FOOD AND DRUG ADMINISTRATION  
COMPLIANCE PROGRAM   PROGRAM   7348.004  
 
  CHAPTER 48    BIORESEARCH MONITORING 
 
SUBJECT:   IMPLEMENTATION  DATE:  
Procedures for FDA Staff:  In Vivo Bioavailability/Bioequivalence   05/01/2018  
Studies (Analytical)  
DATA REPORTING  
PRODUCT  CODES   PRODUCT/ASSIGNMENT  CODES  
Product coding not required for   48004A BIOANALYTICAL IN-VIVO BA/BE  
biopharmaceutical establishments   (ANDAS)  
  48004N BIOANALYTICAL IN-VIVO BA/BE  
(NDAS  AND BLAS)  
48004P BIOANALYTICAL PEPFAR ANDA 
BA/BE  
48004Q BIOANALYTICAL PEPFAR NDA BA/BE  
48004B BIOANALYTICAL BA/BE   
BIOSIMILARS  
FIELD REPORTING REQUIREMENTS:  
To meet  the  established  deadline(s) issued by the Center, notify the Center via  the e-mail address 
identified in the assignment when Establishment Inspection Report (EIR),  EIR attachments, exhibits,  
or any related correspondence  is  available in OSAR.  
 
All EIRs should be completed in accordance with Field Management Directive (FMD) No. 86, 
Establishment Inspection Report  Inspection Conclusions  and District Decisions 
(http://www.fda.gov/downloads/ICECI/Inspections/FieldManagementDirectives/UCM382035.pdf). 
 
When Form  FDA 483, Inspectional  Observations (483)  is issued, a copy should be sent to the  
Center contact, and the Centers email mailbox, generally no later  than 3 business days following the  
close of the  inspection, or upon return from an international inspection.  
 
   
 
Date of Issuance:  05/01/2018   Page 1  of  35    
  PROGRAM   7348.004  
   
Contents  
PART I    BACKGROUND  ...............................................................................................  5 
 
1.   Scope of Document ..................................................................................................... 5 
 
2.   Introduction .................................................................................................................. 5 
 
3.   History and Application of Bioavailability (BA) and Bioequivalence (BE) Regulations . 5 
 
PART II   IMPLEMENTATION ........................................................................................ 7 
 
  Objectives .................................................................................................................... 7 
 
  Regulated Industry:  Analytical Sites ........................................................................... 7 
 
A.   Sponsors ................................................................................................................... 7 
 
B.   Contract Research Organizations (CROs) ................................................................ 7 
 
  Inspection Assignments ............................................................................................... 7 
 
A.   Scheduling an Inspection .......................................................................................... 8 
 
B.   Announced vs. Unannounced Inspections ................................................................ 8 
 
C.   Roles and Responsibilities While Conducting the Inspection .................................... 9 
 
PART III    INSPECTIONAL  ..........................................................................................  10  

  Organization  .............................................................................................................. 10  

A.   Responsible Persons .............................................................................................. 10  

B.   Personnel ................................................................................................................ 10  

C.   Analytical Site and Equipment  ................................................................................ 10  

  Study Administration and Responsibility .................................................................... 11  

A.   Master List of BA/BE or Other Studies .................................................................... 11  

B.   Organizing Information from Selected Studies for Audit  ......................................... 11  

  Stability ...................................................................................................................... 12  

A.   Sample Receipt  ...................................................................................................... 12  

B.   Sample Handling  .................................................................................................... 13  

C.   Storage Chambers    Freezers and Cold Rooms .................................................... 13  

D.   General Considerations for Stability Experiments (Where Applicable)  ................... 14  

E.   Long-term Stability .................................................................................................. 14  

F.   Freeze and Thaw Stability  ...................................................................................... 15  

G.   Benchtop Matrix Stability  ........................................................................................ 15  

H.   Processed Sample Stability and Autosampler Stability ........................................... 15  

I.   Stock Solution Stability  ........................................................................................... 15  

 
Date of Issuance:  05/01/2018   Page 2  of  35
    
  PROGRAM   7348.004  
   
J.	   Reference Standard Storage and Procurement ...................................................... 15  

  Methodology .............................................................................................................. 16  

A.   Precision and Accuracy  .......................................................................................... 16  

B.   Recovery ................................................................................................................. 16  

C.   Calibration Curve .................................................................................................... 17  

D.   Lower  Limit  of Quantification ................................................................................... 17  

E.   Upper Limit of  Quantification ................................................................................... 17  

F.   Selectivity/Specificity ............................................................................................... 17  

G.   Matrix Effect ............................................................................................................ 18  

H.   Dilutions .................................................................................................................. 18  

I.   Carryover ................................................................................................................ 19  

J.	   Partial Validation ..................................................................................................... 19  

  Documentation  .......................................................................................................... 19  

A.   Laboratory Instruments ........................................................................................... 19  

B.   Source Data ............................................................................................................ 20  

C.   Re-integration/Re-analysis ...................................................................................... 20  

D.   Audit Trails .............................................................................................................. 20  

E.   Data Security  .......................................................................................................... 21  

F.   Data Reporting ........................................................................................................ 21  

G. 	  Communications with Internal and External  Parties ................................................ 22  

  Analysis of Study Samples ........................................................................................ 22  

A.   System Suitability.................................................................................................... 22  

B.   Run Acceptance  ..................................................................................................... 22  

C.   Improper Processing ............................................................................................... 23  

D.   Shift in Retention Time of Analyte/IS  ...................................................................... 23  

E.   Re-injection of Study  Samples ................................................................................ 23  

F.   IS Variability/Drift  .................................................................................................... 24  

G.   PK Anomalies  ......................................................................................................... 24  

H.   Incurred sample reanalysis (ISR) ............................................................................ 24  

PART IV   ANALYTICAL  ..............................................................................................  25  

PART V   REGULATORY/ADMINISTRATIVE STRATEGY  .........................................  26  

PART VI    REFERENCES, ATTACHMENTS,  AND PROGRAM CONTACTS  .............  27  

 
Date of Issuance:  05/01/2018 	  Page 3  of  35
    
  PROGRAM   7348.004  
   
  FDA Guidance Documents and References .............................................................. 27  

A.   FDA Laws  ............................................................................................................... 27  

B.   Relevant 21 CFRs................................................................................................... 27  

C.   Relevant FDA Guidelines, Guidance Documents, and Inspection Guides .............. 27  

2.   Program Contacts ...................................................................................................... 28  

PART VII    CENTER AND ORA HQ RESPONSIBILITIES  ...........................................  30  

  CDER Review Divisions    OND, OGD, OPQ, and  OCP ............................................ 30  

  OSIS .......................................................................................................................... 30  

  OSI  ............................................................................................................................ 31  

  Office of Regulatory Affairs (ORA) ............................................................................. 31  

ATTACHMENT A   Abbreviations and Acronyms List  ..................................................  32  

 
 
 
Date of Issuance:  05/01/2018   Page 4  of  35    
  PROGRAM   7348.004  
   
PART I    BACKGROUND 
 
1.   Scope of Document  
 
This  Compliance Program (CP)1 outlines procedures for FDA investigators who inspect domestic and 
international  sites  to ensure that the  analytical portions of  in vivo bioavailability (BA), bioequivalence  
(BE), pharmacokinetic (PK), or pharmacodynamic (PD)  studies2 submitted to the Center for Drug 
Evaluation and Research (CDER) are conducted using the highest laboratory standards and in 
accordance with applicable regulations.   As stated, this CP is designed  to  ensure studies are 
conducted using the highest laboratory standards and in accordance  with applicable regulations. The  
acceptability of any study mentioned herein, including any repeat study, will be determined during 
application  review.  
 
This CP replaces the analytical portions of the prior CP, 7348.001, Chapter 48  Bioresearch  
Monitoring Human Drugs titled, In Vivo Bioequivalence, issued in September 1999. 
 
2.   Introduction  
 
New Drug Applications (NDAs)  may rely on comparative BA studies or  BE studies to demonstrate 
that a new  drug formulation or a new route of administration of a drug has the same pharmacokinetic 
properties3  as a  reference,  marketed product. Abbreviated New Drug Applications (ANDAs) rely on 
BE studies to demonstrate that a generic version of a drug has the same circulatory properties as  an  
approved, reference listed drug (RLD). Regulations pertaining to these studies  are principally found 
under 21 CFR 320. 
 
In vivo  BA/BE studies  with PK endpoints  generally consist  of two distinct components, clinical  and 
analytical.  The clinical  component involves administration of drug products to subjects, monitoring 
of subject safety during the study, and collection of biological samples (usually plasma samples) for  
safety and PK assessments.   The analytical component involves  processing the biological samples 
collected during the clinical phase of the study to measure drug concentrations present  in those  
samples.  Subsequently, the measured drug concentrations are used to generate PK parameters, which 
serve as the basis for determining BA or  BE  between test  and reference formulations.   
 
In addition to BA and BE studies with PK endpoints, this program covers inspections  of  BE studies 
with  PD endpoints, as these  studies rely on PD measurements  other  than systemic drug or metabolite 
concentrations. PD endpoint assignments will usually contain a clinical and analytical  inspection. 
Examples of  PD endpoint studies  are  clinical studies that measure drug effects on surrogate markers  
(e.g., skin blanching, forced expiratory volume (FEV1)), or immunogenic responses.  
  
This CP covers the  analytical component of  BA  and BE  studies only.  History  and Application of 
 
Bioavailability  (BA)  and  Bioequivalence  (BE)  Regulations  

                                                 
1  This  document  represents  procedures  for  the Compliance Program. 
 
2  For  the  purpose  of  this  CP,  all  study  types  listed  fall  under  the  general  term  BA/BE  studies. 
 
3  Pharmacokinetic  properties  in the  context  of  this  CP  are  defined as  the  area  under  the  concentration  curve (AUC)  and the 

peak  or  maximum  concentration  (Cmax).  

 
Date of Issuance:  05/01/2018   Page 5  of  35    
  PROGRAM   7348.004  
   
On January 7, 1977, FDA issued final regulations in part 320 (21 CFR 320) establishing definitions  
and requirements for BA and BE studies (42 FR 1624).  The regulations outline the requirements for  
the submission of  in vivo BA and BE  data as  a condition of marketing a new formulation for an NDA  
(e.g., for a new drug under regulatory review or  an already marketed drug product[s]), or a generic  
drug formulation submitted under  an ANDA.  21 CFR 320 also provides  information concerning the  
design and conduct of BA and BE studies.  Additionally, the  FDA has published draft guidance for  
NDAs/Investigational New Drugs (INDs) (Bioavailability and Bioequivalence Studies Submitted in 
NDAs or INDs -General Considerations  (March 2014)4  and ANDAs  (Bioequivalence Studies with 
Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application, 
(December 2013)5 . 
 
FDA also has published a guidance for industry on Bioanalytical  Method Validation (May 2001)6, 
which informs sponsors on bioanalytical method validation.  A draft update was published in 
September  2013 and it  is currently undergoing revisions7. 
 
     
   
                                                 
4  http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm389370.pdf  
5  http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm377465.pdf   
6  http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070107.pdf   
7  http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm368107.pdf  
 
 
Date of Issuance:  05/01/2018   Page 6  of  35    
  PROGRAM   7348.004  
   
PART II    IMPLEMENTATION  
  Objectives  
 
The objectives of the in vivo  BA/BE Bioresearch  Monitoring  (BIMO) Program are:  
 
 	  To ensure  the  protection of  the rights, safety, and welfare of human subjects participating in 
studies;  
 
 	  To ensure the quality, integrity  and validity  of clinical, analytical, and  statistical  data from 
BA/BE studies; and  
 
   To ensure compliance with applicable FDA regulations and to identify significant deviations.  
 
  Regulated Industry:   Analytical Sites  
   
This  section describes the regulated industry as  it applies to individuals, laboratories, organizations, 
and corporations who conduct bioanalytical operations  to generate data from BA/BE studies used in 
support of drug applications.  
 
A.  Sponsors  
 
Organizations or corporations  that initiate  BA or  BE studies and have been identified by FDA  
through receipt of an investigational  exemption or  marketing application.  Sponsors  can use 
their  own facilities to analyze biological  samples and generate pharmacodynamic or  
pharmacokinetic data in support of their own BA/BE studies or use an alternative, such as the  
ones listed in section B.  
 
B.  Contract Research Organizations (CROs)  
 
Individuals, organizations or corporations that have a  contractual agreement with a sponsor  to 
perform one or more obligations of a sponsor including, but not limited to, analysis of  
biological samples, generation of pharmacodynamic/pharmacokinetic data, statistical  
assessment of BA/BE, and drafting of the study report.  Examples of CROs include academic  
laboratories, clinical sites, and analytical  sites.  
 
  Inspection Assignments  
 
The CDER  Office of Translational Sciences  (OTS)/Office of Study Integrity  and Surveillance (OSIS) 
receives  requests for BA/BE study inspections directly from CDER offices that  review  drug  
applications.   Directed inspections may also originate from complainants and  informants  (self
identified or anonymously) from the public and private sectors, who may  report potential fraud at a  
site, or a sites deviations from  practices that protect subject  safety and data integrity. Additionally, 
OSIS  monitors incoming drug applications that include BA or BE studies to identify sites for  
surveillance inspections.  All assignments will be  generated by the Center and issued to Office of  
 
Date of Issuance:  05/01/2018 	  Page 7  of  35    
  PROGRAM   7348.004  
   
Regulatory  Affairs (ORA) for completion. Center staff  may accompany ORA investigators during 
inspections  as subject matter experts.  
 
A.  Scheduling an Inspection  
 
ORA and OSIS staff together or OSIS  staff alone8may conduct BA/BE analytical  inspections.  
FDA staff  may also participate in BA/BE inspections with non-FDA international regulators,  
domestically and internationally. For  domestic and international inspections, Center  staff  
should collaborate  with  ORA  field investigators to schedule inspections of analytical  sites.  
 
The primary objective of the inspection is to evaluate the overall quality, integrity  and validity  
of analytical data at the site. Except  when inspections are otherwise directed, routine BA/BE  
analytical inspections require approximately one week of on-site  inspection time.  An  
amended assignment  may be issued from the Center  to add studies to the  original assignment  
prior  to the  start of the inspection.  Extension of the inspection is not anticipated, rather, the  
time spent conducting  the inspection  will be apportioned across all  studies to assess 
compliance. When multiple studies are included in the assignment, there is no expectation that  
all aspects of study records for all studies identified in the  assignment will be examined. A  
thorough reconciliation of all study records is not  necessary, except in rare instances when 
those directions are indicated in the assignment. 
 
In the event  that serious deficiencies are noted, the ORA  investigators supervisor and/or 
Center point of contact (POC) should be informed to determine to what extent  the scope of the  
inspection should be expanded. 
 
B.  Announced vs. Unannounced Inspections  
 
Domestic inspections are usually not announced prior  to arriving at the site.  Any instructions  
for announcing the inspection will be in the  inspection assignment.  Should ORA investigators  
have questions on whether or not  to announce the  inspection, the center POC should be  
contacted.  
 
International inspections  will normally be announced prior to arriving at the site, due to the  
logistics  involved in conducting these inspections. If an unannounced international  inspection 
is required,  the Center will contact ORA Office of Bioresearch  Monitoring Operations  
(OBIMO) headquarters  (HQ)  at  ORAHQ BIMO  Inspection POC  to discuss.  
 
Announcement of inspection to the site should not include application numbers, identity of  
test  article, study numbers, and/or study sponsors.   
 
                                                 
8  Memorandum  of  Understanding  between  the Center  for  Drug  Evaluation  and  Research  and  the Office of  Regulatory  
Affairs,  effective  February 6,  2017  to February 6,  2018.  
 
Date of Issuance:  05/01/2018   Page 8  of  35    
  PROGRAM   7348.004  
   
C.   Roles and Responsibilities While Conducting the Inspection  
On inspections that  include both Center and ORA staff, the  ORA investigator  is the Team  
Lead in accordance with  the Investigations Operation Manual  (IOM) Section 5.1.2.5. 
  
On inspections that  include both the  Center and the  ORA staff, the Center staff will:  
  
 	  Provide on-site support  to the ORA investigator, including coordinating or conducting  
parts of the  inspection, as needed.  
 
 	  Provide expert  technical guidance, advice, information, and support to ORA investigators  
prior  to, during, and after inspection, including contacting the  ORA investigator when new  
information becomes available.  
 
 	  Attend daily wrap up meetings held by the inspection Team Lead to discuss findings and 
status of the  inspection and ensure appropriate evidence is  collected to document observed 
violations when warranted. 
 
 	  Draft appropriate sections of the EIR and provide to the ORA investigator within  agreed  
upon timeframes.  
 
The Center  may arrange for a consultative teleconference immediately prior to  an inspection  if, for  
example, there is new information concerning the site or the  studies assigned, or there  are data  
concerns not previously conveyed to ORA in the  assignment.  
   
 
Date of Issuance:  05/01/2018 	  Page 9  of  35    
  PROGRAM   7348.004  
   
PART III    INSPECTIONAL 
 
This section  outlines the  minimum components to be included in an analytical BA/BE inspection6. 
This is not  meant to be an all-inclusive list of components that may be covered during an inspection.  
Deviations from the  minimum components should be documented with appropriate  explanation in the  
EIR.  
 
  Organization  
A.  Responsible Persons  
 
 	  Identify the most  responsible  persons at the site and those who had leading roles at the 
time the studies to be inspected were conducted.   
 
 	  Document the names, titles, duties, roles and responsibilities of these individuals in the  
EIR as per IOM 5.10.4.3.7. 
 
   Issue the  Form FDA 482 and Form FDA 483 to the most responsible person at the  site. 
B.  Personnel  
 
 	  Obtain a  copy of the organizational  chart  that details the most  responsible person  at the  
site  and displays the reporting  relationship of all staff.   If no  organizational chart is  
available, obtain full details/information regarding reporting lines of  management up to 
the Chief Executive Officer (CEO)/President and document  in the EIR.  
 
   Identify the  person who should receive official correspondence. 
 
	   For inspections that  involve a CRO, determine if there is a written agreement between the 
sponsor and the CRO that describes  the study responsibilities the CRO will perform, and 
collect a copy if available.  
 
	   Obtain the name, address, and email of third party entities, if any, who might be  
responsible for any aspect of the study, such as storage of the test  article and reference  
product reserve samples.    
C.   Analytical Site and Equipment  
 
 	  Evaluate the site layout  and consider  whether there are logistical issues that could impede 
site activities.  
 
 	  Evaluate  whether  the analytical site has adequate  space to enable work flow, conduct of  
operations, and separation of functions. 
 
   Inspect  and  evaluate the area where test articles and biological samples are stored.  
 
 
Date of Issuance:  05/01/2018 	  Page 10  of  35    
  PROGRAM   7348.004  
   
 	  Document in the EIR conditions in areas where sample processing and storage occur  that  
may compromise study integrity, and/or contribute to the potential for sample loss, mix-
up, contamination/degradation, etc, during storage, processing, and transit.  
 
	   Determine whether the site has a standard operating procedure (SOP) index and whether  
the current versions of SOPs are readily available in locations where relevant processes 
are conducted. 
 
	   Determine whether calibration and maintenance of equipment are performed in 
accordance with SOPs on scales,  centrifuges, refrigerators,  and other critical equipment  
used  during analysis.  
 
  Study  Administration and Responsibility  
 
A. 	 Master List of BA/BE or  Other Studies  
 
Although sites  are not required  to maintain a list of BA/BE studies, FDA investigators should  
request  a list when possible.  Most  sites maintain a master list  of previously completed and 
ongoing BA/BE or other studies.  The master list  may contain information about these  studies  
including, but not limited to:  
 
	   Study titles  and number  
	   Dates of study conduct  
	   Dates of sample analysis  
	   Drug products tested  
	   Number of subjects analyzed  
	   Methodology and sample processing techniques, amendments, SOPs, etc.  
	   Analytical staff involved 
	   Study Sponsors  
	   Information as to whether the study was conducted to support a drug application submitted 
to a regulatory agency (e.g., FDA, European Medicine Agency (EMA), etc.).  
	   Drug expiration dating period (shelf-life)  
 
B. 	 Organizing Information from  Selected Studies for Audit  
 
To  facilitate the inspection, FDA investigators may request  analytical  run summary tables.  The  
following information may be included in the  tables:  
 
 	  Master stock solution used for preparing quality  control (QCs) samples and calibrators  
 	  Expiration dates  of reference material  
 	  Analytical run number  
 	  Subjects included  
 	  Nominal calibrators  included (single or duplicates)  
 	  Failed calibrators  
 	  Nominal QCs included  (replicates)  
 
Date of Issuance:  05/01/2018 	  Page 11  of  35    
  PROGRAM   7348.004  
   
 	  Failed QCs  
   Analysts involved  
	   Date of extraction  
   Date of instrumental acquisition  
	   Identification of instruments  
   Run  results (Pass/Fail)  
   Comments (Reinjections if any, reason for failure, etc.)  
   Incurred sample reanalysis (ISR) outcome  
   General stability considerations  
 
  Stability  
 
During, or after a clinical study concludes, the analytical  site  will receive  biological samples for 
analysis.  Shipping may  occur via courier, or by hand delivery if the clinical unit and analytical  site  
are located in the same building.  The analytical  site  should store the study samples from sample 
receipt through sample analysis under stability conditions  established during method validation.  
 
A.  Sample Receipt  
 
 	  Evaluate the sample receiving area for adequate space, workflow patterns, and separation 
of operations.  Determine if the area has sufficient space for  receiving, processing, and  
logging samples.  
 
 	  Review the  sample shipment records and determine the  condition of the  samples upon 
arrival to the analytical site.  Check for temperature excursions during sample shipment  
and determine if the site has an SOP for handling shipping temperature excursions. 
Identify if any thawed samples  were documented, and verify if the site conducted an 
assessment to evaluate if thawing affected the validity of data  originating from these  
particular samples.   
 
 	  Review any documentation showing sample tracking.  Sample tracking documentation 
may include, but it is not limited to, logbooks, Laboratory Information Management  
System (LIMS), temperature logs, and shipping receipts.  
 
 	  Request  the SOP  for sample receipt and assess if the analytical  site  has designated a 
receiving area and person(s) responsible for receiving the samples.  Interview the sample 
custodian, if possible.  Ask him or her  to describe the process of sample receipt, visual  
inspection, and sample reconciliation.  
 
   Request  the sample  accountability log.  
 
 	  Verify the  number of samples received by the analytical  site  against the list of samples 
shipped.  
 
 
Date of Issuance:  05/01/2018 	  Page 12  of  35    
  PROGRAM   7348.004  
   
 	  Verify the number of samples analyzed by the analytical  site  against the list of samples 
shipped.  
 
 	  Inquire  if the analytical site  had queries regarding specific study samples.  If so, determine 
how those queries were resolved between the analytical  and  clinical  sites after receiving 
the samples.  
 
 	  Request a copy of written SOPs  for  receipt of study samples during the hours of normal  
operation, and outside of those hours, such as on weekends and holidays.  
 
B. 	 Sample Handling  
 
 	  Determine if the analytical site  handled samples according  to  the specifications listed  in  
the study protocol.  Request the study protocol to  review  this information, if needed.  
 
 	  If the analytes are  light sensitive, verify that the site  implemented appropriate measures 
(e.g., vapor  lamps, amber vials, etc.) to protect study samples from light exposure.  Verify  
if similar procedures are  also implemented for reference standards, if appropriate.  
 
 	  Request documentation that shows the number  of  instances when samples were retrieved  
from and stored again in the storage chambers.  Compare this  documentation with the  
number of freeze thaw cycles allowable in accordance to the  method development  
elements shown below in Section 5 F.  
 
C.   Storage Chambers    Freezers and Cold Rooms  
 
 	  Determine if access to the storage chamber used for study samples is controlled.  
 
 	  Sites typically maintain a sample logging sheet for every storage chamber which 
documents personnel  ingress and egress, and removing and restoring of the study samples.  
If  available, request  the sample logging sheet.  
 
 	  Note the individuals accessing the storage chamber and the individuals requesting the  
study samples.  Determine if these individuals have a legitimate reason to handle the study  
samples.  
 
 	  Note the date and time when the custodian removed and returned study samples. 
 
 	  Request the sites SOP that outlines the necessary steps to handle storage temperature 
excursions.  
 
 	  Document whether the  storage  chambers (cold rooms and refrigerators) are equipped with 
alarm systems that alert custodians  when the power supply fails, equipment malfunctions, 
or when temperature excursions exceed the storage temperature range.  
 
 
Date of Issuance:  05/01/2018 	  Page 13  of  35    
  PROGRAM   7348.004  
   
 	  Request and review the temperature  records for each storage chamber used for storing  
study samples.  Determine if the records cover  the entire storage period during sample  
analysis, including ISR.  Scrutinize temperature excursions exceeding the demonstrated 
storage stability  of  study samples.  
 
	   Document if the analytical site  has a designated contact  in the event of a temperature  
excursion, or  planned equipment servicing or malfunctions, including the name of the  
individual who responded to the  temperature excursion or who serviced the equipment  
(contact person); the  action taken in response  to the temperature excursion or equipment  
servicing, including an assessment of the impact on sample integrity;  and adequate  
coverage for weekends, holidays, and after hours. 
 
	   Verify that samples were stored at temperatures  previously validated and  for the
  
demonstrated stability period.  

 
D.   General Considerations for Stability Experiments (Where Applicable)  
 
 	  Determine if the stability of the stock solution was assessed and confirm  that stock
  
solutions used in experiments did not exceed the period of validated stability. 
 
 
	   If the stability of the stock solution has not  been assessed,  determine if the stability 
assessment  used a set of samples prepared from a freshly prepared stock solution of the  
analyte in the appropriate analyte-free, interference-free biological matrix.   
 
	   Determine if the stability samples were compared to freshly prepared calibrators and/or  
QCs.  
 
	   Determine if the stability experiments included at least three replicates (e.g., at each of the 
low and the  high concentration of QCs). 
 
	   Determine if the deviation from nominal concentrations for  the stability results were 
within those specified  in the current FDA Guidance  on  Bioanalytical Method Validation  
(May 2001).  
 
E. 	 Long-term Stability  
 
 	  Determine if the sample storage time in a long-term stability  evaluation  met or exceeded  
the time between the date of sample collection  at the clinical site  and the  date of last  
sample analysis at  the analytical  site.  
 
	   Determine  if the stability samples used for the long-term stability experiments were stored  
at the same temperature as subject samples.  
 
	   Document whether the stability samples were prepared  in the same matrix  with the same  
additive  as the subject sample matrix.   
 
Date of Issuance:  05/01/2018 	  Page 14  of  35    
  PROGRAM   7348.004  
   
 
 	  Document whether stability  sample  aliquots were taken from  multiple  containers or from a  
single container.  
 
F.	   Freeze and Thaw Stability  
 
Determine if any of the study samples exceeded  the number of freeze and thaw evaluations 
validated during method development. 
 
G.   Benchtop Matrix Stability  
 
Determine if the sample preparation  and storage time on the benchtop for  study samples exceeded  
the validated benchtop stability period. 
 
H.   Processed Sample Stability and Autosampler Stability  
 
Determine if the validated stability period includes the storage conditions  prior  to sample  
analysis, including benchtop, refrigerator, and autosampler. 
 
I.	   Stock Solution Stability  
 
If the stock solution is  in a different state or in a different solvent than the reference standard, 
determine if the stability data for the  stock solution supports  the duration of storage for the stock 
solutions used during sample analysis.  Note, stock solution stability is usually not demonstrated 
in matrix.  The assessment typically involves a comparison of peak areas to a freshly prepared  
stock solution.  Document if stability  was determined for intermediate or working stock solutions.   
 
J.	   Reference Standard Storage and Procurement  
 
Analysis of drugs and their metabolites in a biological matrix  is performed using calibration  
standards and QC samples spiked with the reference standard.  The purity of the reference 
standard used to prepare  spiked samples can  affect accuracy and precision.  For this reason,  
FDAs Guidance on Bioanalytical Method Validation  (May 2001) recommends using  
authenticated analytical  reference  standards of known identity and purity to prepare solutions of  
known concentrations (see below).  When possible, FDA recommends using a reference standard  
that  is identical to  the analyte.  When it is not possible,  an established chemical form (freebase or  
acid, salt or  ester) of known purity can be used with appropriate correction factors.  
 
	   If the reference standard is light sensitive, document whether the  site  uses appropriate  
handling conditions  including amber vials  and/or vapor lamps to prevent  product  
degradation.  
 
	   According to the certificate of analysis (COA) for the reference standard  or other 
appropriate documentation, determine if expired  reference standards were used at any  
point during the period of  method validation and sample analysis.  
 
 
Date of Issuance:  05/01/2018 	  Page 15  of  35    
  PROGRAM   7348.004  
   
 	  If the reference standard is hygroscopic  (i.e, absorbs water), document whether  the raw  
analyte used in creating  calibration standards and QC samples was stored  under dry  
conditions.  
 
 	  Verify whether concentrations were adjusted for salts,  counter ions, water, carriers, and  
impurities.  
 
  Methodology  
 
Determine if the  site has a general and/or study-specific SOP on method validation, and whether the  
site followed it.  
 
A.  Precision and Accuracy  
 
 	  Document how the  site  validated  the within-run (intra-batch)  and between-run (inter
batch)  accuracy and precision of the  analytical method.  Determine whether the  site  
assessed an  intra- and inter-batch assessment with data from  all  accuracy and precision 
analytical  runs.  
 
	   Document if any of the demonstrations of precision and accuracy used calibrators and 
QCs prepared from separate stock solutions.  
 
	   Document how  many precision and accuracy runs were conducted and how  many 
different concentration values were  evaluated in each run.  Also, document how  many 
times each concentration value was measured within each run.   For  example, a precision 
and accuracy evaluation  might include three independent  runs, each run evaluates a  
minimum of four concentrations  (including the  lower limit of quantification [LLOQ]) 
covering the range of expected concentrations  in subject samples, and each concentration 
is measured at least five  times within each run.  
 
	   Determine if all valid  runs (i.e., acceptable  calibration curve) were included in the  
accuracy and precision assessment.   
 
B.  Recovery  
 
The recovery of an analyte in an assay is the detector  response obtained from an amount of the  
analyte added to and extracted from the biological matrix, compared to the detector  response  
obtained for  the true (prepared)  concentration of  the analyte  in pure solvent. 
 
 Determine if  recovery experiments were performed  by  comparing the  analytical results  for  
extracted samples at three concentrations (low, medium, and high) with unextracted  standards 
(analyte  in solvent)  that represent 100% recovery.   Recovery of the analyte need not be 100%, but  
the extent of recovery of an analyte and of the  internal standard (IS)  should be consistent, precise  
and reproducible.  
 
 
Date of Issuance:  05/01/2018 	  Page 16  of  35    
  PROGRAM   7348.004  
   
C.   Calibration Curve  
 
The calibration (standard) curve  is the relationship between instrument response and known 
concentrations of the analyte.  
 
 	  Calibration standards can contain more than one analyte.  However, one calibration curve  
should be generated for each analyte in the sample.  
 
 	  Determine if the calibration curve was prepared in the same biological matrix  as the 
samples in the intended  study by spiking the matrix with known concentrations of the  
analyte.  
 
 	  Document, and collect  evidence, if  the  site provided justification when surrogate matrices  
different from the study sample  matrix are used.  
 
 	  Determine if the calibration curve is representative of the concentration observed in study 
samples.  Any concentrations below (LLOQ) or above the upper  limit of  quantification  
(ULOQ) should not be extrapolated.  Samples with concentrations above the ULOQ  
should be diluted with the appropriate matrix.  The dilution factor for  the samples should 
be supported by the dilution experiments.  Refer to the evaluation of dilution integrity in 
Section 6 H.  The concentration range should include a blank sample, a zero sample, and 
at least six non-zero samples covering the expected concentration range in study samples. 
 
D.   Lower Limit of Quantification  
 
Determine if the analyte response at the LLOQ is at least five times the response compared to  
background noise.  If not, collect relevant documentation demonstrating that the  analytical 
method was sufficiently  sensitive to  measure the analyte of interest.  
 
Determine if the analyte peak (response) is identifiable, discrete, and  reproducible,  and the 
accuracy and precision  of the back-calculated concentration  meets acceptance criteria.  
 
E. 	 Upper Limit of Quantification  
 
Document the precision and accuracy of the ULOQ.  The highest calibration standard defines the  
ULOQ of an analytical  method.  
 
F.	   Selectivity/Specificity  
 
Document whether the site  assessed the selectivity/specificity of each analyte of interest using  at  
least six sources of the appropriate  matrix (e.g., plasma, urine, or other matrix). 
 
Determine whether each blank matrix  sample was tested for  interference and  
selectivity/specificity at the LLOQ.  
 
 
 
Date of Issuance:  05/01/2018 	  Page 17  of  35    
  PROGRAM   7348.004  
   
G.   Matrix Effect  
 
Matrix effect is the direct or indirect alteration or interference  in response  due to the presence of  
unintended analytes (for analysis) or other  interfering substances in the sample. Matrix effect can  
cause inaccuracy in quantitation of the analyte of interest.  
 
 	  Document whether the site  evaluated  matrix effect on the analyte and  IS.  
 
 	  If  matrix effect was evaluated, determine if the site evaluated the matrix effect using at  
least six separate sources of blank matrix.  
 
 	  Document if the  site  evaluated the matrix factor when a matrix effect was observed.   
 
H.   Dilutions  
 
 	  Determine if the concentration of any study sample exceeded the ULOQ.  Check if the  site  
diluted and re-analyzed these sample(s).  
 
 	  If study samples were diluted and re-analyzed, determine if the site conducted a dilution 
integrity experiment during method validation or  sample analysis.  
 
 	  If a dilution integrity experiment was conducted during method validation, determine if  
the dilution factor used on study samples was less than or equal to the dilution factor (  
DF) evaluated in the dilution integrity experiment. 
 
	   If the dilution factor used on study samples exceeded the dilution factor  (> DF)  
o
evaluated in method validation experiment, see (6) below.  
 
	   Determine if the study sample(s) were diluted with like matrix including same  
o
additives.  
 
	   If a dilution integrity experiment was not conducted during method validation, but study 
samples were diluted during sample analysis, determine if the site  included dilution QCs 
in study sample runs.  
 
	   Determine if the run acceptance criteria were based on run QCs (low, mid, high) and 
o
not on dilution QCs.  
 
	   Determine if the dilution  QCs were diluted with like matrix including same additives.  
o
 
	   Determine if the unadjusted concentrations of diluted study samples (prior to applying a  
dilution factor) fell within the calibration curve range.  
 
	   Document if the  site has  an SOP that discusses procedures for diluting study samples and 
reporting concentrations of diluted samples. 
 
Date of Issuance:  05/01/2018 	  Page 18  of  35    
  PROGRAM   7348.004  
   
 
I.   Carryover  
 
Determine if the site assessed carryover during method validation.  
 
J.	   Partial Validation  
 
A partial validation evaluates changes in a bioanalytical method that  is already validated.  The 
evaluation can range from a  minimum of one intra-assay accuracy and precision experiment to nearly 
all  the experiments that are conducted for a full validation.  
  
For specific examples where a partial validation is warranted, please refer to the current  FDA 
Guidance on  Bioanalytical Method Validation (May 2001).  Also, refer  to  Section 4 A for instructions  
on assessing precision and accuracy.   
 
  Documentation  
 
The FDAs current Guidance on Bioanalytical Method Validation  (May 2001)  encourages sites  to  
maintain sufficient documentation throughout study conduct to allow reconstruction and verification 
of all critical activities during method validation and sample handling and analysis.  
 
Determine if documentation is attributable,  legible, contemporaneous, original, accurate, complete  
and consistent.  The determination typically includes auditing the  sites analytical procedure (AP)  
sheets, sample preparation records,  raw chromatograms, records for sample receipt and handling,  
deviation/investigation reports, institutional  SOPs, audit  trails, and correspondence with sponsors  or  
clinical sites.  
 
Records may exist  electronically or  in a paper format.  For electronic records, determine if the site  has 
processes and quality systems to secure and protect network and computerized systems  from 
inappropriate internal  and external access.  Document whether all electronic data and  computer  
systems are validated for their intended uses.   Refer to 21 CFR part 11 Electronic Records and  
Electronic Signatures.  
 
A.  Laboratory Instruments  
 
 	  Determine if calibration  and maintenance records for major instruments used in the  study  
are complete and up-to-date.  Examples of major instruments may include, but are not  
limited to, balances, freezers, spectrometers, and pipettes.   
 
 	  Document whether written SOPs exist that specify how  frequently calibration and 
maintenance activities are performed, and the person(s) responsible for  instrument  
calibration and  maintenance as well  as emergency contacts.  
 
 	  Examine instrument logs and evaluate how instrument  malfunctions  are reported and 
documented. 
 
 
Date of Issuance:  05/01/2018 	  Page 19  of  35    
  PROGRAM   7348.004  
   
 	  Document whether the site has appropriate procedures for handling study samples if  
instrument failure occurs during the sample analysis.  
 
B. 	 Source Data  
 
 	  Determine if source records (paper or electronic format) allow reconstruction of the  study.  
Examples of source records include chromatograms, instrument-generated readings or  
spectra, or any other records from automated instruments. 
 
	   Evaluate the source data and ensure that changes are appropriately traceable and  
documented. Determine if there are adequate systems and/or administrative controls to  
prevent deletion or  alteration of source data.  
 
	   Document whether the site  has an SOP to ensure that  source data are consistently
  
organized and retrievable, and whether the  site follows the SOP.
  
 
C.   Re-integration/Re-analysis  
 
 	  Determine if the  site implements automatic integration of chromatographic peaks and 
applies consistent integration parameters within  a run.   
 
 	  Document whether the site  has an SOP for re-integration of chromatograms and re
analysis of samples.  
 
 	  Determine if the procedure provides  clear and objective criteria for re-integrating 

chromatograms and re-analysis of study samples. 
 
 
 	  Determine whether staff follow the sites SOP during chromatogram re-integration and 
sample re-analysis  including documentation, justification, and supervisory approval.  
 
	   If chromatograms for QCs and calibrators were re-integrated, determine if run acceptance 
was affected.  
 
D.   Audit Trails  
 
 	  Determine if  the software implemented for acquiring, integrating, and regressing study  
data has audit trail capabilities.  
 
	   Determine if the audit trail option was enabled during the sample analysis.  
 
 	  Evaluate the  sites administrative procedures and/or access rights to  determine if adequate 
controls exist over audit trail functionality.  
 
 	  Determine whether the  audit trail records reconstruct the course of events during the  
analysis of study samples.  
 
 
Date of Issuance:  05/01/2018 	  Page 20  of  35    
  PROGRAM   7348.004  
   
 	  Review the audit  trails from selected studies and  determine if there are any indications of  
potential alterations of study data.  Document any changes  captured in the audit  trail  
without adequate justification.  
 
E. 	 Data Security  
 
 	  Document if the  site  has an SOP for  controlling access to operating systems and 

instrument software and that  it is followed.  

 
	   Determine if the operating system and/or the instrument software require unique login for 
individual staff.  
 
	   Determine if a computer lock mechanism is in use to prevent unauthorized  access to open  
workstations and/or data.  
 
	   Review the access rights regarding the ability  to create, integrate, modify,  regress, remove, 
transfer,  and report data.  
 
 	  Review the  sites SOP and requirements for data storage  and protection.  Evaluate  if  
storage, back-up, transfer, and archive of study data are adequate to  ensure data security.  
 
 	  Document whether the site  has an SOP  to prevent deletion of electronic  data.  
 
F.	   Data Reporting  
 
 	  Determine if data found at the  site  are  consistent with those in the  study reports included 
in the FDA submission, when applicable.  
 
 	  Determine if all method validation experiments, whether passed or failed, were reported in 
the method validation report.  Evaluate whether  the  site conducted any investigation to 
identify the  reasons for such failures, if any. 
 
	   Determine if rejected  runs during the study sample analysis were documented and the  
reason for rejecting the  run was reported in the study report.  
 
 	  If study samples were re-analyzed, determine if the re-analysis is justifiable and whether  
final concentrations were reported according  to  established  SOPs.  
 
	   Determine how the  site documents and handles protocol/SOP violations.  If violations  
occurred, describe  in the EIR and collect information to support the Centers evaluation of  
the potential  impact of these events on data quality and integrity. 
 
 	  Determine if reports are accurate and complete by randomly selecting  representative runs.  
 
	   Document whether all failed BE studies were  reported  to the study Sponsor. 
 
Date of Issuance:  05/01/2018 	  Page 21  of  35    
  PROGRAM   7348.004  
   
G.   Communications  with  Internal and External Parties  
 
 	  Request and review communications  between  the analytical site, the  sponsor, clinical  
sites, or study monitors regarding the study and data analysis.  
 
 	  Evaluate  any requests from the sponsor or study monitors that resulted in changes to the  
final study report.  Describe  in the EIR and collect information to facilitate the Centers  
evaluation of the impact of those changes on study data and conclusions.  
 
 	  Inquire whether the  site reported any issues with the analytical  method or study data  to the  
study sponsor, clinical sites, or study monitors.  If so, determine how these issues were  
documented, addressed, and whether they affected data quality and integrity. 
 
  Analysis of Study Samples  
 
A. 	 System Suitability  
 
 	  Document whether the site  has an SOP on system suitability.  
 
 	  Determine if the system  suitability samples were labeled and  identified as such, prior to  
conducting an analytical run containing study samples. 
 
 	  Determine if the system  suitability samples were independent  from the analytical  run  
containing study samples. 
 
 	  Determine if system suitability samples were  injected prior to the analytical run containing  
study samples.  
 
 	  Determine if system suitability samples were  injected after instrument malfunctions, and  
prior  to resuming an analytical  run containing study samples. 
 
B. 	 Run Acceptance  
 
For each analytical  run audited, document if:  
  
 	  At least three concentrations of QCs in duplicate were incorporated  into each study sample  
run.  One concentration should be within three  times the LLOQ (low QC), one in the  
midrange (middle QC), and one approaching the high end (high QC) of the range of the  
expected study concentrations.  See  Part III.4.H.  regarding dilution QCs.  
 
 	  At least 67% of the QC concentration results are within 15% of their respective nominal 
concentrations.  
 
 	  At least 50% of the QCs at each concentration level are within 15% of their nominal  
concentrations.7  
 
Date of Issuance:  05/01/2018 	  Page 22  of  35    
  PROGRAM   7348.004  
   
 
 	  The number  of QCs in a  run meets or exceeds 5% of the total  number of unknown samples  
or six total QCs, whichever number is greater.  
 
 
Determine whether the QCs represent the analyte concentrations observed in study samples.  
 
C.   Improper Processing  
 
 	  Document whether the site  has a procedure to handle samples that were processed
  
improperly and whether  it is followed. 

 
 	  If the  site  determined that study samples were processed improperly, was the incident  
documented contemporaneously and did the  site  conduct an investigation to determine the  
cause?  
 
	   Was this incident isolated or does it affect multiple samples in the same  run or across  
runs?  
 
	   Did the  site  re-inject or re-process the study samples?  If samples were re-injected, was the 
processed  sample stability timeframe exceeded?   
 
D.   Shift in Retention Time of Analyte/IS  
 
 	  Document whether the site  has an SOP for investigating shifts in retention time and 
whether the  site followed it.  
 
 	  Determine if any runs or samples were rejected due to a substantial shift in  retention  time,  
and whether the site was justified  to reject  those runs and/or samples.   
 
 	  Determine if the shift in retention time is isolated  to a single study run or across multiple  
runs.  
 
E. 	 Re-injection of Study Samples  
 
 	  Document whether the site  has an SOP that discusses procedures for re-injecting study 
samples.  If  so, did the  site follow this SOP?  
 
 	  Determine if the  site  re-injected study samples in any of the audited studies.  Did the  site  
document the reason for re-injection?  
 
	   Does the processed sample/autosampler stability support the time of re-injection of study 
samples?  
 
	   Are the final concentrations that  are reported for  reinjected samples acceptable?  
 
Date of Issuance:  05/01/2018 	  Page 23  of  35    
  PROGRAM   7348.004  
   
 
 	  Were  all re-injected samples identified in the study report?  
 
F.	   IS Variability/Drift  
 
 	  Document whether the site  has an SOP describing the acceptable variability  in the peak  
area response of IS.  In addition, determine if the SOP specifies when a run should be  
rejected based on unacceptable IS variability.  
 
 	  Document whether the site  identified all QCs and study samples with  IS variability outside  
the specified limits.   Were study samples repeated if the IS variability exceeded the 
specified limits? Was the SOP followed?  
 
 	  Determine if  IS variability affected run acceptability or study  samples.  
  
G.   PK Anomalies  
 
 	  Document whether the  site has an SOP outlining the procedures for repeating samples  
with PK anomalies. 
 
	   Were study  samples repeated based  on  PK  anomalies? Was the SOP followed?  
 
	   Determine if the  site investigated the  potential  reasons for the  anomalous concentration(s).  
 
	   Determine who requested the sample repeat.  Is there adequate documentation  regarding  
the request?  
 
 	  Determine if the bioanalytical report includes both the anomalous and final reported 
concentrations, including the rationale for selecting the final  concentration.  
 
H.   Incurred sample reanalysis  (ISR) 
 
 	  Document whether the firm conducted the  ISR.  Check the number of samples analyzed.  
 
 	  Did the ISR assessment include study samples representative of the analyte(s) Cmax and  
elimination half-life, where applicable?  
 
 	  Determine and document  if the percentage difference for the original and  ISR values are 
within  pre-defined acceptance criteria.  
 
 	  Document if the  site  has written  procedures  to investigate ISR  failures.   
     
 
   
 
Date of Issuance:  05/01/2018 	  Page 24  of  35    
  PROGRAM   7348.004  
   
PART IV   ANALYTICAL  
Not applicable to  this Compliance Program.  
   
 
Date of Issuance:  05/01/2018   Page 25  of  35    
  PROGRAM   7348.004  
   
PART V   REGULATORY/ADMINISTRATIVE STRATEGY  
If significant violations  are  observed during the inspection, prepare a  Form FDA 483, Inspectional  
Observations, to issue to the most responsible  individual. Form FDA 483 observations should be  
factual statements. Avoid recording unsupported opinions on a Form FDA 483. Observations  
recorded on a Form FDA 483 should include  supporting documentation attached to and discussed  
within the EIR whenever possible.  
 
Analytical sites should conduct bioanalysis using best practices to ensure data quality and integrity. 
Significant  inspectional  observations  may not have specific, corresponding CFRs that support  them. 
When observations  are  made  with a potential to  have significant impact on data quality or reliability,  
but there are no corresponding CFRs, collect the evidence  related to these  observations, discuss  the  
observations with the most responsible individual  and document the observations, discussion and 
evidence  in the EIR. 
  
Center reviewers will evaluate Form  FDA 483 observations, as well as any discussion items and  
evidence  contained in the EIR, and consider  the impact of the sites actions (frequency, scope, and 
severity) on acceptability and reliability of study data. There are often varying gradations in the  
severity among similar  Form  FDA  483 examples. The specific observation(s)  and information 
collected should support the Centers evaluation of the reliability and acceptability of  data for FDA  
decision-making purposes. 
     
 
   
 
Date of Issuance:  05/01/2018   Page 26  of  35    
  PROGRAM   7348.004  
   
PART VI    REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS  
  FDA  Guidance Documents and References  
 
A. 	 FDA Laws  
 
Federal Food, Drug, and Cosmetic Act (FFDCA)  
(https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/FederalFoodDrugandCosme 
ticActFDCAct/FDCActChapterVDrugsandDevices/default.htm)  
 
B. 	 Relevant 21 CFRs  
 
 	  Part 320  Bioavailability and Bioequivalence Requirements   
(http://www.ecfr.gov/cgi-bin/text
idx?SID=93111e2feefbb29bcaba7cb37a13aa9b&mc=true&node=pt21.5.320&rgn=div5)  
 
 	  Part 11  Electronic Records; Electronic Signatures  
(http://www.ecfr.gov/cgi-bin/text
idx?SID=93111e2feefbb29bcaba7cb37a13aa9b&mc=true&node=pt21.1.11&rgn=div5)  
 
C.   Relevant FDA Guidelines, Guidance Documents, and Inspection Guides  
 
For an overview of bioavailability, bioequivalence, and other  clinical pharmacology studies, 
please refer  to the available FDA Guidance Documents  referenced below.  
 
 	  Guidance for Industry:   Bioanalytical Method Validation, 2001 

(http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf)
  
 
 	  Draft Guidance for Industry:  Bioanalytical Method Validation, 2013 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM368107.pdf)  
 
 	  Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally  
Administered Drug Products  General Considerations  
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc 
es/ucm389370.pdf)  
 
 	  Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies, 2002 
(https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan 
ces/ucm070241.pdf)  
 
 	  Draft Guidance for Industry:  General Considerations for Pediatric Pharmacokinetic  
Studies for  Drugs and Biological Products, 1998  
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc 
es/ucm425885.pdf)  
 
Date of Issuance:  05/01/2018 	  Page 27  of  35    
  PROGRAM   7348.004  
   
 	  Draft Guidance for Industry:  Circumstances that Constitute Delaying, Denying, Limiting, 
or Refusing a Drug Inspection, 2013  
(http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm360484.pdf)  
 
 	  Draft Guidance for Industry: Bioavailability and  Bioequivalence Studies for Nasal  
Aerosols and Nasal Sprays for Local  Action, 2003 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM070111.pdf)  
 
 	  Draft Guidance for Industry: Bioavailability and Bioequivalence Studies  Submitted in 
NDAs or INDs   General Considerations, 2014 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM389370.pdf)  
 
 	  Draft Guidance for Industry:  Bioequivalence Studies With Pharmacokinetic Endpoints for  
Drugs Submitted Under  an Abbreviated New Drug Application, 2013 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM377465.pdf)  
 
 	  List of FDA Guidance Documents:
   
(http://www.fda.gov/RegulatoryInformation/Guidances/) 
 
 
 	  Investigations Operations Manual:  (http://www.fda.gov/ICECI/Inspections/IOM/)  
 
 	  FMD-86:  
(http://www.fda.gov/downloads/ICECI/Inspections/FieldManagementDirectives/UCM3820 
35.pd)  
 
 	  Form FDA 483: 
 
(http://www.fda.gov/downloads/ICECI/Inspections/IOM/UCM127434.pdf)
  
 
 	  Form FDA 482: 
 
(http://www.fda.gov/downloads/ICECI/Inspections/IOM/UCM127428.pdf)
  
 
2.	   Program Contacts  
 
When technical or scientific questions or issues arise from a specific assignment, or if additional 
information is required about a specific assignment, consult the  Center POC identified in the  
assignment.  
 
For operational questions, contact:  
 
	   Office of Regulatory  Affairs (ORA)/Office of Medical Products and Tobacco Operations 
(OMPTO)/Office of Bioresearch Monitoring Operations (OBIMO) - ORAHQ BIMO 
Inspection POC  
 
Date of Issuance:  05/01/2018 	  Page 28  of  35    
  PROGRAM   7348.004  
   
 	  Center for Drug Evaluation and Research (CDER)/Office of Translational  Sciences  
(OTS)/Office of Study Integrity and Surveillance (OSIS) - CDER-OSIS
BEQ@fda.hhs.gov  
 
For questions about the  BA/BE compliance program, contact:  
 
 	  Center for Drug Evaluation and Research (CDER)/Office of Translational  Sciences 
(OTS)/Office of Study Integrity and Surveillance (OSIS) - CDER-OSIS
BEQ@fda.hhs.gov  
 
   
 
Date of Issuance:  05/01/2018 	  Page 29  of  35    
  PROGRAM   7348.004  
   
PART VII    CENTER AND ORA HQ RESPONSIBILITIES  
  CDER Review Divisions   OND,  OGD, OPQ,  and  OCP  
 
   Request directed audits of selected  studies, including BA/BE studies.  
 
 	  Send consults for directed audits  to OSIS.  The inspection consults contain the  sites name,  
study(ies)  to be inspected, application number(s), and specific details about the Agencys  
concern with the  sites operations or  study data.  
 
 	  Answer  technical questions and provide  technical guidance related  to the  application to  the  
OSIS subject matter expert (SME) prior to, during, and after the inspection/audit.  
 
	   Review Divisions receive EIR reviews from OSIS, and have  the ultimate authority to accept 
or reject  study data based on inspection findings. 
 
  OSIS  
 
   For  directed inspections/audits, receives  an inspection consult and drafts  assignments. 
 
 	  For surveillance inspections/audits, identifies  the  sites  to be inspected/audited based on the  
current OSIS  surveillance model.  
 
	   Drafts and issues assignments and includes contact information for the OSIS SMEs and  
relevant FDA reviewer.  
 
   Assigns  the audit  for  the inspection  to staff. 
 
	   Provides expert  technical guidance, advice, information, and support to OSIS staff and ORA 
investigator, if applicable, prior  to, during, and after  inspection. 
 
	   Accompanies the ORA investigator  on the analytical inspection or, after contacting ORA, 
may also perform an independent audit without ORA.8  
 
	   May conduct analytical audits and communicate findings and observations with appropriate  
site personnel during the course of the audit, as appropriate.  Conclusions regarding data  
reliability or acceptability are not discussed during the audit.  
 
	   If OSIS and ORA  will perform a directed or surveillance inspection  as a team inspection,  
OSIS staff contacts ORA prior to  the inspection.  OSIS also provides additional details to  
ORA investigators, as needed. 
 
   OSIS staff draft EIRs  and submit them within appropriate  timeframes. 
 
 
Date of Issuance:  05/01/2018 	  Page 30  of  35    
  PROGRAM   7348.004  
   
 	  Reviews an EIR and provides recommendations to Review Divisions regarding the reliability 
and/or acceptability of study data.  
 
 	  Enters the final classification  into Field Accomplishments and Compliance Tracking  System  
(FACTS), or other appropriate electronic system,  and notifies ORA.  
 
 	  May issue untitled letters to inspected sites following voluntary action indicated (VAI) or no 
action indicated (NAI)  final classifications.   
 
 	  Promptly forwards to  the ORA  field investigator and any appropriate district personnel copies  
of post-inspection correspondence issued to the  inspected party.  
 
 	  Contacts the assigned ORA  investigator at least two weeks prior to the  start date to provide  
clarification  on details of the inspection or scientific inquiries that may assist the ORA  field  
investigator when conducting the  assignment or that may change the focus of the inspection.  
 
  OSI  
 
   Receives potential official action indicated (OAI)  cases from  OSIS.  
 
 	  Reviews the EIR for potential OAI cases to determine if the inspection observation(s) 
warrants compliance/enforcement actions for a site. Takes compliance/enforcement  action  as 
warranted.  
 
 	  In collaboration with OSIS and ORA, may determine that a follow-up inspection of an 
inspected site is necessary to verify whether the site has implemented any proposed corrective 
plans, and  that the site is in compliance with applicable regulations.  
 
  Office of Regulatory Affairs (ORA)  
 
 	  ORA OBIMO HQ receives assignment  from OSIS via  ORAHQ BIMO Inspection POC  email.   
OBIMO assigns to the  appropriate division (OBIMO Division I (East) or OBIMO Division II 
(West)).  Management assigns the  inspection to an ORA  field investigator.  
 
 	  International assignments are addressed to OBIMO and sent via ORAHQ BIMO Inspection  
POC  email. OBIMO HQ issues  the assignment to the ORA field investigator  selected to  
conduct the  foreign inspection.  
 
     
 
   
 
Date of Issuance:  05/01/2018 	  Page 31  of  35    
  PROGRAM   7348.004  
   
ATTACHMENT A   Abbreviations and Acronyms List  
A  
   
ANDA   Abbreviated new drug application  
AP   Analytical procedure  
 
 
B  
   
BA   Bioavailability  
BE   Bioequivalence  
BIMO   Bioresearch monitoring  
 
 
C    
 
CDER   Center for Drug Evaluation and Research  
CEO   Chief Executive  Officer  
CFR   Code of  Federal Regulations  
Cmax   Maximum concentration  
COA   Certificate of analysis  
CP   Compliance program  
CRO   Contract research  organization  
 
 
D    
 
DF   Dilution factor  
 
 
 
 
E    
 
EIR   Establishment Inspection Report  
EMA   European Medicines Agency  
etc.   Et  cetera  
 
 
F    
 
FACTS   Field  Accomplishments and  Compliance Tracking System  
FMD   Field management directive  
FDA   Food and Drug Administration  
   
 
Date of Issuance:  05/01/2018   Page 32  of  35    
  PROGRAM   7348.004  
   
H  
 
HQ   Headquarters  
 
 
I    
 
IND   Investigational new drug application  
IS   Internal standard  
IOM   Investigations  operations  manual  
ISR   Incurred sample  reanalysis  
 
 
L    
   
LIMS   Laboratory Information Management System  
LLOQ   Lower limit of quantification  
 
 
N    
 
NAI   No action indicated  
NDA   New drug application  
 
 
O    
 
OAI   Official action indicated  
OCP   Office of Clinical Pharmacology  
OGD   Office of Generic Drugs  
OMPTO   Office of Medical Products and Tobacco Operations  
OND   Office of New Drugs  
OPQ   Office of Pharmaceutical Quality  
ORA   Office of Regulatory Affairs  
OSI   Office of Scientific Investigations  
OSIS   Office of Study Integrity and Surveillance  
OTS   Office of Translational Science  
 
 
P    
 
PD   Pharmacodynamic  
PK   Pharmacokinetic  
POC   Point of contact  
 
   
 
Date of Issuance:  05/01/2018   Page 33  of  35    
  PROGRAM   7348.004  
   
Q  
 
QC   Quality control  
 
 
R    
 
RLD   Reference listed drug  
 
 
S    
 
SME   Subject matter expert  
SOP   Standard operating procedure  
 
 
U    
 
ULOQ   Upper limit of quantification  
 
 
V    
 
VAI   Voluntary action indicated  
 
 
   
 
Date of Issuance:  05/01/2018   Page 34  of  35    
  PROGRAM   7348.004  
   
Change History  
 
Item   Change   Date  
Document   New  Document   05/01/2018  
 
 
Date of Issuance:  05/01/2018   Page 35  of  35