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REGULATIONS OF THE NATIONAL SYSTEM FOR THE CONTROL OF

HUMAN PHARMACEUTICAL PRODUCTS

PRELIMINARY CHAPTER

SCOPE AND COMPETENT AUTHORITIES

ARTICLE 1 - These regulations include technical and administrative standards and other terms or

conditions to be met for registering, importing, exporting, manufacturing, storing, possessing, and

distributing (either free or for good and valuable consideration) pharmaceutical products, for

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

ARTICLE 2 - The Ministry of Health, through the Department of Public Health, shall be required to

play a guiding and regulatory role in the field of pharmaceutical products, implementing a national

drug policy and issuing technical and administrative standards to be met by public and private

entities engaging in the activities outlined in the previous article and which shall be approved by

relevant administrative acts.

ARTICLE 3 - The Institute of Public Health is the national health authority responsible for the

sanitary surveillance of pharmaceutical products and for ensuring compliance with the provisions

set forth herein, the Sanitary Code and its supplementary regulations, and other laws on the

subject.

The Institute is furthermore responsible for verifying the quality of pharmaceutical products in any

of the stages referred to in article 1; authorizing the installation and operation of pharmaceutical

laboratories; licensing and registering pharmaceuticals and other products subject to these forms

of control; supervising conditions for import, admission, export, manufacturing, and distribution of

this products, and likewise any advertising and information about the same; controlling 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; and monitoring compliance with the provisions hereunder and other

regulations governing such matters.

ARTICLE 4 - The Regional Health Departments shall be responsible for authorizing the admission of

pharmaceutical products according to the provisions set forth in article 2 of law no. 18,164. In

addition, Regional Health Departments shall be required to enforce and monitor the compliance

with the provisions herein regarding the distribution, storage, and possession of pharmaceutical

products, insofar as these activities are carried out by authorized pharmaceutical facilities, except

for pharmaceutical laboratories.

ARTICLE 5 - For the purposes hereof, the definitions below shall be construed and interpreted as

follows:

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1) Biological activity: Measurable response of in vivo or in vitro activity or potency

characterizing a certain amount of a pharmaceutical product with respect to a

reference standard.

2) Administration: The act whereby a drug comes into contact with humans, so that a

local or systemic action may be exerted upon absorption thereof.

3) Quality assurance: A comprehensive system designed to ensure that the processes

and their results meet certain quality requirements previously set out.

4) Bioavailability: The amount of an active ingredient from a pharmaceutical form that

reaches the systemic circulation and the speed at which this occurs.

5) Good Laboratory Practice (GLP): A set of rules, operating procedures and practices to

ensure that the data generated by a quality control system is reproducible and

representative, and to guarantee the validity and reliability of such results. Said

technical standards shall be required to be approved by order of the Ministry at the

proposal of the Institute.

6) Good Manufacturing Practice (GMP): Minimum technical standards established for all

procedures with a view to ensure a constant and satisfactory quality in pharmaceutical

products within statutory limits currently in force. Said standards shall be required to

be approved by order of the Ministry at the proposal of the Institute.

7) Drug quantity: Appropriateness of the drug for the use for which it is intended as

determined by its efficacy, safety, and stability, according to its identity, strength,

purity, and others features in accordance with the relevant sanitary registration.

8) Sanitary registration certificate: A document issued by the health authority of the

country of origin or manufacture upon request of the interested party, stating that:

The manufacturing facilities meet the conditions required by sanitary

legislation in the relevant country for the manufacture and packaging of the

registered product.

The product is registered in the country issuing the certificate in accordance

with current regulations, indicating the authorized formula in full detail.

The sale or distribution of the product under any conditions is subject to a

restrictive regime or other special sanitary supervision, if applicable.

9) Quality control: Activities aimed at ensuring the uniformity of product batches at all

manufacturing stages in accordance with identity, strength, purity, and other quality

requirements set out in the respective monograph and authorized in the

corresponding sanitary registration.

10) Shelf control: Product quality checking during retail and distribution to the public

conducted by the Institute or an appointed health authority in accordance with

programmes developed by the Ministry at the proposal of the Institute.

11) Code: Distinctive alphanumeric or numeric combination which makes it possible to

identify a pharmaceutical product unambiguously during its manufacture, storage,

distribution and retail for the purposes of ensuring the traceability thereof.

12) Counter-sample: A limited sample of analyzed products that is kept under the same

conditions as reference samples.

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13) Quarantine: A transitional period of physical or other type of isolation of raw

materials, materials in any shape or form, and intermediate, semi-manufactured, bulk,

semi-finished or finished products during which their use or distribution is forbidden

while a decision is reached on their release, rejection or reprocessing, in the light of

the results of the respective quality control.

14) Dispensation: The act whereby the professional pharmaceutical chemist supplies a

drug to a person, usually following the prescription of an authorized practitioner, and

provides guidance on its use, influence of food, drug interactions, potential adverse

reactions, storage conditions and other relevant information, as authorized in the

corresponding registration.

15) Distribution: Delivery of the pharmaceutical product to manufacturing facilities,

importers, distributors or other authorized agents.

16) Dosage: The administration interval and period of treatment provided for the dose of

a drug or a pharmaceutical product.

17) Dose: The total amount of a drug or pharmaceutical product in the approved dosage

form administered each time.

18) Plant drug or material: Plant or raw parts thereof used for medicinal or

pharmaceutical purposes.

19) Effectiveness: The capacity of a drug or pharmaceutical product to produce the

desired therapeutic effect as determined by scientific methods and clinical trials in

humans.

20) Insert: Sleeve made of cardboard or other material that protects the blister or strip

and contains the patient information leaflet and/or the authorized graphic label.

21) Dissolution assay: In vitro test performed under predefined experimental conditions

for determining the dissolution rate of a solid active ingredient from a pharmaceutical

form.

22) Dispenser: A package intended for retail of pharmaceutical products authorized for

sale in blisters, strips, envelopes, protective inserts, or other primary packaging

protective systems under the conditions established in the registration.

23) Primary packaging: A material used to hold and envelop pharmaceutical products in

their final pharmaceutical form.

24) Secondary packaging: A tamper-resistant container that holds and protects the

primary packaging.

25) Clinical packaging: A package intended for use only in pharmacies or with medical kits

at healthcare facilities that is supplied or delivered to patients according to the

prescribed dosage and form.

26) Pharmaceutical equivalents: Pharmaceutical products containing identical amounts of

the same active ingredients or salts or esters thereof and having the same

pharmaceutical form and route of administration, but not necessarily the same

excipients, and meet the same or similar quality specifications .

27) Therapeutic equivalents: Pharmaceutical equivalents meeting the same or similar

quality specifications and producing essentially the same effects upon administration

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under conditions described in their labels insofar as potency and effectiveness are

concerned as determined by appropriate tests.

28) Pharmaceutical drug: Registered pharmaceutical product having a distinctive

packaging adapted for its use and designated under a generic name or other

designation. It shall be construed as including elements or devices for its

administration where appropriate.

29) Specifications: Technical document defining the characteristics of a raw material,

material, product, or service and determining which variables should be assessed in

them, further describing the tests, assays and analyses used to determine them and

establishing the criteria for acceptance or rejection.

30) Stability: The capacity of an active ingredient or a finished pharmaceutical product to

keep its original properties according to the specifications set forth and authorized in

their monograph, which guarantees its physical, chemical, biological and

microbiological properties, as appropriate, within specified limits throughout the

effectiveness period.

31) Manufacturing status: The status of a pharmaceutical product within the

manufacturing process (semi-manufactured, bulk, semi-finished or finished).

32) Therapeutic equivalence study: A comparative clinical, bioavailability,

pharmacodynamic or “in vitro” test performed on a reference pharmaceutical product

and another one under evaluation.

33) Real-time stability study: A stability test carried out for the time of the effectiveness

period and under storage, temperature, and humidity conditions determined by the

nature of the product.

34) Accelerated stability study: A stability test designed to increase the speed of chemical

degradation or the physical changes of an active ingredient or a pharmaceutical

product in its primary packaging under severe storage, temperature, and humidity

conditions as part of a formal storage programme for a certain period of time

according to the active ingredient under evaluation, resulting in the determination of

stability for a certain period.

35) Stability study: A series of tests, assays and analyses relating to the physical, chemical,

biological, and microbiological characteristics of an active ingredient or a

pharmaceutical product conducted for the purposes of gathering information about its

stability in order to determine the effectiveness period under certain packaging and

storage conditions.

36) Bioavailability studies: Pharmacokinetic tests following a predefined experimental

design which make it possible to determine the bioavailability of an active ingredient.

37) Pharmacokinetic studies: In vivo assays following a predefined experimental design to

help establish the kinetics of the absorption, distribution, excretion, and metabolic

processes of the active ingredients and metabolites of a pharmaceutical product.

38) Evaluation of a pharmaceutical product: Systematic study of information provided by

the interested party requesting a sanitary registration with respect to the relevance of

administrative and technical records such as pharmaceutical, pharmacological,

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toxicological, clinical, and therapeutic properties in order to determine or certify

whether the product is suitable for the prescribed use.

39) Excipient: Any material used in the manufacture of the products described herein

other than an active ingredient.

40) Retailing: Retail sale of a pharmaceutical product to users or consumers.

41) Pharmacovigilance: A set of activities concerned with the detection, evaluation,

understanding, and prevention of adverse effects associated with the use of drugs.

42) Expiry date: The date as indicated by the month and year, and in some cases the day,

according to the relevant sanitary registration, beyond which the product cannot be

expected to remain stable.

43) Pharmaceutical form: Physical form of a drug to facilitate its fractionation,

dispensation, dosage and administration, or use.

44) Master pattern or formula: A document or set of documents indicating raw materials,

amounts, packaging materials, and a description of the procedures and precautions

for producing a specific amount of a finished product, further indicating

manufacturing instructions and process controls.

45) Import: The act whereby a foreign pharmaceutical product enters the country and is

admitted for distribution in compliance with current regulations.

46) Impurity: Any component not defined as constituting the raw material or product.

47) Admission: The act whereby a foreign pharmaceutical product is placed in a duly

authorized storage site pending approval for distribution and use.

48) License: Power of attorney or authorization lawfully granted by an individual or legal

entity to request, amend or cancel a sanitary registration.

49) Plant markers: Chemically defined constituents of the plant active ingredients of

relevance for quality control purposes, regardless of whether they have therapeutic

activity and can be used to calculate the amount of the plant active ingredients in the

final product, provided they have been quantified in the plant preparation or drug

used as raw material in the preparation.

50) Tolerance margins: Officially authorized percentages and maximum and minimum

amount of an active ingredient in a product.

51) Raw material: Any substance of a particular quality directly involved in the

manufacture of the pharmaceutical form, whether it remains unchanged or is

modified or removed during the manufacturing process.

52) Packaging material: Material used for a primary packaging, a secondary packaging, or

an insert.

53) Monograph: A document containing the technical, pharmaceutical, and scientific

description of the characteristics and properties of a product.

54) Medical sample: A unit of a pharmaceutical drug for free distribution only to legally-

qualified prescribing professionals having the same labelling of the registered product

and indicating its status as a medical sample, which may include further information

for healthcare professionals.

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55) Reference samples: Samples taken from each batch of finished product that are

required to be kept for one year after the expiry date of the product in their final

packaging and stored under conditions specified in the sanitary registration.

56) Legal sample or counter-sample: A sample taken by the relevant health authority in

its supervisory capacity, registered in a certificate and under chain-of-custody

conditions.

57) Generic name for a pharmaceutical product: A name accepted by the World Health

Organization (WHO) under the International Non-proprietary Names (INN) system or

otherwise in the pharmacopoeias officially recognized in the country.

58) Country of origin: The country from which a pharmaceutical product has been shipped

for importation into Chile, regardless of any territories through which it travels.

59) Manufacturing country: The country where the manufacturing facilities of a

pharmaceutical product are located, with respect to any of the steps required to

obtain a finished product.

60) Effectiveness period: A period as authorized by the Institute in the relevant sanitary

registration during which a product is required to remain stable under the packaging

and storage conditions set out in the corresponding stability study.

61) Potency: Therapeutic activity of a pharmaceutical product for producing a particular

effect endorsed by appropriate laboratory tests or controlled clinical data obtained by

administering the product under the recommended and authorized conditions of use

as prescribed in accordance with the concentration of active ingredients in the

product formula expressed in weight/weight, weight/volume, unit dose/volume, or

any other units referring to an internationally recognized standard.

62) Plant preparation: A pulverized plant or parts thereof, extracts, dyes, squeezed juice,

fatty or essential oils, gums or other product from a particular process, excluding

chemically defined isolated constituents or mixtures thereof, subject to the possibility

that they may contain other components such as solvents, diluents or preservatives

which shall be required to be declared.

63) Active ingredient: A substance or mixture of substances causing a particular

pharmacological effect or having the capacity to cause such an effect upon

administration.

64) Standard operating procedure (SOP): A written document providing updated

instructions numbered in a logical and continuous sequence to perform general

operations not necessarily confined to a particular product or material, which should

be developed, reviewed and updated by competent authorized staff in order to be

followed by technical professionals in charge of the facilities where they are

implemented with a view to draw up additional documentation on manufacturing

processes and for the purposes of quality assurance and control.

65) Bulk product: A product in its final pharmaceutical form.

66) Associated pharmaceutical product: A product comprising two or more active

ingredients in a single pharmaceutical form.

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67) Combined pharmaceutical product: A product made of two or more pharmaceutical

products included in a single package to be administered sequentially or

simultaneously.

68) Reference pharmaceutical product: A product defined as such by health authorities in

respect of which another requiring a therapeutic equivalence evaluation is compared.

69) Semi-manufactured product: A substance or mixture of partially processed

substances preceding the pharmaceutical form and requiring further manufacturing

steps.

70) Semi-finished product: A product in its final pharmaceutical form and primary

packaging.

71) Finished product: A product in its final packaging, labelled and ready for distribution.

72) Production, production process or manufacture: A set of operations for obtaining a

pharmaceutical product, from the purchase and receipt of materials to the release,

storage and quality control thereof.

73) Adverse drug reaction (ADR): A noxious and unintended reaction occurring at doses

normally used in humans.

74) Serious adverse reaction: An adverse reaction that is fatal or likely to endanger life, or

involving serious disability or incapacity, or that has resulted in hospitalization or its

extension.

75) Unexpected adverse reaction: An adverse reaction undisclosed in the product

monograph or the patient information leaflets, or unknown to the authorized

prescribing professional.

76) Prescription: An order signed by a legally qualified professional so that an amount of

one or more drugs is supplied and administered as indicated.

77) Sanitary registration: The process of evaluation of a pharmaceutical product resulting

in a registration under sequential numbering on a special list held by the Institute prior

to its distribution and use.

78) Graphic label: A graphic representation displaying the officially authorized text in

accordance with the relevant sanitary registration for different types of approved

packaging as appropriate.

79) Batch: A certain amount of raw material, packaging material or processed product

resulting from a single production cycle or continuous steps characterized by its

homogeneity.

80) Sub-batch: A specific and identified fraction of a batch.

81) Possession: The ownership of a pharmaceutical product by an individual or a legal

entity either having the corresponding deed or not.

82) Holder of a sanitary registration: A national or foreign individual or legal entity

domiciled in Chile whose name appears on a sanitary registration.

83) Traceability of analytical data: Features or characteristics of the result of a

measurement or the value of a standard related to specific references, usually

national or international standards, across an unbroken chain of comparisons with

specified uncertainties.

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84) Traceability of a product: The ability to trace a specific unit of a product along any

stage of the manufacturing process and/or a batch along the distribution chain and

across different relevant entities until it is supplied, administrated or used.

85) Unit of sale: An authorized retail presentation for supply and sale.

86) Validation: A documented action performed in accordance with the principles of Good

Manufacturing and Laboratory Practice with a view to demonstrate that the

procedures, processes, activities or systems used during the manufacture and quality

control of a product are conducive to the results indicated within the established

limits.

ARTICLE 6 - The manufacture, importation, possession, distribution and transfer of pharmaceutical

products for any purpose is prohibited under the following circumstances:

1. Contaminated pharmaceutical product: A product containing microorganisms,

parasites or parts thereof capable of causing diseases in humans, or unauthorized

amounts of potentially toxic, carcinogenic or mutagenic substances or other foreign

materials.

2. Altered pharmaceutical product: A finished product which due to inadequate storage,

transportation, preservation or any other reason after being manufactured:

a. has decreased its activity below the limits indicated in the sanitary

registration, or in the case of raw materials, in quality specifications according

to official texts;

b. has lost effectiveness or undergone changes affecting its quality;

c. is in a damaged packaging, or

d. is distributed or sold after the effectiveness period.

3. Adulterated pharmaceutical product: A product whose composition, specifications or

other conditions indicated in the corresponding sanitary registration, or in the case of

raw materials, in quality specifications according to official texts, have been modified

without permission or compliance with said specifications.

4. Counterfeit pharmaceutical product: An unregistered or unlicensed pharmaceutical

product manufactured or imported without prior sanitary authorization. Additionally,

the foregoing definition shall be construed as including counterfeit products

distributed or sold without authorization.

The Institute shall be required to monitor the existence of such pharmaceutical products and

adopt any sanitary measures or impose the corresponding penalties upon conducting a prior

preliminary investigation.

The Regional Health Departments shall be required to monitor the retail and supply of products

under the conditions described above.

The Regional Health Departments shall additionally be required to inform the Institute of any

findings concerning the conditions described in the preceding paragraph so that the Institute can

adopt the necessary measures or conduct investigations with respect to holders of sanitary

registrations, manufacturers, importers or distributors as appropriate.

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Furthermore, the Institute or the Regional Health Departments shall be required to lodge the

corresponding complaint with the Public Prosecutor's Office with a view to conduct an

investigation and impose criminal liabilities if applicable.

CHAPTER I

PHARMACEUTICAL PRODUCTS

SECTION 1

DEFINITION

ARTICLE 7 - A pharmaceutical product or drug is any natural or synthetic substance, or mixtures

thereof, intended for use in humans in the cure, mitigation, treatment, prevention or diagnosis of

diseases or their symptoms, or for producing changes in the physiological system or mental state

of the individual to whom it is administered.

Pharmaceutical products shall be construed as including active raw materials, pharmaceutical

preparations, pharmaceutical drugs and traditional herbal medicines.

ARTICLE 8 - Based on substantiated decisions, the Institute shall impose an appropriate regulatory

regime on all products having or described as having some of the properties listed in the previous

article and labelled or advertised as food items. The decisions made by the Institute shall be

binding both on products currently in the market as well as those distributed and sold for the first

time.

The determination of the applicable regulatory regime may be made either ex officio or at the

request of individuals or other public organizations upon detecting products under the conditions

mentioned in the preceding paragraph in their capacity as supervisory bodies.

For the purposes of determining the applicable regulatory regime as requested, the Regional

Health Departments shall be required to submit a technical report and copies of all records in their

possession, as well as results from inspections and audits if applicable.

Should the Institute establish that the applicable regulatory regime corresponds to a

pharmaceutical product, the corresponding formal resolution shall be required to be published in

the Official Gazette and a notice shall be served on the interested party for the purposes of

requesting a sanitary registration by providing relevant information for all products comprising

components with the alleged therapeutic activity.

Upon service of the aforementioned notice and prior to obtaining a sanitary registration, the

pharmaceutical product shall be recalled by the distributor or retailer, without prejudice to further

sanitary liabilities. These provisions shall also apply for other products comprising the ingredients

of the pharmaceutical product.

In the event of the Institute finding that the applicable regulatory regime does not correspond to a

pharmaceutical product, the records shall be required to be submitted to the Ministry for review

along with a technical report explaining the reasons behind the decision.

ARTICLE 9 - In addition, the determination of the applicable regulatory regime may be made when

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in doubt about the classification of other products such as cosmetics, household and sanitary

pesticides, or medical devices, following the same procedure outlined above.

SECTION 2

PHARMACEUTICAL DRUGS AND THEIR CLASSIFICATION

ARTICLE 10 - According to their nature, pharmaceutical drugs are classified as:

a) chemical products;

b) biological products;

c) radiopharmaceuticals;

d) phytopharmaceuticals;

e) homeopathic products;

f) medical gases; and

g) other drugs not listed above.

ARTICLE 11 - Chemical products are drugs comprising one or more purified and identified active

ingredients obtained from a chemical synthesis or extraction process.

ARTICLE 12 - Biological products are obtained from and/or produced by living organisms and their

fluids or tissues.

Biological products are classified as follows:

a) Vaccines: Biological products formulated to stimulate active immunity.

b) Serum: Biological product formulated to develop passive immunity.

c) Blood products: Human blood or plasma biological derivatives obtained from

industrial processes using human blood or plasma as raw materials. Specifically, these

drugs include albumin, clotting factors and human immunoglobulin, except for human

whole blood, plasma and blood cells.

d) Hormones: Natural biological products like proteins, amino acid derivatives, spheroids

or lipids used to treat some disorders either by increasing or decreasing their levels.

Synthetic hormones are classified as synthetic products under article 10.a.

e) Biotechnological or recombinant drugs: Genetically engineered protein-like biological

products obtained from the combination of recombinant nucleic acids (DNA and RNA)

and monoclonal antibodies, among others.

f) Antibiotics: Biological products made of substances secreted by a microorganism with

antimicrobial capacity. Synthetic antibiotics are classified as synthetic products under

article 10.a.

g) Allergen: Biological product for identifying or introducing a specific and acquired

modification of the immunological response to an allergenic agent.

h) Gene therapy: Biological product obtained by means of a set of processes for the in

vivo or ex vivo transfer of prophylactic, diagnostic or therapeutic genes (DNA or RNA)

to human and animal cells and their subsequent expression in vivo.

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ARTICLE 13 - 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.

ARTICLE 14 - Phytopharmaceuticals are pharmaceutical drugs comprising standardized active

ingredients from aerial or underground parts of plants or other plant material.

ARTICLE 15 - Homeopathic products are pharmaceutical drugs comprising homeopathic

substances made of plant, animal, mineral or chemical raw materials prepared in accordance with

a homeopathic manufacturing procedure described in official regulations approved by order of the

Ministry necessarily including the processes of dilution and dynamization of mother dyes.

Homeopathic products shall be required to have been tested in healthy individuals and

repertorized for prescription or use according to the law of similars. A homeopathic product may

contain one or more homeopathic substances.

ARTICLE 16 - Medical gases are pharmaceutical drugs made of one or more gaseous components

of known concentration and impurity manufactured according to registered specifications and

intended for administration to humans. Such drugs shall be governed by specific regulations.

ARTICLE 17 - In addition to the aforementioned groups, pharmaceutical drugs include any other

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

means, whether curative or for the mitigation, treatment, diagnosis or prevention of diseases or

their symptoms, or for changing physiological systems or mental states for the benefit of the

person to whom it is administered, and which are not classifiable under any of the above

categories.

This group includes the following:

a) Products for parenteral administration products, regardless of their properties or

effects.

b) Vitamins, minerals and other nutrients in therapeutic doses as determined in the

respective technical standard approved by order of the Ministry.

c) Animal or mineral products, as well as those comprising plant drugs and preparations

in association with active ingredients of different nature.

CHAPTER II

SANITARY REGISTRATION OF PHARMACEUTICAL DRUGS

AND OTHER PHARMACEUTICAL PRODUCTS

SECTION 1

CONCEPT AND PURPOSES

ARTICLE 18 - The sanitary registration of a pharmaceutical drug is a process of evaluation and

systematic study of its pharmaceutical, pharmacological, toxicological, and clinical properties with

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a view to verify its quality, safety and efficacy, resulting in a registration under sequential

numbering on a special list held by the Institute prior to its distribution and use in the country.

The sanitary registration of a pharmaceutical product does not release the holder from the

obligation to comply with other laws or regulations governing the marketing of such products.

The sanitary registration may be requested by any national or foreign individual or legal entity duly

represented and domiciled in Chile.

ARTICLE 19 - The administrative proceedings concerning the sanitary registration are unrelated to

other commercial or intellectual property aspects as provided for in article 49 of the Industrial

Property Act, in accordance with the consolidated and coordinated text of law-ranking decree No.

3 of 2006 by the Ministry of Economy, Development and Reconstruction.

ARTICLE 20 - No pharmaceutical product, whether imported or manufactured in the country, shall

be distributed or used without prior sanitary registration.

ARTICLE 21 – Under exceptional circumstances, the Institute may authorize the sale or provisional

use of certain pharmaceutical products without the corresponding sanitary registration in view of

the provisions of article 102 of the Sanitary Code including but not limited to the following

circumstances:

a) Epidemics, emergency situations or disasters that may pose a serious risk to the health

or life of the population.

b) In the case of a pharmaceutical product that is required for urgent medical purposes

without there being any other alternative at such time.

c) In the case of products for use in scientific research or clinical trials, following a

favourable report from the relevant ethic committees in accordance with regulations

on clinical trials in humans approved by the Ministry of Health.

ARTICLE 22 - Applications submitted by interested parties for the sale or temporary use of

pharmaceutical products without prior sanitary registration based on a) and b) above shall require

prior authorization granted by the authorities of the country of origin or manufacturing country as

appropriate. In both cases, the authorizations granted to interested parties may be requested for a

second time within six months, upon receipt of the sanitary registration application or proof that

there is still urgent need for the drug, or that the emergency situations mentioned in the

preceding article remain unchanged.

ARTICLE 23 - Applications for provisional use of a pharmaceutical product in scientific research or

clinical trials shall be required to include a protocol approved by the ethics committee as set forth

in article 21.c, which shall also be required in the case of a registered product intended for a

different use other than as authorized.

ARTICLE 24 - Under the collaboration agreements by and between the Institute and the Regional

Health Departments of regions having customs offices pursuant to the provisions of the

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Constitutional Law of State Administration (law no. 18,575) as consolidated and coordinated by

law-ranking decree No. 1 of 2000 by the General Secretariat of the Presidency, the Regional Health

Departments may authorize the temporary use of pharmaceutical products without prior

registration when they have been imported for personal use directly by the applicant or his

representative, provided that they are prescribed by a qualified healthcare professional stating the

need for the treatment and its duration.

Additionally, Regional Health Departments may authorize the admission of drugs by national or

foreign individuals carrying them upon entering the country for treatment for a period not

exceeding three weeks, except in the case of chronic diseases or other therapies, upon providing

the corresponding justification. Any drugs in excess shall be withheld for later confiscation.

Regional Health Departments shall be required to give the Institute a monthly notification of the

authorizations granted pursuant to this article.

ARTICLE 25 - For the purposes of article 102 of the Sanitary Code, pharmaceutical preparations

shall have an official sanitary registration number also appearing in the Official Preparations

Register which shall be deemed the official record of the Institute of Public Health.

ARTICLE 26 - Active starting materials comprising natural or synthetic bulk drugs shall be deemed

to be registered by the fact of being included in the formula of a registered pharmaceutical

product or by the respective authorization for use thereof when such materials are imported by

authorized businesses.

ARTICLE 27 - Traditional herbal medicines are made of plants or whole or crushed parts thereof,

either fresh or dried, hand packed and labelled, designated as is customary in accordance with

local cultural traditions, and recognized in the corresponding technical standard approved by

order of the Ministry as mentioned in the following paragraph. These drugs shall be deemed to be

registered for retail and distribution purposes upon authorization by the relevant Regional Health

Department of the facilities where they are stored, manufactured, packed or fractionated, or

which perform other processing activities, on the following conditions:

a) They shall be required to be listed under a technical standard issued by the Ministry and

approved by a decision adopted in its legal, technical, and administrative capacity,

indicating the name, therapeutic properties and uses thereof as symptomatic aids.

b) They shall be required to be hand-packed as isolated and unmixed plant species.

c) Reference must be made in the label only to those properties established in the

aforementioned decree.

SECTION 2

SANITARY REGISTRATION REQUIREMENTS

ARTICLE 28 - Sanitary registration applications shall be required to be submitted to the Institute in

compliance with the requirements set forth herein.

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General registration requirements include administrative aspects as well as others relating to the

technical information, pharmaceutical quality, safety and clinical efficacy of the pharmaceutical

product; other special requirements depend on the nature of the product, and the healthcare

professional signing the application shall be responsible both for their origin and veracity.

1. Sanitary registration general requirements

A. Administrative requirements

ARTICLE 29 - A sanitary registration application shall be required to meet the following general

administrative requirements and include the following information:

1. Identification and address of the applicant and legal representative in the case of legal

entities.

2. 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.

3. Name of the pharmaceutical product including:

a) trade name, generic or common international name, or otherwise the

pharmacopoeial or chemical name;

b) pharmaceutical form;

c) unit dose per pharmaceutical form; and

d) route of administration.

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

therapeutic classification.

5. Manufacturing system, including:

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

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

third parties, or;

b) imported products, including:

i. imported finished products manufactured abroad, whether imported

directly or by authorized third parties;

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

fitted in Chile, either directly or by authorized third parties;

iii. imported bulk products in their final pharmaceutical form to be

packed in Chile, either directly or by authorized third parties;

iv. 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.

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

used for prosecution of the registration.

7. Name and address of the domestic or foreign manufacturing facility.

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

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

administration thereof.

9. 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.

10. 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:

a) For products imported during any stage of the production process:

i. Sanitary registration certificate, pharmaceutical product certificate,

sanitary 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 sanitary 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 sanitary supervision, if applicable.

ii. Legalized manufacturing agreement signed by the applicant and the

foreign manufacturing pharmaceutical laboratory.

iii. Legalized license, if applicable.

iv. 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 a.i herein.

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

applicable.

vi. Manufacturing and/or domestic distribution agreement executed

before a notary public, attaching the corresponding sanitary

authorization for each facility.

vii. Quality control agreement entered into with a pharmaceutical

laboratory authorized by the Institute and executed before a notary

public, if applicable.

b) For domestically manufactured products:

i. Manufacturing and/or domestic distribution agreement executed

before a notary public, attaching the corresponding sanitary

authorization for each facility.

ii. Legalized license if applicable.

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iii. Quality control agreement entered into with a pharmaceutical

laboratory authorized by the Institute and executed before a notary

public, if applicable.

ARTICLE 30 - In the case of imported finished, semi-finished, semi-manufactured or bulk

pharmaceutical products, the applicant shall be allowed to prove the manufacturer's compliance

with Good Manufacturing Practices in accordance with the provisions of articles 192 and 193, in

which case the requirements set forth in a.iv above shall not apply.

B. Technical information requirements

ARTICLE 31- A sanitary registration application shall be required to meet the following general

requirements in relation to the technical information of the pharmaceutical product, including the

following:

1. Clinical and pharmacological monograph in Spanish signed by the chief technical

officer or technical adviser.

2. Graphic labelling draft in Spanish intended for retail, clinical sales and medical

samples.

3. Draft of the healthcare professional information leaflet endorsed by relevant scientific

data and including the results of bioavailability and therapeutic equivalence studies in

the case of pharmaceutical products comprising active ingredients that are subject to

this requirement.

4. Draft of the patient information leaflet endorsed by relevant scientific data.

C. Pharmaceutical quality requirements

ARTICLE 32- A sanitary registration application shall be required to meet the following general

requirements to certify the pharmaceutical quality of the product, including the following

information:

1. Qualitative and quantitative composition of the pharmaceutical product in the

following order:

a) Quali-quantitative statement for each active ingredient.

b) Quali-quantitative statement for each excipient.

c) Qualitative statement of any excipient used and removed during the

manufacturing process, if applicable.

d) Quali-quantitative composition expressed in metric system units of mass or

volume, or units of biological activity. Whenever possible, the biological

activity shall be required to be indicated per unit of mass or volume.

e) Active ingredients and excipients shall be required to be designated by their

international non-proprietary names (INN) or otherwise by the existing

pharmacopoeial names. In the case of non-pharmacopoeial substances, the

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chemical name in Spanish shall be used. No abbreviations or marks may be

used for designating active ingredients.

f) Any colourings in the product shall be required to be designated by their

generic names or otherwise by their chemical name or equivalents having

authorized colouring indexes in accordance with the relevant national

technical standard as approved by order of the Ministry; the same provision

shall apply when using coloured capsules.

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

products, the following information shall be required to be supplied:

a) Specifications and quality control methods, conforming to the requirements

listed in official texts or pharmacopoeias currently in force in Chile, or in

pharmacopoeial monographs if not indicated in the official texts.

b) Supplier and manufacturer of the active ingredients, including an analysis

report detailing all the characterizing parameters of the active ingredient.

c) Origin of the primary reference standard, including the corresponding

certificate of analysis indicating at least its origin, potency, traceability and

other relevant characterizing tests.

d) Spectrogram or chromatogram of the active ingredient and the standard

obtained by any instrumental method, if applicable.

e) Storage conditions of the active ingredient used as raw material.

3. Specifications and control methods for every excipient, conforming to the

requirements listed in official texts or pharmacopoeias currently in force in Chile, or in

pharmacopoeial monographs if not indicated in the official texts.

4. Analytical methodology in Spanish signed by the professional filing the application and

by the quality control manager of the pharmaceutical laboratory or the contracted

supplier.

a) The analytical methodology shall characterize the pharmaceutical product and

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

manufactured pharmaceutical form.

b) The analytical methodology of all pharmaceutical products shall be required to

include the following general test methods: sensory description (appearance,

size, shape, colour, odour, 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 ary packaging.

c) Specific test methods according to the pharmaceutical form shall be

established pursuant to current additional technical standards issued by the

Institute.

d) The methodology is required to be validated, if not described in officially

recognized pharmacopoeias.

5. Special tests:

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

prolonged-release forms and others, shall be required to be indicated as such

and endorsed by pharmacokinetic, dissolution or dissemination tests, or other

studies.

b) Therapeutic equivalence and bioavailability studies, in the case of

pharmaceutical products comprising active ingredients subject to this

requirement.

6. Fact sheet including analytical parameters and acceptance criteria characterizing the

product which, upon being made official, shall become the specifications that the

finished product shall be required to meet throughout its effectiveness period.

7. Proposed effectiveness period and storage and packaging conditions for both the

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

corresponding stability tests, including the following:

a) Stability information, including at least: identification of the manufacturer and

the 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 to the Stability of Pharmaceutical Products, a technical standard

approved by the Ministry at the proposal of the Institute.

b) When the product requires dilution prior to administration, the stability tests

for the formulation, the solvent (if included in the presentation) and

reconstituted product. In the event of the product requiring dilution and the

solvent not being included in the presentation, there shall be an indication as

to the recommended solvents; stability tests for the formulation and the

reconstituted product shall be additionally required.

c) If the product is required to be diluted for immediate administration, only a

compatibility study for the corresponding diluents shall be required.

d) 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 established in #2 above.

8. 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.

ARTICLE 33 - 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 Institute shall be required to observe the relevant rules in the following

pharmacopoeias and their supplements:

a) Chilean Pharmacopoeia.

b) International Pharmacopoeia.

c) European Pharmacopoeia.

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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.

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

biological, biotechnological, chemical, radioactive, and similar standards, and the provisions of title

21 of the United States “Code of Federal Regulations” (CFR), section 1.1, shall also be of relevance

for the purposes mentioned above. In the case of a pharmaceutical product that is not listed in any

of the foregoing official documents, the Institute may, with good reasons, accept or reject, either

totally or in part, the technical information supplied by the interested party.

ARTICLE 34- Should reference be made to tolerance margins or other specifications in the texts

mentioned in the preceding article, these shall be indicated in the application for registration so

that the Institute can decide about their adequacy.

ARTICLE 35- Due to the nature, diversity and extent of the general requirements set for the

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

by the Ministry at the proposal of the Institute.

D. Safety and Efficacy requirements

ARTICLE 36- A sanitary registration application shall be required to include information on the

safety and efficacy of the product, including the following:

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

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

their rationale.

2. Preclinical trials such as those conducted in vitro and/or 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.

3. Selective pharmacological studies in animals.

4. 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 pharmacist.

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5. Phase I, II, and III clinical trials endorsing the safety and efficacy of a product for which

registration is sought. 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.

6. Pharmacokinetic tests, if applicable.

7. Studies to prove the bioavailability or therapeutic equivalence of a pharmaceutical

product whose registration is sought, in the event of products comprising active

ingredients that are subject to this requirement.

8. 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.

9. A toxicological and pharmacologic report, including preclinical trials reporting the

toxicity of the product and its proven pharmacological properties.

10. 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.

2. Registration details and conditions for certain pharmaceutical drugs

ARTICLE 37 - The following conditions shall be required to be met for the registration of

pharmaceutical products comprising a combination of fixed-dose active ingredients:

a) 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.

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

treatment shall be required to render the combination safe and effective while

avoiding the danger of adverse reactions.

c) 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.

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

ingredients separately.

ARTICLE 38- Notwithstanding the foregoing, applications for the registration of pharmaceutical

products comprising a combination of fixed-dose active ingredients shall be rejected under the

following circumstances:

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a) The products have been indicated for treating diseases or symptoms having a different

natural course than the one mentioned in the registration for each of its active

ingredients unless proven otherwise.

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

of the components.

ARTICLE 39 - In the case of combined pharmaceutical products, the applicant requesting their

registration shall be required to provide evidence of their safety and efficacy when used in the

combination. In addition, the applicant shall be required to provide further evidence as to the

following:

a) Each pharmaceutical drug should contribute to the therapeutic effect of the combined

product.

b) The dose for each drug as well as the frequency of administration and duration of the

treatment shall be required to render the combination safe and efficient without any

danger of causing adverse reactions.

c) The ingredients used in each pharmaceutical drug, including excipients, shall be

required to be chemically, pharmacologically, pharmacokinetically, and

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

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

ingredients separately.

Combined products may not include phytopharmaceutical or homeopathic products in association

with each other or with other pharmaceutical drugs.

ARTICLE 40 - Given the nature of phytopharmaceutical products, the following considerations shall

be taken into account for their registration:

a) Proof of their safety shall be required by submitting pre-clinical trials and toxicological

and phase I clinical studies, while their effectiveness shall be endorsed by phase II and

III clinical trials. In the event that upon requesting the sanitary registration of a

product there exists information in the official literature of different international or

foreign agencies such as the WHO, FDA or EMEA, such information shall be accepted

as valid in lieu of the above.

b) Applications shall be required to observe the provisions set forth under the general

registration requirements, including the following special rules:

i. Therapeutic equivalence studies shall not be required at the time of

registration or when requesting any subsequent modifications.

ii. The description of the manufacturing process shall be required.

iii. The generic name shall correspond to the taxonomic botanic denomination of

the plant providing the active ingredients.

iv. The quali-quantitative formula shall be required to 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

22

employed in the preparation, plus their scientific name, concentration and its

equivalent plant marker, if applicable.

v. No narcotic or psychotropic substances or allopathic medicines shall be

allowed in the preparation.

vi. The identity and purity of the ingredients shall be determined in accordance

with foreign or international pharmacopoeias or sources of information, and

shall be required for validating the proposed analytical methodology.

vii. 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, or otherwise the

corresponding validation of the proposed analytical methodology shall be

required.

viii. Finished product specifications shall be required 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.

ix. Products comprising isolated or synthetic active ingredients shall not be

deemed to be phytopharmaceuticals, even if prepared from plant raw

materials.

ARTICLE 41 - Given the nature of homeopathic products, the following considerations shall be

taken into account for their registration:

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

i. Generic names of active ingredients shall be required to be in Latin as set

forth in recognized pharmacopoeias.

ii. In qualitative-quantitative formulas, each homeopathic substance shall be

required to be in Latin, followed by the final dilution (i.e. in the finished

product) and concentration.

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

preparation of the homeopathic substance shall be required, in addition to

their characterization, method of preparation, and any physicochemical

controls to which they have been submitted.

iv. A description of the manufacturing methods used for preparing the finished

product.

v. Homeopathic pharmaceutical products shall be required to meet 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.

vi. When homeopathic products are administered as conventional tablets,

disintegration tests shall be required instead of dissolution tests.

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

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

23

pharmacopoeias, documents issued by WHO expert committees, or other references

acknowledged by decree of the Ministry may be authorized under the formula “By

order of the President of the Republic” at the proposal of the Institute.

ARTICLE 42 -In addition to meeting general product registration requirements, applications for the

sanitary registration of biological products shall be required to include the following information:

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

i. Trade name or otherwise the generic (INN) or pharmacopoeial name. Vaccines

shall be designated with a Latin name after the disease against for which they

provide protection.

ii. The manufacturing process when the active ingredients are living or dead

microorganisms, referring to the process as “living”, “attenuated,”

conjugated”, “inactivated” or others.

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

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

“recombinant”.

iv. Pharmaceutical form and dosage, if appropriate.

b) Quali-quantitative composition in the following order:

i. Quali-quantitative statement for each active ingredient.

ii. Quali-quantitative statement for each of excipient.

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

product, if applicable.

iv. Quali-quantitative composition shall be required to be stated (if applicable) in

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

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

alternatively in International Units.

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

composition shall be preferably stated in unit doses.

vi. Active ingredients and excipients shall be required to be designated by their

international non-proprietary names (INN) or otherwise by existing

pharmacopoeial names. Substances other than drugs shall be required to be

named after their chemical or biological denomination, while vaccines shall

bear a Latin name in accordance with disease against which they offer

protection. No abbreviations or marks may be used for designation.

vii. The taxonomic designation of microorganisms shall be required to be stated in

short, including the strain, serotype or other subspecies information when

appropriate.

viii. The nature of any cellular system used for manufacturing biological products

shall be required to be disclosed, as well as the use of recombinant DNA or

RNA technology.

ix. In the event of an active ingredient being a living microorganism, the chemical

compound used in the chemical inactivation method shall also be disclosed.

24

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

aluminium, the quantitative statement shall be required to be in terms of

amount per dose.

xi. Preservatives shall be quantitatively detailed at the end of the formula, if

present, which shall also be required to include qualitative details of antibiotic

residues and antimicrobial agents used in the manufacturing process that may

potentially trigger allergic reactions in certain individuals.

xii. Any colourings in the product shall be required to be designated by their

generic names or otherwise by their chemical name or equivalents having

authorized colouring indexes in accordance with the relevant national

technical standard as approved by a decree of the Ministry. The same

provision shall apply to the use of coloured capsules.

c) Active ingredient requirements, including quality and purity specifications and control

methods therefor, along with following information:

i. Manufacturer and supplier of the active ingredient.

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

describing the active ingredient.

iii. Storage conditions of the active ingredient, including temperature, humidity

and quality of the package.

iv. Description of other desired elements and related compounds, including their

properties and characteristics, structure, biological activity or others.

v. When describing active ingredients obtained from human blood or blood

products, the information shall be required to further indicate the procedures

followed to guarantee to the fullest extent the absence of potentially

pathogenic agents that may be transmitted, including:

1. Donor selection protocols.

2. Plasma fractionation method.

3. 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.

4. Storage temperature of the active ingredient and monitoring method.

5. Validity and expiry date.

6. Methods of inactivating infectious contaminants that the starting

material may contain, as well as intermediate and final products.

d) Manufacturing method:

i. Description of the manufacturing method, including process controls and

tolerance.

ii. Description of the manufacturing process, including raw materials, critical

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

monitoring methods have been selected for controlling the finished product.

25

iii. Description of source and starting materials for the production of the

biological active ingredient.

iv. 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.

v. Description and information about the validation process.

e) Control of excipients:

i. 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.

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

affected by TSE and other transmissible diseases.

f) Control of finished products:

i. At least the following information shall be required:

Description and appearance (shape, colour, odour 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.

ii. Indication of acceptance criteria and minimum and maximum values if

considered to be deciding factors.

iii. Fact sheet, including laboratory parameters and acceptance criteria

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

become the specifications that the finished product shall be required to meet

throughout its effectiveness period.

g) Packaging material:

i. 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.

ii. 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.

iii. When the dosage form is sterile, information shall be required on the integrity

of the package sealing system used to prevent microbial contamination.

h) Stability tests for the formulation, the solvent and the reconstituted product, as

appropriate:

26

i. The information on the stability of the product shall be required to include at

least the following:

Formula under study.

Identification of the manufacturer and the 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 to the Stability of Pharmaceutical Products

referred to in article 32.

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

field of medicine in Chile, the information shall be required to include the

results of studies on forced degradation stability and stress conditions.

iii. Proposed effectiveness period and storage precautions as endorsed by the

corresponding stability test, in addition to the effectiveness period for the

reconstituted product, if applicable.

iv. In the event of the product requiring dilution prior to administration, the

information shall be required to include compatibility and stability tests with

adequate diluents, as appropriate.

i) Efficacy and safety requirements.

In the case of biotechnological products, a technical standard shall be approved by order of the

Ministry at the proposal of the Institute to determine active ingredients and their presentation, for

which abridged clinical studies endorsing the efficacy and safety of the product shall 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 shall be required to 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.

SECTION THREE

REGISTRATION APPLICATION PROCEDURES

ARTICLE 43 - The sanitary registration application and any required information depending on the

type of pharmaceutical product shall be submitted to the Institute of Public Health using the

approved forms upon payment of the corresponding fee.

A register of the application shall be kept on a written or electronic file comprising documents

submitted by interested parties, stating the time and date of presentation and having a reference

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

admissibility phase of the application.

ARTICLE 44 - Within ten working days, the Institute shall be required to review the application

form and the information supplied, and deliver a statement on its admissibility.

27

ARTICLE 45 - Upon acceptance of the application for further evaluation, the interested party shall

be given notice of this decision in order to proceed with the payment of fees corresponding to the

next phase of the procedure.

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

hereunder and any supplementary regulations, according to the type of pharmaceutical drug, and

the Institute shall be required to indicate any missing information required to overcome the

objection, which shall be submitted within five working days, upon which the Institute shall

proceed as provided in the preceding paragraph or eventually turn down the application.

ARTICLE 46 - Upon admission of the registration procedure, the application shall be forwarded to

the appropriate department for the separate analysis of technical and administrative information.

The administrative records referred to in article 29.10 shall be first checked by the legal

consultancy department.

Technical records concerning requirements in relation to the technical information,

pharmaceutical quality, safety and efficacy of the product, as well as any other particular records

as required by the type of product pursuant to the provisions of the preceding paragraph, shall be

separated and forwarded to specialized technical offices for assessment in accordance with these

presents.

ARTICLE 47 - Should the aforementioned assessment result in a favourable outcome and within six

months from the date of payment of the corresponding fee, the requested registration shall be

granted by enactment of a resolution notified to the formal applicant.

ARTICLE 48 - The sanitary registration of a pharmaceutical drug shall be required to contain at

least the following information:

a) Name and address of the holder.

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

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

applicable.

c) Registration number.

d) Name of the pharmaceutical product.

e) Full qualitative and quantitative composition.

f) Pharmaceutical form.

g) Therapeutic group.

h) Storage conditions and effectiveness period.

i) Packaging and presentations.

j) Authorized therapeutic indications.

k) Prescribing and retail conditions pursuant to Ministry regulations.

l) Whether the product is subject to legal control, batch control or others, indicating the

conditions for the same.

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m) Authorization restrictions concerning the validity of the registered product and the

need to supervise the use thereof.

n) Specific obligations of the holder.

o) The obligation to inform about the first batch of production or import for distribution

in any shape or form pursuant to the provisions of article 71 herein.

p) 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.

q) The authorized graphic label, the patient information leaflet 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 shall

be deemed to be an integral part of the registration certificate.

ARTICLE 49 - A sanitary registration may be rejected under the following circumstances:

Incidental issues: upon notification, the applicant shall have 15 working days to make

any submissions as deemed appropriate, after which the Institute shall be required to

issue a final resolution.

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

have 30 working days to provide further information, and the sanitary registration

shall be granted if such information is sufficient to fulfil the conditions listed above.

In the event that such additional information is not submitted within the allowed period of time,

or if despite having been submitted in time such information is once again deemed to be

insufficient, the Institute shall request the Ministry of Health to rule on the rejection of the

registration.

The Ministry shall be required to issue a report on the rejection of the registration within 10

working days and forward it to the Institute so that it passes a substantiated resolution which shall

be notified to the applicant.

ARTICLE 50 - Pursuant to the provisions of law no. 19,880, during the prosecution of a sanitary

registration the interested party may make submissions and furnish documents or other evidence

which shall be considered for the grant or rejection of the relevant sanitary registration.

Upon grant of the sanitary registration, the corresponding resolution shall become available on

the official website of the Institute of Public Health.

In the event that such information cannot be disclosed pursuant to the provisions of law no.

19,039, the provisions under said law and other supplementary regulations shall be observed.

SECTION 4

SPECIAL REGISTRATION PROCEDURES

1. Short registration procedure

29

Article 51 - The regular registration procedure may be simplified to reduce processing times by

order of the Ministry of Health under any of the following circumstances:

1. The pharmaceutical product is required to be supplied to the public in compliance

with health plans or programmes approved by the Ministry to address health risk

situations or particular conditions specific for certain groups of people in the context

of national public health interests.

2. The pharmaceutical product has been included in a list of products under the National

Formulary, in which case the applicant shall be required to use the formulary

monographs to speed up the prosecution of the registration. The Institute shall be

required to reduce registration processing times depending on the stage of the

prosecution. In any case, the entire prosecution may not exceed four months.

2. Simplified registration procedure

ARTICLE 52 - The regular registration procedure may be simplified upon the interested party's

request by leaving out certain information as indicated below:

1. 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 Institute due to

public health reasons, information on safety and efficacy shall not be required to be

submitted, unless the Institute by means of a substantiated decision determines the

need for some or all of such information. In the case of a non-standard release

pharmaceutical product, the corresponding therapeutic equivalence studies shall be

required to be submitted.

2. 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 shall review the application and reasonably

require all the necessary information.

3. 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 shall be

required to be submitted pursuant to specific regulations.

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

exportation, deemed to be a pharmaceutical product under Chilean regulations and a

food product in the country of destination as certified by the relevant health

authorities, 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.

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ARTICLE 53 - The simplified sanitary registration procedure shall not be applicable in the following

cases:

a) The pharmaceutical product for which registration is sought appears for the first time

in the field of medicine in Chile, except under the provisions of article 52.2.

b) The pharmaceutical product for which registration is sought 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.

c) The pharmaceutical product for which registration is sought is concerned with a new

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

administration, or age group.

d) The drug product for which registration is sought health 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.

e) In the event of the pharmaceutical product for which registration is sought being in a

different pharmaceutical form and wherein the release of active ingredients has been

modified.

f) In the case of a combined pharmaceutical product for which registration is sought for

the first time.

g) When requesting the registration of a biological product.

ARTICLE 54 - The registration procedure of homoeopathic pharmaceutical products may only be

simplified upon meeting all of the following conditions:

a) The route of administration is oral or external.

b) Absence of specific therapeutic indications in the graphic label or in healthcare

professional and patient information leaflets.

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

guarantees the safety of the drug.

d) 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.

SECTION 5

TERM, SUSPENSION AND CANCELLATION OF THE SANITARY REGISTRATION

ARTICLE 55 - The sanitary registration of a pharmaceutical product shall be valid for a term of five

years from the date of grant and may be renewed for equal and successive periods provided that

no cancellation is in effect and under the following conditions:

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1. Payment of corresponding fees.

2. The objections for suspending the sanitary registration have been overcome within

the required term. In the event of the sanitary registration expiring before such term,

the renewal shall be requested within 15 days after expiration of the term allowed to

overcome the objections.

3. Absence of outstanding fines or compliance with other sanitary measures or penalties

imposed by the Institute, if applicable, in connection with the registration for which

renewal is sought.

The renewal of the sanitary registration shall be rejected upon the holder failing to fulfil some of

the obligations under such registration.

ARTICLE 56 - The application for renewing a sanitary registration shall be submitted to the

Institute, and in the case of imported products, it shall be required to be accompanied by the

pharmaceutical product certificate, registration certificate, sanitary authorization or official

certifications recommended by the World Health Organization, issued by the relevant authorities

in the country of origin, certifying that the manufacturing or storing facilities comply with health

regulations in their respective country, that the product is registered in said country pursuant to

current legislation, indicating the authorized formula in full, and that the sale of the product is

subject to a restrictive regime or other special sanitary controls, if applicable.

ARTICLE 57 - The renewal of the registration shall be required to bear the same number assigned

upon registration, as well as the year of renewal and the expiry date.

ARTICLE 58 - Sanitary registrations could be suspended for any of the following reasons:

1. If significant changes are noticed in connection with the therapeutic indication,

composition, dosage forms, application or other conditions as indicated on the label or

the healthcare professional information leaflet or advertised, and such changes do not

conform to the approved sanitary registration.

2. If the quality of the product is not up to standard in two batches.

The resolution whereby the sanitary registration is suspended shall be required to indicate the

scope of the suspension and set a deadline for overcoming the objections causing the suspension;

upon failure to overcome said objections, the registration shall be cancelled.

ARTICLE 59 - Sanitary registrations may be cancelled ex officio or upon complaint of any interested

parties by order of the Ministry of Health for any of the following reasons:

a) When on the basis of scientific information from the World Health Organization or

foreign or international bodies or organizations, or arising from its own research, the

Institute has the conviction that a product is not safe or effective as indicated in the

relevant sanitary registration, and one of the following situations develops:

i. Manifest danger to public health.

ii. Unfavourable therapeutic risk - benefit ratio.

iii. Therapeutic inefficacy.

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b) Upon finding that any piece of information provided in the sanitary registration has

been proved to be false.

c) Upon failure to overcome the objections for suspension within the term fixed for such

purpose.

ARTICLE 60 - The holder of the cancelled or suspended sanitary registration shall be responsible

for taking the necessary measures to collect, destroy or denaturate, as required by the Institute,

all pharmaceutical units in storage on the premises or distributed according to current regulations

to other pharmaceutical and healthcare facilities, and for informing users who could potentially

use the concerned product.

ARTICLE 61 - The suspension and cancellation of a sanitary registration shall be determined by the

Institute by means of a substantiated decision notified to the holder.

ARTICLE 62 - Notwithstanding the provisions of article 59, the Institute may cancel a sanitary

registration after conducting relevant preliminary investigations, in addition to penalties imposed

pursuant to the provisions of article 174 of the Sanitary Code.

SECTION 6

SANITARY REGISTRATION AMENDMENTS

1. Technical and sanitary aspects

ARTICLE 63 - Amendments to the sanitary registration of a pharmaceutical drug may be produced

upon a resolution of the Institute, ex officio, or at the request of the holder.

ARTICLE 64 - The Institute may request, by means of a substantiated decision, to introduce

amendments to the registration within a certain period of time to guarantee the quality, safety

and efficacy in the use of one or more pharmaceutical drugs when on the basis of scientific

information from the World Health Organization or foreign or international bodies or

organizations, or arising from its own research, the Institute has the conviction that some of the

authorized use conditions poses a risk to their safety and efficacy.

ARTICLE 65 - Upon the holder's request and by means of a resolution, the Institute may accept

analytical, technical, and legal amendments including the following:

1. Expression of the formula, including the composition of excipients.

2. Specifications of the finished product, methods of control, and effectiveness period.

3. Presentation, content, type of container and additional items or devices for

administration. In the event of the primary container having been modified, the

corresponding stability tests shall be additionally required, if applicable.

4. Retail conditions.

5. Name and graphic label.

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6. Origin, packaging facilities, licensor, distributor, importer, and quality control

pharmaceutical laboratory, or their name or the holder's name.

7. Healthcare professional and patient information leaflets.

8. Therapeutic indications and schemes, new target age group and route of

administration, which shall be subject to relevant technical evaluations pursuant to

the normal procedure for registration of pharmaceutical drugs.

9. Any other changes except those affecting the nature and identity of the

pharmaceutical drug, i.e. the active ingredients, dose, pharmaceutical form or system

of release. These shall require an additional registration.

ARTICLE 66 - Applications for amending the sanitary registration of a pharmaceutical drug shall be

required to be submitted to the Institute using authorized numbered forms and to be

accompanied by technical and scientific information supporting the request.

The Institute shall be required to accept or reject applications for the amendment of a sanitary

registration on the basis of a substantiated decision within a period not exceeding three months

from the date of filing, with the exception of applications concerned with aspects listed under no.

8 in the preceding article.

In the event that during the evaluation of an application the supplied information is not sufficient

to support the request, the applicant shall be served with a notification indicating the objections

and any missing information required to overcome them during a period of not less than ten nor

more than thirty working days.

2. Administrative aspects

ARTICLE 67 - The holder shall give the Institute written notice of any amendments to the sanitary

registration that are not concerned with technical aspects relating to the quality, safety and

efficacy of pharmaceutical products, for the purposes of updating the information on file.

ARTICLE 68 - The Institute may receive requests to change the holder of a registration provided

that the new holder meets the relevant requirements without affecting other conditions as

authorized in the registration and that relevant supporting information is attached to the request

according to the provisions of the preceding articles.

The request shall be supported by appropriate legal instruments duly legalized, translated and

signed by the legal representative.

In the case of sanitary registrations under a license, the change of the holder shall be subject to

the provisions of the relevant document, and if not expressly mentioned, it may only be

authorized under consent of the licensor, the licensee, and upon the request of the new holder.

ARTICLE 69 - The change of the holder and any other amendments to the sanitary registration

shall be introduced jointly, unless said amendments involve a new manufacturer, in which case a

further registration shall be required.

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ARTICLE 70 - Changes shall be required to be recorded in the corresponding registration under the

same terms and conditions set forth in article 66 regarding other amendments to the sanitary

registration.

SECTION 7

OBLIGATIONS FOR ALL HOLDERS OF SANITARY REGISTRATIONS

ARTICLE 71 - The holder of the sanitary registration is ultimately responsible for the safety and

efficacy of the drug.

Without prejudice to the specific obligations imposed in view of the nature of each pharmaceutical

drug, all holders of sanitary registration shall be required to:

1. Fulfil and enforce authorization conditions set forth in the corresponding sanitary

registration and other conditions under these regulations.

2. Meet the obligations under Section X on sanitary surveillance.

3. Immediately notify the Institute and the Department of Public Health of any recalled

products, indicating the reasons and measures to this effect.

4. Inform the Ministry, the Institute and the Supply Centre of the Health Services

National System about the intention to suspend either temporarily or permanently the

distribution of the product three to six months in advance respectively.

5. Keep the sanitary registration updated in accordance with the state of the art,

especially in relation to quality control methods as well as the safety and efficacy of

the pharmaceutical drug.

6. Notify the Institute of any changes to the administrative information within 30 days.

7. Inform the Institute about the manufacturing date of the first industrial batch and

provide the validation schedule for the manufacturing process.

8. Others as herein provided.

CHAPTER III

PACKAGING AND LABELLING

ARTICLE 72 - All pharmaceutical drugs shall be required to be presented in tamper-resistant

primary and secondary packagings containing a patient information leaflet.

Under exceptional circumstances, the Institute may release the holder of the registration upon

request of the latter from the obligation of having a secondary packaging or a patient information

leaflet, provided that the primary packaging in itself guarantees the preservation of the quality of

the pharmaceutical form and includes all the information required for the label of the secondary

packaging or the patient information leaflet.

ARTICLE 73 - The primary packaging of pharmaceutical products shall be required to be suitable

and appropriate for safeguarding its contents in accordance with the stability tests submitted for

the same upon registration of the product or in subsequent amendments.

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ARTICLE 74 - The label of the secondary packaging shall be in Spanish, in clearly visible letters, and

shall be required to include at least the following information without any advertising or

promotional texts.

1. Name of the pharmaceutical drug.

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

3. Unconventional release pharmaceutical forms shall be indicated as such on the

packaging material, as stated in the corresponding registration.

4. Number of dosage units.

5. Formula composition: quantitative and qualitative list of active ingredients and

excipients.

6. Name and address of the holder and the manufacturing laboratory, packer or

importer, as appropriate.

7. Route of administration.

8. Approved retail conditions indicated with the appropriate abbreviation or

full text.

9. Expiry date. Furthermore, the included or recommended solvent shall also be required

to be indicated in the case of extemporaneous preparations, as well as the

effectiveness period after reconstitution, if applicable.

10. Registration number given by the Institute, preceded by the following acronym “Reg.

I.S.P.” (Institute of Public Health registration).

11. Product code. Imported finished products shall keep the original code.

12. Storage and conservation conditions.

13. Incorporation of the caption “More information on www.ispch.cl” and others as set

forth in article 87, if applicable.

14. Any other information specially and additionally required hereunder or deemed

necessary by the Institute upon registration or later.

ARTICLE 75 - The primary packaging shall be required to include at least the information described

in items 1, 2, 7, 9, 10 and 11 in the preceding article.

ARTICLE 76 - Pharmaceutical drugs packed as medical samples shall be required to bear the

caption “MEDICAL SAMPLE NOT FOR SALE” in both the primary and the secondary packaging in

indelible ink, in a clear and visible manner.

ARTICLE 77 - The labels shall be required to be printed or adhered to the outer surface of the

package without being in contact with its contents. Arial or other similar straight fonts shall be

used for labelling purposes, in a minimum size of 6.

ARTICLE 78 - The graphic label of imported finished pharmaceutical products may exceptionally

contain texts in other languages apart from Spanish, provided that the text authorized by the

Institute is not modified.

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ARTICLE 79 - Under their sole responsibility, holders of sanitary registrations may include in the

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

ARTICLE 80 - Graphic labels and healthcare professional and patient information leaflets

submitted upon applying for a sanitary registration shall conform to their final text once

authorized, without prejudice to any amendments introduced by the Institute.

The provisions of article 77 concerning the type and size of fonts for secondary packaging shall be

further applicable to patient information leaflets. The same requirements shall also be applicable

to subsequent amendments to the graphic label and healthcare professional and patient

information leaflets.

ARTICLE 81 - In addition to the information described in article 74 above, pharmaceutical drugs

intended for direct sale shall be required to include the following details:

a) Regular dosing instructions for each indication as authorized in the corresponding

registration.

b) 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 sanitary registration.

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 leaflet, if not enclosed.

ARTICLE 82 - A pharmaceutical drug shall be required to be designated after its generic or trade

name.

Notwithstanding the foregoing, in the event of a pharmaceutical drug not being identified by its

generic name and comprising a single active ingredient, said ingredient shall be required to be

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

a) The name shall be required to be located on the bottom line immediately after the

authorized denomination.

b) The colour of the letters and the background of the authorized designation shall be

required to be the same.

c) The dimensions shall not be greater than fifty percent of said denomination or less

than the size indicated in article 77 herein.

d) The name shall be required to be printed in capital letters.

ARTICLE 83 - A pharmaceutical drug may not be designated with a trade name in the following

cases:

a) The name is the same 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.

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b) The name may be misleading in being the same or similar to the name of another

registered product with different active ingredients or therapeutic properties.

c) 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.

d) The name includes or is similar to the name of a food item, a cosmetic product or any

other product under sanitary control.

e) 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.

ARTICLE 84 - In addition to the provisions of article 74, the containers of all parenteral solutions of

100 ml or more shall be required to bear a label indicating the day, 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 the provisions of the preceding paragraph, in the case of parenteral solutions

comprising electrolytes in a single drug, this shall be required to be indicated on the label in letters

of a particular colour or otherwise different from the corresponding colour. The Institute shall be

required to determine the colours for each cation of the active ingredient in the respective

solutions.

ARTICLE 85 - The amount of pharmaceutical product shall be required to be indicated by weight,

volume or unit, as appropriate.

In the case of blisters or vials, each shall be required to have the indications for primary packaging

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

deems it relevant to waive in whole or part some of these requirements.

ARTICLE 86 - The composition of the product shall be required to be indicated by its active

ingredients as authorized upon granting of the registration and shall be further required to

indicate the equivalence of active ingredients with the parent drug and the qualitative list of all

excipients.

The composition of the formula shall be required to 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 shall be required to be indicated by each unit dose.

38

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

pessaries or the like shall be further required to indicate the active ingredients in the current or

usual administration measures.

ARTICLE 87 - Labels shall be required to highlight the following captions as appropriate:

“SUBJECT TO CONTROL OF NARCOTIC SUBSTANCES”

“SUBJECT TO CONTROL OF PSYCHOTROPIC SUBSTANCES”

“NATIONAL FORMULARY”

“CLINICAL PACKAGING FOR MEDICAL CARE FACILITIES ONLY”

“CLINICAL PACKAGING FOR SALE IN LICENSED PHARMACIES”

“EXTERNAL USE”

“USE UNDER MEDICAL SUPERVISION”

“MEDICAL SAMPLE NOT FOR SALE”

R = Simple Prescription, RR = Prescription Withheld, RCH = Official prescription, VD =

Direct Sale

ARTICLE 88 - Any batch or sub-batch of a pharmaceutical product shall be required to be identified

by a code that will enable tracking at any stage from manufacture to retail or use. For the

purposes of interpretation, the holder of the registration shall be required to notify the Institute of

the code structure. The same procedure shall apply for subsequent amendments or different

codes that may be used.

ARTICLE 89 - The codes shall be required to be indicated on the labels of primary and secondary

packaging containing the pharmaceutical drug.

ARTICLE 90 - The code shall consist of numbers or combinations of letters and numbers, and shall

be required to indicate the month and year of manufacture and the batch number in sequential

and chronological order. Otherwise, any alphanumeric combination may be used as a code, but it

shall be required to indicate the month and year of manufacture on all labels and comply with

general labelling requirements.

ARTICLE 91 - In the case of imported finished pharmaceutical products, the holder shall be

required to declare the code of the country of origin upon applying for registration and to indicate

how it should be interpreted.

ARTICLE 92 - In the event of a pharmaceutical product from a single batch being finished in

discontinuous steps, each shall be deemed to be a sub-batch and shall be required to be identified

by an addition to the original serial number.

CHAPTER IV

IMPORT AND ADMISSION OF PHARMACEUTICAL PRODUCTS.

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SECTION 1

GENERAL PROVISIONS

ARTICLE 93 - Pharmaceutical drugs may only be imported upon prior registration provided that

such import has not been suspended, without prejudice to the cases and conditions set forth in

chapter II section 1 hereunder.

ARTICLE 94 - A pharmaceutically drug may be exceptionally imported as a finished product by any

individual or legal entity without requiring a new sanitary registration for importation and

distribution by individuals other than those who obtained such registration if besides having the

same formula, generic name or designation, the pharmaceutical product is certified to come from

the same manufacturer and country as the previously registered pharmaceutical product, as

attested in the corresponding registration certificate, certificate of pharmaceutical product or

sanitary registration, or official certification recommended by the World Health Organization,

issued by health authorities pursuant to the provisions of article 29.10 herein.

Upon certifying the above, the Institute shall issue a resolution authorizing the import of a certain

amount and the use thereof for the sole merit of the authorization and the respective reports

concerning tests performed on admitted batches by a quality control laboratory.

SECTION 2

IMPORT AND ADMISSION

ARTICLE 95 - Pharmaceutical products may be imported by authorized pharmaceutical

laboratories, pharmacies, pharmaceutical wholesalers and pharmaceutical warehouses, and in

general by any individual or legal entity according to current legislation.

ARTICLE 96 - Any individual or legal entity may import pharmaceutical drugs as well as raw

materials for the manufacture thereof. Notwithstanding the foregoing, for admission into the

country the importer shall be required to have duly authorized facilities for storage, manufacture

or later distribution such as pharmaceutical laboratories, pharmacies, pharmaceutical wholesalers

and pharmaceutical warehouses as appropriate depending on the nature and purpose of the

imported material.

ARTICLE 97 - Only manufacturing pharmaceutical laboratories may store pharmaceutical products

in any stage of production.

Packaging pharmaceutical laboratories may store semi-finished pharmaceutical products.

Pharmaceutical products admitted as finished products may only be received and stored by duly

authorized facilities.

Raw materials for the manufacture of drugs products or for sale to manufacturing facilities may

only be stored by pharmaceutical wholesalers and manufacturing pharmaceutical laboratories.

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SECTION 3

PROCEDURE FOR ADMISSION OF PHARMACEUTICAL PRODUCTS

ARTICLE 98 - For the purposes of admitting pharmaceutical products, a Destination Customs

Certificate shall be required from the Regional Health Department under jurisdiction of the

customs office where the product is to enter the country, for which all relevant information shall

be supplied indicating the admitted material, its quantity and nature, and the route and means of

transport to ship them from the customs area to an authorized facility.

The Regional Health Departments shall be required to issue a decision on the application

mentioned in the preceding paragraph within three working days from the date of filing of the

application, and rejections shall be required to be based on substantiated decisions.

The Regional Health Departments may enter into agreements with public entities for issuing the

aforementioned certificates executed in accordance with the provisions of the Constitutional Law

on General Bases for the State Administration (law no. 18,575) as coordinated and consolidated by

law-ranking decree no. 1 of 2001 by the General Secretariat of the Presidency.

ARTICLE 99 - For the purposes of indicating any customs destination of pharmaceutical products,

the applicant shall be required to submit a certificate issued by the corresponding Regional Health

Departments to the National Customs Service.

Once the customs destination document is processed and the products are withdrawn from the

customs area, they shall be under the responsibility of the consignee, who may not use, consume,

sell, assign or otherwise dispose of them in any way without prior authorization from the Institute,

which may grant or reject such authorization, or set a safety period to conduct appropriate

sanitary controls during which the products may not be used or distributed in any manner.

Said authorization shall be requested from the Institute of Public Health by enclosing import

documents (invoice and bill of lading), the customs destination certificate, and the protocol for

quality control in the manufacturing country, or otherwise the protocol for the analysis conducted

in Chile, except for samples of pharmaceutical products exclusively intended for research and

development or sanitary registration, and the authorization shall be required to be issued within

three working days from the date on which the applicant notifies the authorities of the reception

of the products in the storing facilities.

The granting of the authorization for use and disposal shall not release applicants from compliance

with other legal, regulatory or administrative requirements as necessary for such use or

distribution, nor from observing other third party's rights as established by law.

The National Customs Service shall be required to provide the Institute with a monthly report on

imported pharmaceutical products, indicating their nature and the name of the importer.

In any case, in the event of importing pharmaceutical drugs, the storage facility indicated by the

importer shall be required to be previously authorized by the corresponding Regional Health

Department.

CHAPTER V

41

EXPORT OF PHARMACEUTICAL DRUGS

ARTICLE 100 - Only pharmaceutical products currently registered in Chile may be exported upon

prior notification to the Institute.

ARTICLE 101 - Pharmaceutical drugs for export labelled as “Products for Export” shall be exempted

from regulatory requirements concerning the packaging, label and patient information leaflet,

except with regard to the identification of the finished product, which shall be required to include

the following information:

a) Name of the product, including generic name.

b) Pharmaceutical form.

c) Institute of Public Health registration.

d) Name of the manufacturer.

e) Serial number and expiration date.

ARTICLE 102 - GMP and GLP standards shall be applicable to the manufacture, quality control and

storage of products for export.

ARTICLE 103 - Pharmaceutical products intended exclusively for export shall be required to be

packaged, stored and shipped in a manner appropriate to their nature.

ARTICLE 104 - The holder of the registration may request a Certificate of Pharmaceutical Product

from the Institute which shall be required to be issued within 10 days from receipt of such

request.

ARTICLE 105 - The distribution and use in Chile of products labelled pursuant to the provisions of

article 101 herein or registered solely for exportation is forbidden.

CHAPTER VI

PHARMACEUTICAL LABORATORIES

SECTION 1

GENERAL PROVISIONS

ARTICLE 106 - Only pharmaceutical laboratories licensed in accordance with the provisions

hereunder shall be authorized to manufacture pharmaceutical products. Pharmacies may only

elaborate compounded preparations according to the provisions set forth in specific regulations.

ARTICLE 107 - A pharmaceutical laboratory is a facility for importing, manufacturing, packaging or

checking the quality of pharmaceutical products under these regulations. They are classified

according to the activities carried out as follows:

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a) Manufacturing Pharmaceutical Laboratory: Any facility manufacturing, importing,

fractioning or packaging pharmaceutical products, or engaged in other activities

relating to the production and quality control of pharmaceutical products. These

facilities may also manufacture, import or distribute raw materials used in the

pharmaceutical industry.

b) Fitting Pharmaceutical Laboratory: Any facility exclusively carrying out processes that

do not tamper the primary packaging of a pharmaceutical product in order to produce

the finished product.

c) Quality Control Pharmaceutical Laboratory: Any facility comprising premises specially

intended for analyzing, testing, researching and developing analytical methodologies

and other analytical studies concerned with the products hereunder, such as facilities

conducting therapeutic equivalence studies performed in vitro, among others, at the

request of any individual or legal entity under the corresponding agreement. Quality

control departments of manufacturing pharmaceutical laboratories wishing to provide

quality control services to third parties shall be required to be further authorized by

the Institute.

ARTICLE 108 - All pharmaceutical laboratories shall be required to observe GMP and GLP

standards as appropriate depending on the activities for which they are authorized.

SECTION 2

SANITARY AUTHORIZATION FOR LABORATORIES

ARTICLE 109 - The installation of a pharmaceutical laboratory, whatever its nature, shall be

required to be expressly authorized by resolution of the Institute in terms of its operation and

eventual relocation.

The expansion or modification of the facilities or line of business within each category shall also be

required to be authorized by the Institute.

ARTICLE 110 - The installation and operation license granted by the Institute shall be valid for a

term of 3 years and may be renewed as provided for in section 9 hereunder.

ARTICLE 111 - Any individual or legal entity acquiring a pharmaceutical laboratory or being

responsible for its operation or administration on their own or on behalf of third parties shall be

required to notify the Institute within 30 days and submit the corresponding legal instruments

identifying the legal representative and including a list of professionals in charge of the

management, production, and quality control and assurance as appropriate depending on the type

of facility.

ARTICLE 112 - The Institute may inspect the facilities to supervise operating conditions in

accordance with GMP and GLP standards as well as the provisions hereunder.

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SECTION 3

AUTHORIZATION PROCEDURE FOR INSTALLATION AND OPERATION

ARTICLE 113 - A pharmaceutical laboratory shall be required to be set up on separate premises.

ARTICLE 114 - The authorization for the installation of a laboratory shall be granted by a resolution

issued by the Institute within 30 working days from the date of filing of the following documents:

a) Applicant particulars.

b) Legal instruments certifying the ownership of the facilities and the trade name.

c) Architectural plan of the premises in duplicate, including flow charts or staff

movement diagrams, materials and critical support systems if applicable, as well as

technical specifications concerning the facilities, different areas and distribution of the

premises in accordance with GMP and GLP standards as appropriate.

d) Laboratory category and production lines, analysis and/or activities to be performed

on the premises.

e) Proof of payment of relevant fees.

Prior to requesting authorization for the installation of facilities, the interested party may request

the Institute to evaluate the aforementioned flow charts upon payment of the corresponding fees.

ARTICLE 115 - Upon installation of the relevant facilities and prior to requesting authorization for

operation, the applicant shall request the Institute to verify on-site that the premises conform to

the information provided when requesting authorization for installation and comply with GMP and

GLP standards as appropriate, and the Institute shall be required to record any objections in

writing.

ARTICLE 116 - The operating license of a pharmaceutical laboratory shall be required to be granted

by resolution of the Institute within 30 days upon the interested party submitting the following

information:

a) List of available facilities and equipment as appropriate to the category.

b) Statements signed by professionals who shall be responsible for the technical

management, production, and quality control and assurance as appropriate, without

prejudice to special provisions set forth hereunder.

c) Production lines, quality control and other activities to be performed on the premises.

d) Description of codes used in accordance with the provisions hereunder in the case of

manufacturing laboratories.

e) Any other information as reasonably requested by the Institute.

ARTICLE 117- Upon receipt of the request for authorization to operate, the Institute shall be

required to grant or reject it within 15 days from the filing date of said request on the basis of the

information described in the preceding article, and upon rejecting the request, the Institute shall

be requested to notify the interested party of any missing information so that within 5 working

44

days said information is submitted under penalty of considering the applicant to have desisted

from requesting authorization.

Should the information submitted be insufficient or non-conforming to the premises or the

requirements of the regulations currently in force, the Institute shall be required to issue a

substantiated decision rejecting the request for operation within 30 days.

If such information is correct, the Institute shall be required to issue a resolution within 30 days

authorizing the operation of the laboratory, including the following:

1. Name, category and address of the pharmaceutical laboratory.

2. Legal representative and professionals assuming technical responsibilities.

3. Lines of business, production and/or authorized analysis.

SECTION 4

REQUIREMENTS FOR PHARMACEUTICAL LABORATORY FACILITIES

ARTICLE 118 - All pharmaceutical laboratories shall be required to be specially designed and their

size and construction shall comply with GMP and GLP standards and with the provisions hereunder

as appropriate to their category.

They shall not be located near other facilities engaged in activities that are a source of

contamination, nor shall they be a source of contamination themselves.

ARTICLE 119 - The laboratory shall be required to have special separated premises for storing

flammable substances or other potentially explosive, corrosive, toxic or polluting products. These

areas shall be required to observe strict compliance with security measures as determined by

relevant authorities.

ARTICLE 120 - A laboratory manufacturing or packaging pharmaceutical products comprising

active ingredients such as narcotic or psychotropic drugs or others subject to special supervision

shall be required to have separate and restricted storage areas.

ARTICLE 121 - Establishments importing, manufacturing, packaging or distributing biological

products or other substances requiring special storage conditions as authorized in the

corresponding sanitary registration shall ensure that the temperature is as required and shall

record it until distribution of the product.

1. Manufacturing Pharmaceutical Laboratories

ARTICLE 122 - The premises of a manufacturing pharmaceutical laboratory shall be required to

comprise at least the following areas clearly indicated on the approved drawings submitted to the

Institute:

a) Reception and sampling of materials and products.

b) Quarantine of materials and products.

c) Sampling of raw materials.

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d) Fractionation of raw materials.

e) Storage of approved materials.

f) Storage of rejected materials.

g) Manufacturing.

h) Washing and drying of tools and materials.

i) Primary packaging and labelling.

j) Secondary packaging and labelling.

k) Quarantine of finished products and others submitted to batch controls, if applicable.

l) Storage of approved finished products.

m) Storage of reference samples and counter samples.

n) Storage of recalled products.

o) Storage of rejected products.

p) Storage of returned products.

q) In-process storage.

r) Quality control laboratory.

s) Areas for quality control operations of in-process products.

t) Sterile and aseptic manufacture and fractionation of pharmaceutical products in

accordance with Good Manufacturing Practices as appropriate.

u) Shipment or delivery.

v) Maintenance.

w) Offices for accountable professionals.

x) Toilets and changing rooms for staff use prior to entering or exiting the premises as

appropriate.

In the case of the areas described in b), e), k) and l) above, separate premises shall not be required

if there is an electronic system allowing adequate control of the different states of materials.

Storage areas for finished products may be located outside the facilities on separate premises. If

such premises are owned by the laboratory, they shall be deemed to be an extension of the plant,

while if they belong to a third party, the latter shall be required to have the corresponding sanitary

authorization issued by the respective Regional Health Department, which shall supervise the

activities performed therein in accordance with general storage requirements as provided for

hereunder.

ARTICLE 123 - The manufacturing premises shall be required to be structured and fitted in

accordance with the pharmaceutical forms manufactured and controlled therein to prevent cross-

contamination.

ARTICLE 124 - Manufacturing and packaging areas may be in the same premises provided that

technical systems are used in mass production to prevent separation of different manufacturing

stages, and as long as steps are taken to avoid cross-contamination.

ARTICLE 125 - The manufacture and packaging of sterile pharmaceutical products shall be required

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to be performed on premises specially fitted for this purpose and complying with the necessary

conditions for:

a) The sterile fractionation of non-sterilizable products in final packaging.

b) The aseptic fractionation of sterilizable products in final packaging.

ARTICLE 126 - When using laboratory animals, these shall be required to be kept in isolated

enclosures specially intended for these purposes in such form and manner as authorized by the

Institute.

ARTICLE 127 - The facilities, equipment and other tools used in a manufacturing laboratory shall

be required to be designed, sized and made in accordance with Good Manufacturing Practices

ensuring at least the following:

a) Continuous and organized manufacturing and quality control steps.

b) The maintenance of the necessary hygienic conditions.

c) The verification of the correct operation of the equipment, facilities and instruments.

ARTICLE 128 - Manufacturing laboratories engaged in research and development activities shall be

required to have the appropriate equipment and staff trained for such purposes.

ARTICLE 129 - The manufacture of raw materials or biological drugs obtained from such processes

and intended for the manufacture of biological products may only be performed in specially

authorized laboratories fitted for such purposes or in sections thereof separated from the

manufacturing laboratories requiring, in any case, prior authorization by the Institute.

In addition to complying with the provisions under this chapter, these premises shall be required

to have a system including exclusive facilities and equipment to allow the decontamination,

neutralization, inactivation and incineration of hazardous materials.

ARTICLE 130 - Only premises specially fitted and prepared to minimize the risk of contamination

shall be able to engage in the following activities:

a) Manipulation of microorganisms, toxins, and other cell cultures as determined by the

Institute.

b) Manufacture and package biological products comprising microorganisms, toxins and

other cell cultures.

c) In any case, the packaging of the manufactured products must be made in areas

where contamination is controlled.

2. Fitting Pharmaceutical Laboratories

ARTICLE 131 - The premises of fitting pharmaceutical laboratories shall be required to include at

least the following areas:

a) Reception and sampling of materials and products.

b) Quarantine of materials and products.

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c) Storage of approved materials and products.

d) Fitting.

e) Quarantine of finished products and of those subject to batch control, if applicable.

f) Storage of approved finished products.

g) Properly restricted storage of rejected and recalled materials and products.

h) Storage of returned finished products.

i) Storage of reference samples and counter-samples.

j) Shipment or delivery.

k) Maintenance, if applicable.

l) Quality control of production lines as appropriate, including at least one area for

analyzing labelling and packaging materials as well as graphic labels of finished

products.

m) Offices for accountable professionals.

n) Toilets and changing rooms.

In the case of the areas described in b), c), e) and f) above, separate premises shall not be required

if there is an electronic system allowing adequate control of the different states of materials.

3. Quality control pharmaceutical laboratories

ARTICLE 132 - The outsourced quality control pharmaceutical laboratory or the quality control

department of a manufacturing pharmaceutical laboratory shall be required to have the following

areas as appropriate to their line of business:

a) Reception and storage of samples.

b) Storage of counter samples.

c) Physiochemical analyses.

d) Washing of materials.

e) Instrument room.

f) Microbiology, if applicable.

g) Analysis of packaging materials and packaging.

h) Biological assays.

i) Animal facilities.

j) Offices for accountable professionals.

k) Toilets and changing rooms.

l) Storage of reagents.

These premises shall be required to have a sufficient number of rooms or areas to ensure that test

systems are isolated from each other.

ARTICLE 133 - The quality control department of a manufacturing pharmaceutical laboratory shall

be required to have the areas listed in the preceding article as applicable to their line of business.

In the event of the premises having a microbiology area, there shall be required to be separate

sterile counting and washing rooms.

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This service may be outsourced, except for quality controls performed during the manufacturing

process until the primary packaging in the manufacture of injectable products and those produced

by aseptic filling.

4. General considerations for all pharmaceutical laboratories

ARTICLE 134 - All premises shall be required to comply with GMP and GLP standards.

ARTICLE 135- The manufacture of highly active products such as hormones, cytostatic products,

beta lactams, radiopharmaceuticals and immunodepressants included in international listings or in

other documents properly authorized and acknowledged by the Institute shall be carried out in

special separate facilities, as appropriate, isolated from those used for the manufacture of other

products, adopting any special measures as necessary concerning the staff handling such products,

in relation to their clothing and protective gears to avoid health risks as provided for in technical

standards approved by the Ministry under the formula “by order of the President of the Republic”

at the proposal of the Institute.

On the basis of a substantiated resolution, the Institute shall establish additional lists of highly

active products which may be manufactured or fitted in the same premises under validated

methods for cleaning areas and equipment.

ARTICLE 136 - Manufacturing and quality control areas shall be physically separated, without

prejudice to the quality control being applicable to the same manufacturing process.

SECTION 5

PROCEDURES AND REGISTERS

ARTICLE 137 - Each action performed during the manufacturing stage shall be required to be

recorded in writing, in compliance with the standard operating procedure of production and GMP

standards.

ARTICLE 138 - A master formula shall be required for each manufactured product and batch size in

conformity with the quali-quantitative unit formula as authorized in the corresponding sanitary

registration.

ARTICLE 139 - The manufacturing process of each batch of a product shall be required to be

registered in foliated documents called “Manufacturing Chart” and “Packaging or Fitting Chart”,

which shall be kept up to date. Only the “Fitting Chart” shall be required for fitting pharmaceutical

labs.

ARTICLE 140 - The manufacturing chart is a document based on the relevant parts of the updated

master formula including at least the following information:

a) Individualization of the product.

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b) Amount to be manufactured.

c) Serial number in accordance with the authorized code.

d) Initial and completion dates for the manufacturing process.

e) Qualitative and quantitative formula proportionally corresponding to the formula

authorized in the sanitary registration.

f) Raw materials used in the manufacture of the product.

g) Number of analysis reports for raw materials used in the manufacture of the product.

h) Theoretical yield expected from operations in different stages of manufacture,

acceptable yield limits and actual yield.

i) Manufacturing standard operating procedure including at least:

i. Detailed instructions and precautions to be observed in the manufacturing

process.

ii. A list of evidence and tests required for quality control during each stage of

production, including the names of the individuals who performed the tests

and analyses.

j) Product analysis reports.

k) Any other information on particular problems, including details for any deviation from

the registered formula, under the authorized signature.

l) Name and signature of the professional accountable for the production.

ARTICLE 141 - The packing chart is a document based on the relevant parts of the master formula

or the packaging instructions currently in force, including at least the following information:

a) Particulars of the product and its presentation.

b) Serial number according to the authorized code as indicated, identifying with other

numbers or letters different sub-batches in accordance with the provisions hereunder.

c) Initial and completion dates for the packaging process.

d) Name and amount of supplies used as authorized in the sanitary registration.

e) Number of analysis reports for materials used in the process.

f) Theoretical yield, acceptable yield limits and actual yield with appropriate comments.

g) Standard Operating Procedure-packing container, including at least:

i. Detailed instructions and precautions to be observed during the process.

ii. A list of the evidence and tests required for quality control during each phase

of packaging process, including the names of persons who performed such

testing, whether from the same analysing laboratory or the outsourced quality

control laboratory as authorized, depending on each stage as appropriate.

h) Reconciliation of bulk printed packaging materials used in the process, destroyed or

returned, among others.

i) Any other relevant information concerning the packaging process such as samples of

printed materials used in the process, including serial number, expiry date and any other

printing and recording of special problems including details as to any deviation from the

packaging instructions.

j) Name and signature of the professional accountable for the process.

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In the case of fitting pharmaceutical laboratories, the chart described in the preceding paragraph

shall be known as “Fitting Chart” and will be subject to the same terms as outlined above, if

applicable.

ARTICLE 142 - All manufacturing and fitting pharmaceutical laboratories shall be required to have

a general production registry including the following entries to date and in chronological order for

each product as appropriate:

a) Date of planning, product name and serial number.

b) Number of “Manufacturing Chart”.

c) Initial and completion dates for the manufacture of the bulk product.

d) Theoretical and actual yield of the bulk product.

e) Number packaging or fitting chart.

f) Initial and completion dates for the fitting or packaging process.

g) Theoretical and actual yield of the finished product.

h) Number of analysis reports on the finished product.

i) Number and date of the resolution authorizing the batch in the case of products

subject to the batch control as set forth herein.

j) Product expiry date set on the basis of the date of manufacture and the effectiveness

period as authorized in the respective sanitary registration.

k) Name and signature of the production manager.

ARTICLE 143 - Pharmaceutical laboratories handling narcotic or psychotropic drugs and other

products subject to special controls shall be required to keep official records in the manner and

conditions required by the relevant regulations.

ARTICLE 144 - Pharmaceutical laboratories shall be required to engage in quality control activities

to ensure compliance with the technical specifications of the product as authorized in the relevant

sanitary registration.

The analytical methods and quality specifications shall be as authorized in the respective

monographs upon granting of the sanitary registration or in subsequently approved amendments.

There shall also be a quality assurance system developed under the concept of integrated security,

which shall be construed as the set of planned and standardized rules and procedures necessary

for guaranteeing the quality of the finished product.

ARTICLE 145 - Pharmaceutical laboratories shall be required to keep records of every action and

test performed on each manufactured batch and on the corresponding raw materials and

packaging material for one year after the product expiry date.

The above records shall be required to include raw material analysis reports, packaging materials,

in-process and finished products, manufacturing equipment calibration protocols, validation of

analytical techniques, operating information, maintenance of facilities, equipment and

instruments, and others in accordance with as GMP and GLP standards.

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ARTICLE 146 - The records under this section shall be required to be constantly updated and easily

accessible, and to show evidence of any changes.

The records may be kept on a computer system insofar as it meets the above requirements.

ARTICLE 147 - Fitting laboratories shall be subject to the provisions of the preceding articles in

connection with the process performed therein as approved under the signature of the

professional accountable for the quality of said process.

SECTION 6

STAFF AND RESPONSIBILITIES

ARTICLE 148 - Manufacturing pharmaceutical laboratories shall be required to have qualified staff

in the following positions:

1. Chief Technical Officer.

2. Production Manager.

3. Quality Control Manager.

4. Quality Assurance Manager.

Notwithstanding the above, considering the complexity of the laboratory concerned, the Institute

may authorize the same professional to hold the position of chief technical officer and production

manager, and/or of quality control and quality assurance manager.

In the case of fitting laboratories, the chief technical officer may additionally assume the

responsibilities of the production manager, while the quality control manager may also perform

the duties of the quality assurance manager.

Without prejudice to the foregoing, these positions are to be held by professional pharmaceutical

chemists who shall be severally accountable for the obligations imposed hereunder.

ARTICLE 149 - Outsourced quality control laboratories shall be required to be under the

responsibility of a pharmaceutical chemist holding the position of chief technical officer.

ARTICLE 150 - Pharmaceutical laboratories manufacturing only drugs or raw materials of biological

origin obtained from processes of the same nature may additionally be under the management of

a biochemist or medical surgeon specializing in microbiology.

ARTICLE 151 - The positions of Chief Technical Officer, Production Manager, Quality Control

Manager and Quality Assurance Manager shall be required to be held on an ongoing and

permanent basis throughout the time of operation of the concerned laboratory, and the Institute

shall be informed of the name of the individuals holding said positions and the address for serving

notifications within 30 days from the date on which the they occupy their positions.

In their absence, another individual of the same profession shall be required to substitute for

them during such term. In any event, the permanent holder shall be ultimately accountable for

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already ongoing processes, without prejudice to any responsibilities for which the substitute could

be liable.

Any professional assuming such positions as substitute shall be required to be registered on

existing forms and registers, giving written notice of this to the Institute on a monthly basis.

Holders who are absent for a period exceeding 48 hours shall be required to be substituted for

under the foregoing conditions upon giving written notice thereof to the Institute. A written notice

shall also be served on the Institute upon substitutes leaving said positions or at the end of their

term of office.

ARTICLE 152 - The Chief Technical Officer shall be the representative of the laboratory before

health authorities for the purposes of observing these regulations in regard to the following

aspects:

a) Guarantee the accuracy of the information contained in the sanitary registration.

b) Keep a file containing resolutions concerning the product registration or amendments

thereof, information for healthcare professionals, advertising material, and all

documents sent to or received from the Institute.

c) Submit any information for which he is responsible, in a timely fashion and as required

by the Institute, in accordance with the provisions hereof.

d) Ensure that advertising and information on pharmaceutical products conforms to the

provisions of the sanitary registration and complies with sanitary regulations currently

in force.

e) Perform all other duties as assigned by laws and regulations.

ARTICLE 153 - The Production Manager shall be generally responsible for the organization and

development of components in the manufacturing process from a technical point of view, and

particularly accountable for the following:

a) Ensure compliance of the formula of the manufactured, packaged or imported

products with the specifications indicated and authorized in the registration.

b) Observe and enforce Good Manufacturing Practices.

c) Ensure proper compliance of instructions concerning the manufacture, packaging and

storage of products, including process controls.

d) Monitor the maintenance of the premises, facilities and equipment in general.

e) Perform all other duties as assigned by laws and regulations.

ARTICLE 154 - The Quality Control Manager shall be responsible for the following:

a) Ensure that the specifications and analytical methodology for each of the raw

materials, packaging materials, in-process products and finished products conform to

the sanitary registration, performing or assuming responsibility for the representative

sampling of each of them in accordance with plans designed and developed on a

statistical basis.

b) Accept or reject raw materials, in-process products, finished products and packaging

materials in accordance with the specifications and methodologies authorized in the

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relevant sanitary registration, recommending their modification, reprocessing or

destruction as appropriate upon leaving the corresponding written record.

c) Run stability tests and other tests for each of the finished products.

d) Provide the Quality Assurance Manager with accurate and true information as needed

for the release of a batch of a product, in addition to any relevant comments.

e) Plan, establish and monitor the implementation of laboratory work, ensuring

compliance with Good Laboratory Practice standards.

f) Ensure proper maintenance of reference samples and/or counter-samples of raw

materials, in-process products and finished products.

g) Guarantee the reliability of analytical results concerning quality controls carried out in

the laboratory on products manufactured, packaged or imported on the premises or

by others.

h) Perform all other duties as assigned by laws and regulations relating their professional

activity at the premises.

ARTICLE 155 - The Quality Assurance Manager shall be responsible for performing activities

related to the implemented quality system and ensuring the required quality of pharmaceutical

products in conformity with the corresponding sanitary registration, especially including the

following activities:

a) Supervise the manufacture of products in accordance with GMP and GLP standards

and oversee compliance therewith.

b) Ensure proper registration of data in each of the registers kept by pharmaceutical

laboratories pursuant to current regulations.

c) Release production batches for distribution to the market, wherein reference shall be

made to the assessment of compliance with sanitary registration specifications, the

compliance with GMP and GLP standards, manufacturing process, test results, review

of batch documentation, in-process controls and analysis of deviations, without

prejudice to other responsibilities resting with the Production Manager or the Quality

Control Manager as appropriate.

d) Implement validation programs for manufacturing processes that may cause variation

in the characteristics of in-process products and finished products and analysis

methodologies.

e) Register and review complaints about the quality of products that have been reported

or returned by users or that have been the subject of an investigation pursued by

health authorities, and take necessary measures to address such faults.

f) Implement and enforce calibration programs for instruments and laboratory

equipment as appropriate.

g) Review and conduct stability tests.

h) Develop and launch a program to check the reliability of methods used for inspecting

and analyzing quality features in materials and products.

i) Develop and implement programs for self-inspections and audits of suppliers and

service providers.

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j) Perform all other duties as assigned by laws and regulations relating their professional

activity at the premises.

ARTICLE 156 - The Chief Technical Officer of outsourced quality control pharmaceutical

laboratories shall be the representative of the establishment before health authorities for the

purposes of compliance with these regulations and shall be required to perform the following

functions:

a) Issue analysis reports on raw materials or in-process or finished products in

accordance with the methodologies and specifications set forth in the corresponding

sanitary registration as appropriate and decide on their approval or rejection.

b) Develop and enforce programs implemented for periodical calibration of instruments

and laboratory equipment as appropriate.

c) Develop and launch a program to check the reliability of methods used for inspecting

and analysing quality features in materials and products.

d) Plan, supervise and monitor the implementation of laboratory work ensuring

compliance with GLP standards.

e) Guarantee the reliability of analytical results from quality controls performed at their

premises on manufactured, packaged or imported products, or on other products for

which an analysis has been requested.

f) Perform sampling of products requiring analysis according to a procedure ensuring its

representativeness.

ARTICLE 157 - The owner of the facilities, whether an individual or legal entity, shall provide the

aforementioned professionals with technical and economic resources required to observe these

regulations.

ARTICLE 158 - The responsibilities resting with the Chief Technical Officer, the Production

Manager, the Quality Control Manager and the Quality Assurance Manager shall additionally fall

on the owner of the premises, if applicable, according to general regulations governing the matter.

ARTICLE 159 - The owner of the premises shall be jointly responsible with the Chief Technical

Officer for the proper distribution or sale of the products manufactured or imported by the facility,

and for any advertisement and information concerning them.

ARTICLE 160 - The owner and the chief technical officer shall be accountable for the acquisition,

maintenance, possession and use of narcotic or psychotropic drugs and other products subject to

special controls in the form and conditions established by the corresponding regulations.

SECTION 7

OUTSOURCING

ARTICLE 161 - The holders of a sanitary registration may outsource services including but not

55

limited to manufacturing, packaging and specific quality control tests to a pharmaceutical

laboratory provided that it has been agreed in writing and authorized in the corresponding

sanitary registration or its subsequent amendments.

ARTICLE 162 - The manufacturing or packaging agreement relating to pharmaceutical products in

any stage of production shall be required to include the technical aspects of said stage in

accordance with Good Manufacturing Practices.

ARTICLE 163 - Reference shall be made in the quality control agreement to the requested actions

considering the requirements set out in GLP standards.

In addition, the contracting party shall undertake to provide all the relevant information needed to

perform the corresponding analysis in accordance with GLP standards and pursuant to the

specifications in the sanitary registration.

ARTICLE 164- In any case, any party engaging in activities pursuant to an agreement shall be

required to comply with the same requirements and conditions set out for those activities and

bear the same responsibilities for them as provided for hereunder.

SECTION 8

SPECIAL MANUFACTURING FACILITIES

ARTICLE 165 - The manufacture of phytopharmaceutical and homeopathic products as well as

those described in article 17 herein shall be required to meet the needs of their manufacturing

processes pursuant to Good Manufacturing Practices or in accordance with standards approved by

order of the Ministry issued at the request of the Institute.

ARTICLE 166 - Facilities manufacturing traditional herbal medicines shall be exempt from the

regulations under this section and shall be licensed and supervised by the corresponding Regional

Ministerial Department within the scope of its competence. The technical standards setting the

requirements for facilities storing, fractionating, packaging or performing other activities related

to the manufacture of traditional herbal medicines by hand shall be required to be approved by

order of the Ministry.

SECTION 9

TERM, CANCELLATION AND SUSPENSION OF THE OPERATING LICENSE

ARTICLE 167 - The operating licence for a pharmaceutical laboratory shall be valid for a three-year

term from the date of grant and may be automatically renewed for successive and equal terms

while not giving grounds for cancellation as provided for herein and as long as manufacturing

specifications from GMP and GLP standards have been observed.

For these purposes, the Institute may inspect and monitor operating conditions at pharmaceutical

laboratories to enforce compliance with current regulations.

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ARTICLE 168 - The operating licence of a pharmaceutical laboratory may be cancelled by a

substantiated decision of the Institute in the following cases:

a) The owners or their legal representatives have informed that they do not wish to

continue operating.

b) The authorized establishment has not been operating for a period of six months.

ARTICLE 169 - Notwithstanding the provisions of the preceding article, the operating license of a

pharmaceutical laboratory may also be cancelled on the basis of the outcome of a preliminary

investigation, among others, in the following cases:

a) Raw materials and finished products, as appropriate, have not been analyzed.

b) One or more counterfeit, contaminated, altered or adulterated products have been

manufactured.

c) There have been numerous defects in the quality of the manufactured or packaged

products, insofar as their efficacy and safety is concerned, in more than three batches

corresponding to the same sanitary registration or more than four batches

corresponding to different sanitary registrations over the period of one year.

d) When upon total or partial suspension of the facilities, there is evidence that the

offences giving grounds for such suspension are still being committed.

ARTICLE 170 - The work or activity on the premises shall be brought to a standstill upon any of the

following conditions:

a) The pharmaceutical laboratory is operating without a Chief Technical Officer, a

Production Manager, a Quality Control Manager or a Quality Assurance Manager, as

appropriate.

b) Failure to overcome the objections raised by the Institute within the fixed time limits.

c) Failure to comply with GMP and GLP standards and manufacturing specifications

according to the category and lines of business of the laboratory, jeopardizing the

efficacy, safety and quality of the product.

The standstill or suspension may be total or partial.

ARTICLE 171 - In the event of suspension, the Institute shall be required to establish the conditions

and deadline to be met so that activities can be resumed.

ARTICLE 172 - Each owner shall be required to notify the Institute within 30 days of the temporary

or permanent closure of the laboratory. In the event of the temporary closure exceeding 6 months

or involving remodelling of the premises, the facilities or a change in the line of business, an

authorization shall be required to resume activities.

CHAPTER VII

QUALITY

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SECTION 1

GENERAL PROVISIONS

ARTICLE 173 - Any manufactured or imported pharmaceutical product shall be subjected to quality

control, except as otherwise provided hereunder.

The responsibility for the quality of the products shall rest with manufacturers, importers,

distributors, retailers or holders in any capacity as relevant and appropriate.

ARTICLE 174 - Any individual or legal entity being the owner of facilities manufacturing

pharmaceutical products shall be required to implement a quality control system to ensure

compliance with manufacturing, raw material and finished product specifications by means of

relevant testing.

Individuals or legal entities importing pharmaceutical products in any stage of production shall

also be required to comply with this requirement, as appropriate.

In addition, individuals or legal entities importing raw materials for the manufacture of

pharmaceutical products shall be required to have a system for certifying their quality.

ARTICLE 175 - The holder of a sanitary registration shall be required to certify that the

manufacture of pharmaceutical products, whether domestic or foreign, conforms to quality

assurance standards, in the sense that the analysis and manufacturing methods have been

validated and are conducive to obtaining products that meet quality requirements set forth in the

corresponding sanitary registration pursuant to general GMP and GLP guidelines.

Notwithstanding the above, a compliance schedule may be accepted for the validation of

manufacturing processes.

ARTICLE 176 - By means of a substantiated decision, the Institute may suspend the distribution of

a pharmaceutical product failing to observe the provisions of the preceding article. In this case, the

holder may make any adjustments as necessary to ensure that processes are validated, in order to

restore the authorization upon prior resolution by the Institute.

ARTICLE 177 - Any individual or legal entity authorized to use a pharmaceutical product

temporarily without prior registration in accordance with the provisions of article 21.a and 21.b

herein shall be required to have appropriate instruments to guarantee the quality of the product

and to perform quality control tests as established in the resolution authorizing the use of said

product.

SECTION 2

QUALITY REQUIREMENTS

ARTICLE 178 - The quality requirements of pharmaceutical drugs shall be set out in the product

specifications, while the control methods shall be those approved in the corresponding sanitary

registration as granted or subsequently amended.

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ARTICLE 179 - The quality requirements for raw materials intended for the manufacture of

pharmaceutical products shall be set out in the specifications of the sanitary registration, while the

manufacturing pharmaceutical laboratory shall be responsible for compliance with quality control

and other requirements prior to distribution of the product.

Any changes in the manufacturer of the active ingredients made after the granting of the sanitary

registration shall be required to be reported to the Institute providing information as necessary to

show that such changes do not affect the quality, effectiveness and stability of the product,

without prejudice to the Institute performing a selective sampling to ensure compliance with the

specifications set out in the granted registration, for which additional information may be

required.

SECTION 3

BATCH CONTROL

ARTICLE 180 - Without prejudice to general provisions on quality control set out hereinbefore, the

Institute may require any product to undergo batch controls either temporarily or permanently,

considering its nature, the variability of testing methods used for their control, or other justified

reasons.

ARTICLE 181 - For the purposes of batch controls, the Institute of Public Health shall require the

performance of all or some of the tests and assays included in the specifications of the finished

product as authorized in the corresponding sanitary registration, determining the frequency for

each product.

ARTICLE 182- The approval of a batch or sub-batch does not release the holder of the registration

from the obligation to perform quality controls as provided for hereunder and set out in

supplementary regulations.

ARTICLE 183 - All biological products shall be subject to batch control procedures.

ARTICLE 184 - The application for batch control shall be required to correspond to a completely

finished batch or sub-batch identified with a different alphanumeric code each time the

corresponding application is filed, and shall be required to include the following:

a) Batch release certificate issued by the Quality Assurance Manager in the case of

domestic manufacture, or by the manufacturer or relevant health authorities in the

case of imported semi-finished or finished products, as appropriate.

b) Analysis report issued in Chile or in the manufacturing country in the case of imported

finished, semi-finished or bulk products.

c) Standards required for completing the analysis.

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ARTÍCULO 185- For the purposes of batch control procedures, the Institute shall be required to

collect two samples, one of which shall be sealed and registered at the sampling premises under

the responsibility of the Chief Technical Officer. The size of each sample shall be required to be

sufficient for performing two full tests pursuant to the specifications of the finished product as

authorized in the corresponding sanitary registration, while the sampling procedure shall be

determined by the Institute by means of a resolution.

ARTICLE 186 - A batch or sub-batch subjected to control shall be required to be approved or

rejected within 20 working days from receipt of the information mentioned in article 184 herein,

except for vaccines, whose batch control shall be performed within 40 working days.

Notwithstanding the foregoing, the Institute may for justifiable reasons increase the period

indicated in the preceding paragraph.

Upon rejection of the batch, the manufacturer or importer shall be required to destroy the

product immediately at authorized premises in the presence of a Chief Technical Officer and a

certifying officer appointed by the Institute, who shall properly record the procedure in writing.

Under exceptional circumstances, the Institute may authorize the reprocessing of rejected

products upon request of the applicant, in which case the conditions for reprocessing the products

shall be set out in the corresponding resolution.

SECTION 4

QUALITY AND BATCH CONTROL EXEMPTIONS

ARTICLE 187 - Upon reasonable request of the holder of the registration, the Institute may

partially or totally exempt imported finished products from quality and/or batch controls if the

holder shows that the turnover of the product is very low and its unit cost is high.

For these purposes, the interested party shall be required to provide sufficient information about

the validation of analytical methods used for batch release in the country of manufacture, an

analysis report from the country of origin, and proof that the cold chain has been maintained, if

applicable.

ARTICLE 188 - The decision granting or refusing the exemption shall be required to be

justified. If granting the exemption, the decision shall be required to indicate the following

information:

1. Name of the pharmaceutical drug.

2. Maximum authorized amount and frequency of import.

3. Exempted tests.

4. Number of counter-samples to be kept.

5. Term of the decision granting the exemption.

SECTION 5

QUALITY CONTROL OBLIGATIONS

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ARTÍCULO 189 - The holder of the sanitary registration shall be responsible for keeping counter-

samples of domestically manufactured or imported products in a sufficient amount so as to

perform two full tests of the products pursuant to the specifications authorized in the

corresponding sanitary registration, said samples being conveniently labelled and kept under the

custody of the Chief Technical Officer of the same pharmaceutical laboratory or of the laboratory

providing outsourced services by virtue of the corresponding agreement.

Counter samples and supporting documentation shall be required to be kept for one year after the

product expiry date.

SECTION 6

QUALITY SUPERVISION

ARTICLE 190 - The Institute of Public Health shall be the health authority responsible for

monitoring the quality of pharmaceutical products by performing shelf controls or other onsite

surveillance activities at manufacturing and packaging laboratories, distributors, retailers, and

health care facilities.

These activities may include bioavailability studies and others aimed at showing therapeutic

equivalence pursuant to the provisions of Chapter X herein.

ARTICLE 191 - Any defects or complaints about the quality of the pharmaceutical products shall be

required to be notified to the Institute, which upon assessment thereof shall take any necessary

measures as appropriate.

In the event of the this failure arising from storage conditions or distribution through

pharmaceutical wholesalers or retailers, the records shall be required to be submitted to the

corresponding Regional Health Departments to attribute any relevant responsibilities by means of

a preliminary investigation.

ARTICLE 192 - In the case of importers of foreign-made finished, semi-finished, mass produced or

semi-manufactured products, the Institute shall be required to oversee compliance of the foreign

manufacturing laboratory with Good Manufacturing Practices according to the corresponding

production lines. For the foregoing purposes, the Institute may hire foreign consultants and

outsource services or enter into agreements with national and foreign public or private entities as

necessary, pursuant to required quality standards.

ARTICLE 193 - Notwithstanding the foregoing, the Institute may accept international

accreditations and certifications for pharmaceutical drugs and manufacturing facilities insofar as

the production and quality control standards enforced by the authority of the manufacturing

country have been declared to be equivalent to Chilean standards by resolution of the Ministry of

Health or are the subject of international treaties.

In the event of such standards not being equivalent, the Institute shall be required to proceed in

the manner described in the preceding article at the cost of the applicant or holder of the sanitary

registration as appropriate.

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ARTICLE 194 - In the event that upon conducting the corresponding preliminary investigation

there is evidence of quality failures in three or more batches of pharmaceutical products from the

same production line of a particular manufacturing laboratory, the Institute shall be required to

amend the sanitary registration, excluding the production line corresponding to faulty products or

suspending the importation and distribution authorized in the sanitary registration of any

pharmaceutical drug whose licensed manufacturer includes said production line.

CHAPTER 8

DISTRIBUTION

ARTICLE 195 - Products shall be required to be distributed by manufacturing and fitting

pharmaceutical laboratories, pharmaceutical wholesalers and stores for pharmaceutical products

for human consumption and dental care, under the conditions set out in the corresponding

sanitary registration, and only to authorized receiving sanitary facilities.

ARTICLE 196 - Retail of pharmaceutical products may only take place in pharmacies,

pharmaceutical wholesalers and stores for dental or other pharmaceutical products under the

conditions set out in the corresponding regulations.

Pharmaceutical laboratories and wholesalers may sell imported or manufactured products in

separate facilities within their premises specially intended for such purposes, under the conditions

of sale authorized in the relevant sanitary registration. These facilities shall be required to operate

under the supervision of the Chief Technical Officer or an appointed professional pharmaceutical

chemist. Such areas shall be required to be authorized in terms of location and operation by the

Institute or the corresponding Regional Health Department respectively.

Additionally, these establishments may sell such products to the public under the authorized

conditions of sale and in separate premises supervised by a professional pharmaceutical chemist

upon being authorized by the corresponding Regional Health Department.

ARTICLE 197 - Retail conditions for a pharmaceutical drug shall be required to be indicated in the

corresponding sanitary registration or resolution in the case of authorizations for use without prior

sanitary registration, considering in both cases the therapeutic indications and the authorized

usage as well as any adverse reactions and interactions of the product.

ARTICLE 198 - Retail conditions for a pharmaceutical drug shall be strictly observed upon selling or

supplying the drug, which may not be distributed for free on any site, by any means or under any

pretext or condition whatsoever.

The provisions of the foregoing paragraph shall not apply to units such as medical samples directly

and exclusively distributed to legally qualified prescribing professionals in their offices or at

scientific meetings, and said products shall be required to be dispensed directly by the healthcare

professional to the patient.

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Notwithstanding the above, pharmaceutical drugs and products mentioned in article 21.a may be

donated to public and private healthcare facilities within at least one year prior to their expiry

date or six months in the case of products under article 21.a, upon prior authorization by the

Institute, and said drugs or products shall bear on their package or container a caption referring to

their free distribution, and shall be required to be dispensed to patients under the same

conditions.

The facilities receiving the donation shall be required to give the products for free.

CHAPTER 9

ADVERTISING AND INFORMATION

SECTION 1

GENERAL PROVISIONS

ARTICLE 199 - Advertising materials and healthcare professional and patient information about

pharmaceutical drugs shall be governed by the provisions of this Chapter, wherein the definitions

below shall be construed as follows:

a) Advertising: A set of procedures or activities aimed at highlighting, announcing, raising

awareness or informing the public directly or indirectly through any broadcasting

medium or means of dissemination about the features, conditions for distribution,

sale and use of products hereunder.

b) Healthcare information for professionals: A set of procedures and activities for

professionals legally qualified to prescribe or dispense pharmaceuticals in order to

introduce them to the products hereunder as authorized in the corresponding sanitary

registration.

c) Healthcare professional information leaflet: A document including at least the features

of the pharmaceutical drug, such as pharmacokinetic, pharmacodynamic and

toxicological aspects, dosage indications, target age group, contraindications,

interactions, warnings, adverse reactions including those that may occur while

pregnant or breastfeeding or in special populations, procedure in case of overdose,

and other aspects deemed relevant by authorities on the basis of the nature and

scientific information available for a pharmaceutical product with a view to inform

professionals legally qualified to prescribe or dispense pharmaceutical products.

d) Patient information leaflet: A document produced to provide the patient with

information about a pharmaceutical drug. It shall be required to include at least

information concerning authorized indications, warnings, contraindications,

interactions with other products, precautions and any additional information as

required by health authorities in the registration, with a view to ensure proper use

thereof. Additionally, leaflets of products sold directly to the public shall be required

to include information about the usual dosage and method of use as authorized in the

registration.

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ARTICLE 200 - Pharmaceutical drugs sold directly to the public may be advertised without prior

authorization from the Institute, and the advertisements shall be required to display totally or

partially the exact contents as authorized in the patient information leaflets and labels approved in

the corresponding registration.

Advertising materials may only relate to therapeutic recommendations approved by the Institute

in the corresponding sanitary registration and under no circumstances may they include titles,

figures, indications, effects or references which are not in accordance with said registration.

Any advertising contrary to the foregoing provisions shall be subject to penalties applicable upon

previously conducting a preliminary investigation.

ARTICLE 201 - Pharmaceutical drugs sold under simple, withheld or official prescriptions may not

be advertised.

However, such drugs may be introduced to professionals qualified for prescribing and dispensing

them without prior authorization from of the Institute, through advertisements exclusively

intended to announce their presence in the market, including only the officially approved name,

their identification on the main label, the name of the manufacturing laboratory, distributor or

importer, and the sign of the establishment, if applicable.

ARTICLE 202 - It is forbidden to donate, give or distribute medicines free for advertising purposes.

The foregoing shall be construed as including any donation or free distribution not provided for in

article 198 herein.

ARTICLE 203 - Based on a justified decision, the Institute may suspend or prohibit the disclosure of

advertisements or healthcare professional information of pharmaceutical products that do not

comply with the provisions hereunder, without prejudice to conducting a preliminary investigation

as appropriate.

For these purposes, the Institute shall require advertising texts and information on such products

from the concerned party.

ARTICLE 204 - In the event that the information intended for professionals does not conform to

the authorized registration, the Institute may issue a decision suspending the sanitary registration

and additionally demand the withdrawal of all leaflets.

ARTICLE 205 - The holder of the registration may request the amendment of healthcare

professional and patient information leaflets, which shall be accepted or rejected by the Institute

on the basis of a substantiated decision. Additionally, the Institute may also introduce

amendments to the authorized leaflets on the basis of a substantiated decision and upon giving

prior notice to the holder of the registration so that any appropriate measures may be adopted.

ARTICLE 206 - The holders of a sanitary registration, importers, manufacturers, distributors and

retailers advertising a particular product or performing activities aimed at providing prescribing

professionals with information on such product on their own or through third parties without

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complying with the provisions hereunder shall be subject to the corresponding penalties upon

previously conducting the relevant preliminary investigation.

ARTICLE 207 - It is forbidden for publications, films, broadcasts or other audiovisual advertising

systems to promote medicinal products or drugs offering medical benefits which have not been

previously authorized or recognized as such by the relevant authorities.

Health authorities may immediately request that such activities be stopped pursuant to the

provisions of article 178 of the Sanitary Code, without prejudice to any liabilities for which the

offender may be accountable as determined in the corresponding preliminary investigation.

SECTION 2

HEALTHCARE PROFESSIONAL INFORMATION

ARTICLE 208 - Information for professionals dealing with pharmaceutical drugs sold under simple

prescriptions shall be required to be directed solely to legally authorized prescribing professionals

and pharmaceutical chemists responsible for dispensing products.

ARTICLE 209 - The information supplied to healthcare professionals shall be true, accurate,

complete and susceptible of verification, and shall further conform to the therapeutic use and

properties of the drug and the contents of the healthcare professional information leaflet as

authorized in the corresponding registration.

Such information shall also be required to include the formula of the product, indications,

interactions, contraindications, precautions and warnings, adverse side effects, dosage, and

toxicity risks, as well as the treatment. The texts and graphic materials shall be required to be true,

accurate, and susceptible of verification, apart from conforming to the type of pharmaceutical

product without alterations, distortions or any other additional words or expressions.

ARTICLE 210 - The healthcare professional information leaflet shall be required to include

information on the proven bioavailability or therapeutic equivalence of the drug if mandatory.

ARTICLE 211 - Any references to clinical, pharmacological or other scientific tests or records shall

be required to be properly identified and faithfully transcribed. Such tests and studies shall be

required to be available for healthcare professionals upon request, if applicable.

Studies that bear no relation to the concerned pharmaceutical drug may not be claimed as

referring to such drug. Reference shall be made clearly and visibly to the relevant literature and

source of reference if charts, tables or references of the product are used, including the name of

the product and the holder of the registration.

ARTICLE 212 - General characteristics shared by several products may not be attributed exclusively

to a particular product. Comparisons with other registered drugs comprising the same active

ingredient shall be required to be demonstrated by relevant studies.

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Any scientific information not included in the corresponding sanitary registration concerning

therapeutic indications and dosages other than those authorized in said registration may be

supplied to legally qualified prescribing healthcare professionals, indicating the status of such

information, and the use thereof shall be the sole responsibility of the professional.

ARTICLE 213 - It is forbidden to give incentives in any shape or form such as money, goods,

services or others to healthcare professionals responsible for prescribing or dispensing medicines,

or to individuals selling them, in order to encourage the prescription, dispensation or sale of a

product over another.

SECTION 3

ADVERTISING IN PHARMACEUTICAL FACILITIES

ARTICLE 214 - Only pharmaceutical drugs under direct conditions of sale may be advertised in

manufacturing and distribution facilities indicating their authorized name, package and sign of the

manufacturer, if applicable.

Notwithstanding the above, vending companies shall be able to inform about the price of

pharmaceutical products, regardless of their condition of sale, by displaying their labels in the

premises of sale. These provisions shall not apply for products subject to special controls, such as

psychotropic and narcotic drugs.

ARTICLE 215 - In the aforementioned premises, it is forbidden to use advertising procedures such

as contests, raffles, sample donation or others that could lead to the purchase, use or selection of

medicines and encourage consumption, misuse or self-medication. In addition, the sale of

pharmaceutical products may not be encouraged by giving incentives in any shape or form to

pharmacy staff.

SECTION X

SANITARY SURVEILLANCE

SECTION 1

PHARMACOVIGILANCE

ARTICLE 216 - The Institute shall be the health authority responsible for monitoring the safety of

registered pharmaceutical drugs or unregistered products that have been approved for use in

temporary or scientific research.

ARTICLE 217 - Healthcare professionals are required to inform the Institute about any noticeable

signs of adverse reactions which could have been caused by a particular pharmaceutical product.

Chief Technical Officers of healthcare facilities shall be required to comply with the same

obligation and keep an updated record of these events.

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The information referred to in this article shall be supplied on forms intended for these purposes

as determined by a resolution of the Institute of Public Health.

In the event of a serious adverse reaction to medication, the Institute shall be informed within 72

hours upon noticing the reaction. Other cases shall be required to be reported within 30 days.

ARTICLE 218 - Holders of sanitary registrations or permits shall be required to implement and

maintain a pharmacovigilance system of their own or by contract from an outside supplier, while

their technical adviser shall be responsible for:

a) Developing, adopting and maintaining a documented system for collecting and

processing information about the alleged adverse reactions in a single file.

b) Preparing and supplying information to the Institute of Public Health about suspected

adverse reactions in the authorized forms on a quarterly basis, unless a shorter period

is indicated by the Institute based on a substantiated decision.

c) Ensuring that any additional information requested by the Institute of Public Health to

assess the benefits and risks of a pharmaceutical drug is promptly submitted within

the fixed time.

In specific cases, the Institute of Public Health may reasonably introduce further special measures

for the pharmacovigilance of certain products.

ARTICLE 219 - Holders of sanitary registrations of pharmaceutical drugs shall be required to have

updated information on the safety of the product and constantly carry out evaluations of the risk-

benefit thereof pursuant to the provisions of chapter II section 7 herein.

ARTICLE 220 - The Institute shall be required to assess available surveillance information and, if

applicable, request studies as necessary to evaluate the safety of a pharmaceutical drug under the

authorized conditions of use. Additionally, the Institute may recommend any necessary measures

to minimize the risks associated with the use of pharmaceutical products and to maintain a proper

risk-benefit balance.

Notwithstanding the provisions of law no. 19,628 on the protection of personal data, the records,

assessments and measures outlined above shall be deemed to be public information and may be

disclosed by any media.

SECTION 2

THERAPEUTIC EQUIVALENCE

ARTICLE 221 - At the proposal of the Institute, the Ministry shall be required to pass a resolution

containing lists of active ingredients in pharmaceutical products that require proof of therapeutic

equivalence and the list of pharmaceutical products used as reference standards.

Also by resolution, the Ministry shall be required to adopt the criteria for determining which

pharmaceutical products require proof of therapeutic equivalence.

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The regulations and other procedures for conducting bioavailability and therapeutic equivalence

tests where appropriate shall be required to be set out by a resolution of the Ministry at the

proposal of the Institute.

SECTION XI

PROCEDURE, PENALTIES AND REMEDIES

ARTICLE 222 - The administrative procedures, notifications and calculation of time periods in

connection with the enforcement of these regulations shall be governed by the provisions of law

no. 19,880 on the basis of administrative procedures concerning the acts of State administration

bodies.

ARTICLE 223 - The infringement of the provisions hereunder shall give rise to penalties imposed by

the Institute upon a prior preliminary investigation pursuant to these regulations and in

accordance with the provisions set forth in Chapter X of the Sanitary Code and other

supplementary sanitary legislation.

Appeals against the penalties imposed hereunder may be filed with the corresponding court in the

manner prescribed in article 171 of the Sanitary Code.

Penalties arising from the infringement of provisions enforced by Regional Health Departments

shall be imposed by said departments pursuant to the preceding paragraphs.

ARTICLE 224 - In its capacity as a sanitary supervisory body, the Institute may reasonably adopt

emergency measures without conducting a previous preliminary investigation. These measures

may be taken by certifying officers appointed by the Institute solely on the basis of a written

statement issued by them upon the existence of an imminent risk to health. Regional Health

Departments or their certifying officers shall have the same powers with respect to regulations

specifically enforced by them.

ARTICLE 225 - Except as provided for in the second paragraph of article 223, an appeal may be

lodged with the Ministry of Health against the acts and decisions of the Director of the Institute in

the performance of his duties in connection with these regulations within five working days from

the date of notification of the corresponding decision.

Should the concerned party require more time to furnish further evidence to support their claim, a

request shall be filed with the Ministry of Health, which shall be required to issue a decision on the

matter.

Upon filing of the appeal, the Ministry shall require the relevant information from the Institute

and issue a decision within ten days of receipt of such information, unless more time is required

from a technical point of view.

If an appeal is filed with the Institute, the claims under the provisions of this article may be

brought subsidiarily within the same period. In this case, the decision reversing a verdict shall be

deemed as a report for purposes stated in the preceding paragraph.

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FINAL SECTION

TERM

ARTICLE 226 - These regulations shall come into force 6 months after publication in the Official

Gazette, upon which resolution no. 1876 of 1995 by the Ministry of Health and any other laws,

decisions or provisions contrary to or inconsistent with the provisions hereunder shall be repealed.

Notwithstanding the above, the provisions of article 175 herein shall come into force upon

publication in the Official Gazette.

PROVISIONAL ARTICLES

FIRST PROVISIONAL ARTICLE:

Sanitary registrations

Sanitary registrations granted under the provisions of resolution no. 1876 of 1995 by the Ministry

of Health shall remain in force and effect. However, by means of a substantiated decision, the

Institute of Public Health may require information as deemed necessary to update sanitary

registrations in compliance with the provisions hereunder within a given period of not less than

one year. Compliance with the provisions hereunder in connection with the labelling of

pharmaceutical products shall be monitored as from one year after such provisions have come

into force.

Sanitary registration applications that are pending upon these regulations coming into force shall

be required to be withdrawn within 30 days and may be filed again within 5 months without prior

payment of fees and in compliance with the requirements and formalities set out herein.

Applications that are not withdrawn within the prescribed period shall be rejected outright.

SECOND PROVISIONAL ARTICLE

Sanitary permits

Sanitary permits granted under the provisions of resolution no. 1876 of 1995 by the Ministry of

Health shall remain in force and effect. However, authorized pharmaceutical laboratories shall be

required to comply with these regulations according to the following schedule:

Physical premises requirements: within 2 years.

Staff and administrative requirements: within 1 year.

Methodology and technical requirements: within 1 year.

Installation permits and operating licenses that are pending upon these regulations coming into

force shall be required to be withdrawn within 30 days and may be filed again within 5 months

without prior payment of fees and in compliance with the requirements and formalities set out

herein. Applications that are not withdrawn within the prescribed period shall be rejected

outright.