Validation, process

New systems or processes may also need to be qualified from an operational safety perspective. This is particularly relevant in the case of chemical synthesis involving exothermic reactions. Critical safety aspects are usually identified using hazard operability or HAZOP assessments and studies. For example, a HAZOP analysis of an exothermic reaction vessel would involve consideration of the consequence of failure of the motors for mixers or circulation pumps for cooling water. Thus, the qualification of such a system would involve checks and assessment to ensure that the system/process can be operated safely and that pressure relief valves or other emergency measures are adequate and functional. 

Situation During the introduction of a new tablet manufacturing process, the operation of a conditioner had to be validated the function of this conditioner is to bring the loaded tablets to a certain moisture content for further processing. 

Question Does the conditioner work in a position-independent mode, that is, all tablets in one filling have the same water content no matter into which corner they were put, or are there zones where tablets are dried to a larger or lesser extent that the average  

Experiment Ten different positions within the conditioner representing typical and extreme locations relative to the air inlet/exhaust openings were selected for analysis. Eight tablets were picked per position their water content was accurately determined on a tablet-to-tablet basis using the Karl Fischer technique. Table 4.7 gives an overview of all results  

Data Evaluation The Bartlett test (Section 1.7.3 cf. program MULTI using data file MOISTURE.dat) was first applied to determine whether the within-group variances were homogeneous, with the following intermediate results A = 0.1719, B = -424.16, C = 1.4286, D = 70, E = 3.50, F = 1.052, G = 3.32. 

Variance within groups Variance between groups Total variance 

In the case of pharmaceutical plants, a HPW system must comply with the mles of the US Food and Drug Administration (FDA) as stated in the 21 CFR (Code of Federal Regulations), Parts 210,211 and 820. According to the FDA regulatory code, validation implies the conformation by documented examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled. These 

The system validation documentation includes but is not limited to Quality Assurance Plan (QAP), Operation and Maintenance Manual (O M), and Factory Acceptance Test (FAT) reports. A properly developed QAP and its supporting documentation help to reduce cost, boost product quality, ensure regulatory compliance and increase profitability. The FAT validation is the first verification step of the customer s validation process, which may include design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). 

Feed water constituents must be analysed prior to designing a membrane system. The ASTM Designation D4195-88 Standard Guide for Water Analysis for Reverse-Osmosis Applications for components and properties that require analysis is given below. Water treatment processes are discussed in Chapter 2. 

Carbon dioxide (CO2) is not rejected by RO/NF membranes. If it is the major dissolved constituent in the permeate, it wiU increase the ionic load on downstream ion-exchange polisher anion resins. 

Free chlorine (CI2) is an oxidant. Polyamide RO and NF membranes are sensitive to chlorine. Hence, water must be dechlorinated by passing it through an activated carbon filter or by the addition of a reducing chemical such as sodium sulphite, sodium bisulphite, or sodium metabisulphite to feed water. However, it is necessary for CA membranes to protect them from bacterial attack. 

As with other products, the amount of data needed to support the manufacturing process will vary from product to product. Development (data) should have identified critical phases of the operation, including the predetermined specifications that should be monitored during process validation. 

As discussed, the manufacture of suspensions presents additional problems, particularly in the area of uniformity. The development data should address the key compounding and filling steps that ensure uniformity. The protocol should provide for the key in-process and finished product tests, along with their specifications. For oral solutions, bioequivalency studies may not always be needed. However, oral suspensions, with the possible exception of some of the over-the-counter antacids, usually require a bioequivalency or clinical study to demonstrate their effectiveness. Comparison of product batches with the biobatch is an important part of the validation process. Make sure there are properly written protocol and process validation reports and, if appropriate, data for comparing full-scale batches with biobatch available during FDA inspection. 

A target purity of 99 % was established for both extract and raffinate. According to the simulation results, one can predict that a variation of the feed concentration range between 7.5 and 11 g will meet the required purity. The system was designed for a feed concentration equal to 10 g The influence of change in feed concentration on the purity of both extract and raffinate illustrates the robustness of SMB, and that the process tolerates fluctuations when critical parameters are stressed during process validation. 

A second simulation study was performed to measure the effect on both extract and raffinate purities of a loss of chromatographic efficiency (Fig. 10.11). 

The graph in Fig. 10.11 shows that the SMB can tolerate a loss of 13 % chromatographic efficiency and still reach a purity of greater than 98 %. The industrial SMB system was designed to operate with 300 theoretical plates without any modification of the operating flowrates. 

Finally, simulation studies were performed to evaluate the influence of change in eluent consumption or variations due to different lots of CSPs on the retention of the second peak. The variation in retention of the second peak is another critical parameter on resulting purity of the extract and raffinate. 

The effect on purity and the influence of retention factor by adjusting operating flowrates is illustrated in Fig. 10.12. 

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Three types of control plan are required. During the product design and development phase, a prototype control plan is required to be produced. During the process design and development phase, a pre-launch or pilot production control plan is required, and during the product and process validation phase, the production control plan is to be issued. 

One question of chief interest concerns the number of runs that can be run with one individual SEC column. The lifetime of the sorbent itself must be tested as well as the maximum run number for the packed column. Because column packing procedures for SEC columns are rather time-consuming and all SEC columns have to be checked very carefully with respect to performance, very frequent repacking of the column is unreasonable. Therefore, CIP protocols are generally necessary. The CIP protocol should be developed as part of the process validation program. 

The guidance document requires calculation of actual yields and percentages of expected yields. The yield should be recorded at the conclusion of each phase of manufacturing of an API. The expected yield and ranges are established during process validation or from a pilot-scale production run [66]. 

The design of the system must take into account possible variation of critical control parameters that could affect performance. The maximum performance of the process should be defined by a reasonable safety margin. In order to comply with cGMP guidelines, established validation protocols, and parameters should allow the process to achieve reproducible purity and yield under stressed conditions. This implies that the industrial SMB system must be stressed to simulate worst-case conditions for process validation. 

Process validation should be extended to those steps determined to be critical to the quality and purity of the enantiopure drug. Establishing impurity profiles is an important aspect of process validation. One should consider chemical purity, enantiomeric excess by quantitative assays for impurity profiles, physical characteristics such as particle size, polymorphic forms, moisture and solvent content, and homogeneity. In principle, the SMB process validation should provide conclusive evidence that the levels of contaminants (chemical impurities, enantioenrichment of unwanted enantiomer) is reduced as processing proceeds during the purification process. 

In order to illustrate the critical process parameters of SMB process validation, we will consider the separation of the racemic drug as described in Process design. The study represents the effect of the influence of feed concentration, number of plates and retention factor on the second eluting enantiomer. The simulation of the process for different values of feed concentration is performed and the variations of the extract and raffinate purities are shown in Fig. 10.10. 

Using computer-aided numerical calculations, one can readily simulate and identify critical parameters for process validation. Thus, one can evaluate the robustness of the process during its design. To ensure performance, optimization of the process and evaluation of critical parameters can be determined before actual operating conditions. 

Process validation is the procedure that allows one to establish the critical operating parameters of a manufacturing process. Hence, the constraints imposed by the FDA as part of process control and validation of an SMB process. The total industrial SMB system, as described, is a continuous closed-loop chromatographic process, from the chromatographic to recycling unit and, with the use of numerical simulation software allows the pharmaceutical manufacturer rapidly to design and develop worst-case studies. 

Medical Devices Draft Global Harmonization Task Eorce Study Group 3 Process Validation Guidance, (1998), Red. Regist., Docket No. 98D-0508. 

Quality system regulation The past good manufacturing practice (GMP) and process validation (PV) was renamed to quality system regulation (QSR). It is important for the medical device industry (that uses an extensive amount of plastics) and also in other product industries where they want to follow strict processing procedures. It sets up an important procedure for many plastic fabricators to consider that targets to ensure meeting zero defects. 

Quality systems for design and manufacture Process validation Design control process... 

Process Validation Scheme for the Drug Product (EU only)... 

Manufacturing process The descriptions of the manufacturing steps for the drug substance and product should include process flow diagrams and discussions of critical scale-up steps and process development history and process validation activities, together with assessment of the equivalence or differences in batches used for various studies. 

Production and Service Provision (Control of production, process validation, product status)... 

Figure 11.11 A graphical illustration of the concept of process capability (from CHTF Guidance Quality Management Systems-Process Validation).

Sec. 820.75 Process validation - Processes that cannot be fully verified must be validated Subpart H Acceptance Activities... 

FDA Guidance Guideline on general principles of process validation. www.fda.gov. 

Brief description of general policy for process validation. 

Raffin, R. P., Jornada, D. S., Re, M. L, Pohimann, A. R. Guterres, S. S. (2006). Sodium pantoprazole-loaded enteric microparticles prepared by spray drying Effect of the scale of production and process validation. International Journal of Pharmaceutics, Vol. 324,1, (October 2006), pp. (10-18), ISSN 0378-5173... 

Critical ( -values for p - 0.05 are available. " - In lieu of using these tables, the calculated -values can be divided by the appropriate Student s t(f, 0.05) and V2 and compared to the reduced critical -vdues (see Table 1.12), and data file QRED TBL.dat. A reduced -value that is smaller than the appropriate critical value signals that the tested means belong to the same population. A fully worked example is found in Chapter 4, Process Validation. Data file MOISTURE.dat used with program MULTI gives a good idea of how this concept is applied. MULTI uses Table 1.12 to interpolate the cutoff point for p = 0.05. With little risk of error, this table can also be used fo = 0.025 and 0.1 (divide q by t(/, 0.025) /2 respectively t f, 0.1) V 2, as appropriate. 

For a completely worked example, see Section 4.4, Process Validation and data file MOISTURE.dat in connection with program MULTI. 

GPMP is concerned with the manufacture of medicines, and includes control of ingredients, plant construction, process validation, production, and cleaning (see also Chapter 22). QC is that part of GPMP dealing with specification, documentation and assessing conformance to specification. 

Process validation can be done in different ways, viz. prospectively, by carrying out a planned program of experiments, before routine production is started concurrently, during routine production retrospectively, by statistical analysis of historical data and during scale-up studies (developmental validation). 

Berg, T., Humphreys, P., Phillips, B. and Scherz, B., Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation , PIC Publication PH 1/96. 

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