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Summary and Discussion of Quality Trends in FDA Warning Letters focus on Pharmaceutical GMP

Abstract

GMPs are provisions provided by organizations such as FDA with the aim of ensuring that quality in the manufacturing of pharmaceutical products is ensured. This is in terms of value and following of manufacturing protocols that are valid ensuring quality of products is not defective and ambiguous. These irregularities are observed in many pharmaceutical companies and have been seen through documented warning letters written by FDA to the concerned companies. They have been found to be posing as risks of disbursement of defective drugs which are contaminated and below the required standards causing deleterious effects to consumers. Recommendations on stringency to enforce these laws and ensure they are implemented in these companies are also of concern as stipulated in this paper.

Introduction

Pharmaceutical good manufacturing practices (GMPs) are requirements predetermined by Food and Drug Administration (FDA) to ensure the manufacturing companies for pharmaceutical products comply with these laws.  They help in ensuring such products are of good quality and purity to ensure safety of the consumers. They also ensure that a clear definition of the protocols of manufacture through scrutiny on how they are done and controlled is provided. These practices also ensure that the manufacturers are well trained and specialized for the job to prevent questioning of the validity of the products. They also assist in the monitoring of the drug ensuring quality is not interfered with during transportation, instructions accompanying the drugs should unambiguous and clearly legible avoiding the possibility of mistaken consumption. These principles must be observed during manufacturing processes though they do not stipulate the precise methods to be used during drug manufacture. These stipulations have also been formulated and enforced by other organizations other than FDA such as WHO and ICH and have been adopted differently by various countries though all of them have a similar mandate to test and approve the active raw materials in pharmaceutical products and deduce if they have deleterious effects to humans. Their enforcement however requires critical consideration to keep the world off sub- standard and lethal products. This paper focuses on the stipulations of FDA concerning these GMPs in pharmaceutical production and gives their implications offering recommendations of the mitigations to be taken.

Current trends in FDA warning letters on pharmaceutical GMPs

FDA communicates using warning letters on its provisions and amendments so that new developments can be made aware of. The issues discussed include those concerning the manufacturing environment in terms of its qualifications and validation¹. These letters report a lack of adherence to the stipulations of FDA’s regulations such as those of using insufficient processes that are not validated in a bid to make cost effective manufacture of such drugs. Procedures to prevent microbial contamination of pharmaceutical products believed to be sterile due to lack of adherence to procedures stipulated by FDA provisions have also been overstepped with the need to produce faster putting the consumers at a big risk as observed in the letters. These letters have been used by this organization to assess its progress in ensuring these laws are adhered to. Issues of noncompliance in the manufacture of Active pharmaceutical ingredients (APIs) are frequent occurrences through the statistics done by FDA and thus require urgent resolutions. The water purification steps were found to be of sub standard quality yet it was meant to be used in parenteral production of drugs thus depriving these drugs off their quality. The program for monitoring the APIs was found to be inconsistence and the quality control unit did not exercise its mandate to recognize these anomalies. These included; the determining the volumetric solutions of the finished drugs, the procedures used in standardization and the values on calculations and the formulas used ². Recognition of these incongruities in most cases results to the withdrawal of production till FDA is assured of the quality of drugs as observed in many of the warning letters.

Such a warning letter was that of the Synbiotics limited³ that was meant to address the issues of lack of preparation, approval and review of the manufacture of APIs. This was during the shipment processes, digressions were also observed in the laboratory practices and also grumble was also reported from the consumers who handled the drug making the quality of the company and product wanting. These warning were supposed to be rectified by the next inspection date by FDA which on lack of adherence would result to stern action being taken. The warning concerning the failure of guarantee that the APIs protocols used would result to the product of specified standards in this company also lacked. This was observed that during shipment where validations on the components of the manufactured drugs and their documentation had not been done³. The production in the company was thus deterred till quality maintenance of these documents was done and approval by FDA was granted.

This problem was also experienced by Macco Organiques⁴ which also had lacked to maintain adequate data making its laboratory controls questionable. In this case they were warned on lack of maintaining analytical notebooks, original raw data and lack of documented protocols according to the US Pharmacopeial (USP). The organization was also found to consult second persons in order to confirm the compliance and completeness of the analytical procedures used thus a lack of quality standards and competence⁴.  The failure of quality in the inspection, performance of study on the expiry dates failure and also the use of tap water for the cleaning purposes who sterility level was wanting was also questioned in the warning letter thus poor quality products. In this company safety hygiene was found lacking where a warning concerning building of facilities that had not been designed for feasible stability studies and validation was also outlined in the warning letter. Contamination was easily possible due to the flying insects which were found on open bags of drugs and also debris and dust found covering those products thus being more of health hazards. In this case a stipulated deadline of about two weeks was issued for the correction of these anomalies to be done which otherwise would result to closure of the company⁴.

In another warning letter to Yuki Gosei Kogyo Limited⁵ also showed some irregularities which required dire and speedy address. The warnings concerning controlled quality in the test methods used in the laboratory such as such as endotoxins and microbial counts were found to be less performed in the company. GMPs were found to be below standards thus improvements needed to be done.  This resulted to the withdrawal of the operations of this company until FDA was ensured that the problematic issues were ironed out and in future would be evaded⁵.

The Vanderveer Centre Company was also found in the same predicaments where the company ⁶which manufactures lipo-dissolving drugs that help in the treatment of human structure dysfunctions was found to have unsubstantiated claims of their on their meso-lipotherapy drugs concerning efficacy. This according to FDA was a false claim and a misleading scenario out of egoism⁶ since these claims were not supported and on trial proved false. A warning concerning unverified claims on safety indicating that these products prevented wrinkles enhancing skin and healthy growth in humans was given since these claims were not valid and had not be tested for feasibility⁶. This consequently lead to these products being misbranded in the Food, Drug Administration and Cosmetic act (FDACA) and an extinction of their sale in the market till the above claims were substantiated^6. These violations were taken gravely since their consequences could be lethal and disease causing if they were allowed to continue minding that the facts were fallacious.

Another warning letter to Tercica limited⁷ was given against the lack of adequate unambiguous direction for the use of the drugs manufactured in this company. This was particularly so for their drug increlex which had anomalies with its misleading claims on its promotion though not an over the counter drug. It also had improper labeling and also had omitted information concerning its contraindications thus greater risk to the consumers. This was also warned against in the letter. There was also a need for the company to broaden indications of the drug and the specific treatment it was used for. This caused a misbranding of the drug above which was claimed to treat conditions only of primary IGF-1 syndrome unlike indications that also specified that it could be used for secondary IGF-1 deficiency, claims that had not been vailidated⁷.

Another warning letter had also been addressed to the CP Pharmaceuticals limited⁸ indication violations which they had contravened on quality GMPs. The company had not introduced a defined control system to prevent contagion in the processes requiring aseptic protocols. This was so because no indications concerning in situ analysis of patterns such as those of smoke had been dealt with thus such stagnant air could result to contamination in the drug manufacture. Their environmental routine examination of equipment and facilities ensuring they were free off contamination had not been done thus questionable quality of products manufactures as indicated in the warning letter⁸. Warnings also concerning the quality of their aseptic techniques to deter the growth of spores, viable APIs protocols and also endotoxin count scrutiny were yet be of quality. Monitoring on their environmental conservation procedures were also outlined in the warning sheet resulting to a decree giving them a fortnight to correct these blunders otherwise risk closure and misbranding of their products.

Another letter was also issued SNBL USA limited⁹ warning this company on the competence of their personnel, it indicated they portrayed that they did not understand the function of the actions they were undertaking in the manufacturing process thus lack of observance of GMPs. The mixtures of their concoctions of APIs were not standard and did not get tested for stability thus the standard operating procedures (SOP) were not appropriately adhered to. The quality assurance officers fail to note this and even nullify it; the directors had not signed the assessment of these reports thus continued incompetence. This warning came along with a two weeks decree where this company should report to FDA with the measures on how to deter this in the future which on failure would face disqualification⁹.

Implications of these warning letters

Warning letters are simply alerts that there is dire problem in GMPs adherence in the manufacturing of pharmaceuticals hence calling for improved systems and processes of manufacture which must be properly managed¹⁰. They indicate the need for an improved system of monitoring the compliance of GMPs with a holistic approach to ensure these laws are enforced. They also portrays the stringency of FDA in ensuring these laws are enforced though not aggressive enough thus the cause for the named anomalies. It also implies that formal communication is not enough to validate that there is disseminations of GMPs but strict monitoring so that sustainable quality can be maintained by FDA among other organizations should be emphasized¹⁰. The irregularities observed in the shipping and the transporting of pharmaceutical products also indicate that there is need for FDA to expand its research to the global supply chain particularly any imports and exports and the protocols used in their manufacture to allow them to be consumed in their member countries. This will safeguard them from accepting falsified drugs that are contaminated through enhanced systematic threat based appraisal on whether GMPs are adhered to. FDA also plans to monitor how local manufacturers meet the criteria of being international suppliers through the warning letters they issue. These letters also imply that FDA has the mandate to bundle with more aggressiveness on companies that are stubborn in a bid to enforce any violations against GMPs ensuring they are adhered to.  This is through pharmaco-vigilance systems but adverse reporting of events before occurrence in the future is encouraged in order to heighten the sensitivity of this issue not only to the drugs consumers but also the manufacturers. This is portrayed by many of the pharmaceutical companies not adhering to the laws stipulated by FDA concerning GMPs.

The issue of quality systems has also been pointed out with many of the units of quality control being inefficient particularly in monitoring of the purity, eminence, strength and confidence in the finished products, these calls for FDA to formulate other strategies to ensure such oversights do not occur since they contaminate all other manufacturing procedures. In the above mentioned letters a picture of lack of regulatory management is also drawn due to companies’ poor adherence to inspection responses which can only be addressed through corrective action and applying the virtues of robustness in all manufacturing units observing quality and hygiene. The changes also encourage adoption of new technology to manufacture, acceptance of industrial approaches during manufacture and also enhancing use of risk based approaches both at the FDA and the company level to enhance GMPs¹¹. Improving the art of pharmaceutical science ensuring that consistency and coordination of GMPs is instilled will enhance quality and the degree of adherence. To achieve this FDA has done collaborations with other governmental organizations such as the CDER, CRADA and ORA for enhanced strategic plan of action thus a new revolution by pre approval of many inspection programs to cover the wide scope of companies¹¹. The issue of drug testing before being disbursed to suppliers has also been initiated without biasness thus a good strategy to ensure quality inspection is done at the company level. This also serves as a warning to the stakeholders involved. Before a drug has been ascertained to have curative properties pre clinical and clinical trials have to be done as one of the requirements so that unsubstantiated claims of cures of drugs can not be formulated ¹¹. Adherence to these stipulations is thus going to bring forth corporate responsibility enhancing performance and adherence to GMPs by pharmaceutical firms.

Recommendations

There is a dire need to address issues concerning the adherence of GMPs in all pharmaceutical manufacturers. This is foreseen as the only way to enhance quality in the processes of manufacture. Recommendations on a testing regime and inclusion of analysis credential with the valid statistical analysis concerning the documented information are advocated for. The assurance that GMPs are being adhered to in the entire industry and its processes should also be encouraged. The campaign for FDA to modify some sections of its stipulations so that they can be flexible is also being advocated for. Every company should also avail FDA with written documents containing protocols they use and also retained some archives on this in case referencing should be required during inspection. Shelf life of these products among other contraindications that are valid should be indicated on these products’ packages without any inaccuracies to ensure correct and appropriate communication is made. The responsibilities of the quality assurance division should be well stipulated particularly in the feasibility and frequency testing on the quality of the drug and the side effects of the drug so that the market has non contaminated drugs that are of good quality. Lack of adherence to these rules should be followed by misbranding of such drugs after issuance of a warning letter as this will avoid endangering exposure of humans to defective drugs and serve as a lesson for other companies.  The joining of other lobby groups and organizations such as WHO and CDER to help in ensuring GMPs are followed will promote enforcement of these policies. Encouragement of performance of clinical and pre clinical trials to validate any drug is for the said treatment thus preventing the release of drugs with claims of treatment that are falsified should be implemented. The testing of the validity of the APIs will help to ensure that the contents of the drugs are in the right amounts and that statistical records concerning these drugs are detailed ensuring defective drugs are not marketed.

Conclusion

The findings in the letters summarized and discussed above show that the adherence of GMPs by many manufacturing companies wants, thus this issue is grave and must be addressed. There is a lack of proper inspection methods on the manufacturing processes, proper documentation of the statistical analysis of the protocols being carried out and also lack of proper monitoring on the issues of quality assurance such as those of contaminations from smoke, bacteria spores which have endotoxins. The analysis of the APIs is also poor and some fabrications of certain drugs to cure various ailments which are unsubstantiated have also been observed. The situations of companies’ organization in terms of its arrangement have also been seen to pose as a threat for stagnating the air around causing pollution. Addresses have been done by organizations such as FDA advocating for misbranding of such sub standard drugs through warning letters. This organization has also called for decrees to such organizations threatening them with closure if they do not follow GMPs requiring them to provide a written document proposing how such problems are going to be resolved. Though these agencies have been vigilant to ensure GMPs are followed still a lot has to be done and thus new agencies have come in to help this organization. Enforcing the adoption of these policies has to be implemented. This is however causing alarm on these policies due to their stringency advocating for flexibility to accommodate some protocols. This is foreseen to ensure that these policies are followed and quality is of focus while producing pharmaceutical products.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Notes

1.      FDA “FDA Posts First Annual Report Measuring FDA’s Success in Receiving Early Warnings about Problems with Food and Animal Feed”

(2011):

2.      FDA administration: Department of Health and Human Services “Klinge Chemicals Limited” (2010): Retrieved on 12^th April 2011 from:

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm238542.htm

3.      FDA administration: Department of Health and Human Services “Synbiotics Limited” (2010): Retrieved on 12^th April 2011 from;

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm237767.htm

1. FDA administration: Department of Health and Human Services “Macco Organiques” (2010): Retrieved on 12^th April 2011 from;

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm236832.htm

1. FDA administration: Department of Health and Human Services “Yuki Gosei Kogyo Company Limited” (2010): Retrieved on 12^th April 2011 from; http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm236841.htm
2. FDA administration: Department of Health and Human Services “Vanderveer Center” (2010): Retrieved on 12^th April 2011 from: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm235714.htm

 

1. FDA administration: Department of Health and Human Services “Tercica” (2010): retrieved on 12^th April 2011 from: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm232779.htm
2.  FDA administration: Department of Health and Human Services “CP Pharmaceuticals, Ltd” retrieved on 12^th April 2011 from: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm233036.htm
3. FDA administration: Department of Health and Human Services “SNBL USA LTD” retrieved on 12^th April 2011 from: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm222775.htm
4. Church Rob and Mahoney Steve. “Trends in FDA Good Manufacturing Practice Warning Letters Recent US Food and Drug Administration warning letters provide clues to pharmaceutical companies about how they can enhance their quality systems, improve their manufacturing processes and more effectively manage future FDA establishment inspections” Informa UK limited, (2009):
5. 11.  Phil Taylor. “The FDA Interview: Is pharma getting worse at manufacturing?” (2010): Retrieved on 12^th April 2011 from; http://www.inpharm.com/news/fda-interview-pharma-getting-worse-manufacturing