Skip to Menu Skip to Search Contact Us Global Websites & Languages Skip to Content

Introduction

Solid, oral-dosage tablets and capsules are the most effective and efficient means of treatment available in the pharmaceutical industry. The drug, taken orally, dissolves in the gastrointestinal fluids and becomes bioavailable as it is absorbed into systemic circulation. Routine in vivo measurement of the active pharmaceutical ingredient (API) in blood and urine is not possible in practice. Measurement methods are inherently error prone due to matrix complications. Therefore, in vitro methods to measure the dissolution rate of the API from the solid oral form are officially recognized by regulatory agencies as an important consideration when formulating solid-oral-dosage forms.

Dissolution tests are established valuable quality-control tools to monitor batch-to-batch consistency. They are also useful in providing pharmaceutical product quality information following post-approval changes to the product such as changes in formulation, changes to the manufacturing process or the site of manufacture, and in process scale-up. In addition, dissolution data can be used in support of a biowaiver for lower strengths of such dosage forms where solid-oral-dosage forms have been proportionally formulated in different strengths. As long as an acceptable bioequivalence study has been carried out on one of the strengths—usually the highest strength—and the API release rate is linearly proportional to the concentration, a bio waiver is preferable.

Adequate release of the API from the dosage form is critical to API absorption. Dissolution and solubility of the API under physiological conditions, and its permeability through the membranes of the gastrointestinal tract, are important physiochemical factors. Due to the critical nature of these factors, dissolution of a pharmaceutical product in vitro is relevant, in certain instances, in anticipating the in vivo characteristics or results.

During the development of a pharmaceutical product, dissolution testing is used as a tool to identify formulation factors that influence and may have a significant effect on the bioavailability of the API. After composition and manufacturing processes are defined, dissolution testing is used in the quality control of scale-up and of production batches. This ensures both batch-to-batch consistency and that the dissolution profiles remain similar to those of pivotal clinical-trial batches. Furthermore, dissolution testing can be used to support the bioavailability of a new pharmaceutical product, the bioequivalence of an essentially equal product, or other product variations. It gauges quality assurance and bioequivalence.

i) Quality assurance is used

  • To establish specifications for quality control on formulated product and API test batches used in bioavailability and bioequivalence studies as well as pivotal clinical studies.
  • To demonstrate consistency in product manufacturing.
  • To benchmark against reference products used in bioavailability and bioequivalence studies and pivotal clinical studies.

ii) Bioequivalence is used

  • To demonstrate similarity between the different product formulations of an active substance (including variations and new, essentially similar products) and the reference medicinal product.
  • As another measure, to collect information on batch-to-batch consistency of the products (test and reference) to be used as a basis for the selection of appropriate batches for the in vivo study.

Biopharmaceutical Classification System and Special Cases

The biopharmaceutical classification system (BCS) is an important classification used for waiver of in vivo bioavailability and bioequivalency decisions by regulatory agencies. This classification system is based on the aqueous solubility and intestinal permeability of the API. The system classifies API into four classes:

Class 1: High Solubility – High Permeability

Class 2: Low Solubility – High Permeability

Class 3: High Solubility – Low Permeability

Class 4: Low Solubility – Low Permeability

This system takes into account dissolution of drug product, its solubility, and API permeability. A BCS based biowaiver can be requested for rapidly dissolving immediate-release (IR) tables containing class 1 API with few additional considerations, such as dissolution profile and original dosage form.

If an active substance is considered highly soluble and if the dosage form rapidly dissolves at physiological pH, it is reasonable to expect that it will not cause any bioavailability problems. In those situations, a bioequivalence study may be waived based on the case history and similarity of dissolution profiles. It is essential to evaluate country-specific regulatory guidelines for proposal of a biowaiver program.

If an active substance is considered to have a low solubility and a high permeability, the rate limiting step for absorption may be dosage form dissolution. This is also the case when one or more of the excipients are controlling the release and subsequent dissolution step of the active substance. In those cases a variety of test conditions is recommended, and adequate sampling should be performed to characterize the dissolution profile completely (e.g., at 10, 15, 20, 30, 45, and 60 minute time interval analysis).

For poorly water soluble drug products, dissolution testing at more than one time point, and preferably a dissolution profile, is recommended for quality control purposes. Alternatively, the use of the United States Pharmacopeia (USP) apparatus 4 (Flow-Through Method) should be considered for the development of dissolution specifications for such products.

If a monograph for a fixed-dose combination is not included in the USP or British Pharmacopoeia (BP), the monographs for the individual components should be used to set the dissolution requirements for each, or an alternate dissolution method should be developed.

Comparison of Dissolution Profiles - Requirements

Dissolution of test and reference products should be performed in USP Apparatus I at 100 rpm or Apparatus II at 50 rpm using 900 ml of the following dissolution media:

  • Acidic media such as 0.1 N HCl or simulated Gastric Fluid USP without enzymes
  • pH 4.5 Acetate Buffer
  • pH 6.8 Phosphate Buffer or simulated Intestinal Fluid USP without enzyme

Two scenarios for comparing the profiles obtained from multipoint dissolution are operative:

  1. If both the test and reference product show more than 85% dissolution within 15 minutes, the profiles are considered similar (no calculations required). If not,

  2. Calculate the f2 value. If f2 ≥ 50, the profiles are regarded as similar and no further in vivo studies are necessary. Note that only one measurement should be considered after 85% dissolution of both products has occurred and excluding point zero. A minimum of 12 dosage units of the drug product should be evaluated.

The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum of squared errors, and is a measurement of the similarity in the percentage (%) dissolution between the two curves.

      f2 = 50 × log{[1+ (1/n)t=1 n (Rt - Tt)2]-0.5 × 100}

Where n is the number of time points, Rt is the dissolution value of the reference batch at time t, and Tt is the dissolution value of the test batch at time t.

A specific procedure to determine difference and similarity factor is as follows:

a) Determine the dissolution profile of two products (i.e., of the test and reference products [using 12 units each]) following a validated dissolution method

b) For f2 calculations, a minimum of three time points (excluding point zero) must be used, and only one measurement after 85% dissolution of both products may be included

c) For curves to be considered similar, f2 values should be greater than 50 (50 to 100) to ensure sameness or equivalence of the two curves and, thus, of the performance of the test and reference products

This model-independent method is most suitable for dissolution profile comparisons when three to four or more dissolution time points are available. The following recommendations should also be considered:

i) The dissolution measurements of the test and reference batches should be made under exactly the same conditions. The dissolution time points for both profiles should be the same (e.g., 10, 15, 20, 30, 45, 60 minutes). For rapidly dissolving products (profiles reaching 85% at 30 minutes) the minimum time points are 10, 15, 20 and 30 minutes

ii) Only one measurement should be considered after 85% dissolution of both products has occurred

iii) To allow use of mean data, the percent coefficient of variation (CV) at the earlier time points (e.g., 15 minutes) should not be more than 20%, and at other time points should not be more than 10%

Reporting of Comparative Dissolution Profile Study

Documentation of a comparative dissolution profile shall be prepared and include at minimum, the:

i) Purpose of study

ii) Product / batch information; e.g.,

  • Batch number, manufacturing/expiry date, packaging
  • Certificates of Analysis (COAs) and batch size for test batches

iii) Dissolution conditions and method

iv) Validated analytical method

v) Results (% API dissolved)

  • Tabulated data
  • Graph representation
  • Similarity determination / calculation

vi) Discussion / Conclusion

vii) Date of analyses and date of report

viii) A GMP compliance declaration by the laboratory. This includes the availability of validation records of test methods and procedures and records of equipment maintenance and instrument calibration

When Can You Request a Biowaiver?

A biowaiver can be requested in the following cases:

  1. Proportionally formulated products of the same API

    • Manufactured by the same manufacturer at the same manufacturing site
    • An appropriate bioequivalence study has been performed on at least one of the strengths of the formulation (usually the highest strength unless a lower strength is chosen for reasons of safety). Dissolution profiles generated for the test and other strength multisource products (i.e., lower and higher strengths) should be compared for each of the specified media
    • When sink conditions do not exist in one or more media, the profiles of the higher and lower strengths may not be similar in those media due to saturation. In this case, supporting data may be generated with the local innovator or reference product of the same strength

  2. Immediate-release tablets

    For different strengths of a multisource formulation, if the dissolution profiles in the three dissolution media specified above are similar.

  3. Extended-release tablets

    When the drug product
  • is in the same dosage form, but
  • in a different strength, and
  • is proportionally similar in its active and inactive ingredients, and
  • has the same drug release mechanism.

In all of the cases, the dissolution profile should be comparable and show that similarity factors met the criteria of f2 ≥ 50 in the three specified dissolution media.

The biowaiver program may not be applicable if there are significant changes in excipients, or if the product is a prodrug, and in cases such as Narrow Therapeutic Index range drugs and products designed to be absorbed in the oral cavity.

However, the biowaiver depends on the approval of the respective countries’ regulatory departments (Table 1). In every case, the submission of additional supporting documents helps to ensure full consideration.

table 1

What Does SGS Provide?

SGS provides the following to assist in the submission of a biowaiver:

  • Study Protocol
  • Systematic method development and the validation package for dissolution profile generation
  • Study report – F1, F2 computation, graph comparisons between the innovator (reference product) and test product
  • The broadest network of contract analytical laboratories with facilities in the US, Canada, Belgium, France, Germany, India, China, Taiwan, Thailand, and Singapore
  • Global Quality System
  • A list of SGS FDA-inspected labs

References

  • Guidance for Industry. Waiver of In-Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 2000.
  • Moore, J.W. and Flanner, H.H. (1996). Mathematical Comparison of Dissolution Profiles. Pharm. Technol. 20 (6):64-74.
  • Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), September 1997.

Authors

Sethu. Ragupathy
Business Manger
SGS Life Science Services (Singapore)

Sunil S Potdar
Formulation Development Manger
SGS Life Science Services (Lincolnshire, IL, USA)