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Improving policies and practices for the extemporaneous compounding of oral liquid dosage forms in Saudi Arabian hospitals
  1. Imraan Joosub1,
  2. Zohair Emara1,
  3. Andy Gray2
  1. 1 Department of Pharmacy, Saudi Arabia Ministry of National Guard, Al-Madina, Madina Province, Saudi Arabia
  2. 2 Division of Pharmacology, Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa
  1. Correspondence to Mr Imraan Joosub, Pharmacy, Saudi Arabia Ministry of National Guard, Al-Madina, Madina Province 41511, Saudi Arabia; joosubi{at}ngha.med.sa

Abstract

Background Pharmacists rely heavily on available reference material to guide the extemporaneous compounding of medicines. Extemporaneous compounding for individual patients has traditionally not been closely regulated, but is necessary in every setting.

Objective To assess the adequacy of the evidence and recommend changes for the master formulae (MFs) used in the extemporaneous compounding manual at five Ministry of National Guard Health Affairs (MNGHA) tertiary care institutions in Saudi Arabia.

Method A descriptive cross-sectional study of all extemporaneous oral liquid dosage forms (n=75) was conducted. Investigators sought to establish if the current list of compounded oral liquid dosage forms were registered commercially, backed by a stability study or followed the Saudi Arabia Food and Drug Administration guidance on assigning beyond-use dates. A literature review of stability studies, tertiary references and package inserts was used to verify the MFs. Findings of each MF were tabulated and compared with available stability studies.

Results It was found that 28 (37.3%) oral liquid dosage forms were registered by a regulatory authority, 8 (10.7%) MFs could not be traced to a stability study, while 3 (4%) MFs used beyond-use dates. The taskforce approved 15 (20%) MFs without changes, while 42 (56%) MFs had to be revised.

Conclusion This review found that, although resources on the compounding of oral liquid dosage forms exist, pharmacies need to carefully assess their quality and relevance and update local policies and practices. The majority (80%) of the current MFs used in MNGHA institutions were rejected due to inappropriate compounding practices and inaccuracies.

  • compounding (individualised preparation)
  • drug formulation
  • good manufacturing practice (gmp)
  • drug stability
  • manufacturing, small scale
  • pharmaceutical excipients
  • validation preparation process
  • drug formulary management
  • shelf life
  • storage conditions
  • quality assurance
  • stability and incompatibility

Data availability statement

Data are available upon reasonable request.

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Introduction

In all settings, pharmacists often face the situation where a registered oral liquid dosage form is unavailable. While this may occur with adult patients, the situation is more commonly confronted in paediatric patients, especially where ‘child-friendly’ oro-dispersible or divisible oral solid dosage forms are not available. Pharmacists often resort to extemporaneous compounding of an oral liquid dosage form, sometimes using the available marketed oral solid dosage form as the starting material and source of the active pharmaceutical ingredient. Such products may, however, lack supportive evidence of their stability, bioavailability, tolerability and efficacy.1 2

Extemporaneous compounding can be considered to be an integral part of the practice of the pharmacy profession, and to rely on the established professional acumen—‘secundum artem’—of its practitioners. However, there are also valid concerns when large-scale compounding is used as a way to avoid obtaining marketing authorisation.3 While there are well-described standards to guide sterile product compounding at the hospital level, such as those issued by the United States Pharmacopoeia (USP),4 the evidence to guide the compounding of oral liquid dosage forms is far more scanty.5 In the Kingdom of Saudi Arabia, the Food and Drug Administration (SFDA) has produced comparable guidelines which also cover small-scale, non-sterile, extemporaneous compounding.6

The reluctance to advocate for widespread reliance on compounding is clearly evident in the FIP-WHO technical guidelines which were published in 2016 as an appendix to the report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations.7 The report stated: ‘The risks and benefits of compounding and of the alternatives should be fully understood by practitioners. Practitioners who do not have appropriate knowledge should seek advice. Compared with the use of authorised medicines there are significant risks associated with compounding; quality, safety and efficacy can rarely all be assured, and many errors have been reported in the preparation of such medicines.’ Nonetheless, the guidance noted that ‘In some situations compounding of a medicine for a child may be the only option, which may be supported by evidence of quality and occasionally evidence of bioavailability by industry or other parties, such as academia’.

Pharmacists working in the hospitals operated by the Saudi Arabian Ministry of National Guard Health Affairs (MNGHA) rely on the master formulae (MFs) listed in the extemporaneous compounding manual (ECM) of the MNGHA formulary. The products compounded in accordance with these formulae are prepared on a per-patient basis. Pharmacy technicians who have completed the MNGHA training and competency evaluation compound, package and label products prepared in the extemporaneous compounding room under the supervision of pharmacists.

The aim of this study was to assess the adequacy of the evidence for the MFs currently relied on and to recommend changes that would improve the quality and safety of extemporaneously compounded oral liquid dosage forms in MNGHA hospitals.

Methods

For each of the 75 MFs on the current ECM of the MNGHA formulary, a search of the peer-reviewed literature was conducted in Medline (accessed via PubMed), Google Scholar and United States Food and Drug Administration-approved package inserts. The search terms included ‘stability studies’ and ‘extemporaneous formulations’ and the searches were conducted up to February 2018. Although no language limits were set, only studies published in English or where an English translation was provided could be included. In addition, standard textbooks and reference sources were consulted.8–12 Abstracts were reviewed for their relevance and full-text articles were sought. In the absence of full-text articles, abstracts were considered if they were clear or supported by the tertiary references mentioned above.

Current utilisation of the 75 selected MFs was checked by requesting the MFs in use at five tertiary care hospitals operated by the MNGHA facilities. All data were reviewed by two pharmacists.

The retrieved literature was used to assess which MFs were supported by at least one stability study showing retention of more than 90% of the initial drug concentration before the expiry date assigned when compounding the preparation. In local documentation, the expiry date is referred to as the beyond-use date (BUD). Where no stability data were available, the application of the current SFDA guidance for the assignment of BUDs was checked.6 The guidelines state that, for aqueous oral formulations, the BUD should not be more than 14 days from the date of compounding provided storage is under controlled temperature conditions. For non-aqueous preparations compounded from a commercial solid dosage form, the BUD should not be more than 25% of the time remaining before expiry of the commercial product or 6 months, whichever is earlier. When a USP or National Formulary (NF) pure chemical is used as the active pharmaceutical ingredient (API), the BUD may not be later than the expiry date on the API or 6 months, whichever is earlier.

Results

At least one stability study could be found for 67 (89.3%) of the 75 MFs in the ECM of the MNGHA formulary. For the remainder, BUDs were assigned in compliance with the SFDA guidelines in 3/8 cases (37.5%). However, a commercially available product was identified in relation to 28/75 MFs (37.3%). Of these 28 MFs, 5 had oral liquid dosage forms registered by the SFDA, 21 by the US Food and Drug Administration and 7 by the European Medicines Agency. For example, a commercially available doxycycline 10 mg/mL syrup is registered by the SFDA. It was therefore concluded that doxycycline syrup would no longer be compounded within MNGHA hospitals and the commercially available form would be procured instead.

A total of 161 relevant publications were retrieved from the literature, and 128 stability studies were reported in 105 publications. However, in each case the applicability of the data retrieved to local practice varied. An example is shown in table 1, which depicts the available stability evidence for extemporaneous amiodarone suspension and the reviewer’s judgement of the applicability of that evidence. Common problems identified included stability data showing a shelf life that would not be practical for ambulatory care or non-availability of the excipients included in the formula. In this case, the standard tertiary resource relied on locally12 referred to a study that was retrieved.13

Table 1

Evaluation of stability data for amiodarone suspension

On the basis of the review conducted, the authors recommended that only 15 of the 75 MFs (20.0%) were acceptable without revision. After corrections, an additional 42 MFs were approved. However, 18 MFs (24.0%) were not recommended for use, even after correction. Only three (4.0%) of the original 75 MFs were approved on the basis of assigned BUDs rather than stability data. In some cases, the existing MFs cited a stability study but, on checking the data recorded, did not match the original source.

The types of changes to the MFs made during the review are shown in table 2. Although some calculation inaccuracies were detected as well as instances where the concentrations did not match the original study, the most common problem identified was where the ingredients (notably excipients) did not match the original study. Other common changes related to stability and storage recommendations. Twenty of the MFs were deleted from the ECM.

Table 2

Changes made to the extemporaneous compounded oral liquid dosage forms

Practical steps should be taken by each hospital pharmacy in order to improve safety and quality. First, all hospital pharmacies should maintain their hospital policies and practices in compliance with the current SFDA guidance.6 Although pharmacists have formal training in compounding extemporaneous preparations, a hospital-specific training programme should be established.14 The steps involved in compounding should be documented as recommended by SFDA6 and USP <795>0.4 The pharmacy should maintain the MF as approved by the local Pharmacy and Therapeutics Committee well as a compounding record. The final product should contain a pharmacy lot number to help identify the compounded preparation. The pharmacist must review each step of the procedure, thus ensuring safety and quality.15 However, where registered oral liquid dosage forms are commercially available, they should not be compounded in the pharmacy.

Discussion

In the absence of registered commercially available medicines, pharmacists need to compound medicines for patients with specific needs, most commonly for paediatric patients. Hospital pharmacists should ensure that the appropriate materials, facilities, training and quality assurance practices are in place when engaging in extemporaneous compounding. The non-availability of excipients can make that difficult. For example, extemporaneously-compounded levothyroxine oral suspension has shown significant degradation on storage.16 17 Although a formula which demonstrated a stability of 47 days at room temperature had been published,18 the required excipients were not available on the MNGHA hospital formulary. In such cases there is alternative advice available: the European Society for Paediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and Management of Congenital Hypothyroidism recommends that, in neonates and infants, the tablets could be crushed and administered as a suspension, with water or breast milk, prepared at the time of dosing.19

If a commercially available product is not available or a stability study cannot be found, assignment of BUDs for compounded preparations can be considered based on existing SFDA guidance.6 However, careful attention needs to be paid to the methods employed in any stability studies relied on. For example, a retrieved stability study suggested that folic acid was stable in syrup simplex at 25°C and 4°C for a period of 60 days.20 As appropriate high-performance liquid chromatography methods were not used in this study, and another study showed a loss of more than 90% in folic acid concentrations within 30 days in aqueous solutions,21 it was decided not to rely on BUD assignment, but to procure a commercial product instead. A further consideration was that adjustment of the pH of the solution required the use of sodium hydroxide, which carries a potential risk through inhalation or contact and requires access to safety apparatus such as a fume hood. Such equipment is not available in all MNGHA pharmacies.

The study also identified the risk of reliance on outdated sources. The most recent editions of standard texts, such as ‘Trissels’ Stability of Compounded Formulations’s8 and 'Extemporaneous Formulations for Paediatric, Geriatric, and Special Needs Patients'9 are suitable sources of updated stability data.

A similar study in the USA found that 78% of 175 compounded formulations used in a tertiary hospital setting needed revision.22 The most common changes related to storage conditions (44%) and extension of BUDs (24%). However, this study also highlighted a factor not considered in our study—namely, the removal of strawberry syrup as a component of 22% of the formulations in order to reduce exposure to red dye.

Our study has several limitations. Two of the tertiary sources used locally11 12 did not use a standardised citation format, which made it difficult to trace the original studies. Not all references could be retrieved in full text. However, where discrepancies were found between the abstract and a tertiary reference, the data were not considered reliable.

Conclusion

This study found that 80% of the 75 MFs currently used in MNGHA hospitals to guide the extemporaneous compounding of oral liquid dosage forms could not be relied on without correction. After correction, 18 MFs (24%) were still not considered acceptable and were not recommended for use. Stability data could be found for most recommended MFs, with only three (4.0%) recommended on the basis of assigned BUDs. A locally registered commercial product was identified for five products being compounded, but another 23 products were available on other markets (21 in the USA and seven in Europe). Where registered commercially available medicines are accessible, these should not be compounded in the pharmacy. Ongoing maintenance of the extemporaneous compounding manual will be needed, with oversight from the Pharmacy and Therapeutics Committee. As an editorial in EJHP pointed out: “Formulation has always been an important skill for pharmacists since the early days of apothecaries”.23 That editorial accompanied a collection of articles on formulations and compatibilities, described by Wiffen as “a rich resource for pharmacists”. As more literature addresses the need for evidence-based formulations suitable for compounding in hospital pharmacies, so hospital pharmacists will need to stay abreast of that evidence and ensure that their policies and practices meet the necessary standards.

Key messages

What is already known on this subject

  • Hospital pharmacists need to compound oral liquid dosage forms where suitable commercial preparations are not available.

  • The master formulae used to guide compounding at the hospital level should be backed by good quality evidence, preferably at least one stability study showing retention of more than 90% of the initial drug concentration, before assigning beyond-use dates.

  • In the absence of relevant stability studies, beyond-use dates should be used judiciously, especially where chemical degradation or interactions may occur.

What this study adds

  • The majority of master formulae relied on in the study setting required revision.

  • Although there are a number of resources to guide compounding of oral liquid dosage forms, the evidence base is weak. Nonetheless, the quality of compounded preparations can be improved by a well-designed periodic review of the available literature and the updating of master formulae.

  • Where registered oral liquid dosage forms are commercially available, such preparations should not be extemporaneously compounded. This study provides practical guidance to hospital pharmacists when developing an extemporaneous compounding manual.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Ethics approval

Ethical approval for the study was received from the institutional review board at King Abdullah International Medical Research Centre (RM17/002/M).

References

Footnotes

  • EAHP Statement 3: Production and Compounding.

  • Contributors The investigators would like to thank the MNGHA task force for providing some of the contextual material.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.