Cleanroom

Typically used in manufacturing or scientific research, a cleanroom is a controlled environment that has a low level of pollutants such as dust, airborne microbes, aerosol particles, and chemical vapors. To be exact, a cleanroom has a controlled level of contamination that is specified by the number of particles per cubic meter at a specified particle size. The ambient air outside in a typical city environment contains 35,000,000 particles per cubic meter, 0.5 mm and larger in diameter, corresponding to an ISO 9 cleanroom which is at the lowest level of cleanroom standards.

Cleanroom Overview

Cleanrooms are used in practically every industry where small particles can adversely affect the manufacturing process. They vary in size and complexity, and are used extensively in industries such as semiconductor manufacturing, pharmaceuticals, biotech, medical device and life sciences, as well as critical process manufacturing common in aerospace, optics, military and Department of Energy.

A cleanroom is any given contained space where provisions are made to reduce particulate contamination and control other environmental parameters such as temperature, humidity and pressure. The key component is the High Efficiency Particulate Air (HEPA) filter that is used to trap particles that are 0.3 micron and larger in size. All of the air delivered to a cleanroom passes through HEPA filters, and in some cases where stringent cleanliness performance is necessary; Ultra Low Particulate Air (ULPA) filters are used.

Personnel selected to work in cleanrooms undergo extensive training in contamination control theory. They enter and exit the cleanroom through airlocks, air showers and/or gowning rooms, and they must wear special clothing designed to trap contaminants that are naturally generated by skin and the body.

Depending on the room classification or function, personnel gowning may be as limited as lab coats and hairnets, or as extensive as fully enveloped in multiple layered bunny suits with self-contained breathing apparatus.
Cleanroom clothing is used to prevent substances from being released off the wearer’s body and contaminating the environment. The cleanroom clothing itself must not release particles or fibers to prevent contamination of the environment by personnel. This type of personnel contamination can degrade product performance in the semiconductor and pharmaceutical industries and it can cause cross-infection between medical staff and patients in the healthcare industry for example.

Cleanroom garments include boots, shoes, aprons, beard covers, bouffant caps, coveralls, face masks, frocks/lab coats, gowns, glove and finger cots, hairnets, hoods, sleeves and shoe covers. The type of cleanroom garments used should reflect the cleanroom and product specifications. Low-level cleanrooms may only require special shoes having completely smooth soles that do not track in dust or dirt. However, shoe bottoms must not create slipping hazards since safety always takes precedence. A cleanroom suit is usually required for entering a cleanroom. Class 10,000 cleanrooms may use simple smocks, head covers, and booties. For Class 10 cleanrooms, careful gown wearing procedures with a zipped cover all, boots, gloves and complete respirator enclosure are required.

Cleanroom Air Flow Principles

Cleanrooms maintain particulate-free air through the use of either HEPA or ULPA filters employing laminar or turbulent air flow principles. Laminar, or unidirectional, air flow systems direct filtered air downward in a constant stream. Laminar air flow systems are typically employed across 100% of the ceiling to maintain constant, unidirectional flow. Laminar flow criteria is generally stated in portable work stations (LF hoods), and is mandated in ISO-1 through ISO-4 classified cleanrooms.

Proper cleanroom design encompasses the entire air distribution system, including provisions for adequate, downstream air returns. In vertical flow rooms, this means the use of low wall air returns around the perimeter of the zone. In horizontal flow applications, it requires the use of air returns at the downstream boundary of the process. The use of ceiling mounted air returns is contradictory to proper cleanroom system design.

Automated manufacturing Practice

Good Automated Manufacturing Practice for Pharmaceutical Industries

The Good Automated Manufacturing Practice (GAMP) Forum was founded in 1991 by pharmaceutical industry professionals in the United Kingdom to address the industry’s need to improve comprehension and evolving expectations of regulatory agencies in Europe. The organization also sought to promote understanding of how computer systems validation should be conducted in the pharmaceutical industry.

GAMP rapidly became influential throughout countries as the quality of its work was recognized internationally. Over time, GAMP has become the acknowledged expert body for addressing issues of computer system validation.

GAMP’s guidance approach defines a set of industry best practices to enable compliance to all current regulatory expectations. More than simply a strict compliance standard, GAMP is a guideline for life sciences companies to use for their own quality procedures. As a result, it can be tailored to a number of computer system types.

Computer system validation following GAMP guidelines requires users and suppliers to work together so that responsibilities regarding the validation process are understood. For users, GAMP provides a documented assurance that a system is appropriate for the intended use before it goes live. Suppliers can use GAMP to test for avoidable defects in the supplied system to ensure quality product leaves the facility.

The GAMP framework addresses how systems are validated and documented. Companies do not need to follow the same set of procedures and processes of a GAMP framework to achieve validation and qualification levels that satisfy inspectors. Instead, GAMP examines the systems development lifecycle of an automated system to identify issues of validation, compliance and documentation.

As a voluntary program, GAMP offers both challenges and benefits. The top three challenges in implementing GAMP are establishing procedural control, handling management and change control, and finding an acceptable standard among the existing variations.

Establishing procedural control is a challenge in using GAMP guidelines because new frameworks may be necessary to gauge the validity of systems. Most pharmaceutical companies have already established a baseline that adheres to standards and regulations that exist today, but they may not have a procedure to check the processes that are in place. This could cause resistance among software developers who may prefer not to work within the confines of specifications and procedures developed by others. Specifications and procedures developed by previous software developers may hinder ways to adjust computer systems, but varying interpretations of GAMP guidelines allow for multiple solutions.

Another hurdle is change control. In the development or modification of computer systems, companies with even the highest of standards can suffer setbacks along the systems development lifecycle. Sometimes minor tweaks by the software programmer may cause breakdowns after validation changes have been implemented. Internal processes and procedures must be established to guard against these occurrences.

Effective documentation management is fundamental for compliance. Any inaccuracies or missing information renders all other efforts moot. Moreover, implementing a formal document management application may be cost-prohibitive for some organizations. Some companies simply use what’s in the GAMP checklists to evaluate their systems. Today’s environment demands a thorough process to show validation.

The benefits of utilizing the GAMP approach for both users and suppliers include:

  • Improved understanding of the subject with the introduction of common terminology
  • Reduced cost and time to achieve compliant systems
  • Reduced time and resources for revalidation or regression testing and remediation
  • Reduced cost of qualification
  • Enhanced compliance with regulatory expectations
  • Established responsibility for all involved parties

When the FDA introduced its current Good Manufacturing Practices (cGMP) for the 21st century initiative, companies shifted their approach to validation. Formerly, they only had to heed a set of rules that accounted for every piece of equipment that was used. Now they can take a risk-based approach to validation by addressing safety, efficacy and quality in the product considerations. This enables the industry to place its investments where it makes the most sense. The onus ultimately falls on manufacturers to accept greater responsibility to validate their systems having the attendant benefits of cost and time to market savings.

GAMP helps provide a quality product from the manufacturer, and helps to limit the pharmaceutical industry’s culpability by ensuring proper steps were placed to deliver a quality product through validated systems. By incorporating input from the full spectrum of stakeholders, fine-tuning and further development of the process is geared towards benefiting the life sciences industry and the general consumer market.

The tools exist for companies to take the steps needed to reap the benefits of validation. Understanding an early adoption of GAMP can increase a company’s competitive position, especially with the implementation of new technologies. By staying aware of technological innovations, companies are able to increase efficiency, minimize risks and reduce costs.

Calibration for Pharmaceutical Industries

The pharmaceutical sector is governed by regulatory norms to ensure that quality standards are met for products in line with pharmaceutical cGMP guidelines. The FDA takes food and pharma production very seriously, which is why these guidelines are in place. Calibration is one such process wherein an instrument or a utility system is adjusted so that its readings are adherent to the defined guidelines. It is usually performed as per approved written procedures.
What is Equipment Calibration?
Equipment calibration is important as equipment is often used to gather critical data and hence calibrating them and keeping them up to date becomes mandatory. This process is carried out regularly since equipment used in pharmaceutical manufacturing depending on its functionality is subjected to a lot of wear and tear.Calibration is usually done component-wise to ensure accuracy of the operating equipment as per defined pharmaceutical cGMP.
Types of Calibration
Calibration types are defined as per the parameter which is crucial for a certain process. The classification is largely done on the basis of the type of reading, and common types include:
Pressure Calibration– This method calibrates pressure readings within barometers, transmitters, test gauges and other kinds of equipment commonly used in manufacturing setups.
Temperature Calibration– Calibration is done based on temperature readings, in simulation of a real-time environment. The equipment in this category includes furnaces, weather stations, bio repositories, thermistors, etc.
Flow Calibration– The calibration which is carried out routinely for flow meters that check product quantity or energy functions in processes. Some of the equipment which requires flow calibration includes flowmeters, rotameters and turbine meters.
Pipette Calibration– Pipettes are used in laboratories to measure liquids in small, precise quantities. This calibration method is utilized in labs that make frequent use of pipettes, and is a fairly stringent process since the degree of precision required is very high.
Electrical Calibration– This particular method is used for checking electrical equipment. The accreditation standards are set as per UKAS outlines, since these are considered the most accurate set of standards for electrical calibration.
Mechanical Calibration– Mechanical calibration checks for the accuracy of various measurements such as torque, mass, force, angle and vibration. All these elements are checked in a temperature-controlled facility, since variations in temperature can adversely impact the calibration process.
Since these instruments are used in real-time environments, they are subject to frequent wear and tear. However, they are used in processes that require a lot of precision in terms of data gathering and measured quantities.Therefore, in order to maintain the accuracy of the process and the measurements taken by equipment, frequent calibration is required.

The frequency with which equipment is to be calibrated depends on various factors such as:

  • The importance of the measurements for which instruments are used
  • The defined standards of the equipment manufacturer to adhere to the pharmaceutical CGMP guidelines.
  • The degree of risk involved in the process for which that equipment is being used
  • The degree of precision required from the equipment and the accuracy with which data is to be gathered from the equipment.
  • The extent to which the equipment is stable. This is evaluated from the historical data on the stability of the equipment

Calibration is a mandatory process in the pharmaceutical space considering the need for reproducible product quality. Lack of precision can lead to huge repercussions and penalties. Calibration forms an essential part of the quality assurance and validation process in the pharmaceutical industry.

Utility System Qualification for the Pharmaceutical Industry

Pharmaceutical equipment manufacturing is a highly regulated industry. Given the stress on product quality and the widespread impact of substandard production on public health and safety, utility system qualification is a critical step that companies must take towards ensuring that all their products comply with federal laws and regulations.

In pharmaceuticals, critical utilities like water and HVAC (Heating, Ventilation and Air Conditioning) systems form the backbone of the manufacturing process. As a result, these are treated, as products that need to satisfy FDA regulatory requirements and pharmaceutical manufacturing standards, just like raw materials and other equipment used in the industry.

The primary use of a utility system is to help pharmaceutical companies check the quality and safety of their products and to ensure they comply with the laws and statutes in the FDA dossier. Without meeting these requirements, a product may fail to be cleared for marketing.

To pass inspection, utilities must pass a string of qualitative and quantitative specifications. Different utility systems have different quality and standard criteria, designed on the basis of inputs from relevant departments and organizations as well as manufacturing and engineering provisions.

When a validation program is set in place for utility systems used in pharmaceutical, critical utilities should be first on the list. It’s important to focus on the design, qualification and monitoring of each utility system used in pharmaceutical or biotech companies, so their end product fulfills all pharmaceutical quality standards.

Utility system qualification is designed to ensure that utilities in use conform to health and safety regulations, as well as pharmaceutical manufacturing standards and cGMP guidelines.

Current good manufacturing practices (cGMPs) are FDA guidelines that check the design, control and monitoring of manufacturing facilities and processes. To comply with cGMP regulations, drugs and medicinal products need to be of the right quality, strength and purity, by way of adequately controlled and monitored manufacturing operations.

Steps in utility system qualification include implementing strong operating procedures, establishing extensive quality control systems, procuring a consistent quality of raw material supplies and maintaining dependable testing labs.

If such a broad control system is implemented in a pharmaceutical facility, it can help to control instances of mix-ups, contamination, errors, defects and deviations during the manufacturing process. Such pharmaceutical products are better able to meet public health and safety laws established by the FDA.

Pharmaceutical cGMP guidelines are flexible enough that all manufacturers are free to decide how to apply FDA controls in ways that fits their unique requirements. They can make use of a variety of processing methods, testing procedures and scientific designs to adapt their manufacturing processes to meet the laws.

Because of the flexibility of these laws, companies can use innovative approaches and sophisticated technology to implement a system of continual improvement in order to achievement a consistent quality of pharmaceutical supplies.

All pharmaceutical manufacturing facilities need to adhere strictly to FDA-approved regulations. There is a lot of stress on the compliance of facility design with cGMP regulations as well as the various procedures associated with pharmaceutical production, so drugs are manufactured under conditions that meet FDA approval.

Failure to meet FDA regulations can result in responsive action by the authorities against the product or the responsible facility, depending upon the seriousness of non-compliance. The company may have to recall the product under orders of the FDA, to ensure it does not cause additional harm or risk to the public.

cGMP requirements can be useful in ensuring the efficacy, quality and safety of pharmaceutical products by making sure facilities are in good operating condition, with sufficiently calibrated and well-maintained equipment, trained and experienced staff and reliable and efficient processes.

While a utility system cannot affect product quality on its own, it forms an integral part of the manufacturing process. Panorama helps you set up validation processes as per your needs.

What is a Validation Master Plan?

A Validation Master Plan or a VMP is a document that outlines the principles and defines which processes and equipment need to be validated and the order of priority in which the same will be done. Validation of products, processes and facilities is an important part of a company’s Quality Management System(QMS). While the FDA doesn’t necessarily require a Validation Master Plan, it is often included in quality engineering services.A VMP should have logical reasoning for including or excluding every system associated with a validation project based on a risk assessment.
Pharmaceutical, biotechnology and medical device manufacturers are the key sectors that require a VMP. It is a key document in the GMP (Good manufacturing practice) regulated pharmaceutical industry as it drives a structured approach to validation projects.
The VMP is the foundation for the validation program and should include process validation, facility and utility qualification and validation, equipment qualification, cleaning and computer validation.The VMP is crucial from a quality and regulatory-compliance standpoint. At times, FDA inspectors may request documentation outlining an organization’s process and equipment validation plan. Thus, VMPs may help companies overcome challenges.

VMPs should include details of:

  • All prospective, concurrent, retrospective validation and revalidation activities
  • Time, location, priority and order of validation activities
  • A statement describing the validation policy of the company
  • An overview of the organization’s scope of operations, describing the facilities, products and processes
  • Facility management/personnel who have agreed upon the plan
  • Details or copies of any corresponding validation plans, existing SOPs, relevant policy documents and validation reports/protocols, etc.
  • Persons who are responsible and provide approval for SOPs, protocols and the VMP, as well as any review and reference tracking systems
  • References to or appendices detailing any plans for validation training programs.

Developing and implementing a VMP offers numerous benefits to manufacturers. A VMP is documented evidence that the manufacturer follows a well-defined strategy and has their validation process under control. This can be essentially useful during a quality system inspection. The VMP can also enhance business efficiency by preventing product or process failures and improving productivity.
VMP also leads to simplification of the validation process. VMP defines validation strategy and requirements, risk management and implementation. Thus, making the validation process simpler.
Operational excellence also benefits from VMP. A holistic approach helps define how the process will be integrated, how risk management will be applied and how validation will be handled for continuous improvement. It also defines how validation will be performed throughout the project life cycle and through regulatory submissions and other phased approval.
While the need of a VMP is not specifically required, it has become common practice in the pharmaceutical industry. The overall objective of a VMP is to ensure that quality requirements for processes and equipment are consistently met. When applied holistically, a VMP will simplify and standardize validation processes, facilitate continuous improvement and operational excellence, ensure smooth integration into quality systems, support design control and the device life cycle, and improve the overall cost of quality.
In conclusion, Validation is an excellent way to minimize risk and maximize production efficiency and quality. The extra cost incurred for validation is directly proportional to the level of risk aversion. Thus, a suitable validation program devised on pharmaceutical manufacturing standards would help build stability and efficiency.

Validation

Validation Protocols for Pharmaceutical Industries

For pharmaceutical industries, product quality is paramount. Minor inconsistencies can lead to major disasters. To maintain quality assurance, consistency and risk assessment, industries conduct a validation of processes and equipment. A validation is a documented evidence of the consistency of processes and equipment. Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ) are an essential part of quality assurance through equipment validation.

DQ IQ OQ PQ protocols are ways of establishing that the equipment which is being used or installed will offer a high degree of quality assurance, so that manufacturing processes will consistently produce products that meet predetermined quality requirements.

Design Qualification (DQ)

Design qualification is a verification process on the design to meet particular requirements relating to the quality of manufacturing and pharmaceutical practices. It is important to take these procedures into consideration and follow them keenly. Along with Process Validation, pharmaceutical manufacturers must conduct Design Qualification during the initial stages. For DQ to be considered whole, other qualifications i.e. IQ, OQ and PQ need to be implemented on each instrument and the system as a whole.

DQ allows manufacturers to make corrections and changes reducing costs and avoiding delays. Changes made to a DQ should be documented which makes DQ on the finalized design easier and less prone to errors. By the use of a design validation protocol it is possible to determine whether the equipment or product will deliver its full functionality and conform to the requirements of the validation master plan.

Installation Qualification (IQ)

Any new equipment is first validated to check if it is capable of producing the desired results through Design Qualification, but its performance in a real-world scenario depends on the installation procedure that follows. Installation Qualification (IQ) verifies that the instrument or equipment being qualified, as well as its sub-systems and any ancillary systems, have been delivered, installed and configured in accordance with the manufacturer’s specifications or installation checklist. All procedures to do with maintenance, cleaning and calibration are drawn at the installation stage. It also details a list of all the continued Good Manufacturing Procedures (cGMP) requirements that are applicable in the installation qualification.

Conformance with cGMP’s requires, that whatever approach is used, it is fully documented in the individual Validation Plan. The IQ should not start with the Factory Acceptance Testing (FAT) or Commissioning tasks, but it should start before these tasks are completed; enabling the validation team to witness and document the final FAT and commissioning testing. The integration of these activities greatly reduces the costly and time consuming replication of unnecessary retesting.

These requirements must all be satisfied before the IQ can be completed and the qualification process is allowed to progress to the execution of the OQ.

Operational Qualification (OQ)

Operational Qualification is an essential process during the development of equipment required in the pharmaceutical industry. OQ is a series of tests which of tests which ensure the equipment and its sub-systems will operate within their specified limits consistently and dependably. Equipment may also be tested during OQ for qualities such as using an expected and acceptable amount of power or maintaining a certain temperature for a predetermined period of time. OQ follows a specific procedure to maintain thoroughness of the tests and accuracy of the results. The protocol must be detailed and easily replicated so that equipment can be tested multiple times using different testers. This ensures that the results are reliable and do not vary from tester to tester. OQ is an important step to develop safe and effective equipment.

Performance Qualification (PQ)

PQ is the final step in qualification processes for equipment, and this step involves verifying and documenting that the equipment is working reproducibly within a specified working range. Rather than testing each instrument individually, they are all tested together as part of a partial or overall process. Before the qualification begins, a detailed test plan is created, based on the process description.

Process Performance Qualification (PPQ) protocol is a vital part of process validation and qualification, which is used to ensure ongoing product quality by documenting performance over a period of time for a certain process.

Equipment qualification through DQ IQ OQ PQ practices is a part of Good Manufacturing Practice (GMP), through which manufacturers and laboratories can ensure that their equipment delivers consistent quality. It reduces the margin for errors, so the product quality can be maintained within industry standards or regulatory authority requirements. When qualification of equipment is not needed very frequently, performing it in-house might not be feasible, so smaller laboratories might benefit from scheduling external equipment validation services on a regular basis instead.

Design of Purified water & WFI Systems

Water is the one of the major commodities used by the pharmaceutical industry. It is widely used as a raw material, ingredient, and solvent in the processing, formulation, and manufacture of pharmaceutical products, active pharmaceutical ingredients (APIs) and intermediates, and analytical reagents. It may present as an excipient, or used for reconstitution of products, during synthesis, during production of finished product, or as a cleaning agent for rinsing vessels, equipment and primary packing materials etc.

There are many different grades of water used for pharmaceutical purposes. Several are described in USP monographs that specify uses, acceptable methods of preparation, and quality attributes. These waters can be divided into two general types: bulk waters, which are typically produced on site where they are used; and packaged waters, which are produced, packaged, and sterilized to preserve microbial quality throughout their packaged shelf life.

There are several specialized types of packaged waters, differing in their designated applications, packaging limitations, and other quality attributes.

Different grades of water quality are required depending on the different pharmaceutical uses.

Types of Water used:

Water is the most common aqueous vehicle used in pharmaceuticals. There are several types of water are used in the preparation of drug product, such as:

  1. Non potable water: It is water that is not of drinking water quality, but which may still be used for many other purposes, depending on its quality. It is generally all raw water that is untreated, such as that from lakes, rivers, ground water, springs and ground wells.
    Purposes:

    • cleaning of outer surface of the factory
    • used in garden
    • washing vehicles etc.
  2. Potable water: It is not suitable for general pharmaceutical use because of the considerable amount of dissolved solids present. These consist chiefly of the chlorides, sulphates & bicarbonates of Na, K, Ca and Mg. A 100 ml portion of water contains not more than 100 mg of residue (0.1%) after evaporation to dryness on a steam bath.
    Purposes:

    • To use as drinking water
    • Washing & extraction of crude drugs
    • Preparation of products for external use
  3. Purified water: It is used in the preparation of all medication containing water except ampoules, injections, some official external preparations such as liniments. It must meet the requirements for ionic & organic chemical purity & must be protected from microbial contamination.
    Purposes:

    • For the Production of non-parenteral preparation/formulation
    • For the Cleaning of certain equipment used in non-parenteral product preparation
    • For Cleaning of non-parenteral product-contact components
    • For All types of tests
    • For the Preparation of some bulk chemicals
    • For the preparation of media in microbiology

Water for Injection (WFI):

Water for Injection is a solvent used in the production of parenteral and other preparations where product endotoxin content must be controlled, and in other pharmaceutical applications.(WFI) is sterile, non pyrogenic, distilled water for the preparation of products for parenteral use.

It contains no added substance and meets all the requirements of the tests for purified water. It must meet the requirements of the pyrogen test. The finished water must meet all of the chemical requirements for Purified Water as well as an additional bacterial endotoxin specification.

Since endotoxins are produced by the kinds of microorganisms that are prone to inhabit water, the equipment and procedures used by the system to purify, store, and distribute Water for Injection must be designed to minimize or prevent microbial contamination as well as remove incoming endotoxins from the starting water. Water for Injection systems must be validated to reliably and consistently produce and distribute this quality of water.

Purposes:

  • For the production of parenteral products/formulation
  • For cleaning of parenteral product-contact components

Preparation technique:

  • Distillation
  • Reverse osmosis
  • Membrane process

Storage condition:

It can be stored for periods up to a month in special tanks containing ultraviolet lamps. When this freshly prepared water is stored and sterilized in hermitically sealed containers, it will remain in good condition indefinitely.

If autoclave is not available, freshly distilled water may be sterilized by boiling the water for at least 60 minutes in a flask stoppered with a plug of purified non-absorbent cotton covered with gauze, tin-foil or stout non-absorbent paper; or the neck of the flask may be covered with cellophane and tightly fastened with cord.

WFI System validation process:

How to preform WFI system validation in Pharmaceuticals and Acceptance Criteria for Water for Injection.

Process:

  1. Perform Installation Qualification. Verify piping, fittings, proper dimensions drawings, wiring, PC software, calibration, and quality of materials.
  2. Check flow rates, low volume of water supply, excessive pressure drop, resistivity drops below set point, and temperature drop or increase beyond set level.
  3. Perform general operational controls verification testing.
  4. Operate system throughout the range of operating design specifications or range of intended use.
  5. System regulators must operate within ±2 psi of design level.
  6. Operate the system per SOP for operation and maintenance of purified water system. Perform sampling over a 1 month period per the sampling procedure and schedule.
    Test samples for conformance to current USP Water for Injection monograph, microbial content and endotoxin content. Identify all morphological distinct colony forming units (CFUs) to at least the genus level
  7. Measure the flow rate and calculate the velocity of the water, or measure the velocity directly at a point between the last use point and the storage tank.
  8. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Operational and Performance Qualification testing.

Acceptance Criteria

  1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
  2. General controls and alarms operate in accordance with design specification.
  3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
  4. The system flow rate must be in compliance with design specifications.
  5. All samples must meet the following criteria:
    1. Chemical Testing: Test samples must meet the acceptance criteria of the chemical tests as described in USP Monograph on Water for Injection.
    2. Bacteriological Purity: All samples must contain no more than 10 cfu/100 ml; no pseudomonas or coliform are detected.
    3. Endotoxins: All samples must contain no more than 0.25 EU/ml.
    4. Physical Properties: The temperature of the hot Water for Injection must be greater than 80°C.
    5. Particulate Matter: Small Volume Injection: The Small Volume Injection meets the requirements of the test if the average number of particles it contains is not more than 10,000 per container that are equal to or greater than 10 µm in effective spherical diameter and not more than 1000 per container equal to or greater than 25 µm in effective spherical diameter.

If you require technical assistance regarding purified water & WFI systems please feel free to contact on +91-22-66735960 or use our technical support form.

Temperature Mapping for Pharmaceutical Industry

Temperature mapping is important for verifying the efficacy of temperature controlled storage systems such as cool rooms, fridges and warehouses. It is vital for businesses that work with temperature sensitive products such as pharmaceuticals or warehouses.

The process of mapping outlines the differences and changes in temperature that occur within a single temperature controlled system. This is due to influences like opening doors, proximity to cooling fans, personnel movement, and the quantity of products being stored at any given time. Temperature mapping locates the points of greatest temperature fluctuation and difference then analyses the causes of these. Conditions are created to verify that a system maintains the correct temperature in all situations when influenced by external factors such as weather and internal factors such as airflow restrictions and the operation of the Heating, Ventilation and Air Conditioning systems. The effects in difference of temperature are calculated to ensure the systems meet industry standards.

The temperature of different spaces within cooling rooms, industrial fridges and other controlled temperature environments can vary by up to 10°C. Generally, the central space within a chamber maintains constant temperature, however the corners and areas surrounding the fans will fluctuate. External seasonal weather must also be taken into account especially for warehouses.

Temperature mapping is important for businesses and organisations dealing with temperature sensitive products, like biochemical products such as medications and vaccines. Verifying that the refrigeration systems maintain an acceptable temperature level for each specific product at all times is what temperature mapping is all about, and this is supported using ongoing monitoring systems.

Once mapping has established where temperature variation points lie within the control system then monitoring can be installed. It is important to re check any back up systems to be sure that the chambers will work in other circumstances.

Different mapping equipment gives different results. It is important to ensure that the equipment being used has sufficient accuracy ratings to give reliable data. For example, better equipment will provide readings that are accurate within plus or minus 0.3°C, whereas budget equipment may only have accuracy ratings of within 2.0°C. For products that must be stored within a limited temperature range, this budget equipment cannot provide sufficiently specific temperature data.

Warehouses must have information regarding the building’s external conditions, as it is vital for effective mapping and monitoring. Warehouses are generally mapped for a full year to ensure all external conditions are accounted for in the data. This also helps to determine placement of monitoring systems due to influence of external conditions.

Temperature-controlled rooms such as fridges or cold rooms can be mapped once as their external environment is controlled. However, it is advisable to make sure that other external forces that could change their temperatures significantly do not heavily influence the HVAC systems of these buildings or environments. The mapping in warehouses should take into account the fluctuation in the warehouse temperatures and conduct the tests during its most extreme levels.

Load testing is important aspect of the temperature mapping process. It investigates how expected product levels interact with individual temperature controlled chambers. This testing takes into account whether the product will arrive in the required condition or if cooling is necessary. Testing should verify whether the chamber could cope with the maximum specified load arriving all at once to then be cooled. If it can operate properly in this situation, as well as operating effectively at full capacity, the chamber can be considered sufficiently load tested. It is also advisable to test the system’s performance by simulating failures, to ascertain whether the system could be used even while experiencing some equipment failures.

Once the mapping process has been completed, sensors should be installed to allow for continued surveillance of the areas that have been identified as being most influenced by temperature change. The stable areas should be monitored to help with any troubleshooting.

Monitoring systems should be planned and documented according to the scientific rationales shown by the temperature mapping procedure. This development strategy should then be reviewed and approved by the system owners as well as by an independent quality unit before being installed. Sensors should be placed around the products, around major potential temperature influences such as doors and cooling fans, and at different heights, especially in larger chambers.

Sensor equipment can be split into zones according to the area affected by similar influences. For example, in a square or rectangular chamber, the zones in corners away from doors will behave much the same as each other, as will the zones adjacent to doors or fans. If the monitoring devices are zoned, data can be compared to provide overall information on how the system usually functions.

To summarize, temperature mapping provides information on warmer and colder areas within temperature-controlled environments. They supply details on the overall operation of the systems. After temperature mapping a system, monitoring equipment can be installed to provide real-time feedback on system operations and its stability for product protection.

Clean steam systems in the Pharmaceutical Industry

What is clean steam?

Clean steam is used in the pharmaceutical and healthcare industries in processes where the steam or its condensate can come into contact with a pharmaceutical or medical product and cause contamination. In such cases, steam from a conventional boiler(often called utility or plant steam)is unsuitable because it may contain boiler additives, rust or other undesirable materials.+

The use of clean steam is determined by the rules of Good Manufacturing Practice (GMP). These are general rules applicable to pharmaceutical manufacture,detailed in the Code of Federal Regulations(CFR Title 21,Part 211). They do not provide any specific recommendations regarding steam, but do present the general requirements offacilities, systems, equipment and operation needed to prevent contamination of pharmaceutical products during their manufacture.

Uses of clean steam:

The main use of clean steaming pharmaceutical manufacturing is for the sterilization of products or, more usually, equipment. Steam sterilization is encountered in the following processes:

  • Manufacture of injectable or parenteral solutions, which are always sterile.
  • Bio-pharmaceutical manufacturing, where a sterile environment must be created to grow the biological production organism(bacterium, yeast or animal cell).
  • Manufacture of sterile solutions,such as ophthalmic products.

Typically in these processes, clean steam is injected into equipmentor piping to create a sterile environment, or into autoclaves where loose equipment, components (such as vials and ampoules)or products are sterilized.

Clean steam may be used for some other functions where conventional utility steam might cause contamination, such as:

  • Humidification in some clean rooms.
  • Injection into high purity water for heating prior to Clean-in-Place (CIP) operations.

Fundamentals of clean steam system design:

Avoidance of corrosion

Unlike utility steam, clean steam has no corrosion inhibitors. Also, low conductivity water or condensate is hungry for ions, causing it to be corrosive to many materials commonly used in utility steam systems. Carbon steel,gunmetal and bronze, all commonly found in utility steam components, would all be rapidly corroded. Metal components for clean steam systems are therefore usually AISI 316 L stainless steel, or sometimes titanium. Non-metallic materials used include EPDM and PTFE.

Then eed to avoid corrosion is not only necessary for safeguarding the integrity of equipment. Corrosion products entering the clean steam could potentially cause contamination of the pharmaceutical product, either as chemical or particulate contamination.

Even where 316l stainless steel is used, a particular form of corrosion, called “rouging”, is often encountered in clean steam systems. The passive layer on the steel surface is disrupted and a red/brown/black film develops over time. Often this film is stable and does not pose a threat to the pharmaceutical product. Sometimes a powdery film develops and this can detach from the steel surface and cause discoloration of equipment which the steam contacts.
If this occurs, and the manufacturer feels that there is a risk of contamination or discoloration of the product, then the clean steam generator or even the full distribution system may be cleaned (“derouging”).

A variety of methods are used, but they all involve a chemical treatment to remove the surface layer of steel – this is essentially an etching process. After de-rouging, a passivation process must be used to restore the passive layer on the steel surface, since it is the passive layer that is responsible for corrosion resistance.

Preventing entry of contaminants into the system

Clean steam must be free of contaminants at the point of use. Chemical and microbial contaminants can enter steam systems in a variety of ways, and in the design of clean steam systems this must be avoided. Pathways for contamination include leakage, air being pulled into the system and “grow through” from a contaminated external environment.

Preventing microbial growth in the system

Steam at typical operating pressures will kill bacteria and their spores, so the parts of a clean system that are continuously exposed to steam will be sterile. However, if condensate is allowed to collect in the system, and it cools, then stagnant water can provide a suitable environment for bacterial growth. Though these bacteria may be killed when the condensate is discharged into equipment, followed by steam, their breakdown products, including endo toxins, may still be present. Endo toxins are not destroyed by typical clean steam system temperatures.

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HAZOP Analysis For Chemical Process Industries

“An ounce of prevention is worth a pound of cure.” As this old saying goes, safety should be an important element in every industry. Safety covers hazard identification, risk assessment and accident prevention. Safety should always come first and remain so despite of costs. Good design and forethought can often bring increased safety at less cost.

Operators of volatile plants must implement measures to ensure that their plants are operated and maintained in a safe manner. In the chemical process industry there are chances of a number of potential hazards. A hazard has the potential of causing an injury or damage to the plant as well as the working members. Raw material and intermediate toxicity and reactivity, energy release from chemical reactions, hightemperatures, high pressures, quantity of material used etc. are some of the hazards that can cause damage in a chemical industry plant.

HAZOP refers to Hazard and Operability studies. HAZOP is a systematic technique for examining potential hazards in the system. With HAZOP, the process is broken down into steps where every parameter is considered to see what could go wrong and where. This is the most common hazard analysis method for complex systems. It can be used to identify problems even during the early stages of project development, as well as identifying potential hazards in existing systems.

An important benefit of the HAZOP study is resulting knowledge that can be of great assistance in determining appropriate remedial measures. There are four steps to the HAZOP process:

  • Forming a HAZOP team:
    A multidisciplinary team is formed under the guidance of a leader. The team includes a variety of expertise such as operations, maintenance, instrumentation, engineering/process design, and other specialists as needed. The fundamental requirement is an understanding of the system and willingness to consider various parameters at each step of the process.
  • Identifying the elements of the system:
    The team must create a strategic plan for the entire process identifying individual steps and elements. This typically involves using a plant model as a guide for examining every section and component of the process. For each element, the team will identify the planned operating parameters of the system at that point: flow rate, pressure, temperature, vibration, and so on.
  • Considering possible variations in operating parameters:
    The team must be open to the idea of considering every possible variation to the parameters identified. Every deviation should be studied and potential hazards to be identified for each scenario.
  • Identifying any hazards or failure points:
    Once the team has identified potential hazards, they must estimate the impact of that failure. Existing systems should be evaluated and their ability to handle deviations in the future must be taken into consideration.

The overall aims to which any HAZOP Study should be addressed are:

  • To identify all deviations from the way the design intended to work, their causes and all the hazards and operability problems associated with these deviations.
  • To decide whether action is required to control the hazard or the operability problem, and if so, to identify the ways in which the problems can be solved.
  • To identify cases where a decision cannot be taken immediately and to decide on what information or action is required.
  • To ensure actions decided are followed through.

HAZOP studies can be implemented for new facilities or existing facilities or processes. When a HAZOP study is performed in the planning stage of a new process, completing the study means that all potential causes of failure will be identified.Whereas in existing facilities,instead of one assessment, the results will be released as each problem is identified and solutions are created.