INTRODUCTION:

It is well known fact that tablets are the most common and frequently used among oral dosage forms. This is due to its relative low cost and ease of administration. Defects in the tablets can arise during manufacturing processes, storage or transport. These visual defects can reduce the acceptability by the users and effectiveness of the product and can harm the patient’s safety. It may also result in product recalls.

A drug recall is an instance to return to the manufacturer a batch or an entire production run of a drug product, usually due to the detection of safety issues or drug product defect. When drug products are known to have potentially harmful effect on users due to their defective quality, safety or efficacy, they may be subjected to recall. The quality management of complaints and drug product recalls are necessary to ensure the safety of customer. Recalls are a suitable alternative providence by the FDA for removing or correcting marketed consumer products, their labelling, and/or promotional literature that violate the laws administrated. The recall shall be initiated by the QA Head in co-ordination with supply chain department or distribution department as per SOP on Product Recall.

Recall Classification:

Class I: A dangerous or defective product that could cause serious health problems or death.

Class II: A product that might cause a temporary health problem, or pose slight threat of a serious nature.

Class III: A products that is unlikely to cause any adverse health reaction, but that violates FDA labelling or manufacturing laws.

Financial implications of Product Recalls

Public notification is generally issued when a product that has been widely distributed or poses a serious health hazard is recalled. Patients also may learn that their medicine has been recalled through notification from the manufacturer, their health care professional or pharmacist. Market withdrawal occurs when a product has a minor violation that would not be subject to FDA. Drug product is removed by the firm from the market or corrects the violation or which involves no violation^{1, 2, 3}. All products undergo 4 different stages in their lifetime, and this is termed as product life cycle. The 4 stages are introduction, growth, maturity and decline stages and depending on the product life cycle stage. In each of these stage, products are in a different position in the minds of the consumer and so is the customer loyalty for such products⁴. The ultimate motive for all industries would be profit maximization with substantial market presence. Profit persistence may be similar in pharmaceutical industry because pharmaceutical companies too have the mission of profit maximization and share holders’ wealth maximization⁵. Whereas the company's returns from all of these technologies can undermine over period, innovation guarantees that the company retains a strong-performance position overall⁶.The time taken for innovation is also pretty long that reduces the Return on Investment (ROI) on such innovation, just a few products move from the discovery phase to the market effectively⁷. And failures effect companies in different manner based on what stage of the Product Life Cycle (PLC) the product is in. About 9.34 % of the drugs withdrawn in the last 60 years have been withdrawn across the world and the rest within a country or geographical area⁸. If a pharmaceutical product fails, it is a distinctive market place scenario. Unlike consumer economies, there are more and more stakeholders in the pharmaceutical industry, including health care providers, government organizations, distributors, and customers. Even though it is reasonable that the withdrawal effects would be felt maximum by way of Pharma industries, it's far possible that different contributors in the drug approval, product choice, and distribution approaches also are afflicted ⁹.

The effect could be visibly felt on impact on the goodwill, negative impact on existing brands by the same company, fall in the stock price of the company, and more importantly the firm’s performance. The buyer discernments of the companies are adversely influenced because of the market withdrawal company productivity has been appeared to endure as well. Considers analysing costs of item review have included the coordinate costs (taken a toll of physically reviewing and crushing the inadequate item) and circuitous costs (negative affect on a firm’s goodwill, counting negative press and resultant misfortune of notoriety for the company creating the reviewed item). Studies evaluating costs of the recalled products have included the direct expenditure (cost of physical recall and destruction of the faulty product) and indirect costs (negative impact on the firm’s business, including negative media and resulting in loss of reputation of the firm producing the product that was recalled). Though these direct costs can be significant, there are greater indirect costs ^{10, 11}.

Competitive advantages are more probable when the drug withdrawn has a high market share as it guarantees that a big proportion of individuals are at possibility of moving to the same class of non-withdrawn drugs¹². The stock market seemed to impose a significant loss of benevolence on a company over and above the cost of withdrawal specific to the product. Specifically examining the pharmaceutical industry, competing companies have experienced significant deluge effects from recalls of competent products¹³. If the customer blames the sector for a product failure, this can have negative implications for the future buy intention of the customer. Also, losses from product development setbacks were sharper than gains from accomplishments in product development. Also, firm’s performance is directly linked to success or failure of product developments¹⁴. Satisfaction is associated with performance that fulfils expectations, while discontent happens when performance needs are not met, suggesting relative rather than absolute judgments are involved in determining satisfaction. It is therefore vital for businesses to give priority to customer satisfaction ¹⁵. Therefore, this research article shall stress on manufacturing defects/quality issues and is just a tip of an iceberg for pharma industry.

MATERIAL AND METHODS:

Materials: Good samples and Defective samples.

Methodology:

Both good and defective samples of multivitamin tablets, enteric coated tablets, film coated tablets, uncoated tablets, hard and soft gelatin capsules were procured from reputed hospital pharmacy/retail outlets in Udupi. Investigation was carried out to find out the root causes of the defects and cross verified with the good samples.

Case studies, investigations and outcomes:

Case study 1:

Fig 1: KUP_4159, Batch over coding defects (Two different pricing on cartons from same batch number)

Dosage form:

Multivitamin Tablets (10’s alu-alu in mono carton)

Generic Name:

Vitamins, Mineral, Zinc and Astaxanthin

Defects:

The mono carton with same batch number had two different MRP values.

Category:

Critical

Probable root causes:

· QC/QA check is not done adequately

· Stereo block may not have been adjusted as per the given MRP details

· Details entered during machine setting was wrong

Remediation:

· As it is specific marketing requirement, QC/QA check should be done and verified properly

· QA line clearance with respect batch over coding details should be done before starting the packaging

Clinical significance:

· As it only affects price, the clinical significance may not be compromised. Patients will become reluctant to take drugs that are not affordable and creates confusion among pharmacists and patients.

Case study 2:

Fig 2a: KUP_4162, Blister having two melted/softened tablets (shown against a good blister).

Fig 2b: KUP_4163, Back side of intact blister (No damages observed).

Dosage form:

Enteric coated Tablets

Generic Name:

Omeprazole magnesium and Domperidone Tablets

Defects:

Two enteric coated tablets found to be melted/softened within intact blister pocket.

Category:

Critical

Probable root causes:

· Sealing temperature set during lidding process was high

· Presence of low melting point substances

· Tablets were exposed to heat because of higher dwell time

· In- Process control check was not done properly

· Area maintained between the product-containing cavities, as well as to the outer edge of the blister was less during the sealing

Remediation:

· Sealing should be done at optimum required temperature to reduce the heat

· Sealing tool should have good flatness and appropriate knurling

· At least 3mm area should be maintained between the product-containing cavities, as well as to the outer edge of the blister

· The sealing die surfaces should be inspected and cleaned regularly before the process

· Appropriate selection of sealing tools i.e, platen or rotary sealing

· Separate cooling systems for the forming and sealing stations can minimize the variations in the sealing parameters and control the process

Clinical significance:

· Active Pharmaceutical Ingredient (API) of the product might undergo deterioration because of high temperature

· Timely released properties may be lost and patient may not get sustained action for the required condition

Case study 3:

Fig 3: KUP_4164, Color/shade variation in film coated tablets

Dosage form:

Film coated Tablets

Generic Name:

Olanzapine Tablets

Defects:

Batch to batch color variation observed and a classic example for dark, medium and light shades.

Category:

Critical

Probable root causes:

· Color variation can be due to error in weighing coloring agents or error during processing or concentration of the coloring dye used

· It can be due to improper spraying process which differs with spray time or spray quantity

· Improper mixing of colored dye solution

· Variation of the frequency or duration of appearance of tablets in the spray zone or the size/shape of the spray zone

· Insufficient coating

· Migration of the soluble dye’s plasticizers during the process of drying

Remediation:

· Using excipients and colorants from an approved suppliers / vendor only and colorants should be compatible with the drug

· Using mild drying conditions

· Use spray patterns with optimum bed coverage and process validation

· Ensuring that the coloring solution ingredients encompasses all the Critical Material Attributes to enable proper functioning of the selected coloring agent

· The composition and grade of the coating solution ingredients has to be established precisely (plasticizer, colorant, opacifier, grade of polymer)

· Ensuring dispensing and addition of all excipients as per the Bill of Materials (BOM).

· Ensuring cleaning and validation of the coating equipment: Pan coater, drum coater, peristaltic pump, spray guns prior to initiation of coating

· Ensuring that the coating load, bed temperature, pan rotation, air cfm, solution spray rate is kept within the validated range during the coating process.

· Ensuring that the coating process is stopped after the required weight gain in achieved.

· In case the colors used are organic, after coating the tablets need to be protected from light to prevent discoloration of the dye (tablets exposed to light changes shades while tablets inside will be of different shade)

· Adequate protection of the tablets from light, moisture and temperature after packaging. Proper weighing and process validation of film coating process should be done. Broken tablet can be captured by installing sensitive camera to primary packing equipment. Additionally, 100% inspection after primary packing shall avoid release of such products into market ¹⁶.

Clinical significance:

· It can create patient dilemma due to coloring effect of the tablets and may intervene with patient adherence to drug treatment regimens.

Case study 4:

Fig 4: KUP_4167, Good and poor quality of batch coding details

Dosage form:

Film coated Tablets

Generic Name:

Olanzapine Tablets

Defects:

Batch over coding: Readable and not readable quality and difficult for the patient to read the batch details, most importantly expiry date.

Category:

Critical

Probable root causes:

· The roller of the batch printing machine (stereos) was not adequately soaked in ink

· Uniformity of the ink on the roller was not achieved

· Trial of the batch printing was not done

· Inadequate QC / in process checks

Remediation:

· Strengthening Quality Assurance system

· The roller of the batch printing machine should be cleaned with Isopropyl alcohol (IPA) and wiped out with a dry linen

· Prior to releasing all labelling information should be checked

Clinical significance:

· Since expiry date and manufacturing date may not be visible properly, the product shelf life is difficult to identify when sold on the counter, which indirectly affects clinical efficacy if the expired drug is unknowingly by the patient

· Improper labelling and packaging can lead to medication errors

Case study 5:

Fig 5.1: KUP_4171, Hair follicle found in bottom right side tablet

Fig 5.2: KUP_4173, Hair follicle found in top right side tablet

Dosage form:

Uncoated Tablets

Generic Name:

Glibenclamide and Metformin Tablets

Defects:

Hair follicle found in two blisters

Category:

Critical

Probable root causes:

· Lack of awareness about personal hygiene

· Not wearing the Personal Protective Equipment (PPEs) (i.e gloves, hairnet, mask during the process)

· SOP was not followed and cGMP was not implemented

Remediation:

· Investigation has to be done to find out the root cause

· The employees should be retrained on Personal Protective Equipment and current Good Manufacturing Practices

· Quality monitoring should be done adequately during the manufacturing and packaging process ¹⁷

Clinical significance:

· It will create dilemma in patients with respect to personal hygiene conditions and affect the patient’s adherence to medications

Case study 6:

Fig 6: KUP_4175, Spoiled / damaged film coated tablets

Fig 6.1: KUP_4202, Backside of blister without any damages

Dosage form:

Film coated Tablets

Generic Name:

Desloratadine Tablets

Defects:

Defective film coated tablet with dust formation within intact blister pocket

Category:

Critical

Probable root causes:

· Film coating ruptured

· Inadequate film coating done on the tablets

· Film cracked due to physical damage during packaging or transportation (loading/unloading process)

· Temperature and humidity were not maintained during processing / storage

· Formulation problems: Inadequate concentration of binder, over drying of granules etc

Remediation:

· Equipment with good exhaust facilities should be used to remove dust and solvent loaded with air

· Select an appropriate coating liquid to improve adhesion^18,19

Clinical significance:

· Desired clinical effect may not be achieved and patient’s acceptance of the medicine will decrease

Case study 7:

Fig 7: KUP_4209, Sandwiched capsule

Dosage form:

Capsules

Generic Name:

Hydroxyurea Capsules

Defects:

One capsule sandwiched between printed foil and PVC film.

Category:

Critical

Probable root causes:

· Equipment setting was not done adequately

· Inadequate trained operators

· In process quality checks not performed

Remediation:

· Proper training should be given to the personnel involved in packaging

· Machine settings should be checked and verified by the QA

· In process quality check should be done and verified by Quality Assurance personnel

Clinical significance:

· Actual ingredients may not be available in the sandwiched capsules and required quantity of drug may not be delivered to the patient

· It leads to decrease in the clinical effectiveness

· It might result in missing of dose and deterioration of drug

Case study 8:

Fig 8: KUP_4212, Improper sealing of foil with PVC film

Dosage form:

Capsules

Generic Name:

Hydroxyurea Capsules

Defects:

Improper sealing

Category:

Critical/Major/Minor

Probable root causes:

· Knurling done inadequately

· Sealing temperature not set properly

· Improper equipment setting

Remediation:

· Use different appropriate machine settings such as temperature, pressure, dwell time for different lidding

· Clinical significance:

· Improper sealing will lead to deterioration of product hence, desired clinical effect cannot be obtained

Case study 9:

Fig 9: KUP_4213, Improper sealing of foil with PVC film

Fig 9.1: KUP_4215, Picture showing intact blister pocket

Dosage form:

Soft Gelatin Capsules

Generic Name:

Primose oil and Vitamin E gelatin capsules

Defects:

Dried soft gelatin capsules within intact blister pocket

Category:

Critical

Probable root causes:

· The drying conditions of soft gelatin capsules like temperature and humidity were not controlled. Drying at high temperatures will affect the quality of the dried item

· In process quality check not carried properly

Remediation:

· Adequate training of the personnel to be cautious while performing drying process

· In process quality check should be done appropriately

· QC check must be done properly ²⁰

Clinical significance:

· Drug release will be affected and required quantity of vitamin D may not be delivered

· Patient acceptance decreases because of non–uniformity of capsules

· Product may be deteriorated due to increase in temperature and oxidized product may lead to adverse reactions

Note:

Since few defects/case studies are unique and no standard references are available for the same and the authors have tried to write expert comments based on their expertise and experience.

DISCUSSIONS:

This detailed research work involved identification of the product; defects investigation by physical analysis; probable root causes; remediation and clinical significance of each defect. The patients may not receive the required clinical efficacy due to the defects in the products and thus acceptance of the products decreases. In some cases, these product defects might cause adverse reactions because of its degraded contents. These types of defects shall attract penalty and recall by regulators. Product recall is a nightmare to the pharmaceutical industries as it leads to loss of consumer confidence, financial impact to fix the issues, market withdrawals, share price reduction and affects the reputation of the company.

CONCLUSION:

Manufacturing defects can be avoided by proper training of manufacturing staff, updating existing equipment, automation and identifying the probable root cause for any such manufacturing defects coupled with 100% inspection of manufactured products before release to markets. Ensure industry and government comply with FDA regulations and standards. Improving other processes of performance and increasing operational transparency by combining with other control systems at the company level can improve the quality of products. We can conclude that the pharmaceutical companies are lacking quality by not following the Standard Operating Procedures (SOPs) and the guidelines established by the regulatory bodies. It is very important to carryout in process quality control tests and establish a defined quality. Adequate training should be imparted to the employees to protect the quality, safety, and efficacy of the drugs manufactured and it should be implemented to ensure patient’s safety.

ACKNOWLEDGEMENTS:

We would like to acknowledge the support and timely help of Hospital Pharmacy, Kasturba Hospital, Manipal (Teaching hospital of KMC Manipal, a unit of MAHE), Radha Medicals, and Manipal Drug House, Audio Visual unit of MAHE and MAHE, Manipal for providing the necessary facilities and support for the research.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 11.10.2019 Modified on 31.10.2019

Research J. Pharm. and Tech. 2019; 12(12): 6124-6132.

DOI: 10.5958/0974-360X.2019.01064.3

Sl. No	Dosage form	Generic name	Defect	Remarks
1.	Multivitamin Tablets (10’s alu-alu in mono carton)	Vitamins, Mineral, Zinc and Astaxanthin	The mono carton with same batch number had two different MRP values.	Brand name, generic details, manufacturing license number, company logo and any such information hidden for maintaining confidentiality
2	Enteric coated Tablets	Omeprazole magnesium and Domperidone Tablets	Two enteric coated tablets found to be melted/softened within intact blister pocket.	Brand name, generic details, manufacturing license number, company logo and any such information hidden for maintaining confidentiality
3	Film coated Tablets	Olanzapine Tablets	Batch to batch color variation observed. A classic example for dark, medium and light shades.	Nil
4	Film coated Tablets	Olanzapine Tablets	Batch over coding: Readable and not readable quality. Difficult for the patient to read the batch details, most importantly expiry date.	Brand name, generic details, manufacturing license number, company logo and any such information hidden for maintaining confidentiality