How are APIs covered under the MRA? Do APIs from
non-MRA states have to be retested?
An API has to be re-tested on receipt no matter where it comes from.
In this case the MRA is irrelevant. Testing can only be reduced or
eliminated (but the ID still must be done) until the supplier has
been fully qualified and has provided materials over a period of
time with no issues. An on site audit of the supplier would also
have to be undertaken to ensure the supplier is meeting the required
How should a QP proceed in case the CEP of the API
manufacturer is suspended for example because of GMP violations? Can
the QP release the finished product after doing a risk assessment?
It would depend on why the CEP was suspended. The QP would certainly
have to carryout a risk assessment and get assurance that the API
being manufactured was compliant and had not had its safety, quality
or efficacy compromised. If I was the QP I would want to discuss
with the regulatory authorities before approving any product made
from the API
How many QPs have actually been sent to jail in
case of violations?
We are currently not aware of anybody in EC sent to jail. The
penalties for nonconforming behaviour of QPs are mostly leading to
fines and no to terms of imprisonment. The last may be relevant in
cases of intentional release of unsafe products or danger for
Annex 13 requires that the QP must have experience
with clinical trials. What do inspectors/ regulators expect with
respect to QP experience with GCP.
I would expect knowledge of GCP-basics, and besides the usual GMP,
galenic experiences and experiences in handling new materials and
knowledge of the various processes from phase 1 to phase 3.
What is the minimum requirement/ expectation for
supplier qualification of excipients? Are on-site audits required?
The minimum requirement is that starting materials (including
excipients and others) and packaging materials are only purchased
from approved suppliers named in the specification.
There is no regulatory requirement for on-site audits for excipient
suppliers, this is only mandatory for APIs that are manufactured
Nevertheless, own audits or qualified third party to audits or joint
audits must be considered the most appropriate way to approve
suppliers and distributors of excipients.
This will from time to time be problematic or impossible, as unlike
APIs, excipients are not usually manufactured specifically for use
in medicinal products and only very limited amounts are delivered
for pharmaceutical use. In this case a preliminary approval based on
delivery history, fully analysis and performance based tests to show
equivalent drug performance and stability should be performed.
Outsourcing the QP batch release:
- what are the pre-requisites (GMP and legal)?
- what experience is needed?
- are there any existing models as a reference?
The QP must be named in the manufacturing authorisation (in
Germany). The QP must be endorsed by the competent local authority
according to the national law. There must be a written agreement
between the QP and the manufacturer, clearly describing the role and
responsibility. The permanent availability of the QP must be
assured, the frequency of on-site availability and the way the QP
gets all relevant information must be defined.
The QP must be appropriately experienced in the manufacture and
quality control of the product type manufactured by the contract
giver. In case the products need additional formal education or
experience like blood products, the QP must comply with these
PQR: A contract manufacturer is responsible for
batch release but is not the MA-holder. Does the MA-holder have to
have a copy of the PQR?
The answer is given in the full text of the EU Guidelines to Good
Manufacturing Practice Part I, Chapter 1, Quality Management, 1.4
Product Quality Review, chapters 2 and 3:
The manufacturer and marketing authorisation holder, where
different, should evaluate the results of this review and an
assessment should be made whether corrective and preventative action
or any revalidation should be undertaken. Reasons for such
corrective actions should be documented. Agreed corrective and
preventative actions should be completed in a timely and effective
manner. There should be management procedures for the ongoing
management and review of these actions and the effectiveness of
these procedures verified during self-inspection. Quality reviews
may be grouped by product type, e.g. solid dosage forms, liquid
dosage forms, sterile products, etc. where scientifically justified.
Where the marketing authorisation holder is not the manufacturer,
there should be a technical agreement in place between the various
parties that defines their respective responsibilities in producing
the quality review. The Qualified Person responsible for final batch
certification together with the marketing authorisation holder
should ensure that the quality review is performed in a timely
manner and is accurate.
The marketing authorisation holder is a key player and must have a
copy of the PQR. How else could he be able to evaluate the result of
Does the QP have to confirm acceptance of the
company's QA-System in writing or is signing of job descriptions
and/or signing key-SOPs sufficient?
There is absolutely no regulatory or GMP requirement or expectation
that a QP has to sign off job descriptions or key SOPs. In addition
there is no formal requirement that a QP has to "confirm acceptance"
of the company's QA-System.
Pharmaceutical manufactures usually run regular Quality Management
Reviews that include a documented management assessment of the
suitability of the Quality System. Therefore I consider it
appropriate and adequate that the QP is a regular member of this
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