usp dissolution

No. of Cumulative

Tier Units No. of Units USP <711>Tested Tested

1 6 6 All units > Q+5%

-2 6 12 X2>0

All units > Q-15%

-3 12 24 X3 >0

All units > Q-25%

At least 22 units > Q-15°1c:

USP criterion has the form of a three-stagesequential design, with possibility of stoppingat each stage

So, can evaluate as a statistical hypothesistestNull hypothesis would be unacceptabledissolutionAlternative hypothesis would be acceptabledissolution

Regulatory Negotiation~ New Approach for Pioneer

Pick a time, To, at which to assess dissolutionDetermine distribution of dissolution values inrelevant batches; preferably ones thatdemonstrate acceptable clinical safety andefficacyChoose a minimum proportion of dissolutionvalues to target, R; this number should belarge, but not too large; suggest 80% or 90%Q is then the value of percent dissolved at To,that is exceeded by a proportion R of values

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• In a new batch, what proportion shoulddissolve more than Q?

• This value, say P, needs to be smaller thanR, else very high producer riskIf P not near R, then at least perception of arelaxation of a quality standardSuggest P = R-5°10; e.g., 75°10 if R = 80°10

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Pass batch if one-sided lower tolerance limitexceeds Q;i.e., X - kS > Q

• The constant, k, is chosen so as to limit theprobability, a, of a batch passing if theproportion exceeding Q falls to P

• k will also depend on design; will vary withtier for multi-tier designsThis approach lends itself to flexible sample.sizes

USP <711> JP Proposal New Proposal

All units > Q+5%

-X2>Q

All units > Q-15%

-X3>Q

All units > Q-25%

At least 22 units > Q-15%

~ -2.01~/F6 >0*

All units > Q*-lO%

X2 -1.7~/f12 >0*

All units > Q*-lO%

-~-1.91~>Q**

INTERPRETA TION

Immediate-Release Dosage Forms

Unless otherwise specified +in the individual monograph ,the requirements are met if the quantities+

of active ingredient dissolved from the dosage units tested conform to Acceptance Table 1. Continuetesting through the three stages unless the results conform at either S1 or S2. The quantity, Q, is the

amount of dissolved active ingredient + specified in the individual monograph ,expressed as a+

percentage of the labeled content of the dosage unit; the 5%, 15%, and 25% values in AcceptanceTable 1 are percentages of the labeled content so that these values and Q are in the same terms.

Acceptance Table 1

INumberl'Stage I Tested Acceptance Criteria~S1 I 6 IEach unit is not less than Q + 5%.

~-S;-1-6~lAv~-rage of 12-units (S1 ~ S2) is eq-ua-I-to-or~

I greater than Q, and no unit is less thanj Q- 15%.

S3 I 12 Average of 24 units (S1 + S2 + S3) is equal toI or greater than Q, not more than 2 units

are less than Q - 15%, and no unit is less,than Q - 25%.

+Immediate-Release Dosage Forms Pooled Sample- Unless otherwise specified in the individualmonograph, the requirements are met if the quantities of active ingredient dissolved from the pooledsample conform to the accompanying Acceptance Table for a Pooled Sample. Continue testing throughthe three stages unless the results conform at either S1 or S2. The quantity, Q, is the amount of

dissolved active ingredient specified in the individual monograph, expressed as a percentage of thelabeled content.

Acceptance Table for a Pooled Sample[Number

Stagel Tested Acceptance Criteria

S1 6 jrAVerage amount dissolved is not lessthan Q + 10%.

52 6 Average amount dissolved (51 + S2) isequal to or greater than Q + 5%.

S3 12 Average amount dissolved (51 + 52 +S3) is equal to or greater than Q.

+

© 2009 USPC Official 5/1/08 - 7/31/08 General Chapters: <711> DISSOLUTION Page 1 of3

Extended-Release Dosage Forms

Unless otherwise specified -+-inthe individual monograph ,the requirements are met if the quantities-+-of active ingredient dissolved from the dosage units tested conform to Acceptance Table 2. Continuetesting through the three levels unless the results conform at either L1 or L2. Limits on the amounts of

active ingredient dissolved are expressed in terms of the percentage of labeled content. The limitsembrace each value of Qi' the amount dissolved at each specified fractional dosing interval. Where

more than one range is specified -+-inthe individual monograph ,the acceptance criteria apply-+-individually to each range.

Acceptance Table 2Number

Level Tested Criteria

L1 6 No individual value lies outside each of thestated ranges and no individual value isless than the stated amount at the final testtime.

L2 6 The average value of the 12 units (L1 + L2)lies within each of the stated ranges andis not less than the stated amount at thefinal test time; none is more than 10% oflabeled content outside each of the statedranges; and none is more than 10% oflabeled content below the stated amountat the final test time.

----

-12-IThe average value of the 24 units (L1 + L2 +L3

L3) lies within each of the stated ranges,and is not less than the stated amount at thefinal test time; not more than 2 of the 24units are more than 10% of labeled contentoutside each of the stated ranges; not morethan 2 of the 24 units are more than 10%of labeled content below the stated amountat the final test time; and none of the units is

more than 20% of labeled content outsideeach of the stated ranges or more than 20%

of labeled content below the stated amountat the final test time.

Delayed-Release Dosage Forms

NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA.


Acid Stage- Unless otherwise specified ·in the individual monograph ,the requirements of this•portion of the test are met if the quantities, based on the percentage of the labeled content, of activeingredient dissolved from the units tested conform to Acceptance Table 3. Continue testing through alllevels unless the results of both acid and buffer stages conform at an earlier level.

Acceptance Table 3

INumberl

Level Tested CriteriaAi 6 No individual value exceeds 10% dissolved.----------------------------------------A2 6 Average of the 12 units (Ai + A2) is not more

than 10% dissolved, and no individualunit is greater than 25% dissolved.

--+-----A3 12 Average of the 24 units (Ai + A2 + A3) is not

more than 10% dissolved, and no individual unit is greater than 25% dissolved.

Buffer Stage- Unless otherwise specified +in the individual monograph ,the requirements are met if+

the quantities of active ingredient dissolved from the units tested conform to Acceptance Table 4.Continue testing through the three levels unless the results of both stages conform at an earlier level.

The value of Q in Acceptance Table 4 is 75% dissolved unless otherwise specified ·in the individual

monograph . The quantity, Q, + specified in the individual monograph is the total amount of active+ +

ingredient dissolved in both the Acid and Buffer Stages, expressed as a percentage of the labeledcontent. The 5%, 15%, and 25% values in Acceptance Table 4 are percentages of the labeled contentso that these values and Q are in the same terms.

Acceptance Table 4Numberl

Level Tested I CriteriaB1 I 6 rEaCh unit is not less than Q + 5%.

82 6"---rAverage of 12 units (81 + 82) is equal t~

jor greater than Q, and no unit is less than____r- I_Q_-__1_5o_~_. _

B3 12 ,Average of 24 units (B1 + B2 + B3) is equalto or greater than Q, not more than 2 unitsare less than Q - 15%, and no unit is lessthan Q - 25%.


1074 FJP Working Group on Dissolution

TABLE 1Dimensions of the Paddle/Basket Apparatuses (Millimeters)

Ph.J.12 ProposalPh.Eur.2 USP 23 (Suppl. 1) (EFPIA)

VesselHeight 168 ± 8 160-175 160-175 160-210Internal Diameter 102 ±4 98-106 98-106 102 ± 4

PaddleShaft Diameter 9.75 ± 0.35 9.4-10.1 9.75 ± 0.35 9.75 ± 0.35

(before coating)

BladeUpper chord 74.5 ± 0.5 74.0-75.0 74.5 ±0.5 74.5 ± 0.5Lower chord 42.0 42.0 ± 1.0 42 ± 1 42.0 ± 1.0Height 19.0 19.0 ± 0.5 19.0±0.5 19.0 ± 0.5

Radius of the disk ofwhich the blade is cutout 41.5 41.5 ± 1.0 41.5 41.5 ± 1.0Radius upper corners 1.2' 1.2* 1.2** 1.2

Thickness 4.0± 1 4.0 ± 1.0 3-5 4.0 ± 1.0

Positioning the stirringdevice

Distance betweeninside of the bottom ofthe vessel and theblade 25±2 25±2 25±2 25 ± 2

Distance betweenshaft axis and verticalaxis of the vessel $2 $2 $2 $2

Stirring characteristic smoothly with- smoothly without smoothlyout significant significant without signifi-wobble wobble cant wobble(s 0.5 mm) ($ 0.5 mm)

BasketShaft diameter (9.75 ± 0.35) 6.3-6.5 or (9.75 ± 0.35) 9.4±10.1

6.4 ± 0.1 9.4-10.1 6.4 ± 0.1

ScreenWire diameter 0.254 0.254 (0.01 inch) No. 36 wire 0.254t

or 0.016 inch! gauze

Openings 0.381 0.381 (0.015 0.425 0.381tinch)or 0.034 inch"

Height of screen 27.0 ± 1 27.0± 1.0 27.0 ± 1 27.0±1.0Total height of basket 36.8 ± 3 36.8 ± 3.0 36.8 ± 3 36.8 ± 3.0Internal diameter ofbasket 20.2 ± 1 20.2± 1.0 20.2 ± 1 20.2 ± 1.0External diameter ofbasket 22.2 ± 1 22.2 ± 1.0 22.2 ± 1 22.2 ± 1.0External diameter ofring 25.4 ± 3 25.4 ± 3.0 25.4 ± 3 25.4 ± 3.0

FIP Guidelines 1075

TABLE 1Continued

Ph.J.12 ProposalPh.Eur.2 USP 23 (Suppl. 1) (EFPIA)

Vent hole diameter 2 2.0 2 2.0 ± 0.5

Height of couplingdisk 5.1 ± 0.5 5.1 ± 0.5 5.1 ± 0.5 5.1 ± 0.5

Positioning of thestirring device:

Distance betweeninside of the bottom ofthe vessel and thebasket 25 ±2 25± 2 25 ±2 25±2

Distance between theshaft axis and thevertical axis of thevessel $;2 $;2 $;2 $;2

Stirring characteristic smoothly with- smoothly without smoothly with-out significant significant out significantwobble wobble wobble

* proposalsto come (Re: USP 23 Suppl. 2 and PNPH/SG(94)83, May 94)** proposed in JP Forum Vol. 3 NO.3 (July, 1994),see Figure 1t basket to be used is indicated in the individualmonographs:j: should correspondwith the requirementsfor standards,eg, InternationalStandard ISO2194-1972

ternative dissolution apparatuses should beencouraged. If an individual drug productcannot be accommodated by one of the appa-ratuses, described above, altemative modelsor appropriate modifications have to be de-veloped. In such a case, however, superiorityof the alternative or the modification has tobe proven in comparison to the well estab-lished and standardized apparatuses. In thepast, many papers intended to justify an alter-native model by proving that in vitro dissolu-tion results were equivalent or similar tothose obtained with, for example, the paddlemethod. According to the understanding ofthese guidelines, the latter provides clear evi-dence that the paddle method should be used!

Modification ofthe apparatus as describedin the Pharmacopoeias or the harmonizationproposal in Table I can be intended for auto-mation, for example, of the sampling proce-dure. In such cases, whether it is, for exam-ple, sampling via the hollow shaft of paddleor basket or permanent sampling probes in

the beaker, which could potentially influenceagitation characteristics (7), or any othermeasure, that results are equivalent with andwithout the modification should be validatedon a product-by-product basis.

EXPERIMENTAL TESTINGCONDITIONS

For all applications, in vitro dissolution datashould at least allow some interpretation withregard to in vivo biophannaceutical perfor-mance. In order to increase their predictivevalue, attempts have been made to adjust invitro test conditions (8-11) as close as possi-ble to physiologic conditions. Nevertheless,several examples demonstrate that such con-ditions can also lead to misinterpretationsand are not able to guarantee in vitro resultsroutinely relevant to the in vivo situation(12).

In general, an aqueous medium should beused. Attempting to strictly mimic the physi-

limit is specificated to ensure (almost) quantitative drug release, which is generallyunderstood as ::::80 %. The dissolution run in quality control therefore should be extendedfor the time interval until at least 80 % of drug substance is dissolved. Shorter test intervalscan be acceptable in special cases but require justification on the basis of an in vitro-in vivocomparison study and should at least cover 24 hours.

The acceptance range for the dissolution pattern at the time intervals specified should bedefined case-by-case on the basis of the in vitro-in vivo comparison study and taking intoconsideration the capability of the manufacturing process and the commonly accepted rangeof 95 to 105 % of stated amount for the average content of drug substance. Where bothupper and lower limits are specified at any time point, the difference between them shouldusually not exceed. 20 % of the labelled content of drug substance in the formulation unlesslimits have been shown to provide reproducible and acceptable in vivo performance [13].

8. Interpretation, Acceptance Criteria

Dissolution test specifications should include the defmition of limits, the number of units tobe examined and respective acceptance criteria. The procedure of data interpretation shouldbe hannonised internationally, the existing compendial requirements should be uniform.

As pharmacopoeial approaches are still not fully hannonised it is recommended to followthe acceptance criteria in accordance with USP for immediate/conventional-release products,modified-release (extended-release) products and gastro-resistant (delayed-release) products(Table 5). The approach with a maximum of these stages and individual units tested fordeviation from stated ranges corresponds well to requirements for content uniformity.Although there is preference in common practice in pharmaceutical industries to decide uponbatch release not later than stage 2, the three step approach is the best solution for formalspecifications, especially when referring to end-of-shelf life specification. Reference tolabelled content does not apply for products with intentional different content at time ofmanufacturing, such as in cases of stability average.

9. Special Applications

A specific value of dissolution testing is recognized in its applications in scale-up andmanufacturing changes for immediate/conventional-release and modified-release oralproducts. The AAPSfFDAfUSP Scale-up workshops [34, 35] recommend certain types and

ranges of changes for which the sameness of in vivo product performance is assumed, basedon in vitro dissolution data. In addition, the Scale-Up and Post-Approval Change (SUPAC)document 0 f FDA [36] defines the level of changes with respect to components andcomposition, site of manufacturing, the scale of manufacturing, and process and equipmentchanges in manufacturing for an immediate-release oral formulation. Depending on the levelof change, different levels of dissolution testing are recommended to assure continuingproduct quality and performance characteristics. Respectively, the documentation needed toassure the product performance varies, depending on therapeutic range, solubility andpermeability factors of the drug. For changes greater than the acceptable values in the scale-up workshop report, additional dissolution profile determinations in several media arerecommended for inunediate-reIease products.

For major changes, that are likely to have a significant impact on formulation quality andperformance, an in vivo bioequivalence study is reconunended in addition to extensivedissolution profile testing. For manufacturing site change, scale-up, equipment changes andminor process changes dissolution testing is deemed sufficient to assure product quality andperformance.

In vitro dissolution tests have also been used to try to simulate food-effects onbioavailabilitv. So far, these different attempts [37 - 43] have had extremely limited successin prediction [44]. Assuming that gastro-intestinal transit times are significantly contributingto potential food-effects on bioavailability, the value of an in vitro model for food-effectswill be limited to an evaluation whether direct drug-food-interaction could be of relevance forthe observed changes in bioavailability in the in vivo study.

Test media that may reflect gastric conditions (fasted) and intestinal conditions (fasted/fed)and thus may give additional information for research and development purpose aresurnmarised ill Table 6 [45]. Special tests have also bee suggested for consideration ofspecific situations, such as achlorhydric elderly patients [46].

10. Conclusions

In many international discussions, mainly over the years 1988 to 1993, consensus wasreached on some essential aspects, to which these Guidelines refer. On the other hand, manyaspects have either not yet been sufficiently explored or have not been harmonised. In thesecases, e.g. more precise specifications of dissolution media and proposals for in vitro-in vivocomparison approaches and verification of specifications for immediate/conventional-release,

Page 8 ofl2

delayed-release and modified-release preparations, the revised Guidelines will providecontributions for reasonable standardisation, while acknowledging that for a number of drugse.g. with special physico-chemical or pharmacokinetic properties, case-by case developmentis required.

These Guidelines should be helpful and applicable for all involved in in vitro dissolutiontesting. However, there was special emphasis on providing reliable guidance for industrialresearch and development, process val idation and quality control, making the Guidelinesespecially applicable for industry, drug authorities and control laboratories but also foruniversities, hospitals, pharmacies or others, when involved in (bio )pharmaceutical qualityevaluation.

In general these Guidelines should be understood as recommendations based on scientificknowledge and experience. They should be helpful in the dialogue with drug regulatoryauthorities. However they are not intended to represent any official requirements in this field.

Table 1: Dissolution. Paddle and Basket Apparatus, Dimensions (mm) of theVessel and the Paddle

Item I EP III I USP23 I JP XIII IProposal(Suppl. 5)

VesselHeight 163 ± 8 160 - 175 1160 - 175 1160 - 210Internal diameter [02±4 98 - 106 98 - 106 [02 ±4

PaddleShaft diameter 9.75 ± 0.35 9.4 - 10.1 19.4 - 10.1 19.4 - 10.1

before coatingBladeUpper chord 74.5 ± 0.5 74.0 - 75.0 74.0 -75.0 74.5 ± 0.5Lower chord 42.0 ± [ 42.0 ± [0 42.0 42.0 + [0Height 19.0± I 19.0±0.5 19.0 ± 0.5 19.0±0.5Radius (disk) 41.5 41.5 ± [0 41.5 41.5 ± [0

Radius (upper comers) 1.2 1.2 1.2 12Thickness 4.0± [ 4.0 ± 1.0 4.0 ± 1.0 4.0 ± 1.0

Positioning of the stirring

deviceDistance from the bottom 25 ± 2 25 ± 2 25 ±2 25 ± 2Distance between shaft axisand vertical axis of the vessel :52 :52 :52 :52

Stirring characteristics Smoothly Smoothly No comment Smoothlywithout without withoutsignificant significant significant

wobble wobble wobble(:50.5 mm)

Table 2: Dissolution. Paddle and Basket Apparatus, Dimensions (mm) of theBasket.

Item EP III USP23 JP XIII Proposal

(Suppl. 5)BasketShaft diameter (9.75 ± 035) 63 - 6.5 or 9.75 - 035 or 9.4-10.1

6.4 ± 0.1 9.4-10.1 6.4 ± 0.1 (ccrrcs. to shaft dia.of the paddle)

ScreenWire thickness 0.245 0.254 or N° 36 sieve 0.25 t )

Openings 0.381 0.406 0.425 0.400' )

Heigh of screen 270± 1 0.381 or 27.0± I 270 ± 1.0

Total height ofbasket 36.8 ± 30.864

36.8 ± 3 37.0 ± 3.0Internal dia. of basket 20.2 ± 1

270 ± 1.020.2 ± I 20.0 ± 1.0

External dia. of basket 22.2 ± 1 36.8 ± 3.0 22.2± 1 22.0 ± 1.0

External dia. of ring 25.4 ± 3 20.2 ± 1.025.4 ± 3 25.0 ± 3.0

Vent hole diarnenter 222.2 ± 1.0

2 2.0 ± 0.5Height of coupling disk 5.1 ± 0.5

25.4 ± 35.1 ± 0.5 5.0 ± 0.5

25.1 + 0.5

Page 9 of 12

Positioning of the stirringdeviceDistance from the bottom 25 ± 2 25 ± 2 25 ± 2 25 ± 2Distance between shaft axisand vertical axis of the vessel ~2 ~2 ~2 ~2

Stirring characteristics Smoothly Smoothly Nocommcnt Smoothlywithout without withoutsignificant significant significantwobble wobble wobble

(max. runout (max. runout± Imm) at the basis of

the basket ± Inun)

i ) Test sieve (40 mesh) according to DIN ISO-Nonn 3310 (Part I): 1990 (dimensionsrelevant for the plain wire cloth)

Table 3: Proposed Dissolution Media

Medium Proposed Comoosition

O.IN hydrochloric acid 3.636 g of HCl, corresponding to 8.3 ml hydrochloric acid37% (m/m) per 1000 ml of aqueous solution

Buffer solution pH 4.5 Acetate buffer solution pH 4.5:

2.99 g of sodium acetate trihydrate and 1.66 g of glacial aceticacid are dissolved in water to 1000 mlor

Phosphate buffer solution pH 4.5:

13.61 g monobasic potassium phosphate are dissolved in 750ml of water. After adjusting the pH to 4.5 with 0.1 Nhydrochloric acid or O.IN sodium hydroxide, water is addedto make 1000 mI

Simulated intestinailluid 250 ml of a solution containing 6.8 g monobasic potassiumwithout pancreatin pH 7.5 phosphate

+ 190 ml ofO.2N sodium hydroxide+ water to make 1000 rnl

0.05M phosphate buffer 50 volumes of 0.2M monobasic potassium phosphatesolution of pH 5.8 to 8.0 solution

+ specified volume of 0.1 N sodium hydroxide+ water to 200 volumes

pH 5.8 6.0 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6 7.8 8.0

NaOH 3.6 5.6 8.1 11.6 16.4 22.4 29.1 34.7 39.1 42.4 44.5 46.1(volumes)

Table 4: Possible reasons for poor in vivo-ill vitro correlations

Fundamentals

in vivo dissolution is not the rate limiting step for drug absorptionno in vitro test is able to model in vivo dissolution

Study design

Page 10 of12

• inappropriate in vitro test conditions• inappropriate in vivo test conditions

Dosage form

drug release not controlled by the dosage form• drug release strongly affected by intestinal transport kinetics

Drug substance

• non-linear pharmacokinetics (e.g. saturable first pass effect), absorption window,chemical degradation in the gastrointestinal tractabsorption of undissolved particles

• large intra individual variability

Table 5: Acceptance Tables According to USP 23 <711>

Sa: Immediate/conventional-Release Drug Products

Stage Number Tested Acceptance Criteria

SI 6 Each unit is not less than Q + 5 %

S2 6 Average of 12 units (SI + ~) is equal toor greater than Q, and no unit is less thanQ -15 %

S3 12 Average of24 units (Sl + S2 + S3) is equalto or greater than Q, not more than 2 unitsare less than Q - 15 %, and no unit is lessthan Q - 25 %

5b: Modified (Extended-Release) Drug Products


LI

~

L3

6

6

12

No individual value lies outside eaeh ofthe stated ranges and no individual valueis less than the stated amount at the finaltest time

The average value of the 12 units (LI +L2) lies within each of the stated rangesand is not less than the stated amount atthe final test time; none is more than 10 %of labelled content outside each of thestated ranges; and none is more than 10 %of labelled content below the statedamount at the final test time

The average value of the 24 units (L] +L2 + L3) lies within each of the statedranges, and is not less than the statedamount at the fmal test time; not morethan 2 of the 24 units are more than 10 %of labelled content outside each of thestated ranges; not more than 2 of the 24units are more than 10 % of labelledcontent below the stated amount at thefinal test time; and none of the units ismore than 20 % of labelled contentoutside each of the stated ranges or morethan 20 % of labelled content below thestated amount the final test time

Page 11 ofl2

5c: Gastro Resistant (Delayed-Release) Drug Products

Acidic stage


Al 6 No individual value exceeds 10 %dissolved

A2 6 Average of 12 units (A I + A2) is not morethan 10 % dissolved, and no individualunit is greater than 25 % dissolved

A3 12 Average of the 24 units (A I + A2 + A3) isnot more tban 10 % dissolved, and noindividual unit is greater than 25 %dissolved

Buffer stage

Stage Num ber Tested Accepta nee Cri teria

B1 6 Each unit is not less than Q + 5 %

B2 6 Avcrage of 12 units (B I + B2) is equal toor greater than Q, and no unit is less thanQ -15 %

B3 12 Average of the units (B I + B2 + B3) isequal to or greater than Q, not more than 2units are less than Q - 15 %, and no unit isless than Q - 25 %

Table 6: Dissolution media that may reflect gastric conditions (fasted: SGF) andconditions in small intestine (fasted: FaSSIF; fed: FeSSIF)

SGF FaSSIF

HCI 0.01-0.05 N KH2 P04 0.029 M

Sodium lauryl sulfate 2.5 G NaOH q.s pH 6.8

Sodium Chloride 2.0 G NaTaurocholate 5mM

Distilled Water qs. 1000 ml Lecithin 1.5mM

KCI 0.22 M

Distilled Water q.s. 1000 m l

FeSSIF

Acetic acid 0.144 M

NaOH q.s. pH 5

NaTaurocholate 15 mM

Lecithin 4mM

KCI 0.19 M

Distilled Water Q.S. 1000 ml

Page 12 of 12

usp dissolution

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