DESIGN AND VALIDATION OF A

RISK MATRIX FOR THE

ASSESSMENT OF STERILE
COMPOUNDED PREPARATIONS

Ana Mª Martín de Rosales

Carmen López Cabezas
Ana Lozano Blázquez
Hospital de
Cabueñes. Asturias
 SPANISH GROUP OF PHARMACEUTICAL
COMPOUNDING

• Promote the consensus of compounding and preparation

practices in Hospital Pharmacies, in order to ensure the
best quality, efficacy and safety for the patient.
• Provide useful tools for the daily practice of compounding.
• Organize Educational and training programmes for
pharmacist and technicians.
• Develop research projects in compounding.
• Interdisciplinary connections with scientific groups
related with compounding and preparation.
 QRM & QbD

Sterile preparations in Hospital Pharmacies

should be performed according to an
appropriate Quality System in which Quality
by design and Quality Risk Management
should be considered.
 RISK RELATED TO STERILE
PREPARATIONS
- Injectable drugs more frequently related
to medication errors
- Greater damage potential in patients
- Contamination risk during manipulation

- Centralized compounding in
Pharmacy service
- Ready to use
 STERILE PREPARATIONS

Mostly prepared by nurses in

medical wards

> 500 injectable products

Hospital Pharmacy Compounding

Units:: Limited production capacity
Units
to prepare all sterile products
required

NEED OF A SELECTION OF STERILE

PREPARATIONS COMPOUNDED IN
PHARMACY
 STERILE PREPARATIONS IN HOSPITAL
PHARMACY

Aseptic Handling of medicines: Reconstitution and

Dilution.

Preparation of small batches of sterile preparations:

ready to use siringes, infusión bags.

Sterile Mixtures.

Unique preparation for an individual patient.

Sterile compounding or formulation.
 Resolution CM/
CM/ResAP
ResAP (2011)1

“Before preparation, a risk assessment

should always be carried out in order to
define the level of the quality assurance
system which should be applied to the
preparation of the medicinal product.”

RISK ASSESMENT
 Resolution CM/
CM/ResAP
ResAP (2011)1

Risk assessment should consider:

a. dosage form and administration route;
b. amount prepared;
c. pharmacological effect of the medicinal product for the
envisaged route of administration;
d. therapeutical window (dose range for therapeutic doses);
e. type of preparation process;
f. supply.
 Resolution CM/
CM/ResAP
ResAP (2011)1

Numeric Risk assessment

Values 1-5 for each item; result after multiply:

if <100: low risk (=> PIC/S GPP Guide);
if >100: high risk (=> GMP Guide)

other decision models would be

possible according to national
legislation or guidance.
 GUIA DE BUENAS
PRÁCTICAS DE
PREPARACION DE
MEDICAMENTOS EN
SERVICIOS DE FARMACIA
HOSPITALARIA

1. LITERATURE REVIEW
2. IDENTIFICATION OF RISKS: FMEA
Numeric scoring had
several problems of
concordance.

ALPHABETICAL CLASSIFICATION

1. The preparation process.

2. The route of administration of the preparation.
3. The safety profile of the active ingredient.
4. The amount of units prepared.
5. The distribution of the preparation.
6. The microbiological contamination susceptibility.

3. SEVERITY OF THE RISK DETECTED

 Preparation process
1. Combinations of 4 or more different medications.
2. Preparations requiring 4 or more punctures in the final container or which
require the reconstitution and/or extraction of 4 or more ampoules/vials to
obtain the necessary dose to include in final container
3. Preparations which require complex calculations1 in 2 or more steps to
determine the dose for the patient and/or amount to prepare C
4. Processes in which foam is formed, or entail a risk of physico-chemical instability
(light, O2), precipitation, turbidity, pH-dependent degradation, colorations, phase
separation, during the preparation process.
5. Difficult reconstitution-dilution lasting over 10-20 minutes2 (i.e.: non-pegylated
liposomal doxorubicin, paclitaxel-albumin, Palivizumab, etc.).
1. Combinations of 3 different medications.
2. Preparations requiring 3 punctures in final container or which require
reconstitution and/or extraction
of 3 ampoules/vials to obtain necessary dose to include in final container
B
1. Preparations which require simple calculations3 in one single step to ascertain
the dose for the patient and/or the amount to be prepared
1. Combinations of 2 different medications
2. Preparations only requiring 1 or 2 punctures in the final container or which
require the reconstitution and/or extraction of 1 or 2 ampoules/vials to obtain the
necessary dose to include in the final container.
3. Products not requiring calculations for preparation. A
4. Reconstitution and dilution of vials in solution, concentrates and freeze-dried
powders for total use or fractions of simple doses4 on the basis of injectable
solutions of a known concentration
5. Simple unitary reconstitution-dilution lasting less than 5 minutes2.

3. SEVERITY OF THE RISK DETECTED

 Route of administration
1. Intrathecal. D

1. Intraocular (intravitreous, intracameral), central venous line (in techniques

C
requiring a sterile field), epidural/peridural.

1. Central venous line, peripheral intravenous, intramuscular, subcutaneous,

intradermal, intrapleural, intralesional, intraperitoneal, intra-articular, inhaled, B
nebulised.
1. Ophthalmic topical, otic topical, intravesical, oral, rectal, topical. A
Safety profile of the active ingredient
1. Vesicant substances, irritant substances, corrosive substances, with
C
mutagenic potential, carcinogenic properties or infectious properties5.
1. Narrow therapeutical window and/or need for monitoring
2. Considered to be high risk in the event of error6.
B
3. Opiates, sedatives and psychotropic substances
4. Clinical trial medications
1. Rest of medication with low toxicity profile A
Amount of units prepared
1. More than 25 units/batch C
1. Between 3 and 25 units/batch B
1. 1 or 2 units A

3. SEVERITY OF THE RISK DETECTED

 Susceptibility to microbiological contamination7
1. Transfer of products via open systems8.
2. Preparation using non-sterile products, containers or non-sterile transfer systems D
requiring terminal sterilisation at the end of the preparation.
1. Substances which are highly susceptible to microbiological contamination which are
administered via iv infusion in 8h or more.
C
2. Eyedrop preparation without preservatives in sterile containers via the dropper tip (not
considered open) to be used in multi-dose form.
1. Preparations of substances with low contamination risk which are administered over 24
hours (patient-controlled pumps, elastomeric infusion devices).
2. Substances with low risk of microbial contamination where the time lapsed from
B
preparation to start administration is >12 hours.
3. Preparation of eyedrops with preservatives in sterile containers via the dropper tip
(not considered to be an open transfer system) to be used in multi-dose form.
1. Simple transfer of medication in closed systems
2. Preparations with low risk of contamination for immediate administration. A
3. Preparations whose administration duration is equal or under 24 hours.
Distribution of the preparation
1. Exclusive use for other hospitals. C
1. Combined use (for the hospital that prepares it and for other hospitals). B
1. Exclusive use by hospital that prepares it. A

3. SEVERITY OF THE RISK DETECTED

 1 2 3 4 5 6

Risk level
If the set of letters contains at least a D, the preparation is considered to be
a high risk preparation.
If the set of letters contains at least one C or three or more B (and no D), it
is considered to be an intermediate risk preparation.
If the set of letters contains fewer than three B (and no C or D) it is
considered to be a low risk preparation.

12 Epidural
Solutions of
Intermediate risk
Fentanyl and CCBBAA
preparation
Bupivacaine in
Saline 120 ml.

Only Low-risk preparation can be done on the wards.
Reconstitution always following Summary of Product
Characteristics.

Medium and High risk preparations should be
centralised in hospital pharmacy clean areas.

Reconstitution and preparation regulations in
Europe are not harmonised. Some countries follow
GMP for reconstitution at hospital pharmacy.

RISK CLASSIFICATION IN DAILY PRACTICE


Any change of the preparation, for example, extended
shelf life to reconstituted products, or remnant
solutions in vials are considered a preparation and
should have specific rules.

CM /ResAP2011 an opportunity to define specific rules
based on real Hospital Pharmacy Practice
◦ “As reconstitution is not generally considered a process in the
frame of pharmacy preparations, national authorities should
develop, in co-operation with the relevant professional bodies,
specific legislation or guidance”

Adaptation from USP 797 the practical point of view.

RISK CLASSIFICATION IN DAILY PRACTICE


BEYOND USE DATE
◦ Drug’s chemical stability .
◦ Microbiological limits based on Risk Level.
 RISK LEVEL AND PREPARATION/ BEYOND USE DATE / CONSERVATION REQUIREMENTS
Risk level
If the set of letters contains at
least a D, the preparation is
considered to be a high risk
preparation.
If the set of letters contains at
least one C or three or more B
(and no D), it is considered to be
an intermediate risk
preparation.
If the set of letters contains fewer
than three B (and no C or D) it is
considered to be a low risk
cabinet located in no controlled
preparation.
Preparation requirements
Pharmacy service.
Preparation in laminar flow
cabinet in a controlled
environment (clean area)
Pharmacy service.
Preparation in laminar flow
cabinet in a controlled
environment (clean area)
Pharmacy service.
Preparation in laminar flow
cabinet in a controlled
environment (clean area)
Pharmacy service.
Preparation in laminar flow
environment
Nursing unit on ward, no
controlled environment
Beyond Use Date & Storage
requirements (1)
• 24 hours / room temperature
• 3 days / refrigerator (2 ˚C – 8
˚C)
• 45 days / freezer (≤ -20 ˚C)
• 90 days/ freeze-dried
• 30 hours / room temperature
• 9 days / refrigerator (2 ˚C – 8
˚C)
• 45 days in freezer (≤ -20 ˚C)
• 90 days freeze-dried
• 48 hours/ room temperature
• 14 days / refrigerator (2 ˚C –
8 ˚C)
• 45 days / freezer (≤ -20˚C)
• 90 days freeze-dried
• 12 hours / room temperature
• 24 hours / refrigerator (2 ˚C
– 8 ˚C)
• 7 days / freezer (≤ -20˚C)
• 1 hour / room temperature,
• 1 hour / refrigerator (2 ˚C – 8
˚C)
• Do not freeze
(1) Beyond-use date of preparations according to storage conditions. It is
assumed:

• That the physicochemical stability of the preparation is equal or above

the indicated beyond-use date. Otherwise, the beyond-use date must
coincide with the maximum period of physical-chemical stability of the
preparation.
• That there is no risk of physical-chemical instability of the preparation
when kept in the refrigerator/freezer or freeze-dried.

When longer beyond-use dates are allocated these must be evidence

based documented in a valid publication and the formulation must be
the same as that indicated in the bibliography.
In those cases where the Pharmacy department prepares high risk
sterile preparations in a number above that established (*) or allocates
beyond-use dates longer than those established without documentary
justification, a sterility test of the finished product must be carried out
on every batch produced.

(*) batches > 25 units of high risk medications: a microbiological

analysis must be performed. The control will be carried out once the
preparation has been finished, but before the batch is released.
 Risk Tª amb 2-8ºC -10-30ºC

12 Epidural Solutions of
Fentanyl and Bupivacaine in Medium 30h 9d
Saline 120 ml CCBBAA

Anfotericin B-liposomal Medium 30h 9d 45d

300 mg fon an individual BBAAAB
patient
20 Cefuroxime 1 mg/0,1ml Medium 30h 9d 45d
solution in prefilled syringes CCABBA

Voriconazole Bajo 48h 14d 45d

280 mg prepared in laminar
flow cabinet in a controlled ABBAAA
environment
Voriconazole 280 mg Bajo 1-2h 1-2h NO
prepared on the ward ABBAAA
Risk associated to patient
Difficult to know in advance

Special attention to:

• immunocompromised
patients
• Preterm infants
• Critical patients
Risk associated to personnel compounding
A responsibility to the institution/ Pharmacy S.
• Hygienic behaviour and
appropriate clothing should be
ensured
• Appropriate training must be
documented.
• Qualification of personnel
should be checked

• written procedures and

ensure that the staff involved
in reconstitution are
appropriately trained.
Validation process

Qualitative tool => needs to be validated

Checking validity and reliability

VALIDATION
Validation process

Validity: does it properly measure what
it's supposed to measure?
◦ Content validity:
 Expert assessment (4 senior specialists in
Pharmaceutical Compounding)
◦ Construct validity:
 All the criterion were based on current
international guidelines
Validation process

Reliability: degree of reproducibility

◦ Inter-rater reliability: 15 representative sterile
preparations evaluated by 10 pharmacists working in
Compounding area
◦ Test-retest reliability: 3 preparations evaluated in
three different times

Identification, discusion and correction of

discrepancies by adding a list of exceptions and
clarifications
Validation process

Reliability results:

Phase 1 Phase 2 Phase 3

Overall agreement (%) 83.9 86.8 96.4
Light’s kappa 0.23-0.95 0.31-0.86 0.68-1

Target: overall agreement > 95%; Kappa ≥ 0.6

Conclusion
Risk matrix

=> reproducible tool adapted to daily
practice

=> increase patient safety and allows a
better use of resources in sterile
preparations
Gracias!!