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European Journal of Hospital Pharmacy: Science and Practice

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Eur J Hosp Pharm 2012; 19:469-473 doi:10.1136/ejhpharm-2012-000194

Cover story

GMP and preparation in hospital pharmacies

Yvonne Bouwman 1, Lilli Mller Andersen 2
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Author Af f iliations

Correspondence toY v onne Bouwman, Laboratory Dutch Pharmacists, KNMP, Alexanderstraat 11, Den Haag 2514 JL, The Netherlands; y .bouwman@knmp.nl Received 24 August 2012 Accepted 28 August 2012 Published Online First 2 October 2012

Abstract
The suitability of good manuf acturing practice (GMP) f or the quality assurance of the preparation in hospital pharmacies is inv estigated. It is expected that the recent expansion of GMP with quality by design (QbD) and quality risk management (QRM) will signif icantly improv e the applicability f or all ty pes of preparation in hospital pharmacies. QbD and QRM acknowledge the importance of targeting the need of the patient, of a good design and of risk assessment, thereby of f ering more f lexibility to the hospital pharmacist to respond to ev ery day requests f or patient care. For European hospital pharmacy an elaboration of GMP principles f or specif ic preparation processes is desirable. The dev elopment of models f or risk assessment will also be v ery helpf ul. The usef ulness of the Council of Europe Resolution f or these aims is discussed. This article aims to prov ide a small contribution towards a transparent, predictable though f lexible and cost-ef f ectiv e pharmacy preparation.

Introduction
In January 2011 the Resolution on quality and saf ety assurance requirements f or medicinal products prepared in pharmacies f or the special needs of patients (Council of Europe (CoE) Resolution) was adopted by the Committee of Ministers of the CoE. In the introduction it is emphasised that patient saf ety and the achiev ement of the therapeutic aim require that medicinal products prepared in pharmacies meet appropriate and specif ic criteria f or quality , saf ety and added v alue. 1 Basically this Resolution is an approach to enf orce a standardised quality sy stem f or preparation in pharmacies. The initiativ e has been expected but when av ailable the possible consequences of enf orcement hav e giv en some hospital pharmacists reason f or doubts and concerns. These seem mainly related to a f oreseen loss of f lexibility to prepare indiv idual highly needed medications and a concern about the extra cost, time, personnel, knowledge and skills needed to apply the requirements. The primary task f or the hospital pharmacist is to take care of patients and if patients really need medications any quality concerns hav e to be considered against this need. In light of this we take a closer look at the general implications of good manuf acturing practice (GMP) in relation to preparations in hospital pharmacies.

GMP in general and its origin

GMP as a paradigm stands f or incorporating documented quality into products by enf orcement of GMPs contrary to ensuring quality by simply assay ing the f inal product. The modern history of GMP started in the 1960s and laws and guidelines hav e subsequently been expanded as a consequence of new experiences and acknowledged quality problems. In Europe, GMP requirements are primarily described in EudraLex Vol 4 (EU GMP), 2 the European Pharmacopoeia and in national requirements. In EU GMP each chapter starts with a f ormulation of a principle that is important f or building in quality ; see examples in table 1.
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Table 1
Examples of EU good manuf acturing practice (GMP) principles

The principle of each chapter is elaborated in sev eral guidelines, some of them rather general, some of them detailed and directed at the production env ironment in the pharmaceutical industry . Table 2 shows a f ew examples.
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Table 2
Examples of GMP guidelines

Hospitals are mentioned in the introduction to EU GMP: The principles of GMP and the detailed guidelines are also relev ant f or pharmaceutical manuf acturing processes, such as that undertaken in hospitals. In the Netherlands this statement triggered the dev elopment of GMP guidelines f or hospital pharmacy preparation. In Denmark the authorities basically expect hospital pharmacies to be f ully compliant with GMP. A surv ey among European countries 3 shows a wide range of quality assurance and standards. Theref ore the authorities of dif f erent European countries appear to enf orce GMP requirements to dif f erent extents, f rom inspections on a regular basis similar to pharmaceutical industries to no inspections at all.

Changes in GMP
In recent y ears f undamental changes in the GMP paradigm hav e taken place in the regime of the International Conf erence on Harmonisation of Technical Requirements f or Registration of Pharmaceuticals f or Human Use (ICH) guidelines. These changes ref er to pharmaceutical dev elopment/quality by design (QbD) 4 and quality risk management (QRM). 5 Principles f rom these guidelines are integrated in a rev ised EU GMP chapter 16 and will certainly be integrated into other chapters as well. QbD is about quality built into the design of the product, the f ormulation and the design of the preparation. QbD starts when the need f or a therapeutic product emerges, f or example, due to a particular clinical problem (target product quality prof ile) and thereby stresses the importance of meeting patient requirements. A control strategy needs to be def ined and in-process controls planned correspondingly in connection with the design of the preparation. The manuf acturing and subsequent use of a medicinal product will alway s entail some risk of harm to the patient. With the new paradigm the authorities acknowledge this risk; consider the v ery def inition of harm: Harmdamage to health, including the damage that can occur f rom loss of product quality or availability . 5 QRM prov ides a f ramework to manage and document this risk. QRM has to be based on scientif ic knowledge and should ultimately link to the protection of the patient. The lev el of ef f ort, f ormality and documentation of the QRM process should be commensurate with the lev el of risk. The authorities acknowledge the risk of loss of product quality as well as the risk of loss of av ailability of the product. It would be interesting to know whether lack of av ailability f or economical reasons in the pharmaceutical industry is also included in this def inition. If so, it may pressure a pharmaceutical company not to cease production if there is no alternativ e f or the patient. If not, it might emphasise the prof essional task of the hospital pharmacist to prepare a necessary medicine, ev en if the quality sy stem may not be targeted f or preparation of this product. More about this is cov ered in the section Meaningf ul risk assessments.

GMP in relation to preparation in hospital pharmacies

From the current GMP regulations, especially requirements related to documentation, training, qualif ication of f acilities and equipment, and prev ention of contamination are of importance f or pharmacy preparations. The requirements related to training of people and prev ention of contamination are inev itable. Furthermore, preparation has to f ollow standard procedures and critical aspects should be well documented as it enables reconstruction of what happened if quality def ects or ev en adv erse ev ents are reported. Qualif ication of critical equipment like balances and autoclav es is also important in a pharmacy to ensure continuous control. Some of the GMP principles hav e to be enf orced dif f erently when processes ty pical f or pharmacy preparation are apparently not f oreseen in EU GMP. Examples of these processes are giv en in box 1.

B ox 1 Preparation processes typical f or hospital pharmacies Preparation of small batches, of capsules and suppositories

Manipulating or adapting authorised medicines, like conv erting tablets into mixtures f or children Aseptic handling at reconstitution or diluting injections f or inf usion Release of a prepared medicine immediately af ter preparation Unique preparation f or an indiv idual patient

The basic principles of GMP inclusiv e of the new initiativ esQbD and QRMare well known by preparation pharmacists as assay s of the numerous preparations and small batches are too expensiv e and of ten technically not f easible. For extemporaneous preparations an assay is not possible within acceptable timef rames. Consequently , the pharmacists hav e to base their prof essional responsibility on knowledge, appropriate designs, experience, in-process controls, the application and v alidation of model preparation processes and QRM. In addition, the pharmacist has alway s balanced the medical need of the patient with the risks f rom an unv alidated or ev en a consciously suboptimal design or preparation process. This brings us to the conclusion that GMP seems to be applicable to pharmacy preparation on the condition that QbD and QRM are included. Howev er, this leads to the challenge of elaborating principles into guidelines f or specif ic pharmacy processes and to meaningf ul risk assessments. Activ ities should be directed at a signif icant improv ement in quality assurance. Improv ements hav e to be implemented in a f ormalised way , taking into account that changes may be necessary in premises and equipment bef ore f ull compliance is achiev ed. Consequently the necessary GMP improv ements will v ery of ten be a y earlong process (light green line in f igure 1). The usual limited resources in healthcare (blue line) will on the one hand slow down this implementation; on the other hand, they will hopef ully prev ent going bey ond the optimal quality f or the patient (dark green line) by irrelev ant (orange line) or ev en destructiv e activ ities (red line). Healthcare quality experts regard this as a too common phenomenon. 7

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Figure 1

The relation between quality improv ement in healthcare and increasing requirements and audits (adapted with permission f rom Peters 7).

Specific guidelines for pharmacy preparation processes

Alongside the general GMP requirements regarding an appropriate quality assurance sy stem and reporting of quality and saf ety issues, the CoE Resolution giv es specif ic requirements f or pharmacies. Examples include: requirements f or reconstitution of medical products; products dossier f or stock preparations; bef ore preparation the pharmacist should v erif y whether a pharmaceutical equiv alent is av ailable on the national market, taking into consideration the pharmaceutical f orm and the strength; if not, av ailability as a EU-licensed medicine should be inv estigated; the prof essionals inv olv ed in patient care should jointly assume responsibility f or determining whether a pharmacy preparation could be of added v alue. The requirements are v ery high lev el or v ery detailed. As an example, the risk-based decision matrix f or the preparation process is v ery detailed compared with general QRM principles, whereas demands f or documentation are only mentioned indirectly . Some of the requirements hav e to be specif ied nationally according to national requirements, f or example, section 7 regarding labelling. We recommend the topics of the Resolution and the ty pical processes mentioned in box 1 as a sort of working list to the EAHP working group on guidelines that has been started recently .

Meaningful risk assessments

How do we balance the need of the patient against a potential risk connected with the pharmacy preparation? The CoE Resolution say s: For extemporaneous preparations, howev er, the pharmacist and the prescriber should alway s consider the risks f or the patient, which include the risks posed by a medicinal product without documentation specif y ing the added v alue of the pharmacy preparation and the quality assurance sy stem applied to its production v ersus the risks related to the unav ailability of this medicinal product. The draf t European Pharmacopoeia monograph Pharmaceutical preparations 8 states: In dev eloping an unlicensed pharmaceutical preparation, an appropriate risk assessment is undertaken, which includes consideration of the suitability and f itness f or purpose of the pharmaceutical preparation. The risk assessment also considers the contribution of the excipients and containers to the saf ety prof ile of the unlicensed pharmaceutical preparation. We think it is right that this monograph specif ies that all unlicensed medicines require a risk assessment instead of just the extemporaneous pharmacy preparations. Howev er, using the QRM principle The lev el of ef f ort, f ormality and documentation of the QRM process should be commensurate with the lev el of risk will generally lead to more quality inv estments in stock preparation compared with extemporaneous preparations due to the higher number of patients that will be exposed . The Resolution does not prov ide a tool, a f ramework or a checklist f or this ty pe of risk assessment that is ty pical f or an ev ery day situation in hospital pharmacy . Theref ore we prov ide here some more materials, apply ing general QRM principles. First is the chapter Risk management in the textbook by Jackson and Lowey . 9 It describes practical way s to av oid preparation, specif ic extemporaneous preparation errors, therapeutic risks, and so on. The risk management puts quality risks, saf ety /ef f icacy risks and health and saf ety risks into a matrix to get a risk rating. The second tool is a f orm that is in use in the Netherlands f or assessing a request f or a non-standardised preparation (f igure 2). A similar f orm is used f or stock preparation, just replacing indiv idual patient characteristics by a description of an indication or care situation.

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Figure 2
Form f or the risk assessment of a request f or an indiv idual non-standardised preparation.

Some of the rationales behind this f orm are as f ollows. The risk of unav ailability can also be def ined as the assumed added therapeutic v alue f or the patient. This added v alue will be documented in some way or another, as is common practice in at least some countries. To be more specif ic about the assumed added v alue one can discern: unique therapeutic v alue as there is no comparable authorised medicine av ailable; improv ed patient f riendliness and with this better compliance to therapy ; improv ed saf ety of healthcare processes; improv ed health and saf ety of healthcare personnel. Sev eral medical products are only av ailable as a pharmacy preparation. The number certainly dif f ers among European countries as it is inf luenced by the expected f inancial benef it f or the pharmaceutical industry of the country and by traditions. Properties of the preparation that might improv e patient f riendliness are, f or example, indiv idually targeted strength, dif f erent dosage f requency , easier to swallow dosage f orm, better taste and/or handier packaging. The saf ety of the healthcare process will improv e if one diminishes opportunities that a nurse, caretaker or patient makes an error during the process of reconstitution and administration of a medicine or causes microbial contamination. Health and saf ety risk of care personnel will be reduced if the preparation is done by pharmacists and technicians trained f or the purpose and with premises and equipment designed to protect the staf f against chemicals, just as in pharmacies. To be more specif ic about the risks f or the patient one can discern: uncertainty about therapeutic saf ety and ef f icacy ; design f ailure causing, f or example, poor bioav ailability or poor content unif ormity ; preparation risk: the actual pharmaceutical quality sy stem cannot guarantee that the preparation will f ully meet relev ant specif ications. Specif y ing the v arious risks is a prerequisite f or a transparent risk assessment and transparent design of product and processes. Pharmacists are prof essionally trained to weigh these dif f erent risks (f igure 3) and they are experienced in f ulf illing this task. Documentation of the process and the risk balance is necessary f or transparency and clarif ies which prof essional is allowed to decide whether to prepare the product. In addition, documentation makes knowledge sharing, targeted training and continuous improv ements possible.

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Figure 3
Balancing added v alue with therapeutic and pharmaceutical risks.

Conclusion
Establishment of common quality requirements f or pharmacy preparation in all EU countries seems to be f easible using principles of current GMP, including the new paradigms introduced with QbD and QRM. For products prepared f or stock, GMP should be implemented to a f urther extent than f or extemporaneous preparations. In addition, GMP principles hav e to be elaborated f or specif ic pharmacy preparation processes and situations. Risk assessments, using the principles of QRM, should be dev eloped f or assessing requests f or extemporaneous preparations and f or stock preparations. The CoE Resolution was prepared simultaneously with the new EU GMP initiativ es and with the draf t monograph of the European Pharmacopoeia Pharmaceutical preparations. Consequently , these documents are not f ully integrated. Bey ond this, the principles in QbD and QRM are not used in the Resolution and the detailed requirements still need some elaboration to take into consideration national and cultural dif f erences.

An EAHP working group will start the elaboration of the Resolution on a European lev el. Hopef ully this will result in a common prof essional EU f ramework f or GMP/QbD/QRM in hospital pharmacies. Such a common, targeted approach should prov ide a backbone f or detailed national requirements and prov ide a tool to deal with the v ery dif f erent situations regarding healthcare f inances. For hospitals such a way of implementing GMP will require huge ef f orts but the long-term gain is predictability in quality , cost ef f ectiv eness and transparency of hospital-based preparations. Key messages GMP principles including the new paradigms QbD and QRM can be utilised f or pharmacy preparation quality sy stems. The importance of the design of the preparation and the preparation process, as well as the risk of unav ailability hav e to be included in risk assessment models that should be part of the quality sy stem.

Footnotes
Competing interests None. Provenance and peer review Commissioned; internally peer rev iewed.

References
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