MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION
GENERAL MONOGRAPH
Содержание
Drug formulations GPM.1.4.1.0001.15
First introduced
In this General Monograph the list of drug formulations is considered, general requirements to their manufacturing, preparation, parameters and methods of quality evaluation are given.
MAIN TERMS AND DEFINITIONS
Medicinal products are substances or combinations thereof that come into contact with the human or animal body, penetrating organs, tissues of the human or animal body used for prophylaxis, diagnosis (except for substances or combinations thereof that do not contact the human or animal body), treatment of the disease, rehabilitation, for the maintenance, prevention or interruption of pregnancy, and derived from blood, blood plasma, from the organs, tissues of the human or animal body, plants, minerals by synthesis or biological technologies. Medicinal products include pharmaceutical substances and drugs.
Drug formulation is the state of a drug that corresponds to the methods of administration and use thereof, and ensures the achievement of the necessary therapeutic effect.
Drugs are medicinal products in a form of drug formulations, used for prevention, diagnosis, treatment of the disease, rehabilitation, for the maintenance, prevention or interruption of pregnancy.
Pharmaceutical substance is a medicinal product in the form of one or several pharmacological active ingredients, regardless of the nature of the origin, which is intended for manufacturing and preparation of drugs and determines their efficacy.
Excipients are substances of inorganic or organic origin, used in the process of the manufacturing and preparation of drugs for giving them the necessary physical and chemical characters.
The manufacturing of medicinal products is the activity of manufacturing medicinal products by manufacturers of medicinal products at one stage, several or all stages of the technological process, as well as storing and selling of manufactured medicinal products.
Preparation is the activity of preparing medicinal products by pharmaceutical companies, veterinary pharmacy organizations and individual entrepreneurs licensed for pharmaceutical activities, on prescriptions of drugs, according to the requirements of medical organizations, veterinary organizations, in conformity with the rules of preparation and release of drugs approved by an authorized federal executive body.
Stability is the ability of a medicinal product to maintain chemical, physical, microbiological, biopharmaceutical and pharmacological characters within certain limits throughout the shelf life.
The route of administration is a method of delivery of a medicinal product to the human or animal body.
CLASSIFICATION AND LIST OF DRUG FORMULATIONS All drug formulations can be hierarchically classified: by the aggregate state, type of disperse system, route of administration and type of release (classification is given in Table below).
Table – Classification of drug formulations
| Level | Classification characteristic | ||||
|---|---|---|---|---|---|
| 1 | Drug formulations by the aggregate state | ||||
| solid | liquid | soft | gaseous | ||
| 2 | Drug formulations by the type of disperse system | ||||
| homogeneous | heterogeneous | combined | |||
| 3 | Drug formulations by route of administration | ||||
| for
oral administration |
for
external administration |
for
topical administration |
for
parenteral administration |
||
| 4 | Drug formulations by the type of release | ||||
| immediate release | modified release | ||||
Solid drug formulations include tablets, capsules, powders granules, pills, lozenges, lyophilizates, implants, pencils, tampons, doses, films, etc.
Liquid drug formulations include solutions, drops, syrups, suspensions, emulsions, liquid extracts, tinctures, elixirs, concentrates, shampoos, infusions, decoctions, etc.
Soft drug formulations include ointments, creams, gels, liniments, pastes, suppositories, patches, chewing gums, etc.
Gaseous drug formulations include medical gases, aerosols, sprays, inhalation drug formulations, etc.
Drug formulations by the type of disperse system can be homogeneous, heterogeneous and combined.
Drug formulations by the route of administration can be for oral administration, external use, topical application and parenteral drug formulations.
Drug formulations by the type of release may have immediate and
modified release. Modified (non-standard) release may be sustained, continuous, pulsatile, delayed and rapid.
Assignment of drug formulations to a particular classification subgroup determines approaches to the evaluation of its quality.
Depending on the route of administration and prescription of the drug formulations, the tests demonstrating the features of a certain drug formulation, if necessary, are included in the list of tests of its quality.
GENERAL REQUIREMENTS TO MANUFACTURING AND PREPARATION OF DRUG FORMULATIONS
Manufacturing of medicinal products in various drug formulations should be implemented in conformity with the Rules of the organization of manufacturing and the quality control of medicinal products – Good Manufacturing Practice (GMP). GMP rules are applied to all types of medicinal products and establish general requirements for the organization of their manufacturing and quality control, as well as special requirements for the organization of manufacturing of certain types of medicinal products.
Preparation of medicinal products in various drug formulations must be implemented in conformity with the current requirements for the preparation of medicinal products in pharmacy organizations.
Non-sterile drug formulations are manufactured and prepared with the aid of materials and methods that prevent the contamination and growth of microorganisms and provide the conformity with the requirements of the GM “Microbiological purity”.
Sterile drug formulations (parenteral, ophthalmic drug formulations, as well as drug formulations for application to damaged skin and mucous membranes, drug formulations for newborns) are manufactured and prepared with the aid of materials and methods that prevent contamination and provide their sterility in conformity with the requirements of the GM “Sterility”.
QUALITY EVALUATION OF DRUG FORMULATIONS
Quality evaluation of drugs in various drug formulations is performed, as a rule, according to the attributes characterizing the particular drug formulation, as well as the attributes of the active ingredient/ingredients and, if necessary, the excipient/excipients of the given drug (“Identification”, “Quantification”, etc.).
The attributes that are mandatory for the quality evaluation of a drug regardless of the drug formulation include the “Description”, “Identification”, “Assay”, “Microbiological purity” (for non-sterile drug formulations) and “Sterility” (for sterile drug formulations).
Description. The given information most fully characterizes the requirements imposed on the appearance and organoleptic characteristics (color, odor) of the drug in the given drug formulation.
Identification. Conducted tests are determined by the composition of the drug:
by the active ingredients and, rarely the excipients (antimicrobial preservatives, antioxidants, stabilizers, etc.) included in the composition of the drug. A combination of physical and chemical (HPLC, GC, TLC, etc.), as well as chemical analysis methods is recommended for identification evaluation.
Assay. The given test as well as the identification, depends on the composition of the drug: the active ingredients and excipients. It is recommended to use physical and chemical (HPLC, spectrophotometry) and chemical methods of analysis (titrimetry) for assay, other pharmacopoeia methods of analysis may be used.
The content of the ingredients to be determined is expressed in mg or U in a single dose for metered-dose drug formulations or in 1 g of the drug for not metered-dose drug formulations, unless otherwise specified in the monograph or regulatory documentation.
When adding antimicrobial preservatives to drugs, the method of their determination and criteria for evaluating their efficacy should conform to the requirements of the GM “Determination of the efficacy of antimicrobial preservatives”.
Microbiological purity. It is under control in all non-sterile drug formulations in conformity with the requirements of the GM “Microbiological purity”.
Sterility. Drugs for use in open wounds or damaged skin, drug formulations for newborns, as well as parenteral and ophthalmic drug formulations must be sterile and tested in conformity with the requirements of the GM “Sterility”.
Attributes of the drug can be determined by the method of its manufacturing (for example, the use of organic solvents) and the characters of the active ingredient (the ability to form isomers, degradation impurity, etc.).
The content of residual organic solvents in the drug is evaluated in conformity with the requirements of the GM “Residual organic solvents”.
In case of the possible presence of impurities in the composition of the drug (for example, as a result of accumulation of impurities (products of destruction) during the drug storage) it is necessary to control their content by the parameter “Related impurities”.
Specified attributes can be identified for certain drug formulations.
Solid dosage formulations, transdermal patches, suppositories on a lipophilic basis, as a rule, are tested for the parameter “Dissolution”.
Evaluation of disinsertion may be provided for tablets, capsules, suppositories and vaginal tablets.
Powders are evaluated on the basis of the parameters “Particle size”, “Loss on drying”.
Drug formulations for parenteral use should meet the requirements for the content of bacterial endotoxins and/or pyrogens, visible and invisible particulate contamination.
Eye drops should meet the requirements of the content of visible particulate contamination.
A number of drug formulations are evaluated according to the attributes that are controlled at manufacturing site. For example, for tablets they are “Tablet friability” and “Tablet hardness” parameters, for sterile ointments it is “Packaging air-tightness” parameter, for powders the flow rate, the angle of natural slip, the settled volume and others are determined.
For liquid drug formulations such as solutions, in some cases, transparency, color, pH and osmolality are evaluated.
Aerosols and sprays are evaluated on the basis of the parameters such as “Packaging air-tightness”, “Packaging contents release” (for not metered-dose aerosols and sprays), “Uniformity of dosage mass” (for metered-dose aerosols and sprays), etc. For aerosols for inhalation, aerodynamic distribution of finely particles, respiratory fraction and others are evaluated.
Uniformity of weight. Dosage drug formulations, including in single dose individual packaging, should withstand the test of uniformity of mass for a drug formulation unit. The test is carried out in conformity with the GM “Uniformity of mass of metered-dose drug formulation”. If the content uniformity test is provided, the determination of uniformity of mass is not required.
Uniformity of dosage units. Dosage drug formulations, including in single dose individual packaging, must withstand the test of uniformity of dosage units in compliance with the GM “Uniformity of dosage units”, unless otherwise specified in the monograph or regulatory documentation.
Minimum fill. Tests are carried out for not metered-dose drug formulations in compliance with the GM “Minimum fill”, except for liquid drug formulations for parenteral and oral administration.
Extractable volume. The test is carried out for liquid drug formulations for oral administration in conformity with the requirements of the GM “Extractable volume”. Tests are not carried out for drug formulations in single-dose packaging, if the uniformity of dosage unit test is included in the monograph or regulatory documentation.
Extractable volume of drug formulations for parenteral administration. The drug formulations are tested
that are for parenteral administration in conformity with the requirements of the GM “Extractable volume of drug formulations for parenteral administration”.
PACKAGING
The packaging must provide the quality of the drug within the established shelf life in the declared storage requirements. Primary and secondary packaging materials must be allowed to produce this type of packaging, taking into account the route of administration of the drug formulation.
LABELLING
For metered-dose drug formulations the active ingredients and their quantity in the single dose of the drug are to be named, unless otherwise specified in the monograph or regulatory documentation. For not metered-dose drug formulations the active ingredients and their quantity in a certain volume (weight) of the drug are to be named. The active ingredients, their quantity and the list of all excipients are to be named for parenteral drug formulations, drug formulations for inhalations, drug formulations for external and (or) topical application, ophthalmic drug formulations. For drug formulations for infusions the active ingredients and excipients and their quantity are to be named.
STORAGE CONDITIONS
In accordance with the requirements of the GM “Storage of medicinal products”. The storage requirements must provide the stability of the drug throughout its established shelf life in the declared form of packaging.
SHELF LIFE
Shelf life of medicinal products in various drug formulations is established in conformity with the requirements of the GM “Shelf life of medicinal products”.