Filling Operations and Controls
Filling operations and controls should be such that the identity, strength, purity, and quality of the product are maintained throughout the process. The requirements for filling and packaging controls are covered in 21 CFR 211, Subpart G. Written procedures that govern the filling processes of each product fill, and the execution of these procedures, must be documented as process controls, and any deviations must be documented and reviewed. These procedures help prevent contamination and ensure that filled product is of the strength, identity, purity, and quality it is purported to have.
MATERIALS CONTROL
Filling operations begin after the bulk manufacturing process has been completed. At this point the blend/bulk has been tested to be uniform, passed all bulk specifications, and been released for filling. Filling processes should be such that the identity, strength, and purity of the bulk are not altered. Clear written filling procedures (filling assembly procedures) specific to each type of product are required. Filling assembly procedures (FAPs) should be maintained through a change control process to ensure the correct versions are being used in operations. Each FAP is to be verified against the master FAP before a filling operation. The FAP should contain the product name, strength of dosage, dosage form, dosage unit, net contents, and all details and specifications regarding its filling process. The FAP or bill of materials (BOM) will contain the appropriate components, their part numbers, the process of assembly, and specifications of assembling to complete the filling process. The quality unit (QU) group will ensure that all components and bulk product needed for filling have been appropriately tested and released for filling operations.
FILLING ASSEMBLY PROCEDURES
FAPs are formally authorized packaging instructions that should exist for each product, pack size, and type. These should normally include, or make reference to, the name of the product; a description of its pharmaceutical form, strength and, where applicable, method of application; the pack size expressed in terms of the number, weight, or volume of the product in the final container; and a complete list of all the packaging materials required for a standard batch size, including quantities, sizes, and types, with the code or reference number relating to the specifications for each packaging material. Where appropriate, an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked, should be included, as well as any special precautions to be observed, including a careful examination of the packaging area and equipment to ascertain the line clearance before and after packaging operations; a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; and details of in-process controls with instructions for sampling and acceptance limits.
FILLING EQUIPMENT CONTROLS
Filling equipment should be qualified through valid installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) protocols to ensure it is installed as per its design specifications, and can operate and perform as required to yield desired results within preset specifications. The equipment should be maintained regularly and is to be included in the preventive maintenance program. Any replacement of parts should be like for like and should be managed within a change control process. Each piece of equipment should be assigned a unique identifier, and this number should be noted in filling records of operations that use the equipment.
Filling operations of a pilot or test batch of product should be used to determine the appropriate filling equipment needed for the process to yield filled product for preset specifications. This process should be incorporated in the FAP and is to be validated to ensure uniformity in every fill. Further, at predetermined intervals filled goods from every fill should be taken and tested for fill criteria to ensure that filling operations are under control throughout the run. These data are recorded in a filling record that is verified by a second person or QA as part of filled goods release.
CONTAMINATION CONTROLS
Contamination in filling of a product can occur from other filling processes, from the environment, or from personnel. Filling operations should be such that there is physical or spatial separation between different product filling operations to prevent contamination. Filling areas should be inspected immediately before use to ensure that all materials not required for the next fill have been removed, and this inspection should be documented.
Filling of dry powders requires special precautions to prevent generation and spreading of dust. Proper air control measures are needed for such filling operations, with a regulated supply and extraction of air of suitable quality. Contamination of one product by another product must be avoided. The significance of the contamination risk varies with the type of contaminant and type of product being contaminated. Facilities manufacturing highly sensitive materials such as hormones, biologic preparations, living organisms, cytotoxic substances, or highly active materials should use dedicated equipment in self-contained areas. Products in which contamination is likely to be most significant are products administered by injection, products applied to open wounds, and those given in large doses or for a prolonged time. Several measures can help avoid cross-contamination (Figure 49.1). Measures to prevent cross-contamination and their effectiveness should be checked periodically according to standard operating procedures (SOPs). Production areas where susceptible products are processed should undergo periodic environmental monitoring (for example, for microbiological monitoring and particulate matter where appropriate [ISO 14644]).
STAGED MATERIALS
Staging materials properly is a key process that prevents contamination or substitutions in a filling process and is accomplished through good line-clearance procedures with appropriate checklists and documentation of activities for each fill. The staging area for filling should be clearly marked for each filling process or line. All components needed for that fill should be brought to the corresponding staging area for the fill, and only components needed for that fill should be there. QA should check and ensure that all components are tested and released before staging for fill. Filled goods should have a location of their own and should not be commingled with components staging. Different products should not be packaged in close proximity unless there is clear physical segregation. The name and batch/lot number of each product being staged for fill, and the fill line, should be clearly displayed in the area. Filled goods should also be labeled immediately with the product name, batch number, and its release status. All staged materials should be reconciled at the end of the fill process, including any labels printed during the fill process.
STATUS LABELING
Products should be labeled immediately after fill, preferably in-line with the fill process to avoid any mistakes. Appropriate procedures for labeling in-line and off-line should be in place in case of any delays. All products at all stages should have a status label. The product should at a minimum have the batch number, product name, and release status. If a particular filled product is removed from the line for any reason, then the status label for that product should contain the reason, for example, QA sample, retain, nonconforming sample, and so on. Any filled goods without a status label are considered contaminated product. Therefore, care must be taken to have status assigned to products at all stages. Once the filling process is completed, all filled goods are removed from the line and located in a designated area with the status of “Hold.”
For each batch/lot of drug product, appropriate laboratory tests should be used to determine conformity to the finished product specifications. The filled goods taken from the filling process periodically as per filling procedures for quality control (QC) testing are tested for the criteria specified. Once these tests have been satisfactorily completed, the filled goods of that lot can be released. The products of that lot can be moved to released inventory. Products failing to meet the established specifications must be quarantined and a nonconformance process initiated. Products not meeting the specifications must be rejected and appropriately disposed of.