The USP Performance Verification Test, Part I: USP Lot P Prednisone Tablets—Quality Attributes and Experimental Variables Contributing to Dissolution Variance

Purpose Beyond instrumental qualification, proficiency testing is not usually a prerequisite for many analytical procedures, given reliance on a manufacturer’s assay validation coupled with regulatory review and inspection. Given the special features of the dissolution procedure, proficiency testing was put in place initially by pharmaceutical manufacturers and carried on by USP. Proficiency testing is designed to help ensure that execution of a dissolution procedure for solid oral dosage forms adequately supports administrative and legal decisions so that measurements made at different times, by different analysts, or with different methods can be confidently compared. USP has applied metrological principles to aid practitioners in carrying out the dissolution procedure alone and in collaborative studies to facilitate understanding potential sources of variability. Materials and Methods The present study aimed to identify key dissolution variables associated with USP Lot P Prednisone Tablets in conjunction with the USP Performance Verification Test (PVT). Using five dissolution test assemblies from different manufacturers, at least four of six analysts determined percents prednisone dissolved on dissolution Apparatus 1 (basket) and Apparatus 2 (paddle) on each assembly. Six replicate experiments were performed on each analyst–assembly combination with a set of six to eight tablets in each experiment. Results and Conclusions Statistical analysis demonstrated that dissolution test assemblies were the largest factor contributing to dissolution variability. Inherent tablet variability was low, and USP Lot P Prednisone Tablets did not contribute importantly to dissolution variability. Contributions from analyst and analytical procedure also were estimated to be low. This article is Part I of a two-part article appearing in this issue.     

The USP Performance Verification Test, Part II: Collaborative Study of USP’s Lot P Prednisone Tablets

Purpose Periodic performance verification testing (PVT) is used by laboratories to assess and demonstrate proficiency and for other purposes as well. For dissolution, the PVT is specified in the US Pharmacopeia General Chapter Dissolution <711> under the title Apparatus Suitability Test. For Apparatus 1 and 2, USP provides two reference standard tablets for this purpose. For each new lot of these reference standards, USP conducts a collaborative study. Methods For new USP Lot P Prednisone Tablets, 28 collaborating laboratories provided data. The study was conducted with three sets of tablets: Lot O open label, Lot O blinded, and Lot P blinded. The blinded Lot O data were used for apparatus suitability testing. Results Acceptance limits were determined after dropping data due to failure of apparatus suitability, identification of data as unusual on control charts, or protocol violations. Conclusions Results yielded acceptance criteria of (47, 82) for Apparatus 1 and (37, 70) for Apparatus 2. Results generally were similar for Lot P compared to results from Lot O except that the average percent dissolved for Lot P is greater than for Lot O with Apparatus 2. This article is Part II of a two-part article appearing in this issue.     

Metrologic approaches to setting acceptance criteria: unacceptable and unusual characteristics

Decisions regarding acceptance criteria in regulatory or compendial contexts are among the most difficult to make. Acceptance criteria aid in the identification, on the one hand, of materials with unacceptable characteristics that should not pass the tests and procedures or, on the other hand, of unusual characteristics that indicate materials that are unlikely to pass the tests and procedures. For relatively complex procedures metrological approaches can differentiate between intra- and inter-laboratory variation and clarify unacceptable and unusual data. Such testing requires collaborative studies in which each participating laboratory essentially compares itself to the other laboratories in the collaborative study. Laboratories that use the reference standard established by the collaborative study are conducting a performance verification test in which they compare their capabilities to those of laboratories in the collaborative study. This paper considers aspects of a series of complex issues involving unacceptable/unusual characteristics primarily in the context of USP's work but with implications for manufacturing science via considerations of process capability and Quality by Design and to measurement science. Ultimately, acceptance criteria support the availability of good quality, safe, and effective medicines for patients and consumers.     

外用半固体制剂的体外释放试验和等效性评价

外用半固体制剂包括乳膏剂、软膏剂和凝胶剂等。药物活性成分（active pharmaceutical ingredient，API）的释放对于外用半固体制剂的质量影响至关重要，药物释放在很大程度上取决于其配方组成和制备过程。体外释放试验（in vitro release test，IVRT）可用来评估API的释放速率，检测由于制剂变化或API理化性质的差异而可能引起的释放速率之间的不同。已有大量研究表明，IVRT方法参数的差异会影响IVRT结果，因此保持IVRT方法参数的一致性才能保证结果的可靠。本文讨论了IVRT方法开发和验证，及关于半固体制剂仿制药等效性评价的实验和数据统计分析方法。     

The Science of USP 1 and 2 Dissolution: Present Challenges and Future Relevance

Since its inception, the dissolution test has come under increasing levels of scrutiny regarding its relevance, especially to the correlation of results to levels of drug in blood. The technique is discussed, limited to solid oral dosage forms, beginning with the scientific origins of the dissolution test, followed by a discussion of the roles of dissolution in product development, consistent batch manufacture (QC release), and stability testing. The ultimate role of dissolution testing, “to have the results correlated to in vivo results or in vivo in vitro correlation,” is reviewed. The recent debate on mechanical calibration versus performance testing using USP calibrator tablets is presented, followed by a discussion of variability and hydrodynamics of USP Apparatus 1 and Apparatus 2. Finally, the future of dissolution testing is discussed in terms of new initiatives in the industry such as quality by design (QbD), process analytical technology (PAT), and design of experiments (DOE).     

A comparative study of different release apparatus in generating in vitro–in vivo correlations for extended release formulations

The importance of hydrodynamics in the development of in vitro–in vivo correlations (IVIVCs) for a BCS Class II compound housed in a hydrophilic matrix formulation and for a BCS Class I compound housed in an osmotic pump formulation was assessed. In vitro release data were collected in media simulating the fasted state conditions in the stomach, small intestine and the ascending colon using the USP II, the USP III and the USP IV release apparatuses. Using the data collected with the USP II apparatus, the plasma profiles were simulated and compared with human plasma profiles obtained after administration of the same dosage forms to healthy fasted volunteers. Data obtained with the USP III and USP IV apparatuses were directly correlated with the deconvoluted human plasma profiles. In vitro hydrodynamics affected the release profile from the hydrophilic matrix. For both formulations, based on the values of the difference factor, all three apparatuses were equally useful in predicting the actual in vivo profile on an average basis. Although some hydrodynamic variability is likely with low solubility drugs in hydrophilic matrices, the hydrodynamics of USP II, III and IV may all be adequate as a starting point for generating IVIVCs for monolithic dosage forms in the fasted state.     

Content uniformity testing: suitability of different approaches for marketed low dose tablets

Context: Content uniformity (CU) testing was developed and improved to control the effectiveness and safety of dosage units. Many modifications of compendial CU test have been introduced and several alternatives have been suggested.

Objectives: This study aims to evaluate the degree of suitability of current USP CU test for low dose tablets and to compare the performance of the current test with that of the former USP27-NF22 and other alternatives for different sample sizes.

Methods: All locally marketed risperidone (RSP) tablets were analyzed using newly developed and validated isocratic UPLC method. The CU results were statistically analyzed in groups with sample sizes comparable to the USP sampling plans.

Results: Seven out of eleven products failed the different requirements of the former and current USP <905>chapters as well as of several alternative CU tests with several substantial deviations.

Conclusion: The current USP <905> chapter was found to have some deficiencies that allowed such failed products to exist in the market. The dependence of compendial CU test on two-staged sampling plan and the use of arithmetic mean to calculate the reference and acceptance values were obvious shortcomings.     

Active compounds release from semisolid dosage forms

The aim of this paper is to review all the aspects of the in vitro release testing (IVRT) from semisolid dosage forms. Although none of the official dissolution methods has been specified for use with semisolid dosage forms, their utility for assessing release rates of drugs from semisolid dosage forms has become a topic of considerable interest. One can expect to overcome such complexity in the future, when the official “Topical and Transdermal Drug Products—Product Performance Tests” will be published in an issue of the Pharmacopeial Forum. Many factors such as type of the dissolution medium, membrane, temperature, and speed have an influence on the mechanism and kinetics of the release testing from gels, creams, and ointments; therefore, those parameters have been widely discussed.     

Three-Stage Sequential Statistical Dissolution Testing Rules

Abstract

The U.S. Pharmacopoeia (USP) general monograph provides a standard for dissolution compliance with the requirements as stated in the individual USP monograph for a tablet or capsule dosage form. The USP monograph sets performance limit on dissolution in terms of a specific percentage Q that the drug product is required to be dissolved at a specified time. Japan Pharmacopoeia provides acceptance rules different from USP. However the objective of the acceptance rules was not defined in terms of the inference of the whole lot by either USP, European Pharmacopoeia (EP) or Japan Pharmacopoeia (JP). The operating characteristics’ curves of these rules are all shown to be sensitive to the true mean dissolution and do not reject a lot which has a large percentage of tablets that dissolve with less than the specified limit Q. This is especially true when the mean dissolution is close to the specification value. We proposed that the goal of the dissolution test sampling plan is to accept a lot at least 90% of the tablets dissolved more than a pre-specified amount Q at the specific time. The group sequential procedure derived accordingly is shown to outperform both USP and JP in controlling the type I error rate under normality assumption.     

A mini review of scientific and pharmacopeial requirements for the disintegration test

Disintegration is a performance test for oral dosage forms that is described in the United States Pharmacopeia (USP), the European Pharmacopeia (EP) and the Japanese Pharmacopeia (JP, chapter 14, 2001). This review lists changes that have been made since the USP 23 and compares them to those in the USP 30, EP 5.3 and JP XIV. The differences between the disintegration test methods in the three pharmacopeias are discussed. Examples are provided where disintegration can be used as a performance test for ensuring the drug release.     

Drug release from semisolid dosage forms: a comparison of two testing methods

Abstract

The aim of the present work was to extend our previous in-vitro drug release studies using semisolid dermatological bases with non-impregnated cellulose acetate membranes. A comparison of the performances of two apparatuses, the more commonly used Franz cell and the new modified USP (mini paddle with ointment holding cell) systems were applied to this work. Five different semisolid as well as two marketed preparations containing 1% diclofenac sodium were used. Complex, slightly non-linear release curves indicating sink conditions were found. This was explained by the co-diffusion of excipients modifying the characteristics of the membrane and the receiving medium dynamically. Although our test model is, as a rule, not suitable to establish an in-vivo–in-vitro correlation, good qualitative as well as quantitative correlations were found within some types of dermatological bases. The correlation between the results of the two in-vitro methods also depends on the type of semisolids studied. The release curve characteristics and the amount of diclofenac sodium released at 6?h were measured. Their repeatability and reproducibility were calculated. The slopes and Q-values were correlated with in-vivo data. In general, the modified USP method provided more precise results than the Franz cell method.     

Establishing New Acceptance Limits for Dissolution Performance Verification of USPC Apparatus 1 and 2 Using USPC Prednisone Tablets Reference Standard

Purpose  

On 1 March 2010, the US Pharmacopeial Convention released into commerce Lot P1I300 of its Prednisone Tablets Reference Standard for use in periodic performance verification testing (PVT) of dissolution Apparatus 1 and 2. This report presents the collaborative study data, development of the acceptance limits, and results from supporting work for this Lot.     

French and/or European perspectives on biopharmaceutical characterization of drug dosage forms

In order to bring definitions of drug dosage forms up to date, it was necessary for the French Pharmacopoeia to propose assays allowing the quality control of the dosage forms to be based on the kinetics of drug release in vitro. Currently, five examples can be cited of dosage forms that can be characterized by release in vitro. (1) Oral solid dosage forms--for tablets, all the parameters of powders before compression (e.g., flowability, tableting properties) are being studied in addition to the dissolution tests, (2) Rectal dosage forms--the disintegration test of suppositories will be discarded and a new dissolution test using a special flow-through cell is now being studied. (3) Inhalations--since particle diameter is the most important factor for inhalation activity, a method has been developed to give the correct answer to this question. (4) Modified release drug dosage forms--these have been defined separately from the conventional forms. For the peroral route, they are: (i) accelerated release drug dosage forms, (ii) sustained release drug dosage forms and (iii) delayed release drug dosage forms. To emphasize the differences in the release kinetics, use of the paddle method, well known in the USP, and the flow-through cell has been suggested and described in the European Pharmacopoeia. Some associations and/or in vitro-in vivo correlations have increased the interest in the last method. (5) Transdermal delivery systems--these are defined separately from plaster and sticking-plaster. The use of a cell method was suggested to study the drug release and some comparisons between different techniques are presented.     

Oral Dosage Form Performance Tests: New Dissolution Approaches

No Heading The performance test is one of a series of tests that compose the specification in a United States Pharmacopeia (USP) dosage form monograph. For an orally administered, nonsolution dosage form, it is usually satisfied by either a dissolution or disintegration procedure. Dissolution acceptance criteria are usually set in private negotiations between an applicant and a regulatory agency. With information about this private agreement and other information provided in a sponsors Request for Revision to USP, the USPs Council of Experts elaborates a public dosage form monograph. Based on the relationship between the regulatory decisions and the Request for Revision, the USP dissolution procedure links to a regulatory judgment about bioavailability and bioequivalence and, ultimately, to a judgment about safety and efficacy. The current dissolution procedure and acceptance criteria are perceived as having worked well over the years and are generally accepted. This article discusses new approaches that merit consideration. These approaches focus on a) explicit use of hypothesis testing, b) use of parametric tolerance intervals, c) improved ways to set dissolution acceptance criteria, and d) a more flexible protocol to assess conformity. Application of the proposed approaches may better assess, manage, and communicate both manufacturer and consumer risk for dissolution testing.     

The Development of USP Dissolution and Drug Release Standards

Dissolution tests have been in use in the pharmaceutical industry for over 20 years, and they are official in The United States Pharmacopeia since the early 1960s. The dissolution test, reviewed primarily as a quality control tool, replaced the use of disintegration tests which had been official in The United States Pharmacopeia since 1950. Refinements in the dissolution test equipment and methodology have occurred over the years in order to enhance its relevance. The Subcommittees of the USP Committee of Revision dealing with these issues have developed and refined compendial dissolution standards and policies for conventional solid-oral dosage forms and modified-release dosage forms.     

Quantitative analysis of trimethobenzamide hydrochloride by ion-pair column chromatography and semiquantitative analysis of 3,4,5-trimethoxybenzoic acid by thin-layer chromatography

An ion-pair column chromatographic/UV spectrophotometric method for assaying trimethobenzamide hydrochloride in capsules and injections is presented, as well as a method for the detection of 3,4,5- trimethoxybenzoic acid in trimethobenzamide hydrochloride bulk drug and dosage forms. Results obtained by the USP XX, Pharmacopeial Forum, and ion-pair column assay procedures are compared, and results of a collaborative study of the proposed assay and impurity detection methods are presented.     

Permeability assessment for solid oral drug formulations based on Caco-2 monolayer in combination with a flow through dissolution cell.

The aim of our study was to develop an apparatus assessing in vitro permeation through Caco-2 monolayers of oral solid dosage forms as a possible tool to forecast in vivo performance. Therefore, flow through dissolution and permeation modules were connected by means of a stream splitter. Permeation was measured in a specially designed cell, dissolution took place in the apparatus 4, USP. In order to test the apparatus for its reproducibility and conclusiveness, different tablet strengths and varying release profiles of propranolol HCl tablets were produced and evaluated. It was shown that for both tablet species, immediate and extended release, the apparatus was able to measure permeation through Caco-2 monolayer as well as dissolution simultaneously with high precision and reproducibility. The permeated amount of the three immediate release tablets with increasing dosage strength showed linear dependency on the dosage strength. Furthermore, the effect of retarded release on permeation could be detected and conclusive data for dissolution and permeation were obtained. In summary, connecting cell culture based permeability assessment with compendial flow through dissolution equipment led to promising results and poses the base for more advanced studies for detecting influences of dosage forms on permeation process.     

THEOPHYLLINE CONTROLLED-RELEASE FORMULATIONS: IN VIVO--IN VITRO CORRELATIONS

Four experimental controlled-release oral solid dosage formulations were developed and the in vitro dissolution characteristics of theophylline from these formulations were studied in USP apparatus I. Pharmacokinetic evaluation of these formulations was carried out in eight beagle dogs under fasting conditions. Theophylline in a 5% dextrose injection USP, oral solution, and Slo-Phyllin® were used as controls to estimate the in vivo dissolution of these four formulations in the GI tract. The percentage cumulative amounts of drug absorbed and the percentage cumulative amounts of drug released into the GI tract from these four controlled-release formulations were obtained by numerical deconvolution methods. The in vivo and in vitro dissolution data demonstrated good correlation indicating that in vitro dissolution tests can be used to optimize the further design of controlled drug release oral solid dosage formulations for theophylline.     

Theophylline granule formulation prepared by the wet granulation method: comparison of in vitro dissolution profiles and estimation of in vivo plasma concentrations.

The primary and secondary objectives of this study were to develop and evaluate the predictability of in vitro-in vivo correlation models for theophylline sustained release (SR) granules. Theophylline SR granules meeting the USP Drug Release Test criteria were prepared using ethyl cellulose (EC) and/or stearyl alcohol (SA) and the wet granulation method. In vitro dissolution studies of granule formulation were performed, and a commercial dosage form was prepared using USP XXIII apparatus II at pH 4.5. Differences and similarities between in vitro dissolution curves were compared using both model-dependent (t-test) and -independent (f1, f2 test) statistical techniques, and it was shown that the three dissolution profiles i.e model-dependent, model-independent, and methods based on ANOVA were very similar. The in vivo performance of the commercial dosage form was tested by oral route using male rabbits and in vitro-in vivo correlations were established. This study indicates that the dosage forms with similar in vitro dissolution profiles may have a similar in vivo performance, and that this performance could be estimated using appropriate correlation equations.     

Comparative <Emphasis Type="Italic">in vitro</Emphasis> dissolution testing of indapamide prolonged-release tablets

The results of dissolution testing of five modified release dosage forms of indapamide are presented. It is shown that comparative analysis of dissolution profiles can be used to develop in vivo – in vitro correlations and to establish the similarity of drug bioavailability in various ready-to-use dosage forms for which the composition, technology, or scale of manufacturing may have been changed. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 12, pp. 52–55, December, 2008.