Pharmaceutical Defects: A Critical Review on Defects of Various Dosage forms and Regulatory Impacts

 

Hemanth KG¹, Mahendra Joshi², Richa Dayaramani³, Damodharan N⁴,

Ravindra Shenoy⁵, Girish Pai K¹*

¹Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India

²Research and Development, IDRS Labs Pvt. Ltd, Bangalore-560099, Karnataka India.

³Department of Pharmaceutical Quality Assurance, Khyathi College of Pharmacy, Palodiya,

Ahmedabad-382115, Gujarat, India

⁴Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur-603203, Tamil Nadu, India

⁵Department of Commerce, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India.

 

ABSTRACT:

In treatment of diseases, Quality and safe medicines are required which would save the human lives. Pharmaceutical Industry is one of the sectors with most stringent guidelines since it deals with human lives. Defective products from this sector is least anticipated. Defective product is the one which couldn’t fulfill the need of customer and may possess some degree of risk if it is used. If such product is released into the market, there are few consequences which manufacturing company would go through. Though Global Regulatory authorities, ICH and WHO have laid guidelines, we aren’t successful in preventing even minor defects such as discrepancies in label specification. The objective of this review article is to briefly discuss about the Pharmaceutical defects, Real-life product defects compared to textbooks recorded defects, their consequences and recent voluntary product recalls published by US-FDA which could help the Pharmaceutical Industry in enhancing their quality system.

 

 

 

INTRODUCTION:

As said by Johann Wolfgang, “Certain defects are necessary for the existence of individuality”¹, but the same is not expected in pharmaceutical products. Pharmaceutical products are referred to be the golden sword for the treatment of ailments and any defects in them would cause a threat to precious human life. Cambridge dictionary defines a defect as “A fault or problem in something or someone that spoils that thing or person or causes it, him, or her not to work correctly”².Pharmaceutical product defect holds a way different meaning since it is essential to save lives. Pharmaceutical product defect can be any change in the product that outweigh the drug’s positive benefits.

 

General Classification of Defects:

1.       Manufacturing defects: These are defects that arise during the production or negligence in the Quality assurance department. E.g. Packed Broken tablets in a batch of production³

2.       Design defects:this type may lead to defects in the entire line of manufacturing unless it is rectified. The manufactured product composition or the design differs from the intended specifications. E.g. Altered uniformity in dispersion of Amoxicillin trihydrate dispersible tablets⁴

3.       System failure defects: There are standard regulatory guidelines for each sector to be followed during the manufacture. This type of defect occurs when the manufacturing system fails to follow those guidelines. E.g. Contaminated dosage forms ^5,6

 

Types of Pharmaceutical Defects classified by the Regulatory authorities:

1.       Minor: These are insignificant to the patients’ health and product performance. Most of these defects may or may not be identified by the patient. E.g. Spelling mistake in Product information leaflet (PIL) ⁶

2.       Major: The harm caused by this kind of defect is higher than minor. The customer can easily identify this type of defect. Major defects may affect the intended action of the product. E.g. Broken film coated sustained release tablets within intact blister ⁷

3.       Critical: This type of defect is most serious than the above two. The products with critical defects are unfit to use and cause an adverse effect. This may cause liability to the company’s reputation and the patient's health. E.g. Softened enteric coated tablets, improper sealing of vials^5,8

 

COMPARISON OF REAL-LIFE PHARMACEUTICAL DEFECTS AND TEXTBOOKS RECORDED DEFECTS:

During the course of becoming a Pharmacy graduate our education system educates with all the knowledge to face the challenges in the Pharmaceutical Industry. The bitter truth is that real life is way different than the anticipated one. We would like to present an example for the above said lines. Table 1. Gives a comparison of Defects recorded in standard books and real-life defects which occur in the Pharmaceutical industry.

 

Table 1: Comparison of Defects recorded in textbooks and real-life Pharmaceutical defects

Dosage form type	Defects recorded in textbooks	Real-life defects
Solid Dosage forms
Enteric coated tablets	Picking Orange peel effect Mottling Lamination Blooming Double impression9	Melted/Softened tablets in the blister 8
Uncoated tablets		Hair follicle inside intact blister8
Film coated tablets		Dust formation inside tablet pocket with intact blister8
Hard gelatin Capsules	Weight variation Content Uniformity In Vitro testing	Capsule sandwiched between foil and PVC film8
Soft Gelatin Capsules		Dried soft gelatin capsules8
Parenteral
Dry powder parenteral	Visible particulate matter (Hair, Glass, Fibers) inside the ampoule or vial 10	Product on stopper 5
Patient information leaflet (PIL)
PIL of Carbapenem Dry powder injectable	Nil	Missing instructions for reconstitution Discrepancies in storage conditions mentioned in PIL and primary carton 6

 

Every dosage form manufactured by the Pharmaceutical industry involves a number of unit operations which increases its vulnerability to be defective. But it is mandatory of time that defects shouldn’t occur in medicines which are intended to save human lives. The Pharmaceutical Industry has to take all the necessary precautions and follow the regulatory guidelines.

 

CONSEQUENCES OF PHARMACEUTICAL DEFECTS:

1. Market complaints:

When a market compliant is received it just implies that something is wrong with the sold product and customer is not satisfied. In Pharmaceutical industry market complaint indicates dissatisfaction regarding the clinical indication, quality or packaging which is lodged verbally or in written format^11,12.

 

Types of complaints:

1.       Quality related: This category of complaints is related to physical, chemical or biological specifications or labelling and packaging condition of the product.

2.       Adverse drug reactions related: Any noxious or unintended drug effects are reported by physician or patient to the Pharmacovigilance department.

3.       Others: Lack of intended clinical efficiency or clinical response^11,12

 

Fig 1: Sources of complaints

Fate of Market complaints:

The journey of market complaint follows the Standard Operating Procedure (SOP) which is designed by the company. The complaint is received in customer complaint communication form with required details regarding the complaint. QA head in coordination with QC head reviews documents such as analytical records, sampling and release records, and other raw data. Compliant is confirmed by QA head if there is significant difference in recorded values against the values of product in compliant. QA head checks for the stability data and if no issues are observed he shall process the compliant to Research and Development Head and QC head. Once the inputs are received from respective departments QA head shall prepare summary of findings and shall share it in Customer compliant report format with customer and the management. Corrective and preventive actions have to be implemented to prevent any such incidents in future. The compliant is closed or in worst case scenario QA order for the product recall from the market. By coordination between supply chain and marketing department, marketed products can be recalled of that particular batch or lot¹².

 

2. Drug recall or Product recall:

It is a process of removal of products from the market that are not manufactured according to FDA’s rules and regulation, to protect the public health from such defective products ¹³ or It is a voluntary decision taken by the company or FDA’s request to get back all the defective products which are in market manufactured by their company to prevent public from harmful products^14,15. Fig 2. Gives classification of drug recalls based on degree of health hazard that recalled product could implicit¹³. Drug recalls can also be classified based on who is initiating the product recall:

a)       Voluntary or firm-initiated recall: When the firm believes that the product released could impose risk to the public, it notifies the FDA to issue public notification.

b)       Involuntary or FDA initiated recall: This is initiated only during urgent situation where FDA monitors and coordinates with the recall procedure and strategy.

 

Both type of recalls is subjected to legal action by FDA on the manufacturing firm. But a when the manufacturing firm takes the step of recall it has a huge impact on its customer’s trust and would affect the customer’s decision in buying their company drugs ^13,16.

 

Fig 2: Classification of Drug recalls ¹⁴

 

RECENT DRUG PRODUCT RECALLS BY US-FDA:

Due to lack of integrity in quality and safety of manufactured drug products, FDA is issuing product recalls order to number of companies whether they may be an innovator company or generic company. Table 2. Gives an overview of a few recent voluntary drug recalls published by US-FDA¹⁵. The observation made from the table is that all types of defects and product recalls are imposed even for products of reputed pharma companies and we aren’t able to take necessary actions to prevent even the minor defects such as discrepancies in labelling.

 

Table 2: Recent voluntary drug recalls by reputed Pharma companies

Date	Generic name	Reason for Recall	Company name	Class of Defect	Class of Recall
4/15/2020	Nizatidine Oral Solution 15mg/mL	Presence of NDMA (N-Nitrosodimethylamine)	Amneal Pharmaceuticals	Critical	Class I
4/13/2020	Hydromorphone HCL Injection, USP	Presence of empty and cracked vials	Hospira, Inc	Major	Class II
4/09/2020	Alka-Seltzar Plus	Discrepancies in primary label and secondary label	Bayer	Minor	Class III
3/26/2020	Phytonadione single dose ampoules USP, 10mg/mL	Inefficient strength of ampules resulting breakage	Dr. Reddy’s Laboratories Ltd	Major	Class II
12/17/2019	Ranitidine tablets 150mg and 300mg	Presence of NDMA (N-Nitrosodimethylamine)	Glenmark Pharmaceuticals, Inc	Critical	Class I

 

To prevent the unforeseen defects and issues in manufacturing the Pharmaceutical manufacturers have to enhance their quality system. For Pharmaceutical Quality enhancement, ICH recommends to follow ICH Q10 guidelines which is comprehensive guideline of “Q8 Pharmaceutical Development and Q9 Quality risk management”.

Four elements of Pharmaceutical Quality System are:

1.       Process performance and product quality monitoring system

2.       Corrective action and preventive actions (CAPA) system

3.       Change management system

4.       Management review of process performance and product quality

 

The management review process is the most important one since it monitors the functioning of other three elements. Management review process include observation of regulatory inspections and findings, enquiry on previous management reviews, training of personnel, improvements to manufacturing processes, confirmation of effectiveness of CAPA and most importantly measures which have been taken to minimize the customer complaints on product quality and product recalls from the market¹⁷.

 

CONCLUSION:

Learning starts after the professional education from the University. None of us are aware of real-lifeproduct defects which could occur. The only measure which can be taken is learn from the past and implement required rules and regulation in the present to prevent any such defects in the future. Even though India being called as the Generic Capital of the World, several recalls have been initiated by Indian Pharma firms. The defects mentioned in this article may serve to alert the Pharmaceutical Industry to realize the type of defects which also could occur and take necessary measures to prevent them in future. To ensure the production of quality products each personnel from the stage of API manufacturing till the dosage form is placed into packaging material are responsible and required to stay alert thereby guarding the safety of patients and trust of customers in their company.

 

CONFLICT OF INTEREST:

The Authors confirm that this article content has no conflict of interest.

 

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Accepted on 24.07.2020                                 © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(9):4499-4504.