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

Products ("Regulation").

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

Responsibilities

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.

V -Imports

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

authority.

(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

Inactive Ingredients

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

audits..

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

suspension/withdrawal.

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

Regulation.

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

Regulation.

Authors:

Gönenç Gürkaynak, Esq., Ceren Yıldız and Ecem Elver, ELIG, Attorneys-at-Law

First published in Mondaq on October 24, 2017.