11.I In-process control - GMP Publishing

1 (1)GMP Manual (Up07) Maas & Peither AG GMP PublishingC. Gausepohl / P. In-process controlAuthors: Dr. Christian Gausepohl / Paolomi Mukherji / Update 07In- process controls (IPC) are checks that are carried out before the manufacturingprocess is completed. The function of In-process controls is monitoring and ifnecessary adaptation of the manufacturing process in order to comply with thespecifications. This may include control of equipment and environment, materials should be tested for identity, strength, quality and purityas appropriate and approved or rejected by the Quality control unit during theproduction process . Rejected In-process materials should be identified and con-trolled under a quarantine system designed to prevent their use in procedures should be established and followed that describe the In-proc-ess 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.

2 In-process controls may be performed in regular intervals during a process step( tabletting, encapsulation) or at the end of a process step ( granulation,blending). The objectives of In-process control are both quality control and proc-ess 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?(2)11 ProductionGMP Manual (Up07) Maas & Peither AG GMP PublishingC. Gausepohl / P. Objectives Quality controlThis function is performed by documenting production parameters. In a broadersense, this includes the following In-process controls: measured values obtained from process equipment, temperatures measured values obtained by persons, times product attributes, weight, hardness, friability measured values obtained from the room environment, particle counts tests following completion of intermediate productsThe classic interpretation of the term In-process control includes the recording ofmeasured values by members of the In-process control group.

3 Finished product assessment should embrace all relevant factors, including [..]results of In-process testing, [..] ( EU-GMP-Guide, see chapter ). The documented In-process data are therefore evaluated by quality control . Inaccordance with 21 CFR , In-process results are evaluated by quality con-trol in the context of batch record review (see chapter 21 CFR 211 CurrentGood Manufacturing Practice for Finished Pharmaceuticals). This evaluation ispart of the release procedure (see chapter Batch release).The investigation of intermediate manufacturing steps also falls into the cate-gory of In-process controls. An example of this is the homogeneity investigationcarried out on a blend. Normally, such quantitative determinations are the directresponsibility of quality control .

4 In a broader sense, yields of the various interme-diate products are also In-process control values. process control During manufacturing and packaging a lot of data are recorded which representcontrol factors of the manufacturing process . These data may be process param-eters ( outlet air temperature of a fluid bed dryer) or product attributes ( of tablet cores). The results of the measurements may indicate that acorrective action is required to maintain the process and the product within thespecified ranges. The limits within which modifications may be carried out tomatch measured values must be determined in advance. The drying of a granulate is described here as an example.

5 The objective, resultant granulate humidity, is determined within the scope of the manufac-turing instructions. If the specified range has not yet been achieved, the normalcourse of action is to extend the drying time. In this case, it is irrelevant whetherthe control is automatic, by means of online measurement within a fluid beddryer or manual sampling. The principle of this control function is shown in figure (3) In-process controlGMP Manual (Up07) Maas & Peither AG GMP PublishingC. Gausepohl / P. Organisation and responsibilities Precise information about the area of responsibility to which the accomplishmentof In-process controls is to be assigned cannot be found in the is merely the requirement that the procedures have to be authorized byquality control .

6 All the In-process controls, including those made in the production area byproduction personnel, should be performed according to methods approved byQuality control and the results recorded. ( EU-GMP-Guide, see chapter ).Usually, the tests are carried out by production personnel. This is favourable fororganizational and timely reasons, in a multi-shift operation. The personnel inthe production area referred to here do not have to be directly responsible to thehead of production with disciplinary responsibility. On the basis of organisationalinstructions and process descriptions, quality control personnel may also carryout the necessary tasks. The head of production is responsible for carrying out thecontrols in every case.

7 He or she must ensure that the controls are used as a meansof controlling processes in accordance with the instructions, and that the resultsare taken into control by means of In-process controlsIPCP rocessing step ASpecification fulfilled?Processing step BUnit of measurementNOYES(4)11 ProductionGMP Manual (Up07) Maas & Peither AG GMP PublishingC. Gausepohl / P. the case of quality assurance checks, it is recommended from a disciplinarypoint of view that In-process control personnel are organised independently ofproduction personnel, that they report directly to their area manager. Thisgroup therefore gains more autonomy in relation to production personnel. This isnecessary as the group must occasionally make decisions to stop or cancel manu-facturing steps (see figure ).

8 21 CFR (c) states that the responsibilityfor quality assuring tests lies within the quality control unit (see chapter ).The responsibilities and tasks for the In-process control must be clearly laid down inorganisational instructions. A number of aspects has to be considered (figure )When deviations occur, or where release analyses of intermediates are carriedout outside of production, a method must be defined that prevents continuedprocessing of the material until the decision or the result is available. Material maybe rejected by means of operating data management whereby the process chainis interrupted. Physical designation of the product affected by means of labellingis Carrying Scope and kind of tests The In-process control requirements are documented in the manufacturinginstructions.

9 For logical reasons, these requirements are compiled together byFigure of an organisational structureProduction groupControl function HeadProcessIPC groupCheck function(5) In-process controlGMP Manual (Up07) Maas & Peither AG GMP PublishingC. Gausepohl / P. , manufacturing and quality control . The parameters and experi-ences accumulated during the process validation determine the scope of thetests as well as the limits. The scope of the tests depends on the extent of processcontrol, the more reliable the process , the smaller the scope of the tests. Thetypes of tests carried out depend on the dosage forms being produced. Physical and attributive features are mainly checked (see figure ).

10 Physical parameters are checked using only suitable measuring instruments are normally calibrated by In-process control personnel. It mayalso be advantageous to have measuring instruments in production areas ( ) calibrated by In-process control personnel. Operating procedures (SOPs) are used as the basis for the tests together withthe manufacturing instructions. The approval of these instructions by quality con-trol ensures that the test complies with the requirements (normally according tothe pharmacopoeia). The testing of attributive criteria is an important In-process control task. This isparticularly of importance in relation to the filling of solutions and solid dosageforms as well as packaging.