cGMPs

Pharma Water Everywhere, but Little Consistent Guidance

Guidelines for pharma grade water have varied and often been a moving target. Pfizer's Cameron Sipe explains the importance of ISPE's new guidelines.

Harmonization of regulations for high-purity pharma water systems, “although a noble goal, has not been achieved,” says Cameron Sipe, P.E., a Principal Project Engineer and Subject Matter Expert with Pfizer.

It is for this reason that there are significant hopes within the industry that ISPE’s new Baseline Guide for Water and Steam Systems (available from ISPE.org) will provide some much-needed coordination. Sipe has chaired the committee to revise ISPE’s original guidance (published eons ago, in 2001), and answers our questions about what the new baseline guide will mean. Note: The interview is followed by a roundup of new technologies in pharma grade water.

PhM: What does the industry still struggle with in regards to use and control of water and steam systems, and how will the new guide address these issues?

C.S.: The most significant struggle in the industry for many years has been the numerous guidelines and books out there that provide guidance and recommendations for high purity water systems and clean steam systems, many of which have conflicting information. Additionally, the pharma/biotech industry has been a global industry for a number of years now. Therefore, the clean utilities utilized to manufacture our products must meet the numerous requirements of a multitude of regulatory agencies around the world.

As you can imagine, there are numerous differences in the regulations from various countries. These regulations continue to change but often times slower than water purification technology. Harmonization of these regulations, although a noble goal, has not been achieved. The desire to utilize emerging technologies for purification and especially for monitoring the quality of clean utility systems has added to the struggle. Recognizing these struggles and addressing them was the major goal for the revision to the ISPE Baseline Guide for Water and Steam Systems. The team attempted to build on the significant original content of the first edition by addressing the regulations for a global market while recognizing the advances in purification and monitoring technology.

PhM: It was time for a revision of this baseline guide, but how much of it is in response to and reflects changes in industry and FDA’s risk- and science-based initiatives?

C.S.: Edition 1 of the baseline guide was published in 2001 but the content was written several years earlier. There have been numerous changes in the industry, many changes in regulations, and new guidelines/regulations published over the past 10 years approximately. When edition 1 was written, the industry was in a “cover all the bases” mode for documentation. Therefore edition 1 was written in that light. Additionally, since the Baseline Guide for Water and Steam was one of the first ISPE Baseline guides, the core team of authors felt they had to cover numerous areas relating to water and steam that had no guidance documents.

Since that original publication, numerous other baseline guides, good practice guides, and regulatory guidelines have been published which cover most of these related areas. Edition 2 of the Water and Steam Guide references these other guides heavily and tries not to duplicate information. The “risk-based” or “science-based” approach is one of the latest industry trends covered in other baseline guides or good practice guides. Edition 2 mentions these approaches and how they apply to water and steam systems but then references other guides for specific details. 

PhM: How will the updates reflect the increased use of PAT and support real-time monitoring and control? In your view, are manufacturers realizing the potential of PAT to monitor and optimize their water and steam systems?

C.S.: When edition 1 was published, on-line monitoring had been utilized for a number of years. However, many people in the industry were skeptical about its use for documenting the quality of the water and steam. This skepticism was due in part to questions on reliability of instruments and part to reluctance to change and answer questions associated with the change. Therefore, the on-line instrumentation, in many cases, was utilized primarily for maintenance monitoring and early detection of quality issues. Advances in instrument technology and reliability have promoted the recent industry trend toward PAT and reliance on on-line instrumentation. Edition 2 addresses this trend by significantly enhancing the instrumentation and controls chapter. This chapter not only provides specifics on applying on-line instrumentation and PAT but also discusses emerging technologies such as rapid micro testing.  

PhM: In terms of C&Q, what are the major points of emphasis, and are there major changes from the 2007 guide for commissioning & qualification of water and steam systems?

C.S.: Good Practices Guide (GPG) for C&Q of Water and Steam Systems was published after Edition 1 of the Baseline Guide for Water and Steam. Edition 2 of the Baseline Guide for Water and Steam recognizes the detailed information included in the C&Q GPG. Many of the authors for the C&Q guide also participated in the Edition 2 team. We attempted to maintain consistency between the two guides but allow the C&Q guide to be the primary source for detailed information. Therefore, the C&Q chapter of Edition 2 heavily references the C&Q GPG and attempts to avoid repetition of content. However, the recent industry trend for a risk-based approach to C&Q is discussed and how it may be applied to water and steam systems. 

PhM: Are manufacturers embracing new technologies for microbial ID and control in their water and steam systems, and how are they covered in this guide?

C.S.: The instrumentation and controls chapter was significantly enhanced to include micro ID and rapid microbiological measurements (RMM) as two of the emerging technologies for the industry. These technologies, being cutting edge technology, are becoming more available and being placed into service with verification by traditional laboratory culturing methods. However, edition 2 also cautions that these new technologies should follow accepted cGMPs and applicable compendial mandates.

PhM: Given the industry’s trend towards greening its operations, are environmental issues such as water conservation, wastewater quality, etc. addressed in more detail than previously?

C.S.: Energy and Water conservation was one of the themes for the recent ISPE Spring conference during which the major “green” topics included in edition 2 of the water and steam baseline guide were presented. During the revision process the edition 2 team recognized that conservation issues were becoming more prevalent in the industry. Numerous chapters of edition 2 include options for water and energy conservation. Specifically, the chapter on Pretreatment includes alternative technologies and operational techniques which reduce waste water. The chapters on Final Treatment include discussions on possible uses for the waste water generated. The chapters on Design Philosophies and Storage/Distribution include the Pros/Cons for energy and water conservation on many of the alternatives discussed. The goal of these conservation discussions in each of the chapters was to allow the reader to make an educated decision on their unique approach to conservation.

PhM: What prompted a new chapter on passivation/rouge, and what can we expect from it?

C.S.: Rouge is one of the “hot topics” in the industry for critical utilities. The formation of rouge and its removal or “de-rouging” continues to be somewhat a mystery to many professionals in the industry. These are the main reasons the team decided to devote a complete chapter on the topic. Edition 1 discussed the topic in a number of places throughout the guide but did not provide the detail that the new chapter in edition 2 provides. The new chapter provides detail on the formation of rouge, some of the contributing factors for rouge formation, the different types of rouge and some of the standard practices utilized to address rouge in critical utility systems. The chapter includes significant input from European experts as well as passivation professionals. It also touches on other types of corrosion that systems may encounter and provides a methodology for deciding on a rouge remediation plan if deemed necessary.

PhM: And can you share some insight into the other new chapters?

C.S.: The new guide also includes a new chapter addressing non-compedial waters that may be utilized in non-regulated laboratories. The team felt that this chapter was needed to address water systems of various purity levels utilized in the industry for numerous laboratory facilities. This chapter references aspects of a number of other chapters but points out different philosophies as applied to non-compendial systems. It provides a step-by-step approach to deciding the type of water system for a particular application.

There’s also a new microbiology chapter. Discussions of microbiology as applied to water systems were included in numerous chapters of edition 1 of the water and steam guide. The edition 2 team decided to consolidate and enhance these discussions in a new chapter. The new microbiology chapter includes details for pretreatment through use point management on mechanisms that promote biofilm proliferation, microbial control strategies, microbial sampling/monitoring, and compendial compliance issues.   

Pharma Grade Water: A Roundup of New Technologies

Mettler-Toledo Thornton has just introduced the UniCond conductivity/resistivity sensor, which transmits to the new M300 ISM multiparameter transmitter. The sensing range of the UniCond is 0.02μS/cm to 50,000μS/cm, making it suitable for various water applications. Embedded circuitry communicates the type, model, serial number, and calibration data digitally to the transmitter. UniCond meets USP, EP, and JP Pharmaceutical water monitoring requirements.

Millipore Milli-Q
                 Millipore Milli-Q

Millipore has added to its Milli-Q line of lab water systems with the Milli-Q Direct. The new system aims to be an economical, single source for pure and ultrapure water from tap. It can be bench- or wall-installed, and water can be dispensed either manually or automatically, at low or high flow rate.

The new Sievers InnovOx Total Organic Carbon Analyzer provides on-line monitoring of TOC levels for various pharma applications. Designed by GE Power & Water’s analytical instruments unit, the InnovOx On-Line uses a Supercritical Water Oxidation (SCWO) technique traditionally used to treat aqueous waste streams, sludges and contaminated soils, but now is used in a TOC analyzer.

The PAT700 from Anatel (a Hach company) is an on-line TOC and conductivity analyzer that meets the requirements of USP <643> for TOC and <645> for conductivity. It can analyze 4 grab samples and measure 3 replicates from each bottle, Hach says, and can validate points-of-use and clean steam condensate.

Chata Biosystems has begun offering a closed system for storage and delivery of USP Purified Water 50L, 100L, 200L drums and 1,000L totes. The system consists of an internal bag, a tubing and valving system,and a cGMP filling process. The bag material, Chata says, is chemically inert, has extremely low levels of extractables, low moisture-vapor transmission rate and does not contain chlorine or DEHP plasticizers. As such, the bags can be used with a wide range of solutions. The tubing for solvent-based products is Teflon, though Tygoprene for large volume USP Purified Water and buffer packaging.    

Hach Anatel PAT700
                            Anatel's PAT

3M Purification (Cuno) has just released a new white paper on the various uses of cartridge filtration in the production of pharma grade water. The paper, available on PharmaManufacturing.com, illustrates the use of cartridge filters for applications such as the removal of particulates, elimination of Pseudomonades and other microorganisms, reduction of endotoxins, and protection of storage tanks during draw-down.

Finally, Pall Corp. has donated more than 6,000 pounds of leftover polypropylene membrane from its Pensacola, Florida manufacturing facility to help protect local beaches from the Gulf oil spill. Pall employees helped to bag the material into netting “socks” to soak up the oil and help contain environmental damage. Polypropylene is widely used in the Life Sciences to filter water.

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