The European Medicines Agency (EMA) guideline on the quality of water for pharmaceutical use was published on 20 July 2020 and came into effect on 1 February 2021, replacing the 2002 Note for guidance on quality of water for pharmaceutical use and the CPMP Position Statement on the quality of water used in the production of vaccines for parenteral use. This guideline serves as a cornerstone of the pharmaceutical industry, outlining the rigorous standards and best practices that must be followed to maintain the integrity of medicinal products. In this comprehensive exploration, we will delve into the importance of the EMA’s guideline, dissecting its key elements, and examining its profound impact on the pharmaceutical landscape.
Understanding the EMA’s Guideline
The EMA’s ‘Guideline on the quality of water for pharmaceutical use’ addresses the various grades of water used in pharmaceutical processes, including Water for Injections, Purified Water, and Water for Preparation of Extracts, each with its unique set of requirements. It applies to the manufacture of active substances and medicinal products for both human and veterinary use, including Advanced Therapy Medicinal Products (ATMPs), and its principles may also be applied to investigational medicinal products where relevant.
What Changed from the 2002 Guidance
The guideline was updated to reflect three changes in the European Pharmacopoeia (Ph. Eur.):
- Revised Water for Injections monograph (0169): methods other than distillation may now be used to produce WFI.
- New monograph for Water for preparation of extracts (2249).
- Suppression of the Highly Purified Water monograph (1927).
Until April 2017, Water for Injections could only be produced by distillation. The revised monograph, effective from 1 April 2017, permits a purification process equivalent to distillation, such as reverse osmosis (single or double pass) coupled with techniques such as electro-deionisation, ultrafiltration or nanofiltration. This brings the Ph. Eur. more closely in line with the US and Japanese Pharmacopoeias.
Potable Water: The Starting Point
Potable water is not covered by a pharmacopoeial monograph, but it must comply with the regulations on water intended for human consumption, and the manufacturer should carry out testing to confirm its quality. It may be used in the manufacture of active substances and in the early stages of cleaning equipment, unless higher grades are technically required. Most importantly, potable water is the prescribed feed water for producing pharmacopoeial grades of water, so its quality underpins every grade that follows.
Water Needed for Drug Formulations
Water for Injections is the most critical grade of water used in pharmaceutical manufacturing. It is used to prepare medicines for parenteral administration, both as a vehicle in the formulation and for dissolving or diluting substances or preparations before administration. To ensure patient safety, it must meet the most rigorous quality standards. For its production and control, the EMA guideline refers to Ph. Eur. monograph 0169, which sets out the requirements, including microbial and endotoxin requirements, that safeguard the quality and safety of this water grade.
Versatility and Quality of Purified Water
Purified Water is a versatile grade used in various pharmaceutical processes. It serves as an ingredient in drug formulations, is utilised for equipment cleaning, and is present in various pharmaceutical products. The guideline defines Purified Water as water for the preparation of medicines other than those required to be both sterile and apyrogenic, and refers to Ph. Eur. monograph 0008 for its production and control.
Water for Preparation of Extracts
Water for Preparation of Extracts is a grade used for the preparation of herbal drug extracts. It must either comply with the requirements for Purified Water, or be water intended for human consumption that is monitored in line with the production section of Ph. Eur. monograph 2249. These requirements help ensure the efficacy and safety of these extracts, which are fundamental in the development of pharmaceutical products.
Key Elements of the Guideline
The EMA’s guideline is comprehensive, encompassing various crucial elements, including but not limited to:
Quality Standards for Different Grades of Water: The guideline categorises water into distinct grades based on its intended use. These grades include Water for Injections, Purified Water, and Water for Preparation of Extracts. It sets out the minimum acceptable grade for each use, with the Ph. Eur. monographs defining the quality parameters for each grade, ensuring that water used at different stages of pharmaceutical manufacturing meets the requisite standards.
Minimum Acceptable Water Quality by Use: The guideline recommends a minimum water grade based on the product and the stage at which water is used, applying a risk-based approach. Examples include:
- Water for Injections: parenteral products, biologics (including vaccines and ATMPs), haemofiltration and haemodiafiltration solutions, peritoneal dialysis solutions, irrigation solutions, and formulations prior to sterile lyophilisation.
- Purified Water: oral, nasal/ear, cutaneous and rectal/vaginal preparations, nebuliser solutions, sterile ophthalmic preparations, granulation, tablet coating, and formulations prior to non-sterile lyophilisation.
- Potable Water: synthesis of intermediates for active substances with no sterility or apyrogenicity requirement, and fermentation or cell culture media for most fermentation and biological active substances (excluding vaccines and ATMPs).
In some cases, a risk assessment will require a higher grade, for example WFI for nebulised products used in certain disease states such as cystic fibrosis. The grade of water used should also be discussed in the marketing authorisation application.
Quality of Water for Pharmaceutical Use: Validation and qualification of water purification, storage, and distribution systems are fundamental components of Good Manufacturing Practices (GMP). The guideline highlights the necessity of complying with GMP regulations to establish and maintain water systems that consistently produce water of the required quality. It also notes that these systems form an integral part of GMP inspection.
Water Used for Cleaning/Rinsing: In pharmaceutical manufacturing, water serves not only as a raw material in drug formulations but also as a critical component for cleaning and rinsing equipment. Contaminants in cleaning water pose a significant risk to product quality. The guideline underscores the importance of monitoring and maintaining the quality of water used for cleaning and rinsing to prevent potential cross-contamination and ensure product quality. In general, the final rinse should use the same quality of water as the related manufacturing stage. For example, potable water may be used for the initial rinse of equipment for non-sterile products, but the final rinse for sterile parenteral products requires WFI. Where detergents or alcohol are used, they should be diluted in water of the same quality as the final rinse.
Microbiological Quality of Pharmaceutical-Grade Water: Microbial contamination is a significant concern in the pharmaceutical industry. It can compromise the safety and efficacy of medicinal products. The guideline acknowledges that control of water quality, in particular microbiological quality, is a major concern, and that the industry devotes considerable resources to the development and maintenance of water purification systems.
Impact on the Pharmaceutical Industry
The EMA’s guideline on the quality of water for pharmaceutical use has a profound impact on the pharmaceutical industry, affecting various aspects of pharmaceutical manufacturing and quality assurance. Here are some key areas where its influence is evident:
1. Patient Safety: The guideline places patient safety at the forefront by setting stringent standards for Water for Injections, the grade of water used in medicines for parenteral administration. Adhering to these standards is crucial to prevent any potential contamination that could harm patients.
2. Regulatory Compliance: The guideline applies to new marketing authorisation applications and relevant variations to existing authorisations, while the validation of water systems is assessed during GMP inspection. Failing to meet these expectations can result in regulatory action and jeopardise product integrity, potentially leading to product recalls and legal consequences.
3. Process Optimisation: By following the guideline’s recommendations, pharmaceutical companies can optimise their production processes. This includes reducing the risk of contamination, minimising the need for costly corrective actions, and enhancing overall operational efficiency.
4. Product Quality: Water quality is a critical factor in ensuring the quality and safety of pharmaceutical products. By adhering to the guideline, pharmaceutical companies can maintain the highest standards of product quality, safeguarding their reputation and ensuring that patients receive safe and effective medications.
Conclusion
The European Medicines Agency’s ‘Guideline on the quality of water for pharmaceutical use’ is a cornerstone of the pharmaceutical industry.
- Ensuring the integrity and safety of pharmaceutical products, this guideline is a critical resource for pharmaceutical manufacturers.
- As pharmaceutical companies continue to advance in research and development, adherence to these water quality standards remains paramount, underscoring the importance of the EMA’s guidance.
- In a world where the health and well-being of patients are paramount, the EMA’s commitment to water quality in pharmaceutical use is a testament to its dedication to ensuring the highest standards in the pharmaceutical industry.
Meeting these standards starts with reliable data on the water entering your process. Southern Scientific Ireland has more than 30 years of experience in analytical testing, holds INAB accreditation to ISO 17025, and analyses 10,000+ drinking water samples per year. Our chemical and microbiological laboratories support pharmaceutical and healthcare clients across Ireland with bespoke testing programmes, method development and validation, alongside drinking water testing.
