In-process control

 

In-process controls (IPC) are checks that are carried out before the manufacturing process is completed. These controls also perform a process-controlling function.

11.I.1 Objectives

Quality control

This function is performed by documenting production parameters. In a broader sense, this includes the following in-process controls:

• measured values obtained from process equipment, e.g. temperatures
• measured values obtained by persons, e.g. times
• measured values obtained from the room environment, e.g. particle counts
• tests following completion of intermediate products

The classic interpretation of the term in-process control includes the recording of measured values by members of the in-process control group.

„Finished product assessment should embrace all relevant factors, including [...] results of in-process testing, [...]." (6.3 EU GMP Guideline). The documented in-process data is therefore evaluated by quality control. The scopes of the various tests are coordinated with one another. Validated, process-stable products require fewer release analyses by the control laboratory if sufficient in-process control tests have been carried out. However, any reduction in the analysis expenditure must conform with the registration (see figure 11.I-1).

The investigation of intermediate manufacturing steps also falls into the category of in-process controls. An example of this is the homogeneity investigation carried out on a blend. Normally, such quantitative determinations are the direct responsibility of quality control.

In a broader sense, yields of the various intermediate products are also in-process control values.

Process control

Much of the data recorded represents control parameters for the manufacturing process. The test point is checked and corrective action is taken in the process as required. The limits within which modifications may be carried out to match measured values must be determined in advance.

The drying of a granulate is described here by way of example. The objective, i.e. the resultant granulate humidity, is determined within the scope of the manufacturing instructions. If the specified range has not yet been achieved, the normal course of action is to extend the drying time. In this case, it is irrelevant whether the control is automatic, e.g. by means of online measurement within a fluid bed or manual sampling.

11.I.2 Organisation

The in-process controls are normally carried out by production personnel. Precise information about the areas of responsibility to which they are to be assigned cannot be found in the EU GMP Guideline.

„All the in-process controls, including those made in the production area by production personnel, should be performed according to methods approved by Quality Control and the results recorded." (6.18 EU GMP Guideline). The personnel in the production area referred to here do not have to be directly responsible to the head of production with disciplinary responsibility. On the basis of organisational instructions and process descriptions, quality control personnel may also carry out the necessary tasks. The head of production is responsible for carrying out the controls in every case. He or she must ensure that the controls are used as a means of controlling processes in accordance with the instructions, and that the results are taken into account.

In the case of quality assurance checks, it is recommended from a disciplinary point of view that in-process control personnel are organised independently of production personnel, i.e. that they report directly to their area manager. This group therefore gains more autonomy in relation to production personnel. This is necessary as the group must occasionally make decisions to stop or cancel manufacturing steps (see figure 11.I-3).

11.I.3 Carrying out

"In-process controls may be carried out within the production area provided they do not carry any risk for the production." (3.17 EU GMP Guideline). This means that particular care must be taken when carrying out sampling or testing. Examples of possible influences of in-process control methods on production are shown below:

• Particle measurements (influence on air flow pattern)
• Direct contact tests (matrix residues on surface)
• Disintegration tests (influence on room humidity)
• Leak test on blisters (blue bath with microbial contamination risk)

Tests are therefore normally carried out in a segregated area and not directly at the manufacturing location. To keep equipment expenditure to a minimum, central in-process laboratories are occasionally set up to carry out tests relevant to all areas. In these cases, it must be clarified who is responsible for sampling. Depending on the organisational structure, personnel involved in production, in-process controls or other areas such as quality assurance (sometimes referred to as monitors) may carry out the sampling.

Furthermore, analytical equipment and instruments are protected from dust by segregating them physically from the manufacturing location.

The types of tests carried out depend on the dosage forms being produced. Physical and attributive features are mainly checked (see figure 11.I-4).

  

Physical parameters are checked using only suitable measuring instruments. These instruments are normally calibrated by in-process control personnel. It may also be advantageous to have measuring instruments in production areas (e.g. balances) calibrated by in-process control personnel. Operating procedures (SOPs) are used as the basis for the tests together with the manufacturing instructions. The approval of these instructions by quality control ensures that the test complies with the requirements (normally according to the pharmacopoeia).

The testing of attributive criteria is an important in-process control task. This has an important role to play particularly in relation to the filling of solutions and solid dosage forms as well as packaging. AQL lists (AQL = Acceptance Quality Limit) are normally used as the basis for the test procedures/specifications. (See chapter 13.A.5 Packaging material testing.)

With many manufacturing operations, release tests are an important in-process control task for starting up equipment or processes. These are special control loop applications (see figure 11.I-5).

Samples can be differentiated according to their representativeness. Non-representative random samples that intentionally provide a snap-shot of the manufacturing process are used for the purposes of process control. Samples that are generated for the final control are designed as representative samples. Following this principle, uniform sampling is carried out throughout the entire production (batch).

11.I.4 Documentation

When documenting the results of the analysis, care must be taken to ensure that the samples investigated can be assigned to a specific time during the process or to a specific phase of the process. If the analysis is not carried out directly after sampling, e.g. in the case of central IPC laboratories, the sampling time (date, time) must be documented in addition to the analysis time.

In addition to the fields for numerical values, a graphic representation of process control values is recommended. This provides a more simplified overview that makes it possible for trends to be easily detected at an early stage.

"Any necessary in-process controls and environmental controls should be carried out and recorded." (5.38 EU GMP Guideline). This documentation must include: "[...] a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained [...]", data on special problems as necessary with details on each deviation from the manufacturing formula and processing instructions with the signature of the person who approved the deviation (4.17 EU GMP Guideline) (see figure 11.I-6). It is hereby clearly stated that each deviation from the specifications must be countersigned by Qualified Persons (see chapter 15.B GMP-conforming documentation). The responsibility for this is carried by the head of production.

In addition to the fields for numerical values, a graphic representation of process control values is recommended in order to be able to detect trends at an early stage. The manufacturing of tablets is used for the purposes of the following example (see figure 11.I-7). The average weight of 10 tablets is regularly checked in addition to the control of mass uniformity. The values are entered in the graphic. The control and tolerance limits are added. The measured values should ideally be within the control limits. The machine settings must be adjusted where measurement results fall into the range between the control and tolerance value. Production must be stopped where results are outside the tolerance limits and the cause of this must be found. Reasons must be given for results outside the tolerances. These tests may be carried out mechanically or manually.

11.I.5 Scope of tests and limits

The in-process control requirements are documented in the manufacturing instructions. For logical reasons, these requirements are compiled together by development, manufacturing and quality control. The parameters and experiences accumulated during the process validation determine the scope of the tests as well as the limits. The scope of the tests depends on the extent of process control, i.e. the more reliable the process controllability, the smaller the scope of the tests.

11.I.6 Responsibilities

The responsibilities and tasks for the in-process control must be clearly laid down in organisational instructions. The answers to a number of questions are required in this case (see figure 11.I-8)

When deviations occur, or where release analyses are carried out outside of production, a method that excludes continued processing of the material must be defined. Material may be rejected by means of operating data management whereby the process chain is interrupted. Physical rejection by means of labelling is recommended..