Manufacturing Compliance Updates In Brief: A Reduced Focus On Data Integrity

US FDA has issued at least 10 GMP warning letters in February and March to drug and API manufacturers in China, India, France, South Korea, Hong Kong, the Dominican Republic and the US. Common problems seen are failure to validate manufacturing processes, inadequate testing to conform that products meet specifications, and inadequate safeguards to prevent microbiological contamination, yet in a recent turn, only a few manufacturers had data integrity problems. FDA posts Form 483 reports issued to four manufacturers in India for GMP violations and adds six facilities to its drug GMP import alert.

The predominance of data integrity issues in FDA drug GMP warning letters appeared to diminish in February and March, when there was a greater focus on traditional manufacturing quality issues. Typical issues raised in 10 warning letters issued during that span include failure to validate manufacturing processes, inadequate testing to confirm that products meet specifications, and inadequate safeguards to prevent microbiological contamination.

FDA also posted Form 483 reports issued to four manufacturers in India for GMP violations and added six facilities to its drug GMP import alert.

Malladi Had Birds And Insects Near Open Equipment

API maker Malladi in Chennai, India, was the target of a March 9 warning letter for its lax approach to contamination controls and validating manufacturing processes.

US FDA said that parts of the facility are open to the outdoors, and birds and insects were found near open equipment. FDA said that “their presence puts your drugs at risk of contamination.”

The firm was also criticized for having manufacturing equipment partially filled with water, which FDA said is a problem because this increases the risk of drug contamination.

FDA said that the firm also lacked a robust process validation program and could not demonstrate that the manufacturing process could reproducibly make an API meeting its predetermined quality attributes. “During our inspection, you acknowledge that you failed to adequately validate [an] API drug manufacturing process.” This may have caused 24 batches yielding out-of-specification test results over a two-year period.

The firm was advised to hire a GMP consultant, and was placed on an import alert on Dec. 13, 2017.

French Testing Lab Not Validating Products

FDA investigators found that Quali Controle, a contract testing laboratory in Meru, France, had not validated certain non-compendial test methods it was using to analyze drug products, and also telling customers on the Certificate of Analysis (CoA) that the methods had not been validated.

In a March 5 warning letter to the firm, FDA stressed that “it is essential for a contract test laboratory to use validated or verified methods to ensure that results of a pharmaceutical subject to cGMP are accurate. Accountability in the supply chain is compromised when a CoA reports that results conform to specifications without assurance that the test methods used are reliable. Including a disclaimer does not release you from the GMP requirement to ensure that your test  methods are validated and suitable for their intended use.”

In its response to FDA's inspectional observations, the company indicated that a comment has been added to its CoA to inform customers that the analyses are conducted using invalidated test methods and that the firm would inform customers that all future test methods will need to be properly transferred or validated to “legitimize” the results obtained in the laboratory.

The firm also failed to investigate the root cause of batch failure. The company affirmed that dirty glassware was the root cause of the problem, and that rinsing the glassware before testing would resolve the issue. FDA said that “your response was inadequate because you have no scientific justification for the assigned root cause, nor have you implemented adequate corrective and preventive actions (CAPA).”

South Korean Drug Manufacturer Nowcos Criticized For Not Validating

FDA’s Feb. 14 warning letter to Nowcos in Seoul, South Korea, faulted the firm for not validating its manufacturing processes in making over-the-counter drug products.

The firm did not perform process qualification studies and lacks an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.

The company was also criticized for not conducting validation studies to demonstrate that cleaning procedures for non-dedicated production equipment are adequate to prevent cross-contamination.

FDA “strongly” recommended that the firm hire a GMP consultant. The agency placed the firm on an import alert Dec. 27, 2017.

FDA Faults Chinese OTC Manufacturer For Inadequate Sampling

Chinese OTC manufacturer Shanghei Weierya Daily Chemicals was lambasted in a Feb. 7 warning letter for not adequately testing drug products for objectionable microorganisms.

Following an inspection of the plant’s site in Shanghai from April 10 to April 14, 2017, investigators found that that the firm did not test each batch prior to release and distribution. The company only tests one lot every six months.

The firm also failed to adequately test incoming components, including excipients in manufacturing OTC drugs. The company said it only tests a subset of lots of incoming APIs.  FDA reminded the company that “you must test all lots of incoming components for identity prior to release by the quality unit.”

Further, the quality unit was not “effectively exercising its responsibilities” by failing to approve raw materials, including API and packaging and labeling materials to ensure their suitability prior to use in OTC drugs, and failed to review batch records prior to releasing products.

The firm was advised to hire a GMP consultant. FDA placed the firm on an import alert Sept. 14, 2017.

Keshava Organics Cited For Not Investigating Batch Failures

FDA issued a warning letter on March 15 to API maker Keshava Organics in Thane, India, for lack of rigor in investigating out-of-specification results.

Investigators found that “in multiple instances, you disregarded the original failing based on a retest., but you lacked a Phase 1 laboratory investigation to support invalidation of the result. You also often lacked Phase 2 investigations to evaluate your manufacturing operation for potential root causes.”

In response, Keshava conducted a retrospective review of OOS results, yet FDA said that the review is insufficient in that it shows a pattern of recurring, similar OOS results for which investigations were insufficient, including a lack of corrective actions and preventive actions, or CAPAs.

FDA said that “notably, your response adds that it was impossible to make reliable retrospective root cause determinations for the failing results and provide scientific rationales for decisions because considerable time had elapsed since the original OOS occurrences.” FDA reminded the company that “timely investigations are essential for providing credible information and scientific evidence of laboratory error hypotheses.”

The firm also mislabeled numerous OOS results between February 2015 and April 2017 and labeled them as “incidents” and not as OOS results.

FDA also faulted the company for not maintaining complete data sets for APIs tested and distributed to the US. Test data sheets had missing sample weights for identity testing as well as batch and lot numbers for reference standards and reagents as well as data for equipment identification and complete thin layer chromatography data for related compounds.

Similar deficiencies were also observed in previous inspections conducted in 2011 and 2014. FDA said that “these recurring deviations demonstrate that your facility’s oversight and control over the manufacture of drugs is inadequate.”

The firm was advised to hire a GMP consultant.

OTC Maker In Hong Kong Not Testing Drug

OTC maker Nan San Pharmaceutical Factory in Hong Kong was the recipient of a Feb. 23 warning letter for failing to ensure that drugs conform to specifications, not performing microbial limit tests for topical liquid analgesics, and failure to validate manufacturing processes.

FDA said that the firm did not perform microbial limit tests for each batch of its Easy-Flex analgesic lotion released between 2013 and 2016. The letter said that “instead, you performed microbial limit testing on one batch in 2013, and reported the same results to release subsequently manufactured batches to the United States.” Further, the firm’s contract testing laboratory only tested for the strength and identity of only one ingredient in the finished product testing.

The firm also did not validate the processes used to manufacture OTC drug product and did not perform process qualification studies and lacked an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.

The firm was advised to hire a GMP consultant.

Dominican Facility Faulted For Cross-Contamination Risks

Labocont Industrial SRL in the Dominican Republic came under fire in a March 9 warning letter for failing to have separate areas when manufacturing OTC drugs and other products, having incomplete laboratory records and not validating analytical methods.

FDA urged the firm to dedicate a certain facility to the manufacture of a certain undisclosed product, saying, "it is unacceptable to produce any other products in the same physical facility."

FDA acknowledged that the firm could continue to make other products in the facility, but only after fully decontaminating the facility -- something FDA said would be "profoundly difficult" due to residues from the undisclosed product.

Laboratory data was also not complete. The letter states that “your firm does not ensure that complete data from assay testing of your finished drug products and active pharmaceutical ingredients (API) are maintained and reviewed by your quality unit. For example, our investigator observed that an analyst failed to document absorbance data generated during assay analysis, and only reported calculated results.”

Further, the analytical methods that are used to determine assays of the API and finished drug products were not validated and lack specificity and instruments were not verified or calibrated to perform laboratory tests.

The firm was advised to hire a GMP consultant.

The company was placed on an import alert on Feb. 8.

Manufacturer Made Cosmetic Wipes Using 'Unacceptable' Water

Contract manufacturer and cosmetic brand owner Diamond Wipes International of Chico, Calif., was the recipient of a March 7 warning letter for a multitude of GMP violations, including making cosmetic wipes using water of "unacceptable" quality.

FDA said that “you used water for manufacturing operations that exceeded your microbiological total count action limit in eight instances and exceeded your alert limit numerous times during a 14-month period. You failed to adequately investigate the lack of water systems control, and implement adequate corrective actions and preventive actions.”

High numbers of microbes, in some cases too numerous to count, were in the water systems, including Pseudomonas spp, Burkholderia spp, and other potentially pathogenic gram-negative bacteria.

FDA said, “you used water from this system to manufacture your topical drug products over an extended period. For example, you released several lots of antibacterial and acne treatment wipes that were formulated with unacceptable quality "(b)(4)" water.”

FDA also lambasted the firm for not investigating the root cause of batch failures. It states that one lot of acne treatment facial wipes and one lot of acne treatment pads were found to contain fungal levels “significantly beyond” specifications.

Cosmetics aside, Diamond’s involvement in manufacturing antibacterial and acne treatment wipes make it subject to GMP regulations for drug products. (Also see "Diamond Wipes’ FDA Headaches Suggest Cosmetic Recall Hangover" - HBW Insight, 27 Mar, 2018.)

The firm was advised to hire a GMP consultant.

Zhejiang Ludao Cited For Data Integrity Problems

FDA chastised OTC drug maker Zhejiang Ludao Technology in Taizhou, China, in a Feb. 23 warning letter letter for problems relating to data falsification and not adequately testing incoming components.

During an inspection conducted from Aug. 14 to Aug. 18, investigators said that the firm “lacks basic laboratory controls to prevent changes to paper and electronic records.”

The firm was unable to provide analytical test data for three batches of OTC sprays and one batch of OTC product. FDA said it found that the firm had created certificates of analysis for these four batches before they were manufactured and tested. When questioned, FDA said the firm “acknowledged falsifying the analytical tests results on the CoA” to support release and distribution of these products to the US.

In addition, investigators found three electronic data files in the electronic recycle bin for its stand-alone high-performance liquid chromatography (HPLC) systems used to test finished drug product sprays.

Investigators could not determine how frequently test data obtained prior to official batch testing was discarded. The letter said that “because this instrument lacks backup and audit trail capabilities, we could not determine how frequently test data obtained prior to ‘official’ batch testing was discarded. You were unable to explain why these electronic files were deleted.”

FDA also found that the firm failed to conduct at least one test to verify the identity of each component of a drug product. The firm also failed to establish the reliability of component supplier analyses on which it relied in lieu of certain tests.

The warning letter told the company to establish a data integrity remediation program. The program, said FDA, should include a comprehensive investigation into the extent of the data inaccuracies. The investigation should include a summary of all laboratories, manufacturing operations and systems and all current and former employees should be interviewed to identify the nature, scope and root cause of data inaccuracies.

FDA recommended that the firm hire a GMP consultant.

The firm’s products were placed on an import alert on Dec. 28, 2017.

Alchymars Dinged For Data Integrity Violations and Dirty Facilities

FDA sent a warning letter on Feb. 26 to API maker Alchymars ICM in Tamil Nadu, India, for a multitude of GMP problems, including data integrity failings, having a deteriorating facility and dirty equipment.

The letter said that “our investigator found that your firm was falsifying laboratory data.” For example, the number of colony-forming units found on plates on water point-of-use tests differed substantially from the number recorded on the water report. And for multiple points of use tests, the analyst reported “far fewer” CFUs than observed on the plate by the investigator.

Investigators also found the equipment and the facility in a state of disrepair. Manhole gaskets were deteriorating and wrapped in peeling tape. Deteriorating gaskets were also the root cause for finished API particle complaints.

The equipment washroom was also found in “filthy” condition with damaged tiles and standing water, and the hand washing stations were “visibly dirty.” In addition, the hand washing stations in the ISO 8 area were also “visibly dirty.’

In addition, hand washing stations were “inconveniently located” and also not fully functional. Stations lacked hot water, soap and hand drying equipment, as FDA also had observed during a February 2015 inspection.

FDA “strongly recommended” that the firm hire a GMP consultant, and also wants the firm to provide a data integrity remediation plan to address the data problems found during the inspections.

Dr. Reddy’s API Facility In India Cited in 483 For Multiple GMP Violations

The failure to close corrective and preventive action (CAPA) investigations, and not following up on complaints were two problems found by FDA investigators and cited on a March 21 Form 483 report following an inspection of Dr. Reddy’s API plant in Medak, India.

The firm was also cited for not following up on handling written and oral complaints related to particle size OOS. The 483 states that the firm “require sample from the customer to confirm the particle size variation observed.” However, the investigation did not reveal if the firm received and tested the requested sample from the customer. A final investigation report has not been issued.

The report also noted that the buildings used in the manufacturing, processing and packing of APIs are not maintained in an adequate state of repair, with a cracked ceiling. Also there are no separate or defined areas to prevent contamination or mix-ups for drums that were quarantined.

Cipla Receives 483 for Not Investigating OOS Failures

FDA on March 27 targeted Cipla Ltd. in Goa, India, in a Form 483 report for seven GMP deficiencies, including failure to investigate batch failures. deficient batch production and control records, and not following established test procedures, and having deficient laboratory records.

Laboratory records did not always include a complete record of all data obtained during testing. For example, test procedures did not specify the stability of the standard and sample solutions, and the firm did not document the date and time to ensure standard and sample solutions were stable at the time of testing.

Established test procedures were also not followed. An investigator reported that “on January 24, 2017, I observed a QC analyst use scissors to cut off an end from each capsule and squeeze the contents of each capsule into a beaker. The aforementioned procedure does not state to use scissors to cut off an end from each capsule.”

Aurobindo Gets 483 for Lack Of Contamination Controls

US FDA issued a Form 483 report to Aurobindo in Hyderabad, India, at its sterile manufacturing plant for several GMP problems, including inadequate contamination controls and having equipment in a state of disrepair.

FDA investigators found that during the machine set-up and filling preparation, “dirty black stains” were on the filling machine, and while this was mentioned to management nothing was done to follow up.

In addition, equipment and utensils were not cleaned, maintained and sanitized at appropriate intervals to prevent contamination.

Also the buildings used in the manufacture of drug products were susceptible to infestation by rodents, birds, insects and other vermin. “During the walkthrough of the facility on February 12, 2018, a large mosquito which appeared to be a female, was observed inside a semi-finished product storage area.”

FDA Cites High Contamination Risks At Sun In 483

FDA’s Feb. 23 Form 483 report of inspectional observations to Sun Pharmaceutical in Gujarat, India, criticized the manufacturer for having run-down facilities.

The investigator noted that “on 14 February 2018, I observed rough, cracked and uneven [redacted] surfaces (with dislodged gaskets) used to create operational barriers separating Grade A filling areas…. from the surrounding Grade B environment. These rough surfaces create difficult to clean surfaces in the immediate vicinity of aseptic filling operations.”

Also the ceiling above the filling equipment had “channels” surrounding each high-efficiency particulate air filters that preclude easy cleaning and sanitizing.

Recent Drug GMP Import Alerts

FDA recently added six drug facilities to its drug GMP import alert, banning imports of drug substances and drug products made there until the firms resolve undisclosed manufacturing issues. The company, location and dates added are:

• Reine Lifescience, Gujarat, India, March 30;
• Sichuan Friendly Pharmaceutical Co., Sichuan China, March 22;
• Jalco Cosmetics, New South Wales, Australia, March 8;
• Hanbul Cosmetics, Cungceongbug-do, South Korea, March 8;
• Goran Pharma Pvt Ltd, Gujarat, India, March 5; and
• Jilin Shulan Synthetic Pharmaceutical Co., Jilin, China, March 1.

From the editors of The Gold Sheet.