Quality Initiatives – Biotech Products

Steven Kozlowski, M.D., DirectorOffice of Biotechnology Products

OPS/CDER

IFPAC PreCon Workshop 1/25/2009

Considerations & Implementation

FDA Started with Quality• 1902 Biologics Control Act

– Regulatory authority over the processes used to make biological products, or biologics

• Responsibility for safety– A horse named Jim whose tetanus-contaminated

serum was used to produce a diphtheria antitoxin that caused the deaths of thirteen children

• 1938 Federal Food Drug & Cosmetic Act– New Drug Application (NDA)

• Drug composition, manufacturing & quality• Report on safety

– A preparation of sulfanilamide using diethylene glycol (DEG) as a solvent caused more than 100 deaths

• Elixir Sulfanilamide

Pharmaceutical Quality for the 21st Century• In 2002, FDA identified a series of…problems…• Initiatives to achieve the Desired State

• CGMP for the 21st Century– risk-based (ICH Q9)– Quality Systems (ICH Q10)

• Process Analytical Technology– material attributes– on or at line

measurements– impact process

parameters• Quality by Design (QbD):

– A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management (ICH Q8R1)

Overview

• QbD Definitions• Design Space

– CQA– Risk Assessment for likely CPP– Design of Experiments (DOE)– Lifecycle & implementation

• OBP Pilot• Benefits of QbD

─Knowledge of the APImechanisms of action

─Knowledge of API attributes and their impact on S and E

─Knowledge regarding how impurities impact Q, S and E

─Knowledge on how formulation impacts product quality

Product Knowledge

Moheb Nasr

Products are designed to maximize efficacy while minimizing adverse affects (i.e., to meet patient needs including availability, value and convenience)

Process Knowledge

─Knowledge of critical attributes of incoming raw materials

─Knowledge of equipment and operating parameters

─Knowledge of output performance parameters (Impact on CQA)

Processes are designed to be robust and consistently deliver the desired product

Use of risk assessment tools for

product design & process controls

Qualityby

Design

Moheb Nasr

ICH Q8: Design Space

ProcessKnowledge

ProductKnowledge

ICH Q8: Design Space• Definition

– The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality

• Regulatory Flexibility– Working within the design space is not considered a

change• Important to Notice

– Design space is proposed by the applicant and is subject to regulatory assessment and approval

• Process Importance– The product is the process…a biologics mantra

Manufacturing Process

RawMaterial

ProductManufacturing Process

LockedProcess Variables

Variability

Jon Clark

Measurement DependantProcess Variables

EndpointResponse

InputResponse

Overview

• QbD Definitions• Design Space

– CQA– Risk Assessment for likely CPP– Design of Experiments (DOE)– Lifecycle & implementation

• OBP Pilot

87 Ao

Fab = ~1/3 mAb

• post-translational modifications

• heterogeneity

11 Ao

Statin

Structure of complex molecules• 1° structure• higher order structure

K

pyro-E OD

G

G

D

OD

O

O pyro-E

D

D

D

G

G

K

• (9600)2≈ 108

Functional Event Sequence Diagram

OxidationSite 1

Is Oxidation Without Impact

on Activity?Y

BatchFailure

Y

Is Level Low Enoughnot to Matter?

N

Detectability of Oxidation with Impact?

N

ClinicalFailure

N

AcceptableProduct

Y

Y

Biological Activity Matrix

One to some lots

Many lots

Validated Bioassay

Clinical Studies

Clinical Pharmacology (PK/PD)

Small Animal/Complex Bioassay

Multiple Binding/Cellular Assays

Clin

ical

Lot

s

Clin

ical

Lot

Ext

rem

es

Purif

ied/

Indu

ced

Varia

nts

Stre

ssed

Lot

s

Dev

elop

men

tal L

ots

Monoclonal Antibodies

Mouse

Chimeric

Human

Humanized

Fc binding & Effector Function

Nature of target interaction

From Attributes to Spaces

Glycoform 1

Cha

rge

Glyc

ofor

m2

Critical Attributes

Critical Quality Attribute (CQA): 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[Q8R1] Agitation

Med

ia

Tim

e Critical Process

Parameters

Biotechnology Manufacturing Process

Harvest

Proteolytic Steps

Diafilt./Conc.

Lyophilization

Conjugation

FormulationFermentor

ChromatographyColumns

Flow throughion exchange

column

Removes– Sub-potent charge

variants– Impurities

• Assign relative risk for each factor

Risk assessment includes process develop.,

manufact., QC staff, etc.

Severity

Occ

urre

nce

FMEA

= [severity]x [occurrence]x [detectability] • Optimization

• Screening DOE

Risk Assessment to DOE

SurfaceResponse

Plot

Surface Responses of Important Product Attributes

Acidic Variants10-25%

Impurity<50 ng/mg

Basic Variants10-20%

pH

Pro

tein

Loa

d 50

20

40

30

60

5%

10%

25%20%

15%

5%

10%15%

25%20%

Overlay of Response Surfacesinto an Initial Design Space

pH

Prot

ein

Load

Load

pH

Conductivity

Region 4

Region 1

Region 2

Overlay of Regulatory Spaces

Region 3

Thoughts on Submission• DOEs that are important for quality• Narrative for FMEA

– prior knowledge and rationales of experts shared– support for factors not further studied

• Surrogate for HETP and thus column packing (detectability)

• Rationale for quality related responses• Validity of scale-down model• Narrative story of DOE

– Screening to optimization…– DOE often done as iterations

• Adding experimental points; Changing model; Statistics

• Worksheets, Results & Graphics

Initial Design Space Weaknesses• Based on model (DOE)

– Predictions are extrapolations • inside as well as outside explored space

• Missed factors• Missed interactions at screening

– Each factor alone has little impact– e.g cycle# and regeneration buffer salt– Larger risk with complex processes

• Missed important responses– Larger risk with complex products– Interactions between responses

• Experiments done at lab scale

Lifecycle Approach

Adapted fromT. Kourti

Load

pH

• Managing uncertainty– Lack of 1st Prin.

Models– Complex products– Complex processes

• Multivariate SPC– Facilitates moving

across scales

Moving Forward• Knowledge in submissions

– Data needed to support knowledge• Platform Strategies• Link to small-molecule learnings

– ONDQA pilot; PMP• Mock Case Studies

– ISPE PQLI, EFPIA– Conformia

• Novel approach to CQAs• Future workshops

OBP Pilot Program

• To define clinically relevant attributes for protein products (regulated by OBP) and link them to manufacturing processes

• To consider quality-by-design (QbD) approaches to unit operations in supplements (10) as well as original applications (5)

• To explore the use of protocols submitted under (21 CF 314.70(e) and 601.12(e))

• One application accepted (full BLA)• Three more under consideration• Applications close 9/30/2009

FR Notice July 2, 2008

Some Considerations for Acceptance

• Description of drug; stage of development• Timeline for submission and requested

meetings • Soundness of the applicant’s proposal

– Overall Product & Process Design strategy– Potential to affect the development of a quality-by-design, risk-based

approach for complex products

• Summary of approaches defining relevant attributes & process parameters– Types of data linking attributes to S&E– Types of data defining design space

Some Considerations for Acceptance

• Applicant’s approaches to risk management– Use of prior knowledge– Risk assessment strategies– Risk mitigation (Application to lifecycle control strategy)

• Mfg changes in the Expanded Change Protocol– Across multiple products– Across multiple process steps– Across multiple changes (scale/equipment/facility)

• Diversity of product types, companies and processes

• For original applications, linked QbDapproaches for multiple unit ops

Expanded Change Protocols• Discussion of CQAs (links to clinical performance)• Discussion of CPPs and raw material attributes

(links to critical attributes)• Risk Assessments and supporting documentation • Description of the Design Space and supportive

data• Description of the Control Strategy (risk mitigation)• The Change Control plan

– Types of changes (change space)– Change Evaluation strategy– Risk management plans– Regulatory reporting mechanism– Quality system approaches

Moheb Nasr

Cost & Benefit of QbD

Potential Benefits for Embracing the New Paradigms

• Smoother transitions from IND to Licensure• Increase productively/efficiency• Less lot rejections, recalls, and investigations for

manufacturing deviations• Expedited implementation of process changes• Manufacturing processes that are adaptable• Reliable supply of high quality products• Fewer inspections• Fewer submissions to the Agency

2007 FDAAA• Postmarket safety surveillance

– Section 905 of FDAAA calls for the HHS Secretary to develop methods to obtain access to disparate data sources and to establish a postmarket risk identification and analysis system

• Access to data from – 25 million patients by 7/1/2010– 100 million patients by 7/1/2012

• Sentinel Initiative– Detect rare events early

Heparin Adverse Event Review

• The serious adverse events include:– allergic or hypersensitivity-type reactions– nausea– vomiting– sweating– shortness of breath– severe hypotension requiring treatment.

FDA Website: http://www.fda.gov/cder/drug/infopage/heparin/default.htmOverview & 2/11/08 Public Health Advisory

• High doses (5000-50,000 units) given bolus• Most events developed within minutes

Baxter Press Release1:10,000

Heparin was a Wakeup Call

• Up to 30% contamination of finished product• Present worldwide in various APIs• Undetected by acceptance and release tests

– Analytical methods were critical in identifying and resolving the problem (CE and H-NMR)

CE

Biomaterials. 2008 (36):4808-14.

Chondroitin

Nat Biotechnol. 2008 Jun;26(6):669-75

UPDATE ANALYTICS

QUALITYMATTERS

• Persisted until serious adverse events noted• Active surveillance may reveal more Quality

issues

Credits

• Barry Cherney• Patrick Swann• Christine Moore• Keith Webber• Susan Kirshner

• Janet Woodcock• Moheb Nasr• Ali Al-Hakim• Jon Clark