WATER FOR PHARMACEUTICAL PRODUCTION
Water is the one of the major commodities used by pharmaceutical industries. It may be 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. Control of quality of water, in particular, the microbiological quality, is a major concern and the pharmaceutical industry devotes considerable resource to the development and maintenance of water purification systems.
Types of water used in pharmaceutical industries for pharmaceutical productions
Water for injection: is used as an excipient in the production of parenteral and other preparations where product endotoxin content must be controlled, and in other pharmaceutical applications, such as cleaning of certain equipment and parenteral product-contact components. The minimum quality of source or feed water for the generation of Water for Injection is drinking water as defined by the U.S. EPA, EU, Japan, or the WHO. This water source may be pre-treated to render it suitable for subsequent distillation. 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.
Purified Water is used as an excipient in the production of non-parenteral preparations and in other pharmaceutical applications, such as cleaning of certain equipment and non-parenteral product-contact components. Unless otherwise specified, Purified Water is also to be used for all tests and assays for which water is indicated. Purified Water must meet the requirements for ionic and organic chemical purity and must be protected from microbial contamination. The minimal quality of source or feed water for the production of Purified Water is Drinking Water. This source water may be purified using unit operations that include deionization, distillation, ion exchange, reverse osmosis, filtration, or other suitable purification procedures. Purified water systems must be validated to reliably and consistently produce and distribute water of acceptable chemical and microbiological quality. Purified water systems that function under ambient conditions are particularly susceptible to the establishment of tenacious biofilms of microorganisms, which can be the source of undesirable levels of viable microorganisms or endotoxins in the effluent water.
Sterile Purified Water is Purified Water, packaged and rendered sterile. It is used in the preparation of non-parenteral compendial dosage forms or in analytical applications requiring purified water where access to a validated purified water system is not practical, where only a relatively small quantity is needed, where sterile purified water is required, or where bulk packaged purified water is not suitably microbiologically controlled.
Others include, Sterile Water for Injection, Bacteriostatic Water for Injection, Sterile Water for Irrigation, Sterile Water for Inhalation, Potable water and pure steam.
Reading exercise: Read on the following and write short notes on their applications,
Sterile Water for Injection
Bacteriostatic Water for Injection
Sterile Water for Irrigation
Sterile Water for Inhalation
Potable water
Pure steam
CLEANING VALIDATION
Cleaning validation is documented evidence with a high degree of assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits. The objectives of good manufacturing practices (GMP) include the prevention of possible contamination and cross-contamination of pharmaceutical starting materials and products. Pharmaceutical products can be contaminated by a variety of substances such as contaminants associated with microbes, previous products (both active pharmaceutical ingredients (API) and excipient residues), residues of cleaning agents, airborne materials, such as dust and particulate matter, lubricants. Adequate cleaning procedures play an important role in preventing contamination and cross-contamination. Validation of cleaning methods provides documented evidence that an approved cleaning procedure will provide clean equipment, suitable for its intended use.
Cleaning validation is a documented process that proves the effectiveness and consistency in cleaning a pharmaceutical production equipment. It helps to attain documented evidence that provides a high degree of assurance that a cleaning procedure performed can effectively remove residues of a product and a cleaning agent from the manufacturing equipment, to a level that does not raise patient safety concerns.
Validations of equipment cleaning procedures are mainly used in pharmaceutical industries to prevent cross contamination and adulteration of drug products hence is critically important
ADVANTAGES OF CLEANING VALIDATION
These includes;
Assurance of quality & safety, Government regulations, Product, Microbial, Cross contamination and Batch integrity
Equipment reuse
Reduction of quality costs.
Making good business sense.
Less down time and fewer batch failures
Cleaning Agents For Pharmaceutical Industry.
Selecting suitable cleaning agents and determining justifiable cleaning process parameters are critical prerequisites for cleaning validation in pharmaceutical industries. Proper selection of these cleaning agents and parameters could simplify cleaning validation efforts immensely. Process cleaners may range from a single component, such as an organic solvent, to multicomponent formulations that use multiple cleaning mechanisms such as solvency, solubilization, emulsification, wetting, chelation, dispersion, hydrolysis and oxidation.
Cleaning Mechanisms
Depending on the type of cleaning agent selected, one or more of the following mechanisms are involved in the removal of the soil (product contaminant) from the surface. These mechanisms include;
Solubility: The solubility of one substance in another is commonly defined and reported as the maximumamount that can be dissolved (uniformly dispersed at the molecular or ionic level) at a giventemperature and pressure. Solvents are either polar (e.g., water, alcohol) or non-polar (e.g., hexane). Solubility provides useful information on the capacity ofthe solvent for dissolving the solute, but does not address the issue of the required dynamics or timetaken for that solute to be removed from a product contact surface. The dissolution process worksfast when the soil is broken down into small fragments, thus increasing the interfacial surface area. Pharmaceutical product soils can, however, be attached to surfaces by a combination of van derWaals forces, electrostatic effects and mechanical adhesion making cleaning a more complexprocess
Solubilization: This is a term used for the process of converting a normally insoluble material to a soluble one. This is usually achieved with the use of surfactants in detergent formulations, but a simple change in the pH may aid the process.
Emulsification: Emulsification, as applicable to process cleaning, is the process of suspending a water insoluble liquid material, such as an oil, in an aqueous solution and preventing its re-deposition. The lipophilic or oil loving end of surfactants could attach to the soil, leaving the hydrophillic or water loving end exposed to the water, thus completely covering the surface of the soil and converting it into a micelle or an easily removable droplet. In cases where the soil is not soluble in an aqueous solution, emulsification could be an easier and faster way to remove the soil out of the system without re-deposition.
Wetting: When cleaning a surface, the surface energy of both the substrate and the liquid, and the interfacial energy are important. This determines how well the cleaning solution will wet and spread into the soil and surface irregularities. This in turn will determine its ability to displace particles and penetrate the soil, providing a larger surface area which will allow for an increased rate of other mechanisms such as solubilization and diffusion. Wetting agents in formulated detergent systems lower the surface energy of the solution very significantly.
Chelation:Complexing agents, or chelants, are used in formulations to improve the cleaning effectiveness forinorganic soils. Chelants can grab onto metal ions to form strong complex bonds preventingthese ions from other adverse influences. Chelants are also used for iron oxide removal in derougingand passivating agents.
Dispersion: Dispersants are used in formulated cleaning agents to prevent particulates from clumping, and thushelping to ease their transport by the cleaning solution flow. This mechanism can be useful also inpreventing hard water scale from depositing on the surface while rinsing alkaline cleaning solutions.
Hydrolysis: This is the process of using acids or bases to break chemical bonds, thus creating smallermolecules that are more easily solvated. When this mechanism is employed, it is important foranalytical methods to be able to target and account for such breakdown products.
Oxidation: Oxidants, like sodium hypochlorite, can be used to break down proteins and other organiccompounds that cannot be cleaned by other mechanisms. Since these aggressive agents can also acton the substrate, they are used for process cleaning applications only when other mechanisms are inadequate.
Cleaning Agent Options
Broadly, three categories of cleaning agents are used for cGMP processes. These are organic solvents, commodity acids and alkalis, and formulated detergents.
Organic Solvents: Organic solvents are used mainly in the bulk pharmaceutical manufacturing industry. They rely primarily on solubility for residue removal. There are some advantages of using organic solvents. If the solvent is the same as the process solvent that is used in the manufacture of the next batch, there is no external contaminant introduced. The solvent being usually a single component cleaning agent, analytical methods are simplified. Unlike aqueous cleaning agents, solvents also have some, although limited, cleaning action when vaporized and refluxed. Safety, environmental and disposal issues, and cost are the main disadvantages and reasons why manufacturers prefer aqueous cleaning agents when possible.
Commodity Alkalis and Acids: Aqueous solutions of commodity alkalis (such as sodium hydroxide or potassium hydroxide) and acids (such as phosphoric acid or citric acid) are commonly used for process cleaning. The advantages of these agents are that they are widely available, relatively inexpensive, and are simple, single component cleaning systems. They utilize cleaning mechanisms such as solvation and hydrolysis, but do not take advantage of the other mechanisms described above, particularly wetting, emulsification, and dispersion. For these reasons, sodium hydroxide alone, which is a very commonly used cleaning agent, has drawbacks such as precipitation of water hardness, limited soil suspending ability, and insufficient penetration into soil due to low wetting characteristics. The commodity alkalis are generally difficult to rinse and often require follow up with acid rinsing.
Formulated Detergents: Formulated detergents take advantage of several of the above cleaning mechanisms. Surfactants inthese formulations may provide better wetting, surface action, and emulsification, depending on thechemistry and concentrations used. Multiple mechanisms could provide faster and more effectivecleaning of a broader spectrum of soils. This is important because pharmaceutical product residuesmay be complex formulations of different chemistries that comprise the actives and the excipients.Over a period of time there could also be other contaminants from the water, such as scale, or fromthe substrate, such as iron oxides, that could build up. Addressing a broad spectrum of soils with asingle cleaning agent can also help in using product grouping strategies, thus simplifying validationefforts. The disadvantages of using formulated detergents are that they are often proprietaryformulations, there are a limited number of sources, and their selection process and mechanism ofaction are not always well understood.
Factors that Influence Choice of Cleaning Materials for a Pharmaceutical Plant
For a given cleaning agent and soil, the most important parameters that determine cleaning performance are the cleaning time, the action or impingement on the surface, the concentration of the cleaning agent and the temperature of the cleaning solution. These parameters- time, action, concentration and temperature- are closely related. It is therefore possible to compensate one for the other and obtain the same cleaning performance.
Basic Principles for Hygienic Design of Pharmaceutical Plants
There are ten principles of sanitary/hygienic design of pharmaceutical plants which are;
Cleanability: Equipment must be constructed/fabricated to ensure effective cleaning of equipments should be designed to prevent bacteria, toxins and pyrogen ingress on both the product and equipments. The equipments should be easy to disassemble for inspection and cleaning. The design should prevent pathogenic growth of micro-organisms, Surfaces should be accessible for cleaning and treatment, cleaning protocols and cleaning processes should be a part of the design process.
Construction materials: The construction materials for product inspection equipment must fulfill specific requirements for pharmaceutical production. Materials used for equipment must be completely compatible with the product, environment, cleaning and sanitizing chemicals and the methods of cleaning and sanitation. They must be corrosion resistant. Non-toxic, mechanically stable and easy to clean. Materials shouldn’t support pathogenic growth or contribute toxins through break down.
Accessibility: All parts of product inspection equipment should be readily accessible for inspection, maintenance, cleaning and sanitation without the use of tools. Extra care must be taken during design and construction to avoid crack and crevice areas where products can seep but cleaning solution can’t reach with sufficient flow to remove all traces. If there are areas where this cannot be accomplished, then those areas have to be identified for disassembly and manual cleaning methods
No Liquid Collection: Equipment should be self-draining to ensure that liquids from products, cleaning processes or condensation which can habour and promote the growth of bacteria doesn’t accumulate or pool on the equipment. This is of particular importance where wet wash down routines are used or the ambient working environment is prone to large temperature fluctuations or high humidity.
Hermetic Sealing: Hollow areas of equipments such as frames must be eliminated whenever possible or permanently sealed. Bolts, studs, mounting plates, brackets, junction boxes, name plates, end caps, sleeves and other such items should be continuously wielded to the surface not attached via drilled and tapped holes.
No Niches: Equipment parts should be free from niches such as pits, cracks, corrosion, open seams, gaps and protruding ledges. Tight corners are difficult to clean and also trap particles. It is quite important that parts are constructed to be compatible with various product inspection equipment designs. These parts normally have several series of non-functional tapped holes to accommodate different designs
Operational Performance: During normal operation, the product inspection system must perform in such a way that doesn’t contribute to unsanitary conditions or the haborage and growth of bacteria. The characteristics of the product being produced will have the greatest impact on the equipment operational construction specifications. Avoidance of spillage and the effective separation of product contact and non-contact zones are of paramount importance. To ensure hygienic operation it is essential that the design also takes into account components and parts which will be touched by the operator who will almost certainly have had contact with the product to minimize the possible spread of contamination.
Maintenance Enclosures: Product inspection equipment maintenance and Human Machine Interfaces (HMI) such as push buttons, valve handles, switches and touch screens must be designed to ensure drug products, water and liquid products does not penetrate or accumulate in or on the enclosure or interface. Also a physical design of the enclosure should be sloped or pitched to avoid use as storage area. A special control function to temporarily disable the touch screen during cleaning is extremely advantageous as it prevents mis-operation.
Hygienic Compatibilty: Design features for hygienic compatibility should be identifiable in the graphic overview of the design. Product inspection equipments interfaces and connections to all electrical , mechanical, pneumatic and mounting interfaces need to be identified to enable integration into the production line, environment and sanitary processes
Cleaning Validation and Sanitizing Protocols: Procedures for cleaning and sanitization must be clearly written, designed and proven effective and efficient. Chemicals recommended for cleaning and sanitation must be compatible with the product inspection equipment construction materials, contamination risk and manufacturing environment and must be able to remove product residue as no aggressively as possible. The product inspection equipment supplier must consider the cleaning and maintanence of the machine at the start of the design and not as an afterthought.
PLANT LAYOUT
A plant is a place where Men, Material, Method, Money and Machinery are brought together for the main purpose of manufacturing a product. Plant layout refers to the arrangement of physical facilities such as machinery, equipment, furniture etc. within a factory building in such a manner so as to have quickest flow of material at the lowest cost and with the least amount of handling in processing the product from the receipt of material to the shipment of the finished product. The overall objective of plant layout is to design a physical arrangement that economically meets the required output – quantity and quality. Plant layout ideally involves allocation of space and arrangement of equipment in such a manner that overall operating costs are minimized.
DETERMINENTS OF PLANT LAYOUT
1. TYPE OF PRODUCT: (size, shape, quality, dosage forms etc)
2. TYPE OF PROCESS: (technology employed, manufacturing process employed either batch or continuous, sequencing etc)
3. VOLUME OF PRODUCTIONS (Mass production or small scale)
IMPORTANCE OF PLANT LAYOUT
It is long-term commitment
It facilitates the production process, minimizes material handling, time and cost, and allows flexibility of operations
It facilitates easy production flow, makes economic use of the building, promotes effective utilization of manpower, and provides for employee’s convenience, safety, comfort at work, maximum exposure to natural light and ventilation.
it affects the flow of material and processes, labour efficiency, supervision and control, use of space and expansion possibilities .
OBJECTIVES OF PLANT LAYOUT
(1)Proper and efficient utilization of available floor space (2) To ensure that work proceeds from one point to another point without any delay (3) Provide enough production capacity (4) Reduce material handling costs (5)Reduce hazards to personnel (6)Utilize labour efficiently (7) Increase employee morale
(8) Reduce accidents (9) Provide ease of supervision and control (10) Provide employee safety and health (11) Allow ease of maintenance (12) Allow high machine or equipment utilization (13) Improve productivity (14) To minimize cost of productions (15) For better inter-department relationship
FACTORS RESPONSIBLE FOR PLANT LOCATION CHOICE
Availability of raw materials
Nearness to potential market
Location should be near to source of operating power
Easy supply of labor
Easy access to transport and communication facilities
Safety requirements
Miscellaneous conditions. Considerations such as low interest on loans, attitude of residents towards the industry, living standards etc should be considered
FACTORS INFLUENCING PLANT LAYOUTS
Factory building:- The nature and size of the building determines the floor space available for layout. While designing the special requirements, e.g. air conditioning, dust control, humidity control etc. must be kept in mind.
Nature of product:- Product layout is suitable for uniform products whereas process layout is more appropriate for custom-made products.
Production process:- In assembly line industries, product layout is better. In job order or intermittent manufacturing on the other hand, process layout is desirable.
Type of machinery: General purpose machines are often arranged as per process layout while special purpose machines are arranged according to product layout.
Repairs and maintenance:-Machines should be so arranged that adequate space is available between them for movement of equipment and people required for repairing the machines.
Human needs :- Adequate arrangement should be made for cloakroom, washroom, lockers, drinking water, toilets and other employee facilities, proper provision should be made for disposal of effluents, if any.
Plant environment:- Heat, light, noise, ventilation and other aspects should be duly considered, e.g. paint shops and plating section should be located in another hall so that dangerous fumes can be removed through proper ventilation etc. Adequate safety arrangement should also be made.
Management policies:- management policies regarding size, quality, employee facilities and delivery schedules should be considered while deciding plant layout.
PRINCIPLES OF PLANT LAYOUT
PRINCIPLE OF MINIMUM MOVEMENT/DISTANCE: As far as possible materials and labour should be moved over minimum distances i.e movement of men and materials should be minimized
PRINCIPLE OF FLOW: The work areas should be arranged according to the sequence of operations so that there is continuous flow of materials without congestion. The layout should allow for easy movement of materials without interruption or delay. This arranges the work station for each operation process in the same order or sequence that forms treats or assembles the materials.
PRINCIPLE OF CUBIC SPACE UTILIZATION: All available cubic space should be effectively used both vertically and horizontally. The best layout utilizes cubic space i.e space available both in vertical and horizontal direction is most economically and effectively utilized.
PRINCIPLE OF SAFETY: There should be consideration for safety and convenience of workers. There should be built in provision for the safety and comfort.
PRINCIPLE OF FLEXIBILITY: Layout should be designed in the manner that production facilities can easily be rearranged when it becomes necessary in future on account of expansion and technological advancement. In pharmaceutical industries were products change after sometime the principle of flexibility provides adoption and rearrangement at a minimum cost and least inconvenience.
PRINCIPLE OF INTERDEPENDENCE: Interdependent operations and processes should be located in close proximity to each other.
PRINCIPLE OF OVERALL INTEGRATION: All the plant facilities and services should be fully integrated into a single operating unit so as to maximize efficiency and minimize costs of production.
PRINCIPLE OF MINIMUM INVESTMENT: The layout should yield savings in fixed capital investment through optimum utilization of available facilities.
FEATURES OF A GOOD LAYOUT
There should be sufficient space for the workers as well as for the equipment to perform their functions. This will ensure smooth and continuous flow of production processes
It must provide adequate safety and security to workers against accidents or injury. For example, provision of firefighting equipment , first aid boxes etc
The arrangement of machines and equipment should be such that minimum material handling is necessary for low cost processing
The store for in-process materials should be such that minimum material handling is necessary for low cost processing.
The supervision, coordination and control of the activity should be effectively and easily executed.
There should be sufficient scope for making adjustments and modifications whenever the need arises.
TYPES OF LAYOUTS
1. PRODUCT OR LINE LAYOUT
2. PROCESS OR FUNCTIONAL LAYOUT
3. FIXED POSITION OR LOCATION LAYOUT
4. COMBINED OR GROUP LAYOUT
PRODUCT OR LINE LAYOUT: Under this, machines and equipments are arranged in one line depending upon the sequence of operations required for the product. The materials move from one workstation to another sequentially without any backtracking or deviation. Under this, machines are grouped in one sequence. Therefore materials are fed into the first machine and finished goods travel automatically from machine to machine, the output of one machine becoming input of the next. e.g. in a paper mill, bamboos are fed into the machine at one end and paper comes out at the other end. The raw material moves very fast from one workstation to other stations with a minimum work in progress storage and material handling.
The grouping of machines should be done keeping in mind the following general principles.
(a)All the machine tools or other items of equipments must be placed at the point demanded by the sequence of operations.
(b)There should no points where one line crossed another line.
(c)All the operations including assembly, testing, packing must be included in the line
ADVANTAGES OF PRODUCT LAYOUT
Low cost of material handling, due to straight and short route and absence of backtracking.
Smooth and uninterrupted operations
Continuous flow of work
Lesser investment in inventory and work in progress
Optimum use of floor space
Shorter processing time or quicker output
Less congestion of work in the process
Simple and effective inspection of work and simplified production control
Lower cost of manufacturing per unit
DISADVANTAGES OF PRODUCT LAYOUT
High initial capital investment in special purpose machine
Heavy overhead charges
Breakdown of one machine will hamper the whole production process
Lesser flexibility as specially laid out for particular product.
SUITABILITY OF PRODUCT LAYOUT
Mass production of standardized products
Simple and repetitive manufacturing process
Operation time for different process is more or less equal
Reasonably stable demand for the product
Continuous supply of materials Therefore, the manufacturing units involving continuous manufacturing process, producing few standardized products continuously on the firm’s own specifications and in anticipation of sales would prefer product layout e.g. chemicals, sugar, paper, rubber, refineries, cement, automobiles, food processing and electronics etc.
PROCESS OR FUNCTIONAL LAY OUT : In this type of layout machines of a similar type are arranged together at one place. e.g. Machines performing granulation operations are arranged in the granulation department, machines performing capsulating operations be grouped in the capsulating department. Therefore the machines are installed in the plants, which follow the process layout. The work, which has to be done, is allocated to the machines according to loading schedules with the object of ensuring that each machine is fully loaded. Used when the operations system must handle a wide variety of products in relatively small volumes (i.e., flexibility is necessary).
The grouping of machines according to the process has to be done keeping in mind the following principles;
(1.) The distance between departments should be as short as possible for avoiding long distance movement of materials.
(2) The departments should be in sequence of operations
(3) The arrangement should be convenient for inspection and supervision.
ADVANTAGES OF PROCESS LAYOUT
(1). Lower initial capital investment in machines and equipment. There is high degree of machine utilization, as a machine is not blocked for a single product
(2). The overhead costs are relatively low
(3). Change in output design and volume can be more easily adapted to the output of variety of products
(4). Breakdown of one machine does not result in complete work stoppage
(5). Supervision can be more effective and specialized
(6). There is a greater flexibility of scope for expansion
DISADVANTAGES OF PROCESS LAYOUT
(1) Material handling costs are high due to backtracking
(2) More skilled labour is required resulting in higher cost.
(3) Time gap or lag in production is higher
(4) Work in progress inventory is high needing greater storage space
(5) More frequent inspection is needed which results in costly supervision
SUITABILITY OF PROCESS LAYOUT:
Quantity produced is small units
There are frequent changes in design and style of product
Machines are very expensive Thus, process layout or functional layout is suitable for job order production involving non-repetitive processes and customer specifications and non-standardized products.
Reading exercise: Design/draw a product/line and process or functional plant layout for a pharmaceutical product of any dosage form
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