Generally the product life cycle consists of four main processes:

This description will usually do for pharmacy preparations. Pharmacy preparation sees that the patient’s need is combined with a knowledge of pharmacotherapy with a known active substance. The assumption of a positive benefit/risk ratio regarding this pharmacotherapy leads to a request, commonly a physician’s prescription, for the active substance in a suitable dosage form. Next a formulation, a way of preparation and packaging have to be designed, specifications set and assays developed. The actual preparation has to be started. If more patients need this medicine, the preparation has to become predictable and reliable to deliver more preparations or even batches with a constant quality and yield. Quality control has to be defined, as well as release, storage, distribution and transport. The actual use of the preparation by the patient should lead to any form of feedback about effectiveness and safety, patient friendliness and fitness for the healthcare process that it serves. The life cycle of a pharmacy preparation will end with a discontinuation, usually because of a new licensed medicine with a better benefit/risk ratio. Sometimes its life cycle ends due to e.g. unavailability of substances or packaging materials or to stability problems.

The life cycle of a licensed medicine follows this sequence as well, although it is much more regulated and with formally separated processes, due to larger batches and widespread use.

For industrial production the Product Life Cycle for new and existing products is characteristically defined by ICH Q10 as a sequence of four groups of technical activities, with subgroups:

Pharmaceutical Development

Technology transfer

Commercial manufacturing

Product discontinuation

The following sections discuss the Product Life Cycle in more detail, mainly based on the four main processes for preparation in pharmacies.

Pharmacotherapeutics for pharmacy preparation is about prescription assessment, information of physician and patient, and pharmacovigilance. The therapeutic quality of the product is the outcome of a benefit/risk balance. It accounts for efficacy and effectiveness, patient friendliness and the contribution to the safety of healthcare processes (see Sect. 2.​2). The benefit risk balance at the start of the life cycle is assumed to be positive, which has to be proven to a reasonable extent before the patient gets the medicine. For pharmacy preparation a review of literature, medical opinion and sound thinking usually provides the start. The benefit risk assessment is the duty of care of all health professionals involved, as it is put in the Ethical guidance and considerations of the Ph Eur monograph Pharmaceutical Preparations (see Sect. 35.5.3). The CoE Resolution on Pharmacy Preparation (Sect. 35.5.4) also mentions this duty: the pharmacist has to prove the ‘added value’ compared to licensed medicines. Documentation of these professional decisions is essential for building up knowledge, communication between healthcare professionals and from a liability point of view. Forms for this type of documentation are given in Sect. 2.​2.

After the introduction or start of use of any medicine, the benefit risk ratio may be changed, because of:

These possible changes necessitate monitoring: pharmacovigilance. Pharmacovigilance has been defined by the World Health Organisation as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem [2]. For the monitoring of the pharmacotherapy of licensed medicines, the qualified person for pharmacovigilance (QPPV see also Sect. 25.​4.​4) has to handle complaints and reports of suspected adverse events. Monitoring occurs by a regulated system of pharmacovigilance. Patients, caregivers and health care personnel may be questioned, and regular product reviews are created, including the analysis of complaints and of literature. This monitoring may lead to a conclusion that the active substance is not beneficial any more, the dosage form should be changed, indications added, volume or packaging improved etcetera.

Pharmacovigilance for pharmacy preparations has not yet been developed very well. However in some countries the competent authority expects pharmacies to have pharmacovigilance procedures.

The information about the therapeutic qualities of licensed medicines is part of the product dossier to obtain and keep a marketing authorisation. For pharmacy preparations information about therapeutic quality and about its monitoring can be part of the product file (see Sect. 33.​8).

The formulation has to meet the needs of the patient with active substances, excipients, dosage form and package, it has to meet (regulatory or professionally set) product specifications and it should support a sound production process (see Chap. 17 Product design). The preparation’s stability plays a large role, its shelf life has to be predicted and analysed (see Chap. 22 Stability) and instructions for use have to be developed (see Chap. 37 Instructions for use).

A good and well-organised documentation of the design process can be very supportive and time-saving on many moments in the product’s life cycle. It will help when process deviations need to be explained or changes need to be made.

For the design of pharmacy preparations the pharmacist refers to knowledge sources, such as this textbook. Chaps. 4–14 describe the essentials of the design processes for most dosage forms.

For the specifications of the active substances, excipients and dosage forms the pharmacist can refer to the Ph. Eur. If it is necessary to deviate from these requirements to meet the needs of the patient, the pharmacist should document the rationale for that decision in the product file (see Sect. 33.​8). For the documentation of the decisions about the design and the risk assessment, some checklists and forms are available, see Sect. 2.​2. The process of formulation design may be laid down in SOPs for different dosage forms.

For licensed medicines the description of the design has to be given by the manufacturer in the registration dossier. Notices to applicants contain instructions for a registration dossier, which can be used in consultation with national professionals and the EMA. Furthermore, scientific recommendations from the Committee for Medicinal Products for human use (CHMP), Reflection papers, and Scientific guidelines (see Sect. 35.5.1: Volume 3 of the Rules) are available. So-called European Assessment Reports (EPARs) of specific licensed medicines can be quite informative about design backgrounds. They are published at the EMA website. The national registration authority or the EMA (pan-European) have to approve the quality of the design.

The production process is the most visible and most extensive part of the Product Life Cycle. Several pharmaceutical quality systems in use support ’just’ the preparation process. These PQSs may extend from the involvement of senior management, handling complaints, change management, maintenance of facilities and documentation, self-inspection to analysis and knowledge management. These elements are elaborated in Sect. 35.6. Structures to group these elements in a logical way are discussed in Sect. 35.7.

A PQS usually covers the distribution process as well. GMP (see Sect. 35.5.7) specifies the distribution being part of the PQS in Chap. 1 Pharmaceutical Quality System:

Information on storage of medicines, transport and distribution is dealt with in Chap. 36 Logistics.

The quality characteristics of medicinal products and quality objectives of a preparing pharmacy or manufacturer are generally and sometimes in detail covered by European and national legislation and guidelines. A quality system for medicinal products will therefore have to connect with the appropriate legislation and professional guidelines that are meant to support their quality.

Legislation is aimed at the protection of the citizen, and are nowadays often supranational. The professionals, for instance the national pharmaceutical society, may have defined standards for the implementation of or complementing the regulations.

This section deals at first with the basic European legislation on medicines. Then follows the monograph Pharmaceutical Preparations of the Ph. Eur. This is legally binding for preparation in pharmacies as well as for industrial manufacturing and it covers three parts of the product life cycle: pharmacotherapeutics, product design and preparation process. It states the need for a PQS by: “Manufacture/preparation must take place within the framework of a suitable quality system and be compliant with the standards relevant to the type of product being made.”

With regard to preparation in pharmacies three other guidelines are relevant: the Council of Europe (CoE) Resolution on Pharmacy Preparation, the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) – Good Preparation Practice (GPP) Guide, and the professional guideline USP Compounding standards. Some other European professional guidelines are mentioned as well, which however are not easily accessible due to their language.

For licensed medicines the GMP guidelines are legally binding, insofar that other practices are allowed on the condition that the same principles are fulfilled. They give many details on production and a PQS. The EU GMP (see Sect. 35.5.7) states that a manufacturer should establish, document and implement a “comprehensively designed and correctly implemented QMS incorporating Good Manufacturing Practice and Quality Risk Management”. The GMP principles apply as well to preparation in pharmacies. The global International Conference on Harmonisation (ICH) guidelines Q8, Q9 and Q10 are mainly in use in industrial production. The regulatory function of the Qualified Person, with functional connections to a PQS, is dealt with in Sect. 35.5.7 and Chap. 25 Human Resources. Regulations about Investigational Medicines are shortly dealt with in Sect. 35.5.10 with focus on the tasks of hospital pharmacists.

European legislation on medicines for human use consists of several directives and regulations, further referred to as ‘Rules’. They are clustered in Volumes, to be found at [3]. The main series that are relevant for the production of medicines are in Volume 1 and 4.

In Volume 1, EU pharmaceutical legislation for medicinal products for human use, the main directive is Directive 2001/83/EC on the Community Code relating to medicinal products for human use. It is directed at licensed medicines. Pharmacy preparations are however mentioned in Article 40:

However, such authorisation shall not be required for preparation, dividing up, changes in packaging or presentation where these processes are carried out, solely for retail supply, by pharmacists in dispensing pharmacies or by persons legally licensed in the Member States to carry out such processes.

Directive 2001/83/EC points with Article 47 2nd paragraph at the Commission Directive 2003/94/EC laying down the principles and guidelines of good manufacturing practice (see Sect. 35.5.7) in respect of medicinal products for human use and investigational medicinal products for human use. In the introduction on GMP it is stated that

The principles of GMP and the detailed guidelines are applicable to all operations which require the authorisations (..). They are also relevant for pharmaceutical manufacturing processes, such as that undertaken in hospitals.

The definition of pharmaceutical manufacturing processes is however not given.

Articles 48 49, 51 are about the Qualified Person that has to be at disposal of any Manufacturer’s Authorisation Holder (see further Sect. 25.​3.​4).

This basic legislation is supported by a series of guidelines:

Guidelines are meant to guide the implementation of legislation, as it is stated for instance: “Volume 4 contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use laid down in Commission Directives 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC respectively.”

This monograph [4] had its first edition in 2011. It applies to all pharmaceutical preparations: licensed medicines as well as pharmacy preparations; or in other words: to licensed as well as unlicensed medicines.

Pharmaceutical Preparations Ph. Eur. monograph contains the sections:

Especially the Ethical considerations are important for a PQS for pharmacy preparation:

The underlying principle of legislation for pharmaceutical preparations is that, subject to specific exemptions, no pharmaceutical preparation may be placed on the market without an appropriate marketing authorisation.

The exemptions from the formal licensing requirement allow the supply of unlicensed products to meet the special needs of individual patients. However, when deciding to use an unlicensed preparation all health professionals involved (e.g. the prescribing practitioners or the preparing pharmacists or both) have, within their area of responsibilities, a duty of care to the patient receiving the pharmaceutical preparation.

In considering the preparation of an unlicensed pharmaceutical preparation, a suitable level of risk assessment is undertaken.

The risk assessment identifies:

• 
  
  the criticality of different parameters (e.g. quality of active substances, excipients and containers; design of the preparation process; extent and significance of testing; stability of the preparation) to the quality of the preparation; and
  
  
• 
  
  the risk that the preparation may present to a particular patient group.

Based on the risk assessment, the person responsible for the preparation must ensure, with a suitable level of assurance, that the pharmaceutical preparation is, throughout its shelf life, of an appropriate quality and suitable and fit for its purpose. For stock preparations, storage conditions and shelf life have to be justified on the basis of, for example, analytical data or professional judgement, which may be based on literature references.

These guidance points at three processes that are part of pharmacy preparation’s life cycle: pharmacotherapeutics, product design and preparation process. Therefore to be in accordance with this Ph. Eur. monograph, the corresponding quality system should cover all three processes, including responsibilities, to be most useful. The monograph gives further guidance to the process of formulation design.

The full title of this resolution is: Resolution CM/ResAP(2011)1 on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients [5]. The aim of this resolution is “to set a standard for national requirements for quality and safety assurance for pharmacy preparation in community and hospital pharmacies.” It mentions many levels of pharmacy preparation: from industrial manufacturing of unlicensed medicines to extemporaneous preparation for a single patient and reconstitution on the wards.

For the quality management system of the preparation process, reference is made to the GMP and the PIC/s GPP, the PIC/S seen as ‘GMP light’ (see Sect. 35.5.5). The choice between these should be determined by a risk assessment that has to include the scale of preparation.

If the pharmacist however has to assess which products are ‘less critical’ he may as well use the GMP principles as starting point. These principles are valid for any sort of preparation; they just have to be detailed and specified (by a risk assessment, see Sect. 21.​6.​3) for any pharmacy preparation situation.

For the quality management of therapeutic assessment of the physician’s request and formulation design (two other processes of pharmacy preparation’s life cycle), no reference is made other than to professional responsibility and education. In this way, the Resolution (and thus its example model for a risk assessment) is rather unbalanced, because too much is focussed on the preparation process itself.

The Resolution seems valuable as a starting point for further standards, and will play its role in complicated legal discussions about how to regulate large-scale preparation of unlicensed medicines. However because its risk assessment procedure is not covering therapeutic qualities and formulation design, it may not lead to the best way to assure the quality of patient medication. The Ph. Eur. monograph (Sect. 35.5.3) puts the different aspects in better balance.

The Guide to good practices for the preparation of medicinal products in healthcare establishments (PIC/S-GPP Guide) [6] was published in 2008. It states: “the basic requirements presented in this Guide apply to the preparation of medicinal products normally performed by healthcare establishments for direct supply to patients.”

It is considered as a GMP for pharmacy preparation, has a GMP-like structure and starts from the same principles. It is easier to read than the GMP because details not referring to pharmacy preparation are left out. Deviations from GMP (for instance in Annex 1 on Sterile Preparation) are however not explained. It was developed before the CoE Resolution (Sect. 35.5.4), which refers to it, or the Ph. Eur. monograph (Sect. 35.5.3). The Resolution limits the use of PIC/S GPP to ‘less critical products’.

The PIC/S GPP Guide approaches pharmacy preparation from an industrial production process perspective, only marginally acknowledging specific qualities of the preparation process in pharmacies. Only a differentiation based on scale is made: between extemporaneous and stock production.

GPP touches upon the processes: assessment of the physician’s prescription or formulation design in the Documentation paragraph: “a pharmaceutical assessment of therapeutic rationale, safety data, toxicity, biopharmaceutical aspects, stability and product design should be carried out, before preparation takes place.” No further details are established however.

So from a quality system viewpoint the PIC/S GPP can only be used for quality of the preparation process, not for prescription assessment or design of formulation.