1. REFERENCE DOCUMENTATION. INDUSTRIAL DRUGS TECHNOLOGY ACCORDING GMP. MATERIAL BALANCE. Lecture 1

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

3. 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.

4. 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.

5. 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.

6. The focus of Good Manufacturing Practice for all products is on a quality control unit that has the responsibility and authority to approve or reject all components, drug product containers, closures, in process materials, finished product, and production and control documentation. ‘‘Quality Control Unit’’ refers to any person or organizational element designated by the firm to be responsible for the duties relating to quality control.

7. 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. These requirements apply to human and animal drugs.

8. 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.

9. 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.

10. CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURES This section of GMP relates to the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures, and the requirements for written procedures for each. It also covers the use of approved materials, retesting of approved material, and prevention of use of rejected materials.

11. GMP also requires the use of oldest approved stock first, retesting of approved stock ‘‘as appropriate,’’ and controls for drug product containers and closures. It prohibits use of rejected components and drug product containers and closures. PRODUCTION AND PROCESS CONTROLS

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

13. 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).

14. 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)

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

16. 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

17. 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.

18. 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.

19. 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.

20. Production process of pharmaceuticals is guided by production rules - the manufacturing and technical ones. 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.

21. 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.

22. 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.

23. 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

24. Tables of Material balance of the stage TP 2. “Obtaining of the granules" Name of starting materials & intermediates Content of the basis substance, % mass. Input and output Mass, kgVolume L Number, p Genera l Basis substan ce kg- mol 1234567 Input on the stage TP 2. “ Obtaining of the granules ”: Raw material: Analginum 5,26 Lactosae 25,78 Starch 3,75 Cellulose microcrystality 16,66 Total:52,31

25. Tables of Material balance of the stage TP 2. “Obtaining of the granules" Name of starting materials & intermediates Content of the basis substanc e, % mass. Input and output Mass, kgVolume L Number, p GeneralBasis substance kg- mol Input on the stage TP 2. “Obtaining of the granules”: Intermediate product: Granules including:45,41 Analginum4,0 Lactose22,522,5 Starch3, 5 Cellulose microcrystal15,0 Losess including:6,9 Analginum1.26 Lactose3,28 Starch0,7 Cellulose microcrystal1,66 Total:52,31

26. 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 of the batch

27. Several parameters are used for characteristic of manufacturing process. They are calculated from material balance: 1. output of product ( ,%) 2. losses ( ,%) 3. factor of account (or input-output characteristic - K) (Fa)

28. Account parameters of material balance 1. Output of product ( ,%) - product yield η = m fp /m rm *100 % 2. Production loss ( ,%) ε = m l /m rm* 100 % 3. Factor of account ( consumption factor – F (K) F = m rm /m fp

29. Process flowsheet (flowchart) - a sequence and description of all stages pharmaceutical preparations production. Flowcharts are used in analyzing, designing, documenting or managing a process or program in various fields. 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.

30. 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.

31. 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.

32. Data flows are not typically represented in a flowchart, in contrast with data flow diagrams; rather, they are implied by the sequencing of operations. The most common type of boxes in a flowchart is processing step, usually called activity, and denoted as a rectangular box;

33. 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.

34. 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. Generic processing steps Represented as rectangles.

35. Flowchart of tablet production

36. Thank you for your attention