Transcript HG067-2.27_Stability Program

Stability Programs from
Development to Approval
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211.166 Stability testing.
There shall be a written testing
program designed to assess the
stability characteristics of drug
products. The results of such
stability testing shall be used in
determining appropriate storage
conditions and expiration dates.
Course Agenda
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Stability Before Clinical Trials

Discovery Research

Pre-clinical development
Stability During Clinical Trials

Early and Mid Clinical Development (IND Phases 1-2)

Late Clinical Development (IND Phase 3)
Stability for Marketed Products

The “Peri-approval” Period

Mature Products
Special Topics

Biotech/Biologics Stability, Evaluation of Stability Data;
Bracketing and Matrixing; OOS and OOT; Inspection Prep;
Outsourcing, etc.
Resources
Wrap-up and Conclusions
Pharmaceutical Development
Phase
 Pre-clinical
 Phase 1
 Phase 2
 Phase 3
 Post-approval


“Peri”-approval (Phase 4)
Mature Product
FAR = Field Alert Report
BPDR = Biological Product
Deviation Report
Regulatory Filings
 Phase 1 IND at end
 Phase 2 IND at end
 Phase 3 IND at end
 MAA at end of phase
 Reports
 Supplements/Amendments
 Annual Reports
 New Approvals
 FARs and BPDRs
Product Lifecycle and Events
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Discovery
Pre-clinical
Pre-IND meeting
Clinical Phase 1 (IND Filing)
End of Phase 1 Meeting
Clinical Phase 2 (IND Filing)
End of Phase 2 Meeting
Clinical Phase 3 (IND Filing)
End of Phase 3 Meeting
MAA Filing
Pre-Approval Inspection
Peri-approval/Post Approval
Annual Report
GMP Inspection
Development
Commercial
Terminology and Definitions
U.S. Acronyms

FDA

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CBER


FDA Center for Drug Evaluation and Research
CDRH


FDA Center for Biologics Evaluation and Research
CDER


U.S. Food and Drug Administration
FDA Center for Devices and Radiologic Health
ORA

FDA Office of Regulatory Affairs
More U.S. Acronyms

CMC


FOIA


FDA Investigative New Drug (application)
BLA


U.S. Freedom of Information Act
IND


The Chemistry, Manufacturing, and Controls section
of an Application
FDA Biologics License Application
NDA

FDA New Drug Application
European Acronyms
 EMEA

European Medicines (Evaluation) Agency
 CHMP

Committee for Medicinal Products for Human
Use
 “Volume


4….
of the Rules Governing Medicinal Products in
the European Union”
The EU CGMPs
Acronyms Used Internationally
 CGMP

Current Good Manufacturing Practices
 CTD

The Common Technical Document
 Drug


API = Active Pharmaceutical Ingredient
The unformulated active ingredient
 Drug

Substance (DS)/BDS/API
Product (DP)/FP (Final Product)
The formulated product / in its final packaging
More International Acronyms
 ICH


The International Conference on
Harmonization (of Technical Requirements
for Registration of Pharmaceuticals for
Human Use)
The EU, Japan, The US, The Observers
 MAA

Marketing Authorization Application
“FDA Speak”

PAI
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
483
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No Action Indicated
VAI
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
FDA Notice of Deficiency
NAI
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
Pre-approval Inspection
Voluntary Action Indicated
OAI

Official Action Indicated
More “FDA Speak”
 210/211

The U.S. Drug CGMPs
 600

– 680
U.S. Biologics CGMPs
 Barr

The decision in US v. Barr Laboratories
Favorite FDA Sayings
If it isn’t written down
it didn’t happen
In god we trust. All
others show data
It depends
Systemic
The era of doing less
with less
What else…?
Case-by-case
Benefit:Risk
CGMP: not just a
regulation, but a state
of mind
Key Definitions
 Stability

“The capacity of a drug substance or a drug
product to remain within specifications
established to ensure its identity, strength,
quality, and purity throughout the retest period
or expiration dating period”
More Key Definitions
 Shelf

Life
Shelf life of a drug product is defined as
the length of time under specific
conditions of storage that the product will
remain within specifications established to
ensure its identity, strength, quality, and
purity.
More Key Definitions
 Expiration

or Expiry date
Date until which time, under specific
conditions of storage, the product will
remain within specifications established to
ensure its identity, strength, quality, and
purity.
More Key Definitions

Retest Date


The date until which a product can be used without
further testing
After retest date product must by tested to
specification
• Can be used if passes all specifications

The trend is to use retest dates for:
• Process intermediates
• Bulk drug substances and products
• Some raw materials

Retest dates must be supported by data!
More Key Definitions
2 Types of Stability Data
1. Primary (“GMP work”)
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
Used to directly predict/support/confirm expiration
date, shelf life, or retest date
For biotech usually “real time, real temperature”
Must have pre-determined
•
•
2.
Protocol
Acceptance Limits
Supporting (“Part 300 work”) [310 – 314]


All other studies
Used to determine the stability characteristics of the
drug substance (API) and drug product
The Discovery Stage

No regulatory requirements
 Some things should/might be done

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Stability as part of feasibility
Stability of samples for preliminary safety and efficacy
testing in model systems
Stability as part of molecular characterization
Attitude adjustment (from Research mindset into
Development mindset)
Self-study to gain in-depth knowledge of stability
requirements
Stability During:
Pre-clinical Development

Overview of this section
1.
2.
3.
4.
5.

Regulations
Guidance
Goals and Objectives
Activities
Avoiding Common Problems and Pitfalls
Understanding the stability profile and
characteristics of the drug substance is
fundamental in laying the foundation for
subsequent stability testing and eventual
product approval!
Pre-clinical Development:
Regulations

Directly Applicable Regulations:

The Good Laboratory Practices (GLPs)
• 21CFR Part 58
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
21CFR Part 312.23: IND Content and Format
Target-setting Regulations:

21CFR:
• Part 312.23: IND Content and Format [near-term]
• Part 314.50: Content and format of an application to market a
new drug [long-term]

CGMPs in:
• 21CFR 211 and 600-680 (US) [long-term]
• Volume 4 (Europe) [near-term]
• ICH Q7, API CGMPs (regulation in Europe) [near-term]
The GLPs

U.S. Stability regulations at 21CFR:
• 58.31, Testing facility management
• 58.47, Facilities for handling test and control
articles
• 58.105, Test and control article characterization
• 58.113, Mixtures of articles with carriers
• 58.185, Reporting of non-clinical laboratory study
results
• 58.195, Retention of records
U.S. Stability Regulations:
Pre-clinical Development (21 CFR GLPs)

58.31 Testing facility management
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•
For each nonclinical laboratory study, testing facility
management shall:
 (d) Assure that test and control articles or mixtures have
been appropriately tested for identity, strength, purity,
stability, and uniformity, as applicable.
58.47 Facilities for handling test and control articles

As necessary to prevent contamination or mixups, there shall be
separate areas for:
 b) Storage areas for the test and/or control article and test
and control mixtures shall be separate from areas housing
the test systems and shall be adequate to preserve the
identity, strength, purity, and stability of the articles and
mixtures.
U.S. Stability Regulations:
Pre-clinical Development (21 CFR GLPs)

58.105 Test and control article characterization

•
(b) The stability of each test or control article shall be
determined by the testing facility or by the sponsor either: (1)
Before study initiation, or (2) concomitantly according to written
standard operating procedures, which provide for periodic
analysis of each batch.
58.113 Mixtures of articles with carriers


a) For each test or control article that is mixed with a carrier,
tests by appropriate analytical methods shall be conducted:
(2) To determine the stability of the test and control articles in
the mixture as required by the conditions of the study either:
 (i) Before study initiation, or
 (ii) Concomitantly according to written standard operating
procedures which provide for periodic analysis of the test and
control articles in the mixture.
U.S. Stability Regulations:
Pre-clinical Development (21 CFR GLPs)

58.185 Reporting of nonclinical laboratory study
results
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
•
(a) A final report shall be prepared for each nonclinical
laboratory study and shall include, but not necessarily
be limited to, the following:
(5) stability of the test and control articles under the
conditions of administration.
58.195 Retention of records

(b)(2) A period of at least 5 years following the date
on which the results of the nonclinical laboratory
study are submitted to the Food and Drug
Administration in support of an application for a
research or marketing permit.
GLP Inspection Case Study

From FDA Inspection of a Non-Clinical Testing
Lab

Testing facility management failed to assure that all
test and control articles or mixtures:
• were appropriately tested for identity, strength, purity,
stability, and uniformity

Results of test article analysis were not provided to
the Study Director in a timely manner for:
• evaluation and inclusion in the Final Reports

Final Study Reports are deficient:
• Do not include a statement addressing the absence of the
results of test article analysis
312.23 IND content and format
(for pre-clinical work)
 (a)(7)(iv)(a)

Drug substance.
information sufficient to support stability of
the drug substance during the
• toxicological studies
• and the planned clinical studies.
Target-setting Regulations

312.23 IND content and format

(a)(7)(ii) It should be emphasized that the amount of
information to be submitted depends upon the scope
of the proposed clinical investigation.
 For example, although stability data are required in all
phases of the IND to demonstrate that the new drug
substance and drug product are within acceptable chemical
and physical limits for the planned duration of the proposed
clinical investigation, if very short-term tests are proposed,
the supporting stability data can be correspondingly limited.
312.23 IND content and format
(for clinical work)
 (a)(7)(iv)(a)

Drug substance.
information sufficient to support stability of
the drug substance during the
• toxicological studies
• and the planned clinical studies.
312.23 IND content and format
(continued)
 (a)(7)(iv)(b)

Drug product.
information sufficient to assure the product's
stability during the planned clinical studies.
Pre-clinical Development:
Stability Guidance
 Directly Applicable

None
 Target-setting



Guidance
Guidance
Guidance for Industry, INDs—Approaches to
Complying with CGMP During Phase 1,
CDER and CBER, January 2006
ICH Q7, API CGMPs (guidance in U.S.)
Annex 13 to the EU CGMPs (Vol. 4)
• Manufacture of Investigational Medicinal Products
Target-setting Guidance: ICH
(www.ich.org)
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Q1A
Q1B
Q1C
Q1D
Q1E
Q1F
Q5B
Q5C
Q7
Q2 (R1)
New DS and DP
Photostability
New Dosage Forms
Bracketing and Matrixing
Evaluation of Stability Data
Climatic Zones III and IV
Genetic Stability
Stability of Biotech/Biological Products
APIs
Method Validation
More Target-setting Guidance
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FDA Phases 2 and 3 IND Guide (2003)
Container and Closure Integrity Testing in Lieu of
Sterility Testing as a Component of the Stability
Protocol for Sterile Products (1998)
Exploratory INDs (2006)
Various CMC Guidances
Guideline for Submitting Documentation for the
Stability of Human Drugs and Biologics (1987)
FDA Stability Guidance (1998)
Pre-clinical Development:
Stability Goals and Objectives
 The


Big Goal:
Alleviate stability as a safety concern
The only reasons for a CMC-based clinical
hold at IND Phase 1
• A safety concern
• Insufficient information to assess safety

How do you do this?

Characterize your drug substance

Have plenty of DATA!
From FDA’s old Phase 1 IND
Guidance (withdrawn 2006)
 For
Phase 1 Studies: “The identification of
a safety concern or insufficient data to
make an evaluation of safety is the only
basis for a clinical hold based on the CMC
section.”
 Cause for safety concern

Product of unknown stability or which
cannot remain stable for testing period
Pre-clinical Development:
Stability Goals and Objectives

To Generate Stability Data for IND Application

To have a Characterized Drug Substance
 1st, Impurities profile, and then
 Stability/degradants profile


To have a Characterized experimental Drug Product (what you
plan to use in your Phase 1 human studies)
To have a battery of “good enough” Stability-indicating methods
 Initial development and some optimization
 Characterization
 “Qualification”
 Possibly some validation (based on reviewer interest or…..)

To Assess and Report stability of your preclinical “drug product”
 Test article
 Test article in carrier
 During course of animal toxicology trials
Pre-clinical Development:
Stability Goals and Objectives


To develop a Sampling Plan for Phase 1 studies
To have an expiry date for investigational drug
product



Required in EU
Not required in US.
To have an expiry date for reconstituted drug
product (if applicable)

Required in US and EU
211.137(g): Where new drug products for investigational use
are to be reconstituted at the time of dispensing, their
labeling shall bear expiration information for the reconstituted
drug product.
Expiry Dating for Clinical Drug Product:
EU vs U.S.
 EU

Annex 13, Section 26 (j): The following
information should be included on labels
• period of use (use-by date, expiry date or re-test
date as applicable),
• in month/year format and in a manner that avoids
any ambiguity
Expiry Dating for Clinical Drug Product:
EU vs U.S.
 U.S.

211.137, Expiration Dating, (g):
• New drug products for investigational use are
exempt from the requirements of this section,
provided that they meet appropriate standards or
specifications as demonstrated by stability studies
during their use in clinical investigations.
• Where new drug products for investigational use
are to be reconstituted at the time of dispensing,
their labeling shall bear expiration information for
the reconstituted drug product.
Pre-clinical Development:
Stability Goals and Objectives
 To
obtain data to justify release and
stability specifications for DS/API and DP
 To get Stability Chambers/Rooms
prepared:


Purchase
Qualify/Validate (before start of Phase 3
studies)
• Mapping studies
• Full (actual conditions of use), NOT Empty!
Pre-clinical Stability Activities

Generate a Stability/degradants Profile




Forced-degradation (stress) studies
Accelerated studies
Real Time/Real temperature studies
Initially develop stability-indicating methods,
and:

Assess stability of pre-clinical material
• Test article as stored at tox facility
• Test article in carrier for appropriate time period

Assess stability of Phase 1 investigational drug
product (in its investigational formulation)
• Stress, accelerated (if appropriate), real time/temperature
Pre-clinical Stability Activities

Write Reports for:



Pre-IND Meeting
Phase 1 IND Application
Reports to include




Stability characterization of the drug substance
Stability characterization of experimental drug product
Stability assessment of material used in pivotal toxicology
study/studies
Stability-indicating methods
• Rationale for each method (seen in stress, accelerated, real
time/temp studies)
• Data that they are stability indicating
 Including: Qualification or Validation

Expiry/retest/period of use dates, if needed
• Rationale and Data!
More Pre-clinical Stability Activities

Lay down a Working Reference Standard

For:
• Release and stability assessment of Phase 1 clinical material
• Showing linkage and comparability between and among:



Should be material used in pivotal tox. trials
Determine stability of any of these materials
where you will not be simply using vendor’s
expiration date:



Pre-clinical/Phase 1-3/Commercial Material (API/DS)
Raw materials and other components
Excipients
Get started Qualifying chambers and rooms
More Pre-clinical Stability Activities
 Develop

your Sampling Plan
How will you prove sample is representative
of the lot or batch as whole?
Stress Testing:
what, why and how?

Forced degradation
studies not conducted
to identify/quantify
potential degradants

excerpt from FDA 483
What is Stress Testing?

Forced decomposition using extreme conditions
 Temperature
• heat
• freeze/thaw
 Chemical
• pH
• high oxygen tension
• hydrogen peroxide, chloramine T oxidation
• ozone oxidation
What is Stress Testing?



Photolysis
Mechanical
• agitation
• shear
Humidity (if appropriate)
• e.g. 75% RH or more

Combination
Purposes of Stress Testing





Gain experimental evidence of possible
degradation pathways and kinetics
Gain experience with degradation products
Gain information to guide analytical
development
Prepare special reference materials for method
validation
Assess likely effects of excursions outside of
label conditions during distribution
Stability Method Development:
A Systematic Approach (D.O.C.)
Generate a degradants profile
1.
•
Isolate and retain degradants for later use
Develop method(s) based on chemical differences of
2.
degradants from:
A.
B.
Optimize and Characterize methods for:
3.
A.
B.
C.
D.
4.
Drug substance
Non-degradant impurities
Method-specific parameters
Validation Parameters (ICH Q2, if applicable)
System suitability/assay acceptance criteria
Robustness
Qualify or, if necessary, validate method
Some Typical Stability-Indicating
Methods for a Phase 1 Clinical Trial





Content
Potency/Activity
Degradant Quantification
Appearance/color/clarity, pH
Microbial methods:



(Endotoxin, Bioburden, Microbial Limit)—maybe
Sterility or Container/Closure Integrity—at
beginning and end
Particulates (for parenterals)
Sampling Plan
 Must
prove sample is representative of
the lot or batch as a whole



Statistical methods such as random sampling
Sample from beginning, middle, end
Do homogeneity studies
• API/BDS container
• Process (e.g. tablet pressing, vial fill)

Other?
• Class participation: what strategies are you using?
Validation During Early Clinical
Development
Many call this “Qualification”
Focus on assay characterization
 Report Results in a Method Technical Report
 Do not need formal Protocol
 Do not need pre-determined acceptance criteria
 Focus on data showing method is suitable and
appropriate
 Present this at Product Development Committee
Meeting
 Circulate to appropriate Departments, including QA
 Try to get all stability methods to this point before you file
your Phase 1 IND


Method Qualification

Focus especially on subjects of reviewer interest:
 If you don’t attend meetings/phone conferences: Look
at the minutes!
 You may have to do a formal validation of some
methods, but be sure before you start
 When reviewers say “validate,” they often mean
characterize
• They often want Phase-appropriate data showing suitability
of method for its intended use
• Sometimes they really do want a formal validation, but be
absolutely certain
Assay Qualification Reference
 What
is Test Method Qualification? Ritter,
N., et al., BioProcess International,
September 2004, pp 2-11.
Setting an Expiry Date for Phase 1
 Gather



and review data from studies:
Stress
Accelerated (if any)
Real time real temperature
 Determine

duration of trial
Including storage, shipping, safety factor for
delays
 Do
a prospective study that is a bit longer
than the anticipated trial length
Avoiding Common Pitfalls:
Pre-clinical Development
Pitfall or Problem



Poorly-characterized
DS and DP
Inadequate stability
methods
Difficulty showing
comparability between
pivotal tox and Phase
1 human material
Avoidance Strategy





Do your science; start
early and be rigorous
Do systematic method
development (D.O.C.)
Use the same material
Or: try to avoid major
process changes
Or: practice excellence
in analytical
chemistry/biochemistry
Stability During:
Phase 1 Clinical Development
Overview of this section

1.
2.
3.
4.
5.

Regulations
Guidance
Goals and Objectives
Activities
Avoiding Common Problems and Pitfalls
“Let’s start the way we mean to continue”
Phase 1 Clinical Development:
Regulations

Directly Applicable Regulations:

CGMPs in:
• The FD&C and PHS Acts
• 21CFR 211 and 600-680 (US)—possibly
• Volume 4 (Europe)—certainly


312.23: IND content and format
Target-setting Regulations:


CGMPs
314.50: Content and format of an application to
market a new drug
U.S. Expiry Data Exemption

211.137, Expiration Dating, (g):


New drug products for investigational use are exempt
from the requirements of this section, provided that
they meet appropriate standards or specifications as
demonstrated by stability studies during their use in
clinical investigations.
Where new drug products for investigational use are
to be reconstituted at the time of dispensing, their
labeling shall bear expiration information for the
reconstituted drug product.
Expiry Dating for Clinical Drug Product:
EU
 Annex
13, Section 26 (j): The following
information should be included on labels
• period of use (use-by date, expiry date or re-test
date as applicable),
• in month/year format and in a manner that avoids
any ambiguity
Stability Guidance:
Phase 1 Clinical Development
 Directly Applicable



Guidance for Industry, INDs: Approaches to
Complying with CGMP During Phase 1,
CDER and CBER, January 2006
Exploratory INDs, 2006
Vol. 4, Annex 13
 Target-Setting


Guidance
Guidance
ICH Q1 Documents
ICH Q2 (R1)
FDA Phase 1 CGMP Guide on Stability
 Section

F.2. Stability
We recommend that sponsors initiate a
stability study using:
 representative samples of the investigational new
drug to:

monitor the stability and quality of the product
during the clinical investigation
(i.e. date of manufacture through date of last
administration).
Phase 1 Development:
Stability Goals and Objectives

To continue/complete any unfinished work from
previous stage/phase
 To refine your sampling plan


To assess stability of Phase 1 material (API/DS
and DP)


Working toward proving samples are representative
Concurrent studies during trial
To move toward well-developed and validated
method methods
 To move toward a Primary Reference Standard
Stability Activities:
Phase 1 Clinical Development

Continued work on:



Concurrent stability studies for:



sampling plan
Incomplete activities from previous phase
API/DS
DP
Continued Method D.O.C.


Especially biological potency assay
All stability methods validated before start of Phase 3!
Avoiding Common Pitfalls:
Phase 1 Clinical Development
Pitfall or Problem



Poorly-characterized
DS and DP
Inadequate stability
methods
Difficulty showing
comparability between
pivotal tox and Phase
1 human material and
between Phase 1 and
Phase 2 material
Avoidance Strategy



Do your science; start
early and be rigorous
Do systematic method
development (D.O.C.)
Practice excellence in:
• Process Development
• Analytical
chemistry/biochemistry
Stability During:
Phase 2 Clinical Development
Overview of this section

1.
2.
3.
4.
5.

Regulations
Guidance
Goals and Objectives
Activities
Avoiding Common Problems and Pitfalls
Stability work during Phase 2 sets the
stage for success in the all-important
Phase 3 efficacy trials
Phase 2 Clinical Development:
Regulations
 Directly Applicable



CGMPs
312.23 IND content and format
ICH Q7, API CGMPs (regulation in EU)
 Target-setting


Regulations:
Regulations:
CGMPs
21CFR 314.50:
• Content and format of an application to market a
new drug
Stability Guidance:
Phase 2 Clinical Development
 Directly Applicable




Annex 13
ICH Q2 (R1) [validate methods before
production of Phase 3 clinical material]
FDA Phases 2 and 3 Guide (1993)
ICH Q7, API CGMPs (guidance in U.S.)
 Target-Setting

Guidance
Guidance
ICH Q1 Documents
Phase 2 Development:
Stability Goals and Objectives

To continue/complete any unfinished work from previous
stage/phase
 To assess stability of Phase 2 material (DS and DP)
 To have a validated or “validatable” biological potency
assay for the End of Phase 2/pre-Phase 3 meeting
 Concurrent studies during trial
 Before Start of Phase 3:
 To have all stability methods validated
 To have approved Stability Protocol
 To have approved Stability Specifications
 To have primary and working reference standards
 To begin to characterize degradants seen in real
time/temp. studies
Phase 2 Development:
Stability Goals and Objectives

To begin to assess and establish Retest Dates
for in-process materials




To start to evaluate container/closure systems


Shown by studies to be unstable for less than 30 days
Held for more than 30 days (general rule for chemical
synthesis processes)
Made by biosynthesis
Integrity studies, if appropriate
To be able to write a Protocol for use in:


Phase 3, clinical efficacy studies
Post-marketing studies, especially the first 3
commercial batches
Stability Activities:
Phase 2 Clinical Development
 Concurrent
study during Phase 2 trial
 Qualify reference standards


Primary
Working
 Rigorous
and thorough method
Development, Optimization,
Characterization

Especially biological potency assay
 Degradant
characterization
Stability Activities:
Phase 2 Clinical Development
 Stability
method validation
 Write Stability Protocol


Including specifications
Remember: you will have to live with this
protocol “forever”
• At least through first 3 commercial lots
Information on
Degradation Products









Procedure for isolation and purification
Identity and chemical structure
Degradation pathways
Physical and chemical properties
Detection and quantification levels
Biological effects and pharmaceutical actions
Acceptance criteria
Test methods
Method Validation data
Validating
Stability Indicating
Methods
Validating Stability Indicating Assays

Use material and knowledge generated during
stress testing/forced degradation
 Have Robustness Assessment completed
 Validate per ICH Guidelines Q2 (R1)
• For example:
 For Impurities Quantitation Methods:
• Accuracy, Precision, Specificity, Linearity, Range,
Detection Limit, Quantitation Limit
 For content or potency assay:
• Accuracy, Precision, Specificity, Linearity, Range
ICH Validation Table
Assay Type
Validations
Identity
Specificity
Impurities Quantitation
Accuracy, Precision, Specificity,
Detection Limit, Quantitation Limit,
Linearity, Range
Impurities Limit
Specificity, Detection Limit
Content/Potency; Dissolution
Accuracy, Precision, Specificity,
Linearity, Range
You ARE Doing Validation If:
•
YES You have written protocols (following ICH)
•
•
•
Finalized assay procedure
Finalized validation protocol
YES You know the values for the relevant
characteristics/parameters
• YES You have pre-determined acceptance limits
YES
• YES
• YES
• YES
•
These have been Reviewed and Approved
No significant changes are being made
You are using qualified equipment
You are using the actual analyte and matrix
You Are NOT Doing Validation If:
You cannot
answer YES to all
items on the
previous slide
Validation:
Terminology and
Methodology
Accuracy
 Closeness
to reference value
 Methods



Assay of reference material
Comparison of results to reference
procedure
Infer from precision, linearity, and
specificity data
Precision
 Closeness
of agreement of a series
of measurements



repeatability
intermediate precision
reproducibility
Repeatability (AKA intra-assay
precision)
 Precision


under
Same operating conditions
Over a short time interval
 Methods


9 determinations (minimum) covering
range
6 determinations at 100% test
concentration
Intermediate Precision

Precision within laboratory variation
 Methods, perform analysis using different:
 Days,
 Analysts
 Equipment
 Also known as ruggedness (not
robustness)
 Good place to use experimental design
Reproducibility
 Expresses
precision between
laboratories
 Inter-laboratory trial
 Used for method standardization
 Not necessarily part of marketing
application dossier
Specificity
 Ability


to
Unambiguously assess analyte
In presence of all expected
components
 Methods


Identification
Assay and Impurity Tests
Specificity for ID Tests
 Discrimination

may be shown by
Obtaining
• Positive results from samples containing
the analyte
AND
• Negative results from samples not
containing the analyte

Obtaining negative results on materials
similar in structure to the analytes
Specificity for Assay
and Impurity Tests

Spike with impurities and demonstrate
resolution


From active
From each other

Spike with degradation product standards
 Perform peak purity tests


Collection and analysis
Detection (DAD, MS)
Specificity for Assay
and Impurity Tests (continued)
 For

Chromatographic Methods:
Always include a “worst-case” chromatogram
• All impurities and degradants present at or near
their upper limits
Detection Limit

Lowest amount of analyte in a sample
which can be


Detected
Not assigned an exact value
 Approaches



Visual evaluation
By signal to noise ratio (3:1 or 2:1)
Based on SD and slope of response
• DL = 3.3 sigma/S

Analysis of samples at the detection limit
Quantitation Limit


Lowest amount of analyte in a samples
which can be quantitatively determined
with suitable
 precision
 accuracy
Approaches



Visual evaluation
By signal to noise ratio (10:1)
Based on SD and slope of response
• QL = 10 sigma/S
Linearity
 Ability
to obtain test results which
are directly proportional to the
concentration of analyte in the
sample
 Establish across the range (5 conc.
min.)
 Dilution or separate weighings
 Visual inspection of plot
 Statistical analysis of regression line
For Linearity Include
 A plot
of the data
 Correlation coefficient, y-intercept, slope of
the regression line and residual sum of
squares
 Analysis of the deviation of the actual data
points from the regression line (may also
be helpful for evaluating linearity)
Range
 Interval
for which procedure has
suitable



precision
accuracy
linearity
 Normally
derived from linearity
studies
 Minimum ranges
Minimum Ranges for
Different Methods

Quantitation of drug substance or final
product
 80% - 120%
 Quantitation of impurities
 From LOQ or 50% of spec. (whichever
is greater) to 120% of spec.
 Content uniformity
 70% - 130% of test concentration
Avoiding Common Pitfalls:
Phase 2 Clinical Development
Pitfall or Problem



Clinical hold due to
inadequate potency
assay
Difficulty validating
stability methods
Difficulty showing
comparability between
pivotal tox, Phase 1, 2
and Phase 3 human
material
Avoidance Strategy



Focus on this early
and with great rigor
and thoroughness
Do systematic method
development (D.O.C.)
Practice excellence in
analytical
chemistry/biochemistry
and process
development
Stability During:
Phase 3 Clinical Development

Overview of this section
1.
2.
3.
4.
5.

Regulations
Guidance
Goals and Objectives
Activities
Avoiding Common Problems and Pitfalls
Now things get really serious. Lock down your
process and product. Do you studies under a
formal Protocol that you can live with “forever”
Phase 3 Clinical Development:
Regulations

Directly Applicable Regulations:



CGMPs
312.23 IND content and format
21CFR 314.50:
• Content and format of an application to market a new drug



Other parts for 21CFR 300
Vol. 4, including ICH Q7 (EU)
Target-setting Regulations:


CGMPs
310.303 Continuation of long-term studies
The CGMP “Ballet”

Step 0: Have Rationale for and Data supporting
everything you are going to do
 Step 1: Write down exactly what you are going
to do (a Protocol)
 Step 2: Write down exactly what you expect to
find (Acceptance Criteria or Specifications)
 Step 3: Have Protocol Reviewed/Approved by:



The appropriate departments of your choice
Quality Assurance (per 211.22)
Before you start Protocol execution!
The CGMP “Ballet” (continued)
 Step
4: Do precisely what you said you
were going to do in the Protocol



Generate R.A.W. data (Run As Written)
Record data in compliant manner (controlled)
Full-blown change control for any deviations
• Formal process
• Investigation and impact assessment

Don’t just check “No Impact”
• Corrective and Preventive Actions (CAPA)
The CGMP “Ballet” (continued)
 Step




5: Write a Report that includes
Data and calculations (raw and transformed and
summary)
Deviations/Investigations/CAPA/Closeout/Follow-up
Conclusions (including: specifications met?)
Step 6: Have Report Reviewed/Approved by:
 The appropriate departments of your choice
 Quality Assurance (per 211.22)
 Before
official use!
U.S. Stability Regulations:
Commercial Product (21 CFR CGMPs)





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 211.166.
(b) Expiration dates shall be related to any storage
conditions stated on the labeling, as determined by
stability studies described in 211.166.
(c) If the drug product is to be reconstituted at the time of
dispensing, its labeling shall bear expiration information
for both the reconstituted and unreconstituted drug
products.
(d) Expiration dates shall appear on labeling in
accordance with the requirements of 201.17 of this
chapter.
U.S. Stability Regulations:
211.137 (continued)




(e) Homeopathic drug products shall be exempt from the
requirements of this section.
(f) Allergenic extracts that are labeled "No U.S. Standard of Potency"
are exempt from the requirements of this section.
(g) New drug products for investigational use are exempt from
the requirements of this section, provided that they meet appropriate
standards or specifications as demonstrated by stability studies
during their use in clinical investigations. Where new drug products
for investigational use are to be reconstituted at the time of
dispensing, their labeling shall bear expiration information for the
reconstituted drug product.
(h) Pending consideration of a proposed exemption, published in the
Federal Register of September 29, 1978, the requirements in this
section shall not be enforced for human OTC drug products if their
labeling does not bear dosage limitations and they are stable for at
least 3 years as supported by appropriate stability data.
211.166 Stability testing

(a) There shall be a written testing program designed to
assess the stability characteristics of drug products. The
results of such stability testing shall be used in
determining appropriate storage conditions and
expiration dates. The written program shall be followed
and shall include:





(1) Sample size and test intervals based on statistical criteria for
each attribute examined to assure valid estimates of stability;
(2) Storage conditions for samples retained for testing;
(3) Reliable, meaningful, and specific test methods;
(4) Testing of the drug product in the same container-closure
system as that in which the drug product is marketed;
(5) Testing of drug products for reconstitution at the time of
dispensing (as directed in the labeling) as well as after they are
reconstituted.
U.S. Stability Regulations:
Commercial Product (21 CFR CGMPs)

211.170 Reserve samples

(b) An appropriately identified reserve sample that is
representative of each lot or batch of drug product shall be
retained and stored under conditions consistent with product
labeling.

The reserve sample shall be stored in the same immediate
container-closure system in which the drug product is marketed
or in one that has essentially the same characteristics.

The reserve sample consists of at least twice the quantity
necessary to perform all the required tests, except those for
sterility and pyrogens.

Reserve samples from representative sample lots or batches
selected by acceptable statistical procedures shall be examined
visually at least once a year for evidence of deterioration unless
visual examination would affect the integrity of the reserve
sample.

Any evidence of reserve sample deterioration shall be
investigated in accordance with 211.192. The results of the
examination shall be recorded and maintained with other
stability data on the drug product.
U.S. Stability Regulations:
211.170 (Continued)




The retention time is as follows:
(1) For a drug product other than those described in paragraphs (b)
(2) and (3) of this section, the reserve sample shall be retained for 1
year after the expiration date of the drug product.
(2) For a radioactive drug product, except for nonradioactive reagent
kits, the reserve sample shall be retained for:

(i) Three months after the expiration date of the drug product if
the expiration dating period of the drug product is 30 days or
less; or

(ii) Six months after the expiration date of the drug product if the
expiration dating period of the drug product is more than 30
days.
(3) For an OTC drug product that is exempt for bearing an expiration
date under 211.137, the reserve sample must be retained for 3
years after the lot or batch of drug product is distributed.
U.S. Stability Regulations:
Commercial Product (21 CFR CGMPs)


211.194 Laboratory records
(a) Laboratory records shall include complete
data derived from all tests necessary to assure
compliance with established specifications and
standards, including examinations and assays,
as follows:
 (1) A description of the sample received for
testing with identification of source (that is,
location from where sample was obtained),
quantity, lot number or other distinctive code,
date sample was taken, and date sample was
received for testing.
211.194 Laboratory records
(continued)


(2) A statement of each method used in the testing of the sample.
The statement shall indicate the location of data that establish that
the methods used in the testing of the sample meet proper
standards of accuracy and reliability as applied to the product
tested. (If the method employed is in the current revision of the
United States Pharmacopeia, National Formulary, Association of
Official Analytical Chemists International, Book of Methods, 1 or in
other recognized standard references, or is detailed in an approved
new drug application and the referenced method is not modified, a
statement indicating the method and reference will suffice). The
suitability of all testing methods used shall be verified under actual
conditions of use.
(3) A statement of the weight or measure of sample used for each
test, where appropriate.
211.194 Laboratory records
(continued)



4) A complete record of all data secured in the course of
each test, including all graphs, charts, and spectra from
laboratory instrumentation, properly identified to show
the specific component, drug product container, closure,
in-process material, or drug product, and lot tested.
(5) A record of all calculations performed in connection
with the test, including units of measure, conversion
factors, and equivalency factors.
(6) A statement of the results of tests and how the results
compare with established standards of identity, strength,
quality, and purity for the component, drug product
container, closure, in-process material, or drug product
tested.
211.194 Laboratory records
(continued)



(7) The initials or signature of the person who performs
each test and the date(s) the tests were performed.
(8) The initials or signature of a second person showing
that the original records have been reviewed for
accuracy, completeness, and compliance with
established standards.
(b) Complete records shall be maintained of any
modification of an established method employed in
testing. Such records shall include the reason for the
modification and data to verify that the modification
produced results that are at least as accurate and
reliable for the material being tested as the established
method.
211.194 Laboratory records
(continued)

(c) Complete records shall be maintained of any
testing and standardization of laboratory
reference standards, reagents, and standard
solutions.
 (d) Complete records shall be maintained of the
periodic calibration of laboratory instruments,
apparatus, gauges, and recording devices
required by 211.160(b)(4).
 (e) Complete records shall be maintained of all
stability testing performed in accordance with
211.166.
U.S. Stability Regulations:
Product Approval

314.50 Content and format of an application to market a
new drug

(d)(1) Chemistry, manufacturing, and controls section. A section
describing the composition, manufacture, and specification of the
drug substance and the drug product, including the following:

(i) Drug substance. A full description of the drug substance
including its physical and chemical characteristics and stability;

(ii)(a) ...the specifications necessary to ensure the identity,
strength, quality, purity, potency, and bioavailability of the drug
product, including, for example, tests, analytical procedures, and
acceptance criteria relating to sterility, dissolution rate, container
closure systems; and stability data with proposed expiration
dating.
314.50 Content and format of an application
to market a new drug (continued)

(ii)(b) Unless provided by paragraph (d)(1)(ii)(a) of this
section, for each batch of the drug product used to
conduct a bioavailability or bioequivalence study
described in 320.38 or 320.63 of this chapter or used to
conduct a primary stability study:

The batch production record; the specification for each
component and for the drug product; the names and addresses
of the sources of the active and noncompendial inactive
components and of the container and closure system for the
drug product; the name and address of each contract facility
involved in the manufacture, processing, packaging, or testing of
the drug product and identification of the operation performed by
each contract facility; and the results of any test performed on
the components used in the manufacture of the drug product as
required by 211.84(d) of this chapter and on the drug product as
required by 211.165 of this chapter.
U.S. Stability Regulations:
Product Approval

314.81 Other postmarketing reports
 (b)(2)(viii) Status of other postmarketing studies.
A status report of any postmarketing study not
included under paragraph (b)(2)(vii) of this
section that is being performed by, or on behalf
of, the applicant. A status report is to be included
for any chemistry, manufacturing, and controls
studies that the applicant has agreed to perform
and for all product stability studies.
U.S. Stability Regulations:
Product Approval

314.125 Refusal to approve an application.
 (b) FDA may refuse to approve an application for
any of the following reasons:
 (1) The methods to be used in, and the facilities
and controls used for, the manufacture,
processing, packing, or holding of the drug
substance or the drug product are inadequate to
preserve its identity, strength, quality, purity,
stability, and bioavailability.
U.S. Stability Regulations:
Commercial Product (Part 201 Labeling)


Subpart A--General Labeling Provisions
Sec. 201.17 Drugs; location of expiration date. When
an expiration date of a drug is required, e.g., expiration
dating of drug products required by 211.137 of this
chapter, it shall appear on the immediate container and
also the outer package, if any, unless it is easily legible
through such outer package. However, when single-dose
containers are packed in individual cartons, the
expiration date may properly appear on the individual
carton instead of the immediate product container. [43
FR 45076, Sept. 29, 1978]
U.S. Stability Regulations:
Commercial Product (Part 201 Labeling)
 201.57
Specific requirements on content
and format of labeling for human
prescription drugs


Each section heading listed in 201.56(d), if
not omitted under 201.56(d)(3), shall contain
the following information in the following
order:
(j) Dosage and Administration …….. storage
conditions for stability of the drug or
reconstituted drug, when important; ………..
Other U.S. Stability Regulations
 21CFR


601.2 Applications for biologics licenses
601.12 Changes to an approved application
Stability Guidance:
Phase 3 Clinical Development
 Directly Applicable







Guidance
ICH Q1 Documents
ICH Q2 (R1)
Annex 13
ICH Q7 (U.S)
CMC Guides and IND Guides (U.S)
Inspection Guides (U.S.)
Misc. U.S Guidance Documents
Guidance Documents
 The

status of Guidance:
“Chalk talk”
• FDA Guidance



Final Guidance
Draft Guidance
“For Comment Purposes Only” Guidance
• ICH Guidance

Adopted at Step 4 by EU, Japan, U.S., Observer
Regions, and most of the ROW
• EU Annexes and Guidance Documents
U.S. Regulatory Guidance
 Guidance
For Industry For The
Submission Of Chemistry, Manufacturing,
And Controls Information For A
Therapeutic Recombinant DNA-derived
Product Or A Monoclonal Antibody Product
For In Vivo Use (1996)
U.S. Regulatory Guidance
(continued)
 Guidance
For Industry: Content And
Format Of Chemistry, Manufacturing And
Controls Information And Establishment
Description Information For A Vaccine Or
Related Product (1999)
 Guideline for Submitting Documentation
for the Stability of Human Drugs and
Biologics (1987)
U.S. Regulatory Guidance
(continued)
 FDA Phases
2 and 3 IND Guide (2003)
 Container and Closure Integrity Testing in
Lieu of Sterility Testing as a Component of
the Stability Protocol for Sterile Products
(1998)
U.S. Regulatory Guidance
(continued)
 ORA Inspection



Guides:
Biotechnology Inspection Guide (1991)
Pharmaceutical QC Labs (1993)
Microbiological QC Labs (1993)
Regulatory Guidance: ICH
(www.ich.org)








Q1A (R2)New DS and DP
Q1B
Photostability
Q1C
New Dosage Forms
Q1D
Bracketing and Matrixing
Q1E
Evaluation of Stability Data
Q5B
Genetic Stability
Q5C
Stability of Biotech/Biological
Products
Q7
APIs (Part 2 of CGMPs in EU)
ICH Q1A
nd
(2 revision, Feb., 2003)
Stability Testing of New Drug
Substances and Products
ICH Q1A: Objective
 Define
the stability data package
requirements for

a new drug substance or drug product
 At
the time of submitting registration
application within the three regions of:



the European Union (EU)
Japan
the United States
ICH Q1A: Objective (cont.)
 Alternate
procedures are permitted
 These may be necessary due to:


specific scientific considerations
characteristics of the materials being
evaluated.
 Any
alternate approaches used need to be
justified based on scientific reasoning.
ICH Q1A: Scope
 This
guidance addresses only the
information to be submitted in registration
application of:

new molecular entities and associated drug
products.
ICH Q1A: General Principles

The purpose of stability testing is:



to provide evidence on how the quality of a drug
substance or drug product varies with time under the
influence of a variety of environmental factors (such
as temperature, humidity, and light)
to establish a retest period for the drug substance or
a shelf life for the drug product
To recommend appropriate storage conditions
ICH Q1A: General Principles (cont.)
 The
choice of test conditions defined in
this guidance is based on an analysis of
the effects of climatic conditions in the
following three regions:




European Union
Japan
United States
These constitute climatic zones I and II.
ICH Q1A: General Principles (cont.)
 The
principle has been established that
stability information generated in any one
of these three regions would be mutually
acceptable to the other two regions,
provided that:


Stability data is consistent with this guidance.
The labeling requirements at
national/regional level have been met.
ICH Q1A (R2)

The guidance addresses the stability testing
requirements of
 Drug substance


The unformulated drug substance that may
subsequently be formulated with excipients to
produce the dosage form.
Drug product

The dosage form in the final immediate packaging
intended for marketing.
ICH 1QA (R2)

Drug substance Topics:









Stress testing (photostability as an integral part of
stress testing)
Selection of batches
Container closure system
Specifications
Testing frequency
Storage conditions
Stability commitment
Evaluation
Statement and labeling
ICH 1QA (R2)

Drug product Topics:









Photostability testing
Selection of batches
Container closure system
Specifications
Testing frequency
Storage conditions
Stability commitment
Evaluation
Statement/labeling
Drug Substance: Stress Testing
 Stress




testing:
Identifies the likely degradation products.
Helps to establish degradation pathways.
Establishes the intrinsic stability of the
molecule.
Necessary for validation of the stabilityindicating power of the analytical procedure
used.
Drug Substance: Stress Testing (cont.)

Stress testing is carried out on:


a single batch of the drug substance
additional batches if necessary
Drug Substance: Stress Testing (cont.)
 Stress

testing identifies the effects of:
Temperature variations
• in 100C increments above that for accelerated
testing (or, in increments above long-term storage
conditions for most biotechnology products)





Humidity (e.g. 75% RH or more)
Oxidation
Photolysis
Hydrolysis
Additional conditions as appropriate
Drug substance: Selection of Batches
 Data
from formal stability studies should
be collected on at least three primary
batches of the drug substance.
 The batches should be manufactured to a
minimum of pilot scale and using the
same manufacturing process as for
production batches.
Drug Substance: Container Closure System
 The
stability studies should be conducted
on the drug substance packaged in a
container closure system that is similar to
or simulates the packaging proposed for
storage and distribution.
Drug Substance: What to Test

Stability studies should include testing of those
attributes (physical, chemical, biological, and
microbiological) of the drug substance that are
susceptible to change during storage and are
likely to influence quality, safety, and/or efficacy.
 Validated stability-indicating analytical
procedures should be applied.
Drug Substance:Testing
Frequency
 Long-term

study:
frequency of testing should be sufficient to
establish stability profile of the drug
substance.
• Example: If the proposed retest period is a
minimum of 12 months, testing should be
performed:



Every 3 months (first year)
Every 6 months (second year)
Annually (through the rest of the retest period)
Drug Substance:Testing
Frequency (cont.)
 At
accelerated storage condition, a
minimum of three time points, including
the initial and final time points (e.g. 0, 3,
and 6 months), from a 6-month study is
recommended.

Note: If there is reason to suspect that
significant change may occur , increase the
testing frequency by adding a forth time point
to the study design.
Drug Substance:Testing
Frequency (cont.)
 Perform
testing at intermediate storage
condition, if significant change is observed
at the accelerated storage condition.
 For a 12-month study, a minimum of four
time points (including the initial and final
time points) are recommended.
Drug Substance: Storage
Conditions

Generally:


A drug substance should be evaluated for stability as
appropriate under storage conditions that test both
thermal stability and stability at conditions of elevated
humidity.
The storage conditions and length of studies chosen
should be sufficient to cover storage, shipment, and
subsequent use.
Drug Substance: Storage
Conditions (cont.)

The long-term testing should cover a minimum
of 12 months’ duration on three primary batches
at the time of submission and should be
continued for a sufficient period to cover the
proposed retest period.
 Data from the accelerated storage condition or
from the intermediate storage condition may be
used to evaluate the impact of short-term
excursions outside the label storage conditions
(such as might occur during shipping).
Drug Substance: Storage
Conditions (cont.)
•
•
•
•
General Storage Conditions
Drug products intended for storage in a
refrigerator
Drug products intended for storage in a
freezer
Drug Products Intended for Storage below
–200C
Drug Substance: Storage
Conditions (cont.)

General Conditions:
• Study: Long-term



Storage condition: 25 °C ± 2 °C/60% RH ± 5% RH
Or 30 °C ±2 °C/65% RH ± 5% RH
Available data at submission: 12 months
• Study: Intermediate


Storage condition: 30 °C ±2 °C/65% RH ± 5% RH
Available data at submission: 6 months
• Study: Accelerated


Storage condition: 40 °C ± 2 °C/75% RH ± 5% RH
Available data at submission: 6 months
Drug Substance: Storage
Conditions (cont.)

When ‘‘significant change’’ occurs at any time
during 6 months’ storage at the accelerated
storage condition, additional testing at the
intermediate storage condition should be
conducted and evaluated against significant
change criteria. The initial application should
include a minimum of 6 months’ data from a
12-month study at the intermediate storage
condition.
Drug Substance: Storage
Conditions (cont.)
 Drug
Substances Intended for Storage in a
Refrigerator

Study: Long-term
• Storage condition: 5 °C ± 3 °C
• Available data at submission: 12 months

Study: Accelerated
• Storage condition: 25 °C ± 2 °C/60% RH ± 5% RH
• Available data at submission: 6 months
Drug Substance: Storage
Conditions (cont.)



If significant change occurs between 3 and 6 months’
testing at the accelerated storage condition, the
proposed shelf life should be based on the real-time
data available at the long-term storage condition.
If significant change occurs within the first 3 months’
testing at the accelerated storage condition, data
should be supplied to address the effect of short term
excursions outside the label storage condition.
It is not necessary to continue to test a product to 6
months when a significant change has occurred
within the first 3 months.
Drug Substance: Storage
Conditions (cont.)

Drug Substances Intended for Storage in a
Freezer

Study: Long-term
• Storage condition: -20 °C ± 5 °C
• Available data at submission: 12 months

The retest period should be based on the real-time
data presented at the long-term storage condition.
• Test a single batch at an elevated temperature (e.g., 5 °C ± 3
°C or 25 °C ± 2 °C) to assess the effect of short term
excursions outside the proposed label storage condition
( such as during shipping or handling).
Drug Substance: Storage
Conditions (cont.)
 Drug
substances intended for Storage
Below -20 °C should be treated on a caseby-case basis.
Drug Substance: Stability
Commitment

If the submission does not include long-term
storage data from three primary batches
covering the proposed retest period, postapproval commitment is necessary.



If the submission includes stability data on at least three
production batches, a commitment should be made to continue
these studies through the proposed retest period.
If the submission includes stability data on fewer than three
production batches, a commitment should be made to continue
these studies and place three production batches on long-term
stability studies through the proposed retest period.
If the submission does not include stability data on production
batches, a commitment should be made to place the first three
production batches on long-term stability studies through the
proposed retest period.
Drug Substance: Stability
Commitment
• The stability protocol used for long-term studies for
the stability commitment should be the same as
that for the primary batches unless otherwise
scientifically justified.
Drug Substance: Stability Data
Evaluation
 The
purpose of stability study is to
establish, based on testing a minimum of
three batches of the drug substance and
evaluating the stability information, a retest
period applicable to all future batches of
drug substances manufactured under
similar conditions.
Drug Substance: Data Evaluation
(cont.)
 The
degree of variability of individual
batches affects the confidence that a
future production batch will remain within
specification throughout the assigned
retest period. It also determines the
approaches taken to evaluate data.
Drug Substance:
Statements/Labeling

Statements/Labeling



A storage temperature range may be used in
accordance with relevant national/regional
requirements. The range should be based on the
stability evaluation of the drug substance.
Where applicable, specific instructions should be
provided, particularly for drug substances that cannot
tolerate freezing. The use of terms such as ‘‘ambient
conditions’’ or ‘‘room temperature’’ is unacceptable.
A retest period should be derived from the stability
information.
Drug Product
 The
design of the formal stability studies
for the drug product should be based on
knowledge of the behavior and properties
of the drug substance, results from
stability studies on the drug substance,
and experience gained from clinical
formulation studies.
Drug Product: Photostability
 Photostability

testing:
Standard conditions are described in ICH
Q1B.
Drug Product: Selection of Batches



Data from formal stability studies should be collected
on at least three primary batches of the drug product.
The batches should be of the same formulation and
packaged in the same container closure system as
proposed for marketing
The manufacturing process used for primary batches
should simulate that for the production batches and
should meet the same criteria for quality.
Drug Product: Selection of Batches
(cont.)



Two of the three batches should be at least
pilot scale batches.
If possible, different batches of drug
substance should be used to manufacture the
primary batches.
Stability data is required on each individual
strength and container size of the drug
product unless bracketing or matrixing is
applied.
Drug Product: Container Closure
System
 The
stability studies should be conducted
on the drug product packaged in the same
container closure proposed for storage
and distribution, including any secondary
packaging and container label.
Drug Product: Specification

Stability studies should include testing of those
attributes (physical, chemical, biological, and
microbiological) of the drug product that are
susceptible to change during storage and are
likely to influence quality, safety, and/or efficacy.
 Validated stability-indicating analytical
procedures should be applied.
Drug Product:Testing Frequency

Long-term study:


frequency of testing should be sufficient to establish
stability profile of the drug product.
Example: If the proposed retest period is a minimum
of 12 months, testing should be performed:
• Every 3 months (first year)
• Every 6 months (second year)
• Annually (through the rest of the shelf life)
Drug Product:Testing Frequency
(cont.)
 At
accelerated storage condition, a
minimum of three time points, including
the initial and final time points (e.g. 3, and
6 months), from a 6-month study is
recommended.

Note: If there is reason to suspect that
significant change may occur , increase the
testing frequency by adding a forth time point
to the study design.
Drug Product:Testing Frequency
(cont.)
 Perform
testing at intermediate storage
condition, if significant change is observed
at the accelerated storage condition.
 For a 12- month study, a minimum of four
time points ( including the initial and final
time points) are recommended.
Drug Product: Storage
Conditions

Generally:


A drug product should be evaluated for stability as
appropriate under storage conditions that test both
thermal stability and stability at conditions of elevated
humidity.
The storage conditions and length of studies chosen
should be sufficient to cover storage, shipment, and
subsequent use.
Drug Product: Storage
Conditions (cont.)
 Stability
testing of drug product after
constitution or dilution should be
conducted to provide information for the
labeling on the preparation, storage
condition, and in-use period of the
constituted or diluted product
Drug Product: Storage
Conditions (cont.)

The long-term testing should cover a minimum
of 12 months’ duration on three primary batches
at the time of submission and should be
continued for a sufficient period to cover the
proposed shelf life.
 Data from the accelerated storage condition or
from the intermediate storage condition may be
used to evaluate the impact of short-term
excursions outside the label storage conditions
(such as might occur during shipping).
Drug Product: Storage
Conditions (cont.)






General Storage Conditions
Drug products packaged in impermeable containers
Drug products packaged in semi-impermeable
containers
Drug products intended for storage in a refrigerator
Drug products intended for storage in a freezer
Drug Products Intended for Storage below –200C
Drug Product: Storage
Conditions (cont.)

General Conditions:
• Study: Long-term



Storage condition: 25 °C ± 2 °C/60% RH ± 5% RH
Or 30 °C ±2 °C/65% RH ± 5% RH
Available data at submission: 12 months
• Study: Intermediate


Storage condition: 30 °C ±2 °C/65% RH ± 5% RH
Available data at submission: 6 months
• Study: Accelerated


Storage condition: 40 °C ± 2 °C/75% RH ± 5% RH
Available data at submission: 6 months
Drug Product: Storage
Conditions (cont.)

When ‘‘significant change’’ occurs at any time
during 6 months’ storage at the accelerated
storage condition, additional testing at the
intermediate storage condition should be
conducted and evaluated against significant
change criteria. The initial application should
include a minimum of 6 months’ data from a
12-month study at the intermediate storage
condition.
Drug Product: Storage
Conditions (cont.)

A significant change for a drug product is
defined as:



A 5% change in assay from its initial value; or failure
to meet the acceptance criteria for potency
Any degradation product exceeding its acceptance
criteria
Failure to meet the acceptance criteria for
appearance, physical attributes, and functionality test
(color, phase separation, caking, etc.)
Drug Product: Storage
Conditions (cont.)
 Drug
products packaged in impermeable
containers:

Sensitivity to moisture or potential for solvent
loss is not a concern (2.2.7.2)
Drug Product: Storage
Conditions (cont.)

Drug products packaged in semi-permeable
containers:
• Aqueous-based products should be evaluated for
potential water loss and demonstrated that they
can withstand low relative humidity environments.
Drug Product: Storage
Conditions (cont.)
 When
significant change other than water
loss occurs during the 6 months’ testing at
accelerated storage condition, additional
testing at intermediate testing should be
conducted
Drug Product: Storage
Conditions (cont.)
 Drug
Products Intended for Storage in a
Refrigerator

Study: Long-term
• Storage condition: 5 °C ± 3 °C
• Available data at submission: 12 months

Study: Accelerated
• Storage condition: 25 °C ± 2 °C/60% RH ± 5% RH
• Available data at submission: 6 months
Drug Product: Storage
Conditions (cont.)



If significant change occurs between 3 and 6 months’
testing at the accelerated storage condition, the
proposed shelf life should be based on the real-time
data available at the long-term storage condition.
If significant change occurs within the first 3 months’
testing at the accelerated storage condition, data
should be supplied to address the effect of short term
excursions outside the label storage condition.
It is not necessary to continue to test a product to 6
months when a significant change has occurred
within the first 3 months.
Drug Product: Storage
Conditions (cont.)

Drug Products Intended for Storage in a Freezer

Study: Long-term
• Storage condition: -20 °C ± 5 °C
• Available data at submission: 12 months

The shelf life should be based on the real-time data
presented at the long-term storage condition.
• Test a single batch at an elevated temperature (e.g., 5 °C ± 3
°C or 25 °C ± 2 °C) to assess the effect of short term
excursions outside the proposed label storage condition
(such as during shipping or handling).
Drug Products: Storage
Conditions (cont.)
 Drug
products intended for Storage Below
-20 °C should be treated on a case-bycase basis.
Drug Product: Stability
Commitment

Stability Commitment:


When available long-term stability data on primary
batches do not cover the proposed shelf life granted
at the time of approval, the studies should be
continued post-approval in order to firmly establish
the shelf life.
Where the submission includes long-term storage
data from three production batches covering the
proposed shelf life, no post-approval commitment is
necessary.
Drug Product: Stability Commitment
• If the submission does not include long-term
storage data from three production batches
covering the proposed shelf life, post-approval
commitment is necessary.



If the submission includes stability data on at least three
production batches, a commitment should be made to
continue these studies through the proposed shelf life.
If the submission includes stability data on fewer than
three production batches, a commitment should be made
to continue these studies and place three production
batches on long-term stability studies through the
proposed shelf life.
If the submission does not include stability data on
production batches, a commitment should be made to
place the first three production batches on long-term
stability studies through the proposed shelf life.
Drug Product: Stability
Commitment
• The stability protocol used for long-term studies for
the stability commitment should be the same as
that for the primary batches unless otherwise
scientifically justified.
Drug Product: Stability Data
Evaluation
 The
purpose of stability study is to
establish, based on testing a minimum of
three batches of the drug product and
evaluating the stability information, a shelf
life applicable to all future batches of drug
product manufactured under similar
conditions.
Drug Product: Data Evaluation (cont.)
 The
degree of variability of individual
batches affects the confidence that a
future production batch will remain within
specification throughout the assigned shelf
life. It also determines the approaches
taken to evaluate data.
Drug Product:
Statements/Labeling

Statements/Labeling



A storage temperature range may be used in
accordance with relevant national/regional
requirements. The range should be based on the
stability evaluation of the drug product.
Where applicable, specific instructions should be
provided, particularly for drug products that cannot
tolerate freezing. The use of terms such as ‘‘ambient
conditions’’ or ‘‘room temperature’’ is unacceptable.
A shelf life should be derived from the stability
information.
Phase 3 Development:
Stability Goals and Objectives

To continue/complete any unfinished work from
previous stage/phase
 To initiate primary stability studies on:



To use stability data to assist in establishing
linkage between:




3 lots of DS/API
3 lots of DP
Preclinical material
Clinical material
And eventually commercial material
To be ready for the Pre-approval Inspection
Stability Activities:
Phase 3 Clinical Development
 Complete
all unfinished work
 Write Protocols and Reports for primary
stability studies
 Execute primary stability studies under full
CGMP compliance
 Do special protocol stability studies (e.g.
as part of Comparability Protocol)
 Begin rigorous self-inspection and CAPA
 Set up tracking and trending systems
Establishing Linkage

Considerations include:









Source
Manufacturing facility
Manufacturing process
Quality
Purity
Stability
Formulation
Containers and closures
Looking for lack of consistency/changes
Stability Protocols and
Reports
What goes into a
stability protocol?
“It is recommended that the final stability
protocol be well defined prior to the
initiation of phase 3 IND studies”
 1998 FDA Stability Guide (guidance
was withdrawn in 2006, but the way
FDA thinks about this remains the
same!)
The Stability Protocol
 Detailed
plan to generate and analyze
data to support retest period or expiration
date
 Items to include:




Manufacturer of DS, DP, and excipients
Proposed retest or expiration dating period
Type, size, number of batches
Type, size, source of containers and closures
The Stability Protocol, continued
 More







items to include:
Test parameters
Validated stability-indicating test methodology
for each parameter assessed
Storage conditions
Container orientations
Sampling plan
Test time points
Acceptance criteria
The Stability Protocol, continued
 More



items to include:
How data will be presented
Statistical approaches and methods for
evaluation of results and determining retest or
expiration dates
Stability commitment
What should go into a
stability report?

Deficiencies (excerpts from FDA
483s):


No summary reports or trending
data included in stability study
Original stability report differs from
application copy
The Stability Report

For IND, ANDA, BLA, NDA, Supplements,
Annual Reports
 Items to be included:








General Information
Summary Information
Specifications and Test Methodology
Study Design and Conditions
Stability Data
Data Analysis
Degradation product information
Conclusions
General Information for
Stability Reports


Product Name
Study Number
 Reporting Period
 Length of Study
 Storage Conditions
 Sampling Plan
 Formulation Code/#
 Composition & Supplier:
 Container
 Closure
 Seal
More General Information for
Stability Reports

Drug Substance
 Manufacturing. Site
 Manufacturing Date
 Batch Type & Size
 Batch Number
 Drug Product
 Mfg. Site & Date
 Batch Number
 Dosage & Strength
 Packager Site & Date
More General Information for
Stability Reports
 Statement
assuring that long-term testing
will continue for duration of expected
retest period and shelf life
 Contract firms used
Summary Information for
Stability Reports










Physical, chemical, microbiological attributes
Stability-indicating profile
Regulatory release specs
Regulatory stability Specs
Stability-indicating Test Methods
Description of the biological assay used for potency
determination (if applicable)
Location of validation information
Statement of changes likely to occur upon storage
Rationale for selection of parameters monitored
Description of sampling plan
More Summary Information for
Stability Reports







Expected duration of study
Conditions for storage
Location of Data
Summary of Data
Specification Failures
Summary of information on previous
formulations and container/closures during
product development
Conclusions
Specification Information for
Stability Reports

Individual and total limits
 impurities
 degradation products
 Justification, levels seen in:
 preclinical material
 clinical material
“Recommendations for maximum acceptable losses of activity, limits for
physicochemical changes, or degradation during the proposed shelf
life have not been developed for individual types or groups of
biotechnological/biological products but are considered on a caseby-case basis.”
Sampling Plan Information for
Stability Reports







Batches selected
Different containers and closure systems and
number of each
Number of units selected
Statistical method used to select units
Whether tests conducted on individual units or
composites
Sampling time points
Reconstitution studies
Stability Data for Stability Reports
 Individual




Data, plus
source of each data point
batch type (research, pilot, production)
batch number
manufacturing date
 Data
tabulated by storage condition
Data Analysis for Stability Reports
 Data
Tables, Plots, graphs and evaluations
 Documentation for statistical methods
used
 Estimated dating periods
Degradation Product Information
for Stability Reports









Procedure for isolation and purification
Test methods and validation data
Identity and structure
Physical and chemical properties
Degradation pathways
Levels detectable and quantifiable
Individual and total acceptance criteria
Biological and pharmacological relevance
Analysis of potential hazards
Conclusions Section of
Stability Reports
 Proposed
dating periods and justifications
 Regulatory specifications
Stability Information for the
BLA/NDA
 Stability
Method Validation Protocols,
Data, and Reports
 Proposed Dating


Retest Dates for in-process materials
Expiration Dates for final container material
 Primary
Stability Data to support the
proposed Expiration Dating and Shelf Life
 Specifications
Avoiding Common Pitfalls:
Phase 3 Clinical Development

Pitfall


Major process
changes invalidate or
call stability studies
into question, making
it hard to interpret
stability data
Pitfall



Not following the
Protocol
Inadequate handling of
deviations
Avoidance Strategy


Don’t do this! Work
with Process
Development and
Formulation so that
this doesn’t happen;
lock the process down
Avoidance Strategy


Effective CGMP
training
Vigorous QA auditing
Avoiding Common Pitfalls:
Phase 3 Clinical Development

Pitfall

Inconsistent stability
characteristics among
the 3 pre-approval lots
leads to approval
problems

Avoidance Strategy

Practice excellence in
Process Development
and in Manufacturing,
and in Analytical
Chemistry
Stability During:
Early Commercial Production
Overview of this section

1.
2.
3.
4.
5.

Regulations
Guidance
Goals and Objectives
Activities
Avoiding Common Problems and Pitfalls
Avoid major changes. Keep your
promises (stability commitments). Watch
for trends
Early Commercial Production:
Regulations
 Directly Applicable


CGMPs
310.303 - Continuation of long-term studies
 Target-setting

Regulations:
CGMPs
Regulations:
310.303

Sec. 310.303 Continuation of long-term studies,
records, and reports on certain drugs for which
new drug applications have been approved.



(a) A new drug may not be approved for marketing
unless it has been shown to be safe and effective for
its intended use(s).
After approval, the applicant is required to establish
and maintain records and make reports related to
clinical experience or other data or information
necessary to make or facilitate a determination of
whether there are or may be grounds under section
505(e) of the act for suspending or withdrawing
approval of the application.
Stability Guidance:
Early Commercial Production
 Directly Applicable



ICH Q1 Documents
ICH Q2 (R1)
Inspection Guides
Guidance
Early Commercial Production:
Stability Goals and Objectives

To continue/complete any unfinished work from
previous stage/phase



To have primary stability data on first 3
commercial lots of DS/API and DP





Keep your commitments!
Especially crucial for accelerated approval
Same Protocol as was used for Phase 3 clinical
efficacy studies
To confirm proposed dating
To meet stability commitments
Possibly to extend or shorten dating
To run stability studies, if needed, for changes
Stability Activities:
Early Commercial Production
 Continue
and complete primary studies
initiated during Phase 3
 Initiate and complete primary studies on
first 3 commercial lots (API and DP)
 Other stability commitment activities
 Special studies for changes and
reprocessed lots
Avoiding Common Pitfalls:
Early Commercial Production

Pitfall


Major process
changes invalidate or
call stability studies
into question, making
it hard to interpret
stability data
Pitfall



Not following the
Protocol
Inadequate handling of
deviations
Avoidance Strategy


Don’t do this! Work
with Process
Development and
Formulation so that
this doesn’t happen;
lock the process down
Avoidance Strategy


Effective CGMP
training
Vigorous QA auditing
Avoiding Common Pitfalls:
Early Commercial Production

Pitfall



Inadequate handling of
OOS and OOT Stability
Results
Pitfall

Failure to put reprocessed
batches on special protocol
studies
Avoidance Strategy


Major Protocol changes
Pitfall


Avoidance Strategy


Effective CGMP Training
and Vigorous QA
Leadership
Don’t do it!
Avoidance Strategy

Just do it!
Avoiding Common Pitfalls:
Early Commercial Production

Pitfall


Adverse Pre-approval
Inspection due to
inadequate stability
program
Pitfall


Failure to report
stability failures to
FDA
Avoidance Strategy


Start stability early and
provide resources;
Rigorous selfinspection
Avoidance Strategy

Regulatory knowledge;
Effective QA and RA
Leadership
Big Mistake!

Pivotal batch does not
represent current
process due to
process change made
prior to approval

excerpt from FDA 483
Stability For:
Mature Commercial Products
Overview of this section

1.
2.
3.
4.
5.

Regulations
Guidance
Goals and Objectives
Activities
Avoiding Common Problems and Pitfalls
Annual stability batches; new stability
studies for changes and for new products
Mature Commercial Product:
Regulations
 Directly Applicable

CGMPs
Regulations:
Stability Guidance:
Mature Commercial Products
 Directly Applicable


ICH Q1 Documents
ICH Q2 (R1)
Guidance
Mature Commercial Product:
Stability Goals/Objectives/Activities
 To
do an Annual Stability Batch each year
for the:


Annual Product Quality Review (APQR)
Annual Product Report
 To
put reprocessed batches on stability
 To do special studies for:



Changes
New dosage forms
New indications
Stability Information for the
Annual Report

Additional data from ongoing commitment
studies
 Tracking and Trending Data (OOT Results)
 Changes
 Deviations and OOS Results


Investigation, Impact, CAPA
Stability studies for reprocessed batches
 Data from regular annual batches
 Data to support post-approval changes
Avoiding Common Pitfalls:
Mature Commercial Products

Pitfall


Inadequate handling of
OOS and OOT
Stability Results
Pitfall


Protocol changes
Avoidance Strategy


Effective CGMP
Training and QA
Leadership
Avoidance Strategy

Don’t do it!
Special Stability Topics
Biotech
Stability
Evaluation of Stability Data
Bracketing and Matrixing
OOS and OOT Results
Inspection Preparation
Outsourcing
What’s special about
biotech stability?
Stability Testing of Biotech Products:
Special Considerations



Complex test articles and methods
Many degradation pathways/products
Activity and Potency usually depend upon:



Liquid and lyophilized dosage forms




3-dimensional conformation
non-covalent forces as well as covalent bonds
Diluent
Reconstituted material
Container/closure contact studies
Involve biological assays (usually) for
potency/activity
Stability Testing of Biotech Products:
Special Considerations

Accelerated testing assumptions generally do
not apply
 Primary data typically “real time”
 Especially labile





temperature
oxidation
shear forces
ionic strength
light
Stability Testing of Biotech Products:
Special Considerations
 Often
made by aseptic processing
 Microbial testing is usual




Endotoxin
Microbial limit
Bioburden
Sterility or container/closure integrity
Evaluation of Stability Data
What statistics
do I need to know?

“No entry without
mathematics”.


Sign above the
entrance to Plato’s
Academy
“There are three kinds
of lies: lies, damned
lies, and statistics.”

Benjamin Disraeli
Essential Statistics for
Stability Work

Sampling
 Regression Analysis
 Descriptive Statistics




Mean
Standard Deviation
Relative Standard Deviation
95% Confidence Limits and Bands
 Test for equivalence of slopes
 Experimental Design (for I.P. and Matrixing)
Accelerated Stability Data
Arrhenius Equation
 Definition
•
•
•
This equation expresses the logarithmic
relationship between the rate constant of a
reaction and the reciprocal of the temperature
(expressed in K, which is degrees Kelvin)
Degrees Kelvin = Degrees Centigrade + 273.16
For example:
• Water Freezes: 0 0C = 273.16 0K
• Water Boils: 100 0C = 373.16 0K
Arrhenius Plot
Using the Arrhenius Equation
To determine incubation time at accelerated temperature
for stability claims:
1.
Acceleration Time = Time at T1/Q10 (T2-T1/10)
2.
Q10 = 2.0 (conservative; “Rule of Two”. For every 10
degree increase in temperature the rate of degradation
doubles)
3.
For T2= 45C, T1 = 23C and Q10= 2.0 and time at T1 =
12 months (365 Days)
•
T2-T1 = 22C
Acceleration Time = 12/2 22/10, = 12/2 2.2,
4.


= 12/4.6,
= 2.6 Months at 45C = 1 Year at 23C.
Using the Equation (continued)
Time at Room
Temperature (Years)
1
Time at 45C (Days)
2
158
3
237
4
316
5
395
79
Real Time Stability
Determining Stability Endpoints

For characteristics that decrease with time:



use 95% one-sided confidence limit for mean
degradation curve
end is time point at which confidence band intersects
the lower specification limit
For characteristics that increase with time:



use 95% one-side confidence limit for mean
degradation curve
end is time point at which confidence band intersects
the upper specification limit
remember: individual and total
From ICH Q1E
Shelf life Estimation with Upper and Lower Acceptance Criteria Based on Assay at
25C/60%RH
120
Assay (% of Label Claim)
115
110
105
Raw Data
100
Upper confidence limit
95
Lower confidence limit
Regression line
90
85
Upper acceptance
criterion: 105
80
Lower acceptance
criterion: 95
0
3
6
9
12
15
18
21
24
27
30
Time Point (Months)
33
36
39
42
45
48
From ICH Q1E
Shelf life Estimation with Upper Acceptance Criterion Based on a Degradation
Product at 25C/60%RH
3.0
Degradation Product (%)
2.5
2.0
1.5
Raw Data
Upper confidence limit
1.0
Regression line
Upper acceptance
criterion: 1.4
0.5
0.0
0
3
6
9
12
15
18
21
24
27
30
Time Point (Months)
33
36
39
42
45
48
Determining the Date of
Manufacture
 The

date of QA release
OK if not more than 30 days from start of
manufacture
 The
date of the last processing step
 The date of the final lot release assay
results

For biotech often the date the biological
potency assay results are obtained
Special Stability Topics
Bracketing and Matrixing
(ICH Q1D)
ICH Q1D: Objective
 This
guidance is intended to address
recommendations on the application of
bracketing and matrixing to stability
studies conducted in accordance with
principles outlined in the ICH Q1A (R2).
ICH Q1D
 General
considerations
 Applicability of reduced designs
 Bracketing
 Matrixing
 Creating Bracketing and Matrixing study
designs (Class participation)
ICH Q1D: General

Full Study Design


Samples for every combination of all design factors
are tested at all times
Reduced Study Design




Samples for every factor combination are not tested
at all times
Suitable alternative to a full design when multiple
design factors are involved
Should have the ability to adequately predict the
retest period or shelf life
It has to be justified
ICH Q1D: General (cont.)
 Potential

It is possible to establish a shorter retest
period or shelf life than can be derived from a
full design due to reduced amount of data
collected.
 Potential

Risk of reduced designs:
benefit of reduced design:
Smaller sample size is needed.
ICH Q1D: General (cont.)
 During
the course of a reduced design
study, a change to full testing or to a less
reduced design is possible provided that:


There is good justification for the change
Proper adjustments are made to statistical
analysis to account for the increase in sample
size
Applicability of Reduced Designs
 Reduced
designs can be applied to formal
stability study of most drug products.
 Reduced designs have limited utility for
the stability studies of drug substances.
Bracketing

Definition:


Bracketing is the design of a stability schedule such
that only samples on the extremes of certain design
factors (such as strength, container size, fill size) are
tested at all time points as in a full design.
Logical Assumption:


The design assumes that the stability of any
intermediate level is represented by the stability of the
extremes tested.
Bracketing is not considered appropriate if it can not
be demonstrated that the selected design factors are
indeed the extremes.
Bracketing: Design Factors
 Design
Factors are variables to be
evaluated in a study design for their effect
on product stability.
 Strength, container closure size, and fill
size are most common design factors
considered in bracketing designs.
Bracketing: Strength

Bracketing can be applied to studies with
multiple strengths of identical or closely related
formulations.


Example: oral solutions of different strengths with
formulations that differ only in minor excipients, such
as colorants or flavoring
In cases where different excipients are used
among strengths, bracketing is not applicable.
Bracketing: Container Closure sizes
and/or Fills

Bracketing can be applied to studies of the same
container closure system where either container
size or fill varies while the other remains
constant.
 In a bracketing design where both container size
and fill vary, it should not be assumed that the
largest or the smallest containers represent the
extremes of all packaging configurations.
Bracketing: Container Closure sizes
and/or Fills (cont.)

In selecting the extremes, compare the various
characteristics of the container closure system
that may affect product stability.
 Examples: container wall thickness, closure
geometry, surface area to volume ratio,
headspace to volume ratio, water vapor
permeation rate or oxygen permeation rate per
dosage unit or unit fill volume
Bracketing: Design Considerations

If ,after a study has started, one of the extremes
is no longer expected to be marketed, then the
study design should be adjusted to support the
bracketed intermediates.
 If the stability of the extremes is shown to be
different, the intermediates should be considered
no more stable than the least stable extreme.
Matrixing

Definition:


Matrixing is the design of a stability schedule such
that a selected subset of the total number of possible
samples for all factor combinations would be tested at
a specified time point.
Logical assumption:

The design assumes that the stability of each subset
of samples tested represents the stability of all
samples at a given time point.
Matrixing (cont.)

When using matrixing designs, consider the
differences in the samples for the same drug
product; such as different batches, different
strengths, different sizes of the same container
closure system.
 Each storage condition should be treated
separately under its own matrixing design.
Matrixing: Design Factors
 Matrixing
can be applied to studies with
multiple strengths of identical or closely
related formulations.

Example: Tablets of different strengths
manufactured by compressing varying
amounts of the same granulation.
Matrixing: Design
Considerations
 A matrixing
design should be balanced as
far as possible so that each combination of
factors is tested to the same extent over
the intended duration of the study and
through the last time point prior to
submission.
 Is it possible to achieve a completely
balanced matrixing design?
Matrixing: Design
Considerations (cont.)
 It
is difficult to achieve a complete balance
in a design where time points are
matrixed, because full testing at initial and
final time points are required.
Matrixing: Design
Considerations (cont.)

Prior to submission:


Stability data at 12 months or at the last time point
should be available for all selected combinations of
batch, strength, container size, and fill.
At accelerated or intermediate storage condition,
stability data is required at a minimum of 3 time
points, including initial and final, for each selected
combination of factors.
Matrixing: Applicability and Degree of
Reduction
 When
a matrixing design is contemplated,
consider the following:





Knowledge of data variability
Expected stability of the product
Availability of supporting data
Stability differences in the product within
factor or among factors
Number of factor combinations in the study
Matrixing: Applicability and Degree of
Reduction (cont.)
 A matrixing



design is appropriate if
Supporting data indicate predictable product
stability
Supporting data exhibit minor variability
Supporting data exhibit moderate variability
(with statistical justification)
Matrixing: Applicability and Degree of
Reduction (cont.)

The degree of reduction from a full design
depends on the number of factor combinations
being evaluated. The more factors associated
with a product and the more levels in each
factor, the larger the degree of reduction that
can be considered for a matrixing design.
 The ultimate goal is that any reduced design
should have the ability to adequately predict the
product shelf life.
Matrixing: Potential Risk

Due to the reduced amount of data collected, a
matrixing design on factors other than time
points generally has less precision in shelf life
estimation and yields a shorter shelf life than the
corresponding full design
 A matrixing design may be inadequate to detect
certain main or interaction effects, thus leading
to incorrect pooling of data from different design
factors during shelf life estimation.
Reduced Designs: Data Evaluation
 Stability
data from studies in a reduced
design should be treated in the same
manner as data from full design studies.
Handling OOS and OOT
Stability Results
What to do in case of
OOS results?


No SOP to handle
investigations of unusual
stability study results
Unapproved method
results used to pass
stability even though
samples failed approved
method

excerpts from FDA 483s
OOS Stability Results:
Primary Studies
 Lab
Investigation
 Failure Investigations (211.192)
 Recall of clinical or marketed material
may be necessary
 Notification of FDA may be necessary
 Shortening of expiration dating period
may be necessary
 Reformulation may be needed
OOS Handling Resources
 ICH
Q7: GMPs for APIs
 FDA Guidance for Industry: Investigating
Out of Specification (OOS) Test Results
(2006)
 IVT Report on OOS Results
(www.ivthome.com)
 EIRs, 483s, Warning Letters
As if handling OOS was not
enough…….
 OOT
stability data identification and
investigation is rapidly gaining regulatory
interest


An OOT result is a stability result that does
not follow the expected trend, either in
comparison with other stability batches or with
respect to previous results collected during a
stability study.
The result is not necessarily OOS but does
not look like a typical data point.
OOT Results
 OOT



Stability Results
Within batch
Between batch
See Pharmaceutical Technology:
• April, 2003, pp 38-52
• October, 2005, pp 66-78
Preparing for FDA
Inspection of Your
Stability Programs
The Pre-Approval Inspection





Data authenticity and integrity
Accountability/reconciliation of stability
samples
Accessibility of raw data
Assay validation Protocols and Reports
Plant capability
The CGMP Inspection
 State
of Control
 Commitment to Quality
 Follow-through
 Failures
The CGMP Inspection
 Description

of ongoing stability program
Tracking and Trending
 Changes
since BLA/NDA
 OOS Results


Investigation
CAPA
 Validation


and Qualification Data
Assays
Chambers
The Systems Inspection
 Quality
System
 Facilities and Equipment System
 Materials System
 Production System
 Packaging and Labeling System
 Laboratory Controls System
Systems Inspections
 Full


Inspection
The Quality System
3 Other Systems
 Abbreviated


Inspection
The Quality System
1 Other System
The Best Ways to Prepare
for an Inspection




Self-assessment
Continuous Improvement
Internal Auditing
Special Emphasis on:




Sample accountability
Document availability: SOPs, Batch Records,
Development Reports, Raw Data
Validation
Deviation and OOS investigation and closure
• CAPA

Who will host the inspection
Inspection Preparation Resources
 ICH
Guides
 FDA Inspection Guides
 EIRs, 483s, Warning Letters
 Inspector Technical Guide (ITG): Stability
Section (Appendix 4)
Points to Consider in Assessing a
Stability Program









Written program?
QA review and approval of all procedures and data
Data to support all dating?
Does data reported match raw data found on site?
Separate expiration dates product before and after
reconstitution?
Similar equipment used to produce stability batches?
At least three batches on long-term studies?
Ongoing program for both DS and DP?
Can all samples be accounted for?
Points to Consider in Assessing a
Stability Program

Acceptable test intervals?
 Actual temperature and humidity conditions of storage
recorded?
 Validated method to quantify degradation products?
 Primary studies performed in marketing container
closure system?
 Preservatives being monitored?
 Sterility testing being performed?
 What is done when an OOS result is obtained?
 Have anomalies gone unquestioned?
 Do computers have adequate security and audit trails?
Special Stability Topics
Outsourcing
What if I contract out my studies?




Contract laboratory not
specified in NDA was used
Stability data from contract lab
was not reviewed or evaluated
No clear responsibility for QA
functions between contractor
and firm
Stability SOP not available at
study site

excerpts from FDA 483s
Outsourcing Stability Work
 General
Considerations
 Quality Agreements
 FDA Notification
 Auditing for compliance
Special Considerations for
Outsourcers





Contract facility is considered an extension of
your facility
Your quality organization is responsible for all
data and all products
Higher risk of having changes requiring repeat
studies
Need for ongoing external audit program
Have on file:


copies of all analytical procedures
documentation assuring validity of analytical
procedures
Outsourcing
 Items




of intense regulatory scrutiny:
Technology transfer
Change Control
Deviations and OOS results
Product release
Quality Agreements
 General


Points:
Contracting arrangements and Quality
Agreements are items of increasing regulatory
scrutiny
Quality Agreement should precede and be
separate from Business Contract
Quality Agreements

The Quality Agreement should address:



GMP compliance commitment
Respective roles in achieving compliance
Clear definition of auditing conditions
• Periodic
• For cause




Lot release
Change control
Deviation and OOS handling/investigations
Validation
Auditing for Compliance








Should be done by QA
Focus on Items in Quality Agreement
Look for changes which have not been
communicated
Look for proper data recording and storage
Look at deviations and OOS results
See next section: Inspection Preparation
See Warning Letters and 483s
See FDA/ORA Inspection Guides
5 “Target Rich” Areas at Contract
Facilities
1.
2.
3.
4.
5.
Personnel training
Equipment handling
Data and Records
Discrepancy investigation
Test method validation
Quality Agreement Reference
 See
The Gold Sheet, November, 2002
(Vol. 36 No. 11)
 Published by FDC Reports, a division of
Elsevier
 www.thegoldsheet.com
 Customer Service


[email protected] or
call 800-332-2181
Stability Resources
Online Access:
Laws, Regulations, and Guidance
•
U.S. Laws, Regulations and Guidance
•
www.fda.gov
•
•
•
•
•
European Regulations and Annexes
•
•
Laws FDA Enforces
Code of Federal Regulations
Guidance Documents
Federal Register
http://pharmacos.eudra.org/F2/eudralex/vol4/home.htm
ICH
•
www.ich.org
Other Resources
 FDA





Compliance Policy Guides (CPGs) and
CPGMs (manuals)
Establishment Inspection Reports (EIRs)
483 Notices of Deficiency
Warning Letters
Inspection Guides
 PDA Technical

Reports!
www.pda.org: “Science and Technology”
FDA e-mail Alerts
 www.fda.gov
 CDER:

http://www.fda.gov/cder/cdernew/listserv.html
 CBER:

http://www.fda.gov/cber/pubinfo/elists.htm
The PSDG
 Pharmaceutical
Stability Discussion
Group:

www.microbiol.org/psdglist.htm
Course wrap-up and
conclusions
Typical API & Drug Product Stability
Activities at Each Stage of a Product’s Life
Pre-clinical
No GMP
Requirements
Early Clinical
Late Clinical
Post-marketing
I.D. Degradants
Seen Real Time
First 3
Commercial
Scale Batches
On Real Time
Studies
GMP
Requirements
Forced
Degradation
[Accelerated]
GLP Real
Time Study
Concurrent
CGMP Studies
Pivotal Studies
for MAA
Studies for
Changes, etc.
Studies for
Annual Reports
A Review of Common
Stability Deficiencies
Common Stability Deficiencies
 Lack
of stability program
 Failure to follow stability program
 Not investigating failing stability
results/products
 Stability failures not reported to FDA
 Stability samples stored in different
container than product
Common Stability Deficiencies
 Testing
does not include analysis of
reconstituted products
 Stability retest protocol allows failed
sample retest without an investigation
 No moisture content specification even
though known to impact stability
 Lot failing moisture specification released
with shortened expiration date
Common Stability Deficiencies
 Reprocessed/reworked
lots not placed on
stability
 Stability samples not tested for sterility or
container integrity
 Product re-dating performed after a single
potency test
 Expiration date extended without agency
approval
Common Stability Problems
 Analytical
method not stability indicating/
Inadequate validation of stability indication
 Missing stability samples/all stability
samples not accounted for
 Inadequate qualification of stability
chambers
Stability 483s
The Quintessential 21st Century 483
 Firm’s
investigation into this deviation is
deficient in that it:



Failed to note and provide root causes
Failed to note and provide corrective and
preventative actions (CAPA)
Failed to address all the systemic deficiencies
implicated in this observation
Stability 483
“On five occasions 5 valid tests (4 IEF Western blot assays
and 1 SDS-PAGE Western blot assay) for stability
samples……….were invalidated. Resampling and
retesting were performed by the same analyst for one of
the assays and OOS results were obtained. A laboratory
investigation was then initiated and found no assignable
cause. The OOS investigation…concluded that the initial
OOS and repeat OOS results would be qualified as
invalid due to insufficient training of the analyst.
Resampling and retesting were performed and reported
as the final results. The investigation performed was not
adequate to support invalidating the initial valid test
results obtained.”
Very Illustrative Stability 483


Deficient stability program for US licensed products:
Does not include sterility testing at any point after
release (time 0)
 Does not include any other microbiological evaluation
after time 0
 No data to demonstrate product remains sterile
throughout shelf life
 Does not adhere to stability SOPs
 No SOP for final product stability programs
 Stability time points not always assigned and tested per
SOP
 Samples are tested later than their assigned dates
 Current sample testing in not based upon labeled
expiration dates
Very Illustrative Stability 483 (continued)

No evidence to indicate stability data have been
reviewed and approved
 Records not available to demonstrated when samples
were received by stability lab
 No acceptance criteria/specifications for pH testing
included in stability program
 Incorrect information entered into LIMS; e.g. stability
testing listed as complete, but:
 pH samples never delivered to lab and pH testing never
done
 Inconsistencies between LIMS-described stability testing
and that actually performed
 There is no review or approval of the stability program
 Inaccuracies and failures of the LIMS-based stability
system have gone uncorrected
More 483s
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Stability storage room not
validated for heat and
humidity distribution
Preservative effectiveness
testing not performed as
part of stability program
Raw material shelf life not
supported by historical data
Stopper extractable studies
did not assure drug contact
during stress studies

excerpts from FDA 483s
More 483s
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An unknown peak, observed during stability studies, has
not been identified
No assurance assigned and reported potency values are
accurate for:
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Stability test results for 3 released finished product lots within
expiry
Release test results for 3 distributed finished product lots within
expiry
Bulk release and in-process test results for 7 lots
Stability test results for 4 lots of distributed product past expiry
Ongoing stability study test results on 6 BLA conformance lots to
extend dating
More 483s
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No lab instructions for storage of stability
samples between receipt and testing
 Discrepancy Event Reports not closed within 30
days as required by SOP, e.g.:
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Stability failure investigation still ongoing, no
assignable cause determined after 6 mo.
Deficient investigation into OOS stability result:


Discrepancy Report not issued when lab investigation
showed no assignable cause
Root cause of OOS result was not determined
More 483s
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Inadequate handling of potency testing failure at 12
month time point:
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Firm has not performed hold time studies to determine
stability of product:


No assignable cause was determined, results were deemed
valid, and
A re-test was performed even though initial results were deemed
valid
Retest (passing) results were averaged with failing results to get
passing result
This stability testing failure was not reported to CBER
After sterile filtration and prior to dispensing into final containers
Maximum in-process hold times were not defined for
drug substances
More 483s
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Stability Data Tables contained discrepancies in
reporting of potency assays:
Stability Program SOP did not specify the number of
vials to be tested for potency at each interval
Stability samples not tested at least quarterly as required
by Stability Program SOP
Product appearance is evaluated as a lot release spec.,
but is not included as a stability spec.
Current stability testing SOP does not reflect actual
practices
Discrepancies were found in sample inventory records
for ongoing stability studies
More 483s
 All
analytical methods used in release and
stability testing have not been validated
 Reprocessed batches were not placed on
stability
 QA has not oversight over the stability
program