Seas. Chapter 11 Pharmaccutical Process Validation 1. Definition Validition is the action of proving, according to guideline of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results, Validation is an integral part of Quality Assurance. The term validation, in manufacturing often scares people as a very difficult subject. Actually it is nothing much new but organized approach for establishing GMP. Validation may be defined as a systematic study which helps to prove that the systems, facilities and processes perform the job adequately and consistently as specified. To be more precise, a validated operation is one which has been proved to have the potentials for the manufacture of uniform batches meeting the required specifications. = ~~~ The concept of validation will become more clear by explaining what it involves. It includes all aspects that influence the quality and therefore it is most important to combine the efforts of everyone who has a role in attaining the product quality. Thus validation requires understanding the entire operation (Fig. 11.1)*#7832- 42 Understanding equipment Understanding Materials and formulation Understanding process and its contro! Understanding manufacturing environment Validation Understanding critical system / services / Understanding QC procedures Understanding the final pack ‘ Understanding the people Figure 11.1 : The spectrum of validation (Modified from ref, : 24) 2, Advantages of Validation ‘We are often faced with the question these validation troubles?" (i) One thing is clear that for ‘sterile’ preparations validation is the Is it worth going though all 245only approach to ensure quality. Now-a-days most regulatory authorities consider it obligatory to validate all processes associated with parenteral preparations Apart from this, the validation exercise helps the company in many ways; it will (ii) Minimize rejection toss (iii) Help timely corrective actions iii) Assure consistent production performance (iv) Ensure achievement of quality goals (v) Reduce extensive end product testing (vi) Allow parametric release (vii) Sort out the major risk of product liability ‘The cost-effectiveness of the validation exercise can be judged from all the above factors. A well understood process or equipment in the first place can save a lot of management time and confusio1 . Types of validation - ‘The guidelines on general principles of process validation mention four options: (1) Prospective process validation (also called pre-market validation) (2) Retrospective process validation (3) Revalidation (Post market validation) and (4) Concurrent validation A brief description of each type is given below: Prospective Process Validation In prospective process validation, an experimental plan called the validation protocol is executed before the process is put into commercial use or the product going to the market. It is also called pre-market validation. Most validation efforts require gome degree of prospective experimentation to generate validation support data. This particular type of process validation is normally carried out in connection with the introduction of new drug products and their manufacturing processes. The formalized process validation program should never be undertaken unless and until the following operations and procedures have been completed satisfactorily: I. The facilities and equipment in which the process validation is to be conducted meet cGMP requirements (completion of installation qualification). The operators and supervising personnel who will be ‘running’ the 246validation batch have an understanding of the process and its requirements. 3. The design, selection, and optimization of the formula have been completed. 4, The qualification trials using pilot laboratory batches have been completed, in which the critical processing steps and process variables have been identified, and the provisional operational control limits for each critical test parameter have becn provided. 5, Detailed technical information on the product and the manufacturing process have been provided; including documented evidence of product stability. 6. Finally, at least one qualification trial of a pilot-production batch has been made_and shows, upon scale-up, that there were no sign’ficant deviations from the exacted performance of the proce: 7. The objective of prospective validation is to prove or demonstrate that the process will work in accordance with a validation master plan or protocol prepared for pilot-product trials. In practice, usually two or three pilot-production batches are prepared forvalidation purposes. Retrospective Validation ‘The retrospective validation option is chosen for established products whose manufacturing processes are considered stable and when on the basis of economic considerations alone and resource limitations, prospective validation programs could not: be justified. Prior to undertaking retrospective validation, wherein the numerical in- process and/or end-product test data of historic production batches are subjected to statistical analysis, the equipment, facilities and subsystems used in connection with the manufacturing process must be qualified in conformance with cGMP requirements. The basis for retrospective validation is stated as - “Valid in-process specifications for such characteristics shall be consistent with drug produét final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate Using cither data-based computer systems or manual methods, retrospective validation may be conducted in the following manner: 1, Gather the numerical data from the completed batch record and include assay values, end-product test results, and in-process data. 2472. Organize these data in a chronological sequence according. to batch manufacturing data, using a spreadsheet format 3. Include data from at Icast the last 20-30 manufactured batches for analysis. If the number of batches is less than 20, then include all manufactured batches and commit to obtain the required number for analysis, 4, Trim the data by eliminating test results from non-critical processing steps and delete all gratuitous numerical information 5. Subject the resultant data to statistical analysis and evaluation 6. Draw conclusions as to the state of control of the manufacturing process based on the analysis of retrospective validation data 7. Issue a report of the findings. One or more of the following parameters, which have been shown to be critical in terms of the specific manufacturing process being evaluated, are usually selected for statistical analysis. i, Solid Dosage Forms . ao 1. Individual assay results from content uniformity testing. 2. Individual tablet hardness values. 3. Individual tablet thickness values. 4, Tablet or capsule weight variation, 5. Individual tablet or capsule dissolution time (usually at tsox) oF disintegration time. 6. Individual tablet or capsule moisture content. ii, Scmisolid and Liquid Dosage Forms 1, pH value (for aqueous system). 2. Viscosity. 3. Density. 4, Color or clarity values. i 5, Average particle size or distribution. 6. Unit weight variation and/or potency values The statistical methods that may be employed to analyze numerical output data from the manufacturing process are listed as follows: 1. Basic statistics (mean, standard deviation, and tolerance limits). 2. Analysis of variance (ANOVA and related techniques). 3. Regression Analysis. 4, Cumulative sum analysis (CUSUM). 5, Cumulative difference Analysis. 6. Control charting (averages and range), Control charting, with the exception of basic statistical analysis, is 248probably the most useful statistical technique to analyze retrospective and concurrent process data. Control charting forms the basis of ngdern statistical process control ‘Concurrent Validation In-process monitoring of critical processing steps and end-product testing of current production batch can provide documented evidence to show that the manufacturing process is in a state of control. Such validation documentation can be provided from the test parameter and data sources disclosed in the section on retrospective validation. Not all of the in-process tests enumerated above are required to demonstrate that the process is in a state of control. Selections of test parameters should be made on the basis of the critical processing vagidibles to be evaluated Revalidation Conditions requiring revalidation study and docume! as follows: 1. Change in a critical component (refers to raw materials). 2. Change or replacement in a critical piece of capital equipment 3. Change in a facility and/or plant (location or site). 4. Significant increase or decrease in batch size. 5. Sequential batches that fail to meet product and process specifications. In some situations performance re-qualification studies may be required prior to undertaking specific revalidation assignments, ‘The FDA process validation guidelines refer to a quality assurance system in place that requires revalidation whenever there are changes in packaging (primary container-closure, system), formulation, equipment or processes which could impact/on product effectiveness or product characteristics and whenever there are changes in product characteristics. . Approved packaging is normially selected after completing package performance qualification testing as well as product compatibility and stability studies 11.4. Parametérs of validation and their brief description There are at least ten (10) parameters of validation. Each parameter must be satisfie inividually for overall validation to be satisfactory. ‘These parameters arc - 1. Accuracy 2. Precision tation are listed 249Particular attention should be accorded to the validation of . cleaning procedures” (WHO statement about cleaning), (iii) “Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure” and (iv) “The data should support a conclusion that residues have been reduced to an ‘acceptable’ level” (FDA statement about cleaning) 11.9. Possible contaminants The potential sources of contamination are presented in Fig, 8.1. In case of cleaning validation, some more sources of contamination are (i) product residues, (ii) cleaning agent residues and breakdown, (iii) airborne matter, (iv) lubricants, (v) ancillary material, (vi) decomposition residues, (vii) microbiological agents such as bacteria, fungi, mould and (viii) pyrogens 11.10. Names of chemical laboratory equipments’ for which validation is required A list of equipments necessary for chemical laboratory is given and their validation is very essential to attain quality: Balances Chromatography HPLC, HPTLC, GC, TLC Dissolution or disintegration apparatus Karl Fischer moisture determination apparatus Melting, softening or freezing point apparatus Ovens, refrigerators, incubators pH meter Polarimeter - optical rotation Refractometer Spectrophotometer (UV/VIS, IR, FTIR, Raman, AAS, NMR, COSY) Timers / Viscometer Volymetric equipment 2 1. Validation master plan (VMP) ‘Validation master plan (VMP) consists of four elements, viz Design qualification (DQ), (ii) Installation qualification (1Q). (iii) Operational qualification (OQ) and (iv) Process Validation or Performance qualification (PQ) and some other related components, Figure 11.4 shows the interrelationship among various components of validation master plan . In brief, VMP= DQ#IQ+OQ+PQ 26111.11. 1. Content of VMP The Validation Master Plan: Three basic elements, (ii) Content and (iii) Strategy (i) Philosophy: Philosophy of the validation master plan ‘gives ‘a description of - -Recommendations -Manufacturer’s validation policy and needs -Information on validation organization -Describe: why? what? where? by whom? how? when? a valdation work has been perfomed. - (i) Philosophy, [i genea, [certteation | gars, = Process ( Under Control Review _\ pettedieay Rae ‘Change. Control Fig 11.4: Components of validation master plan (Ret: 23) (ii) Content : Content of the validation master plan gives description of types of validation, such as (1) Prospective validation, (2) Concurrent validation, (3) Retrospective validation, (4) Revalidation and (5) Change control. (iii) Strategy : The strategy of the validation master plan helps - (1) Management, (2) Validation team members, (3) Project leaders and (4) GMP inspectors to decide about validation protocols and next validation activiti 262