WO2007098446A2

WO2007098446A2 - Method for minimizing variation in dosage forms

Info

Publication number: WO2007098446A2
Application number: PCT/US2007/062436
Authority: WO
Inventors: Lawrence Solomon
Original assignee: Accu-Break Pharmaceuticals, Inc.
Priority date: 2006-02-21
Filing date: 2007-02-20
Publication date: 2007-08-30
Also published as: WO2007098446A3

Abstract

Described are dosage forms and methods of manufacture of dosage forms containing one or more active ingredients, principally pharmaceuticals, which have, inter alia, less tablet-to-tablet variation,

Description

METHOD FOR MINIMIZING VARIATION IN DOSAGE FORMS

FIELD OF THE INVENTION

The invention is directed to novel dosage forms and novel methods of manufacture of dosage forms containing one or more active ingredients, principally pharmaceuticals.

BACKUKOUNU Ob THh INVbN 1 ION

Specifications and standards that arc set for the manufacture of pharmaceutical dosage forms take into account the inevitable but imdcsired variation within unit doses produced from the same materials during the same production run according to the same formula (content uniformity issues), as well as variation from lot to lot wilh regard to the average amount of active drug found in the dosage forms comprising each lot. There may be variation between the mass or quantity of drug contained in dosage forms such as tablets.

Examples of these specifications may be found within the current editions of the United States Pharmacopoeia ("USP") and the European Pharmacopoeia ("EP'^"), which are incorporated herein by reference. 'Hie USP and EP have propounded both general and product-specific standards on these product variation matters. Regulatory authorities such as the US Food and Drug Administration (1''DA) also set specifications, including acceptable variation ranges, on which to base approval or rejection of marketed drug prodticts. Such standards are intended to provide limits on the undesired variation between doses.

These standards are further beneficial because many products undergo subdivision, such as tablets that are broken from time to time into (wo parts usually intended to be equal halves. Such subdivision is, however, generally imprecise and may provide dosage variations between each of the tablet halves.

This dosage variation in tablet portions is undesirable on its own. but is further undesirable given tablet to tablet variation in the intact, whole dosage forms, Therefore, breaking each of two whole tablets (each likely differing in dose) may provide four portions having a greater variation between those portions than the variation between the original whole tablets.

Unintended variation in dosing on a day to day basis thus occurs for essentially all users of pharmaceuticals, and may have adverse effects. These effects may be especiaily important for medications such as warfarin. L-lhyroxine and other drugs such as those in the classes of narcotics, hypoglycemic agents, and vasoactive drugs, for which physicians closely regulate blood levels or their effects. Thus, these drugs are especially preferred to be given in a dose that is as precise as possible.

SUMMARY OF THE INVENTION The current invention is directed to a method of manufacturing a composition, e.g., a dosage form, such as a pharmaceutical product or drug product, in a manner that diminishes both the variation of mass and/or the amount or content of active drug(s) in these dosage forms in comparison to techniques currently known in the art.

The subject invention also concerns a composition produced by the subject method. The novel composition, e.g., a dosage form made in accordance with the subject method is advantageously adapted for increased dosing accuracy of active ingredients contained therein.

The subject invention is especially concerned with a method for diminishing the variation within a "lot^"' of dosage forms; or between the average amount of drug per dosage form present in different lots of dosage forms produced according to the same formula, and with dosage forms that accomplish this improvement in the art.

More specifically, the subject invention includes but is not limited to a method of producing a composition comprised of material also herein called "fill material." "Fill material" is material which is, or is intended to be, dispensed or placed, (i.e., "filled") into Λ receptacle to make a desired composition. Fill material may for example be solid (e.g., a powder or granulation for placement into a die to form a compressed tablet), a liquid (e.g., a mixture, a solution, or melted wax or polymeric solution filling into a mold), or a gas (e.g., an gas anesthetic for dispensing into a compressed- gas container), ^'ihe receptacle may be such as a tablet die, a capsule, a glass container such as an ampoule, a vial, a bottle, a mold, a canister, and the like. ^'Ihe term "receptacle" is non-limiting. Generally the receptacle will provide a shape or form to a solid composition or a liquid or gas that solidifies and will contain a liquid or gas composition that remains a liquid or a gas.

The subject method includes but is not limited to the following embodiments:

(1) Using a plurality of dispensing steps to dispense fill material that has been prepared as a single batch (e.g., dispensing A first portion of the batch, then dispensing a second portion of the batch, both of said portions comprising the unit dosage form;

(2) Dispensing from a first batch of fill material a portion of a final desired amount into a receptacle followed by dispensing a into the receptacle a portion of fill material from a second, separately-produced batch of fill material produced according to the same formula or similar formulae, both of said portions comprising the unit dosage form; and

(3) Dispensing into a receptacle a fill material from a batch that has been prepared from sub- batches produced according to the identical formula. The term "sub-batch" is utilized herein to refer to the situation in which, for example, a first batch of a fill material is mixed or added together with a second batch of fill material, which is compositionally substantially identical to the first batch, to produce a new batch comprising both of the aforementioned batches that are considered "sub-batches" when they are mixed or combined together. The "new batch" is not a sub-batch unless it is subsequently mixed or otherwise combined with

A dosage form may be produced using one or more of the above three embodiments (or other related embodiments as may be apparent from the disclosures herein).

The method of embodiment (1) above, as applied to the manufacture of a 500 mg pharmaceutical tablet can, for example, comprise the following steps: a) dispensing 250 mg fill material from a batch of a granulation (the fill material) into a tablet die (a "receptacle"), followed by dispensing a second 250 mg of the same batch of granulation into the tablet die.

Thus, the subject method can comprise the steps of (a) providing a batch of fill material, (b) partially filling the receptacle with the fill material and (c) completing the filling of the receptacle with the fill material. The sequential filling of a tablet die per this example of the invention is most conveniently done during high-speed production by dividing the batch into a plurality of hoppers, but no limitation to this technique is intended.

'lhe subject method further comprises the embodiment wherein a plurality of batches are produced according to the same formula (or substantially similar formulae) and are used as separate partial fills into the receptacle Io produce the tinal dosage form.

Another embodiment of the subject method considered as the invention includes making according to the same formula (or substantially similar formulae) a first and a second sub- batch of fill material and mixing the sub-batches to form a new batch of fill material. This new batch of fill material can be dispensed one time into the receptacle to form the final composition, or, according to (1) above, it can be dispensed a plurality of times as portions of the final composition.

The subject invention advantageously provides a method of minimizing variation between or within production lots of units of a composition. The method comprises, generally, the steps of providing a plurality of subportions of said composition or unit and forming the composition or unit as a whole from said subportions. The preferred composition made by the subject method is a pharmaceutical product. Λ more preferred composition made according to the subject method is a pharmaceutical tablet or fill for a pharmaceutical capsule,

Certain preferred pharmaceutical tablets of the subject invention arc -substantially homogeneous yet are stratified, having been produced in a layered fashion, An example is a tablet comprising two layers, each derived from substantially compositional Iy identical (though with each layer potentially containing slightly or substantially different quantities of material) granulations introduced separately and sequentially into the same tablet die. Another preferred embodiment of the subject invention involves a tablet comprising three or more compositionally substantially identical layers, produced by a method wherein each of the three or more layers is introduced separately into the same die.

Also preferred is a pharmaceutical capsule that is filled more than once with a substantially compositionally identical mixture or powder. Another embodiment of the invention comprises a capsule that contains a pharmaceutical tablet produced by a method of the invention.

The subject invention provides its benetit(s) in part because of the statistical phenomenon of reversion to the mean (also called regression to the mean). The current art for such products as single-agent products or fixed dose combinations consists of creating a substantially homogeneous tablet or fill to be used in a capsule by one fill of powder, paniculate, granulation, pellets, or the like, comprising a drug or drugs. Variation of the quantity of fill is acknowledged as the usual situation by persons of ordinary skill in the art. Assuming substantially homogeneous distribution of drug(s) within said powder (or fill, etc,)- the variation of drug(s) contained in the final dosage form will reflect the variation of quantity or weight of material containing or comprising that drug used in dosage form production. The use of two half-quantity fills in accordance with the subject invention, however, results in less variation from the desired quantity as compared to the variation resulting from a complete fill in a single till step. The addition of more fills per dosage form, e.g., two fills of approximately one-half dose each, or three fills of approximately one-third dose each, will result in decreased variation of drug content between different unit doses as compared to one fill of the total dose. A wide variety of dosage forms may benefit from the subject invention, including without limitation tablets, capsules, liquids and aerosols.

In the case of tablets, a further benefit is realized from the invention because the process of creating layered or stratified tablets using a conventional tablet layer press involves non-random fillings. Thus, in a tablet produced by two fills (creating a bilayer tablet), a second fill tends to compensate in the opposite direction from any error introduced by a first fill. In the case of liquids and aerosols, novel means of manufacture are disclosed utilizing the principles described above of utilizing a plurality of fills of a liquid, suspension, or gas, with the result of increasing the accuracy of the dosage forms created, as described above.

DRTAl LED DESCRIPTION OF THE INVENTION The subject invention concerns a novel method of manufacture, and product of that method, preferably wherein the method leads to less variation between dosage forms, or lots of dosage forms, than conventional methods. For example, in the pharmaceutical industry, the subject method can be applied so that the variation of the actual value for a measured parameter from a theoretical or expected value for that parameter is lessened for each lot or batch of product, as compared to the variation of the actual values from theoretical values of each lot or balch of conventionally manufactured product.

Dosage forms of most of the embodiments of the subject invention are created in a manner more complex than has heretofore been described or taught for homogeneous products. For example, it is known to create a substantially homogeneous pharmaceutical tablet with exactly one fill of material into a tablet die. followed by compression of the material and ejection from the die. In contrast, many preferred embodiments of the subject invention comprise creation of the tablet in layers. Layers have generally been taught to be different from each other within a tablet or capsule fill, except as has been disclosed in WO 2005/1 12900. In one example of the subjeel invention, two successive fills from the same batch of a granulation are placed into a die and a tablet comprising those fills is compressed. In another embodiment, three or more successive compositionatly substantially identical fills could be utilized to form the tablet. Within the tablet as a whole, all fi lls could be identical, all fills could contain an active ingredient, or one or more fills could contain inactive ingredient. Immediate release or controlled release granulations or drug products can be made using the method of the subject invention. Controlled release coatings may be applied after tablet compression.

Λ pharmaceutical liquid disposed in an ampoule also typically is placed in the ampoule in a single fit! step. The method of the invention involves filling an ampoule more than once, with two or more fills used to provide a final volume that technically would have been feasible to create with one fill.

Variations of the methods of the subjeel invention include, in one embodiment, a batch of precursor materials (such as a granulation for tablets and capsules, or solution for liquid drug products) created and placed into a plurality of hoppers or appropriate container. Dosage form creation per these embodiments involves both or more than two such "fills."' This counterintuitive approach in fact has a benefit not heretofore recognized: diminished variation between individual dosage forms within a production lot. In a related but different embodiment, the different "fills^"' are deliberately created from batches that are separately produced according to the same formula or similar formulae. This also counterintuitive approach produces diminished variation between the average amount of drug per dosage form found between different production lots.

In a variation of the immediately-above method, separately-made batches of material to be "filled'^" to produce the finished dosage form are mixed together. In that case, only one fill is needed to preserve the novelty and advantages of the method involving separate fills of separately -made material from the same formula. In this specific example, there is limited prior art: sub-batches that have been made of necessity in wet-granulated products. Due to volume constraints in the production of wet granulations, smaller sub-batches of wet granulations arc typically produced separately according to the same formula, blended or otherwise combined together, and then used to produce pharmaceutical tablets (or capsule fill). It has not been taught to systematically use sub-batches for dry granulations For tablets or capsule fill, ior liquids or gases, and other pharmaceutical forms, at least those involving "small molecules" rather than "large molecules" as are typically utilized in the biotechnology industry.

Λ preferred embodiment of the above methods involves utilizing material, especially but not limited to active drugs, from different production lots, fhis could be useful in any of the above embodiments, and can further minimize unwanted variation.

For purposes of the subject invention, certain terms are used herein to clarify and communicate meaning to persons of ordinary skill in the pharmaceutical arts. However, the terms are not intended to be limiting as to the scope or breadth of the subject invention. Nor do the above teims depart from, and arc not intended to depart from, their ordinary and accepted meaning, as would be understood by persons of ordinary skil! in the art. Accordingly, the following definitions, as provided in 21 CFR 210.3(b)(2)-{4), (9). ( 10), and ( 16), are offered for clari fication and contextual purposes:

Title 2 KTR

PΛRT_ 210 _r CUR RBNT GOOD MANUFACTURING PRACTJC L_. IN MANUFAC I URlNG₅ PROCESSING. PACKING, OR HOLDING QF DRUGS; GENERAL

Section 210.1 Definitions (2) Batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.

(3) Component means any ingredient intended for use in the manufacture of a drtig product, including those that may not appear in such drug product. (4) Drug product means a finished dosage form, for example, tablet, capsule, solution, etc., that contains an active drug ingredieni generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo. (...)

(9) In-process material means any materia! fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product.

( 10) Lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uni form character and quality within specified limits.

(Λs used herein, "lot" refers to the latter part of the above definition when it applies to either a drug dosage form or to an amount of a raw material used in formulations, such as an active pharmaceutical ingredient or excipient; i.e., to a raw material or to a drug product but not to a composition such as a granulation that has been prepared and is portioned out for use in a dosage form. )

(...)

{ 16) Strength means: (i) The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or

(ii) The potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard). (...).

In accordance with the subject invention, the subject method tends to provide less variation in drug product, rhis improved variation may involve the difference of the actual measured value with a production run (lot) from a theoretical value for the range, number, or frequency of certain measured parameters.

A Method's of diminishing variation between lots

One object of the invention is to diminish the amount of variation between one Sot and a different lot produced according to the same formula and intended to have identical characteristics, including the average amount of drug per dosage form in each lot.

Actual or measured values for a tablet component, e.g., active ingredient, from different batches tend to vary from the theoretical or expected value for several reasons, including error in the weighing/measuring of the component(s) used in the formulation. These values will tend to differ between iterations despite the identical formula of ingredients. Another reason for variation of actual value from theoretical value in a batch may result from differences in the purity of an active ingredient between different lots of material. Other reasons may also be offered to account for variations between batches or lots.

In a preferred embodiment of the invention relating to tablets, a first layer is utilized from a first granulation batch, and a second layer is added onto the first layer in the die. This second layer comes from a different granulation batch produced from an identical formula as said first layer. Optionally, a third layer, and then a fourth or fifth layer, etc., may be added, as the tablettiπg equipment permits, with all layers preferably being derived from different granulation batches but identical formulations. Optionally, an inactive layer may be utilized, either as an outer layer or as in interior, interposed layer. The different batches may further utilize different lots of ingredients, especially different lots of the active ingredient(s). This will tend to further minimize the effect on the final dosage form of any variation in the purity of the active ingredient.

A benefit of this invention is that a batch such as a granulation batch has certain variation, so that the average amount of active ingredient(s) tends to vary from the desired amount. Standards are set by the USP and IiP in this regard, but any variation is undesirable. By producing a dosage form that utilizes more than one separately-produced batch, the errors in each batch will tend to cancel each other out, tending to improve (diminish) the variation of the average amount of drug per dosage form from the predicted, desired amount. Because one cause of variation involves different purities of active drug, utilizing di fferent lots of active drug will tend to improve (diminish) unwanted variation of the average amount of drug per dosage form from the predicted, desired amount.

Various statistics can be used to measure variation. These include, without limitation, median, mode and average amount of drug per dosage form. Standard deviation assuming a Gaussian curve will likely be relevant.

It will be recognized that while in general the identical formula will be used for the different layers, small differences in these formulae, such as differences in pharmaceutically equivalent excipients or differences of ratios of the same excipients. are contemplated within the scope of the invention so long as the ingredients used are pharmaceutically acceprable.

This aspect of the invention, which relates to tablets, may apply to all known tableting processes, including wet or dry blends or granulations (with the limitation as it applies to wet granulations as mentioned above), pelleti/ation, or the like, and various methods of production, such as slugging. direct compression, or roller compaction, without limitation, as are known in the art. further, there is no limitation of this technique to tablets. Similar techniques may be utilized to fill capsules with capsule fill material a plurality of times from separately-produced batches that utilize the same formula. Similar techniques may be utilized to 1111 a canister, ampoule, or other container with a gas or a liquid a plurality of times.

Another embodiment of the invention involves the mixing of different sub-batches of granulation, whether applied to stratified or layered tablets as described herein, or to tablets or other dosage forms manufactured by conventional processes. For example, it is known to make relatively small batches of wet granulated material and then to combine them to allow adequate quantities of tablets to be produced in one production run. However, it has not been taught until the invention to mix separately made sub-batches together to reduce variation of a single lot or batch of a granulation. 1 hus. an embodiment of the invention involving tablets is the use of a plurality of dry granulations made from substantially similar or identical formulae to be mixed together, thus decreasing any variation or error of average drug content introduced by one granulation, again by the regression to the mean phenomenon. Dosage forms other than tablets may equally usefully utiiize this same technique, such as gases, solutions and other liquids, and capsule fill.

In addition, with regard to wet granulations and any other tabietting procedure, it has not been taught until the subject invention to deliberately utilize different lots of an active ingredient when mixing different batches of the same granulation and making such a technique a standard part of a production technique. Methods of diminishing variation within lots of dosage forms

1 . Tablets

Under similar principles of regression to the mean, novel dosage forms such as tablets and novel methods ol manufacture of both novel and conventional dosage forms represent embodiments of the invention. Differeni fills of the same granulation entering a tablet die sequentially diminish variation of weight on a tablet-to-tablet basis, assuming substantial fy homogeneous dispersion of the active ingrcdient(s) throughout the fill material. The subject method advantageously provides diminished variation of the active mgredieπt(s) on a tablet-to-tablet basis as well. This will be the case should the quantity of fill material be independent from one layer to the next. In other words, the inevitable errors that occur when filling powder or other material into a tablet die will balance each other out, so that measurements of tablet weight/drug content, such as standard deviation, are diminished.

In addition, tablet layer presses generally have a second Jill which is dependent on a fu st or preceding fill, which therefore tends to correct or compensate for an error occurring in the first or preceding fill. For example, i f the quantity of a first fill into the die is less than predicted, there will be more space in the die for the second fill. If this second fill is of identical fill material to the first, then the tablet will be closer to predicted weight and active drug content than if the second fill were independent of the volume/weight of the first fill.

Recent advances in the art of divisible tablets, e.g., a tablet having two substantially identical layers or segments separated from each other via an interposed different layer or segment such as an inactive layer or segment have been disclosed. See. for example, International Applications WO 2005/1 12870, WO 2005/1 12897. WO 2005/1 12898, WO 2005/1 12900, and PCT/US05/47499. The subject invention also applies to dosage forms made in accordance with these disclosures. However, it is only now appreciated that this layering process serves to diminish variation of the total amount of active drug between tablets, in addition to its benefit if the tablet is split through the interposed layer or segment. A preferred embodiment of^' the subject method can be carried out as follows: step (a) introduce into a die or mold two successive layers that are substantially identical, derived from the same batch, and contain a drug; step (b) introduce an inactive layer lacking drug in contact with the second layer of step (a); and step (c) repeat step (a) contact the inactive layer of step (b) with the first layer of step (c). The result is a novel tablet that, assuming adequate dimensions of the inactive middle layer, may be broken through said middle layer to produce two '"tablettes" without breaking through the material entering in either step (a) or step (c). The first tablette consists of all of the fill from step (a) plus a part of the fill from step (b). The second tablette consists of all of the fill from step (c) plus a part of the fill from step (b). Each "tablette^" thus formed comprises a first, "active" part that contains drug and second, "inactive" part formed from a fill lacking a drug. Each tablette thus represents a dosage form. This dosage form embodies the invention, as it consists of two substantially Identical layers, and thus demonstrates diminished tabletle-to-tablettc (dosage form to dosage form) variation.

Thus, a variety of pharmaceutical tablets and methods of manufacture are disclosed by the subject invention.

It will be readily appreciated that tablets may be created utilizing both of the above techniques, i.e.. minimization of variation Irons batch-to-batch and tablet-to-tablet. For example, a mixture of two batches of a dry granulation may be sequentially added to a layered tablet. In another example, a five layered tablet may be created. The bottom and top (first and fifth) layers may be identical and from the same granulation batch; the second and fourth layer may be identical, from a different granulation batch, but of the same formula as the first and fifth layers, and the third (middle) layer may be inactive.

2. Dosage Forms other than Tablets

It is apparent from the description herein that the novel lechniqucs may be applied to other dosage forms. Capsules are typically filled once with a compact that is generally not considered to be a tablet, although special cases exist in which capsules comprise a plurality of tablets (as in Dilacor XROD) or a tablet plus other fill (as in Lotrel®). In a preferred embodiment of the invention, a capsule lacking a tabϊet is filled a plurality of times, either (Λ) with di fferent fills from the same granulation batch or other filling material, thus diminishing variation of capsule content within a production run. or (B) from separately made batches according to the same formula, thus diminishing variation between the average amount of active drug found in different lots (production runs) of capsules thus produced.

Advantages realized by the method and compositions from the subject invention include:

1 . Pharmaceutical dosage forms exhibiting diminished within-lot variation of active drug;

2, Pharmaceutical dosage forms having diminished tablet-to-tablet (or capsule-to-capsule) variation within a batch; and 3. Pharmaceutical dosage forms having diminished within-lot variation of the average dose of a pharmaceutical dosage form.

It will be appreciated that other dosage forms that are able to be created by repeated additions of a partial dose to create a larger dosage form represent embodiments of the subject invention as well, both with regard to the principles of reduced variation of the material being provided in a final dosage loπn, e.g., being compressed into a tablet, as well as reduced variation in the filling of a tabiet die, as described herein. Another example involves solutions and mixtures. In these cases, unlike the situation for tablets and capsules, where evidence of the use of layers and separate filling steps may be discerned by use of a magnifying lens, dosage forms such as solutions, mixtures, and aerosols may be improved by lhe processes described herein, but the dosage forms thereby produced will not be inherently distinguishable from conventionally produced dosage forms.

Λn exemplary production method for solutions, per the subject invention, follows:

For production of an ampoule of 0.50 cubic centimeters ("cc") of a solution containing a drug, conventional practice is to measure 0.50cc at one time and cause it to enter a container, such as a glass container. Certain variation from this quantity may be expected. If, however. O.25cc were measured, entered the container, and then another 0.25cc from the same solution then sequentially entered the container, it is likely that the quantity and direction of the percent variation from the predicted 0,25cc fills would al low greater accuracy in filling as close to 0.50 cc as possible than from filling 0.50cc at one time. Thus the content uni formity of the production run of these dosage forms contained with ampoules would be enhanced.

There is no limitation to the types of phaπnaceuiicals that are suitable for the techniques and dosage forms of the invention. Of greatest use are drugs for which dosing precision is of greatest importance, as well as dosage forms that are frequently subdivided. Warfarin sodium is an example of a drug that fits both of the above criteria. Λ benzodiazepine such as alprazolam is another example.

With regard to non-pharmaceutical embodiments of the invention, liquids that are applied to plants, such as those containing insecticides or fungicides, may be improved with regard to content uniformity or lot to lot uniformity. Similarly, powders such as fertilizers have one or more active ingredients, and the accuracy of the concentration of the active ingredient(s) will be improved by utilizing more than one lot to produce the material that is packaged or utilized at one time, again by reversion to mean phenomena.

In the biotechnology field, where accuracy is of great importance, and where the techniques of the subject invention may be utilized in creation of injectable material, for example, the same techniques may be utilized earlier in the manufacturing process to diminish variation of intermediate substances. The invention is not limited to any therapeutic class of pharmaceutical agent. Of especial interest are the cardiovascular, psychiatric, neurologic, oncologic, endocrinoiogic, analgesic, and antiinflammatory classes.

The invention is not limited to homogeneous tablets. The invention may comprise novel tablets as are described in WO 2005/1 12898 in which an active drug is separated in a tablet from a different active drug via a preferably substantially inactive segment or layer. Due to the broad nature of the applicability of the subject invention, no limitation should be inferred except as specified herein.

The invention involves production methods and solid dosage forms. Substances such as liquids and gases, in which mixing occurs, cannot be readily differentiated from conventionally manufactured dosage forms, however. Also comprising the subject invention are the product specifications from implementing the methods of the invention. For example, consider a production run of amlodipine besylate plus suitable excipients, as are qualitatively disclosed in the Norvasc ® Package Insert (see Physicians Desk Reference. 2006 Ed.. which is incorporated by reference). Currently, Pfizer, Inc., the manufacturer of Norvasc®, has established certain specifications for within-lot ("content uniformity^*') and between- lot variations. Utilizing the same formula to produce amlodipine besylate tablets, but utilizing the production methods disclosed herein will produce less variation from a theoretical value for one or both of those within-lot or between- lot parameters identified as the product specifications. These improved ("tighter") specifications for one or more parameters, as applied to a particular product produced according to a particular formula or similar formulae as disclosed herein, are an advantageous result of the methods of the subject invention.

It will be recognized by ones of ordinary skill in the art that various other embodiments will be apparent because of knowledge of the novel processes, dosage forms, systems, and the like disclosed herein.

Claims

1. A method for producing a composition made by dispensing a fill materia! into a receptacle, said method comprising producing a batch of said fill material and dispensing a portion of said batch into a receptacle:

(a) more than once to produce the composition: and

(b) dispensing, to produce the composition, a portion of a separately made fill material produced according to the same formula or a substantially similar formula; and/or (c) in which said fill material comprises a gas, a liquid, or solid material that has not been subject to wet granulation.

2. The method of claim 1 wherein said composition comprises a pharmaceutical dosage form.

3. The method of claim 2 wherein said pharmaceutical dosage form comprises a tablet.

4. The method of claim 1 wherein the receptacle is selected from the group consisting of a die, a mold, and a container.

5. The method of claim 4 wherein said die is a tablet die for producing a compressed tablet.

6. Λ method of producing a composition comprising an active pharmaceutical ingredient, said method comprising: a) providing a plurality of different lots of an ingredient of the composition: b) selecting from each of said plurality of lots a portion of a total amount of said ingredient to be used in said composition; c) combining a plurality of the selected portions of said ingredient to make a total amount of said ingredient used in the composition.

8. ^r! he method of claim 1 wherein said composition and fill material are selected from the group consisting of a liquid and a gas.

9. A method of minimizing variation between or within production lots of units of a composition or unit, said method comprising: providing a plurality of subportions of said composition or unit; and forming the composition or unit as a whole from said subportions.

10. The method of claim 9 wherein said composition or unit is a pharmaceutical product. 1 1 , A composition produced by the method of any one of claims 1- 10.

12. The composition of claim 1 1 wherein the composition is a pharmaceutical tablet.