Two new FDA Warning Letters for API Manufacturers in China
In June 2016, two API manufacturers in China received a Warning Letter from the FDA. Both companies had major deficiencies regarding data integrity. For instance, manipulations were found in HPLC analyses as well as in GC analyses. You will find more information on the current FDA Warning Letters for Chongqing Lummy and Shanghai Desano here. http://www.gmp-compliance.org/enews_05496_Two-new-FDA-Warning-Letters-for-API-Manufacturers-in-China_15488,15484,Z-QCM_n.html
The Chinese Company Chongqing Lummy Pharmaceutical Co., Ltd. received a Warning Letter from the FDA on June 21, 2016. This Warning Letter referred to both the FDA inspection from March 14-16, 2016 and the response which the API manufacturer had sent to the FDA on March 31, 2016.
It was claimed that Chongqing Lummy Pharmaceuticals had no adequate control in place to prevent data manipulation or deletion. The FDA investigator’s review of the audit trail revealed that an analyst had manipulated the computerized gas chromatography (GC) system to falsify residual solvent results for several API batches.
The analyst had set back the clock of the GC computer to make it appear that the test had been done 7 months earlier. Then he analyzed 5 different injections in order to determine the 12-month value of the long-term stability test. Afterwards, the analyst deleted the original data and only reported the five new results that were conform. The FDA inspection revealed that this procedure of setting back the clock was conducted with at least five other API batches.
During the review of the HPLC system, the FDA inspector found that the HPLC system was configured in a way that analytical results were automatically deleted whenever a test was aborted prior to completion. The review of the audit trail for the Chemstation software indicated that during the analyses of content and impurities, the partial results of aborted tests were automatically deleted from the HPLC system’s records of these analyses. The clock was also set back on the computer for the HPLC analyses in order to retrospectively obtain “conform” results for stability tests.
The company’s response on March 31, 2016 wasn’t satisfactory for the FDA, either. In summary, the FDA writes: “Your response does not indicate how the software upgrades, the SOP revisions or trainings suggested by you can prevent data deletion in the future nor how your quality unit intends to guarantee that the data critical for approval are complete and correct. A response to the FDA is expected within 15 working days. And if you plan to discontinue the delivery of API to the U.S. altogether, FDA requests that you contact CDER’s Drug Shortages Staff immediately.”
Also with the second API manufacturer (Shanghai Desano Chemical Pharmaceutical Co., Ltd.), the data of the laboratory tests were targeted. Here, the main complaint was that laboratory staff performed “unofficial” tests without adequate documentation, justification or investigation:
The original, unofficial analyses were stored in a separate “test folder” and were not part of the official QC data. The inspection revealed that this company had performed about 8,400 of these unofficial chromatographic analyses between 2012 and 2014. According to their internal SOP, all these tests should have been documented. The volume of data in these auxiliary “test folders” suggests that performing unofficial analyses is a common practice at this facility.
You can open the two Warning Letters using these links:
Chongqing Lummy Pharmceutical Co., Ltd.http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm508291.htm
Shanghai Desano Chemical Pharmaceutical Co., Ltd.http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm508554.htm
/////////Chongqing Lummy Pharmceutical Co., Ltd, Shanghai Desano Chemical Pharmaceutical Co., Ltd, warning letters
October 31, 2015 — 2:22 AM IST,
The Pfizer Ltd. research and development plant in Dalian, China.
Bernardo De Niz/Bloomberg
A Pfizer Inc. plant in China that was being inspected by Food and Drug Administration regulators in order to ship drugs to the U.S. kept a second set of quality and manufacturing records that didn’t match official ones, according to an FDA review of the facility.
Though careers in this field are cropping up, it’s tough for entrepreneurs to find a foothold. “When I started my business, I took whatever work came my way. Beggars can’t be choosers and neither can start-ups,” says Mehul Parekh, MD and founder, Unimark Remedies. Parekh always knew he wanted to be an entrepreneur but couldn’t make up his mind about the field. He studied to become a chartered accountant and worked for six months to learn the ropes of running a business.In 1982, Parekh set up Rainbow Fine Chemicals, a pharmaceutical marketing company with Rs 3 lakh as seed money. However, Parekh knew that the opportunity and money were in making medicines. So, after his brother got a master’s degree in organic chemistry, Parekh decided to venture into the field confident in the knowledge that he could bank on his brother’s expertise. In 1995, he set up a manufacturing unit and renamed his company Unimark Remedies. “The biggest challenge is always funding. I bought the premises simply because the owner was the only one willing to sell it on credit,” says Parekh. In 1997, he purchased another plant, this time promising the owner that if he put in the capital, he would get to share the profits. “I avoid putting in huge amounts because it blocks the money that can be invested in more important areas,” he adds.
Besides funding, another roadblock faced by entrepreneurs is government regulations. Concurs Das: “Some subjects, such as highway emergency, are nobody’s baby. The police dumps it on the Transport Department, which says it’s a Health Ministry issue, which, in turn, states accidents to be a police matter.” If such issues were to deter people like Das, the healthcare sector would be in a comatose state. The fact that it has begun to emerge from it speaks volumes about the healthy outlook of such entrepreneurs.
Kerala Nalsarovar Road, Kerala Village, Bavla, Ahmedabad District, India,
The Warning Letters the FDA sent to active ingredient manufacturers last fiscal year, show similar patterns. Find out more about the frequent deficiencies found in the area of responsibility of quality assurance and in the handling of electronic data in production facilities for active pharmaceutical ingredients.
Taking a look at the Warning Letters the FDA issued after inspections of activesubstance manufacturers in the 2015 fiscal year, which ended on 30 September 2015, it is first of all striking that only non-American companies are among the addressees. Almost half of them are Indian companies. Overall the numbers look like this: India (3 WLs); China (2 WLs); Canada (1 WL); Thailand (1 WL); Czech Republic (1 WL).
The top issue in the Warning Letters is the non-GMP compliant handling of electronic data or missing data integrity. Each of the 8 warning letters contains the following comment in the same wording:
“Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.”
The lack of access control on electronic (raw) data is an issue the FDA investigators have been observing for a long time, especially during inspections in pharmaceutical companies. In this as well as in the last fiscal year there were significant deficiencies in several companies – medicinal product as well as API manufacturers – as the comments in the appropriate Warning Letters show. For more information also see the GMP news Another FDA Warning Letter with Focus on “Data Integrity” and FDA Warning Letter on Data Integrity.
Ultimately these deficiencies can be traced back to a failure of the quality assurance unit which also affects other areas. In the Warning Letters, the following examples can be found for this:
- “Failure of your quality unit to ensure that materials are appropriately tested and the results are reported.”
“Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity.”
Data were manipulated by laboratory staff (change of the file name), to fake results from identity tests in batches which in reality were not performed. Quality assurance was not able to uncover this manipulation.
Despite an unknown peak in the examination for residual solvents the relevant batches were released. Upon receipt of a complaint regarding this peak an examination was conducted with the result that the contamination originated in the production process itself. Preventive control measures to avoid this contamination were not established.
- “Failure to adequately investigate complaints and extend the investigations to other batches that may have been affected.”
As a result of a complaint (bad smell), a cause study was initiated which was completed prior to implementation of the preventive measures again. The CAPA measures subsequently carried out were obviously not associated with the reason for the complaint.
- “Failure to have appropriate controls for issuance of batch records”.
The use of document templates for batch records is out of control. These can be printed out from the production staff’s personal computers. Although there is an SOP for the control of batch records there are no appropriate training records.
- “Failure to have appropriate documentation and record controls.”
Data for tracing raw materials are not available. Log entries are without date/visa and partly corrected with Tippex. There is an SOP prohibiting the use of correction fluid, however this was not trained.
- “Failure to record activities at the time they are performed and destruction of original records.”
Original records of critical process data on uncontrolled memos were transferred subsequently in new report templates (after batch approvals) and then destroyed.
This selection of examples shows the lack of fundamental GMP principles which leads to a blatant misconduct of staff and ultimately to quality defects in the final product. The main responsibility usually has the quality unit, which task it actually would be to ensure a thorough training in production and quality control and to monitor compliance with the appropriate regulations. These examples of non-GMP-compliant behavior are not limited to active ingredient manufacturers; there are very similar findings in Warning Letters issued to medicinal product manufacturers. An analysis of these Warning Letters issued in the fiscal year 2015 will be part of one the coming newsletters.
/////Warning Letters, FDA, active ingredient manufacturers
A Warning Letter issued by the US Food & Drug Administration (FDA) to an Indian API manufacturer on 13 July 2015 shows again a clear focus on the missing integrity of data. Specifically, the following issues are addressed:
1. Activities were not recorded at the time they were carried out and original data were deleted:
Entries in the manufacturing protocols were made only days after the relevant activities had been conducted. Further, batches were released before all results were available.
In particular the use of “rough notes” was criticised as these original data were completely destroyed after transfer in the batch records.
2. Due to unauthorised access to data systems, data could be modified or deleted:
Specifically HPLC, GC, and Karl Fischer Titrators were concerned. For instance, for the GC instrument multiple copies of raw data were found in the waste. And there was no password regulation for the data systems of HPLC and GC equipment, and there were no audit trail functions either.
3. There were no training protocols for the cGMP training of employees.
Altogether there were great concerns about the authenticity and reliability of the data produced in this company. Thus the FDA requested a comprehensive CAPA plan within 15 working days upon receipt of the Warning Letter.
For detailed information please see the full Mahendra Chemicals Warning Letter.
Source: FDA, United States
//////////FDA, Warning Letter, Data Integrity, Mahendra Chemicals
Statement “non compliance GMP”. Officina Farmaceutica: Parabolic Drugs Limited – INDIA (30/07/2015)
Following the inspection, conducted by the inspectorate Italian, under the program of inspections of the EDQM, at the Indian site in question, the same was not “in compliance” with the GMP.
It calls on companies to verify, with urgency, if the medicines containing the following active substances / intermediate production Dicloxacillin SODIUM, amoxicillin trihydrate, PIVAMPICILLIN, Flucloxacillin SODIUM, SODIUM cloxacillin, AMPICILLIN trihydrate, AMPICILLIN ANHYDROUS, Bacampicillin HYDROCHLORIDE authorized for the Italian market and / or products for export, showing this as a possible supplier of active / intermediate Officina Farmaceutica: PARABOLIC DRUGS LIMITED, PDL-2 – Plot No. 45, Industrial Area, Phase II, Panchkula District of Haryana, 134113 , INDIA .
The communication must be sent only by all companies Holders of marketing authorizations or Officine pharmaceutical manufacturers of medicines containing these materials pharmacologically active / production intermediates produced at the Indian site in question.
Recall of batches already released
Each involved NCA should evaluate, following assessment conducted in conjunction with MAHs, if a recall of medicinal product is needed. Evaluation should take into account if there are alternative suppliers and potential risk of shortage. Given the nature of non-compliances, assessment should include a complete retest of all imported batches of active substance.
Prohibition of supply
Due to the nature of non compliances, prohibition of supply is recommended.
Suspension or voiding of CEP (action to be taken by EDQM)
Withdrawal of all CEPs is ongoing.
PARABOLIC DRUGS LIMITED
2015-07-28 16:41:08 GMT
Italian Medicines Agency
Report No : IT/NCR/API/2/2015
STATEMENT OF NON-COMPLIANCE WITH GMP
Exchange of information between National Competent Authorities (NCAs) of the EEA following the discovery of serious GMP non-compliance at a manufacturer (1)
The competent authority of Italy confirms the following:
The manufacturer : PARABOLIC DRUGS LIMITED
The US FDA has warned Mylan about manufacturing concerns at three of its plants in India.
In a warning letter to the generic drug manufacturer, the FDA said it had found ‘significant violations of current good manufacturing practice’ during inspections at the plants in August and September last year and in February this year.
The inspections relate to Mylan’s Agila Specialty Formulation Facility (SFF), Sterile Product Division (SPD), and Onco Therapies Limited (OTL) sites in Bangalore.
Some of the violations cited were failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products, such as the use of gloves with tears and pinholes, as well as deficiencies in environmental monitoring and poor monitoring of staff……..http://www.manufacturingchemist.com/news/article_page/FDA_warns_Mylan_about_cGMP_violations_at_its_Indian_facilities/111318/cn48579?dm_i=8EU,3MBVR,9ETTTY,D0ENC,1
Recently the Food and Drug Administration (FDA) began ramping up inspections of offshore manufacturing facilities and the results are shocking. Although cGMP violations have been found worldwide, experts are particularly worried about drugs made in China and India.
Earlier this month the FDA cited three facilities in Bangalore, India that manufacture drugs for Mylan. Headquartered in the U.K., Mylan is the second largest generic and specialty pharmaceutical company in the world. With approximately 30,000 employees worldwide and revenues of $7.72 billion (USD), Mylan certainly qualifies as big pharma.
The FDA says it inspected three of Mylan’s Indian plants between August of 2014 and February of this year. It found “significant” cGMP violations at all three facilities.
Worse, the FDA says that in all three instances Mylan’s response to the three inspections lacked “sufficient corrective actions.”
cGMP standards are in place throughout the manufacturing process to insure the potency and quality of the finished pharmaceuticals. The FDA wants to insure that there are no contaminants in the finished product as well as insuring the finished product is neither stronger nor weaker than advertised.
As a result of the inspections, the FDA concluded a likelihood that the finished drugs from all three plants were adulterated. Those findings are certainly bad news for consumers. It’s also bad for physicians as well. It’s hard for doctors to get dosages correct or monitor for side effects if a drug has inconsistent potency or the presence of contaminants.
In the case of Mylan’s Bangalore, India facilities, the violations were numerous and included:
gloves and sterile gowns for use in aseptic environments had holes and tears
personal sanitation violations
clean room violations
discolored injection vials
lots with failed assays or contaminants
At least one of the facilities had similar violations dating back to a 2013 inspection.
Overall, the FDA noted, “These items found at three different sites, together with other deficiencies found by our investigators, raise questions about the ability of your current corporate quality system to achieve overall compliance with CGMP. Furthermore, several violations are recurrent and long-standing.”
The FDA declared that continued noncompliance could result in drugs from these facilities being blocked from importation and distribution within the United States.
Mylan has had previous problems with U.S. regulators. In 2000 Mylan paid a $147 million fine to settle charges that the company raised the price of generic lorazepam by 2,6000% and generic clorazepate by 3,200%. The FTC had charged that the company raised the price of lorazepam, the generic equivalent of the brand name antianxiety medication Ativan, from $7 per bottle to $190. Although Mylan agreed to the payment of the fine, it denied any wrongdoing.
Only the FDA can punish drug companies for cGMP violations but if there is proof of an adulterated product entering the commerce stream, the federal False Claims Act can come into play. That law allows private individuals to file a lawsuit against a wrongdoer and receive a percentage of whatever is recovered by the government. Last year the Justice Department paid $635 million in whistleblower awards under the False Claims Act.
Whistleblowers in cGMP cases have received tens of millions of dollars. Dinesh Thakur, a former Ranbaxy executive, received $48 million for information about adulterated generic drugs.