Vaccines Europe Position Paper on a proposal for a revision of
the Annex to the European Commission guideline on
Excipients in the labelling and package leaflet of medicinal
products for human use (SANTE-2017-11668)
30 October 2020
A D D R E S S
EFPIA / Vaccines Europe
TABLE OF CONTENTS
1. BACKGROUND AND OBJECTIVE .......................................................................... 3
2. VACCINES EUROPE ASSESSMENT ...................................................................... 5
2.1.
Para-aminobenzoic Acid (PABA) .................................................................. 5
2.2.
Phenylalanine ............................................................................................... 6
2.3.
Sodium and potassium ................................................................................. 6
2.4.
Ethanol ......................................................................................................... 7
3. DISCUSSION AND RECOMMENDATION ............................................................... 8
4. LITERATURE REFERENCES ................................................................................. 9
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1.
Background and objective
The requirements with regards to the information about excipients that should be included in
the label ing and package leaflet of medicinal products are described in the European
Commission (EC)
Excipients in the label ing and package leaflet of medicinal
products for human use SANTE-2017-11668) that was revised in March 2018. The list of
excipients which should be stated on the label and the information for those which must appear
on the package leaflet (PL) are presented in an annex to the guideline. In October 2017, the
European Medicines Agency (EMA) published an update of the annex to the EC guideline with
a corrigendum on 19 November 2018 (EMA/CHMP/302620/2017 corr 1) and a final revision
on 22 November 2019 (EMA/CHMP/302620/2017 Rev. 1).
Article 59(1) of Directive 2001/83/EC requires that the package leaflet shal be drawn up in
accordance with the Summary of Product Characteristics (SmPC) (DIRECTIVE 2001/83/EC
). Therefore, consistent information should be stated in both documents for al excipients listed
in the Annex to the guideline. Article 59(1)(f)(iv) requires the ful qualitative composition (in
active substances and excipients) and the quantitative composition in active substances to be
included in the package leaflet. Article 59(1)(c) states that the package leaflet must include a
list of information which is necessary before taking the medicinal product. Article 59(2)(c)
provides that the aforementioned information shal list those excipients whose knowledge is
important for the safe and effective use of the medicinal product and which are included in this
guideline published pursuant to Article 65(e).
Excipients are defined in Directive 2001/83/EC as any constituent of a medicinal product other
than the active substance and the packaging material. According to Annex I of Directive
2001/83/EC, such constituents may include: colouring matter, preservatives, adjuvants,
stabilisers, thickeners, emulsifiers, flavouring and aromatic substances, etc.; constituents
intended to be ingested or otherwise administered to the patient, of the outer covering of the
medicinal products (hard capsules, soft capsules, rectal capsules, coated tablets, film-coated
tablets, etc.). Of note,
that excipients should have little or no pharmacological action of their own, some do indeed
have a recognised action or effect in certain circumstances. The
Excipients
in the label ing and package leaflet of medicinal products for human use
It is
accepted that excipients may only show an effect above a certain amount. This potential effect
has been taken into account in the overal benefit/risk evaluation of the approved medicinal
product It is also important to highlight that the guideline indicates that in the context of the
guideline, residues of substances arising from the manufacturing process, impurities, residual
solvents, degradation products, etc. are not included in the definition of excipients.
Vaccines Europe (VE) understands and supports the intended purpose of the EC excipients
guideline and associated annex in making healthcare practitioners and patients aware of the
risks due to exposure to certain excipients in medicinal products, especial y when the use is
chronic. It is the position of VE, however, that there are key differences between drugs and
vaccines, that result in very different levels of exposure and risk that needs to be taken into
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consideration when applying precautionary language from the guideline annex in the
SmPC/PL.
Medicines are designed to achieve a therapeutic dose level in the individual and can
potential y be administered over prolonged periods (years), leading to substantial lifetime
exposure to the medicinal components, including excipients. Prophylactic vaccines are
formulated to induce an immune response in the recipient. As such, pharmacokinetic and
pharmacodynamic factors relating to drug absorption, metabolism and excretion do not apply
to vaccines (EMEA/CHMP/VWP/164653/2005). Vaccines also differ from other medicinal
products in that they are given infrequently over a lifetime; typical y, 1-4 doses, although some
may be administered more frequently, for example annual y (influenza) or decennial y
(tetanus-diphtheria boosters). Compared to medicines, the exposure of excipients in vaccines
is punctual and the cumulative life-time exposure is very smal .
It should be noted that these specificities of vaccines have been acknowledged for fructose
and sorbitol
Information for the package leaflet regarding fructose and
sorbitol used as excipients in medicinal products for human use (EMA/CHMP/460886/2014).
This document states that due to the low levels of sorbitol as an excipient and given the fact
that vaccines containing sorbitol have been administered for a long time without any known
incidence of severe events due to hereditary fructose intolerance, the warning for vaccines
should differ from the warning for products administered intravenously. As a consequence, a
threshold above zero is applied for vaccines and other oral and parenteral (other than
intravenous products) to avoid misleading warning in the package leaflet of vaccines.
As the intent of safety-related information in SmPC/PL is to provide meaningful information to
help healthcare providers and patients understand the benefit/risk of product use, it is
imperative that the safety-related information in the product information is proportional to the
risk. The inclusion of extraneous precautionary text, based solely on a threshold from the
guideline, may unintentional y result in addition of unnecessary precautionary text to the
SmPC/PL. This additional text introduces complexity to the label ing which may reduce the
prominence of other text describing important safety issues, or potential y divert their attention
from the more important information to read. Moreover, it raises unfounded safety concerns
that could contribute to vaccine hesitancy.
The aim of this position paper is to outline that the updated annex, as currently written, does
not provide optimal guidance about excipients that should be included in the label ing of
vaccines. To il ustrate VE
, some examples of vaccine excipients and related
assessment are presented in section 2 (non-exhaustive list).
VE therefore proposes to revise the guideline and annex on excipients to exempt vaccines
from the mandatory inclusion of warnings based solely on the limits currently listed in the
annex. Instead, it is proposed that for selected excipients, the inclusion of safety text in the
product label ing should be based on a safety evaluation that takes into account the negligible
cumulative exposure fol owing vaccination, the extensive post-marketing experience with
certain excipients that have been used in vaccines for decades and the benefit of vaccination.
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2.
Vaccines Europe assessment
Vaccine manufacturers have reviewed the excipients listed in the Annex that are present in
vaccines (i.e., excipients associated with potential risks through oral, parenteral and/or al
routes of administration) and have evaluated their potential safety risk based on the level
above the threshold determined in the EC guideline. The examples below il ustrate the specific
issues associated with the implementation of the thresholds and related statements as
currently described in th
Excipients in the label ing and
package leaflet of medicinal product for human use
Il ustrative examples are presented below (non-exhaustive list).
2.1.
Para-aminobenzoic Acid (PABA)
Exposure level
The Company A has a portfolio of several vaccines registered in Europe to prevent infectious
diseases. These vaccines are administered subcutaneously or intramuscularly to infants and
children according to a 2 or a 3-dose vaccination regimen, with potential y one booster dose
administered later in life in accordance with official recommendations.
The total quantity of PABA present in the final dose of these vaccines ranges from <0.07
ng/dose to 0.26 ng/dose.
What is the safety concern highlighted in the Annex?
PABA is included in the Annex (i.e., category parahydroxybenzoates and their esters) with a
threshold of zero triggering a warning due to a potential safety concern for sensitized subjects.
Safety risk assessment
PABA may induce type IV delayed hypersensitivity reactions in sensitive individuals
(Eggleston et al., 1996; Mackie et al., 1999).
No safety limit has been established by International Health regulatory bodies. For impurities
and leachables, the Product Quality Research Institute (PQRI), an industry consortium, has
recommended an acceptable safety limit of 5 µg/day for leachable classified as skin sensitizer.
As such, provided the potential leachable would remain at quantities below the threshold limit
of 5 µg/dose, it would not be expected to present a risk for patient safety (Error! Reference
source not found.Paskiet et al., 2013).
Amounts of PABA in the vaccines from the Company A are substantial y lower (>104-fold) than
the PQRI acceptable level of sensitizing impurities.
It is considered unlikely that levels of PABA present in the vaccines of Company A would
represent a safety concern. Therefore, including the amount of PABA and a warning
concerning its use to the SmPC and package leaflet is considered unwarranted.
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2.2.
Phenylalanine
Exposure level
The Company B has a portfolio of several vaccines registered in Europe to prevent infectious
diseases. These vaccines are administered oral y, subcutaneously or intramuscularly to
infants, children, adolescents and adults according to a 1,2 or a 3-dose vaccination regimen.
The total quantity of phenylalanine present in the final dose of these vaccines ranges from
0.0298 µg/dose to 828 µg/dose.
What is the safety concern highlighted in the Annex?
Phenylalanine is included in the Annex with a threshold of zero triggering a warning due to a
potential safety concern for individuals with phenylketonuria (PKU). PKU is an autosomal
recessive disorder of amino acid metabolism characterized by the accumulation of
phenylalanine in blood and brain due to a deficiency in phenylalanine hydroxylase. Toxic
levels of phenylalanine may result in permanent intel ectual disability (van Wegberg et al.,
2017).
Safety risk assessment
The treatment of patients with PKU includes a diet restricted in phenylalanine to lower blood
levels to within a recommended range that supports optimal growth, development, and mental
functioning. The recommended minimum intake of phenylalanine for 0-6 months old infants is
20-70 mg/kg (100-350 mg/day if 5 kg body weight); and 10-35 mg/kg for 7-12 months old
(MacLeod et al., 2010).
The amount of phenylalanine contained in the vaccines from Company B (maximum of 828
µg/dose) represents a negligible contribution to the overal daily intake of phenylalanine in
individuals with PKU. It is considered unlikely that levels of phenylalanine present in vaccines
would represent a safety concern to vaccinated subjects with PKU. PKU is not a
contraindication for vaccination, and vaccination of individuals with PKU should not be
withheld due to concerns about phenylalanine content (van Wegberg et al., 2017). Therefore,
including a warning concerning the presence of phenylalanine to the SmPC and package
leaflet is considered unwarranted.
2.3.
Sodium and potassium
Exposure level
Several companies have seasonal influenza vaccines registered in Europe to prevent
(seasonal) influenza. These vaccines are administered subcutaneously or intramuscularly to
infants, children, adolescents and adults. They are administered on annual basis according to
a single dose vaccination regimen (with a one-time booster for infants if they have not been
vaccinated before).
The SmPC/PL of these products has the fol owing statement on the presence of sodium and
potassium in the product:
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This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essential y
-
This medicine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essential y
-
What is the safety concern highlighted in the Annex?
For products, administered oral y or parental y, which have the above-mentioned statements
and information in the labeling, the Annex has the fol owing comments on sodium and
potassium:
Sodium:
1 mmol of sodium (Na) = 23 mg Na = 58.4 mg salt (NaCl). Information relates to a threshold
based on the total amount of sodium in the medicinal product.
It is especial y relevant to products used in children or in patients on a low sodium diet, to
provide information to prescribers and reassurance to parents or patients concerning the low
level of sodium in the product.
Potassium:
Information relates to a threshold based on the total amount of K+ in the medicinal product.
It is especial y relevant to products used in children or in patients on a low sodium diet, to
provide information to prescribers and reassurance to parents or patients concerning the low
level of K+ in the product.
Safety risk assessment
Seasonal influenza vaccines usual y contain per dose far less sodium and potassium salts
than the above mentioned 1 mmol per dose (typical y even < 5 mg of sodium and potassium
salts per dose). Given that these vaccines are only administered once a year (initial y fol owed
by a second vaccination), the informative value of these statements is limited, and the need
for inclusion of these statements in the product labeling may be re-considered.
2.4.
Ethanol
Exposure level
The Company D has a portfolio of several vaccines registered in Europe to prevent infectious
diseases. These vaccines are administered subcutaneously or intramuscularly to infants,
children, adolescents and adults. They are administered either according to a 1,2 or a 3-dose
vaccination regimen (with a booster for some of them) or decennial y.
The maximum quantity of ethanol present in the final dose of these vaccines is 2.5 µL
corresponding to 2 mg.
What is the safety concern highlighted in the Annex?
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Ethanol is included in the Annex with a threshold of zero triggering a warning due to a potential
safety concern for adverse effect on children (feeling sleepy, changes in behavior, ability to
concentrate), on healthy adults (ability to drive or use machines), on patients with epilepsy,
liver diseases, addicted to alcohol, and pregnant or lactating women.
Information for the package leaflet regarding ethanol used as an excipient in
medicinal products for human use
required to convert the quantity of ethanol in ml beer and wine. Below is an example of how it
would translate for a vaccine:
This medicine contains 2 mg of alcohol (ethanol) in each 0.5 ml dose. The amount in 1 dose
of this medicine is equivalent to less than 0.1 ml beer or 0.1 ml wine. The smal amount of
alcohol in this medicine wil not have any noticeable effects.
Safety risk assessment
As mentioned as above-mentioned guideline, ethanol is present in a number of food stuffs,
such as fruit, bread and yogurt. It has been estimated that the diet of a 6 year old would result
in exposure to ethanol from food of 10.3 mg/kg/day (Gorgus et al., 2016). Therefore, the
amount of ethanol (2.5 µL or 2 mg) contained in vaccines represents a negligible contribution
to the overal intake of ethanol and is unlikely to have any adverse effects on vaccine
recipients.
Therefore, including the amount of ethanol and a warning concerning its use to the SmPC and
package leaflet is considered unwarranted. Moreover, the conversion to quantity of alcoholic
beverage for injectable vaccine could be misleading.
3.
Discussion and recommendation
The product label is a primary source for healthcare providers and for the general public to
inform them on how to use the medicinal product safely and effectively. According to the
European guideline on Summary of Product Characteristics, information on a specific risk
should be given in section 4.4 of the SmPC only when the risk leads to a precaution for use
or when healthcare professionals have to be warned of this risk.
Prophylactic vaccines are intended for use by the whole population and they also differ from
medicines in their targeted action, and in how they are used over a lifetime. Compared to
some medicines, the lifetime exposure to vaccine excipients is almost immeasurably smal .
The need to include warnings linked to the presence of some excipients in vaccines should
be evaluated on a case-by-case basis based on a thorough review of the potential safety risks
for vulnerable persons based on the level of excipient in each vaccine, balanced with the
responsibility to encourage vaccination of all individuals. The present evaluation highlights
major differences between medicines given over long periods, and vaccines for which the
immediate (at the time of vaccination) and lifetime exposure to excipients is extremely smal .
These fundamental differences between vaccines and other medicinal products justify a
distinction in label ing requirements, notably with respect to the inclusion of excipients and
accompanying warning statements which are not relevant in the context of vaccine
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administration. The vaccine particularities were taken into consideration in the guideline for
sorbitol, a similar approach is also relevant for other excipients.
Vaccines Europe proposes to revise the guideline and annex on excipients to exempt vaccines
from the mandatory inclusion of warnings based solely on the limits currently listed in the
Annex. Instead, it is proposed, for selected excipients, to perform a safety evaluation that
takes into account the negligible cumulative exposure fol owing vaccination, extensive post-
marketing experience with certain excipients have been used in vaccines for decades and the
benefit of vaccination.
4.
Literature References
DIRECTIVE 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the
Community code relating to medicinal products for human use.
Eggleston ST, Lush LW. Understanding allergic reactions to local anesthetics. Ann Pharmacother Jul-
Aug 1996;30(7-8):851-7.
European Commission. Notice to Applicants. Excipients in the label ing and package leaflet of medicinal
products for human use. March 2018. SANTE-2017-11668. Revision 2.
and package leaflet of medicinal product
-2017-11668).
EMA/CHMP/302620/2017 Rev. 1* 22 November 2019
Gorgus, E, Hittinger, M, Schrenk, D, Estimates of Ethanol Exposure in Children from food not label ed
as Alcohol-Containing, Journal of Analytical Toxicology, 2016, p. 1 6.)
MacLeod E L, Ney D M. Nutritional management of phenylketonuria. Ann Nestle 2010;68:58-69
Mackie BS, Mackie LE. The PABA story. Australas J Dermatol 1999;40:51 3.
Error! Reference source not found.Paskiet D, Jenke D, Ball D, Houston C, Norwood D. l., and
Markovic I, The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group
Initiatives for Parenteral and Ophthalmic Drug Product (PODP) PDA J Pharm Sci and Tech
2013;67:430-447
van Wegberg, A.M.J., MacDonald, A., Ahring, K. et al. The complete European guidelines on
phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 12, 162 (2017).
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