Youll be surprised with our findings.
In which parts of the world, can a company whose manufacturing operations, are approved year after year by the local ministry of health, always found to be in GMP compliance, have the same facility inspected by an international regulatory agency, and fail the inspection?
After the failure of the international inspection, would it be appropriate for the local ministry of health, to renew the GMP certificate?
You will be surprised with our findings since the answer is not so obvious.
An in-depth analysis of the inspection statistics available at the EDQM and USFDA websites, (summarized in tables 1 and 2 below), have revealed some startling facts:
- There is no obvious consistency in the results of inspections conducted by European and USFDA inspectors. Facilities, which have been approved by one agency, fail to meet the requirements of the other.
- EU-GMP Certificates are issued to European companies who fail USFDA inspections, and even to those who are on the FDA Import Alert List.
Table 1/ List of companies - USFDA Non-Compliance, EU Compliance
|
Site Name |
Country |
USFDA Inspection Date |
FDA Warning Letter Issue Date |
Other Updates |
EU GMP Inspection Date |
EU GMP Compliance Issued |
|
Poland |
Sep 2011 |
Import Alert - Mar 2012 |
||||
|
Austria |
Oct 2012 |
|||||
|
Denmark |
Mar 2012 |
WL Closed Out - Jan 2014 |
||||
|
Germany |
Nov 2011 |
|||||
|
Ireland |
Oct 2013 |
|||||
|
Italy |
Jan 2014 |
|||||
|
Serbia |
Nov 2011 |
|||||
|
United Kingdom |
Nov 2011 |
|||||
|
Spain |
Jul 2011 |
|||||
|
Germany |
Jun 2012 |
|||||
|
Germany |
Mar 2013 |
Import Alert - July 2013 |
Table 2/ List of companies - USFDA Compliance, EU Non-Compliance
|
Site Name |
Country |
FDA Inspection Date |
FDA Inspection Outcome |
EU GMP Inspection Date |
EU GMP Non-Compliance Issued |
|
United States |
Voluntary Action Indicated |
||||
|
United States |
Voluntary Action Indicated |
||||
|
United Kingdom |
Voluntary Action Indicated |
||||
|
China |
No Observations (2010) / Voluntary Action Indicated (2014) |
If we take the case of Huashu Pharmaceutical Corporation (Shijiazhuang, China), it is even more puzzling, as within the course of a year, their assessment varied from being issued a non-compliance report by the United Kingdom Ministry of Health in September 2011, to being found in compliance by both the USFDA and the Greek Ministry of Health in January 2012 and June 2012 respectively.
How about the performance of companies in Asia?
In table 3 we summarized the overall inspection statistics from the EDQM and USFDA websites, here are some other surprising facts:
-
The success rate of Indian and Chinese companies in USFDA and European inspections is more than 90%.
- Two out of three (about 66%) non-compliance reports issued by European regulators are to Indian and Chinese companies. Comparatively the USFDA issues only 20% of their negative assessments in India and China.
- The highest number of non-compliances observed by the USFDA were for facilities in the United States.
- The inspections in Taiwan have the highest possibility of a non-compliance report being issued by both European and US inspectors, Europe has the lowest probability.
Table 3/ Summary of Inspection Statistics obtained from the EudraGMP and FDA Data Dashboard
|
|
European Directorate of Quality Medicines Statistics (EDQM 2006-2015) |
FDA Dashboard Statistics FY2012-2015 |
||||
|
Country |
Total Inspection Results |
Non-Compliance Reports |
% Non-Compliance Reports |
Drug Quality Assurance Inspections |
Non-Compliance Reports (OAI) |
% Non-Compliance Reports |
|
China |
314 |
26 |
8.3% |
192 |
10 |
5.2% |
|
India |
591 |
39 |
6.6% |
295 |
25 |
8.5% |
|
United States |
609 |
4 |
0.7% |
3200 |
98 |
3.1% |
|
Europe |
10538 |
16 |
0.15% |
785 |
12 |
1.5% |
|
Canada |
18 |
0
|
0.00% |
91 |
4 |
4.4% |
|
Australia |
84 |
0
|
0.00% |
14 |
2 |
14.3% |
|
Japan |
45 |
2 |
4.44% |
75 |
3 |
4.0% |
|
Taiwan |
21 |
2 |
9.52% |
20 |
3 |
15.0% |
|
Others |
455 |
10 |
2.20% |
235 |
13 |
5.5% |
|
Overall Total |
12675 |
99 |
0.78% |
4907 |
170 |
3.5% |
*the European results indicate total records and not total inspections, for this reasons the non-compliance percentages have not been used to draw comparative conclusions.
These statistics clearly demand the need to define a uniform set of global compliance standards, along with a global system of evaluation for drug manufacturing facilities.
However, it is also important to understand if there are other issues, which create all the negative press.
So where are the compliance problems?
With India being the largest exporter of medicines and accounting for almost 40% of the generic and over-the-counter drugs used in the United States, global pharmaceutical majors continue to expand their manufacturing operations across India.
Almost 20% of the inspections, which resulted in non-compliances in India, were at the Indian operations of global companies like Apotex, Watson (now Actavis), Hospira and Fresenius Kabi.
This brings about another question, which needs to get answered; if the same company has facilities across the world failing inspections, is it a problem of the company, or the country where they are located?
There seems to be a pattern emerging as some corporates cannot seem to be in compliance regardless of location (see table below).
Table 4/ USFDA Warning Letters Issued to global pharmaceutical companies. Source: FDA Website.
|
Company |
Warning Letter Issue Date |
Country |
Closeout Date |
|
NOVARTIS |
|||
|
May 2013 |
Austria |
||
|
Nov 2011 |
United States & Canada |
Jul 2014 |
|
|
GSK |
|||
|
Oct 2011 |
United Kingdom |
Mar 2013 |
|
|
Mar 2014 |
Ireland |
||
|
APOTEX |
|||
|
Feb 2013 |
Canada |
||
|
Jun 2014 |
India |
||
|
Jan 2015 |
India |
||
|
HIKMA |
|||
|
Oct 2014 |
Portugal |
||
|
Feb 2012 |
United States |
Mar 2014 |
|
|
HOSPIRA |
|||
|
Sep 2014 |
Australia |
||
|
Apr 2010 |
United States |
||
|
May 2013 |
India |
||
|
Mar-15 |
Italy |
||
|
BOEHRINGER INGELHEIM |
|||
|
June 2013 |
Germany |
06/05/2014 |
|
|
Nov 2007 |
United States |
||
|
NOVACYL |
|||
|
Dec 2014 |
China |
||
|
Feb 2015 |
Thailand |
The data above clearly indicates a much more deep rooted problem on the actual reasons why companies globally fail inspections.
Our take:
Drug manufacturing quality is facing a monumental perception challenge. In the quest for affordable, safe drugs, the pharmaceutical world needs to know more about the over 90% success rate in European and U.S. inspections by companies in India and China.
While some Indian companies like Granules India and Kemwell Biopharma do announce their recent successes in their FDA inspections (both had zero Form 483 observations in their March 2015 inspections), much more needs to be done by Indian and Chinese companies to change the perception of their manufacturing quality. Celebrating and communicating their positive outcomes would be a good start.
As the United States and Europe do not have consistency on standards, conversations of trade protectionism and individual inspector bias get initiated but little happens to improve overall product quality.
The difference in standards has already started conversations where Indian and Chinese inspectors may start global inspections of manufacturing sites that supply into two of the world's largest populations.
It's worthwhile to mention that additional inspections and tests do not mean better quality; after all that is the fundamental principle of Good Manufacturing Practices (GMP)!
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