Global Pharmaceutical Water Standard System--FDA cGMP: Pharmaceutical Water

Related reading recommendations:

" Global Pharmaceutical Water Standard System-WHO GMP: Pharmaceutical Water "

" Global Pharmaceutical Water Standard System-EU GMP: Pharmaceutical Water "

(1) United States Pharmacopoeia

"United States Pharmacopoeia" (United States Pharmacopoeia, USP) was prepared by the United States Pharmacopoeia Commission
.
The United States Pharmacopoeia is the technical regulation made by the US government on drug quality standards and testing methods, and it is also the legal basis for drug production, use, management, and testing
.
The general rules numbered less than 1000 in the USP are general testing and testing, which are officially legal methods and are mandatory, such as USP<645>water conductivity and USP<643>Total organic carbon; in the USP The general rules numbered 1000~1999 are general information, which is an official legal method but does not need to be enforced, such as USP<1231> water for pharmaceutical purposes and USP<1230> water for hemodialysis applications
.
The general rules with numbers above 2000 in the USP only apply to substances whose uses are dietary ingredients and dietary supplements
.
The National Formulary (NF) contains new drugs and new preparations that are not yet included in the USP
.
The first edition of the "United States Pharmacopeia/National Formulary" was officially released on December 15, 1820.
Currently, the latest edition is USP43-NF38
.

The "United States Pharmacopeia" contains many detailed standards on the quality, purity, packaging and labeling of pharmaceutical water, including bulk type of Pharmacopoeia water, including purified water, hemodialysis water, bulk water for injection, and pure steam; in addition, the "United States The Pharmacopoeia also includes packaged pharmacopoeial waters, including bacteriostatic water for injection, sterile inhalation water, sterile water for injection, sterile rinse water and sterile purified water.
For details, please refer to the USP1231 chapter of the United States Pharmacopoeia (Table 2)
.

Table 2 Classification of pharmaceutical water in the United States Pharmacopoeia

 (2) U.
S.
cGMP and supporting guidelines

FDA cGMP is the statutory standard for the production and operation of food, nutritional supplements and pharmaceuticals in the United States
.
Each specific standard of cGMP is determined according to the specific product type, and its content includes plant construction, personnel requirements, sanitary conditions, production, quality management and records, etc.
The supervision and implementation of this standard is carried out by the FDA
.
The United States Code of Federal Regulations (CFR) is a collection of general and permanent regulations published in the Federal Register into a book of statutes
.
The CFR regulations cover various topics.
Among them, Title 21 "Food and Drugs" is the main regulatory basis for the U.
S.
Food and Drug Administration (FDA) to regulate food and drugs.
This article has 9 volumes, 3 chapters, and 1499 parts
.
Among them, Volumes 1 to 8 are Chapter 1 "Ministry of Health and Human Services, Food and Drug Administration; Volume 9 contains Chapter 2 "Department of Justice Drug Enforcement Bureau and Chapter 3 "Drug Control Policy Office"
.

There are not too many direct requirements for pharmaceutical water in the text description of the US FDA cGMP, and there are very few design requirements related to pharmaceutical water
.
The US FDA cGMP requires that "surfaces in contact with pharmaceutical ingredients, process raw materials or pharmaceutical products should not react, adhere or adsorb with the materials to change the safety, uniformity, strength, quality or purity of the drug
.
" The following are some of the default requirements of the US FDA cGMP for pharmaceutical water systems: the discharge port must meet the requirements of air blocking; the heat exchanger for pharmaceutical water must use a double-plate tube heat exchanger to prevent cross-contamination; the storage tank must be equipped with a breather It needs to have a daily maintenance plan; it needs to have written procedures for cleaning and disinfection and keep records; it needs to have standard operating procedures for the pharmaceutical water system
.

Since the US FDA issued the "Guide to Inspections of High Purity Water Systems" (English name: Guide to inspections of high purity water systems) in 1993, it has not been updated
.
After entering the 21st century, under the official comments of the FDA, American pharmaceutical companies have more to refer to the official cooperation group standards to guide the design and implementation of water and steam systems
.
Its main group standards include "International Pharmaceutical Engineering Association Benchmark Guide Book IV-Water and Steam Systems" and "American Society of Mechanical Engineers-Biological Processing Equipment" and so on
.

(1) cGMP Guidelines-"Guidelines for Inspection of High Purity Water System"

High-purity water system is an essential part of every pharmaceutical company
.
The quality of water often affects every important link in the drug research and production process.
It plays a vital role in controlling the quality of drug products.
Naturally, the water system has become the focus of the FDA's on-site inspections
.
Among them, the test results of water samples, summary data, survey reports and other data, printed system drawings and related SOPs are the focus of FDA inspectors.
From the design of high-purity water system to daily operation and maintenance, there are many things that require corporate staff.
The high idea
.

The "Guidelines for Inspection of High Purity Water System" mainly discusses and evaluates the high purity water system used in the production process of APIs and preparations from the perspective of microorganisms
.
This guide also discusses different types of water system designs and issues related to these systems
.
Like other guidelines, this guide is not exclusive, but provides background information and guidance for the review and evaluation of high-purity water systems
.
The "Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories" (Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories) implemented in 1993 also provides relevant guidance information
.
The "Guidelines for Inspection of High Purity Water System" have some key requirements for pharmaceutical water as follows: minimum dead space is required; no filter is required at the point of use of the water for injection circuit; most of the pipes of the water for injection distribution system are made of 316L stainless steel; heat exchangers are used Double-end plate design or use of differential pressure monitoring; storage tanks are required to use respirators to prevent external pollution; pipeline slopes must meet the requirements; use sanitary sealed pumps; use within 24 hours of static storage; when producing sterile drugs, the final flushing water The quality needs to meet the standards of water for injection; pure steam does not contain volatile additives
.

(2) Group standard --- "International Pharmaceutical Engineering Association Benchmark Guide Book IV-Water and Steam System"

The International Society For Pharmaceutical Engineering (ISPE) was founded in 1980 and is one of the world's largest non-profit organizations dedicated to training experts in the pharmaceutical field and improving the level of the pharmaceutical industry
.
At that time, in the pharmaceutical industry, there was a group of industry insiders who were at the forefront of the industry.
They hoped to communicate and cooperate with other companies in the same industry to improve production efficiency.
A world-wide organization could provide technical experts in the pharmaceutical industry with practical information.
Application information
.

Since its establishment more than 40 years ago, ISPE has more than 25,000 members worldwide, and has become an exchange platform for providing industry information, regulatory trends, and production technology, and is playing an increasingly important role in the global pharmaceutical industry
.
It has a global headquarters in Tampa, USA, a European headquarters in Brussels, and an Asian headquarters in Singapore
.
In 1997, the US FDA made the following comment on ISPE: "Thank you for your cooperation with the FDA for your outstanding contribution to the education of the US and global pharmaceutical industry
.
"

ISPE established a China office in April 2008 to provide services to all members in China
.
With the development in China, ISPE launched a new Chinese COP forum in China in October 2011, aiming to build a platform for people in the industry to communicate, share best practices, solve problems at work, and expand contacts at the same time
.
The ISPE Pharmaceutical Forum currently covers major pharmaceutical topics such as "key public works, biotechnology, drug life cycle, debugging and validation, bulk drugs, sterile, oral solid preparations, and good automation practices"
.
Whether face-to-face meetings or communication through online virtual communities, all ISPE members facilitate communication, sharing and coordination with each other
.

"International Pharmaceutical Engineering Association Benchmark Guide Volume 4-Water and Steam Systems", the English name is "ISPE Baseline Volume 4: Water and Steam Systems", which belongs to the group standard under the FDA cooperation framework
.
The guide is mainly to adjust and adapt to the domestic market in the United States, and to comply with American standards
.
European and other non-US standards may be combined in future revisions
.
At present, the latest edition of "International Association of Pharmaceutical Engineers Benchmark Guide Volume IV-Water and Steam Systems" is the third edition revised in 2019
.

"International Pharmaceutical Engineering Association Benchmark Guide Volume IV-Water and Steam Systems" is used to design, construct and operate new water and steam systems.
It is neither a standard nor a detailed design guide
.
For the commissioning and verification of water and steam systems, please refer to "International Pharmaceutical Engineering Association Benchmark Guide Book 5-Commissioning and Verification"
.
The guide focuses on engineering issues and provides effective cost management for water and steam systems
.
Where non-engineering issues (such as microbiological issues) are included, this information is also included to emphasize the importance of problems and their effects in the design of water and steam systems.
Therefore, these non-engineering issues are not widely included.
, Where technical input is permitted, the QA department and technical experts should be asked for advice
.

(3) Group standard --- "American Society of Mechanical Engineers-Biological Processing Equipment"

The "American Society of Mechanical Engineers-Bioprocessing Equipment" standard (referred to as ASME BPE standard) issued by the American Society of Mechanical Engineers (ASME) is the only biomedical production equipment standard in the world.
The ASME BPE standard was first published in 1997 and aims to Ensure that the production equipment used in the production of products in the pharmaceutical, biopharmaceutical and personal care industries can reach a uniform and acceptable quality level.
These industries have strict sanitary requirements, especially sanitary pipe fittings, joints and accessories, which generally use ASME BPE standard
.
At present, this international standard has been recognized by more than 30 countries, and the latest version is "ASME BPE" (2019 edition) revised in 2019
.

The ASME BPE code is a construction specification for biological process equipment.
The specific biological process equipment covered includes pressure equipment, pipelines and pipe fittings; it covers the design and manufacturing of the system, the design, materials, manufacturing, processing, inspection, testing and testing of equipment and pipelines.
Certification and other links
.
Among them, ASME Volume VIII is cited more frequently in the manufacture of pressure equipment, and B31.
3 is cited for process pipelines.
Therefore, while implementing the ASME BPE standard, it must be combined with the relevant ASME pressure vessel and pipeline construction standards cited.
And these construction standards quoted other codes, such as materials citing ASME material specifications (Volume II) and ASTM material standards, welding citing ASME welding specifications (volume IX), and non-destructive testing citing ASME non-destructive testing specifications ( Volume V) standards, these documents and ASME BPE standards together form a standard system for biological process equipment
.
For the relevant content of the water and steam system, please refer to the SD-4 chapter clean utilities of the "American Society of Mechanical Engineers-Biological Processing Equipment"
.

   About the Author:

Zhang Gongchen, Member of the Research Group of the Chinese Pharmacopoeia Pharmaceutical Water Standard System