pm1210_holistic_west_final.pdf

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Holistic

QbD

Holistic Qb

Developing a Qb

Componen

The Lifecycle

Syringe Plung

QbD for Pharm

Packagin

Componen

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2/13

Since FDA introduced the term to the pharma-

ceutical industry in 2005, the concept o phar-

maceutical Quality by Design (pharma QbD), a

ramework or building quality into pharmaceu-

ticals during drug development has been slowly

gaining ground. Today, the leading name branddrug companies and a number o generic drug

manuacturers are using Quality by Design meth-

ods to optimize product development. Case

studies have been published or solid dosage

orms; biopharmaceuticals; and even, on a pre-

liminary basis, or vaccines.

The concepts behind QbD grew out o work

published decades ago by such quality experts

as Joseph Juran. They have been used in other

industries or some time, but pharmaceutical

manuacturers are now applying them to ensure

consistent product quality despite variations in

raw materials and other variables.

Discrete industries are no strangers to QbD.

Now, however, some vendors to the pharma-

ceutical industries are applying pharma QbD

principles to develop their pharmaceutical in-

dustry products. This e-book oers general

resources in the area o QbD, and discusses

how West has been bringing a QbD approach

to its packaging components. We hope that

you ind it useul.

2

Contents3 Holistic QbD

by Andy Polywacz, VP o QA,Americas, West Pharmaceutical

Services

6 Developing a QbDComponent:The Liecycle oSyringe Plungerby Tibor Hlobik, director, Global

Prellable Syringe Platorm,West Pharmaceutical Services, Inc.

9 QbD or PharmaPackagingComponentsby Paul Thomas, senior editor,

Witt-Kieer

13 Online Resources

tPrevious Page Next Pageu


3/13

3

Modern GMP expectations are transorm-

ing the way drug products are being devel-

oped, manuactured, evaluated and con-

trolled. The movement rom ascertaining

drug product quality predominantly by end

product testing to achieving quality by de-

sign (QbD) or eective and ecient manu-

acturing processes is reinventing the GMP

landscape. Harmonized guidances associ-

ated with pharmaceutical development,quality risk management and pharmaceuti-

cal quality systems (ICH Q8, 9 and 10) have

initiated a ramework or science-based

quality manuacturing.

The goal during development is to have pre-

dened objectives with emphasis on the

product and understanding the manuac-

turing process; controls are then based on

knowledge to build the manuacturing sci-

ence while employing quality risk manage-ment principles. Drug product ormulation

development summaries should highlight

the evolution rom initial concept to nal de-

sign and take into consideration the choice o

drug product container closure systems.1 An

in-depth understanding o container closure

components along with their manuacturing

process will enable science-based decisions to

support pharmaceutical manuacturing con-

trol strategies. Aspects o container closure

systems critical to drug product quality can

be established during the drug development

cycle by identiying potential attributes o the

component and utilizing various risk

management tools to evaluate risks.

The level and ormality o risk as-

sessments should be commensurate

with the level o risk to drug product

quality.2 It is possible to combine and coor-

dinate process knowledge rom multiple unit

operations to achieve a holistic picture o the

entire drug manuacturing process, which can

incorporate the science o component manu-

acture. A mechanistic understanding o how

drug ormulation and component manuac-

turing process actors aect pharmaceutical

quality will lead to:

Eectieteclytatwillreduceset-

backs when moving rom development to

commercialization, realizing time and cost

savings

Data-driekwledetidetifycriti-

cal quality attributes and establish control

strategies

H Qay by DegnBy Andy Polywacz, vice president, Quality Assurance,Americas, West Pharmaceutical Services, Inc.



4/13

4

Specicatisbasedwadwyte

rubber ormulations, components and pro-

cess actors impact drug product quality

Beetstruuttelifecyclefa

given product through trending o data or

proactive management and eective con-

tinuous improvements

West NovaPure elastomeric components

are ormulated and manuactured using

a QbD approach that is holistic in nature.

This approach takes into consideration

the entire supply chain rom raw materials

through distribution and drug packaging.

Quality characteristics are engineered to

meet the requirements o the pharmaceuti-

cal manuacturer and help promote protec-

tion/compatibility o drug product.

The ollowing important QbD elements were

used to develop and produce NovaPure

components with a commitment toward en-

hancing drug product quality:

QualityTaretPrductPrle(QTPP)

CriticalQualityAttribute(CQA)

QualityRiskMaaemet(QRM)

KwledeMaaemet(KM)

CriticalPrcessParameter(CPP) CtrlStratey(CS)

LifecycleMaaemet(LCM)

CtiuusImpremet(CI)

Consideration o all these actors during

development o NovaPure components

has achieved a well-understood compo-

nent and robust processes that 1) deliver

a component meeting the QTPP and 2)

are controlled by dened steps within the

manuacturing process. During commer-cial-scale manuacturing, the proactive

trending o component perormance on

a continuous basis provides a major ad-

vantage through early detection o poten-

tial issues and urther optimization o the

control strategy to ensure reliable level o

high-quality components.

The holistic approach to the development

o NovaPure components encompassed the

actors associated with raw materials, as well

as manuacturing process parameters re-

lated to multiple acets o component qual-

ity. A cross-unctional team o subject matter

experts was employed to dene the scopeo the risk assessments and quality attributes

to be evaluated. The risks were sorted and

ranked based on the relative criticality o the

various properties and attributes o the com-

ponent. The analysis o unctional relation-

ships distinguished the level o risk and pri-

oritized relevant studies to evaluate risk.

Manuacturing trials were conducted to as-

sess quantitatively the relationship between

process parameters and identiying CQAs.Desifexperimets(DE)quatitatiely

predicted the eects o process parameters

on quality attributes and multivariate analy-

sis was employed to predict interaction o

multiple process parameters, reducing un-

certainty o areas having the greatest im-

pact to component quality. Critical process

parameters were identied through ull ac-

torial analysis so that interactions o multiple

process parameters were established within

a given range or particular componentquality attributes. As multiple parameters

were simultaneously examined to under-

stand interactions between actors, an e-

cient process to acquire and analyze data

with higher precision or component qual-

ity was achieved. The acquired data led to

a well-understood component and revealed

the sources o process and component vari-

ability to be monitored and controlled. As

holistic QbD practices were implemented

or NovaPure components, upstream con-trols were put in place rather than quality

by conormance related to capability o the

process based on discrete actions.

The demands o drug product regulation

continue to evolve as a result o the increas-

ingly global economy in which the supply



5/13

5

chain has become central to assuring drug

product quality. Qualication and procure-

ment o raw materials or NovaPure com-

ponents is initiated at concept develop-

ment, employing risked-based assessment

to achieve the desired component quality.

Vendor quality and business practices areevaluated to ensure reliable supply o raw

materials. These materials are proled to

understand variability and enable control

strategies. Monitoring raw materials used to

manuacture NovaPure components secures

the inventory through enhanced component

and process understanding. Assurance o

a reliable and readily available inventory is

an important consideration or preservation

o marketed drug product supply; a holistic

QbD process or components contributesto this aspect. Additionally, other aspects o

supply chain are considered relating to mini-

mized, standardized lead time or commer-

cial volumes, immediate shipment or small

volumes and aspects o supply chain secu-

rity built into the shipping cartons to rein-

orce tamper evidence.

The quality management system was tied

into the data starting at development stages

enabling science-based decisions to develop-ment o control strategies. Activities were o-

cused on maintaining component quality as a

result o knowledge gained to support CQAs

and impact to the manuacturing process.

Procedures were optimized or testing and

analysis to develop specications to maintain

a state o control and produce reliable com-

ponent quality. Scientic data that supported

control strategies are evaluated continually

and include annual reviews, considerations o

investigations and complaints to enhance un-derstanding o component and process.

A distinguishing eature o NovaPure com-

ponents is that attributes are assured

based on identication and control o criti-

cal process parameters (CPP) rather than a

rigid, static manuacturing operation that is

more susceptible to multiple manuactur-

ing changes. Current regulatory expecta-

tions are to have reduced uncertainty using

data-supported evidence o suitable com-

ponents during development through com-

mercialization. The variability o NovaPure

components has been minimized throughscientic-based assessments and is veried

continuously with a course o action or con-

tinuous improvement.

Most importantly, the NovaPure brand pro-

vides a shared quality commitment with

pharmaceutical manuacturers, allowing

greater predictability o component per-

ormance, which can contribute to achiev-

ing drug product with the quality attributes

appropriate to meet the needs o patients,health care proessionals, regulatory au-

thorities and internal customer require-

ments. Transparency between pharmaceu-

tical manuacturer and component supplier

is realized through managing knowledge

that is grounded in the nuances and com-

plexities revealed through implementing

holistic QbD. Included in this model is a

24/7 customer support knowledge center

to provide comprehensive inormation on

the NovaPure product and QbD processes.The transition rom the GMP era o qual-

ity management through checkbox compli-

ance to science-driven assessment and jus-

tications can be acilitated greatly through

use o NovaPure components; a reliable

supply o high-quality sterile components

in a ready-to-use ormat.

Reerene1 Guidance for Industry: Q8 (R2) Pharmaceu-

tical Development Revision 2, US Depart-ment of Health and Human Services Food

and Drug Administration, CDER/CBER, ICH

November, 2009.2 Guidance for Industry: Q9 Risk Manage-

ment, US Department of Health and Human

Services Food and Drug Administration

CDER/CBER, ICH June 2006.



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6

DEvELoPIngAQbDCoMPonEnT:

the leye

syrnge PngerBy Tibor Hlobik, director, Global Prellable Syringe Platorm,West Pharmaceutical Services, Inc.

Market trends toward home-use and patient sel-administration o drugs

used to treat chronic conditions (e.g., multiple sclerosis, rheumatoid ar-

thritis and autoimmune) have made prellable syringe systems an ideal

choice or single-dose drugs. Prelled syringe systems or vaccines,

pharmaceuticals and biopharmaceuticals oer convenient, xed dosing

and are adaptable to automated injection devices.

For patients, use o a prelled syringe system has the potential to

minimize microbial contamination and reduce medication dosing

errors. The syringe systems oer ease o use and enhanced con-

venience or those who require requent dosing, and when com-

bined with an auto-injector system, can provide a more portable

drug delivery system.

Pharmaceutical and biopharmaceutical manuacturers who se-

lect a prellable syringe system or their drug product may be

able to reduce therapy and injection costs, as well as signi-

cantly reduce overll when compared to single-dose vials.

The system may also optimize the number o doses rom

the existing drug supply, while oering a delivery option

that will help to dierentiate the system in a crowded

market and potentially increase patient preerence.

Strategies employed in early phases o drug develop-

ment that consider delivery devices such as prell-

able syringes and their components can mitigate

risk to quality, and position the product to meet

needs o the ongoing drug product liecycle. The

return on investment can be realized once a drug

product is commercialized and has gained pa-

tient loyalty through ease o use, therapeu-

tic benet and high condence in the delivery



7/13

7

device. While it is not easy to meet these

challenges, a drug product manuacturer

can benet rom early investment in the

right drug delivery system and high-qual-

ity components.

Hgh-Qay cmpnen Faae

Efen Manarng

Most subcutaneous drug product injections

utilize a staked needle 1mL long prelled

syringe ormat that can retain a ll volume

1.0mL. This syringe ormat is convenient,

ts most auto-injectors and is widely usedor sensitive pharmaceutical and biotechnol-

ogy drug applications.

The use o high-quality components in pre-

llable syringe systems will acilitate ecient

manuacturing processes and support a reli-

able supply o drug products. An elastomeric

plunger is a critical element because it serves

as the primary seal or container closure in-

tegrity, maintains purity o drugs during shel

lie, and unctions to expel contents o thebarrel and deliver drugs to the patient.

Plungers (also named pistons and stoppers)

are typically made rom butyl rubber and

can be coated with a fuoropolymer lm,

such as FluroTec lm, that can increase lu-

bricity and serve as a barrier between the

drug and the elastomer, reducing the poten-

tial or extractables inherent in all materi-

als. The phenomena o chemicals migrating

rom the elastomers into the drug prod-uct is known as leachables, but the reverse

process o the drug product adsorbing or

absorbing onto the plunger can also occur.

Extractablesadleacablescabesii-

cantly reduced with a barrier lm.

For improved manuacturing processes, the

pharmaceutical industry has moved toward

ready-to-use (RU) plungers or prellable

syringe systems. These components are

washed and sterilized prior to delivery to the

drug manuacturer with specications or

particulate and endotoxin, thereby reducing

the risk o introducing microbiological con-

tamination to the drug product during nal

packaging. There are several methods orsterilization o plungers and an increase in

extractable breakdown products have been

observed under gamma radiation; thereore,

autoclave steam sterilization o these com-

ponents is a preerred choice.

Qay by Degn: A New Way Mee

inreang Regary and Qay

Reqremen

Quality by Design (QbD) promotes under-

standing o the product and manuacturingprocess starting with product development.

When designing and developing a product

using QbD principles, manuacturers must

dene desired product perormance and

identiy Critical Quality Attributes (CQAs).

The product and process is then designed

to meet those product attributes, which

leads to understanding the impact o ma-

terial attributes and process parameters

on the CQAs and identication and control

o sources o variability. As a result o thisknowledge, a company can continually mon-

itor and update its manuacturing process to

assure consistent product quality.



8/13

8

Since prelled syringes are considered a

combination product, which is dened

by the agencies as A product comprised

o any combination o a drug and device; a

device and biological product; a biological

product and a drug, or a drug, a device and

biological product, two regulations apply:

cgMPFiisedParmaceuticalspart21

CFR 210-211

QSRReulatifrDeices21CFR820

Some o the primary areas covered by CFR

820 and that dier rom CFR 210-211 in-

clude management responsibility, purchas-

ing controls, corrective and preventive

action and design controls. As part o the

industrialization o plungers using the QbD

approach, aspects o CFR 820 must be in-

corporated into the manuacturing process.

Plungers that it 1mL long staked needle

syringes were originally developed or a

manual injection action. As customer de-

mand or higher quality and patient need

or sel-injection have evolved, demand

or a high-quality plunger rose. Using QbD

principles, West developed its NovaPure

components or preillable syringe sys-

tems to provide high reliability or break-

loose and glide orce, dimensional consis-

tency, sub-visible and visible particulate

control, and low parts per million (ppm)

deect attributes.

The 1mL long NovaPure plunger ollowed

a development liecycle program, which

used a Quality Target Product Proile

(QTPP) to establish CQAs or control o

breakloose and glide orces. As the prod-

uct which included risk-based design

iputs,FiiteElemetAalysis(FEA)

modeling, data generation on multiple

concepts, and inal product perormance

veriication with glass barrels rom mul-

tiple suppliers o a 1mL long staked nee-

dle syringe was developed, the QTPP

served as a guideline to assure that tar-

geted speciication values or breakloose

and glide orce were met.

Using QbD philosophy and principles can

help to optimize breakloose and glide

orces and signicantly reduce plunger

variation rom part-to-part. Use o QbD

principles ensures that components are

developed based on science and data-

driven decisions, as well as meet critical

specication or deects, visible and sub-

visible particulate and extractables con-

sistently. In order to achieve a high-qual-

ity product, QbD components are washed

and steam sterilized or optimized material

compatibility and the knowledge gained

throughout the process used on an ongo-

ing basis to maintain continuous improve-

ment by the manuacturer. Selecting a

manuacturing partner like West early in

the development process can help phar-

maceutical companies choose a high-qual-

ity component or use in prellable syringe

systems that will meet demands or high

quality, improved total cost, and increased

saety and security or the drug product.

NovaPure and FluroTec are registered trade-

marks of West Pharmaceutical Services, Inc.,

in the United States and other jurisdictions.



9/13

At the PDA Annual Meeting

in Phoenix in April 2012, West

Pharmaceutical Services rein-

troduced its NovaPure line o

drug packaging components

including serum and lyophili-

zation stoppers and syringe

plungers. What is unique

about the new NovaPure is

that, or the products design

and development, West lever-

aged the principles o Qual-

ity by Design. West has long

viewed itsel as a supporter

o the industrys QbD eorts,

but has now taken that sup-

port one step urther. Its a

vast change rom the way the

company developed prod-

ucts in the past, and may be

seen as a sign that the infu-

ence o Quality by Design is

expanding beyond drug and

device manuacturing and

taking root in the vendor and

solution provider community

as well. (West has posted a

video on YouTube with more

details on how QbD played

into the development o No-

vaPure.)

In anticipation o the Nova-

Pure announcement, we spoke

with Fran DeGrazio, Wests

vice president or marketing

and strategic business devel-

opment. DeGrazio has nearly

30 years o experience in the

industry, is a requent speaker

and author on pharmaceutical

packaging and injectable drug

products, and is a member o

PDA, ACS and AAPS.

9

QbDFoRPhARMAPACKAgIngCoMPonEnTS:

A sn Prvder Ge

Mre sene-BaedBy Paul Thomas, senior editor, Witt-Kieer

ViDEo NovaPure Components

http://www.youtube.com/watch?v=JOpnD2y_oJ4&feature=plcphttp://www.youtube.com/watch?v=JOpnD2y_oJ4&feature=plcphttp://www.youtube.com/watch?v=JOpnD2y_oJ4&feature=plcp


10/13

10

PharmaQbD: How did the idea o apply-

ing Quality by Design to the manuacture o

components arise? What drove this initiative

rom a business perspective?

FlD: West initiated an intensive Voice o the

Customer process several years ago to en-

gage directly with key customers to identiy

and assure that our direction and resource

investments would correlate to the needs o

our customers. As a result o that engage-

ment, we provided guidance to R&D, Opera-

tions and other unctions on customer ex-pectations. Although Quality by Design was

never directly mentioned by a customer at

that point, what was conveyed was the act

that we needed a better understanding o

our customers challenges and the perspec-

tive o what they need to deal with rom a

regulatory and end-user standpoint.

As we do try to stay very close to the mar-

ket and regulatory issues, we identied

Quality by Design as a way to provide aproduct with improved understanding and

less variability to our customers. We elt this

was the ultimate eort to put ourselves in

their shoes.

PharmaQbD:Where did you begin the pro-

cess? Who took the lead, and how challeng-

ing were the training and other eorts to get

buy-in rom all involved?

FlD: The key to this program is that it ismulti-disciplinary i it is executed correctly.

Initially this requirement was dened by our

Marketing organization, but our R&D group

quickly picked up the banner to help drive

the program, along with our Operations and

Quality organizations. It was exciting to see

the understanding as people engaged ur-

ther with the program and could see the re-

sults and benets.

The training or the organization has been

intensive. O course, those directly in-

volved with the development and manu-

acture had more intensive training than

those in the support areas. However, the

entire organization has received training

on Quality by Design rom the pharma-

ceutical market perspective and how West

has approached this initiative with our new

West NovaPure brand.

PharmaQbD: What was the biggest de-

parture rom your previous manuacturing

methods? In what ways were the old meth-

ods non-QbD-like, i you will?

FlD: The biggest change is a total reliance

on data and science-based decisions versus

a reliance on experience. At West we have

many long-term employees who add value

on a daily basis because o their experience.Our tendency in the past, however, was to

rely too heavily on this aspect in both de-

velopment and problem resolution. QbD is

driven systematically through the genera-

tion o data, so you are working based on

acts and not assumptions.

PharmaQbD:Lets take extractables and

leachables as an example. How did you ad-

dress them dierently in a QbD context?

FlD: In respect o extractables, we have

taken a multi-pronged approach: First, we

have developed the VeriSure technical pack-

age. This technical package provides in-

depth extractables data to our customers

and allows them to move into leachables

testing more quickly.



11/13

11

Second, using the VeriSure technical pack-

age, we have conducted our own risk as-sessment o the identied extractables in

order to study and evaluate anything that

may be considered high risk.

Third, as a part o the NovaPure product,

we provide a lot-by-lot extractables nger-

print. This is in addition to the QbD work.

This provides condence to our customers

that the extractables prole as indicated

by our method is consistent over time.

This minimizes risk or variation with drugproduct leachables.

We realize that drugs take years to be de-

veloped and approved rom a regulatory

standpoint. They can then be on the market

or years. This ngerprint approach helps

provide an assurance o material consis-

tency over those extended years.

PharmaQbD:QbD requires coordination

between those who research and develop aproduct and those will ultimately manuac-

ture it. Can you share examples o how you

have achieved better integration between

key personnel throughout the development

liecycle?

FlD: Our R&D and Operations teams were

engaged globally in this program. This was

not a development and a hand-o but a co-

operative eort o both parties. Additionally,

we have instituted a global Knowledge Man-agement system to assure that inormation

is stored and shared on an ongoing basis.

PharmaQbD:What were the challenges in

building a Quality Target Product Profle

(QTPP)? What did your team learn rom the

QTPP process?

FlD: Marketing was responsible or den-

ing the QTPP. However, the biggest chal-lenge was being able to provide the spe-

cics and not assume anything. We ound

the hardest part to be dening the Criti-

cal Quality Attributes (CQA) with the R&D

unction, as the CQAs needed to be mea-

surable and specic.

PharmaQbD: What are the critical qual-

ity attributes (CQAs) or components such

as stoppers and syringe plungers, and how

were they determined?

FlD: There may be multiple CQAs deined

to achieve a target QTPP. We have these

clearly deined, but the speciics are

conidential and will only be shared spe-

ciically with customers. The CQAs were

determined through a combination o

marketing, technical, R&D, laboratory and

other experts working together, along

with customer input.

PharmaQbD:What key leanings rom the

development o the NovaPure products will

you incorporate into how you design and

manuacture syringes and other products?

FlD: We will continue to use these tech-

niques or new products that are intended

or customers and markets that will value

this approach. A component built by Qual-

ity by Design brings numerous benets to

our customers. This involves things such asin-depth process and product understand-

ing, a QTPP built around the patient and

our customer, improved transparency due

to a greater understanding and sharing o

inormation and ultimately a lower total

cost o ownership or the pharmaceutical

or biopharmaceutical company.



12/13

The Advantage ofUnrivaled Quality...by Design

Ensuring a drug product maintains its

safety and efcacy from concept to

commercialization while reducing total

cost of ownership requires high-quality

packaging components.

West designed NovaPure components

within a Quality by Design framework.Our data-driven process provides a

deeper understanding of our product

development and manufacturing

processes. We apply this knowledge

to components that can help customers

build quality, safety and efcacy into

their drugs.

Our holistic approach encompasses

a thorough process review, from raw

materials to commercial manufacturing

to transportation of components to the

customers facility.

NovaPure serum stoppers, lyophilization

stoppers and syringe plungers areglobally available with a reduced lead

time, and are provided in optimized

packaging that helps ease the transition

through manufacturing environments.

West NovaPure

#6669

The New Definition of High-Quality Components

West and the diamond logo and NovaPure are registered trademarks of West Pharmaceutical Services, Inc., in the United States and other jurisdictions.

Copyright 2012 West Pharmaceutical Services, Inc.

Unrivaled Qualityby Design

To learn more about Wests

NovaPure technology, call your West

account manager or a Technical

Customer Support representative.

Contact West today.

North America +1 800-345-9800

Europe +49 2403 7960

Asia Pacic +65 6860 5879

www.westpharma.com

12tPrevious Page Next Pageu
http://www.westpharma.com/http://www.westpharma.com/


13/13

nne rerefor more informationclick on the links below

cAN You sEEtHE REAl QbDGawayne Mahboubian-Jones

http://www.pharmamanuacturing.

com/articles/2011/068.html?page=ull

iMPlEMENtiNGQbDby Helen Winkle, FDA

http://www.da.gov/downloads/

AboutFDA/CentersOfces/CDER/

ucm103453.pd

CLICKhERE

CLICKhERE
http://www.pharmamanufacturing.com/articles/2011/068.html?page=fullhttp://www.pharmamanufacturing.com/articles/2011/068.html?page=fullhttp://www.pharmamanufacturing.com/articles/2011/068.html?page=fullhttp://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm103453.pdfhttp://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm103453.pdfhttp://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm103453.pdfhttp://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm103453.pdfhttp://www.pharmamanufacturing.com/articles/2011/068.html?page=fullhttp://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm103453.pdfhttp://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm103453.pdfhttp://www.pharmamanufacturing.com/articles/2011/068.html?page=full

pm1210_holistic_west_final.pdf

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