Principles and Practice of Pharmaceutical Medicine

Good manufacturing practices

Directive 2001/20 required that compliance with
GMP guidelines was introduced into the national
laws of all MS and (see European Commission
Directive 2003/94/EC). GMP inspections have
long been standard for all companies at the time
of a MA application, but there had previously been
no such requirement for IMPs. This gap has now
been closed.
Briefly, the components of GMP are

a quality assurance system (Article 6);

appropriately qualified personnel with training
documentation, organizational charts and job
descriptions that define roles, responsibilities
and hierarchy (Article 7);

premises and equipment appropriate and docu-
mented (Article 8);

documentation system for all processes with
appropriate record keeping; up to date and free
of errors (Article 9);

production to pre-established standard operating
procedures and appropriate, validated in process
controls (Article 10);

a quality control system and independent audit
staff. Samples from each batch must be retained
for testing and archiving, if at all practicable
(Article 11);

any out-contracted work is subject to the same
conditions and cannot be further delegated; pre-
cise contracts must define roles and responsibil-
ities (Article 12);

a system in place for complaints and product
recall and notification of the RA (Article 13);

self-inspection by the manufacturer with appro-
priate record keeping (Article 14).

Directive 2001/20 also requires that any site where
IMPs are manipulated (other than pure adminis-

tration to the trial subjects) should have a valid

manufacturer’s license for GMP-compliant IMP

preparation. Hospitals, health centers or registered

pharmacies are exempt from needing an IMP

manufacturer’s license, provided that changes to

the IMP are done under the supervision of a doctor

or pharmacist for use at that site. A further exemp-

tion is when manipulation of the IMP is simply a

reconstitution activity directly prior to drug

administration (e.g. adding diluent to a lyophi-

lized injectable). Contract research organizations

(CROs) and commercial phase I units are not

exempt from these requirements, but can apply

for a manufacturer’s license in the usual way, and

are subject to inspection. The regulatory authori-

ties issue IMP manufacturer’s authorizations after

a comprehensive GMP inspection of the applicant.

Importation of IMPs from non-EU countries is

also strictly regulated by Directive 2001/20.

Directive 2001/83 defines rules and circumstances

under which retesting or recertification of manu-

factured products have to be performed, whether

manufactured within the EU or imported from

elsewhere.

Qualified persons (QPs)

A holder of a manufacturer’s license must have a

QP. The QP’s central role is to authorize batch

release. The QP must be qualified by training and

experience, and the manufacturer must notify the

competent authority of the name of the QP with

supporting documentation for his/her qualification

to fulfill this role.

34.7 Scientific advice and

protocol assistance

Scientific advice

Scientific advice is provided by regulatory autho-

rities so that sponsors can design drug development

plans that eventually are likely to satisfy the

reviewers for MA. The individual national compe-

tent authorities offer scientific advice, on written

request, and does the EMEA through the CHMP.

34.7 SCIENTIFIC ADVICE AND PROTOCOL ASSISTANCE 453