phase 1: formulating for success goals for phase i (first-in-human) studies koppenol, aaps, 2015,...

Phase 1: Formulating for Success

Sandy Koppenol, PhD Gilead Sciences, Inc. (Foster City, CA) AAPS Sunrise Session Wednesday, October 28, 2015

The Goals for Phase I (First-in-Human) Studies

Koppenol, AAPS, 2015, Sunrise Session

Phase 1

– Test a new drug or treatment in a small group of humans to evaluate safety, determine a safe dose range, and identify side effects.

– Typically this is done in two parts, 1.) single-ascending dose followed by 2.) multiple-ascending dose study.

– Performed in a well-controlled clinic where subjects are closely monitored.

2

The Role of the Formulation Scientist in Phase I Studies

Provide a dosage form that allows evaluation of the safety of subjects in the proposed study.

– Provide dose flexibility (OK to dose multiple tablets/capsules)

– Use excipients with known safety profile

– Be manufactured using a well-controlled process under GCP /GMP

– Must be chemically/physically stable

– Develop acceptable limits and analytical methods to assure the identity, strength, quality and purity of the drug product

FDA Guidance, “Content and Format of Investigational New Drug Applications for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products.” November 1995

Koppenol, AAPS, 2015, Sunrise Session 3

Challenges for the Formulation Scientist in Phase I Studies

Challenges for the development of the Phase 1 formulation scientist

– Uncertain/changing wide dose range

– Limited amount of representative drug substance (API)

– Limited knowledge of API physical/chemical characteristics

– Limited stability data available on API ± excipients

– Short timelines

– Balancing resource commitment vs. likelihood of success


The Drug Must be in Solution to be Absorbed


The Most Common Oral Formulation Options for Phase 1

Powder in Bottle API in Capsule

(Blend/solution)

Tablet

Advantages • Fast

• Small amount of API

• Manufacture at the

API site or weighed

at the clinic

• Fast

• Small amount of API

• Have PK data on a

solid dosage form

• Have PK data on

intended dosage

form

• Faster transition

to Phase 2

Disadvantages • May need

taste/color-masking

for placebo

• Not acceptable for

Phase 2

• Likely need to do an

rBA study to

transition to Phase 2

dosage form

• Formulation

development has

been delayed

• Not ideal for Phase

2

• Likely need to do an

rBA study to

transition to Phase 2

dosage form

• Formulation

development has

been delayed

• Requires more

development time

• API needs are

larger

• Must be

manufactured in

advance of the

clinical trial


Powder in Bottle (PIB)

Typically put 8 to 10 doses in one bottle

Can be reconstituted to a solution or suspension

Diluents/suspending agents

– Water or juice

– Ora-sweet: may provide taste-masking

– Ora-plus: suspending agent

Suspension challenges

– Particle size can impact bioavailability

– Need to demonstrate uniformity of dosage units

– Suspension may require homogenization

– Recovery of the dose may require rinsing of oral syringe/dose cup

– Placebo must be blinded with insoluble powder

Manufacture

– API manufacturer can usually weigh bulk powder into a bottle

– Phase 1 clinical site pharmacy will perform reconstitution


API (Powder or Solution) in Capsule

Manual Filling

– Can be performed in Phase 1 pharmacies as a compounding operation*

– Analytical balance limitations for dose.

*USP <795>

Automated Filling with Capsugel’s Xcelodose

– Must be manufactured under cGMPs

– Can fill as low as 100 mcg

– Capable of filling up to 600+ capsules/hour


Prototype Solid Dosage Form

Likely need 2 to 3 unit doses to span Phase 1 dosing range (10-100x)

Excipient compatibility

– Diluents: Lactose, Mannitol, Microcrystalline cellulose, Dicalcium phosphate

– Binders: HPMC, HPC, PVP

– Disintegrant: croscarmaellose Na, Crospovidone

– Lubricant: Mg stearate, stearic acid

Development of tablet need 0.5kg+ of a granulation/batch

– Direct compression

– Dry or wet granulation

Clinical batches must be manufactured under cGMPs


Analytical Methods, Stability and Specifications for Tablets

Analytical method development

– Blend and content uniformity

– Dissolution

Stability

– In-use stability of reconsitituted solutions and suspensions must be examined

– ICH stability protocols are recommended for the dosage form provided to the clinic (ICH Q1A).

Specifications for excipients and drug product


Test Acceptance Criteria

Appearance Round, plain-faced, film-coated, white tablets

Identification by HPLC Consistent with reference standard

Water Content Report

Strength by HPLC 90.0-110.0% of Label Claim

Impurity Content

Uniformity of Dosage Units Meets current USP<905>

Dissolution Report amount dissolved at 15, 30 and 45 min

Microbiological Examination Meets current USP

Regulatory Requirements for Tablets

Regulatory requirements*

– Pharmaceutical development and manufacturing

Section 3.2.P.2 Pharmaceutical Development

Section 3.2.P.3 Manufacture of Drug Product

– Acceptable limits and analytical test methods must be described.

– Certificate of Analysis must be provided

– Information to support the stability of the drug product packaged in the proposed container/closure and storage conditions for at least one month


*FDA Guidance, “Content and Format of Investigational New Drug Applications for Phase 1 Studies of Drug, Including Well-Characterized, Therapeutic, Biotechnology-derived Products.: November 1995.

Case Study 1: API Solution-Filled Capsule

Dose range for Phase 1: 5 to 250 mg

BCS Class I/II compound

API is amorphous

– Tg (dry) = 56°C

– Spray drying yields are low

– Solid is hygroscopic

– Compound has a bitter taste


Aqueous

Solubility

(mg/ml)

P/ (x10-6

cm/s)

A to B

P/ (x10-6

cm/s)

B to A

Ratio

0.66 2.10 6.72 3.2

Solution Formulation has Good Oral Bioavailability in Monkeys

Species Formulation Dosing Route Dose Level AUC (ng.h/ml) F % (estimate) CV%

Rat PEG 400 Solution Oral

Intravenous

10 mg/kg

10 mg/kg

278

5808

5 N/A

Dog PEG 400 Solution Oral 10 mg/kg 22786 74

Monkey PEG 400 Solution Oral

Intravenous

10 mg/kg

10 mg/kg

12257

18197

50 40

50

Formulate compound as a solution for optimal bioavailability and because of difficult physical properties of API.


Hard Gelatin Capsules can be Filled with Certain Solvents


Propylene glycol and low MW PEGs are hygroscopic and cause the capsule to soften but can be used when dosing is completed within a short time window.

Capsules Were Filled Manually at the Phase 1 Pharmacy


Powder in bottle was supplied to the Phase 1 pharmacy • Each bottle contained a pre-weighed

quantity of API to make 10 unit doses (1 bottle per clinical cohort)

• API was weighed into bottles by the API manufacturer using a batch record

• Weight was checked by 200% inspection • Bottles were released by QA based on batch

record and ID and appearance testing.

Solution was prepared by adding specified amount of PEG400 and shaking at RT overnight.

Capsules are filled and dispensed by the Phase 1 pharmacy • Compounding instructions and preparation

worksheets were created. • Capsules were filled based on weight and

density of the drug solution. • Weight was checked by 200% inspection • All steps are documented in worksheets • Capsules were stored upright and

administered to the patient within 12 hours • QA reviews the worksheets.

API Solution-Filled Capsule has Good Oral Bioavailability

Species Formulation Dosing Route Dose Level AUC (ng.h/ml) F % (estimate) CV%

Rat PEG 400 Solution Oral

Intravenous

10 mg/kg

10 mg/kg

278

5808

5 N/A

Dog PEG 400 Solution Oral 10 mg/kg 22786 74

Monkey PEG 400 Solution Oral

Intravenous

10 mg/kg

10 mg/kg

12257

18197

50 40

50

Human Gel capsule with PEG

400 Solution

Oral 100 mg

250 mg

24881

42207

55

13


Case Study 2: Prototype Tablet

Dose range for Phase 1: 0.1 to 9 mg

BCS Class I compound

Weak base

API has good physical properties

– Crystalline, Tm = 165°C

– Non-hygroscopic:1.4% water at 25°C/90% RH

– Small particle size of the API: d50 = 4.39µm

0.5 kg of API available

Good oral bioavailability from a powder in capsule in dog model


Formulation (Dog PK) Average AUClast (nM*hr) Average Cmax (nM)

0.25mg/Kg PIC 1120 ±415 583 ±209

0.25mg/Kg solution 1563 ±663 334 ±88

Excipient Compatibility Studies

Ingredient Function %w/w

Drug 1 1 1

Lactose Diluent 43

Mannitol Diluent 43

Dicalcium Phosphate Diluent 43

Microcrystalline Cellulose Diluent 50 50 50

Croscarmellose Sodium Disintegrant 5 5 5

Magnesium Stearate Lubricant 1 1 1

Final Blends and

compacts were stored

at:

• 40ºC/75%RH

(open and closed)

• 60ºC closed

18


Drug 1 1

HPMC Binder 5

PVP K30 Binder 5

Mannitol Diluent 38 38

Microcrystalline Cellulose Diluent 50 50

Croscarmellose Sodium Disintegrant 5 5

Magnesium Stearate Lubricant 1 1


Drug 1 1

Mannitol Diluent 43 43

Microcrystalline Cellulose Diluent 50 50

Croscarmellose Sodium Disintegrant 5

Crospovidone Disintegrant 5

Magnesium Stearate Lubricant 1

Stearic acid Lubricant 1


Phase 1 Film-Coated Tablet Formulation

19

Components

Composition

0.1 mg 1 mg 5 mg

% w/w mg/tablet % w/w mg/tablet % w/w mg/tablet

Intragranular

Drug 0.1 0.1 1 1 1 5

Diluent 1 50 50 50 50 50 250

Diluent 2 45.9 45.9 45 45 45 225

Disintegrant 3.0 3.0 3.0 3.0 3.0 15

Lubricant 0.5 0.5 0.5 0.5 0.5 1.5

Extragranular

Lubricant 0.5 0.5 0.5 0.5 0.5 1.5

Total 100 100 100 100 100 500

Tablet Coating

Opadry blue 3 3 3 3 3 15

Total 103 103 103 103 103 515


Development Lot Stability Protocol

Materials

– 0.1 mg tablets

– 1 mg tablets

– 5 mg tablets

Container/closure: 30 count tablets in a 60 cc white, high density polyethylene (HDPE) bottles with polyester fiber coil, capped with a white, continuous thread, child-resistant, polypropylene screw cap fitted with an induction-sealed, aluminum-faced liner.

Tests: Content uniformity (T0), Strength, Impurities/Deg products, Dissolution, Disintegration, and water content

20

Time (months)

T0 0.5 1 2 3 6 9 12

Condition

25 ºC/60%RH X

X X X X X

40 ºC/75%RH X X X

40 ºC/75%RH, open X X X


Even Though The Tablets Reach >80% Dissolved at 15 Minutes, the Oral Bioavailability in Dogs is Lower Than a Solution

21

Formulation (Dog PK) Average AUClast (nM*hr) Average Cmax (nM)

0.25mg/Kg* PIC 1120 ±415 583 ±209

0.25mg/Kg solution 1563 ±663 334 ±88

0.25mg/Kg

1 mg tablets, 3 tablets/animal 732 ±158 265 ±93

Dissolution conditions: Type II apparatus with 50 mM sodium citrate buffer, pH 5.5 with 0.5% SDS

with 75rpm paddle speed

* ¼ of the clinical dose Koppenol, AAPS, 2015, Sunrise Session

Prototype Tablet Shows Good Bioavailability in Humans with Dose Proportional AUC and Cmax

S/MAD : Doses are 0.1, 0.3, 1, 3 and 9 mg (SAD only), MAD dosing is 10 days

– Single doses exhibit dose-proportional PK over the studied dose range

– Multiple dose plasma concentrations suggest moderate accumulation

– The terminal half-life is approximately 16 hours

– No significant safety observations

22 Koppenol, AAPS, 2015, Sunrise Session

Summary

Phase 1 studies are challenging

– require flexibility in dosing and may require large dose range

– Limited time and material

– Difficulty to predict dose linearity from animal models and in-vitro dissolution

– Not a lot of information available on the physical/chemical properties of the API

– Analytical methods not optimized

There are 3 common approaches to Phase 1 oral formulations

– Powder in bottle

– API in capsule

– Prototype tablet

Opportunities

– Phase 1 formulation scientists work closely with clinicians to optimize the drug product for safety and bioavailability

– Good early understanding of the physical/chemical properties of the API and the link to product performance can accelerate products to the market. Koppenol, AAPS, 2015, Sunrise Session 23

phase 1: formulating for success goals for phase i (first-in-human) studies koppenol, aaps, 2015,...

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