M13A BIOEQUIVALENCE FOR IMMEDIATE-
RELEASE SOLID ORAL DOSAGE FORMS 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is 
not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements 
of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page.  The draft guidance has been left in the original 
International Council for Harmonisation format.  The final guidance will be reformatted and edited to 
conform with FDAs good guidance practice regulation and style. 
For questions regarding this draft document, contact (CDER) Lei Zhang, 
Leik.Zhang@fda.hhs.gov.  FOREWORD  
  
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained in 
the most resource-efficient manner.  By harmonizing the regulatory expectations in regions around 
the world, ICH guidelines have substantially reduced duplicative clinical studies, prevented 
unnecessary animal studies, standardized safety reporting and marketing application submissions, 
and contributed to many other improvements in the quality of global drug development and 
manufacturing and the products available to patients.   
  
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines.  The commitment to consistent adoption of these consensus-based 
guidelines by regulators around the globe is critical to realizing the benefits of safe, effective, and 
high-quality medicines for patients as well as for industry.  As a Founding Regulatory Member of 
ICH, the Food and Drug Administration (FDA) plays a major role in the development of each of the 
ICH guidelines, which FDA then adopts and issues as guidance to industry.   
   
 
 
INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL 
REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE 
  
ICH HARMONISED GUIDELINE 
 
 
 
 
 
BIOEQUIVALENCEFORIMMEDIATE-RELEASE
     
SOLIDORALDOSAGEFORMS  
     
M13A 
 
 
Draft version  
Endorsed on 20 December 2022 
Currently under public consultation 
 
 
 
 
 
 
 
 
At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate 
ICH  Expert Working Group, is  transmitted by  the ICH  Assembly to the  regulatory 
authorities of the ICH regions for internal and external consultation, according to national 
or regional procedures. 
 
   
M13A 
Document History 
 
Code  History  Date 
M13A  Endorsement by the Members of the ICH Assembly  20/12/2022 
under Step 2 and release for public consultation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Legal notice: This document is protected by copyright and may, with the exception of the ICH logo, 
be used, reproduced, incorporated into other works, adapted, modified, translated or distributed 
under a public license provided that ICH's copyright in the document is acknowledged at all times.  
In case of any adaption, modification or translation of the document, reasonable steps must be taken 
to clearly label, demarcate or otherwise identify that changes were made to or based on the original 
document.  Any impression that the adaption, modification, or translation of the original document 
is endorsed or sponsored by the ICH must be avoided. 
The document is provided "as is" without warranty of any kind. In no event shall the ICH or the 
authors of the original document be liable for any claim, damages or other liability arising from the 
use of the document. 
The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for 
documents where the copyright vests in a third party, permission for reproduction must be obtained 
from this copyright holder. 
   
ICH HARMONISED GUIDELINE 
BIOEQUIVALENCE FOR IMMEDIATE-RELEASE 
SOLID ORAL DOSAGE FORMS  
M13A 
ICH Consensus Guideline 
 
TABLE OF CONTENTS 
1  INTRODUCTION ........................................................................................................ 1 
1.1  Objective ........................................................................................................................ 1 
1.2  Background .................................................................................................................... 1 
1.2.1  Bioequivalence ................................................................................................... 1 
1.2.2  Data Integrity ..................................................................................................... 2 
1.3  Scope ............................................................................................................................. 2 
2  GENERAL PRINCIPLES IN ESTABLISHING BIOEQUIVALENCE ....................... 3 
2.1  Study Design for Pharmacokinetic Endpoint Bioequivalence Studies................................ 3 
2.1.1  Study Population ................................................................................................ 3 
2.1.2  Study Design ...................................................................................................... 4 
2.1.3  Sample Size for Bioequivalence Studies ............................................................... 4 
2.1.4  Comparator and Test Products ............................................................................ 5 
2.1.5  Fasting and Fed Study Conditions ....................................................................... 5 
2.1.6  Dose or Strength to be Studied ............................................................................ 8 
2.1.7  Moieties to be Measured ..................................................................................... 9 
2.1.7.1  Parent versus Metabolite .............................................................................. 9 
2.1.7.2  Enantiomers versus Racemates ................................................................... 10 
2.1.8  Sampling .......................................................................................................... 10 
2.1.8.1  First Point C ...........................................................................................11 
max
2.1.8.2  Long Half-life Drugs and Truncated AUC Considerations ............................11 
2.1.8.3  Early Exposure ...........................................................................................11 
2.2  Data Analysis for Non-Replicate Study Design .............................................................. 12 
2.2.1  Considerations for the Bioequivalence Analysis Population ............................... 12 
2.2.1.1  Removal of Data Due to Low Exposure ....................................................... 12 
2.2.2  Presentation of Data ......................................................................................... 13 
i   
2.2.2.1  Concentration Time Data ........................................................................... 13 
2.2.2.2  Pharmacokinetic Analysis .......................................................................... 13 
2.2.2.3  Potency Differences in Lots ........................................................................ 14 
2.2.3  Statistical Analysis ............................................................................................ 14 
2.2.3.1  General Considerations ............................................................................. 14 
2.2.3.2  Crossover Design Studies ........................................................................... 15 
2.2.3.3  Carry-over ................................................................................................. 15 
2.2.3.4  Parallel Design Studies .............................................................................. 16 
2.2.3.5  Multi-Group Design Studies ....................................................................... 16 
2.2.4  Bioequivalence Criteria .................................................................................... 17 
2.2.5  Multiple Comparator and Multiple Test Product Studies .................................... 17 
2.2.5.1  Multiple Comparator Products ................................................................... 17 
2.2.5.2  Multiple Test Products................................................................................ 17 
3  SPECIFIC TOPICS .................................................................................................... 18 
3.1  Endogenous Compounds ............................................................................................... 18 
3.2  Other Immediate-Release Dosage Forms ....................................................................... 19 
3.2.1  Orally Disintegrating Tablets ............................................................................ 19 
3.2.2  Chewable Tablets.............................................................................................. 20 
3.2.3  Oral Suspensions .............................................................................................. 20 
3.3  Fixed Dose Combination............................................................................................... 20 
3.4  pH-Dependency ............................................................................................................ 21 
4  DOCUMENTATION .................................................................................................. 22 
5  GLOSSARY ................................................................................................................ 23 
 
ii  ICH M13A Guideline 
1  1   INTRODUCTION  
2  1.1  Objective 
3  This guideline is intended to provide recommendations on conducting bioequivalence (BE) studies 
4  during both development and post approval phases for orally administered immediate-release (IR) 
5  solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, 
6  capsules, and granules/powders for oral suspension. 
7  Deviations from the recommendations in this guideline may be acceptable if appropriate scientific 
8  justification is provided. Applicants are encouraged to consult the regulatory authority(ies) when 
9  an alternate approach is proposed or taken. 
10  1.2  Background  
11  1.2.1  Bioequivalence 
12  BE  for IR  solid oral dosage forms with systemic action is largely established via clinical 
13  pharmacokinetic (PK) BE studies or comparative in vitro dissolution studies. In addition to the 
14  oral dosage forms stated above, the PK principles of this guideline are generally applicable to non-
15  orally administered drug products with immediate action in which reliance on systemic exposure 
16  measures is suitable for establishing BE, e.g., certain rectal, inhalation, and nasal drug products. 
17  BE assessment for these oral dosage forms is important for establishing therapeutic equivalence 
18  for generic drug products to their respective comparator products. In addition, there may be 
19  situations in new (innovator) drug development when demonstration of BE may be critical for 
20  approval decisions. Furthermore, BE studies are used by innovator and generic product developers 
21  for supporting post-approval formulation and/or manufacturing process changes. 
22  Two drug products containing the same drug substance(s) are considered bioequivalent if their 
23  relative bioavailability (BA) (rate and extent of drug absorption) after administration in the same 
24  molar dose lies within acceptable predefined limits. These limits are set to ensure comparable in 
25  vivo performance, i.e., similarity in terms of safety and efficacy. 
26  The Biopharmaceutics Classification System (BCS)-based biowaiver may be used to waive in vivo 
27  BE studies for certain orally administered IR solid oral dosage forms as delineated in ICH M9, 
1  ICH M13A Guideline 
28  Biopharmaceutics Classification System-Based Biowaivers. 
29  1.2.2  Data Integrity 
30  BE studies should be conducted according to the principles and recommendations in ICH E6, Good 
31  Clinical Practice. In conducting BE studies, sponsors, study investigators, and service providers, 
32  e.g., contract research organisations or laboratories, should ensure that the data generated are 
33  attributable,  legible,  contemporaneously  documented,  original  (or  a  certified  copy), 
34  accurate, complete, and traceable. The ultimate responsibility for the quality and integrity of the 
35  study data submitted to a regulatory authority lies with the applicant. 
36  1.3  Scope 
37  M13A is the first guideline in the series to describe the scientific and technical aspects of study 
38  design and data analysis to support BE assessment for orally administered IR solid oral dosage 
39  forms. How regulatory decisions may be made based on BE assessment is out of the scope of this 
40  guideline. 
41  Acceptance of comparator products across regulatory jurisdictions could reduce the burden of 
42  multiple clinical trials demonstrating BE against local comparator products. However, in many 
43  regions this is governed by local laws rather than scientific guidelines. Therefore, the acceptance 
44  of comparator products across regions is not in the scope of M13A. However, study designs 
45  containing multiple comparator products or test products are included in M13A to take some initial 
46  steps to reduce the associated burden without prejudice to regional legal requirements. 
47  The second guideline in the series, M13B, will describe biowaiver considerations for additional 
48  strengths not investigated in BE studies.  
49  The third guideline in the series, M13C, will include data analysis and BE assessment for 1) highly 
50  variable drugs, 2) drugs with narrow therapeutic index, and 3) complex BE study design and data 
51  analysis considerations, e.g., adaptive BE study design.  
52  These guidelines do not cover PK study design or data analysis to support BA assessment for new 
53  drug development in support of intended use or dosing recommendations in drug labelling, e.g., 
54  relative BA assessment, food effect, drug-drug interactions, special population studies, bridging 
2  ICH M13A Guideline 
55  formulations without the necessity to demonstrate BE, and studies to support changes in dosing 
56  regimens or routes of administration. In such cases, study design and decision criteria may be 
57  based on the objective of the study and availability of other information including exposure-
58  response and proposed labelling.  
59  2  GENERAL PRINCIPLES IN ESTABLISHING BIOEQUIVALENCE 
60  2.1  Study Design for Pharmacokinetic Endpoint Bioequivalence Studies   
61  2.1.1  Study Population 
62  The subject population for BE studies should be selected with the aim of permitting detection of 
63  differences in the in vivo release characteristics between pharmaceutical products. In order to 
64  reduce variability not related to differences between products, the studies should normally be 
65  performed in healthy subjects unless the drug carries safety concerns that make this approach 
66  unethical. Conducting BE studies in healthy subjects is regarded as adequate in most instances to 
67  detect formulation differences and to allow extrapolation of the results to populations for which 
68  the product is intended. 
69  The subject inclusion and exclusion criteria should be clearly stated in the study protocol. Subjects 
70  should be at least 18 years of age and preferably have a Body Mass Index between 18.5 and 30.0 
71  kg/m2. If a drug product is intended for use in both sexes, it is recommended the study include 
72  male and female subjects. 
73  Subjects should be screened for suitability by means of clinical laboratory tests, a medical history, 
74  and a physical examination. Depending on the drugs therapeutic class and safety profile, special 
75  medical investigations and precautions may have to be carried out before, during, and after the 
76  completion of the BE study. The risk to women of childbearing potential should be considered, 
77  and the investigators should ensure that female subjects are not pregnant or lactating during the 
78  BE study and the follow-up. Subjects should preferably be non-nicotine users and without a history 
79  of alcohol or drug abuse. Phenotyping and/or genotyping of subjects may be considered for safety 
80  or PK reasons.  
81  If the investigated active substance is known to have adverse effects and the pharmacological 
82  effects or risks are considered unacceptable for healthy subjects, the study may instead be 
3  ICH M13A Guideline 
83  conducted in a targeted patient population under suitable precautions and supervision. 
84  2.1.2  Study Design 
85  A randomised, single-dose, two-period, two-sequence crossover study design is recommended 
86  when comparing two formulations, as single-dose studies provide the most sensitive conditions to 
87  detect differences in the rate and extent of absorption. Treatment periods should be separated by a 
88  sufficiently long washout period, e.g., at least 5 elimination half-lives. In general, the highest to-
89  be-marketed strength should be used in a BE study. If the highest strength of a product cannot be 
90  administered to healthy subjects for  safety and/or tolerability reasons, a  single-dose study 
91  conducted in healthy subjects using a lower strength may be possible (see Section 2.1.6) or 
92  alternatively, if feasible given the drug product under investigation, a single-dose study conducted 
93  in patients using the highest proposed strength could be considered. 
94  A multiple-dose study may be conducted in patients if a single-dose study cannot be conducted in 
95  either healthy subjects for safety and/or tolerability reasons or in patients for ethical reasons. For 
96  a multiple-dose study, the study protocol should include an appropriate number of dosage 
97  administrations to reach steady-state, which could be justified using an appropriate sampling 
98  scheme, i.e., concentrations at the end of the dosing interval should be sampled sequentially until 
99  C  is stable. The washout of the last dose of the first treatment period can overlap with the 
tau
100  accumulation of the second treatment. The accumulation period should be sufficiently long to 
101  reach the new steady-state after switching and allow the elimination of the drug from the previous 
102  treatment, e.g., at least 5 elimination half-lives. 
103  For drugs with long elimination half-lives, a parallel design may be employed when a crossover 
104  design is impractical due to the need for a prolonged washout period. In this situation, special care 
105  should be taken to ensure similar subject demographics in each of the treatment groups. 
106  Alternative study designs are acceptable, if scientifically justified. 
107  2.1.3  Sample Size for Bioequivalence Studies 
108  The number of subjects to be included in the BE study should be based on an appropriate sample 
109  size calculation to achieve a pre-specified power and pre-specified type 1 error. A sufficient 
110  number of subjects should be enrolled in the BE study to account for possible dropouts and/or 
4  ICH M13A Guideline 
111  withdrawals. The use of spare subjects is not acceptable. Additional cohort(s) of subjects may 
112  be added to the study, e.g., if the number of evaluable subjects falls below the calculated sample 
113  size; however, this should be specified in the study protocol and done prior to any bioanalysis. The 
114  number of evaluable subjects in a pivotal BE study should not be less than 12 for a crossover 
115  design or 12 per treatment group for a parallel design. 
116  2.1.4  Comparator and Test Products 
117  A comparator product is the drug product accepted by regulatory agencies that an applicant can 
118  use to compare against the test product in conducting a BE study.  
119  The selection of the batch of the comparator product used in the BE study should be based on assay 
120  content. It is advisable to investigate more than one batch of the comparator product when selecting 
121  the batch of comparator product for use in the BE study. 
122  The test product used in the BE study should be representative of the product to be marketed and 
123  this should be discussed and justified by the applicant.  
124  For pivotal BE studies, the test product used should meet the following criteria: 
125  a)  The production of batches used should provide a high level of assurance that the product 
126  and process will be feasible on a commercial scale.  The test product should usually 
127  originate from a batch of at least 1/10 of production scale or 100,000 units, whichever is 
128  greater, unless otherwise justified. In case of a production batch smaller than 100,000 units, 
129  a full production batch is required.  
130  b)  Unless otherwise justified, the assayed content of the batch used as test product should not 
131  differ by more than 5% from that of the batch used as comparator product, as determined 
132  with the test procedure proposed for routine quality testing of the test product.  
133  2.1.5  Fasting and Fed Study Conditions 
134  BE studies should be conducted under standardised conditions that minimise variability to better 
135  detect potential PK differences between drug products. For IR solid oral dosage forms, single-dose 
136  BE studies conducted under fasting conditions typically provide greater discrimination between 
137  the PK profiles of two products. Therefore, for the majority of these drug products, BE may be 
138  demonstrated in a single study conducted under fasting conditions.  
5  ICH M13A Guideline 
139  However, food can have a differential, formulation-dependent impact on the absorption of drug 
140  substances from drug products that are of high risk (see High-risk products section below), 
141  which would preclude the extrapolation of BE under fasting conditions to fed conditions. In such 
142  cases, BE under fed conditions also needs to be demonstrated. 
143  The design of a BE study with regard to the use of fasting and/or fed conditions depends on the 
144  dosing instructions of the comparator product as well as the properties of the drug substance and 
145  product formulation. A rationale should be provided for the selection of the type of BE study(ies) 
146  (fasting or fed or both) and meal type, e.g., fat and calorie content, based on the understanding of 
147  the comparator product and the test product (high or non-high risk) as described below. The 
148  rationale can be supported by modelling, e.g., appropriately validated/qualified physiologically-
149  based pharmacokinetic (PBPK) modelling or semi-mechanistic absorption models. 
150  In addition, safety-related aspects need to be considered when selecting the appropriate condition 
151  for a BE study regarding food intake.   If safety concerns make it unethical to administer a single 
152  dose of the drug product under either fed or fasted conditions, the BE study should be conducted 
153  under the condition with less safety concerns. 
154  For non-high-risk products, the following is recommended: 
155    For a product that is labelled to be taken only under fasting conditions or can be taken 
156  under fasting or fed conditions i.e., without regard to food, a single BE study conducted 
157  under fasting conditions is recommended to demonstrate bioequivalence. 
158    For a product that is labelled to be taken only with food due to PK reasons, e.g., enhancing 
159  absorption or reducing variability, a single BE study conducted under fed conditions is 
160  recommended to demonstrate bioequivalence.  
161    For a product that is labelled to be taken only with food due to tolerability reasons, e.g., 
162  stomach irritation, a single BE study conducted under either fasting or fed conditions is 
163  acceptable. 
164   
165  High-risk products: 
166  High-risk products are those where the complexity of the formulation design or manufacturing 
6  ICH M13A Guideline 
167  process leads to an increased likelihood that in vivo performance will be impacted differently by 
168  varying gastrointestinal (GI) conditions between the fasted and fed states. For these products, 
169  performance differences related to differences in formulation and/or manufacturing process may 
170  not be detected with a single BE study, i.e., results from a fasting BE study may not be extrapolated 
171  to predict fed BE study outcome or vice versa, thus both fasting and fed BE studies should be 
172  conducted. For example, some drug products containing low solubility drug substances (as defined 
173  by the BCS low solubility criterion described in ICH M9) have complex formulation and/or 
174  manufacturing methods (such as solid dispersions, microemulsions, lipid-based formulations, 
175  nanotechnologies, or other specialised technologies) to ensure sufficient solubility of the drug 
176  substance and dissolution of the drug products or to manage the impact of food. For these high-
177  risk products, BE studies should be conducted under both fasting and fed conditions, irrespective 
178  of the product labelling with regard to food intake, except when safety concerns make it unethical 
179  to administer a single dose of the drug product under either fed or fasted conditions. Then the BE 
180  study should be conducted under the condition with less safety concerns. 
181  Especially for low solubility drug substances, the comparator product may be the result of an 
182  extensive formulation and/or manufacturing process development program, obtaining for instance 
183  a specific formulation without a food effect. If the test product uses a substantially different 
184  manufacturing technology or particle size control method from the comparator, or if substantially 
185  different excipients are used in the test and comparator that are likely to impact dissolution, 
186  solubility, or permeability, this may warrant the need for BE studies under fasting and fed 
187  conditions. 
188  The above principles with regard to fasting and fed study conditions also apply when BE studies 
189  are deemed necessary to bridge formulation and/or manufacturing process changes during pre- or 
190  post-marketing phases.   
191  Standardisation with regard to meals and water: 
192  For studies conducted under fasting conditions, subjects should be fasted for at least 10 hours 
193  before drug administration. Subjects should be allowed water as desired, except for 1 hour before 
194  and 1 hour after drug administration. The dose should be administered with a standardised volume 
195  of water, in the range of 150 to 250 millilitres (ml).  No food should be allowed for at least 4 hours 
7  ICH M13A Guideline 
196  post-dose on each day of drug administration and meals taken should be standardised with respect 
197  to composition and timing. 
198  In the case of studies conducted under fed conditions, the same controls should be employed with 
199  the exception that a pre-dose meal should be provided. For a fed BE study, it is recommended that 
200  subjects start the meal 30 minutes before administration of the drug product and consume the meal 
201  within 30 minutes. 
202  If BE studies are conducted under both fasting and fed conditions, i.e., for high-risk products, the 
203  BE study conducted under fed conditions should be conducted using a meal that has the potential 
204  to cause the greatest effect on GI physiology. The meal should be a high-fat (approximately 50% 
205  of total caloric content of the meal) and high-calorie (approximately 800 to 1000 kcal) meal, which 
206  should derive approximately 150, 250, and 500-600 kcal from protein, carbohydrate, and fat, 
207  respectively.  It is recognised that there may be situations where it is appropriate to administer a 
208  pre-dose meal with a different caloric/fat content from these recommendations, e.g., for studies 
209  performed in patient populations who cannot tolerate the recommended meal composition.   
210  If, however, only one BE study conducted under fed conditions is needed for a non-high-risk 
211  product, either a high-fat, high-calorie meal or a low-fat, low-calorie meal, e.g., a meal of 
212  approximately 500 kcal with approximately 25% of calories from fat, may be administered. If the 
213  type of meal to be consumed at the time of drug product administration is clearly specified in the 
214  comparator product labelling, then this meal should be employed in the BE study.  
215  The composition of the meal to be administered should be described with regard to protein, 
216  carbohydrate, and fat content (specified in grams, kcal, and relative caloric content (%)) in the 
217  study protocol. 
218  In all situations, subjects should abstain from foods and drinks that may interact with circulatory, 
219  GI transporter, GI enzymatic, hepatic, or renal function, e.g., alcoholic or caffeinated drinks, or 
220  certain fruit juices such as grapefruit juice, during a suitable period before and during the study. 
221  2.1.6  Dose or Strength to be Studied 
222  In case of an application with multiple strengths, the strength to be used in the BE study depends 
223  on the dose proportionality in PK and solubility of the analyte. Generally, the highest to-be-
8  ICH M13A Guideline 
224  marketed strength can be administered as a single unit. Selection of a lower strength may also be 
225  accepted if the highest strength cannot be administered to healthy subjects for safety and/or 
226  tolerability reasons and dose proportional PK, i.e., area under the concentration vs time curve 
227  (AUC) and C , has been documented over the range of strengths. If warranted to achieve 
max
228  sufficient bioanalytical sensitivity, multiple units of the highest strength can be administered, 
229  provided the total single-dose remains within the labelled dose range and the total dose is safe for 
230  administration to the study subjects.  
231  For non-proportional increases in AUC and/or C  with increased dose there may be a difference 
max
232  between different strengths in the sensitivity to detect potential differences between formulations. 
233  To assess dose proportionality, the applicant should consider all available data regarding dose 
234  proportionality. Assessment of dose proportionality should consider single-dose studies only. 
235  For drugs with a more than proportional increase in AUC and/or C  with increasing dose over 
max
236  the therapeutic dose range, the BE study should in general be conducted at the highest strength.  
237  For drugs with a less than proportional increase in AUC and/or C  with increasing dose over the 
max
238  therapeutic dose range, BE should be established at the lowest strength if this situation is due to 
239  saturation of absorption. If the less than proportional increase in AUC and/or C with increasing 
max 
240  dose is due to limited drug solubility, BE studies should be conducted at both the lowest and highest 
241  strengths.  If the reason for non-dose proportionality is unknown, BE studies should generally be 
242  conducted at both the lowest and highest strengths. 
243  2.1.7  Moieties to be Measured 
244  2.1.7.1 Parent versus Metabolite 
245  Demonstration of BE should be based on the analysis of the parent drug because the concentration-
246  time profile of the parent drug is usually considered more sensitive to detect a difference between 
247  formulations than metabolite data. This also applies to prodrugs. However, some prodrugs are 
248  rapidly eliminated resulting in difficulties in demonstrating BE based on parent drug data, because 
249  the parent drug levels are too low to allow reliable bioanalytical measurement. In this situation, it 
250  is acceptable to demonstrate BE based on a primary metabolite, i.e., a first-step metabolite of the 
251  parent drug, without measurement of the parent compound. 
9  ICH M13A Guideline 
252  In rare cases, demonstration of BE based on the parent drug alone may not be sufficient and the 
253  primary active metabolite should also be considered, e.g., drugs that have metabolites formed 
254  through gut wall or gut lumen metabolism that contribute to efficacy or safety. This is intended to 
255  address situations in which the formation of the metabolite could be influenced by formulation 
256  differences, which may not be detectable when measuring systemic levels of the parent drug. 
257  2.1.7.2 Enantiomers versus Racemates 
258  The use of an achiral bioanalytical assay to measure the racemate is  generally acceptable. 
259  However, a stereoselective assay measuring individual enantiomers in BE studies should be 
260  employed when it is known that all of the following conditions have been met: 
261  a)  the enantiomers exhibit different pharmacodynamic properties, 
262  b)  the enantiomers exhibit different PK properties, and 
263  c)  the exposure (AUC) ratio of enantiomers is  modified by a difference in the rate of 
264  absorption. 
265  It is sufficient to demonstrate BE for only the active enantiomer in cases where one enantiomer is 
266  inactive (or makes a low contribution) with respect to both safety and efficacy. 
267  2.1.8  Sampling 
268  The sampling schedule in a BE study should cover the concentration-time curve, including a pre-
269  dose sample, samples in the absorption phase, frequent samples around the expected T , and 
max
270  sufficient samples after T  to ensure a reliable estimate of the extent of exposure, which is 
max
271  achieved when AUC  covers at least 80% of AUC . This period is usually at least three times 
(0-t) (0-inf)
272  the terminal halflife of the drug, unless a suitable truncated AUC, e.g., AUC  is used. To 
(0-72h),
273  permit calculation of the relevant PK parameters, a sufficient number of samples should be 
274  collected per subject per period, distributed across all phases of disposition. 
275  The exact times at which the samples are taken should be recorded to obtain the elapsed time 
276  relative to drug administration and sampling should be spaced such that C , AUC , and k  can 
max (0-t) el
277  be estimated accurately.  
278  There may be considerable inaccuracies in the estimates of k  if the constant is estimated from 
el
279  linear regression based on a small number of data points. To reduce these inaccuracies, it is 
10  ICH M13A Guideline 
280  recommended that three or more data points in the terminal log-linear phase of the concentration-
281  time curve be used to estimate kel. 
282  In multiple-dose studies, the pre-dose sample should be taken immediately before dosing, i.e., 
283  within 5 minutes of dosing, and the last sample is recommended to be taken within 10 minutes of 
284  the nominal time for the dosage interval to ensure an accurate determination of AUC . 
(0-tauSS)
285  2.1.8.1 First Point C  
max
286  The sampling schedule should include frequent sampling around the anticipated T  to provide a 
max
287  reliable estimate of C . In particular, the occurrence of C  at the first post-dose sampling time 
max max
288  point should be avoided by careful consideration of the known pharmacokinetic properties of the 
289  drug and selection of a suitable early sampling schedule. Datasets where C  occurs at the first 
max
290  post-dose sampling time may result in exclusion of the data from affected subjects from the 
291  analysis.  
292  2.1.8.2 Long Half-life Drugs and Truncated AUC Considerations 
293  Truncating AUC for orally administered IR drug products known to exhibit longer elimination 
294  half-lives, i.e., 24 hours or longer, mitigates the clinical challenge of prolonged sampling and 
295  follow-up. For such products, AUC  may be used in place of AUC  for comparison of the 
(072h) (0-t)
296  extent of absorption. Seventy-two hours is considered to be adequate to ensure completion of GI 
297  transit of the drug product and absorption of the drug substance.  
298  2.1.8.3 Early Exposure 
299  For orally administered IR drug products, BE can generally be demonstrated by measurement of 
300  rate and extent of absorption, i.e., C  and AUC . However, in some situations, C  and 
max (0-t) max
301  AUC  may be insufficient to adequately assess the BE between two products, e.g., when the 
(0- t)
302  early onset of action is clinically relevant. In these cases, an additional PK parameter, such as area 
303  under the concentration vs. time curve between two specific time points (pAUC), may be applied. 
304  This pAUC is typically evaluated from the time of drug administration until a predetermined time-
305  point that is related to a clinically relevant pharmacodynamic measure.  Samples should be spaced 
306  such that the pAUC can be estimated accurately. 
11  ICH M13A Guideline 
307  2.2  Data Analysis for Non-Replicate Study Design 
308  2.2.1  Considerations for the Bioequivalence Analysis Population 
309  It is imperative that all criteria for study subject inclusion into the BE analysis population be clearly 
310  defined in the  study protocol. Any exclusions from the  BE  analysis population should be 
311  documented prior to bioanalytical analysis, e.g., subjects that are withdrawn from the study, have 
312  protocol violations, or experience GI disturbances potentially affecting absorption. 
313  2.2.1.1 Removal of Data Due to Low Exposure 
314  BE studies are studies with a smaller number of subjects compared to other clinical trials. An 
315  extreme value in the dataset can have a large impact on the outcome of the BE study. Although 
316  statistical tests may identify extreme values in the PK variables, such data should not be removed 
317  from the statistical analysis of BE studies solely on this basis. Data should only be removed from 
318  the statistical analysis based on protocol violations which are contemporaneously documented. A 
319  prospective plan should be included in the study protocol for removing data from the BE statistical 
320  analysis. 
321  An exception to the above can be made for a subject without measurable concentrations or only 
322  very low concentrations following either comparator or test product administration. A subject is 
323  considered to have very low concentrations if the AUC for that period is less than 5% of the 
324  geometric mean AUC of the product in question, which should be calculated without inclusion of 
325  data from the subject. These very low concentrations are considered the result of subject non-
326  compliance and should, as far as possible, be avoided by documenting mouth check of subjects 
327  after administration of study medication to ensure the subjects have swallowed the drug product. 
328  The exclusion of data for this reason will only be accepted in exceptional cases (in general with 
329  no more than 1 subject in each study) and may bring the reliability of dose administration into 
330  question. 
331  Data from redosing studies are not considered evidence to support removal of extreme values from 
332  the statistical analysis. 
333  Note that  all  subject data  should be submitted and potential extreme values flagged with 
334  appropriate documentation as part of the application. 
12  ICH M13A Guideline 
335  2.2.2  Presentation of Data 
336  2.2.2.1 Concentration Time Data 
337  For both the test and comparator products, the drug concentration in a suitable biological fluid, 
338  e.g., plasma, serum or blood, determined at each sampling time point should be tabulated for each 
339  subject participating in the study, along with descriptive statistics. These data should be presented 
340  on the original scale, i.e., as unadjusted, measured drug concentrations. Deviations from the 
341  protocol, e.g., missed samples or samples with significant time deviation, should be clearly 
342  identified. Drug concentrations in study samples should be measured in accordance with ICH M10, 
343  Bioanalytical Method Validation and Study Sample Analysis. 
344  Two concentration-time graphs (linear and log-linear) should be provided for both the test and 
345  comparator products for each individual subject. In addition, two concentration-time graphs (linear 
346  and log-linear) should be provided for both the test and comparator products for the mean drug 
347  concentrations of all subjects. For the individual subject concentration-time graphs, the drug 
348  concentrations should be plotted against time using the actual sampling times. For the mean 
349  concentration-time graphs the drug concentrations should be plotted using the nominal sampling 
350  times.   
351  2.2.2.2 Pharmacokinetic Analysis 
352  For single-dose studies, the following PK parameters should be tabulated for each subject-
353  formulation combination: 1)  primary  parameters  for  analysis: AUC ,  C , and,  where 
(0-t) max  
354  applicable, pAUC, and 2) additional parameters for analysis to assess the acceptability of the 
355  bioequivalence study: AUC , AUC /AUC , T , k , and t . For single-dose studies, 
(0-inf) (0-t) (0-inf) max el 1/2
356  AUC  should cover at least 80% of AUC . If the AUC /AUC percentage is less than 
(0-t) (0-inf) (0-t) (0-inf) 
357  80% in more than 20% of the observations, then the validity of the study may need to be discussed 
358  in the submission. If the AUC is truncated at 72 hours for long half-life drugs, the primary AUC 
359  parameter for analysis is AUC  and the following additional parameters are not required: 
(0-72h)
360  AUC  AUC /AUC , k  and t  
(0-inf), (0-t) (0-inf) el, 1/2. 
361  Summary statistics to be reported include geometric mean, median, arithmetic mean, standard 
362  deviation, coefficient of variation, number of observations, minimum, and maximum. Each 
13  ICH M13A Guideline 
363  variable should be computed using the actual time of sampling for each concentration data point. 
364  The non-compartmental methods used to derive the PK parameters from the raw data should be 
365  reported, e.g., linear trapezoidal method for AUC and the number of data points of the terminal 
366  log-linear phase used to estimate the terminal elimination rate constant (k ). 
el
367  For multiple-dose studies, applicants should document appropriate dosage administration and 
368  sampling to demonstrate the attainment of steady-state. For steady-state studies, the following PK 
369  parameters should be tabulated: 1) primary parameters for analysis: C  and AUC , and 2) 
maxSS (0-tauSS)
370  additional parameters for analysis: C , C , C , degree of fluctuation, swing, and T .  
tauSS minSS avSS max
371  Any concentration reported as below the lower limit of quantification (LLOQ) should be treated 
372  as zero in PK parameter calculations. Values below the LLOQ are to be omitted from the 
373  calculation of K  and t . 
el 1/2
374  2.2.2.3 Potency Differences in Lots 
375  The results from the potency assay of the test and comparator products should be submitted and 
376  the test product batch should be within 5% of the comparator product batch. In exceptional cases 
377  where a comparator product batch with a measured drug content within 5% of a test product batch 
378  cannot be obtained, a potency correction may be accepted with supporting justification, e.g., 
379  potency data  from  multiple  lots  of  comparator product, pending market  availability, and 
380  considering the totality of evidence. If potency correction is to be used, this intention should be 
381  pre-specified in the study protocol. Analysis should be provided for both uncorrected data and for 
382  potency-corrected data.  If the potency correction is justifiable, the applicable BE standards should 
383  be met on potency-corrected data.   
384  2.2.3  Statistical Analysis 
385  2.2.3.1 General Considerations 
386  The statistical analyses should include all data for all subjects who provide evaluable data for the 
387  products being compared. Decisions made to exclude subjects from the BE analysis population, 
388  e.g., due to incomplete sampling or protocol violation, should be documented at the end of the 
389  clinical blood sampling portion of the study and prior to subject sample analysis. A study will not 
390  be considered acceptable if there are fewer than 12 evaluable subjects for a crossover analysis or 
14  ICH M13A Guideline 
391  for each treatment arm for a parallel analysis. 
392  The assessment of BE  is based on 90% confidence intervals for the geometric mean ratios 
393  (test/comparator) for the primary PK parameters under consideration. This method is equivalent 
394  to two one-sided t-tests with the null hypotheses of bioinequivalence at the 5% significance level. 
395  The data should be transformed prior to analysis using a logarithmic transformation. 
396  The model to be used for the analysis should be pre-specified in the study protocol. The statistical 
397  analysis should take into account sources of variation that can be reasonably assumed to have an 
398  effect on the response variable.  
399  The report on the data analysis should be sufficiently detailed to enable the PK and the statistical 
400  analyses to be repeated, e.g., data on actual time of blood sampling after dose, drug concentrations, 
401  the values of the PK parameters for each subject in each period, and the randomisation scheme 
402  should be provided. 
403  2.2.3.2 Crossover Design Studies 
404  Conventional two-treatment, two-period, two-sequence randomised crossover design studies 
405  should be analysed using an appropriate parametric method, e.g., ANOVA. The tables resulting 
406  from such analyses including the appropriate statistical tests of all effects in the model should be 
407  submitted, e.g., a summary of the testing of Sequence, Subject within Sequence, Period, and 
408  Formulation effects should be presented. In general, the primary analyses should include all data 
409  for all subjects who provide evaluable data for both the test and comparator products. 
410  2.2.3.3 Carry-over 
411  A test for carry-over is not considered relevant and no decisions regarding the analysis, e.g., 
412  analysis of the first period only, should be made on the basis of such a test. In crossover studies, 
413  the potential for carry-over can be directly addressed by examination of the pre-treatment plasma 
414  concentrations in period 2 and beyond if applicable, e.g., period 3 in a 3-period study. 
415  If there are subjects for whom the pre-dose concentration is greater than 5% of the C  value for 
max
416  the subject in that period, then the pivotal statistical analysis should be performed excluding the 
417  data from that subject.  
15  ICH M13A Guideline 
418  2.2.3.4 Parallel Design Studies   
419  The  statistical  analysis  for  parallel  design  studies  should  reflect  independent  samples. 
420  Demographic characteristics or other relevant covariates known to affect the PK  should be 
421  balanced across groups, to the extent possible. The use of stratification in the randomisation 
422  procedure based on a limited number of known relevant factors is therefore recommended. Those 
423  factors are also recommended to be accounted for in the pre-defined primary statistical analysis. 
424  Post hoc and data-driven adjustments are not acceptable for the primary statistical analysis. 
425  2.2.3.5 Multi-Group Design Studies 
426  Sample size requirements and/or study logistics may necessitate studies to be conducted with 
427  groups of subjects. The BE study should be designed to minimise the group effect in the study. 
428  The combination of multiple factors may complicate the designation of group.  
429  BE should be determined based on the overall treatment effect in the whole study population. In 
430  general, the assessment of BE in the whole study population should be done without including the 
431  Group by Treatment interaction term in the model, but applicants may also use other pre-specified 
432  models, as appropriate. However, the appropriateness of the statistical model should be evaluated 
433  to account for the multi-group nature of the BE study. Applicants should evaluate potential for 
434  heterogeneity of treatment effect across groups, i.e., Group by Treatment interaction. If the Group 
435  by Treatment interaction is significant, this should be reported and the root cause of the Group by 
436  Treatment interaction should be investigated to the extent possible. Substantial differences in the 
437  treatment effect for PK parameters across groups should be evaluated. Further analysis and 
438  interpretation may be warranted in case heterogeneity across groups is observed. 
439  In multicentre BE studies, when there are very few subjects in some sites, these subjects may be 
440  pooled into one group for consideration in the statistical analysis. Rules for pooling subjects into 
441  one group should be pre-specified and a sensitivity analysis is recommended.  
442  Statistical methods and models should be fully pre-specified. Data-driven post hoc analysis is 
443  highly discouraged but could be considered only in very rare cases where a very robust scientific 
444  justification is provided. 
16  ICH M13A Guideline 
445  2.2.4  Bioequivalence Criteria 
446  For the majority of drug products, the PK parameters to demonstrate BE include C  and AUC .   
max (0--t)
447  For drugs with a long elimination half-life, AUC  may be used in place of AUC  (see Section 
(072h) (0-t)
448  2.1.8.2). For drugs where it is clinically relevant to assess the early exposure or early onset of 
449  action, an additional PK parameter, pAUC, may be used to establish BE (see Section 2.1.8.3).   
450  The 90% confidence interval for the geometric mean ratio of these PK parameters used to establish 
451  BE should lie within a range of 80.00 - 125.00%. 
452  2.2.5  Multiple Comparator and Multiple Test Product Studies 
453  2.2.5.1 Multiple Comparator Products 
454  It may be necessary to demonstrate BE between a test product and multiple comparator products 
455  to meet requirements from multiple jurisdictions. In such case, including comparator products 
456  from different regions in one trial is acceptable to streamline the BE demonstration by conducting 
457  one single higher-order crossover BE study with multiple comparator products. 
458  Although there are  multiple comparator products tested, multiplicity correction, i.e.,  alpha 
459  adjustment, is not needed because comparator products are considered independent and region-
460  specific. Decisions will be made independently about a test product relative to a single comparator 
461  product within a single jurisdiction. It is preferred for the statistical analysis to only test two at a 
462  time and not all at once, making pairwise comparison within the analysis. 
463  It is possible that the results meet the BE acceptance criteria with one region-specific comparator 
464  product but not meet BE acceptance criteria with the other region-specific comparator product. In 
465  such case, BE is demonstrated with one comparator product and not demonstrated with the other 
466  comparator product. The protocol should specify the main objectives of the study and which 
467  comparisons are to be performed. 
468  Complete study results from all comparisons performed should be included in the clinical study 
469  report. 
470  2.2.5.2 Multiple Test Products 
471  It may be necessary to demonstrate BE between multiple test products and the comparator product, 
17  ICH M13A Guideline 
472  e.g., in order to include different test formulations that may be required due to drug development 
473  needs. To streamline the demonstration of BE, it is permitted to conduct one single crossover BE 
474  study with multiple test products.   
475  The need to apply multiplicity correction in pivotal trials depends on the underlying objectives of 
476  the trial: 
477  a)  If the objective is to achieve BE for all test formulations versus the comparator product, 
478  then no alpha adjustment is needed.   
479  b)  If the objective is to show BE for any of the test formulations, then multiplicity adjustment 
480  may be needed.  
481  The objective of the trial and method for multiplicity correction should be pre-specified in the 
482  study protocol. 
483  3  SPECIFIC TOPICS 
484  3.1  Endogenous Compounds 
485  As endogenous compounds are identical to the drug that is being administered it can be challenging 
486  to determine the amount of drug released from the dosage form and absorbed for BE assessment. 
487  Therefore, in most cases, it is important to measure the baseline endogenous concentrations in 
488  biological matrices, e.g., blood, plasma, or urine, and subtract these concentrations from the total 
489  concentrations measured from each subject after the drug product is administered. 
490  When the endogenous concentrations are influenced by diet, restricting or standardising the dietary 
491  intake of the substance before and during the study should be considered.  
492  The exact method for baseline correction should be pre-specified and justified in the study 
493  protocol. Multiple baseline endogenous concentrations should be measured from each subject in 
494  the time period before administration of the study drug. The time-averaged baseline or time-
495  matched baseline concentrations are subtracted from post-dose concentrations for those subjects 
496  in an appropriate manner consistent with the PK properties of the drug. For the time-averaged 
497  method, either the mean or median value may be used.  
498  Baseline concentrations should be determined for each period and baseline correction should be 
18  ICH M13A Guideline 
499  period specific. It should be ensured that the washout period is of an adequate duration because 
500  carry-over effects cannot be readily detected. If  a baseline correction results in a negative 
501  concentration value, the value should be set equal to zero. 
502  PK and statistical analyses should be performed on both baseline uncorrected and baseline 
503  corrected data. In general, determination of BE should be based on the baseline corrected data.  
504  Alternatively, the need for baseline correction may be avoided by enrolling study subjects with 
505  low or no production of the endogenous compounds. 
506  3.2  Other Immediate-Release Dosage Forms 
507  3.2.1  Orally Disintegrating Tablets 
508  Orally Disintegrating Tablets (ODTs) should be administered in BE studies according to the 
509  comparator product labelling with regard to intake of water.  
510  If the comparator product labelling states that the ODT can be taken with or without water, the test 
511  and comparator products should be administered in the BE  study without water, as this is 
512  considered to be the more discriminating scenario. BE of the test and comparator ODT products 
513  taken with water can then be inferred.  
514  For new intended label use/instructions, e.g., ODT as an extension to another orally administered 
515  IR drug product, BE studies may be conducted to determine whether the ODT is BE to the 
516  comparator product. In this scenario, the ODT product should be administered according to its 
517  intended labelling and compared with the comparator product administered as per its labelling.   
518  If the new intended label use/instructions states that the ODT can be taken with or without water, 
519  a 3-arm BE study is recommended to determine BE of the ODT administered with and without 
520  water compared to the comparator product administered as per its labelling.  
521  In studies evaluating ODTs without water, it is recommended to wet the mouth by swallowing a 
522  small amount of water, e.g., 20 ml, directly before applying the ODT on the tongue. It is 
523  recommended not to allow fluid intake earlier than 1 hour after administration. 
524  Other oral formulations such as orodispersible films, buccal tablets or films, and sublingual tablets 
19  ICH M13A Guideline 
525  may be handled in a similar way to that described above for ODTs.  
526  3.2.2  Chewable Tablets 
527  Chewable tablets should be administered in BE studies according to the comparator product 
528  labelling with regard to intake of water.  
529  If the comparator product labelling states that the chewable tablets can be taken with or without 
530  water, the test and comparator products should be administered in the BE study without water, as 
531  this is considered to be the more discriminating scenario. BE of the test and comparator chewable 
532  tablet products taken with water can then be inferred.  
533  For new intended label use/instructions, e.g., chewable tablets as an extension to another orally 
534  administered IR drug product, BE studies may be conducted to determine whether the chewable 
535  tablet is BE to the comparator product. In this scenario, the chewable tablet product should be 
536  administered according to its intended labelling and compared with the comparator product 
537  administered as per its labelling. 
538  If the new intended label use/instructions state that the chewable tablets can be taken with or 
539  without water, a 3-arm BE study is recommended to determine BE of the chewable tablets 
540  administered with and without water compared to the comparator product administered as per its 
541  labelling. 
542  3.2.3  Oral Suspensions 
543  For tablets, granules, and powders labelled as being only intended to be dispersed in a liquid before 
544  administration as an oral suspension, BE studies should be conducted according to the comparator 
545  product labelling. 
546  For new intended label use/instructions (not included in the comparator product labelling), the test 
547  product should be administered according to  its intended labelling and compared with  the 
548  comparator product administered as per its labelling. 
549  3.3  Fixed Dose Combination 
550  The BE study design for fixed-dose combination products should follow the principles described 
551  in  this guideline. BE  should be determined using a  PK  sampling scheme suitable for  the 
20  ICH M13A Guideline 
552  determination of  the PK  parameters of  the  individual components (drugs) and employing 
553  bioanalytical methods validated for the determination of the individual drugs in the presence of 
554  the other component(s) in the combination product. PK parameters to be assessed and reported are 
555  those that would normally be required for each drug if it were in the formulation as a single entity. 
556  BE should be demonstrated for all components (drugs) in the fixed-dose combination product 
557  according to the principles described in  this guideline. Failure to demonstrate BE  for one 
558  component of the fixed-dose combination results in failure to demonstrate BE for the proposed 
559  fixed-dose combination product as a whole. 
560  3.4  pH-Dependency 
561  The absorption of drug substances with pH-dependent solubility may be influenced by the gastric 
562  pH. This impact on drug absorption can be altered due to the use of, for instance, pH stabilising 
563  excipients or a specific salt-form in the formulation. Moreover, the formulation of the final 
564  marketed comparator product may be the result of an extensive formulation development program, 
565  obtaining for instance a specific formulation without an effect on drug absorption due to gastric 
566  pH differences. This is especially relevant in cases where it is foreseen that the product will be 
567  taken with acid reducing drug products, e.g., proton pump inhibitors, or is going to be used in 
568  certain populations, e.g., patients with achlorhydria. Therefore when, relative to the comparator 
569  product, there are qualitative or quantitative differences in  the pH  stabilising excipient(s), 
570  significant differences in manufacturing process, or differences in salt form that possess a different 
571  pH dependent solubility, BE under normal fasting conditions between the two products may not 
572  ensure BE of the two products in a gastric pH-altered situation, e.g., in the presence of a pH-
573  modifying drug product. In such a situation, an additional BE study with concomitant treatment of 
574  a pH-modifying drug product would generally be necessary to demonstrate BE.  
575  Applicants may provide a scientific justification to demonstrate that a BE study in a gastric pH-
576  altered situation may not be needed. Such a justification should be based on the totality of evidence 
577  referring to the pH-solubility profile of the drug substance, impact of excipients, formulation and 
578  manufacturing design, e.g., formulation designed to overcome pH effects, extent of the differences 
579  between the test and comparator products, and comparative dissolution testing at multiple pHs. 
580  Modelling,  e.g.,  appropriately  validated/qualified  PBPK  modelling  or  semi-mechanistic 
581  absorption models, and virtual  BE  simulation may be  used to  further assess the  risk  of 
21  ICH M13A Guideline 
582  bioinequivalence. 
583  4  DOCUMENTATION 
584  The report of the BE study should include the complete documentation of its protocol, conduct, 
585  and evaluation. It should be written in accordance with ICH E3, Structure and Content of Clinical 
586  Study Reports.  
587  Names and affiliations of the responsible investigator(s), the site of the study, and the period of its 
588  execution should be stated.  
589  Listing of inspection history for BE studies conducted at the relevant clinical and bioanalytical 
590  site(s) for the 5 years preceding completion of the study should also be provided in the study report 
591  (but may alternatively be provided elsewhere in the Common Technical Document (CTD)). 
592  Comparator product name, strength, pharmaceutical form, batch number, manufacturer, expiration 
593  date, and country of purchase should be stated. 
594  Certificates of analysis, or equivalent documents, of comparator and test batches used in the study 
595  should be included in an appendix to the study report. 
596  The identity of the of the test product(s) used in the study should be provided, i.e., pharmaceutical 
597  form, strength, batch number, and measured content (%  of  label  claim). The  batch size, 
598  manufacturing date (and, if available, the expiry date) as well as the qualitative and quantitative 
599  composition of the test product should also be indicated (but may alternatively be provided 
600  elsewhere in the CTD). 
601  Concentrations and PK data and statistical analyses should be presented in the level of detail 
602  described in this guideline (see Section 2.2). The reporting format should include tabular and 
603  graphical presentations showing individual and mean results and summary statistics. 
604  Information on bioanalytical method validation and study sample analysis according to ICH M10 
605  should be included in the appropriate section of Module 5 of the CTD. 
606  The data generated should be properly documented and available for audit and inspection. 
22  ICH M13A Guideline 
607  Essential documents should be archived in accordance with ICH E6 and applicable regulatory 
608  requirements. 
609  Data in a suitable electronic format should be submitted to enable the PK and the statistical 
610  analyses to be repeated, e.g., data on actual times of blood sampling, drug concentrations, the 
611  values of the PK parameters for each subject in each period, and the randomisation scheme. 
612  Module 2.7.1 of the CTD should list all relevant BE studies conducted regardless of the study 
613  outcome.  Full study reports should be provided for the BE study(ies) upon which the applicant 
614  relies for approval. For all other studies, synopses of the study reports (in accordance with ICH 
615  E3) are sufficient. However, complete study reports for these studies should be available upon 
616  request. 
617  5  GLOSSARY   
618  Applicant: 
619  The entity submitting the application for marketing authorisation to the relevant regulatory 
620  authority. 
621  AUC: 
622  Area under the concentration vs. time curve 
623  AUC (0-inf): 
624  Area under the concentration vs. time curve extrapolated to infinity 
625  AUC (0-t): 
626  Area under the concentration vs. time curve from time zero to the time of last quantifiable 
627  concentration 
628  AUC (0-tauSS): 
629  Area under the concentration vs. time curve for one dosing interval at steady state 
23  ICH M13A Guideline 
630  AUC(0-72h): 
631  Area under the concentration vs. time curve from time 0 to 72 hours 
632  Batch (or Lot): 
633  A specific quantity of material produced in a process or series of processes so that it is expected to 
634  be homogeneous within specified limits. In the case of continuous production, a batch may 
635  correspond to a defined fraction of the production. The batch size can be defined either by a fixed 
636  quantity or by the amount produced in a fixed time interval.  
637  Batch Number (or Lot Number): 
638  A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from 
639  which the production and distribution history can be determined.  
640  CavSS: 
641  Average concentration observed during dosing interval at steady state (AUC /tau) 
0-tau
642  Chewable Tablets: 
643  An oral dosage form designed to facilitate chewing and swallowing by the patient rather than 
644  swallowing a whole tablet. They must be chewed or crushed before swallowing.  
645  Cmax: 
646  Maximum concentration after dosing 
647  CmaxSS: 
648  Maximum concentration observed during dosing interval at steady state 
649  CminSS: 
650  Minimum concentration observed during dosing interval at steady state 
651  Comparator (Product): 
24  ICH M13A Guideline 
652  An investigational or marketed product, i.e., active control, or placebo, used as a reference in a 
653  clinical trial. In the context of this guidance, a comparator product is the drug product accepted by 
654  regulatory agencies that an applicant can use to compare against the test product in conducting a 
655  BE study.   
656  Ctau: 
657  Concentration observed at end of dosing interval 
658  CtauSS: 
659  Concentration observed at end of dosing interval at steady state 
660  Enantiomers: 
661  Compounds with the same molecular formula as the drug substance, which differ in the spatial 
662  arrangement of atoms within the molecule and are nonsuperimposable mirror images.  
663  Endogenous Compounds: 
664  Compounds already present in the body either because the body produces them or because they 
665  are present in a normal diet. 
666  Fluctuation: 
667  [(C -C ) / C ] 
maxSS minSS avSS
668  Immediate-Release: 
669  Allows the drug to dissolve in the GI contents, with no intention of delaying or prolonging the 
670  dissolution or absorption of the drug.  
671  kcal: 
672  A unit used to describe amount of energy in relation to food or energy burned with exercise. When 
673  it comes to nutrition and exercise, kilocalories (kcal) and calories equal the same amount of energy. 
674  One kcal (kilocalorie) equals 1 calorie in nutrition. 
25  ICH M13A Guideline 
675  kel: 
676  The apparent terminal elimination rate constant of the drug. 
677  Orally Disintegrating Tablet:  
678  A solid dosage form which is designed to disintegrate and dissolve rapidly on contact with saliva 
679  when placed on the tongue or in the oral cavity, thus eliminating the need to chew the tablet, 
680  swallow an intact tablet, or take the tablet with water.  
681  pAUC: 
682  Area under the concentration vs. time curve between two specific time points 
683  Protocol: 
684  A document that describes the objective(s), design, methodology, statistical considerations, and 
685  organisation of a trial. The protocol usually also gives the background and rationale for the trial, 
686  but these could be provided in other protocol referenced documents. Throughout ICH E6, Good 
687  Clinical Practice, the term protocol refers to protocol and protocol amendments.  
688  Racemate: 
689  A composite (solid, liquid, gaseous, or in solution) of equimolar quantities of two enantiomeric 
690  species. It is devoid of optical activity. 
691  Spare Subject: 
692  A study subject that is included in the drug administration and sample collection regimens of a 
693  study but, as per study protocol, whose data will only be included in the PK and statistical analysis 
694  if the number of evaluable study subjects drops below a pre-specified number due to subject 
695  dropouts and/or withdrawals (use of spare subjects is not acceptable). 
696  Sponsor: 
697  An individual, company, institution, or organisation which takes responsibility for the initiation, 
698  management, and/or financing of a clinical trial.  
26  ICH M13A Guideline 
699  Swing: 
700  [(C   C ) / C ] 
maxSS minSS minSS
701  Tau: 
702  Dosing Interval 
703  Tmax: 
704  Time to maximum observed concentration 
705  t1/2: 
706  Half-life 
27