Lecture 20A.ppt

8/14/2019 Lecture 20A.ppt

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Validation in Biotech Facilities:What ? Why ? How?

Dr. PK Yegneswaran


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Presentation Outline

Validation OverviewCleaning ValidationProcess ValidationSterilization ValidationCitation ExamplesRegulatory References


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Typical Project Schedule

1 2 3 4 5 6

Scope

Design

Procurement

Construction

IQ/OQ

Startup / Validation

100%

YEAR

APPROVAL

% S

p e n

t

Phase III

APPROVAL


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Validation Overview

[To establish] documented evidence which provides ahigh degree of assurance that a specific processwill consistently produce a product meeting pre-determined specifications and quality attributes.

(FDA , May 1987 )


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Validation Overview

Why validate ? The FDA requires that we validate all of our

systems and processes according to 21 CFR part

211 Improves our understanding of our manufacturing

processes Right thing to do !


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Why Validate?

Consistent yield &qualityRapid decisions whenmishaps occurFewer discardsLess time hostinggovernment agencies,more timemanufacturing

to ensure that theoutput is consistent;

first time, every time!!


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What do we Validate ?

ProcessCleaningSterilizationFiltersContainersAssays


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How do we Validate ?Cleaning, Process, Sterilization etc.

Define Critical Process Parameters, Critical Quality Attributes

Develop protocol describing validation studies

Consider fractional study approach for cleaning, sterilization

Execute studies

Address deviations

Compile report

Review / Approve report

GMP Documentation all the way.

This pro cess appl ies to a l l val idat ion


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Definitions

Critical Process Parameter (CPP):An input variable that must be controlled within a specified rangeto ensure success.

Critical Quality Attribute (CQA):An output parameter from a unit operation that must be within aspecified range to demonstrate control, consistency, andacceptable product quality.

CPP CQAIonic Strength Ion Exchange YieldColumn Load Chromatography Purity

Flow rateCleaning

ConductivityTemperature TOCConcn.

Sat. Steam Steri l izat ion BIs Time


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Style-ogen Facility BuiltIQ/OQ Complete What Next ?

Sterilization Validation Development, validation studies

Practice Lots Define validation parameters for process, cleaning, cleaning

validation Validation Lots

Process validation, cleaning validation File license Pre-Approval Inspection Facility / Product approval


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Typical Post OQ Schedule

Cleaning Dev.

Sterilization

Dev.

Practice Lots

IQ/OQ/Facility/Utility Qualification

Validation Lots

YEAR

APPROVAL

Phase III

APPROVAL

1H Y4 2H Y4 1H Y5 2H Y5

Cleaning Valdn.

SterilizationValdn.

FileLicens

e


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Cleaning Validation

Cleaning Validation overviewCycle development for Style-ogenequipmentValidation of cleaning cycles


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Equipment cleaning validation is the processof establishing documented evidence that aparticular cleaning procedure will consistentlyreduce equipment surface residuals to apredetermined acceptable level.

Residuals are any product, degradate,

intermediate, excipient, raw material/reactantor cleaning agent that may reside on anyequipment surface following processingand/or cleaning.

What is Cleaning Validation ?


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21 CFR Part 211 Subpart D - Equipment

211.67 Equipment Cleaning and Maintenance (a) Equipment and utensils shall be cleaned,

maintained, and sanitized at appropriate intervals to

prevent malfunctions or contamination that would alterthe safety, identity, strength, quality, or purity of thedrug product.


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21 CFR Part 211 Subpart F - Production andProcess Controls

211.113 Control of MicrobiologicalContamination (a) Appropriate written procedures, designed to prevent

objectionable microorganisms in drug products notrequired to be sterile, shall be established andfollowed.

(b) Appropriate written procedures, designed to preventmicrobiological contamination of drug productspurporting to be sterile, shall be established andfollowed.


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One-Third Of Recent Drug GMP Warning LettersCite Cleaning Practices (2002 survey)

Year # of WarningLetters

# of WarningLetters relatedto Cleaning

% Related toCleaning

1999 65 23 35%

2000 71 20 41%

2001 71 20 28%


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Cleaning ValidationWhere Do I Start?

Validation Strategy

ManufacturingProcess

CleaningProcess

Mfg. Equipment& Design

ManufacturingProcess

CleaningProcess

Mfg. Equipment& Design


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Obtain a Process Flow Diagram Is Product Inactivation Required ?(Important to ensure inactivation procedure is defined before starting validation)

Define Applicable Hold Times Dirty: End of Process to Start of Cleaning Clean: End of Cleaning to Next Process Use Sterile: End of SS/SIP to Next Process Use

What Residuals Need to Be Cleaned by the CIP ? Product (includes degradates, excipients, raw materials, etc. ) Cleaning Agents

Are the Residuals Representative of the Process ? (Important to consider when validating during Practice Runs or Demonstration)

Is the Equipt. Sanitized or Sterilized after CIP ?

Considerations:

Manufacturing Process


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Define CIP Type (Manual, Automated)

Are the Individual Steps of the CIP Procedure Defined ?

Critical Process Parameters Defined ? (e.g. Flow, Temp.)

Is the Cleaning SOP available ?

Does CIP Procedure Clean All Product Contact Surfaces?

(Highlight and Compare Mfg Process to CIP Process on Same P&ID) What CIP Cycle Development Work is Planned?

Considerations:

Cleaning Process


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Are All Equipt/Systems IQ/OQd ? Define Surface Materials of Construction (Prod. Contact)

Ensure General CIP Design Principles Followed Minimal to No System Deadlegs Turbulent Flow Maintained During CIP Full Coverage to Vessel During the CIP Lines Flooded Completely During the CIP

Complete System Drainability Assess Validation Sample Locations

Accessibility Availability

Considerations:

Mfg. Equipment Design


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Challenge Strategy: Hold Times Fractional Cycle Approach

No. of Lots Tested Product/Equipment Matrix Required

Test Methods and Sampling Plan: Rinse Sampling Swab Sampling Visual Inspection

Analytical Methods Assay Selection (Chemical/Micro) Assay Validated (Includes Swab Recovery)

Acceptance Criteria

Defined in a Protocol and Includes:

Validation Strategy


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Overall surface evaluation: final rinse sampling & analysis

USP chemical- purified water methodologypH 5.0 - 7.0

Conductivity < 3 S/cmEndotoxin < 0.25 EU/mL to < 10.00 EU/mL

TOC < 1.0 ppm +(based on system capability)Bioburden* < 100 cfu/10mLProduct specific varies, typically non-detect

+ Over Negative Control

* Bioburden sampli ng is performed in systems that are not steamed or ster i l ized forbiobur den contr ol

Typical cceptance Criteria


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Back to Style-ogen :Bulk Portable Tanks CIP

Next UseEnd of Use Cleaning24 HourDirty Hold Time

7 DayClean Hold Time

Manufacturing Process:

Product is Inactivated with Hypochlorite Prior to CIP (SOP) Only 100L Portable Tanks Cleaned at Bulk PTS

One Tank Can Be Cleaned At A Time At Bulk PTS

Each Tank Can Contain One of the Following Product Soils : Active Ingredient Manny Active Ingredient Moe Active Ingredient Jack 25% Sucrose

Tank is Not SS/SIP After Cleaning


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Style-ogen - BULK PTS CIP

Cleaning Process : Automated CIP Cycle Cycle Steps Defined Cleaning SOP Available

Cycle DevelopmentPlanned Concurrent toOQ & Engineering Lots

Mfg. Equipment & Design: Bulk PTS & 100L Style-ogen Tanks will be IQ/OQd All Product Contact Surfaces Constructed of Stainless Steel Good CIP Design Principles Followed Validation Sample Locations Readily Accessible & Available (Rinse Sample Port)

Hold Time or CycleStep Description

ProductionCycle

Dirty Hold Time < 24 hrs.HWFI Rinse 2 min.2% Caustic Wash 15 min.HWFI Rinse 2 min.1% Acid Wash 5 min.Final Rinse #1 2 min.

Final Rinse #2 2 min.Final Rinse #3 2 min.Final Rinse #4 2 min.Final Rinse #5 2 min.Clean Hold Time < 7 days


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Styleogen - BULK PTS CIP

Validation Strategy: Residual

NameTime to Clean toAcceptable Level

"Manny" 150"Moe" 300"Jack" 150

25% Sucrose 100

Lab Scale Cleanability Results

How Many Validation Lots?

Hold Time or CycleStep Description

ProductionCycle

ValidationCycle

Dirty Hold Time < 24 hrs. > 24 hrs.HWFI Rinse 2 min. 2 min.

2% Caustic Wash 15 min. 10 min.HWFI Rinse 2 min. 2 min.1% Acid Wash 5 min. 5 min.Final Rinse #1 2 min. 2 min.Final Rinse #2 2 min. 2 min.Final Rinse #3 2 min. 2 min.Final Rinse #4 2 min. 2 min.Final Rinse #5 2 min. N/A

Clean Hold Time < 7 days > 7 days

Cleaning Cycle Description Use a Fractional Cycle Approach

Caustic Wash Time Reduced 33% Final Rinse #5 Eliminated

Dirty & Clean Hold TimesChallenged During Validation

3 Lots Moe (Hardest to Clean)

1 Lot Equivalency Each Others


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Style-ogen - Bulk PTS CIP

Execute Protocol Document deviationsCollect samplesAnalyze samples

Check vs Acceptance Criteria Pass / Fail / InvestigationWrite Report Address deviationsReview / Approve Report StakeholdersInclude summary in license document


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2001 ms 3767


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Process Validation - Definition

[To establish] documented evidence which provides ahigh degree of assurance that a specific processwill consistently produce a product meeting pre-determined specifications and quality attributes.

(FDA , May 1987 )

2001-ms-3767


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Demonstrate process control and consistency

Comply with regulatory requirements forlicensure

Provide assurance that release tests will be met;the need for some release testing may beeliminated.

Why Validate the Process ?

Process Validation


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Key ProcessVariables

Optimization/Process

Understanding

RobustnessWorst case challenges?

Process Validation atFull-scale

ProcessCharacterization

ProcessValidation

Phase I/II Clinicalprocess

Lab-scaleprocess

Manufacturingprocess

Lab Scale Validation

Process Validationrequires a rational approach


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Characterization vs. Validation

Characterization Validation studies at bench -scale using scaled-down

models, if possible. Well-documented in Lab notebooks and key technical

reports (no protocol) Learning, not Validating

Validation Usually at Full-scale in actual process equipment (except

for viral clearance and resin/filter re-use)

Conducted by Manufacturing under Protocol Testing what we already know, NOT EXPERIMENTING!


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Understand Your Process

Ruggedness Multiple lots of raw materials Multiple lots of resins/filters Explore failure limits at laboratory/pilot scaleScaled-down process should reflect fullscale manufacturing performance asclosely as possible so that data generatedare relevant.


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Definitions

Critical Process Parameter (CPP):An input variable that must be controlled within a specifiedrange to ensure success.

Critical Quality Attribute (CQA):

An output parameter from a unit operation that must bewithin a specified range to demonstrate control,consistency, and acceptable product quality.

CPP CQA

Ionic Strength Ion Exchange YieldColumn Load Chromatography Purity


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Example-Homogenization Step

Homogenization Pressure Conc. # of passes Temperature Residence time Back-pressure

Cell breakage

CPPs? CQA

Function in the manufacturing process: Cell breakage - cell breakage must be 70% by Hematocrit assay.

Process knowledge Scientific rationale

Tools are simply to provide a basisfor discussionand to facilitate the PV process.


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1. Select CPPs, CQAs

2. Process Validation Protocol

3. Execute

4. Assay

5. Report6. File

Back to Style-ogen : Process Validation


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Process Mapping: Step & Purpose

Fermentation

Thaw/Cell Breakage

Microfiltration/Chromatography 1

UF/Chromatography 2

Sterile Filtration

Dilution/Adjuvant Addition

Antigen Release

Antigen capture

Polishing purification

Sterilization

Dose/ adjuvant


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Detailed Step Description

Chromatography

Step Goal: Primary purification

Equipment constraints:flow rate pressure drop

Cycle time Column size Flow distribution

Sampling plan:

Feed Flow-through Product

Characterization

Size Potency Lipid Carbohydrates Yield Purity

Monitoring

Flow-pressure UV Conductivity HETP

Other parameters:Feed properties/composition, salt concentration , temperature, lot-to-lot feed/resin variability,feed concentration, load

Support Documents

Technical memos: Effect of load Cleaning/reuse

SOPs Batch summaries Equipment FRS


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Impact on product quality does the parameter have an impact on a CQA?

Controllability how easy is the parameter to control?

Recovery potential is there a redundant downstream step?

Use tools such as Criticality Index Analysis

Select CPPs, CQAs Factors to Consider


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Example of a Criticality Index Analysis

Cell breakage

Enzymetreatment

Microfiltration


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Process Validation Protocol

CPPs, CQAs w/ acceptance criteria Background / rationale for ranges

How will they be sampled / monitored ?How many validation lots ?How will deviations be handled ?

Define Roles and ResponsibilitiesManufacturing, Quality, Technology

l d l


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Process Validation Protocol

Step Goal CPPs CPPRange

Howcontrolled

CQA Samples CQARange

Methods

Fermentation

Highcelldensity

pH

Temp

7.0 0.5 DCS FinalGlucoseConcn.

Broth final timepoint

1 3g/L

AnalyticalmethdSOP XYZ


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Style-ogen - Process Validation

Complete 3 Validation Lots Obtain, Analyze data Address deviations

Transient deviations

Equipment malfunctions Additional lots if needed Complete / approve report Include in license


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Sterilization Validation

Sterilization Validation overviewValidation of sterilization cycles (Protocol,Acceptance criteria,.)

l


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Steam Sterilization

Cell death by protein denaturationSimple, reliable & economicalSpores are more resistant than cellsSpores ~100x more resistant to dry heatthan steamTypical cycle: >121C for 5-45 minutes

Saturated steam is critical!


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Kinetics of Microbial Death

Generally observed to be first-orderkineticsNon-logarithmic behavior is knownKinetic models

)( kt o

oo

eN N

t t at N N

kN dt

dN


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Kinetics of Cell Death


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Logarithmic decline most applicable tovegetative cellsSpores can show non-log rates Spore germination Sequential events for death

S S R R S

R R R

D

k

S

k

R

N k N k

dt

dN

N k dt

dN N N N

S R


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Temperature Effect

Kinetic rate is a function of temperature

Arrhenius model typically employed:

Linear correlation between ln(k) and 1/T

)/( RT E e Ak

T t Eff t


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Temperature Effect

Characterization of Steam


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Characterization of SteamSterilization Cycle Lethality

Organism-related D-value (log reduction time) Z-value (deg. of temp. to reduce D by 1 log)

Cycle-related F-value (integrated lethality delivered)

Log reduction = F/D

Typically, T R = 121.1 C, D = 1-3 min (spores) Target F o = 36-72 minutes (full cycle)


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D-value

A measure of the sensitivity of anorganism to a sterilization methodDecimal reduction time - time at a given

temperature required to reduce apopulation by 1 log

k Dt

eN

N

eN N

kt

o

kt o

303.2

101 )(

)(


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Z-value

A measure of sensitivity of organism to differenttemperaturesNumber of degrees needed to alter the D-valueby one log

Allows for integration of the lethal effect of heatas the temperature changes.Depends on sterilization method Steam: Z = 10 C Dry heat: Z = 21 C

Z value


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Z-value

Spores, Z = 8 - 12C10 C usually assumed


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F-value

Integrated amount of lethality deliveredduring a sterilization cycle

For T R = 121 C and Z = 10 C, F = F o

t F Z T T R /)(10

t F T o

10/)121(10

F l


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F-value

Extremely sensitive to temperature Fo = 1 min at 121 C for t = 1 min Fo = 2 min at 124 C for t = 1 min

Fo = 8 min at 130 C for t = 1 minLog reduction = F/D D = 2 min, F o = 16 min, Log reduction = 8 For SAL = 10 -6, initial population


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Typical SIP Cycle

Come-up Purge air Add steam

Wait to reach sterilization temperatureDwell Hold at T>121 C for fixed time or F o

Cool-down Turn steam off and cool system down Pressurize with air



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Fractional cycle approachChallenge with 10 6 G. stearothermophilus sporesRun validation studies to obtain a 6 log reduction ofG. stearo. sporesProduction cycle will be based on a theoretical 12log reductionEstablish continuing validation schedule and changecontrol for validated cycle.

Sterilization Validation (SIP)


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Sterilization Validation (SIP)

Place spore challenges throughout the system targetingworst case locations ( Geobaci l lus s tearotherm oph i lus )

Run a fractional sterilization cycle (reduced temperatureand/or time)

Evaluate the temperatures (F o) at each location

Evaluate saturated steam conditions

Evaluate the kill/inactivation of the spores

Perform 3 fractional cycle studies followed by 1 productioncycle study

Sterilization Validation Positioning of


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gThermocouples

Validation Complete What Next?


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Validation Complete What Next?

Cleaning Dev.

SterilizationDev.

Practice Lots

IQ/OQ/Facility/Utility Qualification

Validation Lots

YEAR

APPROVAL

Phase III

APPROVAL

1H Y4 2H Y4 1H Y5 2H Y5

Cleaning Valdn.

SterilizationValdn.

FileLicens

e

StartChangeControl

Implement Change Control


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Implement Change Control

Changes happen. Need to Document changes Assess impact on

validation Revalidate as necessary File as necessary



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Recent FDA Observations - Cleaning

Recent FDA Observations -


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Sterilization

Recent FDA Observations Process


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Recent FDA Observations - Process

Regulatory References


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Regulatory References

FDA guidance documents CMC Guidance

http://www.fda.gov/cber/gdlns/cmcvacc.pdf

Sterilization Validationhttp://www.fda.gov/cber/gdlns/sterval.pdf

Process Validationhttp://www.fda.gov/cder/guidance/pv.htm

PAT approach

http://www.fda.gov/cder/guidance/6419fnl.htm

FDA guidance documents CMC Guidance

http://www.fda.gov/cber/gdlns/cmcvacc.pdf

Sterilization Validationhttp://www.fda.gov/cber/gdlns/sterval.pdf

Process Validationhttp://www.fda.gov/cder/guidance/pv.htm

PAT approach

http://www.fda.gov/cder/guidance/6419fnl.htm
http://www.fda.gov/cber/gdlns/cmcvacc.pdfhttp://www.fda.gov/cber/gdlns/sterval.pdfhttp://www.fda.gov/cder/guidance/pv.htmhttp://www.fda.gov/cder/guidance/6419fnl.htmhttp://www.fda.gov/cber/gdlns/cmcvacc.pdfhttp://www.fda.gov/cber/gdlns/cmcvacc.pdfhttp://www.fda.gov/cber/gdlns/sterval.pdfhttp://www.fda.gov/cder/guidance/pv.htmhttp://www.fda.gov/cder/guidance/6419fnl.htmhttp://www.fda.gov/cder/guidance/6419fnl.htmhttp://www.fda.gov/cder/guidance/pv.htmhttp://www.fda.gov/cber/gdlns/sterval.pdfhttp://www.fda.gov/cber/gdlns/cmcvacc.pdfhttp://www.fda.gov/cder/guidance/6419fnl.htmhttp://www.fda.gov/cder/guidance/pv.htmhttp://www.fda.gov/cber/gdlns/sterval.pdfhttp://www.fda.gov/cber/gdlns/cmcvacc.pdf