Parenteral Product Inspection
Filled containers of parenteral products must be inspected individually for extraneous contamination and other defects that may adversely affect the integrity of the product. Units found defective in this manner must be rejected. Such inspection is one of many activities that a parenteral manufacturer uses in its effort to assure that its drug product meets the quality and purity characteristics that it purports or is represented to possess. Parenteral product inspection can be accomplished through manual visual inspection or by fully automated methods of inspection.
The inspection process must be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates. Every container whose contents show evidence of visible particulates must be rejected. Likewise, evidence of any other serious (critical or major) product/container defect provides grounds for rejecting that final container. Defect rates should be calculated at the end of each inspection process. Maximum allowable reject rates must be established.
Trends in types and size of particulates should be monitored and evaluated (for example, as part of an overall quality system). Intrinsic particulates (from the manufacturing process) are to be treated separately from extrinsic particulates (from environmental sources external to the manufacturing process itself). Three classifications of common defects have been defined (Table 52.1). Container or closure defects include cracked containers, broken finish (vial), damaged stopper or seal that compromises integrity (vial), or wrong or missing component (for example, a vial stopper or seal) or container. Examples of product defects include foreign material or particulate matter, precipitates and agglomerates, underfills and overfills, and melted cake (or a collapsed cake in some cases) for lyophilized products.
Each person engaged in parenteral product inspection operations must have the education, training, and experience, or any combination thereof, to perform his or her assigned function, whether that function involves a manual, semiautomated, or automated visual inspection process or operation. Likewise, written production and process control procedures must be followed in the execution of the parenteral product inspection, and those inspection activities are documented at the time of their performance. These personnel, procedural, and documentation requirements apply to reinspection activities as well.
Parenteral product inspection activities must be performed in accordance with established specifications, standards, sampling plans, and test procedures that are scientifically sound and appropriate to assure that the drug product conforms to appropriate standards of identity, strength, quality, and purity. The inspection process can occur as a separate process or in-line with an associated process such as filling, labeling, or packaging. Drug product containers undergoing inspection are fully assembled (container/closure assembly) and as such can be inspected in an unclassified area. Adequate facilities, equipment, and materials must be available and used to execute the inspection process, regardless of the methodology and technology being used. Special considerations must be given to drug product solutions that are prone to forming product-related particulates (for example, protein formulations). The consideration should include specific product-related training and inspection techniques, and/or characterization data for product storage time and conditions.
Reinspections may be permitted, but the number of reinspections should be limited, specified, and justified, and any special characteristics of the product should be taken into consideration, if applicable (for example, temperature and light exposure and sensitivity). The need for any reinspection event should be evaluated and authorized by the appropriate quality function. Additional, and oftentimes specialized, training and/or qualification for a reinspection activity is customary and expected.
Quality control (QC) acceptance criteria must be applied to the parenteral product inspection process, and the results must be considered when assessing a drug product batch’s condition for approval and release. Each appropriate specification and appropriate statistical quality control criterion must be met. The statistical QC criteria must include appropriate acceptance levels and/or appropriate rejection levels. Statistically sound sampling plans for acceptable quality level (AQL) inspection must be used. ISO 2859.1 or ANSI/ASQ Z1.4 level II sampling commonly is used for the quality assurance acceptance sampling, after the inspection event, and serves as a quality assurance (QA) audit of the entire process (the manufacturing process, as well as the 100 percent inspection process). AQLs for particulate and other serious defect attributes are generally within the range of 0.065% to 1.0%. Reinspections are also subject to additional AQL sampling and inspection.
MANUAL VISUAL INSPECTION
The basic manual visual inspection process typically involves the individual viewing of 100 percent of the filled containers of a parenteral drug product lot. Viewing distance, particle motion in the liquid, and container volume are important factors to be considered in the design of any manual visual inspection program. The viewing must be performed against a nonglare black-and-white background under a specified nonglare light intensity. The viewing is performed by a person who has been trained and qualified to inspect for specified defects.
The purpose of the inspection is to detect container or drug product solution defects according to the established training and qualification procedures, under a controlled setting and specified inspection parameters. Containers considered defective are segregated from containers considered acceptable. Further handling of the segregated containers must be delineated in the firm’s procedures.
Lighting may be fluorescent, incandescent, spot, and/or polarized, and must be nonglaring. The light intensity at the container viewing area must be specified and of a strength that facilitates defect detection. Common acceptable illumination intensities are between 2000 and 3750 lux. Higher intensities can be used for colored glass and plastic containers, and for certain types of products (for example, colored solutions). Higher intensities should be justified and characterized by the firm. Light intensity must be monitored to ensure it is within the parameters specified in the inspection procedures. Procedures should be in place to ensure sufficient relamping frequency.
The rate of the manual visual inspection process must be specified. This rate is oftentimes referred to as the “pace.” A common pace, per container, is five seconds of viewing against the black background and five seconds of viewing against the white background. Otherwise, the pace or rate must be defined and characterized. Rate consistency is customarily accomplished with the aid of a pacing mechanism (for example, an LED or other type of light prompting). Pacing is the methodology used for achieving a uniform and effective rate of inspection within the defined and acceptable quality standards and levels.
Another form of manual visual inspection of parenteral products typically involves a presentation machine. These machines typically use many of the same features of the standard manual inspection process (that is, lighting, inspection zone, container movement to create particle movement), yet handle and present the vial to the operator in a controlled and repeatable manner. Although this process is referred to as semiautomated visual inspection of parenteral product, it has many of the same requirements for operator training and qualification. The machine manipulates the container during viewing, yet the operator performs the inspection.
Training
Each person engaged in manual visual inspections must have the education, training, and experience, or any combination thereof, to perform the visual inspection with reproducibility. Inspectors must be trained in relevant inspection-related procedures, theory discussion, and defect recognition (using examples). Training and testing conditions should be in alignment with those of the actual inspection process and environment. Should trainees inspect product during probationary periods, all units inspected by the trainees should be reinspected by qualified inspectors to assure the quality of the inspection and the development of the trainee.
Qualification
The qualification process consists of passing an eye examination, successful completion of the training and qualification activities, and a number of successful consecutive passes of the qualification kits as established by the firm’s procedures. The qualification process tests the trainee’s ability to identify and segregate defective units from acceptable units by using a test panel (qualification kit) composed of known defective and acceptable containers representative of the process and product, if applicable. Inspectors should be re-qualified at least annually, and the re-qualification process should include at least one successful test on the qualification kit. Quality personnel assigned to perform the verification of inspected lots (AQL inspection) should have, as a minimum, the same training and qualification as would be expected for personnel performing 100 percent manual visual inspection.
As an alternate method to the 100 percent visual inspection, fully automatic inspection machines exist for particle, cosmetic defect, and leak detection (container/closure defect) inspection. When using an automated method, it must provide at least the same level of inspection security as the manual visual inspection method. Any automated method used must provide detection rates at confidence levels that are equal to or greater than those achieved by manual inspection. Automated inspection machines should be challenged using defects obtained from the production operation.
As with any other process, equipment, or system used in the manufacture of finished pharmaceuticals, automated inspection machines and processes must be validated and documented under the company’s overall validation policy. Typical performance qualification for automated inspection equipment would involve the inspection of three consecutive lots to assure reproducibility of results. Likewise, the equipment must be routinely calibrated, inspected, and checked according to a written program designed to assure proper performance. Written procedures for cleaning, operating, and maintaining the automated equipment are required. All such programs and procedures must be approved and followed.
Defect libraries, or sample sets (also referred to as qualification/test panels or kits), should be representative of those particles and defects found in the operation. Particle sizes and the types of defects present in the sets should represent the range of sizes and defects that have been, or could be, found in the production environment. When automated inspection equipment is used, it can be calibrated using the standard sets. Defect libraries must be reviewed at some appropriate frequency and modified, augmented, or revised to assure that the kits are maintained in a state that supports the inspection program’s needs.
Personnel assigned to perform 100 percent manual visual inspection must pass eye examinations as part of their initial qualification and on some routine basis thereafter. Vision may be corrected, as long as acceptable results are achieved. The examinations should include visual acuity and a color and contrast assessment as well. Routine annual eye examinations for these parameters are common.
Inspector concentration, ergonomic comfort, and level of fatigue are important considerations for successful visual inspection results. Inspectors should be provided appropriate relief from the inspection rigor, which can be accomplished through rest breaks and/or job rotation.