Stability

Pharmalytik©

Key Factors to Design Quality Stability Program for Drug Product and API

Kim Huynh-BaPHARMALYTIK

AAPS_0409: 2Pharmalytik©

OVERVIEW

• Stability role in the drug development process

• Review cGMP and ICH stability requirements

• Develop Global Stability Protocols

• Design stability program by Phases of Development

• Presentation will focus on small molecules.


Goals of Stability Testing

• ACTIVE PHARMACEUTICAL INGREDIENT (API)– To establish a retest date for API

– Data to support setting API specifications

– Data to support submission of drug product

• PHARMACEUTICAL DRUG PRODUCT– Data to support setting specifications for drug product

– To establish a shelf-life for the commercial product


Critical Role of Drug Stability• Quality must be established for identity, strength, quality and

purity (CFR 211.137) to assure Safety and Efficacy during its shelf life when stored under the intended labeled condition.

• Safety and Efficacy of drug product are established during development via clinical studies

• If drug product stability changes beyond established acceptance criteria, established safety and efficacy are no longer applicable.

• Change of Drug Stability would risk patient safety– Quality of finished products decrease– Potential sub-potent or over-dose products– Potential toxic unknown impurities– Potential new degradants of unknown toxicity

• Uncontrolled process → product investigation → product recalls• cGMP violations → consent decree → criminal prosecution


Drug Product Stability

• Stability characteristics of API or Drug Product is a critical quality attribute of pharmaceutical product

• Stability Studies are used to:– Establish how product changes over time under critical

environmental factors (temperature, heat and light)

– Determine appropriate product specifications

– Select marketing container closure system

– Determine appropriate storage conditions

– Justification of expiry of commercial product

– Provide necessary medical supplies


Factors affecting Drug Stability

• Stability of the API from storage

• Interaction between the API and excipient – Form. Dev.

• Selection of dosage form

• Manufacturing process of drug product

• Selection of container closure packaging system

• Effect of storage (temperature, humidity and light)

• Selection of marketing image

• Handling of the finished products


DRUG DEVELOPMENT PROCESS

Excipients

•API Stability•Process impurity

•Packaging interaction•Storage conditions•Storage configuration

•Drug Product Stability•Excipient compatibility•Formulation interaction

PACKAGING SELECTION

FORMULATIONDEVELOPMENT


Drug Development Process

Years

TestPopulation

Purpose

SuccessRate

3.5

Lab andAnimal Studies

Safety, biological

activity and formulation

5,000 evaluated

DiscoveryPre-clinical

1.5

20 - 100healthy

volunteers

Safety and

Dosage

5 enter clinical trials

Phase I Phase II Phase III

EvaluateEffective-

ness,look for

side effects

Confirm effectiveness,

monitor adversereactions fromlong-term use

1,000 - 5,000patient

volunteers

100 - 500patient

volunteers

3.52

Clinical Trials

File IND

File NDA

Rev

iew

and

App

rova

l

Additionalpost-

marketingtesting

requiredby FDA

1

1.5

Phase IV


Purpose of Stability Testing• The purpose of stability testing is to provide

evidence on how the quality of a drug substance or drug product varies with timeunder the influence of a variety of environmental factors such as temperature, humidity and light.

• Stability testing permits the establishment of recommended storage conditions, retest periods, and shelf-lives.

– ICH harmonized Tripartite Guideline for Stability Testing of New Drug Substances and Products [ICH Q1A]


211.166 Stability Testing

• Stability program must be written and followed:

– (a) used in determining appropriate storage conditions and expiration date.

– Written program must include: Sample size and test intervals, Storage conditions for samples,

– Reliable, meaningful, and specific test methods,

– Testing of drug product in marketed container,

– Testing of drug product for reconstitution at dispensing time and reconstituted time.


211.166 Stability Testing

• (b) An adequate number of batches must be tested to determine an appropriate expiration date. A record of such data must be maintained.

• Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates.

• Full shelf-life studies, if not available, are being conducted.


211.137 EXPIRATION DATING

(a) To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in Sec. 211.166.

(b) Expiration dates shall be related to any storage conditions stated on the labeling, as determined by stability studies described in Sec. 211.166.


International Conference on Harmonization (ICH)

• Purpose: To provide a forum for dialogue between Health Authorities and Industry on the disparities with respect to requirements of US, Europe and Japan (Zone 1 & 2)

• Goal: To develop guidelines that are acceptable for regulatory review by US, Europe and Japan

• ICH Steering Committee: 6 Parties– PhRMa, FDA, – EFPIA, EU, – MHLW, JPMA– and IFPMA (non voting member)– Official Observers: Canada, WHO, EFTA– Interested Parties: Pharmacopeia, IGPA, WSMI


5 Major Steps in ICH Process

STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

ConsensusBuilding

By EWG ConsensusAgreed

by 6 parties

RegulatoryConsultation

AdoptionOf ICHGuideline

Implemen-tation

Harmonizing Stability Storage Conditions

Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best PracticesK. Huynh-Ba (ed.), Springer, Springer, November 2008, Chapter 2.


ICH Guidances•M4: Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human Use (CTD) (October 2001);•Q1A(R2): Stability Testing of New Drug Substances and Products (November 2003);•Q1B Photostability Testing of New Drug Substances and Product (November 1996);•Q1C Stability Testing of New Dosage Forms (May 1997);•Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (January 2003);•Q1E Evaluation of Stability Data (June 2004);•Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV, Revision 1 (July 2004);

•Ref: US FDA, Guidance for Industry on Chemistry, Manufacturing, and Controls Informations; Withdrawal and Revision of Seven Guidances, Federal Register 71 (105), 31194-31195 (June 1, 2006) DOCID: fr01jn06-73


ICH Storage Conditions

12 months- 20 ºC/ ambientLong TermFreezer

6 months25 ºC/60%RHAccelerated

12 months5 ºC/ ambientLong Term

Refrigerated

6 months40 ºC/75%RHAccelerated

6 months30 ºC/65%RHIntermediate*

12 months25 ºC/60%RHLong Term

RoomTemperature

Submission Requirement

Study ConditionStability StudiesIntendedStorageCondition

* Significant change


Significant Change

5. Dissolution exceeding the acceptance criteria for 12 dosage units.

4. The pH exceeding its acceptance criteria; and

3. Failure to meet acceptance criteria for appearance and physical properties (e.g., color, phase separation, resuspendibility, delivery per actuation, caking, hardness); and as appropriate to the product type;

2. Any specified degradant exceeding its acceptance criteria

1. A 5 percent potency change from the initial assay value;

DrugProduct

Significant change is defined as failure to meet the specification.

API


Global Climatic Zones

• Zone I: Temperate less than 20oC– e.g. Germany, Russia, Canada

• Zone II: Sub-tropical with possible high humidity– averaging 20.5-24oC

– e.g. France, Peru, Australia, USA

• Zone III: hot and dry– e.g. Botswana, Chad, Syria, Iraq

• Zone IV: hot and humid– averaging more than 24oC

– e.g. Taiwan, Singapore, India, parts of South America


WHO Meetings• WHO Draft Guidance – Nov 2003

– Zone IV --long term testing at 30°C/65% RH

• Association of Southeast Asian Nations (A.S.E.A.N.)

Cambodia, Brunei, Indonesia, Laos, Malaysia, Philippines, Singapore, Thailand, Vietnam.

WHO Decision - 2005Split current Climatic Zone IV into

– IVA – long term testing at 30°C/65% RH– IVB – long term testing at 30°C/75% RH

Members decide of which condition


Why?

• Storage conditions listed in ICH and WHO guidelines based on average values in 23 cities

• Conditions of other cities are more stressful in term of temperature and humidity not representative

• Poor storage conditions, especially in rural areas.• Average temperature and humidity is 27ºC and 79%RH• Recommend long term storage to be 30ºC/75% RH, and 40 ºC/75%

RH for accelerated condition – June 2004• This condition is also preferred by some South American countries

such as Brazil

• ASEAN prefers more stressful condition than 30°C/65% RH. Chosen condition reflects extremes rather than average as ICH.


Typical Global Stability Protocol

DLOH5 C

XXXXXXXX25 C

60%RH

XXXXXXX(X)30 C

65%RH

XXXXXXX(X)(30 C

75%RH)

XXX40 C

75%RH

X50 C

(X)Photo

36mo24mo18mo12mo9mo6mo3mo2mo1moTZCond.

Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer, Springer, November 2008


Global Stability Summary

• Registration Storage Conditions– Long-term (ICH) 25C/60%RH

– Intermediate (ICH) 30C/65%RH (HOLD)

– Long-term (WHO) 30C/65%RH

– Long-term (ASEAN & Brazil) 30C/75%RH

– Accelerated (ICH & WHO) 40C/75%RH

• Other stress conditions– 30C/90%RH

– 50C

– 60C

• Ideally, a global stability program for all registrations of a drug product

– Photostability

– Freeze-thaw

– Thermal cycling


Environmental Chambers

• Two basic types: Reach-In and Walk-In

Reach-in chambers can be a self-contained units with good profile control, but have limited space.

Walk-in chambers have more storage space but are more difficult to control and validate

All chamber units must have temperature and humidity control over a defined range with suitable tolerances to meet ICH specifications. Must have continuous monitoring of parameters to allow documentation of chamber integrity at all times.


Key Factors of Stability Chambers

• Chamber should be calibrated to appropriate technical specs.• Chamber should be validated with profiling matrix.• Temperature and humidity should be recorded continuously.• SOPs for operation of chamber should be prepared and

controlled.• Units should have logbooks for maintenance and repairs.• Units should have secured access to prevent tampering.• If electronic information is collected, the system should be

compliant with 21CFR11 requirements.• Alarm and backup systems should be in place to detect power

failures and prevent station from crashing.• Procedures should be in place for man-made or natural

disasters.


Selection of batches

Must commit to put up 3 production batches with same protocol

Stability Commitment

Same to proposed commercial packagingContainer Closure

Similar to those used in pre-clinical and clinical studies

Acceptance Criteria

Representative of Commercial ProductionManufacturing Process

3 batches/strength(2 pilot + 1 lab scale)

3 batches(pilot scale)

Selection of Batches

DRUG PRODUCTAPI


Key Factors of Q1A(R2)

• Must use Validated Stability-Indicating analytical methods• Methods must cover physical, chemical, biological and microbiological attributes• Studies evaluated under thermal and elevated humidity to cover storage, shipment and subsequent use• Accelerated and intermediate used to evaluate impact of short-term excursions.• Acceptance criteria should include individual and total upper limits for impurities and degradation productsNo formal statistical analysis is needed if data show little

degradation or variability.


ShelfShelf--Life ProjectionLife Projection•• The shelf life is the time point where the 95 % confidence interThe shelf life is the time point where the 95 % confidence interval for val for

the regression line crosses the specification.the regression line crosses the specification.


Example 2 Example 2 -- One Batch One Batch


Q1E examplesQ1E examples


ShelfShelf--Life ProjectionLife Projection--Multiple batchesMultiple batches


Multiple BatchesMultiple Batches


Example Example -- Multiple BatchesMultiple Batches


Important Dates of Stability Study

Batch Manufactured

Release Testing

Stability Scheduled Testing

Drug Product Expiry

Expiration Date(Study End Date)

ReleaseDate

Stability Pull DatesManufacturing

Date

Study Start Date

TZ Testing

Packaging Date

Stability Testing in Pharmaceutical Development Handbook: Regulations, Methodologies and Best Practices, K.Huynh-Ba, ed., Nov. 2008.


Considerations for Generics•OGD believes that stability of drug products is best ensured through Quality by Design (QbD)

•OGD’s Question-based Review (QbR) covers quality by design

•Include stress testing studies or studies incorporated by DMF reference

•Stability data is still needed to verify quality product quality and establish a shelf-life consistent with that quality

•Three batches if it is a complex drug product

One batch

One batch

# of Batches

3 months(0, 1, 2, and 3 months)

40°C ± 2°C75% RH ± 5% RH

Accelerated

Additional data as it becomes available

25°C ± 2°C60% RH ± 5% RH

Long-term

Minimum data at submission

Storage ConditionStudy


Considerations for OTC•Draft guidelines from CHPA available in March 2004 for OTC Drug Products in the U.S. (that are not regulated by an NDA/ANDA).•Draft guidelines for changes to OTCs (major, moderate, minor)•Reduce some stability burden especially for those with extensive experience and history and excellent safety profiles.

LT – 5 pointsAccel – at least 3 pts

LT – 8 pointsACC – 4 points

Testing Intervals

May beAt least 1 BatchPhotostability

Accelerated3 Months Data

Long Term & Accelerated12 Months Data

Expiry Dating

1/10th Scale (justification needed for smaller size)

2 at 1/10th scale3rd may be smaller

Batch Size

At least 13# Batches

CHPA SWG Guideline(for OTCs)

ICH Q1A(R2)(for NCEs)

Pharmalytik©

Design Stability Program by Phases


Design Program by Phases

• Stability Program varies depending on the phase and clinical study it supports

• Stability Study Goals...– Identify problems early – Know your product– Minimize repeat study– Identify critical control attributes

• i.e., Particle size• Develop a stable commercial product• Maintain database--stability informatics• Establish systems to cycle back learning • Develop stability strategies to expedite product

development


Pre-Phase I strategies...

• Identify problems early– Test drug substance stability at:

• 25 °C (sealed glass ampul (SGA))

• 25 °C/85%RH (open container)

• 40 °C (SGA)

• 40 °C/75%RH (open container)

• 40 °C plus 5% water

• 60 °C (SGA)

• 60 °C plus 5% water (w/w)

• ICH photostability

• twice ICH photostability


Early Phase strategies...

• Know your product– Aqueous solubility

– pH-solubility profile

– Solubility in various solvents used in AMES

– Hygroscopicity

– Crystallinity (XRPD, Polarized light microscopy)

– Thermal Analysis (DSC, TGA)

– Excipient compatibility studies (start early Phase I)


Phase I Strategies...• Goals

– Reduce cycle time

– Get into man fast

– Determine pK and tolerability

• Pick the best in a cluster nomination

• Select formulation to minimize development time

– Standard solid dosage formulations

– Powder in a bottle (PIB)

– Liquid filled gel caps

• Begin work on Phase II dosage form--solid, liquid, etc.

• Understand the stability of your product


Powder in a Bottle (PIB)• Drug substance in a bottle

– Constitute at site as solution or suspension prior to oral administration to subjects

– Constitute with commercially available Vehicles--Simple Syrup; sodium lauryl sulfate (SLS), etc.

• Advantages:– Uses same methods as used for drug substance– Uses stability of drug substance to support product and

establish retest date– Demonstrates stability in solution and no interference

from excipients– Gives formulators opportunity to develop Phase II

dosage form in parallel


Phase I/II Stability Protocol

XXXXX(X)X25 C

60%RH

XXXXX(X)(X)(30 C

65%RH)**

XX(X)X40 C

75%RH

X40 C/75%RH

(Exposed)

End of Study

12mo9mo6mo3mo2mo1moTZConditions

**30 C/65%RH if clinical study is done in Zone III/IV


Phase II/III Stability Protocol

• Stability profile of clinical materials must be monitored

• Test stations– 25 °C/60%RH

– 30 °C/65%RH (if trial conducted in zone III and IV)

– 40 °C/75%RH (Open Dish, 2 wks, 1mo)

– 40 °C/75%RH

– ICH Photostability (Open Dish & in container)

• What packaging will be required– Is your product moisture, light or heat sensitive

– Desiccant needed/filler


Phase II Strategies and Goals...

• Finalize formulation and process• Finalize drug substance process• Define market image (Product definition, Packaging)• Develop global stability protocol• Support clinical trials• Prepare for End-of-Phase II meeting

– Enough stability data to support matrixing or bracketing design if desired

– Microbiology testing needed? Moisture? Chiral purity• Scale-up/Optimization of process parameters

– Stability studies on product made at the extremes of process asdefined by experimental design

– Wet granulation/Compression force• Demo/scale-up batch

– On stability one to three months prior to start of Phase III


Phase III Strategies...• Manufacture submission batches (representative of commercial

production)– 12 month stability by time of filing

– Cover zone III and IV and Japan

• Three batches per strength– 2 at least pilot-scale (NLT 10%) - >100,000 units

– 1 lab-scale (25,000-50,000 units)

• In the container and closure proposed for marketing

• Implement global stability protocol

• Outsource stability testing if needed

• Automate as possible

• Data to support setting specifications


Typical Phase II/IIIStability Protocol

(x)Photo

XXXXXXXX25C

60%RH

DLOH30C

65%RH

XXXXXXXX(30C

75%RH)

XXX40C

75%RH

36mo(EOS)

24mo18mo12mo9mo6mo3mo2mo1moTZCond.

30C/75%RH if clinical study is done in Zone III/IV


Stability Testing Recommended

1. ICH Photostability: Test 1st lot in open dish. Test immediate package on if significant change.

2. 30°C/65%RH : HOLD, to be tested if 40°C/75%RH meets ICH significant change criteria. If clinical study is done at Zone 3 or 4, test 30°C/65%RH at 9, 12, 24 and 36 or LPO.

4. X-ray powder diffraction: Test 1st lot at 25°C/60%RH (TZ, 12, 18, 24 and 36) and 40°C/75%RH (6 mo)

5. Chiral assay: Test 1st lot at 25°C/60%RH (TZ, 12, 18, 24 and 36)


Global Protocol NDA/MAA Considerations

• Conforms to ICH and regional guidelines, especially storage conditions)

• Generate data to support registrations worldwide (all 4 climate zones)

• Global Packaging, Container/closure requirements, including regional specific packages

• Support registration of drug substance & drug product - Analytical Tests and Global Specifications

• Ideally, a global stability program for all registrations of a drug product


Typical NDA/MAAStability Protocol

DLOH5 C

XXXXXXXX25 C

60%RH

DLOH30 C

65%RH

XXX40 C

75%RH

X50 C

(X)Photo



Typical Global Protocol(For all 4 zones)

DLOH5 C

XXXXXXXX25 C

60%RH

XXXXXXX(X)30 C

65%RH

XXXXXXX(X)(30 C

75%RH)

XXX40 C

75%RH

X50 C

(X)Photo


Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer, Springer, November 2008


Testing Recommended

• ICH Photostability: open dish testing on 1st lot. • 5°C: Sufficient samples must be placed at this condition to allow for

testing at 4 timepoints.• 30°C/65%RH : HOLD, to be tested if 40°C/75%RH meets ICH

significant change criteria. • X-ray powder diffraction: Test first lot at 25°C/60%RH annually and

40°C/75%RH (6 mo)• Chiral assay: Test first lot at 25°C/60% every 6 months • Microbial bioburden: test at least one lot at 25°C/60%RH (TZ) unless

data supports not testing. If moisture is 2 x TZ and water activity is NLT 0.6, test at 25°C/60%RH every 6 months

• For liquid, extractable at TZ and EOS (plastic containers only) when package and label adhesives are defined for the marketed product.


Special Storage Conditions

• Liquids in Semi-Permeable Containers

– Long-Term: 25oC/40±5%RH (Zone I/II) or

30oC/35±5%RH (all zones)

– Intermediate: 30oC/65±5%RH

– Accelerated: 40oC/NMT25%RH

a. or 25C/60RH and calculate wt. loss equiv. to 25C/40RH

b. if 30C/35RH is long-term condition, no intermediate condition is needed

c. Test one lot exposed at 40°C/NMT 25%RH for aqueous only; not needed for impermeable containers.


Adverse Shipping Conditions

• Thermal Cycling– e.g., 40oC, 4 days, then 25oC/60%RH, 3 days

– Repeat cycle twice

– Perform full testing at end of complete cycling

– Helpful in addressing questions from marketing and sales

• Freeze-Thaw Cycling– e.g., -20oC, 4 days then 25oC/60%RH, 3 days

– Repeat cycle twice

– Perform full testing at end of complete cycling


Additional Considerations

• Based on developmental info, add time points around expected expiry to improve confidence in shelf-life estimates

• If time permits, extend studies for longer shelf-life

• Climatic Zones III & IVa– Continue testing at 30oC/65%RH for establishing

shelf-life

• Continue 40oC/75%RH testing to 12 months


Benefits of Global Stability Program

• Improve efficiency

– All tests are done at the same time

– All tests are conducted at the same site/lab

– Good use of testing resources

– Avoids repeat testing due to regional packages

– Reduce cycle time

– Improve consistency

– Improve quality


Cycle Diagram

AnalyticalMethods

Protocols

SOPs

DataReports

Metrology

cGMP, ICH, Global

Stability Program


Conclusion• Understand the Regulatory Requirements versus Scientific

Requirements

• Understand stability role in the drug development process

• Stability profile needs to be established for drug product to assure safety, efficacy and quality.

• Design strategy for stability study based on data of development batches

• Need to understand the product to design Formal stability studies

• Develop stability program and maximize efficiency


STABILITY NETWORKS

• AAPS Stability Focus Group

• Pharmaceutical Stability Discussion Group

• Upcoming Meetings:– Stability Workshop, Bethesda, MD – Sep. 09

– AAPS Annual Meeting, Los Angeles, CA – Nov. 09

– EAS Annual Meeting, Somerset, NJ – Nov. 09


References• “Handbook of Stability Testing in Pharmaceutical Development:

Regulations, Methodologies and Best Practices”, Kim Huynh-Ba (ed.), Springer Springer Science and Media PublishingScience and Media Publishing, available November 2008, ISBN: 978-0-387-85626-1 www.springer.com or www.amazon.com

• Molzon J. (2007), FDA, “Current International Harmonisation Efforts: Opportunities and Challenges - A Regulator's Perspective”.

• Kopp S. (2007), WHO, “Update on WHO Guidelines”.• Slamet L. (2007), National Agency of Drug and Food Control, Indonesia,

“Requirements for South East Asian Markets”.• Saleh A. (2007), WHO EMRO, “Regional Guidelines on Stability Testing of API

and Pharmaceutical Products for the Eastern Mediterranean Region”.• Zahn M. et al. (2006), 3RPharma “A risk-based approach to establish stability

testing conditions for tropical countries”, Journal of Pharmaceutical Sciences 95: 946-965 / Erratum 96: 2177 (2007)

• G. Buehler (2007), FDA OGD, “Regulatory Requirements for Stability Testing of Generics”.

• J. Needels & M. Seibel, Novartis & Procter Gamble, “Stability Design for Consumer Healthcare Products”.

• W. Grimm (1987), “Stability Testing of Drug Products”.


THANK YOU!!!THANK YOU!!!

•Any question?

Kim Huynh-BaPHARMALYTIKKim.huynhba@pharmalytik.comwww.pharmalytik.com

Stability

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