Chile ds 03 eng

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Chile ds 03 eng

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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