Attachment No. 15

to the Rules of Good Manufacturing Practice

QUALIFICATION AND VALIDATION

I. PRINCIPLE

1. This Attachment contains qualification and validation requirements applicable to the manufacture of medicines. To prove that the parameters of critical processes (equipment) comply with the set requirements, manufacturers shall perform validation of processes and equipment used for the manufacture of medicines. Validation shall be also performed in case of significant changes in premises, equipment and processes that may influence the quality of products. To determine the scope of validation works, it is necessary to use an approach based on the risk assessment.

II. VALIDATION PLANNING

2. All validation activities shall be planned. Key elements of the validation program shall be clearly defined and documented in the validation master plan or similar documents.

3. The validation master plan shall be a summary document prepared in a compact, clear and exact form.

4. The validation master plan shall contain the following information, without limitation:

а) (a) the purpose of the validation process;

b) (b) the validation organization plan;

c) (c) a list of all rooms, systems, equipment and processes subject to validation;

d) (d) documents represented by forms to be used for protocols and reports;

e) (e) planning and the work schedule;

f) (f) management of changes;

g) (g) references to corresponding documents.

5. In case of implementation of large projects it may be necessary to prepare separate validation master plans.

III. DOCUMENTS

6. It is necessary to develop a written protocol indicating how qualification and validation shall be performed. This protocol shall be checked and approved. The protocol shall indicate critical stages and acceptance criteria.

7. It is required to prepare a report with cross references to the qualification and (or) validation protocol summarizing obtained results, containing comments on any detected deviations and conclusions, including recommended changes necessary to correct deviations. Any changes introduced to the plan described in the protocol shall be documented with a corresponding justification.

8. After the qualification has been successfully completed, it is necessary to issue an official written permit to proceed to the following stage of qualification and validation.

IV. QUALIFICATION

Design qualification

9. The first element of validation of new premises, systems or equipment shall be the design qualification.

10. It is necessary to prove and document the compliance of the design with the requirements of these Rules.

Installation qualification

11. Installation qualification shall be performed for new or modified premises, systems and equipment.

12. Installation qualification shall include the following elements (without limitation):

а) (a) checking of compliance of the installation of the equipment, pipelines, auxiliary systems and devices with the approved design, including technical documents, drawings and specifications;

b) (b) assessment of the completeness and comparison of operation instructions of the supplier, and maintenance requirements;

c) (c) assessment of calibration requirements;

d) (d) checking of materials used in the design.

Operational qualification

13. Installation qualification shall be followed by operational qualification.

14. Operational qualification shall include the following elements (without limitation):

а) (a) tests based on the knowledge about processes, systems and equipment;

b) (b) tests of the equipment operation when performance parameters equal the upper or the lower thresholds, i.e. in the situation of the ‘worst case’.

15. Successful operational qualification shall contribute to the completion of instructions for calibration, use and cleaning, training of operators, as well as determination of requirements to preventive maintenance. Only after this operation the client shall accept premises, systems and equipment.

Performance qualification

16. Performance qualification shall be performed after successful installation qualification and operational qualification.

17. Performance qualification shall include the following elements (without limitation):

а) (a) tests with materials used in the manufacturing process, selected substitutes with similar properties or the model medicine developed on the basis of knowledge about the process, and technical facilities, systems or equipment;

b) (b) tests when performance parameters equal the upper or the lower thresholds.

18. Though performance qualification is deemed a separate stage of work, in some cases it may be reasonable to perform it together with operational qualification.

Qualification of installed (used) technical facilities, premises and equipment

19. It is necessary to have data justifying and proving the adherence of the critical performance parameters to the set requirements. The instructions for calibration, cleaning, preventive maintenance and operation, as well as training of operators and preparation of reports shall be documented.

V. PROCESS VALIDATION

General Requirements

20. Requirements and principles specified in this Attachment shall apply to the manufacture of pharmaceutical forms. They shall cover initial validation of new processes, subsequent validation of modified processed and re-validation.

21. Process validation shall be generally completed before the beginning of sale of medicines (prospective validation). In exceptional cases when such validation is impossible, it may be necessary to perform process validation in the course of current manufacturing activities (concurrent validation). Processes that have been carried out already for some time are also subject to validation (retrospective validation).

22. Used premises, system and equipment shall be qualified, and analytical testing methods shall be validated. The staff taking part in validation shall be properly trained.

23. It is required to conduct periodical assessment of premises, systems, equipment and processes to confirm that they operate in accordance with the set requirements.

Prospective validation

24. Prospective validation shall include the following elements (without limitation):

а) (a) a brief description of the process;

b) (b) a list of critical process stages subject to testing;

c) (c) a list of used premises and equipment (including measuring, monitoring and recording equipment) with their calibration information;

d) (d) specifications for finished products in case of release;

e) (e) a list of analytical methods, if necessary;

f) (f) suggested control points in the manufacturing process and acceptance criteria;

g) (g) if necessary, additional tests that shall be conducted, acceptance criteria and validation of analytical methods;

h) (h) the sampling plan;

i) (i) methods of registration and evaluation of results;

j (j) functions and duties;

k) (k) the suggested work schedule.

25. With the help of the set process (using component corresponding to specifications) it is possible to manufacture a number of batches of finished products under standard conditions. In theory, the number of completed production cycles and observations shall be sufficient to determine the usual degree of variation and trends, and to obtain the required amount of data for assessment. For process validation it shall be sufficient to manufacture three subsequent batches or perform three subsequent cycles, if the parameters stay within the set limits.

26. The batch size for validation shall equal the batch size for industrial production.

27. If it is expected to sell or deliver batches manufactured during validation, their manufacturing environment shall fully comply with the registration dossier and the requirements of these Rules, including satisfactory results of validation.

Concurrent validation

28. In exceptional cases it is allowed to start batch manufacturing before the validation program has been completed.

29. The decision on concurrent validation shall be well-grounded, documented and approved by the person having appropriate powers.

30. Requirements to documents for concurrent validation shall be the same as the requirements set for prospective validation.

Retrospective validation

31. Retrospective validation may be performed only for flawless processes. It is prohibited to perform retrospective validation if the product, the manufacturing process or the equipment have been recently modified.

32. Retrospective validation of the said processes shall be based on the previous data. In this case it is required to draw up a special protocol and report and to review the data on the preceding operation with provision of conclusions and recommendations.

33. The sources of data for such validation shall include (without limitation) records of the manufacture and packaging of batches of products, inspection sheets for manufacturing operations, maintenance logbook, data on change of the staff, tests of the process capability, data on finished products, including trend maps, and results of the study of their stability during storage.

34. Batches of products selected for retrospective validation shall constitute a representative sample for all batches manufactured during the studied period, including all batches that do not comply with the specifications. The quantity of batches of products shall be sufficient to prove the stability of the process. The retrospective validation of the process may require additional tests of retention samples to get the necessary amount or the necessary type of information.

35. To assess the stability of the process in case of retrospective validation it is necessary to analyse data for 10-30 successive batches, however if there are appropriate justifications, the number of studied batches may be reduced.

VI. CLEANING VALIDATION

36. Cleaning validation shall be performed to confirm the effectiveness of the cleaning procedure. The justification for selected limits of transferred remains of products, cleansers and microbial contamination shall be based on the properties of used materials. These limits shall be objectively attainable and testable.

37. It is necessary to use validated analytical procedures to detect remains or contaminants. The detection limit for each analytical procedure shall be sufficient to detect the set acceptable level of remains or contaminants.

38. As a rule, it is necessary to validate only cleaning procedures of the surface of equipment contacting the products. However it is required to pay attention also to the parts of the equipment that do not touch the products. It is necessary to validate the time intervals between the completion of a process and the cleaning operation, as well as between the cleaning operation and the beginning of the next process. It is required to define cleaning methods and time intervals between cleaning operations.

39. In case of cleaning procedures connected with very similar products and processes it is allowed to select a representative number of similar products and processes. In such cases it is possible to perform one validation study using the approach of the ‘worst case’ which takes into account all critical factors.

40. To validate a cleaning procedure it is sufficient to successfully conduct three consecutive cleaning cycles.

41. The method ‘test till clean’ shall not substitute validation of the cleaning procedure.

42. If removed substances are toxic or hazardous, as an exception, it is allowed to replace them by products simulating physical and chemical properties of such substances.

VII. MANAGEMENT OF CHANGES

43. The manufacturer shall approve procedures describing actions that shall be taken if it is expected to change the starting raw materials, product components, technical equipment, parameters of the manufacturing environment (or the site), the manufacturing method or the control method or to introduce any other change which may influence the quality of the products or the process repeatability. Procedures of management of changes shall ensure that a sufficient amount of data is obtained to confirm the fact that the changed process enables the manufacture of products of required quality pursuant to the approved specifications.

44. It is necessary to file applications in the framework of the pharmaceutical quality system for all changes which can influence the quality of products and the process repeatability. Such changes shall be documented and approved. It is required to assess the probable influence of changes in premises, systems and equipment on the products, including to conduct a risk analysis. The necessity and scope of re-qualification and re-validation shall be determined.

VIII. RE-VALIDATION

45. It is required to conduct periodical assessment of premises, systems, equipment and processes, including cleaning procedures, to confirm that they meet the set requirements. If there are no significant changes, it shall be sufficient to prepare instead of re-validation a report confirming that the premises, systems, equipment and processes meet the set requirements.

IX. TERMS AND DEFINITIONS

For purposes hereof, in addition to the terms and definitions stipulated in Chapter II of these Rules, the following basic terms are used:

risk analysis: a methods of assessment and description of critical parameters in case of operating equipment, systems or a performed process due to determined danger;

cleaning validation: a documented confirmation that the approved cleaning procedure ensures the level of cleanness of the equipment required for the manufacture of medicines;

process validation: a documented confirmation that the process performed within the set parameters is effective, repeatable and enables the manufacture of medicines corresponding to the specifications and quality characteristics set in advance;

installation qualification: a documented confirmation that premises, systems and equipment (installed or modified) have been assembled in accordance with the approved design and the recommendations of their manufacturer;

design qualification: a documented confirmation that the proposed design of manufacturing premises, equipment or systems is suitable for the intended purposes;

operational qualification: a documented confirmation that premises, systems and equipment (installed or modified) function according to the set requirements in all specified operating modes;

performance qualification: a documented confirmation that, when jointly used, premises, systems and equipment demonstrate effective performance with reproducible parameters according to approved requirements and process characteristics;

management of changes: a documented procedure according to which qualified representatives of different professions study proposed or already introduced changes that may influence the validated condition of the premises, equipment, systems or processes. The objective of such control is to determine the necessity of measures which shall ensure and prove in writing that the systems are kept in a validated condition;

modelling product: a material whose physical and, if possible, chemical properties (e.g. viscosity, particle size, pH) are similar to the product which is subject to validation. In most cases these characteristics may belong to a placebo batch (a product that contains no pharmaceutical substances);

the worst case: conditions or a set of conditions determined by standard operating procedures that are related to the upper and lower limits of performance parameters of the process and factors connected with them and define the maximum possibility of a failure in the process or defective products as compared to ideal conditions. These conditions do not always lead to a failure in the process or defective products;

prospective validation: validation completed before the beginning of batch manufacturing of products intended for sale;

re-validation: repeated validation of the process to guarantee that changes in the process and (or) equipment introduced in accordance with the procedure of management of changes do not affect the characteristics of the process or the quality of products;

retrospective validation: validation of the batch manufacturing process of sold products based on the collected data on the manufacturing process and monitoring of batches of products;

concurrent validation: validation performed in the course of current (batch) manufacturing of products intended for sale.