11.I In-process control Authors: Dr. Christian Gausepohl / Paolomi Mukherji / Update 07

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1 In-process control In-process control Authors: Dr. Christian Gausepohl / Paolomi Mukherji / Update 07 Here you will find answers to the following questions: What are the in-process control tasks? Where should the in-process control group be established in organisational and disciplinary terms? How are the responsibilities regulated? How are in-process controls carried out? In-process controls (IPC) are checks that are carried out before the manufacturing process is completed. The function of in-process controls is monitoring and if necessary adaptation of the manufacturing process in order to comply with the specifications. This may include control of equipment and environment, too. In-process materials should be tested for identity, strength, quality and purity as appropriate and approved or rejected by the Quality Control unit during the production process. Rejected in-process materials should be identified and controlled under a quarantine system designed to prevent their use in manufacturing. Written procedures should be established and followed that describe the In-process controls and tests as specified: Tablet or capsule weight variation, Disintegration time, Content uniformity and homogeneity, Dissolution time and rate, Clarity, completeness or ph of solutions. In-process controls may be performed in regular intervals during a process step (e.g. tabletting, encapsulation) or at the end of a process step (e.g. granulation, blending). The objectives of in-process control are both quality control and process control. (1)

2 11 Production.1 Objectives.1.1 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 product attributes, e.g. weight, hardness, friability 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-Guide, see chapter C.4). The documented in-process data are therefore evaluated by quality control. In accordance with 21 CFR , in-process results are evaluated by quality control in the context of batch record review (see chapter D CFR 211 Current Good Manufacturing Practice for Finished Pharmaceuticals). This evaluation is part of the release procedure (see chapter 14.J Batch release). 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..1.2 Process control (2) During manufacturing and packaging a lot of data are recorded which represent control factors of the manufacturing process. These data may be process parameters (e.g. outlet air temperature of a fluid bed dryer) or product attributes (e.g. hardness of tablet cores). The results of the measurements may indicate that a corrective action is required to maintain the process and the product within the specified ranges. 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 as an 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 dryer or manual sampling. The principle of this control function is shown in figure -1.

3 In-process control Processing step A IPC Unit of measurement Specification fulfilled? YES NO Processing step B Figure -1 Process control by means of in-process controls.2 Organisation and responsibilities Precise information about the area of responsibility to which the accomplishment of in-process controls is to be assigned cannot be found in the EU-GMP-Guide. There is merely the requirement that the procedures have to be authorized by quality control. 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-Guide, see chapter C.4). Usually, the tests are carried out by production personnel. This is favourable for organizational and timely reasons, e.g. in a multi-shift operation. 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. (3)

4 11 Production 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 -2). 21 CFR (c) states that the responsibility for quality assuring tests lies within the quality control unit (see chapter D.1.2). Head Production group IPC group Control function Check function Process Figure -2 Example of an organisational structure The responsibilities and tasks for the in-process control must be clearly laid down in organisational instructions. A number of aspects has to be considered (figure -3) When deviations occur, or where release analyses of intermediates are carried out outside of production, a method must be defined that prevents continued processing of the material until the decision or the result is available. Material may be rejected by means of operating data management whereby the process chain is interrupted. Physical designation of the product affected by means of labelling is recommended..3 Carrying out.3.1 Scope and kind of tests (4) The in-process control requirements are documented in the manufacturing instructions. For logical reasons, these requirements are compiled together by

5 In-process control Responsibilities in the context of in-process controls Task Definition of tests Compilation and approval of the test procedure Taking samples (mechanical/manual) Transportation of the samples to the test laboratory Performing tests Responsibility Head of manufacturing Head of quality control and Head of manufacturing IPC personnel, production personnel, monitors Process control information paths Approval of equipment Head of manufacturing Measures in the event of deviations Evaluation of IPC results Quality Control Quality Assurance / Quality Unit Figure -3 Responsibilities 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, the smaller the scope of the tests. The types of tests carried out depend on the dosage forms being produced. Physical and attributive features are mainly checked (see figure -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 is particularly of importance 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 -5). (5)

6 11 Production Examples of in-process controls Physical parameters temperature time pressure weight hardness disintegration time particle size loss on drying viscosity osmolarity ph Attributive features visible impurity colour completeness integrity fractional part Figure -4 Examples of in-process controls Preparation of tablet press IPC Start-up sample Specification fulfilled? YES NO Start of production Figure -5 Example of approval for tablet production (6)

7 In-process control.3.2 Location 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-Guide, see chapter C.4). 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 control 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..3.3 Sampling 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). As a first step, a sampling plan has to be established, which identifies process steps and/or locations for sampling, as well as number and amount of samples. When defining the amount to be sampled, statistical criteria should be considered and justified, e.g. Component variability Confidence levels Degree of precision Quantity needed for analysis Reserve amount needed (7)

8 11 Production The sampling plan should also contain precise instructions on the sampling procedure, as listed in figure -6. Contents of a sampling procedure State type of sample container to be used Describe collection technique: Prevent contamination of product being sampled, Prevent contamination of sample taken, Aseptic technique if required Specify sampling utensils: Define type and requirements (clean, sterile, pyrogen free) Justify any use of composite sample Describe method for obtaining representative samples Describe scheme for identifying samples: Name of item Lot number Date taken Sampler s name Other Figure -6 Contents of a Sampling Procedure.3.4 Testing Samples are tested to verify conformance with specifications: Identity Component conformity to written specifications Container/Closure conformity to written specifications Examination for contamination As a result, components, containers or closures will be approved or rejected. The tests to be performed and the methods to be used have to be defined. A list of specifications has to be established. Beyond this, procedures for the use of Certificates of Analysis (COA) or Certificate of Conformance have to be established..4 Documentation and evaluation of data (8) 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

9 In-process control sampling, e.g. in the case of central IPC laboratories, the sampling time (date, time) must be documented in addition to the analysis time. Any necessary in-process controls and environmental controls should be carried out and recorded. (5.38 EU-GMP-Guide, chapter C.4). This documentation must include a record of the in-process controls, the initials of the person(s) carrying them out, and the results obtained. If problems or deviations from the manufacturing formula and processing instructions occurred, all relevant information associated with this have to be documented as well. In case of deviations, the signature of the person who approved the deviation is required (4.17 EU-GMP-Guide, chapter C.4). 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 head of production is responsible for the deviation procedure. Figure -7 shows the information required for documentation of in-process controls. Documentation of in-process controls Date (poss. time), Name of person carrying out the test Results Description of problems In case of deviations: Reasons for deviations Measures incl. justification date and name of authorising person Figure -7 Documentation In-process controls In addition to the numerical compilation of data, a graphical presentation 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. The manufacturing of tablets is used for the purposes of the following example (see figure - 8). The average weight of 10 tablets is regularly checked in addition to the control of mass uniformity. The values are entered in the graphic data sheet. 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. (9)

10 11 Production Logo GMP Pharma Mat. Des.: Antistress N Mat. no.: Batch des.: 17865A 198 Tolerance level Specified limit Totals weight (n=10) Target 186 Specified limit Tolerance level Sample number Date/ signature / ga Figure -8 In-process control as means of controlling production Summary In-process control not only provides a means of controlling production, it also performs a quality assurance function. The in-process control group personnel may be assigned to production or quality control depending on the relevant company structure. In each case, autonomy in relation to the production process must be ensured. The in-process control methods that are part of the manufacturing formula are compiled and validated under the supervision of quality control. Statistical evaluation and periodic review of in-process data contributes to the general assessment of process performance and product quality. (10)