See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/344125579

Pharmaceutical Defects: A Critical Review on Defects of Various Dosage forms

and Regulatory Impacts

Article  in  Research Journal of Pharmacy and Technology · September 2020

DOI: 10.5958/0974-360X.2020.00794.5

CITATION READS
1 3,518

6 authors, including:

Hemanth Katta G. Richa Dayaramani

Manipal Academy of Higher Education Gujarat Technological University
5 PUBLICATIONS   7 CITATIONS    8 PUBLICATIONS   69 CITATIONS   

SEE PROFILE SEE PROFILE

Ravindra U Shenoy Girish PAI Kulyadi

Manipal Academy of Higher Education Manipal Academy of Higher Education
11 PUBLICATIONS   6 CITATIONS    8 PUBLICATIONS   7 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Papers in ethical leadership View project

To prepare research papers on using ancient Indian wisdom for better leadership and management in the modern context. Looking for any interested academician who
would like to collaborate View project

All content following this page was uploaded by Hemanth Katta G. on 12 September 2020.

The user has requested enhancement of the downloaded file.

 Research J. Pharm. and Tech. 13(9): September 2020

ISSN 0974-3618 (Print) www.rjptonline.org

0974-360X (Online)

REVIEW ARTICLE

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*
1
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher
Education, Manipal-576104, Karnataka, India
2
Research and Development, IDRS Labs Pvt. Ltd, Bangalore-560099, Karnataka India.
3
Department of Pharmaceutical Quality Assurance, Khyathi College of Pharmacy, Palodiya,
Ahmedabad-382115, Gujarat, India
4
Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology,
Kattankulathur-603203, Tamil Nadu, India
5
Department of Commerce, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India.
*Corresponding Author E-mail: girish.pai@manipal.edu

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.
KEYWORDS: Pharmaceutical Defects, ICH, Real-life products, Product recalls.

INTRODUCTION: General Classification of Defects:

As said by Johann Wolfgang, “Certain defects are 1. Manufacturing defects: These are defects that arise
necessary for the existence of individuality”1, but the during the production or negligence in the Quality
same is not expected in pharmaceutical products. assurance department. E.g. Packed Broken tablets in a
Pharmaceutical products are referred to be the golden batch of production3
sword for the treatment of ailments and any defects in 2. Design defects:this type may lead to defects in the
them would cause a threat to precious human life. entire line of manufacturing unless it is rectified. The
Cambridge dictionary defines a defect as “A fault or manufactured product composition or the design differs
problem in something or someone that spoils that thing from the intended specifications. E.g. Altered uniformity
or person or causes it, him, or her not to work in dispersion of Amoxicillin trihydrate dispersible
correctly”2.Pharmaceutical product defect holds a way tablets4
different meaning since it is essential to save lives. 3. System failure defects: There are standard
Pharmaceutical product defect can be any change in the regulatory guidelines for each sector to be followed
product that outweigh the drug’s positive benefits. during the manufacture. This type of defect occurs when
the manufacturing system fails to follow those
guidelines. E.g. Contaminated dosage forms 5,6
Received on 25.05.2020 Modified on 21.06.2020
Accepted on 24.07.2020 © RJPT All right reserved
Research J. Pharm. and Tech. 2020; 13(9):4505-4508.
DOI: 10.5958/0974-360X.2020.00794.5

4505
 Research J. Pharm. and Tech. 13(9): September 2020

Types of Pharmaceutical Defects classified by the Softened enteric coated tablets, improper sealing of
Regulatory authorities: vials5,8
1. Minor: These are insignificant to the patients’ health
and product performance. Most of these defects may or COMPARISON OF REAL-LIFE
may not be identified by the patient. E.g. Spelling PHARMACEUTICAL DEFECTS AND
mistake in Product information leaflet (PIL) 6 TEXTBOOKS RECORDED DEFECTS:
2. Major: The harm caused by this kind of defect is During the course of becoming a Pharmacy graduate our
higher than minor. The customer can easily identify this education system educates with all the knowledge to face
type of defect. Major defects may affect the intended the challenges in the Pharmaceutical Industry. The bitter
action of the product. E.g. Broken film coated sustained truth is that real life is way different than the anticipated
release tablets within intact blister 7 one. We would like to present an example for the above
3. Critical: This type of defect is most serious than the said lines. Table 1. Gives a comparison of Defects
above two. The products with critical defects are unfit to recorded in standard books and real-life defects which
use and cause an adverse effect. This may cause liability occur in the Pharmaceutical industry.
to the company’s reputation and the patient's health. E.g.

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 Melted/Softened tablets in the blister 8
Uncoated tablets Orange peel effect Hair follicle inside intact blister8
Film coated tablets Mottling Dust formation inside tablet pocket with intact blister8
Lamination
Blooming
Double impression9
Hard gelatin Capsules Weight variation Capsule sandwiched between foil and PVC film8
Content Uniformity
In Vitro testing
Soft Gelatin Capsules Dried soft gelatin capsules8
Parenteral
Dry powder parenteral Visible particulate matter (Hair, Product on stopper 5
Glass, Fibers) inside the ampoule or
vial 10
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 2. Adverse drug reactions related: Any noxious or
industry involves a number of unit operations which unintended drug effects are reported by physician or
increases its vulnerability to be defective. But it is patient to the Pharmacovigilance department.
mandatory of time that defects shouldn’t occur in 3. Others: Lack of intended clinical efficiency or
medicines which are intended to save human lives. The clinical response11,12
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 format11,12.

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. Fig 1: Sources of complaints
4506
 Research J. Pharm. and Tech. 13(9): September 2020

Fate of Market complaints: a) Voluntary or firm-initiated recall: When the firm

The journey of market complaint follows the Standard believes that the product released could impose risk to
Operating Procedure (SOP) which is designed by the the public, it notifies the FDA to issue public
company. The complaint is received in customer notification.
complaint communication form with required details b) Involuntary or FDA initiated recall: This is initiated
regarding the complaint. QA head in coordination with only during urgent situation where FDA monitors and
QC head reviews documents such as analytical records, coordinates with the recall procedure and strategy.
sampling and release records, and other raw data.
Compliant is confirmed by QA head if there is Both type of recalls is subjected to legal action by FDA
significant difference in recorded values against the on the manufacturing firm. But a when the
values of product in compliant. QA head checks for the manufacturing firm takes the step of recall it has a huge
stability data and if no issues are observed he shall impact on its customer’s trust and would affect the
process the compliant to Research and Development customer’s decision in buying their company drugs 13,16.
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. Fig 2: Classification of Drug recalls 14

2. Drug recall or Product recall: RECENT DRUG PRODUCT RECALLS BY US-

It is a process of removal of products from the market FDA:
that are not manufactured according to FDA’s rules and Due to lack of integrity in quality and safety of
regulation, to protect the public health from such manufactured drug products, FDA is issuing product
defective products 13 or It is a voluntary decision taken recalls order to number of companies whether they may
by the company or FDA’s request to get back all the be an innovator company or generic company. Table 2.
defective products which are in market manufactured by Gives an overview of a few recent voluntary drug recalls
their company to prevent public from harmful published by US-FDA15. The observation made from the
products14,15. Fig 2. Gives classification of drug recalls table is that all types of defects and product recalls are
based on degree of health hazard that recalled product imposed even for products of reputed pharma companies
could implicit13. Drug recalls can also be classified based and we aren’t able to take necessary actions to prevent
on who is initiating the product recall: 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 Presence of NDMA (N- Amneal Critical Class I
15mg/mL Nitrosodimethylamine) Pharmaceuticals
4/13/2020 Hydromorphone HCL Presence of empty and cracked Hospira, Inc Major Class II
Injection, USP vials
4/09/2020 Alka-Seltzar Plus Discrepancies in primary label Bayer Minor Class III
and secondary label
3/26/2020 Phytonadione single dose Inefficient strength of ampules Dr. Reddy’s Major Class II
ampoules USP, 10mg/mL resulting breakage Laboratories Ltd
12/17/2019 Ranitidine tablets 150mg Presence of NDMA Glenmark Critical Class I
and 300mg (N-Nitrosodimethylamine) Pharmaceuticals,
Inc

To prevent the unforeseen defects and issues in Four elements of Pharmaceutical Quality System are:
manufacturing the Pharmaceutical manufacturers have to 1. Process performance and product quality monitoring
enhance their quality system. For Pharmaceutical system
Quality enhancement, ICH recommends to follow ICH 2. Corrective action and preventive actions (CAPA)
Q10 guidelines which is comprehensive guideline of system
“Q8 Pharmaceutical Development and Q9 Quality risk 3. Change management system
management”.
4507
 Research J. Pharm. and Tech. 13(9): September 2020

4. Management review of process performance and 7. Krishna TV, Kumar L, Reddy MS, Rao R, Ankineedu M, Pai
KG. Investigation to find out the root cause for presence of
product quality
broken tablet in the marketed blister pack. Res J Pharm Technol.
2015;8(6):707–9.
The management review process is the most important 8. Abhinaya N, Thunga G, Muddukrishna B, Pai R, U RS, Khan S,
one since it monitors the functioning of other three et al. A Research on Effective Management of Manufacturing
Defects to Avoid Product Recalls: A Challenge to Pharmaceutical
elements. Management review process include
Industry. Res J Pharm Technol;12 (12):6124–32. Available from:
observation of regulatory inspections and findings, URL: http://rjptonline.org/AbstractView.aspx?PID=2019-12-12-
enquiry on previous management reviews, training of 87
personnel, improvements to manufacturing processes, 9. Lachman L, Lieberman HA. The Theory and Practice of
Industrial Pharmacy. 4th ed. CBS Publishers and Distributors Pvt
confirmation of effectiveness of CAPA and most
Ltd; 2013. 488-492,522 p.
importantly measures which have been taken to 10. Tawde SA. Particulate Matter in Injectables: Main cause for
minimize the customer complaints on product quality Recalls. J Pharmacovigil;03(01). Available from: URL:
and product recalls from the market17. http://www.esciencecentral.org/journals/particulate-matter-in-
injectables-main-cause-for-recalls-2329-6887-3-
e128.php?aid=39495
CONCLUSION: 11. SOP on Market Complaint. PharmaState Blog. 2019. Available
Learning starts after the professional education from the from: URL: https://pharmastate.blog/sop-on-market-complaint/
University. None of us are aware of real-lifeproduct 12. Krishna TV, Kumar L, Reddy MS, Muddukrishna B, Pai KG.
Market Complaints in Pharmaceuticals: A Brief Review on its
defects which could occur. The only measure which can Handling, Investigation and Reporting. Res J Pharm Technol.
be taken is learn from the past and implement required 2013;6(11):1314–6.
rules and regulation in the present to prevent any such 13. Center for Devices and Radiological Health. Recalls, Corrections
defects in the future. Even though India being called as and Removals (Devices). FDA. FDA; 2019. Available from:
URL: https://www.fda.gov/medical-devices/postmarket-
the Generic Capital of the World, several recalls have requirements-devices/recalls-corrections-and-removals-devices
been initiated by Indian Pharma firms. The defects 14. Center for Drug Evaluation and Research. FDA’s Role in Drug
mentioned in this article may serve to alert the Recalls. FDA. 2018 Nov 3; Available from: URL:
Pharmaceutical Industry to realize the type of defects https://www.fda.gov/drugs/drug-recalls/fdas-role-drug-recalls
15. Center for Drug Evaluation and Research. Drug Recalls. FDA.
which also could occur and take necessary measures to FDA; 2019. Available from: URL: https://www.fda.gov/drugs/
prevent them in future. To ensure the production of drug-safety-and-availability/drug-recalls
quality products each personnel from the stage of API 16. Bortoli L, Freundt V. Effects of Voluntary Product Recall on
manufacturing till the dosage form is placed into Consumer’s Trust. Braz Bus Rev. 2017 Mar 1;14(1):204–24.
Available from: URL: http://bbronline.com.br/index.php/bbr/
packaging material are responsible and required to stay article/view/36
alert thereby guarding the safety of patients and trust of 17. Center for Drug Evaluation and Research. Q10 Pharmaceutical
customers in their company. Quality System. 2009. Available from: URL: https://www.
fda.gov/media/71553/download
CONFLICT OF INTEREST:
The Authors confirm that this article content has no
conflict of interest.

REFERENCES:
1. Johann Wolfgang von Goethe-Certain defects are necessary.
Available from: URL: https://www.brainyquote.com/
quotes/johann_wolfgang_von_goeth_150534
2. DEFECT | meaning in the Cambridge English Dictionary.
Available from: URL: https://dictionary.cambridge.org/
dictionary/english/defect
3. Kumar L, Reddy S, Pydi C, T V, Krishna M, Pai K. A Research
on Market Complaint Product: Detailed Investigation and a
Report on Broken Film Coated Tablet inside an Intact Blister
Pack. Lat Am J Pharm. 2018 Feb 9;37.
4. Krishna VT, Pai GK, Singh M, Kumar L, Reddy SM.
Comparative Evaluation of Few Marketed products of
Amoxicillin Trihydrate Dispersible Tablets IP. Asian J Pharm
Clin Res. 2014;7 (2):109–10.
5. Mehta SB, Roy S, Yang H-C (Cathy). “Product on Stopper” in a
Lyophilized Drug Product: Cosmetic Defect or a Product Quality
Concern? J Pharm Sci. 107(6):1736–40. Available from: URL:
https://linkinghub.elsevier.com/retrieve/pii/S0022354918300753
6. Tippavajhala VK. A Critical and Comparative Study on Patient
Information Leaflet, Primary Label and Primary Carton of a
Carbapenem Dry Powder Injectable. Indian J Pharm Educ Res.
2019;53(1):178–85.

4508

View publication stats