IVIV CORRELATION PDF

Different batches of atorvastatin, represented by two immediate release formulation designs, were studied using a novel dynamic dissolution apparatus, simulating stomach and small intestine. A universal dissolution method was employed which simulated the physiology of human gastrointestinal tract, including the precise chyme transit behavior and biorelevant conditions. The multicompartmental dissolution data allowed direct observation and qualitative discrimination of the differences resulting from highly pH dependent dissolution behavior of the tested batches. While satisfactory correlation could not be achieved using a conventional deconvolution based-model, promising results were obtained through the use of a nonconventional approach exploiting the complex compartmental dissolution data. An orally administered drug has to be released from its dosage form, dissolved in the surrounding fluid and absorbed by the gut wall, in order to enter the blood stream.

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In vitro — in vivo correlation IVIVC is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. The main objective of an IVIVC is to serve as a surrogate for human bioequivalence BE studies, which may reduce the number of BE studies performed during the initial approval process as well as with certain scale-up and postapproval changes.

It is hoped that awareness of the deficiencies presented in our article would help the generic drug applicants to submit complete and appropriate information related to IVIVC data, ultimately, resulting in a more timely approval of ANDAs. An in vitro — in vivo correlation IVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is plasma drug concentration or amount of drug absorbed 1.

The in vitro dissolution testing of dosage forms has been extensively used for quality control purposes, to determine stable release characteristics of the product over time, to ensure batch-to-batch similarity, and formulation discrimination, etc.

However, these in vitro dissolution tests may or may not be predictive of the in vivo performance of the dosage form 1 — 3. Thus, a main objective of developing and evaluating an IVIVC is to establish the dissolution test as a surrogate for human bioequivalence BE studies, which may reduce the number of BE studies required, when certain preapproval and postapproval changes are made in formulation composition, manufacturing process, equipment, and site.

In recent years, there has been considerable interest within the pharmaceutical industry, academia, and regulatory sectors in IVIVCs. There are many published studies related to development and validation of IVIVC for various drugs and dosage forms oral immediate release and extended-release dosage forms, modified-release parenteral dosage forms, and transdermal drug delivery systems, etc.

In the USA, the IVIVC has been used by both the innovator and generic drug companies in the regulatory submissions due to the abovementioned applications. The generic drug approval process requires that abbreviated new drug applicants demonstrate both pharmaceutical equivalence and BE between the generic product and its corresponding reference listed drug RLD product innovator or brand to be approved for marketing Demonstrating BE in vivo in humans is the most preferred method of ensuring the therapeutic equivalence of generic drug product to the RLD product Generally, in in vivo BE studies, the plasma concentration profile of the generic drug product is compared to that of RLD product, and two products are considered to be bioequivalent if they show the same rate and extent of absorption In the presence of an established IVIVC, in vivo performance can be predicted from in vitro dissolution testing.

We hope that this information will help generic drug applicants to submit complete and appropriate information related to IVIVC data, which, in turn, will make the ANDA approval less time-consuming. In brief, for generic drug products, a predictive IVIVC can be used to serve as a justification for waiver of in vivo BE studies during the initial approval process as well as with certain scale-up and postapproval changes SUPAC and setting of dissolution specifications.

Generally, for multiple strength products, the highest strength of innovator drug product is listed as the RLD in the Orange Book, with some exceptions, mainly due to safety reasons Mostly, in vivo BE studies are recommended only for the strength listed as RLD, and other strengths of the modified-release drug products may be deemed bioequivalent to the corresponding strengths of the reference product, if 1 the other strengths are in the same dosage form and are proportionally similar in its active and inactive ingredients to the strength on which acceptable BE studies were conducted; 2 the drug release mechanism from all strengths of the formulations is the same; and 3 the dissolution profiles of all strengths are similar in multimedia 14 , In case all strengths of the product line are not proportionally similar 14 , 15 , in vivo BE study is required to demonstrate that non-proportionally formulated strength of the generic drug product is bioequivalent to its corresponding reference product.

In the presence of an established IVIVC, the requirement for an in vivo BE study for not proportionally similar strengths of the generic drug product line may be waived, if all strengths are qualitatively the same, have the same release mechanism, have similar in vitro dissolution profiles, and are manufactured using the same type of equipment, and the same manufacturing process at the same site as the strength on which BE study is conducted.

In scenarios, where in vivo BE study is recommended on the lower or higher strengths of the test products due to non-linear pharmacokinetics, the waiver of in vivo BE study for these strengths in the presence of an established IVIVC is not applicable. To set dissolution specifications, the sufficient number of sampling points should be selected to adequately characterize the dissolution profile.

Once an IVIVC is established, specifications should be established in such a way that optimally, all the lots that have dissolution profiles within the upper and lower limits of the specifications are bioequivalent and less optimally but still possible bioequivalent to an appropriate reference batch 1. The main reasons why the majority of the IVIVCs were not deemed adequate are presented in the case studies discussed below.

Three different formulations having slow, medium, and fast release were developed to obtain in vitro dissolution and in vivo plasma concentration-time data. The in vivo study was carried out as a four-way crossover study using three formulations with different release rates and a reference formulation. To develop a multiple level C IVIVC, in vitro dissolution data at different time points was correlated with the peak plasma drug concentration C max and area under the plasma concentration-time curve AUC values.

The developed regression equations were then used to set dissolution specifications. To ensure that final specifications would result in formulations bioequivalent to the reference formulation, C max and AUC were back-calculated from the final specification limits using regression equations. The results showed that the back-calculated C max and AUCs fall within the bioequivalence acceptance criteria.

The agency confirmed that back-calculated C max and AUC determined using the proposed dissolution specifications are bioequivalent. After clarification of the rationale for selecting reference formulation, the agency accepted the IVIVC data and concurred with the proposed changes to the dissolution specifications.

The applicant submitted an amendment containing IVIVC data to support proposed changes to dissolution method for its marketed drug product. The applicant considered the reference product formulation as the second formulation for IVIVC development. The limited multimedia dissolution testing data under different pH conditions was submitted. Internal and external predictabilities were not evaluated. Since the IVIVC development is formulation specific, it is not appropriate to use different formulations, i.

Also, use of bioequivalent formulations, i. However, in this case, the applicant did not provide the complete dissolution data to show that in vitro dissolution is independent of dissolution conditions.

Accordingly, the agency requested the applicant to submit additional in vitro dissolution data under different conditions to show that in vitro dissolution is independent of dissolution conditions. The applicant was also requested to develop IVIVC using formulations with different release rates if dissolution is condition dependent.

The applicant proposed a level 2 change for a non-release controlling excipient. However, this level 2 change in non-release controlling excipient resulted in a change in the dissolution behavior.

The IVIVC was developed using the original test product formulation and the reference product formulation, which were shown to be bioequivalent in the BE studies. External and internal predictabilities were not evaluated. However, in this case, in vitro dissolution data showed that drug release from the test formulation is condition dependent.

Also, as mentioned above in case 2, use of different formulations test and reference , each from a different manufacturer to develop IVIVC, is not acceptable. The agency determined that the relationship between the in vivo dissolution and the in vitro dissolution was formulation dependent as the regression equations for the test and reference formulations were different.

Ultimately, the applicant conducted in vivo BE studies comparing its reformulated test product to the RLD product. The dissolution specifications were then recommended by the agency based on in vitro dissolution testing conducted on the bio-lot reformulated test product used in the new BE studies.

To seek approval for marketing of its generic drug product, the applicant developed a test product formulation that was shown to be bioequivalent to the corresponding reference product in in vivo BE studies. However, the applicant proposed quantitative variation in almost all the inactive ingredients used in the manufacture of its test product from batch to batch depending on the manufacturing in-process control.

In this case, the applicant reformulated its test product and conducted new BE studies on the reformulated test product to seek approval for marketing. In this case, the applicant submitted IVIVC data from the literature to support its claim that batch-to-batch variation in pellet coating does not impact the BE of the test product compared to the reference product.

Thus, the applicant was recommended to conduct its own IVIVC study using a minimum of two new test formulations that differed adequately in release rate from the original test formulation used in the acceptable BE studies. The applicant did not submit the IVIVC data as recommended by the agency and withdrew its submission for other reasons. The applicant proposed a level 3 manufacturing site change. To support this change, the applicant submitted a level A IVIVC developed using three formulations with different release rates i.

In vitro dissolution profiles and in vivo plasma concentration profiles were obtained for these three formulations. The percent of dose released in vivo as a function of time was determined by using deconvolution technique. In vivo data of an IR formulation was used to generate unit impulse response. Both internal and external predictabilities were assessed. The fast- and slow-releasing formulations had similar dissolution profiles, despite the fact that these two formulations showed marked differences in C max and AUC, and ii internal and external predictabilities were not confirmed.

To challenge the results of failed BE study, the applicant established a level A IVIVC using the lower and higher strengths of the to-be-marketed product line. The lower strength was used as fast-releasing formulation, and the higher strength was used as slow-releasing formulation. The internal and external predictabilities were assessed.

The agency determined that in vitro dissolution profiles of the lower and higher strengths of the to-be-marketed product line are similar, and in vitro dissolution is dependent on the dissolution conditions. Thus, the applicant was requested to develop IVIVC using formulations with different release rates or alternatively conduct an in vivo BE study. The applicant conducted a new in vivo BE study, which met the BE limits.

Besides the major deficiencies discussed above in the case studies, the most commonly, the applicants did not submit the complete IVIVC report to the agency. Only the summary report was submitted. Employment of formulation with only one release rate for the establishment of IVIVC without evidence to show that the dissolution is condition independent.

The majority of deficiencies presented above are avoidable. The above information is provided to assist applicants who submit IVIVC data in support of generic drug applications to the Office of Generic Drugs to prepare high-quality submission containing complete information needed to make assessment within first review cycle. A validated IVIVC adds in vivo relevance to the in vitro dissolution, which presents the opportunities to avoid in vivo BE testing in humans.

National Center for Biotechnology Information , U. AAPS J. Published online Apr Author information Article notes Copyright and License information Disclaimer. Paramjeet Kaur, Email: vog. Corresponding author. Received Jan 16; Accepted Mar This article has been cited by other articles in PMC. Abstract In vitro — in vivo correlation IVIVC is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response.

Open in a separate window. Case Study 2 The applicant submitted an amendment containing IVIVC data to support proposed changes to dissolution method for its marketed drug product. Case Study 3 The applicant proposed a level 2 change for a non-release controlling excipient. Case Study 4 To seek approval for marketing of its generic drug product, the applicant developed a test product formulation that was shown to be bioequivalent to the corresponding reference product in in vivo BE studies.

Case Study 5 In this case, the applicant submitted IVIVC data from the literature to support its claim that batch-to-batch variation in pellet coating does not impact the BE of the test product compared to the reference product. Case Study 6 The applicant proposed a level 3 manufacturing site change. Rockville: Food and Drug Administration.

Accessed 15 Dec Open Drug Deliv J. Qureshi SA. In vitro-in vivo correlation IVIVC and determining drug concentrations in blood from dissolution testing—a simple and practical approach.

Uppoor VR. J Control Release. Pharm Res.

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In vitro-In vivo Correlation: Perspectives on Model Development

Use of the human volunteers in bioequivalence studies is being discouraged by the Food and drug administration after the introduction of biowaiver approaches. In the present study deconvolution technique with numeric approaches was applied after compressing and in vitro validating the mg Nimesulide immediate, intermediate and slow release tablets. Single centered, crossover, randomized study was conducted in four phases with a two-week washout period to obtain the plasma drug concentration data after administrating test and reference products in male healthy volunteers. Kinetica TM 4. The low values of prediction errors demonstrate that the correlation model is projecting the in vivo response of each formulation. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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What is IVIVC?

Food and Drug Administration FDA as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response". Generally, the in-vitro property is the rate or extent of drug dissolution or release while the in-vivo response is the plasma drug concentration or amount of drug absorbed. The United States Pharmacopoeia USP also defines IVIVC as "the establishment of a relationship between a biological property, or a parameter derived from a biological property produced from a dosage form, and a physicochemical property of the same dosage form". Typically, the parameter derived from the biological property is AUC or Cmax , while the physicochemical property is the in vitro dissolution profile. Fabs vs.

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In vitro — in vivo correlation IVIVC is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. The main objective of an IVIVC is to serve as a surrogate for human bioequivalence BE studies, which may reduce the number of BE studies performed during the initial approval process as well as with certain scale-up and postapproval changes. It is hoped that awareness of the deficiencies presented in our article would help the generic drug applicants to submit complete and appropriate information related to IVIVC data, ultimately, resulting in a more timely approval of ANDAs. An in vitro — in vivo correlation IVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is plasma drug concentration or amount of drug absorbed 1. The in vitro dissolution testing of dosage forms has been extensively used for quality control purposes, to determine stable release characteristics of the product over time, to ensure batch-to-batch similarity, and formulation discrimination, etc. However, these in vitro dissolution tests may or may not be predictive of the in vivo performance of the dosage form 1 — 3.

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J P harm P harmaceut S ci www. PDF Version. Correspondence: Dr. ABSTRACT: A key goal in pharmaceutical development of dosage forms is a good understanding of the in vitro and in vivo performance of the dosage forms. One of the challenges of biopharmaceutics research is correlating in vitro drug release information of various drug formulations to the in vivo drug profiles IVIVC. Thus the need for a tool to reliably correlate in vitro and in vivo drug release data has exceedingly increased. Such a tool shortens the drug development period, economizes the resources and leads to improved product quality.

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