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Author Archive | Mike Tousey

Magnesium Stearate in Tablets

Magnesium Stearate in Tablets

Many “health experts” are forcing tablet and capsule manufacturers to eliminate the use of Magnesium Stearate. I have never seen anything work as well and without it tablet quality will suffer. I’m hearing from more and more companies that they must make their tablets without magnesium stearate because of some false claim that it is harmful to cardiovascular health.

Now Foods has a nice write-up and does about as good a job as anything I have read… http://nowfoods.com/Quality/QualityNotes/M093528.htm

Magnesium stearate is used two ways for tablet making.

The first and most common use is as a lubricant. Without it the tablet would bind in the die during compression and ejection forces will break the tablet apart. Without it tooling life would be greatly reduced and the cost of the final product would rise significantly. Too much mag. stearate will reduce tablet hardness and prevent dissolution because it is non-soluble in water. So if it coats a particle completely than the chances that it will dissolve properly are limited. However, most formulas require less 1% magnesium stearate and only a few require as much as 2%.

The second use is to use Mag. Stearate in a pre-blend to reduce positive charges. It can help combine products that want to push each other away. A very small quantity can make a big difference.

The bottom line is that alternative products are not as effective and until something else comes along its use will continue.

Punch Life

Punch Life

I really want to thank you for sending your questions, praise, and for your patience while waiting for my reply. We have been really busy launching two new items.

Our New Training Center: Hands-on training with small groups of people. We have several machines set up to demonstrate how tablets are made and we are teaching individuals the basics of setting up a press, operating it and cleaning. This happens next week, then we have a bigger program in March…come join us.

Our new ILS: An Interactive Learning System designed to incorporate our theory and operations sessions with the clients own equipment and operating procedures. This system allows the new or experienced operator the ability learn or review the procedure(s). There are also self examinations that are recorded to show employee improvement. We have a lot more information on our website.

Ok, back to the question at hand:
Please tell me is there is any method to decide Average punch life?

Determining punch life involves analyzing many variables.

  1.  Punch tool steel type selection has to do the press condition, press speed, compression force required. Premium grades are not always the best choice, it depends of these variables.
  2. Punch Head design: Domed or non-domed heads. Domed heads tend to offer about 20-30% longer life. Round tips last much longer than irregular shaped tooling likes a caplet or oval shape (non-keyed vs. keyed)
  3. Punch Tip design: A good design improves compressibility, air release, and a strong blender land will result in greatly extending the life of a set of punches.
  4. Tablet press condition of: punch sockets, cams, pressure rolls
  5. Powder Abrasiveness: Many powders are very abrasive and will quickly shorten the life of the punch tip
  6. Fine Powders: the higher the percentage of fine dusty powders the greater the potential for binding, poor ejection, tight punches, and exaggerated wear patterns.
  7. Lack of compressibility: Non-granulated powders tend to require higher compression force. The higher the force the greater the wear.
  8. Handling: If tooling is mistreated it can easily shorten the life of a set of tooling from years, to a few months, to only a few days.
  9. Environments variations: Consistency is the key to manufacturing. Big changes in operating temperature and humidity can change the manufacturing dynamics.

Over the years I have inspected tooling that lasted for years and tooling that only lasted a few hours. In the pharmaceutical industry I expect tooling to exceed the 50 million mark. In the Nutritional industry I expect it to last 35 million. For Herbal Products the minimum expected life is 20-25 million. If tooling does not at least make these numbers I would start to look at why and ways to improve. On the other hand I have seen tooling last considerably longer, into the hundreds of millions and still going.

Integrated Learning System

Integrated Learning System

Welcome everyone to 2010 and Happy New Year! We had a great year last year and a great deal of new and exciting things that have us all very pumped! Our new Integrated Learning System is so exciting I can’t wait to tell everyone about it. It takes our work in manufacturing training and puts into everyones facility. Anyone can access a specific unit operation, review an SOP, provides Theory and even can be used test operator knowledge. The approach is simple; we can provide a touch screen kiosk that can be used in a training room or right on the production floor. We can incorporate your processes, equipment, batch records, and all procedures into this system. The ILS (Integrated Learning System) is interactive and can be easily updated with new procedures, testing, and improvements without costing an arm and a leg. We will be posting more information on our website in the next few weeks…please stay tuned.

Compression Force

Compression Force

It is important to first understand that there are a few factors that relate to maximum compression force to take into consideration. The point maybe made easiest when talking about older tablet presses because newer presses can have interchangeable turrets which requires that the tablet press be capable of the higher compression force rated turret. Traditional “B” & “BB” type presses like a Stokes BB2 or a Manesty BB3B type tablet presses have a maximum rating of 4.5 tons (45kn), while a “D” type press like the Stokes D3 and Manesty Unipress 20 have maximum rating of 7-10 tons (70-100kn).

How much compression force do you need? This depends more on the tool tip size than it does on the maximum force rating of the tablet press. As an example I could use a 10 ton press to make a ¼” round diameter tablet. I would simply need to reduce the overload compression force setting to make certain that the press will release to whatever load rating I require. In the case of a ¼” diameter tablet the maximum load a tool can take before bending or breaking would be in the range of 1.0-2.5 tons (10-25kn), so having a press that can exert 10 tons of pressure does little good, unless of course I also need to produce a big ¾” wafer or caplet.

If the formulation is not prepared properly (which happens on a very regular basis) it may take more tonnage to make the tablet than should be safely applied to the tooling (also a very common issue). This is where proper press setup comes into play. The operator should always set the overload pressure release set point (compression force) to the maximum limit of the tooling tip size configuration. Most tablet press manuals contain a chart with the maximum load rating based on tip size. This same information is available in the TSM (Tablet Specification Manual) which is published by the APHA. However, I would suggest that when ordering the tooling from your vendor that you specify that they provide the maximum compression force rating with the tooling order.

If you cannot make a satisfactory tablet within the tooling compression force rating than you must not blame the tooling or the press…you must formulate or process the powders to work within that acceptable force range, period! Many companies make the mistake of going beyond the maximum load rating and damaging the tooling and the press (when a punch breaks nothing good happens).

In summary; most companies do not use the compression force overload adjustment settings correctly which does result in premature wear and damage to the tooling and sometimes the press. Many formulas are not proven and tested properly. Too many companies “validate” a process that turns out to be a mess and does not perform under demands of production.

Sticking

Sticking

Sticking occurs when granules attach themselves to the faces of tablet press punches. Picking is a more specific term that describes product sticking only within the letters, logos, or designs on the punch faces. This article explains the causes of sticking and picking and describes the steps you can take to resolve both problems.

Regardless whether it’s sticking or picking, the result is a defective tablet. To salvage the batch, you may have to visually inspect the tablets. This certainly will slow production and decrease yields, but there is no alternative. The formulation is completed; you can’t send it back down the hallway for reprocessing.

Sticking can happen at any time throughout a batch. It occurs most often at the initial setup of the tablet press, but it might just as easily appear randomly in a production run. It might also appear at regular, predictable times. With some products, sticking is so predictable that operators consider it a success when they can run for 2 hours without any sticking.

Knowing the moisture content, particle size distribution, and other product properties will help you predict whether a product will compress without sticking. However, even products that meet your specifications may stick and pick. The fact is, you may not know how well a product will compress until it is on the tablet press.

The source of the problem may relate to the product, the tooling, the upstream processes, or the operation of the tablet press. It might also be a combination of these factors.

Sticky granules make good tablets…right?

When a tablet press is set up for the first production run, the operator will first adjust the weight cams to get the correct tablet weights. (Actually, you adjust the position of the lower punch in the die. In doing so, you control the volume of the die cavity. At a given bulk density, the die volume will correspond directly to tablet weight.)

Once you have the weights right, adjust tablet thickness next. Tablet hardness is determined by a combination of variables, including tablet weight, tablet thickness, press speed, and the dwell time of the upper punch in the die at full compression force.

Products with granules that are super-sensitive to compression—call them sticky granules—can form excellent tablets. But they are also prone to sticking to the punch faces. If this is the problem on your press, you are likely to see the problem worsen over the course of the production run. That’s because granules super-sensitive to compression will readily compact as they flow through the hopper and into the feed frame.

If a powder compacts before it reaches the die cavity, the bulk density of the formulation increases, impeding your ability to control the tablet weights. As the weight of the tablets fluctuates, so does the compressive force. This variation in force, in turn, can exacerbate the product’s tendency to stick. That starts a downward trend, and that’s why the sticking gets worse and worse.

Experienced tablet press operators know a trick about compression: If sticking is a problem, they quickly over-compress the product and make very hard tablets for a few press revolutions. This quick action, known as “shocking the press” can work very well. Why? The answer is fairly simple: The stronger compaction forces cause the granules to bind with the tablet and pull the stuck granules away from the punch face. Be careful when using this method to shock the press. If you overload the punches, you will damage them or even break them.

Experienced operators can also “save” a sticking batch when inexperienced operators don’t know where to start. Experienced operators, for example, often hear changes in the sound of the press and know that the product is sticking. Their first action might be to change the compression settings, such as by increasing the force, reducing tablet thickness, or by decreasing pre-compression thickness (which makes the tablet thinner and harder). They may even slow the press. A good operator always pays attention to the tablet and the tablet press. The sooner you identify a sticking problem, the faster you can resolve it.

The P’s and Q’s of Tooling:

Sticking and picking are usually the result of many factors, but because they happen on the face of the punch, it’s easy to blame the tooling. Sometimes the blame is placed there correctly, especially in the case of picking.

Picking occurs on the letters, logos, and other designs of the punch face. Usually you’ll find the picking within the “closed” numbers and letters that form “islands.” These numbers are 0, 4, 6, 8, and 9. Some of the letters are A, a, B, b, D, d, e, P, p, Q, q, and so on.

Tooling manufacturers know about these problematic numbers and letters and do a good job of making punch faces that prevent picking. You can even order tooling with a “pre-pick” feature. A pre-pick feature means that the punch face has islands that are not as deep as the rest of the embossing. Despite the shallower islands, the punch still makes a clean, legible indentation. Another strategy is to change the height and angle of the embossing. Doing so produces a tablet with the same appearance but without the picking problem.

Note that tablets destined to receive a coating will have lettering that is less severely angled, wider, and shallower than the lettering on non-coated tablets. Thus, the design of coated tablets helps reduced sticking and picking.

The choice of steel and the degree of polish on the punch will also affect picking. Type D2 and Type 440C steel contain more chromium than other steels, which reduces sticking and picking. High-chrome steels also allow you to achieve a mirror-like polish. Another option is to specify a chrome-plated finish for a hard-faced, wear-resistant surface. However, if the product is abrasive, the chrome-plated finish can wear away quickly. Ask your tooling supplier about these options.

In some cases, changing the tool design and its surface finish is enough to stop sticking and picking. But changing designs could well be a waste of time and money, because many products will stick and pick no matter what changes are made to the punch design.

Air Entrapment:

The act of compression can trap air in the concave cup of the punch face. The deeper the cup, the more likely it is to trap air. This trapped air creates a soft area on the very top of the tablet. In such cases, the granules don’t know whether to stick to each other or to stick within the punch cup. It is similar to making a tablet that is too soft: The granules aren’t sure where or what to stick to.

The solution here is to make certain the punch dwell time is correct and that air evacuation is adequate. The primary way to reduce entrapped air is to increase the force of the pre-compression stage so that there is less air to evacuate during final compression. You should also be certain that the tablet is compressed as high in the die as possible. This is referred to as the depth of upper punch penetration. The higher it is, the easier and faster the air can escape during compression.

If those adjustments are not possible, consider using tapered dies to help get the air out. Talk with your tooling manufacturer. Tooling manufacturers are specialists and they can probably help you solve the problem by adding a taper.

Another possible solution is to specify a tablet shape that uses a compound radius. Doing so “flattens” the very top of the tablet, eliminating the air pocket. The change is slight but effective. Furthermore, it will not cause a noticeable change in the tablet shape or design.

When making a compound radius change to tablet tooling (specifically small tip tooling) you should have the tooling manufacture evaluate the change for additional compression force stress (tooling life) that may come about due to a compound radius change. Otherwise, you maybe exchanging one problem for another.

It is also important to note that a slight change to a tablet shape (even a slight radius change) can negatively impact blister feeding and tablet count when packaging in bottles. This is especially true on high speed blister and bottle packaging lines. Go over this change with the packaging professionals before you committ your site to the new design.

You may discover that new punches are more likely to entrap air than used punches simply because of their tighter clearances. Tight clearances are good, but they can cause air to escape more slowly during compression. With the old tooling, air escapes more quickly so particle-to-particle bonding is more likely. When customers tell me that brand new tooling gives them more hardness, sticking, and capping problems than the older used tooling, I attribute the problems to the tighter clearances of the new tooling and a decrease in the evacuation of air.

Lubricating the Right Way:

The function of a lubricant in the product formulation is to prevent powder from sticking to the punches, dies, and other metal components of the tablet press. A lubricant also facilitates the ejection of compacted tablets. It is not a liquid or oil, but a light, fine powder. Typically, lubricants account for a small percentage of the formula’s content, from 0.25 percent to 2 percent. The most common lubricant in pharmaceutical formulations is magnesium stearate.

Despite the small particle size and the small quantity of the lubricants, they strongly affect your ability to make a good tablet. If they are not blended correctly in the mixture, they will not function as designed. There are two common errors when processing lubricants. The first error is neglecting to pre-screen the lubricants to remove the lumpy, over-size particles. The second error is failing to blend the lubricant evenly into the product formulation. The lubricant must be able to contact the metal parts to work correctly. However, it is better to under-blend the lubricant than to over-blend it. Over-blending will hide the lubricant within the other particles, rendering it useless.

If you run a press without lubricant, you may hear the powder squeaking as it compresses. You will also notice an increase in the force needed to eject the tablet. In fact, the increase may be so great that it damages the punches and the ejection cams. The absence of lubricant or the presence of incorrectly blended lubricant will also lead to sticking.

If you don’t recognize that poor lubrication is causing the sticking problem, you or your colleagues are likely to blame the tooling. The next step in this misdiagnosis is to stop the press, remove the stuck products, and polish the punches before restarting the press. Because polishing the punches can provide short-term relief from sticking, you may repeat this cycle throughout the production campaign. By the time you’re done, you’ll have convinced yourself and your team that the tooling’s loss of polish is the source of the problem. But that is incorrect.

True, polishing the punches can solve a sticking or picking problem temporarily, because many polishes act as mold-release agents. So the act of polishing did nothing more than work this mold-release agent into the surface of the punch. The satisfactory—but temporary—result is a successful production run. Then the product begins to stick again, and you re-polish. Sometimes polishing does no good whatsoever. Other times you might go for an hour or so before sticking resumes.

Some companies accept these short production runs as part of doing business. They expect some products to start OK, and then to stick eventually. They will remove the punches and polish them throughout the run. Ask your operator about the polishing routine. The secret that every press operator knows is that some polishing compound must remain on the punch tips for sticking to stop. They know not to clean the punch tips with isopropyl alcohol, as is standard. If they did, the sticking would return immediately. So is polishing really solving the problem? Not likely.

Even so, a combination of factors may convince you that poorly polished punches are indeed the source of the sticking. Recall that many sticking problems occur at startup, when all the metal components are clean and free of any lubricant. Thus, the punches are prone to sticking. The reaction of most operators when they see sticking is to stop the press, pull the punches, and polish again, even though the punches were just polished.

While they polish the punches, operators might give the press itself only a cursory cleaning. Excess powder is removed, but a thin dusting of the product is left behind. When the punches are reinstalled, the press runs without sticking. Thus, the operators walk away believing that polishing the punches solved the problem when the distribution of the lubricant within the product was actually the source of success.

To prevent sticking at startup, some companies routinely distribute lubricant by hand before tableting. This puts a dusting on the press that prevents sticking at the start. Excess lubricant is gone after the first few press revolutions. Some people think this is unacceptable. But is it any less acceptable than not cleaning the punches after polishing?

Process-Related Sticking:

Some sticking and picking relates to upstream processing. Improperly applying binders or poor drying of the product, for example, can make polishing the punches an hourly event at some companies.

Application of Binder:

During the granulation process, a liquid binder is often added to a powder blend, thus bonding (binding) the ingredients together to form granules. Binders are often called pharmaceutical glue, and to work as planned, the distribution must be even throughout the batch of product and the binders must be uniformly dried.

If binders are not distributed evenly and dried completely, some portions of the blend will contain concentrations of binder. In the drying process, these overly wet granules become dry on the outside, but not on the inside. This is called case-hardening.

Case-hardening can occur even when binder is added correctly but drying was too rapid. Removing the moisture too quickly causes some binder to move to the granule’s exterior. This migration of binder to the granule surface creates a hard shell around other material that may not be completely or evenly dry. This phenomenon leads to two possible causes of sticking: Entrapped moisture and concentrated binder on the granules’ surfaces. Slowing the drying process will sometimes eliminate both problems.

Changing the way you add binders or dry a granulation is easier said than done. Nonetheless, scrutinize all the steps of your methods to find and prevent problems. After all, proper granulating is a fundamental issue when sticking is the problem. Some of you may opt to polish the punches again and again instead of addressing the true cause. Sometimes a company buys new punches which may work better than the old ones, but often only because the new punches are very polished. As discussed earlier, new punches may create a bigger problem because their tighter clearances lead to air entrapment.

Milling:

Many times mills are viewed as ancillary pieces of equipment that you just roll into a vacant room to perform a quick task. That attitude raises several questions: Is this milling step controlled and predictable? Will the operators mill a batch on a Monday at 8 a.m. the same way they do on Friday at 4 p.m.?

Overly fine particles, known as fines, often exhibit poor compression characteristics and may cause sticking. The fines are usually the result of milling friable powders incorrectly or at inconsistent feed rates. With too many of these dust-like particles in the product formulation, it won’t flow or compress well. The fines also create a dusty atmosphere and cause tablet-to-tablet weight fluctuations. Furthermore, fines can get trapped within the logos and lettering on the punch face, especially if the punch design was made to handle a different particle size range.

Non-friable powders can also cause problems. Especially problematic are the powders that are readily compressible, because they can compact during the milling step. Furthermore, some products may re-agglomerate if they are stored too long. In that case, they will need to be de-agglomerated in a low-shear mill before going any further in the process. Products that have re-agglomerated flow poorly and cause weight fluctuations which, in turn, create hardness variations that increase the potential for sticking and picking.

Pinning the Problem on R&D:

Why do products compress into a tablet well in the lab but not on the production floor? We have all had this question at some time. More accurately, you might think that if only the product development team and the R&D people had developed the product correctly, we wouldn’t have sticking, picking, or other problems on the production floor.

There may be some truth to such thinking, but you should understand that identifying operational differences between lab and production equipment is difficult, especially when the product is still under development. Because of scale-up problems, many companies use production-capacity machines when developing products. The substitution of critical ingredients during product development can also hamper scale-up success.

Scale-up:

Some machines scale up better than others. Changing the batch size or a machine’s capacity may or may not give your product its intended attributes. Scale-up guidelines are general, and they don’t always work. I’ve seen plants that use identical or comparable processing machinery to make the same product, but the properties of the products at each plant differ. You can attribute these differences to environmental factors, the skill of the people who work at the plant, or both. There is still a lot of art in the science of tablet making.

Ingredient Substitution:

Many of the ingredients in tablet formulations are expensive, especially in the pharmaceutical industry. Therefore, sometimes a company substitutes a cheap ingredient for an expensive one during product development. Or the company may not have enough of the active pharmaceutical ingredient to make tablets and to perform all the developmental tests. In that case, the company will again use a substitute.

If the substitute doesn’t have the exact attributes of the true ingredient, then test results can lead you in the wrong direction. Time and storage conditions may also cause the ingredient to behave one way in the lab and another way on the plant floor. This may include more fines, de-mixing at the tablet press, and heat sensitivity, all or which may cause sticking.

Conclusion:

The one conclusion you should draw from this article is that a sticking or picking problem can have one or several causes. Polishing the punches during a production run is a temporary fix, not a long-term solution. Environmental factors can affect how well a tablet will form. Some products are so sensitive to temperature and humidity that they may compress differently or not at all with the slightest change in the environment.

If you’re the troubleshooter in charge of solving a sticking problem, evaluate the problem at the press and work upstream from there. Study all the process variables and record as much data as possible. Finally, if you make a change, try to make just one change at a time. This will help you link each change to a result.

Reader’s Solutions:

1. Sticking can also be caused by an incomplete blend and not prescreening the lubricant before the final blend. No two blends are exactly the same! If lubricant is not prescreened then the problem is magnified. Lumps of lubricant will not be properly dispersed within the blend. This will definitely create a picking problem and a dissolution problem.

Also, sticking is not always caused by moisture. Many times the air becomes entrapped during compression, which creates a soft area on the top of the tablet where granules don’t know whether to stick to each other or to the upper punch tip. The solution here is to make certain dwell time and air evacuation is adequate. Increasing precompression hardness and getting the air out during compression is what will solve this problem. Using tapered dies will help get the air out. Sometimes talking to your tooling manufacturer about this problem can help. We see sticking in lettering, due to improper engraving angles, as a common issue. Using a compound radius to flatten out the very top of the tablet, will eliminate the air pocket. This change can be very slight but it can solve the problem without causing any noticeable change in the tablet shape or design.

2. While it may be impractical for a company to completely change their granulating and drying methods, they may be able to modify it somewhat.The case hardening occurs when a granulation is dried too rapidly and the moisture is removed too quickly to carry some of the binder with it to the outside of the granule. This migrating binder is what forms the hard shell on the outside of the granule. This leads to two possible causes of material sticking to the punch faces – the entrapped moisture that Mike referred to and the concentrated binder on the surface of the granule. Sometimes slowing the drying process will eliminate the problem.

If you make it, they will come!

If you make it, they will come!

They being the FDA that is… If you manufacture, package, or label drugs or dietary supplements, you will see the FDA at some point. I have had clients who didn’t think they had to comply if they manufactured the products but someone else packaged and labeled them. I’ve had the opposite too where someone who bought bulk tablets and capsules, then packaged and labeled them didn’t think they needed to comply because they were not manufacturing them. Well, both companies need to comply!

Typically, GMP inspections take place every two years. Drug companies are used to seeing the FDA, but Dietary Supplement companies are new to this. Just to refresh everyone’s memory, supplement companies with more than 500 employees had to be in compliance with the supplement GMP’s, 21 CFR Part 111, by June 25th of 2008. The FDA has been out inspecting these companies and several EIR’s, along with their 483’s are on the FDA’s website. Go to http://www.fda.gov/AboutFDA/CentersOffices/ORA/ORAElectronicReadingRoom/default.htm You’ll need to navigate through them to find the supplement ones, but there is some interesting reading there.

This past June 25th, companies with 20-500 employees had to be in compliance with Part 111. A couple of my clients have already seen the FDA at their facility so that’s proof that FDA is out on the job. So, anyone that didn’t think this was real or that FDA wouldn’t be able to get these inspections done, think again! As I said earlier, if you make it, they will come.

Next June 25th, companies with fewer than 20 employees hit their compliance deadline. My hope is that every company making supplements reads the regulations, apply them to their organization, and be ready when the FDA shows up at your facility.

If you are wondering if you are ready or not, no worries! Techceuticals can definitely help. Contact me at carol@techceuticals.com or give me a call at 843-815-7441 and I will be happy to help answer your questions and provide you with the help you need.

Until next time, have a quality day!

Carol (Brennon) Tousey, ASQ CQA

Blending Basics for Tablet Making

Blending Basics for Tablet Making

Blending in solid dose manufacturing has two objectives; 1) To achieve blend uniformity and 2) to distribute the lubricant. In (objective 1) the blend step(s) are designed to achieve homogeneity of all components prior to the final blend of the lubricant (objective 2). The challenge is that there is no such thing as a perfect blend. Blending is like shuffling a deck of playing cards; there is just no such thing as a perfect shuffle. As with shuffling playing cards, blending powders is even more of a challenge due to particle size, moisture content, structure, bulk density and flow characteristics. The bottom line is that blending techniques for tablet making must produce predictable and repeatable results to achieve content uniformity and proper function. The first step in achieving predictable results in a blend is to introduce the proper particle profile within a range; between 40 – 180 mesh for most oral solid dosages. We do not want any particles larger than 20 mesh and try hard to limit the percentage of fines to less than 20% smaller than 200 mesh. The next step is to complete pre-blending steps in a carefully planned order of addition. In other words we need to blend powders with a strategy. Many formulators blend actives and then excipients, others add based on percentages. Over the years I have found that the best success is to know your objective. Simply realize the goal to deliver an active ingredient that holds together, produces predictable results, disintegrates correctly and dissolves when you want it to, only after having sustained the correct shelf life…so what could be the problem? The best thing is an example of an existing formula; say I have a dry granular formula and a number of overly fine waxy actives, along with a flow agent, bulk agent, and a binder. My first question is how does it flow, then how does it compress and the how does it eject, then how does it disintegrate, dissolve and stability and shelf life. I would use the waxy fine particles to coat the larger dry particles to aid compressibility. Then I would add the binder and bulk agents and test between steps for proper parameters of the deleveloping tablet. Too many formulas are old recipes without rhyme or reason. Many formulas are excellent but are not blended correctly; the key to a successful formula is the order of addition. Since each formula is different there are many factors to be considered for each and every formula. When all ingredients are dumped into the blender, optimization is rarely achieved and many times flow, compression and ejection are put into jeopardy. The key is proper addition including the lubricant. Add the lubricant last, by itself; never blend it with anything else, and only blend for a short duration. Under blending a lubricant is better than over blending it.

I hope this helps….any questions or comments please let us know.

Confused about Raw Material identification Requirements?

Confused about Raw Material identification Requirements?

I understand there is still a great deal of confusion surrounding the Raw Material Identification requirements in the Dietary Supplement GMP’s. I hear from clients daily that they still don’t know what to do, how to do it, and when to do it. Let’s see if we can help clear up some of the questions folks are having out there!

First off, let’s review the regulations so we know why ID testing is required. According to 21 CFR Part 111, Subpart E, 111.75, “before you use a component, you must conduct at least one appropriate test or examination to verify the identity of any component that is a dietary ingredient” What that means is that for every unique lot of incoming dietary supplement ingredients, you will need to conduct at least one test or examination that will confirm the identity of that material before use approve it for use and use it in manufacturing.

Let’s be clear about the unique lot of incoming components before we move on. Let’s say you receive a shipment of Vitamin C. You ordered 500 kilograms of Vitamin C and the shipment arrives at your dock. When you do your receiving inspection, you have 2 50 kilo boxes of lot#A360, 4 50 kilo boxes of lot#B720, and 4 50 kilo boxes of lot#A470. To comply with the regulations, you would need to conduct your identity test of a sample from lots A360, B720, and A470, so you would need to do three identity tests on this incoming shipment because it contains three different lots of material, even though it’s the same material, received at the same time. Its always a good idea to request that your order be filled with one lot of material whenever possible.

Now that you’ve ID tested those three lots, the next time you get a shipment of Vitamin C, it has two lots; A470 and C220. Provided you have it written in your inspection SOP correctly, you would not need to ID test lot A470 again since you’ve already tested it, but you would need to test C220. Make sense?

The next thing to look at is how to do the ID testing. Since no one test or examination will give you all the identity information you need, you really have to know your materials well to specify what test or examination you will do. I once talked with a client who was struggling with how to test one of his incoming materials. He used broccoli in one of his powders. Yup, raw broccoli! He bought fresh broccoli, dehydrated it, then ground it into a powder and used that in his product. We made the examination simple – if you have raw broccoli, a visual and organoleptic test will definitely identify the material as broccoli since nothing else will look and taste like raw broccoli. If he were to buy the broccoli all dried and powdered, then his test would be different. Then he would need a more complex method like FTIR, HPLC, or some other way to detect the chemical markers that provide broccoli’s unique fingerprint. You must spend the time to get to know your materials well so that you can pick the test or examination that will provide you with certainty that the material is in fact what it needs to be. That may be an HPTLC test or it could be a simple microscopic analysis. The thing is, you get to decide what the test is, as long as you can show it is scientifically valid and will provide you with verification that the material is what it says it is. The regulations state that you can use, “gross organoleptic analysis, Macroscopic analysis, microscopic analysis, chemical analysis, or other scientifically valid methods” so as you can see, you have the ability to be creative with your identity testing. Just be sure whatever method you decide to use provides you with verification that the material is what it needs to be.

I’ll give you another example, back in my manufacturing days, the company I worked for used Zinc Oxide as an active ingredient for an OTC drug product. All OTC ingredients need to be identity tested also. The USP listed several different ways to identify this material. One of them was that when heated strongly, zinc oxide would turn from its original white powder form to a yellow powder, then return to white when cooled. I could have sent the material out for IR testing or another form of chemical analysis, but instead, we specified that heat test as the ID test and it worked. It was scientifically valid, fast, and provided verification that the material was in fact what it needed to be. So you see, you can use a test that may seem too simple, but gives you the information you need. But you MUST spend the time getting to know your materials well first!

I hope this helps answer some of the questions out there.

Carol Brennon, ASQ CQA

What is Over-Granulating?

What is Over-Granulating?

What Exactly is “Over-Granulating?”

Over-Granulating results from using too much mechanical energy to mix the wet mass. It may also occur from mixing too long, past the end point. It may also occur from adding too much binding solution. Granules are created through a combination of mechanical energy and the quantity and addition rate of a binder. To some extent, it is also a result of the concentration of the binder in the solution. Over granulating is over processing or over working the powders while the liquid is being added and results in having a negative impact on the final tablet. An over worked granulation my not flow well, compress or eject properly. It may impact hardness, disintegration and dissolution profiles.

Determining Factors for Particle Size of Tablet Formulation

Determining Factors for Particle Size of Tablet Formulation

What are the determining factors for achieving the correct particle size distribution of a tablet formulation? I recall some 30 years ago being taught that the general rule of thumb is: particle size distribution needs to be small enough to go through an 18 mesh screen yet big enough as to not go through a 200 mesh screen. While machine type and condition play a role, the following list of items should also be considered.

Flowability: Generally speaking the smaller the particle the worse the flow. Compare powdered sugar with granular sugar. The fine small particles in powdered sugar aide dissolution but not flow.

Feeder clearance: Particle size must be larger than the feeder clearance to prevent leakage.

Die table run-out: If die table run-out increases, feeder clearance and particle size must also increase proportionately. To check run-out, use a dial indicator to determine the variation of the die table.

Die fill: Wide variations in particle sizes can cause inconsistent fill volumes.

Weight control: Final volume is final weight. Larger particles pulled out of the die can reduce the final weight. Fine particles require more precise scrape-off and increase the need for a good scraper blade.

Compressibility: Improves with increased particle size and decreases as particles become smaller and smaller. Small particles have less ability to lock together during compaction.

Hardness: Smaller particles are more sensitive to over-compression.

Ejection force: Small particles decrease interstitial space and increase drag and friction.

Lubrication levels: In general higher percentages of small particles require increased quantities of lubricant. Magnesium stearate is the most commonly used lubricant and should be de-agglomerated before use.

Disintegration & Dissolution: Small particles decrease disintegration time, and increase dissolution.

Friability: Larger particles usually lock together better which results in reduced friability while small particles often increase the potential for failure (higher friability).

Electro Static effects: Electro static charge is increased as the percentage of small particles increases.

Dust control: Fine particles create a dusty operation, creating a need for frequent production stoppages and press clean-ups.

Environmental conditions: Many products are hygroscopic and sensitive to heat. Variations in room conditions can result in poor flow, compression and ejection conditions.

Lamination & Capping: Small particles are the heart of the most common defects.

Punch lubrication: Dust and super fine particles become airborne and combine with the oils and greases which can produce black specks in tablets.

Tooling condition: Punch tip & die clearance are designed to control air release allowing for improved compaction.

Machine condition: Cleaning and maintenance are downtime issues. A high percentage of fine particles and dust increases the potential for greater wear, increased cleaning frequency, reduced yield, greater particle segregation, and more tablet defects.

Cost: Fines (small dusty particles) increase operating costs, require increased levels of dust collection, decreased yields, increased frequency of cleaning, and generate greater machine & tool wear. Reducing fines will improve tablet quality.

Summary: Establishing an appropriate particle size distribution will improve tablet quality and will reduce overall costs in the long run. Fine dusty particles are the source of most tablet defects.