By Tim Clarot, Industry Consultant
Water is vitally important for all living things and is found everywhere on earth—from the polar ice caps to steamy geysers. Wherever water flows, you will also find living organisms. Water-borne microorganisms are ubiquitous and varied in their ability to survive and grow under different conditions. Pharmaceutical manufacturing, like life itself, depends on water. It is widely used as a raw material, ingredient, a cleaning agent, and as a solvent for various formulations. Whether water is a principal component of the drug product or only used in the cleaning process, its purity is fundamental to the integrity of the finished pharmaceutical product. This article will cover (1) pharmaceutical water standards, (2) purification methods, and (3) discuss potential water purification problems.
FDA has clearly stated that equipment and utensils must be cleaned and maintained in a state that prevents contamination that would alter the safety, identity, strength, quality or purity of the drug and has identified eight classifications for water:
- Potable (drinkable) water
- USP purified water
- USP water for injection (WFI)
- USP sterile water for injection
- USP sterile water for inhalation
- USP bacteriostatic water for injection
- USP sterile water for irrigation
The USP designation means that the water is the subject of an official monograph in the current United States Pharmacopeia with various specifications for each type. For pharmaceutical processing and cleaning, USP purified water is required. The supply source of water can be from a private well or a municipality. While either of these sources might meet potable water standards, it is unlikely that they will meet the USP standard for purified water—either chemically or microbiologically. At this point, a firm must consider supplementing the supplied water with a purification system.
Selection and maintenance of a water system is one of the most important investments that a pharmaceutical manufacturer will make. Unfortunately, there is no single design or blueprint for a system. Each system must be scaled to water chemistry, demand, and complexity of the facility. Operation and maintenance are also critical attributes that must be considered; the most advanced, state-of-the-art system will fail if it is not properly maintained. Service of the purification unit is also a major consideration—will it be maintained by inhouse technical staff or will a third party handle the routine maintenance? From an output quality perspective, the water system must consistently provide water that meets specific USP standards for chemical and microbiological requirements. The chemistry portion of the specification is fairly straightforward and can be met and maintained through filtration and various methods of ion exchange. The microbiological portion, however, is a challenge. While the chemical composition of water can be determined and adjusted quickly to ensure a rapid response to a problem, the microbiological assessment is slower and less accurate. This means that bioburden results are not available until several days have elapsed, placing considerable emphasis upon good design, maintenance and monitoring.
While most well-designed water systems can be maintained in a state of control, microbiological problems can develop. The primary issue is biofilm formation—slime-like microbiological communities that occur when microorganisms adhere to a surface. A biofilm develops because bacterial cells, once attached, secrete a polysaccharide that enables each bacterium to encapsulate itself. Biofilms are of particular concern with water systems since gram-negative bacteria constitute the majority of the bacterial populations found in aquatic environments. A gram-negative organism of major concern is Burkholderia cepacia complex.
In a July 12, 2021, advisory to drug manufacturers, FDA warns drug manufacturers of non-sterile water-based drug products that “Burkholderia cepacia complex (BCC or B. cepacia) continues to pose a risk of contamination. BCC is a group of gram-negative bacteria comprising more than 20 species that has been linked to multiple instances of opportunistic infections.” The advisory can be found here. Historically, FDA’s enforcement of BCC contamination is well-established and has a threshold tolerance of zero. Extreme diligence is necessary to ensure that the water system and all phases of water use are free of BCC.
As in all pharmaceutical processes, validation and documentation of the water purification system are necessary. Beyond the qualification and validation steps, documentation (at a minimum) should also include: (1) procedures for operating the system, (2) monitoring programs (to include sampling locations) for critical quality attributes, (3) operating conditions including calibration of critical instruments, (4) defect action limits, (5) schedule for periodic sanitization, (6) preventive maintenance of components, and (7) control of changes to the mechanical system and to operating conditions.
This article offers a high-level outline of the basic elements of a pharmaceutical-grade, UPS purified water system. A water system is complex and requires a sizeable capital investment prior to installation and on an on-going basis. Based on the cost and commitment, it is strongly advised that the manufacturer consult with a subject matter expert to ensure that the selected purification system is properly designed to meet the facility demands and its technical expertise. The good news is that there are numerous technical resources available to support the planning, installation and operation of the purification equipment.
Author: Tim Clarot is a consultant for Church & Dwight, where he was formerly Senior Vice President of R&D and Product Quality. With 40 years’ experience working directly with federal, state, and local regulators, Tim specializes in the regulatory framework of food (including dietary supplements), medical devices, and drugs (homeopathic and allopathic), both in the United States and internationally. He has also chaired company-sponsored scientific and medical advisory boards. He has served on AAHP’s Legal and Regulatory Committee since 2015 and on the Board of Directors since 2018. He can be reached at TClarot@gmail.com.