Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators from National Medicines Regulatory Authorities in East

Evaluation of quality and interchangeability of medicinal productsTraining workshop for evaluators from National Medicines

Regulatory Authorities in East Africa Community

10-14 September 2007, Dar Es Salaam, Tanzania

Presented by

Rutendo Kuwana

Dissolution Testing

Dissolution Testing2 |

Dissolution testing: conventional tablets and capsules

Dissolution testing: conventional tablets and capsules

It measures the portion (%) of the API that (1) has been released from tablets/capsules and (2) has dissolved in the dissolution medium during controlled testing conditions within a defined period– The tablet thus first disintegrates– Then the API will be able to dissolve– Slow disintegration ➜ slow dissolution– The % API dissolved is determined with an appropriate

validated method: UV/VIS, HPLC, AA, GC, etc

Dissolution testing is also applicable to suspensions and suppositories


Solid oral dosage formsSolid oral dosage forms

Immediate release typically means that 75% of the API is dissolved within 45 minutes

– Rapidly dissolving: ≥ 85% in ≤ 30 minutes– Very rapidly dissolving: ≥ 85% in ≤ 15 minutes


Challenges in Dissolution TestingChallenges in Dissolution Testing

Dissolution testing in immediate-release (IR) solid dosage forms poses many challenges

developing and validating the test method

ensuring that the method is discriminatory

addressing the potential for an in vivo–in vitro relationship (IVIVR) or correlation (IVIVC).


Why in-vitro dissolution testing? Why in-vitro dissolution testing?


ApplicationsApplications

1. For selection of the formulation in the development phase– By comparison of the dissolution profiles of innovator

product with those of formulations– Hint: start with comparator product to see:

• Immediate release?• Rapidly dissolving?• Very rapidly dissolving?• Disintegration testing can aid in the early phases

– This should be a basic strategy in R&D to maximize the chances of bioequivalence


Applications (cont.)Applications (cont.)

2. It is a requirement for comparative dissolution data for the bio-batch and innovator batch– Same batches as used in bioequivalence study

– Submit report with data, profile comparison & discussion (see report requirements)

– This report forms part of pharmaceutical development report• Inclusion of the same report in the bioequivalence study report is

recommended



3. Demonstration of in vivo bioequivalence of one or more of the lower strength(s) of an FPP may be waived based on1. an acceptable in vivo BE study of the highest strength

against the comparator product

2. demonstration of similarity of dissolution profiles,

3. if the lower strength is proportionally similar in formula to the higher strength (bio-batch) and

4. if all pharmacokinetic requirements are met



4. Comparison of the release properties of pivotal batches– To demonstrate in vitro similarity of such batches

• This is considered essential for retention of efficacy and safety• Note that bioequivalence studies are done normally only once on a

bio-batch during development• It must be demonstrated that the product retains the dissolution

characteristics up to production scale– The studies should be submitted in dossier as part of the

FPP development report



5. Selection of the dissolution specifications for product release & stability purposes Conditions and acceptance criteria to be set The dissolution profiles of the bio-batch should be used for

this purpose A dissolution specification should be able to detect

inadequate release properties of the commercial batches• A “generous” dissolution limit has no quality selectivity



6. Post-approval amendment application– Assessment of formulation changes to demonstrate that the

profiles of the amendment batch and the current batch are similar


Variables affecting dissolution Variables affecting dissolution

characteristics of the API e.g., particle size, crystal form, bulk density

product composition e.g., drug loading, and the identity, type, and levels of excipients

manufacturing process e.g., compression forces, equipment

effects of stability storage conditions e.g., temperature, humidity


Mechanism of dissolution Mechanism of dissolution

Dissolution test determines the cumulative amount of drug that goes into solution as a function of time

Steps involved

liberation of the solute or drug from the formulation matrix (disintegration)

dissolution of the drug (solubilization of the drug particles) in the liquid medium

The overall rate of dissolution depends on the slower of these two steps


Mechanism of dissolutionMechanism of dissolution

First Step

Cohesive properties of the formulated solid dosage form drug play a key role disintegration and erosion

semi- solid or liquid formulations, the dispersion of lipids or partitioning of the drug from the lipid phase is the key factor

If the first step of dissolution is rate-limiting, then the rate of dissolution is considered to be disintegration controlled


Mechanism of dissolutionMechanism of dissolution

Second Step

Solubilization of the drug particles depends on the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical attributes


Dosage form type and design affect dissolution testing (1)Dosage form type and design affect dissolution testing (1)

For intrinsic dissolution-limited absorption (i.e., the disintegration of the dosage form is rapid, but dissolution is slow) reduce the particle size of the API

Small particle size creates challenges as they can pass through filters and subsequently dissolve


Dosage form type and design affect dissolution testing (2)Dosage form type and design affect dissolution testing (2)

For solubility-limited absorption (intrinsic- solubility controlled) enhance the transient solubility of the API

different salt forms of the API

surfactants in the formulation

solubilized liquid formulations in hard or soft gelatin capsules

non-crystalline materials


Media selectionMedia selection

For batch-to-batch quality testing medium selection may be based on the solubility data and the dose range of the drug product to ensure that sink conditions are met

The term sink conditions is defined as the volume of medium at least greater than three times that required to form a saturated solution of a drug substance.


Media selection (2)Media selection (2)

When the dissolution test is used to indicate the biopharmaceutical properties - closely simulate the environment in the GIT than sink conditions

First evaluate using test media within the physiologic pH range of 1.2–6.8 (1.2–7.5 for modified-release formulations)


Apparatus selectionApparatus selection

Described in the United States Pharmacopoeia (USP) under the General Chapters of Dissolution and Drug Release


Discriminatory power Discriminatory power

The discriminatory power of the dissolution method is the method’s ability to detect changes in the drug product.

Once a discriminating method is developed, the same method should be used to release product batches for future clinical trials, if possible.


Alternative methods to dissolution testing Alternative methods to dissolution testing

In ICH Q6A permits use of disintegration testing as a surrogate for conventional Compendial dissolution tests, provided

highly soluble drug substances

intrinsic rate of solubilization is rapid

overall drug release rate is dominated by cohesive properties of the formulation


Alternative methods to dissolution testing (2)Alternative methods to dissolution testing (2)

APIs with good solubility at gastric pH levels may be granted BCS Class I and III classification i.e. may be characterized by disintegration testing alone

In liquid filled capsule drug dissolved in solubilization aids offering a true mechanism for drug release is likely to be the rupture of the capsule use disintegration as a surrogate for the QC dissolution test


Multi-point dissolution?Multi-point dissolution?

In multipoint dissolution– multiple (≥ 3) samples are withdrawn from the dissolution

medium during dissolution testing– at pre-determined time points and– each sample is analysed for the % API dissolved– A graph of % API dissolved against time:

• The dissolution profile


Multi-point dissolutionExample of dissolution profile

Multi-point dissolutionExample of dissolution profile

0

20

40

60

80

100

120

0 10 20 30 40 50

WITHDRAWAL TIME IN MINUTES

Dis

solu

tio

n (

%)

Clarithromycin 250 mg tablets


Comparative dissolution testingThe principle

Comparative dissolution testingThe principle

Two or more products or batches containing the same API are compared

The strength of products / batches may or may not be the same (depending on purpose of test)

The dissolution conditions are similar, e.g.• Apparatus, medium, volume, rotation speed & temp.• Minimize possible experimental differences in conditions

Samples are taken at the same time points and the data (dissolution profiles) compared

Calculations: correct for volume change of dissolution medium


Comparative dissolution testingProfile similarity determination

Comparative dissolution testingProfile similarity determination

Two conditions to determine if the dissolution profiles of two products/batches in a particular dissolution medium are similar: 1. If both the test and reference product show more than 85%

dissolution within 15 minutes, the profiles are considered to be similar• No calculations are required

If this is not the case, apply point 2

2. Calculate the f2 value (similarity factor):

• If f2 ≥ 50, the profiles are normally regarded similar


Comparative dissolution testingSimilarity factor f2

Comparative dissolution testingSimilarity factor f2

n = number of time points

R(t) = mean % API dissolved of reference product at time point x

T(t) = mean % API dissolved of test product at time point x

Minimum of 3 time points (zero excluded)

12 units (each in own dissolution vessel) for each product (for “official” purposes)

Only one measurement should be considered after both products have reached 85 % dissolution

RSD at higher time points ≤ 10%


Comparative dissolution testingDissolution conditions (study design)

Comparative dissolution testingDissolution conditions (study design)

Apparatus

(choice)

• Paddle, 50 (75) rpm or

• Basket, 100 rpm

Dissolution media

All three media for full comparison

1. Buffer pH 6.8 or simulated intestinal fluid without enzymes

2. Buffer pH 4.5

3. 0.1 M HCl or buffer pH 1.2 or simulated gastric fluid without enzymes

Volume of media 900 ml or less

Temperature 37°C ± 0.5°C

Sampling points 10, 15, 20, 30, 45, (60, 120) min. (typical)

Units (individual) 12 for “official” studies


Typical time pointsImmediate release tablets (capsules)

Typical time pointsImmediate release tablets (capsules)

Rationale:

1. Condition 1– ≥ 85% dissolution of both products within 15

minutes

– 15 minute time point thus essential

2. Condition 2, for calculation of f2– a minimum of 3 points are required

– Only one measurement should be considered after 85 % dissolution (both tablets)

– 20 minute time point thus first possible one (if 15 minute fails 1st condition)

Point Time

1 10

2 15

3 20

4 30

5 45


Comparative dissolution testingComparison of products

Comparative dissolution testingComparison of products

Dissolution properties of two products (batches) regarded as similar when

– The profiles are similar– in all three media

• Statements of instability or insolubility are not acceptable, but should be demonstrated / justified


Example Determination of similarity of profiles

Example Determination of similarity of profiles

Example 1-B

% API dissolved

Time(min)

Tablet D (Ref)

Tablet E (Test)

10 55 57

15 72 78

20 85 91

30 97 100

45 102 100

60 103 101

f2 required? Yes

f2 (n = 3 ?) 64 (similar)

Example 1-A

% API dissolved

Time(min)

Tablet A (Ref)

Tablet B (Test)

10 87 94

15 96 99

20 99 99

30 100 99

45 101 99

60 101 99

f2 required? No, ≥ 85% in 15 min

f2 (n = N/A ?) profiles similar


ExampleDetermination of similarity of profiles (cont.)

ExampleDetermination of similarity of profiles (cont.)

Example 1-D

% API dissolved

Time(min)

Tablet A(Ref)

Tablet Y (Test)

10 87 55

15 96 72

20 99 85

30 100 97

45 101 102

60 101 103

f2 required? Yes

f2 (n = 3 ?) 31 (not similar)

Example 1-C

% API dissolved

Time(min)

Tablet X(Ref)

Tablet Y(Test)

10 29 34

15 38 41

20 47 50

30 63 64

45 80 79

60 95 91

f2 required? Yes

f2 (n = 6 ?) 74 (similar)


Reporting Comparative dissolution data

Reporting Comparative dissolution data

Full report, including Purpose of study Products / batches information

Batch number, manufacturing/expiry date, packaging, etc. CoA & size for “own” batches (and BMR for bio-studies report)

Dissolution conditions and method Analytical method or reference to part of dossier Results (% API dissolved)

Tabulated Graphically Similarity determination / calculation

Conclusion


GuidelinesGuidelines

WHO Prequalification

1. Supplement 1 [for use from July 2005 (CPH25)] to:

Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of

HIV/AIDS, Malaria and Tuberculosis

Dissolution testing

Others

Guidance for Industry. Waiver of In-Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 2000.

CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence. The European Agency for the Evaluation of Medicinal Products CPMP/EWP/QWP/1401/98, July 2001

SADC Guidelines (Draft)


Some conclusionsSome conclusions

Comparative dissolution– should form an essential part of R&D of solid oral dosage forms

(including suspensions),– supports bio-studies,– is required for comparison of pharmaceutical release properties of

pivotal batches,– is used to set dissolution specifications, and– assists in post-approval changes

It is thus important– to conduct the studies under controlled conditions in the 3 media,

all as required by the guidelines,– to take samples for analysis at meaningful intervals and– to be able to determine similarity of profiles

Documents

Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators from National Medicines Regulatory Authorities in East