Good Quality Practice (GQP) in Pharmaceutical Manufacturing: A Handbook

Pharmaceuticals are specialized products because of their characteristics and use and also because of their meticulous regulation. A failure in the quality of a pharmaceutical can put life at risk. Consequently, a specialized manufacturing standard (GMP) is applied with the intention of ensuring quality. Although still different GMP texts exist, there is a steady effort towards their harmonization. GMP is not just practical pharmaceutical common sense, but also a guideline which determines the organization of a pharmaceutical plant. The aim of the pharmaceutical industry is not only manufacturing products with the purported quality, but also delivering them to the patients timely and without any loss of quality. This is why attention should be paid to the whole supply chain of pharmaceuticals and thus complementary standards (GSP, GDPs, and GTDP) have been developed. The globalization of the pharmaceutical market has not only supposed an increase in complexity of the supply chains, but also of contract manufacturing or analysis (outsourcing). Keeping under control such a complex and global market is not easy and this explains why counterfeiting has become a significant matter of concern.

The performance of any process is both the consequence of its previous development studies and of the adequate transfer of these experimental concepts into practical operation. This is the lifecycle model which reminds us that quality has to be designed, transferred to real routine operation and then maintained within controlled conditions. There is no other way, at least nowadays, to ensure that quality by design will become produced quality too. In a pharmaceutical unit the lifecycle model can be usefully applied both to pharmaceutical products and pharmaceutical projects (premises, facilities, or equipment) and to processes like documentation and personnel. The different lifecycle stages are united like the links of a chain. Therefore, in order to achieve quality, control has to be exerted in a global way. The significance and management of the lifecycle stages of a project (URS, commissioning, admittance, qualification, maintenance and calibration) are analyzed. The practical organization of a qualification program is described in detail, starting with the redaction of a QMP, following with the writing and executing of qualification protocols and finishing with the qualification reports.

The quality of pharmaceutical products is permanently threatened by hazards that are potential sources of harm. And hazards have an associated risk, defined as the combination of the probability of occurrence and of the severity of that harm. Therefore, it is necessary to keep these hazards under control by diminishing as much as possible the related risks. This approach to quality assurance is known as risk management. Different tools allow for the assessment of risk. Then, risk can be routinely monitored. Yet, there are no magic tools. Risk assessment requires a good amount of knowledge on the matter submitted to study. This does not exclude, however, that by skillfully using the existing tools it is possible to appraise adequately the level of risk and decide on its acceptance. A high residual risk is, in principle, inacceptable and requires the implementation of measures for its reduction (changes in the process or system or in the way it is monitored), whereas a low residual risk can be accepted. And this allows for the introduction of continual improvement, understood as the progressive diminution of the residual risk level. The whole process of risk management is explained step by step and the most useful tools used in risk assessment are described providing practical examples.

Pharmaceuticals are manufactured in purpose-build premises which are provided with controlled environment, with specialized equipment and with the necessary utilities. There, trained personnel following approved procedures transform inputs (materials) into outputs (pharmaceutical products). Therefore, the quality of these pharmaceuticals is linked to the quality of the above mentioned aspects. This was long understood and became the base of GMP: “keep the factors influencing quality under control and you will get quality”. Nowadays it is possible, and necessary, to implement risk management to better recognize and control these quality factors. But, be that as it may, it is evident that without knowing and understanding the hazards which threaten quality, any quality assurance policy is doomed to failure. Thus, premises, utilities, equipment and personnel are analyzed in order to detect which hazards loom on the quality of pharmaceutical products. Then, these quality hazards are described and their causes determined with the aim of proposing measures for reducing their likelihood or keeping them under control. It is interesting to underline that changes in systems and equipment and in approaches to hazard handling have contributed in diminishing the risk, but most of the hazards remain basically the same. There is a wide coverage of the hazards linked to harmful products and microorganisms and the preventive measures, according to the risk level.

The Quality System is the nervous system of the GMP-body. The ruling brain is the Quality Manual, whereas the procedures which develop it are the nerves that control this GMP-body. The Pharmaceutical Quality System (PQS), as proposed by ICH Q10, has a slightly wider scope than GMP, as includes pharmaceutical development too. In terms of responsibility the senior direction of the company is a key factor of the quality system because determines its policy and objectives. The PQS is composed of two enablers and four elements. Enablers facilitate the attainment of the PQS objectives. A couple of elements were already in place relatively long ago (change management and CAPA system), whereas the other two are newcomers and focus on control on processes and products and on the PQS itself. The different approaches to the Quality Manual and its contents are described and commented. As a modern quality system is based on continual improvement it is necessary to identify and analyze the processes in the manufacturing plant. Processes can be kept in state of control by monitoring of variables/indicators. The latter can be monitored either during the same process (on-line or off-line) or after it by evaluation of data. Thus, improvement means variable/indicator improvement. The performance of the quality system itself must be reviewed by the management in order to ensure that it remains appropriate. The practical organization of the system is developed in documents known as general procedures of the system. The contents of these procedures are commented and their interrelations are analyzed.

Documentation is an essential GMP feature. If the PQS is something like a nervous system, then the documents are the nerves which carry information and which keep an organism alive and operational. This information has to be exact, clear and delivered safely where it is necessary. This is why the lifecycle of documents is critical. It is indispensable ensuring that they are well written and reviewed and approved by the right persons. Personnel using these documents have to receive copies and get well acquainted with them. This is vital, but not easy to ensure. Documents should reflect reality. This is why they have to be kept updated and superseded documents have to be returned to QA. Documents are crucial because they define how operations have to be performed, but also because they allow for traceability in the operations. The documents of a PQS are so numerous that document management requires hard work. Consequently there is always the risk of considering it something unworthy and boring, to be allotted to unlucky novice technicians. As a matter of fact documents reflect so trustworthy reality that is almost impossible doing wrong and showing good documentation or doing right and providing poor documentation, and this is why inspectors pay particular attention to documentation. Disorganized documentation is the hallmark of a disorganized company. Although documentation is usually associated to paper, this is not exact. Documentation is information on any support, ensuring traceability, safety and readability at any time. Tentative lists of the documents which are required in a manufacturing laboratory are given in this chapter.

Personnel are certainly the weakest ring of the quality chain of the pharmaceutical industry. On one side, their adequate level of training is difficult both to reach and to monitor. On the other, they are the only known source of contamination and mix-up which is voluntarily allowed to enter a manufacturing unit. It is true that automation and computer-assisted monitoring systems have contributed in diminishing this problem. Nevertheless personnel still holds the center of the scene. Education and a good deal of training can provide an acceptable level of knowledge and skills, but keeping this “state of training” is not easy. Training programs are a must for any laboratory, but ensuring their efficiency requires a good deal of dedication, not to say of ingenuity. It is well known that when the root causes for a deviation are investigated often one of them is “lack of adequate training”, then training is repeated and rather commonly this becomes a vicious circle because the problem was not lack of training but inadequate training. Hygiene is a must too, but can training change behavior? The answer should be yes, of course, but this requires convincing people of the real impact of hygienic practices on the quality of products. This chapter describes the GMP approach to personnel and training, analyses well-known problems and proposes solutions for them. The organization and documentation of training is studied in detail. Particular attention is drawn to the existing methods of training and to the measure of their effectiveness.

Pharmaceutical premises determine the manufacturing flows and provide the setting for manufacturing equipment and for the complementary utilities. Clean rooms, where production operations can be performed within a controlled environment, are the result of combining sanitary internal architecture and HVAC systems. Premises have to be well designed in order to impede the entrance of outside contamination and the diffusion of internal cross-contamination. Moreover, personnel, because of their inherent contamination, put at risk the quality of the internal environment of the premises and therefore their access has to be controlled and performed through changing rooms, where operators put on appropriate clothing for the operations to be performed. When products happen to be potentially harmful, it is necessary to protect operators and outside environment too. This requires specially designed premises where the above-mentioned protection of products is coupled with the protection of operators and environment. This latter requirement is fulfilled by means of two steps of contention, primary within closed devices and secondary within the rooms by a combination of differential pressure and air filtration. Qualification allows for the demonstration that premises perform as intended.

Utilities are the blood who keeps alive and functional a pharmaceutical plant. Utility systems are very diverse and range from electricity to compressed air but they share the common fact of possessing points of use. They can be divided into “industrial” utilities which may interact with equipment but not with products and “pharmaceutical” utilities that may interrelate with both. These latter are critical and as such they have to be qualified and closely monitored. This is the only way for ensuring that they do not affect negatively the quality of the products. Utilities are normally tailor-made for each plant and as such a good study of their design is essential. Two utilities are particularly relevant: HVAC and water for pharmaceutical use. The HVAC system, in combination with the internal architecture, provides the controlled setting for the development of the pharmaceutical operations. Any failure puts at risk the production environment. The water for pharmaceutical use is a utility which provides water for cleaning but also water for compounding. This latter function turns water into a very particular starting material. It is obtained in situ and differently from other starting materials it is often used before formal sampling, testing and liberation by QC. This explains why it is one of the points of highest level of risk in a pharmaceutical plant. This chapter analyzes all these aspects and provides keys to the most effective approaches for protecting the quality of products.

Equipment plays an active role in a pharmaceutical unit by conveying, transforming and protecting from the environment materials and products. Pharmaceutical equipment should observe hygienic rules in its design, construction, installation, utilization and maintenance, as stated by GMP. As most equipment is controlled by computerized systems, it is necessary restricting access to them and ensuring that these can provide the same level of safety than operators (in fact higher). Equipment is as varied as existing operations and technical approaches for performing them, but it can be practically distributed into several groups. The first one is represented by weighing/measurement equipment. The second one is very large and comprises preparation equipment which is basically defined by the physical type of dosage form (liquid, semi-solid, solid). A third group would include secondary packaging equipment. Then a fourth group would be constituted by the booths, cabinets, benches and RABS, which provide limited protected operational environments. And finally we could still mention a fifth group collecting up other varied items of equipment. With the exception of disposable equipment, it is essential securing appropriate cleaning. Qualification, maintenance, calibration and, as required, requalification are essential activities for ensuring appropriate equipment performance.

The application of the lifecycle model to the pharmaceutical products has modified existing approaches to quality assurance. The quality of a product is not simply the outcome of a GMP-compliant manufacturing, but the result of a GMPcompliant lifecycle. Product development means devising a formula and a manufacturing process, but most importantly, understanding thoroughly the product. This, known as quality by design, goes from defining its quality target profile to identifying the quality attributes of the starting materials and the quality parameters of the manufacturing process. Critical variables are the hallmark of a product during its lifecycle. They are identified and studied during the development stage and knowledge on them is increased during the product’s lifetime. Technological transfer means confirming that what worked in the development center will also work in the manufacturing plant, but also increasing and improving knowledge on the critical variables under industrial-scale conditions. Validation means verifying that the production process can be successfully controlled by means of the critical variables and that if these remain within proven acceptable ranges the process can be deemed under control and consequently yielding quality products. Thus, by monitoring critical variables each batch can be considered concurrently validated. The application of the above described approaches will enhance the level of quality insurance of the new products, but what happens with legacy ones? The model can be usefully applied to these latter too by using the same principles but proceeding step by step in a reverse approach, from knowledge to development instead of development to knowledge.

Current pharmaceutical quality requires a global approach based on a quality system established on GMP and on risk analysis. Quality can be only ensured if hazards are identified and controlled to be kept at an acceptable risk level. Consequently, nowadays quality audits are not seen anymore as a simple compilation of checklist questions (yes/no/n. a.), but as an investigation to see if existing problems are detected and solved/controlled satisfactorily. This requires good knowledge and deep analysis on processes and products. As for the rest, it is also necessary to ensure that those pharmaceutical products which are dispatched from the warehouse, after being certified and released, maintain their quality when they reach their final consumers. Thus, it has been paid progressively attention to the hazards that waylay them in the often very complex distribution chain, including the risk of theft and counterfeiting. Taking into account the successful experience of GMP equivalent GDPs (good distribution practices) have been developed. It is also necessary to ensure the soundness of studies on drug products which are performed in different laboratories. And this requires a homogeneous quality approach. This is why, following again the same track, GLP (good laboratory practice) was prepared. And, finally, it is necessary to bear in mind that once a drug product has been licensed it is used by much more people than when it was tested during development, and this opens the door to unexpected reactions. Thus a pharmacovigilance system is necessary to keep updated its benefit-risk safety profile.