INTRODUCTION:

Dissolution testing is one of the most prominent tools for assessing drug products' in-vitro performance for pharmaceutical industries. Dissolution testing is a quality-indicating parameter throughout the drug product life cycle, i.e., formulation development, stability testing, batch release, scale-up, regulatory submission, and post-approval changes. Assessment of drug release is essential for all solid oral products and to other dosage forms like suspensions, transdermal systems, suppositories, chewing gums, powders for suspensions, inserts, and implants. The United States Food and Drug Administration (USFDA), Division of Biopharmaceutics, Office of Pharmaceutical Quality provides recommendations of dissolution methods in the form of a database based on approved drug products. The European Medicines Agency provides paper on the dissolution specification of generic solid oral immediate release products for systemic action. Current expectation of the regulators is to perform thorough assessment of the drug product and systematically derive on most suitable product specific dissolution testing conditions. Any kind of in-vitro assessment for the dissolution method's selection and specification setting should be based on the 12 units of dissolution data generated on the drug product. Agency asks for a Dissolution method development report as a part of submission documents while requesting review of a New drug application (NDA) or abbreviated new drug application (ANDA) dossier. The report should include complete data on (1) solubility, (2) rationale for selection of apparatus, rotation speed, medium, volume, sampling times, (3) validation/verification of the robustness of the finalized dissolution method (4) validation/verification of the analytical method used to assay the dissolution samples(5) demonstration of the discriminating ability of the dissolution method for modified release products and immediate-release drug products containing low soluble drug substance(s). In –vitro drug release data is used for prediction of in-vivo drug performance to acts as important tool to optimize prototypes, reduce the number of bioequivalence studies during the development and serves as back bone for post-approval changes¹.

From previous many years, pharmaceutical industries used existing USP dissolution method or FDA recommended methods or its own method that demonstrates its discriminatory power when applicable². However, the current FDA prospect considers the dissolution methods to be drug product specific, and therefore, the selection of the dissolution method and setting of the acceptance criterion is based on the dissolution data generated for the proposed drug product. Agency recommends that irrespective of the source (USP, FDA or in-house) of the proposed dissolution method, additional dissolution studies be conducted, to demonstrate the suitability of the method selected for the dissolution testing of the proposed drug product like impact of agitation speed, medium volume and apparatus. They also recommend that an in vitro dissolution method which can distinguish the batches with meaningful variations of most relevant formulation and process attributes that are expected to impact drug bioavailability/ bioequivalence to be developed.

The quest of this review is to discuss methodology, summarize current strategies concerning dissolution methods and factors to be considered to develop a most suitable dissolution procedure as per current regulatory norms.

US FDA Recommended Dissolution methods Database:

The USFDA dissolution database (https://www.accessdata.fda.gov/scripts/cder/dissolution/) is open access and it is typically updated quarterly³. To date, it has about 1388 dissolution references based on FDA approved products. Method references are provided in four formats: 1 - Refer USP monograph, 2 - Dissolution guidance, 2018, 3 - Development of new method, 4 - Dissolution methodology based on approved products. The database provides information in terms of the drug name, dosage form, apparatus type, speed (rpm), medium, volume (mL), recommended sampling points (min.). The database serves as the starting point for developing the dissolution method for the drug products.

A summary based on the latest update to date is summarized in Figure 1

Figure 1: (a) Dissolution recommendation in the FDA database

Figure 1: (b) Dosage forms in the FDA database

Figure 1 (c) Dissolution apparatus in the FDA recommended methods

Figure 1: (d) Agitation speed in the FDA recommended methods

Figure 1 (e) Media volume in the FDA recommended methods

Figure 1 (f) FDA recommended practices of the Tablet dosage form.

USP General Chapter⁴:

USP General Chapter <711>DISSOLUTION:

The chapter defines the dissolution conditions for solid oral products, i.e., Tablets, Capsules. Design and specification of four dissolution apparatus are explained (1) Apparatus 1 (Basket apparatus), (2) Apparatus 2 (Paddle Apparatus), (3) Apparatus 3 (Reciprocating Cylinder), and (4) Apparatus 4 (Flow-Through Cell). The chapter also provides information on the interpretation and acceptance criteria for immediate release, extended-release, and delayed-release formulations.

USP General Chapter <724>DRUG RELEASE:

The test conditions for the Transdermal delivery systems and other dosage forms are explained in chapter <724>. Design, specification, procedure, and interpretation of three additional dissolution apparatus are described as Apparatus 5 (Paddle over Disk), Apparatus 6 (Cylinder), and Apparatus 7 (Reciprocating Holder).

USP General Chapter <1092>the dissolution procedure: Development and Validation:

This chapter provides recommendations for dissolution test method development and its validation. It guides scientists in implementing automation, setting validation criteria, interpreting results, and deriving specification for immediate and modified release dosage forms. Step by step flow is mentioned in the chapter for systematic development of appropriate dissolution method and its validation.

DISSOLUTION METHOD DEVELOPMENT:

1. Performing Filter Compatibility:

Accurate and precise results of testing method are subject to appropriate selection of Filter. The primary purpose of filtration is to remove the undissolved particles, which might interfere with downstream processing of the sample. Therefore, filter selection should be experimentally justified and proven during the early dissolution method development stage. Filter selection criteria should be based on, but not limited to; type of filter (syringe filters, membrane filters, cannula filters, frit filters), chemical compatibility with analyte and dissolution medium, pore size, pore morphology, percentage porosity, low levels of extractable and low analyte binding (Table 1)^{5, 6}. Experimental verification for filter suitability can be achieved by comparing the filtered and without filtered known and test solutions. Compared with the unfiltered solutions, the acceptable recovery range for a filtered standard or sample solution needs to be estimated⁵.

4. Choosing a Medium and Volume:

The dissolution is a two-step process involving disintegration of formulation into drug particles followed by subsequent drug solubilization in the dissolution medium. Disintegration controlled dissolution is primarily dependent on the ability of the formulation to disintegrate, i.e., cohesive properties of the formulation matrix. Whereas solubilization controlled dissolution is dependent on physicochemical properties such as polymorphic form, Particle surface area, the solubility of the drug in dissolution medium, type of dissolution medium, the volume of dissolution medium, and thereby sink conditions during dissolution assessment^17-20.

Dissolution testing assesses expected drug dissolution in the gastrointestinal tract (GI) tract. Hence, the dissolution medium must resemble the in vivo liquid interface in the GI tract²¹. The selection of suitable dissolution medium and volume should be assessed based on physicochemical characteristics of the active substance(s) and the intended dose range of the drug product, and the formulation to be tested. As outlined in USP, it is recommended that the saturation solubility of a drug in the dissolution medium is at least three times more than the drug concentration. If this occurs, 'sink conditions' are maintained⁴. Therefore, the volume of the dissolution media should be such that it requires maintaining sink conditions. However in some cases where the dissolution method is more discriminatory, even though “sink conditions” are not maintained. For Apparatus 1 (basket) and Apparatus 2 (paddle), dissolution medium volume can range from 0.5 L to 1 L, which in specific cases, can be increased to 2-4 L^22,
23.

Considerations while choosing a dissolution medium and volume are enlisted as:

Physicochemical properties of the active substance(s):

Drug substance equilibrium solubility across physiological pH range of 1.2 – 7.2 at 37°±1°C is important for the selection of suitable pH as well as volume of dissolution media. Solubility of drug at particular pH should not rate limiting factor for complete dissolution of product. In case if acidic media is selected, preference is given to diluted hydrochloric acid and for alkaline media, acetate and phosphate buffers are utilized because alkaline media are directly mimic to the fed in vivo condition. The water may be used as a dissolution medium only if there is no pH influence on the dissolution characteristics of the product and if it is the most discriminative medium²².

Sink condition:

Typically, Sink conditions should be maintained to ensure that solubility characteristics of drug substances do not significantly limit dissolution. Surfactant can be incorporated in the media for poorly soluble drugs if sink conditions is not achieved at any pH in the physiological pH range. The minimum concentration of surfactant required to achieve sink condition should be used. The typical concentration of surfactant is above its critical micellar concentration (CMC)²². Overview of commonly used surfactants and their CMC is available in USP <1092>. The use of surfactants in typical modified-release formulations is more complex due to the interaction between surfactants and cellulose ethers. Therefore, special consideration is required to add surfactants to modified-release formulations containing poorly water-soluble drugs. Few other approaches to maintain sink conditions are the use of large solvent volumes, use of co-solvent, and use of alternate dissolution systems such as USP apparatus 4 (flow-through cell apparatus), which have some resemblance to the physiological environment of the gastrointestinal tract by continuously extracting the drug from the dissolution vessel, thus mimicking the absorption into the systemic circulation. USP apparatus 4 can be used in two configurations: (i) closed-loop, where a specified medium volume is recirculated throughout the analysis, and (ii) open-loop, where a fresh medium is continually passed through the cell¹⁷.

Drug substance stability in dissolution media:

Drug substance stability must be evaluated in the dissolution medium at room temperature, 32°C (for products applied to the skin) and 37°C (product for internal use). For compounds that are not stable, impurities evaluation should be performed alone or in combination with a drug substance⁵.

Use of enzymes:

In the presence of certain compounds such as aldehydes or when exposed to high humidity and temperature, gelatin cross-links, rendering it insoluble in an aqueous medium and thereby altering the in vitro dissolution behavior of gelatin capsule or gelatin-coated tablets. Capsules will not open and release their contents into a dissolution medium, or it will open in a non- uniform way, and dosage form will disintegrate partially or not disintegrate at all. Consequently, dissolution will fail and/or will have high variability. However, these cross-linking may not reflect the possible failure in vivo due to the presence of proteolytic enzymes such as pepsin, bromelain, papain, and pancreatin. USP recommends adding a proteolytic enzyme to the dissolution medium in such a scenario. For pH ≤ 4.0, use of pepsin is recommended, for pH between 4.0 to6.8 papain or bromelain, whereas for ≥6.8, use of pancreatin is recommended. The office of generic drugs recommends to use pepsin and pancreatin enzyme in FDA-approved drug products. A careful consideration is required while using surfactant in dissolution medium containing enzymes because it readily denatures the enzymes that are used to limit the cross-linking Hence, pre-treatment (mostly of not more than 15 min.) of drug product i.e. gelatin capsules is required with enzymes before addition of surfactant¹³. The addition of enzymes into the dissolution medium is not recommended, as per European Pharmacopoeia and Japanese Pharmacopoeia²².

Formulation properties

In addition to the role of API properties, formulation properties also need to be evaluated during dissolution method development. In a formulation, excipients also play a significant role in drug product dissolution. Sometimes, a formulation change such as the addition of anionic polymer may also results into change in dissolution method i.e. anionic polymer requires more alkaline dissolution medium. In addition to that, surfactant may also requires if drug substance is a weak base. In formulation containing polymer, the interaction between polymer and surfactant in aqueous medium results into the formation of intermediate structures thereby the properties of medium changes and affecting the dissolution of dosage form. i.e An improved dissolution method for immediate release combination capsule product was developed based on understanding of the synergistic effect of surfactant i.e. 1% tween 20 and 0.1M acetic acid ¹¹. Researchers are utilizing different techniques like solid dispersion, change in salt to derive on the formulation that provide desired in-vitro dissolution^24-27.

5. Choosing an Apparatus:

Generally, compendial apparatus are selected based on formulation design and type of dosage form. For example, USP apparatus 1 (Basket) and USP apparatus 2 (Paddle) are typically used for solid oral dosage forms. It is recommended that testing should be carried out under mild test conditions, basket method at 50/100 rpm or paddle method at 50/75 rpm. In general, 40 mesh basket mesh size is used however other mesh baskets like 10, 20 or 80 meshes can also be used with justification. Table 3 describes a proper selection of apparatus based on the dosage form²⁷.

Modifications of compendial apparatus and non-compendial apparatus like mini-vessels, mini- paddles, and modified flow-through cells can also be used with appropriate justification

6. Deaeration:

Air bubbles present in dissolution media may affect the dissolution process on the dosage unit or basket mesh. These air bubbles are responsible for particles clinging to the apparatus and vessel walls. These bubbles on the dosage unit may promote buoyancy, ultimately affecting the dissolution rate. Even this condition is worse for poorly soluble drugs. Hence, deaeration may require during the dissolution of products. Different deaeration methods are available. Medium is heated, filtered and bubbles are drawn by application of vacuum. Other methods like sonication and helium sparing are also beneficial for the deaeration of the medium. When an appropriate deaeration process is recognized, it should be documented as part of the dissolution methodology. The extent of deaeration can be evaluated by measuring the total dissolved gas pressure or oxygen content in water. Recommended techniques result in dissolved oxygen between 4 and 7 mg/L, equivalent to the USP recommended technique²⁸.

Reaeration is also a significant problem during dissolution due to reaching equilibrium. Extreme deaeration of dissolution media only increases the re-aeration rate during media transfer and paddle agitation ¹⁴. The percent saturation of total dissolved gases in dissolution media must be kept below 100% saturation to avoid the effect of dissolved gases on dissolution testing. Faster stirring rates and transfer of the deaerated medium results in more rapid reaeration of the dissolution media^{29, 30}. To describe deaeration's effect, compare dissolution results obtained from non-deaerated medium and deaerated medium using a compendial technique. If difference in dissolution profile is not detected, this confirms that deaeration is not required.

7. Sinkers:

When USP apparatus II (Paddle) is used certain dosage forms may exhibit floating / sticking behavior like capsules, a sinker is needed to regulate the buoyancy of dosage forms. To avoid floating, a small loose piece of a non-reactive material such as stainless steel wire helix may be attached to the dosage units³¹. Sinkers can ominously impact the dissolution behavior by hindering the medium flow around the dosage form. Thus sinker design can significantly influence the dissolution of formulations in different pH media^{32, 33}. The release rate is hindered due to the trapping of dosage form between the parallel spirals of the helix-shaped sinkers or inside the loops.

Selection:

Selection is based on the size and shape of the dosage form. The sinker should be large enough to assemble the dosage form because this may allow the dosage form to interact with the medium. Contrariwise, if wrapped too loosely, release of the dosage form may be faster after the test begins. Dimension of sinker should be chosen based on the capsule shell size, elongated 12X0.8cm sinker is used for #0 capsule, 10X0.7cm sinker is used for #1 and #2 and 8X0.55cm sinker is used for #3 and#4. The sinker size should be augmented so that the capsule does not change its direction within the sinker⁵.

Types:

Various new sinker designs are fabricated and tested which are available in commercially. Four classes of sinker shapes are categorized: longitudinal, lateral, screen enclosures, and internal weights. Longitudinal sinkers contact the dosage forms on the long axis. Lateral sinkers either wrap around or contact capsule dosage forms in the middle, such as the line where the top and bottom halves of a capsule shell come together. Screen enclosures are of two types: either a wire cage, which holds the entire capsule, or a circular piece of wire screen placed on top of the capsule. Internal weights consist of two steel ball bearings, one inserted into each end of the dosage form³¹. Few examples of longitudinal sinkers are U-clip, Paper Clip and examples of Lateral sinkers are Loose Stainless Steel Helix, Glass helix, Bow type sinker etc.

8. Agitation:

The USP Apparatus 2 (paddle) is the most widely used in dissolution testing. However, based on the available literature, it is evident that the paddle apparatus is subjected to different variables such as vibration, rotational speed variations, the shape of the vessel, and imperfections in vessel design, leading to inaccuracy and variability dissolution rates of a drug substance. The variability in dissolution rates is more noticeable at 50 rpm due to radial flow in the cylindrical vessel. A 'dead zone' forms at the bottom of the vessel where the agitation rate is low. The disintegrated dosage form settles in this zone, forming a 'heap' of trapped drug particles leading to low dissolution rates. To avoid such 'heap' formation, an increased rotation speed of apparatus 2 is generally recommended^{9, 34}.

To allow maximum discriminating power and detect products with poor in vivo performance, mild agitation conditions should be maintained during dissolution testing. Agency recommendation is 50-100 rpm agitation for the basket method and 50-75 rpm for the paddle method. Apparatus 3 and 4 are rarely used to assess the dissolution of immediate-release drug products.

9. Time Points:

For immediate release dosage form, three categories of dissolution test specifications are described³⁵,

(1) Single point specifications: For highly soluble and fast-dissolving drug products [Biopharmaceutical classification system (BCS) classes I and III], a single-point dissolution test specification of not less than 85% (Q=80%) in 60 minutes or less is appropriate as a routine quality control test for a lot to lot uniformity.

(2) Two-point specifications: For poorly soluble or slow dissolving drugs (BCS class II), a two- point dissolution specification, one at 15 minutes to include a dissolution range (a dissolution window) and the other at a later point (30, 45, or 60 minutes) to ensure 85% dissolution, is recommended to evaluate the quality of the drug product.

(3) Dissolution profile comparison: For demonstration of product sameness under Scale-up and Post- approval changes (SUPAC) related changes, to support a waiver of in vivo study for other strengths.

The product is projected to comply with dissolution specifications throughout its shelf life. However, to ensure continuous lot-to-lot similarity of the product after scale-up and post- approval changes (SUPAC), dissolution profiles should remain comparable to those of the approved bio-batch or pivotal batches³⁶.

For testing an extended-release dosage form, a minimum of three-time points are selected^37,
38

(1)An early time point to identify if dose dumping Example 2 hours NMT 20% , (2) A time point to ensure release progression and to characterize rate, Example 12 hours-45% to 65% and (3)A time point to prove that complete dose is delivered Example 20 hrs-NLT 80%.

Delayed-release dosage forms require a minimum of two-time point specifications. First acid stage is performed to ensure minimal release in acidic medium Example NMT 10% release in 2 hours in 0.1N HCl, followed by a demonstration of dissolution in an alkaline pH medium.

10. Dissolution Procedure Assessment:

The developed dissolution procedure as a combination of dissolution medium, apparatus, volume, and agitation should be sensitive, sufficiently rugged, reproducible, and transferrable between laboratories. Assessment is done by challenging the dissolution method by comparing dissolution profiles of the finished product by, (1) Product is intentionally prepared by meaningful formulation and process variables. Detailed formulation variables and process variables risk assessment is performed. Variables likely to impact the dissolution are rated as high, medium, and low, along with the justification. The test products that are intentionally manufactured with meaningful variations for the most relevant critical material attributes, critical formulation variables, and critical process parameters (± 10 to 20% change to the specified values or ranges for these variables). Mostly one variable each from formulation and process is selected to assess dissolution methodology. Formulation variables could be excipient ratio, API particle size, binder and/or disintegration concentration, lubricant level. Process variables could be lubrication time, compression force, granulation time, bed temperature, spray rate, inlet airflow. The overall objective is to differentiate dissolution profile by an intentional change in the most effective formulation and process variable⁵.

(2) Finished products samples are stressed to demonstrate sensitivity to changes during storage.

The dissolution profile can be compared by using similarity factor (f2) calculation. Removal of excipient (binder/ disintegrant) to demonstrate discriminatory power of dissolution method is discouraged. For the formulation with highly soluble actives over the physiological pH range, the possible differentiation in the dissolution profile is more diminutive. In such cases, the dissolution method can be considered adequate with the same justification, or dissolution can be replaced with a disintegration test with appropriated justification³⁵.

11. Acceptance criteria:

Previously, dissolution specifications were driven by the in-vitro performance of the formulation without any thought to in vivo behavior. Regulatory agencies expectation is the extended role of dissolution specifications from simply release testing to scale-up and post-approval changes during the product's life. As per guidance document, if dissolution of scaled-up batches or a minor post- approval variation batches are similar then in-vivo studies can be waived off. Thus, the ideal situation would be to set the dissolution specifications such that scaled up and post- approval changed formulations and the stability lots fall within the dissolution acceptance criteria. In the development stage, dissolution specification serves as a guide rather than depending on multiple bioequivalence studies for optimization for formula and process. This broadened goal requires that the dissolution no longer serves as a quality control test but a possible substitute for bioequivalence study. Hence, the specifications can be set to minimize the possibility of releasing batch that would be different in their clinical performance. It is mandatory to consider in bioequivalence batch data while setting dissolution limits to accomplish this. Dissolution specifications can be set so that all formulations with dissolution profiles are bioequivalent or minimally; all formulations should be bioequivalent to the pivotal bioequivalence batch³⁷. Specifications should be established based on an average of 12 units' dissolution. Agency expectation is all the batches should pass in stage 1 testing and may pass in stage 2 occasionally and stage 3 rarely. Stepwise guidance followed in the industries for setting specifications for immediate release and the modified release dosage form is provided in Table 4.

CONCLUSION:

In vitro dissolution testing plays an essential role in formulation development, quality control, and supporting scale-up and post-approval changes and manufacturing variations. Nowadays, scientists have increasing access to in vitro tools that can build a link to in vivo performance to assess and respond to bioequivalence risks and routine release of a product. Detailed insights of the systematic approach for the development of the indigenous dissolution method for the drug product have been provided in the paper. The finalized method should be validated against different parameters like specificity/ placebo interference, linearity/range, accuracy, precision, reproducibility, and robustness.

Regulatory considerations and information for dissolution testing methods for immediate release and modified release products are thoroughly discussed; however, an agency may publish guidelines and recommendations for dosage from specific development methodology in the future. Advance dissolution diagnostic tools, which include modeling and simulation for both in vitro and in-vivo dissolution and real-time dissolution imaging, would interest the developer and regulators. Agency expects more automation systems to minimize manual intervention and reduce inevitable errors.

Scientists should correlate biopharmaceutical risk against all sets of dissolution conditions to derive a robust, precise, and accurate method for transferring to the quality control department. Transferring inappropriate methods to a routine QC environment with strict adherence to procedures and where data are usually adjudged as pass or fail is concerning, as failing results due to method-related issues cause significant problems in the release of a product and thus supply of product to patients. Appropriate precautions for handling (withdrawal and dilutions) of aliquot samples and critical steps should be highlighted and writtern part of standard testing procedures because the degree of interference in dissolution results are directly related to aliquot samples.

CONFLICT OF INTEREST:

No conflict of interest has been declared by the author(s).

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Received on 26.05.2023 Modified on 24.07.2023

Res. J. Pharma. Dosage Forms and Tech.2023; 15(4):293-302.

DOI: 10.52711/0975-4377.2023.00047

Challenges	Trouble Shooting
“Heap” Formation/Problem of Coning at the bottom of the dissolution vessel either formulation dependent, i.e., presence of a higher amount of dense insoluble excipients or dissolution method dependent, i.e., the existence of dead zone at the bottom of USP vessel observed during perturbation study	Increasing stirring speed may be sufficient if the problem is formulation dependent or use of apex vessel if the problem is method dependent and use of it is also corroborated by the fact that the U.S. Food and Drug Administration (FDA) and USP dissolution database mentions of apex vessels.
“Floating” of the dosage form to the surface of the dissolution medium	To overcome this, the use of a sinker is the preferred choice
“Filter Clogging” can block online UV measurement using USP apparatus IV set up	Selection of appropriate filter.
"Gelling," which is usually formulation-dependent. While USP Apparatus I (basket), granules after disintegration remains inside the basket or formulation gelled up and remained inside the basket	Apparatus selection is essential. Sinkers can be used, and the selection of sinkers also becomes crucial.
“Pellicle formation” results from the cross-linking interaction of gelatin in the presence of aldehyde or high humidity and high-temperature conditions. Cross- linking is irreversible, and it prevents capsule fill from being released, which results in slower drug release or no release at all.	Add the proteolytic enzymes such as pepsin, bromelain, papain, and pancreatin to the dissolution medium depending on its pH.
“Bubbles” in dissolution medium can lead to variable drug release during dissolution testing	Deaerated/Degassed medium should be used to reduce variable dissolution results. Deaeration removes dissolved oxygen. Different deaeration methods are manual vacuum filtration; Dissofill mechanical filtration, and helium sparing. USP<711> suggests heated vacuum filtration as one method of deaeration.
“Location” of disintegrating or non-disintegrating dosage forms in the dissolution vessel significantly affects the drug release and produces variable results in widely used USP apparatus II (paddle).	Dissolution significantly improves by altering hydrodynamics of USP apparatus II (paddle) through slight off-centering of the vessel, which avoids the "dead" zone formation at the bottom of a vessel. Use of novel OPI (off-center paddle impeller), metal strip, crescent-shape spindle, permanent in-line probes acting as baffles in dissolution testing apparatus produces reproducible dissolution. It thereby alleviates the problem of variable dissolution obtained due to differences in the location of dosage forms in the vessel.

Bio batch dissolution results	Q point selection
If Biobatch dissolution ≥ 95% in 15 minutes	Than specification set as Q=85% at 15 minutes
If Biobatch dissolution < 95% but ≥85% in 15 minutes	Than specification set as 75% or 80% or 85% whichever is close to Q=biobatch result -10% at 15 minutes
If Biobatch dissolution ≥ 85% only after 30 minutes	Than specification set as 75%, 80% or 85% whichever is closer to Q=biobatch result -10% at 30 minutes
If Biobatch dissolution ≥ 85% only after 45 minutes	Than specification set as 75%, 80% or 85% at 45 minutes
If Biobatch dissolution ≤ 85% after 45 minutes	Than specification set as 75% at 45 minutes
If Biobatch dissolution Biobatch ≤ 75% after 45 minutes	Dissolution specification should be based on more than one-time point.