Though pharmaceutical manufacturing executives today are all familiar with industry regulations such as Title 21 CFR Part 11 and current good manufacturing practices (cGMPs), many drug companies are still struggling to comply with these and other U.S. Food and Drug Administration (FDA) requirements.

In 2008 alone, the FDA issued 43 warning letters to pharmaceutical companies for regulatory infractions. Among the violations were production records that lacked second-person verifications, manufacturing procedures without validated processes for detecting and removing drug impurities, and a laboratory computer system without security features—all issues that could have been prevented with the proper controls.

The potential costs of such non-compliance have been illustrated by recent high-profile cases, such as a 2002 fine of US $500 million for one drug maker’s cGMP infractions. Violating the Federal Food, Drug, and Cosmetic Act could result in product seizures and criminal prosecution with penalties of up to a year in jail and a US $100,000 fine for each non compliant shipment or Act. Why, if FDA regulations are well known and non-compliance is so costly, are pharmaceutical manufacturers still making avoidable compliance mistakes?

The problem for many companies often lies in the reality of running a business within the limitations of systems that have not kept up with the changes of the industry. Pharmaceutical manufacturers are responsible for making sure their companies are always in compliance with FDA regulations, or they could face recalls, fines, seizures, or injunction.

FDA’s guidance issued in April 2009 highlights the three main objectives to complement GMP. Firstly, the quality system needs to be established and maintained in order to deliver quality products to patients, health care professionals, regulators and internal and external customers. Secondly, there needs to be an effective monitoring and control system to assess the performance of processes and product quality. Quality risk management tools can be used in identifying the monitoring and control system to ensure suitability and capability of processes. Lastly, there should be continual improvement of processes, reduction of variation and consistency in meeting the quality needs of manufacturers. Again, the quality risk management tools can be helpful in prioritizing areas for continual improvement.

The guidance also confirms that the ‘enablers’ for an effective and successful quality system are:1) the product and process knowledge managed through the product life cycle, and 2) the quality risk management approach to identify, scientifically evaluate and control the potential risks. Knowledge includes prior knowledge from public domain or internal documents before product development, to pharmaceutical development studies, technology transfer, process validation studies, manufacturing activities, continual improvement and change management. The quality risk management will enable the identification, evaluation and the control of potential risks to quality.

The companies must understand that getting a company in GMP compliance is a process and has to be implemented in a systematic approach. There is no magic wand that could automatically take a company down this path to compliance. Here are few of the steps as suggested by Alan Schwartz ( Executive VP, mdi Consultants, Inc., Great Neck, NY) to achieve GMP compliance:

Each company should set up a team that would be responsible for this project.

This team should be trained in the FDA cGMPs as well as have an understanding of the FDA policies related to their operations and products.

A project timeline should be agreed upon for achieving these goals.

An evaluation of the processes and products that the company would like to export to the US and whether they want API and/or the finish dosage form approved for export.

Most companies should start with manufacturing and exporting APIs and then move to the finish dosage form.

A flow chart of the operations should be made defining the critical operations.

A gap analysis should be made to determine how far the company is from achieving FDA cGMP compliance by someone who has a thorough understanding of the FDA cGMP issues and what would be required to pass an FDA on-site inspection.

A list of the corrective actions required to bring the company into compliance should be prepared defining:
● Who will be responsible for making the corrective action and implementing it
● When it should be
completed
● The date completed
● The date verified

Weekly meetings should be held to monitor the process and determine delays and rectify unexpected issues.

If process validations are required have a validation expert assist in preparing the validation protocols and monitoring the validation process.

Upon completion of the process and implementation of GMPs, have an outside audit conducted by someone with extensive and up-to-date FDA experience to determine your compliance to the cGMP.

Stay prepared for your upcoming FDA pre-award audit.

Have a GMP expert, who is familiar with your system on site during the FDA inspection to assist with monitoring the audit and provide guidance and assist with responses to the FDA.

‘There is no “silver-bullet” (a simple guaranteed solution for a difficult problem) to achieving FDA cGMP compliance, but there is a road map that if followed will lead to successful conclusion.’ says Alan Schwartz. The pharmaceutical companies that would succeed in working towards understanding and implementing GMP regulations would definitely become stronger and more competitive.

Mrunali R. Patel is
faculty Indukaka Ipcowala College of Pharmacy,
New Vallabh Vidyanagar , Gujarat and Rashmin
B. Patel & Bharat G. Patel are faculty A. R. College of Pharmacy and G. H. Patel Institute of Pharmacy, Vallabh Vidyanagar, Gujarat.