Analyst, October- 1996, Vol. 121 (9/K-IOOK) 9lR Analytical Challenges in the Development of Modified-release Oral Solid Dosage Forms A Review Michael J. Bowker Analytical Cheniistw Department, RhBne-Poulenc Roru Ltd., Du~qridzam, Esw-t-, UK RMIO 7XS Summary of Contents In trod-uct i on and Definitions Scope Analytical Involvement in the Development Process for Modified-release Dosage Forms Product Concept Preformulat ion Studies Formulation Development Studies and Design of the Tablet Core Establishment of the Need for a Film-coat and Optimization of the Coating Level to Achieve the Required Release Rate Formulation Development Studies Leading to a Pelleted Product Probe Stability Studies and Establishment of the Preliminary S he1 f- 1 i fe Specifications Scale-up Studies and Production of the Validation Batches Stability Studies on the Validation Batches Technology Transfer to Quality Control Post-approval Studies Conclusions References Keywords: Modified, delayed, prolonged and extended release; tablets; pellets and c.apsrtles; dissolution testing; I-eiyiew Introduction and Definitions Modified-release oral solid dosage forms encompass a wide range of types of pharmaceutical finished products with different types of drug-release mechanisms.Over the past 30 years, there has been a plethora of different names applied to such products in order to attempt classification of their release mechanisms. As often happens in such situations, different names have been adopted in different countries and confusion abounds. Within Europe, there have been proposals in a guideline by the Committee on Proprietary Medicinal Products to define the categories of ‘Modified Release’ in two main groups: ‘Delayed Release’ and ‘Prolonged Release’.At the draft guideline stage, it was originally proposed to sub-divide the latter further into ‘Slow Release’ and ‘Extended Release.’ However, as this was resisted by a significant body of opinion in the pharmaceutical industry, this attempt at further sub-division was abandoned in the final guideline. In 1984, the United States Pharinacopeial Convention revised2 its published definition of Modified-Release dosage forms, Extended-Release dosage forms and Delayed-Release dosage forms in the Pharmacopeial Forum. It has recently3 again revised its definition of an Extended-Release dosage form.In 1092, a working party co-ordinated by the Italian Association of Industrial Pharmacists published proposals for guidelines on modified release doyage forms.4 These proposals also included definitions. Surprisingly, there are no definitions of these types of dosage forms in the Japanese Pharmaco- poeia. ( I ) Definitions proposed by the CPMP Working Party on Quality of Medicinal Products: Modfied Release-‘This term is defined in the European Pharmacopoeia as a modification of the rate or place at which active ingredient is released. Modified release products cover a wide range of rdease models, the principal types of which would include “delayed release” and “prolonged relea4e” products. ’ Deluyed Releus-‘ A modified release product i n which the release of active substance is delayed for a finite “lag time,’‘ after which release is unhindered (e.g., enteric coated or ‘&gastro resistant” (Ph.Eur.) oral tablets or capsules which remain intact in the stomach and only disintegrate in the higher pH of the small intestine. Delayed release rewlts in a longer t,,,,,, but with C,,,,, ’ and elimination half life unchanged.’ PI-olongcd Release---‘A product in which the rate of release of active substance from the formulation after admini5tration has been reduced. in order to maintain therapeutic activity, to reduce toxic effects, or for some other therapeutic purpose.’ (2) Definitions proposed by the Unitcd States Pharmacopeial Convention: Modified Releu.se2-‘Products for which the drug-relcasc characteristics of time cour\e and/or location are chosen to accomplish therapeutic objectives not offered by conventional dosage forms.’ Dcluyed Releuse2-‘Products that release a diw-ete por- tion(s) of drug at times other than promptly after administra- tion.’ Extended Releux-‘An extended-release dosage form is defined as one that allows a therapeutically beneficial reduction in dosing frequency.’ (3) Definitions proposed by a working party co-ordinated by the Italian Association of Industrial Pharmacists: Modified Release-’Modified releax pharmaceutical dosage forms are capable of modifying the rate, and/or the time and/or the location of drug release.They make it possible to achieve therapeutic objectives beyond the scope of conventional do\age forms administered viu the same route.’ Deluyed Release or Reputed Relcwse--‘Delayed- or re- peated-release dosage forms release the dose, or a portion (or portions) of the dose, at a time (or timeh) other than soon after administration.’ Extended Release or Pi-oloiiged Kclcuse-These forms release the active component from the formulation more slowly than does the corresponding conventional do\age form that is intended for the same route of administration. The prolonged- or The various definitions proposed are as follows: ~~ ~ ~- Incoriectly vtated i n the giudelines A\ T,,,,,.92R Airalyst, Oc.tohei- I996, Vol. 121 extended-release dosage form releases the drug at a given rate for a given time.’ Scope It is the author’s intention to focus on the two main categories of modified-release products and not to cover other forms, such as buccal or chewable products, even though many of the issues and principles raised may also need to be considered or addressed in the development of these specialized dosage forms.Over the past 25-30 years, there has been a wide coverage in the literature of different dissolution testing methodologies and strategies; it is proposed also not to focus specifically on these aspects. The reader is directed to three pivotal text books5 7 which give an excellent insight into the principles and practice of dissolution testing and stability enhancement. Those aspects involving dissolution testing which are not considered to be adequately addressed in the analytical and pharmaceutical literature, especially those with a significant analytical bias, will be discussed in this review.Analytical Involvement in the Development Process for Modified-release Dosage Forms There are normally several discrete phases in the development process; these can be conveniently classified into the following: (i) the product concept; (ii) preformulation studies; (iii) formulation development studies and design of the tablet core; (iv) establishment of the need for a film-coat and optimization of the coating level to achieve the required release rate; (17) formulation development studies leading to a pelleted product; (I?) probe stability studies and establishment of the preliminary shelf-life specifications; (Irii) scale-up studies and production of the validation batches; (Iyiii) stability studies on the validation batches; ( i - ~ ) technology transfer to quality control; and (1-) post- approval studies.Product Concept Many drug substances have pharmacokinetic or physico- chemical properties which make them inappropriate for the preparation of modified-release products. Cabana8 provided a rationale for the development of such dosage forms: (i) the toxicity and occurrence of adverse reactions is decreased; (ii) there is better control on the rate and site of release of the drug substance; (iii) there is a more uniform concentration in the blood due to the provision of a more predictable delivery of drug; (iv) such a form provides much greater convenience and/ or better patient compliance; (v) there is better utilization of drug. For the majority of drug substances intended for oral administration, an immediate release product is developed and marketed first.For a small percentage of these drug substances it may be considered more beneficial to develop and market a delayed-release (e.g., enteric-coated) product first. Either of these can then be followed some time later with the prolonged/ extended release form. The pharmacokinetic monitoring of human clinical trials conducted during the product development phase of the immediate release product generates a wealth of information and data on the fate of the drug substance and its metabolites. These data can often be used to judge approximately the likely theoretical in L ~ L W profile required and the dosage strength for the modified release form. In some cases.these data can be used directly to compute more accurately the required in viiw profile (and sometimes also the corresponding iFz t1iti-o profile). There are, however, very few examples of this latter approach to formulation design in the literature.’-17 In parallel with these considerations of the likely in vivo and in \it?-o characteristics, there should be a rapid evaluation of the various types of dosage form most suited to the drug substance, bearing in mind its physico-chemical characteristics. Will the required in iivo profile be best achieved by a simple or complex tablet or an encapsulated pelleted product‘? If it is a tablet, will it require film-coating or enteric-coating? It is here that the analyst may be expected to advise on issues such as: (i) What are the likely physico-chemical changes that the drug substance might undergo in the formulation? (ii) What will be the likely chemical stability of the drug substance in the formulation‘? (iii) Will there be any photo-instability problems for either the drug substance or any of the dyes which may be proposed for use in the film-coat (if a film-coat is necessary)? Preformulation Studies Preformulation studies are a combination of simple or short- term studies, often involving a high thermal, photochemical or mechanical stress. They are designed quickly to force changes that would otherwise be slow to appear. If an immediate-release dosage form has been previously developed to modem standards, then much information would already have been generated on the likely requirements for the particle size distribution of the drug substance and the basic physico- chemical and stability characteristics of the drug substance. l 4 This would include a full evaluation of the lability of the molecule to the various stresses outlined above and an in-depth study of the relative stabilities of any polymorphs which may have been previously discovered.If the drug substance was substantially amorphous, the potential for crystallization under compression, using pressures which are representative of those in a tabletting press or capsule filling machine, should also have been evaluated. If the immediate-release product was a simple capsule and a modified-release tablet is being considered, it may be advantageous to repeat part of the compression studies at significantly higher pressures.Relatively simple studies on many drug substances’s-32 have shown that mechanical stress such as compression, grinding or micronization can have a profound effect on the crystalline form of the drug substance, often resulting in a complete change of polymorphic state. Preformulation studies directed towards immediate-release and modified-release formulations are normally undertaken on binary or tertiary mixtures of the drug substance and a range of possible excipients that might be considered for use in the formulation. The aim of these screening studies is to permit the rapid identification of those excipients with which the drug substance is chemically or physically incompatible. This incompatibility can manifest itself as a significant chemical change (e.g..drug substance decomposition and loss of potency) or a significant physical change (e.g., a colour change, a polymorphism change or the formation of a eutectic mixture). Various approaches are undertaken within different organi- zations;33 some groups simply prepare 1 + 1 mixtures of the active ingredient as a loose, but uniform, powder, and store samples under a variety of accelerated conditions for periods which usually exceed 1 month. Others compress the mixtures using one or more different pressures in a tabletting press or 1R (potassium bromide) disk press normally used in TR spectrome- try and then store the pellet and/or loose compacts under a variety of conditions. The pivotal tests undertaken on these stored samples usually involve HPLC, for the detection of decomposition products, and an evaluation of more subtle physical changes using differential scanning calorimetry (DSC), occasionally reinforced by other thermal analytical techniques, such as thermogravimetric analysis (TGA) and hot- stage microscopy, and X-ray powder diffraction (XRPD).Analyst, 0ctolx)r- 1996, Vol.121 93R With these early studies using HPLC. it is normal to use only a partially validated method which is known to separate the major decomposition products formed during preliminary accelerated stress studies on the drug substance. Validation can be restricted to linearity of response for the drug substance and one or two major decomposition products, an assessment of the limit of quantification and an assessment of excipienl inter- ference.It is always advantageous to have samples of the stressed excipients as a method blank since they can occasion- ally be used to identify correctly spurious peaks on an HPLC trace. There are excellent texts available on the use of a wide range of techniques which are used in preforinulation and compatibil- ity studiesj4 and for the specific use of thermoanalytical techniques.3’ The results from DSC thermograms should be interpreted with care as there are a few excipients which invariably create a variety of changes to the thermogram of the drug substance. it is our experience that magnesium stearate, s t e a k acid and the various oligoniers of polyethylene glycol modify the thermograms of most candidate drug substances.With the frequency of changes seen with these three excipients, it might be expected that they would be rarely used. This is not the case, however, and many perfectly acceptable and stable oral solid dosage forms contain these excipients at low concentrations. We have also observed changes occasionally with various grades of polyvinylpyrrolidone, talc and colloidal silicon dioxide with some candidate drug substances. If these early studies show evidence of the formation of alternative polymorphs of the drug substance, that excipient should be abandoned or studied in much greater detail using a wider range of techniques such a s XRPD, isothermal calorimetry, intrinsic dissolution studies and IR and Raman spectrotnetry in order to confirm the observation.It is imperative that significant physical changes are detected at a very early stage to save the huge costs in time and money wasted and expensive clinical studies to be repeated. There are a few publications where different polymorphs have been detected well after develop- ment and stability studies have finished on those marketed products. ih-.iX Formulntion Development Studies and the Design of the Tablet Core Once the results from the preformulation studies have been assessed and the range of acceptable excipients agreed, it i s possible for the forniulation team to finalize their ideas for the proposed dosage form and present them to the marketing organization for prioritization and approval. For example, the product may be proposed as one of the many forins of prolonged-release tablets (swelling matrix, erodible matrix, tablet with rate controlling membrane, etc.) or it may be a simple tablet core coated with a membrane imparting delayed- release (gastro-resistant) properties.The expected dose(s) of the drug substance may limit the formulation team in their choice of formulation approach. Highly active (potent) drug substances will generally allow more freedom in the choice of dosage form since the ratio of excipients to drug substance will be high. This may allow the choice of excipients which are suitable for a direct compression producl since any adverse drug substance properties can be outweighed by the appropriate choice of excipients with very advantageous properties. As the potency reduces, generally, the amount of drug substance required per unit dose increases and any adverse physico-mechanical properties of the drug sub- stance may start to predominate.This gradually forces the formulation towards a granulated product (or a pelleted product). Eventually, a limit is reached where even pelletization becomes impossible owing to the restrictions on capsule volume unless multiple capsules are acceptable as a unit dose. When the finished dosage form is known and the range of excipients has been chosen, the analyst and the formulator together must consider the acceptability (or otherwise) of the excipient specifications. For many products, the different grades and sources may markedly affect the dissolution process. This is especially so for the polymeric excipients chosen for their rate-controlling properties.Generally, pharmacopoeia1 monographs are inadequate for full control and additional tests should be considered. These may measure directly, or indi- rectly, the molecular mass distribution, degree of cross-linking, crystallinity, particle size, moisture content, glass transition temperature, ctc. As different batches are used in development trials, many of the key properties of each excipient become apparent and a database of information is developed. It is becoming apparent that excipient ‘fingerprinting’ using NIR spectrometry will bc extremely useful to help define the boundaries between acceptable and unacceptable batches of excipient or sources of excipient, where they are available from more than one source.In modern processing equipment, the sampling of the intermediate powder blend or granule prior to compression into a tablet is often judged unnecessary and tablets are often compressed directly without this in-process control. For modern products, a specification needs to be established for the tablet core, even though it may be considered as an intermediate en route to the product intended for marketing. For the regulatory filing, the specification for the tablet cores would be expected to contain most of the following possible tests: appearance (general colour and shape; presence of breakline); key dimen- sions and column height; hardness; identity test for the active ingredient; average weight and/or uniformity of mass; assay and/or uniformity of content; impurities/decomposition prod- ucts; disintegration time (or a test for the absence of disintegra- tion, if appropriate); and dissolution rate.In many cases, it is advisable to monitor other parameters as ‘in-house tests’. Tests that may be considered in this category are friability; water (or solvent) content; and microbial contamination. Many of these are standard tests for the pharmaceutical analyst; requirements and specification limits for many of the tests are given in the British or United States Pharmacopoeias. It is important to monitor hardness (together with friability on occasions) especially when those products are intended for film- coating. It is also important to determine the uniformity of mass at the tablet core stage if the product is to be film-coated, since the film-coat applied may vary slightly from tablet to tablet and mass uniformity may otherwise be difficult to determine accurately later once the product has been coated.Prior to film- coating it is often useful to determine the dissolution rate, whether disintegration does or does not occur (it may be designed not to occur) and whether the assay and/or uniformity of content are correct. Products intended for sale in the European Community (EC) must comply with an assay limit of +S% of nominal, unless otherwise justified. The uniformity of content requirements for tablets intended for sale in the EC and the USA differ considerably. The EC requirement to undertake uniformity of content testing applies if the individual tablets contain 2 mg or less of drug substance or 2% m/m or less of drug substance.The requirement in the USA is invoked if the tablets contain 50 mg or less of drug substance. Undertaking a significant amount of testing on tablet cores before film-coating does often permit their recovery if any individual test result is outside specification. Recovery can often be achieved by grinding down the tablets back to a granular state. This is usually impossible if a film-coat has been applied (at considerable cost!). For the uncoated tablet cores, there must be a specification, for which the analyst must develop and validate the methodology to be used in the following specification tests: (i) identity; (ii) assay (drug substance content per tablet of average mass); (iii) uniformity ofcontent of i n d i \, id 11 a 1 t ii b 1 e t s : ( i 19) i in p u ri t i e s/decom po s it i on products; ( 1 9 ) the dissolution rate test conditions and the analytical method used for assessing the content and stability of drug substance released into the dissolution medium; and (vi) water (or solvent) content.I t is not the author’s intention to detail the means by which each of these tests can be validated since these are adequately addressed in many texts and i n a recent draft documentj9 arising through the International Conference on Harmonisation proc- ess. TI‘ the tablet is intended for film-coating, an extra dimension of complexity is added for the analyst, especially when the coating also is designed to modify the rate of‘ release of‘the drug substance in the dissolution test.EstablisIii?terzt of the Need j o r a Film-coat and Optimization of the Coating Level to Achieve the Required Release Hate Delayed release tablets are tlie simpler of the two forms as they are usually a relatively standardized tablet core which is coated with ;I game-resistant film-coat. Celliilose acetate phthalate is the mo\t frequently used film-coating agent; to aid the coating process and to yield a more durable tablet, a plasticizing additive is used. These additives arc norrnally phthalates or other polyerters and a coat mass adding approximately 2% m/m to the tablet mass is usually necessary to impart resistance to the acidic environment of the stomach. This level of coating is usually rapidly di\solved away in the more alkaline environ- ment of the large intestine, leaving the tablet to dicintegrate and the drug substance to diswlve prior to absorption through the intestine wa 11.The film coaling is frequently achieved using a mixture of organic solvents such as methanol and drchloromethane and the tablet is dried. Test\ for residual solvents40.4i and decomposi- tion products are iiwally undertaken as an in-proces\ control for t hi operat ion. Cellulo~e acctate phthalate may contain up to 3% (6% in the USA) of unreacted phthalic acid, which would be expected t o diswlve in ;i solvent for extraction of the drug substance from the matrix; the diethyl phthalate or other plasticim- alro may be soluble in the solvent used Ihr extraction of the drug substance and impurities from the matrix. Detail\ of studies using thin- layer chromatographic detection of some coiiinioii plasticizers have been publis1ied.J’ Unles\ additional validation is under- taken for thcce soluble excipients at an early \tage, there is a danger that they could be misinterpreted a s unidentified related substance\ of the drug substance.Obviously, they are best incorporated into one comprehensive method developmelit and validatioii programme once the core tablet and film-coating formulae are known. The detailed evaluation of a compre- hen,ice range of physical properties of coated tablets has been de\cribed.4 i-J‘’ The presence of ;I fi Im-coat also adds extra complications for the analyst who may wish to follow the RP method for grinding down ;I representative sample of 20 tablets and assaying a portion equivalent to the average mass of one tablet.It is almo\t impossible to grind down many of the film-coats to the same sizc range as that which can be achieved with the tablet corc. Significant errors are introduced into the sampling process if partially broken sheets of film-coat rernaiii in the powdered tablet mix. IJnder these circumstances, we adopt a procedure where 10 or 20 tablets are added to a large flask and allowed to disintegrate and dissolve in a large volume of extraction solvent . An identity tect is required for each of the colouring agents, including ‘TiO? used in the film-coating formulation. This identity test mu\t be validated for use on the finished product. Pro1 ong ed/e x t e nde d- re I e asc tab 1 e t \ in ay be con1 pre s sed di - rcctly from a mixture 01’ excipients ( c .~ . , cellulose derivatives) such that the tablet exerts its own rate controlling mechanism. During the formulation development phase. a range of tablet batches with different amounts of the main rate-controlling excipients can be prepared. Alternatively. for some products, it may be more appropriate to produce a range of tablet batches using different compression forces. These can be tested i n either dogs or human volunteers to determine the optimum formula- tion. The two common types are a swellable matrix and an erodible matrix. The former is the more popular and is based on the properties of certain cellulosic derivatives which can swell slowly in aqueous media. As it swells, micro-channels form in the matrix; the dissolution medium permeates these channels and dissolves the active ingredient.Erodible tablets are designed to disintegrate slowly. present- ing a constantly renewable surface to the dissolution mediuni. Generally, it is not necesw-y to film-coat these types of tablets with an additional rate-controlling membrane, although they may be coated with a rapidly dissolving film-coat to aid recognition, for marketing reasons, to reduce friability or to protect the product from photodecomposition. Analytical controls similar to those described earlier are usually sufficient for the analysis of these types of tablets. The specification for the dissolution test would be expected to comprise at least a three-point control which limits both rate and extent of release within a relatively narrow ‘window’ over the range 10-80% of the release.Limits are normally expected for both minimum and maximum amount released after 10-20% and 40-60% release. An additional control to limit only the minimum amount released is usually specified at 70-85% of nominal released. In setting these limits, it is standard practice to manufdcture a range of tablets with different release rates and to test these in dog\, together with the immediate release product to generate the pharmacokinetic profile of each product. Froin the range of dissolution data and their corresponding pharmacokinetic profiles, it is normally possible to choose at least three candidate formulations which may be expected to be: (i) slightly faster releasing than would normally be acceptable; (ii) the idcal release profile; and (iii) slightly slower releasing tlian would normally be acceptable.Typical dissolution profiles for the immediate-release prod- uct and tlie three experimental products, together with their corresponding typical pharmacokinetic profiles are given in Figs. 1 4 . 110 100 90 80 1 E 70 E $- 60 2 50 a, 40 h Q, v) - 30 20 10 0.0 / i t i / Fig. I Typical dissolution profile for an immediate-release product.These formulations should be fully characterked analytically and also evaluated in human volunteers. It is occasionally necessary to refine the formulations slightly on the basis of the human pharmacokinetic data obtained. Following these mod- ifications, additional clinical studies are normally necessary to confirm the profiles are optimized and the dissolution 'win- dows' must be set such that batches of tablets with unacceptable profiles are always excluded. These pharrriacokinetic evaluations should be augmented ideally by evaluations of how the optimized product releases in the presence of food, especially a meal with high fat content.This is necessary because of the dramatic changes in the pH of the stomach contents and the potential modification to the drug absorption process as a result of the fat content of digestive fluids. The determination of pH values, typical volumes of fluid ,0150 r -i .0140 ,0130 ,0120 ci I Y .0050 ,0040 ,0030 .0020 .0010 s \ i Ti m e/m i n Typical ill l-irw profile for an immediate-relcase pioduct. Fig. 2 110 r 100 90 80 - 701 E 30 20 10 A involved and average residence times in the various regions of the digestive tracl has been the subject of several publica- tions;"'- j7 typical ranges are given in Table I .Some 01' the potential interaction\ with food can be studied using isothermal m icrocal o rime t r y , fol1 ow i tip pu bl i ca t i on o f t he1 r in i t 1 a1 s t ud i es by Buckton and co-workers,5x-.50 or by other forms o i modcl- liiig.6O.h' Various workers and companies have also used gamma scintigraphy in order to probe the tran\it of a finished Fadiolabelled tablet down the intestinal tract.(12 O7 There i \ one additional type of study where the analy\t can make a significant coiitribution. A small number of controlled- release tablets have been de\igned with a breakline and, occasionally, there may be a need to 'blind' a competitor'\ product as a comparator product for use in a clinical trial.One common means of blinding the products is to encapsulate them in a strongly coloured capsule shell. Some tablet\ do not fit into a convenient sized capsule \hell and it has been the practicc to consider breaking the tablets in half. To stop the products rattling to difierent extents it may be nece\sary to con\ider filling the void remaining inside the capsule with an inert and rapidly dissolving agent. Lactose and inannitol are frequently used for this purpwe. The analyst should investigate the dissolution properties of half tablets in compariwn with the intact product.68 (jC) Data should be generated on the dissolution properties of' tablets with a breakline and on potential clinical comparators as half tablets.Formulation Development Studies Leading to a Pelleted Product The decision between the developrnent 01. the drug substance as a modified release tablet or as multiple units (pellets) is a difficult one. 'Tablets generally are cheaper to produce i n bulk ,0060 r .0010 1 p I Ti me/mi n Fig. 4 and C me as in Fig. 3. Typical 111 rV\v protiles for prolonged-release product\. whcre A, R, Table 1 Typical physiological environnients o.OL-Li-. I.. _ i - I I _ I L _ L . - L . _ J 0 0 0 0 0 0 0 0 0 0 0 0 0 o n J ! b c D c o o N d c D c o O N d c u F l * c O b " O r n g n J ~ ~ Timelm i n Fig. 3 Typical dissolution profiles for prolonged-release products, where product releasing at: A. upper range of acceptability; B, middle of range of acceptability: and C, lower range o f acceptability.Region pH Stomach 1.1-2 7 (facting) 1.1-3.5 (aftel food) 1.92 (men) 2.92 (women) 4.5-5.8 (after food) Small intestine 4.7-7.3 (fasting) Large inte\tinc 7.0-8.0 (tasting) A verdge re3 idence ti me /h 0.5 -0 75. 3 Illax. Vo I ume/ni 1 Mem SO Range 0 I80 ( f o r \olid\) (at ter tood) S--lOO max. 4.5-6 50.- I 0 0 tnax. 8-1 2 ' Defined as half of the time required for total discharge.96R Amlyst, Oc-tohci- 1996. Vol. 121 and can be coated, if required, with a high degree of confidence in currently available commercial coating equipment. Their ir? vivo performance, however, is sometimes erratic owing to differences in physiological factors from one patient to another.Pelleted products are generally more difficult to produce and they usually need to be coated. The pellets invariably require to be filled into capsules, although as a fairly recent innovation microcapsules may be tabletted70-7x by normal processer such as direct compression. The benefit of pelleted or micro- encapsulated products arises from there being normally at least 100 individual dosage units which can quickly spread through- out the gastrointestinal tract. The advantages of multiple unit delivery are discussed in excellent papers by Bechgaard,79 Bechgaard and Nielsenxo and Davis.67 The mechanisms by which various dosage forms, including pelleted products, are distributed throughout the gastrointestinal tract have been followed by radiolabelling57 and gamma scintigraphy.As may be -expected, depending on the drug substance and other excipients chosen, considerable differences in density can be achieved. The density and pellet size should be considered as important factors.xl.x’ There are two commonly adopted procedures for formulating pellets with modified-release prop- erties. For most of the products currently marketed, the pellet diameter is normally close to I mm. Pellets of this size can be conveniently manufactured directly by extrusion and spher- onization, then filled into capsules. In this process, a ‘wet mass’ is prepared with the drug substance evenly distributed at the required concentration and the ‘wet mass’ is extruded through a screen of the appropriate diameter (about 1 mm). The extrudate is chopped automatically to give cylinders with a length of approximately 1 mm and these are rolled whilst still damp until they are approximately spherical; the pellets are then dried.These pellets normally require coating with a rate controlling, insoluble membrane such as ethylcellulose or an acrylate derivative in conjunction with soluble component, such as hydroxypropylmethy Ice1 lulose. ‘The second commonly employed process involves spraying a solution or suspension of the drug substance. normally in combination with excipients. on to an inert core. The inert cores commonly used are confectionary-grade non-pareil seeds.xi By this procedure and with careful balancing of the spraying rate to the drying rate in the coating pan, the pellet is gradually built up to the required size range.Because there is disproportional build-up, it is usually necessary to sieve the product regularly to remove those pellets at (or above) the required size; the undersize pellets are returned to the coating pan for additional applications of coating. Alternatively, the cores may be rendered tacky by spraying with polyvinylpyrrolidone or shellac and the dry drug substance particles fed into the vessel at a rate such that they adhere to the core surface. By alternating the addition, a pellet is gradually built up. Because of the totally different mechanisms of production. the development studies, analytical controls and amount of involvement by the analyst differ considerably for these two processes. For the extrusion/spheronization/drying process, the unifor- mity of distribution of drug substance from pellet to pellet and within each pellet is virtually guaranteed; simple assays on both individual pellets and multiples of pellets from throughout the bulk should confirm this.It should be noted that the drug content should be 2-3% higher than theoretical if the pellets are to be coated. Depending on the lability of the drug substance, a determination of the content of degradation products and an assessment o f the polymorphic form of the drug substance would be expected to be considered, at least for the first few batches produced. Because the pellets are extruded from a ‘wet mass’ and dried, they normally have a rough surtxe texture, they are generally porous and have a partial honeycombe structure internally.The initial film-coating layers may be expected to be at least partially absorbed into the pores and surhce defects. As the pellets are rolled or tumbled in the coating apparatus or as they collide with each other in the fluid bed coater, the rougher edges and defects tend to be at least partially abraided, creating a new surface which may have a slightly lower level of coating at the end of the process. As the coating proceeds, the mass of coating applied can be calculated and occasionally confirmed by a determination of the mass increase; often it is necessary to use spectroscopy to determine indirectly the coat mass through the measurement of coat thickness. Samples should be taken at regular intervals, quickly dried to constant or equilibrium mass and tested for release rate.For in-process control purposes, it is useful to consider a set of conditions for the dissolution test which give results more rapidly than those which might be expected to be in the finished product specification. Additional samples should be examined by microscopy and/ or electron microscopy. As the coating procedure reaches the end-point in terms of assay and dissolution profile, smaller applications of film-coat, more frequent analytical in-process control checks and the use of the dissolution test intended for regulatory and quality control use are necessary. IJsing this process, it is possible to consider manuficturing several batches with slightly or significantly different dissolution profiles and blending them in appropriate proportions to give a final batch with exactly the required dissolution profile.Alternatively, it is possible to mix two or more batches with release maxima several hours apart to give a product which gives ‘pulsatile’ release.x3 Mixing different batches requires careful analytical study to ensure that there is the required number of pellets of each type in each capsule. In the alternative process, the diameter of the pellets is usually built up over several hours or days. After several applications of coating, the pellets should be dried to an appropriate water or residual solvent content before further coating is allowed to proceed. The outer surfaces of the pellets are usually more perfectly coatcd than those produced by extrusion/spheronization and it is more difficult to dry ade- quately the water or solvent from the interior if a thick layer of coating has been applied.As with the pellets produced by the extrusion/spheronization process. it is necessary to undertake frequent in-process controls on assay and dissolution rate. Because the rate of build-up varies from pellet to pellet, controls on the pellet dimensions are critical for this type of product. If the pellet build-up process involves spraying a suspension of drug particles, or if dry drug substance is fed into the coating apparatus. larger crystals of drug substance may not be bound into the growing surface. If this occurs, it is possible to create nuclei from these drug crystals, which are themselves capable of being coated. The pellets which are produced from a crystal seed have a much higher drug content but usually they have a significantly lower diameter. They can be easily removed by sieving before their size increases to a significant extent.By careful monitoring of pellet dimensions, drug content and residual water or solvent content at regular intervals, it is possible to create a batch with uniform appearance, size distribution, dissolution rate and drug content when sampled at the nominal content mass of the encapsulated product. If the pellets produced require additional film-coating, perhaps using an enteric coat, because the surface of the pellets is more uniform after build-up than by spheronization, the amount of coating required to give the required release characteristics is usually small. A coated, pelleted product gives the formulator ample opportunity to produce a range of small batches with different release characteristics if samples are reserved from the bulk after each application of film-coat.As with the tabletted products discussed earlier, it is possible to choose batches withAnalyst, October 1996, Vol. 121 97R appropriate dissolution profiles and evaluate their pharmaco- kinetic characteristics in animals or human volunteers. Even- tually a range of acceptable and unacceptable profiles can be obtained by evaluation in humans. The in ititro dissolution profiles from acceptable batches can then be used to establish an appropriate dissolution specification range for further batches. The pellets produced by either process are considered as an intermediate product and require full control testing.An appropriate regulatory specification must be established; it should contain most of the following tests: appearance of the pellets; typical size range; identity test for active ingredient; density of the pellets; assay; impurities/ decomposition products; and dissolution rate. As discussed previously for tablets, other parameters that may be considered as 'in-house' tests, and that may be usefully monitored, at least for the first few batches, are: water (or residual solvent) content; and microbial contamination. The pellets can then be filled into capsules for establishment of the finished product release specification which would be expec'ted to contain most of the following tests: appearance of capsule shell and contents; dimensions of the capsule; typical size range of the pellets; identity tests for the active ingredient and capsule colouring agents; density of the pellets; average mass and/or uniformity of content mass; assay and/or unifor- mity of content; impurities/decomposition products; disinte- gration time; dissolution rate; and water (or solvent) content.Microbial contamination may be monitored as an 'in-house' test. Validation requirements are the same as those for the methods used for the analysis of tablets. Probe Stability Studies and Establishment of the Preliminary Shelf-life Specifications Once the production of moderately large batches of tablet cores and coated tablets or pellets and encapsulated pellets has been achieved, their preliminary stability profiles should be deter- mined.Stability studies should incorporate the requirements of the recent ICH Guidelines.xs The stability parameters evaluated in these probe studies can range from an evaluation of changes likely to be observed in the results from the pivotal tests (appearance, disintegration, assay, decomposition products and dissolution rate) to a full evaluation of all probable specification tests and others that are likely to be stability-indicating. The objective of these probe stability studies is to confirm quickly that the formulation chosen is likely to be stable in the packaging intended for marketing before extensive resources are poured into the product to allow scale-up and the eventual transfer of the product to the manufacturing or industrialization group.Stability should be ensured also before major commitments are made for larger (Phase 111) clinical trials. Stability information generated in these early studies is also invaluable when used to establish the preliminary end of shelf-life specifications for the intermediates and finished products. Stability studies on these early batches should be continued for at least 12 months. There have been several reports in the literature of the types of changes which may be detected with enteric coated tablets,86>87 film-coated tablets,x6-x7 and pellets.g5,96 Also, over the last few years, it has been determined that some of the changes seen in the disintegration and dissolution characteris- tics of hard gelatin capsules may be due to cross-linking of gelatin by aldehyde~~7,')~ or, less frequently, by hydrogen bonding to colouring agents9X399 in the gelatin shell.HPLC,l~)O~lO' fluorimetricl02 and colorimetric microdiffusion methods103 are available, if required, for the determination of traces of formaldehyde and acetaldehyde in gelatin products. It is imperative that documented specifications are estab- lished before moving to the next phase where scale-up studies are initiated. Scale-up Studies and Production of the Validation Batches Once the product developed on a small scale has been demonstrated to be suitably stable for marketing, a larger-scale manufacturing process must be developed and validated. The scale-up studies involve the preparation of a small number of batches, typically for tablets, or a larger number of batches, typically for pellets.These studies usually initiate the handover of responsibility for manufacture to the manufacturing or industrial operations group and individuals from both develop- ment and industrial operations contribute usually to the manufacturing of these batches. This stage should also be the initiation of handover of analytical responsibility from develop- ment to QC personnel. The QC personnel should start to become involved in project meetings and planning at the start of scale-up studies and should ideally be prepared to contribute to any of the analytical methodology changes and decisions that are made. The scale-up studies themselves require extra vigilance on the part of the analyst, who should be prepared to test many samples, especially during the coating stages.Coating larger batches generally gives a more uniform coat to the products but balancing the drying as the coating progresses is often problematic in the early stages. As confidence is gained in the larger scale manufacture of the finished products, planning of the validation batches is usually initiated. The analyst contributes to the establishment of sampling protocols and final acceptance protocols for these validation studies. Also, at the stage immediately prior to the initiation of validation batch manufacture, the analyst should consider undertaking an in-depth evaluation of the validation that has been completed on the various analytical methods that have been developed. If additional validation is considered necessary, it should be completed and thoroughly documented as a new, comprehensive, validation report.If not already sent, copies of the methodology and validation reports should be given to QC personnel to contribute to their familiarization process. Once all the appropriate documentation (analytical metho- dology, testing protocols and stability protocols) is in place, the manufacture of the validation batches should commence. There are usually a minimum of three batches required, each involving different batches of drug substance. Consideration should be given also to using at least two different batches of each excipient. The purpose of the three-batch campaign is to confirm that the process can be operated on a large scale to manufacture batches within specification and with uniform properties.Each batch of intermediate tablet core or pellet and each batch of finished tablet or encapsulated pellets must be tested in full to the proposed specification. If all batches are satisfactory in all respects they can be forwarded for packag- ing. If the analytical testing on the validation batches indicates an unexpected result or a failure to meet the requirements of the proposed specification for any batch, the manufacture of a replacement batch must be planned whilst the cause of rejection or problem is investigated and fully documented. Stability Studies on the Validation Batches The three validation batches of each formulation should be submitted for stability evaluation in each of the packs intended for marketing.For tablets and capsules, these are normally a blister pack and a random pack such as a plastic or glass bottle. The protocol setting out the aims of the study, the packs andstorage conditions to be used and the criteria of stability to be evaluated should be issued before the study starts. The protocol should also specify what form of statistical evaluation will be used on the results in order to establish a meaningful shelf-life statement. The core conditions of temperatures and humidity are now storage conditions used but not in terms of the range of tests employed. It is normal to store production batches at the recommended maximum labelled temperature (25 f 2 "C and 60% RH k 5%) and only one other accelerated condition. Post-approval Studies specifiedx' at: 25 TL: 2 "C/60% RH k 5% (long-term testing); 40 k 2 "C/75% RH k 5% (accelerated testing). Where tl 'significant change' is seen during the first 6 months of storage at 40 k 2 "C/7S% RH k 5%, additional testing at an intermediate condition such as 30 k 2 "C/60%) KH k 5% is permitted.Obviously it is sensible to initiate storage on samples at this third temperatiire/humidity condition as a fall-back position in case unpredicted changes are detected. It is also advantageous to include storage of samples under a small range of other conditions. Typically, these would include 4-8 "C for the full duration of the \tudy and 40 "C/ambient RH and 45 or SO "C/ambient RH for a shorter duration (c.s.. 6-12 months maximum). The regulatory submission can proceed with a minimum of 12 months' data generated at 25 TL: 2 "C/60% RH k 5% and 6 months under the acceleratcd condition(s) for products prepared from previously unregistered drug substances. If the modified release product is a new dosage form (line extension) of an existing inimediate-release product or an alternative route of administration, it is possible to justify a reduction in storage time ( c .~ . , 6 months' data at 25 k 2 "C/60% RH k 5% and under the accelerated cotiditions) before the data can be submitted. When the stability data are collated, the assay results and the results from the evaluation of decomposition products and total impurities should be analysed statistically, preferably ufing a programme acceptable to the FDA.8' The stability data should also be used to finalke the shelf-life specifications for the drug substance and drug product(.;).Technology Transfer to Quality Control If not already initiated or under way, at the time of submission, discussions should commence with the appropriate QC person- nel on training programmes for their analysts, the content and acceptance criteria for the technology transfer protocol and the collaborative studies needed to ensure a well documented transfer. We have found that this training can be achieved successfully by demonstration of all methods and procedures to all the QC analysts by a well trained development analyst. The QC analysts then try the method on the same equipment under one to one tuitions. before thcy try the procedure on their equipment again with a development analyst standing by as the different steps are completed.The next phase is a collaborative 5tudy. testing samples of the same batch at exactly the same time in the two laboratories. The results are then evaluated statistically and the whole study is documented fully. If differences between the results obtained by the two groups are large, compared with the proposed tolerance in the specifica- tion, the causes should be investigated and the collaborative study should be repeated. If there is a significant time delay between the date training was completed and the date that the first batches for sale are manufactured and due to be tested, consideration should be given to a short period of retraining. When the first batches for testing by QC personnel arrive, consideration should be given to seconding thc trainer temporarily into the QC laboratory to help if problems arise. As more batches are prepared to give an adequate launch stock, the increased involvement by QC personnel is normally matched by a decreased involvement by the development group.It is standard practice that the first three production batches o f each dosage strength are placed on stability trial by the QC stability group. The stability protocol for these batches can be considerably reduced in terms of There are several types of studies that occur post-approval when the product(s) are marketed. Some involve the QC analysts (complaints and returned samples, counterfeit products, re- quests from hospital pharmacists for information on the likely stability of the product under 'abnormal' storage conditions, modifications to the existing methodology or evaluation of new methodology, etc.), others are referred back to the development section.Typical of the changes to analytical methodology which may be considered is the use of NIR for identity testing for packaged products.104 There has been a substantial increase in the number of pharmaceutical companies investing in NlR in the last few years to permit the rapid identity testing and release of excipients, packaged clinical trials materials and packed finished products for sale. It seems likely that the use of NTR by QC groups will increase substantially over the next few years because of its sensitivity to crystal form, particle size distribu- tions and source of supply of excipients.With all major pharmaceutical products, it is normal for generic copies to appear in the marketplace soon after the patent expires. A worrying trend is also the increase in the number of counterfeit copies which have appeared over the last decade. Generic copies of modified-release oral solid dosage forms are obviously more difficult to produce than the equivalent immediate-release product. The natural reaction of the market- ing department as soon as generic copies appear is to instigate an investigation to determine how closely the originator product has been copied. Often this is linked to an evaluation of the source of the drug substance and whether drug substance process patents may have been infringed. One procedure that we have used successfully to determine the abnormal dissolution characteristics of generic copies of a modified release product is topographical dissolution characterization.105,IOh In this proce- dure, samples of the generic copy and the originator's product are separately tested for dissolution rate using a range of media of different pH values for 8-24 h. We typically use media of pH 1.5, 4.5, 6.6, 6.8, 7.2 and 7.5 and monitor the dissolution rate continuously. Three-dimensional plots are then constructed of amount dissolved against pH and against time. This procedure often gives an indication of 'dose dumping' which is more readily seen using this technique than by using single-pH dissolution tests. Examples of typical dissolution 'surfaces' obtained using this technique are given in Figs.5,6 and 7 for the RPR product, a generic copy which partially 'dose dumps' and a close generic copy, respectively. We have also made good use of this technique for the comparison of batches of the same RPR product made at two different sites and were able to use the information to help to convince regulatory authorities that both sites were able to produce products which gave identical dissolution profiles over a wide range of pH values. Conclusions The development of modified-release oral solid dosage forms is a lengthy process which continues to attract regulations and guidelines from the various regulatory bodies world-wide. In the recent spirit of international harmonization, there is adequate scope for harmonization of the definitions of such dosage forms and hopefully this might lead to greater harmonization of the guidelines for their development and clinical evaluation.The analytical contribution to the development programmes for such products, as exemplified in this text, must be of theAncrlyst, October 1996, Vol. 121 99R 0 Fig. 5 product. Topographical dissolution characterization surface for RPR UK Fig. 6 which ‘dose dumps.’ Topographical dissolution characterization surface for generic copy highest calibre if the project is to succeed and achieve expectations. The analytical team must be continually aware of the changing regulatory environment and must be ready to incorporate and adapt to new requirements. They must anticipate trends in regulatory requirements.Looking to the future, it is to be hoped that the various regulatory bodies world-wide will become more familiar with the emerging technique of NIR spectrometry. This is now proving to be a valuable method for the identification of all types of oral dosage forms, the identification and characteriza- tion of excipients, film-coats and even the core tablets. Supported by sound science, it will prove to be of great value to the analysts involved in the development of the modified- release solid oral dosage forms of the future. 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