Materials of Pharmaceutical Plants Use

Chapter 11

MATERIALS OF PHARMACEUTICAL PLANT CONSTRUCTION, CORROSION AND ITS PREVENTION

INTRODUCTION

• A number of equipment have been used in the manufacture of pharmaceuticals, bulk drugs, antibiotics, biological products etc. A wide variety of materials are used in making number of equipment. At the dawn of the new millennium, the pharmaceutical and biotechnology industries are seeking ways to leave behind the currently used troublesome materials of construction and to accelerate conversion to problem-freeing, leading-edge, improved material. Throughout this century, the materials of processing equipment construction used in these industries include stainless steel and glass that imposed constant and increasing problems such as rouging, pitting, corrosion, metallic-poisoning, aggravated compliance issues, cost and environmentally adverse cleaning protocols, and inadvertent fracture etc. The development of increasingly sophisticated pharmaceutical manufacturing products and processes are being limited by what can be synthesized, manufactured and stored in glass-lined or, particularly, stainless steel components. Equipment made with wetted surfaces of fluoropolymers, especially Teflon® PFA HP, represents the most functional 21st century material of construction for pharmaceutical and biotechnological research and manufacturing. The non-polar, high service temperature, chemically inert, hydrophobic nature of a fluoropolymer surface provides non-interactive, essentially “force field”-like containment for pharmaceutical and biotechnological process fluid streams. These attributes promise reduced production cost and lessened downtime for regulatory compliance procedures, plus synthesis and process design freedoms. Proven service in the chemical and microelectronics industry for a quarter century give ready evidence of high purity, non-wetting and non-corrosive performance, and a supply of ample equipment for adoption by the pharmaceutical and biotechnology industries. Moreover, fluoropolymer fabricators with similar years of experience can provide desired specialty items. And new fluoropolymer resin offerings from DuPont and other fluoropolymer resin suppliers further enhance the adaptability of this material to satisfy ongoing industries’ needs.

• Pharmaceutical and biotechnology industries confront major challenges such as increased competition, industry consolidation and globalization, high research and development costs, pervasive government guidelines, and extremely demanding manufacturing and distribution requirements.

Objectives:

• To study physical, chemical and mechanical properties of materials used in construction pharmaceutical plants. 
• To study new materials of plant construction for more productive pharmaceutical and biotechnology industry. 
• To understand corrosion, its mechanisms and types and to know about methods of corrosion prevention. 
• To compare the material science of the current materials of construction stainless steel and glass with that of the increasingly adopted material of construction. 
• To compare biochemical and microbiological impact on materials of plant construction. 

• In building a process plant, there are many materials of construction options available to consider. In addition to the applications that dictate what materials are to be needed previous experiences, continuity and plant standards can also play a crucial role in this decision. Common building materials used for process industry include carbon steel, stainless steel, steel alloys, graphite, glass, titanium, plastic, Monel, and many more.

FACTORS AFFECTING MATERIALS SELECTED FOR PHARMACEUTICAL PLANT CONSTRUCTION 

• There are several variables that influence the decision of selecting the best material of construction for any plant. In some cases, the root cause of metal corrosion is selection of materials that are inherently incompatible with the environment. In other cases, corrosion is a result of mechanical design, where incompatible metals are joined together or components meet in a manner that results in narrow spaces between the components. Corrosion can also be the result of faulty manufacturing processes that result in microstructures that render an alloy susceptible to corrosion. The three major variables are corrosion resistance, cost and expected operating life. There are other minor variables such as compatibility of material of construction with existing plant installations, plant operating conditions, ease of maintenance, and cleaning requirements to name a few. While these are less critical, they are still important to keep in mind as you establish the criteria for particular plant. The selection of a material for the construction of equipment depends on the following factors:

Chemical Factors 

Whenever a chemical substance is placed in a container or equipment the chemical is exposed to the material of construction of the container or equipment. Therefore, the material of construction may contaminate the product, or the product may destroy the material of construction.

• Contamination of product: Iron contamination may change the colour of the products (like gelatin capsule shells), catalyze some reactions that may enhance the rate of decomposition of the product. Leaching of glass may make aqueous product alkaline. This alkaline medium may catalyze the decomposition of the product. Heavy metals such as lead inactivate penicillin.

• Destruction of material of construction: The products may be corrosive in nature. They may react with the material of construction and may destroy it. The life of the equipment is reduced. Extreme pH, strong acids, strong alkalis, powerful oxidizing agents, tannins etc. reacts with the materials. It is important to know what chemicals are to be processed. Selection should be done consciously and while selecting appropriate materials that comply with the chemical composition of process it should be ensured that it will perform to the expectations. 

• Chemical inertness: Aggressive reaction environments tend to dissolve metals from unlined mild steel or alloy reactors. Extractable metals, such as chromium, nickel, molybdenum, and copper, can leach into and contaminate product, producing undesired catalytic effects that can cause harmful fluctuations in the process reactions. These metals can compromise product quality, negatively affect product yield, and in some cases even cause runaway reactions.

Physical Factors 

• Strength: The material should have sufficient physical strength to withstand the required pressure and stresses. Iron and steel possess these properties. Tablet punching machine, die, upper and lower punches are made of stainless steel to withstand the very high pressure. Glass though has strength but is brittle. Aerosol container must withstand very high pressure, so tin plate container coated with some polymers (lacquered) are used. Plastic materials are weak, so they are used in some packaging materials, like blister packs.

• Mass: For transportation purpose light weight packaging materials are used. Plastic, aluminum and paper packaging materials are used for packing pharmaceutical products. Wear properties: When there is a possibility of friction between two surfaces the softer surface wears off and these materials contaminate the products. For example, during milling and grinding the grinding surfaces may wear off and contaminate the powder. When pharmaceutical products of very high purity are required ceramic and iron grinding surfaces are not used.

• Thermal conductivity: In evaporators, dryers, stills and heat exchangers the materials employed have very good thermal conductivity. In this case iron, copper or graphite tubes are used for effective heat transfer.

1. Thermal expansion: If the material has very high thermal expansion coefficient, then as temperature increases the shape of the equipment changes. This produces uneven stresses and may cause fractures. In such cases materials used should be able to maintain the shape and dimensions of the equipment at the working temperature conditions.
2. Ease of fabrication: During fabrication of equipment, the materials undergo various processes such as casting, welding, forging and mechanization etc. For example, glass and plastic may be easily molded into containers of different shape and sizes. Glass can be used as lining material for reaction vessels.
3. Cleaning: Some materials of construction can pose housekeeping issues when it comes to ease of cleaning. A smooth and polished surface makes cleaning easier. Glass with an anti-adhesive and nonporous surface resists the build-up of viscous or sticky products. Borosilicate glass is a popular choice for processes where ease of cleaning is critical. Upon completion of an operation the equipment is cleaned thoroughly to avoid contamination of the previous product in to the next product. Glass and stainless-steel surfaces generally being smooth and polished are easy to clean.
4. Sterilization: The ideal feature of glass, the transparency, allows us to see when equipment needs to be cleaned without the need for interrupting the process and performing an internal inspection. In the production of parenteral, ophthalmic and bulk drug products all the equipment are required to be sterilized. This is generally done by introducing steam under high pressure. The materials must withstand this high temperature (121°C) and pressure (15 lb/inch2 ). If rubber materials are being used it should be vulcanized to withstand the high temperature.
5. Transparency: Unlike most plastic and metal materials, glass equipment provides transparency to give an unobstructed view of what is going on inside system, enhancing the observation of process. In reactors and fermenters, a visual port is provided to observe the progress of the process going on inside the chamber. For this purpose, borosilicate glass is often used. In parenteral and ophthalmic containers, the particles, if any, are observed from with polarized light. The walls of the containers must be transparent to see through it. In this case glass is the most preferred material of choice. For photosensitive substances, brown coated glass is also available to offer extra protection. If there is concern over potential mechanical stresses inflicted on the glass, Sectrans coating is applied. This coating covers the glass surface an
d provides protection against scratches, blows and splintering

 Economic Factors

• Owner’s budget is very important. Initial cost of the equipment depends on the material used. Several materials may be suitable for construction from physical and chemical point of view, but from all the materials only the cheapest material is chosen for construction of the equipment. Materials those require lower maintenance cost are used because in long run it is economical. Thus, capital expenditures need to be taken into consideration to ensure that the cost do not exceed the financial limits.

Expected Operating Life  

• Although operational life is less critical, they are still important to keep in mind as we establish the criteria for the plant. It is important to know how long we plan to keep the system in operation. Whether it’s a continuous or batch process, how frequently it is run, and how many years of service we hope to get out of it are all questions that need to be accounted for when determining type of system components to employ

CORROSION 

• Corrosion is defined as the reaction of a metallic material with its surrounding environmental components, which causes a measurable change to the metal and can result in a functional failure of the metallic component or of a complete system.

•  Classification of Corrosion: 

•  According to the environment, corrosion can be classified as. 

1.  Dry corrosion: It involves the direct attack of gases and vapor on the metals through chemical reactions. As a result, an oxide layer is formed over the surface. 
2. Wet corrosion: This corrosion involves purely electrochemical reaction that occurs when the metal is exposed to an aqueous solution of acid and alkali. For example, Zn + 2HCl → ZnCl2 + H2

THEORY OF CORROSION

Corrosion Reaction on Single Metal 

• Corrosion is a natural process, which converts a refined metal to a more chemically stable form, such as its oxide, hydroxide, or sulfide. The mechanisms of corrosion are same at microscopic level and various microstructures, composition, and mechanical design issues leads to different manifestations of corrosion. For example, a single piece of metal, Fe, when comes in contact with acid, HCl, small galvanic cells may be set-up on the surface. Each galvanic cell consists of anode and cathode regions. The interaction taking place at these two regions is as follows.

• Reaction at anode: Fe on the iron liberates two electrons to the metal and itself becomes Fe++ ion. Since Fe++ ion is soluble in water it is released in the medium. This causes corrosion of iron surface.

• Reaction at cathode: The released electron is conducted through the metal piece to the cathode region. Two electrons are supplied to two protons (H+) to form two atoms of hydrogen. Hydrogen atoms being unstable, two H atoms combine to form a stable molecule H2. In the absence of acid, water itself dissociates to generate H+ ion. 2H+ + 2e− → H2 … (11.2) Hydrogen (H2) forms bubbles on the metal surface. If the rate of hydrogen formation is very slow then a film of H2 bubbles will be formed that will slow down the cathode reaction, hence the rate of corrosion will slow down. If the rate of hydrogen production is very high, then hydrogen molecules cannot form the film on the surface. So, the corrosion proceeds rapidly.

Corrosion Reactions between Metals  

• As is known corrosion of metals is an electrochemical reaction involving changes in metal as well as environment in contact with the metal. If two metals come in contact with a common aqueous medium, then one metal will form anode and the other will form cathode. Now, if both the metals are connected with a wire the reaction will proceed. Anode metal will be corroded, and hydrogen will form at the cathode. For example, if zinc and a copper plate are immersed in an acidic medium then zinc will form anode and will be corroded while hydrogen will be formed at copper plate.

• Anode reaction: Zn → Zn++ + 2e− … (11.3) Cathode reaction: 2H+ + 2e− → H2 … (11.4) So anode will be corroded, and hydrogen will be evolved at cathode.

Corrosion Involving Oxygen  

• The oxygen dissolved in the electrolyte can react with accumulated hydrogen to form water. Depletion (reduction) of hydrogen layer allows corrosion to proceed. At cathode: O2 + 2H2 → 2H2O … (11.5) The above reaction takes place in acid medium. When the medium is alkaline or neutral oxygen is absorbed. The presence of moisture also promotes corrosion.

FACTORS INFLUENCING CORROSION:

• The pH of the solution: Iron dissolves rapidly in acidic ph. Aluminum and zinc dissolves both in acidic and alkaline ph. Noble metals such as gold and platinum are not affected by ph. 

• Oxidizing agents: Oxidizing agents may accelerate the corrosion of one class of materials whereas retard another class. For example, O2 reacts with H2 to form water. When H2 is removed corrosion is accelerated. The presence of Cu in NaCl solution also follows this mechanism. Oxidizing agents forms a surface oxide (like Aluminum oxide) and makes the surface more resistant to chemical attack.

• Velocity: When corrosive medium moves at a high velocity along the metallic surface, the rate of corrosion increases. This is due to rapid formation and washing away of corrosion products to expose new surfaces for corrosion reaction. The corrosion is rapid in the bends in the pipes, propellers, agitators and pumps. Due to high velocity the accumulation of insoluble films on the surface is prevented.

• Surface films: thin oxide films are formed on the surface of stainless (rusting). These films absorb moisture and increase the rate of corrosion. For example, zinc oxide forms porous films. Fluid medium can enter inside the surface and thus corrosion continues. Nonporous films of chromium oxide or iron oxide prevent corrosion. Grease films protect the surface from direct contact with corrosive substances. 

TYPES OF CORROSION 

• The corrosion when generally confined to a metal surface as a whole, it is known as general corrosion. This corrosion occurs uniformly over the entire exposed surface area, for example, swelling, cracking, softening of plastic materials. Whereas localized fluid corrosion includes inter-granular, pitting, stress, fretting corrosion and corrosion fatigue. Metabolic action of micro-organisms either directly or indirectly causes deterioration of a metal called biological fluid corrosion.

• As corrosion most often occurs in aqueous environments, the different types of corrosion a metal can experience in such conditions is described below.

Uniform Corrosion 

• Uniform corrosion is the most common type of corrosion and is due to the uniform attack across the surface of a metal. The driving force for this type of corrosion is the electrochemical activity of the metal in the environment to which the metal is exposed. It is most simple to identify as the extent of the attack is judged easily, and the resulting impact on material performance is fairly evaluated due to an ability to consistently reproduce and test the phenomenon. This type of corrosion typically occurs over relatively large areas of an exposed material’s surface. Rust on a steel structure or the green thin layer (patina) on a copper roof are examples of uniform corrosion

Galvanic Corrosion

• Galvanic corrosion, or dissimilar metal corrosion, occurs when two different metals are located together in a corrosive electrolyte. Galvanic corrosion is the degradation of one metal near a joint or juncture that occurs when two electrochemically dissimilar metals are in electrical contact in an electrolytic environment; for example, when copper is in contact with steel in a saltwater environment. However, even when these three conditions are satisfied, there are many other factors that affect the potential for, and the amount of, corrosion, such as temperature and surface finish of the metals. The driving force for the corrosion reaction is the difference in electrode potentials between the two metals. A galvanic couple forms between the two metals, where one metal becomes the anode and the other the cathode. The anode, or sacrificial metal, corrodes and deteriorates faster than it would alone, while the cathode deteriorates more slowly than it would otherwise. Large engineered systems employing many types of metal in their construction, including various fastener types and materials, are susceptible to galvanic corrosion if care is not exercised during the design phase. Choosing metals that are as close together as practicable on the galvanic series help to reduce the risk of galvanic corrosion. In areas where corrosion is a concern, stainless steel products offer value and protection against these threats. Stainless’ favourable chemical composition makes it resistant to many common corrosives while remaining significantly more affordable than specialty alloys such as titanium and Inconel® alloys.

Flow-Assisted or Erosion Corrosion 

• Flow-assisted corrosion (FAC) or erosion corrosion results when a protective layer of oxide on a metal surface is dissolved or removed by wind or water, exposing the underlying metal for further corrosion and deterioration. It leads to erosion-assisted corrosion, impingement and cavitations

 Fretting Corrosion

• Fretting corrosion occurs as a result of repeated wearing, weight and/or vibration on an uneven, rough surface. Corrosion, resulting in pits and grooves, occurs on the surface. Fretting corrosion is often found in rotation and impact machinery, bolted assemblies and bearings, as well as to surfaces exposed to vibration during transportation.

Crevice Corrosion  

• Crevice corrosion is also a localized form of corrosion and usually results from a stagnant micro-environment in which there is a difference in the concentration of ions between two areas of a metal. Crevice corrosion occurs in shielded areas such as those under washers, bolt heads, gaskets etc. where oxygen is restricted. It also occurs in crevices between components and also under polymer coatings and adhesives. These smaller areas allow for a corrosive agent to enter but do not allow enough circulation within, depleting the oxygen content, which prevents re-passivation. As a stagnant solution builds, pH shifts away from neutral. This growing imbalance between the crevice (microenvironment) and the external surface (bulk environment) contributes to higher rates of corrosion. The driving force for the corrosion is the difference between the oxygen concentration inside the crevice and outside the crevice. Crevice corrosion can often occur at lower temperatures than pitting. Proper joint design helps to minimize crevice corrosion.

 Pitting Corrosion 

•  Pitting is one of the most destructive types of corrosion as it can be hard to predict, detect and characterize. Pitting is a localized form of corrosion, in which either a local anodic point, or more commonly a cathodic point, forms a small corrosion cell with the surrounding normal surface. Pitting occurs in metals that are normally passive, when the passive layer breaks down. Once a pit has initiated, it grows into a “hole” or “cavity” that takes on one of a variety of different shapes. Pits typically penetrate from the surface downward in a vertical direction. Pitting corrosion can be caused by a local break or damage to the protective oxide film or a protective coating; it can also be caused by non-uniformities in the metal structure itself. Pitting is dangerous because it can lead to failure of the structure with a relatively low overall loss of metal. Examples of passive metals are aluminum and stainless steel. Pitting is a problem if it leads to weakening or perforation of the metal. In applications where appearance is important pitting is a problem.

EXFOLIATION CORROSION

• Exfoliation corrosion is a more severe form of intergranular corrosion that can occur along aluminum grain boundaries in the fuselage empennage and wing skins of aircraft. These grain boundaries in both aluminum sheet and plate are oriented in layers parallel to the surface of the material, due to the rolling process. The delamination of these thin layers of the aluminum, with white corrosion products between the layers, characterizes exfoliation corrosion. Exfoliation corrosion is often found next to fasteners where an electrically insulating sealant or a sacrificial cadmium plating has broken down, permitting a galvanic action between the dissimilar metals. Where fasteners are involved, exfoliation corrosion extends outward from the fastener hole, either from the entire circumference of the hole, or in one direction from a segment of the hole. In severe cases, the surface bulges outward, but in less severe cases, there may be no telltale blisters, and you can only detect the exfoliation corrosion by nondestructive inspection methods that are not always very effective.

Dealloying 

•  De-alloying, or selective leaching, is the selective corrosion of a specific element in an alloy. This results in the formation of a porous structure that is not strong enough to support the applied mechanical loads. The specific type of corrosion that occurs depends on the several factors including metal composition, metal microstructure, environment, component geometry, stress on the component, contact between metals, and the manner in which components are joined together. The common examples are dezincification of brass alloys used for plumbing, where the zinc is leached out of the alloy forming unsterilized brass. The result of corrosion in such cases is a deteriorated and porous copper.

Intergranular Corrosion 

• Intergranular corrosion is a chemical or electrochemical attack on the grain boundaries of the affected metal. It often occurs due to impurities in the metal, which tend to be present in higher contents near grain boundaries. These boundaries can be more vulnerable to corrosion than the bulk of the metal. The result is that the metal grains fall away, and the metal is weakened. The close microstructure of a metal reveals that the grains are formed during solidification of the alloy as well as at the grain boundaries between them. Intergranular corrosion can be caused by impurities present at these grain boundaries or by the depletion or enrichment of an alloying element at the grain boundaries. It occurs along or adjacent to these grains, seriously affecting the mechanical properties of the metal while the bulk of the metal remains intact. An example of intergranular corrosion is carbide precipitation, a chemical reaction that can occur when a metal is subjected to very high temperatures (800 °F - 1650 °F) and/or localized hot work such as welding. Austenitic stainless steels and precipitation strengthened aluminum alloys are examples of metals that can suffer from intergranular corrosion if the alloys are not properly processed and if they are exposed to corrosive environments. In stainless steels, during these reactions, carbon consumes the chromium forming carbides and causes the level of chromium remaining in the alloy to drop below the 11% needed to sustain the spontaneously forming passive oxide layer. The SS 304L and 316L are enhanced versions of 304 and 316 stainless steel that contain lower levels of carbon providing best corrosion resistance to carbide precipitation. 

Stress Corrosion Cracking  

• Stress corrosion cracking (SCC) is a result of the combination of tensile stress and a corrosive environment, often at elevated temperatures. In most cases, the stress or environment by themselves are insufficient to cause degradation of the metal. That is, if the stress is below the metal’s yield strength the metal would not corrode in the specific environment. It is net result of external stress such as actual tensile loads on the metal or expansion/contraction due to rapid temperature changes. It may also be result of residual stress imparted during the manufacturing process such as cold forming, welding, machining, grinding etc. In stress corrosion, the majority of the surface usually remains intact; however, fine cracks appear in the microstructure, making the corrosion hard to detect. The cracks typically have a brittle appearance and form and spread in a direction perpendicular to the location of the stress. Selecting proper materials for a given environment can mitigate the potential for catastrophic failure due to SCC.

Fatigue or Environmental Cracking Corrosion

• Environmental cracking is a corrosion process that can result from a combination of environmental conditions affecting the metal. Chemical, temperature and stress-related conditions can result in the following types of environmental corrosion: 

1. Stress corrosion cracking. 
2. Corrosion fatigue.
3. Hydrogen-induced cracking. 
4. Liquid metal embrittlement

 High-Temperature Corrosion

• Fuels used in gas turbines, diesel engines and other machinery, which contain vanadium or sulfates during combustion can form compounds with a low melting point. These compounds are very corrosive towards metal alloys normally resistant to high temperatures and corrosion, including stainless steel. High-temperature corrosion can also be caused by high-temperature oxidization, sulfidation, and carbonization. The American Society of Metals (ASM) classified various corrosion.

PREVENTION OF CORROSION

• Although corrosion is a natural process, it can be controlled by using effective methods and strategies. There are mainly five primary ways to control corrosion. Thus, following methods may be adopted for preventing or reducing corrosion:

1. Materials selection
2. Design 
3. Cathodic and anodic protection 
4. Inhibitors
5. Coating

Material Selection

• The most common and important method of controlling corrosion is the selection of the right and proper materials for particular corrosive environments. Corrosion behavior of each metal and alloy is unique and inherent and corrosion of metal and alloy has a strong relation with the environment to which it is exposed. A general relation between the rate of corrosion, corrosivity of the environment and corrosion resistance of materials can be elucidated as follows: Rate of corrosive attack = Corrosion resistance of metal Corrosivity of environment

• The rate of corrosion directly depends upon the corrosivity of the environment and inversely proportional to the corrosion resistance of the metal. Hence, the knowledge of the nature of the environment to which the material is exposed is very important. Moreover, the corrosion resistance of each metal can be different in different exposure conditions. Therefore, the right choice of the materials in the given environment (metal corrosive environment combination) is very essential for the service life of equipment and structures made of these materials. It is possible to reduce the corrosion rate by altering the corrosive medium. The alteration of the corrosive environment can be brought about by lowering temperature, decreasing velocity, removing oxygen or oxidizers and changing concentration. Consideration of corrosion resistance based on the corrosion behavior of the material and the environment in which it is exposed is an essential step in all industry. The alternative materials for some of the corrosive materials are listed.

1. Pure materials have fewer tendencies towards pitting, but they are expensive and soft. Therefore, only aluminum can be used in pure form.
2. Improved corrosion resistance can be obtained by adding corrosion resistant elements. For example, inter-granular corrosion occurs in stainless steel. This tendency can be reduced by addition of small amount of titanium. 
3.  Nickel, copper and their alloys are used in non-oxidizing environment, whereas chromium containing alloys are used in oxidizing environment. 
4.  Materials those are close in electrochemical series should be used for fabrication.
5. Corrosive materials are taken with suitable material of construction:

Proper Design of Equipment 

• The structural design of equipment is equally important as that of choice of materials of construction. It greatly reduces the time and cost associated with corrosion maintenance and repair. The proper design of equipment or tools made-up of metals and alloys must consider mechanical and strength requirements along with corrosion resistance. Prior knowledge about the corrosion resistance of the probable material and the environment in which it is supposed to be functioned is very essential for proper design of any equipment. The most common rule for design is avoiding heterogeneity. As corrosion frequently happens in dead spaces or crevices thus it is recommended to eliminate or minimize such areas while designing. All the components of structures should be designed by considering its expected service life. If not, premature collapse of the component or structure is the inevitable and large sum of money should be spent for its repair or replacement or can go waste. The everchanging environment during the different stages of manufacture, transit and storage as well as the daily and seasonal variations in the environment in which the components are exposed should be taken into consideration for its maximum service life. It is highly important to avoid bimetallic corrosion cells in components by coupling dissimilar metals. The metals involved in coupling should be widely separated in the galvanic series to have a maximum service life of components. Dissimilar corrosion rate can also be minimized by keeping the anodes as large as possible in the particular component or location to reduce the current density. Corrosion using proper design can be minimized in the following conditions:

1. Design for complete drainage of liquids. 
2.  Design for ease of cleaning. 
3. Design for ease of inspection and maintenance
4. A direct contact between two metals should be avoided.
5. They may be insulated from one another.

 Coating or Lining

• Corrosion resistant coating may be applied on metal surface to improve corrosion resistance. It also separates the metal from corrosive environment. Protective coatings are the most generally used method for preventing corrosion. The function of a protective coating is to provide a satisfactory barrier between the metal and its environment. Coatings can be broadly classified as metallic coatings, inorganic coatings and organic coatings. Usually, an anticorrosive coating system is multifunctional with multiple layers with different properties. A typical multifunctional coating can provide an aesthetic appearance, corrosion control, good adhesion, and abrasion resistance. The functioning of any protective coatings is based upon barrier protection, chemical inhibition and galvanic (sacrificial) protection mechanisms. The metals and alloys can be completely isolated from its environment to achieve barrier protection. Protection of metals through chemical inhibition is achieved by adding inhibitor molecules into the coating system. An active metal is coated on the surface of the metal to achieve sacrificial or galvanic protection.

Cathodic and Anodic Protection 

• Cathodic protection is an electrochemical way of controlling corrosion. The object to be protected is the cathode. Cathodic protection is achieved by suppressing the corrosion current in a corrosion cell and by supplying electrons to the metal to be protected. The principle of cathodic protection can be explained with the help of a typical corrosion reaction of a metal ‘M’ in an acid (H+ ) medium. For example, consider an electrochemical reaction in which metal dissolution and hydrogen evolution are taking place; M → Mn+ + ne … (11.7) 2H+ + 2e → H2

• Equations shows that the addition of electrons to the structure would reduce the metal dissolution and increase the rate of evolution of hydrogen. Cathodic protection of a structure can be achieved by an external power supply and appropriate galvanic coupling. Cathodic coupling by galvanic coupling is realized by using active metal anodes, for example, zinc or magnesium, which is connected to the structure to provide the cathodic protection current. In this case, the anode is called a sacrificial anode, since it is consumed during the protection of the steel structure. In contrast to cathodic protection, anodic protection is one of the more recently developed electrochemical methods for controlling corrosion. Anodic protection is based on the principles of passivity, and it is generally used to protect structures used for the storage of sulphonic acid. The difference of anodic protection from cathodic protection is how the metal to be protected is polarized. The component that is to be protected is made as anode in anodic protection. Since the anodic protection is based on the phenomenon of passivity, metals and alloy systems, which exhibit active passive behaviors when subjected to anodic polarization, can be protected by anodic polarization. The corrosion rate of an active-passive metal can be significantly reduced by shifting the potential to the passive range. Anodic protection is used to make a protective passive film on the metal or alloy surface and thereby controlling the corrosion. 

Inhibitors   

• Corrosion inhibitor is a substance that retards corrosion when added to an environment in small concentrations. An inhibitor can be considered as a retarding catalyst that reduces the rate of corrosion. The mechanism of inhibition being complex is not yet well understood. It is established that inhibitors function in following way: 

1. Adsorption of a thin film on the corroding surface of a metal. 
2. Forming a thick corrosion product, or
3. Changing the properties of the environment and thereby slows down the corrosion rate. 

• Corrosion inhibitors can be broadly classified as passivators, organic inhibitors and vapour phase inhibitors. The inhibitors can also be classified based on their mechanism of inhibition and composition. A large number of inhibitors fall under the category of adsorption type inhibitors. These are generally organic compounds and function by adsorbing on anodic and cathodic sites and reduces the corrosion current. Another class of inhibitors is hydrogen evolution poisons. Arsenic and antimony are generally used as hydrogen evolution poisons, and they specifically retard the hydrogen evolution reactions.

• This type of inhibition is very effective only in those environments where hydrogen evolution is the main cathodic reactions and hence these inhibitors are very effective in acid solutions.

• The inhibitive substances, which act by removing the corrosive reagents from solution are known as scavengers. Sodium sulfite and hydrazine are these types of inhibitors, which remove dissolved oxygen from aqueous solutions. These inhibitors function very effectively in those solutions where oxygen reduction is the main cathodic reaction. Oxidizers are also a kind of inhibitors. Substances such as chromate, nitrate, and ferric salts act as corrosion inhibitors in certain systems. Generally, they inhibit the corrosion of metals and alloys that exhibits active-passive transitions. Inorganic oxidizing materials such as chromates, nitrites and molybdates are generally used to passivate the metal surface and shift the corrosion potential to the noble direction. Paint primers containing chromate pigments are widely used to protect aluminum alloys and steel. Inhibitors that are very similar to organic adsorption type with very high vapor pressure are known as vapor phase inhibitors. They are also known as volatile corrosion inhibitors (VCI). VCI’s are secondary-electrolyte layer inhibitors that possess appreciable saturated vapor pressure under atmospheric conditions and thus allow vapour-phase transport of the inhibitive substance. These inhibitors are generally placed very near to the metal surface to be protected and they are transferred by sublimation and condensation to the metal surface. Hence, these inhibitors can be used to protect metals from atmospheric corrosion without being placed in direct contact with the metal surface. Vapour phase inhibitors are very successful, if they are used in closed packages or the interior of equipments. 

MATERIALS USED IN CONSTRUCTION OF PHARMACEUTICAL PLANT   

• Metal is used as structural framework for larger buildings, or as an external surface covering. There are many types of metals used for building and for equipment's. Steel is a metal alloy whose major component is iron and is the usual choice for metal structural construction. It is strong, flexible, and if refined well and/or treated, lasts a long time. Corrosion is metal’s prime enemy when it comes to longevity. The lower density and better corrosion resistance of aluminum alloys and tin sometimes overcome their greater cost. Brass was more common in the past but is usually restricted to specific uses or specialty items today. It requires a great deal of human lab our to produce metal, especially in the large amounts needed for the building industries. Other metals used include titanium, chrome, and gold, silver. Titanium can be used for structural purposes, but it is much more expensive than steel. Chrome, gold, and silver are used as decoration, because these materials are expensive and lack structural qualities such as tensile strength or hardness. Classification of materials used in construction of pharmaceutical plant is as follows.

 Metals:

  Ferrous 

1.  Cast iron
2.   Stainless carbon
3.   Stainless steel  

Non-ferrous 

1.  Lead 
2. Aluminum 

Non-metals: 

Inorganic

Glass 

Organic

1.  Rubber 
2.  Plastic

 FERROUS METALS 

• Steels and cast irons are basic materials of construction for the chemical and pharmaceutical industries. Carbonyl iron and electrolytic iron which contain relatively pure low carbon iron are not suitable for structural materials.

Cast Iron 

• Cast iron consists of more than 1.5% carbon. A different proportion of carbon gives different properties of the steel. Steel is an alloy of iron and carbon, along with small amounts of other alloying elements or residual elements as well. The plain iron carbon alloys contain 0.002 - 2.1% by weight carbon. Steel is manufactured from iron ore. In the blast furnace, pig iron is produced by reducing iron ore. Due to impurities present in pig iron, it becomes hard and brittle. Alloy contents are controlled in order to obtain suitable properties of alloy material. In the newer method of producing steel pure oxygen is blown through the molten metal. Steel may be killed (i.e., made to diequietly in the mold by the addition of deoxidants such as silicon or aluminium), to prevent the reaction of residual oxygen with dissolved carbon during solidification. Killed steels are used down to −28.9 °C in thinner sections, because of their improved Nil-Ductility Transition Temperature (NDTT) as compared with ordinary steels. Permissible temperatures vary with thickness and limits of −60 ºC are sometimes invoked for vessels in cold temperature service.

Properties:

• Cast iron is resistant to concentrated sulfuric acid, nitric acid and diluted alkali. 

• It is attacked by dilute sulfuric acid, dilute nitric acid and dilute and concentrated hydrochloric acid. It has low thermal conductivity. 

• It is not corrosion resistance hence it is alloyed with silicon, nickel or chromium to produce corrosion resistance. 

• It is brittle so it is tough to machine. 

Applications:

• It is used as supports for plants.

• Thermal conductivity is low hence used as the outer wall of steam jacket.

• It is cheap hence used in place of more expensive materials by coating with enamel or plastic.

Carbon Steel or Mild Steel  

• Stainless steel has historically been adopted for containment of chemical processing because it is resistant to more chemicals than is iron or mild steel. It is an inorganic chemical combination of essentially iron, chromium, and nickel. Mild steel (or carbon steel) is an iron alloy that contains a small percentage of carbon (less than 1.5%). Iron and carbon are the two prime constituents of carbon steels. Carbon steels also contains small amounts of manganese. Structural membranes, sheet, pipe, plate and tubing are generally made from carbon steel. Steels that have been worked or wrought while hot are covered with a black mill-scale (i.e., magnetite, Fe3O4) on the surfaces, and are sometimes called black iron. Cold rolled steels have a bright surface, accurate cross-section, increased yield and tensile strength. The latter are preferred for bar-stock to be used for rods, shafts etc.

Properties: 

• Carbon steel has greater mechanical strength than the cast iron. 
• It is easily weldable. 
• It has limited resistance to corrosion. This property can be increased by proper alloying.
• It reacts with caustic soda, brine (conc. NaCl solution) etc.

Applications:

• Carbon steel is used for construction of bars, pipes and plates. 
• It is used to fabricate large storage tanks for water, sulfuric acid, organic solvents etc. 
• It is used as the supporting structures of grinders and bases of vessels.

Stainless Steel  

• Stainless steel is an alloy of iron usually of nickel and chromium. For pharmaceutical use stainless steel contains 18% chromium and 8% nickel. This steel is called 18/8 stainless steel. Products of stainless steel are strong and their initial cost, though higher than iron or mild steel, are often less than other exotic metallurgical materials of construction. Surface physical chemistry of stainless steel is another significant negative for its use in the pharmaceutical and biotechnology industries as it is wettable by aqueous solutions, a characteristic which enhances not only chemical corrosion, but also biofilm adhesion.

• The chemical resistance of stainless steel to certain chemicals can be improved by manipulating the amount of the minor ingredients in the metallurgical formulation. Such improved chemical resistance comes with a corresponding increase in cost. But even such chemical resistance improvement is not sufficient to overcome chemical attack. Stainless steel can be further chemically treated to be made less reactive, i.e., passivated. It is a time consuming and expensive treatment that must be performed regularly to ensure that the iron in this material does not oxidize i.e., rust. Passivation is only temporarily durable. It must be repeated if additional weldments are incorporated into the system. Passivated or not, stainless steel is reactive to many harsh chemicals, particularly chloride and other halides, preventing their beneficial use in pharmaceutical and biotechnological applications.

• The surface irregularities of stainless-steel ranges from 180 grit to 400 grit and can be improved, although with only temporary beneficial effect, to double digit micro inches by electro polishing. Electropolishing is expensive, non-permanent and needs to be repeated often to maintain such a surface.

Properties:  

• Stainless steel has good heat resistant. 
• It exhibits good corrosion resistance.
• Ease of fabrication. 
• Cleaning and sterilization is easy.
• It has good tensile strength. 

• During heat welding the corrosion resistant properties of stainless steel may be reduced due to deposition of carbide that precipitate at the crystal grain boundaries. This steel is stabilized by addition of minor quantities of titanium, molybdenum or niobium.

Advantages:  

• Stainless steel has good corrosion resistance.

• It requires little maintenance, meaning the purchase price is quickly recovered because stainless steel does not require additional coating.  

• It is easy to machine, with most types being easy to cut, malleable, ductile, able to be welded etc.  

• It has good heat resistance and resistance to temperature fluctuations. 

• Very hygienic properties: unaffected by micro-organisms and easy to clean. 

• Attractive appearance, with a variety of possible finishes.

Advantages:

• Stainless steel has good corrosion resistance. 

• It requires little maintenance, meaning the purchase price is quickly recovered because stainless steel does not require additional coating. 

• It is easy to machine, with most types being easy to cut, malleable, ductile, able to be welded etc. 

• It has good heat resistance and resistance to temperature fluctuations. 

• Very hygienic properties: unaffected by micro-organisms and easy to clean. 

• Attractive appearance, with a variety of possible finishes.

NON-FERROUS METALS 

Lead 

• Lead is a weak, heavy metal. It has good resistance to sulfuric acid. In nature, it is usually associated with copper and silver. Applications of lead have been greatly diminished in modern practice, because of toxicity problems associated with its joining.

Properties of Lead:

• Lead is a bluish-white lustrous metal. 
• It is very soft, highly malleable, ductile, and a relatively poor conductor of electricity.
• It is very resistant to corrosion but tarnishes upon exposure to air. 
• Lead isotopes are the end products of each of the three series of naturally occurring radioactive elements.

• Chemical lead: Chemical lead is lead with traces of copper and silver left in it. It is costly to recover the silver and copper content from it to improve the corrosion resistance. 

• Antimonial lead: It is an alloy of lead and antimony. Antimony (2 - 6%) is used to improve the mechanical properties. This is effective up to approximately 93°C, above which both strength and corrosion resistance of the antimonial lead rapidly decreases. 3. 

• Tellurium lead: It is an alloy of lead and tellurium. Tellurium is used to improve its strength. It has better resistance to fatigue failure induced by vibration.

Material Handing Equipements 

• When a large volume has to be moved from a limited number of sources to a limited number of destinations the fixed path equipment's like rollers, belt conveyors, overhead conveyors and gantry cranes are preferred. For increased flexibility varied path equipment's are preferred. Broadly material handling equipment’s can be classified into two categories. 

• Fixed path equipment's: Fixed path equipment's moves in a fixed path. For example, conveyors, monorail devices, chutes and pulley drive equipment's. A slight variation in this category is the overhead crane can move materials in any manner within a restricted area by virtue of its design. Overhead cranes have a very good range in terms of hauling tonnage and are used for handling bulky raw materials, stacking and at times palletizing.

• Variable path equipment's: Variable path equipment have no restrictions in the direction of movement. For example, trucks, forklifts, mobile cranes and industrial tractors. The size of these equipment's is an important factor to be considered. Forklifts are available in many ranges; they are maneuverable and various attachments are provided to increase their versatility. The choice of material-handling equipment among the various possibilities that exist is not easy. In several cases the same material may be handled by various types of equipment's, and the great diversity of equipment and attachments available does not make the problem any easier. In several cases, however, the nature of the material to be handled narrows the choice. Material handing equipment's may be classified in following major categories. 

Plant Layout and Material Handling  

There is a close relationship between plant layout and material handling. A good layout ensures minimum material handling and eliminates rehandling in the following ways: 

• Material movement does not add any value to the finished product so, the material handling should be kept at minimum though not avoid it. This is possible only through the systematic plant layout. Thus a good layout minimizes handling.

• The productive time of workers will go without production if they are required to travel long distance to get the material tools etc. Thus, a good layout ensures minimum travel for workman thus enhancing the production time and eliminating the hunting time and travelling time.

• Space is an important criterion. Plant layout integrates all the movements of men, material through a well designed layout with system. It helps to keep material handling shorter, faster and economical. A good layout reduces material handling system.

• Good plant layout helps in building efficient material handling the material backtracking, unnecessary workmen movement ensuring effectiveness in manufacturing. Thus a good layout always ensures minimum material handling.