INTRODUCTION:

Pharmaceutical products are treasurable to human life and thus are viewed as ‘golden sword’ for treating any ailment related to human-beings and thus defects in them can be truly harmful¹. Drugs are the most important elements in healthcare and must be manufactured to the highest quality levels². Parenteral preparations are sterile, isotonic, pyrogen-free liquids which contain one or more active ingredients along with added excipients, packaged in a single-dose or multi-dose containers. They are injected, infused or implanted in the body³.

Figure 1- Various routes of administration that are used for administering parenterals (Created with BioRender.com).

Generally, oral route is favored for administering drugs but parenterals are used in case of drugs that are not effective orally and in case of severe illness. Intravenous (IV) route provides quick onset of action and is favored route in case of emergencies^4,5. Parenterals must be extremely pure and devoid of any biological, chemical or physical contaminants as they are injected directly into bloodstream⁶. Stability, safety and efficacy of the parenteral product largely depends on the type of packaging and the integrity of the package⁷. Medication error can occur during administration, distribution or in the course of prescribing certain drug products. These errors can cause harm to patient, increase the cost of medical care, lead to improper medical usage or wastage of scanty medical materials but can be prevented by taking adequate measures^8,9,10. There is a good customer equity built up if customer complaints are handled properly, which also has a direct impact on the trust of the customer, this can even nullify the negativity which might have emerged in customer’s minds due to the fault of the product¹¹. Customer Relationship Management (CRM) of the companies plays a major role not only in ensuring that the customers are handled with utmost care but also ensuring the customers that their opinion and feedback counts. Quality is key requirement and must be guaranteed by all personnel handling the production, testing and distribution of the product¹². The companies are now moving from Six Sigma¹³ to a Zero-defect theory. This theory goes with eliminating waste and unproductive processes. It speaks of doing it right the first time, every time. If a manufacturing company attains zero defects, it will result in cost reduction (which may translate into price reduction), which will help achieve higher customer satisfaction^14,15.

1. Packaging of parenteral products

Glass or plastic is generally used as a primary packaging material for parenteral products. Both of them are associated with certain advantages and disadvantages¹⁶. Glass is generally the preferred choice for most parenterals. There are different classes of glass based on the material used to make it like type I borosilicate glass, type II treated soda-lime glass and type III soda-lime glass^17,18. Type IV is general purpose glass but is usually not used for parenterals due to low hydrolytic resistance¹⁹. There are 5 possible packaging options for parenteral products-

Table 1- Parenteral Packaging²⁰

Container	Tubing Glass	Moulded Glass
Ampoules	ü
Pre-fillable syringes	ü
Vials	ü	ü
Bottles		ü
Cartridges	ü

1.1 Unique products and container considerations

1.1.1 Sterile powdered products²¹

These products should be packed in containers that are light-resistant and provide protection against microbial contamination and water vapour. Solid dosage form until reconstituted has greatest chance of interacting with its container closure system components. Thus, the USP Biological Reactivity Test and possibly extraction/ toxicological evaluation is essential.

1.1.2 Amber coloured containers²²

Amber glass is one variety of very attractive packaging. Light can cause photooxidation within a container which can greatly compromise a product. This is prevented by amber coloured bottle.

1.1.3 Single dose and multiple dose vial closure material²³

The most commonly used type of closure is the elastomeric closure. An elastomer is any material that is able to resume its original shape when a deforming force is removed, which is known as viscoelasticity. For the manufacturing of closures, the elastomer is either natural or, as is more common, a synthetic rubber, such as butyl rubber or chlorobutyl rubber. The advantage of synthetic rubbers is that the materials are strongly resistant to permeation by oxygen or to water vapor.

2. PRODUCT RECALL:

The reason for drug product recall is may be due to wrong drug, unapproved drug, microbial contamination in the formulation, incorrect usage information on package, may contain particulates prior to expiration date, etc²⁴.

2.1 FDA’s product recall categories²⁵

· Class I recall is for products that may cause severe adverse drug reactions or death

· Class II recall denotes products that cause adverse reactions that are reversible

· Class III recall is for products that are unlikely to cause any adverse reactions

2.2 CDSCO product recall categories²⁶

· Class I recall denotes a reasonable probability that the use of, or exposure to, a defective product will cause serious adverse health consequences or death and as well as banned under 26A of Drugs and Cosmetics Act 1940.

· Class II recall is when use of, or exposure to, a defective product may cause temporary adverse health consequences or where the probability of serious adverse health consequences is remote.

· Class III recall is done when the use of, or exposure to, a defective product is not likely to cause any adverse health consequences.

2.3 Corrective and Preventive Actions²⁷

Corrective and Preventive Actions (CAPAs) as stated by FDA (Food and Drug Administration), identifies and examines product quality and associated issues and also suggests appropriate and efficient corrective and/or preventive action to avoid their recurrence.

2.4 Current Good Manufacturing Practices

Current Good Manufacturing Practices (cGMP) puts down certain requirements that are necessary for a manufacturer to ensure that their products sustain quality during its shelf life²⁸. Good manufacturing practices for pharmaceutical products require that critical processes, which may affect product quality, have to be validated²⁹.

3. TYPES OF INSPECTION TO PREVENT DEFECT

3.1 Manual Visual Inspection³⁰

Manual visual inspection is the most common method for performing 100% visual inspection of parenteral liquids. After 100% visual inspection, a sampling of accepted units of each batch is inspected to ensure that the remaining level of defects is statistically acceptable. Manual visual inspection brackets visual inspection from the beginning (qualification) to the end (acceptance quality limit, or AQL) of the process.

Table 2-Acceptable quality limit (AQL) standard range of defects for visual inspection³¹

Defect Category	AQL Range (%)
Critical	0.01
Major	0.25
Minor	4.0

3.2 Semi-automated visual inspection³²

The sample in its primary container (vial, prefilled syringe and cartridge made of glass) is rotated under standardized conditions. Then, images or entire videos of the liquid are captured in the spinning and/or subsequently stopped container. Later, processing algorithms are applied to quantify the number of visible particles detected within the video frames.

3.3 Automated visual inspection³³

These systems use cutting edge computer visual technology to detect deformities, contamination and other abnormalities. For each inspected container, a collection of images is acquired using high resolution video cameras under designed illumination conditions. Defects on the package are identified and/or measured by dedicated image processing algorithms and the package is classified as conforming or non-conforming accordingly.

4. MATERIALS AND METHODS:

4.1 Materials- Both good and defective marketed products were compared in this study. Products included IV infusion, unlabelled vial and empty package of IV cannula.

4.2 Methodology- The defective products were obtained from Hospital Pharmacy, KMC hospital, Attavara (An associate hospital of MAHE, Manipal), Mangaluru, Karnataka state, India. The good and defective samples of each product were compared and investigated³⁴.

Table 3- Overview of defects investigated in the study

Dosage form	Generic name	Defect/Issue	Category of defect
Large volume parenteral (IV infusion)	Essential amino acids	Foreign particulate matter and fungal growth seen	Critical
Small volume parenteral (Vial)	Cyanocobalamin (Vit B12)	Batch over coding details missing on primary label	Major
IV Cannula	Medical device	Empty packet of cannula	Minor

Case Study I

· Dosage form- IV infusion

· Generic name- Essential amino acids

· Therapeutic category- Growth and health enhancers³⁵

· Methodology- The container was observed in front of the white panel as well as black panel for 5 seconds by gently swirling it and it was ensured that air bubbles were not formed. In addition, container was screened for clarity using the magnifying lens. The containers that display certain observable particulate matter were rejected³⁶.

· Defect- The infusion container had foreign material and fungal growth.

Figure 2a-Defective infusion container as observed against a light background

Figure 2b-Defective infusion container as observed against a dark background

Case Study II

· Dosage form- Injection vial

· Generic name- Cyanocobalamin (Vit B12)

· Therapeutic category- Vitamin B12 deficiency

· Methodology- The label must remain in place and should be readable throughout distribution, storage and usage of the product³⁷. The product is considered misbranded if an incorrect batch number is printed on it or batch over coding is missing³⁸.

· Defect- Key batch over coding details such as batch number, manufacture and expiry date were missing on the primary label.

Figure 3-Batch over coding details missing on the primary label of the vial

Case Study III

· Equipment- Cannula

· Therapeutic category- Medical device

· Methodology- The received IV cannula packet was investigated and checked thoroughly.

· Defect- Empty packet of IV cannula.

Figure 4-Empty pack of IV cannula v/s filled packs of IV cannula

5. RESULTS AND cGMP LEARNINGS

5.1 Case Study I- Contaminated IV Infusion

· Category of defect- Critical

· Description- Contamination can occur due to packaging and as well as the environment of production area. Manufacturers can avoid such issues by employing better filtration methods, training employees, improving washing methods for equipment and glassware as well as conducting particle analysis in laboratories, but still certain factors may contribute to contamination³⁹.

· Probable root causes-

· Improper evaluation of environmental controls⁴⁰

· GMP requirements⁴¹ were not implemented properly

· It may happen if the personnel involved in manufacturing or packing of the product did not maintain hygienic conditions or due to improper gowning⁴²

· Improper closure system used for sealing of the container cap can also lead to such a defect⁴³

Remedial measures:

· The personnel should be properly trained on gowning procedures^44,45 and should demonstrate adequate ability towards aseptic compounding, environmental controls and related activities⁴⁶

· There must be quality control unit that keeps track of, reviews and rejects such defective products⁴⁷

· The manufacturing unit should have sufficient space so as to avoid mix-up, contamination or cross-contamination during production⁴⁸

· There should be adequate control over temperature, dust, air pressure, humidity during all processes of manufacture to avoid such unwanted growth⁴⁹

Clinical significance- Injection of a drug product containing particulate matter may result in serious and potentially life-threatening adverse events, such as infection, allergic reaction, toxicity, or other reactions⁵⁰. Such defects may also lead to decrease in patient adherence⁵¹.

cGMP lessons learnt-

· Raw materials should be thoroughly checked

· Water used in formulation should be sterile having highest quality

· Closures present on the parenteral products should be properly sealed.

· Proper stability studies should be carried out for each batch

5.2 Case Study II- Absence of batch-over-coding details on primary label

Category of defect- Major

Description- Label functions to inform the medical features of given product and reducing risk of product liability claims. Thus, it is necessary to have legally and scientifically correct information on label⁵².

Probable root causes-

· Inspection and rejection systems were inefficient

· Blank label can arise when a fresh label is introduced for a new batch and ink (containing details) is not sufficiently wet leading to blank labels

· Line-clearance system⁵³ may be incompetent

Remedial measures-

· Each label on the packaged item should be spot checked⁵⁴

· Camera-based or alarm-based systems can be put in place to reject unlabelled bottles⁵⁵

· Quality control and quality assurance checks should be strengthened⁵⁶

· Incorporation of regular operator and development trainings

Clinical significance- As the manufacturing and expiry date are not mentioned, clinical efficacy of product is affected and may lead to severe reactions if product is administered post its expiration. Absence of batch number can seriously affect product recall/withdrawal of one lot, multiple lot, or all lots that have ever been manufactured⁵⁷. Labelling defects may cause adverse events⁵⁸ or can have minimum impact^59,60 but should be strictly avoided.

cGMP lessons learnt-

· Personnel can be assigned to visually inspect labels present on the containers before cartoning

· If possible, companies can go for complete automation of labelling procedures

· Camera and alarm-based systems can be put in place and if already present, they can be regularly audited to ensure smooth functioning

· Line-in charge of the respective packaging line should ensure that line clearance is done properly and in accordance with cGMP requirements

5.3 Case Study III- Empty IV Cannula Pack

Category of defect- Minor

Probable root cause-

· IPQC⁶¹ checks during primary packaging were not done properly

· Personnel may not be properly trained to reject such packages⁶²

Remedial measures-

· The personnel involved should be properly trained and should remain familiar with the cGMP requirements applicable to each process⁶³ to avoid recurrence

· Automatic weighing balance can be installed on packaging lines to check for such empty packages⁶⁴

· 100% visual inspection before cartoning can be done or camera-based inspections can be carried out⁶⁵

Clinical significance- Such an issue may cause a serious harm in case of emergency cases or at night shifts in hospitals when the nurses or doctors are presented with such an empty cannula pack. This can also lead to reduced patient compliance.

cGMP lessons learnt-

· Automation (automatic weight checker) is the key while dealing with such a defect

· Personnel involved in the packaging line should be well trained

· Regular audits can be done to ensure proper functioning of the packaging line

6. CONCLUSION:

Sufficient training and strict adherence to GMP guidelines should be ensured throughout the manufacturing process. Product recalls affects reputation of brand as well has certain financial implications and thus should be avoided. There are a few ways of reducing or eliminating manufacturing defects; prominently among them are automation, training the operators and shop floor employees, working towards six-sigma compliance, and investment in the state-of-the-art equipment.

7. ACKNOWLEDGEMENT:

Authors would like to mention their gratitude towards Hospital Pharmacy, KMC Hospital (An associate Hospital of MAHE, Manipal), Attavar, Mangaluru, India for their constant support and the Audio-Visual unit of MAHE for their timely assistance and for providing the needed resources.

8. CONFLICT OF INTEREST:

Mr. Hemanth KG currently works with Novartis Healthcare Pvt Ltd, Hyderabad, and it has no role or involvement in this research work. There was no potential conflict of interest amongst the remaining authors.

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Received on 14.09.2021 Modified on 19.11.2021

Research J. Pharm.and Tech 2022; 15(2):729-735.

DOI: 10.52711/0974-360X.2022.00121