Critical process steps

Identification and evaluation of critical product and process parameters affecting Q attribute Allocating critical process steps (where)... 

Manufacturing validation data, which should aim to identify the critical process steps, especially for nonstandard manufacturing processes such as for new dosage forms, should be discussed in the development pharmaceutics section of the application. Validation data may be accepted based on closely related products. In-process control tests and acceptance limits should be included for any aspect where conformity with the finished product tests cannot otherwise be guaranteed (e.g., mixing, granulation, emulsification and nonpharmacopeial sterilization processes). 

Critical process steps List of manufacturing equipment... 

The qualification trials using (10 x size) 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 been provided... 

In-process monitoring of critical processing steps and end-product testing of current production 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. 

What criteria are used to select critical process steps and quality control tests for which data will be collected ... 

In the preceding discussion of areas of interest to the validation organization, two concepts were introduced that deserve further clarification (1) critical process steps and quality control tests that characterize the operation, and (2) validation protocol. 

Critical process steps are operations performed during dosage-form manufacture that can contribute to variability of the end product if not controlled. Since each type of dosage form requires different machinery and unit operations to produce the end product, the critical process steps will also differ. For each product considered suitable for retrospective validation, a list of these steps must be compiled following careful analysis of the process by technically competent persons. In a similar manner, in-process and finished-product tests should be screened to identify those that may be of some value. As a rule, tests in that the outcome is quantitative will be of greatest interest. 

Comprehensive records of complaints received either directly from the customer or through a drug problem reporting program should be reviewed. Furthermore, a record of any follow-up investigation of such complaints is mandatory [6] and should be part of this fde. Review of customer complaint records can furnish a useful overview of process performance and possibly hint at product problems. Complaint analysis should therefore be viewed as a meaningful adjunct to the critical process step and control test selection process. 

The following discussion will focus on how to apply the previously discussed concepts to the validation of marketed products. To provide a fuller understanding of this procedure, the manufacture of several dosage forms designed for different routes of administration will be examined. For each dosage form, critical process steps and quality control tests will be identified. Useful statistical techniques for examining the assembled data will be illustrated. It is also important to note that not all of the collected information for a product lends itself to this type of analysis. This will become more apparent as we proceed with the evaluation of the five drugs under consideration. 

Table 1 Drug A Selected Critical Process Steps and Quality Control Tests...

The powder produced in the prior operation is combined with the second active ingredient (B2), as well as several other excipients in a twin-shell blender and mixed for several min. For reasons previously discussed, mix time is of interest, and thus it is listed as a critical process step. 

Table 11 lists the critical process steps that should be considered for evaluating batch-to-batch uniformity. Although other information such as melting... 

For API processes, the FDA does not expect validation of all manufacturing steps, but accepts validation of critical process steps. Section XI.A of the March 1998 draft API guidance document states, Validation should embrace steps in the processing of APIs that are critical to the quality and purity of the final API. The FDA, however, does not specify what it considers critical, but wants the manufacturer to determine the critical process steps and critical process parameters. For new chemical entities, data used to identify critical processing steps and critical parameters would be derived from research or pilot scale batches. For established API processes this information could be obtained from previously manufactured production scale batches. 

Critical process steps are usually determined by analyzing process parameters (factors in a process that are controllable and measurable) and their respective outcomes. Not all process parameters affect the quality and purity of APIs namely its impurity profile and physical characteristics. For validation purposes, manufacturers should identify, control, and monitor critical process parameters that may influence the critical quality attributes of the API. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in process validation. 

DNA Synthesis for Nanoconstruction Single strands of DNA, otherwise known as oligomers, are most commonly produced using a solid-support synthesis process [161, 162], This is a cyclic process where each nucleotide is sequentially coupled to form a nucleotide chain (working from the 3 end to the 5 end). The 3 end is initially covalently linked to a solid support and the nucleotide monomers are added sequentially. This is a well-established process and its key parameters and critical process steps are well documented in the literature [163,164],The DNA strands can be tailored according to the desired nanoconstruction scheme and target structure [165]. 

There arc several critical processing steps the authors have observed, during which contamination with taint components or dieir precursors can occur. All of those potential sources for taint development need to be eliminated in order to regain winery and consumer confidence in wine bottle closures made from cork bark. 

If you have a complicated process, you can do a macro C E Matrix using just the process steps (omitting the process inputs). This will tell you which steps have the most impact on the outputs. Then you can do a more detailed C E Matrix using the inputs for only the critical process steps. 

The wafer is not exposed to the clean room ambient between critical process steps. This can result in a more repeatable process. Selective tungsten deposition should benefit greatly from such an approach. 

The written procedure should specify critical process steps and factors (such as extraction time, temperature and solvent purity) and acceptance criteria, as well as the type of validation to be conducted (e.g. retrospective, prospective or concurrent) and the number of process runs. 

The policy and approach to process validation should be documented, e.g. in a validation master plan, and should include the critical process steps and parameters. 

From this point on, appropriate good manufacturing practice (GMP) as defined in this guidance should be applied to these intermediate and/or API manufacturing steps. This would include the validation of critical process steps determined to impact the quality of the API. However, it should be noted that the fact that a company chooses to validate a process step does not necessarily define that step as critical. 

The development of a VMP requires several decisions. If the facility is new, due consideration is given to determine, on time, the target dates for routine production to ensure completion of validation for facility approval otherwise manufacturing at risk is the alternative choice. The deadline determination provides ample opportunity to perform validation of utilities, critical equipment installation, and qualification prior to construction work. In addition, it provides a sufficient time frame to identify the critical processes and steps involved. The parameters critical for each step shall be established. The critical equipment required shall be determined. Critical processes, steps involved, parameters, and equipment are identified. For existing facilities, establish the criteria for revalidation based on known vulnerabilities and engineering projects in progress. 

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