14 BioPharm FEBRUARY 2002

remain solely withthe quality depart-ment.

One approach toPAI model develop-ment is constructingand collecting toolsdesigned to identifyaction plans, track

progress, capture issues, report performance,manage documents, and maintain critical infor-mation. One deliverable then produced is a three-ring binder containing all the information neces-sary to support areas that may be inspected byregulatory agencies. However, that information isnot for submission to regulatory authorities, but isinstead a resource book for corporate staff sup-porting the inspection. Cataloging that informa-tion in one place enables rapid retrieval and man-agement of documents and data requested byregulatory inspectors and identifies appropriatepersonnel with specific technical expertise. An-other deliverable generated by this model is astandardized graphic representation of compli-ance status that can be used to update the organi-zation. Such a tool is most crucial for companieswith multiple products on the market or in PAIpreparation.

I D ENT I FY ING TH E TO O LSPreparing and using a set of common, well-defined tools ensures that training is institutional-ized and that PAI readiness activities are proac-tive rather than reactive. Such tools ensure thatall teams within the company develop a commonunderstanding of the current regulatory compli-ance environment, of recent inspection focuswithin the industry, and of their own company-specific inspection experiences. The tools can

Barbara W. Unger

An effective, well-developed, and versatile

preapproval inspectionmodel focuses

management andinspectors on

conclusions, minimizesprocess reinvention, and

tracks inspectionreadiness, especiallywhen you are using a

contract manufacturer.

he most visible corporate focus in thedevelopment of new pharmaceuticalchemical entities or biologicalproducts is generally on conduct ofclinical trials and preparation ofregistration applications. But compli-ance inspection of the company’s

manufacturing site is equally necessary toproduct approval and commercialization. Often,preapproval inspection (PAI) activity begins latein the timeline and allows little or no opportunityto correct deficiencies. Added to that, eachfunctional area maintains a list of activities tocomplete before a PAI, but those multiple plansmust be coordinated to prevent duplication ofeffort, lack of harmonization among documents,and items falling through the cracks because eachgroup assumes that another is “taking care of thatone.”

Using contract manufacturers increases thecomplexity of preparing for a PAI because itrequires coordinating staff and information at twoor more companies with different corporatecultures, inspection histories, and inspectionexperiences. Developing a model for thoughtful,planned preparation of inspection activities canprovide common objectives for identifying andtracking strengths and deficiencies early and soallow for corrections or refinements.

BU I LD ING A PA I MODELThe design of a PAI-preparation model will varybased on the organizational structure and opera-tional specifics of each company. But all modelsshould be well defined and easy to use. Imple-menting an integrated PAI preparation model en-sures that the entire project team is responsibleand accountable for inspection readiness andcompliance rather than having responsibility

T

the European Union expect written agreements tospecify roles and responsibilities of each partneror contractor. A quality agreement betweenpartners can form the basis for identifying high-level roles and responsibilities relative to pre-approval inspection. A shared planning matrixgives partners a common set of detailed actionitems and identifies PAI responsibilities that areconsistent with contractual agreements.

The planning matrix should be reviewedroutinely by a team representing the functionalareas participating in an inspection. Suchmeetings allow the team to track activities and toidentify the need for additional resources inspecific areas. The planning matrix can be modi-fied to indicate whether items are completed bythe projected due date. The due date cell withinthe tables can be shaded or colored, with green(for example) indicating an item that is on trackfor completion by the projected due date, blue in-dicating a completed project, and red indicatingthe need for a revised due date.

The instruction manual. The line items in Tables 2 and 3 are quite general. An instructionmanual can help a project team identify and addproject-specific activities. An instruction manualexplains the general line items and suggests func-tional areas or specific individuals accountablefor providing that information. The instructionmanual identifies information, where possible,that is presented in the registration application —and so provides a direct link between quality andCMC regulatory activities, minimizing duplica-tion of effort.

For example, an instruction manual might in-dicate that an analytical scientist should be re-sponsible for the stability data line item identified

minimize situations in which each project teamrediscovers and applies its own version of aprocess.

It may be advantageous (depending on thestructure and organization of the company) toalign the appearance and structure of tools usedfor PAI-readiness preparation with those that maybe used to prepare the chemistry, manufacturing,and controls (CMC) section of regulatory submis-sions. That link between CMC regulatory andquality activities simplifies the work assignmentsfor those involved in document preparation andcollection to support both regulatory and qualityactivities. Three basic tools can reasonably be in-corporated into a model for PAI preparation: aplanning matrix, an instruction manual, and com-pliance status tracking forms.

A planning matrix is a “to do” list of activities,collected as a series of spreadsheets, which iden-tify high-level inspection readiness categories forthose areas that regulatory agencies will reviewduring inspection. Agencies inspect manufactur-ers to ensure that a plant site is capable, thatequipment is properly installed and qualified, thatemployees are trained, and that data in eachapplication are authentic. Additionally, datasupporting scale-up and site changes betweenproduction of the product used in pivotal clinicalstudies and commercial production are generallyevaluated to ensure that product is comparable orbioequivalent.

The identification of high-level inspectioncategories (as shown in Table 1) can be followedby a subset of project- and product-specific items,assignment of accountability, and projected duedates, with brief narrative comments in support ofeach line item (Tables 2 and 3). The project teamcan expand Tables 2 and 3 to meet the specificneeds of the projects within those areas.

For example, the regulatory documents cate-gory, listed as section 2 of Table 1, can be di-vided into multiple subcategories (Table 2) andinclude copies of submissions to regulatory agen-cies, development history reports, primary andsupporting stability data, key lot identification,validation summaries, and site-specific documen-tation such as drug master files (DMFs). Foritems provided to regulators, such as primary andsupporting stability data, identifying the pages ina submission where that information can befound is preferable to duplicating those pages fora three-ring binder of summary information.

When a cooperative manufacturing option isused, preparation for inspection should take intoaccount the nature of the business alliance andwritten contractual agreements. Both CBER and

Available Regulatory Documents Who Due Date Status

A. Regulatory submissions and communication Cindy 4/15/02 �B. Development history reports Cindy 4/12/02 �C. Stability data Mike 3/15/02 �D. Key clinical trial lots Tom 11/03/01 �E. Key manufacturing lots Mary 1/15/02 �

revised to �2/02/02 �

F. Validation summaries Cindy 6/2004 �G. Site-specific documentation Cindy 6/2004 �

Colors in the “Status” column are part of the tracking process with green indicating aproject that is on track for completion by the projected due date, blue indicating the item iscompleted, and red indicating the need for a revised due date. When a due date is missed,the box does not become green again.

Table 2. Section 2, available regulatory documents

Section Title

1 State of CGMP compliance

2 Available regulatory documents

3 Key batch records

4 Analytical methods history

5 Analytical methods transfer

6 Analytical data

7 Preparation of launch materials

8 Other project-specific issues

9 PAI logistics and execution

BioPharm FEBRUARY 2002 15

Table 1. High-level categories forpreapproval inspection planningmatrix

16 BioPharm FEBRUARY 2002

in the planning matrix as item C in Table 2. Theinstruction manual may further direct the readerto the section of the registration application thatprovides primary and supporting stability data.Although the instruction manual can suggestfunctional areas responsible for specific tasks, theproject team should assign accountability foreach line item to specific people and incorporatethose names into the planning matrix. Assigningspecific names to specific tasks ensures owner-

ship of a responsibility and encourages timelycompletion of assignments.

An instruction manual can also identify the na-ture and scope of the deliverable for each lineitem. For example, the manual can clarifywhether the deliverable should be a reference topages within the registration application, identifi-cation and location of specific developmenthistory reports, or specific printouts from the cor-porate analytical database. This provides consist-ency across project teams and clearly identifiesthe expectations for deliverables.

An instruction manual should also listreferences to regulations, regulatory agencyguidance, corporate policy, guidelines, and SOPsfor each line item within the planning matrix.Some line items may have no references, whereasreferences for others may be quite extensive.References help team members understand thebasis behind a request for information.

For example, item D in Table 3 lists samples,and the “Sample Instruction Manual” sidebar de-tails information that might be included in the in-struction manual for that line item. The instruc-tion manual explains that this line item includessamples required for methods validation as de-scribed in 21 CFR 314.50(e), in-house retentionsamples, and samples of nonpharmacopoeialactive substances in support of Article 4 of Direc-tive 75/319/EEC that are submitted to some regu-latory authorities. In addition, the instructionmanual may identify the corporate SOP thatdescribes the retention of house samples. Thechoice of references to be included should reflectthe company’s registration strategy (that is,global or United States only) and its corporateorganization.

Compliance status tracking form. Another usefultool in preparing for a PAI is a tracking form thatprovides a standardized graphic representation ofcompliance status for major inspection cate-gories. A standardized format is particularly use-ful for presentations to management because it isconsistent across different projects and providessummary conclusions without unnecessary detail.

Table 4 shows a sample status tracking form.The form can be keyed alphanumerically or colorcoded. The example shown uses “U” to indicatean unacceptable status, meaning that the item hasserious deficiencies; “NI” to indicate a categoryin need of improvement, that is, it has less seriousdeficiencies; and “S” to indicate satisfactorycompliance status. The compliance status of anitem can be established through audits performedby the quality department. Follow-up statusshould be reviewed at predetermined intervals.

Key Batch Records Who Due Date Status

A. Conformance to regulatory requirements,clinical trial lots Bob 3/15/02 �

B. Conformance to regulatory requirements,commercial lots Mary 11/29/01 �

revised to �12/15/02 �

C. Identification of clinical trial lots Tom 11/03/01 �D. Samples Sue 3/20/02 �

Colors in the “Status” column are part of the tracking process with green indicating aproject that is on track for completion by the projected due date, blue indicating the item iscompleted, and red indicating the need for a revised due date. When a due date is missed,the box does not become green again.

Table 3. Section 3, key batch records

3.D. SamplesPurpose: Samples are needed for testing by FDA labs and for in-house retention.

Responsibility: CMC team

Deliverable content: Identify the location of the following samples: 1) methodsvalidation samples, 2) house retention samples, and 3) samples for EUcountries. Samples provided to FDA for methods validation cannot exceed theexpiry dating. The method validation samples are provided for the United Statesonly.

1. The samples required for methods validation are described in the FDAGuideline for Submitting Samples and Analytical Data for Methods Validation(February 1987) in support of 21 CFR 314.50(e). This includes fourrepresentative samples, each in sufficient quantity to perform three (3) timeseach test that is described in the application for:

• Drug product proposed for marketing

• Drug substance used to make the drug product as provided above

• Reference standards (those from official compendia need not be submitted)

• Samples of finished market package if requested by FDA

2. The quantities of in-house retention samples are specified in the corporateGMP (SOP procedure number 12345-67-89). Samples should be retainedconsistent with the current version of this procedure.

3. For the purposes of implementing Article 4 of Directive 75/319/EEC, samplesof the (nonpharmacopoeial) active substances, and of the finished medicinalproduct must be supplied at the same time as the submission of the dossier asa matter of course to the competent authorities in Italy (see table in actualpublication), Luxembourg, Spain, Sweden, and Portugal in accordance with therequirements set out in this table in section 5.2 for national and mutualrecognition submissions. In other cases, samples should be provided at therequest of the competent authorities.

Example from an Instruction Manual

18 BioPharm FEBRUARY 2002

IMPLEMENT ING THE TO O LSAs with any tool, those suggested here are usedmost effectively by a knowledgeable, coordinatedteam. The project team develops action plans toprioritize and address specific deficiencies identi-fied during audits. The penultimate test of a PAImodel’s usefulness can be measured during amock PAI, frequently performed by experts fromoutside the company. Remember that tools arenot an end result but rather a standardized meansfor achieving common goals across and betweencompanies.

Training and coordination. A successful PAImodel ensures that all project team membersunderstand the process, their responsibilities, andthe corporate and regulatory expectations. Toachieve that, the quality department representa-tive on the project team can train the team on theprocess. That allows team members to understandexpectations and coordinate the required activi-ties with their other responsibilities.

For example, team members who know thattheir functional units should expect qualitydepartment audits as part of the process canaccommodate that within their timelines. Amember of the quality department may beassigned to coordinate overall preparation for aPAI, making that member the owner of theplanning matrix and the status tracking forms.That member can also be responsible to the teamfor guidance regarding document identification,preparation, and auditing.

Baseline quality audits. Key to PAI preparation isdetermining the compliance status of the majorinspection categories presented in the planningmatrix. When the project team has completed theplanning matrix, the quality department (oranother unit depending on corporate structure)

can be made responsible for establishing compli-ance status. Compliance status evaluation shouldbe an ongoing process, rather than an activityundertaken for the first time just before a PAI.

A first step in planning focused audits is toidentify what may best be termed auditable units.Auditable units are those related activities thatcan be audited simultaneously by a small auditteam. For example, a cell bank preparation auditcan include evaluation of the host cell linehistory, preparation of the expression constructand the history of the construct’s genetic compo-nents, selection of the production cell line, andevaluation of the cell banking process. Moredetailed audits of those tasks might include eval-uating personnel training, identifying existence ofand compliance with appropriate SOPs, evaluat-ing record documentation, and evaluating thefacility relative to containment and prevention ofcross contamination. Identifying and groupingauditable units allows the quality department todevelop an orderly plan and timeline for its activ-ities — and also encourages status capture oftasks on the tracking sheets.

When audits have been completed, an initialassessment (such as “U,” “NI,” or “S”) is appliedrelative to the line items on the tracking sheets.Functional areas, with assistance from local qual-ity department staff, can monitor ongoing com-pliance status of major categories periodically.Action plans developed by those functional areasto address audit findings can be incorporated intothe planning matrix, and progress toward resolu-tion can be monitored routinely.

Mock PAI. Conducting a mock PAI is stronglyrecommended: It is essentially a dress rehearsalfor an inspection and can help participants iden-tify areas in which additional coordination, train-ing, and data are necessary. Using experts fromoutside the company to conduct the mock PAIcan be useful. Before the mock PAI, the PAImodel has dealt mainly with evaluation of sys-tems and the identification and review of docu-ments. A mock PAI is the time to test the integra-tion of those efforts and the ability of staff andoperators to confidently and concisely representtheir activities consistent with the batch records,SOPs, and the registration application.

Ultimately, the PAI readiness plan is only that,a plan and a collection of tools with which toprepare for the inspection. The success of a PAIdepends on the knowledge, confidence, andconsistency of the individuals presenting the sys-tems, facilities, and operations to the inspectors.

Statusa

Topic Jan Feb Mar Apr May JunEquipment IQ and OQb NI S S S S S

HVAC systems NI NI NI S S S

Water systems NI S S S S S

Computer systems U NI NI NI S S

Procedures U U NI NI S S

Change control NI NI NI S S S

Cleaning U U U NI NI S

Training U NI S S S S

Process validation NI NI NI S S S

aS = satisfactory compliance status; NI = compliance item needs improvement; and U = compliance status is unsatisfactory

bIQ = Installation qualification and OQ = operational qualification

Continued on page 71

Table 4. Readiness status tracking form using some major activities for drug substancepurification as an example

LITERATURE LITERATURE LITERATURE LITERATURELITERATURE LITERATURE LITERATURE LITERATURE

LITERATURE LITERATURE LITERATURE LITERATURELITERATURE LITERATURE LITERATURE LITERATURELITERATURELITERATURELITERATURE

BioPharm FEBRUARY 2002 71

Depth filterA brochure from SeitzSchenkFiltersystems describes theSUPRAdisc II, designed for higherflows and increased contaminantloading in critical applications.Design features, applications, andbenefits are explained with listsand illustrations. SeitzSchenkFiltersystems North America,Timonium, MD.www.seitzschenk.com

Info #137

Chromatographic resinsTOSOH Biosep is a virtualmanufacturing partner with manypharmaceutical and biotechnologycompanies. The company’s TSK-GEL, Toyopearl, and Amberchromchromatographic resins areelements in the analysis, isolation,and purification of biomolecules. Acompany brochure describesservices offered and includes moreinformation about the company.TOSOH Biosep, Montgomeryville,PA. www.tosohbiosep.com

Info #138

Methods developmentA brochure from WatersCorporation describes an eight-step approach for rapidlydeveloping stability-indicatingmethods. The kit described by thebrochure includes four columnsand a “how-to” handbook. Theapproach is based on InternationalConference on Harmonisationguidelines for registeringpharmaceuticals for human use.Waters Corporation, Milford, MA.www.waters.com

Info #139

Enzymes The Worthington catalog featuresresearch products, cell biology andtissue dissociation kits, andapplication notes. The companyaccommodates bulk purchasingand provides standing-orderdiscounts and technical assistanceby phone or Internet. All animalproducts are collected in USDA-approved facilities. WorthingtonBiochemical Corporation, Lakewood,NJ. www.worthington-biochem.com BP

Info #140

B E ING PREPAREDDeveloping and implementing a successful modelfor PAI preparation unifies the company’sapproach and focuses on the links between qual-ity activities and CMC regulatory activities. Aneffective model provides a common set of toolsto different functional areas and a basic, flexibleframework to respond to project needs and coop-erative manufacturing arrangements. An optimalmodel institutionalizes training and sharingamong project teams and minimizes the instancesin which individual teams rediscover expecta-tions and reinvent processes. When contract man-ufacturers are used, a well-defined model ensuresthat multiple corporate entities work from a com-mon set of expectations and shared standards totrack inspection readiness.

The model and the process are versatile andcan be used for drugs, biologics, and combinationproducts to identify inspection issues, establishaccountability, and track status. The instructionmanual can be updated easily to reflect changesin regulations, guidelines, corporate experience,or the regulatory compliance environment andprovides the company with a current, consistent

set of expectations regarding PAIs. The statustracking forms are valuable for managementpresentations because they provide a commonreporting graphic for a variety of projects andfocus attention on conclusions. PAI readinessmodels can be tested by conducting mock PAIsthat illustrate the company’s ability to accuratelyand concisely represent its product and facility toinspectors.

ACKNO WLED G MENTThe author would like to acknowledge the valuablecritical review of the paper by Glenn E. Wright, director,regulatory affairs, Eli Lilly and Company.

FOR FU RTH ER R EA D INGCenter for Drug Evaluation and Research, Guideline for

Submitting Samples and Analytical Data forMethods Validation (FDA, Rockville, MD, February1987). Available at www.fda.gov/cderguidance/ameth.htm.

Code of Federal Regulations, Food and Drugs, “Contentand Format of an Application,” Title 21 Part314.50(e) (U.S. Printing Office, Washington, DC,revised April 2000).

Enterprise Directorate General, “Notice to Applicants:General Information,” Pharmaceutical Legislation:Procedures for Marketing Authorisation, Ch. 7, Vol.2A, ENTR/F/2/LVD(2001) (European Commission,Brussels, July 2001). BP

PAI Preparation continued from page 18Barbara W. Unger is a regulatoryconsultant for Don Hill Associates,Inc., PO Box 6215, Silver Spring, MD20916, 317.582.1504, fax317.582.1528, bwunger@midlink.com.