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861Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice © 2009, Elsevier Inc.

37.1 BACKGROUND FOR PRODUCT REGISTRATION IN THE UNITED STATES

All new drug products must be registered and approved by the regulatory agency governing the intended market before the products can be intro-duced into the market. The registration process is to ensure the quality, safety, and efficacy of drug prod-ucts. The requirements for the development and reg-istration of new drug products in the United States are defined in the Federal Food, Drug, and Cosmetic Act (FD & C Act) 1 and the regulations promulgated by the Food and Drug Administration (FDA) ( Figure 37.1 ). The FDA is an agency of the Department of Health and Human Services within the United States government.

This chapter presents an overview of the process of regulatory review and approval in two parts of (1) New Drug Applications (NDA), and (2) Abbreviated New Drug Applications (ANDA) in the United States, using the various laws enacted by Congress, the FDA regulations found in Chapter 21 of the Code of Federal Regulations (21CFR) and guidance documents issued by the FDA. References will be provided to the Internet websites for many of these documents for the reader’s information.

37.2 THE NEW DRUG APPLICATION (NDA) AND REVIEW PROCESS

The FDA has a complex organization for review and approval of new drug applications (NDAs) and

abbreviated new drug applications (ANDAs). When NDAs and ANDAs are submitted to the FDA, the review and approval of the applications are conducted by the Center for Drug Evaluation and Research (CDER), which reports directly to the Office of the Commissioner of the FDA, as shown in Figure 37.1 . Within CDER there are a number of offices organized under the Office of the Center Director as shown in Figure 37.2 . For the purposes of drug development, the majority of the industry interactions with the FDA will be with the Office of New Drugs.

During the new drug review process, the Office of Pharmaceutical Sciences is involved in the review of the Chemistry, Manufacturing and Controls (CMC) information. After approval, the Office of Surveillance and Epidemiology and the Office of Medical Policy, Division of Drug Marketing, Advertising and Communication (DDMAC) become closely involved with the post-marketing activities of new drugs.

37.2.1 Food and Drug Administration (FDA) Interactions

Generally, a sponsor (applicant, person or entity who assumes the responsibility for the marketing of a new drug, including the responsibility for compliance with the FD & C Act, and other related regulations—a sponsor can be an individual, partnership, company, government agency or institution) will have been interacting with the FDA during the new drug devel-opment process through submissions and meetings with the reviewing division. Approximately six to

C H A P T E R

37 37

Product Registration and Drug Approval Process in the United States

Steven F. Hoff and Yisheng Chen

IV. SELECTED TOPICS IN PRODUCT DEVELOPMENT

37. PRODUCT REGISTRATION AND DRUG APPROVAL PROCESS IN THE UNITED STATES862

Office of the Commissioner

Office of the Chief of Staff Office of Equal EmploymentOpportunity and Management

Office of Regulatory Affairs Center for Devices andRadiological Health

Office of International and Special Programs

Office of Policy, Planning, andPreparedness

Office of Operations Office of Scientific andMedical Programs

Center for Biologics Evaluationand Research

Center for Food Safety andApplied Nutrition

Center for Drug Evaluation and Research

Center for Veterinary Medicine

Office of the AdministrativeLaw Judge

Office of the Chief Counsel

FIGURE 37.1 Food and Drug Administration organization. Source of information: http://www.fda.gov/oc/orgcharts/FDA.pdf , as of March 12, 2008

Office of the Center Director

Office of PharmaceuticalScience

Office of Regulatory Policy Office of Management Office of Training andCommunications

Office of Surveillance andEpidemiology

Office of Medical Policy Office of New Drugs Office of InformationTechnology

Office of Business ProcessSupport

Office of ExecutivePrograms

Office of ComplianceOffice of Counter Terrorism

and EmergencyCoordination

Office of TranslationalScience

FIGURE 37.2 Center for Drug Evaluation and Research, FDA. Source of Information: http://www.fda.gov/oc/orgcharts/cder1.pdf , as of March 12, 2008

nine months prior to submitting an NDA, a sponsor should have a pre-NDA meeting with the FDA. This meeting will be scheduled by the FDA within 60 days of receipt of the request for the meeting, as discussed in the FDA Guidance, Formal Meetings with Sponsors and Applicants for PDUFA Products. 2 The procedures and information package required for scheduling and conducting the meeting are described in the above guidance. This meeting can be used for a discussion of the format and content of the NDA, including the presentation of data, types of statistical tables, types of documents to be included, electronic submission requirements, and any other questions related to the submission of the NDA.

37.2.2 New Drug Applications (NDA)

Preparation of a New Drug Applications

An NDA brings together the drug development effort by a company for the registration of a new drug product for the US market. The NDA is comprised primarily of the chemistry manufacturing and controls (CMC), non-clinical studies, clinical studies, and the proposed labeling for the new drug product. Content, format, and organi-zation for a NDA are listed in the FDAs Conformance Review Checklist for NDAs. 3 This checklist can be used to guide the preparation of a successful NDA.

The NDA can be filed in the form of a traditional NDA ( Table 37.1 ) or formatted as a Common Technical

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Document (CTD) ( Figure 37.3 ). A combination of the two formats has also been used, using the NDA for-mat with documents written for the CTD. This pro-cedure can be arranged with the FDAs reviewing division. NDAs may be submitted on paper or elec-tronically, though electronic submission is highly rec-ommended. Paper submissions are rapidly becoming obsolete at the FDA. FDA Guidance for electronic sub-missions is available on the FDA website. 4

Format and content of a New Drug Application (NDA)

The format and content of a NDA are specified in the regulations (21 CFR 314.50). 5 The NDA starts with FDA Form 356h, 6 which provides a listing of the 20 sec-tions expected in a NDA (Table 38-1). However, this is

not an absolute order of the data presentation, though highly recommended. The sections may be presented in other arrangements, but must be clearly documented in the detailed index. The Form 356h is completed and signed by the sponsor or the sponsor’s authorized US agent, who resides or maintains a business site in the United States.

Index

A detailed index of the NDA is an absolute neces-sity, as it provides a guide through the entire appli-cation for the FDA reviewers. The index must clearly describe the contents and location of each section by volume and page number.

Labeling

Draft or final copies of the labeling for the drug product must be included in the NDA. It is recom-mended that the draft labeling be provided in the NDA, as the FDA will often propose alternative word-ing to the submitted label. This usually occurs at the end of the FDAs NDA review cycle. Labeling is now required to be submitted electronically in all cases, using structured product labeling (SPL) 8,9 formatting, and in compliance with the Physician’s Labeling Rule (PLR, which was being implemented in June 2006). SPL was implemented in October 2005, and is a stand-ard electronic format that allows the FDA to process, review, and archive the labeling.

Summary

The NDA summary provides an overview of the NDA, describing the safety and efficacy of the drug product for its proposed use. Content of the summary is listed in Table 37.2 . The summary is one of the most important sections of the NDA, because every FDA reviewer receives a copy of the summary, which can provide some assurance about the quality and accu-racy of the information in the application. A poorly prepared summary may raise questions about the information in the application, and cause unnecessary delays in the review process.

Chemistry

The chemistry, manufacturing and controls (CMC) section provides detailed information on the composi-tion, manufacture, test methods, and specifications of the drug substance (active ingredient), and the final drug product. The physical and chemical characteris-tics are presented, as well as the stability data. Samplesand method validation package are also provided in


TABLE 37.1 New drug application (NDA) content and regulatory source documents for drugs and biologics

1. Index

2. Labeling (check one) � Draft Labeling � Final Printed Labeling

3. Summary (21 CFR 314.50 (c))

4. Chemistry section

A. Chemistry, manufacturing, and controls information (e.g., 21 CFR 314.50(d)(1); 21 CFR 601.2)

B. Samples (21 CFR 314.50 (e)(1); 21 CFR 601.2 (a)) (Submit only upon FDA’s request)

C. Methods validation package (e.g., 21 CFR 314.50(e)(2)(i); 21 CFR 601.2)

5. Nonclinical pharmacology and toxicology section (e.g., 21 CFR 314.50(d)(2); 21 CFR 601.2)

6. Human pharmacokinetics and bioavailability section (e.g., 21 CFR 314.50(d)(3); 21 CFR 601.2)

7. Clinical Microbiology (e.g., 21 CFR 314.50(d)(4))

8. Clinical data section (e.g., 21 CFR 314.50(d)(5); 21 CFR 601.2)

9. Safety update report (e.g., 21 CFR 314.50(d)(5)(vi)(b); 21 CFR 601.2)

10. Statistical section (e.g., 21 CFR 314.50(d)(6); 21 CFR 601.2)

11. Case report tabulations (e.g., 21 CFR 314.50(f)(1); 21 CFR 601.2)

12. Case report forms (e.g., 21 CFR 314.50 (f)(2); 21 CFR 601.2)

13. Patent information on any patent which claims the drug (21 U.S.C. 355(b) or (c))

14. A patent certification with respect to any patent which claims the drug (21 U.S.C. 355 (b)(2) or (j)(2)(A))

15. Establishment description (21 CFR Part 600, if applicable)

16. Debarment certification (FD & C Act 306 (k)(1))

17. Field copy certification (21 CFR 314.50 (l)(3))

18. User Fee Cover Sheet (Form FDA 3397)

19. Financial Information (21 CFR Part 54)

20. OTHER ( Specify)

Source of information: FORM FDA 356h (10/05), page 2 of 4



the CMC section. The FDA and ICH have introduced many guidance documents regarding CMC informa-tion.10,11 The required content of the CMC section (21 CFR 314.50(d)(1)) includes information on the drug substance, drug product, environmental impact, and the field copy certification.

The drug substance section contains information on the stability, physical and chemical characteristics of the drug substance, the name and address of the manufacturer, the method of manufacture and packag-ing, and the specifications, and analytical methods, for the drug substance. The drug product section provides information about the components, composition, phar-maceutical development specifications, and analytical methods of the inactive ingredients, name and address of the manufacturer(s), methods of manufacturing and packaging, specifications and analytical meth-ods for the drug product, and stability information.

Regionaladministrative

information1

1.1 SubmissionT of C

Module 1

CTD Table of Contents2.1

CTD Introduction2.2

Nonclinicaloverview

2.4

Qualityoverall

summary2.3

Nonclinicalwritten andtabulated

summaries2.6

Clinicaloverview

2.5

Clinicalsummary

2.7

Quality3

3.1 T of C

Nonclinicalstudy reports

44.1 T of C

Clincialstudy reports

55.1 T of C

Module 3 Module 4 Module 5

Not part ofthe CTD

Module 2

CTD

FIGURE 37.3 Graphic presentation of the common technical document. Source of information: http://www.fda.gov/cber/gdlns/m4ctd.pdf page 5 7

TABLE 37.2 Required content of an NDA summary (21CFR314.50(c))

● Proposed labeling with annotation to support information in the summary and technical sections of the NDA

● Pharmacological class of the drug ● Scientific rationale for the drug ● Intended use ● Potential clinical benefit ● Market history (if any) ● CMC section summary ● Nonclinical pharmacology/toxicology section summary ● Human pharmacokinetics and bioavailability section summary ● Microbiology section summary (for anti-infectives only) ● Clinical data section summary ● Discussion of the risk-benefit considerations of the drug

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The environmental impact analysis is required by the FDA or a claim for categorical exclusion. In 1997 the FDA issued a final regulation that stated environmental impact analysis would be required only under extraor-dinary circumstances. 12 Most applications are granted the categorical exclusion (i.e., exemption). A field copy certification is submitted only by US sponsors of a NDA. The applicant must certify that a field copy of the chemistry section has been provided to the sponsor’s home district office.

The second part of the chemistry section is for samples. However, samples of the drug substance or drug product should not be submitted with the origi-nal NDA, but only provided upon an FDA request for these samples.

The final part of the chemistry section contains the methods validation package, which provides the FDA with all of the necessary information needed to validate all of the analytical methods for the drug sub-stance and drug product (see ICH Guidelines, Q2A Text on Validation of Analytical Procedures and Q2B Validation of Analytical Procedures: Methodology). 13

Nonclinical pharmacology and toxicology

The nonclinical pharmacology and toxicology sec-tion contains all of the nonclinical animal and labora-tory studies conducted with the drug. The FDA looks for toxic effects of the drug that are inconsistent or have not been adequately characterized. Table 37.3 shows the expected content of the nonclinical phar-macology and toxicology section.

Details on the content of nonclinical pharmacol-ogy and toxicology can be found in the FDA and ICH guidance to industry on the same topic. 14,15

Human pharmacokinetics and bioavailability

This section provides the data and analysis from the various pharmacokinetic and bioavailability studies

conducted in human subjects, along with the analytical and statistical methods used in each study. There should also be a discussion that summarizes the pharmacoki-netics and metabolism of the drug, and the bioavailabil-ity (BA) of the drug product. BA studies may need to be repeated during the drug development process, if dos-age forms are reformulated during the process.

Clinical microbiology

The microbiology section is provided only for anti-infective, antiviral, special pathogens, sterile, and some nonsterile drug products. The FDA can estab-lish effectiveness only if it has adequate information on the effects on the microbiological physiology of the targeted microorganism. Content and format for this section includes the drug action on microbial physi-ology, antimicrobial spectrum, resistance mechanism to the drug, and clinical microbiology laboratory methods used to evaluate the drug’s use. 16

Information regarding sterile and some nonsterile drugs, such as liquids that can support microbial growth, should be provided in the CMC section of the application.

Clinical data

The clinical data section is perhaps the most impor-tant section of the NDA, because data from human clinical trials will greatly impact the FDAs determina-tion of safety and effectiveness for the drug product. Table 37.4 shows the content of the clinical dataset.

There is an extensive set of FDA and ICH guidance documents related to clinical studies and the presenta-tion of the clinical data in a NDA. 10,17

Safety update

This section is not filed with the original NDA, but is provided during the NDA review period at specific time points. Usually the first safety update report is filed as an amendment to the original NDA at four months after the original submission date, after receiv-ing an approval letter, and at other times specified by the FDA reviewing division.

The format of the safety update report is like the ISS, and contains new safety information from ongo-ing studies, animal studies, and any other source. Sponsors should work with their reviewing division at the FDA on the exact content and format of these reports, in order to facilitate their review.

Statistical section

This is a key section of the NDA, closely linked to the clinical data section. 18 Applicants should work


TABLE 37.3 Content of the nonclinical pharmacology and toxicology section of the NDA

● Pharmacological action and properties of the drug ● Toxic effects of the drug including acute, subacute and chronic

toxicity and carcinogenicity ● Other studies of toxicity associated with administration and use

of the drug ● Effects on reproduction and the development of the fetus ● ADME in animals ● Good laboratory practice (GLP) compliance statement for

each study or a brief reason why a study was not conducted under GLP



the NDA. The reviewing division may require addi-tional CRFs. This can be discussed at the pre-NDA meeting or the FDA will request the CRFs after the submission of the NDA.

Patent information

Patent information must be provided on the patent(s) for the drug or a method of use for the drug, using FDA Form 3542a. 6

Patent certification

Patent certification is required for any relevant pat-ents that claim the listed drug or that claim any other drug on which the investigations relied or that claim a use for the listed or other drug.

Establishment information (for biologics only)

This is to be used for certain biological product applications only.

Debarment certification

Debarment certification is required under the Generic Drug Enforcement Act of 1992, which empow-ered the FDA to debar individuals convicted of crimes relating to the development, approval or regulation of drugs. The individual may not provide any services to sponsors of an application. 19

Field copy certification

Applicants based in the United States must submit a “ field ” copy of the CMC section, application form, and summary of the NDA to the relevant FDA dis-trict office. The information will be used during the pre-approval inspection (PAI) at the manufacturing site. Within the NDA, the applicant must certify that an exact copy of the CMC section has been sent to the district office.

User fee cover sheet

The FDA uses the information in FDA Form 3397 to determine the applicability of a user fee. 6 If one is required, this form also states that the check has been mailed to an FDA account at the same time the NDA is submitted to the FDA. More information on Form 3397 is available on line at www.fda.gov/oc/pdufa/coversheet.html

Financial information

The financial information section contains clinical investigator financial disclosures (FDA Form 3455),

TABLE 37.4 Content of the clinical data section

● List of investigators supplied with the drug ● List of INDs ● Other NDAs submitted for the same drug substance ● Overview of the clinical studies ● Description and analysis of ● Clinical pharmacology studies ● Controlled clinical studies relevant to the proposed use of the

drug product ● Uncontrolled studies ● Other data pertaining to the evaluation of the drug product ● Integrated summary of effectiveness (ISE) including support for

the dosage and administration of the drug as proposed in the product labeling

● Integrated summary of safety (ISS), which would include a discussion of the adverse events of the drug, clinical significant drug-drug interactions, pertinent animal data and other safety concerns

● Discussion and analysis of studies related to the abuse potential of the drug, if appropriate

● This includes studies related to drug overdosage ● Integrated summary of risk-benefit (ISRB) which should clearly

explain how the benefits of the drug product outweigh the risks, when used according to the approved label

● Good clinical practices (GCP) compliance statement regarding the Institutional Review Board (IRB) and informed consent (IC) regulations

● If any study did not follow IRB regulations, then that study must be clearly identified

● A statement regarding any transfer of obligations for the conduct of a clinical study to a third party (Contract Research Organization, CRO)

● A listing of those studies audited or reviewed during the monitoring process by the sponsor

● The FDA is also expecting data regarding special populations such as geriatrics, pediatrics, renal and hepatic impairment patients

closely with their reviewing division at the FDA prior to the NDA submission, to come to an agreement on the format, content, tabulations, and statistical analy-ses to be presented. This section should be carefully addressed during the pre-NDA meeting with the review division.

Case report tabulations

Discuss with the FDA at the pre-NDA meeting about the submission of tabulations of patient data, data elements in the tables, and which case report forms (CRF) will be needed. 18

Case report forms

The CRFs for patients who died during a clinical study, and patients who discontinued because of an adverse event, should be included in this section of

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and certification (FDA Form 3454), 6 which provide disclosure regarding investigator financial interests and sponsor–investigator financial arrangements that could affect the reliability of the submitted data. The FDA guidance provides detailed explanations of which investigators and studies are covered under this rule. 20

Other information

This section can be used to incorporate, by cross-reference, any information that was submitted before the NDA. A sponsor may propose other uses of this section at the pre-NDA meeting.

37.2.3 Common Technical Document (CTD)

The CTD is a major product of the international har-monization process done by the ICH. This body is com-posed of the pharmaceutical regulatory and industry representatives from the European Union, Japan, and the United States. The FDA highly recommends that sponsors submit their marketing applications in CTD format. This has the advantage of preparing, for the most part, a single compiled marketing application usa-ble in all three regions. This saves time and resources during the submission process. While the CTD provides an alternative format for the marketing application, it does not alter the data or information required for a standard NDA in the US ( Figure 37.3 ). The ICH and the FDA have issued guidance documents on CTD. 21,22

Format and Content of a Common Technical Document (CTD)

Module 1 administrative and labeling information

Module 1 of CTD ( Figure 37.3 ) contains the regional administrative forms and documents required by each region, as well as the proposed prescribing information (label). The content of Module 1 is determined by each region. In the US, this section contains the cover let-ter, form 356h, complete table of contents of the entire CTD, and other administrative documents, such as the field copy certification, debarment certification, patent information, labeling, and the annotated labeling text.

Module 2 summaries

Module 2 contains the CTD summaries for quality, nonclinical and clinical information. This module is very important, as it provides detailed summaries of the various sections of the CTD. These include:

1. a very short introduction ( � 1pg); 2. quality overall summary ( � 40 pgs);

3. nonclinical overview ( � 30pgs); 4. clinical overview ( � 30 pgs); 5. nonclinical written and tabulated summaries for

pharmacology, pharmacokinetics, and toxicology; 6. clinical summary (50–400 pgs), including

biopharmaceutics and associated analytical methods, clinical pharmacology studies, clinical efficacy, clinical safety, and a synopses of the individual studies.

Module 3 quality

Module 3 contains all of the quality documents for the chemistry, manufacture, and controls of the drug substance, and the drug product.

Module 4 nonclinical study reports

Module 4 contains copy of all of the final nonclini-cal study reports.

Module 5 clinical study reports

Module 5 contains a copy of all of the final clinical study reports.

37.2.4 User Fees

Since the implementation of the Prescription Drug User Fee Act in 1994, the FDA has been allowed to charge a fee for the review of an original NDA, and cer-tain other NDA submissions. These fees vary according to their type, and the need to review clinical data. The fees have allowed the FDA to add new personnel and resources to the review process, and shorten the overall review time. Each year the FDA publishes the user fee schedule in the Federal Register, and these fees have been increasing each year ( Table 37.5 ).


TABLE 37.5 User fee schedules for 2006 and 2007

Fee category Fee 2006 Fee 2007 Fee 2008

Applications $ $ $

Requiring clinical data 767 400 896 200 1 178 000

Not requiring clinical data

383 700 448 100 589 000

Supplements requiring clinical data

393 700 448 100 589 000

Establishments 264 000 313 100 392 700

Products 42 130 49 750 65 030



37.2.5 New Drug Application (NDA) Review Process

Background

While there is a prescribed review process within the CDER, there are some general aspects to dis-cuss. The NDA is received by the FDAs central docu-ment room (CDR), which administratively processes the application, and gives the application a NDA number. The receipt date is also noted, and this starts the review time clock under the PDUFA guidelines. The various sections of the NDA are separated and distributed to the review division and other divisions reviewing certain technical sections.

When the NDA arrives at the review division, an acknowledgement letter is sent to the sponsor. The regu-latory project manager (RPM) does an initial screening of the application, to identify any obvious deficiency in the completeness of the NDA according to the NDA check-list.3 If the file appears to be usable, the RPM distributes the sections to the various assigned reviewers, who then do a final screening of the application. A summary of the NDA review process is shown in Figure 37.4 .

Timing

Within 45 days after receipt of the NDA, the review-ing division will meet, and determine if the application is fileable. If the application is to be filed, then a review plan is established for that NDA, its review priority depending on the importance of the drug. If not file-able, a refuse to file (RTF) letter is sent to the sponsor.

Refuse to File

The refuse to file letter will explain to the sponsor the deficiencies, which make the application not review-able unless some changes are made. Under PDUFA, the quality of market applications has increased, and the refuse to file letter rate has decreased from 26% in 1993 to 4% in 2001.

Review

The FDA reviewers conduct comprehensive scien-tific examination of information and data submitted in the NDA, to evaluate the quality, safety, and efficacy of the drug product, and determine the approvability of the application. During the review, questions often arise with the reviewers, necessitating communication with the sponsor. A mid-review communication may be in the form of an email, informal teleconference or a face-to-face meeting between the FDA and the sponsor. The communications usually take the form of either a discipline review (DR) letter or an information

request. The discipline review letter may include com-ments from one or more reviewers, who have identi-fied potential deficiencies in a part of the NDA. The information request asks the sponsor for additional information or needed clarification that would aid in the final review of that particular section of the NDA.

Much of the FDA-sponsor communications are done by email, which provides a very rapid method of exchanging large amounts of information. Emails however, are not considered an official communica-tion at the FDA, and so any information needed for the review and decision-making process must be offi-cially submitted as an amendment to the NDA.

Each reviewer prepares a written evaluation of their discipline review, and usually the medical reviewer will reconcile these documents in consulta-tion with the other reviewers (institutional decision). This may also involve the division or office director. If significant issues arise during the review process, the reviewing division can have an advisory committee meeting to evaluate any concerns.

Labeling

Final discussions about the package insert will usu-ally take place at the end of the review period, pos-sibly two to four weeks before the PDUFA action date. At this time, the FDA will propose any changes needed in the labeling, and engage the sponsor in bringing these negotiations to a successful close, prior to the action date. The final negotiations for the labe-ling are often done by email or teleconferences, until the labeling has been finalized. Once this is complete, the sponsor will submit a final version as an amend-ment to the NDA. This labeling must be submitted to the FDA in specific electronic formats, including SPL, and using the recently approved PRL format. 8,9

Four Month Safety Update

Four months after the submission of the NDA, the regulations require the sponsor to submit a safety update report to the NDA. This will be similar to the integrated summary of safety, but contain safety information not included in the original NDA. This information will come from ongoing clinical trials, and foreign marketing infor-mation. The FDA can also request a safety update report at other times during the review process, if necessary.

Advisory Committee

During the course of a few NDA reviews, issues or controversies may arise, and the FDA may call for a consultation with one of its advisory commit-tees. These are composed of subject matter experts in


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various medical and scientific fields. Table 37.6 pro-vides a listing of the advisory committees available to the CDER, and the FDA.

Food and Drug Administration (FDA) Action Letter

Final action on the NDA is taken by a review of the “ institutional ” decision by the division director, with

final sign-off of the action letter by the office director. The action letter can be in three forms: approval, approvable, and not approvable. An approval letter allows a product to be marketed in the US after the approval date. This assumes that the sponsor is agreea-ble to the negotiated labeling, and any post- marketingcommitments made to the FDA. An approvable let-ter is sent to an applicant if the FDA believes the application can be approved, if the sponsor submits


Applicant (drug sponsor)

NDA

Applicationfileable?

Review by CDER

No

Yes

Yes

Yes

Yes

No

NoNo

Medical

Pharmacology

Chemistry

Biopharmaceutical

Statistical

Microbiology

Meetings withsponsor

Advisorycommitteemeeting

Sponsor revises

Reviewscomplete andacceptable?

Labelingreview

acceptable?(1)

Inspectionof sites

acceptable?(2)

NDA action

Pendingsatisfactory

results

Additional Information orrevisions requested or

submitted (amendment)

Refuse to file-letter issued

(1) Labeling in this context meansofficial instructions for use

(2) Manufacturing sites and sites where significant clinical trials are performed

FIGURE 37.4 The new drug application (NDA) review process. Source of information http://www.fda.gov/cder/handbook/nda.htm as of March 23, 2008

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additional information or agrees to certain conditions. This could include labeling changes, another safety update report or additional clinical information. The sponsor has 10 days to respond to an approvable letter with a formal response or a plan to file a resubmission, a hearing request regarding the unapprovability of the NDA, a withdrawal of the application or a request for an extension of the review period to allow the spon-sor time to evaluate its options. Not approvable letters mean the application did not meet FDA requirements, and the letter will describe the deficiencies in the NDA. The sponsor can take one of the above options within 10 days. If no action is taken by the sponsor, the FDA will consider the NDA to be withdrawn.

37.3 GENERIC DRUG PRODUCT REGISTRATION AND REVIEW PROCESS

37.3.1 Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Office of Generic Drugs

The Office of Generic Drugs (OGD) is part of the Office of Pharmaceutical Science within the CDER, as shown in the organization chart in Figure 37.5 . As indicated by the name of the office, OGD is responsi-ble for review and approval of generic drug products.

37.3.2 Abbreviated New Drug Application (ANDA)

The Abbreviated New Drug Application (ANDA) is provided for the marketing of generic drug prod-ucts after all forms of exclusivity have expired for the reference-listed drug (innovator drug). ANDAs are filed under the FD & C Act section 505(j). 1 The numbers of ANDAs submitted to the FDA has been rising steadily since 2001 ( Figure 37.6 ), likely due to the high demand for lower cost generic products than brand prod-ucts, and more companies entering the manufacture of generic products.

Generic drug products must be bioequivalent to the innovator product, though waivers of in vivobioequivalence study are available in certain cases. 23

The active pharmaceutical ingredient, dosage form, dose strength, labeling, route of administration, and conditions must be the same as the reference listed drug (RLD). Also, a generic drug product must meet the same specifications as the RLD, if the RLD is listed in the USP, and meet the same cGMP requirements for manufacturing as the RLD. A sponsor of an ANDA must file a patent certification with the FDA. Table 37.7 shows the difference in the information required for the submission of an ANDA, versus a NDA.

Format and Content of an Abbreviated New Drug Application (ANDA)

The FDA strongly recommends that an ANDA be sub-mitted in the CTD format, either paper or electronic. 24

The requirements from CFR, and the corresponding sections in the CTD for ANDAs, are summarized in Table 37.8 . More information on the ANDA checklist for CTD or e-CTD can be found from the FDA website. 25

In the FDAs Guidance to Industry—Organization of an ANDA , the agency provides a suggested table of contents per 21CFR314.94, as discussed below. 21

Application form

The ANDA begins with the FDA Form 356h, as was seen with the original NDA. Table 37.7 provides a comparison of the content of a NDA, and an ANDA. A substantial amount of information is not required for the filing of an ANDA.

Basis for an ANDA submission

Patent certification and exclusivity statement

Sponsors of an ANDA must file a patent certification under one of the following paragraphs:

I. That no patent information on the drug product that is the subject of the ANDA has been submitted to the FDA;

TABLE 37.6 Center for Drug Evaluation and Research (CDER) advisory committees

Anesthetic and Life Support Drugs Advisory Committee

Anti-Infective Drugs Advisory Committee

Antiviral Drugs Advisory Committee

Arthritis Advisory Committee

Cardiovascular and Renal Drugs Advisory Committee

Dermatologic and Ophthalmic Drugs Advisory Committee

Drug Safety and Risk Management Advisory Committee

Endocrinologic and Metabolic Drugs Advisory Committee

Gastrointestinal Drugs Advisory Committee

Nonprescription Drugs Advisory Committee

Oncologic Drugs Advisory Committee

Peripheral and Central Nervous System Drugs Advisory Committee

Pharmaceutical Science, Advisory Committee for

Psychopharmacologic Drugs Advisory Committee

Pulmonary-Allergy Drugs Advisory Committee

Reproductive Health Drugs, Advisory Committee for

Source of information: http://www.fda.gov/oc/advisory/acphonecodes.html as of March 23, 2008

http://www.fda.gov/oc/advisory/acphonecodes.html

http://www.fda.gov/oc/advisory/acphonecodes.html


871

II. That such patent(s) has expired; III. The date on which such patent expires; or IV. That such patent is invalid or will not be infringed

by the manufacture, use or sale of the drug product from which the ANDA is submitted.

The above are commonly referred as Paragraphs I, II, III or IV Certifications.

If the ANDA applicant files the Paragraph IV certi-fication, the applicant must also notify the innovator within 20 days of filing of an ANDA, and the innovator has 45 days to take action upon receiving the notifica-tion. The FDA may hold the approval up to 30 months, depending on the outcome of the litigation, if any.

Comparison between generic drug and reference listed drug

This section should compare the active ingredients, as well as the route of administration, dosage form, and strength of the drug products.


Office of pharmaceutical science301-796-2400

fax 301-796-9734

Division of labeling and programsupport (HFD-610)

301-827-5846fax: 301-594-0183

Laboratory and clinicalpharmacology301-796-1211

fax: 301-796-9818

Division of therapeutic proteins(HFD122)

301-827-1790fax: 301-480-3256

Division of pre-marketingassessment I301-796-2410

fax: 301-796-9747 Division of bioequivalence

(HFD-650)301-827-5847

fax: 301-594-0181 Division of applied pharmacology

research301-796-0200

fax: 301-796-9859

Division of monoclonal antibodies(HFD123)

301-827-0850fax: 301-827-0852

Division of pre-marketingassessment II301-796-2420

fax: 301-796-9850 Division of chemistry I (HFD-620)

301-827-5848fax: 301-594-0180 Division of pharmaceutical

analysis (HD920)314-539-3869

fax: 314-539-2113

Division of pre-marketingassessment III & manufacturing

science301-796-2430

fax: 301-796-9850

Office of testing and research(HFD-900)

301-796-0200fax: 301-796-9859

Office of generic drugs (HFD-600)240-276-9310

fax: 240-276-9327

Office of biotechnology products(HFD-121)

301-796-2390fax: 301-796-9743

New drug microbiology team301-796-2470

fax: 301-796-9737

Operations staff301-796-2400

fax: 301-796-9733

Science and research staff301-796-2400

fax: 301-796-9734

Informatics and computationalsafety analysis staff

301-796-1645fax: 301-796-9743

Office of new drug qualityassessment

301-796-1900fax: 301-796-9748

Program activities review staff301-796-2400

fax: 301-796-7934

Standards and technology team301-796-2400

fax: 301-796-7934

Division of chemistry II(HFD-640)

301-827-5849fax: 301-443-3839

Division of chemistry III(HFD-600)

301-827-9275fax: 301-827-9274

Division of product qualityresearch

301-796-0016fax: 301-796-9816

Process analytical technology301-796-2400

fax: 301-796-9734

Division of post-marketingevaluation

301-796-2440fax: 301-796-9749

FIGURE 37.5 Office of Generic Drugs within the Office of Pharmaceutical Science. Source of information: http://www.fda.gov/cder/cderorg/ops.htm as of March 23, 2008

307361

449

563

766 793

880

2001 2002 2003 2004 2005 2006 2007

Fiscal year

Receipts of original ANDAs

Num

ber

of s

ubm

issi

ons

1000

900

800

700

600

500

400

300

200

100

0

FIGURE 37.6 Increase in numbers of abbreviated new drug applications (ANDAs) filed to the Office of Generic Drugs. Source of information: GPhA Fall Technical Workshop, October 11, 2007, http://www.gphaonline.org/AM/Template.cfm?Section � Presentations1 & TEMPLATE � /CM/ContentDisplay.cfm & CONTENTID � 3866 as of March 2008

http://www.fda.gov/cder/cderorg/ops.htm

http://www.fda.gov/cder/cderorg/ops.htm

http://www.gphaonline.org/AM/Template.cfm=SectionPresentations1&TEMPLATE=/CM/ContentDisplay.cfm&CONTENTID=3866





Labeling

According to 21CFR314.94(8), differences between the applicant’s proposed labeling, and labeling approved for the reference listed drug, may include differences in expiration date, formulation, bioavailability or phar-macokinetics, labeling revisions made to comply with current FDA labeling guidelines or other guidance or omission of an indication or other aspect of labeling protected by patent or accorded exclusivity under sec-tion 505 (j)(4)(D) of the act. All labeling for a generic drug product must be provided in SPL formatting, and in compliance with the Physician’s Labeling Rule (PLR).

Bioavailability/bioequivalence

This section provides the key information for gaining approval of an ANDA.

Bioavailability is the rate and extent of drug available at the site of action.

Bioequivalence is the absence of a significant difference in the rate and extent of drug available at the site of action after dosing of a test product, compared to a reference product. In general, bioequivalence is evaluated by comparing the bioavailability of the test, and the reference products, in crossover clinical studies on healthy subjects. The study may include the evalu-ation of bioavailability of products administered with, and without, food. Recommendations of study designs and data evaluation for bioequivalence study are listed in regulatory guidance. 26,27 Bioequivalence is achieved when the 90% confidence interval (CI) for the ratio of Cmax and AUC of the test product over the reference product on log transformed data is within 80%–125%.

CMC Information

The quality sections listed below contain very much the same information as would be submitted in a NDA. The content of the CMC for an ANDA includes the following:

● Components and composition statements; ● Raw materials; ● Description of manufacturing facility; ● Outside firms; contract testing laboratories; ● Manufacturing and processing instructions; ● In-process information; ● Packaging materials controls; ● Controls for the finished dosage form; ● Analytical methods; ● Stability of finished dosage form; ● NOTE: RESERVED; ● Samples; ● Environmental considerations; ● Generic enforcement act, and US agent letter of

authorization;● Other; ● Sterilization assurance information and data.

To modernize the CMC review for science and risk-based pharmaceutical quality assessment of ANDA applications, the FDA has developed and imple-mented a question-based review (QbR) approach, this includes a requirement for the sponsor to submit a quality overall summary (QoS). 28 To facilitate the QbR, the FDA has developed model quality overall summaries for immediate-release (IR) or extended-release (ER) solid oral dosage forms. 28

37.3.3 Abbreviated New Drug Application (ANDA) Review Process

The Office of Generic Drugs (OGD) process for the review and approval of an ANDA is shown in Figure 37.7 .

TABLE 37.7 Comparison of NDA and ANDA content

NDA index ANDA index

Basis for submission

Comparison between generic drug and reference listed drug

Request for waiver for in vivoBA/BE studies (if applicable)

Labeling Labeling

Summary

Chemistry Chemistry

Nonclinical pharmacology and toxicology



Clinical microbiology (if applicable)

Clinical data

Safety update report

Statistical section

Case report tabulations

Case report forms Case report forms

Patent information Patent information

Patent certification Patent certification

Establishment description

Debarment certification Debarment certification

Field copy certification Field copy certification

User fee cover sheet

Financial information Financial information

Other

References



Background

The FDA recommends that an applicant file an ANDA using CTD, either paper or electronic. 24 A complete ANDA checklist for CTD or eCTD format is located on the FDA website at http://www.fda.gov/cder/ogd/anda_checklist.pdf . The order of presenta-tion of the information in the ANDA is slightly differ-ent from that presented in the Guidance to Industry, as shown above.

As discussed earlier, the Office of Generic Drugs (OGD) has developed a question-based review (QbR) approach, including the requirement for submitting a quality overall summary (QoS) for an ANDA. 28 The QbR will transform the CMC review into a modern, science and risk-based pharmaceutical quality assess-ment, that incorporates and implements the concepts and principles of the FDAs “ 21st Century cGMP initiatives. ”29

TABLE 37.8 Content and format of an ANDA

CFR citation source CTD heading

Number Title Module Number

314.94(A)(1) Application form 1 1.2

GDEA Debarment certification 1 1.3.3

314.94(a)(2) Table of contents N/A N/A

314.94(a)(3) Basis for abbreviated new drug application submission 1 1.12.11

314.94(a)(4) Conditions of use 1 1.11.11

314.94(a)(5) Active ingredient 1, 2 ,3 1.11.12, 2.3S, 3.2S

314.94(a)(6) Route of administration, dosage form and strength 1, 2 ,3 1.11.12, 2.3, 3.3

314.94(a)(7) Bioequivalence 2, 5 2.7, 5.3.

314.94(8)(i) Listed drug labeling 1 1.14.3.2

314.94(8)(ii) Copies of proposed labeling 1 1.14

314.94(8)(iii) Statement of proposed labeling 1 1.14.3.1

314.94(8)(iv) Comparison of approved and proposed labeling 1 1.14.3.1

314.94(9) Chemistry, manufacturing and control 2, 3 2.3, 3.2

314.94(11) Reference to information previously submitted by sponsor 1 1.4.4

314.94(12) Patent Information 1 1.3.5

314.95 Notice of certification of nonvalidity or noninfringement of patent

1 1.3.5.3

314.94(13) Financial certification and disclosure 1 1.3.4

314.96 Amendment to an unapproved application: Chemistry 3 As needed

314.96 Amendment to an unapproved application: Chemistry (information no fitting under Module 3)

1 1.11.1

314.96 Amendment to an unapproved application: Clinical 5 As needed

314.96 Amendment to an unapproved application: Clinical (information not fitting under Module 5)

1 1.11.3

314.102 Communications: Meetings 1 1.6.1



314.103(c) Scientific and medical disputes 1 1.10.1

314.103(c) Scientific and medical disputes 1 1.10.2

314.150(c) Request for withdrawal of approval 1 1.5.7

314.150(b) 314.151

Withdrawal or suspension of approval by the FDA 1 1.5.7

314.420(a) Drug master files 1, 2, 3, 4, 5 As needed

314.420(b) Incorporating DMF information by reference 1 1.4.1

314.420(d) List of authorized persons to incorporate by reference 1 1.4.3

http://www.fda.gov/cder/ogd/anda_checklist.pdf

http://www.fda.gov/cder/ogd/anda_checklist.pdf



The QbR has two purposes:

1. To aid the reviewer’s evaluation of product quality and determination of the risk level associated with the manufacture and design of drug products; and

2. To provide transparency to sponsors regarding the logic used by reviewers during the conduct of the CMC reviews.

Advantages of this new QbR approach include:

1. Stimulating the application of the quality by design (QbD) concept for product development, and the concept of developing performance-based specifications.

2. Enabling risk-based assessment to facilitate continuous improvement with minimized additional supplements.

3. Standardizing the questions for CMC evaluation in the agency for the entire pharmaceutical industry, hence improving the quality and transparency of review.

4. Increasing the CMC review efficiency, reducing the review time, shortening the time for the products to reach patients.

To facilitate the QbR, the FDA has developed a model QoS for solid oral dosage forms. 28 Some of the ques-tions listed in the drug product sections of the model QoS are listed in the following:

● Which properties of the drug substance affect drug product development, manufacture or performance?

● How were the excipients, and their grades, selected?

● What evidence supports compatibility between the excipients and the drug substance?

● What attributes should the drug product possess? ● How was the drug product designed to have these

attributes?● Were alternative formulations or mechanisms

investigated?● How was the final formulation optimized? ● Why was the manufacturing process selected for

this drug product? ● How are the manufacturing steps related to the

drug product quality? ● How were the critical process parameters

identified, monitored, and/or controlled?

Timing

The timing for an ANDA filing and approval depend on the exclusivity and patent status of the reference listed drug (RLD), which has been discussed in the section for patent certification and exclusivity statement in Section 37.3.2 of this chapter. If the appli -cation is of a Paragraph IV filing, the FDA may hold the approval on an ANDA for up to 30 months, depending on the outcome of the litigation between the innovator and the ANDA applicant. As more and more RLDs come off patents, and more companies engage in generic drug manufacturing, the number of

APPLICANT

Application review

Acceptable&

complete

Request for plantinspection

Chemistry & MicroReview

Labelingreveiw

Bioequivalencereview

PreApprovalinspection results

ok?

Chem/Microok?

Labelingok?

Bioequivalenceok?

NNN

N

Y

N

Y Y Y Y

Approvalwithheld

until resultssatisfactory

Notapprovable

letter

Refuse toreceiveletter

ANDA

Biodeficiency

letterAPPROVEDANDA

Genericdrugreviewprocess

FIGURE 37.7 Abbreviated new drug application (ANDA) review process. Adapted from http://www.fda.gov/cder/handbook/anda.htm as of March 23, 2008

http://www.fda.gov/cder/handbook/anda.htm

http://www.fda.gov/cder/handbook/anda.htm


875

ANDA applications and approvals has been increas-ing over the past decade, while the mean approval time remains fairly steady at approximately18 months as shown in Figure 37.8 .

Refuse to file

As with NDAs, the Office of Generic Drugs can refuse to file an ANDA application, and will pro-vide the sponsor a listing of the deficiencies in the application.

Amendments

Amendments can be submitted to an ANDA, depending on the information requests received from the FDA. Based on past experience, informa-tion requests are most likely to involve the CMC sec-tion (stability, specifications, analytical methods) or the BE/BA section (adequate study provided in the ANDA).

Labeling

Labeling should also be provided with the ANDA application, and this should clearly correspond to the labeling of the innovator product.

Food and Drug Administration Action Letter

The FDA action letter on an ANDA can be the same type as seen with the standard NDA, as discussed in

Section 37.2.5. At this writing, the Office of Generic Drugs does not impose a user fee for ANDA applica-tions, and does not have a PDUFA timing requirement for its review of an ANDA application.

If the Office of Generic Drugs completes the ANDA review process prior to the expiration of all exclusivity for the innovator drug product, it can issue a notice of tentative approval, which does not allow the generic drug manufacturer to enter the market. Once all exclu-sivity has expired for the innovator drug, then the FDA will issue an approval letter, allowing the generic product onto the market. If the ANDA applicant and the innovator are engaged in patent litigation, the FDA action may be affected, based on the outcome of the litigation. For more details, readers are referred to FD & C Act, section 505.

37.4 POST-APPROVAL ACTIVITIES FOR NEW DRUG APPLICATIONS AND ABBREVIATED NEW DRUG

APPLICATIONS

37.4.1 Reports

Annual Report (21CFR314.81)

Sponsor’s holding a NDA or ANDA must submit an annual report each year, within 60 days of the anniver-sary date of US approval of the application, to the FDA

37.4 POST-APPROVAL ACTIVITIES FOR NEW DRUG APPLICATIONS AND ABBREVIATED NEW DRUG APPLICATIONS

Generic drug approvalsMedian times, approvals

17.0 15.7 16.4 17.518.023.0

18.6 18.319.3 18.2

380 371344

263

212273

225186

244 234

321

0

18

36

Calendar year

Mon

ths

0

200

400

App

rova

ls

Median approval times Number of generic approvals

18.1

2006200520042003200120001999199819971996 2002

FIGURE 37.8 Approvals for generic drug products. Source of information: Steven Galson, CDER Facts and Figures. August 8, 2007



division responsible for reviewing the application. The report is required to contain in the order listed:

● Form FDA 2252 (Transmittal of Periodic Reports for Drugs for Human Use); 6

● Summary; ● Distribution data; ● Labeling; ● CMC changes; ● Nonclinical laboratory studies; ● Clinical data; ● Status reports of post-marketing study

commitments;● Status of other post-marketing studies (CMC); ● Log of outstanding regulatory business (optional).

Annual Adverse Drug Experience Report (21CFR314.80)

A report of each adverse drug experience not reported previously during the year is reported to the FDA at quarterly intervals, for three years from the date of approval of the application, and then at annual intervals.

Adverse Event Reporting (21CFR314.80)

Sponsors must promptly review all adverse drug experience information obtained from any source, for-eign or domestic, including information derived from commercial marketing experience, post-marketing clinical investigations, post-marketing epidemiological/ surveillance studies, reports in the scientific literature, and unpublished scientific papers. Sponsors also need to develop written procedures for the surveillance, receipt, evaluation, and reporting of post-marketing adverse drug experiences to the FDA.

The applicant needs to report adverse drug experi-ence information to the FDA. Post-marketing 15-day alert reports are to be submitted by the sponsor for each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible, but in no case later than 15 calendar days of initial receipt of the information by the sponsor. Follow-up reports to the post-marketing 15-day alert reports must be submitted within 15 calendar days of receipt of new information or as requested by the FDA. If additional information is not obtainable, records should be maintained of the unsuccessful steps taken to seek additional information.

37.4.2 Changes to an Approved Application (21CFR314.70)

Changes may be made to an approved NDA or ANDA.30,31,32 Such changes may include compositions,

manufacturing process, equipment, manufacturing equipment, specifications, packaging, labeling, and others. The changes can be classified as major, moder-ate, and minor changes, and should be reported to the FDA via prior approval supplement, changes being effected/changes being effected in 30 days, and annual report, respectively. These reporting categories are described in the following.

Prior Approval Supplement

Sponsors must submit a supplement to their NDA or ANDA for any change in the drug substance, drug product, production process, quality controls, equip-ment or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product, as these factors may relate to the safety or effectiveness of the drug product. The guidance documents 30,31,32 should be consulted for more specific examples of allowed changes, which may provide some flexibility for specific changes.

Per the regulations, these changes include, but are not limited to:

1. Changes in the qualitative or quantitative formulation of the drug product, including inactive ingredients or in the specifications provided in the approved application.

2. Changes requiring completion of studies to demonstrate the equivalence of the drug product to the drug product as manufactured without the change or to the reference listed drug.

3. Changes that may affect drug substance or drug product sterility assurance, such as changes in drug substance, drug product or component sterilization method(s) or an addition, deletion or substitution of steps in an aseptic processing operation.

4. Changes in the synthesis or manufacture of the drug substance that may affect the impurity profile and/or the physical, chemical or biological properties of the drug substance.

5. Labeling changes are also affected by this requirement and are specified in the regulations.

6. Changes in a drug product container closure system that controls the drug product delivered to a patient or changes in the type (e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl chloride, vial to syringe) or composition (e.g., one HDPE resin to another HDPE resin) of a packaging component that may affect the impurity profile of the drug product.

7. Changes solely affecting a natural product, a recombinant DNA-derived protein/polypeptide or a complex or conjugate of a drug substance with a monoclonal antibody for the


877

following: (a) changes in the virus or adventitious agent removal or inactivation method(s); (b) changes in the source material or cell line; and (c) establishment of a new master cell bank or seed.

8. Changes to a drug product under an application that is subject to a validity assessment because of significant questions regarding the integrity of the data supporting that application.

Supplement: Changes Being Effected (CBE-30)

These are changes requiring supplement submis-sion at least 30 days prior to distribution of the drug product made using the change (moderate changes).

A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment or facilities that has a mod-erate potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. Examples of types of changes that can be reported under the CBE category can be found in the FDA guidance for industry. 30

A supplement submitted for CBE-30 is required to give a full explanation of the basis for the change and identify the date on which the change is to be made. The supplement must be labeled “ Supplement—Changes being effected in 30 days. ” Pending approval of the supplement by the FDA, distribution of the drug product made using the change may begin not less than 30 days after receipt of the supplement by the FDA.

The sponsor cannot distribute the drug product made using the change if the FDA informs the spon-sor within 30 days following the FDAs receipt of the supplement that either: (a) the change requires approval prior to distribution of the drug; or (b) any of the required information is missing.

Supplement: Changes Being Effected (CBE)

With CBE changes, the holder of an approved application may commence distribution of the drug product involved upon receipt by the agency of a sup-plement for the change. Examples of changes that can be reported in this category are available in the FDA guidance on changes to approved NDAs or ANDAs. 30

Under the CBE and CBE-30 changes, if the agency disapproves the supplemental application, it may order the manufacturer to cease distribution of the drug product(s) made with the changes.

Annual Reportable Changes

Changes that may be reported in an annual report reflect changes in the drug substance, drug product,

production process, quality controls, equipment or facil-ities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product.

These changes include, but are not limited to: (1) any change made to comply with a change to an offi -cial compendium that is consistent with the FDA statutory and regulatory requirements; (2) the deletion or reduction of an ingredient intended to affect only the color of the drug product; (3) replacement of equipment with that of the same design and operat-ing principles, with some exceptions; (4) a change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form drug product, without a change from one container closure system to another; (5) a change within the container closure system for a nonsterile drug product, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compen-dium; (6) an extension of an expiration dating period based upon full shelf life data on production batches obtained from a protocol approved in the applica-tion; (7) the addition or revision of an alternative ana-lytical procedure that provides the same or increased assurance of the identity, strength, quality, purity or potency of the material being tested as the analytical procedure described in the approved application or deletion of an alternative analytical procedure; (8) the addition by embossing, debossing or engraving of a code imprint to a solid oral dosage form drug product other than a modified-release dosage form, or a minor change in an existing code imprint; (9) a change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form; and (10) an editorial or similar minor change in labeling, including a change to the information.

37.5 OTHER CONSIDERATIONS FOR NEW DRUG APPLICATIONS AND ABBREVIATED NEW DRUG

APPLICATIONS

37.5.1 Supplemental Applications (21CFR314.71)

All procedures and actions that apply to an appli-cation under 21CFR314.50 also apply to supplements, except that the information required in the supple-ment is limited to that needed to support the change.

37.5 OTHER CONSIDERATIONS FOR NEW DRUG APPLICATIONS AND ABBREVIATED NEW DRUG APPLICATIONS



A sponsor is required to submit two copies of a sup-plement to the appropriate FDA reviewing division, and a field copy of the CMC information to the appro-priate regional office of the FDA. Foreign applicants should submit the field copy to the OGD of the FDA. If the supplement is only for a labeling change for the product, a field copy is not required.

37.5.2 Establishment Registration and Drug Listing Requirements for Foreign Establishments (21CFR 207.40)

Foreign drug establishments whose drugs are imported or offered for import into the United States must comply with the establishment registration and drug listing requirements, unless exempt by regulation or unless the drugs enter a foreign trade zone and are re-exported from that foreign trade zone without having entered US commerce.

No drug may be imported or offered for import into the United States unless it is listed and manufactured, prepared, propagated, compounded or processed at a registered foreign drug establishment, however, this restriction does not apply to a drug imported or offered for import under the investigational use pro-visions in 21CFR312 part 312 or to a component of a drug imported under section 801(d)(3) of the FDC Act. Foreign drug establishments must submit all listing information, including labels and labeling, and regis-tration information, in the English language.

Each foreign drug establishment required to reg-ister must submit the name, address, and phone number of its United States agent as part of its initial and updated registration information. Each foreign drug establishment can designate only one United States agent.

1. The United States agent must reside or maintain a place of business in the United States.

2. Upon request from the FDA, the United States agent will assist the FDA in communications with the foreign drug establishment, respond to questions concerning the foreign drug establishment’s products that are imported or offered for import into the United States, and assist the FDA in scheduling inspections of the foreign drug establishment. If the FDA is unable to contact the foreign drug establishment directly or expeditiously, the FDA may provide information or documents to the United States agent, and such an action shall be considered to be equivalent to providing the same information or documents to the foreign drug establishment.

3. The foreign drug establishment or the United States agent must report changes in the United States agent’s name, address or phone number to FDA within ten business days of the change.

37.6 PRE-APPROVAL INSPECTION (PAI)

37.6.1 Background and Purpose

The FDA may approve a NDA or an ANDA to enter the US market only if the drug is safe, effective, and if the methods used in, and the facilities and con-trols used for, the manufacture, processing, packing, and testing of the drug are found adequate to ensure and preserve its identity, strength, quality, and purity. The review and approval process include two parts: (1) scientific review based on data provided in the appli-cation, and (2) audit of the data authenticity and eval-uation of cGMP compliance. Detailed scientific review of data in the application is conducted by the review scientists at the headquarters of the FDA, specifically by the Office of Pharmaceutical Science (OPS) in the CDER. The scientists review has lately been developed into a question-based review (QbR) to raise the level of scientific understanding, and for risk- assessment and management. By contrast to relying on testing of the final products to prove the quality, the FDA has been promoting new approaches to build product quality by design (QbD) in recent years, and will hence expect to review information on QbD, including the identi-fication of critical process parameters (CPP), critical quality attributes (CQA), design space, etc., to deter-mine if the proposed method of manufacturing and specifications meet the agency’s standards on quality. In the meantime, an onsite audit, commonly referred as a pre-approval inspection (PAI), may be conducted prior to the agency’s decision-making regarding the application. The purposes of the PAI are to audit the authenticity of the data submitted in the appli-cation, and to evaluate the applicant’s compliance with cGMP, and the commitments made in the appli-cation for the manufacture of the product in the sub-mission. It is the author’s opinion that one of the purposes of a PAI is to determine if the applicant com-mitted fraud in manufacturing, testing, and in clinical studies, or misrepresented data in the application.

PAI is applicable for all domestic and international firms intending to market any drug substances or products in the United States. The procedures that the FDA use to carry out PAI are described in the FDAs Compliance Program Guidance Manual (7346.832), revised March, 2005. According to this guidance man-ual, the FDA may determine if the PAI is necessary for


879

each new drug application by a risk-based approach, 33

based on the most current knowledge and cGMP com-pliance status of a firm. If it is decided that such inspec-tion is necessary, a request will be made by the CDER review office to the responsible ORA district office governing the area of the applicant. The ORA will then schedule the inspection, and typically give the appli-cant short notice or no notice for the inspection.

37.6.2 On-site Inspection

The DA may conduct on-site inspections into a firm for many reasons such as: (1) routine cGMP inspection every two years; (2) pre-approval inspection (PAI); (3) follow-up to prior warning letter(s); (4) recall effec-tiveness check; (5) complaints from customers, indus-try, etc.; and (6) any other specific causes. The PAI is conducted by the FDAs inspection team from the field or district offices under the Office of Regulatory Affairs (ORA). The inspection teams may consist of investiga-tors, analysts, engineers, and/or computer experts, as appropriate. During the PAI, the FDA investigators conduct on-site inspection at the manufacturing and testing facilities, and clinical sites when applicable, to audit the accuracy and adequacy of information submitted in the application against the sponsor’s manufacturing and clinical practices. The key tasks of the PAI include the following:

● Evaluate the manufacturer’s compliance with cGMP and manufacturing-related commitments made in the application;

● Verify the authenticity, accuracy, and adequacy of data in the submission, including in-process and release testing results, bioequivalency, and bioavailability data.

● Determine whether the firm has the necessary facilities, equipment, controls, and skills to manufacture the new drug for which it has applied for approval;

● Collect a variety of drug samples for analysis by FDA field and CDER laboratories. These include samples for methods validation, methods verification, and forensic screening for substitution.

For data verification, the audit is to ensure that all data submitted in the NDA or ANDA are real, verifi-able, and no fraud has been committed during the course of product manufacturing and testing.

To audit the cGMP compliance, the inspection can cover all areas related to pharmaceutical manufactur-ing. Since 2002, the FDA has adopted a system-based inspection approach. The systems in this include: (1) quality; (2) facilities and equipment; (3) materials;

(4) production; (5) packaging and labeling; and (6) laboratory controls. During each inspection, the inspectors may or may not have enough time to cover all the areas. The quality system will be included any time, and the inspector can decide or change other systems to inspect. For more information on what may be audited, readers are referred to the FDAs Compliance Program Guidance Manual, Program 7346.832 for Pre-approval inspections/Investigations, and ORAs internal Guide to Inspections of Drugs. 34

In recent years, the FDA has also taken a risk-based approach to inspection. More thorough inspection may be warranted if there is a higher level of risk existed in any specific system of a firm. GMP defi-ciencies in US domestic and foreign inspections by the FDA ( Tables 37.9, 37.10, 37.11 ) 35 indicate that the level of risk in quality, laboratory controls, and facil-ity/equipment systems is substantially higher than other systems. Similar results were found in Europe by European Medicines Agency (EMEA) inspections


TABLE 37.9 Most common cGMP deficiency by systems, 2004–2005 US Domestic Inspection

System % deficiency

Quality 47.5

Laboratory controls 18.8

Facility and equipment 17.6

Production 10.6

Materials 5.5

Packaging and labeling 0

Reference 35

TABLE 37.10 GMP deficiencies for foreign dosage manufacturers in 2004

System % deficiency

Failure/OOS investigation 11

Laboratory controls 9

Equipment/cleaning validation 8

Lack of or inadequate SOP 7

Water system 5

Production/process control 5

Materials control 5

Analytical method validation 5

Media fill 5

Environmental control 5

Others 35

Reference 35



during 1995–2005. According to EMEA, deficiencies in quality, facility/equipment, manufacturing, and test-ing are highest among different categories of deficien-cies36 ( Table 37.10 ).

As indicated above, globally, quality system has the highest rate of cGMP deficiency among other systems. The reason for such a high deficiency rate is likely due to the complexity, and the strict regulatory expec-tation, of the system. The following aspects are the important components of, and questions to ask for a quality system:

● Management controls, responsibility of a leader with executive power to develop and control of an effective quality organization and system;

● Written SOPs, GMP, and technical training and documentations;

● Corrective and preventive actions (CAPA): ● Is there a CAPA system? ● Are failure investigation procedures followed

and recorded? ● Are the root causes of quality problems

identified?● What are the corrective and preventive actions? ● Are the corrective actions implemented? ● Are the corrective actions effective?

● Design controls;

● Deviation and OOS investigations; ● Production and process controls; ● Equipment and facility controls; ● Material controls; ● Records, documents, and change controls.

Deficiencies could exist in different ways and areas in pharmaceutical manufacturing. Examples of common deficiencies observed in the past include: 35

1. Written procedures were not followed in production and process control.

2. The responsibilities and procedures for QC unit were not written or followed.

3. There were no written procedures for production and process controls designed to ensure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

4. Testing and release of drug products did not include appropriate laboratory determination of satisfactory conformance to specifications prior to release.

5. Batch production and control records were not prepared for each batch of drug product or did not include complete information relating to each batch.

6. Control procedures were not established to monitor and validate the manufacturing processes that could be responsible for causing variability in the characteristics of in-process material and the drug product.

7. Employees were not trained in the particular operations they performed as part of their function.

8. Laboratory controls did not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans or test procedures designed to ensure that the materials/components conform to appropriate standards of identity, strength, quality, and purity.

9. Drug product production and control records were not reviewed or approved by the quality control unit to determine the compliance with all established, approved written procedures before a batch is released or distributed.

10. Procedures describing the handling of all written and oral complaints regarding a drug product were not written or followed.

The minimum cGMP requirements for other systems related to manufacturing pharmaceutical products, and hence may be audited for compliance, can be found in 21 CFR Part 210 and 211. It should be noted that

TABLE 37.11 Top ten GMP deficiencies in European communities during 1955–2005

No Category of GMP deficiency Number of incidences %

1 Documentation—quality system elements/procedures

1341 14.1

2 Design and maintenance of premises

634 6.7

3 Design and maintenance of equipment

594 6.2

4 Documentation—manufacturing 526 5.5

5 Contamination, microbiological—potential for

463 4.9

6 Documentation—specification and testing

432 4.5

7 Status labeling—work in progress, facilities and equipment

371 3.9

8 Environmental monitoring 323 3.4

9 Process validation 317 3.3

10 Sampling—procedures and facilities

297 3.1

Reference 36


881

although process validation of batch manufacturing is required by cGMP, it is not required prior to approval, and not required for audit during PAI. Process valida-tion for commercial manufacturing can be conducted later, but must be completed successfully before the product is shipped for marketing.

Early product R & D activities are not required to comply with cGMP, and, in the past, R & D data were not commonly audited during inspection. This is no longer the case at the present time. With the current requirement of using the common technical document (CTD) for filing, firms are required to submit a phar-maceutical development report in Section 3.2.P.2 and in the quality overall summary (QoS) for NDAs and ANDAs. It is common for industry to use R & D data in these sections for filing. Remember that one of the objectives of PAI is to audit the authenticity of data included in the submission. It is therefore apparent that the development data can be audited in the PAI with the current regulatory requirement.

37.6.3 Preparation

Preparation for a successful PAI is not a simple task to complete at the last minute of the new drug appli-cation process. The best way to prepare is to follow cGMP (21 CFR Parts 210 and 211) in all aspects, from the beginning and throughout the product devel-opment cycle. Among others, this includes cGMP training and education of all personnel involved to understand the regulatory requirements and the pro-spective of the FDA for PAI, implementing a quality system, having adequate written procedures, and fol-lowing the procedures in all systems, to ensure that the drug development works are done right from the beginning and consistently throughout the develop-ment cycle, and finally putting all things into order for the inspection. It would be very difficult to prepare at the last minute if the work performed does not meet cGMP requirements. For information on what may be audited in PAI, readers are referred to the ORAs Guide to Inspections of Drugs. 34

References for PAI preparation are available in the literature. 37 In order to coordinate and facilitate the PAI, a firm should establish a knowledgeable PAI team or task force responsible for the preparation, audit-ing, execution, and follow-up, with observations if there are any. Team members of this task force should include empowered people from product/analytical R & D, operation, quality, and regulatory affairs, depending on the complexity of the inspection. The responsibility of each team member should be clearly defined, and be coordinated by the team leader.

Overall, the responsibility of the PAI team includes the following:

● Develop a checklist for PAI; ● Conduct a gap analysis, and identify the tasks to be

completed;● Establish a schedule for completing the tasks, and

follow up on the activities; ● Identify suitable people to assume the

responsibility for the inspection, including subject experts and other roles, provide training to staff;

● Gather necessary documents and organize the documents in a suitable location to facilitate the inspection;

● Review or coordinate internal audit of all the documents, and prepare corrections or explanations if necessary;

● Verify the locations and amount of samples that may be collected by inspectors;

● Develop the logistics for audit; ● Work with the FDA inspectors during audit; ● Follow up with observations if there are any.

As discussed in the above section, the FDA inspectors will audit the authenticity of data in the submission, and evaluate the compliance with cGMP in pharma-ceutical manufacturing. Documents that should be readily available for audit may include, but are not limited to, the following:

● Supportive document and data for the CMC sections in the NDA or ANDA: ● Executed batch record of the biobatches or the

primary stability batches, ● Analytical method development and validation, ● Specifications, laboratory test results, and

stability data, ● Dissolution profiles of oral solid dosage forms, ● Product development report, ● Process development report.

● SOPs. ● Exceptional document and investigation report. ● Cleaning validation protocol and results. ● Master batch record for commercial manufacturing. ● Design and validation/qualification of building/

facility and water system. ● Validation/qualification/calibration records for

equipment.● Organization chart. ● Employee training record.

Inspectors may also collect the following samples of finished products and raw materials. The quantity of each sample can be found in FDA Program 7346.832.




● Method validation/verification sample of the biobatch, must be collected by the FDA, notprepared and packaged by the firm for pick-up, and not forwarded to the FDA by the firm.

● Profile samples: ● Sample of biobatch. ● Sample of the biotest portion of the biobatch sent

to biotest laboratory. ● Sample of innovator product sent to biotest

laboratory. ● Samples of excipients.

● Biotest sample: ● Biobatch and innovator’s product, collected at

the biotest laboratory. ● Innovator sample:

● Collected by the FDA from the innovator firm.

For the inspection, the site being audited should estab-lish a dedicated conference room that is close to the documentation room, and is equipped with all nec-essary communication tools such as telephone, fax machine, copier, and documentation aids. The company should also assign people to assume different roles during the inspection, such as administrator, escort, scribe, runner, coordinator, and subject expert. Training should be provided for these roles. During the inspec-tion, it is expected that the requested information/document will be readily available. If the requested information cannot be delivered in the expected time frame, an explanation should be provided. It is impor-tant to be honest in answering all questions. Don’t lie or fabricate any information, under any circumstance. It is acceptable to ask for clarification if any question is not clear. You can also refer the questions to other qual-ified persons, if you are not in the position to answer or if you do not have the answers. Do not guess or speculate when you do not have the information or say anything that will not happen in a limited time frame. It is not recommended to be confrontational or argue destructively with inspectors or make a flat refusal to a request. Professional, truthful, respectful, and collabo-rative approaches are helpful to facilitate the audit and the decision-making processes for the NDA or ANDA.

37.6.4 Outcome of the Pre-approval Inspection

During the audit, inspectors may record any cGMP deficiency or deviations on FDA Form-483, Inspectional Observations. At the close of the inspec-tion, Form 483 is provided to the company. It is a for-mal notification of the inspection findings. Items listed on the form are the opinion of the investigators, not yet the FDAs official position at the time inspection is

completed. The company has an initial opportunity to respond to the observation during an exit discus-sion with the inspector. Subsequently, a formal writ-ten response to the observations should be sent to the FDA. After leaving the inspection site, the inspectors will report the observations to the district office for review. If the deficiency is confirmed as significant, and the response from the company is not satisfac-tory, the FDA may issue a warning letter to the com-pany, confirming the finding of significant deficiency as the FDAs position, and providing the opportunity to the company for voluntary correction. Based on the findings of the PAI, the district office will make a recommendation to the headquarters regarding the approval of the NDA or ANDA. The recommenda-tion can be either approval or withholding approval. No application will be recommended for approval if the company is found to have significant cGMP violation, until satisfactory correction is made. If an unsatisfactory recommendation is made to the head-quarters, the FDA will issue a not approval letter to the applicant. For generic drugs, approval will not occur until a reinspection is satisfactory, and an approval recommendation is made.

The warning letter may serve three purposes: (1) to officially notify the company and the public about the finding of significant regulatory violation; (2) to stimulate voluntary corrective action promptly; and (3) to establish a background of prior warning should further regulatory action by the FDA be needed at a later date.

Both Form 483 and the warning letter are serious documents that must be responded to carefully and promptly, e.g., within a week or two. In the response:

● Address the impact of each item on product quality.

● Determine the root cause of the problems. ● Provide a plan on how, when, and who will correct

each of the observations, including the preventive actions to assure a true fix of the problem.

● If corrections have been made, provide pertinent documentation in support of corrective actions.

● If you do not agree with the FDA, provide reasons and documents to support your position.

In the response, develop the corrective actions from the quality system level. It is important not to com-mit any unworkable plans or unrealistic timelines, and any commitment made must be carried out promptly. Any undelivered promise will damage the cred-ibility of the company, and raise more problems in the follow-up reinspection, leading to not approval of the NDA or ANDA. Persistent and significant GMP vio-lations may lead to enforcement actions by the FDA.


883

For a company with approved products on the market, enforcement actions, such as recall, injunction, seizure, consent decree, prosecution, debarment or closing plant may be taken, if the significant violation in manufacturing is not corrected adequately in a timely manner.

37.6.5 Summary

To summarize, PAI is an integral part of the NDA or ANDA approval process. The purposes of the PAI are to verify the authenticity of data submitted in the applications, and to evaluate the cGMP compliance of the applicant. Application will not be approved if the applicant is found to have significant violation of cGMP. The best way to prepare for a successful PAI is to comply with cGMP consistently throughout the product development cycle. Proper training for per-sonnel, good organization of documents, professional presentation, and honest and cooperative interaction with inspectors will facilitate the PAI process. When Form 483 or a warning letter is received after a PAI, careful response to the FDA in a timely manner to ensure that corrective actions are taken adequately and promptly will help to obtain the approval of the application from the FDA.

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