dissolution profiles

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Dissolution Profiles

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Dissolution Profiles

Dissolution ProfilesAgenda• Types of Drug Release• Drug Release Profiling• Alcohol-Induced Dose Dumping• Dissolution Release Specification

Types of Drug Release

Types of Drug Release Delayed Release Orally Disintegrating

In-vitro disintegrating time of NMT 30 seconds

Releases a discrete portion or portions of drug at a time other than promptly after administration.

Drug Release Profiling• Places to check first

• USP• FDA Dissolution Method

Database http://www.accessdata.fda.gov/scripts/cder/dissolution/

• Summary Basis of Approval

• FDA Bioequivalence Recommendations for Specific Products

Drug Name Dosage Form USPApparatus

Speed (RPMs) Medium Volume (mL)

Recommended Sampling Times (minutes)

Date Updated

Abacavir Sulfate

Tablet II (Paddle) 75 0.1 N HCl 900 5, 10, 15, and 30

03/22/2006

Abacavir Sulfate/Lamivudine

Tablet II (Paddle) 75 0.1 N HCl 900 10, 20, 30, and 45

01/03/2007

Abacavir Sulfate/Lamivudine/Zidovudine

Tablet II (Paddle) 75 0.1 N HCl 900 5, 10, 15, 30 and 45

01/03/2007

In addition to the method above, for modified release products, dissolution profiles on 12 dosage units each of test and reference products generated using USP Apparatus I at 100 rpm and/or Apparatus II at 50 rpm in at least three dissolution media (pH 1.2, 4.5, and 6.8 buffer) should be submitted in the application. Agitation speeds may have to be increased if appropriate. It is acceptable to add a small amount of surfactant, if necessary. Include early sampling times of 1, 2, and 4 hours and continue every 2 hours until at least 80% of the drug is released, to provide assurance against premature release of drug (dose dumping) from the formulation. Specifications will be determined upon review of the data submitted in the application.

Drug Release Profiling (IR)

Drug Release Profiling (IR)• Things to do first (Immediate Release)

• 0.1 N HCl, 900 mL, paddles, 50 RPM, 15 min.If NLT 85% is dissolved, then product behaves like a solution.

• Using release method, sample dissolution every 15 minutes until two points past the asymptote is obtained.For dissolution profiles, select NMT 4 time points with NMT 2 points past the asymptote. Asymptote should be NLT 85% amount released.

Drug Release Profiling (ER)

Drug Release Profiling (ER)• Things to do first

• Generate RLD profile as per FDA Dissolution Data Base.• Using same apparatus, volume, speed and time points as

FDA method, generate additional profiles* with

• Water• 0.1N HCl• Buffer pH 6.8• Buffer pH 4.5

All together, there should be 4 dissolution profiles: FDA’s plus three.

*Surfactants may be used to achieve sink conditions

Drug Release Profiling (DR)

• Demonstrate product is stable at pH 1.2 for 2 hrs.

• Demonstrate drug is released at pH 6.8.

• No multimedia dissolution testing required.

Alcohol-Induced Dose Dumping• Not required for all products.

• Verify FDA’s guidance – Individual Products Bioequivalence Recommendations Guidance http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm

• Check if it was requested by FDA on RLD SBoA.• Media: 900 mL 0.1N HCl media on a V/V basis to give the following percentages:• 0% ethanol (no ethanol added)• 5% ethanol (beer)• 20% ethanol (mixed drinks)• 40% ethanol (neat liquor)

Beware!Ethanol ≠ Alcohol

Alcohol is about 94.5% Ethanol…

Alcohol-Induced Dose Dumping• Sampling is done every 15 minutes until 2 hrs are reached.

• Acceptance criteria: Generic drug is not worst than the RLD.

• It is only performed once in the lifetime of a drug product formula. Prior to approval.

Data • No decimal points• Assays

• RLD should be 95 – 105% LC• Test product should be within 5%

of RLD• RLD satisfactory Content

Uniformity• The following may indicate the

need to investigate results out of the lab• RSD should be NMT 20% in first

time point.• RSD should be NMT 10% for all

other points.• Asymptote should be NLT 85%.

• F2 calculations• Only one measurement

should be considered after 85% dissolution of the product.

• Data needs to be generated and handled as per cGMP.

Data Reporting

Data Reporting

Dissolution Release Specification• For sampling time points, go to:

• USP• Summary Basis of Approval

Dissolution Release SpecificationAnalytical method to be followed should be the same as that provided by FDA Individual Dissolution Guideline.

Release time points would be selected from dissolution profile time points.

Dissolution Release Specification

• IR• One point with release

of NLT 85%• DR

• Two points• 0% @ 2 hr in 0.1N HCl• Either

• 85% in 6.8 buffer• Multipoint Dissolution

• ER• NMT 4 time points• NMT 2 points past

asymptote• Asymptote NLT 85%• Ranges:

• 1st is NMT __%• 2nd and 3rd with a range of

NMT 20%• 4th time point NLT 85%

Questions