[PDF+ PPT] WIPO – Functions Objectives Treaties Salient Features Role World Intellectual Property Organization (WIPO)

objectives of World Intellectual Property Organisation (WIPO)

In this article we are going to discuss World Intellectual Property Organisation (WIPO) What is WIPO?, Functions of WIPO, History of WIPO, How WIPO functions, Simple explanation with PDF of WIPO and its functions, World Intellectual Property Organization, Indian and WIPO relations, WIPO treaties objectives and functions of WIPO,importance of WIPO, salient features of WIPO, powers and functions of WIPO, organs of WIPO,
objectives of WIPO and mainly role of WIPO in protection of ipr.

The World Intellectual Property Organization (WIPO) is one of the 16 specialized agencies of the United Nations. WIPO was created in 1967 “to encourage creative activity, to promote the protection of intellectual property throughout the world.”

History of WIPO

WIPO currently has 184 member states, administers 24 international treaties, and is headquartered in Geneva, Switzerland. The current Director-General of WIPO is Francis Gurry, who took office on October 1, 2008.

183 of the UN Members as well as the Holy See are Members of WIPO. Non-members are the states of Cook Islands, Kiribati, Marshall Islands, Federated States of Micronesia, Nauru, Niue, Palau, Solomon Islands, Timor-Leste, Tuvalu, Vanuatu and the states with limited recognition. Palestine has observer status.

Amongst the many roles that WIPO carries out to support the worldwide promotion of intellectual property rights, is its role in the administration of specific treaties and conventions. The international protection for trademarks,industrial designs and appellations of origin is carried out through three registration systems: The Madrid System for trademarks, the Hague System for industrial designs, and the Lisbon Agreement for the protection of appellations of origin

objectives of World Intellectual Property Organisation (WIPO)

  1. a) The Hague System covers the deposit of industrial designs, the Madrid System the registration of trademarks and the Lisbon Agreement concerns the registration of appellations of origin.
  2. b) The two treaties in the Madrid System are the Madrid Agreement concerning the International Registration of Marks (1891) and the Madrid Protocol relating to the Madrid Agreement (1989).

Role of World Intellectual Property Organisation (WIPO)

Strategic partnership through carefully formulated national IP strategy commensurate with the country’s existing development policies and objectives
Providing technical expertise and advice Support and assistance in the implementation of national IP strategy.

Functions of WIPO -World Intellectual Property Organisation (WIPO)

Enable a country to use its IP system in an effective and optimal manner while ensuring that it contributes to overall national development policies and goals
Provides a clear picture of where a country wants to go and how it will get there by using the IP system Helps ensure the development of a balanced national IP system that fits with the specific needs and expectations of a country
Provides an effective framework of cooperation between the country concerned and WIPO (and other agencies providing technical assistance in the areas related IP)
Other advantages

World Intellectual Property Organisation WIPO Functions Objectives PDF PPT

More tangible/concrete results Better coordination and cohesion among all parties concerned (increasing synergies) Optimal use of available resources

Functions of WIPO
Functions of WIPO

What does WIPO do?

The activities of WIPO are basically of three kinds:

  • assistance to developing countries,
  • setting international norms and standards for the protection of intellectual property
  • registration activities.

All these activities serve the overall aim of WIPO, namely, to maintain and increase respect for intellectual property throughout the world, in order to promote industrial and cultural development by stimulating creative activities and facilitating the transfer of technology as well as the dissemination of literary and artistic works.

1. Assistance to developing countries constitutes the first pillar of WIPO’s activities, and takes the form of
training (groups and individuals, in general or specialized courses, seminars to provide for an exchange of information and experience),
promotion of creative activities and of technology transfer,
the provision of technological information contained in patent documents,
the provision of advice on laws and regulations as well as
the management of industrial property offices and copyright collective administration societies, as well as
the provision of equipment.

2, The second pillar relates to activities in the setting of international standards and norms for the protection and administration of intellectual property. They are concerned with revision of existing treaties or creation of new ones,
simplifying procedures at the national, regional or international levels for the granting of intellectual property rights,
the effective enforcement and protection of such rights,
the efficient management of collections of industrial property documents used for search and reference, and devising means for making access to the information they contain easier;
the maintenance and updating of international classification systems,
the compilation of statistics;
collection of laws on industrial property and copyright law administration.

Under this heading could be included the work of the WIPO Arbitration and Mediation Center. Promotion of the acceptance–or wider acceptance–of treaties, by countries is also an important activity of WIPO.

3.The registration activities are the third pillar of WIPO and involve direct services to applicants for, or owners of, industrial property rights. These activities concern the receiving and processing of international applications for the protection of inventions, or for the international registration of marks or deposit of industrial designs.

Such activities are financed normally from the fees paid by the applicants, which account for about 85% of the annual total income of WIPO for the 1996/97 budget. The rest of the budget is covered mainly by contributions from member States under various treaties administered by the Organization, as well as by the sale of publications and miscellaneous income.

Strategic Goals

WIPO’s revised and expanded strategic goals are part of a comprehensive process of strategic realignment taking place within the Organization. These new goals will enable WIPO to fulfill its mandate more effectively in response to a rapidly evolving external environment, and to the urgent challenges for intellectual property in the 21st Century.

The nine strategic goals were adopted by Member States in the Revised Program and Budget for the 2008/09 Biennium [PDF].  They are:

  • Balanced Evolution of the International Normative Framework for IP
  • Provision of Premier Global IP Services
  • Facilitating the Use of IP for Development
  • Coordination and Development of Global IP Infrastructure
  • World Reference Source for IP Information and Analysis
  • International Cooperation on Building Respect for IP
  • Addressing IP in Relation to Global Policy Issues
  • A Responsive Communications Interface between WIPO, its Member States and All Stakeholders
  • An Efficient Administrative and Financial Support Structure to Enable WIPO to Deliver its Programs

Objectives of WIPO World Intellectual Property Organization (WIPO)

The objectives of WIPO are, firstly, to promote the protection of and the respect for intellectual property throughout the world through cooperation among States; and, where appropriate, in collaboration with other international organizations; secondly, to ensure administrative cooperation among the intellectual property Unions established by the treaties that are administered by WIPO

  • To make IP speaks the language of the economic circumstances and social context that it serves.

  • To create better functional linkages between the national economic objectives, development priorities and resources, and the IP system of the country concerned.

Treaties and Unions of World Intellectual Property Organization (WIPO)

  • The constitution, the “basic instrument,” of WIPO is the Convention, mentioned above, signed at Stockholm in 1967.

The treaties administered by WIPO fall into three groups.

The first group consists of treaties which establish international protection, that is to say, they are treaties which are the source of legal protection agreed between countries at the international level. Four treaties on industrial property fall into this group.

They are
the Paris Convention for the Protection of Industrial Property,
the Madrid Agreement for the Repression of False and Deceptive Indications of Source on Goods,
the Lisbon Agreement for the Protection of Appellations of Origin and their International Registration, and
the Nairobi Treaty on the Protection of the Olympic Symbol.

Two treaties in the field of copyright and neighboring rights fall into this group, namely
the Berne Convention for the Protection of Literary and Artistic Works and
the Rome Convention for the Protection of Performers, Producers of Phonograms and Broadcasting Organizations.

  •  The second group consists of treaties which facilitate international protection. Seven treaties on industrial property fall into this group. They are
    the Patent Cooperation Treaty which provides for the filing of international applications for patents,
    the Madrid Agreement Concerning the International Registration of Marks,
    the Protocol Relating to the Madrid Agreement just mentioned (both of them provide for the filing of international applications for marks),
    the Lisbon Agreement which has already been mentioned because it belongs to both the first and the second groups,
    the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure,
    the Hague Agreement Concerning the International Deposit of Industrial Designs and
    the Trademark Law Treaty which entered into force on August 1, 1996.
  • Two treaties in the field of neighboring rights may also be considered as falling into this group, namely
    the Geneva Convention for the Protection of Producers of Phonograms Against Unauthorized Duplication of Their Phonograms and the Brussels Convention relating to the Distribution of Programme- Carrying Signals Transmitted by Satellite.
  • The third group consists of treaties which establish classification systems and procedures for improving them and keeping them up to date.
  • The following four treaties, all dealing with industrial property, fall into this group:
    the Strasbourg Agreement concerning International Patent Classification (IPC),
    the Nice Agreement Concerning the International Classification of Goods and Services for the Purposes of the Registration of Marks,
    the Vienna Agreement Establishing an International Classification of the Figurative Elements of Marks and
    the Locarno Agreement Establishing an International Classification for Industrial Designs.

Revising these treaties and establishing new ones are tasks which require a constant effort of intergovernmental cooperation and negotiation, supported by a specialized secretariat. WIPO provides the framework and the services for this work. Recent examples of such work include the above-mentioned Madrid Protocol and Trademark Law Treaty, which entered into force on December 1, 1995, and August 1, 1996, respectively. Currently, at least four possible treaties are being negotiated under the aegis of WIPO: The proposed Patent Law Treaty, a possible Protocol to the Berne Convention, a possible Treaty on Neighboring Rights and a proposed Treaty on the Settlement of Disputes between States in the Field of Intellectual Property.

Why is an intergovernmental intellectual property organization needed?

Intellectual property rights are limited territorially; they exist and can be exercised only within the jurisdiction of the country or countries under whose laws they are granted. But works of the mind, including inventive ideas, cross frontiers with ease and, in a world of interdependent nations, should be encouraged to do so. Therefore, governments have negotiated and adopted multilateral treaties in the various fields of intellectual property, each of which establishes a “Union” of countries which agree to grant to nationals of other countries of the Union the same protection as they grant to their own nationals.

Functions of WIPO, History of WIPO, Simple Explanation of WIPO

objectives and functions of WIPO,importance of WIPO,
salient features of WIPO,powers and functions of WIPO, organs of WIPO,
objectives of WIPO,
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role of WIPO in protection of ipr

What are the Unions?

The Unions administered by WIPO are founded on the treaties. A Union consists of all the States that are party to a particular treaty. The name of the Union is, in most cases, taken from the place where the text of the treaty was first adopted (thus the Paris Union, the Berne Union, etc.).

WIPO’s Unions are

the Paris Union, the Berne Union, the Madrid Union,
the Hague Union, the Nice Union, the Lisbon Union,
the Locarno Union, the PCT Union, the IPC Union,
the Vienna Union and the Budapest Union.

Hope you like this article on World Intellectual Property Organisation (WIPO) What is WIPO?, Functions of WIPO, History of WIPO, How WIPO functions, Simple explanation with PDF of WIPO and its functions, World Intellectual Property Organization, Indian and WIPO relations, WIPO treaties objectives and functions of WIPO,importance of WIPO, salient features of WIPO, powers and functions of WIPO, organs of WIPO, objectives of WIPO, what is WIPO and its function, role of WIPO in protection of ipr.

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WORLD TOP 10 PHARMA COMPANIES – Best Pharmaceutical Manufacturing Industries List

WORLD TOP 10 PHARMA COMPANIES - Best Pharmaceutical Manufacturing Industries List

Now we see here the Pharma companies which leads the word in the top 10 list as best Pharmaceutical Industries. Lets begin.

TOP 10 PHARMA COMPANIES IN THE WORLD

  1. Gilead Sciences

Gilead Sciences is an US based biopharmaceutical company. The company since its inception has concentrated on antiviral drugs that are used in the treatment of HIV, Hepatitis B, Hepatitis C and Influenza. The company offers products that include Atripla, Complera, Emtriva, Viread and many more. The company was founded and is headquartered in Foster City, California. The company is a member of the NASDAQ Biotechnology Index and the S&P Index.

  1. Bayer

Bayer is a German multinational chemical and pharmaceutical company founded in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, and Germany. The company focuses primarily in the areas of human and veterinary pharmaceuticals; consumer healthcare products; agricultural chemicals and biotechnology products; and high value polymers. It is best known for its first product aspirin.

  1. AstraZeneca

AstraZeneca is a British-Swedish multinational pharmaceutical and biologics company founded in 1999. It is headquartered in London, United Kingdom. The company has operations in over 100 countries. The company provides products for major diseases such as cancer, cardiovascular, gastrointestinal infection, neuroscience, respiratory and inflammation.

  1. GlaxoSmithKline

GlaxoSmithKline is a British pharmaceutical company founded in 2000. It is headquartered in Brentford, London. It was established as a result of merger of Glaxo Wellcome and SmithKline Beecham. The company develops a wide array of products in the areas of pharmaceuticals, vaccines and consumer healthcare. It also has products across various areas including cardiovascular and respiratory diseases, asthma, mental health, infections, cancer, digestive conditions and diabetes.

  1. Merck

Merck & Co. is an American pharmaceutical company doing business as Merck Sharp & Dohme outside the US and Canada. The company was established in 1891 as a US subsidiary of the German company Merck. The company is headquartered in Kenilworth, New Jersey. The expert and specialised areas of the company include oncology, neurodegenerative diseases, fertility and endocrinology. The company is also well-known for publishing The Merck Manuals; these are a series of medical reference books for physicians, nurses and technicians.

  1. Sanofi

Sanofi is a French multinational pharmaceutical company founded in 2004. It is headquartered Gentilly, France. The company is majorly involved in the research and development, manufacturing and marketing of the pharmaceutical drugs in the prescription market. The company also develops over the counter medication. The company’s major areas of speciality include cardiovascular, diabetes, vaccines, oncology, central nervous system, thrombosis and internal medicine.

Click here WORLD TOP 10 PHARMA COMPANIES – Best Pharmaceutical Manufacturing Industries List WORLD TOP 10 PHARMA COMPANIES – Best Pharmaceutical Manufacturing Industries List

  1. Pfizer

Pfizer is an American global pharmaceutical corporation founded in 1849. The company is headquartered in New York City and its research is headquartered in Groton, Connecticut. The company produces medicines and vaccines for a various therapeutic areas such as oncology, cardiology, immunology, neurology and endocrinology. The company’s products include drugs such as Lipitor, Lyrica, Diflucan, Zithromax, Viagra and Celebra. The company operates in the divisions of primary care, speciality care, established products, animal health, capsugel, consumer healthcare, emerging markets, oncology and nutrition.

WORLD TOP 10 PHARMA COMPANIES - Best Pharmaceutical Manufacturing Industries List

  1. Roche

Roche is a Swiss global healthcare company that operates on a worldwide basis in two divisions, that is, pharmaceuticals and diagnostics. It was founded in 1896. The company has headquarters located in Basel and also has pharmaceuticals and diagnostic sites around the world. The company produces and sells drugs for cancer treatments MebThera, Avastin, Herception and Xeloda. It is the market leader in personalised medicines and was also one of the first companies to bring targeted treatments to patients.

  1. Novartis

Novartis is a Swiss multinational pharmaceutical company founded in 1996 as a result of a merger. The company is headquartered in Basel, Switzerland. The company’s expert and specialist areas of operation include prescription pharmaceuticals, eye care and generics and biosimilars. Its most sold pharmaceutical drugs include Gleevec for cancer and Gilenya for multiple sclerosis. The company has operations in more than 140 countries worldwide and has a combined workforce of more than 100,000 employees.

  1. Johnson & Johnson

Johnson & Johnson is an American multinational pharmaceutical, consumer packaged goods and medical devices manufacturer that was founded in 1886. The company is headquartered in New Brunswick, New Jersey. The consumer division of the company is located in Skillman, New Jersey. The company has operations in more than 57 countries with 250 subsidiary companies in those countries. The company is a household name due to its consumer healthcare division. It has more than 182 marketed drugs, with the company being market leaders in divisions of Hepatitis C, arthritis, HIV/AIDS and digestive conditions. The company brand includes various household names of medications and first aid supplies. Its consumer products include brand lines of bandages, Johnson’s baby products, Tylenol medications, Neutrogena beauty and skin products and many more.

B. Pharmacy First Year Subjects – B Pharma 1st Sem 2nd Sem Books Syllabus

Subjects for First Year Pharmacy

B Pharmacy First Year Subjects

Bachelor of Pharmacy or B. Pharmacy is one of the most studied courses of present time.  Many students ever year enroll under B. Pharmacy colleges to study the course.  It is a three year course, which is scheduled to be studied semester wise.  It is an under graduation level course that is chosen to be studied by many students after their intermediate.  Students who have studied intermediate with Bi.Pc background will go for under graduation into B. Pharmacy course.  Qualified students from intermediate with Bi.Pc background will study B. Pharmacy in their under graduation level.  The study of Pharmacy is all about art and science of preparing and dispensing new drugs and medicines for various illnesses and diseases.

Pharmacy is studied in various semesters.  The number of semesters of Pharmacy varies from state to state.  Students of Pharmacy along with gaining theoretical knowledge will also be able to gain practical knowledge as they get to perform various experiments.  Pharmacy Council of India (PCI) is the one that is responsible to govern and manage the Pharmacy graduate level education in the entire country.  It is a statutory body that is governed by the provisions of the Pharmacy Act, 1948 that was passed by the Indian Parliament.

Students who have completed their under graduation in Pharmacy can be able to live as a Pharmacist.  They can manage their own medical shops; they can work in various labs to experiment new medicines for illnesses.  Along with Pharmacy College’s offline, there are also named online Pharmacy colleges that offer good range of study to the students of the world.  Many named universities around the globe offer online Pharmacy courses to the interested candidates.  Those universities also provide Pharmacy degree to the qualified candidates.  The online Pharmacy degree providing Schools include University of Florida, Kaplan University, Baker College, Lehigh University, University of Phoenix, Grand Canyon University and University of Liverpool.

b pharmacy first year subjects

Subjects for First Year Pharmacy

The first year of B. Pharmacy consists of various subjects.  Students who are willing to attain Bachelor Degree in Pharmacy needs to clear their intermediate with at least 50% of marks.  They need to do their intermediate in Physics, Chemistry, Maths, or Physics, Chemistry, Biology or Physics, Chemistry, Maths and Biology subjects.  The first year B. Pharmacy students need to study the subjects that were mentioned below.  Students who have cleared all their subjects in B. Pharmacy first year will be promoted to second year.  As it is a three year course and is a semester pattern, the subjects in the later two years will be divided into semesters.

  • Remedial Mathamaticla BiologySubjects for First Year Pharmacy
  • Advanced Mathematics
  • Anatomy
  • Physiology and Health Education
  • Physical Chemistry
  • Organic Chemistry
  • Physical Pharmacy
  • Basic Electronics and Computer Applications
  • Pharmaceutical Analysis
  • Inorganic Pharmaceutical Chemistry
  • Pharmacognosy

Students who have entered into B. Pharmacy after their intermediate level education needs to study these subjects in their first year of Pharmacy.  They need to clear all these subjects in order to get promoted to second year of Pharmacy.  Few universities offer semester wise study, while few universities offer year full of study.  Candidates who have plans to do Master Degree in research will do this B. Pharmacy course.  Qualified candidates can either go for post graduation or can work in teaching profession.

B. Pharmacy First Year Subjects – B Pharma 1st Sem 2nd Sem Books Syllabus B. Pharmacy First Year Subjects – B Pharma 1st Sem 2nd Sem Books Syllabus

 

 

B. Pharmacy First Year Result – B Pharma 1st year Results – Download Latest

B. Pharmacy First Year Results Download

  1. Pharmacy first year exams were held all over the country in various states. The exam was held in various centers of the state in the month of March this year. Bachelor of Pharmacy is one of the most studied courses of present time.  It is an undergraduate academic degree that is given in the field of pharmacy.  The degree from B. Pharmacy is a prerequisite for registration to practice as a pharmacist in various parts of the country.  It will allow the candidates to perform researches and to invent new drugs.

The Bachelor of Pharmacy degree is called a B. Pharmacy in India.  It is a three year degree that is studied semester wise.  Candidates need to pass in the intermediate with at least 50% marks.  Candidates need to give entrance examination in order to get a seat in B. Pharmacy degree.  They need to take the entrance exam and once they are qualified they will be allotted with seats in B. Pharmacy colleges of the respective state.  Different states of the country will have different schedules and syllabus for B. Pharmacy.  The institutes in various states will hold B. Pharmacy exams in various months.

Almost all the B. Pharmacy institutes have conducted B. Pharmacy first year exams in the month of June this year.  Now all the institutes are planning to dispense the results of the same.  It is said that the results of B. Pharmacy first year will be out soon.  The universities will dispense the results of B. Pharmacy at various times.  Pharmacy Council of India (PCI) or All Indian Council of Technical Education (AICTE) is the authoritative body that is responsible to govern the Pharmacy exams in the entire country.

B. Pharmacy first year Syllabus

Universities conducting B. Pharmacy 1st yr examinations & Result

There are various universities and colleges that provide B. Pharmacy education to the students.  Few named universities that offer B. Pharmacy course to the students include Faculty of Pharmacy, Hamdard University, Gyani Inder Singh Institute of Professional Studies, Dehradun, Nims Institute of Pharmacy, Nims College of Pharmacy, ISF College of Pharmacy, Dr. Hari Singh Gour Central University, Alwar Pharmacy college, Bihar College of Pharmacy, Birla Institute of Technology and Science, Nirma Institute of Pharmacy, Madurai Medical College, Bharti Institute of Pharmaceutical Sciences, Delhi Institute of Pharmaceutical Sciences and Research, Shri Baba Mast Nath Institute of Pharmaceutical Sciences and Research, Banaras Hindu University, SGRR Institute of Pharmacy, Madras Medical College, Nalanda College of Pharmacy, Noida Institute of Engg and Technology, Gyan Vihar School of Pharmacy, Srinivas College of Pharmacy, Indira College of Pharmacy, Alard College of Pharmacy etc.

  1. Pharmacy First Year Result

The results of B. Pharmacy first year are going to be released soon by all the universities.  As there are many universities and colleges all around the country, they will release their respective B. Pharmacy first year results on specific dates decided by the respective universities.  Like every year this year too scores of students have enrolled under the universities and colleges to take the B. Pharmacy exam.  Now all the students are waiting to know their results.  All the universities will be dispensing the results of B. Pharmacy first year soon or later.  One by one the universities will announce the results date and will announce the results too.  As the exams were already completed, now all the students are eager to know their results.

Students can check their results by visiting the official sites of respective colleges and universities.  The official sites of the exam conducting authorities will be uploaded with the results date and time.  Soon there will be an announcement about the results release date by the board.  Candidates are advised to follow up with the official pages of the examination conducting bodies to know the latest information.  Students of Pharmacy can also follow up with our page to know more updates from the colleges and universities.  We will update all the latest updates about Pharmacy results from all universities and colleges in our page.  You can check your results online subject wise from the official site.  Candidates can check their results online by visiting the official sites of respective universities and colleges.  Students can also check their results from other sites that provide results like manabadi.com, school9.com etc.

B. Pharmacy first year Books list

B. Pharmacy First Year Result - B Pharma 1st year Results - Download

How to check B. Pharmacy first year results?

  • Go to the official site of your respective college or university or manabadi.com or schools9.com.
  • Click on the B. Pharmacy First Year results link and enter your particulars.
  • After entering the details press on submit button.
  • Your result will be displayed on the screen with subject wise marks.
  • Save your result for future use.
  • B. Pharmacy First Year Result - B Pharma 1st year Results - Latest

Top 6 Pharmacy Institutes (COLLEGES) in India Bangalore Delhi Pune Mumbai – Pharmaceutical Universities

Top 6 Pharmacy Institutes (COLLEGES) in India Bangalore Delhi Pune Mumbai - Pharmaceutical Universities

Top Pharmacy Institutes in India.

In today’s articles, I am going to tell you about the top 6 institutes in India that are specialised in Pharmacy.

The top 6 Pharma Colleges:

Best Pharmacy College in Bangalore Karnataka:

  • Manipal College of Pharmaceutical Sciences, Manipal, and Karnataka: It was established in the year 1963. It aims at providing value based pharmaceutical education to meet the needs of the industry, hospital and community in order to improve the infrastructure and facility for learning, practice and research. It offers DPharm. , BPharm. , MPharm. , PharmD. , Post Baccalaureate and Ph. D programmes. The facilities that it provides are library, laboratories, classrooms, lecture hall, Computer Center, seminar hall, sports & games. The college provides various courses that include Bachelor of Pharmacy, Doctor of Pharmacy, Bachelor of Pharmacy, Master of Pharmacy and Diploma in Pharmacy. Its main moto is to excellent in this field and to provide a good environment to its staff and students.

Good Pharmacy College in Chandigarh:

  • University Institute of Pharmaceutical Sciences (UIPS), Chandigarh: This was established in the year 1994 as it was a department earlier and now it has turned out into an institute. It is also collaborating with other different institutions, both at the national and international level in order to provide good teaching. It gives us a progressive environment and aims for professional excellence. The facilities that it provides include library, laboratories, class rooms, internet, sports and also guarantees placements to all the students. The courses that it offers are Bachelor of Pharmacy, Master of Pharmacy and Doctor of Philosophy in Pharmacy.

Top Pharmaceutical Sciences College in New Delhi:

  • Jamai Hamdard, New Delhi: It is located in New Delhi, established in 1989, and has also been awarded ‘A’ grade by the national Assessment and Accreditation Council of India. The university offers many graduate programmes in the field of Modern Medicine and other post graduation programmes as well. The faculties include, Pharmacy, Management studies and Information Technology, Medicine, Nursing, Islamic studies and social sciences, and Science that further includes Biotechnology, Biochemistry, Botany, Toxicology, Chemistry and Clinical Research. The university also provides the activities that are required for placements and many companies visit the companies that include HCL technologies, Infosys Lupin, Biocon, Quark, Headstrong, Cisco and many more.

Best Pharma College in Pune:

  • Poona College of Pharmacy, Pune, Maharashtra: It was established in the year 1981 and is affiliated to University of Pune, Pune. It provides a variety of teaching and learning techniques which gives good skills and knowledge to the students in various sections and departments. It provides facilities that include library, laboratories, hostels, medical facilities, canteen, placements, sports, games and gymnasium. It offers many courses like Advance Diploma in Technical and Analytical Chemistry, Bachelor of Pharmacy and Master of Pharmacy. It has also constituted a placement cell that guides and helps students for the training and placement. The institute is well quipped and has a very spacious library with LCD projector facilities as well.
  • Institute of Pharmacy, Nirmal University, Ahmadabad: It was established 2003 and provides many graduation and post graduation courses. It aims at providing excellence in pharmaceutical education and providing knowledge in such a way to young men and women that they can go through all the challenges in this field. It focuses on the overall development of the candidates; it not only provides good professionals but also help the candidates in their progress. It provides facilities that include library, laboratories, class rooms, internet, animal house, canteen, hostel, bank, sports and transportation. It offers various courses like Bachelor of Pharmacy, Master of Pharmacy in Pharmaceutical Analysis, Master of Pharmacy in Pharmaceutical Technology and Bio-Pharmaceutics, Master of Pharmacy in Regulatory Affairs and Quality Assurance and Master of Pharmacy in Pharmacology.
  • Top 6 Pharmacy Institutes (COLLEGES) in India Bangalore Delhi Pune Mumbai - Pharmaceutical Universities

Top Pharmacy College in Mumbai Maharastra:

  • Bombay College of Pharmacy, Mumbai: It was established in the year 1957 and comes on the 6th It was founded by the Indian Pharmaceutical Association, Maharashtra State Branch with financial assistance from Government of Maharashtra and other several cooperation’s. Its mission is to educate and provide training to students in such a way that it results in improvement of health in the society. It provides facilities that include library, laboratories, class rooms, internet and sports. It offers two courses which are Master in Pharmacy and Bachelor in Pharmacy.
  • Top 6 Pharmacy Institutes (COLLEGES) in India Bangalore Delhi Pune Mumbai – Pharmaceutical Universities Top Pharmacy Institutes in India

Thus, we see the top 6 institutes in the field of Pharmacy we mean Top 6 Pharmacy Institutes (COLLEGES) in India Bangalore Delhi Pune Mumbai – Pharmaceutical Universities.

 

[PPT PDF] Pharmaceutical Water System Validation – IDENTIFICATION OF MICROORGANISMS

[PPT PDF] Pharmaceutical Water System Validation - IDENTIFICATION OF MICROORGANISMS

IDENTIFICATION OF MICROORGANISMS – Pharmaceutical Water System Validation

Identifying the isolates recovered from water monitoring methods may be important in instances where specific waterborne microorganisms may be detrimental to the products or processes in which the water is used. Microorganism information such as this may also be useful when identifying the source of microbial contamination in a product or process. Often a limited group of microorganisms is routinely recovered from a water system. After repeated recovery and characterization, an experienced microbiologist may become proficient at their identification based on only a few recognizable traits such as colonial morphology and staining characteristics. This may allow for a reduction in the number of identifications to representative colony types, or, with proper analyst qualification, may even allow testing short cuts to be taken for these microbial identifications.

ALERT AND ACTION LEVELS AND SPECIFICATIONS

Though the use of alert and action levels is most often associated with microbial data, they can be associated with any attribute. In pharmaceutical water systems, almost every quality attribute, other than microbial quality, can be very rapidly determined with near-real time results. These short-delay data can give immediate system performance feedback, serving as ongoing process control indicators. However, because some attributes may not continuously be monitored or have a long delay in data availability (like microbial monitoring data), properly established Alert and Action Levels can serve as an early warning or indication of a potentially approaching quality shift occurring between or at the next periodic monitoring. In a validated water system, process controls should yield relatively constant and more than adequate values for these monitored attributes such that their Alert and Action Levels are infrequently broached.

As process control indicators, alert and action levels are designed to allow remedial action to occur that will prevent a system from deviating completely out of control and producing water unfit for its intended use. This “intended use” minimum quality is sometimes referred to as a “specification” or “limit”. In the opening paragraphs of this chapter, rationale was presented for no microbial specifications being included within the body of the bulk water (Purified Water and Water for Injection) monographs. This does not mean that the user should not have microbial specifications for these waters. To the contrary, in most situations such specifications should be established by the user. The microbial specification should reflect the maximum microbial level at which the water is still fit for use without compromising the quality needs of the process or product where the water is used. Because water from a given system may have many uses, the most stringent of these uses should be used to establish this specification.

Where appropriate, a microbial specification could be qualitative as well as quantitative. In other words, the number of total microorganisms may be as important as the number of a specific microorganism or even the absence of a specific microorganism. Microorganisms that are known to be problematic could include opportunistic or overt pathogens, nonpathogenic indicators of potentially undetected pathogens, or microorganisms known to compromise a process or product, such as by being resistant to a preservative or able to proliferate in or degrade a product. These microorganisms comprise an often ill-defined group referred to as “objectionable microorganisms”. Because objectionable is a term relative to the water’s use, the list of microorganisms in such a group should be tailored to those species with the potential to be present and problematic. Their negative impact is most often demonstrated when they are present in high numbers, but depending on the species, an allowable level may exist, below which they may not be considered objectionable.

[PPT PDF] Pharmaceutical Water System Validation – IDENTIFICATION OF MICROORGANISMS IDENTIFICATION OF MICROORGANISMS – Pharmaceutical warer system ppt [PPT PDF] Pharmaceutical Water System Validation - IDENTIFICATION OF MICROORGANISMS

As stated above, alert and action levels for a given process control attribute are used to help maintain system control and avoid exceeding the pass/fail specification for that attribute. Alert and action levels may be both quantitative and qualitative. They may involve levels of total microbial counts or recoveries of specific microorganisms. Alert levels are events or levels that, when they occur or are exceeded, indicate that a process may have drifted from its normal operating condition. Alert level excursions constitute a warning and do not necessarily require a corrective action. However, alert level excursions usually lead to the alerting of personnel involved in water system operation as well as QA. Alert level excursions may also lead to additional monitoring with more intense scrutiny of resulting and neighboring data as well as other process indicators. Action levels are events or higher levels that, when they occur or are exceeded, indicate that a process is probably drifting from its normal operating range. Examples of kinds of action level “events” include exceeding alert levels repeatedly; or in multiple simultaneous locations, a single occurrence of exceeding a higher microbial level; or the individual or repeated recovery of specific objectionable microorganisms. Exceeding an action level should lead to immediate notification of both QA and personnel involved in water system operations so that corrective actions can immediately be taken to bring the process back into its normal operating range. Such remedial actions should also include efforts to understand and eliminate or at least reduce the incidence of a future occurrence. A root cause investigation may be necessary to devise an effective preventative action strategy. Depending on the nature of the action level excursion, it may also be necessary to evaluate its impact on the water uses during that time. Impact evaluations may include delineation of affected batches and additional or more extensive product testing. It may also involve experimental product challenges.

Alert and action levels should be derived from an evaluation of historic monitoring data called a trend analysis. Other guidelines on approaches that may be used, ranging from “inspectional”to statistical evaluation of the historical data have been published. The ultimate goal is to understand the normal variability of the data during what is considered a typical operational period. Then, trigger points or levels can be established that will signal when future data may be approaching (alert level) or exceeding (action level) the boundaries of that “normal variability”. Such alert and action levels are based on the control capability of the system as it was being maintained and controlled during that historic period of typical control.

In new water systems where there is very limited or no historic data from which to derive data trends, it is common to simply establish initial alert and action levels based on a combination of equipment design capabilities but below the process and product specifications where water is used. It is also common, especially for ambient water systems, to microbiologically “mature” over the first year of use. By the end of this period, a relatively steady state microbial population (microorganism types and levels) will have been allowed or promoted to develop as a result of the collective effects of routine system maintenance and operation, including the frequency of unit operation rebeddings, backwashings, regenerations, and sanitizations. This microbial population will typically be higher than was seen when the water system was new, so it should be expected that the data trends (and the resulting alert and action levels) will increase over this “maturation” period and eventually level off.

Pharmaceutical water System

A water system should be designed so that performance-based alert and action levels are well below water specifications. With poorly designed or maintained water systems, the system owner may find that initial new system microbial levels were acceptable for the water uses and specifications, but the mature levels are not. This is a serious situation, which if not correctable with more frequent system maintenance and sanitization, may require expensive water system renovation or even replacement. Therefore, it cannot be overemphasized that water systems should be designed for ease of microbial control, so that when monitored against alert and action levels, and maintained accordingly, the water continuously meets all applicable specifications.

An action level should not be established at a level equivalent to the specification. This leaves no room for remedial system maintenance that could avoid a specification excursion. Exceeding a specification is a far more serious event than an action level excursion. A specification excursion may trigger an extensive finished product impact investigation, substantial remedial actions within the water system that may include a complete shutdown, and possibly even product rejection.

Another scenario to be avoided is the establishment of an arbitrarily high and usually nonperformance based action level. Such unrealistic action levels deprive users of meaningful indicator values that could trigger remedial system maintenance. Unrealistically high action levels allow systems to grow well out of control before action is taken, when their intent should be to catch a system imbalance before it goes wildly out of control.

Because alert and action levels should be based on actual system performance, and the system performance data are generated by a given test method, it follows that those alert and action levels should be valid only for test results generated by the same test method. It is invalid to apply alert and action level criteria to test results generated by a different test method. The two test methods may not equivalently recover microorganisms from the same water samples. Similarly invalid is the use of trend data to derive alert and action levels for one water system, but applying those alert and action levels to a different water system. Alert and action levels are water system and test method specific.

Nevertheless, there are certain maximum microbial levels above which action levels should never be established. Water systems with these levels should unarguably be considered out of control. Using the microbial enumeration methodologies suggested above, generally considered maximum action levels are 100 cfu per mL for Purified Water and 10 cfu per 100 mL for Water for Injection. However, if a given water system controls microorganisms much more tightly than these levels, appropriate alert and action levels should be established from these tighter control levels so that they can truly indicate when water systems may be starting to trend out of control. These in-process microbial control parameters should be established well below the user-defined microbial specifications that delineate the water’s fitness for use.

Special consideration is needed for establishing maximum microbial action levels for Drinking Water because the water is often delivered to the facility in a condition over which the user has little control. High microbial levels in Drinking Water may be indicative of a municipal water system upset, broken water main, or inadequate disinfection, and therefore, potential contamination with objectionable microorganisms. Using the suggested microbial enumeration methodology, a reasonable maximum action level for Drinking Water is 500 cfu per mL. Considering the potential concern for objectionable microorganisms raised by such high microbial levels in the feedwater, informing the municipality of the problem so they may begin corrective actions should be an immediate first step. In-house remedial actions may or may not also be needed, but could include performing additional coliform testing on the incoming water and pretreating the water with either additional chlorination or UV light irradiation or filtration or a combination of approaches.

Source : USP

Expert Committee : (PW05) Pharmaceutical Waters 05

USP29–NF24 Page 3056

Pharmacopeial Forum : Volume No. 30(5) Page 1744

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[PPT PDF] Pharmaceutical Water System Design Validation -UNIT OPERATIONS CONCERNS

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UNIT OPERATIONS CONCERNS

The following is a brief description of selected unit operations and the operation and validation concerns associated with them. Not all unit operations are discussed, nor are all potential problems addressed. The purpose is to highlight issues that focus on the design, installation, operation, maintenance, and monitoring parameters that facilitate water system validation.

Prefiltration

The purpose of prefiltration—also referred to as initial, coarse, or depth filtration—is to remove solid contaminants down to a size of 7 to 10 µm from the incoming source water supply and protect downstream system components from particulates that can inhibit equipment performance and shorten their effective life. This coarse filtration technology utilizes primarily sieving effects for particle capture and a depth of filtration medium that has a high “dirt load” capacity. Such filtration units are available in a wide range of designs and for various applications. Removal efficiencies and capacities differ significantly, from granular bed filters such as multimedia or sand for larger water systems, to depth cartridges for smaller water systems. Unit and system configurations vary widely in type of filtering media and location in the process. Granular or cartridge prefilters are often situated at or near the head of the water pretreatment system prior to unit operations designed to remove the source water disinfectants. This location, however, does not preclude the need for periodic microbial control because biofilm can still proliferate, although at a slower rate in the presence of source water disinfectants. Design and operational issues that may impact performance of depth filters include channeling of the filtering media, blockage from silt, microbial growth, and filtering-media loss during improper backwashing. Control measures involve pressure and flow monitoring during use and backwashing, sanitizing, and replacing filtering media. An important design concern is sizing of the filter to prevent channeling or media loss resulting from inappropriate water flow rates as well as proper sizing to minimize excessively frequent or infrequent backwashing or cartridge filter replacement.

Activated Carbon

Granular activated carbon beds adsorb low molecular weight organic material and oxidizing additives, such as chlorine and chloramine compounds, removing them from the water. They are used to achieve certain quality attributes and to protect against reaction with downstream stainless steel surfaces, resins, and membranes. The chief operating concerns regarding activated carbon beds include the propensity to support bacteria growth, the potential for hydraulic channeling, the organic adsorption capacity, appropriate water flow rates and contact time, the inability to be regenerated in situ, and the shedding of bacteria, endotoxins, organic chemicals, and fine carbon particles. Control measures may involve monitoring water flow rates and differential pressures, sanitizing with hot water or steam, backwashing, testing for adsorption capacity, and frequent replacement of the carbon bed. If the activated carbon bed is intended for organic reduction, it may also be appropriate to monitor influent and effluent TOC. It is important to note that the use of steam for carbon bed sanitization is often incompletely effective due to steam channeling rather than even permeation through the bed. This phenomenon can usually be avoided by using hot water sanitization. It is also important to note that microbial biofilm development on the surface of the granular carbon particles (as well as on other particles such as found in deionizer beds and even multimedia beds) can cause adjacent bed granules to “stick” together. When large masses of granules are agglomerated in this fashion, normal backwashing and bed fluidization flow parameters may not be sufficient to disperse them, leading to ineffective removal of trapped debris, loose biofilm, and penetration of microbial controlling conditions (as well as regenerant chemicals as in the case of agglomerated deionizer resins). Alternative technologies to activated carbon beds can be used in order to avoid their microbial problems, such as disinfectant-neutralizing chemical additives and regenerable organic scavenging devices. However, these alternatives do not function by the same mechanisms as activated carbon, may not be as effective at removing disinfectants and some organics, and have a different set of operating concerns and control measures that may be nearly as troublesome as activated carbon beds.

Additives

Chemical additives are used in water systems (a) to control microorganisms by use of sanitants such as chlorine compounds and ozone, (b) to enhance the removal of suspended solids by use of flocculating agents, (c) to remove chlorine compounds, (d) to avoid scaling on reverse osmosis membranes, and (e) to adjust pH for more effective removal of carbonate and ammonia compounds by reverse osmosis. These additives do not constitute “added substances” as long as they are either removed by subsequent processing steps or are otherwise absent from the finished water. Control of additives to ensure a continuously effective concentration and subsequent monitoring to ensure their removal should be designed into the system and included in the monitoring program.

Organic Scavengers

Organic scavenging devices use macroreticular weakly basic anion-exchange resins capable of removing organic material and endotoxins from the water. They can be regenerated with appropriate biocidal caustic brine solutions. Operating concerns are associated with organic scavenging capacity, particulate, chemical and microbiological fouling of the reactive resin surface, flow rate, regeneration frequency, and shedding of resin fragments. Control measures include TOC testing of influent and effluent, backwashing, monitoring hydraulic performance, and using downstream filters to remove resin fines.

Softeners

Water softeners may be located either upstream or downstream of disinfectant removal units. They utilize sodium-based cation-exchange resins to remove water-hardness ions, such as calcium and magnesium, that could foul or interfere with the performance of downstream processing equipment such as reverse osmosis membranes, deionization devices, and distillation units. Water softeners can also be used to remove other lower affinity cations, such as the ammonium ion, that may be released from chloramine disinfectants commonly used in drinking water and which might otherwise carryover through other downstream unit operations. If ammonium removal is one of its purposes, the softener must be located downstream of the disinfectant removal operation, which itself may liberate ammonium from neutralized chloramine disinfectants. Water softener resin beds are regenerated with concentrated sodium chloride solution (brine). Concerns include microorganism proliferation, channeling caused by biofilm agglomeration of resin particles, appropriate water flow rates and contact time, ion-exchange capacity, organic and particulate resin fouling, organic leaching from new resins, fracture of the resin beads, resin degradation by excessively chlorinated water, and contamination from the brine solution used for regeneration. Control measures involve recirculation of water during periods of low water use, periodic sanitization of the resin and brine system, use of microbial control devices (e.g., UV light and chlorine), locating the unit upstream of the disinfectant removal step (if used only for softening), appropriate regeneration frequency, effluent chemical monitoring (e.g., hardness ions and possibly ammonium), and downstream filtration to remove resin fines. If a softener is used for ammonium removal from chloramine-containing source water, then capacity, contact time, resin surface fouling, pH, and regeneration frequency are very important.

Deionization

Deionization (DI), and continuous electrodeionization (CEDI) are effective methods of improving the chemical quality attributes of water by removing cations and anions. DI systems have charged resins that require periodic regeneration with an acid and base. Typically, cationic resins are regenerated with either hydrochloric or sulfuric acid, which replace the captured positive ions with hydrogen ions. Anionic resins are regenerated with sodium or potassium hydroxide, which replace captured negative ions with hydroxide ions. Because free endotoxin is negatively charged, there is some removal of endotoxin achieved by the anionic resin. Both regenerant chemicals are biocidal and offer a measure of microbial control. The system can be designed so that the cation and anion resins are in separate or “twin” beds or they can be mixed together to form a mixed bed. Twin beds are easily regenerated but deionize water less efficiently than mixed beds, which have a considerably more complex regeneration process. Rechargeable resin canisters can also be used for this purpose.

[PPT PDF] Pharmaceutical Water System Design Validation -UNIT OPERATIONS CONCERNS

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The CEDI system uses a combination of mixed resin, selectively permeable membranes, and an electric charge, providing continuous flow (product and waste concentrate) and continuous regeneration. Water enters both the resin section and the waste (concentrate) section. As it passes through the resin, it is deionized to become product water. The resin acts as a conductor enabling the electrical potential to drive the captured cations and anions through the resin and appropriate membranes for concentration and removal in the waste water stream. The electrical potential also separates the water in the resin (product) section into hydrogen and hydroxide ions. This permits continuous regeneration of the resin without the need for regenerant additives. However, unlike conventional deionization, CEDI units must start with water that is already partially purified because they generally cannot produce Purified Waterquality when starting with the heavier ion load of unpurified source water.

Concerns for all forms of deionization units include microbial and endotoxin control, chemical additive impact on resins and membranes, and loss, degradation, and fouling of resin. Issues of concern specific to DI units include regeneration frequency and completeness, channeling, caused by biofilm agglomeration of resin particles, organic leaching from new resins, complete resin separation for mixed bed regeneration, and mixing air contamination (mixed beds). Control measures vary but typically include recirculation loops, effluent microbial control by UV light, conductivity monitoring, resin testing, microporous filtration of mixing air, microbial monitoring, frequent regeneration to minimize and control microorganism growth, sizing the equipment for suitable water flow and contact time, and use of elevated temperatures. Internal distributor and regeneration piping for mixed bed units should be configured to ensure that regeneration chemicals contact all internal bed and piping surfaces and resins. Rechargeable canisters can be the source of contamination and should be carefully monitored. Full knowledge of previous resin use, minimum storage time between regeneration and use, and appropriate sanitizing procedures are critical factors ensuring proper performance.

Reverse Osmosis

Reverse osmosis (RO) units employ semipermeable membranes. The “pores” of RO membranes are actually intersegmental spaces among the polymer molecules. They are big enough for permeation of water molecules, but too small to permit passage of hydrated chemical ions. However, many factors including pH, temperature, and differential pressure across the membrane affect the selectivity of this permeation. With the proper controls, RO membranes can achieve chemical, microbial, and endotoxin quality improvement. The process streams consist of supply water, product water (permeate), and wastewater (reject). Depending on source water, pretreatment and system configuration variations and chemical additives may be necessary to achieve desired performance and reliability.

A major factor affecting RO performance is the permeate recovery rate, that is, the amount of the water passing through the membrane compared to the amount rejected. This is influenced by the several factors, but most significantly by the pump pressure. Recoveries of 75% are typical, and can accomplish a 1 to 2 log purification of most impurities. For most feed waters, this is usually not enough to meet Purified Water conductivity specifications. A second pass of this permeate water through another RO stage usually achieves the necessary permeate purity if other factors such as pH and temperature have been appropriately adjusted and the ammonia from chloraminated source water has been previously removed. Increasing recoveries with higher pressures in order to reduce the volume of reject water will lead to reduced permeate purity. If increased pressures are needed over time to achieve the same permeate flow, this is an indication of partial membrane blockage that needs to be corrected before it becomes irreversibly fouled, and expensive membrane replacement is the only option.

Other concerns associated with the design and operation of RO units include membrane materials that are extremely sensitive to sanitizing agents and to particulate, chemical, and microbial membrane fouling; membrane and seal integrity; the passage of dissolved gases, such as carbon dioxide and ammonia; and the volume of wastewater, particularly where water discharge is tightly regulated by local authorities. Failure of membrane or seal integrity will result in product water contamination. Methods of control involve suitable pretreatment of the influent water stream, appropriate membrane material selection, integrity challenges, membrane design and heat tolerance, periodic sanitization, and monitoring of differential pressures, conductivity, microbial levels, and TOC.

The development of RO units that can tolerate sanitizing water temperatures as well as operate efficiently and continuously at elevated temperatures has added greatly to their microbial control and to the avoidance of biofouling. RO units can be used alone or in combination with DI and CEDI units as well as ultrafiltration for operational and quality enhancements.

Ultrafiltration

Ultrafiltration is a technology most often employed in pharmaceutical water systems for removing endotoxins from a water stream. It can also use semipermeable membranes, but unlike RO, these typically use polysulfone membranes whose intersegmental “pores” have been purposefully exaggerated during their manufacture by preventing the polymer molecules from reaching their smaller equilibrium proximities to each other. Depending on the level of equilibrium control during their fabrication, membranes with differing molecular weight “cutoffs” can be created such that molecules with molecular weights above these cutoffs ratings are rejected and cannot penetrate the filtration matrix.

Ceramic ultrafilters are another molecular sieving technology. Ceramic ultrafilters are self supporting and extremely durable, backwashable, chemically cleanable, and steam sterilizable. However, they may require higher operating pressures than membrane type ultrafilters.

All ultrafiltration devices work primarily by a molecular sieving principle. Ultrafilters with molecular weight cutoff ratings in the range of 10,000 to 20,000 Da are typically used in water systems for removing endotoxins. This technology may be appropriate as an intermediate or final purification step. Similar to RO, successful performance is dependent upon pretreatment of the water by upstream unit operations.

Issues of concern for ultrafilters include compatibility of membrane material with heat and sanitizing agents, membrane integrity, fouling by particles and microorganisms, and seal integrity. Control measures involve filtration medium selection, sanitization, flow design (dead end vs. tangential), integrity challenges, regular cartridge changes, elevated feed water temperature, and monitoring TOC and differential pressure. Additional flexibility in operation is possible based on the way ultrafiltration units are arranged such as in a parallel or series configurations. Care should be taken to avoid stagnant water conditions that could promote microorganism growth in back-up or standby units.

Charge-Modified Filtration

Charge-modified filters are usually microbially retentive filters that are treated during their manufacture to have a positive charge on their surfaces. Microbial retentive filtration will be described in a subsequent section, but the significant feature of these membranes is their electrostatic surface charge. Such charged filters can reduce endotoxin levels in the fluids passing through them by their adsorption (owing to endotoxin’s negative charge) onto the membrane surfaces. Though ultrafilters are more often employed as a unit operation for endotoxin removal in water systems, charge-modified filters may also have a place in endotoxin removal particularly where available upstream pressures are not sufficient for ultrafiltration and for a single, relatively short term use. Charge-modified filters may be difficult to validate for long-term or large-volume endotoxin retention. Even though their purified standard endotoxin retention can be well characterized, their retention capacity for “natural” endotoxins is difficult to gauge. Nevertheless, utility could be demonstrated and validated as short-term, single-use filters at points of use in water systems that are not designed for endotoxin control or where only an endotoxin “polishing” (removal of only slight or occasional endotoxin levels) is needed. Control and validation concerns include volume and duration of use, flow rate, water conductivity and purity, and constancy and concentration of endotoxin levels being removed. All of these factors may have to be evaluated and challenged prior to using this approach, making this a difficult-to-validate application. Even so, there may still be a possible need for additional backup endotoxin testing both upstream and downstream of the filter.

Microbial-Retentive Filtration

Microbial-retentive membrane filters have experienced an evolution of understanding in the past decade that has caused previously held theoretical retention mechanisms to be reconsidered. These filters have a larger effective “pore size” than ultrafilters and are intended to prevent the passage of microorganisms and similarly sized particles without unduly restricting flow. This type of filtration is widely employed within water systems for filtering the bacteria out of both water and compressed gases as well as for vent filters on tanks and stills and other unit operations. However, the properties of the water system microorganisms seem to challenge a filter’s microbial retention from water with phenomena absent from other aseptic filtration applications, such as filter sterilizing of pharmaceutical formulations prior to packaging. In the latter application, sterilizing grade filters are generally considered to have an assigned rating of 0.2 or 0.22 µm. This rather arbitrary rating is associated with filters that have the ability to retain a high level challenge of a specially prepared inoculum of Brevundimonas (formerly Pseudomonas) diminuta.This is a small microorganism originally isolated decades ago from a product that had been “filter sterilized” using a 0.45-µm rated filter. Further study revealed that a percentage of cells of this microorganism could reproducibly penetrate the 0.45-µm sterilizing filters. Through historic correlation of B. diminuta retaining tighter filters, thought to be twice as good as 0.45-µm filter, assigned ratings of 0.2 or 0.22 µm with their successful use in product solution filter sterilization, both this filter rating and the associated high level B. diminuta challenge have become the current benchmarks for sterilizing filtration. New evidence now suggests that for microbial-retentive filters used for pharmaceutical water, B. diminuta may not be the best model microorganism.

An archaic understanding of microbial retentive filtration would lead one to equate a filter’s rating with the false impression of a simple sieve or screen that absolutely retains particles sized at or above the filter’s rating. A current understanding of the mechanisms involved in microbial retention and the variables that can affect those mechanisms has yielded a far more complex interaction of phenomena than previously understood. A combination of simple sieve retention and surface adsorption are now known to contribute to microbial retention.

The following all interact to create some unusual and surprising retention phenomena for water system microorganisms: the variability in the range and average pore sizes created by the various membrane fabrication processes, the variability of the surface chemistry and three-dimensional structure related to the different polymers used in these filter matrices, and the size and surface properties of the microorganism intended to be retained by the filters. B. diminuta may not the best challenge microorganisms for demonstrating bacterial retention for 0.2- to 0.22-µm rated filters for use in water systems because it appears to be more easily retained by these filters than some water system flora. The well-documented appearance of water system microorganisms on the downstream sides of some 0.2- to 0.22-µm rated filters after a relatively short period of use seems to support that some penetration phenomena are at work. Unknown for certain is if this downstream appearance is caused by a “blow-through” or some other pass-through phenomenon as a result of tiny cells or less cell “stickiness”, or by a “growth through” phenomenon as a result of cells hypothetically replicating their way through the pores to the downstream side. Whatever is the penetration mechanism, 0.2- to 0.22-µm rated membranes may not be the best choice for some water system uses.

Microbial retention success in water systems has been reported with the use of some manufacturers’ filters arbitrarily rated as 0.1 µm. There is general agreement that for a given manufacturer, their 0.1-µm rated filters are tighter than their 0.2- to 0.22-µm rated filters. However, comparably rated filters from different manufacturers in water filtration applications may not perform equivalently owing to the different filter fabrication processes and the nonstandardized microbial retention challenge processes currently used for defining the 0.1-µm filter rating. It should be noted that use of 0.1-µm rated membranes generally results in a sacrifice in flow rate compared to 0.2- to 0.22-µm membranes, so whatever membranes are chosen for a water system appliAcation, the user must verify that the membranes are suitable for their intended application, use period, and use process, including flow rate.

For microbial retentive gas filtrations, the same sieving and adsorptive retention phenomena are at work as in liquid filtration, but the adsorptive phenomenon is enhanced by additional electrostatic interactions between particles and filter matrix. These electrostatic interactions are so strong that particle retention for a given filter rating is significantly more efficient in gas filtration than in water or product solution filtrations. These additional adsorptive interactions render filters rated at 0.2 to 0.22 µm unquestionably suitable for microbial retentive gas filtrations. When microbially retentive filters are used in these applications, the membrane surface is typically hydrophobic (non-wettable by water). A significant area of concern for gas filtration is blockage of tank vents by condensed water vapor, which can cause mechanical damage to the tank. Control measures include electrical or steam tracing and a self-draining orientation of vent filter housings to prevent accumulation of vapor condensate. However, a continuously high filter temperature will take an oxidative toll on polypropylene components of the filter, so sterilization of the unit prior to initial use, and periodically thereafter, as well as regular visual inspections, integrity tests, and changes are recommended control methods.

In water applications, microbial retentive filters may be used downstream of unit operations that tend to release microorganisms or upstream of unit operations that are sensitive to microorganisms. Microbial retentive filters may also be used to filter water feeding the distribution system. It should be noted that regulatory authorities allow the use of microbial retentive filters within distribution systems or even at use points if they have been properly validated and are appropriately maintained. A point-of-use filter should only be intended to “polish” the microbial quality of an otherwise well-maintained system and not to serve as the primary microbial control device. The efficacy of system microbial control measures can only be assessed by sampling the water upstream of the filters. As an added measure of protection, in-line UV lamps, appropriately sized for the flow rate (see Sanitization), may be used just upstream of microbial retentive filters to inactivate microorganisms prior to their capture by the filter. This tandem approach tends to greatly delay potential microbial penetration phenomena and can substantially extend filter service life.

Ultraviolet Light

The use of low-pressure UV lights that emit a 254-nm wavelength for microbial control is discussed under Sanitization, but the application of UV light in chemical purification is also emerging. This 254-nm wavelength is also useful in the destruction of ozone. With intense emissions at wavelengths around 185 nm (as well as at 254 nm), medium pressure UV lights have demonstrated utility in the destruction of the chlorine containing disinfectants used in source water as well as for interim stages of water pretreatment. High intensities of this wavelength alone or in combination with other oxidizing sanitants, such as hydrogen peroxide, have been used to lower TOC levels in recirculating distribution systems. The organics are typically converted to carbon dioxide, which equilibrates to bicarbonate, and incompletely oxidized carboxylic acids, both of which can easily be removed by polishing ion-exchange resins. Areas of concern include adequate UV intensity and residence time, gradual loss of UV emissivity with bulb age, gradual formation of UV-absorbing film at the water contact surface, incomplete photodegradation during unforeseen source water hyperchlorination, release of ammonia from chloramine photodegradation, unapparent UV bulb failure, and conductivity degradation in distribution systems using 185-nm UV lights. Control measures include regular inspection or emissivity alarms to detect bulb failures or film occlusions, regular UV bulb sleeve cleaning and wiping, downstream chlorine detectors, downstream polishing deionizers, and regular (approximately yearly) bulb replacement.

Distillation

Distillation units provide chemical and microbial purification via thermal vaporization, mist elimination, and water vapor condensation. A variety of designs is available including single effect, multiple effect, and vapor compression. The latter two configurations are normally used in larger systems because of their generating capacity and efficiency. Distilled water systems require different feed water controls than required by membrane systems. For distillation, due consideration must be given to prior removal of hardness and silica impurities that may foul or corrode the heat transfer surfaces as well as prior removal of those impurities that could volatize and condense along with the water vapor. In spite of general perceptions, even the best distillation process cannot afford absolute removal of contaminating ions and endotoxin. Most stills are recognized as being able to accomplish at least a 3 to 4 log reduction in these impurity concentrations. Areas of concern include carry-over of volatile organic impurities such as trihalomethanes (see Source and Feed Water Considerations) and gaseous impurities such as ammonia and carbon dioxide, faulty mist elimination, evaporator flooding, inadequate blowdown, stagnant water in condensers and evaporators, pump and compressor seal design, pinhole evaporator and condenser leaks, and conductivity (quality) variations during start-up and operation.

Methods of control may involve preliminary decarbonation steps to remove both dissolved carbon dioxide and other volatile or noncondensable impurities; reliable mist elimination to minimize feedwater droplet entrainment; visual or automated high water level indication to detect boiler flooding and boil over; use of sanitary pumps and compressors to minimize microbial and lubricant contamination of feedwater and condensate; proper drainage during inactive periods to minimize microbial growth and accumulation of associated endotoxin in boiler water; blow down control to limit the impurity concentration effect in the boiler to manageable levels; on-line conductivity sensing with automated diversion to waste to prevent unacceptable water upon still startup or still malfunction from getting into the finished water distribute system; and periodic integrity testing for pinhole leaks to routinely assure condensate is not compromised by nonvolatized source water contaminants.

Storage Tanks

Storage tanks are included in water distribution systems to optimize processing equipment capacity. Storage also allows for routine maintenance within the pretreatment train while maintaining continuous supply to meet manufacturing needs. Design and operation considerations are needed to prevent or minimize the development of biofilm, to minimize corrosion, to aid in the use of chemical sanitization of the tanks, and to safeguard mechanical integrity. These considerations may include using closed tanks with smooth interiors, the ability to spray the tank headspace using sprayballs on recirculating loop returns, and the use of heated, jacketed/insulated tanks. This minimizes corrosion and biofilm development and aids in thermal and chemical sanitization. Storage tanks require venting to compensate for the dynamics of changing water levels. This can be accomplished with a properly oriented and heat-traced filter housing fitted with a hydrophobic microbial retentive membrane filter affixed to an atmospheric vent. Alternatively, an automatic membrane-filtered compressed gas blanketing system may be used. In both cases, rupture disks equipped with a rupture alarm device should be used as a further safeguard for the mechanical integrity of the tank. Areas of concern include microbial growth or corrosion due to irregular or incomplete sanitization and microbial contamination from unalarmed rupture disk failures caused by condensate-occluded vent filters.

Distribution Systems

Distribution system configuration should allow for the continuous flow of water in the piping by means of recirculation. Use of nonrecirculating, dead-end, or one-way systems or system segments should be avoided whenever possible. If not possible, these systems should be periodically flushed and more closely monitored. Experience has shown that continuously recirculated systems are easier to maintain. Pumps should be designed to deliver fully turbulent flow conditions to facilitate thorough heat distribution (for hot water sanitized systems) as well as thorough chemical sanitant distribution. Turbulent flow also appear to either retard the development of biofilms or reduce the tendency of those biofilms to shed bacteria into the water. If redundant pumps are used, they should be configured and used to avoid microbial contamination of the system.

Components and distribution lines should be sloped and fitted with drain points so that the system can be completely drained. In stainless steel distribution systems where the water is circulated at a high temperature, dead legs and low-flow conditions should be avoided, and valved tie-in points should have length-to-diameter ratios of six or less. If constructed of heat tolerant plastic, this ratio should be even less to avoid cool points where biofilm development could occur. In ambient temperature distribution systems, particular care should be exercised to avoid or minimize dead leg ratios of any size and provide for complete drainage. If the system is intended to be steam sanitized, careful sloping and low-point drainage is crucial to condensate removal and sanitization success. If drainage of components or distribution lines is intended as a microbial control strategy, they should also be configured to be completely dried using dry compressed air (or nitrogen if appropriate employee safety measures are used). Drained but still moist surfaces will still support microbial proliferation. Water exiting from the distribution system should not be returned to the system without first passing through all or a portion of the purification train.

The distribution design should include the placement of sampling valves in the storage tank and at other locations, such as in the return line of the recirculating water system. Where feasible, the primary sampling sites for water should be the valves that deliver water to the points of use. Direct connections to processes or auxiliary equipment should be designed to prevent reverse flow into the controlled water system. Hoses and heat exchangers that are attached to points of use in order to deliver water for a particular use must not chemically or microbiologically degrade the water quality. The distribution system should permit sanitization for microorganism control. The system may be continuously operated at sanitizing conditions or sanitized periodically.

Source : USP

Expert Committee : (PW05) Pharmaceutical Waters 05

USP29–NF24 Page 3056

Pharmacopeial Forum : Volume No. 30(5) Page 1744

Pharmaceutical Water System Ppt,

Pharmaceutical Water Systems,

Purified Water Specification As Per Usp,

Pharmaceutical Water System Design Operation And Validation Pdf,

pharmaceutical water system design operation and validation,

pharmaceutical water system ppt – What is Pharmaceutical water,

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Pharmaceutical Water Systems: Storage & Distribution Systems,

pharmaceutical water system : Inspection of Pharmaceutical water systems,

pharmaceutical water Production : Water purification systems,

Pharmaceutical Water Systems: Types: Water quality specifications,

Pharmaceutical Water System: principles for pharmaceutical water systems

[PPT PDF] Pharmaceutical Water System Design Validation -SAMPLING CONSIDERATIONS

[PPT PDF] Pharmaceutical Water System Design Validation -SAMPLING CONSIDERATIONS

Pharmaceutical Water System- SAMPLING CONSIDERATIONS

Water systems should be monitored at a frequency that is sufficient to ensure that the system is in control and continues to produce water of acceptable quality. Samples should be taken from representative locations within the processing and distribution system. Established sampling frequencies should be based on system validation data and should cover critical areas including unit operation sites. The sampling plan should take into consideration the desired attributes of the water being sampled. For example, systems for Water for Injection because of their more critical microbiological requirements, may require a more rigorous sampling frequency.

Analyses of water samples often serve two purposes: in-process control assessments and final quality control assessments. In-process control analyses are usually focused on the attributes of the water within the system. Quality control is primarily concerned with the attributes of the water delivered by the system to its various uses. The latter usually employs some sort of transfer device, often a flexible hose, to bridge the gap between the distribution system use-point valve and the actual location of water use. The issue of sample collection location and sampling procedure is often hotly debated because of the typically mixed use of the data generated from the samples, for both in-process control and quality control. In these single sample and mixed data use situations, the worst-case scenario should be utilized. In other words, samples should be collected from use points using the same delivery devices, such as hoses, and procedures, such as preliminary hose or outlet flushing, as are employed by production from those use points. Where use points per se cannot be sampled, such as hard-piped connections to equipment, special sampling ports may be used. In all cases, the sample must represent as closely as possible the quality of the water used in production. If a point of use filter is employed, sampling of the water prior to and after the filter is needed because the filter will mask the microbial control achieved by the normal operating procedures of the system.

Samples containing chemical sanitizing agents require neutralization prior to microbiological analysis. Samples for microbiological analysis should be tested immediately, or suitably refrigerated to preserve the original microbial attributes until analysis can begin. Samples of flowing water are only indicative of the concentration of planktonic (free floating) microorganisms present in the system. Biofilm microorganisms (those attached to water system surfaces) are usually present in greater numbers and are the source of the planktonic population recovered from grab samples. Microorganisms in biofilms represent a continuous source of contamination and are difficult to directly sample and quantify. Consequently, the planktonic population is usually used as an indicator of system contamination levels and is the basis for system Alert and Action Levels. The consistent appearance of elevated planktonic levels is usually an indication of advanced biofilm development in need of remedial control. System control and sanitization are key in controlling biofilm formation and the consequent planktonic population.

Sampling for chemical analyses is also done for in-process control and for quality control purposes. However, unlike microbial analyses, chemical analyses can be and often are performed using on-line instrumentation. Such on-line testing has unequivocal in-process control purposes because it is not performed on the water delivered from the system. However, unlike microbial attributes, chemical attributes are usually not significantly degraded by hoses. Therefore, through verification testing, it may be possible to show that the chemical attributes detected by the on-line instrumentation (in-process testing) are equivalent to those detected at the ends of the use point hoses (quality control testing). This again creates a single sample and mixed data use scenario. It is far better to operate the instrumentation in a continuous mode, generating large volumes of in-process data, but only using a defined small sampling of that data for QC purposes. Examples of acceptable approaches include using highest values for a given period, highest time-weighted average for a given period (from fixed or rolling sub-periods), or values at a fixed daily time. Each approach has advantages and disadvantages relative to calculation complexity and reflection of continuous quality, so the user must decide which approach is most suitable or justifiable.

Pharmaceutical Water System-CHEMICAL CONSIDERATIONS

The chemical attributes of Purified Water and Water for Injection were specified by a series of chemistry tests for various specific and nonspecific attributes with the intent of detecting chemical species indicative of incomplete or inadequate purification. While these methods could have been considered barely adequate to control the quality of these waters, they nevertheless stood the test of time. This was partly because the operation of water systems was, and still is, based on on-line conductivity measurements and specifications generally thought to preclude the failure of these archaic chemistry attribute tests.

USP moved away from these chemical attribute tests to contemporary analytical technologies for the bulk waters Purified Water and Water for Injection. The intent was to upgrade the analytical technologies without tightening the quality requirements. The two contemporary analytical technologies employed were TOC and conductivity. The TOC test replaced the test for Oxidizable substances that primarily targeted organic contaminants. A multistaged Conductivity test which detects ionic (mostly inorganic) contaminants replaced, with the exception of the test for Heavy metals, all of the inorganic chemical tests (i.e., Ammonia, Calcium, Carbon dioxide, Chloride, Sulfate).

Pharmaceutical Water Systems: Pharmaceutical Water Storage & Distribution Systems

Replacing the heavy metals attribute was considered unnecessary because (a) the source water specifications (found in the NPDWR) for individual Heavy metals were tighter than the approximate limit of detection of the Heavy metals test for USP XXII Water for Injection and Purified Water (approximately 0.1 ppm), (b) contemporary water system construction materials do not leach heavy metal contaminants, and (c) test results for this attribute have uniformly been negative—there has not been a confirmed occurrence of a singular test failure (failure of only the Heavy metals test with all other attributes passing) since the current heavy metal drinking water standards have been in place. Nevertheless, since the presence of heavy metals in Purified Water or Water for Injection could have dire consequences, its absence should at least be documented during new water system commissioning and validation or through prior test results records.

Total solids and pH are the only tests not covered by conductivity testing. The test for Total solids was considered redundant because the nonselective tests of conductivity and TOC could detect most chemical species other than silica, which could remain undetected in its colloidal form. Colloidal silica in Purified Water and Water for Injection is easily removed by most water pretreatment steps and even if present in the water, constitutes no medical or functional hazard except under extreme and rare situations. In such extreme situations, other attribute extremes are also likely to be detected. It is, however, the user’s responsibility to ensure fitness for use. If silica is a significant component in the source water, and the purification unit operations could be operated or fail and selectively allow silica to be released into the finished water (in the absence of co-contaminants detectable by conductivity), then either silica-specific or a total solids type testing should be utilized to monitor and control this rare problem.

The pH attribute was eventually recognized to be redundant to the conductivity test (which included pH as an aspect of the test and specification); therefore, pH was dropped as a separate attribute test.

The rationale used by USP to establish its conductivity specification took into consideration the conductivity contributed by the two least conductive former attributes of Chloride and Ammonia, thereby precluding their failure had those wet chemistry tests been performed. In essence, the Stage 3 conductivity specifications (see Water Conductivity  645 ) were established from the sum of the conductivities of the limit concentrations of chloride ions (from pH 5.0 to 6.2) and ammonia ions (from pH 6.3 to 7.0), plus the unavoidable contribution of other conductivity-contributing ions from water (H+ and OH–), dissolved atmospheric CO2 (as HCO3–), and an electro-balancing quantity of either Na+ of Cl–, depending on the pH-induced ionic imbalance (see Table 1). The Stage 2 conductivity specification is the lowest value on this table, 2.1 µS/cm. The Stage 1 specifications, designed primarily for on-line measurements, were derived essentially by summing the lowest values in the contributing ion columns for each of a series of tables similar to Table 1, created for each 5  increment between 0  and 100 . For example purposes, the italicized values in Table 1, the conductivity data table for 25 , were summed to yield a conservative value of 1.3 µS/cm, the Stage 1 specification for a nontemperature compensated, nonatmosphere equilibrated water sample that actual had a measured temperature of 25  to 29 . Each 5  increment table was similarly treated to yield the individual values listed in the table of Stage 1 specifications (see Water Conductivity  645 ).

As stated above, this rather radical change to utilizing a conductivity attribute as well as the inclusion of a TOC attribute allowed for on-line measurements. This was a major philosophical change and allowed major savings to be realized by industry. The TOC and conductivity tests can also be performed “off-line” in the laboratories using collected samples, though sample collection tends to introduce opportunities for adventitious contamination that can cause false high readings. The collection of on-line data is not, however, without challenges. The continuous readings tend to create voluminous amounts of data where before only a single data point was available. As stated under Sampling Considerations, continuous in-process data is excellent for understanding how a water system performs during all of its various usage and maintenance events in real time, but is too much data for QC purposes. Therefore, a justifiable fraction or averaging of the data can be used that is still representative of the overall water quality being used.

Packaged waters present a particular dilemma relative to the attributes of conductivity and TOC. The package itself is the source of chemicals (inorganics and organics) that leach over time into the water and can easily be detected. The irony of organic leaching from plastic packaging is that when the Oxidizable substances test was the only “organic contaminant” test for both bulk and packaged waters, that test’s insensitivity to those organic leachables rendered their presence in packaged water at high concentrations (many times the TOC specification for bulk water) virtually undetectable. Similarly, glass containers can also leach inorganics, such as sodium, which are easily detected by conductivity, but are undetected by the wet chemistry tests for water (other than pH or Total solids). Most of these leachables are considered harmless by current perceptions and standards at the rather significant concentrations present. Nevertheless, they effectively degrade the quality of the high-purity waters placed into these packaging system. Some packaging materials contain more leachables than others and may not be as suitable for holding water and maintaining its purity.

The attributes of conductivity and TOC tend to reveal more about the packaging leachables than they do about the water’s original purity. These “allowed” leachables could render the packaged versions of originally equivalent bulk water essentially unsuitable for many uses where the bulk waters are perfectly adequate.

[PPT PDF] Pharmaceutical Water System Design Validation -SAMPLING CONSIDERATIONS pdf [PPT PDF] Pharmaceutical Water System Design Validation -SAMPLING CONSIDERATIONS

Pharmaceutical Water System-MICROBIAL CONSIDERATIONS

The major exogenous source of microbial contamination of bulk pharmaceutical water is source or feed water. Feed water quality must, at a minimum, meet the quality attributes of Drinking Water for which the level of coliforms are regulated. A wide variety of other microorganisms, chiefly Gram-negative bacteria, may be present in the incoming water. These microorganisms may compromise subsequent purification steps. Examples of other potential exogenous sources of microbial contamination include unprotected vents, faulty air filters, ruptured rupture disks, backflow from contaminated outlets, unsanitized distribution system “openings” including routine component replacements, inspections, repairs, and expansions, inadequate drain and air-breaks, and replacement activated carbon, deionizer resins, and regenerant chemicals. In these situations, the exogenous contaminants may not be normal aquatic bacteria but rather microorganisms of soil or even human origin. The detection of nonaquatic microorganisms may be an indication of a system component failure, which should trigger investigations that will remediate their source. Sufficient care should be given to system design and maintenance in order to minimize microbial contamination from these exogenous sources.

Unit operations can be a major source of endogenous microbial contamination. Microorganisms present in feed water may adsorb to carbon bed, deionizer resins, filter membranes, and other unit operation surfaces and initiate the formation of a biofilm. In a high-purity water system, biofilm is an adaptive response by certain microorganisms to survive in this low nutrient environment. Downstream colonization can occur when microorganisms are shed from existing biofilm-colonized surfaces and carried to other areas of the water system. Microorganisms may also attach to suspended particles such as carbon bed fines or fractured resin particles. When the microorganisms become planktonic, they serve as a source of contamination to subsequent purification equipment (compromising its functionality) and to distribution systems.

Another source of endogenous microbial contamination is the distribution system itself. Microorganisms can colonize pipe surfaces, rough welds, badly aligned flanges, valves, and unidentified dead legs, where they proliferate, forming a biofilm. The smoothness and composition of the surface may affect the rate of initial microbial adsorption, but once adsorbed, biofilm development, unless otherwise inhibited by sanitizing conditions, will occur regardless of the surface. Once formed, the biofilm becomes a continuous source of microbial contamination.

[PPT PDF] Pharmaceutical Water System Design Validation -SAMPLING CONSIDERATIONS

ENDOTOXIN CONSIDERATIONS

Endotoxins are lipopolysaccharides found in and shed from the cell envelope that is external to the cell wall of Gram-negative bacteria. Gram-negative bacteria that form biofilms can become a source of endotoxins in pharmaceutical waters. Endotoxins may occur as clusters of lipopolysaccharide molecules associated with living microorganisms, fragments of dead microorganisms or the polysaccharide slime surrounding biofilm bacteria, or as free molecules. The free form of endotoxins may be released from cell surfaces of the bacteria that colonize the water system, or from the feed water that may enter the water system. Because of the multiplicity of endotoxin sources in a water system, endotoxin quantitation in a water system is not a good indicator of the level of biofilm abundance within a water system.

Pharmaceutical Water System Design Validation – Microbial Testing of Water

Endotoxin levels may be minimized by controlling the introduction of free endotoxins and microorganisms in the feed water and minimizing microbial proliferation in the system. This may be accomplished through the normal exclusion or removal action afforded by various unit operations within the treatment system as well as through system sanitization. Other control methods include the use of ultrafilters or charge-modified filters, either in-line or at the point of use. The presence of endotoxins may be monitored as described in the general test chapter Bacterial Endotoxins Test  85 .

MICROBIAL ENUMERATION CONSIDERATIONS

The objective of a water system microbiological monitoring program is to provide sufficient information to control and assess the microbiological quality of the water produced. Product quality requirements should dictate water quality specifications. An appropriate level of control may be maintained by using data trending techniques and, if necessary, limiting specific contraindicated microorganisms. Consequently, it may not be necessary to detect all of the microorganisms species present in a given sample. The monitoring program and methodology should indicate adverse trends and detect microorganisms that are potentially harmful to the finished product, process, or consumer. Final selection of method variables should be based on the individual requirements of the system being monitored.

It should be recognized that there is no single method that is capable of detecting all of the potential microbial contaminants of a water system. The methods used for microbial monitoring should be capable of isolating the numbers and types of organisms that have been deemed significant relative to in-process system control and product impact for each individual system. Several criteria should be considered when selecting a method to monitor the microbial content of a pharmaceutical water system. These include method sensitivity, range of organisms types or species recovered, sample processing throughput, incubation period, cost, and methodological complexity. An alternative consideration to the use of the classical “culture” approaches is a sophisticated instrumental or rapid test method that may yield more timely results. However, care must be exercised in selecting such an alternative approach to ensure that it has both sensitivity and correlation to classical culture approaches, which are generally considered the accepted standards for microbial enumeration.

Pharmaceutical Water System Design Operation & Validation

Consideration should also be given to the timeliness of microbial enumeration testing after sample collection. The number of detectable planktonic bacteria in a sample collected in a scrupulously clean sample container will usually drop as time passes. The planktonic bacteria within the sample will tend to either die or to irretrievably adsorb to the container walls reducing the number of viable planktonic bacteria that can be withdrawn from the sample for testing. The opposite effect can also occur if the sample container is not scrupulously clean and contains a low concentration of some microbial nutrient that could promote microbial growth within the sample container. Because the number of recoverable bacteria in a sample can change positively or negatively over time after sample collection, it is best to test the samples as soon as possible after being collected. If it is not possible to test the sample within about 2 hours of collection, the sample should be held at refrigerated temperatures (2  to 8 ) for a maximum of about 12 hours to maintain the microbial attributes until analysis. In situations where even this is not possible (such as when using off-site contract laboratories), testing of these refrigerated samples should be performed within 48 hours after sample collection. In the delayed testing scenario, the recovered microbial levels may not be the same as would have been recovered had the testing been performed shortly after sample collection. Therefore, studies should be performed to determine the existence and acceptability of potential microbial enumeration aberrations caused by protracted testing delays.

Source : USP

Expert Committee : (PW05) Pharmaceutical Waters 05

USP29–NF24 Page 3056

Pharmacopeial Forum : Volume No. 30(5) Page 1744

Pharmaceutical Water System Ppt,

Pharmaceutical Water Systems,

Purified Water Specification As Per Usp,

Pharmaceutical Water System Design Operation And Validation Pdf,

pharmaceutical water system design operation and validation,

pharmaceutical water system ppt – What is Pharmaceutical water,

purified water & Water for Injection SOP as per usp,

Pharmaceutical Water Systems: Storage & Distribution Systems,

pharmaceutical water system : Inspection of Pharmaceutical water systems,

pharmaceutical water Production : Water purification systems,

Pharmaceutical Water Systems: Types: Water quality specifications,

Pharmaceutical Water System: principles for pharmaceutical water systems

[PPT PDF] Pharmaceutical Water System Design Validation – Microbial Testing of Water

[PPT PDF] Pharmaceutical Water System Design Validation - Microbial Testing of Water

[PPT PDF] Pharmaceutical Water System Design Validation – Microbial Testing of Water is discussed in detail in this article. 

Pharmaceutical Water System: Classical Culture Approach  for microbial testing of water

Classical culture approaches for microbial testing of water include but are not limited to pour plates, spread plates, membrane filtration, and most probable number (MPN) tests. These methods are generally easy to perform, are less expensive, and provide excellent sample processing throughput. Method sensitivity can be increased via the use of larger sample sizes. This strategy is used in the membrane filtration method. Culture approaches are further defined by the type of medium used in combination with the incubation temperature and duration. This combination should be selected according to the monitoring needs presented by a specific water system as well as its ability to recover the microorganisms of interest: those that could have a detrimental effect on the product or process uses as well as those that reflect the microbial control status of the system.

There are two basic forms of media available for traditional microbiological analysis: “high nutrient” and “low nutrient”. High-nutrient media such as plate count agar (TGYA) and m-HPC agar (formerly m-SPC agar), are intended as general media for the isolation and enumeration of heterotrophic or “copiotrophic” bacteria. Low-nutrient media such as R2A agar and NWRI agar (HPCA), may be beneficial for isolating slow growing “oligotrophic” bacteria and bacteria that require lower levels of nutrients to grow optimally. Often some facultative oligotrophic bacteria are able to grow on high nutrient media and some facultative copiotrophic bacteria are able to grow on low-nutrient media, but this overlap is not complete. Low-nutrient and high-nutrient cultural approaches may be concurrently used, especially during the validation of a water system, as well as periodically thereafter. This concurrent testing could determine if any additional numbers or types of bacteria can be preferentially recovered by one of the approaches. If so, the impact of these additional isolates on system control and the end uses of the water could be assessed. Also, the efficacy of system controls and sanitization on these additional isolates could be assessed.

Duration and temperature of incubation are also critical aspects of a microbiological test method. Classical methodologies using high nutrient media are typically incubated at 30  to 35  for 48 to 72 hours. Because of the flora in certain water systems, incubation at lower temperatures (e.g., 20  to 25 ) for longer periods (e.g., 5 to 7 days) can recover higher microbial counts when compared to classical methods. Low-nutrient media are designed for these lower temperature and longer incubation conditions (sometimes as long as 14 days to maximize recovery of very slow growing oligotrophs or sanitant injured microorganisms), but even high-nutrient media can sometimes increase their recovery with these longer and cooler incubation conditions. Whether or not a particular system needs to be monitored using high- or low-nutrient media with higher or lower incubation temperatures or shorter or longer incubation times should be determined during or prior to system validation and periodically reassessed as the microbial flora of a new water system gradually establish a steady state relative to its routine maintenance and sanitization procedures. The establishment of a “steady state” can take months or even years and can be perturbed by a change in use patterns, a change in routine and preventative maintenance or sanitization procedures, and frequencies, or any type of system intrusion, such as for component replacement, removal, or addition. The decision to use longer incubation periods should be made after balancing the need for timely information and the type of corrective actions required when an alert or action level is exceeded with the ability to recover the microorganisms of interest.

The advantages gained by incubating for longer times, namely recovery of injured microorganisms, slow growers, or more fastidious microorganisms, should be balanced against the need to have a timely investigation and to take corrective action, as well as the ability of these microorganisms to detrimentally affect products or processes. In no case, however, should incubation at 30  to 35  be less than 48 hours or less than 96 hours at 20  to 25 .

Normally, the microorganisms that can thrive in extreme environments are best cultivated in the laboratory using conditions simulating the extreme environments from which they were taken. Therefore, thermophilic bacteria might be able to exist in the extreme environment of hot pharmaceutical water systems, and if so, could only be recovered and cultivated in the laboratory if similar thermal conditions were provided. Thermophilic aquatic microorganisms do exist in nature, but they typically derive their energy for growth from harnessing the energy from sunlight, from oxidation/reduction reactions of elements such as sulfur or iron, or indirectly from other microorganisms that do derive their energy from these processes. Such chemical/nutritional conditions do not exist in high purity water systems, whether ambient or hot. Therefore, it is generally considered pointless to search for thermophiles from hot pharmaceutical water systems owing to their inability to grow there.

[PPT PDF] Pharmaceutical Water System Design Validation – Microbial Testing of Water

The microorganisms that inhabit hot systems tend to be found in much cooler locations within these systems, for example, within use-point heat exchangers or transfer hoses. If this occurs, the kinds of microorganisms recovered are usually of the same types that might be expected from ambient water systems. Therefore, the mesophilic microbial cultivation conditions described later in this chapter are usually adequate for their recovery.

“Instrumental” Approaches  for microbial testing of water : Pharmaceutical Water System

Examples of instrumental approaches include microscopic visual counting techniques (e.g., epifluorescence and immunofluorescence) and similar automated laser scanning approaches and radiometric, impedometric, and biochemically based methodologies. These methods all possess a variety of advantages and disadvantages. Advantages could be their precision and accuracy or their speed of test result availability as compared to the classical cultural approach. In general, instrument approaches often have a shorter lead time for obtaining results, which could facilitate timely system control. This advantage, however, is often counterbalanced by limited sample processing throughput due to extended sample collection time, costly and/or labor-intensive sample processing, or other instrument and sensitivity limitations.

[PPT PDF] Pharmaceutical Water System Design Validation – Microbial Testing of Water

Furthermore, instrumental approaches are typically destructive, precluding subsequent isolate manipulation for characterization purposes. Generally, some form of microbial isolate characterization, if not full identification, may be a required element of water system monitoring. Consequently, culturing approaches have traditionally been preferred over instrumental approaches because they offer a balance of desirable test attributes and post-test capabilities.

Suggested Methodologies : Pharmaceutical Water System

The following general methods were originally derived from Standard Methods for the Examination of Water and Wastewater, 17th Edition, American Public Health Association, Washington, DC 20005. Even though this publication has undergone several revisions since its first citation in this chapter, the methods are still considered appropriate for establishing trends in the number of colony-forming units observed in the routine microbiological monitoring of pharmaceutical waters. It is recognized, however, that other combinations of media and incubation time and temperature may occasionally or even consistently result in higher numbers of colony-forming units being observed and/or different species being recovered.

[PPT PDF] Pharmaceutical Water System Design Validation - Microbial Testing of Water

The extended incubation periods that are usually required by some of the alternative methods available offer disadvantages that may outweigh the advantages of the higher counts that may be obtained. The somewhat higher baseline counts that might be observed using alternate cultural conditions would not necessarily have greater utility in detecting an excursion or a trend. In addition, some alternate cultural conditions using low-nutrient media tend to lead to the development of microbial colonies that are much less differentiated in colonial appearance, an attribute that microbiologists rely on when selecting representative microbial types for further characterization. It is also ironical that the nature of some of the slow growers and the extended incubation times needed for their development into visible colonies may also lead to those colonies being largely nonviable, which limits their further characterization and precludes their subculture and identification.

Methodologies that can be suggested as generally satisfactory for monitoring pharmaceutical water systems are as follows. However, it must be noted that these are not referee methods nor are they necessarily optimal for recovering microorganisms from all water systems. The users should determine through experimentation with various approaches which methodologies are best for monitoring their water systems for in-process control and quality control purposes as well as for recovering any contraindicated species they may have specified.

Pharmaceutical Water System: Drinking Water:

POUR PLATE METHOD OR MEMBRANE FILTRATION METHOD1

Sample Volume—1.0 mL minimum2

Growth Medium—Plate Count Agar3

Incubation Time—48 to 72 hours minimum

Incubation Temperature—30  to 35

Purified Water:

POUR PLATE OR MEMBRANE FILTRATION METHOD1

 

Sample Volume—1.0 mL minimum2

Growth Medium—Plate Count Agar3

Incubation Time—48 to 72 hours minimum

Incubation Temperature—30  to 35

 

Water for Injection:

 

MEMBRANE FILTRATION METHOD

Sample Volume—100 mL minimum2

Growth Medium—Plate Count Agar3

Incubation Time—48 to 72 hours minimum

Incubation Temperature—30 C to 35 C

1  A membrane filter with a rating of 0.45 µm is generally considered preferable even though the cellular width of some of the bacteria in the sample may be narrower than this. The efficiency of the filtration process still allows the retention of a very high percentage of these smaller cells and is adequate for this application. Filters with smaller ratings may be used if desired, but for a variety of reasons the ability of the retained cells to develop into visible colonies may be compromised, so count accuracy must be verified by a reference approach.

2  When colony counts are low to undetectable using the indicated minimum sample volume, it is generally recognized that a larger sample volume should be tested in order to gain better assurance that the resulting colony count is more statistically representative. The sample volume to consider testing is dependent on the user’s need to know (which is related to the established alert and action levels and the water system’s microbial control capabilities) and the statistical reliability of the resulting colony count. In order to test a larger sample volume, it may be necessary to change testing techniques, e.g., changing from a pour plate to a membrane filtration approach. Nevertheless, in a very low to nil count scenario, a maximum sample volume of around 250 to 300 mL is usually considered a reasonable balance of sample collecting and processing ease and increased statistical reliability. However, when sample volumes larger than about 2 mL are needed, they can only be processed using the membrane filtration method.

3  Also known as Standard Methods Agar, Standard Methods Plate Count Agar, or TGYA, this medium contains tryptone (pancreatic digest of casein), glucose and yeast extract.

Source : USP

Expert Committee : (PW05) Pharmaceutical Waters 05

USP29–NF24 Page 3056

Pharmacopeial Forum : Volume No. 30(5) Page 1744

Phone Number : 1-301-816-8353

Pharmaceutical Water System Ppt,

Pharmaceutical Water Systems,

Purified Water Specification As Per Usp,

Pharmaceutical Water System Design Operation And Validation Pdf,

pharmaceutical water system design operation and validation,

pharmaceutical water system ppt – What is Pharmaceutical water,

purified water & Water for Injection SOP as per usp,

Pharmaceutical Water Systems: Storage & Distribution Systems,

pharmaceutical water system : Inspection of Pharmaceutical water systems,

pharmaceutical water Production : Water purification systems,

Pharmaceutical Water Systems: Types: Water quality specifications,

Pharmaceutical Water System: principles for pharmaceutical water systems

Pharmaceutical Water System Design Operation & Validation Pdf PowerPoint

PPT PDF Pharmaceutical Water System Validation Pdf PowerPoint

VALIDATION AND QUALIFICATION OF WATER PURIFICATION, STORAGE, AND DISTRIBUTION SYSTEMS: Establishing the dependability of pharmaceutical water purification, storage, and distribution systems requires an appropriate period of monitoring and observation. Ordinarily, few problems are encountered in maintaining the chemical purity of Purified Water and Water for Injection Nevertheless, the advent of using conductivity and TOC to define chemical purity has allowed the user to more quantitatively assess the water’s chemical purity and its variability as a function of routine pretreatment system maintenance and regeneration. Even the presence of such unit operations as heat exchangers and use point hoses can compromise the chemical quality of water within and delivered from an otherwise well-controlled water system. Therefore, an assessment of the consistency of the water’s chemical purity over time must be part of the validation program. However, even with the most well controlled chemical quality, it is often more difficult to consistently meet established microbiological quality criteria owing to phenomena occurring during and after chemical purification. A typical program involves intensive daily sampling and testing of major process points for at least one month after operational criteria have been established for each unit operation, point of use, and sampling point.

VALIDATION AND QUALIFICATION OF WATER PURIFICATION, STORAGE, AND DISTRIBUTION SYSTEMS

An overlooked aspect of water system validation is the delivery of the water to its actual location of use. If this transfer process from the distribution system outlets to the water use locations (usually with hoses) is defined as outside the water system, then this transfer process still needs to be validated to not adversely affect the quality of the water to the extent it becomes unfit for use. Because routine microbial monitoring is performed for the same transfer process and components (e.g., hoses and heat exchangers) as that of routine water use (see Sampling Considerations), there is some logic to include this water transfer process within the distribution system validation.

Validation is the process whereby substantiation to a high level of assurance that a specific process will consistently produce a product conforming to an established set of quality attributes is acquired and documented. Prior to and during the very early stages of validation, the critical process parameters and their operating ranges are established. A validation program qualifies and documents the design, installation, operation, and performance of equipment. It begins when the system is defined and moves through several stages: installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). A graphical representation of a typical water system validation life cycle is shown in Figure.

PPT PDF Pharmaceutical Water System Validation Pdf PowerPoint

Pharmaceutical Water system validation life cycle.

A validation plan for a water system typically includes the following steps: (1) establishing standards for quality attributes of the finished water and the source water; (2) defining suitable unit operations and their operating parameters for achieving the desired finished water quality attributes from the available source water; (3) selecting piping, equipment, controls, and monitoring technologies; (4) developing an IQ stage consisting of instrument calibrations, inspections to verify that the drawings accurately depict the final configuration of the water system and, where necessary, special tests to verify that the installation meets the design requirements; (5) developing an OQ stage consisting of tests and inspections to verify that the equipment, system alerts, and controls are operating reliably and that appropriate alert and action levels are established (This phase of qualification may overlap with aspects of the next step.); and (6) developing a prospective PQ stage to confirm the appropriateness of critical process parameter operating ranges (During this phase of validation, alert and action levels for key quality attributes and operating parameters are verified.); (7) assuring the adequacy of ongoing control procedures, e.g., sanitization frequency; (8) supplementing a validation maintenance program (also called continuous validation life cycle) that includes a mechanism to control changes to the water system and establishes and carries out scheduled preventive maintenance including recalibration of instruments (In addition, validation maintenance includes a monitoring program for critical process parameters and a corrective action program.); (9) instituting a schedule for periodic review of the system performance and requalification, and (10) completing protocols and documenting Steps 1 through 9.

PURIFIED WATER AND WATER FOR INJECTION SYSTEMS

The design, installation, and operation of systems to produce Purified Water and Water for Injection include similar components, control techniques, and procedures. The quality attributes of both waters differ only in the presence of a bacterial endotoxin requirement for Water for Injection and in their methods of preparation, at least at the last stage of preparation. The similarities in the quality attributes provide considerable common ground in the design of water systems to meet either requirement. The critical difference is the degree of control of the system and the final purification steps needed to ensure bacterial and bacterial endotoxin removal.

Production of pharmaceutical water

Production of pharmaceutical water employs sequential unit operations (processing steps) that address specific water quality attributes and protect the operation of subsequent treatment steps. A typical evaluation process to select an appropriate water quality for a particular pharmaceutical purpose is shown in the decision tree in Figure 2. This diagram may be used to assist in defining requirements for specific water uses and in the selection of unit operations. The final unit operation used to produce Water for Injection is limited to distillation or other processes equivalent or superior to distillation in the removal of chemical impurities as well as microorganisms and their components. Distillation has a long history of reliable performance and can be validated as a unit operation for the production of Water for Injection, but other technologies or combinations of technologies can be validated as being equivalently effective. Other technologies, such as ultrafiltration following other chemical purification process, may be suitable in the production of Water for Injection if they can be shown through validation to be as effective and reliable as distillation. The advent of new materials for older technologies, such as reverse osmosis and ultrafiltration, that allow intermittent or continuous operation at elevated, microbial temperatures, show promise for a valid use in producing Water for Injection.

[PPT PDF] Pharmaceutical Water System Design Operation And Validation Pdf PowerPoint Pharmaceutical Water System Design Operation And Validation Pdf PowerPoint

Validation plan  Pharmaceutical Water System 

The validation plan should be designed to establish the suitability of the system and to provide a thorough understanding of the purification mechanism, range of operating conditions, required pretreatment, and the most likely modes of failure. It is also necessary to demonstrate the effectiveness of the monitoring scheme and to establish the documentation and qualification requirements for the system’s validation maintenance. Trials conducted in a pilot installation can be valuable in defining the operating parameters and the expected water quality and in identifying failure modes. However, qualification of the specific unit operation can only be performed as part of the validation of the installed operational system. The selection of specific unit operations and design characteristics for a water system should take into account the quality of the feed water, the technology chosen for subsequent processing steps, the extent and complexity of the water distribution system, and the appropriate compendial requirements. For example, in the design of a system for Water for Injection, the final process (distillation or whatever other validated process is used according to the monograph) must have effective bacterial endotoxin reduction capability and must be validated.

INSTALLATION, MATERIALS OF CONSTRUCTION, AND COMPONENT SELECTION

Installation techniques are important because they can affect the mechanical, corrosive, and sanitary integrity of the system. Valve installation attitude should promote gravity drainage. Pipe supports should provide appropriate slopes for drainage and should be designed to support the piping adequately under worst-case thermal and flow conditions. The methods of connecting system components including units of operation, tanks, and distribution piping require careful attention to preclude potential problems. Stainless steel welds should provide reliable joints that are internally smooth and corrosion-free. Low-carbon stainless steel, compatible wire filler, where necessary, inert gas, automatic welding machines, and regular inspection and documentation help to ensure acceptable weld quality. Follow-up cleaning and passivation are important for removing contamination and corrosion products and to re-establish the passive corrosion resistant surface. Plastic materials can be fused (welded) in some cases and also require smooth, uniform internal surfaces. Adhesive glues and solvents should be avoided due to the potential for voids and extractables. Mechanical methods of joining, such as flange fittings, require care to avoid the creation of offsets, gaps, penetrations, and voids. Control measures include good alignment, properly sized gaskets, appropriate spacing, uniform sealing force, and the avoidance of threaded fittings.

Materials of construction should be selected to be compatible with control measures such as sanitizing, cleaning, and passivating. Temperature rating is a critical factor in choosing appropriate materials because surfaces may be required to handle elevated operating and sanitization temperatures. Should chemicals or additives be used to clean, control, or sanitize the system, materials resistant to these chemicals or additives must be utilized. Materials should be capable of handling turbulent flow and elevated velocities without wear of the corrosion-resistant film such as the passive chromium oxide surface of stainless steel. The finish on metallic materials such as stainless steel, whether it is a refined mill finish, polished to a specific grit, or an electropolished treatment, should complement system design and provide satisfactory corrosion and microbial activity resistance as well as chemical sanitizability. Auxiliary equipment and fittings that require seals, gaskets, diaphragms, filter media, and membranes should exclude materials that permit the possibility of extractables, shedding, and microbial activity. Insulating materials exposed to stainless steel surfaces should be free of chlorides to avoid the phenomenon of stress corrosion cracking that can lead to system contamination and the destruction of tanks and critical system components.

Specifications are important to ensure proper selection of materials and to serve as a reference for system qualification and maintenance. Information such as mill reports for stainless steel and reports of composition, ratings, and material handling capabilities for nonmetallic substances should be reviewed for suitability and retained for reference. Component (auxiliary equipment) selection should be made with assurance that it does not create a source of contamination intrusion. Heat exchangers should be constructed to prevent leakage of heat transfer medium to the pharmaceutical water and, for heat exchanger designs where prevention may fail, there should be a means to detect leakage. Pumps should be of sanitary design with seals that prevent contamination of the water. Valves should have smooth internal surfaces with the seat and closing device exposed to the flushing action of water, such as occurs in diaphragm valves. Valves with pocket areas or closing devices (e.g., ball, plug, gate, globe) that move into and out of the flow area should be avoided.

SANITIZATION – Pharmaceutical Water System 

Microbial control in water systems is achieved primarily through sanitization practices. Systems can be sanitized using either thermal or chemical means. Thermal approaches to system sanitization include periodic or continuously circulating hot water and the use of steam. Temperatures of at least 80  are most commonly used for this purpose, but continuously recirculating water of at least 65  has also been used effectively in insulated stainless steel distribution systems when attention is paid to uniformity and distribution of such self-sanitizing temperatures. These techniques are limited to systems that are compatible with the higher temperatures needed to achieve sanitization. Although thermal methods control biofilm development by either continuously inhibiting their growth or, in intermittent applications, by killing the microorganisms within biofilms, they are not effective in removing established biofilms. Killed but intact biofilms can become a nutrient source for rapid biofilm regrowth after the sanitizing conditions are removed or halted. In such cases, a combination of routine thermal and periodic supplementation with chemical sanitization might be more effective. The more frequent the thermal sanitization, the more likely biofilm development and regrowth can be eliminated. Chemical methods, where compatible, can be used on a wider variety of construction materials. These methods typically employ oxidizing agents such as halogenated compounds, hydrogen peroxide, ozone, peracetic acid, or combinations thereof. Halogenated compounds are effective sanitizers but are difficult to flush from the system and may leave biofilms intact. Compounds such as hydrogen peroxide, ozone, and peracetic acid oxidize bacteria and biofilms by forming reactive peroxides and free radicals (notably hydroxyl radicals). The short half-life of ozone in particular, and its limitation on achievable concentrations require that it be added continuously during the sanitization process. Hydrogen peroxide and ozone rapidly degrade to water and oxygen; peracetic acid degrades to acetic acid in the presence of UV light. In fact, ozone’s ease of degradation to oxygen using 254-nm UV lights at use points allow it to be most effectively used on a continuous basis to provide continuously sanitizing conditions.

In-line UV light at a wavelength of 254 nm can also be used to continuously “sanitize” water circulating in the system, but these devices must be properly sized for the water flow. Such devices inactivate a high percentage (but not 100%) of microorganisms that flow through the device but cannot be used to directly control existing biofilm upstream or downstream of the device. However, when coupled with conventional thermal or chemical sanitization technologies or located immediately upstream of a microbially retentive filter, it is most effective and can prolong the interval between system sanitizations.

It is important to note that microorganisms in a well-developed biofilm can be extremely difficult to kill, even by aggressive oxidizing biocides. The less developed and therefore thinner the biofilm, the more effective the biocidal action. Therefore, optimal biocide control is achieved by frequent biocide use that does not allow significant biofilm development between treatments.

Sanitization steps require validation to demonstrate the capability of reducing and holding microbial contamination at acceptable levels. Validation of thermal methods should include a heat distribution study to demonstrate that sanitization temperatures are achieved throughout the system, including the body of use point valves. Validation of chemical methods require demonstrating adequate chemical concentrations throughout the system, exposure to all wetted surfaces, including the body of use point valves, and complete removal of the sanitant from the system at the completion of treatment. Methods validation for the detection and quantification of residues of the sanitant or its objectionable degradants is an essential part of the validation program. The frequency of sanitization should be supported by, if not triggered by, the results of system microbial monitoring. Conclusions derived from trend analysis of the microbiological data should be used as the alert mechanism for maintenance.The frequency of sanitization should be established in such a way that the system operates in a state of microbiological control and does not routinely exceed alert levels (see Alert and Action Levels and Specifications).

 Pharmaceutical Water System OPERATION, MAINTENANCE, AND CONTROL

A preventive maintenance program should be established to ensure that the water system remains in a state of control. The program should include (1) procedures for operating the system, (2) monitoring programs for critical quality attributes and operating conditions including calibration of critical instruments, (3) schedule for periodic sanitization, (4) preventive maintenance of components, and (5) control of changes to the mechanical system and to operating conditions.

Operating Procedures—

Procedures for operating the water system and performing routine maintenance and corrective action should be written, and they should also define the point when action is required. The procedures should be well documented, detail the function of each job, assign who is responsible for performing the work, and describe how the job is to be conducted. The effectiveness of these procedures should be assessed during water system validation.

Monitoring Program—

Critical quality attributes and operating parameters should be documented and monitored. The program may include a combination of in-line sensors or automated instruments (e.g., for TOC, conductivity, hardness, and chlorine), automated or manual documentation of operational parameters (such as flow rates or pressure drop across a carbon bed, filter, or RO unit), and laboratory tests (e.g., total microbial counts). The frequency of sampling, the requirement for evaluating test results, and the necessity for initiating corrective action should be included.

Sanitization—

Depending on system design and the selected units of operation, routine periodic sanitization may be necessary to maintain the system in a state of microbial control. Technologies for sanitization are described above.

Preventive Maintenance—

A preventive maintenance program should be in effect. The program should establish what preventive maintenance is to be performed, the frequency of maintenance work, and how the work should be documented.

Change Control—

The mechanical configuration and operating conditions must be controlled. Proposed changes should be evaluated for their impact on the whole system. The need to requalify the system after changes are made should be determined. Following a decision to modify a water system, the affected drawings, manuals, and procedures should be revised.

Auxiliary Information— Staff Liaison : Gary E. Ritchie, M.Sc., Scientific Fellow

Expert Committee : (PW05) Pharmaceutical Waters 05

USP29–NF24 Page 3056

Pharmacopeial Forum : Volume No. 30(5) Page 1744

Phone Number : 1-301-816-8353

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