Johannes Kraemer

FIP/AAPS Joint Workshop Report: Dissolution/ In Vitro Release Testing of Novel/Special Dosage Forms

In 2003, the FIP Dissolution Working group published a position paper on dissolution/drug release testing for special/novel dosage forms that represented the scientific opinions of many experts in the field at that time (1). The position paper has supported activities, programs, and decisions in the scientific, technical, and regulatory community. Due to the rapid evolution of new practices and techniques for in vitro testing, the FIP Special Interest Group (SIG) on Dissolution/Drug Release decided to revise the previous paper and added proposals for further harmonization of in vitro release testing practices for different pharmaceutical dosage forms. This article represents the current updates to the previously published paper. This revision has been aligned to coincide with the USP taxonomy including route of administration, intended site of drug release, and dosage form. The revised paper includes information from current literature, expert discussions, and presentations from recent workshops (2,3). The authors acknowledge and expect further updates to be made as additional progress is made in the relevant areas. Thus, comments and additional contributions are welcome and may be considered for the next revision of the position paper.

Dissolution testing of orally disintegrating tablets

For industrially manufactured pharmaceutical dosage forms, product quality tests and performance tests are required to ascertain the quality of the final product. Current compendial requirements specify a disintegration and/or a dissolution test to check the quality of oral solid dosage forms. These requirements led to a number of compendial monographs for individual products and, at times, the results obtained may not be reflective of the dosage form performance. Although a general product performance test is desirable for orally disintegrating tablets (ODTs), the complexity of the release controlling mechanisms and short time‐frame of release make such tests difficult to establish. For conventional oral solid dosage forms (COSDFs), disintegration is often considered to be the prerequisite for subsequent dissolution. Hence, disintegration testing is usually insufficient to judge product performance of COSDFs. Given the very fast disintegration of ODTs, the relationship between disintegration and dissolution is worthy of closer scrutiny. This article reviews the current status of dissolution testing of ODTs to establish the product quality standards. Based on experimental results, it appears that it may be feasible to rely on the dissolution test without a need for disintegration studies for selected ODTs on the market.

Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms—Workshop Report

Biorelevant in vitro performance testing of orally administered dosage forms has become an important tool for the assessment of drug product in vivo behavior. An in vitro performance test which mimics the intraluminal performance of an oral dosage form is termed biorelevant. Biorelevant tests have been utilized to decrease the number of in vivo studies required during the drug development process and to mitigate the risk related to in vivo bioequivalence studies. This report reviews the ability of current in vitro performance tests to predict in vivo performance and generate successful in vitro and in vivo correlations for oral dosage forms. It also summarizes efforts to improve the predictability of biorelevant tests. The report is based on the presentations at the 2013 workshop, Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms, in Washington, DC, sponsored by the FIP Dissolution/Drug Release Focus Group in partnership with the American Association of Pharmaceutical Scientists (AAPS) and a symposium at the AAPS 2012 Annual meeting on the same topic.

Product Performance Test for Medicated Chewing Gums

The nature and type of performance tests used to characterize dosage forms administered to the oral cavity differ significantly and thus demand different release testing apparatus. For many dosage forms given orally but not limited to muco-adhesive buccal tablets, chewable tablets, and sublingual preparations, product performance tests are adapted from existing procedures and are well characterized in the United States Pharmacopeia (USP). Unlike chewable tablets, medicated gums are not supposed to be swallowed and may be removed from the site of application without resort to invasive means. Moreover, medicated gums require the active and continuous masticatory activities for activation and continuation of drug release. Medicated chewing gums are dosage forms given orally for both local and therapeutic effect, and no performance test has been indicated for medicated chewing gums in USP. This Stimuli article outlines the importance and rationale of in vitro drug release testing and the product quality tests used during the development of medicated chewing gums and their quality control for market release.

FIP Position Paper on Qualification of Paddle and Basket Dissolution Apparatus

The qualification process for ensuring that a paddle or basket apparatus is suitable for its intended use is a highly debated and controversial topic. Different instrument qualification and suitability methods have been proposed by the pharmacopeias and regulatory bodies. In an effort to internationally harmonize dissolution apparatus suitability requirements, the International Pharmaceutical Federations (FIP) Dissolution/Drug Release Special Interest Group (SIG) reviewed current instrument suitability requirements listed in the US, European, and Japanese pharmacopeias and the International Conference on Harmonization (ICH) Topic Q4B on harmonization of pharmacopoeial methods, in its Annex 7, Dissolution Test General. In addition, the SIG reviewed the Food and Drug Administration (FDA) Draft Guidance for Industry, “The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2—Current Good Manufacturing Practice (CGMP)” and the related ASTM Standard E2503-07. Based on this review and several in-depth discussions, the FIP Dissolution/Drug Release SIG recommends that the qualification of a dissolution test instrument should be performed following the calibration requirements as indicated in the FDA (draft) guidance. If additional system performance information is desired, a performance verification test using US Pharmacopeia Reference Standard tablet or an established in-house reference product can be conducted. Any strict requirement on the use of a specific performance verification test tablet is not recommended at this time.

Summary Report from the USP Workshop on Dissolution Testing of Capsules

CAPSULES AND CROSS-LINKING Pharmaceutical capsule preparations consist mostly of either hard or soft gelatin shells filled with nonaqueous liquids, powders, semisolids, or solids (e.g., as multiparticulates). To a minor degree, alternative materials are being used for the manufacture of the shells. The gelatin-containing capsule shell structure may exhibit structural changes by propagating cross-linking phenomena. This process continues during storage and may largely affect the outcome of in vitro dissolution tests. To overcome the poor hydrolysis rate of gelatin capsule shells, USP General Chapter <711> allows the addition of proteolytic enzymes, if needed. This is the so-called two-tier dissolution test procedure. However, the use of enzymes is complex because of the sensitivity of the biochemical reaction. Moreover, enzymatic activities expressed in units per mass are not harmonized internationally, which hinders their use. USP is currently working on a revision of its General Chapter <711> with the goal to facilitate the use of alternative proteolytic enzymes. This revision was the topic of a workshop held at USP headquarters in March 2014. Establishing an understanding of the potential impact of capsules and cross-linking on drug product dissolution is critical not only for method development, but also for definition of appropriate specifications. Components contributing to cross-linking include the manufacturing process, the contents of the capsule (API and excipients), the composition of the capsule shell, and the environmental conditions to which the capsules and the drug product are exposed. The major component of the capsule shell is gelatin, which is a primary contributor to cross-linking. Gelatin sourcing should be tightly controlled, and the molecular weight fraction ratios should be restricted as tightly as possible so as not to contribute to either cross-linking (high molecular weight fractions) or brittleness (low molecular weight fractions). However, the presence of gelatin alone does not induce cross-linking. Components such as microcrystalline cellulose or any oxidizing agents that can degrade to aldehydes, such as formaldehyde, combined with high heat or humidity further promote cross-linking. It is necessary to understand and control each contributing factor as part of capsule and product manufacture. An additional means of minimizing the occurrence of cross-linking is to assure the most appropriate and effective packaging for the drug product. Packaging must protect the product from moisture and oxygen exposure. Development of products using hydroxypropyl methylcellulose (HPMC)-based capsules is underway, and this will eliminate the occurrence of cross-linking. Studies demonstrate that HPMC capsules experience delayed release versus their gelatin capsulebased counterparts. While there are multiple types of HPMC capsule options with different benefits, additional studies will be required to improve robustness of the capsule and to fully understand the impact of the HPMC capsules on measurements of dissolution performance.

Meeting Report: FIP/AAPS Joint Workshop Report: Dissolution/In Vitro Release Testing of Novel/Special Dosage Forms

In 2003, the FIP Dissolution Working group published a position paper on dissolution/drug release testing for special/novel dosage forms that represented the scientific opinions of many experts in the field at that time (1). The position paper has supported activities, programs, and decisions in the scientific, technical, and regulatory community. Due to the rapid evolution of new practices and techniques for in vitro testing, the FIP Special Interest Group (SIG) on Dissolution/Drug Release decided to revise the previous paper and added proposals for further harmonization of in vitro release testing practices for different pharmaceutical dosage forms. This article represents the current updates to the previously published paper. This revision has been aligned to coincide with the USP taxonomy including route of administration, intended site of drug release, and dosage form. The revised paper includes information from current literature, expert discussions, and presentations from recent workshops (2,3). The authors Please send comments to the Co-Chairs of the FIP Dissolution/Drug

Description of the Upcoming Change in Data Analysis for USP Dissolution Performance Verification Tests

As part of its evaluation of the performance verification tests used periodically to affirm the integrity of the USP Performance test when General Chapter Dissolution is relied upon, the Biopharmaceutics Expert Committee of the Council of Experts, working with staff, decided to change the form of the accept/reject decision from one based on the result for each tablet to one based on the mean and coefficient of variation of results from a set of tablets. This paper describes the new approach. The paper also describes an implementation period for the approach, coupled with a period during which USP will discontinue use of the Salicylic Acid tablet in a performance verification test.

Use of Enzymes in the Dissolution Testing of Gelatin Capsules and Gelatin-Coated Tablets— Revisions to Dissolution and Disintegration and Dissolution of Dietary Supplements

A revision to the general chapters Dissolution and Disintegration and Dissolution of Dietary Supplements is being proposed to address the shortcomings of the current chapters regarding the use of enzymes in the dissolution test of gelatin capsules or gelatin-coated tablets. The recommendations are to use the enzymes pepsin (medium with pH equal to or below 4.0), papain or bromelain (medium with pH above 4.0 and below 6.8), and pancreatin (medium with pH equal to or above 6.8) if the dosage form does not comply to the appropriate Acceptance Table or, in the case of dietary supplements, appropriate Tolerances requirements due to the presence of cross-linking in the gelatin. Also, the revision clarifies how the enzyme activity should be determined, the amount of enzymes to be added to the medium, and a pre-treatment procedure to be used when the dissolution medium contains surfactant or any other ingredient known or suspect to inactivate the enzyme being used. This Stimuli article provides the rationale for these revisions and presents data to support the recommendations being made. Readers are encouraged to send any comments, questions, suggestions or data to the corresponding author. Also, see the section Other Related Revisions at the end of this article for information on other related general chapters and monographs.

Practical Aspects of Dissolution Instrument Qualification—a European Perspective

INTRODUCTION Dissolution testing is an important tool to characterize the in vitro performance of dosage forms. It is not an absolute method; strictly speaking, equipment cannot be calibrated. Instead, from the perspective of a quality control (QC) laboratory, reliable instrument qualification is one of the most important requirements of cGMP. While harmonization efforts for qualification strategies of standard laboratory equipment lead, in most cases, to clear and undisputed approaches, the standardization of dissolution apparatus qualification procedures is still ongoing. The most common USP Apparatus 1 and 2 are used in pharmaceutical laboratories worldwide to perform quality control analyses either during the manufacturing process (PAT) or as part of release testing. Moreover, they are used to monitor formulations throughout pharmaceutical development. Drug candidate selection for clinical studies is based on differences attributed to manufacturing variables during a Quality by Design (QbD) oriented development, whereas the release of marketed products relies on the dissolution similarity of manufactured batches in comparison to the models described in the dossiers for registration. This underlines the need for reliable dissolution data. A study of the relevant rules and procedures reveals that dissolution apparatus qualification consists of two parts: a mechanical qualification and a performance test with a reference standard. In detail, the leading documents concerning dissolution apparatus qualification [e.g., United States Pharmacopoeia (USP) and the European Pharmacopoeia (EP) on the one hand and ASTM E2503-07 and FDA Guidance for Industry (1) on the other hand] do not advise identical procedures and specifications. Proposals were made for procedures to match the so-called “chemical” and “mechanical” qualification (2) but are still leaving some uncertainty at QC testing labs. In the past, harmonization efforts like ICH Q4B took effect and harmonized the respective chapters of the USP and the EP. One remaining difference is the EP nonmandatory recommendation of the use of a reference product that is sensitive to hydrodynamic conditions for performance testing, while USP requires the use of its reference tablet. This article describes the authors’ strategy and observations when performing “mechanical” and “chemical” qualification of dissolution Apparatus 1 und 2 in a typical QC laboratory that has to follow both United States and European requirements.