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The manufacture of pharmaceutical products has to be maintained at high standards to ensure the strength of the active ingredients, quality and purity of the final products. These standards ensure safe and effective products for patients.
Minute changes in any of these factors can have serious consequences for patients, therefore the controls and checks put in place need to be far more stringent than, for example, the food industry.
The medical profession and patients expect medicines to be identical to a high level of precision and safe every time they receive a new batch.
The major burden for ensuring consumer safety, lies firmly at the manufacturing stage, where it is essential to use industry-accepted Good Practices to maintain safety and efficacy.
The regulatory authorities and the industry itself put great emphasis on manufacturing pharmaceutical products using practices and processes that ensure high levels of quality and safety are built into every step.
Regulatory requirements emphasise Good Practices for controlling quality and safety, from drug development to distribution:
The WHO defines Good Manufacturing Practices as…
“...that part of quality management which ensures that products are consistently produced and controlled according to the quality standards appropriate to their intended use and as required by the marketing authorization, clinical trial authorization or product specification.” (WHO, 2011).
The US developed the first GMPs for manufacturing, processing, packing and holding finished pharmaceuticals in 1963 (in the US called Current Good Manufacturing Practices and WHO followed with its own GMPs in 1967.
The first attempt at globalising pharmaceutical regulations for harmonisation was made by WHO in 1975 with an action programme for essential drugs and a certification scheme for international trade.
WHO GMPs became widely accepted in pharmaceutical regulations, first by the European Community, followed by Japan and the US.
These three created the International Conference on Harmonisation (ICH) in 1990 to coordinate development of the increasingly complex and expensive regulatory procedures.
Other developed countries and international bodies subsequently adopted GMPs. Each further developed them to comply with strict manufacturing and health requirements, to cover new product types and new technologies:
The trend in pharmaceutical regulation is to become more complex with stronger control mechanisms and mandatory documentation of various processes and test results (Brhlikova et al, 2007).
In recent years, manufacturing and GMP compliance problems have resulted in “chronic supply shortages” of some essential medicines for which there are no alternatives, resulting in public health crises.
Many medicinal products have become ‘victims’ of globalisation.
Manufacturers have moved production to single locations, outside the major markets, making supply chains lengthy and more risky.
Many products are manufactured in single countries with uncertain political, regulatory or environmental situations, increasing the risk of disruption — such as occurred in Japan following the 2011 earthquake and tsunami.
This is compounded by lack of built in redundancy or fail-safe mechanisms for maintaining supplies, resulting in global supply shortage when production has been disrupted.
This has led to importation of unlicensed versions of pharmaceutical products to protect patients who need medicines, on the basis that the poor quality medicine is less risk than no medicine at all (European Medicines Agency, 2012).
EU regulations require all pharmaceutical manufacturers to comply with EU Good Manufacturing Practices (GMPs) if they want to supply products to the EU.
Manufacturers and importers must be authorised and registered by a competent authority from a member state.
Manufacturers and importers are regularly inspected by an EU competent authority or other approved authority to check compliance with the EU GMPs. This applies wherever the manufacturer is located.
The frequency of inspection is based on a risk assessment and in addition the local national competent authority must supply written confirmation that each batch of product conformed to GMPs.
Where products are imported by a separate company the importer is responsible for ensuring compliance with GMP.
The EU legislation governing pharmaceutical products is compiled in the publication “The rules governing medicinal products in the European Union”.
In addition, the European Directorate for the Quality of Medicines and Healthcare (EDQM) of the Council of Europe (separate from the EU and EC), which is responsible for the European Pharmacopoeia, can also inspect manufacturers and issue Certificates of Suitability that can replace most of the data in the EU Marketing Authorisation of medicines (Luigetta R, 2015).
In the US the regulatory standard for human pharmaceutical products is the Current Good Manufacturing Practice regulations, which are enforced by the FDA.
The FDA inspects manufacturers worldwide for compliance with CGMP.
The FDA issues guidance for manufacturers in the Code of Federal Regulations, Current Good Manufacturing Practice for Finished Pharmaceuticals.
These guidance documents do not bind companies to follow them and an alternative approach is acceptable if it fulfils the requirements of the regulations.
Internation Society for Pharmaceutical Engineering (ISPE) has compiled links to GMP regulations and resources for individual countries: Australia, Canada, China, EU, India, Japan, US: ispe.org/gmp-resources/regulations.
In addition to all legal and regulatory requirements, a pharmaceutical business may also need to comply with additional standards for commercial reasons.
Examples of additional standards are:
Good Manufacturing Practices form part of a pharmaceutical quality system. It aims to minimise the risks in manufacture to ensure safety, quality and efficacy.
A manufacturer has responsibility to ensure the pharmaceutical products are fit for use, comply with marketing authorisation requirements and have adequate safety, quality and efficacy.
Senior management has the responsibility to ensure that the pharmaceutical quality system is adequately resourced, roles, responsibilities and authorities are clearly defined and communicated.
Pharmaceutical manufacture requires high levels of sanitation and hygiene at every point of the process, covering personnel, premises, equipment, materials, containers, and cleaning and disinfection products.
It also requires elimination of potential sources of contamination, both for hygiene purposes and for medical effectiveness, which could be affected by, for example, dust from other product ingredients or cleaning compounds.
The basic sanitation and hygiene GMPs below are derived from WHO guidelines (WHO, 2011).
There should be sufficient numbers of qualified personnel who should be aware of the principles of GMP applicable to their role, including hygiene practices.
Waste should be removed from production areas and properly stored in suitable containers in designated areas and disposed of in a timely manner.
Standard operating procedures, with appropriate records should include:
Pharmaceutical products need particular care to prevent contamination and cross contamination from materials and other products such as living microorganisms, hormones, toxic substances, and other active substances.
WHO. WHO Good manufacturing practices for pharmaceutical products: main principles. WHO Technical Report Series, No. 961, 2011, Annex 3. (link)
European Medicines Agency. Reflection paper on medicinal product supply shortages caused by manufacturing/Good Manufacturing Practice Compliance problems. London, 2012. (link)
Luigetti R, et al. GMP Oversight of Medicines Manufacturers in the European Union. PDA Letter, 25 Sept 2015. (link)
Brhlikova P, Harper I, Pollock A, et al. Good Manufacturing Practice in the Pharmaceutical Industry. Working Paper 3, prepared for the workshop on Tracing Pharmaceuticals in South Asia, 2–3 July 2007. The Centre for International Health Policy, University of Edinburgh.