Greg Williford05.01.02
Making a tablet-simple isn't it? Buy the ingredients, mix them all together and punch out the tablets. Piece of cake-or so some people believe. Like many seemingly simple functions tableting is not as easy as it appears. The supplement industry has undergone, and is continuing to see, major changes in the way it does business. Smarter consumers, quality conscious and knowledgeable buyers and ever-increasing scrutiny of analytical factors associated with the products has forced manufactures to better control the factors that collectively determine characteristics of the final product, and ultimately whether it passes or fails today's vigorous quality checks.
The industry is moving toward pharmaceutical standards. In fact, tests performed on many supplements today were designed to test drugs and have been borrowed from that industry and tailored to the supplement industry. As a result, many supplements now require dissolution testing, accelerated stability testing and United States Pharmacopoeia (USP) monograph testing on weight, thickness, hardness, friability and disintegration. A finished tablet compliant with all USP and Dietary Supplement Health and Education Act (DSHEA) testing for dissolution, assay and accelerated stability is something to be proud of but in order to achieve such results several important and interrelated factors have to be considered and controlled by the formulator. Depending upon the specific product and client specification, the following four factors are in the order of importance and should be taken into consideration. These include raw materials, processing steps and equipment, analytical objectives and pricing.
In most cases the nature of the active ingredient will dictate the role of the other factors. If the active ingredient makes up the bulk of the tablet vs. a small amount of active such as B12, biotin or folic acid, or is difficult to tablet, the formulator must construct the excipient base appropriately. Not only the amount of active but type of material is an important consideration.
Herbs, vitamins and minerals, fibrous materials and oil-based products all behave differently under compression depending upon the physical characteristics of the material. In addition to the inherent nature of the material, consideration must also be given to the form in which the material is available. Many raw materials are available in powder form, granular form and a combination of both, all of which could provide different results on the same tablet machine.
The expertise and knowledge of the formulator in deciding which materials to specify cannot be underestimated. The objective is always to end up with a free-flowing uniform mixture that gives consistent weights throughout the run and meets the targeted physical specifications and analytical requirements. Fortunately, the improved processing of raw materials has given formulators greater choices from which to choose and more materials are now available as granular instead of powder.
Furthermore, several traditionally difficult materials are now available as coated or spray dried, or put on a substrate to help in the tableting process. Whether it is the result of competitive environment or improved processing with greater flexibility, raw material vendors are more anxious to work with you on obtaining specific forms of the material needed. The variety of raw material forms are helpful in minimizing internal processing requirements and obtaining desired product tableting performance. Also, disintegration agents, lubricants and flow agents are being refined and more directly address specific functions in the tableting process.
Coating materials and systems have also shown improvement over the "old way" of doing things. What used to be the norm-the use of solvents such as methylne chloride, methanol and IPA-has given way to less offensive water-based systems using cellulose. In addition, Zein-a corn based protein and shellac or food glaze-was and still is used by some manufacturers. Materials like Zein worked well for appearance and sealing tablets but they extended disintegration times and interfered with other analytical procedures. In addition, consumers became more conscious of the origins and uses of some of these coatings and began to exclude these products from use.
Another area of importance, is the excipient category. More customers require that no animal or petroleum-based material be used in products, while others object to the use of acids or solvents. More creative forms of cellulose or other botanical-sourced materials are becoming available, which is helping to increase satisfaction levels. That said, raw materials have come a long way in helping manufacturers meet increasing analytical expectations.
To granulate or not to granulate, mill or oscillate, chilsonate or slug, what sequence to blend and how long to blend-these are all important processing decisions that can affect the physical characteristics of the final mix. As previously mentioned, the technical expertise of the formulator is extremely important. If the wrong choice is made, the material will not compress satisfactorily and will have to be reworked to achieve the proper characteristics.
The granulation process involves wetting the raw material and mixing it to introduce granules that, when dried, will facilitate a uniform flow of the material. It is also used to coat certain materials that are sticky or unstable or tend to leak or bleed into the tablet. However, as more directly compressible (granular) and coated materials become available this step is required less and less.
The blending or mixing process creates a uniform and homogenous mixture. Using the wrong equipment on the wrong material or using the correct equipment but over blending, can change particle sizes or over lubricate the material, creating tableting problems. Correct instructions for production should specify mixing times, equipment, and in some cases, loading sequences of material.
Mills, grinders and oscillators are used to control particle sizes by putting the material through several different types of screens. Speed, screen size and charging rate all play a role in determining the end product. This too is another internal processing step that has become less necessary as more choices become available among raw materials.
Dwell time, precompression and tonnage exerted are processing variables that can also affect the material being tableted. As a result, these variables can yield different results from tableting the same material in the same punch shape on three different tablet machines.
Much of the decision making process in determining raw materials and their forms for a specific product is knowing what is expected during the testing process. A timed release or enteric coated product will require different materials and processing steps than will a 30 minute disintegration product. Several countries have their own standards, which differ from the USP monographs and those differences must also be accounted for in the formulation process.
As the industry evolves and moves forward more test requirements and requests for information will come from both consumers and customers. The ability to meet these standards is dependent upon the formulator's expertise and experience, as well as the material choices available in the marketplace. The increased pressure on manufacturers to comply has, again, motivated raw material suppliers to make available both new and improved materials, which provide the formulator with greater control over a tablet's behavior.
Of course, full analytical support to a customer can be expensive. Not only are FT-NIR's (Fourier Transform – Near Infrared), HPLC's ( high pressure liquid chromatograph's), dissolution apparatus' and micro facilities expensive to purchase and maintain, they also require precious room. Since procedures such as dissolution are expensive to do, batch size of the product must be taken into consideration in terms of pricing. Obviously a charge for additional work is less of an impact if spread over two million tablets rather than half a million. Also keep in mind that although many routine tests are included in a normal pricing structure, several customers routinely request either a unique methodology, available only from a specific lab, or a test using specialized equipment.
Another factor in analytical work that may surprise newcomers in the industry is that results can vary. Without going into all of the variables, suffice it to say that any veteran of the industry, at one time or another, has been embroiled in a spitting contest between labs over who had the correct results. For this reason, it is always smart to have an agreement with customers designating an acceptable third party lab to resolve discrepancies.
In today's competitive environment price is always a factor. Several key components of cost include raw materials, processing requirements and analytical requirements. Since the raw materials comprise the bulk of the cost it is important to review pricing on a regular basis.
The key is to get the best price without sacrificing quality or service from your suppliers. If it is hard to choose, it is best to choose the quality material from established vendors using contracts, volume discounts or other mechanisms to get the best price possible. It is also important, however, for R&D departments to keep an open mind to new vendors in the marketplace and innovative materials that contribute to the bottom line. A new material that is more costly per kilogram than a proven "old reliable" could lower costs overall if it reduces one or more processing steps or solves a marginal dissolution situation. Prudent R&D and quality control (QC) decisions dictate documentation and piloting, prior to making wholesale changes. Costs can be looked at on a one time, short term or long term basis but for client and manufacturer, the long term solution will work best.NW
About the author: Greg Williford is vice president, sales and client services for VitaTech International, Tustin, CA. He can be reached at 714-832-9700 or gregw@vitatech.com.
Moving Toward Higher Standards
The industry is moving toward pharmaceutical standards. In fact, tests performed on many supplements today were designed to test drugs and have been borrowed from that industry and tailored to the supplement industry. As a result, many supplements now require dissolution testing, accelerated stability testing and United States Pharmacopoeia (USP) monograph testing on weight, thickness, hardness, friability and disintegration. A finished tablet compliant with all USP and Dietary Supplement Health and Education Act (DSHEA) testing for dissolution, assay and accelerated stability is something to be proud of but in order to achieve such results several important and interrelated factors have to be considered and controlled by the formulator. Depending upon the specific product and client specification, the following four factors are in the order of importance and should be taken into consideration. These include raw materials, processing steps and equipment, analytical objectives and pricing.
Raw Materials
In most cases the nature of the active ingredient will dictate the role of the other factors. If the active ingredient makes up the bulk of the tablet vs. a small amount of active such as B12, biotin or folic acid, or is difficult to tablet, the formulator must construct the excipient base appropriately. Not only the amount of active but type of material is an important consideration.
Herbs, vitamins and minerals, fibrous materials and oil-based products all behave differently under compression depending upon the physical characteristics of the material. In addition to the inherent nature of the material, consideration must also be given to the form in which the material is available. Many raw materials are available in powder form, granular form and a combination of both, all of which could provide different results on the same tablet machine.
The expertise and knowledge of the formulator in deciding which materials to specify cannot be underestimated. The objective is always to end up with a free-flowing uniform mixture that gives consistent weights throughout the run and meets the targeted physical specifications and analytical requirements. Fortunately, the improved processing of raw materials has given formulators greater choices from which to choose and more materials are now available as granular instead of powder.
Furthermore, several traditionally difficult materials are now available as coated or spray dried, or put on a substrate to help in the tableting process. Whether it is the result of competitive environment or improved processing with greater flexibility, raw material vendors are more anxious to work with you on obtaining specific forms of the material needed. The variety of raw material forms are helpful in minimizing internal processing requirements and obtaining desired product tableting performance. Also, disintegration agents, lubricants and flow agents are being refined and more directly address specific functions in the tableting process.
Coating materials and systems have also shown improvement over the "old way" of doing things. What used to be the norm-the use of solvents such as methylne chloride, methanol and IPA-has given way to less offensive water-based systems using cellulose. In addition, Zein-a corn based protein and shellac or food glaze-was and still is used by some manufacturers. Materials like Zein worked well for appearance and sealing tablets but they extended disintegration times and interfered with other analytical procedures. In addition, consumers became more conscious of the origins and uses of some of these coatings and began to exclude these products from use.
Another area of importance, is the excipient category. More customers require that no animal or petroleum-based material be used in products, while others object to the use of acids or solvents. More creative forms of cellulose or other botanical-sourced materials are becoming available, which is helping to increase satisfaction levels. That said, raw materials have come a long way in helping manufacturers meet increasing analytical expectations.
Processing
To granulate or not to granulate, mill or oscillate, chilsonate or slug, what sequence to blend and how long to blend-these are all important processing decisions that can affect the physical characteristics of the final mix. As previously mentioned, the technical expertise of the formulator is extremely important. If the wrong choice is made, the material will not compress satisfactorily and will have to be reworked to achieve the proper characteristics.
The granulation process involves wetting the raw material and mixing it to introduce granules that, when dried, will facilitate a uniform flow of the material. It is also used to coat certain materials that are sticky or unstable or tend to leak or bleed into the tablet. However, as more directly compressible (granular) and coated materials become available this step is required less and less.
The blending or mixing process creates a uniform and homogenous mixture. Using the wrong equipment on the wrong material or using the correct equipment but over blending, can change particle sizes or over lubricate the material, creating tableting problems. Correct instructions for production should specify mixing times, equipment, and in some cases, loading sequences of material.
Mills, grinders and oscillators are used to control particle sizes by putting the material through several different types of screens. Speed, screen size and charging rate all play a role in determining the end product. This too is another internal processing step that has become less necessary as more choices become available among raw materials.
Dwell time, precompression and tonnage exerted are processing variables that can also affect the material being tableted. As a result, these variables can yield different results from tableting the same material in the same punch shape on three different tablet machines.
Analytical Objectives
Much of the decision making process in determining raw materials and their forms for a specific product is knowing what is expected during the testing process. A timed release or enteric coated product will require different materials and processing steps than will a 30 minute disintegration product. Several countries have their own standards, which differ from the USP monographs and those differences must also be accounted for in the formulation process.
As the industry evolves and moves forward more test requirements and requests for information will come from both consumers and customers. The ability to meet these standards is dependent upon the formulator's expertise and experience, as well as the material choices available in the marketplace. The increased pressure on manufacturers to comply has, again, motivated raw material suppliers to make available both new and improved materials, which provide the formulator with greater control over a tablet's behavior.
Of course, full analytical support to a customer can be expensive. Not only are FT-NIR's (Fourier Transform – Near Infrared), HPLC's ( high pressure liquid chromatograph's), dissolution apparatus' and micro facilities expensive to purchase and maintain, they also require precious room. Since procedures such as dissolution are expensive to do, batch size of the product must be taken into consideration in terms of pricing. Obviously a charge for additional work is less of an impact if spread over two million tablets rather than half a million. Also keep in mind that although many routine tests are included in a normal pricing structure, several customers routinely request either a unique methodology, available only from a specific lab, or a test using specialized equipment.
Another factor in analytical work that may surprise newcomers in the industry is that results can vary. Without going into all of the variables, suffice it to say that any veteran of the industry, at one time or another, has been embroiled in a spitting contest between labs over who had the correct results. For this reason, it is always smart to have an agreement with customers designating an acceptable third party lab to resolve discrepancies.
Pricing
In today's competitive environment price is always a factor. Several key components of cost include raw materials, processing requirements and analytical requirements. Since the raw materials comprise the bulk of the cost it is important to review pricing on a regular basis.
The key is to get the best price without sacrificing quality or service from your suppliers. If it is hard to choose, it is best to choose the quality material from established vendors using contracts, volume discounts or other mechanisms to get the best price possible. It is also important, however, for R&D departments to keep an open mind to new vendors in the marketplace and innovative materials that contribute to the bottom line. A new material that is more costly per kilogram than a proven "old reliable" could lower costs overall if it reduces one or more processing steps or solves a marginal dissolution situation. Prudent R&D and quality control (QC) decisions dictate documentation and piloting, prior to making wholesale changes. Costs can be looked at on a one time, short term or long term basis but for client and manufacturer, the long term solution will work best.NW
About the author: Greg Williford is vice president, sales and client services for VitaTech International, Tustin, CA. He can be reached at 714-832-9700 or gregw@vitatech.com.
