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Figure 19. A vast amount of documentation must be submitted before a drug receives a licence.


		Another important element in the production process is the need to ensure that quality requirements are met.

	Regulation and Quality Assurance

		The systems and equipment used in the manufacture of medicines are highly regulated and need to be validated before a manufacturing licence can be granted. Validation means demonstrating that the systems and equipment consistently produce a product of the required quality. A company cannot just decide to set up in business making and selling medicines. The manufacturing plant has to be inspected and the company is only allowed to manufacture if its processes and quality assurance meet all the requirements. These require high standards of quality and other areas such as health and safety. Any change in production, such as changing the solvent would require revalidation and revision to the licence. This imposes a heavy burden on pharmaceutical companies - they cannot just modify production as they wish, they have to think about the licence implications.

	What is meant by high quality?

		Quality in this context means a product which is pure and which is consistent. Medicines need to avoid any kind of contamination from other substances since this could have damaging effects upon the person taking the medicine. Also it is vital that each dose contains exactly the correct amount of ingredients. Maintaining high quality is particularly important in pharmaceutical manufacture. This is because the consumer will often be ill and weakened when they use the product. There are a number of overseeing bodies worldwide, such as the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK and the Food and Drugs Administration (FDA) in the USA. Their representatives can come and inspect a factory at any time. Medicines are made in batches and the results of the checks are recorded. These results are inspected by a Qualified Person at the end of the process, and if satisfactory, the batch is released. The records are then kept in an archive so that the progress of all the medicines in every batch can be traced at a later date, if necessary. The flow chart in figure 20 shows how Capsulike, another leading UK pharmaceutical manufacturer, keeps a record of all stages of the production of medical creams such as ointments.

		Notice that records are begun when the raw materials are drawn from the store. These records then follow the batch through every stage of manufacture with additional information added at each stage. It is very important to get these procedures right. If the quality of a medicine is not up to standard or impurities find their way into the product during the manufacturing process, then the result could be disastrous. The medicine might be ineffective or in the worst case actually harmful.

Figure 21. Special clothing protects workers and the chemicals used in the production processes.

	Controlling the quality

		The potential hazards mean that pharmaceutical manufacturing has to be heavily regulated - more regulated than almost any other industry including the food industry. Companies follow a strict code of Good Manufacturing Practice (GMP). This is a formal set of rules and guidelines issued by the MHRA. The rules also meet the requirements set out by the European Commission ( Directive 91/356/EEC). An extract from the Code of Good Manufacturing Practice is shown in figure 22. The rules include guidance on what is required to ensure quality management, regulations involving: personnel premises and equipment documentation production quality control contract manufacture and analysis complaints and product recall self-inspection.

The rules for pharmaceutical manufacturers and distributers are produced as a handbook by the Medicines and Healthcare products Regulatory Agency - the regulatory body set up by the government to control this industry. Quality Management is a key part of this regulatory process. Here are some extracts from the booklet.

"To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance (QA) incorporating Good Manufacturing Practice (GMP) and thus quality control (QC)."

Good Manufacturing Practice (GMP) is that part of Quality Assurance (QC) which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation or product specification. GMP is concerned with both production and quality control. The basic requirements of GMP are that:
i.	all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications;
ii.	critical steps of manufacturing processes and significant changes to the process are validated;
iii.	all necessary facilities for GMP are provided including:
	a.	appropriately qualified and trained personnel;
	b.	adequate premises and space;
	c.	suitable equipment and services;
	d.	correct materials, containers and labels;
	e.	approved procedures and instructions;
	f.	suitable storage and transport;
iv.	instructions and procedure are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided;
v.	operators are trained to carry out procedures correctly;
vi.	records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated;
vii.	records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;
viii.	the distribution (wholesaling) of the products minimises any risk to their quality;

Figure 22. An extract from the Rules and guidance for Pharmaceutical Manufacturers and Distributers 2002. © Crown copyright.

Figure 23. A ‘state of the art’ manufacturing plant.

		To ensure that these regulations are met, all operators in manufacturing plants wear protective clothing and sometimes dust masks or other breathing equipment. This provides important protection for the workers from the chemicals, and also prevents contamination of the chemicals by the operators. Below is an example from an actual manufacturing process.

Production occurs in completely sealed units with transfer from one container to another occurring through sealed pipes. The whole system for manufacture has to be inert i.e. there must be no chemical reaction in the containers. This is achieved by purging containers with nitrogen after cleaning and before the next batch preparation.

		Sometimes compounds involved in the manufacturing process may be hazardous, so special precautions need to be taken. One company is building a new facility to produce a new microbicide. This will kill all existing microbes even the ones that are essential to healthy living. If this were to escape into rivers it could have a dramatic effect on the whole environment. The company has responded by building the new facility as a containment plant. This means that the whole process will take place in a totally sealed environment, using a totally sealed system with all waste being collected in a single controlled outlet.

Assignment trigger 4

Every stage of the production of a medicine is carefully documented. Why is this so important? Why are medicines made in batches rather than in a continuous stream? Why do you think that the pharmaceutical industry is so heavily regulated? Does regulation have any advantages for the pharmaceutical companies.

Check your answer

Explore the ways in which safety considerations and government regulation determine the production of a medicine.

Check your answer

What do the terms quality management and Good Manufacturing Practice mean? Why are both so important in the pharmaceutical industry?

Check your answer

Contents	Close

Introduction	4. Human resources - recruitment
1. The market	Recruitment procedures
A competitive success story	5. Human resources - training
2. Making pharmaceuticals	Teamwork
Biotechnology
3. Is manufacturing pharmaceuticals like other industries
Life cycle of a medicine
Quality	6. Conclusion

Our experts' view

Documentation is important because:

mistakes could have disastrous results
it is important to be able to identify where a problem has occurred.

Medicines are made in batches because it is easy to ensure effective quality control. If there was continuous production it would be almost impossible to pinpoint where a problem might have originated from. Regulation occurs because of the severe adverse effects which would result from unsafe medicines.

Regulation does have some advantages for the pharmaceutical companies. It helps protect them against aggrieved consumers since the government has passed a particular medicine as safe. It also helps to protect them from competition from low cost low quality firms.

Our experts' view

Safety considerations and government regulation have a number of significant effects on the production of a medicine

Long lead time before a new product can be introduced.
Difficult to respond quickly to changing costs or market conditions since any change in production methods needs to be approved.
High set-up costs. Ensuring regulations are met involves considerable expense. This makes it far more difficult for small firms to compete in this market.
Importance of investment in human resources particularly training to ensure that regulations are met.

Our experts' view

Good Manufacturing Practice and Quality management are defined in the glossary. Again they are both important because of the nature of medicines which makes the consequences of any mistake very serious.