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I – Introduction
Following the enforcement of the new Communiqué on
Pricing of Human Medicinal Products last September, the Ministry of Health
("Ministry") rolled up its sleeves for a new regulation concerning human
medicinal products: The Regulation on Manufacturing Plants of Human Medicinal
With an eye to regulate human medicinal product
manufacturing and importing in line with internationally acknowledged
standards, the Ministry has published the Regulation on the Official Gazette of
October 21st, 2017.
Upon the publication of the Regulation, the
predecessor Regulation on Human Medicinal Products Manufactories (published in
2013 – "Abolished Regulation") has been abrogated.
II – New Definitions
Somewhere down the list of definitions under Article 4
of the Regulation are definitions of "primarily packaging" and "secondary
packaging" which have been introduced. With this division made on the packaging
definition, procedure on interior packaging (i.e. packaging which directly
interacts with the human medicinal product) of human medicinal products will be
deemed as "primary packaging", whereas procedures such as replacement of the
interior packaging into exterior packaging, packaging changing, printing,
barcoding/patterning, inserting banderole/label, adding or changing prospectus/operating
instructions will be considered as "secondary packaging". Both primary and
secondary packaging will be accepted as part of the "manufacturing" process.
III – License Holder's
The responsibilities of the holders of the license for
manufacturing plants are governed under Article 8 of the Regulation. The
Ministry has added certain provisions to the responsibility list which seem to
bring a strict monitoring liability to license holders.
For instance, license holders will be responsible to
assign a manager within 30 days after the resignation of the current manager
and notify the Ministry accordingly. Also, license holders will have to hold
the documentation proving that their manufacturers, importers or distributors
of active agents are duly registered in their countries. License holders, in
this respect, will have to confirm safety and quality of active agents and inactive
ingredients that they use and ensure necessary control over human medicinal
products as well as active agents during all stages of manufacturing.
Article 8 also brings a notification responsibility to
license holders if they come to the conclusion or even suspect that the
products are counterfeit.
IV – Audit
Article 10 contains detailed arrangements on audit of
human medicinal product manufacturing sites. As per the Article, these sites, as
well as laboratories and importers that provide contractual analysis services
for human medicinal products, are subject to routine inspections within the
program which is the result of the Turkish Drug and Medical Device
Institution's ("Institution") risk-based evaluation. These audits can be done
without notice when necessary.
If following the audits, the sites are determined to
be incompatible with the applicable legislation; the Institution can grant the relevant
site a period of time sufficient to repair the deficiencies. As of the expiration
of this period, if it is deemed necessary, new on-site audits can be carried
out to determine whether the deficiencies are repaired.
Article 13 of the Regulation sets forth principles on
the imports of human medicinal products. According to thearticle, importers should
be able to submit their Good Manufacturing Practices Certificate and/or
production permit to the Institution. If they do not possess a Good
Manufacturing Practices Certificate they should apply to the Institution in
line with the guidelines of the Institution.
Article 13 also brings certain responsibilities to
importers. As per the Article importers will have to:
(i) Supply human medicinal products from the plants approved
by the competent authority of the country of manufacture. If they import clinical
research products, they will have to supply these products from manufacturers that
are approved and the products of which have been notified to competent
(ii) Ensure that all batches of imported human
medicinal products are released into the Turkish market after being tested and
controlled within the frame of product license file/specifications.
Apart from the foregoing, license holders will be
obliged to (i) provide the manufacturer with samples at the sufficient amount
to conduct at least 2 analytical controls or at the amount approved by the Institution and (ii) preserve
expired products for at least 1 year after their expiration date.
VI – Active Agents and
Principles on active agents and inactive ingredients
are regulated under Article 14 of the Regulation. According to Article 14 (2),
permit/license holders should confirm that their manufacturers and distributors
of active agents are in compliance with the principles of Good Manufacturing
Practices and Good Delivery Practices, by way of auditing the manufacturing and
distribution sites of these manufacturers and distributors.
On a side note, as per Article 32 of the Regulation,
Article 14 (2) will be effective one year after the date of publication of the
Regulation (i.e. October 21st, 2018).
VII – Internal Audit
Article 24 of the Regulation brings an internal audit
obligation to manufacturers. Internal audit is deemed necessary for the purposes
of taking required corrective actions within scope of Good Manufacturing
Practices. Manufacturers will also have to take records of these internal
VIII – Administrative Sanctions
Article 27 of the Regulation provides a more detailed
regulation on sanctions to be imposed on license/permit holders as well as
managers. While the Ministry maintains its suspension and withdrawal
authorization, certain changes made in the Article sheds light to aftermath of
As per Article 27 (4), the Institution will determine
how to proceed with products distributed before the suspension or withdrawal by
manufacturers whose licenses are suspended or withdrawn.
If breaches which require suspension of production
permit are not remedied within a year, production permit as to related
operations, if all operations are suspended production permit for the
manufactory, will be withdrawn.
As to sanctions against the managers, Article 27 (7)
regulates that the following audits at the manufactory, in case it is
determined that the manager was absent without duly excuse three times during
its duty, his/her management permit will be withdrawn and the manufactory will
be obliged to appoint a new manager and notify the Institution in line with the
IV – Transition Period
Importers wishing to conduct only batch release operations are obliged to apply
to the Ministry and obtain a permit within one year as of publication of the
Gönenç Gürkaynak, Esq., Ceren Yıldız and Ecem Elver, ELIG, Attorneys-at-Law
First published in Mondaq on October 24, 2017.