International Society of Lyophilization - Freeze Drying

Midwest Chapter Annual Meeting Contemporary Approaches to Lyophilization Process Validation (in the Product Lifecycle)
Edward Trappler, Lyophilization Technology, Inc.

Development Pathway
Early Development
Pre-formulation API Characterization Formulation Presentation

Bench scale

Phase I Clinical
Short term stability Product characterization

Lab scale

Phase II Clinical
Long term stability Product specifications Processing experience

Pilot scale

Phase III Clinical

Development report Technology transfer Large scale batches

Manufacturing

Governing Factors

Product Quality Economics Compliance

Product Life Cycle

Development: Appropriate / reproducible process parameters Consistent finished product quality attributes Adequate long term stability

Product Life Cycle

Tech Transfer / Scale-up to Manufacturing: Qualified Equipment Confirmed process design/reproducible parameters Batch uniformity Consistent product qualities

Product Life Cycle

Routine Manufacturing: Operate within an established envelope Collect and analyze product and process data Routine review and statistical analysis State of control for process Consistent critical quality attributes

Development Objectives
Address and Document
Clear intended outcome of process Established critical independent processing parameters (CPP) Assigned key dependent processing parameters (KPP) Well defined critical quality attributes (CQA) Appropriate in-process and finished product testing Supporting stability data

Development Objectives
Product and Process Knowledge and Understanding
Product Development
Dosage Form Critical Quality Attributes (CQA)

Process Design
Define Critical Process Parameters (CPP) Identify Key Process Parameters (KPP)

Product Characteristics
Compounding Procedures

Order of addition Mixing pH adjustment Physico-chemical aspects

Product Characteristics
Bulk Solution Storage

Storage conditions Expiration

Product Characteristics

Low Temperature Analysis

Phase Transition
Eutectic, glass transition (Tg), collapse

Morphology
Amorphous or crystalline

Product Characteristics

Finished Product Qualities

Morphology / Thermal Properties Dried Cake Appearance Residual Moisture Range Constituted Solution Attributes

Product Characteristics

Finished Product Qualities

Morphology
Amorphous or crystalline

Phase Transition Temperature

Crystalline melt, glass transition (Tg)

Product Characteristics

Finished Product Qualities

Dry Cake Appearance

Color, density, uniformity, shrinkage, collapse, meltback

Moisture Content
Average and range

Product Characteristics

Finished Product Qualities

Reconstitution
Technique Complete dissolution

Constituted Solution Appearance

Clarity Color

Product Characteristics

Finished Product Qualities

Product Assay
Initial Constituted solution (after storage)

pH
Target and Range

Process Parameters
Establish critical independent parameters
Shelf (inlet) temperature Chamber pressure Time

Identify key dependent parameters

Product temperature Condenser temperature

Target Lyophilization Parameters

40 2000 30 1800

Chamber Pressure
20

1600

1400 10 Tem perature ( oC )

Shelf Temperature
0

1200 M icrons

1000 -10 800 -20

Threshold Temperature
-30

600

Product Temperature
-40

400

200

-50 0 200 400 600 800 1000 1200 1400 1600 Time (minutes)

0 1800

Boundary Parameters

Proven Acceptable Range

Define acceptable critical parameter range

Proven Acceptable Range (PAR) Boundary Conditions

Lyophilization Parameter PAR

0

-2

-4

PAR: 5o > Target

-6

T m e tu ( C e p ra re )

-8

-10

-12

-14

PAR: 5o < Target

-16

-18

-20 400

420

440 Time (minutes)

460

480

500

Target Lyophilization Parameters

0 120

-2 110 -4

PAR: 20 Hg > Target

-6

100

90 T m e tu ( oC e p ra re ) -8 M ro s ic n

-10

80

-12 70 -14

PAR: 20 Hg < Target

-16

60

50 -18

-20 400

420

440 Time (minutes)

460

480

40 500

Proven Acceptable Range

Boundary Studies
Three batches at target conditions
Process conducted at ideal parameters

Four batches at boundary conditions

High and low shelf temperatures High and low chamber pressures

Proven Acceptable Range

Boundary Studies
Three batches at target conditions
Demonstrates reproducibility Confirms consistent product qualities

Four batches at boundary conditions

Envelopes processing conditions Establishes proven acceptable range

Proven Acceptable Range Acceptable Boundary Conditions

40 1000 900 20 Temperature ( o C) 800

Shelf Temperature

700 600

-20

500 400

-40

300 200

-60

Chamber Pressure
0 200 400 600 800 1000 1200 1400 1600

100 0 1800

-80 Time (Minutes)

Boundary Parameters

Proven Acceptable Range

Define acceptable critical process parameter range (CPP) Verify with product analysis and stability (CQA)

Target Lyophilization Parameters

0

-2

-4

-6

Action Level: Alert Level: 2o > Target

4o

> Target

PAR: 5o > Target

T m e tu ( oC e p ra re )

-8

-10

-12

Alert Level: 2o < Target Action Level: 4o < Target PAR: 5o < Target

-14

-16

-18

-20 400

420

440 Time (minutes)

460

480

500

Target Lyophilization Parameters

0 120

-2 110 -4

PAR: 20 Hg > Target

-6

100

T m e tu ( oC e p ra re )

-8

Action Level: 15 Hg > Target Alert Level: 10 Hg > Target

90 M ro s ic n

-10

80

-12

Alert Level: 10 Hg < Target Action Level: 15 Hg < Target PAR: 20 Hg < Target

70

-14

60

-16 50 -18

-20 400

420

440 Time (minutes)

460

480

40 500

Proven Acceptable Range Boundary Conditions

Alert Level: If these conditions continue the process will approach an Action Level. Action Level: If these conditions continue the process will approach a Boundary Condition.

Process Qualification

Demonstrate and document capability of reproducible commercial manufacture

Qualification of unit operation Performance Qualification

Process Qualification

Capability of reproducible commercial manufacture

CGMP compliant procedures Successful completion prior to commercial distribution

Process Qualification
Capability of reproducible commercial manufacture
CGMP compliant procedures Successful completion prior to commercial distribution

Laboratory and pilot studies can provide additional assurance

Process Qualification
Address and Document
Intended outcome of process Critical Processing Parameters (CPP) Key Processing Parameters (KPP) Critical Quality Attributes (CQA) In-process and finished product testing Extensive sampling and stability data Additional analysis may be appropriate

Equipment Qualification
Goals

Verify that the equipment is adequate and appropriate. Document the design, construction and installation. Demonstrate the proper functions and performance Prove that the equipment does what it is intended to do

Equipment Qualification
Scope and Objectives

Evaluation of each system function required for processing, including verifying reproducibility and consistency (uniformity) of conditions and outcome. Assure that the system performance is adequate to support the process intended.

Benefits

Effective project management Successful integration Economics Compliance

Equipment Qualification

Maximum Cooling and Heating Rate Shelf Temperature Control Shelf Temperature Uniformity Condenser Cooling Rate Condenser Capacity

Equipment Qualification

System Evacuation Rate Pressure Control Sublimation / Condensation Rate Process Control / Data Acquisition Lyophilization Cycle Run

Shelf Temperature

Maximum Cooling and Heating

Heat Transfer Fluid System Refrigeration for Cooling Heaters for Warming

Shelf Temperature Uniformity

Monitoring Locations
Five locations on each shelf

Each corner and geometric center

Shelf Temperature Uniformity

Monitoring Locations

Five locations on each of the shelves

Maximum Shelf Cooling / Heating Test

80 60 T e m p e ra tu re (C ) 40 20 0
Setpoint Shelf Inlet Shelf Inlet

1000 900 800 700 600 500 400 300 200 100 0 50 100 150 200 250 Time (Minutes) 300 350 400 450 0 500

-20 -40 -60

Shelf Temperature

Cooling Control and Uniformity

Control at loading temperatures Cooling rate determination Control at low temperatures

Shelf Temperature

Heating Control and Uniformity

Heating rate determination Control at high temperatures Control at intermediate temperatures

Shelf Cooling/Heating/Control Test

80 60

40 T e m p e ra tu re (C )

20

-20

-40

-60 0 500 1000 Time (Minutes) 1500 2000 2500

Condenser Cooling

Cooling Rate

Rate of chilling to process limit Ultimate temperature achieved

Blank-Off Temperature

Condenser Cooling Test

FD7 Condenser Cooling Study X60301
10

-10

-20 Temperature (C)

-30 -40

-50

-60

-70

-80 0 10 20 30 40 Tim e (Minutes) COND 1 COND 2 50 60 70 80

Vacuum Pumping

Pull-Down Rate

Rate of evacuation to process limit Ultimate pressure achieved

Blank-Off Pressure

Chamber Evacuation Rate

FD-7 Chamber Evacuation Testing Study X41201 14000 12000 10000 Tem perature (C) 8000 6000 4000 2000 0 0 -2000 Tim e (m in) CH VAC 5 10 15 20 25 30 35 40

Pressure Control

Set Point Control During Drying

Minimum, maximum and selected intermediate set points Setpoint control for vial headspace pressure

Pressure Control During Stoppering

Pressure Control Test

1400 1200

1000 Pressure (Microns)

800

600

400

200

0 0 20 40 60 Time (Minutes) PRESSURE 80 100 120 140

Pressure Control Test

110

108

106

104

Pressure (Microns)

102

100

98

96

94

92

90 20 25 30 35 40 Tim e (Minutes) PRESSURE 45 50 55 60

Pressure Control Test

510

508

506

504

Pressure (Microns)

502

500

498

496

494

492

490 60 65 70 75 Tim e (Minutes) PRESSURE 80 85 90 95

Pressure Control Test

1010

1008

1006

1004

Pressure (Microns)

1002

1000

998

996

994

992

990 86 91 96 101 106 Tim e (Minutes) PRESSURE 111 116 121

Sublimation - Condensation

Sublimation / Condensation Rates

Produce maximum sublimation rate achievable Sublime quantity of water equal to total condenser capacity at the maximum sublimation rate

Condenser Capacity

Process Control
Activities
Computer validation Input and output checks Software development documentation Verification of programs Verification of alarms
hierarchy and response failure challenges

Data Acquisition

Data Acquisition Systems

Prove that the system is capable of the resolution, accuracy and precision necessary for adequate control and documentation of the process

Lyophilizer Uniformity Studies

Objective
Demonstrate uniformity of conditions and product attributes unique to lyophiles throughout batch, independent of location within the lyophilizer.

Goal
Assurance of reproducible processing conditions and consistent dried product characteristics with desirable attributes throughout a batch and for every batch, independent of location.

Lyophilizer Uniformity Studies

Benefits
Allows correlation of sample temperature during processing to dried product attributes. Opportunity for statistical analysis. Identify location within lyophilizer as points for future monitoring and finished product sampling.

Lyophilizer Uniformity Studies

Location in lyophilizer
Includes product temperature range at

critical times during process.

Correlate to dried product attributes. Most representative and extreme location

in the lyophilizer.

Lyophilizer Uniformity

Monitoring & Sampling Locations

Five locations on each shelf

(filled with product)

Monitor for product temperature and evaluate dried product attributes

Lyophilizer Uniformity

Monitoring & Sampling Locations

Five locations on each of the shelves

Product Temperature Uniformity

40 30 20 10 0 -10 -20 -30 -40 -50 Time 0:03:00 1:24:00 2:45:00 4:06:00 5:27:00 6:48:00 8:09:00 9:30:00 0:21:00 1:42:00 3:03:00 4:24:00 5:45:00 7:06:00 8:27:00 14:36:00 15:57:00 17:18:00 18:39:00 20:00:00 21:21:00 22:42:00 10:51:00 12:12:00 13:33:00 14:54:00 16:15:00 17:36:00 18:57:00 20:18:00 21:39:00 23:00:00 9:48:00 11:09:00 12:30:00

End of Primary Drying

End of Freezing

End of Secondary Drying

Left Location A Shelf 02 Centre Shelf 10 Centre Shelf 13 Centre Inlet Shelf 13

Location E Shelf 11 Location A Shelf 06 Centre Shelf 04 Centre Outlet Shelf 13

Location A Shelf 12 Location A Shelf 09 Centre Outlet Shelf 01 Centre Inlet Shelf 07

Centre Shelf 07 Location E Left Shelf 05 Centre Inlet Shelf 01 Centre Outlet Shelf 07

Location E Shelf 08 Location E Right Shelf 03 Centre Shelf 01

Lyophilizer Uniformity Studies

Use of model or actual product

Actual product formulation Placebo vials spiked with active product vials Use of a Surrogate

Surrogate Product Attributes

Presentation
Sufficient size (fill volume) Ease of inspection

Model formulation
Discernable melt back or collapse Distinguishable residual moisture

Representative
May emulate actual product Similar to range of products

Critical Dried Product Qualities

Dried cake appearance
Expected appearance Absence of melt back or collapse

Acceptable Residual Moisture

Average Range

Reconstitution
Time Solution appearance

Lyophilizer Uniformity
Most Extreme

Results of Monitoring & Sampling

Shelf 1

Five locations on each of the shelves

Shelf 3

Most Representative

Lyophilizer Uniformity Studies

Locations in lyophilizer Most representative reflects

the majority of the batch. Most extreme is the outlier that envelopes the entire batch.

FDA Definition: Expectation for Validation

Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.

Validation for Compliance

Example of an Objective

The objective of validation for (product XYZ) is to show that product manufactured and tested in accordance with Master Batch Record ABC and Validation Protocol 123 will consistently meet its predetermined specifications and quality attributes. This will be done using 3 consecutively manufactured batches of product.
Heather Pederson, former Pre-Approval Inspection Program Manager, USFDA (Newark District)

Manufacturing Process Control

PROCESSES TO INCLUDE
Formulation Filling Vial Transfer Lyophilization Sealing / Capping Visual Inspection

Development to Manufacturing
SHOULD BE:
(PRODUCT SPECIFICATIONS)

BIO-BATCHES

OFTEN IS:
BIO-BATCHES SCALE UP BATCHES DEVELOPMENT BATCHES DEVELOPMENT BATCHES DEVELOPMENT BATCHES VALIDATION REPORT
Heather Pederson, former Pre-Approval Inspection Program Manager, USFDA (Newark District)

(PROCESS PARAMETERS)

SCALE UP BATCHES

DEVELOPMENT REPORT VALIDATION PROTOCOL VALIDATION BATCHES VALIDATION REPORT

Performance Qualification
Address and Document
Intended outcome of process Critical processing parameters (CPP) Key processing parameters (KPP) Critical quality attributes (CQA) In-process and finished product testing Stability data

Performance Qualification Studies

Sequence in processing Location in lyophilizer Consistent Product Attributes

Performance Qualification Studies

Sequence in processing
Consistent quality attributes throughout batch Sample beginning, middle, and end of fill Evaluate dispensed liquid and lyophilized samples.

Potency and Purity Attributes

Liquid Preparation

Evaluate starting bulk liquid attributes

Monitor stability of starting liquid product to quantify attributes from beginning to end of batch. Analysis demonstrates achievement of predicted level of quality, purity, efficacy and bulk liquid stability.

Lyophilization as a Unit Operation

Loading Freezing Primary Drying Secondary Drying Stoppering

Process Parameters
Established critical independent parameters (CPP)
Shelf (inlet) temperature Chamber pressure Time

Identified key dependent parameters (KPP)

Product temperature Condenser temperature

Lyophilization Process
40 2000 30 1800

Chamber Pressure
20

1600

1400 10 Tem perature ( oC )

Shelf Temperature
0

1200 M icrons

1000 -10 800 -20

Threshold Temperature
-30

600

Product Temperature
-40

400

200

-50 0 200 400 600 800 1000 1200 1400 1600 Time (minutes)

0 1800

Potency and Purity Attributes

Lyophilized Product

Assess stability of lyophilized attributes

Verify lyophilization process does not alter attributes or magnify any differences for the dried product upon long term storage. Analysis demonstrates achievement of predicted level of quality, purity, efficacy and solid state stability.

Performance Qualification Studies

Consistent Product Attributes Characteristics unique to

lyophilized preparations with potency and purity attributes Correlate initial quality attributes with results upon storage.

Performance Qualification
Loading
Trays Loading order & pattern Shelf temperature Holding time Product temperature & thermocouple placement

Performance Qualification

Loading

Final shelf temperature and range Time Product temperature

Performance Qualificaiton

Freezing

Ramps: Average Controlled Rates of Change Final shelf temperature and range Time Product temperature threshold

Performance Qualification
Primary Drying

Shelf temperature
(soaks and ramps)

Chamber pressure Product temperature

(Phase transition temperature)

Condenser temperature

Performance Qualification
Secondary Drying

Shelf temperature
(soaks and ramps)

Chamber pressure Product temperature

(Phase transition temperature)

Condenser temperature

Demonstrated Process Control

40 1000 900 20 800 700 TEM PE RATURE ( C) 0 SHELF TEMPERATURE 600 500 THRESHOLD PRODUCT TEMPERATURE PRODUCT TEMPERATURES -40 MAXIMUM CONDENSER TEMPERATURE 400 300 200 100 0 1800 M ICRONS

-20

CONDENSER TEMPERATURE -60 CHAMBER PRESSURE

-80 0 200 400 600 800 1000 1200 1400 1600 TIME (Minutes)

Performance Qualification Objectives

Summary Process Parameters
Controlling independent and monitoring dependent process variables assures maintenance within a proven acceptable range.

Product Characteristics
Verifying consistent achievement of predicted level of quality, purity, efficacy and stability.

Development for Quality

Example of an Objective

Design Excellence (DEX) / Design for Six Sigma (DFSS)

Achieving Design Excellence using a set of design tools and methodologies for improving product and process development to consistently provide reliable and manufacturable products that consistently meet customer requirements.
Denise Hudson, VP Worldwide Process Excellence, J&J Pharmaceutical Group

Validation for Quality

Design for Six Sigma
Define
Develop Scope and Charter the Project

Opportunity

Define Measure Analyze Design Verify/Validate Transfer

Measure
Gather & Quantify Design Inputs

Analyze
Develop and Investigate Conceptual Designs

Design
Develop Detailed Product Design & Production Process

Verify/Validate
Confirm design outputs meet design input requirements and ensure specifications conform with Intended Uses and Users

Summary
Achieving Design Excellence
Product design and processing conditions are identified during development. Reproducible process parameters and consistent product quality attributes are verified during scale-up and technology transfer. Control and reproducibility of the process to consistently yield product of acceptable quality, purity, efficacy and stability are validated in manufacturing.

Thank you for participating!

References
Guidelines
Guide to Inspection of Lyophilization of Parenterals (7/93) Formulation of products Aseptic FiIling Cycle, Controls, Validation Sterilization and Aseptic Processing Finished Product Inspection and Testing

References
Inspection Documents
Compliance Program Guidance Manual, 7356.002A - Sterile Drug Inspections (9/93) Identify when using CMO When manufacturing in house
Manufacturer of lyophilizer Percentage of products lyophilized Equipment general description Processing procedures

References
Inspection Documents
Compliance Program Guidance Manual, 7356.002A - Sterile Drug Inspections (9/93) Equipment general description
Heating and cooling systems Vacuum system Gas used to break vacuum (sterile) Temperature controlling system

References
Inspection Documents
Compliance Program Guidance Manual, 7356.002A - Sterile Drug Inspections (9/93) Processing procedures
Preparation of the sterile product for drying Procedures for protecting product from contamination while loading into lyophilizer How are stoppers seating in vials Conditions during stoppering under vacuum, what gas is used and how sterilized

References
Inspection Documents
Compliance Program Guidance Manual, 7356.002A - Sterile Drug Inspections (9/93) Review of production records
Review at least three production records Verify cycle parameters and observed results are within scope of validation studies Identify criteria for acceptable vs unacceptable runs: general appearance, moisture, etc

References
Guidance for Industry
Contents & Format of Chemistry, Manufacturing & Controls Information and Establishment Description Information for a Vaccine or Related Product, Section G (1/99) A validation summary for lyophilization
Narrative description of the validation Certification of completed IQ and OQ Validation data summary Explanation of all excursions or failures Deviation reports and results of investigation

References
Guidance for Industry
Submission of Chemistry, Manufacturingfor Human Plasma Derived Biological Products, Animal or Serum-Derived Products, Part 2, Section III, D (2/99) A validation summary for lyophilization
Narrative description of the validation Certification of completed IQ and OQ Validation data summary Explanation of all excursions or failures Deviation reports and results of investigation

References
Guidance for Industry
Content and Format of Chemistry, Manufacturing for a Biological InVitro Diagnostic Product, Section II, C, Methods of Manufacturing and Packaging (3/99) A complete description of the manufacturing process flowshould be provided. This discussion should include a description of:
Vialing / filling lyophilization labeling packaging

References
Guidance for Industry
Content and Format of Chemistry, Manufacturing for a Biological InVitro Diagnostic Product, Section II, C, Stability (3/99) Stability data supporting the proposed shelf life of the reconstituted in vitro product for all labeled dilutions

References
Regulations
Title 21 CFR, Section 211: GMP Title 21 CFR Sections 600 (applicable to product category) 601.12: Changes to an Approved Application 610.13 Purity (a)(1) Test for Residual Moisture

References
Regulations
211.137 (g) Expiration dating information of reconstituted drugs for investigational use. 211.166 (a) (5) Stability Testing. Perform stability testing of drug after reconstitution.