Vinod Arora, Principal Advisor Institute of Good Manufacturing Practices India–IGMPI, gives insights on ways to enable cGMP to assure safety and efficacy of drug products
Good Manufacturing Practices (GMP) is a part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by marketing authorisation. GMP represents minimum standards that are necessary. Many pharmaceutical manufacturers are already implementing comprehensive, modern quality systems and risk management approaches that exceed these minimum standards.
The first version of GMP guidelines for manufacturing, processing, packing or holding finished pharmaceuticals was introduced by the US FDA in 1963. Four years later, the WHO version of GMP was prepared by a group of consultants at the request of the 20th World Health Assembly. From then there were several amendments and extensions of the guidelines and many countries developed their own GMP guidelines which are based on WHO guidelines
- WHO GMP Guidelines – Primarily used by pharma regulators in developing countries
- International Community of Harmonisation – GMP
- USFDA –GMP
- GMP Standards in other countries – Australia, Canada, Japan , Singapore
- International Organization for Standards (ISO)
- Pharmaceutical Inspection Cooperation Scheme (PIC/s)
- Common practices within the industry license reviews, crisis management, controls also sources of GMP
In 1991, GMP standards were harmonised at EU level (MHRA 2007). In 1999, the ICH, a common project of the EU, Japan and the US brought GMP for Active Pharmaceutical Ingredients which apply in signatory countries, the EU, Japan and the US and also in other countries –Australia, Canada, Singapore. GMP standards is a dynamic process and are upgraded periodically.
The enforcement of GMP rests on individual states; For the US, the responsibility is with the USFDA, in the EU with National Regulatory Agencies (e.g MHRA in the UK), in Australia with Therapeutical Goods Administration, in India with Central Drugs Standards Control Organization, Ministry of Health and Family Welfare
The main regulatory standard for ensuring pharma quality is the Current Good Manufacturing Practice (CGMPs) regulation for human pharma. Consumers expect that each batch of medicines they take will meet quality standards so that they will be safe and effective.
What are cGMPs?
cGMP refers to the Current Good Manufacturing Practice regulations. cGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. Adherence to the cGMP regulations assures identity, strength, quality and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. This includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories. This formal system of controls at a pharma company, if adequately put into practice, helps to prevent instances of contamination, mix-ups, deviations, failures, and errors. This assures that drug products meet their quality standards.
The cGMP requirements were established to be flexible in order to allow each manufacturer to decide individually how to best implement the necessary controls by using scientifically sound design, processing methods, and testing procedures. The flexibility in these regulations allows companies to use modern technologies and innovative approaches to achieve higher quality through continual improvement. Accordingly, the ‘C’ in cGMP stands for ‘current,’ requiring companies to use technologies and systems that are up-to-date in order to comply with the
regulations. Systems and equipment that may have been ‘top-of-the-line’ to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today’s standards.
Why are cGMPs so important?
A consumer usually cannot detect (through smell, touch, or sight) that a drug product is safe or if it will work. While cGMPs require testing, testing alone is not adequate to ensure quality. In most instances, testing is done on a small sample of a batch (for example, a drug manufacturer may test 100 tablets from a batch that contains two million tablets), so that most of the batch can be used for patients rather than destroyed by testing. Therefore, it is important that drugs are manufactured under conditions and practices required by the cGMP regulations to assure that quality is built into the design and manufacturing process at every step. Facilities that are in good condition, equipment that is properly maintained and calibrated, employees who are qualified and fully trained, and processes that are reliable and reproducible, are a few examples of how cGMP requirements help to assure the safety and efficacy of drug products.
How does regulators determine if a company is complying with cGMP regulations?
Regulators inspect pharma manufacturing facilities worldwide, including facilities that manufacture active ingredients and the finished product. Inspections follow a standard approach and are conducted by highly trained staff. Regulator also relies upon reports of potentially defective drug products from the public and the industry. Regulators will often use these reports to identify sites for which an inspection or investigation is needed. Most companies that are inspected are found to be fully compliant with the cGMP regulations.
Top 10 observations as per US FDA Inspection
- Procedure not in writing ,fully followed
- Scientifically sound Laboratory Control
- Investigations of discrepancies, failures
- Absence of written procedures
- Written procedures not established/ followed
- Procedure for sterile drug products
- Testing and release for distribution
- Cleaning/ sanitising/ maintenance
- Calibration/Inspection/ checking not done
- Lack of written stability programme
GMP: Challenges and issues
The challenges faced by manufacturing units are:
- Insufficient adherence to quality standards
- Schedule M compliance not in place
- Compliance problems due to lack of awareness
- Products banned or recalled
- 19 ‘import alerts’ to drug manufacturing factories across India in 2013
The reasons for GMP non-compliance are:
- Complex global regulations
- Compressed time to market
- Difficulty of GMP guideline interpretation
- Lack of uniformity between national and international guidelines
Consequences of GMP Non compliance
- Form 483 issued to no of companies – Lupin/ SUN/ Micro Labs /Aurobindo etc
- Warning letters to Mahendra Chemicals manufacturing facility, Gujarat, India issued by US FDA.
- India and China top 2013’s GMP failures , according to EMA data
- Between 2010 and 2013, 67 warning letters have been about cGMP non compliance by US FDA.
- Generic Drug Manufacturer Ranbaxy pleads Guilty and Paid $500 million to the FDA.
Many a times a debate is there that if a manufacturing facility is inspected/ approved by a Local Regulatory agency how come Foreign regulatory agency finds gaps in c GMP. WHO upgraded 1992 version in 2002, 2006, 2008, 2014 etc with no of supplementary guidance document; PIC/s guidelines on GMP revised every year while in India Schedule M of GMP was incorporated in 1988 and was revised in 2001 as per WHO TRS.
To overcome these non-compliance issues and to fill up the gaps it necessary that every pharma industry must train its employees. This training is scheduled in several ways. There is a basic scheduling distinction between training that is delivered in response to a perceived deficiency in performance or qualification, and training delivered according to the calendar. Training according to deficiency in performance or qualification includes new employee orientation (NEO), training for business process redesign and standard operating procedure (SOP) revision, and most technical training. In each case, trainees lack skill, information, or motivation that can be remedied by the training intervention.
Continuing education programme – The process of on-going learning should be considered an opportunity, an asset to one’s profession. As with any improvement strategy in business, continued education should be thoughtfully considered. A simple analysis of one’s competency status can identify key areas which may warrant improvement or specific attention.
FDA regulations call for continuing cGMP training. The regulations for finished pharma are quite explicit: “Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with cGMP requirements applicable to them”. Three points in this passage should be highlighted: the training shall be “conducted by qualified individuals,” shall be conducted “on a continuing basis,” and shall address “cGMP requirements applicable to them.”
The EU makes a similar point about the need for continuing training in GMPs. “Besides the basic training on the theory and practice of good manufacturing practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given.”
Health Canada also mandates continuing cGMP training, so that “all personnel are aware of the principles of GMP that affect them, and all personnel receive initial and continuing training relevant to their job responsibilities.
IGMPI believes in the statement well quoted by Socrates that “Education is the kindling of a flame, not the filling of a vessel.” Continuing Education Program (CEP) is provided by Institute of Good Manufacturing Practices India (IGMPI).
(With inputs from Soumaya, Asstt Professor, IGMPI)