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Tuesday, June 30, 2009

THE ASEAN COMMON TECHNICAL DOSSIER (ACTD) FOR THE REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE - ORGANIZATION OF THE DOSSIER

PREAMBLE
This ASEAN Common Technical Dossier (ACTD) is a guideline of the agreed upon common
format for the preparation of a well-structured Common Technical Dossier (CTD) applications
that will be submitted to ASEAN regulatory authorities for the registration of pharmaceuticals
for human use. This guideline describes a CTD format that will significantly reduce the time
and resources needed to compile applications for registration and in the future, will ease the
preparation of electronic documental submissions. Regulatory reviews and communication with
the applicant will be facilitated by a standard document of common elements.
This guideline merely demonstrates an appropriate write-up format for acquired data. However,
applicants can modify, if needed, to provide the best possible presentation of the technical
information, in order to facilitate the understanding and evaluation of the results upon
pharmaceutical registration.
Throughout the ACTD, the display of information should be unambiguous and transparent, in
order to facilitate the review of the basic data and to help a reviewer become quickly oriented to
the application contents. Text and tables should be prepared using margins that allow the
document to be printed on either A4 or 8.5 x 11 paper. The left-hand margin should be
sufficiently large that information is not obscured by the method of binding. Font and size,
(Times New Roman, 12-point font), for text and tables should be of a style and size that are
large enough to be easily legible, even after photocopying. Every page should be numbered,
with the first page of each part designated as page 1. For a paper, Common Technical Acronyms
and abbreviations should be defined the first time they are used in each part. References should
be cited in accordance with the 1979 Vancouver Declaration on Uniform requirements for
Manuscripts Submitted to Biomedical Journals.
The Common Technical Document is organized into four parts as follows:
Part I. Table of Contents, Administrative Data and Product Information.
Part I contains initially the overall Table of Contents of the whole ACTD to provide
basicaly the informations that could be looked through respectively. Secondly, the next
content is the Administrative Data where required specific documentation in details is
put together such as application forms, label, package insert etc. The last section of this
part is Product Information where necessary information includes prescribed
information, mode of action, side effects etc.
A general introduction to the pharmaceutical, including its pharmacologic class and
mode of action should be included.
Part II. Quality Document
Part II should provide the Overall Summary followed by the Study Reports. The
quality control document should be described in details as much as possible.
Part III. Nonclinical1 Document
Part III should provide the Nonclinical Overview, followed by the Nonclinical
Written Summaries and the Nonclinical Tabulated Summaries. The document of this
part is not required for Generic Products, Minor Variation Products and some Major
Variation Products. For ASEAN member countries, the Study Reports of this part
may not be required for NCE, Biotechnological Products and other Major Variation
Products if the Original Products are already registered and approved for market
authorization in Reference Countries. Therefore, the authority who requires specific
Study Reports should ask for the necessary documents.
Part IV Clinical Document
Part IV should provide the Clinical Overview and the Clinical Summary. The
document of this part is not required for Generic Products, Minor Variation Products
and some Major Variation Products. For ASEAN member countries, the Study
Reports of this part may not be required for NCE, Biotechnological Products and
other Major Variation Products if the Original Products are already registered and
approved for market authorization in Reference Countries. Therefore, the authority
who requires specific Study Reports should ask for the necessary documents.
The overall organisation of the Common Technical Dossier is presented on the following in
Parts:
Part I : Table of Content Administrative Information and Prescribing Information
Section A: Introduction
Section B: Overall ASEAN Common Technical Dossier Table of Contents
Section C: Documents required for registration (for example, application forms, labelling,
Product Data Sheet, prescribing information)
Part II : Quality Document
Section A: Table of Contents
Section B: Quality Overall Summary
Section C: Body of Data
Part III : Nonclinical Document
Section A: Table of Contents
Section B: Nonclinical Overview
Section C: Nonclinical Written and Tabulated Summaries
1. Table of Contents
2. Pharmacology
3. Pharmacokinetics
4. Toxicology
Section D: Nonclinical Study Reports
1 The word “Nonclinical” replaces “Pre-clinical”
1. Table of Contents
2. Pharmacology
3. Pharmacokinetics
4. Toxicology
Part IV : Clinical Document
Section A: Table of Contents
Section B: Clinical Overview
Section C: Clinical Summary
1. Summary of Biopharmaceutics and Associated Analytical
Methods
2. Summary of Clinical Pharmacology Studies
3. Summary of Clinical Efficacy
4. Summary of Clinical Safety
5. Synopses of Individual Studies
Section D: Tabular Listing of All Clinical Studies
Section E: Clinical Study Reports
Section F: List of Key Literature References



Sunday, June 28, 2009

ASEAN GUIDELINES FOR THE CONDUCT OF BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES

1 INTRODUCTION
To exert an optimal therapeutic action an active moiety should be delivered to
its site of action in an effective concentration for the desired period. To allow
reliable prediction of the therapeutic effect the performance of the dosage
form containing the active substance should be well characterised.
In the past, several therapeutic misadventures related to differences in
bioavailability (e.g. digoxin, phenytoin, primidone) testify to the necessity of
testing the performance of dosage forms in delivering the active substance to
the systemic circulation and thereby to the site of action. Thus the
bioavailability of an active substance from a pharmaceutical product should
be known and reproducible. This is especially the case if one product
containing one certain active substance is to be used instead of its innovator
product. In that case the product should show the same therapeutic effect in
the clinical situation. It is generally cumbersome to assess this by clinical
studies.
Comparison of therapeutic performances of two medicinal products
containing the same active substance is a critical means of assessing the
possibility of altenative use between the innovator and any essentially similar
medicinal product. Assuming that in the same subject an essentially similar
plasma concentration time course will result in essentially similar
concentrations at the site of action and thus in an essentially similar effect,
pharmacokinetic data instead of therapeutic results may be used to establish
equivalence: bioequivalence.
It is the objective of this guidance to define, for products with a systemic
effect, when bioavailability or bioequivalence studies are necessary and to
formulate requirements for their design, conduct, and evaluation. The
possibility of using in vitro instead of in vivo studies with pharmacokinetic end
points is also envisaged.
This guideline should be read in conjunction with other pertinent elements
outlined in current and future ASEAN, EU and ICH guidelines and regulations
especially those on:
• Pharmacokinetic Studies in Man
• Modified Release Oral and Transdermal Dosage Forms: Section I
(Pharmacokinetic and Clinical Evaluation)

• Modified Release Oral and Transdermal Dosage Forms: Section II
(Quality)
• Investigation of Chiral Active Substances.
• Fixed Combination Medicinal Products
• Clinical Requirements for Locally Applied, Locally Acting Products
Containing Known Constituents.
• The Investigation of Drug Interactions
• Development Pharmaceutics
• Process Validation
􀂃 ASEAN Process Validation
• Manufacture of the Finished Dosage Form
• Validation of analytical procedures: Definitions and Terminology (ICH
topic Q2A)
• Validation of analytical procedures: Methodology (ICH topic Q2B)
􀂃 ASEAN Analytical Validation
• Structure and Content of Clinical Study Reports (ICH topic E3)
• Good Clinical Practice: Consolidated Guideline (ICH topic E6)
• General Considerations for Clinical Trials (ICH topic E8)
• Statistical Principles for Clinical Trials (ICH topic E9)
• Choice of Control Group in Clinical Trials (ICH topic El 0)
• Common Technical Document (ICH topic M4)
􀂃 ASEAN Common Technical Document
􀂃 Multisource(Generic) Pharmaceutical Products: Guidelines on
registration Requirements to establish Interchangeability (WHO)
For medicinal products not intended to be delivered into the general
circulation the common systemic bioavailability approach cannot be applied.
Under these conditions the (local) availability may be assessed, where
necessary, by measurements quantitatively reflecting the presence of the
active substance at the site of action using methods specially chosen for
that combination of active substance and localisation (see section 5.1.8). In
this case, as well as in others, alternative methods may be required such as
studies using pharmacodynamic end points. Furthermore, where specific
requirements for different types of products are needed, the appropriate
exceptions are mentioned therein.
This Guidelines does not explicitly apply to biological products.

2 DEFINITIONS
Before defining bioavailability and related terminology some definitions
pertaining to dosage and chemical forms are given:
2.1 Pharmaceutical equivalence
Medicinal products are pharmaceutically equivalent if they contain the same
amount of the same active substance(s) in the same dosage forms that
meet the same or comparable standards.
Pharmaceutical equivalence does not necessarily imply bioequivalence as
differences in the excipients and/or the manufacturing process can lead to
faster or slower dissolution and/or absorption.
2.2 Pharmaceutical alternatives
Medicinal products are pharmaceutical alternatives if they contain the same
active moiety but differ in chemical form (salt, ester, etc.) of that moiety or in
the dosage form or strength.
2.3 Bioavailability
Bioavailability means the rate and extent to which the active substance or
active moiety is absorbed from a pharmaceutical form and becomes
available at the site of action.
In the majority of cases substances are intended to exhibit a systemic
therapeutic effect, and a more practical definition can then be given, taking
into consideration that the substance in the general circulation is in
exchange with the substance at the site of action:
- Bioavailability is understood to be the extent and the rate at
which a substance or its active moiety is delivered from a
pharmaceutical form and becomes available in the general
circulation.
It may be useful to distinguish between the "absolute bioavailability" of a
given dosage form as compared with that (100%) following intravenous
administration (e.g. oral solution vs. iv.), and the "relative bioavailability" as
compared with another form administered by the same or another non
intravenous route (e.g. tablets vs. oral solution).

2.4 Bioequivalence
Two medicinal products are bioequivalent if they are pharmaceutically
equivalent or pharmaceutical alternatives and if their bioavailabilities after
administration in the same molar dose are similar to such degree that their
effects, with respect to both efficacy and safety, will be essentially the same.
Alternatively to classical bioavailability studies using pharmacokinetic end
points to assess bioequivalence, other types of studies can be envisaged
conducted, e.g. human studies with clinical or pharmacodynamic end points,
studies using animal models or in vitro studies as long as they are
appropriately justified and/or validated.
2.5 Essentially similar products
"A medicinal product is essentially similar to an original product where it
satisfies the criteria of having the same qualitative and quantitative
composition in terms of active substances, of having the same
pharmaceutical form, and of being bioequivalent unless it is apparent in the
light of scientific knowledge that it differs from the original original product as
regards safety and efficacy".
By extension, it is generally considered that for immediate release products
the concept of essential similarity also applies to different oral forms (tablets
and capsules) with the same active substance.
The need for a comparative bioavailability study to demonstrate
bioequivalence is identified under 5.1. Concerns about differences in
essentially similar medicinal products lie on the use of different excipients
and methods of manufacture that ultimately might have an influence on
safety and efficacy. A bioequivalence study is the widely accepted means of
demonstrating that these differences have no impact on the performance of
the formulation with respect to rate and extent of absorption, in the case of
immediate release dosage forms. It is desirable that excipients must be
devoid of any effect or their safe use is ensured by appropriate warning in
the package label and not interfere with either the release or the absorption
process.
An essentially similar product can be used instead of its innovator product.
An `innovator' product is a medicinal product authorised and marketed on
the basis of a full dossier i.e. including chemical, biological, pharmaceutical,
pharmacological-toxicological and clinical data. A 'Reference Product' must
be an 'innovator' product . (see 3.5).
If the innovator product is not available in the country, an alternative drug
regulatory approved comparator product can be used. If the innovator

product is not available in the country, an alternative comparator product
approved by drug regulatory authority of the country can be used.
2.6 Therapeutic equivalence
A medicinal product is therapeutically equivalent with another product if it
contains the same active substance or therapeutic moiety and, clinically,
shows the same efficacy and safety as that product, whose efficacy and
safety has been established.
In practice, demonstration of bioequivalence is generally the most
appropriate method of substantiating therapeutic equivalence between
medicinal products, which are pharmaceutically equivalent or
pharmaceutical alternatives, provided they contain excipients generally
recognised as not having an influence on safety and efficacy and comply
with labelling requirements with respect to excipients. (see 2.5).
However, in some cases where similar extent of absorption but different
rates of absorption are observed the products can still be judged
therapeutically equivalent if those differences are not of therapeutic
relevance. A clinical study to prove that differences in absorption rate are
not therapeutically relevant will probably be necessary.
3 DESIGN AND CONDUCT OF STUDIES
In the following sections, requirements for the design and conduct of
bioavailability or bioequivalence studies are formulated. It is assumed that
the applicant is familiar with pharmacokinetic theories underlying
bioavailability studies. The design should be based on a reasonable
knowledge of the pharmacodynamics and/or the pharmacokinetics of the
active substance in question. For the pharmacokinetic basis of these studies
reference is made to the recommendation "Pharmacokinetic studies in
man". The design and conduct of the study should follow ICH/ EUregulations
on Good Clinical Practice, including reference to an Ethics
Committee. The rights, safety, and well-being of all trial subjects must
always be respected and should be given special attention.
A bioequivalence study is basically a comparative bioavailability study
designed to establish equivalence between test and reference products. The
following sections apply mainly to bioequivalence studies. Since
bioavailability studies are comparative in nature, the contents of the
following sections apply to these studies as well, with the necessary
adaptations in accordance with the aim of each specific study. Where
necessary, specific guidance concerning bioavailability studies will be given.

The methodology of bioequivalence studies can be used to assess
differences in the pharmacokinetic parameters in pharmacokinetic studies
such as drug-drug or food-drug interactions or to assess differences in
subsets of the population. In this case the relevant guidelines should be
followed and the selection of subjects, the design and the statistical analysis
should be adjusted accordingly.
3.1 Design
The study should be designed in such a way that the formulation effect can
be distinguished from other effects. If the number of formulations to be
compared is two, a two-period, two sequence crossover design is often
considered to be the design of choice.
However, under certain circumstances and provided the study design and
the statistical analyses are scientifically sound alternative well-established
designs could be considered such as parallel design for very long half-life
substances and replicate designs for substances with highly variable
disposition
In general, single dose studies will suffice, but there are situations in which
steady-state studies
• may be required, e.g. in the case of
- dose- or time-dependent pharmacokinetics,
- some modified release products (in addition to single dose
investigations),
• or can be considered, e.g.
- if problems of sensitivity preclude sufficiently precise plasma
concentration measurements after single dose administration.
- if the intra-individual variability in the plasma concentration or
disposition precludes the possibility of demonstrating
bioequivalence in a reasonably sized single dose study and this
variability is reduced at steady state.
In such steady-state studies the administration scheme should follow the
usual dosage recommendations.
The number of subjects required is determined by
a) the error variance associated with the primary characteristic to be
studied as estimated from a pilot experiment, from previous studies or
from published data,
b) the significance level desired,
c) the expected deviation from the reference product compatible with
bioequivalence (delta , ie percentage difference from 100 %)and
d) the required power.

The clinical and analytical standards imposed may also influence the
statistically determined number of subjects. However, generally the
minimum number of subjects should be not smaller than 12 unless justified.
Washout Period
Subsequent treatments should be separated by periods long enough to
eliminate the previous dose before the next one (adequate wash out periods).
In steady-state studies wash out of the previous treatment last dose can
overlap with the build-up of the second treatment, provided the build-up
period is sufficiently long (at least three times the terminal half-life).
Sampling
The sampling schedule should be planned to provide an adequate estimation
of Cmax and to cover the plasma concentration time curve long enough to
provide a reliable estimate of the extent of absorption. This is generally
achieved if the AUC derived from measurements is at least 80% of the AUC
extrapolated to infinity. If a reliable estimate of terminal half-life is necessary,
it should be obtained by collecting at least three to four samples during the
terminal log linear phase.
For most drugs, 12- 18 samples is enough, e.g. 1 point at zero time, 2 points
before C max, 4-5 points around C max, and 7-8 points during the elimination
phase. However, when elimination half-life of the parent drug or active
metabolites is extremely long, blood samples should be collected for at least
72 hours.
In order to study bioavailability under steady-state conditions when
differences between morning and evening or nightly dosing are known, (e.g. if
it is known that the circadian rhythm is known to have an influence on
bioavailability), sampling should be carried out over a full 24 hours cycle.
For drugs with a long half-life, relative bioavailability can be adequately
estimated using truncated AUC as long as the total collection period is
justified. In this case the sample collection time should be adequate to ensure
comparison of the absorption process.
3.2 Subjects
3.2.1 Selection of subjects
The subject population for bioequivalence studies should be selected with the
aim to minimise variability and permit detection of differences between
pharmaceutical products. Therefore, the studies should normally be
performed with healthy volunteers. The inclusion/exclusion criteria should be
clearly stated in the protocol.

Subjects could belong to either sex; however, the risk to women of
childbearing potential should be considered on an individual basis.
In general, subjects should be between 18 - 55 years old capable of giving
informed consent and of weight within the normal range according to
accepted life tables (cf. Supplement I) or Body Mass Index (BMI) of 18-30.
Normally for Asians the recommended BMI is of 18-25.In general, subjects
should be between 18 - 55 years old capable of giving informed consent and
of weight within the normal range according to accepted normal values for the
Body Mass Index (BMI) of 18-30 . Normally for ASIANs the recommended
BMI is of 18-25. They should be screened for suitability by means of clinical
laboratory tests, an extensive review of medical history, and a comprehensive
medical examination. Depending on the drug's therapeutic class and safety
profile special medical investigations may have to be carried out before,
during and after the completion of the study. Subjects should preferably be
non-smokers and without a history of alcohol or drug abuse. If moderate
smokers are included (less than 10 cigarettes per day) they should be
identified as such and the consequences for the study results should be
discussed.
3.2.2 Standardisation of the study
The test conditions should be standardised in order to minimise the variability
of all factors involved except that of the products being tested. Therefore,
standardisation of the diet, fluid intake and exercise is recommended.
Subjects should preferably be fasting at least during the night prior to
administration of the products. If the Summary of Product Characteristics of
the reference product contains specific recommendations in relation with food
intake related to food interaction effects the study should be designed
accordingly.
The time of day for ingestion should be specified and as fluid intake may
profoundly influence gastric passage for oral administration forms, the volume
of fluid (at least 150 ml) should be constant. All meals and fluids taken after
the treatment should also be standardised in regard to composition and time
of administration during the sampling period.
Prior to and during each study phase, (1) subjects should be allowed water as
desired except for one hour before and after drug administration,(2) hot drink
or juice may be provided after 3 hours of drug administration,(3) standard
meals for each both study periods can be provided no less than 4 hours after
drug administration.

One unit of the highest marketed strength or a clinical usual dose should
generally be given. A higher dose which does not exceed the maximal dose
of the dosage regime or labelled dose range may be employed when
analytical difficulties exist.
However, if the adverse events are too great or too risky, then the smaller
dose unit is allowed.
The subjects should not take other medicines during a suitable period before
and during the study and should abstain from food and drinks, which may
interact with circulatory, gastrointestinal, liver or renal function (e.g. alcoholic
or xanthine-containing beverages or certain fruit juices). As the bioavailability
of an active moiety from a dosage form could be dependent upon
gastrointestinal transit times and regional blood flows, posture and physical
activity may need to be standardised.
3.2.3 Inclusion of patients
If the investigated active substance is known to have adverse effects and the
pharmacological effects or risks are considered unacceptable for healthy
volunteers it may be necessary to use patients instead, under suitable
precautions and supervision. In this case the applicant should justify the
alternative.
3.2.4. Genetic phenotyping
Phenotyping and/or genotyping of subjects should be considered for
exploratory bioavailability studies and all studies using parallel group design.
It may be considered as well in crossover studies (e.g. bioequivalence, dose
proportionality, food interaction studies etc.) for safety or pharmacokinetic
reasons. If a drug is known to be subject to major genetic polymorphism,
studies could be performed in panels of subjects of known phenotype or
genotype for the polymorphism in question.
3.3 Characteristics to be investigated
In most cases evaluation of bioavailability and bioequivalence will be based
upon the measured concentrations of the parent compound. In some
situations, however, measurements of an active or inactive metabolite may be
necessary instead of the parent compound. Such situations include cases
where the use of a metabolite may be advantageous to determine the extent
of drug input, e.g. if the concentration of the active substance is too low to be
accurately measured in the biological matrix (e.g. major difficulty in analytical
method, product unstable in the biological matrix or half-life of the parent
compound too short) thus giving rise to significant variability.

Bioequivalence determinations based on metabolites should be justified in
each case bearing in mind that the aim of a bioequivalence study is intended
to compare the in vivo performance of test and reference products. In
particular if metabolites significantly contribute to the net activity of an active
substance and the pharmacokinetic system is non-linear, it is necessary to
measure both parent drug and active metabolite plasma concentrations and
evaluate them separately.
In bioavailability studies, the shape of and the area under the plasma
concentration versus time curves are mostly used to assess extent and rate
of absorption. The use of urine excretion data may be advantageous in
determining the extent of drug input in case of products predominately
excreted renally, but has to be justified when used to estimate the rate of
absorption. Sampling points or periods should be chosen, such that the timeconcentration
profile is adequately defined so as to allow the estimation of
relevant parameters.
From the primary results, the bioavailability characteristics desired are
estimated, namely AUCt, AUC∞, Cmax, tmax, Aet, Ae∞ as appropriate, or any
other justifiable characteristics (cf Appendix I). The method of estimating
AUC-values should be specified. For additional information t 1/2 and MRT
can be estimated. For studies in steady state AUCτ Cmax, Cmin and fluctuation
should be provided.
In bioequivalence studies the AUCt is the most reliable reflection of the extent
of absorption.
The exclusive use of compartmental based estimates are not recommended.
If pharmacodynamic effects are used as characteristics the measurements
should provide a sufficiently detailed time course, the initial values in each
period should be comparable and the complete effect curve should remain
below the maximum physiological response.
Specificity, accuracy and reproducibility of the methods should be sufficient.
The non-linear character of the dose/response relationship should be taken
into account and base line corrections should be considered during data
analysis.
3.4 Chemical analysis
The bioanalytical part of bioequivalence trials should be conducted according
to the applicable principles of Good Laboratory Practice (GLP). (EMEA/OECD
GLP / WHO GLP STANDARD/ISO/IEC 17025/1999)
The bioanalytical methods used to determine the active moiety and/or its
biotransformation product(s) in plasma, serum, blood or urine or any other

suitable matrix must be well characterised, fully validated and documented to
yield reliable results that can be satisfactorily interpreted. The main objective
of method validation is to demonstrate the reliability of a particular method for
the quantitative determination of an analyte(s) concentration in a specific
biological matrix. The characteristics of a bioanalytical method essential to
ensure the acceptability of the performance and the reliability of analytical
results are: (1) stability of the stock solutions and of the analyte(s) in the
biological matrix under processing conditions and during the entire period of
storage; (2) specificity; (3) accuracy; (4) precision (5) limit of quantification
and (6) response function.
The validation of a bioanalytical method should comprise two distinct phases:
(1) the prestudy phase in which the compliance of the assay with the six
characteristics listed above is verified and (2) the study phase itself in which
the validated bioanalytical method is applied to the actual analysis of samples
from the biostudy mainly in order to confirm the stability, accuracy and
precision.
A calibration curve should be generated for each analyze in each analytical
run and it should be used to calculate the concentration of the analyte in the
unknown samples in the run. A number of separately prepared Quality
Control samples should be analysed with processed test samples at intervals
based on the total number of samples. In addition, it is necessary to validate
the method of processing and handling the biological samples.
All procedures should be performed according to pre-established Standard
Operating Procedures (SOPs). All relevant procedures and formulae used to
validate the bioanalytical method should be submitted and discussed. Any
modification of the bioanalytical method before and during analysis of study
specimens may require adequate revalidation; all modifications should be
reported and the scope of revalidation justified.
According to the requirements of the note for guidance on the "Investigation
of Chiral Active Substances", bioequivalence studies supporting applications
for essentially similar medicinal products containing chiral active substances
should be based upon enantiomeric bio-analytical methods unless (1) both
products contain the same stable single enantiomer; (2) both products contain
the racemate and both enantiomers show linear pharmacokinetics.
3.5 Reference and test product
Test products in an application for a generic product are normally compared
with the corresponding dosage form of an innovator (see 2.5) medicinal
product (reference product). The choice of reference product should be
justified by the applicant and agreed upon by the regulatory authority .

If the innovator product is not available, an alternative comparator product
approved by drug regulatory authority of the coubtry can be used.
The test products used in the biostudy must be prepared in accordance with
GMP-regulations. Batch control results of the test product should be reported.
In the case of oral solid forms for systemic action the test product should
usually originate from a batch of at least 1/10 of production scale or 100 000
units, whichever is greater, unless otherwise justified. The production of
batches used should provide a high level of assurance that the product and
process will be feasible on an industrial scale; in case of production batch
smaller than 100 000 units, a full production batch will be required. If the
product is subjected to further scale-up this should be properly validated.
Samples of the product from full production batches should be compared with
those of the test batch, and should show similar in vitro dissolution profiles
when employing suitable dissolution test conditions (see Appendix II).
The drug contents should not differ by more than 5% between the test and
reference products.
The study sponsor will have to retain a sufficient number of all investigational
product samples in the study for one year in excess of the accepted shelf life or
two years after completion of the trial or until approval whichever is longer to
allow re-testing, if it is requested by the authorities.
Reference and test product must be packed in an individual way for each
subject included in the bioequivalence trial. Every effort should be made to
allow a precise tracking of administration of the reference and test products to
the subjects, for instance by the use of labels with a tear-off portion.
3.6. Data analysis
The primary concern of bioequivalence assessment is to quantify the difference
in bioavailability between the reference and test products and to demonstrate
that any clinically important difference is unlikely.
3.6.1 Statistical analysis
The statistical method for testing relative bioavailability (e.g. bioequivalence) is
based upon the 90% confidence interval for the ratio of the population means
(Test/Reference), for the parameters under consideration.
This method is equivalent to the corresponding two one-sided test procedure
with the null hypothesis of bioinequivalence at the 5% significance level. The
statistical analysis (e.g. ANOVA) should take into account sources of variation
that can be reasonably assumed to have an effect on the response variable. A
statistically significant sequence effect should be handled appropriately.

Pharmacokinetic parameters derived from measures of concentration, e.g.
AUC, Cmax should be analysed using ANOVA. The data should be transformed
prior to analysis using a logarithmic transformation.
If appropiate to the evaluation the analysis technique for t max should be nonparametric
and should be applied to untransformed data. For all
pharmacokinetic parameters of interest in addition to the appropriate 90%
confidence intervals for the comparison of the two formulations, summary
statistics such as median, minimum and maximum should be given.
3.6.2 Acceptance range for pharmacokinetic parameters
The pharmacokinetic parameters to be tested, the procedure for testing and
the acceptance ranges should be stated beforehand in the protocol.
In studies to determine average bioequivalence the acceptance intervals for
the main characteristics are detailed as follows:
AUC-ratio
The 90% confidence interval for this measure of relative bioavailability
should lie within an acceptance interval of 0.80-1.25. In specific cases of a
narrow therapeutic range the acceptance interval may need to be tightened.
In rare cases a wider acceptance range may be acceptable if it is based on
sound clinical
Cmax-ratio
The 90% confidence interval for this measure of relative bioavailability
should lie within an acceptance interval of 0.80-1.25. In specific cases of a
narrow therapeutic range the acceptance interval may need to be tightened.
In certain cases a wider interval may be acceptable. The interval must be
prospectively defined e.g. 0.75-1.33 and justified addressing in particular
any safety or efficacy concerns for patients switched between formulations.
Others
Statistical evaluation of tmax only makes sense if there is a clinically relevant
claim for rapid release or action or signs related to adverse effects. The nonparameterc
90% confidence interval for this measure of relative
bioavailability should lie within a clinically determined range.
For other (see 3.3) pharmacokinetic parameters in comparison relative
bioavailability (e.g. Cmin, Fluctuation, t12, etc.) considerations analogous to
those for AUC, Cmax or tmax apply, taking into consideration the use of logtransformed
or untransformed data, respectively.

3.6.3 Handling deviations from the study plan
The method of analysis should be planned in the protocol. The protocol
should also specify methods for handling drop-outs and for identifying
biologically implausible outliers. Post hoc exclusion of outliers is generally
not accepted. If modeling assumptions made in the protocol ( e.g. for
extrapolating AUC to infinity) turn out to be invalid, a revised analysis in
addition to the planned analysis ( if this is feasible) should be presented and
discussed.
The Outliers could not be omitted, if there is no strong reason on technical
fault reason.. Data analysis should be done both with and/ without these data
and the impact to the final result should be discussed. Medical or
pharmacokinetic explanation is needed for such observations.
3.6.4 A remark on individual and population bioequivalence
To date, most bioequivalence studies are designed to evaluate average
bioequivalence. Experience with population and individual bioequivalence
studies is limited. Therefore, no specific recommendation is given on this
matter.
3.7 In vitro dissolution complementary to a bioequivalence study
The results of "in vitro" dissolution tests, obtained with the batches of test
and reference products that were used in the bioequivalence study should
be reported. The results should be reported as profiles of percent of labelled
amount dissolved versus time.
The specifications for the in vitro dissolution of the product should be
derived from the dissolution profile of the batch that was found to be
bioequivalent to the reference product and would be expected to be similar
to those of the reference product (see Appendix 11).
For immediate release products, if the dissolution profile of the test product
is dissimilar compared to that of the reference product and the in vivo data
remain acceptable the dissolution test method should be re-evaluated and
optimised. In case that no discriminatory test method can be developed which
reflects in vivo bioequivalence a different dissolution specification for the test
product could be set.
3.8 Reporting of results
The report of a bioavailability or a bioequivalence study should give the
complete documentation of its protocol, conduct and evaluation complying
with GCP-rules and related EU and ICH E3 guidelines. This implies that the
authenticity of the whole of the report is attested by the signature of the

principal investigator. The responsible investigator(s), if any, should sign for
their respective sections of the report.
Names and affiliations of the responsible investigator (s), site of the study and
period of its execution should be stated. The names and batch numbers of
the products used in the study as well as the composition(s), finished product
specifications and comparative dissolution profiles should be provided. In
addition, the applicant should submit a signed statement confirming that the
test product is the same as the one that is submitted for marketing
authorisation.
All results should be clearly presented and should include data from subjects
who eventually dropped-out. Drop-out and withdrawal of subjects should be
fully documented and accounted for. The method used to derive the
pharmacokinetic parameters from the raw data should be specified. The data
used to estimate AUC should be reported. If pharmacokinetic models are
used to evaluate the parameters the model and computing procedure used
should be justified. Deletion of data should be justified.
All individual subject data should be given and individual plasma
concentration/time curves presented in linear/linear and log/linear scale. The
analytical report should include the results for all standard and quality control
samples as well. A representative number of chromatograms or other raw
data should be included covering the whole concentration range for all,
standard and quality control samples as well as the specimens analysed. The
analytical validation report should be submitted as well.
The statistical report should be sufficiently detailed to enable the statistical
analysis to be repeated, e.g. randomisation scheme, demographic data,
values of pharmacokinetic parameters for each subject, descriptive statistics
for each formulation and period. A detailed ANOVA and/or non-parameterc
analysis, the point estimates and corresponding confidence intervals including
the method of their estimation should also be included.
4 APPLICATIONS FOR PRODUCTS CONTAINING NEW ACTIVE
SUBSTANCES
4.1 Bioavailability
In the case of new active substances (new chemical entities) intended for
systemic action, the pharmacokinetic characterisation will have to include the
determination of the systemic availability of the substance in its intended
pharmaceutical form in comparison with intravenous administration. If this is
not possible (e.g. not technically feasible or for safety reasons) the

bioavailability relative to a suitable oral solution or suspension should be
determined. In the case of a prodrug the intravenous reference solution
should preferably be made of the active moiety.
4.2 Bioequivalence
During development bioequivalence studies are necessary as bridging
studies between (i) pivotal and early clinical trial formulations; (ii) pivotal
clinical trial formulations, especially those used in the dose finding studies,
and the to-be-marketed medicinal product; (iii) other
comparisons depending on the situation. Such studies may be exempted if
the absence of differences in the in vivo performance can be justified by
satisfactory in vitro data (see 5.1.1 and 5.2).
5 APPLICATIONS FOR PRODUCTS CONTAINING APPROVED
ACTIVE SUBSTANCES
5.1 Bioequivalence studies
In vivo bioequivalence studies are needed when there is a risk that possible
differences in bioavailability may result in therapeutic inequivalence.
The kind of studies to be performed may vary with the type of product, as
follows.
5.1.1. Oral Immediate Release Forms with Systemic Action
This section pertains to dosage forms such as tablets, capsules and oral
suspensions and takes into consideration criteria derived from the concepts
underlying the Biopharmaceutics Classification System, i.e. high solubility,
high permeability for the active substance and high dissolution rate for the
medicinal product. These criteria, along with a non-critical therapeutic range
should be primarily considered; therefore the following characteristics have
to be taken into account in order to justify the request for exemption from in
vivo bioequivalence studies. Hence data must be supplied to justify the
absence of such studies.
a) Characteristics related to the active substance:
i - risk of therapeutic failure or adverse drug reactions:
this risk depends on the requirements of special precautions
with respect to precision and accuracy of dosing of the active
substance, e.g. the need for critical plasma concentrations;
ii - risk of bioinequivalence:

evidence of bioavailability problems or bioinequivalence exists
for some specific active substances;
Iii - solubility:
When the active substance is highly water soluble, the product
could be in general exempted from bioquivalence studies
unless, considering the other characteristics, the exemption
could entail a potential risk. Polymorphism and particle size are
major determinants of dissolution rate and special attention
should be paid to these characteristics. An active substance is
considered highly water soluble if the amount contained in the
highest dose strength of an immediate release product is
dissolved in 250 ml of each of three buffers within the range of
pH 1-8 at 37°C (preferably at or about pH 1.0, 4.6, 6.8);
iv - pharmacokinetic properties:
linear and complete absorption indicating high permeability
reduces the possibility of an immediate release dosage form
influencing the bioavailability.
b) Characteristics related to the medicinal product:
i - rapid dissolution
in case of exemption from bioequivalence studies, in vitro data
should demonstrate the similarity of dissolution profile between
the test product and the reference product in each of three
buffers within the range of pH 1-8 at 37°C (preferably at or
about pH 1.0, 4.6, 6.8). However, in cases where more than
85% of the active substance are dissolved within 15 minutes,
the similarity of dissolution profiles may be accepted as
demonstrated (see appendix II);
ii- excipients
the excipients included in the composition of the medicinal
product are well established and no interaction with the
pharmacokinetics of the active substance is expected. In case
of atypically large amounts of known excipients or new
excipients being used, additional documentation has to be
submitted;
iii - manufacture
the method of manufacture of the finished product in relation
with critical physicochemical properties of the active substance

(e.g. particle size, polymorphism) should be adequately
addressed and documented in the development pharmaceutics
section of the dossier.
5.1.2 Oral solutions
If the product is an aqueous oral solution at time of administration and
contains an active substance in the same concentration as an oral solution
currently approved as a medicinal product, no bioequivalence study is
required, provided the excipients contained in it do not affect gastrointestinal
transit, absorption or in vivo stability of the active substance.
In those cases where an oral solution has to be tested against an oral
immediate release formulation a comparative bioavailability study will be
required unless an exemption can be justified (see 5. 1. 1).
5.1.3 Non-Oral Immediate Release forms with systemic action
In general bioequivalence studies are required.
5.1.4 Modified Release and transdermal dosage forms
Requirements for bioequivalence studies in accordance with the specific
guideline
5.1.5 Fixed combinations products
Combination products should in general be assessed with respect to
bioavailability and bioequivalence of individual active substances either
separately (in the case of a new combination) or as an existing combination.
Criteria under 5.1.1 will apply to individual components. The study in case of
a new combination should be designed in such a way that the possibility of a
pharmacokinetic drug-drug interaction could be detected.
5.1.6 Parenteral solutions
The applicant is not required to submit a bioequivalence study if the product
is to be administered as an aqueous intravenous solution containing the
same active substance in the same concentration as the currently
authorised product.
In the case of other parenteral routes, e.g. intramuscular or subcutaneous, if
the product is of the same type of solution (aqueous or oily), contains the
same concentration of the same active substance and the same or
comparable excipients as the medicinal product currently approved, then
bioequivalence testing is not required.

5.1.7 Gases
If the product is a gas for inhalation a bioequivalence study is not required.
5.1.8 Locally applied products
a) Locally acting
For products for local use (after oral, nasal, inhalation, ocular, dermal,
rectal, vaginal etc. administration) intended to act without systemic
absorption the approach to determine bioequivalence based on
systemic measurements is not applicable and pharmacodynamic or
comparative clinical studies are in principle required. The lack of them
should be justified (see specific Note for Guidance).
Whenever systemic exposure resulting from locally applied, locally
acting medicinal products entails a risk of systemic adverse reactions,
systemic exposure should be measured.
b) Systemically acting
For locally applied products with systemic action a bioequivalence
study is always required.
5.2 In Vitro Dissolution
Dissolution studies are always necessary and consequently required. . In vitro
dissolution testing forms a part of the assessment of a bioequivalence waiver
request based on criteria as described in section 5.1. Dissolution studies must
follow the guidance as laid out in Appendix II.
5.3 Variations
If a product has been reformulated from the formulation initially approved or
the manufacturing method has been modified by the manufacturer in ways
that could be considered to impact on the bioavailability, a bioequivalence
study is required, unless otherwise justified. Any justification presented should
be based upon general considerations, e.g. as per 5.1.1, or on whether an
acceptable in vivo / in vitro correlation has been established.
In cases where the bioavailability of the product undergoing change has been
investigated and an acceptable correlation between in vivo performance and
in vitro dissolution has been established, the requirements for in vivo
demonstration of bioequivalence can be waived if the dissolution rate in vitro
of the new product is similar to that of the already approved medicinal product

under the same test conditions as used to establish the correlation (see
Appendix II)
In all other cases bioequivalence studies have to be performed.
For variations of the innovator product the reference product for use in
bioequivalence and dissolution studies is usually that authorised under the
current formula, manufacturing method, packaging etc. and the product
manufactured in line with the proposed changes is tested against this.
When variations to an essentially similar product are made the reference
product for the bioequivalence study should be the innovator product.
5.4 Dose proportionality in immediate release oral dosage forms
If a new application concerns several strengths of the active substance a
bioequivalence study investigating only one strength may be acceptable.
However the choice of the strength used should be justified on analytical,
pharmacokmetic and safety grounds. Furthermore -all of the following
conditions should be fulfilled:
􀂃 the pharmaceutical products are manufactured by the same manufacturer
and process;
􀂃 the drug input has been shown to be linear over the therapeutic dose
range (if this is not the case the strengths where the sensitivity is largest to
identify differences in the two products should be used);
􀂃 the qualitative composition of the different strengths is the same; except
in the case of flavours/colours.
􀂃 the ratio between amounts of active substance and excipients is the same,
or, in the case of preparations containing a low concentration of the active
substance (less than 5%), the ratio between the amounts of excipients is
similar;
􀂃 the dissolution profile should be similar under identical conditions for the
additional strengths and the strength of the batch used in the
bioequivalence study.
If a new strength (within the approved dose range) is applied for on the basis
of an already approved medicinal product and all of the stated conditions hold
then a bioequivalence study is not necessary.

5.5 Suprabioavailability
If suprabioavailability is found, i.e. if the new product displays an extent of
absorption appreciably larger than the approved product, reformulation to a
lower dosage strength should be considered. In this case, the
biopharmaceutical development should be reported and a final comparative
bioavailability study of the reformulated new product with the old approved
product should be submitted.
In case reformulation is not carried out the dosage recommendations for the
suprabioavailable product will have to be supported by clinical studies. Such a
pharmaceutical product should not be accepted as therapeutically equivalent
to the existing reference product. If marketing authorisation is obtained, the
new product may be considered as a new medicinal product.
To avoid confusion for both prescribers and patients, it is recommended that
the name of suprabioavailable product precludes confusion with the older
approved product
Suprabioavailable products cannot claim "essential similarity" (see section
2.5) with the innovator/comparator product.

APPENDIX I
Explanation of the symbols in paragraph 3.3
Cmax: maximal plasma concentration;
Cmin: minimal plasma concentration;
Cav: average plasma concentration;
tmax: time passed since administration at which the plasma
concentration maximum occurs;
AUCt: area under the plasma concentration curve from administration to
last observed concentration at time t.
AUCco: area under the plasma concentration curve extrapolated to
infinite time;
AUCτ: AUC during a dosage interval in steady state;
MRT: mean residence time;
Aet: cumulative urinary excretion from administration until time t;
Ae∞: cumulative urinary excretion extrapolated to infinite time;
t1/2: plasma concentration half-life;
Fluctuation: (Cmax - Cmin)/Cav
Swing: (Cmax – Cmin)/Cmin

APPENDIX II
Disolution testing
A medicinal product is composed of drug substance and excipients and the
proportion between them, the type of excipients and the manufacturing
method of the final product are chosen based on the content, the
physicochemical and the bulk properties of the drug and on its absorption
properties. Taken as a whole this gives each product certain dissolution
characteristics.
During the development of a medicinal product a dissolution test is used as a
tool to identify formulation factors that are influencing and may have a crucial
effect on the bioavailability of the drug. As soon as the composition and the
manufacturing process are defined a dissolution test is used in the quality
control of scale-up and of production batches to ensure both batch to-batch
consistency and that the dissolution profiles remain similar to those of pivotal
clinical trial batches. Furthermore, a dissolution test can be used to support
the bioavailability of a new drug product, the bioequivalence of an essentially
similar product or variations.
Therefore, dissolution studies can serve several purposes:
i- Quality assurance
􀂃 To get information on the test batches used in bioavailability /
bioequivalence studies and pivotal clinical studies to support specifications
for quality control.
􀂃 To be used as a tool in quality control to demonstrate consistency in
manufacture
􀂃 To get information on the reference product used in
bioavailability/bioequivalence studies and pivotal clinical studies
ii. Bioequivalence surrogate inference
􀂃 To demonstrate similarity between reference products from different
ASEAN member countries
􀂃 To demonstrate similarity between different formulations of an active
substance (variations and new, essentially similar products included) and
the reference medicinal product

􀂃 To collect information on batch to batch consistency of the products (test
and reference) to be used as basis for the selection of appropriate batches
for the in vivo study.
The test methodology should be in accordance with pharmacopoeial
requirements unless those requirements are shown to be unsatisfactory.
Alternative methods can be considered when justified that these are
discriminatory and able to differentiate between batches with acceptable and
non-acceptable performance of the product in vivo.
If an active substance is considered highly soluble, it is reasonable to expect
that it will not cause any bioavailability problems if, in addition, the dosage
system is rapidly dissolved in the physiological pH-interval expected after
product administration. A bioequivalence study may in those situations be
waived based on case history and similarity of dissolution profiles which are
based on discriminatory testing, provided that the other exemption criteria in
5.1.1 are met. The similarity should be justified by dissolution profiles,
covering at least three time points, attained at three different buffers (normally
pH range 1-6.8; in cases where it is considered necessary pH range 1-8).
In the case of a drug or excipients that are insensitive to pH, profiles from only
two buffer systems are required.
If an active substance is considered to have a low solubility and a high
permeability, the rate limiting step for absorption may be dosage form
dissolution. This is also the case when one or more of the excipients are
controlling the release and subsequent dissolution step of the active
substance. In those cases a variety of test conditions is recommended and
adequate sampling should be performed until either 90% of the drug is
dissolved or an asymptote is reached. Knowledge of dissolution properties
under different conditions e.g. pH, agitation, ionic strength, surfactants,
viscosity, osmotic pressure is important since the behaviour of the solid
system in vivo may be critical for the drug dissolution independent of the
physico-chemical properties of the active substance. An appropriate
experimental statistical design may be used to investigate the critical
parameters and for the optimisation of such conditions.
Any methods to prove similarity of dissolution profiles are accepted as long as
they are justified.
The similarity may be compared by model-independent or model-dependent
methods e.g. by linear regression of the percentage dissolved at specified
time points, by statistical comparison of the parameters of the Weibull
function or by calculating a similarity factor e.g the one defined below:




In this equation f 2 is the similarity factor, n is the number of time points, R (t)
is the mean percent drug dissolved of e.g. a reference product, and T(t) is the
mean percent drug dissolved of e.g. a test product.
The evaluation of similarity is based on the conditions of
􀂃 A minimum of three time points (zero excluded)
􀂃 12 individual values for every time point for each
formulation
􀂃 not more than one mean value of > 85% dissolved for each formulation
􀂃 that the standard deviation of the mean of any product should be less than
10% from second to last time point.
An f2 value between 50 and 100 suggests that the two dissolution profiles are
similar. In cases where more than 85% of the drug are dissolved within 15
minutes, dissolution profiles may be accepted as similar without further
mathematical evaluation.
SUPPLEMENT l
Suggested Clinical Laboratory Tests For Bioequivalence Study
• Renal Function Test
• Liver Function Test
• Blood Glucose
• Complete Blood Count
• Serology ( HIV, Hep B ) : Optional
• Pregnancy Test : If necessary
• 12- Lead Electrocardiogram

SUPPLEMENT lI
BIOEQUIVALENCE STUDY REPORTING FORMAT
Study tittle
Name of sponsor
Name and address of clinical laboratory
Name and address of analytical laboratory
Dates of clinical study (start, completion)
Signature Page
Name of Principal and Clinical Investigator(s)
Signature and date
List of other study personnel
Study Protocol
Introduction
Study Objective
Study treatments
Study methods
Reference and Test Product Information
Name, Batch Number, Batch size (test product), formulation, active ingredient,
amount of active ingredient and expiry date, finished product specifications,
comparative dissolution profiles
Clinical and Safety Records
Assay Methodology and Validation
Assay method description
Validation procedure and results
Pharmacokinetic Parameters and Tests
Definition and calculations
Figures and Tables
Statistical Analyses
Results and discussion
Conclusions
Appendices
Study Protocol
Letter of Approval of Institutional Review Board/Independent Ethical Committee

ASEAN GUIDELINES FOR VALIDATION OF ANALYTICAL PROCEDURES

VALIDATION OF ANALYTICAL PROCEDURES
1. Introduction
The objective of validation of an analytical procedure is to demonstrate that it is suitable
for its intended purpose.
This guideline is to provide the guidance and recommendation of validation of the
analytical procedures for submission as part of registration applications within ASEAN.
The document mainly adopts two ICH guidelines “Q2A: Validation of Analytical
Methods: Definitions and Terminology, 27 October 1994” and “ICH Q2B: Validation of
Analytical Procedure: Methodology, 6 November 1996. The methodology applied for
biological and biotechnological products may be approached differently than chemical
entities.
All relevant data collected during validation and formulae used for calculating validation
characteristics should be submitted and discussed as appropriate. Well-characterized
reference materials, with document purity, should be used throughout the validation study.
The degree of purity depends on the intended use.
In practice, it is usually possible to design the experimental work such that the appropriate
validation characteristics can be considered simultaneously to provide a sound, over all
knowledge of the capabilities of the analytical procedure, for instance: specificity,
linearity, range, accuracy and precision. The compendial methods are not required to be
validated, but merely verify their suitability under actual conditions of use.
For Asean requirement : All data related to the validation characteristics should be
submitted to the Drug Regulatory Authority together with the respective acceptance
criteria.
2. Types of Analytical Procedures to be Validated
The discussion of the validation of analytical procedures is directed to the four most
common types of analytical procedures:
- Identification tests.
- Quantitative tests for impurities' content.
- Limit tests for the control of impurities.
- Quantitative tests of the active moiety in samples of drug substance or drug product or
other selected component(s) in the drug product.
A brief description of the types of tests considered in this document is provided below.
- Identification tests are intended to ensure the identity of an analyte in a sample. This is
normally achieved by comparison of a property of the sample (e.g., spectrum,
chromatographic behavior, chemical reactivity, etc) to that of a reference standard.
- Testing for impurities can be either a quantitative test or a limit test for the impurity in a
sample. Either test is intended to accurately reflect the purity characteristics of the sample.
Different validation characteristics are required for a quantitative test than for a limit test.
- Assay procedures are intended to measure the analyte present in a given sample. In the
context of this document, the assay represents a quantitative measurement of the major
component(s) in the drug substance. For the drug product, similar validation characteristics
also apply when assaying for the active or other selected component(s). The same
validation characteristics may also apply to assays associated with other analytical
procedures (e.g., dissolution).
The objective of the analytical procedure should be clearly understood since this will
govern the validation characteristics which need to be evaluated. Typical validation
characteristics which should be considered are listed below:
Accuracy
Precision
Repeatability
Intermediate Precision
Reproducibility
Specificity
Detection Limit
Quantitation Limit
Linearity
Range
Robustness
Each of these validation characteristics is defined in the Glossary. The table lists those
validation characteristics regarded as the most important for the validation of different
types of analytical procedures. This list should be considered typical for the analytical
procedures cited but occasional exceptions should be dealt with on a case-by-case basis. It
should be noted that robustness is not listed in the table but should be considered at an
appropriate stage in the development of the analytical procedure.
Furthermore revalidation may be necessary in the following circumstances:
- changes in the synthesis of the drug substance;
- changes in the composition of the finished product;
- changes in the analytical procedure;
The degree of revalidation required depends on the nature of the changes. Certain other
changes may require validation as well.



- signifies that this characteristic is not normally evaluated
+ signifies that this characteristic is normally evaluated
(1) in cases where reproducibility (see glossary) has been performed, intermediate
precision is not needed
(2) lack of specificity of one analytical procedure could be compensated by other
supporting analytical procedure(s)
(3) may be needed in some cases
3. Analytical Performance Characteristics
3.1 SPECIFICITY
An investigation of specificity should be conducted during the validation of identification
tests, the determination of impurities and the assay. The procedures used to demonstrate
specificity will depend on the intended objective of the analytical procedure. It is not
always possible to demonstrate that an analytical procedure is specific for a particular
analyte (complete discrimination). In this case a combination of two or more analytical
procedures is recommended to achieve the necessary level of discrimination.
3.1.1. Identification
Suitable identification tests should be able to discriminate between compounds of closely
related structures which are likely to be present. The discrimination of a procedure may be
confirmed by obtaining positive results (perhaps by comparison with a known reference
material) from samples containing the analyte, coupled with negative results from samples
which do not contain the analyte. In addition, the identification test may be applied to
materials structurally similar to or closely related to the analyte to confirm that a positive
response is not obtained. The choice of such potentially interfering materials should be
based on sound scientific judgement with a consideration of the interferences that could
occur.
3.1.2. Assay and Impurity Test(s)
For chromatographic procedures, representative chromatograms should be used to
demonstrate specificity and individual components should be appropriately labelled.
Similar considerations should be given to other separation techniques. Critical separations
in chromatography should be investigated at an appropriate level. For critical separations,
specificity can be demonstrated by the resolution of the two components which elute
closest to each other. In cases where a non-specific assay is used, other supporting
analytical procedures should be used to demonstrate overall specificity. For example,
where a titration is adopted to assay the drug substance for release, the combination of the
assay and a suitable test for impurities can be used. The approach is similar for both assay
and impurity tests:
3.1.2.1 Impurities are available
For the assay , this should involve demonstration of the discrimination of the analyte in the
presence of impurities and/or excipients; practically, this can be done by spiking pure
substances (drug substance or drug product) with appropriate levels of impurities and/or
excipients and demonstrating that the assay result is unaffected by the presence of these
materials (by comparison with the assay result obtained on unspiked samples).
For the impurity test, the discrimination may be established by spiking drug substance or
drug product with appropriate levels of impurities and demonstrating the separation of
these impurities individually and/or from other components in the sample matrix.
3.1.2.2 Impurities are not available
If impurity or degradation product standards are unavailable, specificity may be
demonstrated by comparing the test results of samples containing impurities or degradation
products to a second well-characterized procedure e.g.: pharmacopoeial method or other
validated analytical procedure (independent procedure). As appropriate, this should include
samples stored under relevant stress conditions:
light, heat, humidity, acid/base hydrolysis and oxidation.
- for the assay, the two results should be compared.
- for the impurity tests, the impurity profiles should be compared.
Peak purity tests may be useful to show that the analyte chromatographic peak is not
attributable to more than one component (e.g., diode array, mass spectrometry).
3.2 LINEARITY
A linear relationship should be evaluated across the range (see section 3.3) of the analytical
procedure. It may be demonstrated directly on the drug substance (by dilution of a standard
stock solution) and/or separate weighings of synthetic mixtures of the drug product
components, using the proposed procedure. The latter aspect can be studied during
investigation of the range. Linearity should be evaluated by visual inspection of a plot of
signals as a function of analyte concentration or content. If there is a linear relationship,
test results should be evaluated by appropriate statistical methods, for example, by
calculation of a regression line by the method of least squares. In some cases, to obtain
linearity between assays and sample concentrations, the test data may need to be subjected
to a mathematical transformation prior to the regression analysis. Data from the regression
line itself may be helpful to provide mathematical estimates of the degree of linearity.
The correlation coefficient, y-intercept, slope of the regression line and residual sum of
squares should be submitted. A plot of the data should be included. In addition, an analysis
of the deviation of the actual data points from the regression line may also be helpful for
evaluating linearity.
Some analytical procedures, such as immunoassays, do not demonstrate linearity after any
transformation. In this case, the analytical response should be described by an appropriate
function of the concentration (amount) of an analyte in a sample.
For the establishment of linearity, a minimum of 5 concentrations is recommended.
Other approaches should be justified.
3.3 RANGE
The specified range is normally derived from linearity studies and depends on the intended
application of the procedure. It is established by confirming that the analytical procedure
provides an acceptable degree of linearity, accuracy and precision when applied to samples
containing amounts of analyte within or at the extremes of the specified range of the
analytical procedure. The following minimum specified ranges should be considered:
- for the assay of a drug substance or a finished (drug) product: normally from 80 to 120
percent of the test concentration;
- for content uniformity, covering a minimum of 70 to 130 percent of the test
concentration, unless a wider more appropriate range, based on the nature of the dosage
form (e.g., metered dose inhalers), is justified;
- for dissolution testing: +/-20 % over the specified range; e.g., if the specifications for a
controlled released product cover a region from 20%, after 1 hour, up to 90%, after 24
hours, the validated range would be 0-110% of the label claim.
- for the determination of an impurity: from the reporting level of an impurity 1 to 120%
of the specification; for impurities known to be unusually potent or to produce toxic or
unexpected pharmacological effects, the detection/quantitation limit should be
commensurate with the level at which the impurities must be controlled.
Note: for validation of impurity test procedures carried out during development, it may be
necessary to consider the range around a suggested (probable) limit;
- if assay and purity are performed together as one test and only a 100% standard is used,
linearity should cover the range from the reporting level of the impurities 1 to 120% of the
assay specification;
1 see chapters “Reporting Impurity Content of Batches” of the corresponding ICHGuidelines:
“Impurities in New Drug Substances” and “Impurities in New Drug Products”
3.4 ACCURACY
Accuracy should be established across the specified range of the analytical procedure.
3.4.1. Assay
3.4.1.1 Drug Substance
Several methods of determining accuracy are available:
a) application of an analytical procedure to an analyte of known purity (e.g. reference
material);
b) comparison of the results of the proposed analytical procedure with those of a second
well-characterized procedure, the accuracy of which is stated and/or
defined (independent procedure, see 3.1.2.);
c) accuracy may be inferred once precision, linearity and specificity have been established.
3.4.1.2 Drug Product
Several methods for determining accuracy are available:
a) application of the analytical procedure to synthetic mixtures of the drug product
components to which known quantities of the drug substance to be analysed have been
added;
b) in cases where it is impossible to obtain samples of all drug product components, it may
be acceptable either to add known quantities of the analyte to the drug product or to
compare the results obtained from a second, well characterized procedure, the accuracy of
which is stated and/or defined (independent procedure, see 3.1.2.).
c) accuracy may be inferred once precision, linearity and specificity have been
established.
3.4.2. Impurities (Quantitation)
Accuracy should be assessed on samples (drug substance/drug product) spiked with known
amounts of impurities. In cases where it is impossible to obtain samples of certain
impurities and/or degradation products, it is considered acceptable to compare results
obtained by an independent procedure (see 3.1.2.). The response factor of the drug
substance can be used.
It should be clear how the individual or total impurities are to be determined e.g.,
weight/weight or area percent, in all cases with respect to the major analyte.
3.4.3 Recommended Data
Accuracy should be assessed using a minimum of 9 determinations over a minimum of 3
concentration levels covering the specified range (e.g. 3 concentrations/3 replicates each of
the total analytical procedure).
Accuracy should be reported as percent recovery by the assay of known added amount of
analyte in the sample or as the difference between the mean and the accepted true value
together with the confidence intervals.
3.5 PRECISION
Validation of tests for assay and for quantitative determination of impurities includes an
investigation of precision.
3.5.1 Repeatability
Repeatability should be assessed using:
a) a minimum of 9 determinations covering the specified range for the procedure (e.g. 3
concentrations/3 replicates each) or
b) a minimum of 6 determinations at 100% of the test concentration.
3.5.2 Intermediate Precision
The extent to which intermediate precision should be established depends on the
circumstances under which the procedure is intended to be used. The applicant should
establish the effects of random events on the precision of the analytical procedure. Typical
variations to be studied include days, analysts, equipment, etc. It is not considered
necessary to study these effects individually. The use of an experimental design (matrix) is
encouraged.
3.5.3 Reproducibility
Reproducibility is assessed by means of an inter-laboratory trial. Reproducibility should be
considered in case of the standardization of an analytical procedure, for instance, for
inclusion of procedures in pharmacopoeias. These data are not part of the marketing
authorization dossier.
3.5.4 Recommended Data
The standard deviation, relative standard deviation (coefficient of variation) and
confidence interval should be reported for each type of precision investigated.
3.6 DETECTION LIMIT
Several approaches for determining the detection limit are possible, depending on whether
the procedure is a non-instrumental or instrumental. Approaches other than those listed
below may be acceptable.
3.6.1 Based on Visual Evaluation
Visual evaluation may be used for non-instrumental methods but may also be used with
instrumental methods.
The detection limit is determined by the analysis of samples with known concentrations of
analyte and by establishing the minimum level at which the analyte can be reliably
detected .
3.6.2. Based on Signal-to-Noise
This approach can only be applied to analytical procedures which exhibit baseline noise.
Determination of the signal-to-noise ratio is performed by comparing measured signals
from samples with known low concentrations of analyte with those of blank samples and
establishing the minimum concentration at which the analyte can be reliably detected. A
signal-to-noise ratio between 3 or 2:1 is generally considered acceptable for estimating the
detection limit.
3.6.3 Based on the Standard Deviation of the Response and the Slope
The detection limit (DL) may be expressed as:
DL = 3.3 σ/S
where σ = the standard deviation of the response
S = the slope of the calibration curve
The slope S may be estimated from the calibration curve of the analyte. The estimate of S
may be carried out in a variety of ways, for example:
3.6.3.1 Based on the Standard Deviation of the Blank
Measurement of the magnitude of analytical background response is performed by
analyzing an appropriate number of blank samples and calculating the standard deviation
of these responses.
3.6.3.2 Based on the Calibration Curve
A specific calibration curve should be studied using samples containing an analyte in the
range of DL. The residual standard deviation of a regression line or the standard deviation
of y-intercepts of regression lines may be used as the standard deviation.
3.6.4 Recommended Data
The detection limit and the method used for determining the detection limit should be
presented. If DL is determined based on visual evaluation or based on signal to noise ratio,
the presentation of the relevant chromatograms is considered acceptable for justification.
In cases where an estimated value for the detection limit is obtained by calculation or
extrapolation, this estimate may subsequently be validated by the independent analysis of a
suitable number of samples known to be near or prepared at the detection limit.
3.7 QUANTITATION LIMIT
Several approaches for determining the quantitation limit are possible, depending on
whether the procedure is a non-instrumental or instrumental. Approaches other than those
listed below may be acceptable.
3.7.1 Based on Visual Evaluation
Visual evaluation may be used for non-instrumental methods but may also be used with
instrumental methods. The quantitation limit is generally determined by the analysis of
samples with known concentrations of analyte and by establishing the minimum level at
which the analyte can be quantified with acceptable accuracy and precision.
3.7.2. Based on Signal-to-Noise Approach
This approach can only be applied to analytical procedures that exhibit baseline noise.
Determination of the signal-to-noise ratio is performed by comparing measured signals
from samples with known low concentrations of analyte with those of blank samples and
by establishing the minimum concentration at which the analyte can be reliably quantified.
A typical signal-to-noise ratio is 10:1.
3.7.3. Based on the Standard Deviation of the Response and the Slope
The quantitation limit (QL) may be expressed as:
QL = 10 σ/S
where σ= the standard deviation of the response
S = the slope of the calibration curve
The slope S may be estimated from the calibration curve of the analyte. The estimate of S
may be carried out in a variety of ways for example:
3.7.3.1 Based on Standard Deviation of the Blank
Measurement of the magnitude of analytical background response is performed by
analyzing an appropriate number of blank samples and calculating the standard deviation
of these responses.
3.7.3.2 Based on the Calibration Curve
A specific calibration curve should be studied using samples, containing an analyte in the
range of QL. The residual standard deviation of a regression line or the standard deviation
of y-intercepts of regression lines may be used as the standard deviation.
3.7.4 Recommended Data
The quantitation limit and the method used for determining the quantitation limit should be
presented. The limit should be subsequently validated by the analysis of a suitable number
of samples known to be near or prepared at the quantitation limit.
3.8 ROBUSTNESS
The evaluation of robustness should be considered during the development phase and
depends on the type of procedure under study. It should show the reliability of an analysis
with respect to deliberate variations in method parameters. If measurements are
susceptible to variations in analytical conditions, the analytical conditions should be
suitably controlled or a precautionary statement should be included in the procedure. One
consequence of the evaluation of robustness should be that a series of system suitability
parameters (e.g., resolution test) is established to ensure that the validity of the analytical
procedure is maintained whenever used. Examples of typical variations are:
- stability of analytical solutions,
- extraction time
In the case of liquid chromatography, examples of typical variations are
- influence of variations of pH in a mobile phase,
- influence of variations in mobile phase composition,
- different columns (different lots and/or suppliers),
- temperature,
- flow rate.
In the case of gas-chromatography, examples of typical variations are
- different columns (different lots and/or suppliers),
- temperature,
- flow rate.
3.9 SYSTEM SUITABILITY TESTING
System suitability testing is an integral part of many analytical procedures. The tests are
based on the concept that the equipment, electronics, analytical operations and samples to
be analyzed constitute an integral system that can be evaluated as such. System suitability
test parameters to be established for a particular procedure depend on the type of procedure
being validated. They are especially important in the case of chromatographic methods. See
Pharmacopoeias for additional information.
4. GLOSSARY
1. ANALYTICAL PROCEDURE
The analytical procedure refers to the way of performing the analysis. It should describe in
detail the steps necessary to perform each analytical test. This may include but is not
limited to: the sample, the reference standard and the reagents preparations, use of the
apparatus, generation of the calibration curve, use of the formulae for the calculation, etc.
2. SPECIFICITY
Specificity is the ability to assess unequivocally the analyte in the presence of components
which may be expected to be present. Typically these might include impurities, degradants,
matrix, etc. Lack of specificity of an individual analytical procedure may be compensated
by other supporting analytical procedure(s). This definition has the following implications:
Identification: to ensure the identity of an analyte. Purity Tests: to ensure that all the
analytical procedures performed allow an accurate statement of the content of impurities of
an analyte, i.e. related substances test, heavy metals, residual solvents content, etc. Assay
(content or potency): to provide an exact result which allows an accurate statement on the
content or potency of the analyte in a sample.
3. ACCURACY
The accuracy of an analytical procedure expresses the closeness of agreement between the
value which is accepted either as a conventional true value or an accepted reference value
and the value found. This is sometimes termed trueness.
4. PRECISION
The precision of an analytical procedure expresses the closeness of agreement (degree of
scatter) between a series of measurements obtained from multiple sampling of the same
homogeneous sample under the prescribed conditions. Precision may be considered at
three levels: repeatability, intermediate precision and reproducibility. Precision should be
investigated using homogeneous, authentic samples. However, if it is not possible to obtain
a homogeneous sample it may be investigated using artificially prepared samples or a
sample solution. The precision of an analytical procedure is usually expressed as the
variance, standard deviation or coefficient of variation of a series of measurements.
4.1 Repeatability
Repeatability expresses the precision under the same operating conditions over a short
interval of time. Repeatability is also termed intra-assay precision.
4.2 Intermediate precision
Intermediate precision expresses within-laboratories variations: different days, different
analysts, different equipment, etc.
4.3 Reproducibility
Reproducibility expresses the precision between laboratories (collaborative studies, usually
applied to standardization of methodology).
5. DETECTION LIMIT
The detection limit of an individual analytical procedure is the lowest amount of analyte in
a sample which can be detected but not necessarily quantitated as an exact value.
6. QUANTITATION LIMIT
The quantitation limit of an individual analytical procedure is the lowest amount of analyte
in a sample which can be quantitatively determined with suitable precision and accuracy.
The quantitation limit is a parameter of quantitative assays for low levels of compounds in
sample matrices, and is used particularly for the determination of impurities and/or
degradation products.
7. LINEARITY
The linearity of an analytical procedure is its ability (within a given range) to obtain test
results which are directly proportional to the concentration (amount) of analyte in the
sample.
8. RANGE
The range of an analytical procedure is the interval between the upper and lower
concentration (amounts) of analyte in the sample (including these concentrations) for
which it has been demonstrated that the analytical procedure has a suitable level of
precision, accuracy and linearity.
9. ROBUSTNESS
The robustness of an analytical procedure is a measure of its capacity to remain unaffected
by small, but deliberate variations in method parameters and provides an indication of its
reliability during normal usage.

GLOSSARY USED IN ACTD AND ACTR

GLOSSARY USED IN ACTD AND ACTR
The definitions used in this glossary have been developed for the ASEAN Common Technical
Dossier (ACTD) and Common Technical Requirements (ACTR). They are not necessarily
meaningful outside the scope of the specific parts of ACTD and ACTR to which they refer.
Accelerated Testing (from Q1AR)/ Ref: ACTD –Q…
Studies designed to increase the rate of chemical degradation or physical change of a drug
substance or drug product by using exaggerated storage conditions as part of the formal
stability studies.(Data from these studies, in addition to long term stability studies, can be used
to assess longer term chemical effects at non-accelerated condition and to evaluate the effect
of short term excursions outside the label storage conditions such as might occur during
shipping. Results from accelerated testing studies are not always predictive of physical
changes; see also Stability and related terms)
Acceptance Criteria (from Q6B) /Ref: ACTD –Q…
Numerical limits, ranges or other suitable measure for acceptance of the results of analytical
procedures, which the drug substance or drug product or materials at other stages of their
manufacture should meet.
Accuracy (from Q2A) /Ref: ACTD –Q
The accuracy of an analytical procedure expresses the closeness of agreement between the
value which is accepted either as a conventional true value or an accepted reference value and
the value found.
Action Level-( from USP )/Ref: ACTD-Q
Levels or range that, when exceeded, indicate that a process has drifted from its normal
operating range. (Exceeding an action level indicates that corrective action should be taken to
bring the process back into its normal operating range).
Action Limit (from Q6B) /Ref: ACTD –Q
An internal (in-house) value used to assess the consistency of the process at less critical steps.
Active Pharmaceutical Ingredient (API) (from WHO)
A substance or compound that is intended to be used in the manufacture of a pharmaceutical
product as a therapeutically active compound (ingredient).
Adverse Drug Reaction (ADR) (from WHO) /Ref: ACTD –E…
An adverse reaction is a response to a medicine that is noxious and unintended, and which
occurs at doses normally used in man. (In this definition, it is of importance to note that it
concerns the response of a patient, in which individual factors may play an important role, and
that the phenomenon is noxious (an unexpected therapeutic response, for example, may be a
side effect but not an adverse reaction ;see also Adverse Event, Side Effect). (From WHO
Drug Monitoring Programme web site, www.who-umc.org)
Adverse Event (AE) (from WHO) /Ref: ACTD –E…
An adverse event or experience is any untoward medical occurrence that may present during
treatment with a medicine but which does not necessarily have a causal relationship with this
treatment. (The basic point here is the coincidence in time without any suspicion of a causal
relationship; see also Adverse Reaction, Side Effect). (From WHO Drug Monitoring
Programme web site, www.who-umc.org)
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Analytical Procedure (from Q2A) /Ref: ACTD –Q
The analytical procedure refers to the way of performing the analysis; it should describe in
detail the steps necessary to perform each analytical test. (This may include but is not limited
to the sample, the reference standard and the reagents preparations, use of the apparatus,
generation of the calibration curve, use of the formulae for the calculation, etc).
Aneuploidy (from S2A) /Ref: ACTD –S…
Numerical deviation of the modal number of chromosomes in a cell or organism.
Applicant (from WHO)
The company, corporate, person, or legal entity in the field of pharmaceuticals who submits an
application for marketing authorization of a pharmaceutical product, an update to an existing
marketing authorization, or a variation to an existing marketing authorization.
Approval (in relation to Institutional Review Boards) [from E6] /Ref: ACTD –E…
The affirmation affirmative decision of the IRB that the clinical trial has been reviewed and
may be conducted at the institution site within the constraints set forth by the IRB, the
institution, Good Clinical Practice (GCP), and the applicable regulatory requirements.
Audit (from E6) /Ref: ACTD –E…
A systematic and independent examination of trial related activities and documents to
determine whether the evaluated trial activities were conducted, and the data were recorded,
analyzed and accurately reported according to the protocol, sponsor's standard operating
procedure (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement
(s).
Audit Certificate (from E6) /Ref: ACTD –E…
A declaration of confirmation by the auditor that an audit has taken place.
Audit Report (from E6) /Ref: ACTD –E…
A written evaluation by the sponsor's auditor of the results of the audit.
Audit Trail (from E6) /Ref: ACTD –E…
Documentation that allows reconstruction of the course of events.
ASEAN Common Technical Dossier (ACTD)
The part of marketing authorization application dossier that is common to all ASEAN member
countries.
ASEAN Common Technical Requirements (ACTR)
A set of written materials intended to guide applicants to prepare application dossiers in a way
that is consistent with the expectations of all ASEAN Drug Regulatory Authorities (DRA).
Batch (from WHO)
A defined quantity of starting material, packaging material or product processed in a single
process or series of processes so that it can be expected to be homogeneous (In the case of
continuous manufacture, the batch must correspond to a defined fraction of production,
characterized by its intended homogeneity; it may sometimes be necessary to divide a batch
into a number of sub-batches, which are later brought together to form a final homogeneous
batch).
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Batch Number (from WHO)
A distinctive combination of numbers and/or letters which specifically identifies a batch on
the labels, the batch records, and the certificates of analysis, etc.
Batch Records (from WHO)
All documents associated with the manufacture of a batch of bulk product or finished product;
they provide a history of each batch of product and of all circumstances pertinent to the quality
of the final product.
Base Substitution (from S2A) /Ref: ACTD –S…
The substitution of one or more base(s) for another in the nucleotide sequence. This may lead
to an altered protein.
Bioavailability (from WHO)
The rate and extent of availability of an active drug ingredient or metabolite from a dosage
form as determined by its concentration/time curve in the systemic circulation or by its
excretion in urine or other body fluid.
Bioequivalence (from WHO)
Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or
alternatives and their bioavailabilities (rate and extent of availability) after administration in
the same molar dose are similar to such a degree that their effects can be expected to be
essentially the same.
Biological Activity (from Q6B) /Ref: ACTD –Q…
The specific ability or capacity of the product to achieve a defined biological effect.
Potency is the quantitative measure of the biological activity.
Biological Product (from WHO)
Any product of biological origin, prepared with biological processes, derived from human
blood and plasma, or manufactured by biotechnology, consisting of substances of higher
molecular weight whose purity, potency, and composition cannot readily and reliably be
determined by chemical or physicochemical analysis. (Examples of this group include
vaccines, blood products, modified animal tissues, high-molecular-weight hormones,
allergens, and the products of genetic engineering or other newer biotechnological techniques.
This definition does not include antibiotics and substances that, although of biological origin,
are of low molecular weight and can be isolated as pure substances, such as purified steroids
and alkaloids. Biological products cannot usually be approved only on the basis of in vitro
comparison with a comparator product. Different brands may have the same use, for example
pertussis vaccine, but each must independently have been shown to be safe and effective. Data
on plasma concentrations of the “active ingredient” are also usually unhelpful because it is
unclear whether precisely the same entity is being measured. These products cannot therefore
be approved without safety and efficacy data; see also Biotechnological Product).
Biotechnological Product (from WHO)
Any products prepared with genetic engineering or other newer biotechnological techniques.
(All biotechnological products fall into the definition of Biological Products; see also
Biological Product).
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Blinding/Masking (from E6) /Ref: ACTD –E…
A procedure in which one or more parties to the trial are kept unaware of the treatment
assignment(s). (Single blinding usually refers to the subject[s] being unaware and double
blinding usually refers to the subject[s], investigator[s], monitor, and, in some cases, data
analyst(s) being unaware of the treatment assignment[s]).
Bracketing (from Q1AR) /Ref: ACTD –Q…
The design of a stability schedule such that only samples on the extremes of certain design
factors, e.g., strength, package size, are tested at all time points as in a full design.
(The design assumes that the stability of any intermediate level is represented by the stability
of the extremes tested. Where a range of strengths is to be tested, bracketing is applicable if
the strengths are identical or very closely related in composition [e.g., for a tablet range made
with different compression weights of a similar basic granulation, or a capsule range made by
filling different plug fill weight of the same basic composition into different size capsule
shell]. Bracketing can be applied to different container sizes or different fills in the same
container closure system).
Bridging Data Package (from E5) /Ref: ACTD –E…
Selected information from the Complete Clinical Data Package that is relevant to the
population of the new region, including pharmacokinetic data, and any preliminary
pharmacodynamic and dose-response data and, if needed, supplemental data obtained from
bridging study in the new region that allow extrapolation of the foreign safety and efficacy
data to the population of the new region.
Bridging Study (from E5) /Ref: ACTD –E…
A bridging study is defined as a supplemental study performed in the new region to provide
pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new
region that will allow extrapolation of the foreign clinical data to the new region. (Such studies
could include additional pharmacokinetic information).
Calibration (from WHO)/Ref: ACTD-Q
The set of operations which establishes, under specified conditions, the relationship between
values indicated by measuring instrument or measuring system, or values represented by a
material measure, and the corresponding known values of a reference standard. (Limit for
acceptance of the results of measurement should be established).
Case Report Form (CRF) [from E6] /Ref: ACTD –E…
A printed, optical, or electronic document designed to record all of the protocol required
information to be reported to the sponsor on each trial subject.
Cell Proliferation (from S2A) /Ref: ACTD –S…
The ability of cells to divide and to form daughter cells.
Cell Substrate (from Q5D) /Ref: ACTD –Q…
Microbial cells or cell lines derived from human or animal sources that possess the full
potential for generation of the desired biotechnological/biological products for human in-vivo
or ex-vivo use.
Certificate of Pharmaceutical Product (CPP)(from WHO)
A certificate of pharmaceutical product of the type defined in the WHO Certification Scheme
on the Quality of Pharmaceutical Products Moving in International Commerce.
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Change Control (from WHO)
A formal system by which qualified representatives of appropriate disciplines review proposed
or actual changes that might affect an established status. (The intent is to determine the need
for action that would ensure and document that the system is maintained in a validated state).
Chiral (from Q6A) /Ref: ACTD –Q
Not super-imposable with its mirror image, as applied to molecules, conformation, and
macroscopic object, such as crystals.
(The term has been extended to samples of substances, whose molecules are chiral, even if the
macroscopic assembly of such molecules is racemes).
Clastogen (from S2A) /Ref: ACTD –S…
An agent that produces structural changes of chromosomes, usually detectable by light
microscopy.
Climatic Zones-WHO
The four zones into which the world is classified based on the prevailing annual climatic
conditions, i.e :
Zone I : temperate
Zone II: sub-tropical, with possible high humidity
Zone III : hot and dry
Zone IV : hot and humid
Clinical Trial / Study Report (from E6) /Ref: ACTD –E…
A written study description of a trial/study of any therapeutic, prophylactic, or diagnostic
agent conducted in human subjects, in which the clinical and statistical description,
presentations, and analyses are fully integrated into a single report. (See the ICH Guideline for
Structure and Content of Clinical Study Reports).
Clinical Trial/Study (from E 6) /Ref: ACTD –E…
Any investigation in human subjects intended to discover or verify the clinical,
pharmacological and / or other pharmacodynamic effects of an investigational product(s),
and/or to identify any adverse reactions to an investigational product(s), and/or to study
absorption, distribution, metabolism, and excretion of an investigational product(s) with the
object of ascertaining its safety and/or efficacy.
Cloning Efficiency (from S2A) /Ref: ACTD –S…
The efficiency of single cells to form clones. (Usually measured after seedling low numbers of
cells in a suitable environment).
Commitment batches (from Q1AR) /Ref: ACTD –Q…
Production batches of a drug substance or drug product for which the stability studies are
initiated or completed post approval through a commitment made in the registration
application.
Comparator (Product) [from E6] /Ref: ACTD –E…
a) A pharmaceutical product with which the new product is intended to be interchangeable in
clinical practice. (The reference product would normally be the innovator product for
which efficacy, safet and quality have been established. Where the innovator product is
not available the product which is the market leader may be used as a reference
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product, provided it hasbeen authorized for marketing and its efficacy, safety and
quality has been established and documented).
b) An investigational or marketed product (i.e., active control), or placebo, used as a
reference in a clinical trial. (See also Reference Product).
Complete Clinical Data Package (from E5) /Ref: ACTD –E…
A clinical data package intended for registration containing clinical data that fulfill the
regulatory requirements of the new region and containing pharmacokinetic data relevant to the
population in the new region.
Compliance (in relation to trials) [from E6] /Ref: ACTD –E…
Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements,
and the applicable regulatory requirements.
Compounds Insensitive to Ethnic Factors (from E5) /Ref: ACTD –E…
Note: this is really non-specific. Proposal: remove from glossary. A compound whose
characteristic suggest minimal potential for clinically significant impact by ethnic factors on
safety, efficacy or dose response.
Compounds Sensitive to Ethnic Factors (from E5) /Ref: ACTD –E…
Note: this is really non-specific. Proposal: remove from glossary. A compound whose
pharmacokinetic, pharmacodynamic, or other characteristics suggest the potential for
clinically significant impact by intrinsic and/or extrinsic ethnic factors on safety, efficacy, or
dose response.
Concurrent Validation (from PIC)
Validation carried during routine production of products intended for sale.
Confidentiality (from E6) /Ref: ACTD –E…
Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary
information or of a subject's identity.
Container-Closure System (from Q1AR) /Ref: ACTD –Q…
The sum of packaging components that together contain and protect the dosage form. This
includes primary packaging components and secondary packaging components, if latter are
intended to provide additional protection to the drug product. A packaging system is
equivalent to a container closure system.
Container Labeling (from WHO)
All information that appears on any part of a container, including that on any outer packaging
such as a carton.
Contaminants (from Q6B) /Ref: ACTD –Q…
Any adventitiously introduced materials (e.g. chemicals, biochemical, or microbial species)
not intended to be part of the manufacturing process, drug substance, or drug product.
Contract (from E6) /Ref: ACTD –E…
A written, dated, and signed agreement between two or more involved parties that sets out any
arrangements on delegation and distribution of tasks and obligations and, if appropriate, on
financial matters. A protocol may serve as the basis of a contract.
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Contract Research Organization (CRO) [from E6] /Ref: ACTD –E…
A person or an organization (commercial, academic, or other) contracted by the sponsor to
perform one more of a sponsor's trial-related duties and functions.
Coordinating Committee (from E6) /Ref: ACTD –E…
A committee that a sponsor may organize to coordinate the conduct of a multi-centre trial.
Coordinating Investigator (from E6) /Ref: ACTD –E…
An investigator assigned the responsibility for the coordination of investigators at different
centers participating in a multi-centre trial.
Country of Origin
Country where the final dosage form has been manufactured, and/or batch release takes place.
, or from where products are shipped to importing country. There are situations where it is not
possible to identify one country of origin but rather several countries of origin. This may
entail obtaining more than one CPP. (Note: This definition is to be understood in relation to
the practical implementation of the WHO Certification Scheme as applicable in the context of
drug registration procedures).
Critical Manufacturing Process – ASEAN GMP
A manufacturing process that may cause variation which affects the quality of the
pharmaceutical product.
Culture Confluency (from S2A) /Ref: ACTD –S…
A quantification of the cell density in a culture (cell proliferation is usually inhibited at high
degrees of confluency).
Cytogenetic Evaluation (from S2B) /Ref: ACTD –S…
Chromosome structure analysis in mitosis or meiosis by light microscopy.
Degradation Products (from Q6B) /Ref: ACTD –Q…
Molecular variants resulting from changes in the desired product or product-related substances
brought about over time and/or by the action of, e.g. light, temperature, pH, water, or by
reaction with an excipient and/or the immediate container/closure system. Such changes may
occur as a result of manufacture and/or storage (e.g. deamidation, oxidation, aggregation,
proteolyses). Degradation products may be either product-related substances, or productrelated
impurities.
Detection Limit (from Q2A) /Ref: ACTD –Q…
The detection limit of an individual analytical procedure is the lowest amount of analyte in a
sample which can be detected but not necessarily quantitated as an exact value.
Direct Access, in relation to clinical trials (from E6) /Ref: ACTD –E…
Permission to examine, analyze, verify, and reproduce any records and reports that are
important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory
authorities, sponsor's, monitors and auditors) with direct access should take all reasonable
precautions within the constraints of the applicable regulatory requirement(s) to maintain the
confidentiality of subjects' identities and sponsor's proprietary information.
DNA Adduct (from S2B) /Ref: ACTD –S…
(Covalent) binding of chemicals to DNA.
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DNA Repair (from S2B) /Ref: ACTD –S…
Reconstitution of damaged DNA sequence.
DNA Strand Breaks (from S2B) /Ref: ACTD –S…
Single or double strand scissions in the DNA.
Dosage (from E5) /Ref: ACTD –Q…
The quantity of a medicine given per administration or per day.
Dosage Form (from Q1AR) /Ref: ACTD –Q…
A pharmaceutical product type (e.g. tablet, capsule, solution, cream) that contains a drug
substance generally, but not necessarily, in association with excipients.
Dose Regimen (from E5) /Ref: ACTD –E…
The route, frequency and duration of administration of the dose of a medicine over a period of
time.
Drug-WHO
Any substance or pharmaceutical product for human or veterinary use that is intended to
modify or explore physiological systems or pathological states for the benefit of the recipient.
Drug Product (from Q1AR WHO) /Ref: ACTD –Q
See Pharmaceutical Product.
Drug Substance (from Q1AR) /Ref: ACTD –Q
The unformulated drug substance that may subsequently be formulated with excipients to
produce the dosage form.( See also Active Pharmaceutical Ingredient )
Effectiveness – WHO
Measure of the effect of a medicine is supposed to have in the normal clinical setting. It
reflects the impact of its use in the community.
Efficacy – WHO
Ability of a medicine to bring about the intended beneficial effect on individuals in a defined
population with a given medical problem, under ideal conditions of use.
Ethnic Factors (from E5) /Ref: ACTD –E…
The word ethnically is derived from the Greek word “ethnos”, meaning nation or people.
Ethnic factors are factors relating to populations grouped according to common traits and
customs. Ethnic factors that can influence drug safety and efficacy may be classified as either
intrinsic or extrinsic:
• Extrinisic Extrinsic Ethnic Factors : Extrinsic ethnic factors are factors associated
with the environment and culture in which a person resides. Extrinsic factors tend to be
less genetically and more culturally and behaviorally determined. (Examples of
extrinsic factors include the social and cultural aspects of a region such as medical
practice, diet, use of tobacco, use of alcohol, exposure to pollution and sunshine, socioeconomic
status, compliance with prescribed medications, and, particularly important
to the reliance on studies from a different region, practices in clinical trial design and
conduct).
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• Intrinsic Ethnic Factors : Intrinsic ethnic factors are factors that help to define and
identify a sub-population and may influence the ability to extrapolate clinical data
between regions. (Examples of intrinsic factors include genetic polymorphism, age,
gender, height, weight, lean body mass, body composition, and organ dysfunction).
Excipient (from Q6B) /Ref: ACTD –Q…
An ingredient, added intentionally to the drug substance, which should not have
pharmacological properties in the quantity used.
Expiry Date (from Q1AR) /Ref: ACTD –Q…
The date placed on the container label of a drug product designating the time prior to which a
batch of the product is expected to remain within the approved shelf-life specification if stored
under defined conditions. (After the expiry date, there is no guarantee that the product will
remain within the approved specifications and, therefore, it may be unsuitable for use and
should not be used).
Extensive Product Testing – WHO
The final testing of the product to an extent greater than that required in routine quality
control.
(This is one of the most practical forms of process validation, mainly for non-sterile products).
Extrapolation of Foreign Clinical Data (from E5) /Ref: ACTD –E…
The generalization and application of the safety, efficacy and dose response data generated in
a population of a foreign region to the population of a new region.
Finished Product (from WHO)
A product that has undergone all stages of production and quality control, including packaging
in its final container and labeling.
Formal Stability Studies (from Q1AR) /Ref: ACTD –Q…
Long-term and accelerated (and intermediate) studies undertaken on primary and/or
commitment batches according to a prescribed stability protocol to establish or confirm the retest
period of a drug substance or shelf life of a drug product.
Formula (from WHO)
The composition of a dosage form, including the characteristics of its raw materials.
Frameshift Mutation (from S2A) /Ref: ACTD –S…
A mutation (change in the genetic code) in which one base or two adjacent bases are added
(inserted) or deleted to the nucleotide sequence of a gene. (This may lead to an altered or
truncated protein).
Gene Mutation (from S2A) /Ref: ACTD –S…
A detectable permanent change within a single gene or its regulating sequences. The changes
may be point mutations, insertions and deletions.
Generic Product (GP)(from WHO)
Where the term generic product is used, it means A pharmaceutical product usually intended
to be interchangeable with the innovator product, which is usually manufactured without a
license from the innovator company and marketed after expiry of the patent or other
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exclusivity rights. (The term generic product has somewhat different meanings in different
jurisdiction. Use of this term is therefore avoided as much as possible, and the term
multisource pharmaceutical product is used instead. Generic products may be marketed either
under the approved nonproprietary name or under a brand [proprietary] name. They may be
marketed in dosage forms and/or strengths different from those of the innovator products).
Genetic Endpoint (from S2A) /Ref: ACTD –S…
The precise type or type class of genetic change investigated (e.g., gene mutations,
chromosomal aberrations, DNA-repair, DNA-adduct formation, etc.).
Genetic Toxicity, Genotoxicity (from S2A) /Ref: ACTD –S…
A broad term that refers to any deleterious change in the genetic material regardless of the
mechanism by which the change is induced.
Good Clinical Practice (GCP) [from E6] /Ref: ACTD –E…
A standard for the design, conduct, performance, monitoring, auditing, recording analysis, and
reporting of clinical trials that provides assurance that data and reported results are credible
and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.
ICH (International Conference for Harmonization) Regions (from E5) /Ref: ACTD –E…
The region that includes European Union, Japan, and The United States of America.
Immediate Release Dosage Form (from WHO)
A dosage form that is intended to release all the active ingredient on administration with no
enhanced delayed or extended release effect.
Impartial Witness [from E6] /Ref: ACTD –E…
A person, who is independent of the trial, who cannot be unfairly influenced by people
involved with the trial, who attends the informed consent process if the subject or the subject's
legally acceptable representative cannot read, and who reads the informed consent form and
any other written information supplied to the subject.
Impermeable Containers (from QIAR) /Ref: ACTD –Q…
Containers that provide a permanent barrier to the passage of gases or solvents, e.g., sealed
aluminum tubes for semi-solids, sealed glass ampoules for solutions.
Impurity (from Q6B) /Ref: ACTD –Q…
Any component present in the drug substance or drug product which is not the desired
product, a product-related substance, or excipient including buffer components. It may be
either process-or product-related.
Independent Ethics Committee (IEC) [from E6] /Ref: ACTD –E…
An independence body (a review board or a committee, institutional, regional, national or
supranational) constituted of medical/scientific professionals and non-medical/non-scientific
members whose responsibility it is to ensure the protection of the rights, safety and well-being
of human subjects involved in a a trial and to provide public assurance of that protection, by,
among other things, reviewing and approving / providing favorable opinion on the trial
protocol, the suitability stability of the investigator(s), facilities, and the methods and material
to be used in obtaining and documenting informed consent of the trials subjects.(The legal
status, composition, function, operation and regulatory requirements pertaining to
Independence Independent Ethics Committee may differ among countries, but should allow
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the independence Independent Ethics Committee to act in agreement with GCP as described in
the current relevant guideline).
Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board,
Monitoring Committee, Data Monitoring Committee)[from E6] /Ref: ACTD –E…
An independent data-monitoring committee that may be established by the sponsor to assess at
intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and
to recommend to the sponsor whether to continue, modify, or stop a trial.
Informed Consent (from E6) /Ref: ACTD –E…
A process by which a subject voluntarily confirms his or her willingness to participate in a
particular trial, after having been informed of all aspects of the trial that are relevant to the
subject's decision to participate. (Informed consent is documented by means of a written,
signed and dated informed consent form).
In-house Primary Reference Material (from Q6B) /Ref: ACTD –Q…
An appropriately characterized material prepared by the manufacturer from a representative
lot(s) for the purpose of biological assay and physicochemical testing subsequent lots, and
against which in-house working reference material is calibrated.
In-house Working Reference Material (from Q6B) /Ref: ACTD –Q…
A material prepared similarly to the primary reference material that is established solely to
assess and control subsequent lots for the individual attribute in question.(It is always
calibrated against the in-house primary reference material).
Innovator Pharmaceutical Product (from WHO)
The innovator pharmaceutical product is generally that which was first authorized for
marketing (normally as a patented product) on the basis of documentation of efficacy, safety
and quality (according to requirements at the time of the authorization). (When a substance
has been available for many years, it may not be possible to identify an innovator
pharmaceutical product).
Installation Qualification (IQ) – WHO
The performance and documentation tests to ensure that equipment (such as machines,
measuring equipment, utilities, manufacturing areas) used in a manufacturing process is
appropriately selected, correctly installed and work in accordance with established
specifications.
Institution (medical) [from E6] /Ref: ACTD –E…
Any public or private entity or agency or medical or dental facility where clinical trials are
conducted.
Institutional Review Board (IRB) [from E6] /Ref: ACTD –E…
An independent body constituted of medical, scientific and non-scientific members, whose
responsibility is to ensure the protection of the rights, safety and well-being of human subjects
involved in a trial by, among other things, reviewing, approving, and providing continuing
review of trial protocol and amendments and of the methods and material to be used in
obtaining documenting informed consent of the trial subjects.
Integrity Test – ASEAN GMP
Test to determine the functional performance of a filter system.
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Interchangeable Pharmaceutical Product (from WHO)
An interchangeable pharmaceutical product is one that is therapeutically equivalent to a
reference product.
Interim Clinical Trial/Study Report [from E6] /Ref: ACTD –E…
A report of intermediate results and their evaluation based on analyses performed during the
course of a trial.
Intermediate Precision (from Q2A) /Ref: ACTD –Q…
Intermediate precision expresses within-laboratories variations: different days, different
analysts, different equipment, etc.
Internal Environmental Monitoring Program - ASEAN
Defined documented programmed, which describes the routine particulate and microbiological
monitoring of processing and manufacturing areas, and includes corrective action plan when
action levels are exceeded.
Investigational Product (from E6) /Ref: ACTD –E…
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in
a clinical trial, including a product with a marketing authorization when used or assembled
(formulated or packaged) in a way different from the approved form, or when used for an
unapproved indication, or when used to gain further information about an approved use.
Investigator (from E6) /Ref: ACTD –E…
A person responsible for the conduct of the clinical at the trial site. If a trial is conducted by a
team of individuals at a trial site, the investigator is the responsible leader of the team and may
be called the principal investigator. (See also Sub-investigator ).
Laboratory Scale Batches (from WHO)
Batches produced at the research and early development laboratory stage.
(They may be of very small size [e.g. 1/100 to 1/1000 times production batch size]).
Letter of Authorization (from WHO)
A letter from the manufacturer or product owner authorizing the local agent to be the
registration holder and to be responsible for all matters pertaining to the registration of the
product.
Linearity (from Q2A) /Ref: ACTD –Q…
The linearity of an analytical procedure is its ability (within a given range) to obtain test
results which are directly proportional to the concentration (amount) of analyte in the sample.
Long Term Real Time Testing (in relation to Stability)(from Q1AR) /Ref: ACTD –Q…
Stabilities Stability studies under the recommended storage condition for the re-test period or
shelf life proposed (or approved) for labeling.
Major Variation (MaV) – WHO
Variation to authorized pharmaceutical product affecting one or more of the following aspects:
- route of administration,
- strength, posology
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- indications,or
- or that does not fall within the definition of minor variation.
(Applications for major variations usually require the submission of data necessary to establish
quality, safety and efficacy of the new formulation resulting from the variation; (see also
Variation, Minor Variation)
Manufacture (from WHO)
All operations of purchase of materials and products, production, quality control, release,
storage, shipment (from storage related to manufacturing site) of finished products, and
related controls.
Manufacturer (from WHO)
A company that carries out at least one step of manufacture production as well as the final
release of the finished product.
.
Marketing Authorization
An official document issued by the competent drug regulatory authority for the purpose of
marketing or free distribution of a product after evaluation for safety, efficacy and quality. (It
must set out, inter alia, the name of the product, the pharmaceutical dosage form, the
quantitative formula (including excipients) per unit dose [using INNs or national generic
names where they exist], the shelf-life and storage conditions, and packaging characteristics. It
specifies the information on which authorization is based [e.g. “The product(s) must conform
with all the details provided in your the application and as modified in subsequent
correspondence”]. It also contains the product information approved for health professionals
and the public, the sales category, the name and address of the holder of the authorization, and
the period of validity of the authorization).
Marketing Authorization Holder (from WHO)
The company or corporate or person or legal entity in the field of pharmaceuticals in whose
name the marketing authorization has been granted. This party is responsible for all aspects of
the product, including quality and compliance with the conditions of marketing authorization.
The authorized holder must be subjected to legislation in the country that issued the marketing
authorization, which normally means being physically located in that country.
Mass Balance (from QIAR) /Ref: ACTD –Q…
The process of adding together the assay value and levels of degradation products to see how
closely these add up to 100% of the initial value, with due consideration of the margin of
analytical error.
Master Cell Bank (MCB) (from Q5A) /Ref: ACTD –Q…
An aliquot of a single pool of cells which generally has been prepared from the selected cell
clone under defined condition, dispensed into multiple containers and stored under defined
condition. (The MCB is used to derive all working cell banks. The testing performed on a new
MCB [from a previous initial cell clone, MCB or WCB] should be the same as for the MCB,
unless justified).
Master Formula (from WHO)
A document or set of documents specifying the starting materials with their quantities and the
packaging materials, together with a description of the procedures and precautions required to
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produce a specified quantity of finished product as well as the processing instruction,
including in-process control.
Matrixing (in relation to Stability)(from QIAR) /Ref: ACTD –Q…
The design of a stability schedule such that a selected subset of the total number of possible
samples for all factors combinations is tested at a specified time point. (At a subsequent time
point, another subset of samples for all factor combinations is tested. The design assumes that
the stability of each subset of samples tested represents the stability of all samples at a given
time point; the differences in the samples for the same drug product should be identified as,
for example, covering different batches, different strengths, different sizes of the same
container closure system, and, possibly in some cases, different container closure systems).
Mean Kinetic Temperature (from QIAR) /Ref: ACTD –Q…
A single derived temperature that, if maintained over a defined period of time, affords the
same thermal challenge to a drug substance or drug product as would be experienced over a
range of both higher and lower temperatures for an equivalent defined period.
(The mean kinetic temperature is higher than the arithmetic mean temperature and takes into
account the Arrhenius equation).
Medicinal Product
See Pharmaceutical Product.
Micronucleus (from S2A) /Ref: ACTD –S…
Particle in a cell that contains microscopically detectable nuclear DNA, and it might contain a
whole chromosome(s) or a broken centric or acentric part(s) of chromosome(s).
(The size of a micronucleus is usually defined as being less than 1/5 but more than 1/20 of the
main nucleus).
Minor Variation (MiV) (from WHO)
Variation to authorized pharmaceutical product not affecting one or more of the following
aspects:
- route of administration,
- strength, posology
- indications, and
- active ingredient(s)
(Applications for minor variations usually require the submission of data necessary to
establish quality of the new formulation resulting from the variation; see also Variation,
Major Variation)
Mitotic Index (from S2A) /Ref: ACTD –S…
Percentage of cells in the different stages of mitosis amongst the cells not in mitosis
(interphase) in a preparation (slide).
To define "monitoring" only in relation to clinical trials can be misleading. I propose to delete.
Multicenter Trial (from E6) /Ref: ACTD –E…
A clinical trial conducted according to a single protocol but at more than one site, and
therefore, carried out by more than one investigator.
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Multisource(Generic) Pharmaceutical Product (from WHO)
Multisource pharmaceutical products are pharmaceutically equivalent products that may or
may not be therapeutically equivalent. (Multisource pharmaceutical products that are
therapeutically equivalent are interchangeable).
National Regulatory Authority (NRA)/Certifying Authority (from WHO)
A national body that administers the full spectrum of drug regulatory activities, including at
least all of the following functions:
􀂃 marketing authorization of new products and variation of existing products;
􀂃 quality control laboratory testing;
􀂃 adverse drug reaction monitoring;
􀂃 provision of drug information and promotion of rational drug use;
􀂃 Good Manufacturing Practice (GMP) inspections and licensing of manufacture,
wholesalers and distribution channels;
􀂃 enforcement operations; and
􀂃 monitoring of drug utilization.
New Active Substance – WHO
New chemical or biological API not previously authorized for marketing for any
pharmaceutical use in the country in question. (Those provisionally authorized at the time of
the initial market inventory are not new active substances; see also new chemical entity, new
chemical or biological API, new molecular entity, well-established drug, well established
product, well established fixed-dose drug combination).
New Chemical Entity (NCE) (from WHO)
See New Active Substance.
New Chemical or Biological API (from WHO)
See New Active Substance.
New Molecular Entity (from Q1AR) /Ref: ACTD –Q…
A new salt, ester, or non-covalent-bond derivative of an approved drug substance. (It is
considered as a new molecular entity for the purpose of stability testing; see New Active
Substance).
Numerical Chromosome Changes (from S2B) /Ref: ACTD –S…
Chromosome numbers different from the original haploid or diploid set of chromosomes; for
cell lines, chromosome numbers different from the modal chromosome set
Operation Qualification (OQ)(from WHO) (GMP)
Documented verification that the system or sub-system performs as intended throughout all
anticipated operating ranges.
Original Medical Record
See Source Documents.
Package Insert – WHO
A document defining information that may be supplied with a pharmaceutical product by the
marketing authorization holder. (The content of the product package insert is approved by the
NRA at the time market authorization is issued; see also Patient Information Leaflet).
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Patient Information Leaflet (PIL)
A document defining information intended for the patient that may be supplied with a
pharmaceutical product by the marketing authorization holder. (The content of the PIL is
approved by the NRA at the time market authorization is issued; see also Package Insert)
Parent-Child/Fetus Report (from E2B) /Ref: ACTD –E…
Report in which the administration of medicines to a parent results in a suspected
reaction/event in a child fetus.
Performance Qualification (PQ)(from WHO)
Documented evidence that an equipment operation process step, total integrated process
system, or analytical method performs as intended and that it produces an in-process material,
or product, or test result that consistently meets appropriate specifications and the
requirements defined in the protocol. (It is important that clear and specific acceptance criteria
are be established for each critical parameter).
Pharmaceutical Equivalentsce(from WHO)
Two products are pharmaceutically equivalents if they contain the same amount of the same
active substance (s) in the same dosage form; if they meet the same or comparable standards;
and if they are intended to be administered by the same route. (Pharmaceutical equivalence
does not necessarily imply therapeutic equivalence, as differences in the excipients and/or the
manufacturing process can lead to differences in product performance).
Pharmaceutical Product
Any preparation for human or veterinary use that is intended to modify or explore
physiological systems or pathological states for the benefit of the recipient.
Pharmacodynamic Study (from E5) /Ref: ACTD –E…
A study of a pharmacological or clinical effect of the medicine in individuals to describe the
relation of the effect to dose or drug concentration. (A pharmacodynamic effect can be a
potentially adverse effect - anticholinergic effect with a tricyclic -, a measure of activity of
thought related to clinical benefit (various measures of beta blockade, effect on ECG intervals,
inhibition of ACE or of angiotensin I or II response), a short term desired effect, often a
surrogate endpoint (blood pressure, cholesterol), or the ultimate intended clinical benefit
(effects on pain, depression, sudden death)).
Pharmacokinetic Study (from E5) /Ref: ACTD –E…
A study of how a medicine pharmaceutical product is handled by the body, usually involving
measurement of blood concentrations of the product drug and its metabolite(s) (sometimes
concentrations in urine or tissues) as a function of time. (Pharmacokinetic studies are used to
characterize absorption, distribution, metabolism and excretion of a drug pharmaceutical
product, either in a blood or in other pertinent locations. When combined with
pharmacodynamic measures [a PK/PD study], it can characterize the relation of blood
concentrations to the extent and timing of pharmacodynamic effects).
Pilot Scale Batch (from QIAR) /Ref: ACTD –Q…
A batch of a drug substance or drug product manufactured by a procedure fully representative
of and simulating that to be applied to a full production scale batch. (For solid oral dosage
forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or
100,000 tablets or capsules, whichever is the larger unless otherwise justified).
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Plasmid (from S2A) /Ref: ACTD –S…
Genetic element additional to the normal bacterial genome. (A plasmid might be inserted into
the host chromosome or form an extrachromosomal element).
Point Mutations (from S2A) /Ref: ACTD –S…
Changes in the genetic code usually confined to a single DNA base pair.
Polychromatic Erythrocyte (from S2A) /Ref: ACTD –S…
An immature erythrocyte in an intermediate stage of development that still contains ribosomes
and, as such can be distinguished from mature normochromatic erythrocytes (lacking
ribosomes) by stains selective for ribosomes.
Population Pharmacokinetic Methods (from E5) /Ref: ACTD –E…
Population pharmacokinetic methods are a population-based evaluation of measurements of
systemic drug concentrations, usually two or more per patient under steady state conditions,
from all, or a defined subset of, patients who participate in clinical trials.
Potency (from Q6B) /Ref: ACTD –Q…
The measure of the biological activity using a suitably quantitative biological assay (also
called potency assay or bioassay). Based on the attribute of the product which is linked to the
relevant biological properties.
Precision (from Q2A) /Ref: ACTD –Q…
The precision of an analytical procedure expresses the closeness of agreement (degree of
scatter) between a series of measurements obtained from multiple sampling of the same
homogeneous sample under the prescribed conditions. (Precision may be considered at three
levels: repeatability, intermediate precision and reproducibility. Precision should be
investigated using homogeneous, authentic samples. However, if it is not possible to obtain a
homogeneous sample, it may be investigated using artificially prepared samples or a sample
solution. The precision of an analytical procedure is usually expressed as the variance,
standard deviation or coefficient of variation of a series of measurements).
Primary Batch (from QIAR) /Ref: ACTD –Q…
A batch of a drug substance or drug product used in a formal stability study, from which
stability data are submitted in a registration application for the purpose of establishing a re-test
period or shelf-life, respectively. (A primary batch of a drug substance should be at least a
pilot scale batch. For a drug product, two of the three batches should be at least pilot scale
batch, and the third batch can be smaller if it is representative with regard to the critical
manufacturing steps. However, a primary batch may be a production batch).
Product’s Owner
Person, company or entity who is the legal/ registered owner of the product formulation and/
or process with whom the marketing authorization holder has a contract
Process Related Impurities (from Q6B) /Ref: ACTD –Q…
Impurities that are derived from the manufacturing process; they may be derived from cell
substances (e.g., host cell proteins, host cell DNA), cell culture (e.g., inducers, antibiotics, or
media components), or downstream processing (e.g., processing reagents or column
leachables).
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Process Validation (from FDA)/Ref:ACTD-Q
Establishing documented evidence which provides a high degree of assurance that a specific
process will consistently produce a product meeting its pre-determined specifications and
quality.
Product-related Impurities (from Q6B) /Ref: ACTD –Q…
Molecular variants of the desired product (e.g., precursors, certain degradation products
arising during manufacture and/or storage) which do not have properties comparable to those
of the desired product with respect to activity, efficacy, and safety.
Product-related Substances (from Q6B) /Ref: ACTD –Q…
Molecular variants of the desired product formed during manufacture and / or storage which
are active and have no deleterious effect on the safety and efficacy of the drug product. (These
variants possess properties comparable to the desired product and are not considered
impurities).
Production Batch (from QIAR) /Ref: ACTD –Q…
A batch of a drug substance or drug product manufactured at production scale by using
production equipment in a production facility as specified in the application.
Prospective Validation – ASEAN GMP
Establishing documented evidence that a process, procedure, system, equipment or mechanism
used in manufacture does what it purports to do based on a pre-planned validation protocol.
Protocol (in relation to Clinical Trials) (from E6) /Ref: ACTD –E…
A document that describes the objective(s), design, methodology, statistical consideration, and
organization of a trial. (The protocol usually also gives the background and rationale for the
trial, but these could be provided in other protocol referenced documents throughout the ICH
GCP Guideline the term protocol refers to protocol and protocol amendments).
Quality Assurance (QA)[from E6] /Ref: ACTD –E…
The totality of the arrangements, including GMP, made in order to ensure that pharmaceutical
products are suitable for their intended use.
Quality Control (from WHO)
Quality control is concerned with sampling, specifications and testing, and with the
organization, documentation and acceptance/rejection procedures which ensures that the
necessary and relevant tests are actually carried out on starting materials, intermediates and
finished products are not accepted for use, sale or supply until their quality has been judged to
be satisfactory.
Quantitation Limit (from Q2) /Ref: ACTD –Q…
The quantitation limit of an individual analytical procedure is the lowest amount of analyte in
a sample which can be quantitatively determined with suitable precision and accuracy. (The
quantitation limit is a parameter of quantitative assays for low levels of compounds in sample
matrices, and is used particularly for the determination of impurities and/or degradation
products).
Randomization [from E6] /Ref: ACTD –E…
The process of assigning trial subjects to treatment or control groups using an element of
chance to determine the assignments in order to reduce bias.
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Recombination (from S2B) /Ref: ACTD –S…
Breakage and balanced or unbalanced rejoining of DNA.
Reference Country
Countries with established drug evaluation system as recognised by the ASEAN Drug
Regulatory Authorities.
Reference Product (from WHO)
a) A pharmaceutical product with which the new product is intended to be interchangeable in
clinical practice.
(The reference product would normally be the innovator product for which efficacy, safety
and quality have been established. Where the innovator product is not available the
product which is the market leader may be used as a reference product, provided it has
been authorized for marketing and its efficacy, safety and quality has been established and
documented).
b) An investigational or marketed product (i.e., active control), or placebo, used as a
reference in a clinical trial.
(See also Comparator Product)
Repeatability (from Q2A) /Ref: ACTD –Q…
Repeatability expresses the precision under the same operating conditions over a short interval
of time. (Repeatability is also termed intra-assay precision).
Reporter (in relation to clinical studies)(from E2B) /Ref: ACTD –E…
Reporter is the primary source of the information, i.e., a person who initially reports the facts.
(This should be distinguished from the sender of the source of the message, though the
reporter could also be a sender).
Reproducibility (from Q2A) /Ref: ACTD –Q…
Reproducibility expresses the precision between laboratories. (Collaborative studies, usually
applied to standardization of methodology).
Re-test Date (from QIAR) /Ref: ACTD –Q…
The date after which samples of the drug substance should be examined to ensure that the
material is still in compliance with the specification and thus suitable for use in the
manufacture of a given drug product.
Re-test Period (from QIAR) /Ref: ACTD –Q…
The period of time during which the drug substance is expected to remain within its
specification and, therefore, can be used in the manufacture of a given drug product, provided
that the drug substance has been stored under the defined conditions. (After this period, a
batch of drug substance destined for use in the manufacture of a drug product should be retested
for compliance with the specification and then used immediately. A batch of drug
substance can be re-tested multiple times and a different portion of the batch used after each
re-test, as long as it continues to comply with the specification. For most
biotechnological/biological substances known to be labile, it is more appropriate to establish a
shelf life than a re-test period. The same may be true for certain antibiotics).
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Retrospective Validation – ASEAN GMP
Validation of a process for a product that has been marketed based upon accumulated
manufacturing, testing and control batch data.
Revalidation – ASEAN GMP
A repeat of the process validation to provide an assurance that changes in the process /
equipment introduced in accordance with change control procedures do not adversely affect
process characteristics and product quality.
Robustness (from Q2A) /Ref: ACTD –Q…
The robustness of an analytical procedure is a measure of its capacity to remain unaffected by
small, but deliberate variations in method parameters and provides an indication of its
reliability during normal usage.
Semi-permeable Containers (from QIAR) /Ref: ACTD –Q…
Containers that allow the passage of solvent, usually water, while preventing solute loss. (The
mechanism for solvent transport occurs by absorption into one container surface, diffusion
through the bulk of the container material, and desorption from the other surface; transport is
driven by a partial-pressure gradient; examples of semi-permeable containers include plastic
bags and semi-rigid, low-density polyethylene (LDPE) pouches for large volume parenterals
(LVPs), and LDPE ampoules, bottles, and vials).
Sender (in relation to clinical studies) (from E2B) /Ref: ACTD –E…
The person or entity creating the message for transmission. (Although the reporter and sender
may be the same person, the function of the sender should not be confused with that of the
reporter[s]).
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
[from E6] /Ref: ACTD –E…
Any untoward medical occurrence that at any dose:
- results in death;
- is life-threatening;
- requires inpatient hospitalization or prolongation of existing hospitalization;
- results in persistent or significant disability/incapacity; or
- is a congenital anomaly/birth defect.
Shelf-life(also referred to as expiration dating period) (from QIAR) /Ref: ACTD –Q…
The time period during which a drug product is expected to remain within the approved shelf
life specification, provided that it is stored under the condition defined on the container label.
Side effect (From WHO Drug Monitoring Programme web site, www.who-umc.org)
A side effect is any unintended effect of a pharmaceutical product occurring at doses normally
used in man, which is related to the pharmacological proprieties properties of the drug.
(Essential elements in this definition are the pharmacological nature of the effect, that the
phenomenon is unintended, and that there is no overt overdose; see also Adverse Event,
Adverse Reaction).
Source Data (in relation to clinical studies) (from E6) /Ref: ACTD –E…
All information in original records and certified copies of original records of clinical findings,
observations, or other activities in a clinical trial necessary for the reconstruction and
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evaluation of the trial. (Source data are contained in source documents, original records or
certified copies).
Source Documents (in relation to clinical studies) (from E6) /Ref: ACTD –E…
Original documents, data, and records (e.g., hospital records, clinical and office charts,
laboratory notes, memoranda, subjects' diaries or evaluation checklist, pharmacy dispensing
records, recorded data from automated instruments, copies or transcriptions certified after
verification as being accurate copies, microfiches, photographic negatives, microfilm or
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and
at medico-technical departments involved in the clinical trial).
Specification (from Q6B) /Ref: ACTD –Q…
A specification is defined as A list of tests, references to analytical procedures, and
appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests
described. (It establishes the set of criteria to which a drug substance, drug product or
material at other stages of its manufacture should conform to be considered acceptable for its
intended use. "Conformance to specification" means that the drug substance and drug
product, when tested according to the listed analytical procedures, will meet the acceptance
criteria. Specifications are critical quality standards that are proposed and justified by the
manufacturer and approved by regulatory authorities as conditions of approval).
Specifications – Release (from Q1AR) /Ref: ACTD –Q…
The specifications that determine the suitability of a drug product at the time of its release.
(See also Specification)
Specification – Shelf-life (from Q1AR) /Ref: ACTD –Q…
The specifications that determine the suitability of a drug substance throughout its re-test
period, or that a drug product should meet throughout its shelf-life.
Specificity (from Q2A) /Ref: ACTD –Q…
Specificity is the ability to assess unequivocally the analyte in the presence of components
which may be expected to be present. (Typically these might include impurities, degradants,
matrix, etc )
Lack of specificity of an individual analytical procedure may be compensated by other
supporting analytical procedure(s).
This definition has the following implication:
Identification : To ensure the identify of an analyte.
Purity Tests : To ensure that all the analytical procedures performed allow an accurate
statement of the content of impurities of an analyte, i.e. related substances test, heavy metals,
residual solvents content, etc.
Assay (Content or Potency): To provide an exact result which allows an accurate statement on
the content or potency of the analyte in a sample).
Stability (from WHO)
The ability of an active ingredient or a drug product to retain its properties within specified
limits throughout its shelf – life. (The chemical, physical, microbiological and
biopharmaceutical aspects of stability must be considered).
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Formal Stability Studies (from Q1AR) /Ref: ACTD –Q…
Long-term Real time and accelerated (and intermediate) studies undertaken on primary and/or
commitment batches according to a prescribed stability protocol to establish or confirm the retest
period of a drug substance or shelf life of a drug product.
• Long Term Real Time Testing Studies (in relation to Stability)(from Q1AR) /Ref:
ACTD –Q…
Stabilities Stability studies under the recommended storage condition for the re-test
period or shelf life proposed (or approved) for labeling.
• Accelerated Testing Studies (from Q1AR)/ Ref: ACTD –Q…
Studies designed to increase the rate of chemical degradation or physical change of a
drug substance or drug product by using exaggerated storage conditions as part of the
formal stability studies.
(Data from these studies, in addition to long term real time stability studies, can be
used to assess longer term chemical effects at non-accelerated condition and to
evaluate the effect of short term excursions outside the label storage conditions such as
might occur during shipping. Results from accelerated testing studies are not always
predictive of physical changes; see also Stability and related terms)
Standard Operation Procedures (SOPSs) [from E6] /Ref: ACTD –E…
Detailed written instruction to achieve uniformity of the performance of a specific function.
Starting Material – WHO
Any substance of a defined quality used in the production of a pharmaceutical product but
excluding packaging materials.
Sterilization (from WHO)
Validated process used to render a product free of viable organisms.
Sterility Test (from WHO)
Test performed to determine if viable microorganisms are present.
Storage Condition Tolerances (in relation to Stability)(from Q1A) /Ref: ACTD –Q…
The acceptable variations in temperature and relative humidity of storage facilities for formal
stability studies. (The equipment should be capable of controlling the storage condition within
the ranges defined in the current relevant guidelines. The actual temperature and humidity -
when controlled - should be monitored during stability storage. Short-term spikes due to
opening of doors of the storage facility are accepted as unavoidable. The effect of excursions
due to equipment failure should be addressed, and reported if judged to affect stability results.
Excursions that exceed the defined tolerances for more than 24 hours should be described in
the study report and their effect assessed).
Stress Testing (Drug Product) (from Q1AR) /Ref: ACTD –Q…
Studies undertaken to assess the effect of severe condition on the drug product. (Such studies
include photo-stability testing; - see ICH Q1B - and specific testing on certain products, e.g.,
metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).
Stress Testing (drug substance)(from Q1AR) /Ref: ACTD –Q…
Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part
of the development strategy and is normally carried out under more severe conditions than
those used for accelerated testing.
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Sub-investigator (from E6) /Ref: ACTD –E…
Any individual member of the clinical trial team designated and supervised by the investigator
at a trial site to perform critical trial-related procedures and/or to make important trial-related
decisions (e.g., associates, residents, research fellows).
(See also Investigator).
Subject Identification Code (from E6) /Ref: ACTD –E…
A unique identifier assigned by the investigator to each trial subject to protect the subject's
identity and used in lieu of the subject's name when the investigator reports adverse events
and/or other trial related data.
Summary of Product Characteristics (SPC) - EU
Product information as approved by the drug regulatory authority. (The SPC serves as the
source of information for health personnel as well as for consumer information on labels and
leaflets of medicinal pharmaceutical products and for control of advertising; see also Package
Insert, Patient Information Leaflet)
Supporting Data (in relation to Stability)(from QIAR) /Ref: ACTD –Q…
Data, other than those from formal stability studies, that support the analytical procedures, the
proposed re-test period or shelf-life, and the label storage statements. (Such data include (1)
stability data on early synthetic route batches of drug substance, small scale batches of
materials, investigational formulations not proposed for marketing, related formulations, and
product presented in containers and closures other than those proposed for marketing; (2)
information regarding test results on containers; and (3) other scientific rationales).
Survival (in the context of mutagenicity testing) [from S2A] /Ref: ACTD –S…
Proportion of the cells in a living stage among dead cells, usually determined by staining and
colony counting methods after a certain treatment interval.
Transgene (from S2B) /Ref: ACTD –S…
An exogenous or foreign gene inserted into the host genome, either into somatic cells or germ
line cells.
Therapeutic Equivalence (from WHO)
Two pharmaceutical products are therapeutically equivalent if they are pharmaceutically
equivalent or alternatives and, after administration in the same molar dose, their effects with
respect to both efficacy and safety are essentially the same, as determined from appropriate
bioequivalence, pharmacodynamic, clinical or in vitro studies.
Trial Site (from E6) /Ref: ACTD –E…
The location(s) where trial-related activities are actually conducted.
Unexpected Adverse Drug Reaction (from E6) /Ref: ACTD –E…
An adverse reaction, the nature or severity of which is not consistent with the applicable
product information. (e.g., investigator's brochure for an unapproved investigational product or
package inserts/summary of product characteristic for an approved product; see the ICH
Guideline for Safety Data Management: Definitions and Standards for Expedited Reporting).
Unscheduled DNA Synthesis (UDS) [from S2A] /Ref: ACTD –E…
DNA synthesis that occurs at some stage in the cell cycle other than S-phase in response to
DNA damage. (It is usually associated with DNA excision repair).
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Validation ( from WHO GMP)
The documented act of proving that any procedure, process, equipment, material, activity or
system actually leads to the expected results.
Validation Protocol (from Q7A) /Ref: ACTD –Q…
A written plan stating how validation will be conducted and defining acceptance criteria. (For
example, the protocol for a manufacturing process identifies processing equipment, critical
process parameters/operating ranges, product characteristics, sampling, test data to be
collected, number of validation runs, and acceptable test results).
Validation Report – ASEAN GMP
A document in which the record, results and evaluation of a completed validation program are
assembled. (It may also contain proposals for the improvement of processes and / or
equipment).
Variation (from WHO)
A change to any aspect of a pharmaceutical product, including but not limited to a change to
formulation, method and site of manufacture, specifications for the finished product and
ingredients, container and container labeling, and product information.
Viral Clearance (from Q5A) /Ref: ACTD –Q…
Elimination of target virus by removal of viral particles or inactivation of viral infectivity.
Virus-like Particles (from Q5A) /Ref: ACTD –Q…
Structures visible by electron microscopy which morphologically appear to be related to
known viruses.
Virus Removal (from Q5A) /Ref: ACTD –Q…
Physical separation of virus particles from the intended product.
Vulnerable Subjects (in relation to clinical studies) (from E6) /Ref: ACTD –E…
Individuals whose willingness to voluntary volunteer in a clinical trial may be unduly
influenced by the expectation, whether justified or not, of benefits associated with
participation, or of a retaliatory response from senior members of a hierarchy in a case of
refusal to participate. (Examples are members of a group with a hierarchical structure, such as
medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory
personnel, employees of the pharmaceutical industry, members of the armed forces, and
persons kept in detention. Other vulnerable subjects include patients with incurable diseases,
persons in nursing homes, unemployed or impoverished persons, patients in emergency
situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those
incapable of giving consent).
Well-established Drug (from WHO)
Active pharmaceutical ingredient (API) (not product) which:
- has been marketed for at least five years in countries that undertake activity post-marketing
monitoring;
- has been widely used in a sufficiently large numbers of patients to permit the assumption
that safety and efficacy are well known; and
- has the same route of administration and strength, and the same or similar indication as in
those countries.
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(See also Well-established Fixed-dose Drug Combinations and Well-established Drug
Products. Because this definition refers to active pharmaceutical ingredients and not products,
it does not take into account possible sensitivities to excipients and other factors that are
relevant to therapeutic equivalence).
Well-established Drug Combinations (from WHO)
Combinations of drug which:
- have been marketed for at least five years in countries which undertake activities postmarketing
monitoring;
- have been widely used in sufficiently large number of patients to permit the assumption
that safety and efficacy are well known; and
- have the same route of administration and strength, and the same or similar indication as in
those countries
(See also Well-established Drug and Well-established Drug Product. Because this definition
refers to pharmaceutical ingredient and not products, it does not take into account possible
sensitivities to excipients and other factors that are relevant to therapeutic equivalence).
Well-established Drug Products – WHO
Pharmaceutical products that contain well established drugs, and which:
- have been marketed for at least five years that undertake active post-marketing monitoring;
- have been widely have been widely used in sufficiently large number of patients to permit
the assumption that safety and efficacy are well known; and
- have the same route of administration and strength, and the same or similar indication as in
those countries.
Well-established Fixed-dose Drug Combinations (from WHO)
Fixed-dose combinations of drug which:
- have been marketed for at least five years in countries which undertake activities postmarketing
monitoring;
- have been widely used in sufficiently large number of patients to permit the assumption
that safety and efficacy are well known; and
- have the same route of administration and strength, and the same or similar indication as in
those countries
(See also Well-established Drug and Well-established Drug Product. Because this definition
refers to pharmaceutical ingredient and not products, it does not take into account possible
sensitivities to excipients and other factors that are relevant to therapeutic equivalence).
Working Cell Bank (WCB) (from Q5A) /Ref: ACTD –Q…
The WCB is prepared from aliquots of a homogeneous suspension of cells obtained from
culturing the MCB under defined culture conditions.