FOOD AND DRUG ADMINISTRATION

COMPLIANCE PROGRAM GUIDANCE MANUAL PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010
FORM FDA 2438g (electronic-09/2003)
COVER PAGE 1 of 4
CHAPTER 46- NEW DRUG EVALUATION

SUBJECT:
PRE-APPROVAL INSPECTIONS
IMPLEMENTATION DATE

5/12/2010
COMPLETION DATE

5/11/2012
DATA REPORTING
PRODUCT CODES
Use appropriate product codes.
PRODUCT/ASSIGNMENT CODES

46832 NDA Pre-Approval Inspections/Methods
Validation
46832B NDA Forensic Sample Collection/Analysis
46832C NDA Biotest Sample Collection/Analysis
46832M Pre-License Inspections (BLA)
46832D PEPFAR NDA Pre-Approval Presidents
Emergency Plan for AIDS Relief
52832 ANDA Pre-Approval Inspections/Methods
Validation
52832B ANDA Forensic Sample
Collection/Analysis
52832C ANDA Biotest Sample Collection/Analysis
52832E PEPFAR ANDA Pre-Approval
Presidents Emergency Plan for AIDS Relief

FIELD REPORTING REQUIREMENTS

INSPECTIONAL

1. Appointment of Pre-Approval Manager

Each district office (district) will maintain a Pre-Approval Program Manager (PAM) and an alternate
and report these names to ORA Division of Field Investigations (DFI, HFC-130) (see Part 6
CONTACT INFORMATION). DFI maintains and disseminates the Master List of these names for
agency use. PAM decisions are expected to have the concurrence of the district director.

2. Domestic Establishment Evaluation Requests (EERs)

Via the Establishment Evaluation System (EES), CDER/Division of Manufacturing and Product Quality
(DMPQ) will issue an EER to the district PAM. The district should respond to the request with an
evaluation of the firm within 10 business days of the request.
DATE OF ISSUANCE: 4/12/2010 COVER PAGE 2 of 4
FORM FDA 2438g (electronic-09/2003)

PROGRAM 7346.832




3. Reporting for Domestic Inspections (NDA/ANDA)

Approval Recommendation: If the inspection of the facility finds that the application is acceptable,
reports the status in EES by the district goal date.
1
In the event that the district goal date has passed,
2
a
recommendation should be entered no later than 5 calendar days after the inspection completion date.
The establishment inspection report (EIR), FDA-483, and coversheet need to be forwarded to
CDER/DMPQ/New and Generic Drug Manufacturing Team (NGDMT) within 30 business days, either
electronically (CDERPAIPROGRAM), by fax, or by mail. In those cases where information is available
through FACTS, TURBO EIR, MARCS, or any other electronic repository of official records, an email
with a reference to the appropriate database(s) is acceptable.

Withhold Recommendation: If the inspection of the facility finds that the application is unacceptable,
report the status of the application in EES as soon as the determination is made, and no later than the
district goal date. In the event that the district goal date has passed,
3


the status of the application should
be entered no later than 5 calendar days after the inspection completion date. The inspection results
should be summarized in the EES Comments field.

For a withhold recommendation, the following information is to be forwarded electronically
(CDERPAIPROGRAM), by fax, or by mail to DMPQ/NGDMT. In those cases where information is
available through FACTS, TURBO EIR, MARCS, or any other electronic repository of official records,
an email with a reference to the appropriate database(s) is acceptable.

The FDA-483, as soon as it is issued
4
(CDERPAIPROGRAM)
Finalized EIR with coversheet, attachments, and exhibits within 30 business days of the last day
of the inspection
If a concurrent CGMP inspection was performed for marketed product and enforcement action is
recommended, send the completed case recommendation to DMPQ/Case Management Team
(CMT) via MARCS-CMS
Forward any response from the firm as soon as it is received. Include the application number
and Firm Establishment Identification Number (FEI). Copies of responses should be sent by
express mail, scanned, or facsimile (if less than 50 pages) to DMPQ/NGDMT. Alternatively, the
district can request that the firm submit a copy of the response directly to NGDMT at the
conclusion of the inspection. The district should promptly provide any comments on the firms
response to NGDMT. The district will also enter appropriate milestones into EES to document
whether its follow-up activities have changed the withhold recommendation (i.e., FDA-483
response is found to be adequate, or satisfactory follow-up inspection)


1
The district goal date is the date by which the district should complete the inspection process, including entering the site
recommendation into EES.
2
The district PAM should provide advance notification to NGDMT (New and Generic Drug Manufacturing Team) if the
district will be sending a late recommendation, and provide current information on the inspection findings.
3
See Footnote 1.
4
PAMs provide domestic FDA-483s to CDER/DMPQ; investigators provide FDA-483s to CDER/DMPQ immediately upon
completion of a foreign inspection.
D

ATE OF ISSUANCE: 4/12/2010 COVER PAGE 3 of 4
FORM FDA 2438g (electronic-09/2003)

PROGRAM 7346.832



For an inspection that might result in an OAI status, whether or not the inspection is associated with a
pre-approval inspection, the PAM must enter a Potential OAI Alert into EES as soon as possible.
This includes any CGMP surveillance inspection. Once the district decides on its case
recommendation, the PAM must update the Potential OAI Alert. Refer to the EES Instructions
located in the Help section of EES.

NOTE: If a district recommends withholding approval and does not expect the EIR to be completed
before the user-fee due date, the district is responsible for notifying and submitting written
justification to the CDER/DMPQ contact for the EER as soon as possible. The justification should
include the draft or final FDA-483 and a description of concerns related to the approvability of the
application. Withhold recommendations based solely on a draft or final FDA-483 should be an
atypical occurrence.

4. Reporting for International Inspections (NDA/ANDA)

The investigator will submit, via facsimile or email, the initial recommendation (including the FDA-483,
if issued) and any other concerns related to the approvability of the application to DMPQ/International
Compliance Branch (ICB) as soon as possible or within 24 hours after completing the inspection (fax:
(301) 847-8742 or (301) 847-8738, email: CDERICB@fda.hhs.gov). ICB will send a copy of this
recommendation and FDA-483, if issued, to ORA/Division of Field Investigations (DFI) within 5
business days.

At the close of the inspection, investigators will instruct firms to submit all communication to the
International Compliance Branch (10903 New Hampshire Ave, White Oak 51, DMPQ/ICB, Silver
Spring, MD 20993) and to copy the communication to the lead investigator. The lead investigator
should promptly provide any comments on firms response to DMPQ/ICB.

After completion of the EIR, the investigator will forward the following to ICB, either electronically (as
email attachment or intranet weblink), by fax, or by mail:
The final EIR, FACTS endorsement, attachments, and exhibits within 30 business days.
Forward any communication from the firm, if it is received, as soon as possible.

ICB evaluates international pre-approval recommendations. After review, the ICB compliance officer
will promptly update firm profile class codes in accordance with IOM Exhibit 5-14 for international
PAIs. Note that profile class codes are only comprehensively updated after a CGMP surveillance
inspection. For an inspection that only covers pre-approval issues, the profile class code covered during
the pre-approval inspection should be updated. If an initial international inspection of a firm is
classified OAI, no profile information should be entered. This assures the product cannot be marketed
in the U.S. until a follow-up inspection verifies implementation of appropriate corrective actions or until
corrections can be substantially verified through other appropriate means. When changing a profile
status, the ICB compliance officer should explain in the remarks field of MARCS the basis for the
change and include the date and description of applicable correspondence (e.g., mm/dd/yy Warning
Letter Closeout Letter).

For an inspection that might result in an OAI status, whether or not the inspection is associated with a
pre-approval inspection, ICB must enter a Potential OAI Alert into EES as soon as possible.
DATE OF ISSUANCE: 4/12/2010 COVER PAGE 4 of 4
FORM FDA 2438g (electronic-09/2003)

PROGRAM 7346.832




5. Reporting for Biologic Licensing Applications

For Biologic Licensing Applications (BLA), forward the firms response, the final EIR with coversheet,
attachments, and exhibits to DMPQ/MAPCB to coordinate assignment and evaluation, either
electronically, by fax, or by mail. In those cases where information is available through FACTS,
TURBO EIR, MARCS, or any other electronic repository of official records, an email with a reference
to the appropriate database(s) is acceptable.

6. Reporting of Investigational New Drug Inspections

For Treatment Investigational New Drug (IND) inspections, districts and CDER/OC/DMPQ are to
report the inspection findings within 10 calendar days of receipt of the EER into EES. See Part 2
Implementation of this program for further instructions.

LABORATORY

Forward copies of all laboratory reports on the verification of NDA and ANDA analytical methods to
the CDER review unit that requested the verification. Completed analytical worksheets will be
maintained by the analyzing laboratory.

Drug samples connected with applications that are pending a decision may be collected for purposes
other than methods validation. These samples may be analyzed by ORA laboratories or by CDER/DPA
laboratories. All lab results that are classified lab class 2 or 3 samples
5
will be forwarded to the district
compliance branch if the manufacturing facility is domestic, or to CDER/ICB, if the manufacturer is an
international facility. Laboratories performing profile analysis should maintain remaining sample
material and the worksheets for future retrieval.


5
Refer to ORA Laboratory Manual, Volume 3 (Section 3).

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 TABLE OF CONTENTS PAGE 1 of 1
FORM FDA 2438g (electronic-09/2003)



TABLE OF CONTENTS
PART I - BACKGROUND 1 ...........................................................................................................
PART II IMPLEMENTATION 2 ................................................................................................
2.1 Scope 2 ........................................................................................................................
2.2 Strategy 3 ....................................................................................................................
2.3 Program Management Instructions .5 .........................................................................
2.4 Importance of Review Independence 8 .......................................................................
2.5 Knowledge Transfer Program .8 .................................................................................
PART III - INSPECTIONAL .9 ......................................................................................................
3.1 Inspection Scheduling and Preparation 9 ....................................................................
3.2 Inspection Team 10 .....................................................................................................
3.3 Inspection/Audit Strategy 11 ......................................................................................
3.4 Inspection/Audit Coverage, Objectives, and Techniques......................................11
3.5 Inspection Reporting 22 ..............................................................................................
3.6 Sample Collection or Sample Submission Requests 25 .............................................
PART IV - ANALYTICAL 27 .........................................................................................................
PART V - REGULATORY/ADMINISTRATIVE STRATEGY 28 .............................................
PART VI - REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS 30 ................
6.1 References 30 ..............................................................................................................
6.2 Attachments 31 ...........................................................................................................
6.3 Contacts 32 .................................................................................................................
6.4 Acronyms 33 ...............................................................................................................
PART VII - CENTER RESPONSIBILITIES .34 ..........................................................................

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 1 of 35
FORM FDA 2438g (electronic-09/2003)


PART I - BACKGROUND

The Federal Food, Drug, and Cosmetic Act provides that FDA may approve a New Drug Application
(NDA), an Abbreviated New Drug Application (ANDA), and a Biologic Licensing Application (BLA)
if, among other requirements, the methods used in, and the facilities and controls used for, the
manufacture, processing, packing, and testing of the drug are found adequate, and ensure and preserve
its identity, strength, quality, and purity.
6


In 2002, the FDA announced a significant new initiative called Pharmaceutical Current Good
Manufacturing Practices (CGMPs) for the 21
st
Century, to enhance and modernize the regulation of
pharmaceutical manufacturing and product quality. This initiative encourages implementation of risk-
based and science-based approaches that focus agency attention on critical areas and promotes better
and more consistent decisions among regulators. In accordance with the Pharmaceuticals CGMP for the
21
st
Century initiative, this compliance program includes scientific, risk-based approaches that
incorporate inspection of the level of the firms process and product understanding, an evaluation of the
firms manufacturing readiness, and verification of authenticity of submitted data.

In 1992, Congress enacted the Prescription Drug User Fee Act (PDUFA). PDUFA was renewed in 1997
as PDUFA II, in 2002 as PDUFA III, and in 2007, as PDUFA IV. PDUFA establishes User Fee Goals
to ensure that NDAs and BLAs are reviewed in a timely manner based on performance goals. It is an
agency goal based on Congressional mandate that user-fee due dates be met. All agency components
involved in the pre-approval program CDER Office of Pharmaceutical Science; CDER Office of
Compliance; ORA district offices; and FDA analyzing laboratories will coordinate efforts to
communicate and resolve outstanding application issues to assure PDUFA performance goals are met.

Generic drug applications also represent an important agency goal in providing greater availability of
medicines to the American public. As a result of the generic drug manufacturing history and the
Generic Drug Enforcement Act (GDEA) of 1989, this inspectional program was significantly revised to
include more emphasis on data integrity.
7
More than 30 individuals and nine companies admitted or
were found guilty of various fraud and corruption offenses involving generic drugs. Also, refer to the
agencys application integrity policy (AIP) for a discussion of other regulatory enhancements.
8
Unlike
NDAs and BLAs, ANDAs are funded exclusively through congressional appropriations.

FDA is committed to providing applicants with actions on submissions within the established time
periods. Each CDER and ORA component with a role in the drug approval process is responsible for
initiating and completing specific tasks, many of which with time frames established in this compliance
program, in order to meeting these review time performance goals.

6
Federal Food, Drug, and Cosmetic Act 505(d) and 505(j)(4)(A) (21 U.S.C. 355(d)(3) and 355(j)(4)(A))
7
Refer to FDA Consumer magazine March 1997 for additional history about generic drug manufacturing
(http://www.fda.gov/ICECI/EnforcementActions/FDADebarmentList/ucm139627.htm).
8
See http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy/default.htm

PROGRAM 7346.832

D

ATE OF ISSUANCE: 4/12/2010 PAGE 2 of 35
FORM FDA 2438g (electronic-09/2003)

PART II IMPLEMENTATION
2.1 SCOPE

A pre-approval inspection (PAI) is performed to contribute to FDAs assurance that a manufacturing
establishment named in a drug application is capable of manufacturing a drug, and that submitted data
are accurate and complete. This program directs the ORA district office or DMPQ in the evaluation of
establishments by on-site inspections and/or the establishment file review when the firm is named in the
Chemistry, Manufacturing, and Controls (CMC) section of a New Drug Application (NDA),
Abbreviated New Drug Application (ANDA) or Biological Licensing Application (BLA). This includes
original submissions, CMC amendments to pending original submissions, and CMC supplements to
approved drug applications. Domestic and international pre-approval inspections
9
are conducted for
generic and innovator drug applications, and may cover all facilities associated with a submission,
including drug component manufacturing (such as Active Pharmaceutical Ingredients (APIs), which are
also known as drug substances), finished drug product manufacturing, and control testing laboratories.

The CMC section of an application includes analytical test methods for the drug product, specifications
of the drug product and drug components, and a general description of the products manufacturing and
control procedures.
10
Multiple agency operating units collaborate in the evaluation of the general
description of the products manufacturing and control procedures. The assessment of a CMC section
always includes a review by CDER application reviewers of information submitted in the application
and frequently includes an on-site assessment (i.e., inspection of manufacturing operations by the
district office).
11
This program has been designed to maximize the strengths of these FDA functions in
evaluating submitted information.

This compliance program establishes the criteria for deciding whether inspections are to be conducted
for a given application. In some cases, FDA may have sufficient current and pertinent information to
arrive at a scientific decision on site acceptability without conducting a PAI. This program's risk-based
decision criteria for performing an on-site inspection for an application ensure that inspection resources
are directed to the greatest possible protection of public health. This program also provides risk-based
strategies for the scope of inspectional coverage and clarifies roles in order to establish more efficient
communication.







9
The PAI inspection program also includes analytical method evaluations by FDA laboratories. See Part 4 and Appendix B.
10
The requirements for the content of new drug applications are described in chapter 21 of the Code of Federal Regulations
(CFR). For additional guidance, refer to CTD (Common Technical Document) at http://www.ich.org.
11
The objectives of this program may be partly met by an Office of Compliance (or by CDER assignment to ORA) review of
recent inspection reports (e.g., EIRs or reports from a counterpart foreign government regulatory agency, within established
procedures).

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 3 of 35
FORM FDA 2438g (electronic-09/2003)

2.2 STRATEGY

2.2.1 Assignment of Inspections Decision Criteria

There are two types of pre-approval inspections performed: Priority and Discretionary. Refer to Part
2.3, PROGRAM MANAGEMENT INSTRUCTIONS, for the determination of a Discretionary PAI.
If one or more of the following apply, the establishment meets the Priority criteria and an inspection is
to be performed:

Priority Pre-Approval Inspection Criteria:
12

1. Establishment is named in an application to FDA for the first time, including establishments that
have never been inspected or have been inspected only for non-application drugs;
2. First application filed by applicant (for coverage of finished dosage manufacturing and testing);
3. First ANDA filed for an approved drug (for coverage of finished dosage manufacturing and
testing);
4. Finished product contains a New Molecular Entity (NME) (does not apply to supplements);
5. Finished product content assay has a narrow range (e.g., 95-105% labeled strength for narrow
therapeutic index drugs) or drug is expected to require titrated dosing (does not apply to
supplements);
6. Finished product or API is manufactured by a substantially different manufacturing process or
dosage form than previously covered at the establishment;
7. API derivation is high risk (e.g., API is derived from animal tissues) or the intended use has
significantly changed (e.g., API previously used in non-sterile product is now intended for a
sterile drug product);
8. Numerous application submissions or certain site/process/product changes that are expected to
pose significant challenge to the state of control of the facility or process; and
9. Profile class status of application product or API is unacceptable or not updated via a site
inspection within the past 2 years (3 years for control laboratories and 4 years for packaging and
labeling), for original applications or significant pre-approval CMC supplements.

2.2.2 Inspections by Objective

There are three primary inspectional objectives of this PAI program, all of which require an informed
strategy and careful on-site evaluation. These objectives are:

Objective 1: Readiness for Commercial Manufacturing
Objective 2: Conformance to Application
Objective 3: Data Integrity Audit

Specific coverage of these elements, as well as the recommended inspection and audit techniques for
manufacturing and testing operations, are described in Part 3 Inspectional.


12
Priority PAI Criteria is assessed by both the CMC application reviewer and by DMPQ. The inspection coverage for each
of these Priority inspection criteria is described in Part 3 of this program.

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 4 of 35
FORM FDA 2438g (electronic-09/2003)



2.2.3 Roles/Responsibilities of CDER and Field on Reviewing and Assessing A/NDA CMC
Submissions

The FDA organizational levels involved are:
ORA district offices and laboratories
CDER Office of Compliance (OC), Division of Manufacturing and Product Quality (DMPQ)
Manufacturing Assessment and Pre-Approval Compliance Branch (MAPCB)
New and Generic Drug Manufacturing Team (NGDMT)
Biotechnology Manufacturing Team (BMT)
International Compliance Branch (ICB)
CDER Office of Pharmaceutical Science (includes multiple CDER review offices)
Office of New Drug Quality Assessment (ONDQA)
Office of Generic Drugs (OGD)
Office of Biotechnology Products (OBP)
New Drug Microbiology Staff (NDMS)
Office of Testing and Research (OTR)

Part 6 Program Contacts provides contact information for each of the offices that have a role in
implementing this program. Each application entry in EES should list the assigned PAM, CDER
application reviewer, and CDER compliance officer.

Although multiple offices collaborate in the evaluation of establishments named in applications, lead
offices are established in CDER and ORA to accomplish pre-approval program requirements.
ORA responds to inspection requests, inspects sites in accordance with this program, reports
findings, and provides a recommendation on site acceptability to the Office of Compliance.
CDER OC DMPQ evaluates establishments, determines if a PAI must be conducted, reviews
inspection reports and recommendations, provides a site acceptability decision to other CDER
offices, and assures uniform application of program decisions, CGMP policy, and adherence to
this program. For international establishments, the International Compliance Branch (ICB)
serves as the compliance office.
CDER ONDQA, OGD, OBP, NDMS, OC/BMT, and other product review offices perform
review of submitted information (e.g., test methods, manufacturing and control strategy) and
establish specifications and other regulatory commitments where needed to support application
approval decisions.
CDER OND determines and issues the final decision on an application or licensure for NDAs
and BLAs. CDER OGD performs this function for ANDAs.

The process to approve or withhold an NDA, ANDA, or BLA is an important FDA responsibility and is
an important CDER function. The final decision is based on the contributions of multiple FDA sources
of information, including the products safety, efficacy, and quality. The effective implementation of
this program requires coordination between: 1) CDER application reviewers; 2) Office of Regulatory
Affairs; 3) CDER OC; and 4) FDA laboratories. The roles and responsibilities of ORA, the CDER
application reviewers, and CDER OC in performing reviews and inspections are further described in
Part 7 - Center and Field Responsibilities.
DATE OF ISSUANCE: 4/12/2010 PAGE 5 of 35
FORM FDA 2438g (electronic-09/2003)

PROGRAM 7346.832


Specific roles and responsibilities for district and CDER review staff are set forth in the chart attached
as Attachment A of this program. These are organized by topic area for ease of reference.

For analyzing laboratories, CDER OTR/Division of Pharmaceutical Analysis and ORA laboratories may
be tasked with analyzing the drug product or the analytical method validation before approval.
2.3 PROGRAM MANAGEMENT INSTRUCTIONS

2.3.1 New Drug Application Inspection Assignments

2.3.1.1 Product Review Responsibilities for Establishment Evaluation

Establishments named in an application are electronically processed and tracked in the Establishment
Evaluation System (EES).
13
Each establishment is assigned an Establishment Evaluation Request
(EER) within a single submission. The EERs are then forwarded to the necessary offices for review.

Upon the receipt and filing of an application from the applicant, the CDER application reviewing office
will enter the establishment information into EES and generate EERs for all establishments named as
participating in the manufacturing
14
of the product. This information will include the type of
submission, type of manufacturing or testing conducted, including specific intermediate step(s) or type
of laboratory analyses (e.g., microbiology, chemistry), and any other relevant information of the
facilitys function.

2.3.1.2 OC/DMPQ and ORA Responsibilities for Establishment Evaluation

2.3.1.2.1 Determination of Priority or Discretionary Pre-Approval Inspection

OC/DMPQ

DMPQ will receive the EER from CDER Office of Pharmaceutical Science (ONDQA and OGD) for
prompt evaluation. DMPQ will determine if any of the Priority Pre-Approval Inspection Criteria are
met, as provided within Part 2 IMPLEMENTATION: Strategy. The EER will be categorized into
one of two categories and then forwarded to the district for review:
Priority PAI: DMPQ strongly recommends that a pre-approval inspection be performed because
one or more Priority PAI Criteria was met. If only Criteria #9 applies, in that the profile is
unacceptable or has not been recently updated, DMPQ enters GMP Inspection request in EES.
If any of the other criteria apply, DMPQ enters Product Specific inspection request in EES
and forwards it to the district.
Discretionary PAI: DMPQ recommends that no pre-approval inspection be performed because
the Priority PAI Criteria were not applicable to the site or product. DMPQ enters a 10 Day
Letter request for evaluation into EES and forwards it to the district.


13
CDER Review Division enters all facilities named in a drug application into EES. DMPQ then determines which facilities
fall under the Priority PAI Criteria.
14
Refer to 21 CFR 210.3(b)(12). http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 6 of 35
FORM FDA 2438g (electronic-09/2003)

For international establishments, the EER is reviewed by OC/DMPQ and assignments are directly
submitted to ORA/DFI.

ORA/District Office for Domestic Establishments

Districts have 10 calendar days to respond to a Priority Pre-Approval Inspection request by entering
one of the three recommendations into EES:
1. Approval
2. Withhold Approval, or
3. Assigned to IB

The first two of these are often decided using current information and without a new inspection. The
third leads to initiation of an inspection.

Rationale for not conducting a Priority Pre-Approval Inspection

If a district (domestic and ICB) has determined that a Priority PAI is not warranted, the reason for not
initiating the inspection will be entered into EES along with the districts recommendation within 10
calendar days. Examples of rationales for not conducting a Priority Pre-Approval Inspection include the
following:
A facility has an acceptable profile for a similar product with a higher manufacturing
complexity. The EES entry may read: Inspection of ABC Drug Co. for subject application is
not warranted based on a recently completed CGMP inspection that found the establishment
compliant for a related product type (application is for non-sterile liquid; establishment has
acceptable history in sterile liquids) and which also met the other objectives outlined in the
program for this priority situation. This decision was submitted to CDER DMPQ on [insert
date].
The district is currently monitoring the commitments of an establishment with an unacceptable
profile status and has determined that a withhold recommendation is appropriate without need
for a follow-up inspection. The facility and profile status will be reviewed again before a
decision is needed for the current application.
For international facilities, ICB or BMT may consider another recognized regulatory authoritys
inspection report when determining the need for a pre-approval inspection, consistent with
established agency policy regarding the use of such information.

For a new drug application or BLA, a district decision to inspect must take into account the
applications user-fee date.
15
Districts must assure completion of the PAI and the district
recommendation well in advance of the user-fee date to facilitate DMPQs full review and final decision

15
CDERs Good Review Management Practices program has implemented enhanced collaborative team functioning for
NDA and BLA review, in which the responsibility for timely information by each discipline is emphasized. Under GRMPs,
each discipline reports on the latest status of their evaluations throughout the review cycle. For example, Medical Officers
discuss the clinical review status, product reviewers (ONDQA or OBP) discuss the CMC review status, and CGMP
representatives (OC) discuss the GMP/Facility review status. More timely inputs to the process (significantly before the
PDUFA date) will allow the Center sufficient time to make a well-rounded and deliberative decision considering all
information before deciding on application approvability.
DATE OF ISSUANCE: 4/12/2010 PAGE 7 of 35
FORM FDA 2438g (electronic-09/2003)


PROGRAM 7346.832

on the facility evaluation prior to the user-fee date. This careful management of inspection scheduling
also permits consideration of the firms FDA 483 response.

Rationale for Conducting a Discretionary Pre-Approval Inspection

If the district recommends Assigned to IB or Withhold for a Discretionary Inspection EER, the district
will provide written rationale via EES to DMPQ within 10 calendar days. The district will determine
the objectives to be covered during the inspection (refer to Part 3 Inspection/Audit Strategy), and
may also include these objectives in EES. Situations that may justify performance of a Discretionary
Inspection (district or CDER-initiated), include the following:
Multiple applications filed in short period of time involving a single establishment for
manufacture of the finished product;
Significant deficiencies were found during the last pre-approval inspection or the firm has a
history of non-compliant pre-approval inspections; and
Additional potentially adverse information regarding the compliance status of an establishment
not yet known to CDER, such as an expected enforcement action recommendation during an
ongoing inspection, multiple recalls, or new firm management.

The district will use EES to automatically generate an assignment.

2.3.1.2.2 Inspection and Post-Inspection

If the inspection may result in an OAI status, the PAM must enter a Potential OAI Alert into EES as
soon as possible. The district should use EES to record inspectional information and final outcomes for
both Priority and Discretionary inspections. Once the district determines a recommendation, the PAM
must update the Potential OAI Alert. Refer to EES instructions within the Help section of EES.

2.3.2 Investigational New Drug (IND) Applications (Including Treatment IND and Treatment IND
Protocols)

An IND is an application for approval to test a drug in clinical trials for humans. Districts will only
inspect clinical trial manufacturing establishments when specifically requested to do so by CDER. Such
requests will be issued using EES. These sites are not generally required to register and are not subject
to routine drug process inspections.

A Treatment IND is an original IND that contains a protocol providing for extensive use of a promising
new drug, in patients with a serious or immediately life-threatening disease or condition, for which no
comparable or satisfactory alternative drug or other therapy exists. A Treatment IND protocol provides
for administration of the IND drug outside of clinical trials and before marketing of the commercial
drug. This can include use of a drug for diagnostic purposes. Because a Treatment IND is submitted
with a 30 day review period, any establishment inspection request is a top CDER priority. If decision is
made to inspect such a facility, the district is to ensure completion of the inspection within 10 calendar
days of receipt of the inspection request.

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 8 of 35
FORM FDA 2438g (electronic-09/2003)
2.3.3 Biological Licensing Application (BLA) Inspection Assignments

During review of a BLA, DMPQ/MAPCB determines if a pre-license inspection
16
should be performed
and what objectives should be covered. The inspection team consists, as needed, of an investigator
qualified by training and experience in biotechnology inspections, a DMPQ investigator, and an OBP
reviewer. For fill/finish manufacturing operations, an ORA investigator will generally lead the team.
The team should frequently include a MAPCB reviewer and an OBP reviewer. The lead investigator is
responsible for the inspectional strategy, ensuring adequate coverage, consolidation and final issuance
of the 483, and completion of the EIR. All team members are responsible for writing their portions of
the EIR within established time frames.
2.4 IMPORTANCE OF REVIEW INDEPENDENCE

FDA offices involved in the pre-approval inspection program are covered by an equal voice
philosophy. Under equal voice, all appropriate expertise should be brought to bear in the important
decisions we make about applications, and each FDA office assigned a role in reviewing and evaluating
new drug applications is valuable. The review of an application requires the input of multiple
disciplines in FDA, and involves difficult regulatory judgments which may result in differences of
opinion. Therefore, achieving a science-based and ultimately defensible decision about each application
demands that reviews and evaluations be independent and encourage well-informed critical evaluations
by each involved organizational unit. Review independence is accomplished, in practice, when each
organizational unit:
Integrates each contribution to enhance the decision of the multidisciplinary team;
Provides an environment where each member of the team has an opportunity to express his or
her view for the area in which s/he has a recognized responsibility;
Ensures an avenue for promptly raising unresolved differences of opinion through the
management chain for prompt resolution; and
Maintains transparency with a full and adequate record documenting its decisions, including any
significantly differing views.
2.5 KNOWLEDGE TRANSFER PROGRAM

CDER has initiated a program to enhance the risk-based focus of drug pre-approval inspections.
CDER's pre-market assignments and communications will now effectively transfer product and
manufacturing knowledge from CDER to ORA inspections. Specifically, CDER staff will alert the
inspection team to manufacturing and laboratory issues found during the pre-market application review.
CDER/DMPQ will communicate these areas of concern via the Knowledge Transfer Memorandum
(KTM) or by initiating other forms of communication, including meetings, telephone calls, or
participation on inspections.

The pre-approval manager will be alerted in EES that a KTM will be or has been issued. The KTM will
be issued along with the pre-approval assignment. The inspection should not be delayed pending the
issuance of a KTM.

16
For the purpose of this document, pre-license inspections relating to BLAs are referred to as pre-approval inspections.

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 9 of 35
FORM FDA 2438g (electronic-09/2003)
PART III - INSPECTIONAL
3.1 INSPECTION SCHEDULING AND PREPARATION

A PAI should be performed at the earliest opportunity in order to meet the district goal date. It may be
combined with other programs or for-cause inspections as necessary for efficient and effective
inspection coverage. The timing decision should carefully weigh the need for the inspection to provide
an early contribution to the application review process with the need for efficient scheduling by the
district. The district goal date, which is included in EES, is the date by which the district should
complete the inspection process. A systems-based CGMP surveillance inspection pursuant to CPGM
7356.002 will be added if due by work plan or if findings from the PAI raise concerns that indicate the
need for coverage of marketed products, as determined by district management.

Districts may choose to contact firms prior to a PAI to determine their readiness for inspection. Any
postponement of a scheduled inspection by the establishment or applicant that may impact on the
agencys time frames for assessing an application should be reported to DMPQ/MAPCB promptly.
Once scheduled, districts should make every effort not to postpone the inspection. Delays in gaining
access to records and information maintained by an establishment during an inspection should be
reported to DMPQ/MAPCB if the delay is expected to impact the agencys time frames.
17
For
international and domestic facilities, if the inspection planning has started and the establishment is not
ready for inspection, a written response should be obtained from the establishment
18
and include: (1) an
explanation of the reason, and (2) when the facility expects to be available. A withhold
recommendation should be entered in EES by the district.

Investigator preparation before a PAI should involve the following actions:
Review the CMC section of application and any related DMFs for the establishment to be
inspected (using the copy filed with home district of the application applicant, also known as the
field copy, or a copy obtained electronically). If possible, review the development report prior
to initiating the inspection.
Contact the chemistry and microbiology reviewer assigned to the application and discuss his/her
findings, if any, and if available, obtain the Reviews from the PAM or chemistry reviewer.
Determine if the reviewer(s) recommends special areas for data audit coverage during the
inspection. Also, contact the reviewer(s) regarding questions on submitted information, such as
test methods, data tables, raw material attributes, or justifications for finished specifications.
This contact may also be made by the PAM or supervisor, depending on district policy. For a
PAI in the Knowledge Transfer Program, the Knowledge Transfer Memorandum (KTM) will
include specific areas of coverage (Refer to Part 2.5 Knowledge Transfer Program).
Contact a CGMP subject matter expert
(http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm096102.htm) with any questions
about the application of CGMP requirements with respect to the subject application or other
broader deviations from the regulations. This contact may also be made by the PAM or
supervisor, depending on district policy.

17
Refusals of access to information should be referred to ORA/OE by existing procedures (e.g., IOM).
18
Obtain the written response from the most responsible individual at the facility or designee.

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 10 of 35
FORM FDA 2438g (electronic-09/2003)


Develop, with other team members, if applicable, an inspection strategy specific to the
establishment and product being inspected that is consistent with this programs objectives and
inspection/audit techniques. Review the history of the firm and FDA-483 observations from
previous inspections.
Contact DMPQ/MAPCB and the PAM regarding any questions about this program.

The field copy of an application is to be an accurate reproduction of the CMC section of an original
application (21 CFR 314.50(l)(3)). This information often contains trade secret or confidential
commercial information and it is essential that the information be carefully protected to prevent its
release outside the agency. Districts are expected to establish a controlled access filing system to
prevent the unauthorized use or release of application information.
3.2 INSPECTION TEAM

PAI inspections should be, whenever possible, a team approach with at least one investigator and one
analyst. Districts are to assign experienced investigators and analysts to perform PAIs. Investigators
and analysts conducting these inspections will be qualified by appropriate training and experience.
19


Districts are encouraged to request CDER application reviewers or a CDER CGMP subject matter
expert to participate in PAIs, particularly those involving a new molecular entity, novel product
formulation or dosage type, novel unit operation or processing method, and/or novel analytical methods
or techniques. Districts are also encouraged to request support directly from other district offices, DFI
national experts, or a member of the Pharmaceutical Inspectorate. Support from such additional sources
may be especially valuable where local resource limitations impact a districts ability to perform the
PAI.

The Center will be available to participate in certain PAIs. Requests and arrangements for CDER staff
participation are facilitated by DMPQ, as follows:
For NDA/ANDAs:
20
CDER staff, usually from the Office of Compliance or the Office of
Pharmaceutical Science (i.e., ONDQA or OGD), send a request to DMPQ to participate as a
supporting member of an inspection team. DMPQ then informs ORA of CDERs inspection
team participants.
For BLAs: PAIs are performed using a team approach by investigators and analysts with
appropriate training and experience and one or more CDER representatives (i.e., MAPCB or
OBP). DMPQ/MAPCB collaborates with OBP and the district to coordinate the inspection team
participants and inspection timing. See Part 2.3.3 Biological Licensing Application (BLA)
Inspection Assignments for discussion of inspection team member roles.


19
For an example of the training curriculum, refer to
http://inside.fda.gov:9003/EmployeeResources/Training/ORAUCourses/default.htm.
20
CDER Office of Compliance, in conjunction with CDER product reviewers and ORA, will schedule on-site method
validation/verification (MV) inspections for selected applications. These MV inspections can be performed concurrently
with the pre-approval inspection, but may be performed at any time.

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 11 of 35
FORM FDA 2438g (electronic-09/2003)

3.3 INSPECTION/AUDIT STRATEGY

There are three primary inspectional objectives of this PAI program. These objectives are:

Objective 1: Readiness for Commercial Manufacturing
Objective 2: Conformance to Application
Objective 3: Data Integrity Audit

If one or more Priority Pre-Approval Inspection Criteria is met and the district recommends that a PAI
should be performed, at least one objective must be addressed during the PAI. Based on the specific
responsibilities of the establishment to be inspected and whether new profile classes are related
21
to
inspected profile classes, the district determines the degree of coverage. The district should use
Attachment C as a guide and apply additional coverage if there are overlaps.

During the PAI, significant issues may be uncovered. This program allows for adjustments to the
inspectional strategy based on inspectional findings.

Some examples of related profiles
21
include:
The establishment has a history of manufacturing immediate release tablets with a high API
content, and the new application product is an immediate release capsule with a high API
content. The API in both instances is highly soluble. In this case, the profiles would be
considered related.
The establishment has a history of manufacturing an extended release tablet product with low
API content, and the new product is an immediate release tablet with high API content. In this
case, the profiles would be considered related.
The establishment has a history of manufacturing non-sterile API used in solid oral dosage drug
products, and the new drug application names this site as manufacturer of a sterile API. In this
case, the profiles would be considered not related.
The establishment has a history of manufacturing immediate release tablet products with a high
API content and the application product is an immediate release tablet with a lower API content.
In this case, the profiles would be considered not related.
The establishment has a history of manufacturing low dose, highly soluble immediate release
tablets and the application product is a low dose, low solubility immediate release tablet. In this
case, the profiles would be considered not related.

3.4 INSPECTION/AUDIT COVERAGE, OBJECTIVES, AND TECHNIQUES

The type and depth of inspection/audit coverage needed to address each PAI objective is described in
this section, along with appropriate regulatory citations.


21
A related profile refers to a manufacturing process or dosage form that is not substantially different from that previously
covered at the establishment. Also see Priority Inspection Criteria (Part 2.2 Assignment of Inspection Decision
Criteria).

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 12 of 35
FORM FDA 2438g (electronic-09/2003)
3.4.1 Summary and Detailed Description of Objectives

Summary of Objectives

Objective 1: Readiness for Commercial Manufacturing
Determine whether the establishment(s) has a quality system that is designed to achieve sufficient
control over the facility and commercial manufacturing operations.
a. Manufacturing and laboratory changes, deviations, and trends relating to the development of new
drug substance and product manufacturing have been adequately evaluated.
b. A sound and appropriate program for sampling, testing, and evaluation of components, in-
process materials, finished products, containers and closures for the purpose of releasing
materials or products has been established, including a robust supplier qualification program.
c. The establishment has sufficient facility and equipment controls in place to prevent
contamination of and by the application product (or API).
d. Adequate procedures exist for batch release, change control, investigating failures, deviations,
complaints, and adverse events; and for reporting this information to FDA, such as field alert
reporting.
e. The feasibility of the proposed commercial process and manufacturing batch record, including
instructions, processing parameters and process control measures, are scientifically and
objectively justified. This objective is linked to the firms process validation program.

Objective 2: Conformance to Application
Verify that the formulation, manufacturing or processing methods, and analytical (or examination)
methods are consistent with descriptions contained in the CMC section of the application for the
biobatch (and other pivotal clinical batches, when applicable), the proposed commercial scale batch, and
the API(s).

Objective 3: Data Integrity Audit
Audit the raw data, hardcopy or electronic, to authenticate the data submitted in the CMC section of the
application. Verify that all relevant data (e.g., stability, biobatch data) were submitted in the CMC
section such that CDER product reviewers can rely on the submitted data as complete and accurate.

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 13 of 35
FORM FDA 2438g (electronic-09/2003)
Detailed Description of Objectives:



Objective 1: Readiness for Manufacturing
Determine whether the establishment(s) has a quality system that is designed to
achieve sufficient control over the facility and commercial manufacturing operations.
Objective 1(a): Manufacturing and laboratory changes, investigations, and trends relating to the
development of new drug substance and product manufacturing demonstrate that the establishment has
appropriately assessed related issues.

Assess that investigations related to the proposed manufacture of the commercial batch have been
appropriately evaluated, including related laboratory investigations, equipment maintenance
investigations, and related manufacturing (e.g., development batch) investigations. Investigative reports
or resultant change control reports for development issues may not always be as comprehensive as
required for marketed finished drug products. Nonetheless, the firm should appropriately document,
record, and objectively assess all development data and information, including but not limited to data
submitted in or generated after the filing of an application. Examples of deviations related to the
application include:
Laboratory issues which occurred during or after method validation, such as:
Unexpected laboratory events, including out-of-specification results and during current
stability testing, in-process testing, and final product testing for the biobatch(es) or
process validation batches
Discrepancies found while conducting the method validation (particularly issues that may
have occurred in its final stages) or technical transfer
Changes in an analytical method after completion of the method validation or technical
transfer due to an inability to use the method as written
Related equipment maintenance and equipment performance issues which could affect the
proposed commercial batch manufacture, such as:
Recent equipment maintenance issues, such as calibration failures, associated with
commercial equipment planned for use in the proposed commercial batch record, to
ensure that equipment is appropriately maintained
CGMP investigations and trending associated with the performance and capability of the
same commercial equipment planned for use in the proposed commercial batch record
CGMP manufacturing investigations (e.g., significant deviations, rejects,
complaints/returns) and trending associated with similarly manufactured marketed drug
product at the establishment

Evaluate these investigations to determine if the establishment is prepared for the proposed commercial
manufacturing process at commercial scale and has the controls in place to detect and/or mitigate the
most likely and significant problems.

Related Regulations for Finished Pharmaceuticals: 211.67(a) addresses equipment maintenance,
cleaning, and sanitization. For the validation/verification of analytical methods, refer to 211.160 through

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 14 of 35
FORM FDA 2438g (electronic-09/2003)
167, and 211.194. Refer to 211.100, 211.192 and 211.198 for regulations relating to product deviations
and investigations.

Related Guidance for APIs: For active pharmaceutical ingredients, refer to ICH Q7 Section 5.2,
Equipment Maintenance and Cleaning, for equipment preventative maintenance, cleaning and
sanitization. For the validation of analytical methods, refer to ICH Q7 Section 12.8, Validation of
Analytical Methods. Refer to ICH Q7 Section 6.5, Batch Production Records, Section 6.7, Batch
Production Record Review, Section 8.1, Production Operations, and Section 15, Complaints and
Recalls, for guidance relating to product investigations.

Objective 1(b): A sound and appropriate program for sampling, testing, and evaluation of components
(including APIs), in-process materials, finished products, containers and closures for purposes of
releasing materials or products has been established.

Review sampling plans and procedures, including those described in batch records, to evaluate the
establishments intended approach to sampling components, in-process, and finished product. Sampling
plans must assure that representative samples are collected and tested/examined as verification of
product quality. The method of selecting samples, number of samples taken, the statistical criteria for
the number of samples taken, the acceptable quality limit and the unacceptable quality limit should be
scientifically-based and appropriate. The extent of experiences with the specific commercial process
should be considered when determining adequacy of sampling plans. Also, areas of criticality or
process vulnerability should receive special attention, as these points in a process generally require more
extensive sampling. For example, a firm may consider the use of PAT (Process Analytical
Technology).
22


For finished dosage establishments purchasing multiple lots of components
23
from an external supplier,
the suppliers variability and the specification criteria should be evaluated. For finished dosage and API
establishments, the firm should establish statistical criteria for component, in-process, and finished
product variability in comparison with the specification criteria. If the district believes that it is
warranted, a for-cause sample of the component may be collected. The laboratory should be contacted
for instructions prior to collection.
24


Related Regulations for Finished Pharmaceuticals: 211.160 requires all sampling plans (and
specifications) to be scientifically-based and appropriate; 211.165 requires sampling plans for finished
product to be in writing and meet appropriate statistical quality control criteria, prior to batch release;
211.110, 211.134, and 211.166 address sampling in the context of in-process materials, labeling, and
stability, respectively. 211.84 requires that all sampling of components, drug product containers, and
closures be representative.


22
Refer to Guidance for Industry: PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and
Quality Assurance, September 2004.
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070305.pdf).
23
The term component includes APIs, excipients, and processing aids (21 CFR 210(b)(3)).
24
Refer to CPGM 7356.002F, Active Pharmaceutical Ingredient (API) Process Inspection.

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 15 of 35
FORM FDA 2438g (electronic-09/2003)
Related Guidance for APIs: For active pharmaceutical ingredients, refer to ICH Q7 Section 11.1,
Laboratory Controls-General Controls, which requires all sampling plans to be scientifically sound and
appropriate and sampling procedures to be in writing. This section also addresses sampling in the
context of raw materials, intermediates, APIs and labels and packaging materials. ICH Q7 Section 7.3,
Sampling and Testing of Incoming Production Materials, requires that samples should be representative
of the batch of material from which they are taken. ICH Q7 Section 11.6, Expiry and Retest Dating,
addresses sampling in the context of performing a retest.

Objective 1(c): The establishment has sufficient facility and equipment controls in place to prevent
contamination of and by the application product (or API).

Coverage of this element is warranted for new construction or facility design, new uses of existing
equipment that pose potential risks (e.g., addition of a highly potent product), or equipment operations
unique to the application under review. Observe the firms operations as you inspect the facility, and
after reviewing blueprints, floor plans, or as-built diagrams of utility systems (such as the purified water
system piping and air handling systems). It should be verified that the establishment has facility,
equipment, and utility system controls in place (or planned) designed to prevent any contamination that
could be deleterious to the specific application product, and to ensure that controls are in place to
prevent cross-contamination of and by the application product.

Inspect new construction intended for the application product, as well as the installation of new
equipment, and any other significant changes to the existing facility or practices relating to
material/personnel flow. Evaluate the establishments proposed compliance with related CGMP
requirements. Special attention should be given to the new product or marketed products which are
highly potent or potentially sensitizing in humans to ensure that the product is not liable to contaminate
existing products in the facility.

Related Regulations for Finished Pharmaceuticals: 211.42 through 211.67 require facility and
equipment controls to prevent contamination and to ensure well-organized operations.

Related Guidance for APIs: For active pharmaceutical ingredients, refer to ICH Q7 Sections 4.1
(Buildings and Facilities - Design and Construction) through 5.2 (Process Equipment Equipment
Maintenance and Cleaning), that require facility and equipment controls to prevent contamination and
to ensure well-organized operations.

Objective 1(d): Adequate procedures exist for change control; investigating failures, deviations,
complaints, and adverse events; conducting recalls; and for reporting this information to FDA.

Review the establishments quality and change procedures and audit the establishments compliance to
their procedures for already marketed product, as appropriate (e.g., sampling of actual failure,
deviation, and complaint investigations, or related adverse drug experience report handling, including
submissions to FDA if required). Note that the regulations for ADE reporting only cover prescription
and application products. If significant problems are found with the establishments existing complaint

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 16 of 35
FORM FDA 2438g (electronic-09/2003)

handling and reporting procedures, the district should consider recommending a directed inspection of
the ADE reporting system under CP7353.001A.
25


Related Regulations for Finished Pharmaceuticals: 211.192 and 211.198 address failure and
complaint investigations; 211.100 addresses deviations from written manufacturing procedures;
314.81(b) (1) is the requirement for submitting a Field Alert Report to FDA. 314.80 addresses ADE
reporting requirements for application products and 310.305 addresses ADE reporting requirements for
marketed prescription drugs for human use without approved new drug applications.

Related Guidance for APIs: For active pharmaceutical ingredients, refer to ICH Q7 Section 6.5, Batch
Production Records, Section 6.7, Batch Production Record Review, Section 8.1, Production Operations,
and Section 15, Complaints and Recalls, for guidance relating to failure and complaint investigations
and/or deviations from written manufacturing procedures.

Objective 1(e): The feasibility of the proposed commercial process and manufacturing batch record,
including instructions, processing parameters and process control measures, are scientifically and
objectively justified. This objective is linked to the firms process validation program.
26


An essential part of the inspection is evaluating the justification for the proposed commercial process
and the manufacturing batch record. As part of the determination of process feasibility, evaluate
development studies and knowledge gained about manufacturing operation vulnerabilities, including the
influence of raw material variability. Determine the purpose of each study performed by the firm. For
example, review studies conducted to establish process controls or process parameters directly related to
the critical quality attributes of the drug product in the application. These may include studies of worst
case or boundary conditions to establish proven acceptable ranges or more sophisticated studies
involving design of experiment or multivariate analysis modeling. Assess the protocols, execution of the
studies, and reliability of the data and conclusions. Investigators should include the inadequacy of data
to support the filed processing approach, or the proposed Master Batch Record provided during
inspection, on the FDA-483.

This evaluation includes a review of the firms scale-up studies. Select and assess studies (e.g. the
scale-up from the biobatch, or pivotal batches, to a larger (interim or full) scale batch). Note that the
firm may need to change the submitted proposed commercial process as scale-up studies are completed
and knowledge is gained. Such changes alone are not a violation and should not be cited as a
deficiency.

Determine and report the firms projected timeline for completion of any additional studies and the
purpose of each study. Though not required at the time of the PAI, a firm may have completed all of the
planned studies which demonstrate that the product can be reliably manufactured at commercial scale
and meet all established limits and operational standards. If the firm states that all process validation
activities necessary to distribute finished drug product, including commercial scale conformance

25
Contact HFD-330, the CDER/OC division responsible for managing the ADE site inspection program for further guidance
in conducting a specific inspection.
26
Applications for aseptic processes, sterilization processes, and certain biotech processes include summaries of process
validation studies. Review the studies and include deficiencies on the FDA-483.

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 17 of 35
FORM FDA 2438g (electronic-09/2003)

Some information review may overlap between ORA and CDER review, as applicants are being
encouraged to share more product and process development information with CDER in accordance with
agency guidance. When such additional information is submitted to the agency prior to inspection,
CDER should make this information available to the pre-approval manager. The field investigator
batches, have been completed, fully audit and assess these studies and conclusions. These will include
studies and experiments to scientifically establish appropriate processing parameters and other
manufacturing instructions for significant processing steps. Additional studies will typically include
commercial scale batches (conformance batches) which made at the site in accordance with the master
batch and production control record using the qualified commercial scale equipment and utilities and
trained production personnel. This study is typically conducted in accordance with a formal protocol
and is intended as a confirmation of the process design before commercial launch. It also establishes a
level of reproducibility and consistency at nominal processing conditions. One of the firms conclusions
from these process validation studies must be that a high level of assurance was achieved in that the
commercial process is capable of consistently delivering quality product meeting its critical quality
attributes. The manufacturer should also plan for sufficient on-going evaluation of the process once
marketing approval has been granted by CDER.

Results and data to the contrary should be fully examined in detail to determine if unresolved
deficiencies exist. Some examples of situations requiring further follow-up include:
Drug product or API does not meet its critical quality attributes and root cause has not been
determined;
Batch records, in-process data and/or process monitoring records reveal an unexpected highly
variable process and the reason is unknown;
Inconsistent execution of the batch record and manufacturing instructions and/or operator work-
arounds (possible indication of poor process design or training);
Control measures do not appear to align with the critical quality attributes or in-process
parameters based on raw development data reviewed during the inspection (i.e., important
parameters or material attributes are not being monitored or measured at the appropriate
frequency);
Sampling and monitoring plans are not justified and/or not sufficient during process qualification
phase (conformance batch manufacturing) based on raw development data reviewed during the
inspection, and sample results are therefore not considered representative of the entire lot; and
Lack of objective scientific data justifying critical process parameters in that the impact on the
material (in-process or final drug) is unknown.

Completed process validation studies for other drug products may be reviewed to evaluate the firms
capabilities and procedures. Interviewing key employees, such as the lead validation engineer, may be
helpful in assessing a firms capability to implement a sound process and control strategy.

Deficiencies in completed process validation studies should be listed on the FDA-483 and the firm
should be advised that appropriate corrections must be completed prior to distribution of the first batch.

When the investigator is unable to provide sufficient process validation coverage, investigators are to
report as such in the inspection report. Districts should cover these processes during the next
surveillance or post-approval inspection.


PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 18 of 35
FORM FDA 2438g (electronic-09/2003)
should incorporate CDER insights into the inspectional evaluation of the proposed commercial process.
Inspection findings regarding the adequacy of the establishments validation plans may be discussed
with DMPQ/MAPCB. The investigator should discuss validation plan issues with the firm and
document the discussion in the EIR for CDER review. When applicable, pertinent observations will be
documented on an FDA-483.

Center reviewing offices will require that certain data be filed to demonstrate that aseptic filling,
sterilization processes, and certain biotech processes are validated before approval is granted. CDER
application reviewers may evaluate this information for some aseptic/sterilization process validation
studies. Review of this summary information is complimented by FDAs on-site inspection of these
operations. Evaluating the adequacy of process validation at a facility is critical to assure
implementation of reproducible processes.

Related Regulations for Finished Pharmaceuticals: 211.100(a) and 211.110 require developing a
well-designed and reproducible process and 211.22 covers the quality units responsibilities. Aseptic
and sterilization processes are required to be validated by 211.113 and 211.42.

Related Guidance for APIs: For active pharmaceutical ingredients, refer to ICH Q7 Sections 12.1
(Validation Policy) through 12.5 (Process Validation Program) for guidance regarding process
validation.




Verify that the formulation, manufacturing or processing methods, and analytical (or
examination) methods are consistent with descriptions contained in the CMC section
of the application for the biobatch (and other pivotal clinical batches, when
applicable), the proposed commercial scale batch, and the API(s).
Objective 2: Conformance to Application
Directly observe the processing lines, directly observe the unit operations, both scale and type
(including aseptic or sterilization processes), and laboratory methods and compare with the description
and/or batch record submitted in the CMC section of the application (or Drug Master File). Audit the
detailed manufacturing records and ensure their consistency with the more general descriptions of the
processing method described in the application. Review the biobatch (and other pivotal clinical lots)
and assess the comparability with the commercial scale process. Compare actual manufacturing records
to the production method described in the application. Contact CDER product reviewers if the
manufacturing of pivotal clinical lots indicates significant changes as this could undermine product
equivalency.

Inspection coverage of analytical methods validation for tests described in the application should
include methods for testing the components, in-process materials, and finished product. The methods
filed should be compared with the methods in actual use in the facility. The validation data and reports
for each method should be reviewed for significant variations from the filed method, including
variations of the drug specifications. Whenever possible, inspect the actual performance of the methods
during the PAI, including laboratory deviations trends and other indications of a lack of method
reliability. Not all methods need to be covered during the PAI. Coverage should be given particularly

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 19 of 35
FORM FDA 2438g (electronic-09/2003)

Inspections and audits under this objective and Objective 3 are to verify factual and contextual integrity
of the information filed in the application. Information that has factual integrity is information that is
original and corresponds directly to that submitted to the agency (e.g., a chromatogram showing a peak
area that directly calculates to an assay value submitted in a data summary sheet in the application).
Information that has contextual integrity is information supported by additional information about the
testing or manufacturing area and related products/processes that does not negate or significantly
challenge the accuracy of the factual information (e.g., a chromatographic sequence that shows all the
assayed samples and which does not reveal failing assay values). Missing records (batch or testing) and
unexplained losses of inventory of components used in production may call into question the contextual
integrity of the information filed in an application.
to those methods/examinations that are unique to the product application under inspection, that are
technically complicated to perform, or that measure a critical quality attribute. Consultation with the
CDER reviewer may be useful in identifying such methods.

When an inspected establishment also has sent samples to FDA for analysis (as described below and in
Part 4), the PAI coverage of this objective should include an audit of the records. Report as soon as
possible any finding that casts doubt on the authenticity of a biobatch or whether any samples from the
biobatch provided to FDA may not actually be from the biobatch identified in the application (as filed in
the CMC section). Records that are considered good candidates for audit when covering this objective
for assessing biobatch integrity may include shipping records, equipment use logs, inventory records,
analytical testing results, and related research/scale-up batch records.

Examine the records of testing the components used in the biobatch and finished product and records
associated with the production of the biobatch for comparison with raw data not submitted in the
application. Consultation with the CDER application reviewer in advance of the inspection is essential
to learn which component attributes, finished product specifications, and processing methods are critical
to establishing the comparability of the biobatch and proposed commercial process. Comparability of
the biobatch and proposed commercial process is important to assure that batches placed on stability for
expiration date determination will be representative of the marketed product.

Verify that the biobatch and stability batch sizes are as reported in the CMC section. For the biobatches
(or pivotal clinical batches), FDA might not always visit the manufacturing establishment at which it
was manufactured. However, it is important to make every effort to at least evaluate the records
associated with the biobatch and understand its manufacturing context.

Coverage of this objective should also include inspection of laboratory methods, including auditing
Research & Development notebooks. Review of inventory records or receiving records of APIs as well
as other components is a way of verifying and evaluating the context and integrity of biobatch and
stability batch information submitted in applications.

Verify the API manufacturer(s) is/are the same as reported in the CMC section and ensure that no other
records indicate a different API manufacturer or quality from that described in the application. If the
application submission is for an API manufacturer other than the primary supplier, the PAI should audit
the data demonstrating the equivalence (e.g., impurity profiles, physical characteristics), including
quality, of the new API manufacturer with the previous manufacturer.


PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 20 of 35
FORM FDA 2438g (electronic-09/2003)

Related Regulations for Finished Pharmaceuticals: 314.50(d)(1)(ii)(b) addresses submission of
biobatches and stability batch information and finished product testing results; see related CGMP
regulations at 211.165, 211.166, and 211.188. Component quality is addressed at 211.80 and 211.84;
production and process control records are to be created and handled in accordance with 211.188;
records are required to be maintained as per 211.180, especially (a) and (b); methods are to be
scientifically sound and validated as per 211.160 through 211.167.

Related Guidance for APIs: For active pharmaceutical ingredients, refer to ICH Q7 Sections 11.1,
Laboratory Controls-General Controls, 11.2, Testing of Intermediates and APIs, 11.5, Stability
Monitoring of APIs, and 6.5, Batch Production Records, that address results of testing, batch records
and stability monitoring of APIs. Component quality is addressed in ICH Q7 Section 6.3, Records of
Raw Materials, Intermediates, API Labeling and Packaging Materials; ICH Q7 Section 6.1,
Documentation System and Specifications, addresses maintenance of records and ICH Q7 Section 12.8,
Validation of Analytical Methods, and Section 11.1, Laboratory Control-General Controls, discuss the
need for analytical methods to be scientifically sound and validated.




Audit the raw data, hardcopy or electronic, to authenticate the data submitted in the
CMC section of the application and to verify that all relevant data were submitted in
the CMC section such that CDER reviewers can rely on the submitted data as
complete and accurate.
Objective 3: Data Integrity Audit
Audit the accuracy and completeness of data in the CMC section for the quality and specifications of
components and finished product, and if submitted, data in the development report. Not every CMC
data summary must be audited to accomplish this objective. The inspection strategy may select key data
sets or randomly select data filed in the application. Generally, data on finished product stability,
dissolution, content uniformity, and API impurity are good candidates for this audit.

The review should include data summary tables. Typically, applicants also submit additional testing for
the finished products performance and physicochemical attributes. During the inspection, compare raw
data, hardcopy or electronic, such as chromatograms, spectrograms, laboratory analyst notebooks, and
additional information from the laboratory with summary data filed in the CMC section. Raw data files
should support a conclusion that the data/information in the application is complete and enables an
objective analysis by reflecting the full range of data/information about the component or finished
product known to the establishment. Examples of a lack of contextual integrity include the failure by
the applicant to scientifically justify non-submission of relevant data, such as aberrant test results or
absences in a submitted chromatographic sequence, suggesting that the application does not fully or
accurately represent the components, process, and finished product.

When data integrity discrepancies are observed, the inspection should identify firm personnel
responsible for application submissions and any decision to include or exclude data from the
application. Determine what actions or inactions contributed to the data integrity problem and whether

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 21 of 35
FORM FDA 2438g (electronic-09/2003)
any corrective actions were or are to be taken. The inspection should determine if data was not
submitted to the application that should have been. For example:
Was there any passing (i.e., within specification or otherwise favorable) data submitted to the
application that was substituted in place of failing data (i.e., out of specification, or
unfavorable) without a sufficient investigation and resolution of the discrepancy?
Did the firm improperly invalidate OOS results, which were therefore not submitted in the
application?

The following are possible indications of data integrity problems:
Alteration of raw, original data and records (e.g., the use of correction fluid)
References to failing bio-studies
Discrepancies (e.g., color, shape, embossing) between biostudy samples and reserve samples
Inconsistencies in manufacturing documentation (e.g., identification of actual equipment used)
and other information in the submission

The following are some examples of data integrity problems that have been previously observed:
Multiple analyses of assay with the same sample without adequate justification
exclusion of specific lots from the stability program to avoid submitting failed results
Reworking or process modifications not adequately justified and appropriately reported
Manipulation of a poorly defined analytical procedure and associated data analysis in order to
obtain passing results
Backdating stability test results to meet the required commitments
Creating acceptable test results without performing the test
Using test results from previous batches to substitute testing for another batch
Determination that a site does not actually manufacture the drug as described in the drug
application or the Drug Master Files (DMFs)
27
referenced therein

In the event that these situations are found, thoroughly document the unreliable data. The district should
follow the agencys Application Integrity Policy (AIP) and consider submitting an AIP recommendation
to CDER/DMPQ. Contact information and procedures can be found on the AIP website.
28


Related Regulations for Finished Pharmaceuticals: 314.50(d) requires that the CMC section include
data and information in sufficient detail to permit the agency to make a knowledgeable judgment about
whether to approve the application. Several CGMP regulations require laboratory data to be collected
and maintained, including 211.160 (General Requirements), 211.165 (Testing and Release for
Distribution), 211.166 (Stability), and 211.167 (Special Testing Requirements).

Related Guidance for APIs: For active pharmaceutical ingredients, several ICH Q7 sections require
laboratory data to be collected and maintained, including Sections 11.1 (Laboratory Controls-General
Controls) through 11.5 (Stability Monitoring of APIs).


27
Inspection team should determine if the operations appears beyond the capability of the firm and review various
production records to determine if batches were truly produced at the site, or are being produced at a subcontracted shadow
factory without FDA knowledge.
28
http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy%20

PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 22 of 35
FORM FDA 2438g (electronic-09/2003)

3.4.2 Investigator Questions and Concerns during an Inspection

Following the principles of ICH guidelines Q8, Q9, and Q10,
29
the agency is implementing a more
integrated approach towards preparing for and conducting inspections. CDER and ORA will
collaborate in order to provide an efficient and effective use of inspectional resources. Questions that
arise during an inspection should normally be directed to the DMPQ/MAPCB contact, who will
coordinate a response within CDER, and the PAM. More specifically:
Questions/concerns about CGMPs, such as facility control, process control, batch release, quality
assurance, or manufacturing procedures should be addressed to DMPQ/MAPCB.
Questions and concerns about submitted product development summaries, product attributes, or
tests method should be directed to the CDER CMC reviewer. The DMPQ/MAPCB contact
should normally be copied or notified. This notification is critical if the issue discussed may
result in an FDA-483 citation.

The CDER application reviewer and the DMPQ/MAPCB contact are listed on the EER.
3.5 INSPECTION REPORTING

After the inspection is conducted, investigators communicate findings primarily through establishment
inspection reports (EIRs). Telephone calls, emails, or EES are often used for timely update of CDER on
problematic findings, to help resolve a specific issue, or ask a question before the EIR is written. When
the inspection reveals a potentially violative CGMP finding, or data integrity issues, the district should
enter a Potential OAI Alert into EES as soon as possible. For data integrity issues, the investigators
report should clearly indicate how the data/information observed on-site differs from the
data/information filed in the application. It is essential that the district notify DMPQ/MAPCB of data
integrity issues promptly in order to trigger an immediate evaluation of the authenticity of the
application.

During an inspection of a manufacturing establishment, the investigator may find that the firm did not
perform all of the process development and therefore does not have all of the development studies
available for inspection. The investigator should collect information about each establishment involved
in the process development, such as name, address, responsible person, and work performed. This
information should be included in the EIR. If the district determines that a follow-up inspection is
warranted, DMPQ/MAPCB should be notified.

Issuance of an FDA-483
Any reportable inspection observations will be issued to the establishment via an FDA-483 consistent
with instructions in the Investigators Operations Manual (IOM). (If the inspection is a concurrent
CGMP surveillance and PAI, the FDA-483 should be organized by CPGM 7356.002, Drug Process
Inspections, and the IOM.)
30
If these types of findings are observed, they should appear on the FDA-
483:

29
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htm
30
The investigator should indicate in the EIR which of the three objectives in Part 2.2.2 of this program pertain to each
observation.

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 23 of 35
FORM FDA 2438g (electronic-09/2003)
Differences from the filed CMC description of the process for the biobatch, stability; or the lack
of an adequate or sufficiently specific proposed commercial batch record to provide for a
reproducible manufacturing operation
Differences in formulations, processing principles, equipment use logs, or discrepancies
in raw material lot reconciliation (inconsistencies in firms records for receipt, inventory,
or use in production)
Missing data related to the data filed in the CMC section
Data or information that was submitted to the application that was potentially unreliable
or misleading and the relevance of this data or information
Unexplained or inappropriate gaps in a chromatographic or analytical sequence
Any instance of an inappropriately disregarded test result, e.g., the result was not clearly
or thoroughly presented within the application
A pattern of inappropriately disregarded test results when such data was of a type not
required to be filed to the application and which reflects on the quality of biobatch,
stability batch, or other drug quality
Data or information not submitted to an application for which the applicant failed to have
adequate justification for the non-submission
Insufficiency, discrepancy, or failing of an analytical method validation program
Lack of suitability of the facility or equipment or manufacturing operations intended for making
the commercial API or finished product to the CGMP regulations
Other specific non-conformance (e.g., conditions, practices, procedures) to the CGMP
regulations

Completion of the Establishment Inspection Report
The investigation team will prepare a narrative establishment inspection report (EIR) per instructions in
the IOM (Chapter 5) in addition to the following: a description of the objectives and specific data and
areas covered, inspection strategy, and citations and discussion with management organized by objective
(described in Part 2 of this program). If the inspection is a concurrent CGMP surveillance and PAI, the
EIR should be organized by CPGM 7356.002, Drug Process Inspections. Any further instructions for
report content or information organization should be addressed by the report. These further instructions
are in specific objectives of this program or in a focused assignment memorandum.

A streamlined EIR may be submitted only for pre-approval inspections where the district recommends
approval. If the district elects the streamlined option, then the EIR may consist of the following
headings:
SUMMARY
This section should be consistent with the IOM SUMMARY.
MANUFACTURING DESIGN/OPERATIONS
This section should include a brief description of the responsibilities of the inspected firm in
relation to the NDA, ANDA, or BLA application. Additionally, a description of the
manufacturing operation and concise summary of coverage provided during the inspection
should be included in this section.
OBJECTIONABLE CONDITIONS AND MANAGEMENTS RESPONSE
This section should be consistent with the IOM OBJECTIONABLE CONDITIONS AND
MANAGEMENTS RESPONSE. It should include the observation and sufficient information

DATE OF ISSUANCE: 4/12/2010 PAGE 24 of 35
FORM FDA 2438g (electronic-09/2003)

PROGRAM 7346.832

so that other agency staff can readily understand the relevance and significance of the
observation to the product application.
ADDITIONAL INFORMATION
This section should include any additional information necessary for review by other agency
staff. The investigator may include a subheading, REQUIRING FURTHER CDER
EVALUATION. Examples include:
Concerns not cited on the FDA-483 but still needing further evaluation by CDER
compliance and review staff. An investigator should report any information that is
potentially important for CDER to know regarding the application. For questions
regarding which findings are appropriate to include on the FDA-483, contact a CDER
DMPQ Subject Contact and the PAM.
A minor discrepancy regarding stated commitments, data, or information in the
Chemistry, Manufacturing, and Controls (CMC) section of an application. Such
information might also compliment or augment an FDA-483 citation.
Any inability to cover the objectives required for the PAI. For example, the district
should report any instance when it is unable to thoroughly inspect due to a change in
establishment or original records maintained at another location need to be inspected. In
such cases, include sufficient information about the additional location and responsible
personnel to facilitate an inspection request (and notify DMPQ/MAPCB by phone).
Any inability to inspect the biobatch facility or equipment (e.g., the investigator finds that
batches were made at other establishments or the facility or equipment no longer exists).
Inappropriate handling of any samples sent to the designated FDA laboratory by the
establishment.

For data integrity issues, the EIR should identify who was responsible for the submission (including
omitted data) and how the responsible personnel handled the questionable data. The EIR should also
describe the establishments actions and/or inactions surrounding the data integrity problem and
document the establishments actions or inactions to resolve the questionable data results. Any
promised corrective actions provided during the inspection should be included in the EIR so that they
may be considered in the decision about the application.

All completed EIRs should be submitted to DMPQ/MAPCB within 30 business days after the close of
the inspection (even in instances when no FDA-483 was issued) to ensure further evaluation before a
decision is made on the application. If the 30 business day time frame occurs after the district goal date,
the district must notify DMPQ/MAPCB as soon as possible. Refer to FIELD REPORTING
REQUIREMENTS (Inspectional). An accelerated review by DMPQ/MAPCB will then be performed
and all other available information will be considered, such as discussions with the investigator/PAM or
comments on the firms FDA-483 response.

Note that profile class codes are only comprehensively updated after a CGMP surveillance inspection.
For an inspection that only covered pre-approval issues where the firm is distributing product, only the
profile class code covered during the pre-approval inspection should be updated.

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 25 of 35
FORM FDA 2438g (electronic-09/2003)
3.6 SAMPLE COLLECTION OR SAMPLE SUBMISSION REQUESTS
31


Investigators should not routinely collect samples during the pre-approval inspection. The following
types of samples are associated with the drug application review process:
Method Validation/Verification Samples, which are used to evaluate new drug application
methods in FDA laboratories.
Profile Innovator and Applicant Drug Samples (not collected at the Biotest Laboratory), which
are used to establish the profile of the ANDA product and ensure the integrity of the
demonstration of bioequivalence.
Biobatch Facility Samples, which are used to verify that the products used for the ANDA
bioequivalence testing are representative of the authentic innovator and applicant products.

If an official sample is collected at an establishment, use PAC 46832B/46832C (NDAs) or
52832B/52843C (ANDAs) to report sample collection time.

3.6.1 Method validation/verification samples are now requested directly from the establishment at the
request of the agencys Method Validation/Verification coordinators and sent to the agency laboratory.
There are two coordinators for Method Validation Samples. For NDAs, CDER is the lead coordinator
of samples. Please contact DMPQ/MAPCB for the contact information of the current NDA Method
Validations Coordinator. For ANDAs, ORA is the lead coordinator. Please contact ORA's Division of
Field Science for the contact information of the ANDA Methods Validation Coordinator.

Investigators may collect for-cause method validation/verification samples only after approval from
their PAM or supervisor and concurrence by DMPQ, who will check with the other program
coordinators to verify that samples have not already been collected and can be analyzed.

3.6.2 Profile Samples are used to support the integrity of the bioequivalence study, demonstrating
equivalency of a generic product with the innovator product and providing a reference for post-
marketing surveillance samples. These were formerly called forensic or fingerprinting samples.
This sample involves the collection and comparison of the innovator drug and the generic drug biobatch
batch samples. Each solid oral dosage application is a potential candidate for profile sample collection
and analysis.

Profile samples are collected on a for-cause basis only. A determination to collect a profile sample for-
cause may be initiated by DMPQ/MAPCB, an FDA laboratory, or the district. If DMPQ/MAPCB
determines that a profile sample should be collected, MAPCB will issue a for-cause assignment to the
district. If districts and FDA laboratories determine that a for-cause sample should be collected, they
should contact DMPQ/MAPCB for issuance of the assignment. After a for-cause sample is requested,
ORA/Division of Field Sciences (or the servicing laboratory
32
) will coordinate the analysis. Any
collection of a profile sample should be documented in the EIR.


31
For permit information regarding sampled derived from animal sourced material, refer to the Investigations Operations
Manual (IOM) Chapter 3.2.1.6. For the collection of narcotic and controlled prescription drugs, refer to the IOM Chapter
4.2.5.3.
32
Refer to Attachment B.

DATE OF ISSUANCE: 4/12/2010 PAGE 26 of 35
FORM FDA 2438g (electronic-09/2003)


PROGRAM 7346.832

For profile samples at API facilities, investigators should only collect samples upon specific request for
collection from the Forensic Chemistry Center (FCC). Such requests will be made through DFI. This
process is described in CPGM 7356.002F, Active Pharmaceutical Ingredient (API) Process Inspection,
Part IV.

Profile samples from non-US locations: A request for collection of profile samples located from non-
US locations is to be sent to DFI for coordination with inspection scheduling. Sample collection of
APIs from non-US locations is described at CPGM 7356.002F, Part IV. Samples shipped to the US are
to be accompanied by the US Customs Letter (see ATTACHMENT B-3).

3.6.3 Biotest facility samples are analyzed to verify that the products used for the ANDA
bioequivalence testing are representative of the authentic innovator and applicant products. These are
samples of the innovator and applicant products used by and collected from the biotest facility to
determine bioequivalence. These products are compared with the profile sample collected from the
applicant and the innovator sample collected from the innovator or marketplace. Refer to Attachment B
for instructions and CPGM 7348.001, In Vivo Bioequivalence.

The collection of the biotest sample is initiated when the profile laboratory makes a request to the home
district where the biotest facility is located. A list of products from A/NDAs and biotest facilities is
compiled by the profile laboratory and submitted to the district in the first week of each quarter. The
districts are requested to collect the samples within thirty business days of receipt of the assignment.
Additionally, CDER/Office of Compliance/Division of Scientific Investigations may request the
collection of a biotest profile sample via assignment.

Requests for collection of biotest samples located in foreign countries will be sent to the Division of
Field Investigations (DFI) for coordination with foreign inspection scheduling.

For questions during collection or submission, contact the Forensic Chemistry Center (Central,
Southwest, and Pacific Regions) or the Northeast Laboratory (Northeast and Southwest Regions) (refer
to Part 6 References).

DATE OF ISSUANCE: 4/12/2010 PAGE 27 of 35
FORM FDA 2438g (electronic-09/2003)


PROGRAM 7346.832

PART IV - ANALYTICAL

The sampling assignment will provide instructions to the laboratory regarding the type of analyses, the
reporting codes, and the storage of any remaining portion of the sample. Refer to Attachment B for
typical instructions.

Completed analytical worksheets will be maintained by the analyzing laboratory. The analyzing
laboratory will notify CDER/Division of Manufacturing and Product Quality (DMPQ), the review
division and the home district via e-mail of class 3 (adverse) findings. Report adverse findings by
sending a copy of the worksheet to the following three recipients:
The home district of the applicant;
CDER Office of Compliance, Division of Manufacturing & Product Quality (HFD-320); and
CDER Review Division to which the application is assigned for review.

If warranted, district offices will recommend an appropriate regulatory action to CDER Office of
Compliance (HFD-300).

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 28 of 35
FORM FDA 2438g (electronic-09/2003)
PART V - REGULATORY/ADMINISTRATIVE STRATEGY

Districts are asked to either perform an inspection for a specific establishment named in a specific
application or to provide a recommendation of site acceptability. At the conclusion of a pre-approval
inspection, the district needs to make a recommendation to approve or withhold approval based on
outcome of the establishment inspection.

District directors or their designee should enter a Recommend Approval in EES when none of the
criteria for withholding apply. District directors or their designee should enter a Recommend
Withholding Approval in EES when there are significant findings
33
or when there is any other
information that, in the districts judgment, warrants further evaluation by CDER before recommending
approval of the application.

Findings and deficiencies that should result in a district recommendation to withhold approval include:
1. Significant data integrity problems including misrepresented data or other conditions related to
the submission batch
2. Serious CGMP concerns with the manufacture of a biobatch or demonstration batch, such as a
changes to formulation or processing that may cause FDA to question the integrity of the
bioequivalence study
3. Significant differences between the process used for pivotal clinical batches and the NDA
submission batch
4. Lack of complete manufacturing and control instructions in the master production record or lack
of data to support those instructions
5. Lack of capacity to manufacture the drug product or the API (if the firm is not ready for an
inspection, the district should request a letter from the establishment)
6. Failure to meet application commitments
7. Full scale process validation studies were attempted prior to the PAI, demonstrate that the
process is not under control and establishment is not making appropriate changes
8. For products for which full scale summary information is provided in the application,
34

establishment has not demonstrated that the product can be reliably manufactured at commercial
scale and meet its critical quality attributes
9. Incomplete or unsuccessful method validation or verification
10. Records for pivotal clinical or submission batches do not clearly identify equipment or
processing parameters used
11. Significant failures related to the stability study that raise questions about the stability of the
product or API
12. Failure to report adverse findings or failing test data without appropriate justification

Depending on district policy, the district PAM or compliance officer is encouraged to discuss any
findings that are material to the district's recommendation with the firms management to ensure that the
final district recommendation is based on accurate information and understood in its proper context.

33
This includes instances where the district is recommending a Warning Letter due to overall CGMP non-compliance that
significantly impacts marketed products.
34
Products may include aseptic processes, sterilization processes, and certain biotech processes.

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 29 of 35
FORM FDA 2438g (electronic-09/2003)
If the district recommends withholding approval due to findings that apply to commercially marketed
product, districts should investigate further and consider recommending enforcement action. A systems-
based CGMP surveillance inspection pursuant to CPGM 7356.002 will be added if due by work plan or
if findings from the PAI raise concerns that indicate the need for coverage of marketed products, as
determined by district management.

The district director or designee will send a District Notification Letter to the inspected establishment
with the recommendation to approve or withhold approval. The district will submit the report (EIR,
FACTS endorsement, attachments, and exhibits) to DMPQ/MAPCB within the time frame based on the
FIELD REPORTING REQUIREMENTS (Inspectional) section. For cases that are not sent
concurrently to the Domestic Case Management Branch with a regulatory enforcement
recommendation, DMPQ/MAPCB will review and enter a recommendation into EES within 20 business
days of receiving the report. This will be followed by a memorandum to the review division with a copy
sent to the district. This recommendation will include an overall decision and a conclusion regarding
each deficiency contributing to the withhold recommendation. If a firms response and district
evaluation is submitted after the MAPCB review has been entered in EES, MAPCB and the district may
then update the recommendation in EES. A subsequent recommendation to approve the application is
contingent upon satisfactory correction of the findings that led to the initial withhold recommendation.
The district has the discretion of confirming such correction by an on-site visit.

Process Validation

Districts will not recommend withholding approval of applications based on lack of complete
commercial scale process validation (see also CPG 7132c.08, Process Validation Requirements for
Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. ).
35
While
sufficient process validation studies may not have been completed at the time of the pre-approval
inspection in order to release product, the firm must achieve a high degree of assurance that the
manufacturing process consistently produces product which meets all of its quality attributes prior to
distribution. A warning letter, seizure or injunction should be recommended on finding that the firm
distributed product prior to demonstrating that the manufacturing process was in a state of control.

Warning Letter

If the firm does not market FDA regulated products, Warning Letters are not appropriate as regulatory
action to a pre-approval inspection.

If the firm markets other FDA regulated product and the pre-approval deficiencies apply to marketed
drug product, a Warning Letter may be recommended by the district for the pre-approval inspection.
These letters should include the following statement: Due to the deficiencies listed on the attached
FDA-483 and with the support of CDER Office of Compliance, we are recommending that ANDA []
not be approved.

35
Refer to the Draft Guidance for Industry: Process Validation: General Principles and Practices (draft dated November
2008). Note that this statement does not apply to applications that include completed process validation studies, such as
aseptic, sterile, and biotech areas.

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 30 of 35
FORM FDA 2438g (electronic-09/2003)
PART VI - REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS

6.1 REFERENCES

6.1.1 Code of Federal Regulations, Title 21
Part 210 and 211: Current Good Manufacturing Practice in Manufacturing, Processing,
Packing, or Holding of Drugs and Current Good Manufacturing Practice for Finished
Pharmaceuticals
Part 310: New Drugs
Part 314: New Drug Applications

6.1.2 Code of Federal Regulations, Title 29
Part 1910: OSHA Hazard Communications Standards

6.1.3 Compliance Program Guidance Manuals
CPGM 7356.002: Drug Manufacturing Inspections
CPGM 7356.002F: Active Pharmaceutical Ingredients
CPGM 7356.002M: Inspections of Licensed Biological Therapeutic Drug Products
CPGM 7348.001: In-Vivo Bioequivalence Inspections

6.1.4 United States Pharmacopeia

6.1.5 Guidance and Guidelines
Guideline on Preparation of Investigational New Drug Products, March 1991
CPG Sec. 490.100 Process Validation Requirements for Drug Products and Active
Pharmaceutical Ingredients subject to Pre-Market Approval, March 2004
Guideline on General Principles of Process Validation, May 1987
Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing
Practice, September 2004
Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Q7 ICH),
September 2001
Pharmaceutical Development and Annex (Q8(R2) -- ICH), August 2009
Quality Risk Management (Q9 -- ICH), November 2005
Pharmaceutical Quality System (Q10 -- ICH), June 2008
Format and Content of the Chemistry, Manufacturing and Controls Section of an
Application, February 1987
Submitting Documentation for the Manufacturing of and Controls for Drug Products,
February 1987
Submitting Documentation for the Stability of Human Drugs and Biologics, February 1987
Guidance for Industry: Bioanalytical Method Validation, May 2001
Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for
Pharmaceutical Production, October 2006
Guidance for Industry: Analytical Procedure and Methods Validation

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 31 of 35
FORM FDA 2438g (electronic-09/2003)
Chemistry, Manufacturing, and Controls Documentation (DRAFT), August 2000
Reviewer Guidance: Validation of Chromatographic Methods, November 1994
Guidance for Industry: Process Validation: General Principles and Practices (DRAFT),
November 2008

6.1.6 Agency Inspection Procedures and References
Guide to Inspection of Pharmaceutical Quality Control Laboratories, July 1993
Guide to Inspection of Microbiological Pharmaceutical Quality Control Laboratories, July
1993
Guide to Inspection of Validation of Cleaning Processes, July 1993
Guide to Inspection of Lyophilization of Parenterals, July 1993
Guide to Inspection of High Purity Water Systems, July 1993
Guide to Inspection of Foreign Pharmaceutical Manufacturing Plants, September 1993
GWQAP Manual, Profile System, Chapter 15
Regulatory Procedures Manual, Chapters 7 and 8
Staff Manual Guide 4831.3, Validation of NDA Analytical Methods
MAPP 5310.2, Drafting, Circulating, and Signing Chemistry, Manufacturing, and Controls
Letters, 10/27/1998
MAPP 5310.6, Procedures for Assessing Chemistry, Manufacturing, and Controls Data in
NDA Annual Reports, 10/10/2002
Investigations Operations Manual
Chapter 3.2.1.6, Federal Agency Interaction (Animal Plant Health Inspection
Service/USDA (APHIS))
Chapter 4.2.5.3, Dealer Relations (Narcotic and Controlled Rx Drugs)

6.1.7 Prescription Drug User Fee Act (PDUFA)
6.2 ATTACHMENTS
Attachment A Roles of Investigator and CDER Product Reviewers by Specific Area of CMC
Review and Assessment
Attachment B Profile Sampling Instructions
Attachment C Recommended Scope of Coverage for a Priority Pre-Approval Inspection

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 32 of 35
FORM FDA 2438g (electronic-09/2003)
6.3 CONTACTS

6.3.1 Center for Drug Evaluation and Research

CGMP program and related enforcement/compliance issues
Office of Compliance, Division of Manufacturing and Product Quality


Subject Contacts (including program contact names and phone numbers):
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm096102.htm

Laboratories:
Division of Pharmaceutical Analysis (HFD-920)
1114 Market St., Room 1002
St. Louis, MO 63101
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm136991.htm

New Drug Applications:
Contact Offices for NDAs (General):
Application Receipt and Filing Questions:
Business Information Staff (HFD-141)
Application File Management Questions:
The Division of Records Management (HFD-143)
Office of Generic Drugs (HFD-600)
Questions about NDA and ANDA content: Refer to contacts in EES listed in Contact
folder of the application in question

Bioequivalence Study Issues
Office of Compliance, Division of Scientific Investigations (HFD-48)
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090085.htm



Biological Licensing Applications
Refer to CPGM 7356.002M for contact information
http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/default.htm
6.3.2 Office of Regulatory Affairs/Office of Regional Operations
Division of Field Investigations (HFC-130)
Domestic Operations Branch
International Operations Branch
Division of Field Science (HFC-140)
Northeast Regional Laboratories
Forensic Chemistry Center
ORA Program Coordinators
See IOM for updated references
http://www.fda.gov/ICECI/Inspections/IOM/ucm124008.htm

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 33 of 35
FORM FDA 2438g (electronic-09/2003)
6.4 ACRONYMS

ADE: Adverse Drug Experience
ANDA: Abbreviated New Drug Application
API: Active Pharmaceutical Ingredient
BLA: Biologic Licensing Application
BMT: Biotechnology Manufacturing Team (CDER/OC/DMPQ/MAPCB/BMT)
CMC: Chemistry, Manufacturing, and Controls
DMPQ: Division of Manufacturing and Product Quality (CDER/OC/DMPQ)
EER: Establishment Evaluation Request
EES: Establishment Evaluation System
EIR: Establishment Inspection Report
FEI: Firm Establishment Inventory Number
IB: Investigational Branch
ICH: International Conference on Harmonization
ICB: International Compliance Branch (CDER/OC/DMPQ/MAPCB/ICB)
IND: Investigational New Drug
MAPCB: Manufacturing Assessment and Pre-Approval Compliance Branch
(CDER/OC/DMPQ/MAPCB)
NDA: New Drug Application
NDMS: New Drug Microbiology Staff (CDER/OPS/NDMS)
NGDMT: New and Generic Drug Manufacturing Team (CDER/OC/DMPQ/MAPCB/NGDMT)
OBP: Office of Biotechnology Products (CDER/OPS/OBP)
OGD: Office of Generic Drugs (CDER/OPS/OGD)
ONDQA: Office of New Drug and Quality Assessment (CDER/OPS/ONDQA)
OPS: Office of Pharmaceutical Science (CDER/OPS)
OTR: Office of Testing and Research (CDER/OPS/OTR)
PAI: Pre-Approval Inspection
PAM: Pre-Approval Program Manager



PROGRAM 7346.832

DATE OF ISSUANCE: 4/12/2010 PAGE 34 of 35
FORM FDA 2438g (electronic-09/2003)

PART VII - CENTER RESPONSIBILITIES

FDA launched a major initiative, Pharmaceutical CGMP for the 21
st
Century A Risk-Based
Approach, in August 2002. One of the specific goals of the initiative was to ensure that the product
review program and the inspection program operate in a coordinated and synergistic manner. Based on
this goal, CDER organizational components have had several meetings to determine how best to
implement a strategy which can ensure this goal is accomplished in CDER.
In implementing this strategy, CDER focused on the main principles of the initiative which included
comprehensive modern quality systems and risk management approaches for regulating pharmaceutical
quality. The new framework established under the initiative is currently being applied to the review,
compliance, and inspectional components of FDA regulation and is intended to encourage the adoption
of modern and innovative manufacturing technologies. The overarching philosophy articulated in both
the CGMP initiative and in a robust modern quality systems is: Quality should be built into the product,
and testing alone cannot be relied on to ensure product quality.
This strategy will encompass a more synergistic approach to the assessment and the pre-approval
inspection programs. The manufacturer has the primary responsibility for quality control and quality
assurance. Hence, it is critical that a robust quality system incorporate a scientific and risk based
approach to change control to allow the manufacturer to manage appropriate post-approval changes
without the need for regulatory submission. Accordingly, FDA will be reviewing regulations and
drafting guidance to ensure that the agency empowers manufacturers to continually improve
manufacturing processes without unnecessary regulatory oversight.
The CGMP initiative not only modernized the agencys regulatory approaches to pharmaceutical
CGMPs, it also served as the catalyst for establishing a modern product assessment system. The final
report of the initiative issued in September 2004 outlined the establishment of a new risk-based
pharmaceutical quality assessment system (PQAS) to replace the CMC review process. This new
system (1) allows FDA to adopt a scientific risk-based approach to setting product specifications, (2)
facilitates innovation and continual improvement throughout the product lifecycle, and (3) enables FDA
to provide regulatory flexibility to post-approval changes based on scientific knowledge and
understanding of the product and manufacturing process.
Accordingly, FDA pre-approval scrutiny will reflect a manufacturer's demonstration of a meaningful
understanding of the product and its manufacturing process. FDA will also implement steps to reduce
post-approval filing burden for manufacturing changes for all drug products. FDAs revisions to
regulations governing post-approval submissions will be modified to ensure that the agency facilitates
continual improvements without undue regulatory scrutiny for both newly approved product and legacy
products. FDAs objective is to shift responsibility to a manufacturers quality system to evaluate
changes to the manufacturing operation through internal formal change control systems.
Integrated Review-Inspection System

In order to ensure a scientific and risk-based approach to regulatory decision-making, it is essential for
there to be a continuum in the regulatory process from review through inspection. An important part of
this continuum is communication. It is imperative that the Center product reviewers and the field
investigators work together as a team and communicate directly. CDER Office of Compliance will

PROGRAM 7346.832


DATE OF ISSUANCE: 4/12/2010 PAGE 35 of 35
FORM FDA 2438g (electronic-09/2003)
facilitate the interaction between product reviewers and field Investigators to promote direct
communication between product reviewers and field investigators. In addition, CDER compliance
officers will participate, as needed, as members of the review inspection team. The reviewer will assess
the firms identification of critical product quality attributes and critical product performance parameters
proposed by the applicant and the findings will be shared with the investigator prior to the PAI to
facilitate a scientific risk-based inspection. Product attributes and performance parameters should be
limited to those that are surrogates for clinical performance.

In order to facilitate review of proposed product specifications, the Center reviewers may participate on
the pre-approval inspection team. The Center product reviewers may also be called on to provide
information about a product prior to or during a PAI and CGMP inspections in coordination with the
CDER Office of Compliance. When application review raises manufacturing issues that need to be
addressed at the firm, that information will be highlighted in the inspection request (e.g., via the
Knowledge Transfer Program; in the inspection assignment for BLAs). Following the PAI, all findings
will be evaluated by the Office of Compliance for a decision on site acceptance. This integrated review-
inspection system will facilitate a true scientific risk-based regulatory oversight, enhance Center-Field
communication, ensure product quality, expedite the approval process, and provide an atmosphere of
collaboration and trust.



PROGRAM 7346.832 ATTACHMENT A


DATE OF ISSUANCE: 4/12/2010 PAGE 1 of 3
FORM FDA 2438g (electronic-09/2003)
ATTACHMENT A - NEW DRUG APPLICATIONS AND ABBREVIATED NEW DRUG APPLICATIONS

Responsibilities of on-site inspection and CDER review by Specific Area of CMC Review and Assessment:

AREA SITE INSPECTION RESPONSIBILITIES CDER REVIEW RESPONSIBILITIES
1. All sites -- Raw data review
Audits integrity of data submitted in application and
related data not submitted in the application. **This
responsibility applies to all sections in this table.**
Reviews descriptions and submitted data.

For all sites that include
Biobatch and/or Stability Lot
Manufacture
Evaluates establishments compliance with CGMP.
Audits biobatch and stability batch data for authenticity.
Specifically, reviews raw data and records from batches
used for pivotal clinical, bioavailability, bioequivalence,
and stability studies.
Reviews data submitted in the application
with respect to components, batch
composition and general manufacturing/
control instructions, approves product
specifications.
2.
API Manufacturing
(including micronization)
Evaluates CGMP compliance of the manufacturer. Refer
to ICH Q7, CGMP Guidance for Active Pharmaceutical
Ingredients, and CPGM 7356.002F.
Reviews API manufacturing process
descriptions and data submitted in the
application or a properly referenced Type II
Drug Master File.
3.
Novel excipient manufacturing
(e.g., novel manufacturing, non-
compendial excipients used in
specialized dosage forms &
special delivery systems)
Novel excipient manufacturers are not routinely inspected,
unless requested by CDER or District Office (DO) For-
Cause assignment. If inspected, evaluates if
manufacturing and laboratory capabilities are in
compliance with CGMP. For finished dosage form
manufacturers: evaluates adequacy of component vendor
qualification, ongoing QC testing regimen, and
storage/handling practices and procedures.
Reviews manufacturing process descriptions
and data associated with novel excipients,
including starting materials, key
intermediates, reagents and solvents, and
approves excipient specifications.
4. Intermediates
Establishments manufacturing only intermediates are not
routinely inspected unless requested by CDER or DO
assignment. If inspected, refer to ICH Q7 for guidance.
Reviews intermediate specifications as part of
API review.
5. Manufacturing Facility Controls
Evaluates establishments compliance with CGMP (e.g.,
environmental monitoring, equipment, facilities and
processes, and operating procedures and practices).
--

PROGRAM 7346.832 ATTACHMENT A


DATE OF ISSUANCE: 4/12/2010 PAGE 2 of 3
FORM FDA 2438g (electronic-09/2003)
AREA SITE INSPECTION RESPONSIBILITIES CDER REVIEW RESPONSIBILITIES
6.
Control of Components (raw
materials)
When inspecting finished dosage form manufacturer:
evaluates adequacy of finished dosage form
manufacturers component vendor qualification and
ongoing QC testing regimen. For raw material vendors:
assesses manufacturing and laboratory capabilities in
accordance with CGMP. Also, assesses storage/handling
and sampling procedures at dosage, API, and excipient
manufacturers.
Reviews the raw material test methods and
approves specifications (acceptance criteria)
for adequacy and appropriateness.
7.
Manufacturing and Controls of
Finished Product
Evaluates establishments compliance with CGMP.
Determines if facility can meet commitments made in the
application. Assesses equipment and facilities, as well as
details of the manufacturing process and control (batch
records).
Reviews and approves drug product
formulation (components and composition),
test method selection, and specifications.
8. Container/Closure System(s)
Evaluates that container closure systems are consistent
with what is submitted in the application. This
responsibility includes ensuring an ongoing QC program
for incoming containers/closures, and evaluating
investigations of any adverse data on container-closure
system.
Reviews submitted information and approves
the container/closure system for both the API
and drug product.
9.
Packaging and Labeling
Processes and Controls
Evaluates that establishments packaging and labeling
operations comply with CGMP.
Reviews adequacy of packaging and labeling
materials, test method selection, and
acceptance criteria.
10.
Finished Product Test Methods
and Acceptance Criteria
Evaluates integrity of data submitted in application and
reports questionable data to CDER/OC. Assesses whether
laboratory method has been verified to operate under the
specific laboratorys conditions of use. See Part 3
Objective 2. Inspection also assesses whether proper
laboratory controls exist.
Reviews and approves product test method
selection and acceptance criteria submitted in
applications.
11. Stability, Finished Product
Evaluates establishments compliance with CGMPs and
determines whether or not stability test procedures,
method validation, and stability data are consistent with
what is stated in the application.
Reviews stability protocol and data submitted
in support of drug product expiration dating
period and API retest or expiration dating
period. Approves specifications.

PROGRAM 7346.832 ATTACHMENT A


DATE OF ISSUANCE: 4/12/2010 PAGE 3 of 3
FORM FDA 2438g (electronic-09/2003)
AREA SITE INSPECTION RESPONSIBILITIES CDER REVIEW RESPONSIBILITIES
12.
Comparison of Pilot-Scale
Batches and Proposed
Commercial Scale Batches
Compares manufacturing processes for pilot (small scale)
batches with the proposed commercial size batches.
Reports significant manufacturing process changes and
differences in equipment operating principles.
Determines if differences between pilot scale
and commercial batch processes affect the
safety and effectiveness of the product.
13.
Sterility Assurance (if the
finished product purports to be
sterile)
Evaluates the state of control of the process as well as the
manufacturing procedures, practices, and controls
employed to assure sterility of the product.
Performs an initial review of a description of
the sterility assurance program to support the
sterilization validation, e.g., filtration efficacy
validation. Reviews the adequacy of critical
process parameters for the sterilization cycle.
Approves specifications, test method
selection, and sterilization method.
14.
Parametric Release for Moist
Heat Terminal Sterilization
Evaluates establishments CGMP compliance. Emphasizes
state of control and past performance of the terminal
sterilization process. Ensures adequate preventative
maintenance program, facility, equipment and quality
system (investigations and batch release). See CPG
460.800.
Reviews current and proposed terminal
sterilization cycle and acceptance criteria, and
approves specification changes that allows for
measured critical process parameters to act as
a surrogate for sterility testing.



PROGRAM 7346.832 ATTACHMENT B


DATE OF ISSUANCE: 4/12/2010 PAGE 1 of 8
FORM FDA 2438g (electronic-09/2003)
ATTACHMENT B - PRE-APPROVAL SAMPLING

B-1: Description of Pre-Approval Sampling Assignments and Laboratory Analysis
B-2: Example of Sample Collection Instructions for Solid Oral Dosage Finished Product Manufacturers
B-3: Example of Sample Collection Instructions for Independent Biotest Laboratories for Solid Oral
Dosage Products
B-4: U.S. Customs Letter
B-5: Example of memorandum soliciting innovator sample




PROGRAM 7346.832 ATTACHMENT B-1

DATE OF ISSUANCE: 4/12/2010 PAGE 2 of 8
FORM FDA 2438g (electronic-09/2003)

ATTACHMENT B-1 - DESCRIPTION OF PRE-APPROVAL SAMPLING ASSIGNMENTS
AND LABORATORY ANALYSIS

B-1.1 Profile Samples

Profile samples are used to support the integrity of the bioequivalence study, demonstrating equivalency
of a generic product with the innovator product and providing a reference for post-marketing
surveillance samples. These were formerly called forensic or fingerprinting samples. This sample
involves the collection and comparison of the innovator drug and the generic drug biobatch batch
samples. Each solid oral dosage application is a potential candidate for profile sample collection and
analysis.

The following types of samples of drug products may be collected for profile analysis under this
program:
Innovator product
Generic biobatch, collected from the generic drug applicant and/or the independent biotest
laboratory
API samples collected from the source(s) intended for use in the dosage form pending approval

Each of these types of samples has a different method of collection and submission to the FDA
analyzing laboratory, as described in this Attachment.

B-1.2 Instructions if a Profile Sample is Requested from the Manufacturing Establishment

If a for-cause assignment is issued to collect a profile sample at a finished dosage manufacturer, the
investigator will either collect the sample or provide instructions to the manufacturer to collect and
submit the sample to the FDA laboratory.

If the manufacturer is collecting the sample, the profile sample should be submitted to the servicing
FDA laboratory prior to the end of the inspection, so as to permit the investigator to verify that the
sample was submitted. The investigator will state in the EIR how the sample was prepared and
submitted to FDA. For example, the EIR statement might read, Profile sample submission instructions
were provided to [insert name of firm official] on [insert date instructions were provided]. I verified via
[method of verification, e.g., affirmation by firm official or documented receipt from shipped package]
that a profile sample for A/NDA [12-345] was submitted to [insert name of receiving laboratory] on
[insert date of submission].

For questions about the profile sample submission, contact the Forensic Chemistry Center (Central,
Southwest, and Pacific Regions) or Northeast Regional Laboratory (Northeast and Southeast Regions)
(refer to Part 6 Program Contacts).

For innovator samples, the designated analyzing laboratory will typically request the sample directly
from the manufacturer. However, CDER or the field laboratory may request that an investigator collect
an official innovator sample from the innovator or marketplace. Sample sizes and instructions will be
provided by the designated analyzing laboratory. Refer to Attachment B-5 for an example of
memorandum soliciting innovator samples.
DATE OF ISSUANCE: 4/12/2010 PAGE 3 of 8
FORM FDA 2438g (electronic-09/2003)


PROGRAM 7346.832 ATTACHMENT B-1

If an official sample is collected at an establishment, use PAC 46832B (NDAs) or 52832B (ANDAs) to
report sample collection time.

B-1.3 Profile Sample Analysis

FDAs profile sample analysis is used to benchmark the formulation of the drug product biobatch as the
authentic formulation reported in the application. These benchmark analytical results are electronically
stored for future reference to resolve questions of authenticity, either by a future drug product marketed
by the applicant or other entity. This type of profile sample analysis is only performed on solid oral
dosage forms.

One method of ensuring authenticity of the applicants formulation is to determine if substitution
occurred during bioequivalence or bioavailability studies. To rule out substitution or other possible
unscrupulous manipulations, the FDA laboratory compares analytical results of the profile samples
collected under this program against analytical results of the biotest samples collected under CPGM
7348.001.

B-1.3.1 Instructions to FDA Laboratories performing Profile Analysis

FDAs analyzing laboratory coordinates the comparison of the analytical results of the innovator and
generic samples, collected from the biotest laboratory, with the results of the innovator and generic
profile samples collected under this program. In particular, FDAs laboratory compares the biobatch
sample collected from the applicant against the biobatch sample collected from the biotest facility and
compares the innovator sample collected from the innovator or marketplace against the innovator
sample collected from the biotest lab. The two biobatch samples should match, as should the two
innovator samples. The biobatch and innovator samples should be unique and distinctive and capable of
being differentiated based on composition, fingerprint, or physical appearance.

B-1.3.2 Analytical Testing Instructions

Sample profiles, or fingerprints, are analyzed at the Forensic Chemistry Center (Central, Southwest,
and Pacific Regions), Northeast Regional Laboratory (Northeast and Southeast Regions), and DPA. The
type of analysis should be determined prior to the collection of the sample. It may include the following
types of analysis:

An analytical technique capable of assessing the overall makeup of the submission batch and
detecting later changes by comparison with analytical results of future samples of the applicants
product or a suspected counterfeit.
Pantone color identifications to determine any discrepancies of solid oral dosage forms. This
analysis includes photographs of the top, bottom, side and end views of the capsule or tablet,
including any distinctive markings or fragmentation or picking of tablet or capsule shells. In order
to document standard photographic conditions, the Pantone color guide that matches the outer
surface of the tablet or capsule should be included in all photographs. These photographs will be
filed for later use in comparisons with innovator product or with later batches of the applicant
product.

PROGRAM 7346.832 ATTACHMENT B-1

DATE OF ISSUANCE: 4/12/2010 PAGE 4 of 8
FORM FDA 2438g (electronic-09/2003)



Note that innovator and applicant profile and biotest samples are analyzed using the same analytical
method.

B-1.3.3 Profile Sample Analysis Reporting

Report time for sample analysis in FACTS under PAC 46832B for NDA Profile Sample
Collection/Analysis and under PAC 52832B for ANDA Profile Sample Collection/Analysis.

B-1.3.4 Storage of the Profile Sample

The laboratory will maintain any remaining portion of the sample in reserve for at least five years for
future comparisons. Additionally, the laboratory will manage computer storage of the profile and
biotest sample results for the following purposes:
Comparison with samples collected after marketing approval, including samples collected under
the CDER drug surveillance sampling program (CPGM 7356.008) in order to detect unreported
changes
Comparisons of future questionable drug products, either marketed by another manufacturer or
in pending applications by the applicant

PROGRAM 7346.832 ATTACHMENT B-2


DATE OF ISSUANCE: 4/12/2010 PAGE 5 of 8
FORM FDA 2438g (electronic-09/2003)
ATTACHMENT B-2 - EXAMPLE OF SAMPLE COLLECTION INSTRUCTIONS FOR SOLID
ORAL DOSAGE FINISHED PRODUCT MANUFACTURERS

The following checklist is for the collection and submission of samples to the FDA laboratory.

1. Assemble the following:
a. Finished product 20 units
b. Active pharmaceutical ingredients 2-5 grams
c. Excipients 2 grams (e.g., lactose, starch, microcrystalline cellulose)
d. Manufacturing instructions for the lot collected (biobatch batch record)
e. Certificates of analysis for active and excipients

i. Use of plastic spatulas is recommended. Submit an unused plastic spatula with the
sample.

ii. Use necessary precautions to protect the samples from contamination by human hands,
dust, etc. Only opaque, non-reactive, small plastic or glass containers are appropriate as
sample containers. Plastic bags are not recommended due to leakage. Precaution and
care should be taken when shipping amber glass bottles to ensure breakage will not
occur.

iii. Each container should be labeled with the name of the ingredient, the expiry date, the lot
number, the complete name of your establishment, and the application number and name
of product.

iv. For an international establishment shipping the sample through US Customs, a US
Customs Letter should accompany the sample. Refer to Attachment B-4 for a sample
letter.

2. A Material Safety Data sheet for each ingredient, especially for hazardous substances.

3. A copy of the biobatch batch record and a flowchart and brief description of the manufacturing
process. Also, include the impurity test methods and impurity limits for each API. Per FDA
requirements, this information will be kept completely confidential.

4. The complete firm/company name, contact information (telephone number, fax number, email),
and contact person at the manufacturing establishment.

Please indicate on the shipping documents that the sample is intended for laboratory testing and
has no commercial value.

PROGRAM 7346.832 ATTACHMENT B-3


DATE OF ISSUANCE: 4/12/2010 PAGE 6 of 8
FORM FDA 2438g (electronic-09/2003)
ATTACHMENT B-3 - EXAMPLE OF SAMPLE COLLECTION INSTRUCTIONS FOR
INDEPENDENT BIOTEST LABORATORIES FOR SOLID ORAL DOSAGE PRODUCTS

The following checklist is for the collection and submission of samples to the FDA laboratory.

1. Assemble the following:
a. Applicant biotest product no fewer than 6 tablets/capsules

b. Innovator product used during bioequivalence testing no fewer than 6 tablets/capsules

i. Use of plastic spatulas is recommended. Submit an unused plastic spatula with the
sample.

ii. Use necessary precautions to protect the samples from contamination by human hands,
dust, etc. Only opaque, non-reactive, small plastic or glass containers are appropriate as
sample containers. Plastic bags are not recommended due to leakage. Precaution and
care should be taken when shipping amber glass bottles to ensure breakage will not
occur.

iii. Each container should be labeled with the application number and name, manufacturers
batch number, date of receipt by the biotest laboratory, and any number assigned by the
biotest facility.

iv. For an international establishment shipping the sample through US Customs, a US
Customs Letter should accompany the sample. Refer to Attachment B-4 for a sample
letter.

2. A copy of the biobatch batch record and a flowchart and brief description of the manufacturing
process. Also, include the impurity test methods and impurity limits for each API. Per FDA
requirements, this information will be kept completely confidential.

3. The complete firm/company name, contact information (telephone number, fax number, email),
and contact person at the manufacturing facility.

Please indicate on the shipping documents that the sample is intended for laboratory testing and
has no commercial value.

PROGRAM 7346.832 ATTACHMENT B-4


DATE OF ISSUANCE: 4/12/2010 PAGE 7 of 8
FORM FDA 2438g (electronic-09/2003)
ATTACHMENT B-4 - U.S. CUSTOMS LETTER


DEPARTMENT OF HEALTH AND HUMAN SERVICES



Food and Drug Administration
Division of Field Science
Rockville, MD 20857
Telephone:
Fax:

Date:

U.S. Customs Inspector:

The U.S. Food and Drug Administration (FDA) has requested samples of (PRODUCT) from (Company
Name) for the analysis by (Designated Laboratory). We are testing the product in connection with a (n
Abbreviated) New Drug Application that has been filed with the Food and Drug Administration.

For this reason we are requesting that the U.S. Customs Inspector refrain from opening the immediate
container. If for some reason the immediate container must be opened, please contact my office so that
the sample can be opened in the presence of an FDA representative.

If there are any questions regarding this request, please contact me by telephone at (Telephone) or by
fax (Fax Number).



Sincerely,

District Director/DFI Drugs Coordinator/DFS

PROGRAM 7346.832 ATTACHMENT B-5


DATE OF ISSUANCE: 4/12/2010 PAGE 8 of 8
FORM FDA 2438g (electronic-09/2003)
ATTACHMENT B-5 - EXAMPLE OF MEMORANDUM SOLICITING INNOVATOR SAMPLE


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
Laboratory Name
Laboratory address
Telephone:
Fax:




Date:

Firms Name & Address

Dear Sir/Madam:

The U.S. Food and Drug Administration (FDA) will be performing profile studies on (Product Name
and Strength) in connection with an Abbreviated New Drug Application that has been filed. These tests
will enable the FDA to determine that bioequivalence testing was performed appropriately. In order to
rule out substitution or other manipulations, we would like a sample of your product, which was used
for comparison in this testing.

In order to perform the necessary studies, we ask that you provide us with a sample of not less than 20
units each, along with the batch formulas for the lots being sent.

Please forward these materials within ten days of receipt of this letter via express or overnight mail to:

Laboratory Name and Address
Attn: Contact Name

Thank you in advance for your cooperation. Please do not hesitate to call or fax if you have any
questions. You may contact me directly by telephone at (Telephone) or by fax (Fax Number).


Sincerely,

Laboratory Contact/Coordinator/Director

PROGRAM 7346.832 ATTACHMENT C


DATE OF ISSUANCE: 4/12/2010 PAGE 1 of 2
FORM FDA 2438g (electronic-09/2003)
ATTACHMENT C - RECOMMENDED SCOPE OF COVERAGE FOR A PRIORITY PRE-
APPROVAL INSPECTION

If one or more Priority Pre-Approval Inspection Criteria is met and the district recommends that a PAI
should be performed, at least one objective must be addressed during the PAI. Based on the specific
responsibilities of the establishment to be inspected and the difference between profile classes, the
district determines the degree of coverage. The district should use this Attachment as a guide and apply
additional coverage if there are overlaps.

For example, if an establishment has a recently updated and acceptable profile status related to the
application product yet has a history that lends concern from VAI findings, the district should cover
Objectives 1, 2, and 3. As a second example, if an establishment only meets the Priority criteria because
the application product is a new molecular entity and the profile status is related and recently updated,
coverage of Objectives 1 and 3 is recommended. Finally, in the event that the API is derived from
animal tissues, this high risk situation merits coverage of all three objectives.

PROGRAM 7346.832 ATTACHMENT C

















DATE OF ISSUANCE: 4/12/2010 PAGE 2 of 2
FORM FDA 2438g (electronic-09/2003)
Figure 1: Recommended Scope of Coverage for a Priority Pre-Approval Inspection

Establishment History and Profile Status Recommended Objectives***
Does Establishment have FDA inspection
history?
No
1, 2, 3


















Yes
Establishment has an unacceptable profile
status or a history of VAI findings that
raises concern
Yes
1, 2, 3
No
Establishment's latest profile status
history is acceptable, but the new profile
is unrelated*
Yes
Establishment profile status not
recently** updated
Yes
1a, 1b,
1e, 2, 3
Establishment profile status
recently** updated
Yes
1a, 1b,
1e, 2, 3
Establishment has no history of
being named in an application
and/or the applicant has no history
of filing
Yes
1, 2, 3
Establishment profile status not
recently** updated
Establishment profile status
recently** updated
Establishment has no history of
being named in an application
and/or the applicant has no history
of filing
Establishment manufactures only
APIs or excipients
Submitted data was found to be
questionable by CDER product
reviewer and/or indicates the need
for a data integrity audit
*Refer to the Related Profiles section in Part 3.3, Inspection/Audit Strategy.
**The term recently is used consistently with Priority Pre-Approval Criteria #9, in that the profile has been updated within
the past 2 years (or 3 years for control laboratories and 4 years for packaging and labeling).
***When Objective 1 is listed, all subparts should be included.
Establishment profile status is acceptable,
has a history of acceptable inspections,
and profile is related* to the application
product

1, 2, 3
1a, 1e,
2, 3
1a, 1e, 3
2, 3
2, 3
Yes
No
Yes
Yes
Yes
Yes
Yes