QbD Approach to Dissolution Through Understanding of the Release Mechanisms and Critical In Vivo Parameters

Andreas Abend Merck West Point, PA

Outline

General considerations of dissolution

Formulation development QC method BCS based understanding of dissolution methodology in the absence of IVIVC

Part A: Prior knowledge/risk assessment approach

Part B: IVIVC/R approach

Purpose of Dissolution testing

Guide formulation design and assess product quality The only product test that truly measures the effect of formulation and physical properties of the API on the rate of drug solubilization The only test that can monitor if the rate of drug solubilization is impacted by product storage conditions It is the best surrogate for bio-performance if IVIVC cant be established Required by many regulatory authorities for solid oral dosage forms, transdermal patches and oral suspensions

The evolution of our understanding of the DP characteristics from a dissolution perspective

Formulation understanding QC method

Pre Phase 1 --- Phase 1 --- Preliminary and Final Market Image QbD execution QTPP RA tools Design space experiments Monitor process/ refine SUPAC

Evolution of the method

Early development:

Disso method with bio relevant media key in guiding formulation development in the absence of human in-vivo data: Little value having a QC method at this stage

Although required, limited value of a QC method at this stage of clinical development

Post Prove of Concept- preliminary market formulation development:

Dissolution method gains much more importance as a bioperformance/ quality method: Drug Product Process and components are usually defined

Pivotal clinical studies (i.e. dose ranging, Phase III)

Exploring the Design Space and process scale-up: critical to have the right method in place Important to ensure consistent quality (consistency in clinical trials)

Early DP development stage Dissolution Method General Considerations..

Prospective method Desired Method attributes:

Should allow ranking of potential range of drug product formulation types (i.e. DFC, LFC, simple tablets) to maximize drug substance exposure Typically not sensitive of small changes within one formulation type

Case Study 1- Formulation ranking:

Goal to identify the formulation that is likely giving maximum exposure in Phase I Clinical trials:
API properties: BCS Class II with low aqueous solubility 1.3ug/mL in aqueous and 7.7ug/mL in FaSSIF Formulation: Bench mark tox formulation Three Liquid filled capsules Two dry filled capsules (50mg Standard pharmaceutical ingredients present in the formulation)

Dissolution experiment Bio-relevant Medium: FaSSIF Non-sink condition

In-vitro dissolution and in-vivo Dog pK results

FaSSIF Dissolution of MK-6526 110.0 100.0 90.0 80.0 70.0

% Claim

LFCC:I:T C:T
I:T WG:C WG:TPGS SA:TPGS

60.0 50.0 40.0 30.0

In-vitro dissolution Media FaSSIF Apparatus USP II Agitation 100 rpm

20.0 10.0 0.0 0 10 20 30 40 50

Tox formulation
60 70 80 90 100 110 120 time (min)

DFC

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 0

Conc (uM)

LFC

Tox formulation
4 8
DFC (10% Vit. E TPGS) Time (hr) LFC (Im:Tw) SA Vehicle (20% Vit. E TPGS)

DFC

12

16

20

24

Dissolution method development strategy PMF development

Usually limited human pK-data available

Phase I formulation typically not the formulation going forward and process conditions, API, excipients selection, etc. evolve May test further formulations in Bio Comparison studies before making final PMF definition With the additional human pK-data and formulation information opportunity to look for in-vitro and in-vivo relationship

Desired method attributes:

Guide formulation selection and fine-tuning Become more formulation specific Predictive of in-put variables that may impact bio-performance Builds on prior knowledge including BCS classification system

Case Study 2:

API properties: BCS Class IV with low aqueous solubility across pH 1.0-6.0

Formulation: Tablets (doses: 100 -400 mg potency) with 25-50% drug load; Standard pharmaceutical ingredients present in the formulation. Immediate release dosage form.
Process: Roller compaction process; API and excipients are roller compacted. The granules are lubricated with SSF and magnesium stearate followed by compression and film coating. Dissolution mechanism: Spans from fast disintegration of tablets to slow disintegration of tablets

Case Study 2: In-vitro dissolution and in-vivo human pK results

120

% Dissolved

In-vitro dissolution Media water Apparatus USP II Agitation 100 rpm

100 80 60 40 20 0 0 0.5 1 1.5 Time (hr) 2 Formulation I Formulation II 2.5 3

9000 8000

Formulation 1 Formulation 2

Plasma Concentration

7000 6000 5000 4000 3000 2000 1000 0 0 2 4 6 Time (hour) 8 10 12

Dissolution method development strategy Pivotal/ late stage Clinical development

Formulation Identified, Dose(s) Identified -- Initial Quality Risk assessment Evaluate the in-put variables on Drug Product Quality API, Excipients, Drug product manufacturing process Identify Critical Process Parameters Explore the process design space Design Space: where the process works Develop the Control Strategy Desired Dissolution Method requirements: Method should be sensitive to the process parameters/ in-put variables that may affect bio-performance Method should be stability indicating, i.e. pick-up changes that are biorelevant

Closer look at dissolution testing in the context of QbD

Final Formulation going into pivotal clinical studies has been defined CQAs have been identified

Need to ensure adequate methods are in place to control CQAs In-vivo performance is usually always a CQA
Dissolution testing is at this stage often the only test that probes drug substance release

Requirements of a bio-relevant method in a QbD context

In general methods should assure the quality of the drug product Dissolution method (or surrogates) should assure consistent bio-performance of the drug product Should be sensitive to in-puts/ variables that have been identified to impact bio-performance How can this be done? 1. Establish IVIVC (or IVIVR) 2. Use prior knowledge and appropriate risk assessment 3. A combination of both

Part A: Prior knowledge/risk assessment approach

Biopharmaceutical Classification System

10 Apparent Permeability (X 106)

II
Low solubility

I
High solubility

1.0

High permeability

High permeability

0.1

IV
Low solubility Low permeability

III
High solubility Low permeability

0.01
High Low Low

Volume to Dissolve Max Dose (ml) G.L. Amidon et al.

Dissolution Mechanism based on BCS

Formulated drug Solubilized drug Absorbed drug

kd

kp

kd = dissolution rate (solubility, formulation) kp = permeability rate (API structure)

kd & kp fast - Well absorbed

BCS Class I, like dosing an oral solution kd >> kp - permeation control BCS Class III, still like dosing an oral solution kd << kp - dissolution controlled BCS Class I (ER or CR), or Class II & IV (IR)

Dissolution Mechanism based on BCS

Formulated drug or granule Solubilized drug

kdd

kd
Drug Particle

kid

kdd = disintegration (cohesive properties of the formulation)

kid = solubilization of the drug (API particle size or surface area)

Understanding the relative importance of kdd and kid provides a mechanistic framework to assess where dissolution tests adds value

Dissolution Mechanism based on BCS

kdd >> kid - intrinsic dissolution control Critical attribute is API particle size or surface area kdd << kid - disintegration controlled Cohesive properties of the formulation are important Critical attribute is disintegration of product kdd ~ kid Fast release neither cohesive properties nor physical properties are important, Critical attribute is disintegration Slow release - both cohesive properties and physical properties may be important, Critical attribute is dissolution

A Design Perspective on Dissolution Testing

General Dissolution
Intrinsic Rate of API Solubilization
API Surface Area

Disintegration or Erosion

Increased Specificity of Quality Attribute

Porosity

Hardness

API Particle Size

Specific
A Biopharmaceutical Classification System Approach to Dissolution: Mechanisms and Strategies W. E. Bowen, Q. Wang, W. P. Wuelfing, D. L. Thomas, E. Nelson, Y. Mao, B. Hill, M. Thompson, R. A. Reed In "Biopharmaceutics Applications in Drug Development" R. Krishna and Lawrence Yu, Ed.; Springer, 2008, 290.

Merck IR Formulation BCS Experience Space

II I

Papp(x10 )

BCS Class I BCS Class II BCS Class III BCS Class IV

10

0.1

IV
1e+8 1e+7 1e+6 1e+5 1e+4 1e+3 1e+2 1e+1 1e+0 1e-1 1e-2

III
1e-3

Volume to Dissolve Max Dose (ml)

BCS Classification I/III Immediate release Dosage Forms

(N = 15)

Fast dissolution (<15 mins, 85%)?

Yes

Case 3
CQA Tablet disintegration capsule rupture

Disintegration Test or capsule rupture test

(N = 13)

Case Study 3: BCS Class I/III

Fast release with disintegration controlled dissolution

API properties: Borderline BCS Class I/III permeability with high aqueous solubility (>40 mg/mL) at pH 1-7.5 Formulation: tablets (doses: 25 - 200 mg) with 32% drug load; Standard pharmaceutical ingredients present in the formulation Process: Direct compression process; API & excipients are blended and then lubricated with magnesium stearate and sodium stearyl fumarate, followed by compression. Dissolution mechanism: tablet disintegration followed by rapid solubilization of drug particles Critical Quality Attribute: tablet disintegration

Case Study 3: BCS Class I/III

Fast release with disintegration controlled dissolution Dissolution in Physiological pHs
100

% Dissolved

90

80

Test conditions Media varied Apparatus USP I Agitation 100 rpm

pH 1.2 pH 4.5 pH 6.8 water - 50 mM NaCl water

70 0 15 30 45 60

Time, min

Slowest profile has > 90% release in 10 minutes

Case Study 3: BCS Class I/III

Fast release with disintegration controlled dissolution Impact of Tablet Hardness on Dissolution and Disintegration
Dissolution
100
% Dissolved at 10 min
Disintegration, seconds

Disintegration
160 140 120 100 80 60 40 20 0 10 15 20 25

95 90 85 80 75 10 15 20 25 Hardness, kP

Hardness, kP

Disintegration is the more sensitive method and serves as a better indicator for product quality than a dissolution test

BCS Classification I/III Immediate release Dosage Forms

(N = 15)

Fast dissolution (<15 mins, 85%)?

No

Consider reformulation Or process change

Fast dissolution (<15 mins, 85%)?

Yes No Yes Disintegration/erosion control? Characterization of dissolution mechanism Perform Dissolution of dosage form and granules.

Case 3
CQA Tablet disintegration capsule rupture

Yes

Case 4 (N = 1)

Disintegration Test or capsule rupture test

(N = 13)

Case Study 4: BCS Class I/III

Erosion Controlled Dissolution

API properties: API 1: Borderline BCS I/III permeability with high aqueous solubility (>40 mg/mL) at pH 1-7.5; API 2: BCS III with high aqueous solubility (~200 mg/mL) at pH 1-7.5 Formulation: Combination tablets. Standard pharmaceutical ingredients present in the formulation Process: Wet granulation process; Fluid-bed wet granulation of API 1 and API 2. The granules are dried and blended with microcrystalline cellulose and magnesium stearate followed by compression and film coating Dissolution mechanism: Tablet erosion followed by rapid solubilization of drug particles; controlled by tablet erosion

Critical Quality Attribute: tablet disintegration

Case Study 4 BCS Class I/III

Erosion Controlled Dissolution
Correlation of Dissolution and Disintegration
100 80
% Released
Disintegration time: 30 mins

% Dissolved @ 15-minutes

95

90
y = -1.6531x + 121.7 2 R = 0.9968

85

60 40 20 0 0 15 30

Disintegration time: 19 mins Disintegration time: 17 mins granules

80

75

Test conditions Media Water Apparatus USP II Agitation 75 rpm

17 19 21 23 25 27 29

45

60

70 15

31

Time (min)

Strong correlation between dissolution and disintegration Both methods monitor critical quality attributes sufficiently Disintegration is recommended for simplicity

Disintegration Time, minutes

BCS Classification I/III Immediate release Dosage Forms

(N = 15)

Fast dissolution (<15 mins, 85%)?

No

Consider reformulation Or process change

Fast dissolution (<15 mins, 85%)?

Yes No Yes Disintegration/erosion control? Characterization of dissolution mechanism Perform Dissolution of dosage form and granules. No

Case 3
CQA Tablet disintegration capsule rupture

Yes

Case 4 (N = 1)

Case 5
CQA Granule properties or others

Disintegration Test or capsule rupture test

(N = 13)

(N = 1)

Monitor dissolution profiles

Case Study 5: BCS Class I

API properties: BCS Class I with high aqueous solubility (0.1 mg/mL) at pH 1-7.5. Formulation: Tablets (dose: 4 mg); Standard pharmaceutical ingredients present in the formulation Process: Wet granulation process; Granulated in water. The granules were dried, blended with starch and magnesium stearate followed by compression Dissolution mechanism: Fast tablet disintegration followed by drug release from granules and rapid solubilization of drug particles; Controlled by drug release from granules Critical Quality Attribute: Granule particle size

Case Study 5 BCS Class I

Dissolution Controlled by Granule Particle Size
120 100

% Release

80 60 40 20 0 0 15 30 45 60 75 Time (minutes)
Test conditions Media Water Apparatus USP II Agitation 50 rpm

< 150 um > 150 um

Overall dissolution profile is dependent on the granule size distribution Dissolution profile is monitored for quality control

Summary of BCS Class I/III Experience

Overall Design Principle: Rapid dissolution so like dosing an oral solution Formulation: Tablets, Capsules or Oral Disintegrating Tablets Process: Direct compression, Wet Granulation, Roller Compaction, Encapsulation or Freeze Drying Dissolution mechanism: tablet or capsules disintegration followed by rapid solubilization of drug particles, i.e. kdd << kid Critical Quality Attribute: Design for Disintegration (i.e. to make it like dosing an oral solution) Merck Biopharmaceutical Experience: In 3 out of 3 cases examined, the solid oral dosage form has been bio-equivalent to an oral solution

Merck BCS Class II & IV IR Formulations

II
Flexeril BCS Class I BCS Class II BCS Class III Dexamethasone BCS Class IV Proscar

Papp(x106)

10

L000222628

L000854384

0.1

IV

Maxalt L001169872 MK0431 L000845704 L000124467 Pepcid Vasotec Fosamax

III
1e-3

1e+8 1e+7 1e+6 1e+5 1e+4 1e+3 1e+2 1e+1 1e+0

1e-1

1e-2

Volume to Dissolve Max Dose (ml)

Dissolution Media Selections

II
Aqueous Surfactant N/A

Papp(x106)

10

0.1

IV
1e-1

III
1e-2 1e-3

1e+8 1e+7 1e+6 1e+5 1e+4 1e+3 1e+2 1e+1 1e+0

Volume to Dissolve Max Dose (ml)

BCS Classification II/IV Immediate Release Dosage Form

API solubilized in formulation (LFCs, etc.)

Case 6
Yes

Design Target API remains in solution

Disintegration Test or capsule rupture test

Case Study 6: BCS Class II/IV

Capsule Rupture Controlled Dissolution

API properties: BCS Class IV with low aqueous solubility at pH 1.0-7.0. Formulation: Liquid Filled Capsules (LFC). Dose: 0.1 50 mg. The drug is fully dissolved in the liquid core of the LFC Process: API was dissolved in liquid vehicle, which is then filtered, and filled into hard (or soft) gelatin capsules Dissolution mechanism: capsule disintegration followed by dispersion of liquid content Product Design Target: API is solubilized in formulation

BCS Classification II/IV Immediate Release Dosage Form

API solubilized in formulation (LFCs, etc.)

No

Dissolution mechanism characterization Perform Dissolution of dosage form, API (different PSD) and/or granules

kid rate limiting?

No

Yes

Case 6
Yes

Consider reformulation Or process change

kid rate limiting?

Yes Design Target API remains in solution CQA API Particle size, etc

Case 7

Disintegration Test or capsule rupture test

Control API particle size, etc.

Case Study 7: BCS Class II/IV

Drug solubilization controlled dissolution

API properties: BCS Class IV with low aqueous solubility across pH 1.0-7.5. Formulation: Capsules (dose: 100 mg) with 67% drug load; Standard pharmaceutical ingredients present in the formulation Process: API and excipients are dry blended, then lubricated with magnesium stearate. The powder blend is then filled in hard gelatin capsules. Dissolution mechanism: Rupture of capsule shell followed by API dissolution. Controlled by API solubilization Critical Quality Attribute: Physical properties of API

Case Study 7: BCS Class II/IV

Drug solubilization controlled dissolution
100.0

Average % Dissolved

80.0

60.0

Test conditions Media 2% Tween Apparatus USP II Agitation 100 rpm

40.0

20.0

Sieve Cut < 75 microns Sieve Cut 180-250 microns Sieve Cut > 355 microns
0 20 40 60 80 100

0.0

Time, minutes

API particle size modulates dissolution

Case Study 7: BCS Class II/IV

Drug solubilization controlled dissolution
Impact of API PSD on Capsule Dissolution

API PSD should be controlled and monitored

BCS Classification II/IV Immediate Release Dosage Form

API solubilized in formulation (LFCs, etc.)

No

Dissolution mechanism characterization Perform Dissolution of dosage form, API (different PSD) and/or granules

kid rate limiting?

No

Yes

Case 6
Yes

Consider reformulation Or process change

Disintegration or capsule rupture limited? No Design Target API remains in solution

No

kid rate limiting?

Case 8
Yes CQA API Particle size, etc

Case 7

CQA Formulation properties

Disintegration Test or capsule rupture test

Monitor dissolution profiles

Control API particle size, etc.

Case Study 8: BCS Class II/IV

API properties: API 1: BCS II with low solubility across pH 1-7.5; API 2: BCS Class IV with low aqueous solubility across pH 3.0-7.5 Formulation: Combination drugs in capsules (strength: 200/100 mg); Standard pharmaceutical ingredients present in the formulation Process: Roller compaction process; APIs and excipients granulated via roller-compaction. Granules are milled, lubricated with magnesium stearate and encapsulated in hard gelatin capsules. Dissolution mechanism: Rapid rupture of capsule shell followed disintegration of capsule plug and drug release from granules. Controlled by plug disintegration and release from granules. Critical Quality Attribute: granule density

Case Study 8: BCS Class II/IV

Roller Compaction Pressure vs. Dissolution in Capsules
100 80

% Dissolved

Test conditions Media 2% SDS Apparatus USP II Agitation 50 rpm

60 40 20 0 0 15 30 45 60 75
Clinical Batch, 18 mm Disk, Loose Plug Reference Batch 131-B: 60 bar Roll Pressure, Hand-filled Capsule 131-2: 90 bar Roll Pressure, Hand-filled Capsule 131-3: 120 bar Roll Pressure, Hand-filled Capsule

Time (minutes)

Monitor drug release by dissolution

BCS Classification II/IV Immediate Release Dosage Form

API solubilized in formulation (LFCs, etc.)

No

Dissolution mechanism characterization Perform Dissolution of dosage form, API (different PSD) and/or granules

Kid rate limiting?

No

Yes

Case 6
Yes

Consider reformulation Or process change

Case 9
CQA API remains in solution

Disintegration or capsule rupture limited? Yes No

No

Kid rate limiting?

Case 8
Yes CQA API Particle size, etc

Case 7

CQA Tablet disintegration capsule rupture

CQA Formulation properties

Disintegration Test or capsule rupture test

Monitor dissolution profiles

Control API particle size, etc.

Case Study 9: BCS Class II/IV

API properties: BCS Class IV with low solubility across pH 3.0-7.5. Highly soluble at gastric pH (>200 mg/mL) Formulation: Capsules (doses: 200 - 400 mg) with 65% drug load. Standard pharmaceutical ingredients present in the formulation Process: Roller compaction process; API and excipients granulated via roller-compaction. Granules are milled, lubricated with magnesium stearate, and encapsulated in hard gelatin capsules Dissolution mechanism: Capsule rupture followed by rapid release from granules. Controlled by capsule rupture Critical Quality Attribute: Capsule rupture (cross-linking)

Case Study 9: BCS Class II/IV

Dissolution Profiles in 0.1N HCl
100
Test conditions Media 0.1 N HCL Apparatus USP II Agitation 50 rpm

% Dissolved

80 60

Unstressed Capsules
40 20 0 0 10 20 30 40 50

Stressed capsules (40C/75% 48 hrs) Granules

Time (Minutes)

Monitor drug release by disintegration

Summary of BCS Class II/IV Experience

Overall Design Principle: Solubilization enhancement e.g. LFCs, API physical properties reduce particle size, increase surface area add solubilizing agents, etc. Formulation: Capsules, Tablets, ODTs Process: Direct compression, Wet Granulation, Roller Compaction, Freeze Drying, liquid filled gel caps Dissolution mechanism: varied, i.e. kid << kdd, kdd << kid , kdd ~ kid Critical Quality Attribute: Disintegration, API physical properties, dissolution

Conclusions
BCS based drug release testing leads to: Focus on value added specifications in alignment with QbD principles and approaches Removal of non-value added specifications BCS Class I/III IR products ability to eliminate dissolution testing and replace with disintegration testing BCS Class II/IV IR products ability to drill down to key quality attributes and replace dissolution testing consistent with the design of the product some dissolution testing still adds value

Part B
IVIVC/R approach

IVIVC/IVIVR approach
In-vitro Dissolution In-vivo human PK

Dissolution Method Development

IVIVC/R

Patients

Drug Product CQA CPP

IVIVC/ IVIVR

High probability for CR products

Consistent with existing SUPAC guidance, this provides highest degree of regulatory flexibility Disso in BCS I and III formulations often too fast

Lower probability for IR products

Absorption and metabolism may also make it difficult to deconvolute the data Remember dissolution driven by drug solubility Often no relationship between dissolution rate and pK achievable

BCS II higher chance of achieving

BCS IV

Possible relationships between dissolution and drug exposure in subjects Case A

% change in-vivo pK-parameter

0 -10 -20

Case A no IVIVC/R

% drug dissolved in-vitro time per time unit (min)

Dickinson et. al (2008) AAPS Journal 10:380-90 Dickinson (2009), Applied Biopharmaceutics and QbD for Dissolution/ Release Specification setting: Product Quality for Patient Benefit;

Case A

No changes in pK-parameters observed within the tested batches Dissolution method is sensitive to process parameters and other in-put variables

Would suggest using % release/ time Q value(s) to provide process control if required

In-put variable changes are justifiable as long as within the above experience range

Assessment should be based on FMEAC analysis Changes that result in disso profiles outside the experience/ spec range likely require in-vivo justification

Possible relationships between dissolution and drug exposure in subjects Case B

% change in-vivo pK-parameter
0

-20

-40

Case B - IVIVC

-60

% drug dissolved in-vitro time per time unit (min)

Case B

IVIVC is achievable! In-vitro Method can directly assess the magnitude of in-vivo changes due to process or other in-put variable changes As existing SUPAC already suggests, this method can be used to justify scale-up and post approval changes in lieu of BE studies

Possible relationships between dissolution and drug exposure in subjects Case C

0

% change in-vivo pK-parameter

-20

Case C
-40

-60

% drug dissolved in-vitro time per time unit (min)

Case C

Suggests IVIVR or even IVIVC possible

setting the disso spec to the slowest acceptable profile. Any result above appears to provide adequate in-vivo performance Any dissolution result below the proposed spec may indicate non-acceptable change Since IVIVC possible one can directly assess the extent of the pK-changes

Conclusion

Part A of this presentation highlights the use of prior knowledge, QbD tools and good science to assure consistent product quality Establishing IVIVC/R provides most direct link to bioperformance

Stronger link between in-vivo and in-vitro performance as compared to using empirical approaches (F2) Might be costly up-front investment

QbD frame-work allows for regulatory flexibility this should be a strong incentive

But remember- achieving IVIVC/R might not always be possible at least with the current in-vitro and in-silico tools available

Acknowledgements

Bill Bowen Steve Biffar Kim Gallagher John Higgins Brian Hill Craig Ikeda Kiki Luna Yun Mao Eric Nelson Robert Reed Denise Thomas Mark Thompson Qingxi Wang Conrad Winters Pete Wuelfing

Thank you!

References

W. E. Bowen, Q. Wang, W. P. Wuelfing, D. L. Thomas, E. Nelson, Y. Mao, B. Hill, M. Thompson, R. A. Reed, A Biopharmaceutical Classification System Approach to Dissolution: Mechanisms and Strategies, in Biopharmaceutics Applications in Drug Development" by R. Krishna and Lawrence Yu (Editor); Springer, 2008, 290 P.A Dickinson, Wang Wang Lee, Paul W. Stott, Andy Townsend, John Smart, Parviz Ghaharamani, Tracey Hammett, Linda Billet, Sheena Behn, Ryan C. Gibb, Bertil Abrahamsson, AAPS Journal, Vol. 10, No. 2, June 2008, p.380-390 Paul Dickinson et al. (2009), Applied Biopharmaceutics and QbD for Dissolution/ Release Specification setting: Product Quality for Patient Benefit Amidon, G.L., H. Lennerns, V.P. Shah, and J. R. Crison, "A theoretical basis for a biopharmaceutics Drug Classification: The correlation of in vitro drug product dissolution and in vivo bioavailability." Pharmaceutical Research 12 (3, March), 413-420, 1995