validation article.pdf

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http://slidepdf.com/reader/full/validation-articlepdf 1/642 Pharmaceutical Technology MARCH 2005 www.pharmtech.com

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n an industry with scant room for error, flawless validation systems are vitalto successful manufacturing plants. According to industry experts, however,companies vary greatly in both their awareness of the US Food and Drug Ad-ministration’s current regulations on good manufacturing practices (CGMPs)and their ability to properly implement CGMPs into custom-tailored man-ufacturing systems. Thanks to additional resources such as the recently up-

dated Good Automated Manufacturing Practice (GAMP ) Guide, published by the In-ternational Society for Pharmaceutical Engineering (ISPE, Tampa, FL, www.ispe.org),pharmaceutical companies better understand how to ensure that pharmaceutical pro-duction achieves the same end result every time.

“[Validation] is something manufacturers are required to do to show that their sys-tems will perform as they are intended to perform in their environment,” says StephanieMcKiernan, senior validation specialist at Pilgrim Software (Tampa,FL, www.pilgrim-

Validating

Automated SystemsGeorge Koroneos

I

As newer and more

elaborate hardware

and software systems

are installed inautomated

manufacturing

environments,

companies are further

incorporating good

practices into their

validation process.

R O C K W E L L A U T O M A T I O N

P H O T O D I S C ,

I N C .



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software.com). “How to get there is the

hard part. If you don’t have a product withan off-the-shelf [validation component]that goes hand in hand with the applica-tion, you are going to have to build it fromscratch, which could take years.”

In addition,manufacturers need to takein account FDA’s regulations of electronicrecords and signatures, which appear inpart 11 of Title 21 of the Code of Federal

Regulations. Experts explain that 21 CFR

Part 11 should not be viewed as anotherhurdle,but as a part of the overall valida-

tion process.“CFR Part 11 today really shouldn’t be

looked at independently,” says MichaelWyrick, senior director at WashingtonGroup International (Fairfax, VA,www.washingtongroup.com). “Compa-nies need to build their compliance com-ponent into the validation program, be-cause many of the things that have to dowith 21 CFR Part 11 are really just piecesof the validation program.” For example,security, change control, and audit trails

can be built into the validation program,thereby providing compliance to both thevalidation and CFR Part 11 requirements.

The master planExperts recommend that companies withlarge numbers of automated systems takethe time and effort to write up a master val-idation plan detailing the entire installationprocess from qualification to completion.

VTS consultant Ken Christie (Westbor-ough,MA, www.vtsconsultants.com) says

that “If FDA [inspects] a company andthey see that it is highly automated, ratherthan start looking through mounds of

documents, their first question is, ‘What

can you show me that tells me what yourapproach is to the qualification of theseitems?’ ” If the company has clearly de-fined the validation methodology for thesystem, inspectors might pick one or twoitems to focus on rather than evaluate theentire operation.“This is not meant to bea cover-up attempt, but a method of show-ing officials the efficiency of the company,”Christie continues.

“Many investigators have been trainedto ask for either a master plan or valida-

tion plan if it’s for a specific system orpiece of equipment,” says Wyrick.“If they are working on a big system, companiesneed a master plan to detail how they in-tend to do their commissioning and qual-ification and validation.They also have toinclude computers and distributive con-trol systems. The agency also holds com-panies accountable to those plans—didthey execute those plans?”

According to industry experts,one of thebiggest challenges facing companies con-

structing a new automated system is thatthey have not allocated enough time tocomplete the master validation plan in the

rush to get the product to market. “It’s

tough to go back to management and say that a drug has to be kept off the marketfor X months to complete the work,” saysJustin Neway, chief science officer and ex-ecutive vice-president at Aegis Analytical(Lafayette, CO, www.aegiscorp.com).“Thenormal comeback to that is, ‘Find a way todo it faster.’ But when you start takingshortcuts, that’s when you run the risk of things turning up in an inspection.”

Another common challenge is incor-porating traceability into existing systems,

explains Mark Cupryk, vice-president andgeneral manager of North American op-erations at Invensys Validation Technolo-gies (Foxboro, MA, www.invensys-vt.com). “Companies will come to us look-ing to reduce the cost of testing, but they have already built a lot of infrastructureup front. The expectation is that we willbe able to massage everything miracu-lously to show complete traceability of every test that they perform without hav-ing any rework on the front. One of the

major issues that we see is in the planningprocess. A lot of the major multination-als are not keeping the end in mind.”

“If they are working on a

big system, companiesneed a master plan to

detail how they intend to

do their commissioning,

qualification, and

validation.”

Early integration of master planning, requirements, design, and validation can reduce time-to-

validation substantially.

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QualificationWith a master validation plan complete,

a company can contract a vendor to con-struct the equipment based on its specifi-cations. The manufacturer cannot, how-ever, assume that the vendor is qualifyingthe machine during the build process. AtPfizer’s (New York, NY, www.pfizer.com)research group manufacturing facility, en-gineers conduct a battery of site accept-ance tests (SATs) at the vendor’s locationand then a second series of SATs after themachine is brought to the manufacturingplant. If the system passes, local engineers

install the equipment and the official qual-ification process is initiated.

Jose Soto,manager of the technical sup-port group at Pfizer, explains that allequipment goes through three qualifica-tion steps: installation qualification (IQ),operation qualification (OQ), and per-formance qualification (PQ). IQ refers tothe process of checking the installation tomake sure that all the parts purchased areindeed what were ordered. OQ is morespecific: each individual function is tested

page by page to make sure that every com-ponent on the machine works to specifi-cation.Finally, Pfizer engineers run a PQ,which entails a demonstration of the en-tire machine as it would perform in a liveenvironment.

Simplifying validationTo help manufacturers qualify and vali-date their systems more quickly, softwarevendors such as Pilgrim have begun in-cluding validation scripts that standard-

ize acceptance testing. These scripts arestep-by-step instructions, such as “if youdo X the result must be Y” to pass the val-

idation test. Vendors also candevelop and distribute scripts

for future updates to an ap-plication.

Mark Cupryk of Invensysidentifies another trend thattakes validation scripts a stepfurther: libraries of previ-ously validated softwaremodules that can control sys-tems on a larger scale. Al-though he acknowledges that

some companies view the process as costly,Cupryk sees advantages in it. “We do see

the library offering a lot more potentialfor consistency and fewer defects in thelong run.”

Even with these new methods of sim-plifying the validation process, pharma-ceutical manufacturers and consultantsstill say that one of the biggest challenges

in validation is understanding what FDAconsiders to be “good practices.” Many in-volved in validation would like to see de-cisive rules about how to properly validatetheir automated systems.

“If FDA was more specific in what they were looking for it would be a big help.”

Soto says.“Some of the recommendationsare open regulations. Each company cancomply differently to the rules. I under-stand that it’s good to be flexible, but itwould be easier to be compliant with amore definitive set of rules.”

According Neway, FDA is moving to-wards becoming more of a coach than apoliceman.“It’s true that a lot of their roleis as an enforcement agency, but they areshifting much more towards encouraginginnovation and providing a regulatory

framework and other capabilities neededto introduce innovation in pharmaceuti-cal manufacturing.”

Another answer is the Good Automated

Manufacturing Practice Guide.

GAMP groundInitially a European initiative, the GAMP

Guide is a voluntary set of guidelines cre-ated by industry leaders to help compa-nies understand and meet CGMP regula-tions for automated systems. Produced by the GAMP Forum, a technical subcom-mittee of ISPE, the GAMP Guide has beenrevised several times to accommodatechanges to regulatory policies and is now in its fourth edition, GAMP 4.

“I’ve seen a lot of companies suffer fromvery wordy procedural validation practices,”a member of the European GAMP advi-sory board says.“Somewhere along the lineI think we lost track of where the actualvalue of validation was. And I think [theGAMP Forum] was a reaction to that.”

Many companies have foundthe GAMP Guide useful.“Thecorporate guidelines that weuse to set policies at our sitehave lineage back to the ISPE

GAMP 4 guideline,” says MikeDoenlen,manager of manufac-turing process engineering atRoche Colorado Corporation(Boulder, CO, www.rochecol-

orado.com). “The format that we follow is pretty well adopted throughout the in-dustry.”

A risk-based approachAs part of its recent initiative,“CGMPs forthe Twenty-First Century: A Risk-Based

Approach,” FDA has begun applying risk analysis to inspections, including valida-tion inspections.

“FDA has been a lot more open, in thelast few years, to using risk analysis tech-niques to allow manufacturers to make aconscious decision about where to put theirtime and effort in validation,” explainsChristie Deitz, senior principal engineer atEmerson Process Management (St. Louis,MO, www.emersonprocess.com). For ex-ample, if a company has a system that

tracks the quantity of active ingredientthat goes into a batch, and another systemin place that monitors the cooling water

The ultimate goal is to reduce

the regulatory burden, because

there is going to be less rework

on product, less changes and an

overall smoother operation.

G E N M A R K A U T O M A T I O N



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temperature, the system that measures theactive ingredient amount is much more

critical than the cooling water tempera-ture. It would be more important to spendadditional time and effort to verify thatthe active ingredient system is workingproperly than the less-critical coolingwater system.

“By using this risk-based approach,companies can determine which of theirsystems needs the most validation,”Wyrick says.“Because manufacturers havelimited resources, it is important to uti-lize those resources effectively and effi-

ciently. We are finding that high-risk sys-tems are being validated at a higher levelthan medium-or minimum-risk systems.Most companies today are not validatingall systems the same way—it’s a waste of resources.”

It’s not just the manufacturer’s valida-tion resources that have been taxed. Ac-cording to an FDA report, Risk-Based

Method for Prioritizing CGMP Inspections

of Pharmaceutical Manufacturing Sites—

A Pilot Risk Ranking Model , the number

of registered human drug establishmentshas increased by more than 400 percentin the last 25 years. “Over the same timeperiod,“ the report states,“the number of human drug CGMP inspections con-ducted has decreased by more than 60 per-cent. As a result, it is impossible for FDAto achieve uniformly intensive CGMP in-spectional coverage for all registered drugfacilities.”(1)

In a presentation to the FDA ScienceBoard entitled, CDER Risk-based Site Se-

lection Model: An FDA Risk Management Tool , Kate Morgan, of the FDA’s Office of Planning/Office of the Commissioner ex-plains the risk model the agency plannedto use to judge site risk potential (SRP).FDA has assessed an SRP score to every manufacturing site in the United States,and sites that scored higher will be moreprone to inspection.Sites were ranked ona product factor, a facility factor, and aprocess factor.

As explained in the presentation,a site

will be less frequently selected for inspec-tion if:• It has been inspected recently and has

few or no previous viola-tions of GMPs and a

smaller volume of prod-uct (facility weight)

• It makes nonsterile, OTCdrugs,and/or other prod-uct types that are not as-sociated with a high fre-quency of recalls and/orserious defects (productweight)

• It makes products judgedto be relatively straight-forward to manufacture

with consistent quality,and not vulnerable tocontamination (processweight). (2)Plants earmarked for pri-

ority inspections includethose that produce steriledrug products, those thatproduce other prescriptiondrugs, and new registrantsthat had not been inspectedpreviously.

“I don’t think that the in-dustry has really graspedthat this is taking place,” says Neway.“TheFDA is piloting their risk model, whichthey published, and they are using it torank manufacturing site inspections in2005.”

On the audit trailPart 11 requires drug makers to maintainan audit trail. If a company is keeping arecord electronically, and the primary

source is electronic, then they are requiredby law to document changes:who changedit, why they changed it, and when they changed it. Additionally, that audit trailhas to be linked to that record.

According to the updated 21 CFR Part11 guidance, companies are required to “usetime-stamped audit trails to documentrecord changes, all write-to-file operations,and to independently record the date andtime of operator entries and actions.Recordchanges shall not obscure previously

recorded information. Such audit trail doc-umentation shall be retained for a periodat least as long as required for the subject

electronic documents and shall be avail-able for agency review and copying.” (3)

The audit trail is part of the change con-trol program. If an operator or adminis-trator wants to change the steps of an ap-plication, or change set values, the systemwill not allow the change unless security measures are met. The program will alsoautomatically stamp the date of entry, theidentity of the person who made entry,

and capture the change made. So if an au-ditor wants to see changes that have beenmade to the system, the program can printout an audit trail to show when changeswere made and who made them. If a man-ufacturing problem occurs and the fol-low-up investigation goes back to the soft-ware, the audit trail becomes a piece of information that is reviewed as part of theinvestigation.

“A lot of products are being sold withthe logo ‘Designed for 21 CFR Part 11,’

which really means that the product wasdesigned with components such as elec-tronic signature and audit trail capabil-


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ity—things that were not only designedtoward 21 CFR, but also help maintain

validated systems,” says Bart Reitter, mar-ket development manager for life sciencesat GE Fanuc (Charlottesville, VA,www.geindustrial.com). “A lot of those

tools are built into products to help withthe validation process.”

Once a system is validated and put intoproduction,maintenance becomes a prior-ity to make sure that the product is nevermodified beyond its intended form.Experts

suggest that a change-control system be in-stalled to assess the impact of any system

modifications. Change-control procedurescall for a written or electronic signature tobe recorded every time a system is adjusted.This provides both a history of who hasused the unit, and a security measure tomake sure only authorized personnel havehad access to the machine.

Re-evaluationAfter a validated system has been in usefor some time, companies re-evaluate it.“Over time,companies need to take a look

at the overall impact of changes,” Wyrick says.“That’s what we call periodic review.”The onus is on each company to decide,based on the criticality of the system, how frequently the periodic review must bedone.“Typically, you find it to be every 24months, but if it’s a very critical system,they might review it every 12 months,”Wyrick continues.

During the periodic review, a company will look at the number and character of changes to the system,and decide if it is still

operating as effectively and efficiently as itwas designed. Administrators should alsolook at documentation and training recordsto make sure that they are up to date.

Soto explains that at Pfizer, engineersre-evaluate a machine every three yearsafter the initial qualification. They check for any deviations and view the entire his-tory of the machine. A demonstrationbatch is also run to make sure that themachine works properly.“The most chal-lenging part is that you have to protect

the computer from viruses and make surethat every patch added to the software hasbeen verified. We need to go back andrevaluate that those patches don’t affectthe computer system,” Soto says. “Thathas to be done almost every month. Thecomputer is also run through a network system and maintaining that network canbe difficult.”

Risk analysis can be used to determineif a patch needs to be validated. Patches tooperating systems need not be validated,

but product-manufacturing softwareshould be validated through change con-trol.Based upon the impact of that change,

52 Pharmaceutical Technology MARCH 2005 www.pharmtech.com

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administrators can determine whether thesoftware upgrade has altered the end prod-uct. “What a lot of companies will do isbatch the individual patches up into onepatch,” Wyrick says. “A company also hasto have the right processes in place, like

change control, to evaluate the impact of those changes and decide whether thepatches should be installed or not.”

PAT and beyondSo what does the future hold for new val-idation methods?

Normand DuBuc, senior director of au-tomation at Invensys Validation Technolo-gies, says that the much-discussed processanalytical technology (PAT) framework will continue to mold control-system im-

plementation and validation.“There isnow a push by the regulatory bodies toencourage the manufacturing companiesto better understand their processes, tobetter control their processes, and in turnto provide a better product in the end.Theultimate goal is to reduce the regulatory burden, because there is going to be lessrework on product, fewer changes, and anoverall smoother operation.”

The PAT initiative is designed specifi-cally to try to get product through the man-

ufacturing process more quickly and re-duce the time it takes for laboratory testingand cycle time.“[Manufacturers] are mov-

ing towards real-time release,” says JimmiFilice, product-marketing manager at GEFanuc.“They want to get it to where a pow-der goes into one end and out the otherend comes a bunch of pills, without everstopping along the way—that’s a far cry

from where pharma manufacturing istoday.”

References1. Food and Drug Administration, Risk-Based

Method for Prioritizing CGMP Inspections of Pharmaceutical Manufacturing Sites—A Pilot Risk Ranking Model, (FDA, Rockville, MD,2004), www.fda.gov/cder/gmp/gmp2004/risk_based_method.htm (accessed 23 Feb-ruary 2005).

2. Food and Drug Administration, CDER Risk-based Site Selection Model: An FDA Risk Man-agement Tool , (FDA, Rockville, MD, 2004),

www.fda.gov/ohrms/dockets/ac/04/brief-ing/2004-4080b1_07_Kara%20Morgan.ppt(accessed 23 February 2005).

3. Code of Federal Regulations, Title 21, Food and Drugs, Subchapter A—General Part 11 Elec-tronic Records; Electronic Signatures(General Services Administration, Washing-ton DC, 1 April 1973).PT

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