PHA069-SAS-4.pdf

Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP)...

Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ Lesson title: Commercial Manufacturing (Part I) Materials: Scale-up Manufacturing Techniques and Packaging Material 1. Pen, Paper, SAS Sciences Dosage Forms 2. Remington: The Science and Practice of Pharmacy, 21st Edition Lesson Objectives: 1. Identify basic terms applied in the scale – up manufacturing Reference/s: techniques and packaging materials; 1. https://www.pharmtech.com/view/c 2. Discuss the goal of scale – up manufacturing; ontinuous-manufacturing-eases- 3. Classify the different packaging materials used in the production of scale-solid-dosage pharmaceuticals and its requirements. 2. https://www.pharmaceutical- technology.com/sponsored/pharm aceutical-manufacturing-scale-up/ Productivity Tip: “Take regular breaks! Believe it or not, taking a break will actually increase your productivity. Students who try to cram for hours at a time do not perform at their peak. Our brain can only handle so much new information before we begin to tire and lessen our retention.” A. LESSON PREVIEW/REVIEW 1) Introduction (5 mins) Continuous manufacturing can make scale-up and technology transfer easier in several ways. With some continuous process technologies, the same primary equipment can be used for both the smaller and larger scale, and the equipment is simply run longer to obtain the greater volume. Another advantage is that a set of experiments can be run more quickly on a continuous line than in a batch process, making it easier to define scale-up parameters. According to PhRMA Quality Technical Committee, 2003, Manufacturing science is defined as the body of knowledge available for specific product and process, including critical-to-quality product attributes and process parameters, process capability, manufacturing and process control technologies and quality systems infrastructure. 2) Activity 1: What I Know Chart, part 1 (5 mins) Introductions: In this chart, reflect on what you know now. Answer only the first column, “What I Know”. What I Know Questions: What I Learned (Activity 4) 1. What comes to mind upon hearing scale – up manufacturing? 2. Was there a time you made a bunch of (any) product manually? 3. Was uniformity observed during production of your product? B. MAIN LESSON 1) Activity 2: Content Notes (120 mins) SCALE-UP MANUFACTURING TECHNIQUES Goal of Pilot Plant: The goal of the pilot plant is to facilitate the transfer of a product from the laboratory into production. The effectiveness of the pilot plant is determined by the ease with which new products or processes are brought into routine production. This can best be achieved if a good relationship exists between the pilot plant group and the other groups with which they interact, namely, research and development, processing, packaging, engineering, quality assurance/control (QA/QC), regulatory, and marketing. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ Personnel Requirements o The qualifications required for a position in a pilot plant organization are a blend of good theoretic knowledge of pharmaceutics and some practical experience in the pharmaceutical industry. o The personnel should be able to communicate well, both in speaking and in writing. o The personnel should have the ability to develop good relationships with other people o Personnel in the pilot plant must recognize the intent of the formulator, and at the same time, understand the perspective of production personnel. o The number of people in a pilot plant group depends on the number of products being supported and on the level of support required. Space Requirements o A pilot plant has the following four types of space requirements: Administration and Information Processing Documentation is important. Adequate office and desk space must be provided for both the scientists and technicians. This should be adjacent to the work area but sufficiency isolated to permit people to work without undue distractions. Physical Testing Area The second required area is an adequate working area in which samples can be laid out and examined and where physical tests on these samples can be performed. This area should provide permanent bench-top space for routinely used physical testing equipment (e.g., balance, pH meter, and viscometer). Standard Pilot Plant Equipment Floor Space The third area is discrete plant space where equipment needed for manufacturing all types of pharmaceutical dosage forms is located. Utilization of the area is most efficient when it is subdivided into areas for solid dosage forms, semisolid products, liquid preparations, and sterile products. Storage Area The fourth area and the one most often described as inadequate is storage space. Separate provision should be made for the storage of active ingredients and excipients. These should be further segregated into approved and unapproved areas according to GMPs. Review of the Formula o A thorough review of each aspect of the formulation is important and should be carried out early in the scale-up process. o The purpose of each ingredient and its contribution to the final product manufactured on small-scale laboratory equipment should be understood. Raw Materials o One responsibility of the pilot plant function is the approval and validation of the active and excipient raw materials used in pharmaceutical products. Production Rates o The immediate and future market requirements must be considered when determining the production rates and the type and size of production equipment needed. o The size of the equipment should be such that it is properly utilized. o The equipment and process should be chosen so as to produce batches at a frequency that takes into consideration product loss in the equipment during manufacture, the time required to clean the equipment between batches, and the number of batches that will need to be tested for release. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ Process Evaluation o The previous sections have developed the product scale-up program to the point at which the manufacturing process has been proposed and the equipment for production has been evaluated, selected, installed, and debugged. o The next step is to evaluate the process critically and to optimize its performance based on that evaluation. o Items that should be examined include: Order of addition of components Mixing speed Mixing time Rate of addition of granulating agents, solvents, solutions etc. Filter sizes (liquids) Screen sizes (solids) Drying temperatures Drying time o Knowledge of the effect of these important process parameters on in-process and finished product quality is the basis for process optimization and validation Preparation of Master Manufacturing Procedures o The manner in which the manufacturing directions, the chemical weigh sheet, the sampling directions, and the in-process and finished product specifications are presented is of utmost importance, as is the degree to which the processing technician understands and complies with them. o The processing directions should be precise and explicit. They should be written in a style that uses language and terms with which the operators are familiar. o In writing the manufacturing procedures, considerable input should come from the actual operators or from someone with current knowledge and experience in the weighing and processing areas. o The batch record directions should include specifications for addition rates, mixing times, mixing speeds, heating and cooling rates, and temperature, and appropriate ranges should be given. GMP Considerations o Common sense exercised by people who have a good theoretic knowledge of pharmaceutical principles, and who are technically competent and have adequate relevant experience in manufacturing, guarantees compliance to GMP. o A checklist of GMP items that should be part of scale-up or new product or process introduction includes the following: Equipment qualification Process validation Regularly scheduled preventative maintenance Regular process review and revalidation Relevant written standard operating procedures The use of competent, technically qualified personnel Raw Materials o One responsibility of the pilot plant function is the approval and validation of the active and excipient raw materials used in pharmaceutical products. Production Rates o The immediate and future market requirements must be considered when determining the production rates and the type and size of production equipment needed. o The size of the equipment should be such that it is properly utilized. o The equipment and process should be chosen so as to produce batches at a frequency that takes into consideration product loss in the equipment during manufacture, the time required to clean the equipment between batches, and the number of batches that will need to be tested for release. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ Process Evaluation o The previous sections have developed the product scale-up program to the point at which the manufacturing process has been proposed and the equipment for production has been evaluated, selected, installed, and debugged. o The next step is to evaluate the process critically and to optimize its performance based on that evaluation. o Items that should be examined include: Order of addition of components Mixing speed Mixing time Rate of addition of granulating agents, solvents, solutions etc. Filter sizes (liquids) Screen sizes (solids) Drying temperatures Drying time o Knowledge of the effect of these important process parameters on in-process and finished product quality is the basis for process optimization and validation Preparation of Master Manufacturing Procedures o The manner in which the manufacturing directions, the chemical weigh sheet, the sampling directions, and the in-process and finished product specifications are presented is of utmost importance, as is the degree to which the processing technician understands and complies with them. o The processing directions should be precise and explicit. They should be written in a style that uses language and terms with which the operators are familiar. o In writing the manufacturing procedures, considerable input should come from the actual operators or from someone with current knowledge and experience in the weighing and processing areas. o The batch record directions should include specifications for addition rates, mixing times, mixing speeds, heating and cooling rates, and temperature, and appropriate ranges should be given. GMP Considerations o Common sense exercised by people who have a good theoretic knowledge of pharmaceutical principles, and who are technically competent and have adequate relevant experience in manufacturing, guarantees compliance to GMP. o A checklist of GMP items that should be part of scale-up or new product or process introduction includes the following: Equipment qualification Process validation Regularly scheduled preventative maintenance Regular process review and revalidation Relevant written standard operating procedures The use of competent, technically qualified personnel Adequate provision for training of personnel A well-defined technology transfer system Validated cleaning procedures An orderly arrangement of equipment so as to ease material flow and prevent cross- contamination Transfer of Analytic Methods to Quality Assurance o During the scale-up of a new product, the anaytic test methods developed in research must be transferred to the quality assurance department. o Early in the transfer process, the quality assurance staff should review the process to make sure that the proper analytic instrumentation is available and that personnel are trained to perform the tests. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ Product Considerations 1. Solid Dosage Forms a. Material Handling In up-scale process, mechanical means of handling of materials is necessary. These mechanisms range from simple post hoists or other mechanical devices for lifting, and tilting drums, to more sophisticated methods of handling materials, such as vacuum loading systems, screw feed systems, and metering pumps. The type of system selected also depends on the characteristics of the materials, e.g., density or static charge. B. Dry Blending Powders to be used for encapsulation, or to be granulated prior to tabletting or encapsulation, must be well blended to ensure good drug distribution. The dry blend should take place in the vessel in which any subsequent processing such as granulation occurs. With this, screening and/or milling of the ingredients prior to blending usually makes the process more reliable and reproducible. c. Granulation Reasons for granulation: o To impart good flow properties to the material so that the tablet presses and encapsulators can be properly fed and a uniform tablet or capsule weight maintained, o To increase the apparent density of the powders, and o To change the particle size distribution so that the binding properties on compaction can be improved. Traditionally, wet granulation has been carried out using sigma blade or heavy-duty planetary mixers but can also be prepared using tumble blenders equipped with high-speed blades. d. Drying The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either steam or electricity, and in which the granulation is spread on paper- lined trays on a rack truck, which is then wheeled into the oven where evaporative drying occurs. Fluidized-bed dryers are an attractive alternative to the circulating hot air ovens. e. Reduction of Particle Size Particle size, and especially particle size distribution, is important to the compression characteristics of a granulation. High-speed presses with more elaborate feed systems become important that the equipment chosen can yield the desired throughput while controlling the particle size and size distribution of a granulation. Compression factors that may be affected by the particle size distribution: o Flowability o Compressibility o Uniformity of tablet weight o Content uniformity o Tablet hardness o Tablet color uniformity f. Blending The type of blending equipment used in production operations often differs considerably from that used in the product development laboratories, and certainly differs greatly in size. Attention should be paid to the scale-up operation so that equipment of the right design is used and blender loads, mixing speeds, and mixing times are properly established. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ g. Compression The ultimate test of a tablet formulation and granulation process is whether the granulation can be compressed on a high-speed tablet press. During compression, the tablet press performs the following functions: o Filling of empty die cavity with granulation. o Precompression of granulation (optional). o Compression of granulation. o Ejection of the tablet from the die cavity and take-off of compressed tablet. Machine design also determines the usable range of compression forces at which the machine can safely operate, and the press speed at which output can be optimized without negative impact on tablet quality. h. Tablet Coating Tablet coating, which at one time consisted of sugar coating in conventional coating pans, has undergone many changes because of new developments in coating technology and changes in safety and environmental regulations. The conventional sugar coating pan has given way to perforated pans or fluidized- bed coating columns. The development of new polymeric materials has resulted in a change from aqueous sugar coating to solvent film coating, and more recently, to aqueous film coating. Film coating is a specialized operation, and although film coating systems can be developed in a laboratory, the final coating process needs to be defined on production scale equipment. i. Encapsulation of Hard Gelatin Capsules The manufacturing process for encapsulated products often parallels that for tablets. Both tablets and capsules are produced from ingredients that may be either dry blended or wet granulated to produce a dry powder or granule mix with a uniformly dispersed active ingredient. To produce capsules on today’s high-speed equipment, the processed powder blend must have the particle size distribution, bulk density, and compressibility required to promote , good flow characteristics and to result in the formation of compacts of the right size and of sufficient cohesiveness to be filled into capsule shells. Equipment used in capsule filling operations involves one of two types of filling systems: o Encapsulators manufactured by Zanasi or Martelli form slugs in a dosator (a hollow tube with a plunger to eject the capsule plug) o Operating system of the Hofliger-Karg machines is based on formation of compacts in a die plate using tamping pins to form a compact. 2. Liquid Dosage Forms a. Solutions Simple solutions are the most straightforward to scale up, but then require tanks of adequate size and suitable mixing capability. Most equipment has heating/cooling capabilities to effect rapid dissolution of components of the system. Adequate transfer systems and filtration equipment are required, but they must be monitored to assure that they can clarify the product without selectively removing active or adjuvant ingredients. All equipment must be made of suitable, nonreactive, sanitary materials and be designed and constructed to facilitate easy cleaning. Liquid pharmaceutical processing tanks, kettles, pipes, mills, filter housing, and so forth are most frequently fabricated from stainless steel. Types of stainless steel: o Type 316 – most commonly used o Type 308 Interaction with metallic surfaces can be minimized by use of glass or polytetrafluoroethylene (Teflon) liners. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ b. Suspensions Suspensions require more attention during scale-up than do simple solutions because of additional processing needs. The addition and dispersion of suspending agents it may require use of a vibrating feed system or other novel approach when production scale batches are involved. In preparing pharmaceutical suspensions, the type of mixers, pumps, and mills, and the horsepower of the motors, should be carefully selected based on scale-up performance The equipment must be selected according to the size of the batch and the maximum viscosity of the product during the manufacturing process. At the completion of the batch, the transfer and filling of a finished suspension should be carefully monitored. If suspensions are not constantly mixed or recirculated during transfer processes, they may “settle out” and thereby adversely affect the uniform distribution of the active ingredient. c. Emulsions Emulsions are disperse systems similar to suspensions except that the dispersed phase is a finely divided immiscible liquid instead of a solid. Manufacturing of liquid emulsion products entails specialized procedures, and as a result, scale-up, into production equipment involves extensive process development and validation. Processing parameters and procedures that must be adjusted and controlled for the various types of emulsions include temperature, mixing equipment, homogenizing equipment, in-process or final product filters, screens, pumps and filling equipment. Manufacturing systems that utilize high-shear mixers are more likely to lead to air entrapment and may adversely affect the physical and chemical stability. The use of vessels that can be operated with the contents under a controlled vacuum avoids the problem of unwanted aeration. 3. Semi-solid Products a. Pastes, gels and ointments Pastes, gels, ointments, and creams are closely related to suspensions, liquids, and emulsions except that they are products with higher viscosities. The scale-up of these products involves many of the same factors that must be considered in the scale-up of the comparable lower viscosity products already discussed, but the high viscosity renders certain aspects of the scale-up of semisolid products more critical. For these products, the mixing equipment must be capable of effectively and continuously moving the semisolid mass from the outside walls of the mixing kettle to the center and from the bottom to the top of the kettle. This action is required both to distribute the ingredients and to bring about a rapid and efficient heat transfer to and from the product during the heating and cooling steps. Motors used to drive the mixing system of semisolid manufacturing equipment must be sized to handle the product at its most viscous stage. Pharmaceutical equipment used in the homogenization of the emulsion and dispersion of suspended active ingredients includes various types of high-shear mixers, homogenizers, and colloid mills, supplied by a number of different manufacturers. One of the most common pieces of equipment used for these purposes is a colloid mill consisting of a fixed stator plate and a high-speed rotating rotor plate. Transfer pumps for semisolid products must be able to move viscous material without applying excessive shear and without incorporating air. Pumps designed to meet these criteria are known as positive displacement pumps. In choosing the size and type of pump for a particular operation, product viscosity, desired pumping rate, product compatibility with the pump surfaces, and the pumping pressure required should be considered. b. Suppositories Many commercial suppositories are still produced by a fusion method in which: o A molten mass is prepared o The suppository is molded, cooled in a refrigeration tunnel, and removed from the mold o The product is packaged in an off-line wrapping or blistering operation. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ Preparation of the Molten Suppository Mass o The preparation of the suppository mass on a production scale involves heating various wax-like components of the suppository base to a temperature at which they become molten. o To avoid overheating the waxes and altering their melting points, this operation should be carried out in jacketed vessels in which the jacket temperature can be controlled. o Transfer of the molten mass to the filling heads, of the suppository machine must be done through heated lines Molding and Packaging o Current suppository manufacturing technology utilizes equipment that forms, fills, and seals the suppositories in a continuous process. o The mold for the suppositories is formed from special thermoplastics sheets of PVC, polyethylene, and aluminum foil laminates. o The temperature of the mass during filling is also important. If the molten mass is filled at a temperature more than a few degrees above the congealing point, a hole forms in the center of the suppository upon cooling, owing to excessive contraction. o Filling at too low a temperature causes clogging of the transfer lines and filling nozzles and results in erratic fill weights. o After filling, the shells pass through a cooling tower where the suppositories are allowed to solidify before the ends of the PVC or aluminum shell are sealed. o Then the strips of suppositories are trimmed and cut into the specified length. o The temperature in the cooling tower determines the cooling rate of the suppositories. PACKAGING MATERIALS SCIENCES In the pharmaceutical industry, it is vital that packaging material are its fragility and its the package selected adequately preserve the weight. The selection of the package therefore begins with the determination of the product’s physical and chemical characteristics, it’s protective needs and its marketing requirements. The materials selected must have the following characteristics: o They must protect the preparation from environmental conditions o They must not be reactive with the product o They must not impart to the product tastes or odor o They must be nontoxic o They must be FDA approved o They must meet applicable tamper-resistant requirements o They must be adaptable to commonly employed high-speed packaging equipment Types of Packaging Materials I. Glass containers II. Plastic containers III. Collapsible tubes IV. Closure V. Closure liners VI. Rubber stoppers VII. Tamper-Resistant Packaging This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ I. Glass Containers o Advantages of Glass Commonly used in pharmaceutical packaging because it possesses superior protective qualities, it’s economical and containers are readily available in variety of sizes and shapes. Chemically inert , impermeable, strong and rigid Does not deteriorate with age and with a proper closure system Colored bottles provide excellent barrier against light when required Disadvantages of Glass Fragile Heavy Bulky Composition of Glass Glass is composed principally of sand, soda ash, limestone and cullet. Sand – almost pure silica Soda ash – sodium carbonate Limestone – calcium carbonate Cullet – broken glass which act as fusion agent Boron oxide – helps in the melting process Lead – gives clarity and brilliance Aluminum oxide – used to increase hardness and durability and to increase resistance to chemical action Manufacture of Glass Four basic processes are used in the production of glass: 1. Blowing o Uses compressed air to form molten glass in the cavity of a metal mold. o Most commercial bottles are produced by this method 2. Drawing o Molten glass is pulled through dies or rollers that shape the soft glass. o Rods, tubes, sheet glass and other items of uniform diameter are produced via this method. 3. Pressing o Mechanical force is used to press the molten glass against the side of a mold. 4. Casting o Uses gravity or centrifugal force to cause molten glass to form in the cavity of the mold. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ Glass Types for Drugs Type I: Borosilicate Glass Chemically inert than soda-lime glass The addition of approximately 6% boron to form type I borosilicate glass reduces the leaching action, so that only 0.5 ppm is dissolved in a year. Type II: Treated Soda-lime Glass Type II containers are made of commercial soda-lime glass that has been de- alkalized, or treated to remove surface alkali. The de-alkalizing process is known as “sulfur treatment” and virtually prevents “weathering” of empty bottles. Type III: Regular Soda-lime Glass Containers are untreated and made of commercial soda-lime glass of average or better-than- average chemical resistance. Type NF: General Purpose Soda-lime Glass Containers made of soda-lime glass are supplied for nonparenteral products, those intended for oral or topical use. II. Plastic Containers ADVANTAGES OF PLASTICS DISADVANTAGES OF PLASTICS Versatility Permeation Less cost for transport Sorption Lightweight Leaching of additives Resistant to impact Chemical reactions Readily available Non – environment friendly Consumer appeal Materials A. Polyethylene High-density polyethylene is the material most widely used for containers by the pharmaceutical industry It is a good barrier against moisture, but a relatively poor one against oxygen and other gases. Most solvents do not attack polyethylene, and it is unaffected by strong acids and alkalies. B. Polypropylene Polypropylene does not stress-crack under any conditions. Except for hot aromatic or halogenated solvents, which soften it, this polymer has good resistance to almost all types of chemicals, including strong acids, alkalies, and most organic materials. Its high melting point makes it suitable for boilable packages and for sterilizable products. Lack of clarity is still a drawback, but improvement is possible with the construction of thinner walls. C. Polyvinyl Chloride (PVC) Clear rigid polyvinyl chloride bottles overcome some of the deficiencies of polyethylene. They can be produced with crystal clarity, provide a fairly good oxygen barrier, and have greater stiffness. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ D. Polystyrene General-purpose polystyrene is a rigid, crystal clear plastic. It has been used by dispensing pharmacists for years for containers for solid dosage forms because it is relatively low in cost. At present, polystyrene is not useful for liquid products for the plastic has a high water vapor transmission. E. Nylon (Polyamide) Nylon is made from a dibasic acid combined with a diamine. Nylon and similar polyamide materials can be fabricated into thin-wall containers. Nylon can be autoclaved and is extremely strong and quite difficult to destroy by mechanical means. F. Polycarbonate Polycarbonate can be made into a clear transparent container. This relatively expensive material has many advantages, one being its ability to be sterilized repeatedly. The container is rigid, as is glass, and thus has been considered a possible replacement for glass vials and syringes. G. Polyethylene terephthalate (PET) Polyethylene terephthalate, generally called PET, is a condensation polymer typically formed by the reaction of terephthalic acid or dimethyl terephthalate with ethylene glycol in the presence of a catalyst. Its excellent impact strength and gas and aroma barrier make it attractive for use in cosmetics and mouth washes as well as in other products in which strength, toughness, and barrier are important considerations. Drug Plastic Consideration 1. Permeation The transmission of gases, vapors, or liquids through plastic packaging materials can have an adverse effect on the shelf-life of a drug. Permeation of water vapor and oxygen through the plastic wall into the drug can present a problem if the dosage form is sensitive to hydrolysis and oxidation. Temperature and humidity are important factors influencing the permeability of oxygen and water through plastic. An increase in temperature reflects an increase in the permeability of the gas. 2. Leaching Since most plastic containers have one or more ingredients added in small quantities to stabilize or impart a specific property to the plastic, the prospect of leaching, or migration from the container to the drug product, is present. Problems may arise with plastics when coloring agents in relatively small quantities are added to the formula. Particular dyes may migrate into a parenteral solution and cause a toxic effect. Release of a constituent from the plastic container to the drug product may lead to drug contamination and necessitate removal of the product from the market. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ 3. Sorption This process involves the removal of constituents from the drug product by the packaging material. Sorption may lead to serious consequences for drug preparations in which important ingredients are in solution. Since drug substances of high potency are administered in small doses, losses due to sorption may significantly affect the therapeutic efficacy of the preparation. A problem commonly encountered in practice is the loss of preservatives. These agents exert their activity at low concentration, and their loss through sorption may be great enough to leave a product unprotected against microbial growth. Factors that influence characteristics of sorption from product are chemical structure, pH, solvent system, concentration of active ingredients, temperature, length of contact, and area of contact. 4. Chemical Reactivity Certain ingredients that are used in plastic formulations may react chemically with one or more components of a drug product. At times, ingredients in the formulation may react with the plastic. Even micro-quantities of chemically incompatible substances can alter the appearance of the plastic or the drug product. III. Collapsible Tubes 1. Metal o The collapsible metal tube is an attractive container that permits controlled amounts to be dispensed easily, with good reclosure, and adequate protection of the product. o The risk of contamination of the portion remaining in the tube is minimal, because the tube does not “suck back.” o It is light weight and unbreakable, and it lends itself to high-speed automatic filling operations. a. Tin Tin containers are preferred for foods, pharmaceuticals, or any product for which purity is a paramount consideration. Tin is the most chemically inert of all collapsible tube metals. It offers a good appearance and compatibility with a wide range of products. Among the metals used, tin is considered to be the most expensive one. b. Aluminum Aluminum tubes offer significant savings in product shipping costs because of their light weight. They provide the attractiveness of tin at somewhat lower cost. c. Lead Lead has the lowest cost of all tube metals and is widely used for non-food products such as adhesives, inks, paints, and lubricants. Lead should never be used alone for anything taken internally because of the risk of lead poisoning. With internal linings, lead tubes are used for such products as fluoride toothpaste. d. Linings If the product is not compatible with bare metal, the interior can be flushed with wax- type formulations or with resin solutions, although the resins or lacquers are usually sprayed on. A tube with an epoxy lining costs about 25% more than the same tube uncoated. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ 2. Plastic This distinctive style of package, like its counterpart, the metal collapsible tube, excels in functional characteristics. Plastic tubes have a number of inherent practical advantages over other containers or dispensers: They are low in cost Light in weight Durable Pleasant to touch Flexible, facilitating product dispensing Odorless and inert to most chemicals Unbreakable Leakproof Able to retain their shape throughout their use. They have a unique “suck-back” feature, which prevents product ooze. 3. Laminations This tube, constructed of a lamination containing several layers of plastic, paper, and foil, is fabricated from flat, printed stock. This lamination, which is specifically tailored to the product requirements, is welded into a continuous tube by heat sealing the edges of the lamination together in a machine called a “sideseamer.” IV. Closures The closure is normally the most vulnerable and critical component of a container insofar as stability and compatibility with the product are concerned. An effective closure must prevent the contents from escaping and allow no substance to enter the container. o Threaded Screw Cap When the screw cap is applied, its threads engage with the corresponding threads molded on the neck of the bottle. The screw cap is commonly made of metal or plastics. The metal is usually tinplate or aluminum, and in plastics, both thermoplastic and thermosetting materials are used. Metal caps are usually coated on the inside with an enamel or lacquer for resistance against corrosion. o Lug Cap The lug cap is similar to the threaded screw cap and operates on the same principle. It is simply an interrupted thread on the glass finish, instead of a continuous thread. It is used to engage a lug on the cap sidewall and draw the cap down to the sealing surface of the container. Unlike the threaded closure, it requires only a quarter turn. The lug cap is used for both normal atmospheric-pressure and vacuum-pressure closing. o Crown Caps This style of cap is commonly used as a crimped closure for beverage bottles and has remained essentially unchanged for more than 50 years This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ o Roll-on Closures The aluminum roll-on cap can be sealed securely, opened easily, and resealed effectively. It finds wide application in the packaging of food, beverages, chemicals, and pharmaceuticals. The roll-on closure requires a material that is easy to form, such as aluminum or other light- gauge metals. Pilferproof Closures o The pilferproof clo¬ o sure is similar to the standard roll-on closure o except that it has a greater skirt length. This o additional length extends below the threaded o portion to form a bank, which is fastened to the o basic cap by a series of narrow metal “bridges.” o When the pilferproof closure is removed, the o bridges break, and the bank remains in place on the neck of the container. The user can reseal o the closure, but the detached band indicates that o the package has been opened. Non-reusable Roll-on Closures o In some o packaging applications a reusable cap is not de¬ o sired. Non-reusable caps require unthreaded o glass finishes. The skirts of these closures are o rolled under retaining rings on the glass con¬ o tainer and maintain liner compression. Closures o of this type have tear-off tabs that make them o tamperproof and pilferproof V. Closure Liners o A liner may be defined as any material that is inserted in a cap to effect a seal between the closure and the container. Homogenous Liners These one-piece liners are available either as a disk or as a ring of rubber or plastic. Although they are more expensive and more complicated to apply, they are widely used for pharmaceuticals because their properties are uniform and they can withstand high temperature sterilization. Heterogenous liners These are composed of layers of different materials chosen for specific requirements. In general, the composite liner consists of two parts: a facing and a backing. Usually, the facing is in contact with the product, and the backing provides the cushioning and sealing properties required. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ VI. Rubber Stoppers o Rubber is used in the pharmaceutical industry to make stoppers, cap liners, and bulbs for dropper assemblies. o The rubber stopper is used primarily for multiple-dose vials and disposable syringes. The rubber polymers most commonly used are natural, neoprene, and butyl rubber. o The types of ingredients commonly found in a rubber closure are: Rubber Vulcanizing agent Accelerator/activator Extended filler Reinforced filler Softener/plasticizer Antioxidant Pigment Special components eg. Waxes VII. Tamper Resistant Packaging o A tamper-resistant package is one having an indicator or barrier, to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. o Tamper-resistant packaging may involve immediate-container/closure systems or secondary- container/carton systems or any combination thereof intended to provide a visual indication of package integrity when handled in a reasonable manner during manufacture, distribution, and retail display. The following package configurations have been identified by the FDA as examples of packaging systems that are capable of meeting the requirements of tamper-resistant packaging: a. Film Wrappers Film wrapping has been used extensively over the years for products requiring package integrity or environmental protection. Although film wrapping can be accomplished in several ways and varies in configuration from packaging equipment to packaging equipment, it can be generally categorized into the following types: End-folded Wrapper o The End-Folded Wrapper is formed by pushing the product into a sheet of overwrapping film, which forms the film around the product and folds the edges in a gift-wrap fashion Fin Seal o Unlike the end-folded wrapper configuration, fin seal packaging does not require the product to act as a bearing surface against which the overwrap is sealed. o The seals are formed by crimping the film together and sealing together the two inside surfaces of the film, producing a “fin” seal Shrink Wrapper o The shrink wrap concept involves the packaging of a product in a thermoplastic film that has been stretched and oriented during its manufacture and that has the property of reverting back to its unstretched dimensions once the molecular structure is “unfrozen” by the application of heat. o The major advantages of this type of wrapper are the flexibility and low cost of the packaging equipment required. b. Blister Package This packaging mode has been used extensively for pharmaceutical packaging for several good reasons. It is a packaging configuration capable of providing excellent environmental protection, coupled with an esthetically pleasing and efficacious appearance. It also provides user functionality in terms of convenience, child resistance, and now, tamper resistance. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ c. Strip Package A strip package is a form of unit dose packaging that is commonly used for the packaging of tablets and capsules. A strip package is formed by feeding two webs of a heat-sealable flexible film through either a heated crimping roller or a heated reciprocating plate. d. Bubble Pack The bubble pack can be made in several ways but is usually formed by sandwiching the product between a thermoformable, extensible, or heat-shrinkable plastic film and a rigid backing material. This is generally accomplished by heat-softening the plastic film and vacuum drawing a pocket into the film in a manner similar to the formation of a blister in a blister package. e. Shrink Banding The shrink band concept makes use of the heat-shrinking characteristics of a stretch-oriented polymer, usually PVC. The heat-shrinkable polymer is manufactured as an extruded, oriented tube in a diameter slightly larger than the cap and neck ring of the bottle to be sealed. For ease of opening, the shrink bands can be supplied with tear perforations. f. Bottle Seals A bottle may be made tamper-resistant by bonding an inner seal to the rim of the bottle in such a way that access to the product can only be attained by irreparably destroying the seal. Various inner seal compositions may be used, but the structures most frequently encountered are glassine and foil laminations. g. Tape Seals Tape sealing involves the application of a glued or pressure-sensitive tape or label around or over the closure of the package, which must be destroyed to gain access to the packaged product. The paper used most often is a high-density lightweight paper with poor tear strength. h. Breakable Caps Breakable closures come in many different designs: Roll-cap design o Used in the past for carbonated beverages uses an aluminum shell, which is placed over the bottle neck during the capping operation Ratchet-style design o In here, the bottom portion of the closure has a tear-away strip, which engages a ratchet on the bottle neck. o To remove the closure, the bottom portion of the closure must be torn away to disengage the ratchet and allow the removal of the cap. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ Activity 3: Skill-building Activities (7 mins + 3 mins checking) Give what is asked: 1. A pilot plant has the following four types of space requirements: 2. Compression factors that may be affected by the particle size distribution: 3. The types of ingredients commonly found in a rubber closure are: 4. What are the drug plastic consideration? 5. Discuss the goal for scale- up manufacturing in 2 sentences. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ Activity 5: Check for Understanding (10 mins) Multiple Choice. 1. A manufacturing plant has the following types of space requirements except: A. Raw Materials Area B. Physical Testing Area C. Storage Area D. Standard Pilot Plant Equipment Floor Space E. Administration and Information Processing 2. The following are compression factors that may be affected by the particle size distribution except: A. Flowability B. Tablet hardness C. Compressibility D. Spreadability E. Uniformity of tablet weight 3. This is commonly used in pharmaceutical packaging because it possesses superior protective qualities, it’s economical and containers are readily available in variety of sizes and shapes. A. Glass B. Plastic C. Metal D. Paper E. None of the above 4. Which among the following is not a process used in the production of glass? A. Casting B. Blowing C. Drawing D. Pressing E. Milling 5. This process involves the removal of constituents from the drug product by the packaging material. A. Leaching B. Sorption C. Permeation D. Osmosis E. Chemical Reactivity Activity 4: What I Know Chart, part 2 (2 mins) Instruction: To review what was learned from this lesson, please go back to Activity 1 and answer the “What I learned” column. Notice and reflect on any changes in your answers from what you know before answering your SAS and after answering your SAS. This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ C. LESSON WRAP-UP Activity 6: Thinking about Learning (5 mins) Work Tracker. You are done with this session! Let’s track your progress. Shade the session number you just completed. P1 P2 1 2 3 4 5 6 7 8 9 10 A. Think about your Learning. Tell me your thoughts! What struck you the most? Explain. --------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------------- FAQs 1. Is it possible to manufacture drugs at large scale? In the transition from phase 1 to manufacturing, operators may need to scale up their operation several times over, each time making sure they set themselves safe and realistic goals. A successful product may go through the scaling process several times during its commercial time (2). Click this link for the video: https://www.youtube.com/watch?v=daGFjQPizK8&t=93s 2. Which type of package is used by pharmaceutical industry? Some commonly used types of primary pharmaceutical packaging are ampules, vials, blister packs, bottles, and sachet packaging. Click this link for the video: https://www.youtube.com/watch?v=lHtfCjJ8Vis This document is the property of PHINMA EDUCATION  Course Code: PHA 069: Pharmaceutical Manufacturing (with Regulatory Pharmacy, Quality Assurance, and cGMP) Student Activity Sheet #4 Name:______________________________________________________________ Class number: _______ Section: ____________ Schedule:________________________________________ Date:________________ KEY TO CORRECTIONS Activity 3 ESSAY. 1.A pilot plant has the following four types of space requirements: Administration and Information Processing Physical Testing Area Standard Pilot Plant Equipment Floor Space Storage Area 2.Compression factors that may be affected by the particle size distribution: Flowability Compressibility Uniformity of tablet weight Content uniformity Tablet hardness Tablet color uniformity 3.The types of ingredients commonly found in a rubber closure are: Rubber Vulcanizing agent Accelerator/activator Extended filler Reinforced filler Softener/plasticizer Antioxidant Pigment Special components eg. Waxes 4. What are the drug plastic consideration? Permeation Leaching Sorption Chemical reactivity 5.Discuss the goal for scale- up manufacturing in maximum of 2 sentences.. Answers may vary This document is the property of PHINMA EDUCATION