Health Policy 117 (2014) 328–333

Contents lists available at ScienceDirect

Health Policy
journal homepage: www.elsevier.com/locate/healthpol

Regulatory framework of pharmaceutical compounding and

actual developments of legislation in Europe
Paola Minghetti ∗ , Doriana Pantano, Chiara Grazia Milena Gennari,
Antonella Casiraghi
Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via G. Colombo 71, 20133 Milan, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Pharmaceutical preparations are medicines that the pharmacist makes for the special needs
Received 13 December 2013 of the patients that the pharmaceutical industry cannot comply for economic and logistic
Received in revised form 30 April 2014 reasons. Pharmacy compounding is still an important component of pharmacy practice and
Accepted 10 July 2014
a valuable therapeutical service that is an integrant part of the modern health care system,
but its legislation is not harmonized among European and US countries.
Keywords: In 2011 the Committee of Ministers of the Council of Europe has adopted a Resolution on
Extemporaneous
quality and safety assurance requirements for medicinal products prepared in pharmacies
Regulation
for the special needs of patients. Aim of this resolution is to harmonize quality assurance
Resolution
Pharmacy compounding and standards for pharmacy-made medicinal products among European countries and to
Pharmaceutical preparations pass the gap in quality assurance and standards between preparation in pharmacies and
medicines prepared by the pharmaceutical industry. This article will analyze the actual rules
and technical norms that regulate compounding activity and the expectations resultants
from the new European and US laws.
© 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction began to dominate the supply of the mainstream market

[1], moving pharmaceutical preparation from a pharmacy
An active substance can rarely be administrated as such. context to a manufacturing one. Today more than 90% of
In the great majority of cases, compounding is required in medicinal products are of industrial origin. Simultaneously
order to obtain a final product suitable for administration, with the industrial and technological development, the
taking into consideration the characteristics of the active framework of applicable technical standards has also been
substance, the route of administration, the best pharma- developed (see GMP evolution), to guarantee a level of
cokinetic profile and the patients’ compliance. quality, efficacy and safety of the medicinal products con-
Traditionally, compounding was the main activity of the sistent with the current development.
pharmacist of the past, being about 80% of all the pre- The lost of importance in compounding activity both
scriptions until 1950s. In the second half of 19th century, for the pharmacy and the society ensued an impoverish-
drug manufacturing, the mass production of drug products, ment of the pharmacist’s culture and training and a reduced
normative attention as legislation not always evolved and
stayed in line with the public protection requirements [2].
However, pharmacy compounding is still a key component
∗ Corresponding author. Tel.: +39 0250324639; fax: +39 0250324657.
of pharmacy practice and a relevant therapeutic service,
E-mail addresses: paola.minghetti@unimi.it (P. Minghetti),
doriana.pantano@studenti.unimi.it (D. Pantano), chiara.gennari@unimi.it
other than an integral part of the modern health care sys-
(C.G.M. Gennari), antonella.casiraghi@unimi.it (A. Casiraghi). tem. Through this practice, patients with particular needs

http://dx.doi.org/10.1016/j.healthpol.2014.07.010
0168-8510/© 2014 Elsevier Ireland Ltd. All rights reserved.
 P. Minghetti et al. / Health Policy 117 (2014) 328–333 329

may obtain tailored medicaments. Many patients, whose common definitions. Compounding activity rather falls
needs are not met by industrial products, depend on the under the national competencies of individual European
skills of the compounding pharmacist to prepare a medica- countries.
ment in a dosage or in a dosage form, tailored for their The first European directive of medicinal product was
specific situation. Certainly, it is undeniable that pharmacy introduced in the 1965 [9], but the compounding activity
compounding is not as rigidly monitored as industrial pro- of the pharmacies was not considered. This concept was
duction. Compounding of extemporaneous preparations introduced with the Directive 89/341/CE [10] that amended
(magistral formula) in pharmacy is completely different Directives 65/65/CE.
in terms of risk analysis compared to the batch produc- Here was defined:
tion in the pharmaceutical industry. Pharmacy compounds
cannot be tested with the same methods as for manufac- - magistral formula: any medicinal product prepared in a
tured medicinal products and there are several reasons pharmacy in accordance with a prescription for an indi-
to believe that it is even not necessary, namely a trusted vidual patient;
physician–pharmacist–patient relationship, a short-term - official formula: any medicinal product which is prepared
consumption of the product, the compounding activity in a pharmacy in accordance with the prescriptions of a
reserved only to pharmacist or well-trained technician, and pharmacopoeia and is intended to be supplied directly to
the use of simple equipment for the compounding. In any the patients served by the pharmacy in question.
case, all medicinal treatments bear a certain level of risk;
in literature some cases of toxicity caused by the inges- These definitions are repeated in the Directive
tion of bad-quality products, like some deaths and damage 2001/83/CE [11], which is still in force. This directive
in children, or by administration of sterile products are exempts “pharmaceutical preparations” from the indus-
also reported for medicine compounded in pharmacy [3–6]. trial procedures, such as manufacturing and marketing
Safety risks can be minimized through pharmacist knowl- authorizations. This approach has been recently confirmed
edge, training, skill and care but also through appropriate by the European Pharmacopoeia monograph on “pharma-
regulation of this activity. In any case, we have to accept a ceutical preparations” [12]: they are defined as medicinal
different regulation for the pharmacy-prepared medicinal products generally consisting of active substances that may
products respect to regulation applied to industrial prod- be combined with excipients, formulated into a dosage
ucts or we have to consider the possibility to renounce to form suitable for the intended use, where necessary after
this practice. Nevertheless, considering that there are still reconstitution, presented in a suitable and appropriately
many unmet needs, we are convinced that it is not pos- labelled container.
sible to quit this opportunity, so much so that both USA Pharmaceutical preparations may be licensed by the
and Europe recognize the need of medicinal products pre- competent authority or unlicensed and compounded to
pared in pharmacies through their norms. In particular, meet the specific need of a patient according to current
chapters <795> and <797> of US Pharmacopoeia provide legislation. They are distinguished in two categories:
general information to enhance the pharmacist’s ability
in compounding and validate procedures and require- - extemporaneous preparations (according to Directives
ments [7,8]. Moreover, international organizations like the 65/65/CE: magistral formula), i.e. pharmaceutical prepa-
World Health Organization (WHO) and the Pharmaceuti- rations individually prepared for a specific patient or
cal Inspection Convention and Pharmaceutical Inspection patient group, supplied after preparation;
Co-operation Scheme (PIC/S) process standards to lead - stock preparations, i.e. pharmaceutical preparations pre-
the international development, implementation and main- pared in advance and stored until a request for a supply
tenance of harmonized procedures. Then finally, many is received [12].
European countries have already applied similar guide-
lines to guarantee the quality, efficacy and safety of the Following this definition, in some European countries
medicinal products, such as the national or the European it is allowed to prepare in stock other than official formu-
Pharmacopoeia monographs. Nevertheless, it seems fur- las also magistral formulas, in order to have an immediate
ther necessary to develop a suitable regulation to allow availability of the product for the next dispensation.
pharmacies to compound an adequately safe medicinal
product for the patients. 2.2. USA
Aim of this work is to analyze the evolution of the
compounding rules and to make proposals about new reg- In the USA, compounding is currently defined by the
ulations to warrant the patients the possibility to obtain National Association of Boards of Pharmacy (NABP) as
the proper drug with the adequate quality. preparation of components into a drug product as the result
of a practitioner’s prescription drug order or initiative
2. Definition and regulation of pharmaceutical based on the practitioner/patient/pharmacist relation-
compounding ship in the course of professional practice. Compounding
includes the preparation of drugs or devices before receiv-
2.1. Europe ing prescription drug orders based on routine, regularly
observed prescribing patterns [13].
The preparation of medicinal products in pharmacies In chapter <795>, “Pharmaceutical Compounding –
are not harmonized all over Europe; there are only some Nonsterile Preparations” [7], the US Pharmacopoeia defines
330 P. Minghetti et al. / Health Policy 117 (2014) 328–333

compounding as the preparation, mixing, assembling, of traditional compounding pharmacy. The bill also sets up
altering, packaging and labelling of a drug, drug-delivery a tracking drug system: the legislation aims to improve the
device, or device in accordance with a licensed practi- safety of the US drug supply by requiring enhanced moni-
tioner’s prescription, medication order, or initiative based toring of the chain of transactions from the manufacturer
on the practitioner–patient–pharmacist–compounder of a drug to the party that ultimately dispenses the drug to
relationship in the course of professional practice. There- the consumer. It includes serial numbers for drugs and an
fore, the US legislation aims to highlight the importance electronic drug-tracing mechanisms.
of the application field of pharmacy preparations and to
make distinction from the industrial products.
3. The aim of compounding
Traditionally, the boards of pharmacy of each State, sup-
ported by the NABP in creating uniform regulations to
We have to consider that the exemption of the pharma-
protect public health, regulate the activity of pharmacy
ceutical preparations from several procedures is justified
compounding through their general rules and regulations
only by the requirement to meet the special needs of indi-
that are not always uniform among States [14].
vidual patients that cannot be met by the pharmaceutical
In 1938 Federal Food, Drug, and Cosmetic Act (FD&C),
industry [18].
the FDA’s primary source of regulatory authority, passed
Among the main therapeutic needs to meet by a com-
by Congress to protect the public from unsafe prescrip-
pounded product, there are
tion drugs. After Congress in 1938, the FDA did not regulate
compounded medications as new drugs. The FDA consid-
• allergies due to excipients contained in medicinal prod-
ered compounding a part of pharmacy practice, which was
not a part of its regulatory jurisdiction. The regulation of ucts manufactured by the pharmaceutical industry:
pharmaceutical compounding, consequently, was left in the compounder can reformulate the medicament with
the hands of the States in their capacity to license and another excipient that does not compromise the techni-
regulate professional practices. FDA’s deference to State cal properties of the product [19,20];
• medicines for paediatric patients since the pharmaceuti-
regulation of pharmacy compounding continued for over
fifty years. In the 90s, however, safety concerns triggered cal industry does not often develop paediatric dose and
attention to the regulation of compounded drug products dosage forms [21–23]. For the relevance of this activity
and the FDA chose to reinterpret its regulatory authority on it has to consider that some authors estimate that up to
new drugs. Finally, in 1997, the Congress passed the Food forty percent of all paediatric prescriptions in the USA are
and Drug Administration Modernization Act (“FDAMA”), to be compounded;
• association of active principles: to improve the patients’
with a provision meant to regulate and protect the practice
of pharmaceutical compounding [14]. The Act exempted compliance or to obtain an additional or synergic effect
compounded products from the new drug provisions of [24];
• orphan drug: an active ingredient that has been devel-
the FD&C, thereby creating a compounding exception to
the lengthy and costly drug-approval process to protect oped specifically to treat a rare medical condition [25,26].
the practice of pharmaceutical compounding. The FDA has Despite subsidy for the industrial development, com-
unsuccessfully attempted at length to restrict compound- pounding has the main role for these medicines;
• medicines for clinical trials and placebo prepared in the
ing pharmacies and has tried to have its authority over the
subject matter recognized, but its intervention has been so hospital pharmacy [27];
• customize therapy like the pain management therapy
far marginal and only in rare cases [15].
On September 25, 2013 Senate and House commit- [28];
• medicines with stability issues: in this cases the extem-
tees of the USA overseeing health policy announced that
they had reached an agreement on legislation to ensure poraneous preparation is essential [29,30];
• medicines awaiting authorization: compounders may
the safety of compounded drugs and the national phar-
maceutical supply chain [16]. The Pharmaceutical Quality, prepare a medicinal product that has not yet obtained
Security and Accountability Act [17] was prompted by the the market authorization, if the active is already known
2012 meningitis outbreak tied to the New England Com- and commercialized.
pounding Centre (NECC) in Massachusetts which killed at
least 64 people and sickened more than 750. The inspec- 3.1. Regulation for the quality, safety and efficacy of
tions subsequent the outbreak at the company’s facility preparations
found unsanitary conditions. The legislation (title I of the
bill) attempted to draw a distinction between traditional The Good Manufacturing Practices (GMP) are applied to
compounding pharmacies and outsourcing facilities ship- medicinal products manufactured by the pharmaceutical
ping sterile products across state borders, such as NECC industry. GMP is a system for ensuring that products are
[16]. The FDA would have regulated these larger organi- consistently produced and controlled according to quality
zations but exempts from the full spectrum of regulations standards. This guideline is designed to minimize the risks
that are applied to traditional pharmaceutical companies involved in any pharmaceutical production that cannot
remained, and traditional compounding pharmacies have be eliminated through testing the final product [31]. The
still regulated by the State boards of pharmacy. Thus, the European Medicines Agency (EMA) has established that
bill represents a compromise between the need to regulate pharmaceutical companies must follow GMP procedures
the large-scale compounding activity and the maintenance in all EU territory, having as main objectives safeguarding
 P. Minghetti et al. / Health Policy 117 (2014) 328–333 331

the health of the patient as well as producing good quality regulations in accordance with the principles set out in
medicine. this document, applied to both extemporaneous and stock
GMP cannot be applied to the pharmaceutical prepara- preparations. The Resolution has raised some interest-
tions and there are several reasons to believe that this is ing issues. It underlines that all health care professionals
even not necessary: are their own responsibility in the pharmacy prepara-
tions. Moreover, these preparations are of added value if,
• compounded products are prepared for the immediate due to medical, pharmaceutical or personal reasons, they
use; are needed by a specific patient or by specific group of
• compounded products cannot await the long and severe patients with particular needs. In our opinion, the pre-
trials that the manufactured ones have to follow; scriber should be responsible for evaluating the added
• preparation of compounded products is directly carried value of an extemporaneous preparation, while the phar-
out by the pharmacist or a technician under the pharma- macist should consider if it is more risky to supply that
cist’s supervision, while in industries production is made extemporaneous product to the patient, or to leave the
only by technical staff; patient without this medicine. Finally, added value and risk
• compounding is mainly based on a trusted assessment of preparations are to be evaluated and doc-
physician–pharmacist–patient relationship; umented in a suitable product dossier by the dispensing
• pharmacies have less automated equipment than the pharmacy. These ethical considerations are already present
industries, where batches are larger and a major risk must in the European Pharmacopoeia [12] where is considered
be considered. the possibility to prepare an unlicensed pharmaceutical
preparation if a suitable level of risk assessment is under-
Because of these considerations, in 2008 the “PIC/S taken. The risk assessment is based on some considerations
Guide to Good Practices for the Preparation of Medic- such as the dosage form and administration route, the
inal Products in Healthcare Establishments” (Ref.: PE amount prepared, the pharmacological effect, the thera-
010-3) was proposed by the Pharmaceutical Inspection peutic window, the type of preparation process and if the
Convention and Pharmaceutical Inspection Co-operation pharmacy makes preparations for internal or external sup-
Scheme (PIC/S). PIC/S are two international instru- ply.
ments among countries and pharmaceutical inspection The Resolution establishes that pharmacy-prepared
authorities, whose mission is to lead the international medicinal products can be distinguished between two
development, implementation and maintenance of harmo- risk levels (i.e. “high-risk preparations” and “low-risk
nized standard practices of production and quality systems preparations”), and between two different levels of qual-
of inspectorates in the field of medicinal products. Among ity assurance system. GMP Guide is recommended as a
the participating authorities, there are worldwide agencies, reference for an appropriate quality control system for
like FDA, and institutions of many countries in Europe and “high-risk preparations” and the PIC/S Good Preparation
beyond. Practices Guide for “low-risk preparations”.
Whereas PIC/S Guide PE 009 applies to industrial man- Briefly, upon receiving the prescription, the pharma-
ufacture of medicinal products, the basic requirements cist first evaluate the added value of the extemporaneous
presented in Guide PE 010-3 are referred to the preparation product, thus establishing if the preparation can take
of medicinal products normally performed by healthcare place. Then, the compounder undertakes an appropriate
establishments for direct supply to patients [32]. The PIC/S risk assessment in order to determine the level of quality
guide follows the structure of the GMP Guide for industry control system which should be applied to the pharma-
and recognizes that other methods than those described ceutical preparation. Before beginning to compound the
in the Guide are acceptable and desired. The PIC/S guide is preparation, a product dossier must be developed on the
not intended to place any restraint upon the development basis of the risk assessed. Therefore, after evaluating the
of alternative systems, new concepts or new technologies, added value of the compounded preparation along with the
which provide a level of quality assurance at least equiva- related risk assessment and considering the risk linked to
lent to those set in this Guide. the unavailability of that medicinal product, the dispensing
Underlining the need to apply, whether possible, rel- pharmacist can decide whether the preparation has to be
evant international standards, such as those developed by compounded.
the WHO and the PIC/S, in 2011 the Committee of Ministers Authorization by the competent authorities or bodies
of the Council of Europe adopted a Resolution on quality is a prerequisite for a pharmacy to carry out operations. If
and safety assurance requirements for medicinal products considered appropriate to guarantee the quality and safety
prepared in pharmacies for the special needs of patients of pharmacy preparations, the authorities should provide
[33]. for an additional authorization, that can be granted or sus-
This Resolution aims to harmonize quality and safety pended, depending on compliance with its conditions, or
assurance and standards for pharmacy-prepared medici- an appropriate notification for high-risk preparation. These
nal products among the European countries and to fill the procedures could improve the safety assurance and the
gap in quality and safety assurance between preparation quality of preparations. In the USA is already present a sort
in pharmacies and medicinal produced by the pharma- of voluntary accreditation by the Pharmacy Compounding
ceutical industry. This Resolution recommends that the Accreditation Board (PCAB), so patients may have a direct
governments of the States Parties to the Convention on demonstration of the pharmacy certification. Certainly, the
the Elaboration of a European Pharmacopoeia adapt their basis for a quality preparation must be a clear and complete
332 P. Minghetti et al. / Health Policy 117 (2014) 328–333

documentation of all activities and raw materials, proce- propulsive development of this activity, educating phar-
dures, and responsibilities. This point is well explained both macists and prescriptors of the future on the importance of
in the ResAP(2011)1 [33] and in the US Pharmacopoeia compounding and the necessity to comply with regulations
[7,8]. and standards to prepare medicinal product of suitable
The Resolution requires the draft of a “product dossier” quality and safety.
for stock preparations by the pharmacist–compounder. Moreover, in a more harmonized European context, it is
For extemporaneous preparations, it is not possible to the time for a modernization of the regulation of medic-
compile a complete product dossier, because it could lead inal products prepared in pharmacy, even if it must be
to a delay in the supply of necessary medicines, but a recognized that they have a traditional history linked to
batch record must be created. Also the US Pharmacopoeia the national territory. Although compounded products are
affirms that a Master Formulation Record should be cre- not likely to be in international commerce, it is no longer
ated before compounding a preparation for the first time. acceptable to have different quality standards among Euro-
This document helps the compounder to characterize crit- pean countries, because the safety of patients must be
ical processes and establish the risk associated with the considered as a common good and, therefore, cannot exist
preparation. In addition, a Compounding Record should be differences among European patients. Organizations such
completed each time a preparation is compounded. as International Conference on Harmonization (ICH) and
A pharmaceutical preparation is considered safe also if PIC should be further involved to improve regulatory har-
it is correctly labelled. The label should contain complete monization.
information, such as reference of the dispensing phar- Therefore, an improved quality in medicinal prod-
macy, reference of the preparing pharmacy (if it is not ucts prepared in pharmacy can be achieved, or at least
the same), full qualitative composition and the quantity approached, from several fronts: the legislation on medici-
of the active substance, expiring date, special storage con- nal products prepared in pharmacies has to be modernized
ditions or handling precautions, route of administration. and adapted to the needs of the present days, a new reg-
Even if the leaflet containing product-specific information ulation for the pharmacovigilance should be introduced;
to patients, is not required for pharmacy preparations, gen- the technical regulation, i.e. the European Pharmacopoeia
eral information to patients concerning the therapy and the and the national pharmacopoeias for European countries,
use should be given and this is recommended by the Reso- has to provide specific Good Compounding Practice to be
lution. A complete label is synonymous with transparency followed during the compounding activity and specify the
and safety. importance of the risk assessment and the added value of
The Resolution proposes an appropriate system for each preparation.
reporting quality and safety issues to the competent
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