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Reference documentation and drugs production according GMP. Material balance. Lecture 1

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Plan 1. Feature of Industrial drugs technology. 2. Some aspects of creation and registration of medicines. 3. Reference documentation. 4. Structure of chemical-pharmaceutical enterprises. 5. Material balance.

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DRUGS TECHNOLOGY is one of the basic disciplines of pharmaceutical education, which main task is study of the theoretical bases of manufacturing processing of drugs formulation, their standardizing, storage and release.

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Features of Industrial drugs technology: 1. It is characterized by a high degree of development, as wide use machines, devices, mechanized and automated lines lays in its basis. 2. The work of the industrial enterprise is characterized by a strict regulation and planning of manufacture, as the processing of big amount of a material is carried out.

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Good Manufacturing Practices The Current Good Manufacturing Practice (cGMP) regulations for finished pharmaceuticals that have been promulgated by the EU. GMPs were intended to establish minimum manufacturing and control practices for the pharmaceutical industry and focus on what needed to be done rather than how it should be done.

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GMP requires that the buildings and facilities are adequate, provide specifically defined areas for certain operations and are designed to prevent mix-ups. Included are design and construction features; lighting; ventilation, air filtration, air heating and cooling; plumbing; sewage and refuse disposal; washing and toilet facilities; sanitation; and maintenance.

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GMP addresses equipment design, size, and location, as well as construction, cleaning and maintenance. Similar to the requirements for buildings and facilities, it is necessary to provide appropriate equipment for the manufacture of a product and ensure that the equipment material of construction is not reactive, additive, or absorptive.

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Registration of pharmaceutical preparations 1. Chemical-pharmaceutical company can produce medicine only after its state registration. 2. For registration the medicines manufacturer has got to submit the set of documents to the State Pharmacological Center. 3. Ministry of Health provides state registration of medicines on the basis of examination of registrations documents, which is submitted to the State Pharmacological Center. 4. Ministry of Health gives permission in the form of registration certificate on the 5 year.

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State registration of medicines - a procedure that is performed in accordance with current legislation in order to approve medical use of medicines.

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The Common Technical Document (CTD) is a set of specification for application dossier for the registration of Medicines and designed to be used across Europe, Japan and the United States. It was developed by the European Medicines Agency (Europe), the Food and Drug Administration and the Ministry of Health, Labour and Welfare (Japan). The CTD is maintained by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

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The Common Technical Document is divided into five modules: 1. Administrative and prescribing information 2. Overview and summary of modules 3 to 5 3. Quality (pharmaceutical documentation) 4. Safety (toxicology studies) 5. Efficacy (clinical studies)

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Documents for state registration of the medicines 1. Statement 2. CTD 3. Proof of payment for registration fee

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Information which is present in statement Name and address of manufacturer Dosage Name (and trade name) of medicines Conditions of release Name of active substance and its synonyms Methods of application Dosage formTerm and storage conditions Full composition of preparation Information about packing Medical evidence and Contraindications Data about registration in other countries

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Reference documentation is any document establishing rules, general principles or characteristics concerning different kinds of activity or its results. They should provide quality and efficiency of medical products on the basis of science and technology advances. There are uniform requirements for design, order of development, coordination and establishing of the reference documents for pharmaceuticals, medical goods, veterinary production and nutrients manufactured on chemical and pharmaceutical enterprises.

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The reference documents are subdivided into the following categories: 1. Manufacturing and technical rules; 2. State pharmacopoeia (SF); 3. Monographs; 4. Analytical reference documentation (ARD); 5. State standards (StSt); 6. Branch standards (BST); 7. Specifications; 8. Guideline documents - manuals, methodical instructions, etc.; 9. Operating instructions.

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Monograph or Analytical reference documentation is a reference document establishing the requirements for quality monitoring of a drug product, its packing, storage conditions and shelf-life. Monographs or ARD are adopted for any pharmaceutical or crude drug, allowed for medical use and industrial manufacturing by Ministry of Health.

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Manufacturing rules - the reference document describing the consequence of all operating procedures and used equipment, establishing all manufacturing parameters and sites of quality monitoring and containing specifications on starting materials, intermediates and final products. Production process of pharmaceuticals is guided by production rules - the manufacturing and technical ones.

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The sections of MR : 1. The characteristic of a finished product. 2. Manufacturing flowchart and operation process: The flowchart of manufacture; The characteristics of starting material, materials and intermediates; The description of operation stages; Material balance. 3. In-process control. 4. Appendices: The list of technological instructions. The list of report blanks.

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Technical rules represent the reference document establishing the conditions providing an appropriate quality of medical products with respect to a particular complex of the process equipment. Technical rules cover preparing of laboratory, pilot and manufacturing premises and the personnel for work; sanitary-and-hygienic conditioning of manufacture; the requirements for occupational safety, safety precautions, fire safety, environment control; equipment operation etc. Requirements of the given rules guarantee quality of released production, rational carrying out of technical processes, preservation of the equipment, exception of an opportunity of occurrence of failures and environmental contaminations.

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Material balance (mass balance) is a ratio between starting materials and obtained ones as the result of manufacturing process. It allows to compare theoretically possible and actual yields of final goods. In absence of rejects and by-products the material balance equation is simplified as: m raw materials = m finish product + m losses

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InputOutput Name of starting materials & intermediates Amount, kg Name of medicines & waste materials and losses Amount, kg Paracetamol200,00Tablets of Paracetamol1200,0 Lactose389,48Losses, including: Starch707,00Paracetamol50 Magnium stearat32,50Lactose30 Aerosyl10,00Starch15 Magnium stearat 13 Aerosyl12 Total:1339,00Total:1339,00 Tables of Material balance

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Several parameters are used for characterization of technological process, which are calculated from material balance: 1. output of product ( ,%) 2. losses ( ,%) 3. factor of account (or input-output characteristic - K) - Fa

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Formulas for parameters of material balance 1. Output of product ( ,%) - product yield = (m fp /m rm) *100 % 2. Production loss ( ,%) = (m l /m rm)* 100 % 3. Factor of account ( consumption factor ) Fa = (m rm /m fp)

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Technological flowchart Process flowsheet (flowchart) - a sequence and description of all stages in manufacturing of a product.

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A flowchart is a type of diagram that represents an algorithm or process, showing the steps as boxes of various kinds, and their order by connecting these with arrows; This diagrammatic representation can give a step-by-step solution to a given problem; Data flows are not typically represented in a flowchart, in contrast with data flow diagrams; rather, they are implied by the sequencing of operations.

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Flowcharts are used in designing and documenting complex processes. Like other types of diagram, they help visualize what is going on and thereby help the viewer to understand a process, and perhaps also find flaws. Flowcharts are used in analyzing, designing, documenting or managing a process or program in various fields.

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The two most common types of boxes in a flowchart are: a processing step, usually called activity, and denoted as a rectangular box; a decision, usually denoted as a diamond.

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Common alternate names include: flowchart, process flowchart, functional flowchart, process map, process chart, functional process chart, business process model, process model, process flow diagram, work flow diagram, business flow diagram.

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Technological flowchart is the visual display of dosage production. Technological flowchart (Process flowsheet) - a sequence and description of all stages in manufacturing of a product.

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Arrows Showing "flow of control". An arrow coming from one symbol and ending at another symbol represents that control passes to the symbol the arrow points to.

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Thank you for your attention