1. Purpose
The purpose of this International Guideline is to describe the requirements for in- process testing and sampling during manufacture and packing.
2. Scope and Applicability
This Guideline is applicable to:
– Any product including intermediates, bulk drugs and formulated products.
– Any unit, its licensees, joint ventures and contractors.
3. Definitions
3.1 In-Process Testing/In-Process Controls
In-Process Testing/Controls is a test/control that is performed during manufacture, which provides added assurance that when finally tested by QC the product will meet it’s predetermined specification and attributes.
4. Responsibilities
4.1 It is the responsibility of each unit manufacturing and/or packing products to put in place procedures that describe the In-process Testing and Sampling during manufacture and/or packing.
4.2 It is the responsibility of the unit conducting the audits of the joint-ventures licensees, and contractors to ensure that this International Guideline is adhered to.
5. Guideline
5.1 Planning
In-process controls should have the ability to identify when corrective actions are needed and control the performance of processing steps that cause variability in the quality characteristics of products including intermediates and APIs.
In-process control activities should be based on the Master Formula or the Chemistry Manufacturing and Control (CMC) Documentation and on local process capability.
Written in-process control instructions must contain information about for example sample size, sampling frequency, test methods and locally established control limits. Samples must be representative of the batch. When possible, established statistical techniques should be applied and where appropriate, the test methods validated.
The instructions for in-process controls could be given in Batch Records, procedures or in separate in-process control records. The records must have space for entering and signing test results. All raw data generated must be maintained with these records. Qualified production department personnel can perform in-process controls. Sufficient space and qualified testing equipment should be available for the in- process controls.
Whilst normally in-process controls have associated control limits there may be occasions when additional testing is conducted to gather additional information and there are no control limits. If such testing is carried out it must be identified as ‘for information only’ and the purpose of gathering the data should be clearly understood.
5.2 In-process Control Activities
Examples of quality characteristics that can influence the product quality and should be considered when establishing in process controls are:
– weight variations
– Disintegration time.
– Specific resistance of water for processing
– Moisture content
– Clarity of solutions
– pH in solutions
– Volume filled into finished product containers
– Appearance and correctness of packaged units
– Hardness
– Thickness
– Tablet physical appearance.
– Temperature
– Pressure
– Duration of a procedure or process step
Routine tests of such environmental conditions, which can influence the product quality should be considered when establishing in process controls are: Counting of viable micro-organisms and non-viable particles.
Hand and finger tip tests for viable micro-organisms surface tests for viable micro-organisms In the context of API manufacture the acceptance criteria and type and extent of testing can depend on the nature of the intermediate or API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product’s quality.
Less stringent in-process controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., isolation and purification steps). The standards applied to API and intermediate in-process testing may be based on an assessment of the level of process control required and the proximity of the test to the final API.
The assessment will determine the degree of instrument qualification, method validation, calibration and preventative maintenance required. The assessment should be documented unless normal standards of qualification, validation, calibration and maintenance applied to product QC testing are employed.
5.3 Corrective Actions
Corrective actions should be taken immediately when test results are outside the in-process control limits. These limits could be expressed as alert or action limits.
The process can be adjusted without the prior approval of the quality unit if the adjustments are made within pre-established limits approved by the quality unit. If a process out of control cannot be immediately corrected to ensure the product quality, the process should be interrupted when this is practical until corrective actions have been successfully completed.
Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process. All materials manufactured under conditions out of control should be segregated for further investigation.
5.4 Return of Samples
Samples taken for in-process control must not be returned to the batch, if they have been moved from the immediate production area.
5.5 Documentation
In-process control results and any corrective action taken must be recorded and added to the Batch Records in order to be assessed in the quality evaluation. Primary data, control charts and calculations must be included. The number of samples taken during in process control must be recorded.
5.6 Sampling
Samples taken during manufacture and packing which could be used for QC testing must be taken by personnel and by methods approved by Quality Assurance/Quality Control under conditions and with a technique which will give a representative sample and preserve the initial quality of the product.
The samples must be identified with product name, code number and batch number and when they have been taken e.g. beginning, middle and end. It must be recorded in the Batch Records that samples have been taken.