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1. 1
Vilayat A. Sayeed, Ph.D.
Division Director, Chem III, OGD
Lane V. Christensen, Ph.D.
Chemist, Immediate Office, OGD
Albinus D’Sa, Ph.D.
Deputy Country Director, India Office
Opinions expressed in this presentation are those of the speaker and do
not necessarily reflect the views or policies of the FDA
2. 2
Workshop Overview
Session 1
• OGD Overview/QbD Overview
• The Quality Target Product Profile
Session 2
• Product Design and Understanding
Session 3
• Process Design and Understanding
Session 4
• Control Strategy, Risk Assessment, Design of
Experiments
Session 5
• Generic Drug User Fees
3. 3
Workshop Overview
Session 1
• OGD Overview/QbD Overview
• The Quality Target Product Profile
Session 2
• Product Design and Understanding
Session 3
• Process Design and Understanding and Control
Strategy
Session 4
• Generic Drug User Fees
4. 4
Understanding Generic Approval
Process
Vilayat A. Sayeed, Ph.D.
Director, Division of Chemistry III
Office of Generic Drugs
Opinions expressed in this presentation are those of the speaker
and do not necessarily reflect the views or policies of the FDA
FDA, DIA India and Pharmexcil Workshop
April – May 2012
5. 5
Outline
• ANDA/Generic Product Requirement
• Filing and Quality Review Process
• Anticipated Time Line for QbD
Implementation
• Overview of recent changes
• OGD Outreach to Generic Industry
• Compliance
• United States Pharmacopeial Convention
(USP)
6. 6
Generic Product Requirement in US
for 505(j) Application
• Must have an approved reference product in US
• Must be bioequivalent (where applicable) and
Pharmaceutical equivalent to a brand name drug
(Therapeutic equivalent)
• And meet the quality standards
• All related facilities have acceptable CGMP
compliance
7. 7
ANDA Review Process Chart
ANDA Application
Acceptable And Filed
Refuse to Receive
No
Yes
cGMP CMC Review Micro ReviewBA/BE/Clinical Labeling Review
Deficiency Comments
Communicated to
ANDA Applicant
Not Acceptable Acceptable
ANDA Approved
DMF Review
9. 9
Filing and Quality Review Process
• Submission is checked by the regulatory branch for
completeness against a publically available check list
• Failing to meet either regulatory or technical data
requirement, a Refuse to Receive letter is issued
• In 2011, 148 ANDAs were RTR (RTR may have
financial implication starting 10/2012)
• Check list is updated every quarter
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDru
gsareDevelopedandApproved/ApprovalApplications/Abbreviate
dNewDrugApplicationANDAGenerics/default.htm
• Upon filing it is assigned to appropriate quality review
divisions
11. 11
The Timeline for QbD
Implementation
May
2010
May
2011
Fall
2011
Winter
2012
Spring
2012
Spring-Fall
2012
Jan
2013
= QbD Implementation for Generic Drugs
12. 12
QbD Implementation Benefits
• Enhance Knowledge Sharing
• Improve Time to Market (potentially compressing
approval time)
• Reduce cost associated with poor quality (recalls and
rejects)
• Improve Consumer Generic Skepticism
• Minimize Post-approval Changes
13. 13
Overview of Recent Changes
BA/BE Requirement
• Submit all failed bio-studies and related CMC information
required under 21 CFR 320.1(g)
• For certain therapeutic class drugs 90% confidence
interval range may change to 90-111% for AUC – Under
discussion
• Significance of Tmax in BA/BE assessment
CMC Expectations for Generic Drugs
• Office of Generic Drugs is planning to fully adopt Q1
stability guidance's for generic drug applications including
• Q1A (R2) Stability Testing of New Drug Substances and
Products
• Q1B Photostabiltiy Testing of New Drug Substances and
Products
14. 14
Overview of Recent Changes
CMC Expectations for Generic Drugs
• Q1C Stability Testing for New Dosage Forms
• Q1D Bracketing and Matrixing Designs for Stability
Testing of New Drug Substances and Products
• Q1E Evaluation of Stability Data- statistical analysis
• OGD is requesting sponsor to include
• Quality target product profile (QTPP)
• Critical quality attributes (CQAs) of the drug product
• Product design and understanding including identification of
critical excipient and drug substance attributes
• Process design and understanding including identification of
critical process parameters
• Control strategy and justification
15. 15
Overview of Recent Changes
Agency Guidance (Review Related)
• Residual Drug in Transdermal and Related Drug
Delivery Systems (Final – 8/2011)
• Size of Beads in Drug Products Labeled for Sprinkle
(Final – 2/2012)
• Tablet Scoring: Nomenclature, Labeling, and Data for
Evaluation (Draft – 8/2011)
• Limiting the Use of Certain Phthalates as Excipients
in CDER-Regulated Products (Draft – 3/2012)
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInf
ormation/Guidances/ucm064979.htm
16. 16
Overview of Recent Changes
Agency Guidance (CGMP/Compliance)
• Dosage Delivery Devices for Orally Ingested OTC
Liquid Drug Products (Final – 5/2011)
• Process Validation: General Principles and Practices
(Final – 1/2011)
• Non-Penicillin Beta-Lactam Risk Assessment: A
CGMP Framework (Draft - 3/2011)
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInf
ormation/Guidances/ucm064971.htm
17. 17
OGD Outreach to Generic Industry
• Control Correspondence (use only when the
information is not available on Website)
• Quality by design (QbD) for a modified release
dosage form
• Model Bioequivalence data summary table and
more info
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDev
elopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicat
ionANDAGenerics/ucm142112.htm
18. 18
cGMP/Compliance
• All facilities used must be in compliance
• Inspection program is also design to check data integrity
– If data integrity is in question all review will stop
• Post-approval – validation activities is the responsibility
of compliance
– Compliance may use the new PV guidance for validation
• Pre-approval inspection
19. 19
United States Pharmacopeial Convention (USP)
• Compendia articles have to meet or exceed USP
standards (legal requirement)
– Failing to meet can potentially delay the approval process
• Pharmacopeial Forum (PF) - not official but can change
the status and impact the approvability
– Be proactive in this process with USP
• Pending Monographs (Draft and Authorize)
– Refer to USP website for its intent for this process
• Pending monographs not official until the Agency
approves application supporting pending monograph
• Meeting the pending monograph requirement does not
make the product USP
21. 21
GDUFA Goals
• Backlog file review
• ANDA review
• Type 2 DMF assessment
• Facility Inspections
• Communications
• Regulatory Research
• Hiring
22. 22
ANDA Review Goals
• 90% of ANDAs reviewed in 10 months
• Ramp-up over next 5 years of program
• In year 3 on words
– 60% in 15 months
– 75% in 15 months
– 90% in 10 months
23. 23
Backlog Review Goals
• 90% of ANDAs, Amendments, and PASs by end of
5th year.
• Applies to files pending review on 10/1/12.
24. 24
Type 2 DMF Goals
• Applies to all DMFs (eCTD format submission highly
recommended)
• Completeness “Filing” assessment
• Posting on FDA external website
“Available for reference by ANDA”
• DMF list will be updated every week
• Letter to DMF-holder will be issued in support of an ANDA
approval
• Any updates in agency’s opinion that have an adverse
effect on quality and safety of the DS may make it
deficient
27. 27
Regulatory Science Goals
• FDA – Industry Working Group
• Annual list of projects
• Examples:
– BE of locally-acting products
– Excipient effects on permeability & absorption
– Post-marketing surveillance
– Phyisicochemical characterization of complex drug
substances
28. 28
Hiring Goals
• Hiring for:
– CDER
– Office of Regulatory Affairs
– Office of the Commissioner
• Goals:
– 25% in FY-13
– 50% in FY-14
– 25% in FY-15
31. 31
Overview of QbD for Generic
Drugs
Lane V. Christensen, Ph.D.
Chemist, Immediate Office
Office of Generic Drugs
Opinions expressed in this presentation are those of the speaker
and do not necessarily reflect the views or policies of the FDA
FDA, DIA India and Pharmexcil Workshop
April – May 2012
32. 32
Patients
* Benefit *
Regulators Benefit
Manufacturers Benefit
QbD enhances the quality of generic drugs
Pharmaceutical Quality in the 21st
Century
“We will implement QbD together”
-- Lawrence Yu, PhD
OGD Deputy Director for Science and
Chemistry
33. 33
FDA’s Strategic Plan Priority Areas:
1. Modernize Toxicology to Enhance Product
Safety
2. Stimulate Innovation in Clinical Evaluations
and Personalized Medicine to Improve
Product Development and Patient Outcomes
3. Support New Approaches to Improve Product
Manufacturing and Quality
4. Ensure FDA Readiness to Evaluate
Innovative Emerging Technologies
5. Harness Diverse Data through Information
Sciences to Improve Health Outcomes
6. Implement a New Prevention-Focused Food
Safety System to Protect Public Health
7. Facilitate Development of Medical
Countermeasures to Protect Against Threats
to U.S. and Global Health and Security
8. Strengthen Social and Behavioral Science to
Help Consumers and Professionals Make
Informed Decisions about Regulated Products
35. 35
• Differences in product quality is not
acceptable
• The responsibility of OGD/generic industry
is to support public confidence in generic
drug product quality
Importance of Generic Drug Product
Availability
36. 36
What is Pharmaceutical Quality?
• Janet Woodcock
– Free of contamination and reproducibly
delivering the therapeutic benefit
promised in the label
Pharmaceutical Quality
= f(Drug substance, excipients,
manufacturing, and packaging)
• ICH Q8 R(2)
– The suitability of either a drug substance or a drug
product for its intended use
• Quality cannot be tested into products; quality
can only be built into products
37. 37
What is a Generic Drug?
• A generic drug is therapeutically equivalent to
the brand name drug.
• Therapeutic Equivalence
– “have the same clinical effect and safety
profile when administered to patients under
the conditions specified in the labeling”
• FDA Practice
– Pharmaceutical Equivalence +
Bioequivalence
= Therapeutic Equivalence
38. 38
Pharmaceutical Equivalence
• Same active ingredient(s)
• Same dosage form
• Same route of administration
• Identical in strength or concentration
• Meet compendial or other applicable
standards of strength, quality, purity, and
identity
• May differ in shape, excipients,
packaging...
39. 39
Bioequivalence
• Absence of a statistically significant
difference in the rate and extent to which
the active ingredient in pharmaceutically
equivalent products becomes available at
the site of action, when administered to
subjects at the same molar dose under
similar conditions.
41. 41
Claimed to be Acceptable Based Upon
a Passing BE study to the RLD
“Equivalence by Testing”
Past/Present Paradigm QbD Paradigm
Asks Sponsors How They Systemically
Arrived at a Bioequivalent Drug Product
“Equivalence by Design”
ANDA Formulation/Process
Submitted Without Context
Systematic approach
QTPP/CQA: predefined target.
Product & process design and
understanding: pharmaceutical
equivalence to the RLD.
Control strategy: to ensure
intended performance be
consistently delivered.
Paradigm Shift
42. 42
OPS View on Modern Manufacturing
Science
• Moving toward a common view on QbD
• OPS MaPP 5016.1: “Applying ICH Q8(R2), Q9,
and Q10 Principles to CMC Review”
• Focusing on better understanding through QbD
concepts to reduce
postmarketing issues
• QbD examples for the
generic industry and FDA
– Industry’s contribution
Helen Winkle, OPS Director, CDER, FDA
43. 43
New Drug QbD Submissions
0
1
2
3
4
5
6
7
8
9
10
2005 2006 2007 2008 2009 2010 2011 2012
Fiscal Year
NumberofSubmissions
0
10
20
30
40
50
60
70
CummulativeNumber
# of QbD NDAs
# of QbD Supplements
Cummulative
QbD pilot program initiated in 2005
44. 44
ANDA QbD Submissions
• Submissions containing QbD elements are
being tracked
• >60 ANDAs containing QbD elements
reviewed or under review
• Submissions currently being filed for
review?
• 100% by January 1, 2013
45. 45
Quality by Design (QbD) and
Question-based Review (QbR)
Generic Applicant:
Implementing
QbD in development,
manufacturing, and control
FDA OGD:
Developed a QbR System
that assesses applicant’s
QbD ANDAs
FDA’s Pharmaceutical cGMP
for the 21st Century
QbD Initiative, ICH Q8, Q9, and Q10
46. 46
Question-based Review (QbR)
• Implemented for generic drugs in 2007
• QbR is a general framework for a science and risk-based
assessment of product quality
• QbR contains the important scientific and regulatory
review questions to
– Comprehensively assess critical formulation and manufacturing
process variables
– Set regulatory specifications relevant to quality
– Determine the level of risk associated with the manufacture and
design of the product
Generic Drugs Information for Industry>Question based Review webpage:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandAp
proved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm12097
1.htm
47. 47
Reviewer Perspective of QbR
• Allows more focused Scientific Review
less typing and documentation time
• Guides firms to provide more pertinent and
focused information better submissions
• Facilitates a consistent review process
• Facilitates applicant’s product and process
understanding
• Promotes consistency in the information
provided
48. 48
Changes coming for QbR
• Revision of QbR to be presented at the
upcoming GPhA meeting in May.
– Refer to DMF??
– Contain QbD elements
– More focus on understanding of the drug
product, development process and how it is
controlled
• FAQ document and model QOS examples
under development
49. 49
QbD for Generic Drugs
OGD will use the “enhanced” QbD approach as defined in
ICH Q8(R2). It should include the following:
• Quality target product profile (QTPP)
– Including critical quality attributes (CQAs) of the drug product
• Product design and understanding (through, e.g., prior
knowledge, experimentation and risk assessment)
– Critical material attributes (CMAs) of the drug substance and excipients
• Process design and understanding (through, e.g., prior
knowledge, experimentation and risk assessment)
– Critical process parameters (CPPs)
• Control strategy, including justification
50. 50
QbD Examples
• Intended to illustrate the types of development
studies ANDA applicants may use as they
implement QbD
• Provide a concrete illustration of the QbD
principles from ICH Q8, Q9 and Q10
– Both IR and MR illustrate QbD principles
• Development of a real product may differ from
the examples
• Number of experiments may depend on the
experience of the applicant
– This should be explained in the submission
51. 51
QbD IR Example
• IR tablet
– Low solubility drug substance: Acetriptan
– Manufactured by roller compaction
– Uses common excipients in similar amounts to the
RLD
Ingredient Function Weight/tablet (mg) % (w/w)
Acetriptan, USP Active 20.00 10
Intragranular Excipients
Lactose Monohydrate, NF Filler 81.5 40.75
Microcrystalline Cellulose, NF Filler 81.5 40.75
Croscarmellose Sodium, NF Disintegrant 6 3
Talc, NF Glidant/Lubricant 5 2.5
Extragranular Excipients
Magnesium Stearate, NF Lubricant 1 0.5
Talc, NF Glidant/Lubricant 5 2.5
Total Weight 200.0 100
52. 52
QbD MR Example
• MR Tablet with IR and ER components
– High solubility drug substance: Z
– Biphasic release to achieve particular clinical profile
– ER beads coated with release controlling polymer
– IR granules and ER beads compressed into a tablet
– Discussion of scale up issues
53. 53
Quality Target Product Profile
(QTPP)
• A prospective summary of the quality
characteristics of a drug product that will
ideally be achieved to ensure the desired
quality (performance)
• Guide to establish formulation strategy
and keep the product development effort
focused and efficient
54. 54
Basis for Establishing QTPP
for ANDA
• Pharmaceutical equivalence and
bioequivalence
• Analysis of the reference listed drug
product
– Clinical use
– Pharmacokinetics
– Drug release
– Physicochemical characterization
• Product labeling/administration
55. 55
What Does QTPP Include?
• Intended use in clinical setting
– Route of administration, dosage form (delivery
systems), and container closure system
• Quality attributes of drug product
– Appearance, Identity, Strength, Assay, Uniformity,
Purity/Impurity, Stability, and others
• Active pharmaceutical ingredient release or
delivery and attributes affecting
pharmacokinetic characteristics (Safety and
efficacy)
– Dissolution, aerodynamic performance
56. 56
Common QTPP Format
• Include Standard Elements in the First Table
– Dosage form
– Dosage design
– Route of administration
– Dosage strength
– Container closure system
– Pharmacokinetics
– Drug product quality attributes
• Criticality and justification in a separate table (CQA table)
– Stability
– Administration/concurrence with labeling
• Include Target
• Include Justification for Target
59. 59
Critical Quality Attributes (CQA)s
• ICH Q8 (R2) definition:
– CQA is a physical, chemical, biological, or microbiological property or
characteristic that should be within an appropriate limit, range, or
distribution to ensure the desired product quality.
• OGD recognizes the ICH Q8 (R2) definition and identifies CQA
based on the severity of harm to a patient (safety and efficacy)
resulting from failure to meet that quality attribute.
• In the context of product development, only the subset of CQAs that
have a high potential to be impacted by the formulation or process
variables will be investigated and discussed in detail in subsequent
formulation and process development.
– Not all CQAs are impacted by formulation and process development
(i.e. identity) not discussed further in detail
– All quality attributes are target elements of the drug product and should
be achieved through a good quality management system, appropriate
formulation/process design and development.
62. 62
Steps for Product Understanding
1. Identify all possible drug substance and excipient attributes that
could impact the performance of the product as per label claim
2. Use risk assessment and scientific knowledge to identify potentially
high risk drug substance and excipient attributes
3. Determine levels or ranges of these attributes to be investigated
4. Design experiments, using DOE when appropriate
5. Conduct actual experiments
6. Analyze experimental data to determine if an input material attribute
is critical.
– An input material attribute is critical when a realistic change in
that material attribute can significantly impact the quality of the
output materials.
7. Establish the control strategy
– For critical attributes, define acceptable ranges. For non critical
attributes, the acceptable range is the range investigated.
65. 65
Steps for Process Understanding
1. Identify all possible material attributes and process parameters that
could impact the performance of the process
2. Use risk assessment and scientific knowledge to identify potentially
high risk attributes and/or parameters
3. Determine levels or ranges of these variables to be investigated
4. Design experiments, using DOE when appropriate
5. Conduct actual experiments
6. Analyze experimental data to determine if an input material attribute
or process parameter is critical.
– A material attribute or process parameter is critical when a
realistic change in that material attribute or process parameter
can significantly impact the quality of the output materials.
7. Establish the control strategy
– For critical material attributes or process parameters, define
acceptable ranges. For non critical attributes, the acceptable
range is the range investigated.
66. 66
MR QbD Example: Risk Assessment
Process
Variables
Risk
Asses
sment
Justification and Initial Strategy
Product
temperature
High
Product temperature is a function of inlet air
temperature, air volume, and spray rate.
If product temperature is too high, spray drying
may occur and results in large amount of fines.
If product temperature is too low, agglomeration
may occur.
Process efficiency and dissolution profile may be
impacted.
Investigate with DOE
Air volume High
If air volume is too high, spray drying may occur.
If air volume is too low, agglomeration may occur.
Process efficiency and dissolution profile may be
impacted.
Investigate with DOE
Spray rate
per nozzle
High
If spray rate is too high, agglomeration may occur.
If spray rate is too low, spraying time may be too
long and spray drying may occur.
Process efficiency and dissolution profile may be
impacted.
Investigate with DOE
Atomization
air pressure
High
If atomization air pressure is too high, attrition to
the beads may occur.
If atomization air pressure is too low,
agglomeration may occur.
Process efficiency and dissolution profile may be
impacted.
Investigate with DOE
Process
Variables
Risk
Assessme
nt
Justification for the Mitigated Risks
Product
temperature
Low
Product temperature range is identified.
Product temperature is a scale
independent parameter, and can be
applied to other scales.
Air volume Medium
Air volume range is identified at 40 kg
scale. Air volume is a scale dependent
parameter. Further adjustment may be
necessary.
Spray rate Medium
Spray rate range is identified at 40 kg
scale.
Spray rate is a scale dependent
parameter. Further adjustment may be
necessary.
Atomization
air pressure
Low
Atomization air pressure is identified at 40
kg scale. Atomization air pressure is a
scale dependent parameter. However, the
atomization air pressure for each nozzle is
kept the same.
Mitigated risks after process development
Initial risk assessment for the coating process of ER beads
67. 67
Scale Effect on Design Space
10 Fold
=
?
Lab/Pilot Scale Design Space Commercial Scale
Design Space
Generation
Confirmation
To be verified
68. 68
Design Space of What?
• Lab scale design space
• Pilot scale design space
• Commercial scale design space
• Only commercial scale design space can
have meaningful regulatory flexibility as
defined in ICH Q8(R2)
Are sources of variability
defined at this point?
69. 69
Where we are. . .
• IR and MR examples are for illustrative purposes and
have been completed to be used to understand concepts
• Training
• OGD has received >60 submissions containing QbD
elements and receiving meeting requests by applicants
for further clarification.
• Meetings with the Generic Industry/GPhA
– 3 QbD Workshops – June 2009, May 2010, May 2011, Oct 2011
– 4 QbD Roundtable Discussions – Jun 2009, Oct 2009, Feb 2011,
Apr 2011
Prior knowledge, risk analysis
• Other professional meetings, workshops, . . .
70. 70
Publications
• A. Srinivasan, R. Iser. Common Deficiencies in Abbreviated New Drug
Applications (Part 4). Pharm Tech. 35:62-68 (2011).
• A. Srinivasan, R. Iser and D. Gill, Common Deficiencies in Abbreviated New
Drug Applications (Part 3) Pharm. Tech. 35 (2), 58–67 (2011).
• A. Raw, R. Lionberger, and L. X. Yu. Therapeutic equivalence by design for
generic drugs: Modified release products. Pharm. Res. 28, 1445-1453
(2011).
• A. Srinivasan and R. Iser, Pharm. Tech. 34 (1), 50–59, (2010).
• A. Srinivasan, R. Iser and D. Gill, Pharm. Tech. 34 (8), 45–51 (2010).
• D. Skanchy. Question-Based Review: An FDA Reviewer’s Perspective.
Pharm Tech. 33 (10) 2009.
• L. X. Yu, R. Lionberger, M. C. Olson, G. Johnston, G. Buehler, and H.
Winkle. Quality by Design for Generic Drugs. October Issue, pp. 122-127
(2009).
• A. Srinivasan and R. Iser. FDA Office of Generic Drugs QbR Initiative: An
Update. J. Valid. Tech., 15 (2), 2009.
71. 71
Publications (continued)• W. L. Jiang and L. X. Yu. Quality evaluation of generic drugs. J. Prescription
Drugs. 79:39-42. (2008).
• W. Jiang and L. X. Yu. Modern pharmaceutical quality standard: Question-
based review. In Y. Qiu et al. (Ed.). Pharmaceutical Theory and Practice in
Developing Solid Oral Dosage Forms. 2008.
• R. Lionberger, L. X. Yu et al. Quality by design: Concepts for ANDAs. The
AAPS Journal. 10:268-276 (2008).
• L. X. Yu. Pharmaceutical quality by design: Product and process
development, understanding, and control. Pharm. Res. 25:781-791 (2008).
• L. X. Yu et al. FDA Office of Generic Drugs’ pharmaceutical quality initiative:
progress and feedback on Question-based Review. Pharm. Eng. 27,
Nov/Dec, 52-61 (2007).
• L. X. Yu et al. U.S. FDA Question-based review for generic drugs: A new
pharmaceutical quality assessment system. J. of Generic Medicines. 4:239-
248 (2007).
• S. L. Lee, A. S. Raw, and L. X. Yu. Significance of drug substance
physicochemical properties in Quality by Design. In M. C. Adeyeye and H.
G. Brittain (Eds.). Preformulation in Solid Dosage Form Development. 2007.
72. 72
Communication with OGD
We encourage you to apply Quality by Design (QbD) principles to the
pharmaceutical development of your future original ANDA product
submissions. A risk-based, scientifically sound submission would be
expected to include the following:
– Quality target product profile (QTPP)
– Critical quality attributes (CQAs) of the drug product
– Product design and understanding including identification of critical attributes of
excipients, drug substance(s), and/or container closure systems
– Process design and understanding including identification of critical process
parameters and in-process material attributes
– Control strategy and justification
An example illustrating QbD concepts can be found online at FDA's Generic
Drugs: Information for Industry webpage:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugs
areDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugAppl
icationANDAGenerics/UCM286595.pdf
73. 73
The Timeline for QbD
Implementation
May
2010
May
2011
Sep/Oct
2011
Fall
2011
Winter
2012
Spring
2012
Spring-Fall
2012
Jan
2013
= QbD Implementation for Generic Drugs
75. 75
Vilayat A. Sayeed, Ph.D.
Director, Division of Chemistry III
Office of Generic Drugs
Opinions expressed in this presentation are those of the speaker
and do not necessarily reflect the views or policies of the FDA
Quality Target Product Profile (QTPP) in
Generic Drug QbD Development
FDA, DIA India and Pharmexcil Workshop
April – May 2012
76. 76
Outline
• QTPP as it relates to Generic Product
• Essential and Dynamic Components
• Pre-formulation Studies
• Formulation Optimization
• Stability Studies
• Container/Closure System
• BA/BE pilot study/ies
• Process optimization and Exhibit Batch
77. 77
What is Quality Target Product Profile
(QTPP)?
• QTPP - A prospective summary of the
quality characteristics of a drug product
that ideally will be achieved to ensure the
desired quality, taking into account safety
and efficacy of the drug product.
– ICH Q8R(2)
78. 78
What is Quality Target Product Profile
(QTPP) for Generic Products?
QTPP for generics can be divided in two
components
• Essential Components - Generic application has
to be same as reference to meet 505(j)
requirement
• Dynamic Components – These are quality
components where flexibility is allowed with
justification
79. 79
Product Design Objective
• “In a QbD approach the product is designed to
meet patient needs and performance
requirements; the process is designed to
consistently meet product critical quality
attributes; the impact of starting and raw
materials and process parameters on product
quality is understood; and critical sources of
process variability are identified and controlled.”
ICH, Q8
80. 80
Generic Product Design Objective
Essential Components
• DS (e.g., same salt, ester etc)
• Dosage form (tablets, capsules, creams etc)
• Strength (single or multiple)
• Route of administration (oral, topical,
transdermal, IM, IV, IT etc)
• Condition of use/labeling*
– *Exceptions as allowed by regulation
81. 81
Generic Product Design Objective
Dynamic Components
• Quality (Dissolution, appearance, dégradation,
pH, microbial control etc.)
• Dosage form Design (Can be different but
should meet the label recommendation and
product performance)
• Excipients
• DP manufacturing process and controls
82. 82
Generic Product Design Objective
Dynamic Components
• DS manufacturing process and controls
• DS solid state
• Stability
• Container Closure System
• Risk assessment and mitigation
83. 83
Dosage Form and Design
Dosage form provided in RLD Label
• RLD Product labeled as IR - do not chew or break
recommendation (needs close scrutiny of the entire
label)
Dosage Design
• In product description, Dose and Administration or
System Components and Performance
• RLD is multi-layer and test is single layer (needs close
scrutiny)
– provide justification if test different,
• RLD is DR with a laser hole
– test is just DR – provide justification
84. 84
Dosage Form and Design
Dosage Design
• RLD is single-composition osmotic technology (SCOT™)
– check test design prior to using same claim in the label
• RLD label as un-scored but allows to split for use
– Pay attention when the RLD is MR
– Provide supportive data, follow draft guidance
• RLD is multi beads (IR, DR & MR), test single MR bead
– provide justification if test different
• RLD capsule label for sprinkle
– Use sprinkle guidance and pay close attention to target
population
85. 85
Dosage Form and Design
RLD Performance Attributes
• Find out if IVIVC is done on RLD – Information available
publicly
• Analyze the RLD using different dissolution medium and
apparatus
• Choice of medium and apparatus is product and dosage
from dependent
• Method may be available from OGD, published literature
• Method can be developed in-house
• Have a dissolution profile on the RLD
86. 86
Pharmaceutical Quality
• Deliver clinical performance per label claim
outcome
• Does not introduce additional risks due to
unexpected contaminants
• Janet Woodcock, M.D. American Pharmaceutical
Review
87. 87
Quality
• Identification (controls on API susceptible for isomerization)
• Assay (90-110% may not be acceptable in all cases – certain
therapeutics)
• CU (USP <905> may not be acceptable in all cases – product with
very low drug load and closely spaced strength)
• Appearance (look for DP with same size, shape and color, inform
your division)
• Impurities & Degradation (Understand the path of degradation, make
sure this meets ICH and OGD guidance requirements)
• Unknown impurities in compendia item must meet ICH
• Genotox impurities must meet Agency draft guidance requirements
88. 88
Quality Attributes
• pH (may meet the USP and/or RLD range)
– pH target must be establish based on API stability in PD
• Preservative (If not present in RLD needs justification for use,
should provide preservative effectiveness data in PD)
• Antioxidants (If not present in RLD needs justification for use)
• Disintegration (compendia article must meet the requirement
or need a disclaimer on label – inform labeling)
• Dissolution (compendia article must meet the requirement or
need a disclaimer on label – inform labeling)
• Dissolution (dose dumping study is needed in some
therapeutics)
• Fill volume vs. draw volume
90. 90
Workshop Overview
Session 1
• OGD Overview/QbD Overview
• The Quality Target Product Profile
Session 2
• Product Design and Understanding
Session 3
• Process Design and Understanding and Control
Strategy
Session 4
• Generic Drug User Fees
91. 91
Vilayat A. Sayeed, Ph.D.
Director, Division of Chemistry III
Office of Generic Drugs
Opinions expressed in this presentation are those of the speaker
and do not necessarily reflect the views or policies of the FDA
Product Design and Understanding
FDA, DIA India and Pharmexcil Workshop
April – May 2012
92. 92
Generic Product Design and
Development
Product Development
• Quality Target Product Profile
– Product Quality attributes relevant to in-vivo
performance
• Pre-formulation Studies
– Drug substance properties (physical and
chemical)
– Drug substance, excipient compatibility
– Product Design Selection
– Formulation and Process selection (API
attributes and drug load)
93. 93
Generic Product Design and
Development
• Formulation and Process Screening
– Identify the CMAs and CQAs based on DOE
or Prior knowledge
• Formulation and Process Optimization
– Component supply chain variability and its
impact on product performance based on
DOE or Prior knowledge
– Explore operating ranges
• Scale up
94. 94
Drug Substance
DS properties that can affect DP
development, manufacture, or performance
The physicochemical and biological properties of
the drug substance that can influence the
performance of the drug product and its
manufacturability, or the properties specifically
designed into the drug substance (e.g., solid state
properties), should be identified and discussed.
– Guidance for Industry Q8(R2) Pharmaceutical Development
95. 95
Drug Substance
Understanding API properties critical for DP
development and manufacture
• DS characteristics are well established based on
published literature
• DP manufacturer and quality reviewer should have full
understanding of DS physicochemical properties and
impact on product quality and performance
• API solubility as it relates to PSD
• API sensitivity to light, humidity, pH, air/oxygen and
temperature
96. 96
Drug Substance
Understanding API properties critical for DP
development and manufacture
• API flow properties, compressibility, particle size and
shape (for high drug load drugs)
• Functional groups in API (amines, acid, alcohol etc)
• Is API a recemate or single isomer
• Impurities (Follow ICH Q3A, Q3B, Q3C & Q3D-step1)
• At the end of the API characterization one should have
an idea of the DP process
97. 97
Excipients
• Study/Analyze excipient/API physical, chemical and
performance compatibility
• Justify proposed intended function of excipient
• Include IID compliance even for routinely used excipients
(where appropriate safety information should be
provided)
• Justify use of excipients that requires label warning (not
present, inform Labeling)
• Justify use of excipient that can form adduct, chelate or
change product during processing
• Justify/check use of excipients that can modify or
enhance penetration (topical drug products)
98. 98
Excipients
• Buffers and/or preservatives if different from RLD in
ophthalmic (needs justification, inform clinical)
• Buffers and/or preservatives if different from RLD in
injections (needs justification, close scrutiny)
• Certain excipients needs Melamine free certification
(must be part of PD)
• If Dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate
(DEHP) are used inform Division (Draft guidance safety
concern)
• Include excipients specification, adequately justified for
intended performance (compendia specification may not
be appropriate)
99. 99
Generic Product Design and
Development
Product Development
Formulation and Process Selection
• At the end of the API characterization one should have
an idea for the DP process
• At the end of excipient and API study one should have
an idea on formulation and the process
• Make a prototype product and place on stability
• Move to optimization
100. 100
Generic Product Design and
Development
• Describe steps followed in process design
selection
• Describe tools and reasoning used in choosing
an alternative design to reference
• Describe product design and explain its
strategic impact in meeting clinical outcome
101. 101
Generic Product Design and
Development
Formulation and Process Optimization
• Identify CMAs, CQAs and CPPs for each unit operation
• Identify process dependent and process in-depended
parameters
• Identify risk and mitigation controls
• Establish target specifications based on product
therapeutic, intended population and dispensing
recommendations (stability studies may not sufficient)
• At this stage one has a lead product for tech transfer
(scale up)
102. 102
Generic Product Design and
Development
Stability Studies during Development
• API/Excipient compatibility studies includes
stability
• Studies should be done beyond physical mixture
• Perform stability on prototype product
• Follow ICH recommendations
103. 103
Generic Product Design and
Development
Container Closure System
• Provide studies on C/C system suitability on the product
stability and performance over shelf life
• Devises that are critical for DP performance should
include performance data
• May need CDRH consult
• Droppers and cups included with the C/C system needs
calibration data
104. 104
Generic Product Design and
Development
Container Closure System
• Including C/C system presentation not in RLD (needs
close scrutiny)
• Prefilled syringes, needs performance data and may
need a CDRH consult
Risk Assessment and Mitigation
• Should provide risk analysis
• Identify risk to quality and/or performance
• Provide appropriate mitigation and
communication plan
105. 105
Generic Product Design and
Development
BA/BE pilot Study on Prototype Product
• Based on comparable dissolution profiles
between test and reference
• Run a pilot bio study to confirm test product
performance
• Bio study passes move to next step
• Pilot study fails, back to formulation and/or
process optimization
• Justify changes in formulation and/or process
address to address the failure (Cmax or AUC)
106. 106
Generic Product Design and
Development
BA/BE pilot Study on Prototype Product
• Establish ranking order to understand and
justify by using a discriminating dissolution
method
• Failed study reporting is required under 21 CFR
320.1(g)
• Provide a CMC summary report in PD for failed
studies with explanation and justification
107. 107
Example Failed Bio-study
Fasting Bioequivalence Study, Study No. X12-1111,
N=18 (Male=11 and Female=7) Least Squares
Geometric Means, Ratio of Means, and 90%
Confidence Intervals
Test Product A vs. Reference Product C, N=18
• Parameter (units) Test Reference Ratio
90% CI
• AUC0-t (hr *ng/ml) 209.24 240.63 0.87
78.35 to 98.16
• AUC∞ (hr *ng/ml) 230.16 258.10 0.91
79.61 to 100.39
• Cmax (ng/ml) 35.60 41.06 0.91
74.15 to 101.37
108. 108
Repeat Bio-study Passed
Fasting Bioequivalence Study, Study No. S05-1231,
N=18 (Male=11 and Female=7) Least Squares
Geometric Means, Ratio of Means, and 90%
Confidence Intervals
Test Product B vs. Reference Product C, N=18
• Parameter (units) Test Reference Ratio
90% CI
• AUC0-t (hr *ng/ml) 239.32 240.63 0.99
88.10 to 112.28
• AUC∞ (hr *ng/ml) 254.10 258.10 0.98
87.45 to 100.83
• Cmax (ng/ml) 39.04 41.06 0.95
81.33 to 111.18
109. 109
Generic Product Design and
Development
Process scale-up and process optimization
• Explore operating ranges of each unit operation
• Component supply chain variability and its
impact on product performance
• Can be based on developed knowledge (DOE)
and prior knowledge
• Provide basis operating establish ranges and
accepted component variability
110. 110
Generic Product Design and
Development
DP manufacturing process and controls
• Manufacture the exhibit batch following process
and controls identified by the development group
• Place on stability following ICH conditions
Analytics
• All studies must be based on validated methods
• Include justification for each test used and its
relevance to the measurement
112. 112
Vilayat A. Sayeed, Ph.D.
Director, Division of Chemistry III
Office of Generic Drugs
Opinions expressed in this presentation are those of the speaker
and do not necessarily reflect the views or policies of the FDA
Product Equivalency - Considerations
FDA, DIA India and Pharmexcil Workshop
April – May 2012
114. 114
Objective of Generic Product
Therapeutic equivalents (TE):
Generic Product has to be PE + BE to be TE to the reference to meet
505(j) requirement
• 21 CFR 320.1(c) “Pharmaceutical equivalents means drug products
in identical dosage forms that contain identical amounts of the
identical active drug ingredient, ….
• Active Ingredient
• Dosage form
• Strength
• Route of administration
• Performance characteristics and Intended use
• Quality
115. 115
Quality
As Defined Currently
• Identification
• Assay
• Content Uniformity
• Dissolution
• Appearance
• Impurities
• Degradation
• Disintegration
• Microbial quality and etc
• Patient Compliance not addressed
117. 117
Product Equivalency
Tablet size, Shape and Color
• Consumer complains
• Difficulty in swallowing (over 6 million hits in Google)
• Test substantially larger than RLD for same strength
• Same size, shape and color for all strengths (medication
error)
• Include this in PD strategy to address consumer
compliance
119. 119
Product Equivalency
Contents in capsule shell
• Reference has beads/powder – Test has mini tablet
• Final guidance published for capsules label for sprinkle
• Recommends target bead size up to 2.5 mm with
no more than 10 percent variation over this size, to
a maximum size of 2.8 mm
• Pay attention to target population
• Capsule products with no sprinkle recommendation not
covered by this guidance
• Include this in PD strategy to address consumer
compliance
120. 120
Product Equivalency
Tablet Score – Ease of Splitting
• In-house work (OTR/DPQR Laboratory)
– Volpe et al., Int. J. Pharm., 2008, 350, 65-69
– Na Zhao et al., Int. J. Pharm., 2010, 401, 25-31
– Rakhi et al., AAPS PharmSciTech, 2010, 11, 1359-
1367
• Draft developed to address concern and public comment
are closed
• Addressing the public comments and final guidance will
be issued soon
• Include this in PD strategy to address consumer
compliance
121. 121
Points to consider DP Development
• Is the tablet score (bisect, trisect etc)
• Is the tablet modified release (DR or ER)
• Is the tablet a combination product
• Is the tablet a critical dose product
• Is the tablet film coated (possible reason)
122. 122
Points to consider DP Development
• Formulation
• Depth of Score (ease of breaking)
• Hardness
• Loss of mass breaking, crumble (initial and storage)
123. 123
Points to consider DP Development
• Friability of half tablet
• Drug content in each half
• Loss of potency due to stability
• Change in degradation profile between whole
and split tablet
• Dissolution
• Guidance introduces the concept of functional
score
124. 124
Product Equivalency
Taste, Odor masking and Tablet dust
• Is a concern and we are closely monitoring in our post-
marketing surveillance
• DP process difference and non- functional coating (dust
and taste)
• Odor (residual solvents)
127. 127
Workshop Overview
Session 1
• OGD Overview/QbD Overview
• The Quality Target Product Profile
Session 2
• Product Design and Understanding
Session 3
• Process Design and Understanding and Control
Strategy
Session 4
• Generic Drug User Fees
128. 128
Process Design and
Understanding and Control
Strategy
Lane V. Christensen, Ph.D.
Chemist, Immediate Office
Office of Generic Drugs
Opinions expressed in this presentation are those of the speaker
and do not necessarily reflect the views or policies of the FDA
FDA, DIA India and Pharmexcil Workshop
April – May 2012
129. 129
Process development is easy.
• It is just like cooking.
– Buy the ingredients.
– Put the stuff in the mixer,
– Mix it
– Put it on the stove, or in the oven to cook it, or dry it.
– Place a topping on it, if necessary
– Package it to protect it.
• If we write the process that way, it will be easy.
– Just execute the record as stated and we have a
reproducible product.
– But: “Do not over-estimate the intelligence of the staff.”
True statement??
131. 131
Potential Problems
• Case Study-1: XYZ tablets, the initial formulation was submitted to the
Agency, though it was bioequivalent and manufacturable at an exhibit batch
scale, it was not manufacturable at full scale due to the poor selection of the
filler used erratic flow and high variability in tablet weight. The applicant
changed to a different grade of excipient, which by virtue of having better flow
characteristics reduced the variability in tablet weight during commercial
production.
• This required an additional review cycle to evaluate and delayed approval by
several months. (This certainly would have been averted had the sponsor
carefully considered the material properties (e.g. flow properties) of this
excipient during development.)
• Though the above resolved the weight variability, another problem arose due
to the change in excipient tablet chipping during shipping (Because the
sponsor had constraints on its CPP, compression pressure, due to tooling
design). Outcome: Product Withdrawal
Lesson learned: Need better understanding not just for material attributes,
and process parameters, but also potential interactions.
132. 132
Begin with the End in Mind
Pharmaceutical
Development
Exhibit batch
Commercial
Development Studies
- Prior Knowledge
- Product Understanding
- Process Understanding
- Risk Management
- PAT?
Design
Space
Manufacturing
Experience
Enhanced
understanding
(product/process)
Continual Improvement
Regulatory Flexibility
Changes within Design Space
Continuous Process Verification
133. 133
Process Development
• Selection of a process is dependent on
– CQA – How is the CQA affected by the equipment and input materials?
– Input Materials – Is there source variability? (i.e., purity, multiple vendors
using different processes, etc)
– Equipment – Is there an equipment specific attribute that could affect the
product? (shear rate (mixing), heat transfer, mechanical motion leads to
attrition)
– Stability of the product – Can product stability be affected by the process
chosen? (heat labile, moisture sensitive products, polymorphic transistion,
etc)
– Common cause vs special cause variation
134. 134
Process Development (continued)
• No one size fits all
– Just because you are developing a similar process to one you’ve done
before, does not mean you’ll have the same CPP to CQA relationship.
• In some cases it may be possible to manufacture the product using
different manufacturing processes.
– Do any of the potential processes have an added benefit to the desired
product? (i.e., better impurity profile, control of polymorphism, etc)
• More complex processes are dependent on the specialized form or
technology platform that offers specific advantages to patient that
cannot be possible by conventional manufacturing processes.
135. 135
Control your inputs
to reduce variation
e.g., CMAs
Process parameters blend
the inputs to produce
outputs e.g., CPPs
Measure
Performance
e.g., CQAs
Inputs Pharmaceutical
Unit Operation-
Process Parameters
Outputs
CQAs = f (CPP1, CPP2 , CPP3 …CMA1, CMA2, CMA3…)
Establish ranges for
CMAs
Establish ranges for
CPPs
Control Strategy
Understanding the Relationship
between CMAs, CPPs, and CQAs
136. 136
Steps for Process Understanding
1. Identify all possible material attributes and process parameters that
could impact the performance of the process
2. Use risk assessment and scientific knowledge to identify potentially
high risk attributes and/or parameters
3. Determine levels or ranges of these variables to be investigated
4. Design experiments, using DOE when appropriate
5. Conduct actual experiments
6. Analyze experimental data to determine if an input material attribute
or process parameter is critical.
– A material attribute or process parameter is critical when a
realistic change in that material attribute or process parameter
can significantly impact the quality of the output materials.
7. Establish the control strategy
– For critical material attributes or process parameters, define
acceptable ranges. For non critical attributes, the acceptable
range is the range investigated.
138. 138
Quality Risk Management – ICH Q9
“Quality risk management is
a systematic process for the
assessment, control,
communication and review
of risks to the quality of the
drug (medicinal) product
across the product
lifecycle.”
PD
Control Strategy
Continual Improvement
Step 2
139. 139
Principles of Quality Risk Management
Two primary principles of quality risk management
are:
• The evaluation of the risk to quality should be
based on scientific knowledge and ultimately link
to the protection of the patient; and
• The level of effort, formality and documentation
of the quality risk management process should
be commensurate with the levels of risk.
140. 140
Risk assessment in manufacturing versus development
Risk assessment in cGMP
manufacturing
Risk assessment in product and process
development
Status: Established procedure
Risk scenario:
deviation from pre-defined range
Objectives:
identify root cause and suggest
corrective and preventive actions
Characteristics:
• Mainly reactive, some proactive
• Backwards to upper stream operation
• Narrow scope
• Preventive
Status: Uncertainty, undefined range
Risk scenario:
potential impact on CQAs
Objectives:
identify high risk variables and
determine future actions
Characteristics:
• Mainly proactive, some reactive
• Forwards to down stream operation
• Leverage of knowledge, can be
subjective
• Broad scope
• Focus on prioritization
• Informative
141. 141
Risk assessment during development
• To identify (not eliminate) relative risk levels
from the beginning of product development
• To prioritize limited development resources
• To document the decision making process
throughout development
• To assess the critical attributes of raw
materials, solvents, drug substances and
excipients
142. 142
Risk assessment during development
• To identify appropriate specifications, critical
process parameters and manufacturing controls
• To enhance knowledge of product performance
over a range of material attributes
• To decrease variability of quality attributes
(product/material and manufacturing defects)
• To assess the needs of additional studies for
scale up and technology transfer
143. 143
Which method can be used in development?
• Failure Mode Effects Analysis (FMEA)
• Failure Mode, Effects, and Criticality Analysis (FMECA)
• Fault Tree Analysis (FTA)
• Hazard Analysis and Critical Control Points (HACCP)
• Hazard Operability Analysis (HAZOP)
• Preliminary Hazard Analysis (PHA)
• Risk ranking and filtering
• Basic risk management facilitation methods (flowcharts,
check sheets, etc.)
It is neither always appropriate nor always necessary to use a formal risk
management process….. The use of informal risk management processes
can also be considered acceptable. -ICH Q9
A risk based justification based on experience and data is always
necessary!
144. 144
Example of risk assessment: IR Example
• QbD IR example: Acetriptan
IR tablet
– BCS II drug with poor
solubility and high
permeability
– Focus on particle size
flowability, blend uniformity
– Manufactured by roller
compaction
– Uses common excipients in
similar amounts to the RLD
146. 146
QTPP:
• Intended use in clinical setting
• Quality attributes of drug product
• Active pharmaceutical ingredient
release or delivery and attributes
affecting pharmacokinetic characteristics
(Safety and efficacy)
impacted by formulation
or process variables
high risk
quality attributes impact
patient safety and efficacy
Quality target product profile (QTPP)
CQA
Risk assessment
DOE
Control strategy
Riskrankingandfiltering
Examples of risk assessment application
in pharmaceutical product and process development
147. 147
Using tools to enhance
understanding
Y = ƒ(X)
CQAs
Y
Variability fully
understood
Method
Machine
Measurement
Mother Nature
I
N
P
U
T
S
(X)
Manpower
Material
O
U
T
P
U
T
S
(Y)
Steps 3-6
148. 148
B
B
Compare Two Approaches
OFAT ‐ One Factor at A Time
• an univariate approach
• Estimates of effects at set conditions
of the other factors
• Slow and inefficient
• Can miss interactions
DOE – Design of Experiments
• A statistics‐based multivariate approach
• Good coverage of space
• A methodology to achieve a predictive
knowledge of a complex process with
the fewest trials possible
A
B
C
A
149. 149
Type of DOE
• Factorial DOE
– Screening through many factors to find the significant few
– fractional factorial DOE
– Placket-Burman DOE
– etc.
• Optimization DOE (Response Surface Methods, RSM)
– further understanding interactions /curvature (if any) of the few significant factors
and to move towards optimum conditions
– Box-Behnken Design
– Central Composite Design
• central composite face-centered design (CCF)
• central composite circumscribed design (CCC)
– D-optimal DOE
– Three level full factorial DOE
– etc.
• Mixture DOE
– Discover the optimal formulation (1. the components add to a fixed total; 2. the
response is a function of the proportions of the components)
– Simplex-Lattice Design
– Simplex-Centroid Design
– D-Optimal Mixture Designs
– etc.
• Combined DOE
– Combine process variables, mixture components and categoric factors in one
design
150. 150
Factorial DOE: Fraction &
ResolutionMain effect: the average change in the response when a factor is changed from
low to high level: M(1)
Interactions: the effect of one factor on the response depends on the value of
another factor(s): 2FI, 3FI
Aliased: confounded, not distinguishable
Factorial DOE
(e.g. 6 factors)
# of
runs
Aliased
effects
Resolution Resource
Full factorial (26) 64 No N/A Very High
Half fraction (26-1) 32 3FI = 3FI VI High
Quarter fraction (26-2) 16
M(1) = 3FI
2FI = 2FI
IV Medium
Eighth fraction (26-3) 8 M(1) = 2FI III Low
151. 151
• Begin with the end in mind: holistic overview (systematic
approach)
• Define the responses (QTPP/CQAs)
• List all possible process parameters and material attributes
that could impact the responses
• Identify potentially high risk parameters and/or material
attributes (prior knowledge + risk assessment)
• Decide the range of the experimental factors (prior knowledge
+ feasibility study)
• Select appropriate type DOE (fit for the purpose)
• Conduct actual experiments (product/process understanding)
– Use center point for estimation of curvature
– Use replicates to estimate the repeatability
– Block what you can and randomize what you cannot
• Analyze the experimental data
– Identify critical process parameter or critical material attribute
(CPP/CMA)
– Establish relationship between CPP/CMA and CQA: y = f(x)
Steps in DOE Study
152. 152
Summary
• OFAT is an univariate approach: slow, inefficient,
assuming no interaction, leads to rigid manufacture
process with high risk of DP failure.
• DOE is a statistically designed multivariate
approach.
• DOE is an efficient tool to identify CPPs and CMAs
and establish relationship between CPP/CMA and
CQA
• Different DOEs are appropriate for different phases
of pharmaceutical development.
• Use sound science, design space developed at lab
or pilot scale through DOE studies can be
proposed for commercial scale, but it needs to be
verified at production scale.
• Overall, DOE is a valuable tool to facilitate the
implementation of QbD.
153. 153
Design Space
• Design Space
– The multidimensional combination and interaction of
input variables (e.g. Material attributes) and process
parameters that have been demonstrated to provide
assurance of quality
– Use sound science, design space developed at lab or
pilot scale can be proposed for commercial scale, but
it needs to be verified at production scale,
• Regulatory Implication
– Movement out of the design space is considered to
be a change and would normally initiate a regulatory
post-approval change process. Design space is
proposed by the applicant and is subject to regulatory
assessment and approval
154. 154
Scale Effect on Design Space
10 Fold
=
?
Lab/Pilot Scale Design Space Commercial Scale
Design Space
Generation
Confirmation
To be verified
155. 155
Design Space of What?
• Lab scale design space
• Pilot scale design space
• Commercial scale design space
• Only commercial scale design space can
have meaningful regulatory flexibility as
defined in ICH Q8(R2)
156. 156
Availability of Various Tools
Increasing more sophisticated tools !
– Terahertz spectroscopy
– Solid State NMR
– PAT
– Chemometrics
– Real Time Release (RTR)
157. 157
Use of PAT
• Ideally PAT principles and tools should be
introduced during the development phase
• Increased level of inquiries submitted to OGD
• Use of in-line NIRS method in the IR and MR
examples to determine endpoint for BU
158. 158
Define Specifications with Justification
• Specifications Required
– Drug Substance/Intermediates- (Requirement
from DMF holder and applicant)
– Drug Product
– Container Closure System (Nasal, Injectables)
– Device Components (MDI & DPI)
– Stability
• Specifications in support of the above
– In Process Testing
– Raw Material Testing
Step 7
159. 159
***The control strategy ensures CQAs are
met consistently. . . a regulatory commitment***
Control Strategy
• Control Strategy - A planned set of controls, derived from
current product and process understanding that ensures
process performance and product quality.
• Controls can include the following:
– Input material control (e.g., drug substance, excipients, primary
packaging materials)
– Product control (specification)
– Manufacturing process (unit operation) control
– In-process or real-time release testing in lieu of end-product
testing
– A monitoring program (e.g., full product testing at regular
intervals) for verifying multivariate prediction models
163. 163
Why this Matters
By enhancing the process knowledge/understanding
and principles we will achieve:
– Rigorous Science
– More robust manufacturing processes
– Reduce variability
– Ensure safety
– Increase efficiency at all unit operations
– Increased productivity, less failure
– Increased knowledge transfer
– Enhanced communication & collaboration
164. 164
References
• Quality by Design for ANDAs: An Example for Modified Release
Dosage Forms
• Quality by Design for ANDAs: An Example for Immediate Release
Dosage Forms
• Guidance for Industry: Q8(R2) Pharmaceutical Development
• Guidance for Industry: Q9 Quality Risk Management
• Guidance for Industry: Q10 Pharmaceutical Quality System
• Guidance for Industry: Q11 Development and Manufacture of Drug
Substances
• Guidance for Industry PAT: A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance
• 2012 EMEA Guideline on the Use of Near Infrared Spectroscopy
(NIRS) by the Pharmaceutical Industry and the Data Requirements for
New Submissions and Variations.
165. 165
Further questions
• What are your concerns with implementing
QbD?
• What are the limitations?
• What is the “end” in your target
(submission, approval, commercial scale-
up/to the market, discontinuation)?
• What about the rest of ICH Q9, Q10?
167. 167
Inactive Ingredients Database
OGD is working with IPEC to update IID to meet customer
needs
– Posting of historical IID files by quarter for the past 3 years (2009-
2012)
– Acceptance of summary sheet of pharm/tox data with reference to the
specific location of the data as a justification in lieu of complete
pharm/tox submission at time of filing
– Further meetings with IPEC to discuss IID improvements and excipient
issues
Minutes posted on Generic Drugs: Information for Industry webpage
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsare
DevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugA
pplicationANDAGenerics/ucm142112.htm
169. 169
Control Correspondence
• Target response time: 60 days
• Notification
– The Office of Generic Drugs is reviewing your
query but is unable to respond at this time
due to the nature of the inquiry. We will
provide a response once a determination has
been reached. Please refer to Control
#_____ when referencing this inquiry in any
future related correspondence.
170. 170
Controls on Batch Size
Regarding batch size, the following are conditions where batch sizes
<100,000 units are acceptable:
1. The reference product has an orphan drug exemption
2. The reference product is a controlled substance
3. Indication that the batch size is the same as the commercial batch
size with a commitment there will be no scale up post approval without
an approved prior approval supplement (PAS).
In general, applicants should provide a commitment that the
commercial batch will be the same as the exhibit batch and there will
be no scale up post approval. Any subsequent batch scale up would
be subject to review and approval of a PAS.
Cost of the drug alone should not be a factor in allowing a smaller
batch size.
172. 172
Workshop Overview
Session 1
• OGD Overview/QbD Overview
• The Quality Target Product Profile
Session 2
• Product Design and Understanding
Session 3
• Process Design and Understanding and Control
Strategy
Session 4
• Generic Drug User Fees
