Types of Validation & its Aspects PPT.pptx

Types of validation used in pharmaceutical industry. it will help people to understand and develop understanding regarding validations used in industry.

1. Types of Validation & Its Aspects SABA ASIF

2. VALIDATION This term comes from the word “valid or validity” which means “legally defined” “The validation process is the documented evidence which provides a high degree of assurance that a process consistently produces a result or product meeting its predetermined specifications”.

3. Types of Validation There are four types of Validation: Analytical Method Validation Process Validation Cleaning Validation Equipment Validation

4. Type 1: Analytical Method Validation “Analytical method validation is the process of demonstrating that an analytical procedure is suitable for its intended purpose”. “The analytical procedure refers to the way of performing the analysis. It should describe in detail the steps necessary to perform each analytical test ”

5. Types of Analytical Procedures to be Validated The validation of analytical procedures is directed to the four most common types of analytical procedures: - Identification tests - Quantitative tests for impurities content - Limit tests for the control of impurities - Quantitative tests (Assay) of the active moiety in samples of drug substance or drug product or other selected component(s) in the drug product

6. VALIDATION CHARACTERISTICS Typical validation characteristics which should be considered are listed below: Specificity Precision Repeatability Intermediate Precision Reproducibility Accuracy Linearity Range Detection Limit Quantitation Limit Robustness

7. 1. Specificity: “It is the ability to assess clearly the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.” 2. Precision: “The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions”. Precision may be considered at three levels: repeatability, intermediate precision and reproducibility”.

8. 3. Accuracy: “The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found“ This is sometimes termed trueness. 4.Linearity: The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample”.

9. 5. Range: The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity”. The specified range is normally derived from linearity studies and depends on the intended application of the procedure. 6. Limit of Detection (LOD): “The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.”

10. 7. Limit of Quantification (LOQ): “The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy.” 8. Robustness: “The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.”

11. Type 2: Process Validation “It is a documented evidence which provide a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”. or Validation of the individual steps of the process is called process validation.

12. When Process Validation is required Before introduction of a new manufacturing method or new product into routine use. Whenever the conditions change for which a method has been validated, e.g. instruments with different characteristics. Whenever the Source of API or Excipient changed .

13. Significance of Process Validation Effective process validation contributes significantly to assuring drug quality . The basic principle of quality assurance is that a drug should be produced that is fit for intended use. This principle incorporates the understanding that the following conditions exist: Quality, safety, and efficacy are designed or built into the product . It reduce the risk of regulatory non compliance . It may reduce the time to market the new drug product . Reduce the defect cost . Make the process better understood and assuring smooth running of process.

14. Types of Process Validation Process validation Analysis of Historical data Experimental Approach Revalidation Prospective Validation Concurrent Validation Retrospective Validation Periodic Revalidation Revalidation on after change

15. Prospective validation It is done during the product development stage. When develop a new manufacturing process each step in new process is required to be established that it will give us desired result. During this step the parameters are selected and clearly specified Retrospective validation “In this type, Validation of the facilities, processes, and process controls is done using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do”.

16. Concurrent Validation “Concurrent validation is used for establishing documented evidence that a facility and processes do what they purpose to do, based on information generated during actual imputation of the process”. This approach involves monitoring of critical processing steps and end product testing of current production, to show that the manufacturing process is in a state of control. Re-Validation Consider periodic re-validation when the changes occur: Source change of raw materials Batch size enhancement / reduction New product Change in formulation Process validation includes 3 consecutive batches.

17. Why do we take 3 batches for process validation? If we select 2 batches for validation then we can not compare the data of two batches because comparison between two points always gives a linear line so to show a difference we need three points. So generally we take 3 or more than 3 batches for validation.

18. Approach to Process Validation

19. Approach to Process Validation Process validation involves a series of activities taking place over the lifecycle of the product and process that includes;

20. Type 3: Cleaning Validation “The process of providing documented evidence with a high degree of assurance that the cleaning methods employed consistently control potential carryover of product, cleaning agents and extraneous material into subsequent product to the predetermined and acceptable limits”.

21. Objective: The cleaning validation demonstrates The effectiveness of cleaning procedures The cleaning procedure consistently removes residues of the substance previously manufactured down to levels that are acceptable Ensure no risks are associated with cross-contamination of previous products, residues of cleaning agents as well as control of potential microbial contaminants Scope: Three consecutive applications of the cleaning procedure should be performed after manufacturing & filling of Marker compound and before commencing the manufacturing & filling of the next products in order to prove that the procedure is validated. This procedure is applicable to all product contact parts of non-dedicated equipment.

22. Potential Residues 1. Precursors to the Active Pharmaceutical Ingredient 2. By products & / or degradation products of the API 3. The previous product 4. Solvents and other materials employed during manufacturing process 5. Micro-organisms 6. Cleaning agents

23. Bracketing & Worst Case Rating Validation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used. Step 1; By means of a bracketing procedure the substances are grouped. Step 2; A worst case rating procedure is used to select the worst case in each group. The worst case rating priority will then support a conclusion that the cleaning procedures are effective for all drug substances and other chemicals within the bracket, including those not individually tested.

24. Worst Case Rating (WCR) A worst case rating study will prioritize existing drug substances, in a cleaning validation program, based on information on applicable criteria chosen by the company. Company chose the following criteria which are relevant to the molecule preparation in their facility (companies should evaluate individual situations): Hardest to clean Solubility in used solvent Lowest Acceptable Daily Exposure or Permitted Daily Exposure ( If ADE / PDE data are not available, other data such as pharmacological dose, OEL or toxicity data ( LD50 ) may be used. Lowest therapeutic dose

25. Re-Rating Change control should be applied to the WCR. If the conditions for the rating are changed, then a re-rating procedure should be carried out. The following listing gives examples where a formal re-rating procedure may be required: Changed cleaning method / process Changed / additional new product Changed / new equipment

26. Sampling Method A combination of the two methods is generally the most desirable. For all methods the sampling points should be fixed in a manner such that the true contamination of the equipment will be reflected. Swab sampling (direct surface sampling) Rinse or wash solvent sampling

27. Establishment of Acceptance Limit The following should be calculated: Maximum Allowable Carryover (MACO) Target Value for Swab Target value for Rinse Recovery of the methods

28. Recovery This can be achieved, for example, by spiking a surface equivalent to the equipment surface (e.g. material, polish grade) with different known amounts of the impurity. The impurity can then be recovered and analyzed using the same sampling and analytical methods that will be used for the cleaning validation study . The overall results from this procedure are then compared to criteria for detection or quantitation limits as defined in ICH Q2 (R1).

29. Swab recovery technique

30. Recovery ≥ 90% is considered good > 50% is considered reasonable < 50% is considered questionable

31. Type 4: Equipment Validation “Equipment Validation is a detailed process of confirming that an instrument is installed correctly, that it is operating efficiently, and that it is performing without error”. The process of equipment validation is based on the principle that equipment must be designed, constructed, maintained, and adapted to perform the operations which are to be carried out.

32. Types of equipment validation The process of equipment validation is not a single step activity that it has different phases which have further subsections or steps, these are as follow: Design qualification Installation qualification Operational qualification Performance qualification

33. 1. Design Qualification (DQ) “It is a documented verification of design of the equipment and manufacturing facilities. The main purpose of Design qualification is to make sure that all the requirements for the systems should clearly defined at the start. Design qualification process will illustrate that all quality aspects are fully considered at the design stage. It defines the functional and operational specifications of the instrument with all requirements, as mentioned in the user requirement specification (URS) and the applicable cGMP rules and regulations”.

34. 2. Installation Qualifications (IQ) “Installation qualification confirms that the précised equipment has been received and installed as per target and agreement in exact design or format in the undamaged form with parts, spares, services gauges, and other required compounds. It is documental verification of that the equipment has been installed and calibrated appropriately. The purpose of IQ is to ensure that all the aspects of the equipment are installed correctly match with the original (URS) design. As per the manufacture’s recommendations for installation, the working sites working environmental conditions are documented and confirmed that they are suitable for the operation of the instrument”.

35. 3. Operational Qualifications (OQ) “Operational qualification ensures that installed equipment/instrument will function perfectly according to its operation specification in the mention environmental conditions. It also checks that the equipment function perfectly to meet pre-assigned performance criteria and ensure how the testing results are recorded. The purpose of the operational qualification is to make sure that all the dynamic conditions well comply with original (URS) design. For verification, it includes traceable electric stimulators and standards which verify that equipment is processing correctly as required. Operational qualification gave high degree of assurance that the equipment functionally verifies compliance of manufactures specifications and user required specifications (URS). Operational qualification is also known as process validation that it ensures the processing of the equipment from the user and manufacturer point of view with proper documentation verification”.

36. 4. Performance Qualification (PQ) “Performance qualification ensures that the equipment consistently performs functions according to the mentioned specification which appropriates to its daily/routine use. It is a documented verification process which verifies that all aspects of facility, utility, and performance of equipment meeting pre-assigned acceptance criteria from user requirement specification (URS) and manufactures specifications. Performance qualification is performed under controlled conditions that are similar to daily sample analysis and it is performed on daily basis (at least repeated after a week) when equipment is used or functioning performed. It is also known as system suitability testing, its testing frequency is quite higher than that of operational qualification. The test frequency depends not only on functioning of equipment but also on the stability of each unit of entire system which contributes to the analysis result”.

37. Equipment Re-validation after change/modifications Periodic re-validation process refers to the re-validation process which carried out in pharmaceutical industry at periodic intervals and it is mandatory especially when the company made any change in the formulas, procedures, manufacturing systems, packaging, and support system such as electricity/ power supply, water supply, and steam. A separate and well qualified team will come for the process of re-validation in case of equipment re-validation that the analyst will come from the manufacturer side. Minor change in the product may affect the product’s quality up to a great extent hence to carry validation become necessary even after the minute change. Sometimes operational and performance tests were re-performed, which were done even during first time validation.

38. References ICH HARMONISED TRIPARTITE GUIDELINE (Q2R1) Guidance for Industry for process Validation APIC Guideline of aspects of cleaning validation in active pharmaceutical ingredient plants Validation – In pharmaceutical industry: Equipment validation

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