Pharmaceutical Product Inspection

Pharmaceutical products are manufactured with an objective of meeting their predefined objectives of quality, safety and efficacy. However, how hard we try, still there is a possibility of physical product defects that may occur during the entire process of manufacturing at various stages. As a responsible pharmaceutical manufacturer and as per requirement of GMP, every industry shall be fully satisfied w.r.t. to all physical and chemical parameters, Accordingly, they shall have a system of product inspection with respect to visual defects before proceeding to further step of manufacturing or for releasing the same into the market.

We have already published series of articles to understand the manual visual inspection processes, requirements and challenges. Various articles published so far are:

1. Lighting requirements for Manual Visual Inspection of Pharmaceuticals
2. Inspection Rate for Manual Visual Inspection of Pharmaceuticals
3. Container Handling during Manual Visual Inspection of Pharmaceuticals
4. Qualification and Validation of Visual Inspectors and Inspection Processes; and
5. Product and Container Considerations for Manual Visual Inspection of Pharmaceuticals

However, still there are few questions that require further clarification to understand the concept of pharmaceutical product inspections. Few are as follows:

1. What are visual product defects and various types of defects?
2. How to classify various defects?
3. Why such defects occur?
4. What are extrinsic or intrinsic particles?
5. What is Product Inspection?
6. What are the environmental conditions and apparatus required for carrying out the product inspection?
7. Who will carry out product inspection?
8. How to carry out product inspection?
9. What is reinspection?
10. How to avoid human errors?
11. What is the frequency of medical Check-up?

All the above mentioned queries are explained below:

Question 1: What are various types of visual product defects?

Answer: Various formulations like tablets, capsules, injectables etc. have their own defects which are visible to naked eye if observed closely in a validated environment by qualified visual inspectors. The most common defects in various formulations are as follows:

Question 2: How to classify various defects?

Answer: Defects are commonly grouped into classifications based on patient and compliance risk. Various defects are classified majorly into following classification:

Question 3: Why such defects occur?

Answer: Contamination, Cross contamination, moisture, humidity, improper cleaning, inadequate in-process quality checks, inadequate process validation etc. are various reasons for such defects.

Question 4: What are extrinsic or intrinsic particles?

Answer:

Extrinsic Particles – The particles which are not related to manufacturing process are considered as extrinsic particles namely: hair, non-process-related fibers, starch, minerals, insect parts, and similar inorganic and organic materials.

Intrinsic Particles – The particles which are generated from within the manufacturing process are considered as intrinsic particles namely: stainless steel, seals, gaskets, packaging glass and elastomers, fluid transport tubing, and silicone lubricant.

Question 5: What is Product Inspection?

Answer: The visual inspection of semi processed or finished products under validated conditions by the qualified inspectors to detect various types of product defects in the formulations being manufactured.

Question 6: What are the environmental conditions and apparatus required for carrying out the product inspection?

Answer: There are various considerations and facilities that are required to be fulfilled for carrying out effective visual inspection.

1. Lighting: Lighting with an illumination intensity between 2000 and 3750 lux are normally considered acceptable at the inspection table. It should facilitate defect detection. It may be fluorescent, incandescent, spot, and/or polarized, and must be non-glaring. It should be evenly spread across the inspection zone. Higher intensity lights can be used for colored glass and plastic. For such containers light intensity of 10000 Lux may be required. There should be a periodic check of the light intensity using lux meter on the inspection belt and area. Surrounding area shall also be well lit. Read our article on ‘Lighting requirement for Manual Visual Inspection of Pharmaceuticals’ on detailed lighting requirements for visual inspection.
2. Magnifying Glass: This shall be available on site in case the inspector requires to check something critically. However, in routine inspection shall be carried out with naked eye. Read our article on ‘Container Handling during Manual Visual Inspection of Pharmaceuticals’ on requirement of magnification for visual inspection.
3. Background: The viewing must be performed against a non-glare black and white background under a specified non-glare light intensity.

Question 7: Who will carry out product inspection?

Answer: The trained and qualified visual inspectors shall carry out the visual inspection. The identified visual inspectors shall be thoroughly trained on the internal SOP on visual inspection. The training shall be phase wise. Specific number of hours shall be at least provided for each segment or type of defect and product. The trainees shall be trained using defect photographs. The type of defects shall be displayed in the inspection room also. Test sets or defect standards shall be used to provide hands-on training. Read our article on ‘Qualification and Validation of Visual Inspectors and Inspection Processes’ on requirement of qualification and validation of visual inspectors.

Question 8: How to carry out product inspection?

Answer: All the containers of a parenteral preparation must be inspected individually for extraneous contamination and other defects that may adversely affect the integrity of the product. Containers found defective must be rejected. For visible particles, particle motion aids in detection. Stationary particles are difficult to detect. Parenteral product inspection can be accomplished through manual visual inspection or by fully automated methods of inspection.

During product inspection care must be taken to understand the container and product characteristics to perform effective inspection as lyophilized products, amber colored vials etc. pose greater challenge for product inspection and detection of impurities if any. Read our article on ‘Product and Container Considerations for Manual Visual Inspection of Pharmaceuticals’ for details.

The inspection process must be designed and properly qualified. Every container whose contents show evidence of visible particulates must be rejected. Containers with any other defect shall also be rejected. Defect rates should be calculated at the end of each inspection process. Maximum allowable reject rates must be established.

The defects shall be trended, monitored and evaluated. The trends shall be prepared at least once a year but a firm may opt of quarterly trends for high volume products. Alert and action limits may also be established.

A firm must have detailed SOP capturing the minutest details. The entire inspection process shall be well documented. The inspection process can occur as a separate process or in-line with an associated process such as filling, labelling, or packaging.

Question 9: What is reinspection?

Answer: Reinspection shall only be performed if initial 100% inspection is not successful. This includes instances when the established 100% inspection failure rate(s) and/or the accept/reject number(s) associated with the chosen AQL values have been exceeded. Procedure for reinspection shall be pre-approved. The number of re-inspections should be limited. The procedure for reinspection shall consider special characteristics of the product and inspection conditions e.g. temperature, light exposure and sensitivity. The need for any re-inspection event should be evaluated and authorized by the appropriate quality function.

Question 10: How to avoid human errors during inspection?

Answer: The human errors during the inspection may be decreased by:

1. Establishing detailed procedures
2. Establishing adequate Inspection rate
3. Training of the visual inspectors
4. Qualification of the inspectors
5. Preparing proper standard defect kits
6. Having thorough and periodic medical check-up of visual inspectors
7. Providing proper lighting and other accessories
8. Inspector fatigue and ergonomic considerations shall be evaluated. Inspecting for extended periods of time may cause inspector fatigue and hence decrease the inspection performance. At least, the inspectors shall be given a break every hour to give rest to their eyes and mind.

Inspection stations should be designed and operated in a manner that minimizes the inspector’s risk of repetitive-motion injury. Adjustable chairs and careful positioning of light sources as well as incoming and inspected product can reduce the risk of such injury.

The inspection room environment should also be considered. Temperature and humidity should be controlled for inspector comfort. Reduced ambient lighting is recommended to focus the inspection process and to reduce distraction from extraneous reflections. Special care should be given to inspection rooms with exterior windows that allow daylight into the room and thus changing ambient lighting throughout the day and with changing seasons.

Question 11: What is the frequency of medical Check-up?

Answer: Personnel assigned to perform 100 percent manual visual inspection must pass eye examination as a 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. The medical check-up especially eye examination shall be carried out not later than one year.