In Vitro Release Rate IVRT Studies for Semisolid Dosage

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					In Vitro Release Rate (IVRT) Studies for
        Semisolid Dosage Forms
    at Diteba Research Laboratories




    Partnership through Expertise, Innovation and Compliance
        1620 Tech Avenue Unit 3, Mississauga, ON, L4W 5P4, Canada
         ph: 1 800 671-9053; (905) 625-7995; fax: (905) 625-3767
                 e-mail: info@diteba.com; www.diteba.com
 BIOEQUIVALENCE STUDY REQUIREMENT FOR SEMISOLID DOSAGE FORMS
 The guidance on Scale-Up and Post Approval Changes (SUPAC)1
 for drug products is an informal document representing the best
 current scientific judgments of the FDA. Its intended purpose is to
 lower the regulatory burden on the industry while continuing to as-
 sure the safety and effectiveness of drug products. SUPAC guid-
 ance is developed and categorized by the type of dosage form.

 Currently the FDA requires sponsors to conduct bioequivalence
 studies to justify SUPAC Level 1, Level 2 and Level 3 changes for
 semisolid dosage forms. Bioequivalence study is a very costly and
 time consuming activity and can be very impractical to conduct dur-
 ing the early phases of drug development. In addition to the bio-
 equivalence study there is a requirement to carry out additional
 analytical and physical tests2 to justify SUPAC changes


 MODIFIED FRANZ DIFFUSION CELL APPARATUS
 AS AN ALTERNATIVE TO BIOEQUIVALENCE STUDY

 The FDA’s Guidance for Industry on Scale-Up and Post Approval
 Changes for semisolid (SUPAC-SS) dosage forms describes re-
 lease rate studies that use Vertical Diffusion Cells apparatus
 (Modified Franz diffusion cell). The Guidance recommends using
 the In Vitro release rate comparison test between prechange and
 postchange products to approve one or more of the following SU-
 PAC-related changes:2–4

        •     components and composition;
        •     manufacturing (process and equipment);
        •     scale of manufacture;
        •     site of manufacture.

From the regulatory perspective, a bio-waiver in the form of an In Vitro release study can be used as an alternative
to a costly and time consuming bioequivalence study. A well-designed and validated In Vitro release method can be
used in the following processes:

        a) to monitor formulation changes and/or “batch-to-batch” uniformity;
        b) for initial screening of experimental formulation In Vitro;
        c) to confirm a product’s “sameness” during Level 3 changes, according to the FDA’s SUPAC-SS guide-
           lines;
        d) predict In Vivo performance.5–7

In Vitro release rate methodology for semisolid dosage forms carries unique aspects, besides the many common
dissolution parameters. Among these are application of the drug, selection of synthetic support membrane, compo-
sition of receptor medium, drug freely diffuses through the membrane, solubility, sink conditions, drug particle size,
viscosity, sensitivity, stability, and others. The presence of these multitudinous aspects necessitates performing a
comprehensive set of activities for method development and method validation.

                       Partnership through Expertise, Innovation and Compliance
                             1620 Tech Avenue Unit 3, Mississauga, ON, L4W 5P4, Canada
                              ph: 1 800 671-9053; (905) 625-7995; fax: (905) 625-3767
                                      e-mail: info@diteba.com; www.diteba.com
              IN VITRO RELEASE RATE (IVRT) STUDY SERVICES USING
                   MODIFIED FRANZ DIFFUSION CELL APPARATUS


Diteba Research Laboratories Inc has accumulated a
unique combination of expertise and capability to pro-
vide a complete set of services for In Vitro and analyti-
cal method development/validation for semisolid formu-
lations using Modified Franz diffusion cell apparatus.

We have staff with superior scientific expertise dedi-
cated to method development/validation of release
rate studies for these topical formulations: creams,
lotions, ointments, gels, pastes, and less viscous topi-
cal suspension solutions, as well as transdermal
patches.



Our services include:

• In-process testing for formulation optimization;
• Quality control, lot to lot variability;
• Skin penetration studies for bioequivalence/bioavailability evaluation;
• In Vitro and analytical method development & validation in full compliance with SUPAC and FDA require-
    ments;
•   In Vitro release comparison testing for pre- and post-change formulations;
•   Data interpretation and FDA submission for approval of SUPAC-related changes.


We operate the modified Franz diffusion cell systems for semisolid formulation, as well as Paddle over disk
apparatus for transdermal patches. Our scientists can meet the challenges of the most complex tasks while
keeping to strict timelines in a cost-effective manner.

Our service comprises thorough In Vitro release study method development/validation and comparison test-
ing, conducted in a relatively short time period (~4 to 6 weeks). Also included is preparation of all supporting
documentation and FDA submission reports.


       For further information please contact:

       Marc Routhier
       Senior Vice President, Business Development
       ph: 1-800-671-9053; (905) 625-7995 ext.122;
       fax: (905) 625-3767
       e-mail: Marc.Routhier@diteba.com



                        Partnership through Expertise, Innovation and Compliance
                               1620 Tech Avenue Unit 3, Mississauga, ON, L4W 5P4, Canada
                                ph: 1 800 671-9053; (905) 625-7995; fax: (905) 625-3767
                                        e-mail: info@diteba.com; www.diteba.com
APPENDIX

The Appendix contains the general content of the methodology we apply for In Vitro Release Rate (IVRT) Studies
using modified Franz diffusion cell apparatus. There are four main sections in the process, outlined below:

STAGE 1. IN VITRO METHOD DEVELOPMENT

       We operate the modified Franz diffusion cell systems for semisolid formulation consisting of triple 3 x 6
       modified Franz diffusion cell drive systems for In Vitro method development.

           Receptor media selection:

               •      sufficient solubility to maintain sink conditions;
               •      stability at test temperature in media for length of study;
               •      assures no medium/membrane interaction;
               •      assures no medium/formulation interaction.

           Membrane selection:

               •      commercially available;
               •      least resistance to drug free diffusion;
               •      no binding to drug;
               •      no interaction with medium.

           Application of dose:

               •      infinite dose (typically ~300mg of cream/ointment/lotion/gel) preferred over finite dose;
               •      simplifies diffusion kinetics;
               •      reduces result variability;
               •      maintains “30% rule.”

            In Vitro test parameters:

               •      duration of experiment (3h, 6h,…);
               •      sampling points: usually 6;
               •      interval time (30min, 45min, 60min, . . .);
               •      sampling options: 18 cells (A,B,C), 6 cells (A & B);
               •      aliquot volume/wash volume (0.5 ml to 1.5 ml).

      Expected results:

                •     amount of active released µg/cm2 vs. time0.5 gives an R2 value GT 0.9;
                •     “sink conditions” and “30% rule” maintained;
                •     drug release rate-slopes (for each vassal) obtained with RSD value NMT 15%;
                •     method able to detect product “difference” as well as product “sameness.”




                      Partnership through Expertise, Innovation and Compliance
                            1620 Tech Avenue Unit 3, Mississauga, ON, L4W 5P4, Canada
                             ph: 1 800 671-9053; (905) 625-7995; fax: (905) 625-3767
                                     e-mail: info@diteba.com; www.diteba.com
STAGE 2. CHROMATOGRAPHY

   We will define a suitable method of analysis to determine drug diffusion (usually HPLC) before any activities
   commence.

     Analytical Method Validation

       Analytical method will be validated before In Vitro study is performed. The analytical method validation will
       consist of the following tests:

           •     System Suitability (six injections Precision, Resolution, Tailing factor, Capacity Factor);
           •     Linearity and Range;
           •     Specificity;
           •     Accuracy;
           •     Limit of Quantitation;
           •     Stability;
           •     Robustness.

STAGE 3. IN VITRO METHOD VALIDATION

   In Vitro method validation will be carried out following In Vitro method development and HPLC method valida-
   tion. We will carry out In Vitro method validation using sensitivity and reproducibility tests.

     In Vitro Method Sensitivity Test

       The minimum necessary requirement for the designed In Vitro method is to be capable of distinguishing
       concentration differences in the same formulation (usually containing 50%, 100% and 200% actives).

       The following is an example of experiment design in which all three strengths are applied in replicates on
       the same day for the same experiment using the same apparatus (diagram illustrates positions of vessels
       in three groups of six cells):

       •   Suspensions/emulations: a twofold increase in drug concentration should result in a 20.5 = 1.41 in-
           crease in slope.
       •   For fully dissolved systems (real solutions), release rate should be directly proportional to the amount
           of drug.

     In Vitro Method Reproducibility Test

       Reproducibility of the developed In Vitro
       method will be demonstrated by measur-
       ing of its inter-day and intra-day preci-
       sion. At least 6 cells will be loaded with
       the same formulation on the same day
       (intra) and on three different days (inter).
       To review the reproducibility test we will
       apply RSD NMT 15% acceptance crite-
       rion.




                    Partnership through Expertise, Innovation and Compliance
                           1620 Tech Avenue Unit 3, Mississauga, ON, L4W 5P4, Canada
                            ph: 1 800 671-9053; (905) 625-7995; fax: (905) 625-3767
                                    e-mail: info@diteba.com; www.diteba.com
STAGE 4. RELEASE RATE COMPARISON

      Release rates (slopes) from six cells of Test product (T) and six cells of the Reference product (R) will be obtained.
      The test and reference product in each run will be randomized during the applying on cells’ donor compartment to
      ensure unbiased comparison.

            Calculations:

            A 90% confidence interval (CI) for the ratio (T/R) of median release rates will be computed, the eighth and
            twenty-ninth ordered ratios representing the lower and upper limits of the 90% CI for the ratios of median
            release rates. Median In Vitro release rates for comparing the test with the reference range from 75% to
            133%.




REFERENCES:

1.   http://www.fda.gov/cder/guidance/cmc5.pdf

2.   Guidance for industry: Nonsterile Semisolid Dosage Forms. Center for Drug Evaluation and Re-
     search (CDER), Dec. 1998. 5600 Fishers Lane, Rockville, MD 20857. (Tel) 301-827-4573. Internet at
     http://www.fda.gov/cder/guidance/index.htm
3.   FIP/AAPS Guidelines to Dissolution/in vitro Release Testing of Novel/Special Dosage Forms. M.
     Siewert, J. Dressman, C.K. Brown, & V.P. Shah, AAPS PharmSciTech. 4(1): article 7, 2003.
4.   Can In Vitro release differentiate among various topical formulations? J.S. Elkins & V.P. Shah FDA,
     Rockville MD. Presented at the AAPS annual Meeting, Oct. 1996, Seattle WA.
5.   Development and Validation of In Vitro release Testing Methods for Semisolid Formulations. M.
     Corbo, T.W. Schults, G.K. Wong, & G.A. Van Buskirk, Pharmaceutical Technology, Sept. 1993, 112–
     128.
6.   Assessment of value and applications of In Vitro testing of topical dermatological drug products.
     Pharm. Res. 16(9), 1325–1330, 1999.
7.   Development and Validation of In Vitro Release Tests for Semisolid Dosage Forms-Case Study.
     K.D. Thakker, and W.H. Chern, Dissolution Technologies, May 2003.




                    Partnership through Expertise, Innovation and Compliance
                            1620 Tech Avenue Unit 3, Mississauga, ON, L4W 5P4, Canada
                             ph: 1 800 671-9053; (905) 625-7995; fax: (905) 625-3767
                                     e-mail: info@diteba.com; www.diteba.com
             NOTES & QUESTIONS




Partnership through Expertise, Innovation and Compliance
    1620 Tech Avenue Unit 3, Mississauga, ON, L4W 5P4, Canada
     ph: 1 800 671-9053; (905) 625-7995; fax: (905) 625-3767
             e-mail: info@diteba.com; www.diteba.com
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                     Partnership through Expertise, Innovation and Compliance
                           1620 Tech Avenue Unit 3, Mississauga, ON, L4W 5P4, Canada
                            ph: 1 800 671-9053; (905) 625-7995; fax: (905) 625-3767
                                    e-mail: info@diteba.com; www.diteba.com