Kuwait - 361 Ph. Registration Requirements
Kuwait - 361 Ph. Registration Requirements
Kuwait - 361 Ph. Registration Requirements
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STATE OF KUWAIT
MINISTRY OF HEALTH
DRUG AND FOOD CONTROL
Dr Abdullah M. AI-Bader
e.„.„--.4sgistant llersecretary
For Drug & ood Coning
26-17.--Z-0‘5
Introduction
Dr Abdullah M. Al-Bader
ndersecretary
Avcicflnt u
Wage For Drug & C r
Z —I—0 3
In some cases such as GCC centrally registered products or others, customized
set of requirement will be applicable, and in such cases the Administration
will set these requirements and will be communicated via Memo's to Local
Agent.
For Locally manufactured pharmaceutical products or when the marketing
authorization holder is a local pharmaceutical company, The Pharmaceutical
and Herbal Medicines Registration and Control Administration is the
authorized body to issue CPP, Manufacturing License, Good Manufacturing
Practice certificate and any certificate related to pharmaceutical product
registration.
Dr Abdullah M. Al-lader
Assistant Undersecretary
3 I P
r - a°
Mitrol----_,
For Dru & Food Co
Module 1: Regional Administrative Information;
Module 3: Quality
1.3.2 Labeling
1.3.5 Samples
Dr Abdullah M. Al-Bader
A • s retary
Wage
,
1.4 Information on the experts
1.4.1 Quality
1.4.2 Non-Clinical
1.4.3 Clinical
1.5.2 GMO
1.6 Pharmacovigilance
1.8 Pricing
Dr Abdullah M. Allader
Wage
ssistan ndersectgary
For D.4.& Food Contre>--..
— —1,2, /3
1.8.2 Other documents related
2.2 Introduction
Introduction
2.3.S.2 Manufacture
2.3.S.3 Characterization
2.3.S.7 Stability
2.3.P.3 Manufacture
6IPage
Dr Abdullah M. Al-Bader
e../Asisista5PUndersecitacy,
or Drug & Food Control
Zs' - 12 - /
2.3.P.8 Stability
2.3.A Appendices
2.5.7 References
2.6.1 Introduction
Dr Abdullah M. Al-Bader
7IPage Assistaatljndersecretary
c___Lor Drug aood Cord
ThThl"---
2-6 — 2_ -2-0
2.6.2.6 Discussion and Conclusions
2.6.4.3 Absorption
2.6.4.4 Distribution
2.6.4.6 Excretion
2.6.6.4 Genotoxicity
2.6.6.5 Carcinogenicity
DrJbdullahJVI1 Al•Bader
8[Page Assistant U epecretary
For Drug & Food Control
Lé --17_— to f 7
1-
2.6.6.10 References
2.7.1.4 Appendix
2.7.2.5 Appendix
ro
26— 12_-2_0/q
2.7.3.6 Appendix
2.7.4.2.2 Narratives
2.7.4.5.5 Overdose
Dr i bdull. h M. Al-Bader
10Page
For Drug & Food Control
2_6 — 1 2 — 2_0 / q
2.7.6 2.7.6 Synopses of Individual Studies
Module 3: Quality
Section Requirements
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer(s)
3.2.S.3 Characterization
3.2.S.3.2 Impurities
3.2.S.4.1 Specifications
Dr Abdullah M. Al-Bader
11IPage a-cretary
3.2.5.4.3 Validation of Analytical Procedures
3.2.S.7 Stability
3.2.R2.1.2 Excipients
3.2.P.2.2.2 Overages
3.2.P.2.6 Compatibility
3.2.P.3 Manufacture
Dr Abdullah M. Al-Bader
12IPage
As ' n erseci'itaty----
& kood nirol
'o —
2 6 -)Q_-2o/9
3.2.P.3.1 Manufacturer(s)
3.2.P.4.1 Specifications
3.2.P.5.1 Specifications
3.2.P.8 Stability
13 I Page
Abdullah M. Al-BadE
As istant UnderfriTh-r+tsr
For Drug 84 Food Control
gg -2_<2 /9
3.2.P.8.3 Stability Data
3.2.A Appendices
3.2.A.3 Excipients
4.2.1 Pharmacology
4.2.2 Pharmacokinetics
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
4.2.3 Toxicology
4.2.3.3 Genotoxicity
4.2.3.4 Carcinogenicity
4.2.3.7.1 Antigenicity
4.2.3.7.2 Immunogenicity
4.2.3.7.4 Dependence
15 [Page I !1 I ullah M, i
• ary
r
2 - 2_- 2_013
I
4.2.3.7.5 Metabolites
4.2.3.7.6 Impurities
4.2.3.7.7 Other
2_6-12—L00
5.3.4 Reports of Human Pharmacodynamic (PD) Studies
5.3.5.1 Study reports of Controlled Clinical Studies pertinent to the claimed Indication
Dr Abdullah M. Al-Bader
ASSIS4flt Undersec a ry
17IPage
1.3.2. Labeling
The labeling content must be in compliance with the SPC and must be submitted as
per the GCC Guidance for Presenting the SPC, PIL and Labeling Information.
1.3.5. Samples
A sample from each strengths and presentation must be submitted.
Pharmaceutical and Herbal Medicines Registration and Control Administration have
the right to request whenever needed samples in order to perform complete analysis.
Dr Abdullah M. Al-Bader
Asststan • dersecr
18IPage For D I g & Food Control
— t_ —2_t 19
The submitted samples must represent the final finished product to be marketed in
Kuwait.
1.6. Pharmacovigilance
1.6.1. Pharmacovigilance System
It shall contain a detailed description of the pharmacovigilance system including the
proof that the applicant has the services of a qualified person responsible for
pharmacovigilance and the necessary means for the notification of any adverse
reaction.
1.6.2. Risk Management Plan
A detailed description of the risk management system which the applicant will
introduce must be provided, where appropriate.
M. Al-Bader
44331S Undersecretrey
For Drug & Food Control
2- zo/9
1.8. Pricing
The agent shall include the price of the product in countries listed in the GCC
Guidance for Submission.
Non-Clinical Overview
Dr Abdullah M. AI-Bader
22IPage Assistan nders retary
For
Clinical Overview
The Clinical Overview is intended to provide a critical analysis of the clinical data
in the Common Technical Document. The Clinical Overview will refer to
application data provided in the comprehensive Clinical Summary, the individual
clinical study reports (ICH E3), and other relevant reports; but it must primarily
present the conclusions and implications of those data and must not recapitulate
them. Specifically, the Clinical Summary must provide a detailed factual
231Page
bdullah
!stunt Underspnrn
For Drug & Food Control
a —/a_zo
summarization of the clinical information in the CTD, and the Clinical Overview
must provide a succinct discussion and interpretation of these findings together with
any other relevant information (e.g., pertinent animal data or product quality issues
that may have clinical implications).
I. Mouse.
Rat.
Hamster.
Other rodent.
Rabbit.
Dog.
Non-human primate.
Other non-rodent mammal.
Non-mammals.
24IPage
Dr Abduliah M. Al-Bader
Assistan nders
For ug & Food Control
The intended route for human use.
Oral.
Intravenous.
Intramuscular.
Intraperitoneal
Subcutaneous
Inhalation
Topical
Other
Clinical Summary
The Clinical Summary is intended to provide a detailed, factual summarization of
all the clinical information in the Common Technical Document.
This includes information provided in ICH E3 clinical study reports; information
obtained from any meta-analyses or other cross-study analyses for which full reports
have been included in Module 5; and post-marketing data for products that have
been marketed in other regions. The comparisons and analyses of results across
studies provided in this document must focus on factual observations (In contrast,
the CTD Clinical Overview document must provide critical analysis of the clinical
study program and its results, including discussion and interpretation of the clinical
findings and discussion of the place of the test drug in the armamentarium).
Module 3 Quality
3.1 Table of Contents of Module 3
3.2 Body of data
3.2.5 Drug Substance
The number of Active Pharmaceutical Ingredients (API) suppliers must not exceed
two sources for each API, unless reasonably justified.
The drug substance information can be submitted in one of the following options:
Certificate of suitability (CEP); or
Drug master file (DMF); or
Complete information on the "3.2.S drug substance" sections.
Dr Abdullah M. Al-Bader
25IPage
The drug substance information submitted must include the following for each of
the options used:
16 —12--Zoty
Note: In the case of sterile drug substances, data on the sterilization process of the
drug substance, including validation data must be included in the dossier.
6 -1a_2_0
Company or laboratory code;
Other non-proprietary name(s), e.g., National Name, United States Adopted
Name (USAN), British Approved Name (BAN),
Chemical Abstracts Service (CAS) registry number.
3.2.S.1.2 Structure
The structural formula, including relative and absolute stereochemistry, the
molecular formula, and the relative molecular mass must be provided.
For drug substance(s) existing as salts, the molecular mass of the free base or acid
must be provided.
For Biotech: In addition to the above, the schematic amino acid sequence
indicating glycosylation sites or other post-translational modifications and relative
molecular mass must be provided, as appropriate.
3.2.S.2 Manufacture
3.2.5.2.1 Manufacturer(s)
The name, address, and responsibility of each manufacturer, including contractors,
and each proposed production site or facility involved in manufacturing and testing
must be provided. In addition, a valid manufacturing license for the production of
drug substance(s) and a certificate of (IMP compliance must be provided.
Z -)
The description of the drug substance manufacturing process represents the
applicant's commitment for the manufacture of the drug substance. Information
must be provided to adequately describe the manufacturing process and process
controls.
For example:
A flow diagram of the synthetic process(es) must be provided that includes
molecular formulae, weights, yield ranges, chemical structures of starting
materials, intermediates, reagents and drug substance reflecting stereochemistry,
and identifies operating conditions and solvents.
A sequential procedural narrative of the manufacturing process must be
submitted. The narrative must include, for example, quantities of raw materials,
solvents, catalysts and reagents reflecting the representative batch scale for
commercial manufacture, identification of critical steps, process controls,
equipment and operating conditions (e.g., temperature, pressure, pH, time...
etc).
Alternate processes must be explained and described with the same level of detail
as the primary process. If applicable, reprocessing steps must be identified and
justified. Any data to support this justification must be either referenced or filed
in 3.2.S.2.5.
In case there are multiple manufacturing sites for one drug substance manufacturer,
a comprehensive list in tabular form must be provided comparing the processes
at each site and highlighting any differences.
For Biotech: In addition to the above, information must be provided on the
manufacturing process, which typically starts with a vial(s) of the cell bank, and
includes cell culture, harvest(s), purification and modification reactions, filling,
storage and shipping conditions;
Batch(es) and scale definition
An explanation of the batch numbering system, including information regarding
any pooling of harvests or intermediates and batch size or scale must be provided.
Cell culture and harvest
A flow diagram must be provided that illustrates the manufacturing route from
the original inoculum (e.g. cells contained in one or more vials(s) of the Working
Cell Bank) up to the last harvesting operation. The diagram must include all steps
(i.e., unit operations) and intermediates. Relevant information for each stage,
Dr Abdullah M. Al•Bader
29IPage Undersecreat-tiL,..,
Fur Dr ug & Fuud-Gm.I
such as population doubling levels, cell concentration, volumes, pH, cultivation
times, holding times, and temperature, must be included. Critical steps and
critical intermediates for which specifications are established (as mentioned in
3.2.S.2.4) must be identified.
A description of each process step in the flow diagram must be provided.
Information must be included on, for example, scale; culture media and other
additives (details provided in 3.2.S.2.3); major equipment (details provided in
3.2.A.1); and process controls, including in-process tests and operational
parameters, process steps, equipment and intermediates with acceptance criteria
(details provided in 3.2.S.2.4). Information on procedures used to transfer
material between steps, equipment, areas, and buildings, as appropriate, and
shipping and storage conditions must be provided (details on shipping and
storage provided in 3.2.S.2.4.).
Purification and modification reactions:
A flow diagram must be provided that illustrates the purification steps (i.e., unit
operations) from the crude harvest(s) up to the step preceding filling of the drug
substance. All steps and intermediates and relevant information for each stage
(e.g., volumes, pH, critical processing time, holding times, temperatures and
elution profiles and selection of fraction, storage of intermediate, if applicable)
must be included. Critical steps for which specifications are established as
mentioned in 3.2.S.2.4 must be identified.
A description of each process step (as identified in the flow diagram) must be
provided.
The description must include information on, for example, scale, buffers and
other reagents (details provided in 3.2.S.2.3), major equipment (details provided
in 3.2.A.1), and materials.
For materials such as membranes and chromatography resins, information for
conditions of use and reuse also must be provided (equipment details in 3.2.A.1;
validation studies for the reuse and regeneration of columns and membranes in
3.2.S.2.5.). The description must include process controls (including in-process
tests and operational parameters) with acceptance criteria for process steps,
equipment and intermediates (details in 3.2.S.2.4.). Reprocessing procedures
with criteria for reprocessing of any intermediate or the drug substance must be
described (details must be given in 3.2.S.2.5.). Information on procedures used
to transfer material between steps, equipment, areas, and buildings, as
30IPage
E ___Dr_Abcruilaq,1, A
A...a:scant Underse
For Drug & Food Control
- I _2_09
appropriate, and shipping and storage conditions must be provided (details on
shipping and storage provided in 3.2.5.2.4.).
Filling, storage and transportation (shipping)
A description of the filling procedure for the drug substance, process controls
(including in process tests and operational parameters), and acceptance criteria
must be provided (details in 3.2.S.2.4.). The container closure system(s) used for
storage of the drug substance (details in 3.2.S.6.) and storage and shipping
conditions for the drug substance must be described.
Dr Abdullah M. Al•Bader
31IPage is an II a • ecreta ry
For Drug & F rrn Control
r—
- 2_ — 2_ c2/3
used to develop the Master Cell Bank must be provided (as described in Q5B and
Q5D).
Cell banking system, characterization, and testing
Information on the cell banking system, quality control activities, and cell line
stability during production and storage (including procedures used to generate
the Master and Working Cell Bank(s)) must be provided (as described in Q5B
and Q5D).
3.2.S.3 Characterization
3.2.S.3.1 Elucidation of Structure and Other Characteristics
Confirmation of structure based on e.g., synthetic route and spectral analyses must
be provided. This must include copies of the spectra, peak assignments and a detailed
interpretation of the data of the studies performed to elucidate and/or confirm the
structure of the drug substance.
Dr Abdullah M. Al-Bader
33IPage ssistant Unj etar
; • •
oo on ex)
For non-pharmacopoeial drug substance(s), these studies normally include
elemental analysis, infrared (IR), ultraviolet (UV), nuclear magnetic resonance
(NMR) and mass spectra (MS) studies. Other tests could include X-ray
diffraction (XRD) and differential scanning calorimetry (DSC).
For pharmacopoeial drug substance(s), it is generally sufficient to provide copies
of the IR spectrum of the drug substance run concomitantly with a reference
standard.
Information such as the potential for isomerism, the identification of
stereochemistry, or the potential for forming polymorphs must also be included.
For Biotech:In addition to the above, details (for the desired product and product-
related substances) must be provided on primary, secondary and higher-order
structure, post-translational forms (e.g., glycoforms), biological activity, purity, and
immunochemical properties, when relevant.
3.2.5.3.2 Impurities
Information on impurities must be provided, including a discussion on the potential
and actual impurities arising from the synthesis, manufacture, or degradation of the
drug substance.
This must cover starting materials, by-products, intermediates, chiral impurities and
degradation products and must include the chemical names, structures and origins.
Z._ 6- -12_-z_oty
3. Characterization and evaluation of non-official (e.g., non-compendial) reference
standards or reference materials (e.g., method of manufacture, elucidation of
structure, certificate of analysis, calibration against an official standard
3.2.5.7 Stability
3.2.S.7.1 Stability Summary and Conclusions
The GCC guidelines for "Stability Testing of Active Pharmaceutical Ingredients
(APIs) and Finished Pharmaceutical Products (FPPs)" and ICH (Q1A-Q1F) must be
followed for recommendations on the stability data required for the drug
substance(s).
Dr Abdullah M. Al-Bader
36IPage aders
ug ood Control
The results of all testing parameters related to each batch for the entire testing period
must be presented in one table (i.e. presenting the results of one parameter of all
batches in one table is not acceptable).
For quantitative tests (e.g. individual and total degradation product tests and assay
tests), it must be ensured that actual numerical results are provided rather than vague
statements such as "within limits" or "conforms".
Information on the analytical procedures used to generate the data and validation of
these procedures must be included.
Dr Abduliah M. Al-Bader
37IPage ("Cks;Ria-rn)Urid tn.e cretary
For Dt ug & Fee4I-Can
supportive data can be referenced to the relevant nonclinical or clinical sections of
the application.
3.2.P.2.1.2 Excipients
The choice of excipients listed in 3.2.P.1, their concentration, and their
characteristics that can influence the drug product performance must be discussed
relative to their respective functions. Where relevant, compatibility study result must
be included to justify the choice of excipients. Where antioxidants are included in
the formulation, the effectiveness of the proposed concentration of the antioxidant
must be justified and verified by appropriate studies. Where relevant, the
antimicrobial preservatives must be discussed in 3.2.P.2.5.
38IPage
Dr Abdullah Al-Bader
Assistallnders
'rug
a6 z.
Furthermore, the submitted data must demonstrate whether the method is sensitive
to changes in manufacturing processes and/or changes in grades and/or amounts of
critical excipients and particle size where relevant.
Scored Tablets
In order to ensure that the patient will receive the intended dose, the efficacy of the
break mark(s) must be assessed during the development of the product, in respect of
uniformity of mass of the subdivided parts.
If the proposed finished product is a scored tablet or the applicant indicates that it
may be divided, the following must be submitted:
A justification/rationale for the tablet scoring, and
Results of the appropriate compendial tests demonstrating equivalence in
characteristics/correct dosing (i.e. results demonstrating that the proposed tablet
breaks evenly).
The submitted data must include a description of the test method, individual values,
mean and relative standard deviation (RSD) of the results.
3.2.P.2.2.2 Overages
In general, use of an overage of a drug substance to compensate for degradation
during manufacture or a product's shelf life, or to extend shelf life, is discouraged.
Any overages in the manufacture of the drug product whether they appear in the
final formulated product or not, must be justified considering the safety and efficacy
of the product. Information must be provided on the following.
amount of overage
reason for the overage (e.g., to compensate for expected and documented
manufacturing losses)
Justification for the amount of overage.
The justification of an overage to compensate for loss during manufacture must be
provided, including the step(s) where the loss occurs, the reasons for the loss and
batch analysis (assay results).
The overage must be included in the amount of drug substance listed in the batch
formula (3.2.P.3.2).
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For sterile products, the integrity of the container closure system to prevent
microbial contamination must be addressed.
3.2.P.2.6 Compatibility
The compatibility of the drug product with reconstitution diluent(s) or dosage
device(s) (e.g., precipitation of drug substance in solution, sorption on injection
vessels, stability) must be addressed to provide appropriate and supportive
information for the labeling. Where sterile reconstituted products are to be further
diluted, compatibility must be demonstrated with all diluents over the range of
dilution proposed in the labeling. These studies must preferably be conducted on
aged samples. Where the labeling does not specify the type of containers,
compatibility (with respect to parameters such as appearance, pH, assay, levels of
individual and total degradation products, subvisible particulate matter and
extractables from the packaging components) must be demonstrated in glass, PVC
and polyolefm containers.
However, if one or more containers are identified in the labeling, compatibility of
admixtures needs to be demonstrated only in the specified containers.
Where the labeling specifies co-administration with other finished products,
compatibility must be demonstrated with respect to the principal finished product as
well as the co-administered finished product (i.e. in addition to other aforementioned
parameters for the mixture, the assay and degradation levels of each co-administered
finished product must be reported).
3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer(s)
The name, address, and responsibility of each manufacturer, including contractors,
and each proposed production site or facility involved in manufacturing and testing
must be provided.
A valid manufacturing license must be submitted.
A GMP certificate must be submitted for each manufacturing site where the major
production step(s) are carried out.
Dr Abdullah M. Al-Bader
42IPage
r Foistant Unatrsecretary
r Drug & Food Contr---___
Intermediates: Information on the quality and control of intermediates isolated
during the process must be provided.
47IPage
Or Abdullah KAI-Bader
rxssistant retsv_s_
or Drug' dersec
ood Control
The source of reference standards or reference materials (e.g., House, USP, BP,
Ph. Bur.).
Certificate of analysis for reference standards or reference materials.
Characterization and evaluation of non-official (e.g., non-compendial) reference
standards or reference materials (e.g., method of manufacture, elucidation of
structure, certificate of analysis, calibration against an official standard
3.2.P.8 Stability
3.2.P.8.1 Stability Summary and Conclusions
The GCC guidelines for "Stability Testing of Active Pharmaceutical Ingredients
(APIs) and Finished Pharmaceutical Products (FPPs)" and ICH (Q1A-Q1F) must be
followed for recommendations on the stability data required for the finished
product(s).
For registration of reference (innovator) or generic products long term stability
studies covering the complete shelf life and accelerated stability studies covering 6
months are requested.
ullah M. Al-Bader
48IPage
Assistan Undersecretary
FrD
The types of studies conducted, protocols used, and the results of the studies must
be summarized.
The summary must include information on storage conditions, strength, batch
number (including the drug substance batch number(s) and manufacturer(s)), batch
size, batch type, batch manufacturing date, container closure system (including
where applicable the orientation e.g. inverted) and completed (and proposed) testing
intervals, results, as well as conclusions with respect to storage conditions and shelf-
life, and, if applicable, in-use storage conditions and shelf-life.
The discussion of results must focus on observations noted for the various tests,
rather than reporting comments such as "all tests meet specifications".
For quantitative tests (e.g. individual and total degradation product tests and assay
tests), it must be ensured that actual numerical results are provided rather than vague
statements such as "within limits" or "conforms". Dissolution results must be
expressed at minimum as both the average and range of individual results. Where
the methods used in the stability studies are different from those described in
3.2.P.5.2, descriptions and validation of the methodology used in stability studies
must be provided.
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presented in one table (i.e. presenting the results of one parameter of all batches in
one table is not acceptable).
The actual stability results/reports used to support the proposed shelf-life must be
provided in the dossier. For quantitative tests (e.g. individual and total degradation
product tests and assay tests), it must be ensured that actual numerical results are
provided rather than vague statements such as "within limits" or "conforms".
Dissolution results must be expressed at minimum as both the average and range of
individual results.
Information on the analytical procedures used to generate the data and validation of
these procedures must be included. Information on characterization of impurities is
located in 3.2.P.5.5.
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mycoplasma, fungi). This information can include, for example, certification and/or
testing of raw materials and excipients, and control of the production process, as
appropriate for the material, process and agent.
For viral adventitious agents:
Detailed information from viral safety evaluation studies must be provided in this
section. Viral evaluation studies must demonstrate that the materials used in
production are considered safe, and that the approaches used to test, evaluate, and
eliminate the potential risks during manufacturing are suitable.
Materials of Biological Origin
Information essential to evaluate the virological safety of materials of animal or
human origin (e.g. biological fluids, tissue, organ, cell lines) must be provided (See
related information in 3.2.S.2.3, and 3.2.P.4.5). For cell lines, information on the
selection, testing, and safety assessment for potential viral contamination of the cells
and viral qualification of cell banks must also be provided (See related information
in 3.2.S.2.3).
Testing at appropriate stages of production
The selection of virological tests that are conducted during manufacturing (e.g., cell
substrate, unprocessed bulk or post viral clearance testing) must be justified. The
type of test, sensitivity and specificity of the test, if applicable, and frequency of
testing must be included. Test results to confirm, at an appropriate stage of
manufacture, that the product is free from viral contamination must be provided (See
related information in 3.2.S.2.4 and 3.2.P.3.4).
Viral Testing of Unprocessed Bulk
In accordance with ICH Q5A(R1) and Q6B, results for viral testing of unprocessed
bulk must be included.
Viral Clearance Studies
In accordance with ICH Q5A(R1), the rationale and action plan for assessing viral
clearance and the results and evaluation of the viral clearance studies must be
provided.
Data can include those that demonstrate the validity of the scaled-down model
compared to the commercial scale process; the adequacy of viral inactivation or
removal procedures for manufacturing equipment and materials; and manufacturing
steps that are capable of removing or inactivating viruses (See related information
in 3.2.S.2.5 and 3.2.P.3.5).
Dr Abdullah M. Al-Bader
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Assistant Un
ontro
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3.2.A.3 Excipients
3.2.R Regional Information
Any additional information must be provided in this section.
Dr Abdullah M. Al-Bader
52IPage
Studies on primary pharmacodynamics must be provided and evaluated. Where
possible, it would be helpful to relate the pharmacology of the drug to available data
(in terms of selectivity, safety, potency ... etc.) on other drugs in the class.
4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and Validation Reports
This section must contain the methods of analysis for biological samples, including
the detection and quantification limits of an analytical procedure. If possible,
validation data for the analytical method and stability of biological samples must be
discussed in this section.
The potential impact of different methods of analysis on the interpretation of the
results must be discussed in the following relevant sections.
4.2.2.2 Absorption
The following data must be provided in this section:
Absorption (extent and rate of absorption, in vivo and in situ studies).
Dr Abdullah M. Al-Bader
53 1Page ersecr ars'
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Kinetic parameters, bioequivalence and/or bioavailability (serum/plasma/blood
PK studies). 4.2.2.3 Distribution The following data must be provided in this
section:
Tissue distribution studies.
Protein binding and distribution in blood cells.
Placental transfer studies.
4.2.2.4 Metabolism
The following data must be provided in this section:
Chemical structures and quantities of metabolites in biological samples.
Possible metabolic pathways.
Pre-systemic metabolism (GI/hepatic first-pass effects).
In vitro metabolism including P450 studies.
Enzyme induction and inhibition.
4.2.2.5 Excretion
The following data must be provided in this section:
Routes and extent of excretion.
Excretion in milk.
4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity
The single-dose data must be provided, in order by species, by route. In some cases,
it may be helpful to provide the data in the form of a table.
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Dr Abdullah M. AI der
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4.2.3.2 Repeat-Dose Toxicity
Studies must be provided in order by species, by route, and by duration, giving
details of the methodology and highlighting important findings (e.g., nature and
severity of target organ toxicity, dose (exposure)/response relationships, no observed
adverse effect levels, ...etc).
4.2.3.3 Genotoxicity
Studies must be provided in the following order:
In vitro non-mammalian cell system.
In vitro mammalian cell system.
In vivo mammalian system (including supportive toxicokinetics evaluation).
Other systems.
4.2.3.4 Carcinogenicity
The choice of the studies and the basis for the high-dose selection must be explained.
Individual studies must be provided in the following order:
4.2.3.4.1 Long-term Studies
Long-term studies must be provided in order by species; including range-finding
studies that cannot appropriately be included under repeat-dose toxicity or
pharmacokinetics.
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If modified study designs are used, the sub-headings must be modified accordingly.
Dr Abdullah M. AlsBader
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r Assistant • rsecretary
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human
Biomaterials
Human biomaterials is a term used to refer to proteins, cells, tissues and related
materials derived from human sources that are used in vitro or ex vivo to assess PK
properties of drug substances. Examples include cultured human colonic cells that
are used to assess permeability though biological membranes and transport
processes, and human albumin that is used to assess plasma protein binding.
Of particular importance is the use of human biomaterials such as hepatocytes and/or
hepatic microsomes to study metabolic pathways and to assess drug-drug
interactions with these pathways. Studies using biomaterials to address other
properties (e.g., sterility or pharmacodynarnics) must not be placed in the Clinical
Study Reports Section, but in the Nonclinical Study Section (Module 4).
Dr AbsAI ?
58IPage et- reta
istant U
For Drug & Food Control
Z6— z_c19
The PK studies whose reports must be included in Sections 5.3.3.1 and 5.3.3.2 are
generally designed to:
Measure plasma drug and metabolite concentrations over time,
Measure drug and metabolite concentrations in urine or faeces
Measure drug and metabolite binding to protein or red blood cells.
Apart from describing mean PK in normal and patient volunteers, PK studies must
also describe the range of individual variability.
In the ICH E5 guideline on Ethnic Factors in the Acceptance of Foreign Data, factors
that may result in different responses to a drug in different populations are
categorized as intrinsic ethnic factors or extrinsic ethnic factors. In this document,
these categories are referred to as intrinsic factors and extrinsic factors, respectively.
Additional studies can also assess differences in systemic exposure as a result of
changes in PK due to intrinsic (e.g., age, gender, racial, weight, height, disease,
genetic polymorphism, and organ dysfunction) and extrinsic (e.g., drug-drug
interactions, diet, smoking, and alcohol use) factors. Reports of PK studies
examining the influence of intrinsic and extrinsic factors on exposure must be
organized in Sections 5.3.3.3 and 5.3.3.4, respectively.
In addition to standard multiple-sample PK studies, population PK analyses based
on sparse sampling during clinical studies can also address questions about the
contributions of intrinsic and extrinsic factors to the variability in the dose-PK-
response relationship. Because the methods used in population PK studies are
substantially different from those used in standard PK studies, these studies must be
provided in Section 5.3.3.5.
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5.3.3.4 Extrinsic Factor PK Study Reports
Reports of PK studies to assess effects of extrinsic factors, must be placed in this
section.
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summary document, they must be presented in a separate report. Such reports must
be provided in this section.
Examples of reports that would be found in this section include: a report of a formal
meta-analysis or extensive exploratory analysis of efficacy to determine an overall
estimate of effect size in all patients and/or in specific subpopulations, and a report
of an integrated analysis of safety that assesses such factors as the adequacy of the
safety database, estimates of event rates, and safety with respect to variables such as
dose, demographics, and concomitant medications.
A report of a detailed analysis of bridging, considering formal bridging studies, other
relevant clinical studies, and other appropriate information (e.g., PK and PD
information), must be placed in this section if the analysis is too lengthy for inclusion
in the Clinical Summary.
5.3.5.4 Other Study Reports
This section can include:
Reports of interim analyses of studies pertinent to the claimed indications.
Reports of controlled safety studies not reported elsewhere.
Reports of controlled or uncontrolled studies not related to the claimed
indication.
Published reports of clinical experiences with the medicinal product that is not
included in Section 5.3.5.1. However, when literature is important to the
demonstration or substantiation of efficacy, it must be included in Section
5.3.5.1.
Reports of ongoing studies.
5.3.6 Reports of Post-Marketing Experience
For products that are currently marketed, reports that summarize marketing
experience (including all significant safety observations) must be provided in this
section.
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Copies of referenced documents, including important published articles, official
meeting minutes, or other regulatory guidance or advice must be provided here. Only
one copy of each reference must be provided. Copies of references that are not
included here must be immediately available on request.
4.Variations:
Any changes/ additions made to a registered must be submitted to the
pharmaceutical and herbal medicines registration and control administration for
review and approval.
Specific requirements will be set for each type of change/ addition as a memo.
5.Renewal of Registration:
The registration of pharmaceutical product must be renewed every 5 years from
the date of issuing the registration certificate.
The agent must submit the renewal file 6 months prior to pharmaceutical
registration expiration.
Renewal requirements are set as a memo by the administration.
6.Transfer of Agency:
Legalized original Letter of appointment for the new local agent issued by
marketing authorization holder.
Termination letter of the previous local agent mentioning date of termination
issued from MAR.
List of products that are affected by the transfer, including product name,
concentration, dosage form, and manufacturing company if defer from MAH.
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If the product or the manufacturing company is suspended in country of origin.
Lack of safety or efficacy of the product.
If the company does not comply with the current GMP standards.
If the product does not comply with the specification issued by the manufacturer
or by the pharmacopoeial specification, upon repeated analysis.
If discrepancy in the documents submitted were observed.
As per marketing authorization holder request.
Non compliance to Pharmaceutical and Herbal Medicines Registration and
Control Administration laws and regulations.
If the Pharmaceutical and Herbal Medicine Control and Registration
administration come to know by any circumstances other than agent about any
warning issued for a specific drug or manufacturing site by FDA, EMA, WHO,
GCC or any other International Health Forums.
Dr Abdullah M. Al-Bader
65IPage ndersec
oed Control
BA Bioavailability
BE Bioequivalence
BP British Pharmacopoeia
EU European Union
PD Pharmacodynamic
PK Pharmacokinetics
67IPage
Dr Abdullah M. Al-Bader
Assistant Under •
For D • ••• . Ito
USFDA United states food and drug
administration
Dr Abdullah M. Al-Bader
68IPage