In 2015 we published a collection of FDA GMP warning letters that included deficiencies in data governance and data integrity. Here we provide the same information for 2016 drug GMP warning letters. These should serve as a resource for GMP audit staff and QA staff as they evaluate their own firms and contract sites for gaps in these areas. In this introduction, we provide tables and graphs identifying the dates of the warning letters, firms to which they were issued, and the country where the facility is located. We also provide a table that shows the trends over time for location of countries where facilities receiving these warning letters were located, beginning in 2008. And, finally, we provide a tabulation of the regulations most frequently cited for these deficiencies in 2015 and 2016.
Table 1 lists the warning letters that include data integrity deficiencies, the date of issuance, and the country where the facility is located. Note that the first two warning letters were from inspections in 2015 but published in 2016 and were not counted in last years’ tally, so I included them here. I’ve color coded the country column and have included all European countries in a single group.
TABLE 1: Warning Letters with Data Integrity Deficiencies
DATE | COMPANY | Country |
12/15/2015 | Chan Yat Hing Medicine Factory | China |
12/30/2015 | Irvine Stem Cell Treatment Center | US |
1/29/2016 | Ipca Laboratories Limited | India |
3/3/2016 | Emcure Pharmaceuticals | India |
4/1/2016 | Sri Krishna Pharmaceuticals Ltd. Unit II | India |
4/7/2016 | Apotheca Supply Inc | US |
4/12/2016 | Florida Institute of Reproductive Sciences | USA |
4/14/2016 | Polydrug Laboatoreis Pvt Ltd | India |
5/12/2016 | Tai Heng Industry Co Ltd. | China |
5/16/2016 | BBT Biotech GMBH | Germany |
5/19/2016 | Megafine Phrma LImited | India |
6/16/2016 | Shanghai Desno Chemical Pharmaceutical Co. | China |
6/21/2016 | Chongquing Lummy Pharmacuetical Co | China |
6/22/2016 | Guuangzhou Haishi Biological Technology Co | China |
7/12/2016 | GenPak Solutions LLC | USA |
7/19/2016 | Ziamen Origin Biotech Co Ltd | China |
8/2/2016 | Adamson Analytical Laboratories Inc. | USA |
8/4/2016 | Zhejiang Medicine Co Ltd Xinchang Pharmaceutical Factory | China |
8/5/2016 | Noven Pharmaceuticals | USA |
8/10/2016 | Hushou Aupower Sanitary Commodity Co Ltd. | China |
8/11/2016 | Zhejiang Hisoar Pharmaceutical Co | China |
8/12/2016 | Unimark Remedies Ltd | India |
8/15/2016 | Frontida | USA |
8/25/2016 | Pan Drugs Limited | India |
8/25/2016 | Lima & Pergher Industria e Comercio S.A. | Brazil |
9/6/2016 | Hebei Yuxing Bio-Engineering Co. Ltd. | China |
9/12/2016 | Mappel Industria de Embalagens, SA | Brazil |
9/15/2016 | Nippon Fine Chemical Co. | Japan |
9/26/2016 | Delarange Cosmetics and Healthcare BV | Netherlands |
9/29/2016 | Laboratoire Sintyl S.A. | Switzerland |
9/29/2016 | Yangzhou Hengyuan Daily Chemical Plastic Co Ltd | China |
10/13/2016 | Teva Pharmacuetial Works Private Limited Company | Hungary |
10/18/2016 | Interpharm Praha A.S. | Czech Republic |
10/19/2016 | Beijing Taiyang Pharmaceutical Industry Co Ltd | China |
11/8/2016 | Sekisui Medical Co Ltd | Japan |
11/8/2016 | Srikem Laboratories | India |
11/10/2016 | Dongying Taindong Pharmacutical Co Ltd | China |
12/8/2016 | Baoying Couonty Fukang Medical Applicance Co. Ltd | China |
12/8/2016 | Antibioticos Do Brasil Ltda | Brazil |
12/15/2016 | Natura Bisse International S.A. | Spain |
12/23/2016 | Wockhardt Limited | India |
Table 2 identifies the countries where the facilities are located for both this year’s tally and for last year. China received the most warning letters of this type in CY2016, with India close behind. Considering both years together, India received 19 warning letters and China received 16 warning letters with data integrity deficiencies. India received essentially the same number of warning letters in the two years, but China saw a dramatic increase from 2 to 10 in the two years. Note that in CY2016, seven (7) firms in the US received warning letters with data integrity deficiencies. Brazil and Japan are new to the list this year with 3 and 2 warning letters respectively. Figure 1 shows the same information as a graphic.
Table 2: Number of Data Integrity Associated Warning Letters by Country
Country | Number of Warning Letters with Data Integrity | |
CY2015 | CY2016 | |
China | 2 | 14 |
India | 10 | 9 |
US | 0 | 7 |
Europe | 2 | 6 |
Brazil | 0 | 3 |
Japan | 0 | 2 |
Thailand | 1 | 0 |
TOTAL | 15 | 41 |
Figure 1: Data Integrity Warning Letters by Country
Figure 2 captures data from 2008 through 2016 on a country by country basis. Some countries are consistently present in multiple years including the US, China and India and the ‘Europe’ category. A few countries are present only in one or two years. Note that the US has warning letters with data integrity deficiencies in all years except 2013, 2014, and 2015 and is in fact the third most frequent country for 2016 warning letters of this type.
Figure 2
![Figure2png](https://4982731c.rocketcdn.me/wp-content/uploads/2024/01/Figure2png.png)
Table 3 shows the regulations cited in the warning letter deficiencies. Many of the deficiencies identified in the collection for CY2016 do not cite a governing regulation. Many are ‘conclusions’ or ‘Data Integrity Remediation’ instructions from the FDA to which the firm must respond. Many of the letters are issued to API manufacturers and do not cite 21 CFR 211 which applies to finished product. In addition to the regulations cited below, the following regulations were each cited once: 211.100(b), 1271.50(a), 211.165(e), 211.180(e), 211.137(a), 211.180(a), 211.101, 211.186(a) and 211.42(c).
Table 3: Most Frequent Regulation Citations in CY2016
CFR Reference | Number of Times Cited | Title of CFR Section |
211.68 | 7 | Automatic, Mechanical, and Electronic Equipment |
211.22 | 5 | Responsibilities of the Quality Control Unit |
211. 194 | 3 | Laboratory Records |
211.160 | 3 | General Requirements, Laboratory Controls |
211.165 | 2 | Laboratory Controls |
211.188 | 2 | Batch Production and Control Records |
Table 4 shows the same data for the years 2008-2014. In addition to the regulations cited in the table are 211.25, 211.166, 211.182, and 211.192. As in the past fifteen-plus years, FDA has focused on enforcement of the predicate rules. The notable difference between 2016 and 2008 – 2014 is the appearance of 211.22 and 211.165. For both groups, the categories of “Laboratory”, whether controls, records or general requirements is predominant.
Table 4: Most Frequent Regulation Citations 2008-2014
CFR Reference | Number of Times Cited | Title of CFR Section |
211.68 | 13 | Automatic, Mechanical, and Electronic Equipment |
211.194 | 6 | Laboratory Records |
211.160 | 2 | General Requirements, Laboratory Controls |
211.180 | 2 | General Requirements for Records and Reports |
211.186 | 2 | Master Production and Control Records |
211.188 | 2 | Batch Production and Control Records |
Conclusion:
In 2017 I look for much of the same in terms of warning letter deficiencies in the area of data integrity. I would expect the number of warning letters issued to China to continue to increase assuming foreign inspections are not curtailed as part of potential cost cutting under the new administration. I would also expect to see more focus on electronic records issues in batch records and in the manufacturing area as FDA expands their focus out from the laboratory. Compliance in this area continues to bedevil the industry, both domestic and foreign manufacturing sites. Perhaps one potential remedy is to have firms’ internal GMP audits and assessments focus in depth on this area. Remediation here often takes time and can be expensive if new instrumentation or software is required. But, better to identify problems if they exist than wait to have FDA point them out. It’s important to remember that FDA and other health authorities are sharing their findings, so companies with these problems generally need to deal with multiple regulatory authorities. And those who are contract manufacturers must also address potentially unhappy clients. Remediation of official health authority actions are necessarily more expensive than finding and correcting issues internally.