, greater emphasise and importance is given for microbial control and compliance right from the raw water source up to the point of use. It is expected that any water system does not support or promote microbial growth within the system. It is expected the manufacturing facilities follow“Quality by Design”approach and follow strict cGMP norms with GAMP protocol and CFR 21 part 11. There are several guidelines available such as ISPE, WHO, The pharmacopeias’ applicable to pharmaceutical purified water standards are:
· United States Pharmacopeia (USP)
· European Pharmacopoeia (EP)
· Japanese Pharmacopoeia (JP)
· British Pharmacopoeia (BP)
· Indian Pharmacopoeia (BP)
· World Health Organization (WHO) (not a pharmacopoeia, but provides guidelines relevant to international pharmaceutical standards)
These pharmacopoeias set forth comprehensive guidelines for the quality, testing, and use of purified water in pharmaceutical applications. The applicable American and European guidelines for purified water systems are primarily found in:
USP <1231> is titled "Water for Pharmaceutical Purposes." This chapter outlines the requirements, specifications, types, and testing methods related to various categories of water used in pharmaceuticals, including Purified Water (PW) and Water for Injection (WFI).
The chapter emphasizes:
The importance of maintaining water quality during production and storage.
Appropriate testing methods for assessing microbiological limits, chemical purity, and other critical quality parameters.
Compliance with Good Manufacturing Practices (GMP) to ensure safety and efficacy in pharmaceutical products.
By addressing these aspects, USP <1231> serves as a critical guideline to ensure that water used in pharmaceuticals meets the necessary standards for safety and quality.
European Pharmacopoeia (EP):
EP 2.2.44: "Water"— stipulates the quality requirements and testing methods for purified water.
EP 5.1.4: "Water for Injections"— specifies additional standards for water intended for injectables.
Good Manufacturing Practices (GMP):These provide a broader regulatory framework for the manufacturing of medicinal products, including the management and quality of purified water systems to ensure product safety and efficacy.
Guidelines from the European Medicines Agency (EMA):These offer further clarifications and guidance regarding the pharmaceutical industry's compliance with standards, including those related to water systems.
ISO Standards:Certain ISO methodologies may also be referenced in the context of the microbial and chemical testing of water.
These guidelines collectively ensure that purified water used in pharmaceutical applications meets stringent safety and quality requirements. The most important and critical water quality attributes pertains to meeting microbial quality standards and keep pathogens and objectionable organisms. In the context of purified water quality, objectionable organisms are microorganisms that can compromise patient safety and product integrity in pharmaceuticals. Common objectionable organisms include specific bacteria (e.g., Pseudomonas aeruginosa, Burkholderia cepacia, Staphylococcus aureus) and certain fungi (e.g., Aspergillus, Candida).
Determining Objectionable vs. Non-Objectionable Organisms
Regulatory Context:
Organizations like the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP) provide guidelines on which organisms are considered objectionable based on pathogenicity and the potential to cause infections.
Microbiological Testing:
Conduct regular microbiological monitoring of the water supply by using appropriate sampling techniques.
Test methods should align with regulatory requirements, including limits for microbial contamination in purified water.
Identification of Microorganisms:
Utilize identification systems (biochemical tests, molecular methods) to accurately characterize isolated organisms.
Risk-Based Assessment:
Evaluate the objectionability of an organism based on its potential impact on a specific product or process. This risk-based approach helps in determining acceptable limits and the necessary controls.
In essence, understanding objectionable organisms is critical for compliance with regulations ensuring that purified water used in pharmaceutical applications maintains its required quality. Pathogens in water and objectionable organisms are related but not identical concepts.
1.Pathogensare specific microorganisms capable of causing disease in humans, animals, or plants, such as Salmonella, E. coli, and viruses.
2.Objectionable organismsrefer to a broader range of microorganisms that are considered undesirable in a particular context, like pharmaceutical manufacturing. While many objectionable organisms can be pathogenic, not all are. Some objectionable organisms may be non-pathogenic but still negatively affect product quality, safety, or manufacturing processes.
Key Differences:
Pathogens:Always harmful and can cause disease.
Objectionable Organisms:Include both harmful pathogens and non-pathogenic organisms that could compromise product integrity or safety.
In summary, objectionable organisms encompass a wider range of microorganisms, including both pathogenic and non-pathogenic ones, and their classification depends strongly on the specific context of their use.
Meeting and maintaining microbial water quality requirements is the most challenging task in a dynamic pharmaceutical water systems and hence more emphasise is given to several design engineering aspects to ensure the water quality is met reliably and consistently at all times. The fact that dissolve organics in purified water acts as nutrients for microbes to multiply and form biofilms regulatory agencies included TOC (Total Organic Carbon) measurement and control as one of the water quality attributes to be met. It is expected that lower the TOC in water, lower will be the biofilm forming potential within the purified water system and better will be the microbial control. Biofilms once formed are difficult to remove and manage.
In addition to the above guidelines there are specific technical guides available from ISPE for design engineering, sampling, commissioning, qualification, monitoring and control etc. to guide the industries in implementing a robust system that is designed based on“Quality by Design”concept following strict“Sanitary Design”principles that will not support or promote microbial growth within the system. The facilities are required to prove the water system is operating under controlled conditions meeting water quality standards and requirements in every stage of the water purification, storage and distribution system and subject their facility for periodic audit by regulatory authorities. Though these guides are valuable and written by industry experts it only serves limited purpose and does not provide in depth information as to how to and how not to engineer a water system. This comes by practical experience and expertise gained over a period of time. Since microbial control is the centre of focus in pharmaceutical water system, the designer of such system is expected to have adequate knowledge on this aspect so that a system is designed factoring in microbial proliferation and control within the system.
Many pharma industries face the challenge of sourcing the fresh water required for their operations. Challenges include unpredictable raw water quality, availability and dependency on multiple raw sources. In this situation it is even more important to continuously monitor the raw water quality. With the advent of real time microbial monitoring instruments, now it is practically possible to monitor the microbes and other parameters such as TOC, BOD, COD, TDS etc. in real time at strategic locations. Online “Biosense” biofilm sensors installed at strategic locations in the pretreatment system helps monitor and evaluate the microbial control strategy and allows you to take immediate corrective actions. Similar to emphasis on real time online monitoring of the TOC, Conductivity values, one can expect in the near future regulatory agencies mandating online microbial real time monitoring to mitigate the risk associated with microbes in water!
The failure on the part of the users to correctly identify the risk associated with not meeting the water quality requirement and thus regulatory compliance poses a serious risk to the company’s reputation, consumer safety and potential financial loses. The potential financial loses are not just limited to investment risks, regulatory legal frame works, loss of reputation and confidence among consumers, supply chain disruptions, risk of product recall, batch failures and associated disposal costs of rejected batches.
Realising the risks, a proactive risk based decision making procurement and project implementation approach is required right from the concept to commissioning and thereafter. Purified water systems are super critical assets for the pharmaceutical industry and hence an informed decision-making approach is essential and critical for patient safety and pharmaceutical industry to sustain and grow.
In summary a robust “Quality by Design” concept engineered system following good design engineering aspects with deep understanding of the water chemistry and microbial aspects will go a long way in mitigating the risk associated with pharmaceutical water systems. Additionally, specially trained manpower is required to operate, monitor and maintain such critical systems.
If we don’t learn from the past failures and continue to take the wrong decisions without due considerations for all aspects, pharma industries as a whole will continue to suffer as they have been suffering for a very long time.