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Drug Approval System of Chile April 2016 APEC Harmonization Center

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Drug Approval System of Chile

April 2016

APEC Harmonization Center

- 1 -

Abbreviation and Regulatory Terms

Spanish English

Agencia nacional de medicamentos

(ANAMED) National Drug Agency Department

Instituto Bacteriológico Bacteriologic Institute

Instituto de Higiene Institute of Hygiene

Instituto de Salud Pública (ISP) Institute of Public Health

Ministerio de Bienestar Social Ministry of Social Welfare

Ministerio de Salud Ministry of Health

Secretarias Regionales Ministeriales de

Salud (SEREMI) Regional Health Department

Subsecretaría de Salud Pública Department of Public Health

Major Terms in the REGULATIONS OF THE NATIONAL SYSTEM CONTROL OF

PHARMACEUTICAL PRODUCTS FOR HUMAN USE

Actividad biológica Biological Activity

Administración Administration

Aseguramiento de la calidad Quality Assurance

Biodisponibilidad Bioavailability

Buenas Prácticas de Laboratorio (BPL) Good Laboratory Practices (GLP)

Buenas Prácticas de Manufactura (BPM) Good Manufacturing Practices (GMP)

Calidad de un medicamento Quality of a medicine

Certificado de registro sanitario Marketing Authorization Certificate

Control de calidad Quality Control

Control de estantería Shelf Control

Clave Code

Contramuestra Counter Sample

Cuarentena Quarantine

Dispensación Dispensing

Distribución Distribution

Dosificación Dosage

Dosis Dose

Droga vegetal o material vegetal Herbal drug or material

- 2 -

Eficacia Efficacy

Encarte Insert

Ensayos de disolución Dissolution Tests

Envase dispensador Dispenser

Envase primario Primary Packaging

Envase secundario Secondary Packaging

Envases clínicos Clinical Packaging

Equivalentes farmacéuticos Pharmaceutical Equivalents

Equivalentes terapéuticos Therapeutical Equivalents

Especialidad farmacéutica Pharmaceutical Product

E p i i io n Specification

Estabilidad Stability

Estado de producción Production State

Estudio de equivalencia terapéutica Therapeutical Equivalence Study

Estudio de estabilidad a tiempo real Real-time Stability Study

Estudio de estabilidad acelerado Accelerated Stability Study

Estudio de estabilidad Stability Study

Estudios de biodisponibilidad Bioavailability Study

Estudios farmacocinéticos Pharmacokinetics Study

Evaluación de un producto farmacéutico Pharmaceutical product evaluation

Excipiente Excipient

Expendio Retailing

Farmacovigilancia Pharmacovigilance

Fecha de expiración, vencimiento o

caducidad Expiration, due or expiry date

Forma farmacéutica Pharmaceutical form

Fórmula patrón o fórmula maestra Master Pattern or Formula

Importación Importing

Impurezas Impurities

Internación Admission

Licencia License

Marcadores vegetales Herbal markers

Márgenes de tolerancia Margin of tolerance

- 3 -

Materia prima Raw material

Material de envase Packaging material

Monografía Monograph

Muestra médica Medical sample

Muestras de referencia o muestras de

retención Reference sample or retention sample

Muestra o Contramuestra legal Legal sample or Legal counter sample

Nombre genérico de un producto

farmacéutico Generic name of a pharmaceutical product

País de procedencia Country of origin

País de producción Country of production

Período de eficacia Effective period

Potencia Potency

Preparación vegetal Plant preparation

Principio activo Active ingredient

Procedimiento operativo estándar (POE) Standard Operating Procedure (SOP)

Producto a granel Bulk product

Producto farmacéutico de asociación Associated pharmaceutical product

Producto farmacéutico de combinación Combined pharmaceutical product

Producto farmacéutico de referencia o

comparador

Pharmaceutical product of reference or

comparison

Producto semielaborado Semielaborated product

Producto semiterminado Semifinished product

Producto terminado Finished product

Producción, Proceso de producción,

Fabricación, Manufactura o

Faena/Production

Production process, Fabrication,

Manufacturing, Work

Reacción adversa a medicamento (RAM) Adverse drug reaction (ADR)

Reacción adversa seria Serious adverse reaction

Reacción adversa inesperada Unexpected adverse reaction

Receta médica Prescription

Registro sanitario Marketing Authorization

Rotulado gráfico Graphic labeling

Serie o Lote Batch or Lot

Subserie o Sublote Sub-batch or Sub-lot

- 4 -

Tenencia Possession

Titular de Registro sanitario Marketing Authorization Holder

Trazabilidad de datos analíticos Traceability of analytical data

Trazabilidad de un producto Product traceability

Unidad de venta Sales unit

Validación Validation

Notice

1. Due to the purpose of this document, most of the information was quoted directly

from the website or related guidelines of each ountry’ drug r gul tory g n i ,

and reviewed by the agencies.

2. This document is limited only to pharmaceutical products, not applicable to

biological and herbal products.

3. When referring to the contents of this document, check the up-to-date

information including related laws and regulations, and revision of guidelines.

- 5 -

Table of Contents

I. Drug Regulatory Agency ·································································· 8

1. Institute of Public Health (Instituto de Salud Pública)································· 8

1.1 Organization·········································································· 8

1.2 Task···················································································· 9

1.3 Website················································································ 9

II. Related Laws and Regulations························································· 10

1. Approval Regulations of the National System Control of Pharmaceutical Products

for Human Use············································································· 10

1.1 Overview············································································· 10

III. Classification of Pharmaceutical Products ········································ 11

1. Classification by regulation ····························································· 11

IV. Drug Approval System ································································· 12

1. Investigational new drug application ··················································· 12

1.1 Clinical trial application ····························································· 12

1.2 Authorization process of clinical trials ············································ 13

1.3 Priority review ········································································ 13

1.4 Review period ········································································ 13

1.5 Required dossiers ···································································· 14

2. New Drug Application approval························································· 14

2.1 Procedure ·············································································· 14

2.2 Rejection and procedures for appeal··············································· 15

2.3 Priority review ········································································ 16

2.4 Review period ········································································ 16

2.5 Required dossiers ···································································· 16

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3. Generic drug approval application ····················································· 27

3.1 Procedure ··············································································27

3.2 Priority review ········································································ 28

3.3 Review period ········································································ 28

3.4 Required dossiers ···································································· 28

4. Orphan drugs ·············································································· 28

5. Priority review ············································································· 28

5.1 Short Registration Procedure ······················································· 28

5.2 Simplified Registration Procedure ················································· 28

V. Others ······················································································· 31

1. Good Manufacturing Practices ·························································· 31

2. Drug Master File ·········································································· 31

3. Labeling and package inserts···························································· 31

4. Certificate of a Pharmaceutical Product ··············································· 35

5. Manufacturing Licenses ································································· 35

6. Fees ························································································· 35

VI. References ················································································ 36

- 7 -

List of Figures

Figure 1. Organization Chart of Ministry of Health

Figure 2. Organization Chart of ANAMED

Figure 3. Clinical Trials Section

Figure 4. Personnel and Roles

Figure 5. Authorization Process

List of Appendix

Appendix 1. List of Drugs that Requires Bioequivalence Tests

- 8 -

I. Drug Regulatory Agency1

1. Institute of Public Health (Instituto de Salud Pública)

1.1. Organization

The central government organization, which manages overall issues regarding the public

and private health/sanitary services in Chile, is the Ministry of Health of Chile (Ministerio de

Salud de Chile).

The Ministry of Health plays a guiding and regulatory role in the field of pharmaceutical

products by implementing national drug policies and issuing technical and administrative

standards to be met by public and private entities engaging in the activities, such as

registering, importing, exporting, manufacturing, storing, possessing, and distributing

pharmaceutical products, advertising and/or supplying information about them, through the

Department of Public Health. The organization called Regional Health Department

(Secretarias Regionales Ministeriales de Salud, SEREMI) under the Department of Public

Health is responsible for authorizing the admission of pharmaceutical products.

Figure 1. Organization Chart of Ministry of Health

The Institute of Public Health (Instituto de Salud Pública, ISP) under the Ministry of

Health is the national health authority responsible for the sanitary surveillance of

pharmaceutical products and for ensuring compliance with the provisions regarding the

Regulations of the National System Control of Pharmaceutical Products for Human Use, the

Sanitary Code and its supplementary regulations, and other laws on the subject, and

authorizes the marketing registration for pharmaceutical products by issuing the final

resolutions.

The current Institute of Public Health of Chile (ISP) traces its historical roots back to

September 15th of 1892 when the law of the Institute of Hygiene (Instituto de Higiene) was

established. The work of Institute of Hygiene continued to 1924 until the military junta took

power and closed the institute between November and December of that year. In 1929, the

Bacteriologic Institute (Instituto Bacteriológico) was established, as a part of Ministry of

Social Welfare (Ministerio de Bienestar Social), by the Law No. 4,457 dated January 29th of

1 http://www.leychile.cl/Navegar?idNorma=1026879&idVersion=

- 9 -

that year, and was responsible for public health and sanitary until 1980. When the Supreme

Decree No. 79 was newly enacted on April 1st, 1980, today’s Institute of Public Health of

Chile was established.

Among other organizations under the Institute of Public Health of Chile (ISP), the

National Drug Agency Department (Agencia nacional de medicamentos, ANAMED) is

responsible for ensuring the efficacy, safety, and quality of pharmaceutical products subject

to sanitary control used in Chile. This Department consists of 8 sub-departments as shown

inFigure 2.2

Figure 2. Organization Chart of ANAMED

1.2. Task

The major tasks of ISP are:

verifying the quality of pharmaceutical products in any of the stages including

registering, importing, exporting, manufacturing, storing, possessing, and distributing

authorizing the establishment and operation of pharmaceutical laboratories

licensing and registering pharmaceutical products and other products subject to

regulations for pharmaceutical products

supervising conditions for import, admission, export, manufacturing, and distribution

of pharmaceutical products, advertising and providing information regarding these

products

controlling narcotic drugs and pharmaceutical products that cause addiction, and

other psychotropic substances likely to have a similar effect, in relation to the import,

export, and lawful use thereof in the preparation of pharmaceutical products

monitoring and ensuring compliance with the provisions stated in the Regulations of

the National System Control of Pharmaceutical Products for Human Use and other

regulations governing such matters.

1.3. Website

http://www.ispch.cl/

2 http://www.ispch.cl/quienes_somos/organigrama

- 10 -

II. Related Laws and Regulations3

1. Approval Regulations of the National System Control of Pharmaceutical

Products for Human Use (Apruebase Reglamento del Sistema Nacional

de Control de los Productos Farmaceuticos de Uso Humano)

1.1 Overview

The Approval Regulations of the National System Control of Pharmaceutical Products for

Human Use is a decree signed and issued by the President of Chile. The date of promulgation

of this decree is January 25th, 2010; the publication date is June 25th, 2011, and recently

modified on August 28th, 2015.

The decree was established, having regard to the provisions of the fourth and sixth books

and other relevant provisions of Decree-Law No. 725 issued by the Ministry of Health in

1967 approving the Sanitary Code. The purpose of this decree is to update, organize, and

complete existing rules regarding the matter, and by doing so, technical and administrative

standards and other terms or requirements to be met for registering, importing, exporting,

admission, manufacturing, storing, possessing, and distributing pharmaceutical products;

advertising and/or supplying information about them; and for their use for scientific research.

The Regulations of the National System Control of Pharmaceutical Products for Human

Use consists of 12 titles in total including provisional article, as well as preliminary title.

Preliminary Title

Title I Pharmaceutical Products

Title II Marketing Authorization of Pharmaceutical Products and Other Products

Title III Packaging and Labeling

Title IV Import and Admission of Pharmaceutical Products

Title V Export of Pharmaceutical Products

Title VI Pharmaceutical Laboratories

Title VII Quality

Title VIII Distribution

Title IX Advertising and Information

Title X Sanitary Surveillance

Title XI Administrative Procedure, Penalties and Appeals

Provisional Article

3 http://www.leychile.cl/Navegar?idNorma=1026879&idVersion=

- 11 -

III. Classification of Pharmaceutical Products4

1. Classification by regulation

According to the Ministry of Health of Chile, pharmaceutical or medicinal product is

defined as any natural or synthetic substance, or mixture of those substances, which is

intended for use in cure, mitigation, treatment, prevention or diagnosis of diseases or

symptoms, and for physiological systems or mental state of the person to whom it is

administered to be modified5.

There is no specific definition of new drugs, bio-similar drugs, or orphan drugs in the

regulation regarding pharmaceutical products for human use stated in the above section.

Instead, Article 10 in the regulation classifies the pharmaceutical products into 7 categories

according to their nature.

However, the term "Therapeutic equivalents" is defined as pharmaceutical equivalents

meeting the same or similar quality specifications and producing essentially the same effects

upon administration under conditions described in their labels in terms of effectiveness and

safety which are determined by appropriate tests which are considered as generic drugs used

in South Korea.

Chemical or chemical synthesis products are drugs that are compromised of one or

more purified and identified active ingredients obtained from a chemical synthesis or

extraction process.

Biological products are obtained from and/or produced by living organisms and their

fluids or tissues, and includes vaccines, Serum, blood products, hormones,

biotechnological or recombinant drugs, antibiotics, allergen, and gene therapy

products.

Radiopharmaceuticals are products or formulations labelled with radionuclides or

radioisotopes for use in the diagnosis or treatment of diseases, regardless of the route

of administration.

Phytopharmaceuticals are pharmaceutical drugs that are compromised of properly

standardized active ingredients originated from the part above the root or root part of

plants or other plant materials.

Homeopathic products are pharmaceutical drugs that are compromised of

homeopathic substances originated from plant, animal, mineral or chemical raw

materials, and are prepared in accordance with a homeopathic manufacturing

procedure described in official regulations approved by the Ministry of Health.

Medical gases are pharmaceutical drugs made of one or more gaseous components

with known concentration and impurities within the specified range, and are intended

for administration to humans.

Other pharmaceutical drugs not listed above include any other products having

therapeutic properties as indicated in the label, advertised or attributed by any means

with intention for use in cure, mitigation, treatment, diagnosis or prevention of

diseases or symptoms, and for physiological systems or mental state of the person to

whom it is administered to be modified.

4 http://www.leychile.cl/Navegar?idNorma=1026879&idVersion=

5 http://www.ispch.cl/anamed/subdeptoregistro/definicion_medicamentos

- 12 -

IV. Drug Approval System

1. Investigational New Drug application

1.1 Clinical trial application

The unit called Clinical Trials section of the sub-department of Sanitary Registration and

Authorization of ANAMED under the Institute of Public Health of Chile (ISP) is responsible

for evaluating the use of pharmaceutical products without national marketing authorization.

This unit also evaluates the modifications that are required in connection with the

authorization of use of pharmaceutical products in clinical research and follows up on the

activities of the centers and laboratories that conduct such studies in humans6.

Figure 3. Clinical Trials Section

Seven people work in this unit and their roles are shown in Fig 47.

Figure 4. Personnel and Roles

According to the Decree called “Approval Regulations of the National System Control of

Pharmaceutical Products for Human Use”, the phase I, II, and III clinical trials demonstrating

6http://www.ispch.cl/sites/default/files/Instructivo%20procedimiento%20de%20registro%20de%20productos%2

0farmaceuticos.pdf 7 http://www.ispch.cl/sites/default/files/regulacion_estudios_clinicos.pdf

- 13 -

the safety and efficacy of the pharmaceutical products intended for marketing authorization

should be included when applying for the registration. For the pharmaceutical products

comprising active ingredients which need to prove the bioavailability or therapeutic

equivalence however, the studies demonstrating those properties should be submitted when

applying for the registration.

1.2 Authorization process of clinical trials8

Figure 5. Authorization Process

The authorization and registration procedures can be processed manually or electronically

through GICONA (https://gicona.ispch.cl/giconaweb), an online information management

system of ISP. If a person or company that will apply for registration/authorization currently

is not a user of this online system, subscription is required to be granted a password for login

to the system. When the GICONA is used, payment is also made through the online system9.

It seems that the approval of authorization is highly dependent on the opinion or discretion

of the reviewer of Institute of Public Health (ISP).

1.3 Priority review

Not specified in the regulation.

1.4 Review period

Not specified in the regulation.

8 http://www.ispch.cl/sites/default/files/regulacion_estudios_clinicos.pdf

9 http://www.ispch.cl/sistema-informatico-de-tramitacion-en-linea

- 14 -

1.5 Required dossiers10

The requirements to apply for import and use of investigational drugs are:

Approval letter written by Ethics Committee (Comité de É tica) which is corresponding

to the area where the research center is located

Letter of the Director of Service (Director del Servicio) to another Committee (if

applicable)

ICF (Informed Consent Form) dated, signed and stamped by the Ethics Committee

Protocol in English and Castilian

Investigator's Brochure in English and Castilian

Current Certificate of GMP (Good Manufacturing Practices) of the manufacturer

Summary of the manufacturing process (if biological products)

A copy of the letter to the PNI (National Immunization Program) (If vaccines)

Delegation of functions of the sponsor (if applicable)

Simple statement of the applicant stating that the information submitted are true

Proposed labeling

2. New Drug Application11

approval

2.1 Procedure

All pharmaceutical products, whether imported or domestically manufactured, should be

distributed or used with proper marketing authorization. The application for marketing

authorization and any required information depending on the type of pharmaceutical product

must be submitted to the Institute of Public Health (ISP) using the approved forms upon

payment of the corresponding fee.

Anapplication must be kept on a written or electronic file which includes documents

submitted by applicants, stating the time and date of presentation with a reference number for

reference and tracking purposes, upon payment of the fee corresponding to the first

admissibility phase of the application.

The ISP reviews the application form and the information submitted and delivers a

statement on its admissibility within 10 working days. Upon acceptance of the application for

further evaluation, the applicant will receive the notice of this decision to proceed with the

payment of fees corresponding to the next phase of the procedure.

Upon admission of the registration procedure, the application will be forwarded to

appropriate department for the separate analysis for the technical and administrative

information. The administrative records, including the legal documents prepared in Castilian

or translated versions signed by the legal representative, an appointed professional or the

chief technical officer of the company will be checked primarily by the legal consultancy

department. The technical records concerning requirements in relation to the technical

information, pharmaceutical quality, safety and efficacy of the pharmaceutical product, as

10

http://www.leychile.cl/Navegar?idNorma=1026879&idVersion= 11

http://www.leychile.cl/Navegar?idNorma=1026879&idVersion=

- 15 -

well as any other particular records as required by the type of product will be separated and

forwarded to specialized technical offices for evaluation.

If the evaluation results are positive, the requested registration will be granted by the

enactment of a resolution notified to the applicant within 6 months from the date of payment

of the corresponding fee.

The proper marketing authorization of a pharmaceutical product contains at least the

following information:

Name and address of the marketing authorization holder

Name and address of the manufacturer, importer, manufacturing or packaging

pharmaceutical laboratory, quality control laboratory, distributor, and licensor, if

applicable

Registration number

Name of the pharmaceutical product

Full qualitative and quantitative composition

Pharmaceutical form

Therapeutic group

Storage conditions and effectiveness period

Packaging and presentations

Authorized therapeutic indications

Prescribing and retail conditions pursuant to regulations of Ministry of Health

Whether the product is subject to legal control, batch control or others with

information regarding the situation

Authorization restrictions concerning the validity of the registered product and the

need to supervise the use thereof

Specific obligations of the holder

Obligation to inform about the first batch of production or import for distribution in

any shape or form

Other relevant information depending on the nature and specific composition of each

pharmaceutical product and relating to the production, import, quality control, storage,

distribution or delivery of the product, and the protection of undisclosed data.

Authorized graphic labeling, the patient information sheet or insert, the healthcare

professional information leaflet, and the specifications and testing methodology of the

finished product must be included in one or several stamped attachments, which are

considered to be a part of the registration certificate.

2.2 Rejection and procedures for appeal

An application may be rejected in the absence of compliance with the requirements stated

above and any supplementary regulations, according to the type of pharmaceutical product,

and the ISP will inform the applicant of any missing information required to fulfill the

authorization processes. The applicant must submit within 5 working days, upon which the

ISP proceeds to further assessment or rejects the applicant finally.

The application for marketing authorization may be rejected under the following

circumstances:

- 16 -

Incidental issues: upon notification, the applicant must make any submissions as

deemed appropriate within 15 working days, after which the ISP issues the final

resolution.

Inadequate tests or insufficient information: upon notification, the applicant must

provide further information within 30 working days, and the marketing

authorization will be granted if such information is sufficient to fulfill the

conditions listed above.

If such additional information is not submitted within the specified period of time, or if

such information is submitted within the period, but once again, it is determined to be

insufficient, the ISP requests the Ministry of Health to order the rejection of the registration.

Then, the Ministry of Health issues a report on the rejection of the registration within 10

working days and forwards it to the ISP. Based on this, the ISP passes the resolution which

will be notified to the applicant.

2.3 Priority review

Not specified in the regulation.

2.4 Review period

Within 6 months from the date of payment of the corresponding fee

2.5 Required dossiers

2.5.1 Administrative Requirements

An application for marketing authorization should meet the following general

administrative requirements and include the following information:

Identification and address of the applicant, and legal representative in the case of legal

entities.

Name of the chief technical officer in charge of the entity requesting the registration or,

if not applicable, of the professional responsible for the technical information provided.

Name of the pharmaceutical product including:

- trade name, generic or common international name, or otherwise the pharmacopoeial

or chemical name;

- pharmaceutical form;

- unit dose per pharmaceutical form; and

- route of administration

Class or therapeutic group, further indicating the corresponding anatomical-therapeutic

classification.

Manufacturing system, including:

- domestic manufacture, for products manufactured in a legally and technically

qualified pharmaceutical laboratory, whether it is made at its own premises or by

third parties

- 17 -

- imported products, including:

imported finished products manufactured abroad, whether imported directly

or by authorized third parties

imported semi-finished products in their final primary packaging to be fitted

in Chile, either directly or by authorized third parties

imported bulk products in their final pharmaceutical form to be packed in

Chile, either directly or by authorized third parties

imported semi-manufactured products to engage in other subsequent

manufacturing activities in Chile necessary to obtain a finished product,

either directly or by authorized third parties

Identification of the licensor under the name appearing on the license, if the license is

used for prosecution of the registration.

Name and address of the domestic or foreign manufacturing facility.

Product presentation describing the contents of different packages, retail, clinical

packages and/or medical samples, including elements or devices used for the

administration thereof.

Physical description of the packaging material, indicating the type of primary and

secondary packaging materials and other elements or devices used for administration, if

applicable.

Legal documents in Spanish or translated versions there of signed by the legal

representative, an appointed professional or the chief technical officer of the company

including the following:

- For products imported during any stage of the production process:

Marketing authorization certificate, pharmaceutical product certificate,

marketing authorization certificate or official certification recommended by

the World Health Organization, issued by the authorities of the country of

origin and duly legalized, certifying that the manufacturing facilities meet

the requirements established in the marketing legislation of their country,

that the product is registered in the country according to current regulations

(stating the approved formula in full), and whether the sale of the product is

subject to a restrictive regime or special marketing supervision, if

applicable.

Legalized manufacturing agreement signed by the applicant and the foreign

manufacturing pharmaceutical laboratory.

Legalized license, if applicable.

Official certificate issued by the competent health authority of the country

where the manufacturing facilities are located certifying that the foreign

manufacturer is duly authorized in their country and follows Good

Manufacturing Practices in accordance with WHO recommendations,

indicating production areas or types of products authorized for manufacture,

unless such information is included in the document mentioned in e.i herein.

- 18 -

Legalized import agreement executed before a notary public, if applicable.

Manufacturing and/or domestic distribution agreement executed before a

notary public, attaching the corresponding sanitary authorization for each

facility.

Quality control agreement entered into with a pharmaceutical laboratory

authorized by the Institute and executed before a notary public, if

applicable.

- For domestically manufactured products:

Manufacturing and/or domestic distribution agreement executed before a

notary public, attaching the corresponding marketing authorization for each

facility.

Legalized license, if applicable.

Quality control agreement entered into with a pharmaceutical laboratory

authorized by the Institute and executed before a notary public, if

applicable.

2.5.2 Technical information requirements

The application for marketing authorization is required to meet the following general

conditions in relation to the technical information of the pharmaceutical product:

Clinical and pharmacological monograph prepared in Spanish signed by the chief

technical officer or technical adviser

Draft of graphic labeling prepared in Spanish intended for retail, clinical sales and

medical samples

Draft of the healthcare professional information leaflet endorsed by relevant scientific

data. The results of bioavailability and therapeutic equivalence studies are required if

the pharmaceutical products comprise active ingredients that are subject to this

requirement.

Draft of the patient information sheet endorsed by relevant scientific data

2.5.3 Pharmaceutical Quality Requirements

The application for marketing authorization is required to meet the following general

conditions to certify the pharmaceutical quality of the product:

Qualitative and quantitative composition of the pharmaceutical product in the

following order:

- Quali-quantitative statement for each active ingredient

- Quali-quantitative statement for each excipient

- Qualitative statement of any excipient used and removed during the manufacturing

process, if applicable.

- Quali-quantitative composition expressed in metric system units of mass or volume,

or units of biological activity. Whenever possible, the biological activity must be

indicated per unit of mass or volume.

- Active ingredients and excipients must be designated by their INN (International

Non-proprietary Names) or by the existing pharmacopoeial names. For non-

- 19 -

pharmacopoeial substances, the chemical name in Spanish must be used. No

abbreviations or marks can be used for designating active ingredients.

- Any colorants in the product must be designated by their generic names or by their

chemical name. Other names with authorized colorants indexes in accordance with

the relevant national technical standard approved by the Ministry of Heath also can

be used to designate the colorants. The same provision applies when colored

capsules are used.

With respect to the active ingredients used in the manufacture of pharmaceutical

products, the following information must be submitted:

- Specifications and quality control methods, conforming to the requirements listed

in official texts, pharmacopoeias or in pharmacopoeial monographs, currently valid

in Chile

- Supplier and manufacturer of the active ingredients, including an analysis report

detailing all the characterizing parameters of the active ingredient

- Origin of the primary reference standard, including the corresponding certificate of

analysis indicating at least its origin, potency, traceability and other relevant

characterizing tests

- Spectrogram or chromatogram of the active ingredient and the standard obtained

by any instrumental method, if applicable.

- Storage conditions of the active ingredient used as raw material.

Specifications and control methods for every excipient, conforming to the

requirements listed in official texts, pharmacopoeias or in pharmacopoeial

monographs, currently valid in Chile

Analytical methodology in Castilian signed by the professional preparing the

application and by the quality control manager of the pharmaceutical laboratory or the

contracted supplier

- The analytical methodology must characterize the pharmaceutical product and

include controls as necessary to guarantee its quality, depending on the

manufactured pharmaceutical form.

- The analytical methodology of all pharmaceutical products must include the

following general test methods: sensory description (appearance, size, shape, color,

odor, etc.); selective identification of active ingredients; titration, performance or

activity of active ingredients; identification of impurities if applicable; and

description of the type and material of both primary and secondary packaging.

- Specific test methods according to the pharmaceutical form must be prepared

according to current additional technical standards issued by the ISP.

- The methodology must be validated, if not described in officially recognized

pharmacopoeias.

Special tests:

- Modified-release pharmaceutical forms, such as delayed-release or enteric

prolonged-release forms and others, must be indicated as such and endorsed by

pharmacokinetic, dissolution or dissemination tests, or other studies.

- Therapeutic equivalence and bioavailability studies, in the case of pharmaceutical

products comprising active ingredients subject to this requirement.

- 20 -

Fact sheet including analytical parameters and acceptance criteria characterizing the

product which, upon being made official, must be the specifications that the finished

product should meet throughout its effectiveness period.

Proposed effectiveness period and storage and packaging conditions for both the

pharmaceutical product and the reconstituted product, if applicable, endorsed by the

corresponding stability tests, including the following:

- Stability information, including at least: identification of the manufacturer and an

entity or individual responsible for conducting the stability test; temperature and

humidity conditions, packaging material and batches (minimum 3 batches); test

design and analytical procedures; and specifications of the finished product; all of

the above in accordance with the Guide of Stability of Pharmaceutical Products

(Guía de Estabilidad de Productos Farmacéuticos), a technical standard approved

by the Ministry of Health at the proposal of the ISP.

- When the product requires dilution prior to administration, stability data for the

formulation, the solvent (if included in the presentation) and reconstituted product

should be attached. In the event of the product requiring dilution and the solvent

not being included in the package, there must be an indication as to the

recommended solvents; stability tests for the formulation and the reconstituted

product must be additionally submitted.

- If the product requires dilution for immediate administration, only a compatibility

study for the corresponding diluents must be submitted.

- In the case of an active ingredient that is not part of the authorized formula of a

registered pharmaceutical drug, the results of forced degradation studies under

stress conditions, as well as the requirements stated above.

Technical information relating to the manufacturing process and the code for the

product, quality control, and physical-chemical data, presented in a record sheet

including flow charts and controls along the process.

For the purposes of determining the identity, potency, purity, stability, and other

physical, chemical, microbiological and bio-pharmaceutical requirements for drugs

for which a registration is sought, the ISP will observe the relevant rules in the

following pharmacopoeias and their supplements:

a) Chilean Pharmacopoeia.

b) International Pharmacopoeia.

c) European Pharmacopoeia.

d) United States Pharmacopoeia and the National Formulary.

e) British Pharmacopoeia.

f) French Pharmacopoeia.

g) German Pharmacopoeia.

h) German Homeopathic Pharmacopoeia.

i) Wilmar Schwabe Pharmacopoeia.

j) US Homeopathic Pharmacopoeia.

k) Mexican Homeopathic Pharmacopoeia.

l) Japanese Pharmacopoeia.

m) Spanish Pharmacopoeia.

n) Mexican Pharmacopoeia.

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In addition, the technical reports of the World Health Organization Expert Committee

on biological, biotechnological, chemical, radioactive, and similar standards, and the

provi ion o titl 21 o th Unit d St t “Cod o F d r l R gul tion ” (CFR),

Section 1.1, will be used for the purposes mentioned above. In the case of a

pharmaceutical product that is not listed in any of the foregoing official documents,

the ISP can accept or reject, either totally or in part, the technical information supplied

by the applicant with proper reasons. If those official texts do not specify the

tolerances or other specifications, these specifications must be included in the

application for registration so that the Institute can decide about their adequacy.

Due to the nature, diversity and extent of the general requirements for the

pharmaceutical quality of products, they may be listed in additional technical

standards approved by the Ministry of Health at the proposal of the ISP.

2.5.4 Safety and Efficacy Requirements

The application for marketing authorization is required to include information on the

safety and efficacy of the product:

Studies on the development of the pharmaceutical product, including chemical,

pharmaceutical, and biological tests as appropriate for the proposed formulation and

their rationale.

Preclinical trials such as those conducted in vitro with experimental animals usually

designed to gather further information as to whether more extensive studies should be

carried out in humans without exposing them to undue risk.

Selective pharmacological studies in animals.

Toxicological studies in animals, including acute and chronic toxicity, teratogenicity,

embryotoxicity, fertility, mutagenesis, and carcinogenesis tests, as well as any other

assays necessary for a proper evaluation of the safety and tolerance of a

pharmaceutical product.

Phase I, II, and III clinical trials endorsing the safety and efficacy of a pharmaceutical

product to be registered. Trials of products that do not correspond to the formula

intended for registration may be submitted, provided that their pharmaceutical and

therapeutic equivalence has been established by the corresponding studies.

Pharmacokinetic tests, if applicable.

Studies proving the bioavailability or therapeutic equivalence of a pharmaceutical

product to be registered, if the products comprise active ingredients that are subject to

this requirement.

A chemical, pharmaceutical, and biological report, including analytical, chemical,

physical, chemical, biological or microbiological tests to determine if the product

intended for registration is in conformity with the stated composition and has the

appropriate quality, and whether the proposed control methods are in accordance with

the state of scientific knowledge, the formulation and pharmaceutical form are

suitable for their intended purposes, and the container is suitable for proper

preservation.

A toxicological and pharmacologic report, including preclinical trials reporting the

toxicity of the product and its proven pharmacological properties.

- 22 -

A clinical report prepared by independent experts evaluating the tests submitted by

the applicant with regard to the product having an adequate tolerance, the

recommended dosage being correct, and any eventual contraindications or side effects.

Registration Details and Conditions for Certain Pharmaceutical Drugs

The following conditions must be met for the registration of pharmaceutical products

comprising a combination of fixed-dose active ingredients:

1) Each active ingredient is required to contribute to the therapeutic effect of the

product, and the combination should contribute to improving patient compliance

with the treatment.

2) The dose of each component, the frequency of administration, and duration of the

treatment must grant safety and efficacy to the combination, and avoid the

potentiation of adverse reactions.

3) The ingredients including excipients used in the combination are required to be

chemically, pharmacologically, pharmacokinetically, and biopharmaceutically

compatible, either in vitro or in vivo, as appropriate.

4) Toxic or side effects should be at the same or less than those found in each of the

active ingredients separately.

Notwithstanding the foregoing, applications for the registration of pharmaceutical

products comprising a combination of fixed-dose active ingredients will be rejected

under the following circumstances:

1) Natural course of the product’s indication (disease or symptom) is different from

the one described in the registration for each of its active ingredients unless

proven otherwise.

2) Clinical, pharmacological or other tests subject to evaluation are not available for

any of the components.

For combined pharmaceutical products, the applicant applying for marketing

authorization must provide evidence of their product's safety and efficacy when used

at the same time. In addition, the applicant must submit further evidence as to the

following:

1) Each pharmaceutical product should contribute to the therapeutic effect of the

combined product.

2) The dose of each pharmaceutical product, the frequency of administration, and

duration of the treatment must grant safety and efficacy to the combination, and

avoid the potentiation of adverse reactions.

3) The ingredients used in each pharmaceutical product, including excipients, are

required to be chemically, pharmacologically, pharmacokinetically, and

biopharmaceutically compatible, both in vitro and in vivo as appropriate.

4) Toxic or side effects should be the same or less than those found in each of the

pharmaceutical products separately.

Given the nature of phytopharmaceutical products, the following considerations must

be taken into account for their registration:

1) To prove safety, results of pre-clinical trials, toxicity studies, and phase I clinical

studies, with the results of by phase II and III clinical trials for the proof of

efficacy should be submitted. If aforementioned information can be found from

- 23 -

the official documents published by international organizations or foreign

agencies like WHO, FDA or EMEA, it can be used when requesting the

marketing authorization.

2) Applications must comply with the provisions stated in the general registration

requirements, including the following special rules:

- Therapeutic equivalence studies are not required at the time of registration or

when requesting any subsequent modifications.

- The description of the manufacturing process is required.

- The generic name must correspond to the taxonomic botanic denomination of

the plant providing the active ingredients.

- The quali-quantitative formula must include the type of plant preparation

used for the product, such as dry or fluid extracts, soft extracts, powder or

others, followed by the plant or parts thereof that have been employed in the

preparation, plus their scientific name, concentration and its equivalent plant

marker, if applicable.

- No narcotic or psychotropic substances or allopathic medicines is allowed in

the preparation.

- The identity and purity of the ingredients are determined in accordance with

foreign or international pharmacopoeias or sources of information, and are

required for validating the proposed analytical methodology.

- The analytical methodology for evaluating the finished product and the raw

materials should appear in any of the pharmacopoeias officially accepted in

Chile or in foreign sources of scientific information, if not, the corresponding

validation of the proposed analytical methodology is required.

- Finished product specifications must be in accordance with the

pharmaceutical form of the product. Notwithstanding the foregoing, the

titration of active ingredients in the finished product may be replaced with

the titration of specific plant marker.

- Products comprising isolated or synthetic active ingredients are not

considered to be phytopharmaceuticals, even if prepared from plant raw

materials.

Given the nature of homeopathic products, the following considerations will be taken

into account for their registration:

1) Regarding information on the pharmaceutical quality of the product:

- Generic names of active ingredients are required to be prepared in Latin as

specified in the recognized pharmacopoeias.

- In quali-quantitative formulas, each homeopathic substance must be prepared

in Latin, followed by the final dilution (i.e. in the finished product) and

concentration.

- A clear and complete description of the starting raw materials used in the

preparation of the homeopathic substance is required, in addition to their

characterization, method of preparation, and any physicochemical controls to

which they have been submitted.

- A description of the manufacturing methods used for preparing the finished

product.

- 24 -

- Homeopathic pharmaceutical products must meet the finished product

specifications according to the pharmaceutical form in which they are

presented, like any other drugs, except for the titration of the active

ingredients in the finished product.

- When homeopathic products are administered as conventional tablets,

disintegration tests are required instead of dissolution tests.

2) With respect to information endorsing the efficacy and safety of the product, in

addition to the texts particularly mentioned in article 33, the use of other

pharmacopoeias, documents issued by WHO expert committees, or other

references acknowledged by decree of the Ministry of Health may be authorized

und r th ormul “By ord r o th Pr id nt o th R publi ” (Por ord n d l

Presidente de la República) at the proposal of the ISP.

In addition to meeting general product registration requirements, applications for the

marketing authorization of biological products must include the following information:

1) Name of the product, in the following order:

- Trade name or otherwise the generic (INN) or pharmacopoeial name.

Vaccines must be designated with a Latin name after the disease against for

which they provide protection.

- The manufacturing process when the active ingredients are living or dead

mi roorg ni m , r rring to th pro “living”, “ tt nu t d,”

onjug t d”, “in tiv t d” or oth r .

- The manufacturing method, in the case of active ingredients produced by a

living organism that has been genetically modified, referring to the process as

“r ombin nt”

- Pharmaceutical form and dosage, if appropriate.

2) Quali-quantitative composition in the following order:

- Quali-quantitative statement for each active ingredient.

- Quali-quantitative statement for each of excipient.

- Quali-quantitative statement for any adjuvant or adsorbing agent in the

product, if applicable.

- Quali-quantitative composition is required to be stated (if applicable) in units

of mass or volume in the metric system. The protein content or units of

biological activity is required to be stated in units of mass or volume, or

alternatively in international units.

- In the case of products for active immunization, the quali-quantitative

composition must be preferably stated in unit doses.

- Active ingredients and excipients should be designated by their international

non-proprietary names (INN) or by existing pharmacopoeial names.

Substances not included in the pharmacopoeia must be named after their

chemical or biological denomination, and as for vaccines Latin names must

be used according to the name of disease prevented by the vaccine used. No

abbreviations or marks may be used for designation.

- The taxonomic designation of microorganisms should be stated in short,

including the strain, serotype or other subspecies information when

appropriate.

- 25 -

- The nature of any cellular system used for manufacturing biological products

must be disclosed, as well as the use of recombinant DNA or RNA

technology.

- When including living microorganism as part of active ingredient, the

chemical compound used in the chemical inactivation method should also be

disclosed.

- Should the quali-quantitative statement include adsorbing agents such as

aluminum, the quantitative statement must be per dose base.

- Preservatives must be quantitatively detailed at the end of the formula, if

present, which must include qualitative details of antibiotic residues and

antimicrobial agents used in the manufacturing process that may potentially

trigger allergic reactions in certain individuals.

- Any colorings in the product must be designated by their generic names or

by their chemical names. Other names with authorized coloring indexes in

accordance with the relevant national technical standard approved by the

Ministry of Heath also can be used to designate the colorings.

3) Active ingredient requirements, including quality and purity specifications, and

control methods:

- Manufacturer and supplier of the active ingredient.

- Supplier and traceability (if applicable) of the reference standard used for

describing the active ingredient.

- Storage conditions of the active ingredient, including temperature, humidity

and quality of the package.

- Description of other desired elements and related compounds, including their

properties and characteristics, structure, biological activity or others.

- When describing active ingredients obtained from human blood or blood

products, the following information is required to further indicate the

procedures followed to guarantee to the fullest extent the absence of

potentially pathogenic agents that may be transmitted:

Donor selection protocols.

Plasma fractionation method.

Testing of the plasma before and during the process, including the

determination of hepatitis B virus (HBV) surface antigens and antibodies

to Human Immunodeficiency Virus (HIV) and Hepatitis C virus (HCV),

as well as others as appropriate.

Storage temperature of the active ingredient and monitoring method.

Validity and expiry date.

Methods of inactivating infectious contaminants that the starting material

may contain, as well as intermediate and final products.

4) Manufacturing method:

- Description of the manufacturing method, including process controls and

tolerance.

- Description of the manufacturing process, including raw materials, critical

steps and reprocessing if applicable, as well as an indication as to how

- 26 -

routine monitoring methods have been selected for controlling the finished

product.

- Description of source and starting materials for the production of the

biological active ingredient.

- Description of actions taken to prevent or control contamination by both viral

and non-viral adventitious agents such as HIV, HSV, HCV, transmissible

spongiform encephalopathy (TSE), bacteria, mycoplasma or fungi.

- Description and information about the validation process.

5) Control of excipients:

- Quality and purity specifications, as well as methods of controlling

excipients used in the formulation pursuant to the requirements set forth in

official documents authorized hereunder or otherwise in their monographs.

- A certification attesting to the absence of raw materials from animal species

affected by TSE and other transmissible diseases.

6) Control of finished products:

- At least the following information should be included:

Description and appearance (shape, color, odor and clarity if applicable).

Selective identification of active ingredients.

Titration, potency or activity of active ingredients.

Determination of impurities, if applicable.

Description of the nature and type of both primary and secondary

packaging material and accessories, in the event of the latter being in

contact with the pharmaceutical product.

Any other information as required by the Institute according to the

nature and composition of the biological product.

- Indication of acceptance criteria and minimum and maximum values if

considered to be deciding factors.

- Fact sheet, including laboratory parameters and acceptance criteria

characterizing the biological product which, upon being made official, should

be the specifications that the finished product must meet throughout its

effectiveness period.

7) Packaging material:

- Description of the nature and type of both primary and secondary packaging

material and accessories, in the event of the latter being in contact with the

pharmaceutical product.

- Information regarding the choice of primary packaging materials in view of

the protection against light and moisture, and their compatibility with the

pharmaceutical form and its administration.

- When the dosage form is sterile, information on the integrity of the package

sealing system used to prevent microbial contamination is required.

8) Stability tests for formulation, solvent and reconstituted product, as appropriate:

- The information on the stability of the product should include at least the

following:

Formula subject to study.

- 27 -

Information of the person in charge of the stability test and the

manufacturer.

Temperature and humidity conditions, packaging material and batches

(minimum 3 batches), test design and analytical procedures, and

specifications of the finished product must be in accordance with the

Guidance of the Stability of Pharmaceutical Products (Guía de

Estabilidad de Productos Farmacéuticos), which is the technical standard

approved by the Ministry of Health at the proposal of the ISP.

- In the event of a biological product containing a new active ingredient in the

field of medicine in Chile, the information should include the results of

studies on forced degradation stability and stress conditions.

- As for effectiveness period and storage precautions proposed on the basis of

the corresponding stability test, effectiveness period for reconstituted product

(if necessary) should be included.

- In the event of the product requiring dilution prior to administration, the

information should include compatibility and stability tests with adequate

diluents, as appropriate.

9) Efficacy and safety requirements

- In the case of biotechnological products, a technical standard will be

approved by order of the Ministry of Health at the proposal of the ISP to

determine active ingredients and their presentation. And then, abridged

clinical studies endorsing the efficacy and safety of the product will be

accepted based on the existence of another registered biotechnological

product comprising the same active ingredients, unit dose, pharmaceutical

product and route of administration.

- Notwithstanding the foregoing, the applicant must submit comparative

studies including the reference product for each indicated active ingredient in

order to properly characterize the product and provide evidence as to the

similarity in their nature.

3. Generic drug approval application

3.1 Procedure

The marketing authorization of generic drugs can be according to the ordinary approval

pro (“N w Drug Appli tion” in thi do um nt), the simplified approval process

(“Simpli i d R gi tr tion Pro dur ” in thi do um nt), or th bbr vi t d pprov l pro

(“Short R gi tr tion Pro dur ” in thi do um nt). Th r gi tration procedure will depend on

the pharmaceutical product (NDA for new active ingredients, new doses or new routes of

administration; Simplified procedure if there are any products already approved with the

same ingredients in the same dose and with the same route of administration; and Short

procedure if the Ministry of Health requests it either for the implementation of public health

plans and programmes, or if the active ingredient is added to the National Formulary).

- 28 -

3.2 Priority review

Not specified in the regulation.

3.3 Review period

Within 6 months from the date of payment of application fees

3.4 Required dossiers

All pharmaceutical products which require marketing authorization should meet the

same requirements depending on their nature and type. As for the generic drugs, refer to

the various requirements stated in the previous section.

Refer to Appendix 1 for the list of drugs that require bioequivalence evaluation.

4. Orphan drugs

The Resolution 411 of 2015 sets forth recommendations for the marketing authorization of

orphan drugs. This resolution states that the procedures in the Supreme Decree 3 of 2010

must be followed, but in the application the applicant must provide the justification for the

orphan drug designation, and will be able to present evidence of safety and efficacy with a

lower number of patients.

This resolution can be found in the following link:

http://www.ispch.cl/sites/default/files/res_exenta_411_05022015.pdf

5. Priority review12

5.1. Short Registration Procedure

Priority review is applicable for medicines for the following cases:

For serious diseases and life threatening conditions, and when medicines are apparently

expected to contribute to the improvement of quality of healthcare based on overall

evaluation of the seriousness of the target disease and medical usefulness.

When application is submitted for marketing approval and consideration is made based

on the opinions of the external experts.

5.2. Simplified Registration Procedure

The regular registration procedure may be simplified upon the interested party's request

by leaving out certain information as indicated below:

- In the case of pharmaceutical products comprising the same active ingredient, in

the same amounts, pharmaceutical form and route of administration as another

registered product whose registration has not been cancelled by the ISP due to

public health reasons, information on safety and efficacy may not be submitted,

unless the ISP determines the need for some or all of such information by means of

12

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a substantiated decision. In the case of a non-standard release pharmaceutical

product, the corresponding therapeutic equivalence studies should be submitted.

- In the case of widely recognized active ingredients which have been the subject of

ample experimentation so that their efficacy, safety of use and adverse reactions

are widely reviewed in the scientific literature, information on pre-clinical trials

may be replaced with the relevant bibliography. In addition, scientific information

relating to the efficacy and safety of the product intended for registration may also

be partially omitted, in which case the Institute will review the application and

reasonably require all the necessary information.

- In the event of a pharmaceutical product being pharmaceutically equivalent to a

registered product and listed under active ingredients for which evidence of

therapeutic equivalence has been required, the corresponding studies should be

submitted pursuant to specific regulations.

- In the event of a product having been manufactured in Chile for the sole purpose of

export, while it is considered to be a pharmaceutical product under Chilean

regulations and a food product in the country of destination as certified by the

relevant health authorities, the information on safety and efficacy may be omitted

unless the Institute by means of a substantiated decision determines the need for

some or all of such information.

The simplified marketing authorization procedure will not be applicable in the

following cases:

- The pharmaceutical product to be registered appears to have the active ingredient

that is used first time in the field of medicine in Chile, except for the active

ingredients widely known.

- The pharmaceutical product to be registered comprises the same active ingredient

as another registered product, and the disclosure of information about such product

is protected under the provisions of section 2, Title VIII of law no. 19,939.

- The pharmaceutical product to be registered is concerned with a new therapeutic

use, dosage schedule, extension of a previously approved route of administration,

or age group.

- The pharmaceutical product to be registered presents a change in the composition

and concentration of active ingredients over a registered formula, or contains new

salts, esters, complexes or isoforms of the active ingredients in a registered

pharmaceutical product, or comprises combinations of separately registered or

unregistered fixed-dose active ingredients.

- In the event of the pharmaceutical product to be registered being in a different

pharmaceutical form and wherein the release of active ingredients has been

modified.

- In the case of a combined pharmaceutical product to be registered for the first time.

- When requesting the registration of a biological product.

The registration procedure of homoeopathic pharmaceutical products may only be

simplified upon meeting all of the following conditions:

- The route of administration is oral or external.

- Absence of specific therapeutic indications in the graphic labeling or in healthcare

professional and patient information sheets.

- 30 -

- The product comprises a single homoeopathic substance to a degree of dilution that

guarantees the safety of the drug.

- The homoeopathic substance making up the pharmaceutical product is obtained

from a plant, animal, mineral or chemical substances and raw materials described

in officially recognized pharmacopoeias in accordance with homoeopathic

manufacturing procedures also described in such texts.

- 31 -

V. Others13

1. Good Manufacturing Practices

Good Manufacturing Practices (GMP) (Buenas Prácticas de Manufactura, BPM) is the

minimum technical standards established for all procedures with a view to ensure a consistent

and satisfactory quality in pharmaceutical products within statutory limits currently in force.

This standard will be approved by order of the Ministry of Health at the proposal of the ISP.

Both GMP and Good Laboratory Practices (GLP) standards will be applied to the

manufacture, quality control and storage of products for export. All pharmaceutical

laboratories should observe GMP and GLP standards as appropriate depending on the

activities for which they are authorized

Also, the manufacturing or packaging agreement relating to pharmaceutical products in

any stage of production should include the technical aspects of corresponding stage in

accordance with GMP.

The ISP inspects the facilities to supervise operating conditions in accordance with GMP

and GLP standards as well as the provisions stated in REGULATIONS OF THE

NATIONAL SYSTEM CONTROL OF PHARMACEUTICAL PRODUCTS FOR HUMAN

USE.

2. Drug Master File

Not specified in the regulation.

3. Labeling and package inserts

The label of the secondary packaging must be written in Castilian, in clearly visible

letters, and should include at least the following information without any advertising

or promotional texts.

- Name of the pharmaceutical drug.

- Pharmaceutical form and dosage unit in the case of monodrugs.

- Unconventional release pharmaceutical forms should be indicated as such on the

packaging material, as stated in the corresponding registration.

- Number of dosage units.

- Formula composition: quantitative and qualitative list of active ingredients and

excipients.

- Name and address of the holder and the manufacturing laboratory, packer or

importer, as appropriate.

- Route of administration.

- Approved retail conditions indicated with the appropriate abbreviation or full text.

- Expiry date. Furthermore, the included or recommended solvent should also be

indicated in the case of extemporaneous preparations, as well as the effectiveness

period after reconstitution, if applicable.

13

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- 32 -

- Registration number given by the Institute, preceded by the following acronym

“R g. I.S.P.” (In titut o Publi H lth r gi tr tion).

- Product code: Imported finished products must keep the original code.

- Storage and conservation conditions.

- Incorporation o th ption “M yor in orm ión n www.i p h. l" (Mor

information at www.ispch.cl) and other information, if applicable.

- Any other information specially and additionally required hereunder or deemed

necessary by the Institute upon registration or later.

The labeling of the primary packaging should include at least name of the

pharmaceutical drug; pharmaceutical form and dosage unit in the case of monodrugs;

route of administration; expiry date, expiry date of included or recommended solvent

in the case of extemporaneous preparations, as well as the effectiveness period after

reconstitution, if applicable; registration number given by the ISP, preceded by the

ollowing ronym “R g. I.S.P.” (In titut o Publi H lth registration), product code

(Imported finished products must keep the original code).

Pharmaceutical products packed as medical samples should include the caption

“MUESTRA MEDICA PROHIBIDA SU VENTAX” (Medical Sample. Prohibited

from Selling) in both the primary and the secondary packages in indelible ink, in a

clear and visible manner.

The labels must be printed or adhered to the outer surface of the package without

being in contact with its contents. Arial or other similar straight fonts should be used

for labeling purposes, in a minimum size of 6. The graphic labeling of imported

finished pharmaceutical products may exceptionally contain texts in other languages

apart from Castilian, provided that the text authorized by the ISP is not modified.

Under their sole responsibility, marketing authorization holders may include in the

labels industrial property information as required by law to exercise the rights arising

therefrom. Graphic labeling and healthcare professional and patient information

leaflets submitted upon applying for a marketing authorization must conform to their

final text once authorized, without prejudice to any amendments introduced by the

ISP. The font type and size for the secondary packaging stated above paragraph are

applied to the patient information leaflets. The same requirements should be applied

to the subsequent amendments of the graphic labeling and healthcare professional

leaflets and patient information sheets.

In addition to the information described in the above, pharmaceutical drugs intended

for direct sale should include the following details:

- Regular dosing instructions for each indication as authorized in the corresponding

registration.

- Any warnings as deemed necessary for safe and effective use of the product,

indicating contraindications, interactions and adverse reactions if applicable as

determined by the Institute upon granting the marketing authorization.

These products may be presented in dispensers provided that each blister or strip is

placed within an insert or other unit disclosing the full text of the caption approved for

the secondary packaging and the patient information sheet, if not enclosed.

A pharmaceutical product must be designated after its generic or trade name.

Notwithstanding the foregoing, if a pharmaceutical product is not being identified by

- 33 -

its generic name and comprising a single active ingredient, the ingredient should be

identified by its generic name printed in legible characters under the following

conditions:

- The name should be located on the bottom line right after the authorized

denomination.

- The color of letters and the background of the authorized designation must be the

same.

- The font size should not be greater than fifty percent of the size of the product

name or less than the minimum of 6.

- The name should be printed in capital letters.

A pharmaceutical drug may not be designated with a trade name in the following

cases:

- The name is the same with or similar to an international non-proprietary name or

its own chemical or generic name, or other than a name referring to active

ingredients composing the product.

- It could cause confusion because the name is the same with or similar to the name

of another registered product with different active ingredients or therapeutic

properties.

- The name has been used to identify a product whose registration is cancelled or

expired, unless 10 years or more have elapsed in the case of products intended for

direct sales and 5 years or more in other cases, with different therapeutic properties,

or unless evidence is provided that the product has never been marketed in Chile.

- The name includes or is similar to the name of a food item, a cosmetic product or

any other product under marketing control.

- The name encourages misuse and self-medication.

Notwithstanding the foregoing, the holder of a registration may use the same trade

name for a number of registered pharmaceutical drugs provided that their

compositions comprise at least one active ingredient in common producing the main

therapeutic action and that they are intended for direct sale.

The containers of all parenteral solutions of 100 ml or more should include label

indicating the date, month and year of manufacture in a clear, visible and indelible

manner, and a warning to discard the product in case of turbidity or precipitate, unless

such conditions are deemed to be particular specifications of the finished product and

have been authorized in the corresponding registration. In addition to this, if the

parenteral solutions comprise electrolytes in a single drug, this must be indicated on

the label in letters of a particular color or otherwise different from the corresponding

color. The ISP will determine the colors for each cation of the active ingredient in the

respective solutions.

The amount of pharmaceutical product must be indicated by weight, volume or unit,

as appropriate. In the case of blisters or vials, each should have the indications for

primary packaging and the amount of active ingredient, unless that in view of the size

of the packaging, the ISP may issue a resolution relevant to waive in whole or part

some of these requirements.

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The composition of the product should be indicated by its active ingredients as

authorized upon granting of the registration and should indicate the equivalence of

active ingredients with the parent drug and the qualitative list of all excipients.

The composition of the formula should be indicated in percentages and in the

corresponding unit dose in the case of syrups, solutions, emulsions, powders,

ointments, creams, gels and other formulations of similar nature.

In the case of vials, capsules, tablets, pills, pessaries and suppositories, the

composition of the formula should be indicated by each unit dose. Solid or diluted

pharmaceutical forms that are not presented in units such as tablets, lozenges,

pessaries or the like should indicate the active ingredients in the current or usual

administration measures.

Labels must highlight the following captions as appropriate:

- “SUJETO A CONTROL DE ESTUPEFACIENTES" (SUBJECT TO CONTROL

OF NARCOTIC SUBSTANCES)

- "SUJETO A CONTROL DE PSICOTRÓ PICOS" (SUBJECT TO CONTROL OF

PSYCHOTROPIC SUBSTANCES)

- "FORMULARIO NACIONAL" (NATIONAL FORMULARY)

- "ENVASE CLÍNICO SÓ LO PARA ESTABLECIMIENTOS MÉDICO-

ASISTENCIALES" (CLINICAL PACKAGING FOR MEDICAL CARE

FACILITIES ONLY)

- "ENVASE CLÍNICO PARA VENTA EN ESTABLECIMIENTOS

FARMACÉUTICOS AUTORIZADOS" (CLINICAL PACKAGING FOR SALE

IN LICENSED PHARMACIES)

- "USO EXTERNO" (EXTERNAL USE)

- "USO BAJO SUPERVISIÓ N MÉDICA" (USE UNDER MEDICAL

SUPERVISION)

- "MUESTRA MÉDICA PROHIBIDA SU VENTA" (MEDICAL SAMPLE NOT

FOR SALE)

- R = Receta Simple, Simple Prescription, RR = Receta Retenida, Withheld

Prescription, RCH = Receta Cheque, Controlled prescription, VD = Venta Directa,

Non-prescription product

Any batch or sub-batch of a pharmaceutical product should be identified by a code

that will enable tracking at any stage from manufacturing to retail or use. The codes

should be indicated on the labels of primary and secondary packages containing the

pharmaceutical drug. The code must consist of numbers or combinations of letters and

numbers, and indicate the month and year of manufacture and the batch number in

sequential and chronological order. In other cases, any alphanumeric combination will

be accepted as a code, but it should indicate the month and year of manufacturing on

all labels and comply with general labeling requirements. In the case of imported

finished pharmaceutical products, the holder must submit the code of the country of

origin upon applying for registration and indicate how it should be interpreted. If a

pharmaceutical product from a single batch should be go through in discontinuous

steps until being finished, each step will be considered to be a sub-batch and must be

identified by an addition to the original serial number.

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4. Certificate of a Pharmaceutical Product

Certificate is for those products imported during any stage of the production process,

issued by the corresponding health authority of the country where the manufacturing facilities

are located certifying that the foreign manufacturer is duly authorized in their country and

follows Good Manufacturing Practices in accordance with WHO recommendations. It also

indicates that production areas or types of products are authorized for manufacturing, unless

such information is included in the document such as marketing authorization certificate,

pharmaceutical product certificate, marketing authorization certificate or official certification

recommended by the World Health Organization issued by the authorities of the country of

origin and duly legalized.

5. Manufacturing Licenses

Manufacturing and/or domestic distribution agreements notarized by notary public are

submitted with marketing authorization for each manufacturing facility.

6. Fees

The specified fees and charges for registration are as below:

4112126 General approval of pharmaceutical products $279,125

4112127 General registration of pharmaceutical products $837,375

4112124 Approval of simplified application of pharmaceutical products $216,195

4112125 Simplified registration of pharmaceutical products $646,555

4112137 General approval of phytodrug or other pharmaceutical products (Art. 53) $216,195

4112138 General registration of phytodrug or other pharmaceutical products (Art.

53) $646,555

4112139 Approval of simplified application of pharmaceutical products or other

phytodrug (Art. 52) $194,492

4112140 Simplified registration of pharmaceutical product or other phytodrug (Art,

52) $571,480

4112141 General approval of of homeopathic pharmaceutical product (Art. 53) $114,970

4112142 General registration of homeopathic pharmaceutical product $343,495

4112143 Approval of simplified application of homeopathic pharmaceutical product

(Art. 54) $20,358

4112144 Simplified registration of homeopathic pharmaceutical product (Art. 54) $94,758

4112128 Abbreviated application of pharmaceutical product registration $216,195

4112129 Short pharmaceutical product registration $646,555

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VII. References

Website

1. Institute of Public Health (Instituto de Salud Pública):

http://www.ispch.cl/

2. Library of the National Congress of Chile (Biblioteca del Congreso Nacional de Chile):

http://www.leychile.cl/

3. Ministry of Health of Chile (Ministerio de Salud de Chile):

http://web.minsal.cl/

Journal

1. Health Industry Brief - Medical Device/IT Health Vol.33, Information on market trend of

medical devices in Chile, Issued by Korean Health Industry Development Institute

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Appendix 1. List of Drugs that Requires Bioequivalence Tests14

14

http://www.ispch.cl/sites/default/files/uso_tratamiento.pdf

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