VALIDATION OF PHARMACEUTICAL PROCESSES

Contents : Introduction Need of Validation Scope of Validation Documentation of Validation Validation Master Plan Types of Validation Process Validation Cleaning Validation Equipment Validation Validation of Analytical method Conclusion References

Introduction The concept of validation was first proposed by Food and Drug Administration(FDA) officials, Ted Byers and Bud Loftus, in the mid 1970s in order to improve the quality of pharmaceuticals. Validation is "Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. This is to maintain and assure a higher degree of quality of food and drug products.

Need for validation Customer satisfaction Customer mandated Product liability Control production cost The development of the next generation Safety

Scope of validation Analytical Test Methods Instrument Calibrations Process Utility Services Raw Material Equipment Facilities Product Design Cleaning Operators

Documentation of Validation The validation activity cannot be completed without proper documentation of each and every minute activity with utmost details. Documentation of validation is generally different types such as: Validation Master Plan(VMP) Validation Protocol(VP) Validation Reports(VR) Standard Operating Procedure(SOP)

Validation master plan Advantages : It gives idea about future performed: What activities are to be performed? Who is going to perform these activities? When the activities should start and when they should get over? What documents will be generated? What the policy on revalidation?

V.M.P. includes.. Premises Processes Products Format for protocol and other documentation List of relevant SOPs Planning and scheduling Location Estimation of staffing requirements A time plan of the project

Guidelines on Preparing V.M.P. V.M.P. write on A4 size paper. File in a presentable form. Have sufficient explanatory drawings. Clearly divide the V.M.P. in different form. It must be dated and signed properly by authorized persons. If found any step inappropriate is discuss this the F.D.A. people in advance.

Types of Validation The major types of Validation : Process validation Cleaning validation Equipment validation Validation of analytical methods

Process validation Definition As per FDA Nov.2008,‘The collection of data from the process design stage throughout production,which establishes scientific evidence that a process is capable of consistently delivering quality products.

Stage 3. Continued process verification Process validation life cycle: Stage 1. Process design Stage 2. Process qualification Stage 3. Continued process verification

Types of Process validation: Prospective validation. Retrospective validation. Concurrent validation. Revalidation.

Process validation Flow chart:

Cleaning validation : Definition: “A process of attaining and documenting sufficient evidence to give reasonable assurance, given the current state of Science and Technology, that the cleaning process under consideration does, and / or will do, what it purpoes to do.” Objective.. To minimize cross contamination. To determine efficiency of cleaning process. To do troubleshooting in case problem identified in the cleaning process and give suggestions to improve the process.

Source of contamination: Cross contamination product of one product into another. Product contamination by a foreign material. Microbial contamination. Cleaning methods: Manual cleaning method. Semi automated procedures. Fully automated procedures.

Factors Influencing Cleaning validation : Product. Equipment. Facilities. Cleaning methods. Cleaning agents. Sampling. Testing, Limits, and acceptance criteria.

Cleaning validation Flow chart :

Equipment Validation Definition As per FDA, May 1987,‘Action of proving that any equipment works correctly and leads to the expected result is equipment qualification. It is not a single step activity but instead result from many discrete activities.

Steps involved.. Design qualification Installation qualifications User requirement specification Design qualification Installation qualifications Operational qualifications Performance qualification

Process flow chart :

Validation of analytical methods Definition : “The process by, which it is established, by laboratory studies, that the performance characteristics of the method meet the requirements for the intended analytical application”. Accuracy : “The closeness of test results obtained by that method to the true value. This accuracy should be established across its range.” Precision: “The degree of agreement among individual test results when the method is applied repeatedly to multiple sampling of a homogenous sample.”

Specificity : “The ability to assess unequivocally the analyte in the presence of components that may be expected to be present, such as impurities degradation products and matrix components.” Limit of Quantitation : “A characteristic of quantitative assays for low levels of compounds in sample matrices such as impurities in bulk substances and degradation products in finished pharmaceuticals. It is the lowest amount of analyte in a sample that can be determined with acceptable precision and accuracy under the stated experimental conditions.”

Range : “Interval between the upper and lower of analyte (including these levels) that have been demonstrated to be determined with a suitable level of precision , accuracy and linearity using the method as written. The range is normally expressed in the same units as test results. ( e.g. Percentage , parts per million, etc.) obtained by the analytical method.” Ruggedness: The degree of reproducibility of test results obtained by the analysis of the same sample under a variety of conditions such as different laboratories, different analysts, different instruments , different lots of reagents, different elapsed assay times, different assay temperatures, different days, etc.”

Robustness: "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.” Linearity : “Its ability to elicit tests that are directly or by a well defined mathematical transformations proportional to the concentration of analyte in samples within a given range.” Limit of Detection : The lowest amount of analyte in a sample that can be detected but not necessarily quantitated, under the stated experimental conditions.”

Conclusion Validation has been proven assurance for the process efficiency and sturdiness and it is the full fledged quality attributing tool for the pharmaceutical industries. Validation is the commonest word in the areas of drug development, manufacturing and specification of finished products. It also renders reduction in the cost linked with process monitoring, sampling and testing. Apart from all the consistency and reliability of a validated process to produce a quality product is the very important for an industry.

References Fundamental of quality assurance techniques..by Ramesh Sawant and Sandip Hapse,First edition Dec 2011, Career publications. Pharmaceutical Quality Assurance..by Manohar Potdar,Second edition Dec 2007,Nirali Prakashan. IJRPC 2011 ‘An overview of pharmaceutical validation: quality assurance view point’ by Nandhakumar et al. TJPR Review Article ‘An Overview of Pharmaceutical Validation and Process Controls in Drug Development’ Elsie Jatto and Augustine O.Okhamafe

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