Tablet Tooling (Eurostandard & TSM Standard)

Different types of tablet die & punch (tooling) grades and their measurements with figure.

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Storage Condition of Pharmaceutical Products.

Storage Condition of Pharmaceutical Products

To ensure the stability of a pharmaceutical preparation for the period of its intended shelf life, the product must be stored in proper conditions. The labeling of each product includes the desired conditions of storage. The terms generally employed in such labeling have meanings defined by the USP (15):

Cold: Any temperature not exceeding 8°C (46°F). A refrigerator is a cold place in which the temperature is maintained thermostatically between 2° and 8°C (36° and 46°F). A freezer is a cold place in which the temperature is maintained thermostatically between −25° and −10°C (−13° and 14°F).

Cool: Any temperature between 8° and 15°C (46° and 59°F). An article for which storage in a cool place is directed may alternatively be stored in a refrigerator unless otherwise specified in the individual monograph. 

Room temperature: The temperature prevailing in a working area. A controlled room temperature encompasses the usual working environment of 20° to 25°C (68° to 77°F) but also allows for temperature variations between 15°C and 30°C (59° and 86°F) that may be found in pharmacies, hospitals, and drug warehouses.

Warm: Any temperature between 30° and 40°C (86° and 104°F).

Excessive heat: Above 40°C (104°F).

Protection from freezing: Where in addition to the risk of breakage of the container, freezing subjects a product to loss of strength or potency or to destructive alteration of the dosage form, the container label bears an appropriate instruction to protect the product from freezing.

Source: Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (Ninth Edition)

The Need for Dosage Forms

The Need for Dosage Forms

Most drug substances are administered in milligram quantities, much too small to be weighed on anything but a sensitive prescription or electronic analytical balance. When the dose of the drug is minute solid dosage forms such as tablets and capsules must be prepared with fillers or diluents so that the dosage unit is large enough to pick up with the fingertips. Besides providing the mechanism for the safe and convenient delivery of accurate dosage, dosage forms are needed for additional reasons:

• To protect the drug substance from the destructive influences of atmospheric oxygen or humidity (coated tablets, sealed ampoules)

• To protect the drug substance from the destructive influence of gastric acid after oral administration (enteric-coated tablets)

• To conceal the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets, flavored syrups)

• To provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle (suspensions)

• To provide clear liquid dosage forms of substances (syrups, solutions)

• To provide rate-controlled drug action (various controlled-release tablets, capsules, and suspensions)

• To provide optimal drug action from topical administration sites (ointments, creams, transdermal patches, and    ophthalmic, ear, and nasal preparations)

• To provide for insertion of a drug into one of the body’s orifices (rectal or vaginal suppositories)

• To provide for placement of drugs directly in the bloodstream or body tissues (injections)

• To provide for optimal drug action through inhalation therapy (inhalants and inhalation aerosols)

Source: Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (Ninth Edition)

The proper Packaging (Containers) of Pharmaceutical Products,Types of Containers, Types of Glass, Types of Plastic Packing Materials, Permeability of Plastic and Glass Materials, Leaching & Sorption

The proper Packaging (Containers) of Pharmaceutical Products

The proper packaging and storage of pharmaceutical products are all essential for product stability and efficacious use.

Containers

Standards for the packaging of pharmaceuticals by manufacturers are contained in the “Current Good Manufacturing Practice” section of the Code of Federal Regulations (1), in the USP–NF (15), and in the FDA’s Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics (16). When submitting an NDA, the manufacturer must include all relevant specifications for packaging the product. During the initial stages of clinical investigations, the packaging must be shown to provide adequate drug stability for the duration of the clinical trials. As the clinical trials advance to their final stage, information on the chemical and physical characteristics of the container, closure, and other component parts of the package system for the proposed product must be developed to ensure drug stability for its anticipated shelf life. Different specifications are required for parenteral, nonparenteral, pressurized, and bulk containers and for those made of glass, plastic, and metal. In each instance, the package and closure system must be shown to be effective for the particular product for which it is intended. Depending on the intended use and type of container, among the qualities tested are the following:

• Physicochemical properties

• Light-transmission for glass or plastic

• Drug compatibility

• Leaching and/or migration

• Vapor transmission for plastics

• Moisture barrier

• Toxicity for plastics

• Valve, actuator, metered dose, particle size, spray characteristics, and leaks for aerosols

• Sterility and permeation for parenteral containers

• Drug stability for all packaging

Types of Containers

According to the USP, a container is “that which holds the article and is or may be in direct contact with the article.” The immediate container is “that which is in direct contact with the article (products) at all times.” The closure is part of the container. The container must not interact physically or chemically with the drug so as to alter its strength, quality, or purity beyond the official requirements. The USP classifies containers according to their ability to protect their contents from external conditions.

The minimally acceptable container is termed a well-closed container. It “protects the contents from extraneous solids and from loss of the article under ordinary conditions of handling, shipment, storage, and distribution.”

A tight container “protects the contents from contamination by extraneous liquids, solids, or vapors, from loss of the article, and from efflorescence, deliquescence, or evaporation under the ordinary or customary conditions of handling, shipment, storage, and distribution and is capable of tight re-closure.”

A hermetic container “is impervious to air or any other gas under the ordinary or customary conditions of handling, shipment, storage, and distribution.”

Sterile hermetic containers generally hold preparations intended for injection or parenteral administration.

A single-dose container is one that holds a quantity of drug intended as a single dose and when opened, cannot be resealed with assurance that sterility has been maintained. These containers include fusion sealed ampoules and prefilled syringes and cartridges.

A multiple-dose container is a hermetic container that permits withdrawal of successive portions of the contents without changing the strength or endangering the quality or purity of the remaining portion. These containers are commonly called vials.

The packaging materials may be combinations of paper, foil, plastic, or cellophane. Some drugs must be packaged in foil-to-foil wrappings to prevent the deteriorating effects of light or permeation of moisture. The packaging of solid dosage forms in clear plastic or aluminum blister wells is perhaps the most popular method of single-unit packaging. Different dosage forms such as oral liquids, suppositories, powders, ointments, creams, and ophthalmic solutions, are also commonly found in single-unit packages.

Some pharmaceutical manufacturers use unit-of- use packaging; that is, the quantity of drug product prescribed is packaged in a container. For example, if certain antibiotic capsules are usually prescribed to be taken four times a day for 10 days, unit-of-use packaging would contain 40 capsules. Many pharmaceutical products require lightresistant containers. In most instances, a container made of a good quality of amber glass or a light-resistant opaque plastic will reduce light transmission sufficiently to protect a lightsensitive pharmaceutical. Agents termed ultraviolet absorbers may be added to plastic to decrease the transmission of short ultraviolet rays. The USP provides tests and standards for glass and plastic containers with respect to their ability to prevent the transmission of light. Containers intended to provide protection from light or those offered as light-resistant containers must meet the USP standards that define the acceptable limits of light transmission at any wavelength between 290 and 450 nm. A recent innovation in plastic packaging is the coextruded two-layer high-density polyethylene bottle, which has an inner layer of black polyethylene coextruded with an outer layer of white polyethylene. The container provides light resistance (exceeding amber glass) and moisture protection. It is increasingly being used in the packaging of tablets and capsules. The glass used in packaging pharmaceuticals falls into four categories, depending on the chemical constitution of the glass and its ability to resist deterioration.

Constitution of Official Glass Types

Type           General Description

I                   Highly resistant borosilicate glass

II                  Treated soda lime glass

III                Soda lime glass

NP               General purpose soda lime glass

The above Table presents the chemical makeup of the various glasses; types I, II, and III are intended for parenteral products, and type NP is intended for other products. Each type is tested according to its resistance to water attack. The degree of attack is determined by the amount of alkali released from the glass in the specified test conditions. Obviously, leaching of alkali from the glass into a pharmaceutical solution or preparation could alter the pH and thus, the stability of the product. Pharmaceutical manufacturers must use containers that do not adversely affect the composition or stability of their products. Type I is the most resistant glass of the four categories. Today, most pharmaceutical products are packaged in plastic. The widespread use of plastic containers arose from a number of factors, including the following:

• Its advantage over glass in lightness of weight and resistance to impact, which reduces transportation costs  and losses due to container damage

• The versatility in container design and consumer acceptance

• Consumer preference for plastic squeeze bottles in administration of ophthalmics, nasal sprays, and lotions

• The popularity of blister packaging and unitdose dispensing, particularly in health care institutions

Types of Plastic Packing Materials (Containers)

The term plastic does not apply to a single type of material but rather to a vast number of materials, each developed to have desired features. For example, the addition of methyl groups to every other carbon atom in the polymer chains of polyethylene will give polypropylene, a material that can be autoclaved, whereas polyethylene cannot.

If a chlorine atom is added to every other carbon in the polyethylene polymer, polyvinyl chloride (PVC) is produced. This material is rigid and has good clarity, making it particularly useful in the blister packaging of tablets and capsules. However, it has a significant drawback for packaging medical devices (e.g., syringes): it is unsuitable for gamma sterilization, a method that is being used increasingly. The placement of other functional groups on the main chain of polyethylene or added to other types of polymers can give a variety of alterations to the final plastic material. Among the newer plastics are polyethylene terephthalate (PET), amorphous polyethylene terephthalate glycol (APET), and polyethylene terephthalate glycol (PETG). Both APET and PETG have excellent transparency and luster and can be sterilized with gamma radiation. Among the problems encountered in the use of plastics in packaging are

 (a) Permeability of the containers to atmospheric oxygen and to moisture vapor,

 (b) Leaching of the constituents of the container to the internal contents,

 (c) Absorption of drugs from the contents to the container,

(d) Transmission of light through the container, and

 (e) Alteration of the container upon storage. Agents frequently added to alter the properties of plastic include plasticizers, stabilizers, antioxidants, antistatic agents, antifungal agents, colorants, and others.

Permeability of Plastic and Glass Materials.

Permeability is considered a process of solution and diffusion, with the penetrant dissolving in the plastic on one side and diffusing through to the other side. Permeability should not be confused with porosity, in which minute holes or cracks in the plastic allow gas or moisture vapor to move through directly. The permeability of a plastic is a function of several factors, including the nature of the polymer itself; the amounts and types of plasticizers, fillers, lubricants, pigments and other additives; pressure; and temperature. Generally, increases in temperature, pressure, and the use of additives tend to increase the permeability of the plastic. Glass containers are less permeable than plastic containers. The movement of moisture vapor or gas, especially oxygen, through a pharmaceutical container can pose a threat to the stability of the product. Most of these adjuncts are carbohydrates, starches, and natural or synthetic gums, and because of their hygroscopicity, they hold moisture and may even serve as nutrient media for the growth of microorganisms. Many of the tablet- disintegrating agents act by swelling, and if they are exposed to high moisture vapor during storage, they can cause tablet deterioration. Specially developed high-barrier packaging can provide added protection to pharmaceutical products against the effects of humidity. Such packaging meets the drug stability requirements adopted by the International Committee on Harmonization, which call for testing of packaged products for a minimum for 12 months at 25°C (77°F) at 60% relative humidity (18). Drug substances that are subject to oxidative degradation may undergo a greater degree of degradation when packaged in plastic than in glass. In glass, the container’s void space is confined and presents only a limited amount of oxygen to the drug contents, whereas a drug packaged in a gas-permeable plastic container may be constantly exposed to oxygen because of the replenished air supply entering through the container. Liquid pharmaceuticals packaged in permeable plastic may lose drug molecules or solvent to the container, altering the concentration of the drug in the product and affecting its potency.

Leaching & Sorption

Leaching is a term used to describe the movement of components of a container into the contents. Compounds leached from plastic containers are generally the polymer additives, such as the plasticizers, stabilizers, or antioxidants. The leaching of these additives occurs predominantly when liquids or semisolids are packaged in plastic. Little leaching occurs when tablets or capsules are packaged in plastic. Leaching may be influenced by temperature, excessive agitation of the filled container, and the solubilizing effect of liquid contents on one or more of the polymer additives. The leaching of polymer additives from plastic containers of fluids intended for intravenous administration is a special concern that requires careful selection of the plastic used. Leached material, whether dissolved in an intravenous fluid or in minute particles, poses a health hazard to the patient. Thus, studies of the leaching characteristics of each plastic considered for use are undertaken as a part of the drug development process. Soft-walled plastic containers of PVC are used to package intravenous solutions and blood for transfusion.

Sorption, a term used to indicate the binding of molecules to polymer materials, includes both adsorption and absorption. Sorption occurs through chemical or physical means due to the chemical structure of the solute molecules and the physical and chemical properties of the polymer. Generally, the un-ionized species of a solute has a greater tendency to be bound than the ionized species. Because the degree of ionization of a solute may be affected by the pH of a solution, the pH may influence the sorption tendency of a particular solute. Furthermore, the pH of a solution may affect the chemical nature of a plastic container so as to increase or decrease the active bonding sites available to the solute molecules. Plastic materials with polar groups are particularly prone to sorption. Because sorption depends on the penetration or diffusion of a solute into the plastic, the pharmaceutical vehicle or solvent used can also play a role by altering the integrity of the plastic. Sorption may occur with active pharmacologic

agents or with pharmaceutical excipients. Thus, each ingredient must be examined in the proposed plastic packaging to determine its tendency. Sorption may be initiated by the adsorption of a solute to the inner surface of a plastic container. After saturation of the surface, the solute may diffuse into the container and be bound within the plastic. The sorption of an active pharmacologic agent from a pharmaceutical solution would reduce its effective concentration and render the product’s potency unreliable. The sorption of pharmaceutical excipients such as colorants, preservatives, or stabilizers would likewise alter the quality of the product. Methylparaben may be sorbed to some types of plastics, resulting in a decrease in the available concentration of the preservative; this may be reflected in a lowering of its preservative effectiveness. Deformations, softening, hardening, and other physical changes in plastic containers can be caused by the action of the container’s contents or external factors, including changes in temperature and the physical stress placed upon the container in handling and shipping. 

 Source: Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (Ninth Edition)

Friability of Tablets.

Friability

Friability is defined as a percent (%) reduction in the mass of the tablets, occurring when the tablets are subjected to mechanical strain during handling.

For tablets with a unit mass equal to or less than 650 mg, take a sample of whole  tablets corresponding as near as possible to 6.5 g. For tablets with a unit mass of more than 650 mg, take a sample of 10 whole tablets. The tablets are carefully dedusted prior to testing. Accurately weigh the tablet sample, and place the tablets in the drum. Rotate the drum 100 times, and remove the tablets. Remove any loose dust from the tablets as before, and accurately weigh.

Drum RPM: 25

Time: 4 minutes

                       Initial Weight – Final Weight

Calculation = --------------------------------------   x   100

                                    Initial Weight

  Friability   =       %

Source: BP 2013

Fumigation Method for Pest Control Used in Aseptic Area

Fumigation: Fumigation is a method of pest control that completely fills an area with gaseous pesticides or fumigants to suffocate or poison the pests within. It is utilized for control of pests. Process: Fumigation usually involves the following phases: First the area to be fumigated is cleaned and disinfected as per SOP Clean up of Aseptic Area. Next the fumigant (40 % formaldehyde solution is widely used as fumigant) is released (create fume by heating the solution with a heater) into the space to be fumigated. After completely evaporation of  formaldehyde solution the space is held for a set period (eg. 6 hours) while the fumigant gas percolates through the space and acts on and kills any infestation in the product, next the space is ventilated so that the poisonous gases are allowed to escape from the space, and render it safe for humans to enter. Preparation of Fumigation Solution: Prescription:  Use formaldehyde at the rate of 2.5-mg/ liter volume space. [1litre º 0.03531466 cft]                                  Take the required quantity of 40 % formalin according to the prescription and add 25 % distilled water to make the stock solution. Calculation: 40 % commercial formalin i.e., 100ml contains 40gm of formaldehyde. According to prescription 1 litre or 0.03531466 cft require 2.5 mg of formaldehyde.                                                                                                 2.5     1 cft require    =                                         mg of Formaldehyde                                           0.03531466                                             2.5 x V     V cft require  =                                          mg of Formaldehyde                                0.03531466        (Where V = Volume of space to be fumigated).                                                                              = 70.792V mg     = 0.070792V   gm         40 gm Formaldehyde from 100ml Commercial formalin                                                   100      1 gm           ,,                       ,,                    ml  Commercial formalin                                                    40                                                                                                                100 x 0.070792V  0.070792V gm  ,,            ,,                                     ml Commercial formalin                                                            40                                                                                                              = 0.17698 V ml commercial formalin  Widely used fumigants include: Formaldehyde Solution Hydrogen Peroxide phosphine 1,3-dichloropropene chloropicrin methyl isocyanate hydrogen cyanide sulfuryl fluoride Iodoform

Parameters and Specification of Dissolution & Disintegration of Tablets

Tablets (Disintegration & Dissolution)     Tablets are solid preparations each containing a single dose of one or more active  substances. They are obtained by compressing uniform volumes of particles or by  another suitable manufacturing technique, such as extrusion, moulding or freeze- drying (lyophilisation). Tablets are intended for oral administration. Some are  swallowed whole, some after being chewed, some are dissolved or dispersed in  water before being administered and some are retained in the mouth where the active  substance is liberated.    The particles consist of one or more active substances with or without excipients  such as diluents, binders, disintegrating agents, glidants, lubricants, substances  capable of modifying the behaviour of the preparation in the digestive tract, colouring  matter authorised by the competent authority and flavouring substances. Several categories of tablets for oral use may be distinguished:   ·            uncoated tablets; ·            coated tablets; ·               effervescent tablets; ·            soluble tablets; ·            dispersible tablets; ·            orodispersible tablets; ·            gastro-resistant tablets; ·            modified-release tablets; ·            tablets for use in the mouth; ·               oral lyophilisates.

Disintegration:

Type of Tablet	Media	Specification	For Out of Specification
UNCOATED TABLETS	Water (37°C ± 2°C)	Not More Than 15 minutes with disc	Repeat the test on a further 6 Tablets
Film-coated Tablets	Water (37°C ± 2°C)	Not More Than 30 minutes with disc	Repeat the test on a further 6 Tablets
Enteric Coated Tablets	0.1 M hydrochloric acid without disc (37°C ± 2°C) (after 2 hours replace 0.1 M HCl Solution with the phosphate buffer)	2 hours remains intake	Repeat the test on a further 6 Tablets
	phosphate buffer  solution pH 6.8   (with disc)         (37°C ± 2°C)	Not More Than 60 minutes with disc
Effervescent Tablet	200 ml Water (15-25 °C)	Not More Than 5 minutes	Repeat the test on a further 5 Tablets
Soluble Tablet	Water (15-25 °C)	Not More Than 3 minutes	Repeat the test on a further 6 Tablets
Dispersible Tablets	Water (15-25 °C)	Not More Than 3 minutes	-------
Orodispersible Tablets	------	Not More Than 3 minutes	------

Dissolution: Four types of apparatuses are now described in the British and European Pharmacopoeias; the basket, the paddle, the reciprocating cylinder and the flow-through cell. The descriptions are concordant with those published in the United States Pharmacopeia (USP).      Of the two established apparatuses (basket and paddle) the paddle is now the apparatus of choice for many preparations. However, where a published test uses the basket, work to validate a change to the paddle method is not contemplated. The reciprocating cylinder is useful for pH profiling studies while the flow-through cell may be appropriate for preparations of poorly soluble active ingredients (see Annex).    Test conditions The harmonised test conditions included in Appendix XII B1 will be applied to all new monographs of the British Pharmacopoeia. It is not the intention of the British Pharmacopoeia Commission to apply these criteria retrospectively to existing monographs. Where an individual monograph prescribes the use of the requirements stated under Monographs of the British Pharmacopoeia in Appendix XII B1, the following conditions using the basket or paddle apparatus are preferred.    Ø  rotation speed:100 rpm (basket), 50 rpm (paddle) Ø  dissolution medium volume: 900 ml   Ø  dissolution medium composition: aqueous, commonly 0.1M hydrochloric acid  or phosphate buffers of pH 6.8 to 7.6 Ø  number of units tested: 6 (plus 6, if a retest is required).    The number of units tested is specified in Appendix XII B1; other conditions are specified in the relevant individual monographs.    In situations where it has been demonstrated that the harmonised criteria are not applicable (e.g. low solubility preparations, 'coning' of material in the vessel, low concentration of analyte), modifications may be made to the test conditions, such as, adding a surfactant, increasing the paddle rotation speed or using a modified vessel and reducing the volume of dissolution medium used.

    

 

Dissolution:

Type of Tablet	Media	Specification	For Out of Specification
UNCOATED TABLETS	0.1 M hydrochloric acid  / phosphate buffer  solution / Water (37°C ± 0.5°C)	Should not be released less than 70% of labeled amount at 45 minutes	Repeat the test on a further 6 Tablets
Film-coated Tablets	0.1 M hydrochloric acid  / phosphate buffer  solution / Water(37°C ± 0.5°C)	Should not be released less than 70% of labeled amount at 45 minutes	Repeat the test on a further 6 Tablets
Enteric Coated Tablets	(media for 2 hours) 0.1 M hydrochloric acid (37°C ± 0.5°C)	Should not be released more than 10% of labeled amount after 2 hours	Repeat the test on a further 6 Tablets
	Then replace the 0.1 M HCl by phosphate buffer  solution pH 6.8  (37°C ± 0.5°C)	Should not be released less than 70% of labeled amount at 45 minutes

                                     

Source: BP 2013