Risk-Managed GMP

1. Medicinal Products: Quality by Requirement

Medicinal products such as pharmaceuticals, medicines, drugs or drug products can be defined in several, although similar, ways:

A finished pharmaceutical dosage form that contains an active ingredient or drug substance, intended to furnish pharmacological activity or another direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body (US CFR).

A pharmaceutical product technically obtained or elaborated with prophylactic, curative, mitigative or diagnostic purpose (ANVISA).

Any substance or combination of substances presented as having properties for treating or preventing disease in human beings or animals; or any substance or combination of substances which may be used in or administered to human beings or animals either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis (European Commission).

Pharmaceuticals contain Active Pharmaceutical Ingredients (APIs), generally, but not necessarily, in association with one or several inactive ingredients (Figure 1-01).

Figure 1-01. The medicinal product.

APIs, also known as drug substances or active substances, provide the pharmacological action of the drug product, whereas the inactive ingredients, commonly known as excipients, facilitate this action or the manufacturing process and do not possess pharmacological action by themselves. However, the difference between active and inactive ingredients is not always clearcut. There are excipients, which possess a certain physiological action, but cannot be considered as true APIs.

The combination of APIs and excipients enables us to prepare pharmaceutical dosage forms. Unpackaged forms are known as bulk products. Packaging is considered primary when it wraps the dosage form and secondary when the primary packaging is placed in the final presentation of the product (box, leaflet and sometimes ancillary elements for a better administration).

Traditionally, APIs were natural or synthetic products and sometimes semisynthetic products (when the natural raw materials are transformed). Genetic modification and culture of biologic systems constituted by genetically modified cells or microorganisms has increased the spectrum of active substances that can be obtained.

Pharmaceutical dosage forms are designed to facilitate the application of defined quantities of API by means of a given administration route.

Quality of pharmaceuticals

Pharmaceuticals should possess the specified identity, potency and purity, because a drug product lacking the purported quality poses an unacceptable risk to the patient’s health. In the course of time different strategies have been used to ensure the quality of medicinals.

Until the mid-20th century, the quality of the medicinal products was analytical. A sample was taken from each batch of finished product and the analytical results of this sample determined the fate of the whole batch. Unfortunately, this approach has several setbacks: The non-conformity of the batch is just known when it is already finished. Testing is performed on a limited number of units. The trials foreseen for the product cannot ensure the detection of unknown contaminations (Figure 1-02).

Figure 1-02. Analytical quality limitations.

Considering the limitations of analysis, it was deemed that quality had to be considered as another ingredient of the product, at the same level as starting or packaging materials. In order to attain this goal of building quality into the product, Good Manufacturing Practice (GMP) and Quality Management were introduced in the pharmaceutical industry.

At the end of the 20th century, it was reached the conclusion that quality could only be built-in, if it had previously been designed.

In the 21st century, quality is a global concept that comprises all the life cycle of a product and requires a Quality System. Quality is designed with the product, by defining quality variables. Afterwards, the product is manufactured and monitored with these variables (Figure 1-03).

Figure 1-03. The world of pharmaceutical quality.

Good Manufacturing Practice (GMP)

The aim of GMP is to ensure that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation, Clinical Trial Authorisation or product specification. Good Manufacturing Practice is concerned with both production and quality control.

GMP was introduced in the USA in 1963 to provide a roadmap to build quality into medicinal products. It is a part of the code of federal regulations, in which title 21 refers to food and drugs.

GMP comprises several parts of this title 21. Two of them refer specifically to drug manufacturing:

210 (Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; general)

211 (Current good manufacturing practice for finished pharmaceuticals).

Besides, the U.S. Food and Drug Administration (FDA) publishes guidance documents that complete and clarify GMP. It is worth remembering that in the USA, Good Manufacturing Practice is usually referred as Current Good Manufacturing Practice (CGMP).

The World Health Organization (WHO) also prepared in 1969 a GMP text and recommended its adoption by all countries. WHO GMP texts are published as annexes of WHO technical report series.

Subsequently, other bodies have also published their own GMP texts, such as, for instance, the European Commission or the Agencia Nacional de Vigilância Sanitária (ANVISA) of Brazil.

Nowadays, different texts of GMP are applied. They are subjected to regular updating. Inspections are performed on the base of current GMP in the country where the inspected laboratory is located.

However, as the pharmaceutical market is global, the lack of world-wide GMP is felt. This is why important efforts towards GMP harmonization have been carried out over the last years, through mutual recognition agreements and collaboration within international organizations:

The International Council for Harmonization of technical requirements for pharmaceuticals for human use (ICH) is based in Geneva (Switzerland) and publishes harmonized guidelines, describing what could be deemed international GMP. Since its establishment in 1990, the ICH possesses undeniable authority as it is made up of regulatory authorities and laboratories that manufacture and develop pharmaceuticals.

The ICH provides orientation and training. Its guides belong to four groups: Q (Quality), S (Security), E (Efficacy) and M (Multidisciplinary).

Q guidelines provide information on the preparation of the Common Technical Document (CTD) for the registration of drugs, but also on quality management and control.

The Pharmaceutical International Convention/ Pharmaceutical Inspection Co-operation Scheme (PIC/S), also based in Geneva, contributes to homogenize the inspections of the regulatory authorities and releases documents, which develop and interpret GMP. Countries that play significant roles in pharmaceutical production are members of PIC/S.

PIC/S and European Commission GMP are similar, and quite close to ANVISA and WHO GMP, whereas US GMP follows a different approach. Other GMP texts are not considered here because they are outside the scope of this book. Taking these facts into consideration, how should international companies companies cope with these differences in GMP texts? On the one hand, it is possible to say that, in practice, differences are not insurmountable and on the other hand, the application of the most restrictive or demanding requirement make it possible for the laboratories to act in terms of universal GMP. It is evident that if the strictest requirements are met, then the other, less stringent ones, will be also met.

Besides that, nowadays, ICH and PIC/S guidelines can be already considered as unified international GMP.

It is worth noting that following the pharmaceutical GMP model, other good practice texts have been developed, such as Good distribution practices (GDP), Good laboratory practices (GLP), Good clinical practices (GCP), etc.

For pragmatic reasons, GMP initially only regulated the manufacture of pharmaceutical finished products. The production of their ingredients, APIs and excipients, was excluded. More recently, the ICH guide Q7 containing GMP for APIs was released. There is no official GMP for excipients and this might be justified by their supposed lack of activity, even though often they are quantitatively the major component in the dosage form. Presently, the quality of the excipients used in pharmaceutical manufacture has to be managed taking the following three points into account.

1st

The manufacturer authorized to produce pharmaceuticals is responsible for their quality and this comprises both operations and ingredients.

2nd

Manufacturers should evaluate their excipients in terms of risk and establish accordingly quality requirements.

3rd

Most manufacturers of excipients offer to the pharmaceutical industry ingredients produced in an environment similar to the one proposed by GMP.

The life cycle and the supply chain

Medicinal products should be considered in terms of life cycle, because, as it has been said before, quality must be designed prior to manufacturing. Commercial manufacture means that over time patients should receive products meeting quality requirements (Figure 1-04).

Figure 1-04. Pharmaceutical life cycle and supply chain.

The pharmaceutical life cycle is made up of four stages:

1st

Pharmaceutical development: This stage covers not only the development of starting materials, products and processes (including scale-up) but also of analytical methods and the selection of adequate packaging materials. During this stage the quality of products should be systematically designed (Quality by Design – QbD). With this aim, objectives are predefined and, applying science and risk management, the product, its manufacturing process and its control are fully known and mastered.

2nd

Technological transfer: The production process is shifted from the development center (pilot plant) to the manufacturing unit. It is also considered transfer the relocation of a process from one place of production to another (within the same unit or at a different unit) of products already commercialized.

3rd

Commercial manufacturing: This stage comprises the whole supply chain, that is to say, not only the production properly said, but also the purchase of starting materials, packaging materials, quality control, quality management, storage and distribution. The aim is manufacturing quality and supplying the patient with quality products. It is necessary to establish and to maintain a state of control on the production and increase continually the existing knowledge in order to identify opportunities for improvement.

4th

Product discontinuation: When the manufacture of a drug is discontinued, it is necessary to ensure that while there is product on the market, documentation and samples are retained. Vigilance should also be maintained (complaints, adverse reactions, stability, etc.).

Figure 1-05. The drug product life cycle and good practices.

A more detailed representation of the pharmaceutical life cycle and of the good practices applicable to each stage is shown in Figure 1-05. The logical steps of development are shown in the figure: initial studies that allow defining the product, in vitro studies (non-clinical assays) and, subsequently, in vivo (clinical) studies. Once the drug has been developed, it has to be authorized by the responsible authority, prior to its transfer to the manufacturing unit.

The different good practices apply to different areas:

GMP is applied to the activities of manufacture of pharmaceuticals, both authorized for commercial production and in development.

GLP is applied to the Quality Control (QC) laboratory, which can intervene in non-clinical development studies and in control activities related with the commercial manufacture of medicines.

GCP is applied to the assays and clinical studies of the medicinal products, which are under development or already authorized (complementary trials).

GDP is applied to the storage and distribution of finished pharmaceuticals.

It is worth mentioning that GMP encompasses the transference, manufacturing and discontinuation phases, but not the development, with the logical exception of the products under development that are prepared in order to perform clinical essays, considering that these products are administered to patients. The development phase can be kept under control by including it within the scope of the Pharmaceutical Quality System (PQS).

Quality design and verification

As outlined in Figure 1-06, the starting point of the development of a product is the establishment of its Quality Target Product Profile (QTPP), defined as a prospective summary of the characteristics that ideally should be achieved to ensure the desired quality, considering safety and efficacy: dosage form, API and its dosage, specifications, aspect, proprieties, characteristics, etc.

The aim of the development of a medicine is to establish a formula, a manufacturing procedure and also to define the specifications of the starting materials, of the packaging materials and of the products (intermediates, bulk and finished).

The characteristics of the finished product should be linked to the assumed properties for the starting materials and the characteristics of the manufacturing process. This relation between manufacturing process and properties of the yield can be applied both to the starting materials and to the medicinal products. Therefore, for instance, the parameters of the crystallization operation determine the size of the crystals, and the drying time and temperature determine the humidity and the integrity of the finished API.

The knowledge of the relationship between starting materials, manufacturing process and finished product allows for the understanding of the effects of variations regarding, for instance, characteristics of the raw materials, physicochemical conditions, relative proportions of the excipients, etc.

Raw materials used in the production of APIs and starting materials employed in the manufacture of pharmaceuticals, both possess Critical Quality Attributes (CQAs), namely, physical, chemical, biological or microbiological properties or characteristics that should be within a range or adequate limit in order to ensure the quality of the product. CQAs determine if a product is appropriate or not. This is why, processes are monitored by mean of Critical Process Parameters (CPPs). These parameters have an impact on the CQAs and for this reason they should be monitored in order to ensure that the process produces the required quality.

The set of CQAs and CPPs are the critical variables. By means of risk analysis it is possible to identify them and evaluate their criticality. The intended goal is to be able to differentiate between critical and non-critical variables. Critical variables should be monitored, unless that a process modification makes them non-critical. The final result is the approval of an acceptable risk level for the quality of the product, either by reduction or by monitoring. It has to be kept in mind that from the three factors that determine the level of risk, severity, probability and detectability (see Chapter 2) in most of cases is only possible to act on the last two, by introducing technological improvement.

Once that critical variables have been identified, it is possible to establish interdependence relations among them, by defining a design space (DS), i.e. the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality.

The aim is to ensure the quality of the product, either by verifying that all variables are within specified ranges / limits, or by integrating all the data in a DS within which all variables will have acceptable values. The application of statistic methods, e.g. Design of Experiments (DoE), allows to reduce the number of trials that are required to establish multifactorial influences. Although the DS can be graphically represented, ideally it should be provided a predictive mathematical model.

Figure 1-06. Critical variables.

The strategy of control is established as a result of the understanding of product and process and should ensure product quality and process performance (Figure 1-07).

The variables that should be controlled are those related to the product, the starting materials, the operational conditions of equipment and facilities, the in-process controls, the finished product specifications, as well as the associated procedures and the frequency of monitoring and control.

If control of variables is understood as continual verification of process performance and product quality, then, the final analytical controls lose their meaning. Monitoring can be performed by analysis of samples taken during the process or, better, by means of Process Analytical Technology (PAT), which lays aside problems related to sampling.

In parallel to the strategy of control there is a strategy of liberation. Here it is also possible to use the traditional approach of liberation after analysis or perform Real Time Release Testing (RTRT), which can be defined as the ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls.

Figure 1-07. Quality design.

The application of automated systems, e.g. PAT, allows real time liberation of products, with all the guarantees and even more, because the monitored parameters are linked to analytical results, all critical aspects are under control, measures are automated and performed in a timely manner. In other words, all batches are concurrently validated.

The Pharmaceutical Quality System (PQS)

The quality of pharmaceuticals rests on three principles: quality by design (QbD), specific regulation (GMP) and quality management.

The PQS proposed in ICH guide Q10 provides a frame to manage quality in pharmaceutical manufacturing (Figure 1-08).

PQS main goals:

Manufacture quality products meeting their specified requirements.

Establish and maintain a control state, by means of continual monitoring, to ensure that products possess continual adequacy and that processes maintain their capacity.

Enable continual improvement, by identifying the opportunities of progress and by enhancing the capacity of meeting quality requirements.

PQS basic principles:

1st

The system manages quality throughout the whole lifecycles of the products.

2nd

All personnel should be involved in the task of obtaining and maintaining quality but the final responsibility pertains to the high direction.

3rd

There is a permanent control on products and processes.

4th

Decisions are based on science and risk evaluation.

5th

There is a continual improvement process (in product quality, in the reduction of process variability, in the performance of the PQS itself, etc.).

PQS enablers:

Enablers are defined as tools or processes that provide the means to reach an objective. Two enablers are required for the achievement of the three main goals, previously mentioned.

Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the pharmaceutical throughout the product life cycle.

Knowledge management is the systematic approach to acquire, analyze, store and spread information related with the products, manufacturing processes and components.

The objective of knowledge management is gathering facts and data and once they are well understood and filtered, making them available to those who might need them and keeping them for future uses.

Pharmaceutical development is based on a limited number of batches, whereas the number of commercial manufacturing batches is unlimited. As a consequence, the growth of knowledge in the course of time is inevitable.

PQS elements:

The PQS distinguishes four elements of parts.

Process performance and product quality monitoring system

Corrective and preventive actions system

Change monitoring system

Management reviews

Note that the first three are considered systems because they have to operate permanently and this requires the regular systematic application of procedures.

To these elements we would recommend adding three more:

Qualification/Validation

Internal audits

Quality reviews

Figure 1-08. The Pharmaceutical Quality System (PQS).

Process performance and product quality monitoring system

The purpose of this system is to ensure the maintenance of a control state, as in a situation where a set of measures ensures that process performance is adequate and product meets specifications.

This system applies instruments to measure and evaluate critical variables and to identify sources of variation that might affect process performance. In addition to the monitoring of variables, the system also takes into account performance indicators such as deviations, non-conformities, rejects, recalls, complaints and the results of inspections and audits.

Corrective and preventive actions system

This system, widely known as CAPA, is aimed to ensure that deviations are corrected and that necessary actions to prevent recurrences are applied. Let us remember that unlike changes that are deliberate, deviations are unintentional and suppose unattended alterations of the required situation. Deviations check the