Q&A Session at the QP Forum 2008 in Munich, Germany – Part II
API-supplier audit: If a big company is purchasing the API in bulk and
than repackaging it and doing the QC testing and release, do I as the
final QP need to audit the bulk manufacturer?
It is the responsibility of the QP for the MAH to assure that each step
in the supply chain from the starting material onwards has been
manufactured in accordance with the cGMPs. In this example it would be
necessary for the final QP to either audit, or have an approved auditor,
carry out an inspection of the bulk manufacturer. This would be in
addition to having a Quality agreement between the bulk manufacturer and
the drug product producer. There is a provision in Annex 16, 3.2 & 3.3
that the QP of the final drug product can rely on, in part, on the
advice and decision of others. Before doing so they should ensure that
this reliance is well founded, either from personal knowledge or from
the confirmation by other QPs within a quality system which is accepted.
If an API is manufactured at different sites (for example the
intermediate in China and the following steps in the EU), do I also have
to audit the manufacturing site in China or would be an audit at the
site in EU sufficient? And should the QP responsible for the release of
the final product also certify the GMP-compliance of the Chinese
If the API being received originates in China then this site must be
audited .This can be from an actual audit originating from the final QP
( or there approved representative) or from assurance from another QP
(at the European site) that an audit has been undertaken and all
manufacture is done under adequate GMP conditions.
Does the Reflection Paper on QP Discretion apply to release of IMPs?
(with respect to deviations to what has been defined in the IMPD).
It does. It is the responsibility of the QP to ensure IMP
(Investigational Medicinal Product) batches used in Clinical studies
comply with cGMPs, with the CTA and with the Product Specification file,
and to ensure patient safety.
In the introduction part of the reflection paper the Clinical Trial
Direction CTD 2001/20/EC is referred to, a directive mandatory for all
QPs working in an R&D environment.
Also the production of IMPs involves added complexity, in comparison to
production of marketed products, by lacking fixed processes. As such
good communication between the R&D product development departments and
regulatory affairs however is key, to ensure that the filed
specification are broad enough to avoid regulatory impact if changes
In case there are deviations from the filed CTA, amendments can be
submitted to the involved (EU) HAs. In that situation the QP needs to
wait for certifying and releasing the final IMP till approval is granted
by the HAs.
If the QP of a company responsible for the release of IMPs releases a
batch of an IMP that is OOS, would the MHRA (or another authority)
admonish all other QPs of the company (named on manufacturing licence)
although they haven't been aware of the decision of the other QP?
The final QP, responsible for the final release of the IMP, should
ensure that all intermediate QPs are informed of issues related to their
Roles and responsibilities should be well defined and written down in a
quality/QP agreement signed by the different involved QPs.
For Clinical Trials the QP mentioned on the CTA is the QP responsible
for the final certification and release of the IMP. In case the QP
decides to release an OOS batch full documentation should be available
explaining why this decision has been taken and proving that patient
safety has been guaranteed.
The responsible HAs, as well as the intermediate QPs where appropriate,
should be consulted by the final IMP QP before releasing an OOS spec
Normally an amendment will be submitted to the involved (EU) HAs. In
that situation the QP needs to wait for certifying and releasing the
final IMP till approval is granted by the HAs.
How should we realise the requirement of the revised Annex 13 to keep
samples for a double full analysis outside EU at the site where the QC
has been performed and guarantee a timely access?
This should be described in a Quality agreement. The QP should do a
regular assessment to assess whether these samples are kept and whether
EU legislation (for this topic Annex 19) is complied with.
Remark: In the recent Annex 13 draft Article 36 is referring to
reference samples and retains samples. (This was not the case in the
former, still applicable version).
Revision of Annex 13: Does "reconstitution" Art. 93, 2005/ 28/EC include
randomisation and labelling in hospital pharmacies as well? And if yes,
could this be added to the explanatory note for further clarification?
This is at the moment difficult to answer since:
-The new version of Annex 13 is still not finalised.
-There is an absence of specific legislation related to which GMP
activities can be done at the clinical site.
1/Consolidated comments to the latest draft of Annex 13 have been send
by EFPIA related to those topics, mainly focussing on reconstitution,
dilution, and dispensing and specific activities for early phase
For those operations an exempt from the requirement for manufacturing
authorization and certification by a Qualified Person is requested,
under the condition however that the sponsor remains responsible for
ensuring that those activities are adequately documented and carried out
in accordance with the principles of GMP and/or GCP.
Also those dispensation operation steps should be performed by a
pharmacist or medical doctor/nurse or monitor, and should as such not be
considered as a manufacturing operation to be regulated by Annex 13.
Proposed definitions for reconstitution, dilution, dispensing and
specific activities for early phase studies are:
e.g. preparation of an IMP prior to administration from an
individualized subject/patient kit, e.g. dissolution of a lyophilizate
or powder into a solution for immediate administration
e.g. preparation of an IMP ready for administration by diluting a
concentrate into an applicable concentration with an appropriate diluent
Dispensing finished products for individual patient dosing
Additional activities for early phase studies:
-Labelling at clinical investigator sites (e.g. for dispensing
-Weighing for individual dosing prior to immediate administration
2/ Currently Annex 13 only allows for labelling at the clinical site,
when justified, if the use-by date needs to be changed (extension of
expiry date). (Article 33)
3/The statistic department of the sponsor does randomisation of the
The production department on the other hand is performing packaging/
blinding compliant with the randomisation code provided by the
For early development trials dispensing/reconstitution (not
randomisation!) can be done at the clinical site, because of the need
for a flexible dosing regimen in phase1 studies. In that situation the
sponsor supplies bulk active or placebo material to the clinical site.
(Remark: this is not mentioned in the current legislation.)
For higher phase studies, medication is patient specific packed and
labelled at an authorised manufacturing site.
A GMP intermediate or API is isolated over a centrifuge and than packed
in bigbags (PP or with PE-inliner): It might stay in these bags up to 3
months before the drying step. Is it sufficient to show stability at
ambient conditions in the lab? Is it sufficient to rely on historical
data? Are other investigations/ studies needed?
The stability of an intermediate or API must be established under actual
conditions of storage. Therefore it must be conducted under conditions
which may well not be the same as ambient conditions in the laboratory.
In addition the primary contact materials must be the same as in the
bulk. Hence in the question it is likely than more than one study will
be required. It is permitted to use small pack sizes provided that the
packaging materials are made from the same materials and mimic the
contact area of drug to primary contact material. It would not be
sufficient to rely solely on historical data that final batch data were
satisfactory. If these bulk materials are transported between sites it
might be appropriate to conduct some additional trials.
How can the QP rely upon a single result from testing in the lab in EU
instead of full GMP compliance with the manufacturer from third country
that is e.g. authorised by MHRA?
In 2001/EC/2001, Article 51 1(b) it states that ' in the case of
medicinal products coming from third countries, irrespective of whether
the product has been manufactured in the Community, that each production
batch has undergone in a Member State a full qualitative analysis, a
quantitative analysis of at least all the active substances and all the
other tests or checks necessary to ensure the quality of medicinal
products in accordance with the requirements of the marketing
However it would be unlikely for the QP to rely solely on this analysis,
as supplier quality would be assessed as part of a routine audit
programme which would include the status of GMP compliance by the
manufacturer from the third country
Is it possible to name more than one QP for the release of one certain
product and if yes, can each QP be named as responsible for different
sub-types of the product?
It is perfectly possible to name more that one QP and they can be named
for different sub-types of product.
What is the process to assess the competence (knowledge and experience)
of a QP when they are registered?
In the UK the MHRA assesses the suitability of a person for nomination
as a Qualified Person by taking account of the assessment of that
person's eligibility made by a joint assessment panel from the Royal
Pharmaceutical Society, the Institute of Biology and the Royal Society
of Chemistry. The assessment is done by interview, which covers the
criteria laid down in the relevant paragraphs of Title IV of Directive
2001/83/EC. If the person is not a member of one of these professional
bodies, the MHRA carries out a direct assessment of his/her suitability.
The usual practice in other Member States is for the regulatory
authority to conduct the assessment.
<< Back to overview