Q4b Annex 7(R2) Dissolution Test General Chapter

1. INTRODUCTION: Dissolution Test

Dissolution Test :This annex has been developed as part of the Q4B process concerning the Dissolution Test. The proposed texts within this document were submitted by the Pharmacopoeial Discussion Group (PDG), which is responsible for the evaluation and harmonization of pharmacopoeial standards across different regions. The Q4B initiative aims to promote consistency in the use of analytical methods, ensuring that the dissolution test procedure used across different ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) regions is scientifically sound and consistent.

2. Q4B OUTCOME

2.1 Analytical Procedures

The ICH Steering Committee, after reviewing the findings of the Q4B Expert Working Group (EWG), recommends that the dissolution test procedures specified in the pharmacopoeial texts of the European Pharmacopoeia (Ph.Eur.), the Japanese Pharmacopoeia (JP), and the United States Pharmacopeia (USP) are interchangeable across ICH regions under certain conditions. These documents outline the standards for the dissolution test for solid dosage forms, which is a crucial test used to evaluate the release of the active pharmaceutical ingredient (API) from a drug product.

The specific texts recommended for interchangeability include:

Ph.Eur. 2.9.3: Dissolution Test for Solid Dosage Forms
JP 6.10: Dissolution Test
USP <711>: Dissolution

However, this interchangeability is subject to the following conditions:

2.1.1 Applicability of Apparatus Types

The interchangeability applies to the use of three types of dissolution apparatus: the Basket Apparatus (Apparatus 1), the Paddle Apparatus (Apparatus 2), and the Flow-Through Cell. However, the Flow-Through Cell needs to be identified by an unambiguous descriptive title or a specific compendial reference in the application dossier because the apparatus is referred to by different numbers in the three pharmacopoeias. This ensures that there is no confusion when referring to the apparatus in the regional regulatory documents.

2.1.2 Enzyme Use Exclusion

The dissolution test procedure is not considered interchangeable across the ICH regions when enzymes are used in the dissolution media. The presence of enzymes could introduce variability in the dissolution profiles, making it more difficult to ensure consistency and accuracy across the different pharmacopoeial methods. As such, any dissolution tests involving enzymes must be treated as separate from those that do not involve enzymes, and they should be carefully specified in the relevant application.

2.1.3 Calibration and Compliance with GMP

The dissolution apparatus should undergo appropriate calibration to ensure that it is in compliance with regional Good Manufacturing Practice (GMP) requirements. For example, a robust and properly executed mechanical calibration procedure should be followed to guarantee that the dissolution apparatus meets the necessary performance standards. Adhering to GMP guidelines helps to ensure that the test is reliable and reproducible.

2.1.4 Dosage Forms with Special Coatings

Dissolution testing is not considered interchangeable for dosage forms categorized as delayed-release, gastro-resistant, or enteric-coated according to the regional compendia. These dosage forms are designed to release their active ingredients under specific conditions, and therefore, their dissolution characteristics might vary significantly from those of standard dosage forms. As a result, special considerations must be made when performing dissolution tests on these types of dosage forms.

2.1.5 Validation of Thermometer Use

Validation studies must be conducted to demonstrate that the test results are not negatively affected if the thermometer is left in the dissolution vessel. This is important to ensure that the dissolution test adheres to regional GMP requirements. The proper calibration and operation of temperature-measuring equipment are vital to ensuring the accuracy of the test results.

2.1.6 Exclusion of JP Interpretation 2

Dissolution tests are not considered interchangeable in the ICH regions when based on JP Interpretation 2. This interpretation refers to a specific condition that is not uniformly applied across other pharmacopoeial texts, and as such, it is excluded from the standard interchangeability considerations.

2.1.7 Large Vessel Exclusion

The dissolution test is not considered interchangeable when using large dissolution vessels (greater than 1 liter). The size of the vessel can significantly impact the dissolution process and, therefore, it is not suitable for comparison across different pharmacopoeial standards without taking specific considerations into account.

2.1.8 Product-Specific Parameters

Each dissolution test must specify and justify product-specific parameters, including the dissolution media, stirring rate, sampling time, and the type of sinkers used. These parameters should be thoroughly outlined in the application dossier to ensure that the dissolution process is appropriately tailored to the specific drug product being tested.

2.2 Acceptance Criteria

The acceptance criteria for the dissolution test should be clearly specified in the application dossier. These criteria must ensure that the dissolution profile is consistent and meets the expected standards for the specific dosage form being evaluated. The acceptance criteria are an essential part of regulatory compliance and must be defined in the regulatory submissions for each product.

3. TIMING OF ANNEX IMPLEMENTATION

The implementation of this annex into the regulatory process is contingent upon its adoption at ICH Step 5, which is the final stage of the ICH consensus process. Once incorporated into the regulatory framework in a particular region, it will be accepted and can be used as the standard dissolution test procedure. The timing of this implementation may differ across regions depending on the regulatory bodies involved and their specific approval processes.

4. CONSIDERATIONS FOR IMPLEMENTATION

4.1 General Considerations

When pharmaceutical companies or manufacturers decide to switch to the Q4B-evaluated pharmacopoeial texts referenced in Section 2.1 of this annex, they must follow the necessary procedures for change notification, variation submissions, and prior approval according to the regulatory mechanisms established by the regional authorities. This is crucial to ensure that any changes made to the dissolution test methods comply with the requirements of the respective regulatory bodies and are implemented appropriately.

4.2 FDA Considerations

For the U.S. Food and Drug Administration (FDA), the pharmacopoeial texts referenced in Section 2.1 of this annex can be considered interchangeable. However, the FDA may require pharmaceutical companies to demonstrate that the chosen dissolution test method is suitable for the specific product or material being tested, regardless of the origin of the method. Companies should ensure that their mechanical calibration procedures for dissolution apparatus meet the standards outlined in the FDA’s current good manufacturing practice (CGMP) regulations, specifically under § 211.160(b)(4) of Title 21 of the Code of Federal Regulations. This ensures that the dissolution apparatus remains accurate and reliable during testing.

4.3 EU Considerations

In the European Union, regulatory authorities may accept the use of any of the referenced pharmacopoeial texts for dissolution testing in accordance with the conditions outlined in this annex. If a marketing authorization application, renewal, or variation application cites the use of one of the referenced texts, it can be considered compliant with the European Pharmacopoeia (Ph. Eur.) Chapter 2.9.3, provided the interchangeability conditions are met. Additionally, the EU could accept the approach for dissolution testing of delayed-release products as published in the USP, provided that the validation studies are submitted in the marketing authorization dossier.

4.4 MHLW Considerations

For Japan’s Ministry of Health, Labour, and Welfare (MHLW), the pharmacopoeial texts referenced in Section 2.1 of this annex can also be used interchangeably in compliance with the conditions specified. However, specific implementation requirements will be outlined in the notification provided by MHLW when the annex is formally implemented. The MHLW may accept the dissolution test method for the reciprocating cylinder apparatus, as published in both the Ph. Eur. and USP, if appropriate validation studies are included in the marketing authorization dossier.

4.5 Health Canada Considerations

Health Canada also considers the dissolution test procedures referenced in Section 2.1 of this annex to be interchangeable, provided the conditions outlined in this annex are met. In Canada, the dissolution tests for delayed-release or enteric-coated products, as published in both the USP and the Ph. Eur., are considered interchangeable. This ensures that Canadian regulatory authorities maintain flexibility in evaluating dissolution test methods from different pharmacopoeias.

5. REFERENCES USED FOR THE Q4B EVALUATION

The Q4B evaluation process relied on several key documents for reference:

PDG Stage 5B Sign-off Document (Rev. 2): Japanese Pharmacopoeial Forum, Volume 18, Number 1 (April 2009).
European Pharmacopoeia (Ph. Eur.): Supplement 6.6 (Official January 2010), Dissolution Test for Solid Dosage Forms (Reference 01/2010: 20903).
Japanese Pharmacopoeia (JP): 6.10 Dissolution Test as it appears in the Supplement I to the JP Fifteenth edition (September 28, 2007), and in the revisions made official on March 31, 2009, and July 30, 2010.
United States Pharmacopeia (USP): <711> Dissolution as presented in the Pharmacopeial Forum, Volume 35(3), May/June 2009, and published in USP 33-Reissue, official October 1, 2010.

These references form the basis for the evaluation of dissolution testing procedures and are integral to the harmonization process carried out by the PDG and the ICH.