Legislation
Resolution

Resolution - RE nº 483, of March 19, 2002
(Official Journal of 20/03/2002)

The Director of the Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of the attributions vested in him under Administrative Rule 724, issued by the Director-Chairman, on October 10, 2000,

WHEREAS

paragraph 3 of article 111, of the Bylaws approved by Administrative Rule 593, of August 25, 2000, re-published in the Official Journal of the Union of December 22, 2000;
that the matter was submitted to the examination of the Collegiate Board of Directors, which approved the matter in a meeting held on March 13, 2002, decides:

Article 1 - To determine the publication of the "Guide for Dissolution Testing of Oral Solid Immediate Release Dosage Forms (FFSOLI)", attached.

Article 2 - This Resolution enters into force on the date of its publication.

GONZALO VECINA NETO

GUIDE FOR DISSOLUTION TESTING OF ORAL SOLID IMMEDIATE RELEASE DOSAGE FORMS - 1/2002
1. INTRODUCTION

the purpose of this guide is to provide:

1.1 general recommendations for dissolution analysis;
1.2 specifications related to the biopharmaceutical characteristics of drugs;

1.3 statistical methods for the comparison of dissolution profiles;
2. TECHNICAL-SCIENTIFIC PRINCIPLES

The absorption of drugs from the oral solid dosage forms depends on their release, dissolution or solubility of the drugs in physiologic conditions and on their permeability through the membranes of the gastrointestinal tract. Due to the critical nature of the first two, the in vitro dissolution can be relevant to anticipate in vivo performance. Based on these general considerations, the in vitro dissolution analysis of oral solid dosage forms, such as tablets and capsules, is used to ensure batch to batch quality, to guide the development of new formulations and ensure uniformity of quality and performance of the drug product after certain alterations.

Information related to solubility, permeability, dissolution and pharmacokinetics must be taken into consideration for the definition of the dissolution specifications, with a view to the approval of the drug product registration.

3. BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS)

Based on the solubility and permeability of the drugs, the following BCS is recommended in literature:
3.1. case I: high solubility (HS) and high permeability (HP);

3.2. case II: low solubility (LS) and high permeability (HP);

3.3.case III: high solubility (HS) and low permeability (LP);

3.4.case IV: low solubility (LS) and low permeability (LP).

This classification may be used to determine in vitro dissolution specifications and may also provide the basis to predict when the in vitro-in vivo correlation (IVIVC) can be obtained successfully.

A drug solubility is determined by the dissolution of the highest dosage of a drug in 250 mL of buffer solution with pH between 1,0 and 8,0. A drug is considered highly soluble when the result, in volume, of the ratio dose/solubility is less than or equal to 250 mL. A drug of high permeability is, in general, the one whose absolute bioavailability is more than 90% in the absence of instability in the gastrointestinal tract or when this parameter is experimentally determined. The BCS suggests that for a drug which presents HS and HP (case I) and for some HS and LP drugs (case III) the achievement of 85% of dissolution in HCl 0,1M, in up to 15 minutes, may guarantee that the bioavailability of the drug is not limited by the dissolution. In such cases, the limiting step of the drug absorption rate is gastric emptying.
For LS and HP drugs (case II), dissolution may be the limiting step of the drug absorption rate and a in vitro-in vivo correlation may be expected. Dissolution profiles obtained in different dissolution media are recommended for drug products which contain drugs from this category. For drugs which present HS and LP (case III), permeability is the limiting step of the absorption rate, and a limited IVIVC may be expected, depending on the relative rates of dissolution and intestinal transit. Drugs under case IV (LS and LP), generally present significant problems for the release from oral solid dosage forms.

4. DISSOLUTION SPECIFICATIONS

In vitro dissolution specifications are established to guarantee batch to batch consistency and to indicate potential bioavailability problems. For new drug products, dissolution specifications must be based on data obtained from the batch used in the bioavailability assay (biobatch). For generic drugs, the dissolution specifications are generally the same of the reference drug product. These specifications are confirmed by testing the performance of the biobatch dissolution. If the generic drug dissolution is substantially different from the reference drug product dissolution, and the in vivo study had proved the bioequivalence between them, a different dissolution specification for the generic drug can be established, provided it is based upon a validated IVIVC. In that case, the specification must be fulfilled throughout the permanence of the generic drug in the market.
Three categories of dissolution specifications for immediate release drug products can be described:

4.1. Single point specifications
Corresponds to a quality control routine test (for drug product containing highly soluble drug).

4.2. Two points specifications
a) to characterize the drug product quality;

b) as a quality control routine test for certain kinds of drug product (for example, drugs not very soluble in water whose dissolution is slow like carbamazepine).

4.3. Dissolution profile comparison

To avoid the requirement of bioequivalence studies of the immediate release dosage forms of lower dosages, when several presentations with the same formulation exist, the dissolution profiles must be compared and must be identical among all dosages.

4.4. Dissolution Specifications

The specifications must be based on the biobatch dissolution characteristics. If the formulation developed for commercialization differs significantly from the biobatch, the comparison of the dissolution profiles and the bioequivalence study between these two formulations is recommended.

The dissolution tests must be undertaken under such conditions as: basket method at 50/100 rpm or paddle method at 50/75/100 rpm. To generate a dissolution profile, at least five sampling points must be obtained of which a minimum of three must correspond to percentage values of dissolved drug lower than 65% and the last point must be relative to a sample period of time equal to, at least, the double of the former period of time. For drug products of rapid dissolution, samples at shorter intervals (5 or 10 minutes) may be necessary. For drug products with highly soluble drugs that present rapid dissolution (cases I and III of BCS), a dissolution test of a single point (60 minutes or less) that proves a dissolution of, at least, 85% is sufficient for batch to batch uniformity control. For drug products containing drugs poorly soluble in water, which dissolve very slowly (case II of BCS), a two points dissolution test, that is, one at 15 minutes and another at 30, 45 or 60 minutes, to ensure 85% of dissolution is recommended.

4.5. Dissolution Specifications for Generic Drugs
The dissolution specifications for generic drugs are classified in three categories:

4.5.1. Available Pharmacopeial Specifications
In these cases, the dissolution test for quality control is the one described in the Brazilian Pharmacopoeia or, in its absence, in other code book authorized by the legislation in force. The establishment of the dissolution profile, in the conditions referred to in item 4.4 with sampling interval of 15 minutes or less, employing the pharmacopeial method, when available, for the test and the reference drug product, using 12 (twelve) units of each is recommended. Once scientifically justified, additional dissolution data may be presented.

4.5.2. Non-Available Pharmacopeial Specifications; Dissolution test developed for the available innovative drug product (publication)
In these cases, it is recommended to establish the dissolution profiles in the conditions referred to in item 4.4, for the test and the reference drug products (twelve units of each). Additional dissolution data may be requested at the submission, when scientifically justified.

4.5.3. Unavailable Pharmacopeial Specifications; Unavailable dissolution test developed for the innovative drug product
In these cases, it is recommended to establish comparative dissolution profiles employing test and reference drug products, executed under various conditions, that may include at least three different dissolution media (pH 1,0 to 6,8), addition of surfactants and use of paddle or basket with varying agitation. In all cases, the profiles must be established as recommended in item 4.5.1..The dissolution specifications are based on available bioequivalence data.

4.6. Special Cases
4.6.1. Two Point Dissolution Test
For drugs not very soluble in water (for example, carbamazepine), it is recommended to establish dissolution test with more than one sampling point for the routine quality control. Alternatively, a dissolution profile may be used.

4.6.2. Two Media Dissolution Test
To reflect more adequately the physiologic conditions of the gastrointestinal tract, a dissolution test may be used with simulated gastric fluid (SGF), with or without pepsine, or simulated intestinal fluid (SIF), with or without pancreatin, to determine the batch to batch quality, provided the bioequivalence is maintained. Example: in some cases, with aging, a diminution of the gelatin capsules dissolution is observed due to pellicle formation, when tested in SGJ and SEJ without enzymes. Nevertheless, in the presence of enzymes, a significant increase in the dissolution may be verified. Under these conditions, a dissolution profile in different media may be necessary to evaluate the drug product quality.

4.7. Mapping

The term mapping refers to the procedure through which it is possible to determine the relation among critical manufacturing variables (CMV) and a response derived from dissolution profiles (in vitro) and bioavailability data. The CMV include changes in formulation, process, equipment, materials and methods that may significantly affect the dissolution.
The purpose of this method is to develop drug product specifications to ensure the bioequivalence of future batches produced within acceptable limits of dissolution. Various types of experiments may be carried out to study the influence of the CMV over the drug product performance. One of these experiments may be described as:

4.7.1. prepare two or more formulations including CMV and study their dissolution characteristics.
4.7.2. test one formulation presenting a more rapid dissolution and another one of slower dissolution in a group of healthy subjects (for example, n ³ 12), comparing them with the reference drug product or with the formulation to be commercialized;

4.7.3. determine the bioavailability of these drug products and study the in vitro-in vivo correlation.

The drug products presenting extreme dissolution characteristics are also called "limit batches". If these products are bioequivalent to the reference or to drug product to be commercialized, future batches presenting dissolution characteristics within these groups should be bioequivalent to each other. Thus, this method may be considered as a means of verification of limits for dissolution specifications.
The established dissolution specifications employing this method may be better to ensure the quality and performance of the drug product. Depending on the number of products evaluated, this study may provide information about in vitro-in vivo correlation and/or relation between these data.

4.8. In vitro-In vivo Correlation (IVIVC)
For drugs highly soluble in water (cases I and III of BCS), found in immediate release products presenting excipients and manufacturing techniques considered conventional, it is not always possible to obtain an IVIVC. However, an IVIVC for drugs not very soluble in water is likely to be found (case II of BCS).

The importance of dissolution as a quality control assay for predicting the in vivo performance of a drug product increases significantly when a relation is established between in vitro and in vivo data (correlation or association). The in vitro test becomes a "tool" to distinguish acceptable drug products (bioequivalent) from unacceptable ones (bioinequivalent).

To obtain an IVIVC, a minimum of three batches differing in vivo and in vitro must be prepared. When these batches present different in vivo performances, the in vitro conditions may be modified to correspond to the in vivo data in order to obtain an IVIVC. If there are no differences in vivo and the in vitro performance is different, the conditions of this test may be modified to find the same dissolution performance of the batches studied in vivo. The in vitro assay is often more sensitive in distinguishing formulations than the in vivo assay. From the quality assurance point of view, a more discriminating test is preferable, as it may indicate possible alterations in the drug product quality before the modification of the in vivo performance is recorded.

4.9. Validation and Verification of the Specifications
In vivo assays may be necessary to validate the specifications obtained in vitro. In this case, the same formulation must be employed, but other factors related to CMV must be modified. Two batches with different in vitro profiles must be prepared (mapping). Then, these products must be tested in vivo and, if differences are verified, the system may be considered validated. On the other hand, if differences in vivo are not verified, the results may be interpreted as a verification of the dissolution limits, as previously discussed. In this case, new dissolution specifications must be developed until the results in vivo reflect the differences in vitro.

5. COMPARISON OF DISSOLUTION PROFILES

Until recently, single point dissolution tests and specifications have been employed to evaluate scale-up and post-registration changes. When minor alterations are carried out, the single point dissolution test may be adequate to ensure drug product quality and performance.
For major alterations, the comparison of dissolution profiles obtained in identical conditions between the altered formulation and original one, is recommended. In this comparison, the curve is considered as a whole, in addition to each sampling point of the dissolution medium, by means of independent model and dependent model methods.

5.1. Independent Model Method employing the Similarity Factor

A simple independent model method employs a difference factor (f1) and a similarity factor (f2) to compare dissolution profiles. Factor f1 calculates the percentage difference between two the profiles at each sampling point and corresponds to a relative error measure between the profiles:

where:
n = number of sampling points
Rt = value dissolved in time t (percentage), obtained with the reference product or with the original formulation (before the alteration)
Tt = percentage value dissolved from the altered formulation, in time t.
factor f2 corresponds to a similarity measure between the two curves:

The procedure is described as follows:
5.1.1. Determine the dissolution profile of both products, test and reference, using twelve units of each.
5.1.2. Calculate factors f1 and f2 using the equations presented previously.
5.1.3. Criteria for two dissolution profiles to be considered similar:

Also to be considered:

a) use a minimum of five sampling points;
b) consider only one point above 85% of dissolution for both products;
c) to allow use of averages, the variation coefficients for the first points (15 minutes, for example) should not exceed 20%. For the remaining points a maximum of 10% is allowed;
d) the average values of Rt may derived from the last reference batch, without alteration, or from two or more consecutive batches, without alteration.
5.2. Multi-varied Independent Model Method
In cases where the variation coefficient within the batch is greater than 15%, the use of a multi-varied independent model method is more appropriate to compare dissolution profiles. The following steps are recommended:

5.2.1. Determine the similarity limits in terms of the multi-varied statistic distance (MSD) based upon inter-batch dissolution differences, from the approved reference batches.

5.2.2. Estimate MSD between test and reference dissolution averages.

5.2.3. Estimate a 90 % confidence interval (90 % CI) in relation to real MSD between test and reference.

5.2.4. Compare the upper limit of the 90 % CI with the similarity limit. The test batch is considered similar to the reference if the upper limit of the 90 % CI is below or equal to the similarity limit.

5.3. Dependent Model Methods
Several mathematical models have been described in technical literature to interpret dissolution profiles. For their application, the following steps are suggested:

a) select the most adequate model for reference dissolution profiles (unaltered approved batches). A model with a maximum of three parameters (for example, linear, quadratic, logistic, probabilistic or Weibull) is recommended;

b) employ the dissolution profiles generated for each unit, determining the most adequate model;

c) a similarity area is determined based upon the parameters variation for each unit from the approved reference batch;

d) calculate the MSD related to the parameters of the model, between the test and the reference batches;

e) estimate 90% confidence region in relation to the actual difference between both batches;

f) compare the limits of the confidence region with the similarity area. If the confidence region is contained in the similarity area, the dissolution profile of the test batch is considered similar to the dissolution profile of the reference batch.

6. EXEMPTION FROM BIOEQUIVALENCE TESTING
Besides being employed for the quality control routine, the dissolution assays have been used to avoid the requirement of bioequivalence studies for lower strengths of a determined dosage form. Thus, a dissolution profile must be done and evaluated employing one of the methods described in item 5 (Comparison of dissolution profiles) and, also, following the criteria: for multiple strengths of immediate release drug product presenting linear pharmacokinetics, the bioequivalence study may be conducted with the highest strength, avoiding performing the test with lower strengths, provided its dissolution is adequate and the composition is similar. In all the cases, the approval of lower strengths is based upon the comparison of their dissolution profiles and similarity (factor f2) to the profile of the batch submitted to the bioequivalence.