RISING INCIDENCES OF PRODUCT RECALL

Viney Chawla, Manish Pal Singh, Manish Kumar

Rajiv Academy for Pharmacy, Chattikkara, Mathura, India

Corresponding author:  Email: drvineychawla@gmail.com

DOI: http://doi.org/10.22270/ujpr.v1i1.RW2

ABSTRACT

There has been an increasing trend in the number of prescribed and over-the-counter drug recall over the last few years. The recall is usually due to company's discovery, customer's complaint or Food and Drug Administration (FDA) observation. The process of recall involves a planned specific course of action, which addresses the depth of recall, need for public warning, and the extent of effectiveness checks for the recall. Product recalls clashes thousands of companies every year affecting: sales, testing customer relationships and disrupting supply chains. Drug recall is incubus for pharmaceutical companies. It effects the reputation of the company. The reason for the recall can be divided into two categories: manufacturing related and safety/efficacy related. It is essential to follow all the guidelines related to drug development and manufacturing procedure so as to minimize drug recall.

Keywords: Drug product recall, guidelines, process, recall information.

INTRODUCTION

The pharmaceutical industry is at an important crossroads in medical innovations, which develop cures for health conditions. Without this industry, many therapies would not be introduced to the market, and many health problems would remain unsolved. The pharmaceutical industry as a whole has traditionally been very profitable, and the global market had annual growth prediction of 5 to 8%^1,2.  Yet amidst the massive increase in the field, factors like product returns and recalls are giving the companies new challenges, such as litigation problems, negative publicity, loss of patent protection for many major drugs and widespread efforts to contain drug spending³. On the other hand, increased competitiveness, fast-changing structure of competitors, complex strategic positioning, shrinking pipelines, counterfeit drugs and a fight for global market share are adding more burdens to the growth of the industry^4,5.

A recall is a serious problem. It highlights a dangerous situation that requires fast and effective action to protect the public from harm. Product recalls are becoming extensive and have increased radically⁶. For example, the Food and Drug Administration (FDA) reported more than 1984 recalls with more than $700 million dollars

manufacturers penalties, and billions more in lost revenues since 2001^7,8. Companies are turning to set their strategic sight on future moves. In order to operate effectively in an increasingly competitive economic and commercial landscape, they are trying to adopt more formal business processes and stricter reporting methods⁹.

A drug recall is an instance to return to the maker 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 a recall and all related information's are reported to the drug office¹⁰.  Regardless of a company's best efforts, that dangerously defective drug product may reach the customers. These products may cause disasters, leading to adverse verdicts in drug product liability litigations. The quality management of complaints and drug product recalls are necessary to ensure the safety of customer. However, there are certain other cases when all batches or lots of the drug experience recall from the market^11,12. The aim of present review is to focus on issues for drug recall like lack of sterility assurance, presence of particulate matter, unapproved new drugs, presence of undeclared therapeutically active moiety, microbial contamination, container/closure problems and some other miscellaneous reasons. We shall discuss them in two parts with part-I, focusing on lack of sterility assurance, presence of particulate matter and container/closure problems.

ISSUES RELATED TO PRODUCT RECALL

I- Lack of Sterility Assurance

The years 2013-2016 saw eight recalls (Table 1)

that involved a microbiological component, with a clear increase evident in 2015 and 2016. There no evident in 2013 and 2014. If we look at the data from a different perspective, we can evaluate FDA concerns for sterile vs Non-sterile products^13,14. Underlying causes of “Lack of Sterility Assurance” often are the result of packaging concerns (incomplete or weak seals, pinpricks in the sterile barrier, transport issues, etc). Relatively few of these “Lack of Sterility Assurance” recalls actually showed contamination. From this, it seems apparent that “Lack of Sterility Assurance” means either that there is a potential problem with the product or packages, or that the manufacturer cannot document that the product was manufactured and sterilized in a state of control. If the product is obviously contaminated, that is the cited reason for the recall in the vast majority of cases^15,16.

II- Presence of Particulate Matter

Presence of foreign visible or sub-visible particulate matter in injectable/ parenteral formulations has been one of the most commonly seen reasons for recalls. FDA reported 22% recalls for sterile injectable drugs in period of 2013-16 caused due to presence of visible particles^17,18. Recent list of FDA recalls include the products as mentioned in the (Table 2).  All injectables are mostly contaminated with some level of particulate matter. This particulate matter is a critical quality attribute, which has direct impact on product safety. Therefore, the United States Pharmacopoeia has defined the standards for particulate matter. These standards are established for all injectable preparations such as large-volume Injections, single-dose infusion and small-volume

Injections, solutions for injection administered by intramuscular or subcutaneous route, except parenteral for use as irrigating solutions, radiopharmaceutical preparations and parenteral products for which the labeling specifies use of a final filter prior to administration^19,20.

The size of particulate matter is an important factor behind health risk to patients. The smallest diameter of blood capillaries is approximately 6–8 μm. Particles as small as 2μm in diameter are generally associated with micro-thrombi formation in patients. Particles larger than 6–8µm can block pulmonary capillaries, with smaller particles passing through the lungs and depositing in organs such as the liver and spleen, where they are processed by phagocytic cells of the reticuloendothelial system^21,22.

III- Container/Closure Problems

Leaking containers could result in contamination of the solution. If not detected, this could lead to a bloodstream infection, worsened patient condition or other serious adverse health consequences (Table 3). All medicinal products need to be protected and consequently need to be packaged in containers that conform to prescribed standards, particularly with respect to the exclusion of moisture and light and the prevention of leaching of extractable substances into the contents and of chemical interaction with the contents. However, the limits of acceptability in these various respects depend, at least in part, on climatic variables. Recommendations in the International Pharmacopoeia can only be advisory; precise quantitative standards will have to be locally determined. Labels carry the correct information and identification of the product^23,24. The closure

is a part of the container. The container and its closure must not interact physically or chemically with the substance within in any way that would alter its quality^25,26. Both the European and United States pharmacopoeias provide specifications for glass containers for injections²⁷. The latter publication also gives specific guidance for the packaging, repackaging and dispensing of medicinal products. Both the European and United States pharmacopoeias also provide specifications for light-resistant containers and tightly or well-closed closures for capsules and tablets ²⁸.

CONCLUSION

Product Recall is not only a blot on the company’s image but also an unwanted procedure on part of manufacturers. However, in the interest of patients in particular and society in general, this is a welcome step. The manufacturers should check everything before releasing the product in market. In spite of frequent in process quality controls, QC tests past production and cGMPs in place, there has been an alarming rise in the incidences of product recall. Keeping in mind stringest FDA regulations, such an event speaks volumes about the lacunas in the existing system. Therefore, even after launch of the drug in the market, it is essential to carry out post market surveillance and investigate the drug performance in the market.

REFERENCES

1. Shewale S, Parekh S. Reinventing patient recruitment in clinical studies, The Monitor. 2011: 10:523-535.
2. Folland S, Goodman AC, M Stano. Intercontinental Medical Statistics Health, 5^th Edition. 2010.
3. Saddle River NY. Pearson Education. 2007.
4. CBR Pharma Insights. The New Pharmaceutical Sales Force, Key Trends Shaping Future Sales Strategies; Reuters online. 2009.
5. A Edwards. Manufacturing the future Integrated collaboration between CMOs and Sponsors, Contract Pharma; 2010: 5:124-130.
6. http://money.cnn.com/2010/08/16/ news/companies/drug recall_ surge/index.htm (Accessed on May. 25, 2016)
7. Kumar S, Dieveney E, Dieveney A. Reverse logistic process control measures for the pharmaceutical industry supply chain. Int J Prod Perform Manag. 2009: 58:188-204.
8. D’souza A, Keeling D, Phillips R. Improving quality in pharma manufacturing, The McKinsey Quarterly. 2007.
9. Souza D, Danase J, Constatinou D. Business efficiency and regulatory compliance, Pharmaceutical Technology. 2005.
10. Fda.gov//Drugs/Drugsafety/DrugRecalls/default.htm. Accessed on Aug. 13, 2016.

11. Sovasia N, Thacker S, Patel T. Quality management of complaints and recalls of pharmaceuticals as per global GMPs, Pharmacy Infopedia. 2014: 02:21.
12. http://Hsc.unm.edu.///Pharmacistsletter. (Accessed on Aug. 14, 2016].
13. USP. Microbiological Examination of Nonsterile Products: Acceptance Criteria For Pharmaceutical Preparations And Substances For Pharmaceutical Use, USP 34/NF. 2011: 29(1):630-631.
14. Sutton S. The Harmonization of the Microbial Limits Tests, Pharm Technol. 2006: 30(12):66-73.

15.http://www.fda.gov/ICECI/Inspections/Inspection Guides/ucm074914.htm. (Accessed on Feb. 26, 2014)

16. Tuma ED, Kumar SD. Microbial contamination of sterile and non-sterile articles with special reference to Pseudomonas cepacia. Pharm Forum. 1982:8(4):22-39.
17. Shabushnig JG. Detection and Control of Visible Particles in injectable products, Safety alerts for human medical products. 2014:324-345.
18. United States Pharmacopoeia. Particulate matter in injections. 2011:788.
19. United States Pharmacopoeia. Injections.1-2; 2011:1.
20. Tawiah W Manu. Setting threshold limits for the significance of objectionable microorganisms in oral pharmaceutical products, PDA J Pharm Sci Tech. 2015: 5(3):171-175.
21. Kuhn RJ. Bacterial Contamination of Aerosol Solutions Used To Treat Cystic Fibrosis, Amer J Hosp Pharm. 1982:39:308-309.
22. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/default.htm.(Accessed on Feb. 20, 2016).

23. Good manufacturing practices for pharmaceutical products. Geneva, World Health Organization. 1992: Annex 1 (WHO Technical Report Series, No. 823).
24. The International Pharmacopoeia. Tests, methods, and general requirements; Quality specifications for pharmaceutical substances, excipients, and dosage forms. 1994; 3 (4).
25. Report of the international workshop on counterfeit drugs. Geneva; 26–28 November, Geneva, World Health Organization: 1997.
26. In: U.S. Code of Federal Regulations, Food and Drugs. 2000:4:125–126.
27. Assessment of potential risk to the environment posed by medicinal products, London, Medicines Control Agency. 1994.
28. SVW Sutton. Letter to the Editor in Response to Friedman et al, Burkholderia cepacia, PDA J Sci Technol. 2012; 66 (2):91-95.

Table 1: Lack of sterility assurance

Table 2: Presence of particulate matter

Table 3: Container/ closure problems