Chile ds 03 eng
Upcoming SlideShare
Loading in...5
×

Like this? Share it with your network

Share
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
1,204
On Slideshare
1,204
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
16
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. REGULATIONS OF THE NATIONAL SYSTEM FOR THE CONTROL OF HUMAN PHARMACEUTICAL PRODUCTS PRELIMINARY CHAPTER SCOPE AND COMPETENT AUTHORITIESARTICLE 1 - These regulations include technical and administrative standards and other terms orconditions to be met for registering, importing, exporting, manufacturing, storing, possessing, anddistributing (either free or for good and valuable consideration) pharmaceutical products, foradvertising 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 toplay a guiding and regulatory role in the field of pharmaceutical products, implementing a nationaldrug policy and issuing technical and administrative standards to be met by public and privateentities engaging in the activities outlined in the previous article and which shall be approved byrelevant administrative acts.ARTICLE 3 - The Institute of Public Health is the national health authority responsible for thesanitary surveillance of pharmaceutical products and for ensuring compliance with the provisionsset forth herein, the Sanitary Code and its supplementary regulations, and other laws on thesubject.The Institute is furthermore responsible for verifying the quality of pharmaceutical products in anyof the stages referred to in article 1; authorizing the installation and operation of pharmaceuticallaboratories; licensing and registering pharmaceuticals and other products subject to these formsof control; supervising conditions for import, admission, export, manufacturing, and distribution ofthis products, and likewise any advertising and information about the same; controlling drugs andpharmaceutical products that cause addiction, and other psychotropic substances likely to have asimilar effect, in relation to the import, export, and lawful use thereof in the preparation ofpharmaceutical products; and monitoring compliance with the provisions hereunder and otherregulations governing such matters.ARTICLE 4 - The Regional Health Departments shall be responsible for authorizing the admission ofpharmaceutical products according to the provisions set forth in article 2 of law no. 18,164. Inaddition, Regional Health Departments shall be required to enforce and monitor the compliancewith the provisions herein regarding the distribution, storage, and possession of pharmaceuticalproducts, insofar as these activities are carried out by authorized pharmaceutical facilities, exceptfor pharmaceutical laboratories.ARTICLE 5 - For the purposes hereof, the definitions below shall be construed and interpreted asfollows: 1
  • 2. 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. 2
  • 3. 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 3
  • 4. 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, 4
  • 5. 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. 5
  • 6. 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. 6
  • 7. 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. 7
  • 8. 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 pharmaceuticalproducts 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 andadopt any sanitary measures or impose the corresponding penalties upon conducting a priorpreliminary investigation.The Regional Health Departments shall be required to monitor the retail and supply of productsunder the conditions described above.The Regional Health Departments shall additionally be required to inform the Institute of anyfindings concerning the conditions described in the preceding paragraph so that the Institute canadopt the necessary measures or conduct investigations with respect to holders of sanitaryregistrations, manufacturers, importers or distributors as appropriate. 8
  • 9. Furthermore, the Institute or the Regional Health Departments shall be required to lodge thecorresponding complaint with the Public Prosecutors Office with a view to conduct aninvestigation and impose criminal liabilities if applicable. CHAPTER I PHARMACEUTICAL PRODUCTS SECTION 1 DEFINITIONARTICLE 7 - A pharmaceutical product or drug is any natural or synthetic substance, or mixturesthereof, intended for use in humans in the cure, mitigation, treatment, prevention or diagnosis ofdiseases or their symptoms, or for producing changes in the physiological system or mental stateof the individual to whom it is administered.Pharmaceutical products shall be construed as including active raw materials, pharmaceuticalpreparations, pharmaceutical drugs and traditional herbal medicines.ARTICLE 8 - Based on substantiated decisions, the Institute shall impose an appropriate regulatoryregime on all products having or described as having some of the properties listed in the previousarticle and labelled or advertised as food items. The decisions made by the Institute shall bebinding both on products currently in the market as well as those distributed and sold for the firsttime.The determination of the applicable regulatory regime may be made either ex officio or at therequest of individuals or other public organizations upon detecting products under the conditionsmentioned in the preceding paragraph in their capacity as supervisory bodies.For the purposes of determining the applicable regulatory regime as requested, the RegionalHealth Departments shall be required to submit a technical report and copies of all records in theirpossession, as well as results from inspections and audits if applicable.Should the Institute establish that the applicable regulatory regime corresponds to apharmaceutical product, the corresponding formal resolution shall be required to be published inthe Official Gazette and a notice shall be served on the interested party for the purposes ofrequesting a sanitary registration by providing relevant information for all products comprisingcomponents with the alleged therapeutic activity.Upon service of the aforementioned notice and prior to obtaining a sanitary registration, thepharmaceutical product shall be recalled by the distributor or retailer, without prejudice to furthersanitary liabilities. These provisions shall also apply for other products comprising the ingredientsof the pharmaceutical product.In the event of the Institute finding that the applicable regulatory regime does not correspond to apharmaceutical product, the records shall be required to be submitted to the Ministry for reviewalong 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 9
  • 10. in doubt about the classification of other products such as cosmetics, household and sanitarypesticides, or medical devices, following the same procedure outlined above. SECTION 2 PHARMACEUTICAL DRUGS AND THEIR CLASSIFICATIONARTICLE 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 activeingredients obtained from a chemical synthesis or extraction process.ARTICLE 12 - Biological products are obtained from and/or produced by living organisms and theirfluids 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. 10
  • 11. ARTICLE 13 - Radiopharmaceuticals are products or formulations labelled with radionuclides orradioisotopes for use in the diagnosis or treatment of diseases, regardless of the route ofadministration.ARTICLE 14 - Phytopharmaceuticals are pharmaceutical drugs comprising standardized activeingredients from aerial or underground parts of plants or other plant material.ARTICLE 15 - Homeopathic products are pharmaceutical drugs comprising homeopathicsubstances made of plant, animal, mineral or chemical raw materials prepared in accordance witha homeopathic manufacturing procedure described in official regulations approved by order of theMinistry necessarily including the processes of dilution and dynamization of mother dyes.Homeopathic products shall be required to have been tested in healthy individuals andrepertorized for prescription or use according to the law of similars. A homeopathic product maycontain one or more homeopathic substances.ARTICLE 16 - Medical gases are pharmaceutical drugs made of one or more gaseous componentsof known concentration and impurity manufactured according to registered specifications andintended for administration to humans. Such drugs shall be governed by specific regulations.ARTICLE 17 - In addition to the aforementioned groups, pharmaceutical drugs include any otherproducts having therapeutic properties as indicated in the label, advertised or attributed by anymeans, whether curative or for the mitigation, treatment, diagnosis or prevention of diseases ortheir symptoms, or for changing physiological systems or mental states for the benefit of theperson to whom it is administered, and which are not classifiable under any of the abovecategories.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 PURPOSESARTICLE 18 - The sanitary registration of a pharmaceutical drug is a process of evaluation andsystematic study of its pharmaceutical, pharmacological, toxicological, and clinical properties with 11
  • 12. a view to verify its quality, safety and efficacy, resulting in a registration under sequentialnumbering 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 theobligation 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 dulyrepresented and domiciled in Chile.ARTICLE 19 - The administrative proceedings concerning the sanitary registration are unrelated toother commercial or intellectual property aspects as provided for in article 49 of the IndustrialProperty 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, shallbe distributed or used without prior sanitary registration.ARTICLE 21 – Under exceptional circumstances, the Institute may authorize the sale or provisionaluse of certain pharmaceutical products without the corresponding sanitary registration in view ofthe provisions of article 102 of the Sanitary Code including but not limited to the followingcircumstances: 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 ofpharmaceutical products without prior sanitary registration based on a) and b) above shall requireprior authorization granted by the authorities of the country of origin or manufacturing country asappropriate. In both cases, the authorizations granted to interested parties may be requested for asecond time within six months, upon receipt of the sanitary registration application or proof thatthere is still urgent need for the drug, or that the emergency situations mentioned in thepreceding article remain unchanged.ARTICLE 23 - Applications for provisional use of a pharmaceutical product in scientific research orclinical trials shall be required to include a protocol approved by the ethics committee as set forthin article 21.c, which shall also be required in the case of a registered product intended for adifferent use other than as authorized.ARTICLE 24 - Under the collaboration agreements by and between the Institute and the RegionalHealth Departments of regions having customs offices pursuant to the provisions of the 12
  • 13. Constitutional Law of State Administration (law no. 18,575) as consolidated and coordinated bylaw-ranking decree No. 1 of 2000 by the General Secretariat of the Presidency, the Regional HealthDepartments may authorize the temporary use of pharmaceutical products without priorregistration when they have been imported for personal use directly by the applicant or hisrepresentative, provided that they are prescribed by a qualified healthcare professional stating theneed for the treatment and its duration.Additionally, Regional Health Departments may authorize the admission of drugs by national orforeign individuals carrying them upon entering the country for treatment for a period notexceeding three weeks, except in the case of chronic diseases or other therapies, upon providingthe 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 theauthorizations granted pursuant to this article.ARTICLE 25 - For the purposes of article 102 of the Sanitary Code, pharmaceutical preparationsshall have an official sanitary registration number also appearing in the Official PreparationsRegister 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 deemedto be registered by the fact of being included in the formula of a registered pharmaceuticalproduct or by the respective authorization for use thereof when such materials are imported byauthorized 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 withlocal cultural traditions, and recognized in the corresponding technical standard approved byorder of the Ministry as mentioned in the following paragraph. These drugs shall be deemed to beregistered for retail and distribution purposes upon authorization by the relevant Regional HealthDepartment of the facilities where they are stored, manufactured, packed or fractionated, orwhich 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 REQUIREMENTSARTICLE 28 - Sanitary registration applications shall be required to be submitted to the Institute incompliance with the requirements set forth herein. 13
  • 14. General registration requirements include administrative aspects as well as others relating to thetechnical information, pharmaceutical quality, safety and clinical efficacy of the pharmaceuticalproduct; other special requirements depend on the nature of the product, and the healthcareprofessional signing the application shall be responsible both for their origin and veracity. 1. Sanitary registration general requirements A. Administrative requirementsARTICLE 29 - A sanitary registration application shall be required to meet the following generaladministrative 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. 14
  • 15. 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. 15
  • 16. 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 bulkpharmaceutical products, the applicant shall be allowed to prove the manufacturers compliancewith Good Manufacturing Practices in accordance with the provisions of articles 192 and 193, inwhich case the requirements set forth in a.iv above shall not apply. B. Technical information requirementsARTICLE 31- A sanitary registration application shall be required to meet the following generalrequirements in relation to the technical information of the pharmaceutical product, including thefollowing: 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 requirementsARTICLE 32- A sanitary registration application shall be required to meet the following generalrequirements to certify the pharmaceutical quality of the product, including the followinginformation: 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 16
  • 17. 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: 17
  • 18. 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 otherphysical, chemical, microbiological and bio-pharmaceutical requirements for drugs for which aregistration is sought, the Institute shall be required to observe the relevant rules in the followingpharmacopoeias and their supplements: a) Chilean Pharmacopoeia. b) International Pharmacopoeia. c) European Pharmacopoeia. 18
  • 19. 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 onbiological, biotechnological, chemical, radioactive, and similar standards, and the provisions of title21 of the United States “Code of Federal Regulations” (CFR), section 1.1, shall also be of relevancefor the purposes mentioned above. In the case of a pharmaceutical product that is not listed in anyof the foregoing official documents, the Institute may, with good reasons, accept or reject, eithertotally 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 textsmentioned in the preceding article, these shall be indicated in the application for registration sothat the Institute can decide about their adequacy.ARTICLE 35- Due to the nature, diversity and extent of the general requirements set for thepharmaceutical quality of products, they may be listed in additional technical standards approvedby the Ministry at the proposal of the Institute. D. Safety and Efficacy requirementsARTICLE 36- A sanitary registration application shall be required to include information on thesafety 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. 19
  • 20. 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 drugsARTICLE 37 - The following conditions shall be required to be met for the registration ofpharmaceutical 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 pharmaceuticalproducts comprising a combination of fixed-dose active ingredients shall be rejected under thefollowing circumstances: 20
  • 21. 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 theirregistration shall be required to provide evidence of their safety and efficacy when used in thecombination. In addition, the applicant shall be required to provide further evidence as to thefollowing: 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 associationwith each other or with other pharmaceutical drugs.ARTICLE 40 - Given the nature of phytopharmaceutical products, the following considerations shallbe 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 21
  • 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 betaken 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 22
  • 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 thesanitary 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. 23
  • 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. 24
  • 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: 25
  • 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 theMinistry at the proposal of the Institute to determine active ingredients and their presentation, forwhich abridged clinical studies endorsing the efficacy and safety of the product shall be acceptedbased on the existence of another registered biotechnological product comprising the same activeingredients, unit dose, pharmaceutical product and route of administration.Notwithstanding the foregoing, the applicant shall be required to submit comparative studiesincluding the reference product for each indicated active ingredient in order to properlycharacterize the product and provide evidence as to the similarity in their nature. SECTION THREE REGISTRATION APPLICATION PROCEDURESARTICLE 43 - The sanitary registration application and any required information depending on thetype of pharmaceutical product shall be submitted to the Institute of Public Health using theapproved forms upon payment of the corresponding fee.A register of the application shall be kept on a written or electronic file comprising documentssubmitted by interested parties, stating the time and date of presentation and having a referencenumber for reference and tracking purposes, upon payment of the fee corresponding to the firstadmissibility phase of the application.ARTICLE 44 - Within ten working days, the Institute shall be required to review the applicationform and the information supplied, and deliver a statement on its admissibility. 26
  • 27. ARTICLE 45 - Upon acceptance of the application for further evaluation, the interested party shallbe given notice of this decision in order to proceed with the payment of fees corresponding to thenext phase of the procedure.An application may only be rejected in the absence of compliance with the requirementshereunder and any supplementary regulations, according to the type of pharmaceutical drug, andthe Institute shall be required to indicate any missing information required to overcome theobjection, which shall be submitted within five working days, upon which the Institute shallproceed 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 tothe 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 legalconsultancy 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 recordsas required by the type of product pursuant to the provisions of the preceding paragraph, shall beseparated and forwarded to specialized technical offices for assessment in accordance with thesepresents.ARTICLE 47 - Should the aforementioned assessment result in a favourable outcome and within sixmonths from the date of payment of the corresponding fee, the requested registration shall begranted by enactment of a resolution notified to the formal applicant.ARTICLE 48 - The sanitary registration of a pharmaceutical drug shall be required to contain atleast 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. 27
  • 28. 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 beinsufficient, the Institute shall request the Ministry of Health to rule on the rejection of theregistration.The Ministry shall be required to issue a report on the rejection of the registration within 10working days and forward it to the Institute so that it passes a substantiated resolution which shallbe notified to the applicant.ARTICLE 50 - Pursuant to the provisions of law no. 19,880, during the prosecution of a sanitaryregistration the interested party may make submissions and furnish documents or other evidencewhich 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 onthe 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 28
  • 29. Article 51 - The regular registration procedure may be simplified to reduce processing times byorder 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 procedureARTICLE 52 - The regular registration procedure may be simplified upon the interested partysrequest 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. 29
  • 30. ARTICLE 53 - The simplified sanitary registration procedure shall not be applicable in the followingcases: 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 besimplified 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 REGISTRATIONARTICLE 55 - The sanitary registration of a pharmaceutical product shall be valid for a term of fiveyears from the date of grant and may be renewed for equal and successive periods provided thatno cancellation is in effect and under the following conditions: 30
  • 31. 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 ofthe obligations under such registration.ARTICLE 56 - The application for renewing a sanitary registration shall be submitted to theInstitute, and in the case of imported products, it shall be required to be accompanied by thepharmaceutical product certificate, registration certificate, sanitary authorization or officialcertifications recommended by the World Health Organization, issued by the relevant authoritiesin the country of origin, certifying that the manufacturing or storing facilities comply with healthregulations in their respective country, that the product is registered in said country pursuant tocurrent legislation, indicating the authorized formula in full, and that the sale of the product issubject 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 assignedupon 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 thescope 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 interestedparties 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. 31
  • 32. 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 responsiblefor 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 regulationsto other pharmaceutical and healthcare facilities, and for informing users who could potentiallyuse the concerned product.ARTICLE 61 - The suspension and cancellation of a sanitary registration shall be determined by theInstitute by means of a substantiated decision notified to the holder.ARTICLE 62 - Notwithstanding the provisions of article 59, the Institute may cancel a sanitaryregistration after conducting relevant preliminary investigations, in addition to penalties imposedpursuant to the provisions of article 174 of the Sanitary Code. SECTION 6 SANITARY REGISTRATION AMENDMENTS 1. Technical and sanitary aspectsARTICLE 63 - Amendments to the sanitary registration of a pharmaceutical drug may be producedupon 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 introduceamendments to the registration within a certain period of time to guarantee the quality, safetyand efficacy in the use of one or more pharmaceutical drugs when on the basis of scientificinformation from the World Health Organization or foreign or international bodies ororganizations, or arising from its own research, the Institute has the conviction that some of theauthorized use conditions poses a risk to their safety and efficacy.ARTICLE 65 - Upon the holders request and by means of a resolution, the Institute may acceptanalytical, 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. 32
  • 33. 6. Origin, packaging facilities, licensor, distributor, importer, and quality control pharmaceutical laboratory, or their name or the holders 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 berequired to be submitted to the Institute using authorized numbered forms and to beaccompanied by technical and scientific information supporting the request.The Institute shall be required to accept or reject applications for the amendment of a sanitaryregistration on the basis of a substantiated decision within a period not exceeding three monthsfrom 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 sufficientto support the request, the applicant shall be served with a notification indicating the objectionsand any missing information required to overcome them during a period of not less than ten normore than thirty working days. 2. Administrative aspectsARTICLE 67 - The holder shall give the Institute written notice of any amendments to the sanitaryregistration that are not concerned with technical aspects relating to the quality, safety andefficacy 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 providedthat the new holder meets the relevant requirements without affecting other conditions asauthorized in the registration and that relevant supporting information is attached to the requestaccording to the provisions of the preceding articles.The request shall be supported by appropriate legal instruments duly legalized, translated andsigned by the legal representative.In the case of sanitary registrations under a license, the change of the holder shall be subject tothe provisions of the relevant document, and if not expressly mentioned, it may only beauthorized 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 registrationshall be introduced jointly, unless said amendments involve a new manufacturer, in which case afurther registration shall be required. 33
  • 34. ARTICLE 70 - Changes shall be required to be recorded in the corresponding registration under thesame terms and conditions set forth in article 66 regarding other amendments to the sanitaryregistration. SECTION 7 OBLIGATIONS FOR ALL HOLDERS OF SANITARY REGISTRATIONSARTICLE 71 - The holder of the sanitary registration is ultimately responsible for the safety andefficacy of the drug.Without prejudice to the specific obligations imposed in view of the nature of each pharmaceuticaldrug, 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 LABELLINGARTICLE 72 - All pharmaceutical drugs shall be required to be presented in tamper-resistantprimary and secondary packagings containing a patient information leaflet.Under exceptional circumstances, the Institute may release the holder of the registration uponrequest of the latter from the obligation of having a secondary packaging or a patient informationleaflet, provided that the primary packaging in itself guarantees the preservation of the quality ofthe pharmaceutical form and includes all the information required for the label of the secondarypackaging or the patient information leaflet.ARTICLE 73 - The primary packaging of pharmaceutical products shall be required to be suitableand appropriate for safeguarding its contents in accordance with the stability tests submitted forthe same upon registration of the product or in subsequent amendments. 34
  • 35. ARTICLE 74 - The label of the secondary packaging shall be in Spanish, in clearly visible letters, andshall be required to include at least the following information without any advertising orpromotional 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 describedin 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 thecaption “MEDICAL SAMPLE NOT FOR SALE” in both the primary and the secondary packaging inindelible ink, in a clear and visible manner.ARTICLE 77 - The labels shall be required to be printed or adhered to the outer surface of thepackage without being in contact with its contents. Arial or other similar straight fonts shall beused for labelling purposes, in a minimum size of 6.ARTICLE 78 - The graphic label of imported finished pharmaceutical products may exceptionallycontain texts in other languages apart from Spanish, provided that the text authorized by theInstitute is not modified. 35
  • 36. ARTICLE 79 - Under their sole responsibility, holders of sanitary registrations may include in thelabels industrial property information as required by law to exercise the rights arising therefrom.ARTICLE 80 - Graphic labels and healthcare professional and patient information leafletssubmitted upon applying for a sanitary registration shall conform to their final text onceauthorized, 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 befurther applicable to patient information leaflets. The same requirements shall also be applicableto subsequent amendments to the graphic label and healthcare professional and patientinformation leaflets.ARTICLE 81 - In addition to the information described in article 74 above, pharmaceutical drugsintended 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 withinan insert or other unit disclosing the full text of the caption approved for the secondary packagingand the patient information leaflet, if not enclosed.ARTICLE 82 - A pharmaceutical drug shall be required to be designated after its generic or tradename.Notwithstanding the foregoing, in the event of a pharmaceutical drug not being identified by itsgeneric name and comprising a single active ingredient, said ingredient shall be required to beidentified 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 followingcases: 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. 36
  • 37. 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 anumber of registered pharmaceutical drugs provided that their compositions comprise at leastone active ingredient in common producing the main therapeutic action and that they areintended for direct sale.ARTICLE 84 - In addition to the provisions of article 74, the containers of all parenteral solutions of100 ml or more shall be required to bear a label indicating the day, month and year ofmanufacture in a clear, visible and indelible manner, and a warning to discard the product in caseof turbidity or precipitate, unless such conditions are deemed to be particular specifications of thefinished product and have been authorized in the corresponding registration.In addition to the provisions of the preceding paragraph, in the case of parenteral solutionscomprising electrolytes in a single drug, this shall be required to be indicated on the label in lettersof a particular colour or otherwise different from the corresponding colour. The Institute shall berequired to determine the colours for each cation of the active ingredient in the respectivesolutions.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 packagingand the amount of active ingredient, unless that in view of the size of the packaging, the Institutedeems 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 activeingredients as authorized upon granting of the registration and shall be further required toindicate the equivalence of active ingredients with the parent drug and the qualitative list of allexcipients.The composition of the formula shall be required to be indicated in percentages and in thecorresponding 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 theformula shall be required to be indicated by each unit dose. 37
  • 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 orusual 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 SaleARTICLE 88 - Any batch or sub-batch of a pharmaceutical product shall be required to be identifiedby a code that will enable tracking at any stage from manufacture to retail or use. For thepurposes of interpretation, the holder of the registration shall be required to notify the Institute ofthe code structure. The same procedure shall apply for subsequent amendments or differentcodes that may be used.ARTICLE 89 - The codes shall be required to be indicated on the labels of primary and secondarypackaging containing the pharmaceutical drug.ARTICLE 90 - The code shall consist of numbers or combinations of letters and numbers, and shallbe required to indicate the month and year of manufacture and the batch number in sequentialand chronological order. Otherwise, any alphanumeric combination may be used as a code, but itshall be required to indicate the month and year of manufacture on all labels and comply withgeneral labelling requirements.ARTICLE 91 - In the case of imported finished pharmaceutical products, the holder shall berequired to declare the code of the country of origin upon applying for registration and to indicatehow it should be interpreted.ARTICLE 92 - In the event of a pharmaceutical product from a single batch being finished indiscontinuous steps, each shall be deemed to be a sub-batch and shall be required to be identifiedby an addition to the original serial number. CHAPTER IV IMPORT AND ADMISSION OF PHARMACEUTICAL PRODUCTS. 38
  • 39. SECTION 1 GENERAL PROVISIONSARTICLE 93 - Pharmaceutical drugs may only be imported upon prior registration provided thatsuch import has not been suspended, without prejudice to the cases and conditions set forth inchapter II section 1 hereunder.ARTICLE 94 - A pharmaceutically drug may be exceptionally imported as a finished product by anyindividual or legal entity without requiring a new sanitary registration for importation anddistribution by individuals other than those who obtained such registration if besides having thesame formula, generic name or designation, the pharmaceutical product is certified to come fromthe same manufacturer and country as the previously registered pharmaceutical product, asattested in the corresponding registration certificate, certificate of pharmaceutical product orsanitary 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 certainamount and the use thereof for the sole merit of the authorization and the respective reportsconcerning tests performed on admitted batches by a quality control laboratory. SECTION 2 IMPORT AND ADMISSIONARTICLE 95 - Pharmaceutical products may be imported by authorized pharmaceuticallaboratories, pharmacies, pharmaceutical wholesalers and pharmaceutical warehouses, and ingeneral by any individual or legal entity according to current legislation.ARTICLE 96 - Any individual or legal entity may import pharmaceutical drugs as well as rawmaterials for the manufacture thereof. Notwithstanding the foregoing, for admission into thecountry the importer shall be required to have duly authorized facilities for storage, manufactureor later distribution such as pharmaceutical laboratories, pharmacies, pharmaceutical wholesalersand pharmaceutical warehouses as appropriate depending on the nature and purpose of theimported material.ARTICLE 97 - Only manufacturing pharmaceutical laboratories may store pharmaceutical productsin 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 dulyauthorized facilities.Raw materials for the manufacture of drugs products or for sale to manufacturing facilities mayonly be stored by pharmaceutical wholesalers and manufacturing pharmaceutical laboratories. 39
  • 40. SECTION 3 PROCEDURE FOR ADMISSION OF PHARMACEUTICAL PRODUCTSARTICLE 98 - For the purposes of admitting pharmaceutical products, a Destination CustomsCertificate shall be required from the Regional Health Department under jurisdiction of thecustoms office where the product is to enter the country, for which all relevant information shallbe supplied indicating the admitted material, its quantity and nature, and the route and means oftransport to ship them from the customs area to an authorized facility.The Regional Health Departments shall be required to issue a decision on the applicationmentioned in the preceding paragraph within three working days from the date of filing of theapplication, and rejections shall be required to be based on substantiated decisions.The Regional Health Departments may enter into agreements with public entities for issuing theaforementioned certificates executed in accordance with the provisions of the Constitutional Lawon General Bases for the State Administration (law no. 18,575) as coordinated and consolidated bylaw-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 HealthDepartments to the National Customs Service.Once the customs destination document is processed and the products are withdrawn from thecustoms 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 appropriatesanitary 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 importdocuments (invoice and bill of lading), the customs destination certificate, and the protocol forquality control in the manufacturing country, or otherwise the protocol for the analysis conductedin Chile, except for samples of pharmaceutical products exclusively intended for research anddevelopment or sanitary registration, and the authorization shall be required to be issued withinthree working days from the date on which the applicant notifies the authorities of the receptionof the products in the storing facilities.The granting of the authorization for use and disposal shall not release applicants from compliancewith other legal, regulatory or administrative requirements as necessary for such use ordistribution, nor from observing other third partys rights as established by law.The National Customs Service shall be required to provide the Institute with a monthly report onimported 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 theimporter shall be required to be previously authorized by the corresponding Regional HealthDepartment. CHAPTER V 40
  • 41. EXPORT OF PHARMACEUTICAL DRUGSARTICLE 100 - Only pharmaceutical products currently registered in Chile may be exported uponprior notification to the Institute.ARTICLE 101 - Pharmaceutical drugs for export labelled as “Products for Export” shall be exemptedfrom 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 includethe 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 andstorage of products for export.ARTICLE 103 - Pharmaceutical products intended exclusively for export shall be required to bepackaged, stored and shipped in a manner appropriate to their nature.ARTICLE 104 - The holder of the registration may request a Certificate of Pharmaceutical Productfrom the Institute which shall be required to be issued within 10 days from receipt of suchrequest.ARTICLE 105 - The distribution and use in Chile of products labelled pursuant to the provisions ofarticle 101 herein or registered solely for exportation is forbidden. CHAPTER VI PHARMACEUTICAL LABORATORIES SECTION 1 GENERAL PROVISIONSARTICLE 106 - Only pharmaceutical laboratories licensed in accordance with the provisionshereunder shall be authorized to manufacture pharmaceutical products. Pharmacies may onlyelaborate compounded preparations according to the provisions set forth in specific regulations.ARTICLE 107 - A pharmaceutical laboratory is a facility for importing, manufacturing, packaging orchecking the quality of pharmaceutical products under these regulations. They are classifiedaccording to the activities carried out as follows: 41
  • 42. 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 GLPstandards as appropriate depending on the activities for which they are authorized. SECTION 2 SANITARY AUTHORIZATION FOR LABORATORIESARTICLE 109 - The installation of a pharmaceutical laboratory, whatever its nature, shall berequired to be expressly authorized by resolution of the Institute in terms of its operation andeventual relocation.The expansion or modification of the facilities or line of business within each category shall also berequired to be authorized by the Institute.ARTICLE 110 - The installation and operation license granted by the Institute shall be valid for aterm 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 beingresponsible for its operation or administration on their own or on behalf of third parties shall berequired to notify the Institute within 30 days and submit the corresponding legal instrumentsidentifying the legal representative and including a list of professionals in charge of themanagement, production, and quality control and assurance as appropriate depending on the typeof facility.ARTICLE 112 - The Institute may inspect the facilities to supervise operating conditions inaccordance with GMP and GLP standards as well as the provisions hereunder. 42
  • 43. SECTION 3 AUTHORIZATION PROCEDURE FOR INSTALLATION AND OPERATIONARTICLE 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 resolutionissued 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 requestthe 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 foroperation, the applicant shall request the Institute to verify on-site that the premises conform tothe information provided when requesting authorization for installation and comply with GMP andGLP standards as appropriate, and the Institute shall be required to record any objections inwriting.ARTICLE 116 - The operating license of a pharmaceutical laboratory shall be required to be grantedby resolution of the Institute within 30 days upon the interested party submitting the followinginformation: 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 berequired to grant or reject it within 15 days from the filing date of said request on the basis of theinformation described in the preceding article, and upon rejecting the request, the Institute shallbe requested to notify the interested party of any missing information so that within 5 working 43
  • 44. days said information is submitted under penalty of considering the applicant to have desistedfrom requesting authorization.Should the information submitted be insufficient or non-conforming to the premises or therequirements of the regulations currently in force, the Institute shall be required to issue asubstantiated 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 daysauthorizing 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 FACILITIESARTICLE 118 - All pharmaceutical laboratories shall be required to be specially designed and theirsize and construction shall comply with GMP and GLP standards and with the provisions hereunderas appropriate to their category.They shall not be located near other facilities engaged in activities that are a source ofcontamination, nor shall they be a source of contamination themselves.ARTICLE 119 - The laboratory shall be required to have special separated premises for storingflammable substances or other potentially explosive, corrosive, toxic or polluting products. Theseareas shall be required to observe strict compliance with security measures as determined byrelevant authorities.ARTICLE 120 - A laboratory manufacturing or packaging pharmaceutical products comprisingactive ingredients such as narcotic or psychotropic drugs or others subject to special supervisionshall be required to have separate and restricted storage areas.ARTICLE 121 - Establishments importing, manufacturing, packaging or distributing biologicalproducts or other substances requiring special storage conditions as authorized in thecorresponding sanitary registration shall ensure that the temperature is as required and shallrecord it until distribution of the product. 1. Manufacturing Pharmaceutical LaboratoriesARTICLE 122 - The premises of a manufacturing pharmaceutical laboratory shall be required tocomprise at least the following areas clearly indicated on the approved drawings submitted to theInstitute: a) Reception and sampling of materials and products. b) Quarantine of materials and products. c) Sampling of raw materials. 44
  • 45. 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 requiredif 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. Ifsuch 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 sanitaryauthorization issued by the respective Regional Health Department, which shall supervise theactivities performed therein in accordance with general storage requirements as provided forhereunder.ARTICLE 123 - The manufacturing premises shall be required to be structured and fitted inaccordance 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 thattechnical systems are used in mass production to prevent separation of different manufacturingstages, and as long as steps are taken to avoid cross-contamination.ARTICLE 125 - The manufacture and packaging of sterile pharmaceutical products shall be required 45
  • 46. to be performed on premises specially fitted for this purpose and complying with the necessaryconditions 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 isolatedenclosures specially intended for these purposes in such form and manner as authorized by theInstitute.ARTICLE 127 - The facilities, equipment and other tools used in a manufacturing laboratory shallbe required to be designed, sized and made in accordance with Good Manufacturing Practicesensuring 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 berequired to have the appropriate equipment and staff trained for such purposes.ARTICLE 129 - The manufacture of raw materials or biological drugs obtained from such processesand intended for the manufacture of biological products may only be performed in speciallyauthorized laboratories fitted for such purposes or in sections thereof separated from themanufacturing laboratories requiring, in any case, prior authorization by the Institute.In addition to complying with the provisions under this chapter, these premises shall be requiredto 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 contaminationshall 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 LaboratoriesARTICLE 131 - The premises of fitting pharmaceutical laboratories shall be required to include atleast the following areas: a) Reception and sampling of materials and products. b) Quarantine of materials and products. 46
  • 47. 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 requiredif there is an electronic system allowing adequate control of the different states of materials. 3. Quality control pharmaceutical laboratoriesARTICLE 132 - The outsourced quality control pharmaceutical laboratory or the quality controldepartment of a manufacturing pharmaceutical laboratory shall be required to have the followingareas 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 testsystems are isolated from each other.ARTICLE 133 - The quality control department of a manufacturing pharmaceutical laboratory shallbe 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 separatesterile counting and washing rooms. 47
  • 48. This service may be outsourced, except for quality controls performed during the manufacturingprocess until the primary packaging in the manufacture of injectable products and those producedby aseptic filling. 4. General considerations for all pharmaceutical laboratoriesARTICLE 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 inother documents properly authorized and acknowledged by the Institute shall be carried out inspecial separate facilities, as appropriate, isolated from those used for the manufacture of otherproducts, 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 technicalstandards 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 highlyactive products which may be manufactured or fitted in the same premises under validatedmethods for cleaning areas and equipment.ARTICLE 136 - Manufacturing and quality control areas shall be physically separated, withoutprejudice to the quality control being applicable to the same manufacturing process. SECTION 5 PROCEDURES AND REGISTERSARTICLE 137 - Each action performed during the manufacturing stage shall be required to berecorded in writing, in compliance with the standard operating procedure of production and GMPstandards.ARTICLE 138 - A master formula shall be required for each manufactured product and batch size inconformity with the quali-quantitative unit formula as authorized in the corresponding sanitaryregistration.ARTICLE 139 - The manufacturing process of each batch of a product shall be required to beregistered 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 pharmaceuticallabs.ARTICLE 140 - The manufacturing chart is a document based on the relevant parts of the updatedmaster formula including at least the following information: a) Individualization of the product. 48
  • 49. 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 formulaor 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. 49
  • 50. In the case of fitting pharmaceutical laboratories, the chart described in the preceding paragraphshall be known as “Fitting Chart” and will be subject to the same terms as outlined above, ifapplicable.ARTICLE 142 - All manufacturing and fitting pharmaceutical laboratories shall be required to havea general production registry including the following entries to date and in chronological order foreach 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 otherproducts subject to special controls shall be required to keep official records in the manner andconditions required by the relevant regulations.ARTICLE 144 - Pharmaceutical laboratories shall be required to engage in quality control activitiesto ensure compliance with the technical specifications of the product as authorized in the relevantsanitary registration.The analytical methods and quality specifications shall be as authorized in the respectivemonographs 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 necessaryfor guaranteeing the quality of the finished product.ARTICLE 145 - Pharmaceutical laboratories shall be required to keep records of every action andtest performed on each manufactured batch and on the corresponding raw materials andpackaging 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 ofanalytical techniques, operating information, maintenance of facilities, equipment andinstruments, and others in accordance with as GMP and GLP standards. 50
  • 51. ARTICLE 146 - The records under this section shall be required to be constantly updated and easilyaccessible, 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 inconnection with the process performed therein as approved under the signature of theprofessional accountable for the quality of said process. SECTION 6 STAFF AND RESPONSIBILITIESARTICLE 148 - Manufacturing pharmaceutical laboratories shall be required to have qualified staffin 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 Institutemay authorize the same professional to hold the position of chief technical officer and productionmanager, and/or of quality control and quality assurance manager.In the case of fitting laboratories, the chief technical officer may additionally assume theresponsibilities of the production manager, while the quality control manager may also performthe duties of the quality assurance manager.Without prejudice to the foregoing, these positions are to be held by professional pharmaceuticalchemists who shall be severally accountable for the obligations imposed hereunder.ARTICLE 149 - Outsourced quality control laboratories shall be required to be under theresponsibility of a pharmaceutical chemist holding the position of chief technical officer.ARTICLE 150 - Pharmaceutical laboratories manufacturing only drugs or raw materials of biologicalorigin obtained from processes of the same nature may additionally be under the management ofa biochemist or medical surgeon specializing in microbiology.ARTICLE 151 - The positions of Chief Technical Officer, Production Manager, Quality ControlManager and Quality Assurance Manager shall be required to be held on an ongoing andpermanent basis throughout the time of operation of the concerned laboratory, and the Instituteshall be informed of the name of the individuals holding said positions and the address for servingnotifications 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 forthem during such term. In any event, the permanent holder shall be ultimately accountable for 51
  • 52. already ongoing processes, without prejudice to any responsibilities for which the substitute couldbe liable.Any professional assuming such positions as substitute shall be required to be registered onexisting 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 forunder the foregoing conditions upon giving written notice thereof to the Institute. A written noticeshall also be served on the Institute upon substitutes leaving said positions or at the end of theirterm of office.ARTICLE 152 - The Chief Technical Officer shall be the representative of the laboratory beforehealth authorities for the purposes of observing these regulations in regard to the followingaspects: 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 anddevelopment of components in the manufacturing process from a technical point of view, andparticularly 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 52
  • 53. 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 activitiesrelated to the implemented quality system and ensuring the required quality of pharmaceuticalproducts in conformity with the corresponding sanitary registration, especially including thefollowing 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. 53
  • 54. 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 pharmaceuticallaboratories shall be the representative of the establishment before health authorities for thepurposes of compliance with these regulations and shall be required to perform the followingfunctions: 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 theaforementioned professionals with technical and economic resources required to observe theseregulations.ARTICLE 158 - The responsibilities resting with the Chief Technical Officer, the ProductionManager, the Quality Control Manager and the Quality Assurance Manager shall additionally fallon 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 TechnicalOfficer 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 tospecial controls in the form and conditions established by the corresponding regulations. SECTION 7 OUTSOURCINGARTICLE 161 - The holders of a sanitary registration may outsource services including but not 54
  • 55. limited to manufacturing, packaging and specific quality control tests to a pharmaceuticallaboratory provided that it has been agreed in writing and authorized in the correspondingsanitary registration or its subsequent amendments.ARTICLE 162 - The manufacturing or packaging agreement relating to pharmaceutical products inany stage of production shall be required to include the technical aspects of said stage inaccordance with Good Manufacturing Practices.ARTICLE 163 - Reference shall be made in the quality control agreement to the requested actionsconsidering the requirements set out in GLP standards.In addition, the contracting party shall undertake to provide all the relevant information needed toperform the corresponding analysis in accordance with GLP standards and pursuant to thespecifications in the sanitary registration.ARTICLE 164- In any case, any party engaging in activities pursuant to an agreement shall berequired to comply with the same requirements and conditions set out for those activities andbear the same responsibilities for them as provided for hereunder. SECTION 8 SPECIAL MANUFACTURING FACILITIESARTICLE 165 - The manufacture of phytopharmaceutical and homeopathic products as well asthose described in article 17 herein shall be required to meet the needs of their manufacturingprocesses pursuant to Good Manufacturing Practices or in accordance with standards approved byorder of the Ministry issued at the request of the Institute.ARTICLE 166 - Facilities manufacturing traditional herbal medicines shall be exempt from theregulations under this section and shall be licensed and supervised by the corresponding RegionalMinisterial Department within the scope of its competence. The technical standards setting therequirements for facilities storing, fractionating, packaging or performing other activities relatedto the manufacture of traditional herbal medicines by hand shall be required to be approved byorder of the Ministry. SECTION 9 TERM, CANCELLATION AND SUSPENSION OF THE OPERATING LICENSEARTICLE 167 - The operating licence for a pharmaceutical laboratory shall be valid for a three-yearterm from the date of grant and may be automatically renewed for successive and equal termswhile not giving grounds for cancellation as provided for herein and as long as manufacturingspecifications from GMP and GLP standards have been observed.For these purposes, the Institute may inspect and monitor operating conditions at pharmaceuticallaboratories to enforce compliance with current regulations. 55
  • 56. ARTICLE 168 - The operating licence of a pharmaceutical laboratory may be cancelled by asubstantiated 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 apharmaceutical laboratory may also be cancelled on the basis of the outcome of a preliminaryinvestigation, 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 thefollowing 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 conditionsand 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 temporaryor permanent closure of the laboratory. In the event of the temporary closure exceeding 6 monthsor involving remodelling of the premises, the facilities or a change in the line of business, anauthorization shall be required to resume activities. CHAPTER VII QUALITY 56
  • 57. SECTION 1 GENERAL PROVISIONSARTICLE 173 - Any manufactured or imported pharmaceutical product shall be subjected to qualitycontrol, 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 manufacturingpharmaceutical products shall be required to implement a quality control system to ensurecompliance with manufacturing, raw material and finished product specifications by means ofrelevant testing.Individuals or legal entities importing pharmaceutical products in any stage of production shallalso be required to comply with this requirement, as appropriate.In addition, individuals or legal entities importing raw materials for the manufacture ofpharmaceutical 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 themanufacture of pharmaceutical products, whether domestic or foreign, conforms to qualityassurance standards, in the sense that the analysis and manufacturing methods have beenvalidated and are conducive to obtaining products that meet quality requirements set forth in thecorresponding sanitary registration pursuant to general GMP and GLP guidelines.Notwithstanding the above, a compliance schedule may be accepted for the validation ofmanufacturing processes.ARTICLE 176 - By means of a substantiated decision, the Institute may suspend the distribution ofa pharmaceutical product failing to observe the provisions of the preceding article. In this case, theholder may make any adjustments as necessary to ensure that processes are validated, in order torestore the authorization upon prior resolution by the Institute.ARTICLE 177 - Any individual or legal entity authorized to use a pharmaceutical producttemporarily without prior registration in accordance with the provisions of article 21.a and 21.bherein shall be required to have appropriate instruments to guarantee the quality of the productand to perform quality control tests as established in the resolution authorizing the use of saidproduct. SECTION 2 QUALITY REQUIREMENTSARTICLE 178 - The quality requirements of pharmaceutical drugs shall be set out in the productspecifications, while the control methods shall be those approved in the corresponding sanitaryregistration as granted or subsequently amended. 57
  • 58. ARTICLE 179 - The quality requirements for raw materials intended for the manufacture ofpharmaceutical products shall be set out in the specifications of the sanitary registration, while themanufacturing pharmaceutical laboratory shall be responsible for compliance with quality controland other requirements prior to distribution of the product.Any changes in the manufacturer of the active ingredients made after the granting of the sanitaryregistration shall be required to be reported to the Institute providing information as necessary toshow 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 thespecifications set out in the granted registration, for which additional information may berequired. SECTION 3 BATCH CONTROLARTICLE 180 - Without prejudice to general provisions on quality control set out hereinbefore, theInstitute 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 justifiedreasons.ARTICLE 181 - For the purposes of batch controls, the Institute of Public Health shall require theperformance of all or some of the tests and assays included in the specifications of the finishedproduct as authorized in the corresponding sanitary registration, determining the frequency foreach product.ARTICLE 182- The approval of a batch or sub-batch does not release the holder of the registrationfrom the obligation to perform quality controls as provided for hereunder and set out insupplementary 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 completelyfinished batch or sub-batch identified with a different alphanumeric code each time thecorresponding 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. 58
  • 59. ARTÍCULO 185- For the purposes of batch control procedures, the Institute shall be required tocollect two samples, one of which shall be sealed and registered at the sampling premises underthe responsibility of the Chief Technical Officer. The size of each sample shall be required to besufficient for performing two full tests pursuant to the specifications of the finished product asauthorized in the corresponding sanitary registration, while the sampling procedure shall bedetermined by the Institute by means of a resolution.ARTICLE 186 - A batch or sub-batch subjected to control shall be required to be approved orrejected 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 periodindicated in the preceding paragraph.Upon rejection of the batch, the manufacturer or importer shall be required to destroy theproduct immediately at authorized premises in the presence of a Chief Technical Officer and acertifying officer appointed by the Institute, who shall properly record the procedure in writing.Under exceptional circumstances, the Institute may authorize the reprocessing of rejectedproducts upon request of the applicant, in which case the conditions for reprocessing the productsshall be set out in the corresponding resolution. SECTION 4 QUALITY AND BATCH CONTROL EXEMPTIONSARTICLE 187 - Upon reasonable request of the holder of the registration, the Institute maypartially or totally exempt imported finished products from quality and/or batch controls if theholder 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 aboutthe validation of analytical methods used for batch release in the country of manufacture, ananalysis report from the country of origin, and proof that the cold chain has been maintained, ifapplicable.ARTICLE 188 - The decision granting or refusing the exemption shall be required to bejustified. If granting the exemption, the decision shall be required to indicate the followinginformation: 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 59
  • 60. 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 toperform two full tests of the products pursuant to the specifications authorized in thecorresponding sanitary registration, said samples being conveniently labelled and kept under thecustody of the Chief Technical Officer of the same pharmaceutical laboratory or of the laboratoryproviding outsourced services by virtue of the corresponding agreement.Counter samples and supporting documentation shall be required to be kept for one year after theproduct expiry date. SECTION 6 QUALITY SUPERVISIONARTICLE 190 - The Institute of Public Health shall be the health authority responsible formonitoring the quality of pharmaceutical products by performing shelf controls or other onsitesurveillance activities at manufacturing and packaging laboratories, distributors, retailers, andhealth care facilities.These activities may include bioavailability studies and others aimed at showing therapeuticequivalence pursuant to the provisions of Chapter X herein.ARTICLE 191 - Any defects or complaints about the quality of the pharmaceutical products shall berequired to be notified to the Institute, which upon assessment thereof shall take any necessarymeasures as appropriate.In the event of the this failure arising from storage conditions or distribution throughpharmaceutical wholesalers or retailers, the records shall be required to be submitted to thecorresponding Regional Health Departments to attribute any relevant responsibilities by means ofa preliminary investigation.ARTICLE 192 - In the case of importers of foreign-made finished, semi-finished, mass produced orsemi-manufactured products, the Institute shall be required to oversee compliance of the foreignmanufacturing laboratory with Good Manufacturing Practices according to the correspondingproduction lines. For the foregoing purposes, the Institute may hire foreign consultants andoutsource services or enter into agreements with national and foreign public or private entities asnecessary, pursuant to required quality standards.ARTICLE 193 - Notwithstanding the foregoing, the Institute may accept internationalaccreditations and certifications for pharmaceutical drugs and manufacturing facilities insofar asthe production and quality control standards enforced by the authority of the manufacturingcountry have been declared to be equivalent to Chilean standards by resolution of the Ministry ofHealth or are the subject of international treaties.In the event of such standards not being equivalent, the Institute shall be required to proceed inthe manner described in the preceding article at the cost of the applicant or holder of the sanitaryregistration as appropriate. 60
  • 61. ARTICLE 194 - In the event that upon conducting the corresponding preliminary investigationthere is evidence of quality failures in three or more batches of pharmaceutical products from thesame production line of a particular manufacturing laboratory, the Institute shall be required toamend the sanitary registration, excluding the production line corresponding to faulty products orsuspending the importation and distribution authorized in the sanitary registration of anypharmaceutical drug whose licensed manufacturer includes said production line. CHAPTER 8 DISTRIBUTIONARTICLE 195 - Products shall be required to be distributed by manufacturing and fittingpharmaceutical laboratories, pharmaceutical wholesalers and stores for pharmaceutical productsfor human consumption and dental care, under the conditions set out in the correspondingsanitary 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 theconditions set out in the corresponding regulations.Pharmaceutical laboratories and wholesalers may sell imported or manufactured products inseparate facilities within their premises specially intended for such purposes, under the conditionsof sale authorized in the relevant sanitary registration. These facilities shall be required to operateunder the supervision of the Chief Technical Officer or an appointed professional pharmaceuticalchemist. Such areas shall be required to be authorized in terms of location and operation by theInstitute or the corresponding Regional Health Department respectively.Additionally, these establishments may sell such products to the public under the authorizedconditions of sale and in separate premises supervised by a professional pharmaceutical chemistupon being authorized by the corresponding Regional Health Department.ARTICLE 197 - Retail conditions for a pharmaceutical drug shall be required to be indicated in thecorresponding sanitary registration or resolution in the case of authorizations for use without priorsanitary registration, considering in both cases the therapeutic indications and the authorizedusage 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 orsupplying the drug, which may not be distributed for free on any site, by any means or under anypretext or condition whatsoever.The provisions of the foregoing paragraph shall not apply to units such as medical samples directlyand exclusively distributed to legally qualified prescribing professionals in their offices or atscientific meetings, and said products shall be required to be dispensed directly by the healthcareprofessional to the patient. 61
  • 62. Notwithstanding the above, pharmaceutical drugs and products mentioned in article 21.a may bedonated to public and private healthcare facilities within at least one year prior to their expirydate or six months in the case of products under article 21.a, upon prior authorization by theInstitute, and said drugs or products shall bear on their package or container a caption referring totheir free distribution, and shall be required to be dispensed to patients under the sameconditions.The facilities receiving the donation shall be required to give the products for free. CHAPTER 9 ADVERTISING AND INFORMATION SECTION 1 GENERAL PROVISIONSARTICLE 199 - Advertising materials and healthcare professional and patient information aboutpharmaceutical drugs shall be governed by the provisions of this Chapter, wherein the definitionsbelow 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. 62
  • 63. ARTICLE 200 - Pharmaceutical drugs sold directly to the public may be advertised without priorauthorization from the Institute, and the advertisements shall be required to display totally orpartially the exact contents as authorized in the patient information leaflets and labels approved inthe corresponding registration.Advertising materials may only relate to therapeutic recommendations approved by the Institutein 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 uponpreviously conducting a preliminary investigation.ARTICLE 201 - Pharmaceutical drugs sold under simple, withheld or official prescriptions may notbe advertised.However, such drugs may be introduced to professionals qualified for prescribing and dispensingthem without prior authorization from of the Institute, through advertisements exclusivelyintended 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 orimporter, 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 inarticle 198 herein.ARTICLE 203 - Based on a justified decision, the Institute may suspend or prohibit the disclosure ofadvertisements or healthcare professional information of pharmaceutical products that do notcomply with the provisions hereunder, without prejudice to conducting a preliminary investigationas appropriate.For these purposes, the Institute shall require advertising texts and information on such productsfrom the concerned party.ARTICLE 204 - In the event that the information intended for professionals does not conform tothe authorized registration, the Institute may issue a decision suspending the sanitary registrationand additionally demand the withdrawal of all leaflets.ARTICLE 205 - The holder of the registration may request the amendment of healthcareprofessional and patient information leaflets, which shall be accepted or rejected by the Instituteon the basis of a substantiated decision. Additionally, the Institute may also introduceamendments to the authorized leaflets on the basis of a substantiated decision and upon givingprior 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 andretailers advertising a particular product or performing activities aimed at providing prescribingprofessionals with information on such product on their own or through third parties without 63
  • 64. complying with the provisions hereunder shall be subject to the corresponding penalties uponpreviously conducting the relevant preliminary investigation.ARTICLE 207 - It is forbidden for publications, films, broadcasts or other audiovisual advertisingsystems to promote medicinal products or drugs offering medical benefits which have not beenpreviously authorized or recognized as such by the relevant authorities.Health authorities may immediately request that such activities be stopped pursuant to theprovisions of article 178 of the Sanitary Code, without prejudice to any liabilities for which theoffender may be accountable as determined in the corresponding preliminary investigation. SECTION 2 HEALTHCARE PROFESSIONAL INFORMATIONARTICLE 208 - Information for professionals dealing with pharmaceutical drugs sold under simpleprescriptions shall be required to be directed solely to legally authorized prescribing professionalsand 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 andproperties of the drug and the contents of the healthcare professional information leaflet asauthorized 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, andtoxicity 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 pharmaceuticalproduct without alterations, distortions or any other additional words or expressions.ARTICLE 210 - The healthcare professional information leaflet shall be required to includeinformation 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 shallbe required to be properly identified and faithfully transcribed. Such tests and studies shall berequired to be available for healthcare professionals upon request, if applicable.Studies that bear no relation to the concerned pharmaceutical drug may not be claimed asreferring to such drug. Reference shall be made clearly and visibly to the relevant literature andsource of reference if charts, tables or references of the product are used, including the name ofthe product and the holder of the registration.ARTICLE 212 - General characteristics shared by several products may not be attributed exclusivelyto a particular product. Comparisons with other registered drugs comprising the same activeingredient shall be required to be demonstrated by relevant studies. 64
  • 65. Any scientific information not included in the corresponding sanitary registration concerningtherapeutic indications and dosages other than those authorized in said registration may besupplied to legally qualified prescribing healthcare professionals, indicating the status of suchinformation, 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 aproduct over another. SECTION 3 ADVERTISING IN PHARMACEUTICAL FACILITIESARTICLE 214 - Only pharmaceutical drugs under direct conditions of sale may be advertised inmanufacturing and distribution facilities indicating their authorized name, package and sign of themanufacturer, if applicable.Notwithstanding the above, vending companies shall be able to inform about the price ofpharmaceutical products, regardless of their condition of sale, by displaying their labels in thepremises of sale. These provisions shall not apply for products subject to special controls, such aspsychotropic and narcotic drugs.ARTICLE 215 - In the aforementioned premises, it is forbidden to use advertising procedures suchas contests, raffles, sample donation or others that could lead to the purchase, use or selection ofmedicines and encourage consumption, misuse or self-medication. In addition, the sale ofpharmaceutical products may not be encouraged by giving incentives in any shape or form topharmacy staff. SECTION X SANITARY SURVEILLANCE SECTION 1 PHARMACOVIGILANCEARTICLE 216 - The Institute shall be the health authority responsible for monitoring the safety ofregistered pharmaceutical drugs or unregistered products that have been approved for use intemporary or scientific research.ARTICLE 217 - Healthcare professionals are required to inform the Institute about any noticeablesigns 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 sameobligation and keep an updated record of these events. 65
  • 66. The information referred to in this article shall be supplied on forms intended for these purposesas 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 72hours 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 andmaintain a pharmacovigilance system of their own or by contract from an outside supplier, whiletheir 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 measuresfor the pharmacovigilance of certain products.ARTICLE 219 - Holders of sanitary registrations of pharmaceutical drugs shall be required to haveupdated 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, ifapplicable, request studies as necessary to evaluate the safety of a pharmaceutical drug under theauthorized conditions of use. Additionally, the Institute may recommend any necessary measuresto minimize the risks associated with the use of pharmaceutical products and to maintain a properrisk-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 bedisclosed by any media. SECTION 2 THERAPEUTIC EQUIVALENCEARTICLE 221 - At the proposal of the Institute, the Ministry shall be required to pass a resolutioncontaining lists of active ingredients in pharmaceutical products that require proof of therapeuticequivalence and the list of pharmaceutical products used as reference standards.Also by resolution, the Ministry shall be required to adopt the criteria for determining whichpharmaceutical products require proof of therapeutic equivalence. 66
  • 67. The regulations and other procedures for conducting bioavailability and therapeutic equivalencetests where appropriate shall be required to be set out by a resolution of the Ministry at theproposal of the Institute. SECTION XI PROCEDURE, PENALTIES AND REMEDIESARTICLE 222 - The administrative procedures, notifications and calculation of time periods inconnection with the enforcement of these regulations shall be governed by the provisions of lawno. 19,880 on the basis of administrative procedures concerning the acts of State administrationbodies.ARTICLE 223 - The infringement of the provisions hereunder shall give rise to penalties imposed bythe Institute upon a prior preliminary investigation pursuant to these regulations and inaccordance with the provisions set forth in Chapter X of the Sanitary Code and othersupplementary sanitary legislation.Appeals against the penalties imposed hereunder may be filed with the corresponding court in themanner prescribed in article 171 of the Sanitary Code.Penalties arising from the infringement of provisions enforced by Regional Health Departmentsshall be imposed by said departments pursuant to the preceding paragraphs.ARTICLE 224 - In its capacity as a sanitary supervisory body, the Institute may reasonably adoptemergency measures without conducting a previous preliminary investigation. These measuresmay be taken by certifying officers appointed by the Institute solely on the basis of a writtenstatement issued by them upon the existence of an imminent risk to health. Regional HealthDepartments or their certifying officers shall have the same powers with respect to regulationsspecifically enforced by them.ARTICLE 225 - Except as provided for in the second paragraph of article 223, an appeal may belodged with the Ministry of Health against the acts and decisions of the Director of the Institute inthe performance of his duties in connection with these regulations within five working days fromthe date of notification of the corresponding decision.Should the concerned party require more time to furnish further evidence to support their claim, arequest shall be filed with the Ministry of Health, which shall be required to issue a decision on thematter.Upon filing of the appeal, the Ministry shall require the relevant information from the Instituteand issue a decision within ten days of receipt of such information, unless more time is requiredfrom a technical point of view.If an appeal is filed with the Institute, the claims under the provisions of this article may bebrought subsidiarily within the same period. In this case, the decision reversing a verdict shall bedeemed as a report for purposes stated in the preceding paragraph. 67
  • 68. FINAL SECTION TERMARTICLE 226 - These regulations shall come into force 6 months after publication in the OfficialGazette, 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 uponpublication in the Official Gazette. PROVISIONAL ARTICLES FIRST PROVISIONAL ARTICLE: Sanitary registrationsSanitary registrations granted under the provisions of resolution no. 1876 of 1995 by the Ministryof Health shall remain in force and effect. However, by means of a substantiated decision, theInstitute of Public Health may require information as deemed necessary to update sanitaryregistrations in compliance with the provisions hereunder within a given period of not less thanone year. Compliance with the provisions hereunder in connection with the labelling ofpharmaceutical products shall be monitored as from one year after such provisions have comeinto force.Sanitary registration applications that are pending upon these regulations coming into force shallbe required to be withdrawn within 30 days and may be filed again within 5 months without priorpayment 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 permitsSanitary permits granted under the provisions of resolution no. 1876 of 1995 by the Ministry ofHealth shall remain in force and effect. However, authorized pharmaceutical laboratories shall berequired 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 intoforce shall be required to be withdrawn within 30 days and may be filed again within 5 monthswithout prior payment of fees and in compliance with the requirements and formalities set outherein. Applications that are not withdrawn within the prescribed period shall be rejectedoutright. 68