Pharmaceutical regulations

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 normal senses of smell, touch and sight cannot tell whether a pill is safe and will work.
• It is virtually impossible for the consumer, or even a medical or pharmacy professional, to tell that a pharmaceutical product as supplied by the manufacturer is safe or not, or that it contains what it is supposed to contain.

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.

Good practices for drug manufacturing

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:

• Drug discovery: Good Laboratory Practice;
• Drug trials: Good Clinical Practice;
• Manufacture: Good Manufacturing Practice;
• Distribution: Good Distribution Practice;
• Storage: Good Storage Practice.

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).

Good manufacturing practice history

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:

• US cGMPs;
• EU GMPs (now harmonised with the PIC/S GMP Guide);
• Japan, Australia, Canada, Singapore, Russia;
• International Conference on Harmonization GMPs (ich.org). This is gradually being adopted by more countries and regional bodies and has the potential to become a global standard;
• Pharmaceutical Inspection Cooperation Scheme (PIC/S) GMP Guide (www.picscheme.org). This is coordinated with the EU GMPs and is adopted by many countries;
• ISO (International Organization for Standardization;
• Developing countries (less strict).

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).

Risks from globalisation

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 shortagewhen 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).

Regulatory requirements

EU regulations

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).

US regulations

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.

Other countries

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.

Other 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:

• SQF (Safe Quality Food);
• BRC (British Retail Consortium);
• ISO 22000;
• HACCP (Codex Alimentarius);
• Prime Safe;
• American Institute of Baking (AIB)

Sanitation and hygiene GMPs

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).

Personnel

There should be sufficient numbers of qualified personnel who should be aware of the principles of GMP applicable to their role, including hygiene practices.

Personal hygiene

• Health checks: personnel employed in pharmaceutical production should undergo health checks before and during employment.
• Hygiene practices: all personnel involved in the manufacturing process should practice a high level of personal hygiene. Staff should be trained in personal hygiene measures required for pharmaceutical production, in particular washing hands before entering production areas. Staff and contractors working in pharmaceutical manufacturing must be trained in food safety. This must address the following points: the meaning of Hazard Analysis and Critical Control Point (HACCP); methods of controlling hazards which can arise from activities in premises, with particular attention to chemical contamination and good hygiene practices.
• Illness: staff having an illness or open wounds that could affect product quality must not handle starting materials, packaging, in-process materials or medicines, until they have recovered and are no longer a risk. Staff and contractors who may be suffering from a food-borne illness (symptoms include diarrhoea, vomiting, hepatitis) must inform the customer site contact and determine whether they may enter the pharmaceutical company premises.
• Handling goods: there should be no direct contact between hands and starting materials, primary packaging materials, and intermediate or bulk products.
• Clothing: persons in the production areas should wear clean body coverings as appropriate, including production staff, contractors, employees, visitors, managers and inspectors.
• Personal habits: eating, drinking, chewing, smoking should not be allowed in the production, laboratory and storage areas. Food, drink, smoking products and personal medicines should not be allowed in these areas also.

Premises

• Location: premises should be located in an environment that minimises risk of contamination of materials and products.
• Design and layout: the design and layout of the premises must facilitate good sanitation and allow effective cleaning and maintenance to prevent cross contamination and build-up of dirt. As well as being appropriate for the activities for which the premises are used, the design and construction of pharmaceutical premises should not permit the entry of pests and not provide harbourage for pests.
• Pest control: there should be pest control procedures that encompasses an Integrated Pest Management (IPM) approach to reduce or eliminate pests. It would normally include, but is not limited to, the following:
  • exclusion of pests;
  • elimination or reduction of harbourage used by pests;
  • elimination or reduction of food;
  • use of pesticides, baits or traps;
  • a systematic improvement program;
• Cross contamination: measures should be taken to prevent cross-contamination from dust generated during manufacturing operations from handling of ingredients.
• Cleaning: premises should be cleaned and disinfected according to written procedures and records kept.
• Services: lighting, temperature, humidity, ventilation and electrical supply should not adversely affect pharmaceutical products or the functioning of equipment.
• Staff facilities: facilities for changing, washing, toilets, eating and rest should be separate from production and storage areas. Facilities should be appropriate for the number of users.
• Storage areas: these should be designed to ensure suitable conditions: dry, clean, well lit, and maintained within suitable temperature limits.
• Delivery and dispatch areas: these should be designed to protect products from the weather and be designed and equipped to allow cleaning of delivery containers.
• Layout of production areas: premises should be designed to allow production to take place in a logical order and with required cleanliness levels.
• Surfaces: interior surfaces of walls, floors, ceilings should be smooth, free of cracks and loose materials, and allow effective cleaning and disinfection.
• Fittings: pipework, light fittings, ventilation fittings should be designed for ease of cleaning and maintenance.
• Drains: drains should be of sufficient capacity and designed to prevent back flow
• Ventilation: production areas should have suitable ventilation to prevent contamination from external and internal sources, and control temperature and humidity as appropriate.

Equipment

• Layout and design: the layout and design of equipment should allow effective cleaning and maintenance and prevent cross contamination and build-up of dirt or dust. Layout and design should not permit pest harbourages.
• Cleaning: equipment should be cleaned using validated procedures, according to a suitable schedule and records kept of the procedures, times and results of tests.
• Equipment for cleaning: equipment for washing, cleaning and drying should be suitable for use and not contaminate products.

Materials

• Cleaning: materials used for cleaning should be of appropriate grade for use with pharmaceutical equipment and should not come into contact with products.
• Pest control: pest control materials, including rodenticides, insecticides and fumigation gases, should not contaminate equipment, starting materials, packaging materials, materials in process or finished products.
• Water: water used in the manufacturing process should be of suitable quality.

Waste disposal

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 and records

Standard operating procedures, with appropriate records should include:

• maintenance, cleaning and sanitization, including for each piece of equipment;
• relevant personnel matters including qualifications, training, clothing and hygiene;
• pest control: the pest control contractor should have a Standard Operating Procedure (SOP) that complies with HACCP and is designed by the pest manager in conjunction with the pharmaceutical business. The program should support the GMP for the pharmaceutical business and include all legislative requirements and ensures Industry best practices.

Good production practices

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.

• Cross contamination: this can occur from release of dust, gases, particles, vapours, sprays or organisms from materials and products in production processes. Appropriate measures to prevent this include:
  • self-contained production areas;
  • airlocks, pressure differential, air supply and extraction systems, as appropriate for the required cleanliness levels;
  • wearing protective clothing;
  • using effective cleaning and decontamination procedures;
• Contamination: any foreign object or material found in the finished product could also introduce disease or cause poisoning of consumers. Contamination can be physical, biological and chemical eg insects, rodents, rodent droppings, pathogens such as Salmonella, Lysteria, E.coli. Contamination can occur from:
  • residues on equipment;
  • insects and other pests;
  • operators’ clothing, skin, jewellery etc. Staff and contractors must have a documented clothing and jewellery policy.
  • particles from the building structure and fittings;
  • pipe work supplying water, including distilled or deionised water; these should be free of defects and cleaned appropriately;
  • containers in the production line should be cleaned before filling and any physical contaminants removed.

Bibliography

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.