Tuesday, September 19, 2017 OFFICIAL GAZETTE (Third Section) THIRD SECTION GENERAL HEALTH COUNCIL DECISION that determines the type of test to demonstrate the interchangeability of generic drug products and that defines the criteria that are applicable to them. At the margin a seal with the United Mexican States Coat of Arms, which says: United Mexican States.- General Health Council. JESUS ANCER RODRIGUEZ, Secretary of the General Health Council and JULIO SALVADOR SANCHEZ Y TEPOZ, Federal Commissioner for the Protection Against Sanitary Risks, pursuant to articles 3 section XXII, 13 paragraph A section II, 15, 17 sections IV and IX, 17 bis sections II, IV and XIII, 17 bis 2, 368 and 376 of the General Health Act; 2, section XIV, 72, 73, 167, section V and 190 bis 1, section III of the Health Supplies Regulation; 1, 9 sections II and IV of the General Health Council Internal Regulations; 1 and 3 section I, subsection b, 5 and 10 sections IV, VIII, X, XV and XXV of the Federal Commission for the Protection Against Sanitary Risks Regulations, and WHEREAS That, in accordance with article 73 of the Health Supplies Regulation, the General Health Council and the Ministry, through publication in the Federal Official Gazette, will determine the interchangeability tests that must be conducted according to the corresponding regulations. That, based on the foregoing, the Ministry and the Council determined in 2,440 drug products, the tests that must be carried out on them to be considered as generic drug products. That, in order to attest the interchangeability of the drug products stated above, they determined that the tests that must be carried out on them are those of dissolution profile or bio-equivalence profile, pursuant to the criteria set forth herein. That, the following criteria were taken into account to determine the type of test that corresponds to each drug product: dosage form, narrow therapeutic range and critical dose, therapeutic group, pharmacokinetic and physical and chemical characteristics. That, pursuant to the foregoing, and upon preparing the list of the drug products and of the interchangeability tests that must be carried out on each drug product, the authorities referred to above see fit to publish the following: DECISION THAT DETERMINES THE TYPE OF TEST TO DEMONSTRATE THE INTERCHANGEABILITY OF GENERIC DRUG PRODUCTS AND THAT DEFINES THE CRITERIA THAT ARE APPLICABLE TO THEM ARTICLE ONE. Criteria to determine the type of interchangeability test to consider a drug product as a generic drug product. I. The drug products that do not require to be tested for dissolution or bio-equivalence, are: a. Non-liposomal parenteral aqueous solutions, oral solutions and solutions to be inhaled with a nebulizer. b. Gases. c. Non-systemic use drug products whose administration route is ophthalmic, otic, nasal, oral, topical, rectal and vaginal and whose absorption does not pose any risks based on the analysis and research carried out by the Expert Group on Interchangeability Tests of the General Health Council. In the drug product list set forth in Article Two of this Decision, the interchangeability test referred to in subsection (i) is identified with the letter “A”. II. The oral solid drug products that fail to comply with the criteria set out in section I and section III of this decision must undergo a dissolution profile test to demonstrate the interchangeability. The conditions for the dissolution profiles test must be those set forth in the FEUM and its current supplements. When the information is not available therein, other countries’ pharmacopoeias, whose analytical procedures are carried out in accordance with the specifications set forth by specialized agencies and, ultimately, other internationally-recognized scientific literature, may be used. This is a non-official English translation prepared by Servicios Lingüísticos Metáfrasi. For all official purposes, the original Spanish translation, which can be found at www.dof.gob.mx, must be referred to. For information about our translation services, please contact [email protected] (Third Section) OFFICIAL GAZETTE Tuesday, September 19, 2017 When the dissolution profiles are not satisfactory, the gold standard bio-equivalence test or the clinical studies that demonstrate the safety and the efficacy of the product can always be carried out. In the drug product list set forth in article two of this Decision, the interchangeability test referred to in subsection (II) is identified with the letter "B" and in some special cases with the letter B*** three pH conditions ((HCl 0.1N, 1.2), 4.5 and 6.8)) based on the analysis and research of the Expert Group on Interchangeability Tests of the General Health Council. III. The following criteria must be followed to determine if bio-equivalence tests must be carried out on a drug product: CRITERION 1: DOSAGE FORM i. All immediate-release oral dosage forms with systemic action. ii. All the modified-release dosage forms. iii. All the non-oral dosage forms with systemic action (rectal, vaginal, transdermal). iv. Suspension and emulsion dosage forms. v. Drug products to be administered by inhalation of the measured dose and dry powder inhalers (see guide "Interchangeability of Drug Products Administered by Inhalation"). vi. Suspension dosage form for intramuscular administration. vii. Dosage forms with combination of drug substances that have systemic action with effect in the absorption process. CRITERION 2: NARROW THERAPEUTIC RANGE AND CRITICAL DOSE Based on the "Guidelines to Assess the Interchangeability of Drug Products that Have NTI-Drug Substances and Critical Dose": i. All NTI-drug substances, defined as such when a ratio between the lethal dose 50 (LD50) and the effective dose 50 (ED50) lower than 2 is found in the pre-clinical studies, or if unavailable, using the ratio between the toxic concentration 10 and the effective concentration 90, or else, the ratio between the toxic dose 10 and the effective dose 90. ii. Critical dose drug substances are those therapeutic agents where small modifications in the administered doses or small variations in the concentrations in the body may cause serious therapeutic failures or serious adverse reactions. CRITERION 3: THERAPEUTIC GROUP i. All drug products belonging to the following therapeutic groups due to the need to maintain stable plasmatic concentrations and used for the treatment of serious illnesses: 1. Antibiotics 2. Hormones 3. Antineoplastics (subject to case-by-case review; apply the "Guide for Interchangeability Studies of Cancer Drug Products") 4. Inotropic agents 5. Antiepileptic drugs 6. Immunosuppressants 7. Virustatic drugs 8. Hypoglycemic agents CRITERION 4: PHARMACOKINETICS i. Drug products with non-linear pharmacokinetics. ii. Drug products with erratic absorption, with systemic action. iii. Drug products that exhibit pre-systemic metabolism. iv. Drug products that lack information about their pharmacokinetics. v. Drug products associated to efflux transporters or processes in the absorption stage. CRITERION 5: PHYSICO-CHEMICAL Tuesday, September 19, 2017 OFFICIAL GAZETTE (Third Section) i. Drug substances with low solubility or dose-dependent solubility. ii. Drug substances with chemical polymorphism. All the drug substances that meet any of the previous assumptions must submit a bio-equivalence test. In the drug product list set forth in article two of this Decision, the interchangeability test referred to in subsection (III) is identified with the letter “C” and in some special cases with the letters C*, C**, C*** or C****. The attached diagram describes the decision sequence to assign the corresponding interchangeability test to a certain drug product (annex 1). If there is no sufficient information on a drug product, duly attested in the international literature, the bio- equivalence test must be carried in all the cases, even when it is not included in any of the previous assumptions. The tests to demonstrate the interchangeability of generic drug products must be carried out pursuant to the Mexican Official Standard NOM-177-SSA1-2013, Which sets forth the tests and procedures to demonstrate that a drug product is interchangeable. Requirements to be complied with by Authorized Third Parties that carry out interchangeability tests. Requirements to conduct bio-comparability studies. Requirements to be complied with by Authorized Third Parties, Research Centers or Hospital Institutions that carry out bio- comparability tests. ARTICLE TWO. The drug products listed below have been registered with the Ministry of Health and met the requirements set forth in section V of article 167 of the Decree that reforms, adds and repeals several provisions of the Health Supplies Regulations, and any of the criteria referred to above: Dosage form, Non-proprietary name Interchangeability test consideration of use ABACAVIR Oral solution A ABACAVIR Tablet C ABACAVIR / LAMIVUDINE Tablet C/C ABACAVIR / LAMIVUDINE / ZIDOVUDINE Tablet C/C/C ACAMPROSATE Coated tablet C ACARBOSE Tablet C* ACEBROPHYLLINE Capsule C ACEBROPHYLLINE Oral solution A ACECLOFENAC Cream A ACECLOFENAC Powder for suspension C ACECLOFENAC Solution for injection A ACECLOFENAC Tablet C SWEET ALMOND OIL Cream A SWEET ALMOND OIL / LANOLIN / GLYCERIN / Cream A/A/A/A/A PROPYLENE GLYCOL / SORBITOL CASTOR OIL Emulsion A MINERAL OIL Emulsion A ACEMETACIN Capsule C ACEMETACIN Extended-release capsule C ACENOCOUMAROL (ACENOCUMARIN) Tablet C ABIRATERONE ACETATE Tablet C BETAMETHASONE ACETATE / BETAMETHASONE Suspension