gmp vol8 no3.

qxd: gmp vol5 no4

1/10/09

15:37

Page 6

Back to Basics

Contract manufacturing

A brief summary of contract manufacturing

GMP requirements is provided, inlcuding a
template for a contract which can be tailored to
your own requirements, whether you are a
Contract Giver or a Contract Acceptor

by Dr Gero Beckmann

ontract manufacture is sought for reasons of

capacity, or because the technology cannot or
is not due to be implemented in-house. The
scope of the contract assigned can be limited to pure
manufacture or can range from the procurement of
the starting materials to the release of the packaged
product. The contract giver hands over to the
contract acceptor important production information
regarding the marketing authorisation and, if
applicable, about experiences with the manufacture,
analysis and validation. A secrecy agreement
relating to these documents is concluded.

Framework contract for contract

manufacture and quality control

The following framework contract is concluded

between:

Contract Giver [Company, exact address]

- hereafter referred to as CG
and

Manufacturing and testing procedure

Contract Acceptor [Company, address of the plant]

- hereafter referred to as CA
-

The production of development and validation

batches must be established at the start. The resulting
manufacturing instructions are approved by both
parties. All changes to the manufacturing and testing
procedure and deviations from the specifications must
be approved by the contract giver. The contract giver
satisfies itself about the quality assurance measures by
carrying out an audit of the contract acceptor. Personal
contacts between the responsible members of staff
from both parties facilitate communication should
problems arise in day-to-day business.
Audits are compulsory and should take place at
regular intervals (1-2 years). The topics in the EU
GMP Guideline and conformity with the contract
manufacturer agreement are reviewed. An
evaluation of the contract acceptor forms the
conclusion of an audit. Audits are time-consuming
for the contract giver and for the contract acceptor.
Nevertheless, audits should not only be considered
as a compulsory exercise, since in general an
intensive exchange of current practices by this
means is of use for both parties.
Carrying out contract analysis requires the
responsibilities between a contract giver and a
contract acceptor to be established. For this, in line
with the contract manufacturer agreement, it is
essential to establish all arrangements between the
contract giver and the contract acceptor in a
contract. This must also be guaranteed by a contract
acceptor when analysis is assigned to a
"subcontractor laboratory".
If there are changes to the agreements, the
contract acceptor must inform the contract giver.
The changes should be implemented only after
written agreement of the contract giver.

gmp revew

1 Principles

1 CA is the holder of a manufacturing

authorisation and is insofar liable for
supervision by the competent authority. It
observes the legal drug product provisions, the
recognised pharmaceutical regulations and
ensures compliance with the principles of good
manufacturing practice in accordance with the
EU GMP Guideline over the whole term of the
contract. The observation of further instructions
going beyond these should be established
between CG and CA separately in writing.
2 CA is not permitted to transfer the execution of
its contractual obligations to a third party
without the written agreement of the CG.
3 CA communicates to the CG subsequent,
fundamental changes to the rooms and facilities
relevant to the subject of the contract
immediately. The CA indicates to the CG
without delay the suspension, the withdrawal or
the
retraction
of
the
manufacturing
authorisation and the voluntary surrender of the
same during the term of the contract.
4 CA grants the CG access to the rooms and
facilities relevant to the subject of the contract
and makes documentation relevant to the subject
of the contract available for it to inspect.
5 The relevant contact persons for the subject of
the contract from the CG and the CA are listed in
Appendix 1. The contract partners should
indicate subsequent changes without delay.

vol 8 no 3 October 2009

gmp vol8 no3.qxd: gmp vol5 no4

1/10/09

15:37

Contract manufacturing

Page 7

(cont.)
only purchased from qualified manufacturers or
suppliers. The costs of the qualification are borne
by the CG. If the CA conducts the quality control
on the basis of its own specifications, it is liable
for ensuring that the methods correspond to the
state of the scientific and technical knowledge
and are validated. If the CG provides testing
standards, the responsibility for their suitability
lies with the CG.
5 The print release of printed materials is always
on the basis of the artwork approved by the CG.
6 The CA is responsible for carrying out sampling
and storage of retention samples of the starting
materials.

2 Subject of the contract

1 The subject of this contract is the manufacture

and quality control of the medicinal product and
dosage form listed in Appendix 2, hereafter
referred to as contract manufactured products.
2 The batch size and labelling, the processing of
the order and all commercial agreements, such
as prices, delivery conditions/transfer of perils
are established in separate, batch-related supply
contracts according to the model in Appendix 3.
3 A supply contract results from the written
placing of an order by the CG with the
specifications of the contract manufactured
products according to paragraph (1) and the
specifications according to paragraph (2) and the
written order confirmation from the CA.

4 Manufacture and quality control of the

contract manufactured products/retention
samples

1 Manufacture and quality control of the contract

manufactured products is carried out on the
basis of manufacturing instructions and test
procedures to be compiled by the CA. To this
end, the CG surrenders to the CA the required
submittals, if applicable the extracts from the
application file for marketing authorisation, in
the form of manufacturing formula and testing
standard. Each newly compiled or changed
manufacturing or testing procedure should be
approved by CG and CA jointly.
2 The CA guarantees that the applied
manufacturing and analytical procedures
employed are validated and the facilities used
are qualified. The costs for the necessary
validation work are borne by the CG.
3 The CA draws up a manufacturing and test
report for each batch on the basis of the
directions in accordance with 1. The CG is
authorised to see the originals of the
manufacturing and test protocols and to have
copies made of them.
4 All deviations from the manufacturing or testing
procedure should be documented in the
manufacturing and test protocol. The CA
informs the CG promptly of any deviation which
could possibly affect product quality or process
reliability. Possible measures are established in
mutual agreements.
5 The CA is responsible for ensuring that
manufacturing/test procedures and records are
retained at least six years.
6 The CA is responsible for ensuring that retention
samples from every batch manufactured are
retained at least six years.

3 Starting materials and packaging

materials

1 The specifications and permissible manufacturers/

suppliers of the starting materials and packaging
material to be processed by the CA are
established in Appendix 4. Subsequent changes
require the written agreement of both parties.
2 Responsibility for the procurement, quality
control and release of starting materials and
packaging materials is established in the supply
contracts in accordance with 2 (2).
3 In the event that the CG provides to the CA the
starting materials or packaging materials to be
processed, the CG also provides the
corresponding batch-related certificate of quality.
The CA must always carry out a container
identity and labelling inspection and an external
integrity check. Additional quality controls to be
carried out by the CA should be agreed in the
respective supply contract. The costs of
transportation from the CG to the CA and of the
transport insurance linked to the provision of the
starting materials and packaging materials is
absorbed by the CG. The CG takes over the
responsibility for guaranteeing the quality of the
starting materials and packaging materials during
transportation to the CA. The starting materials
and packaging materials provided by the CG can
only be used to manufacture the contract
manufactured products as part of the contract.
4 If the CA provides starting materials or
packaging materials itself, it is responsible for the
proper verification of their quality on the basis of
the specifications in Appendix 3. It ensures that
the starting materials or packaging materials are

vol 8 no 3 October 2009

gmp revew

gmp vol8 no3.qxd: gmp vol5 no4

1/10/09

15:37

Contract manufacturing

Page 8

(cont.)

5 Release of the contract manufactured

products

8 Waiver of recourse

1 If, after processing, the CG launches the subject

of the contract for sale as a finished medicinal
product and loss or damage under the
pharmaceutical liability insurance occurs, that
can be traced to a deficiency in the area of
responsibility of the CA, the CG asserts waiver
of recourse.
2 The CG is aware that this waiver of recourse
requires the agreement of its insurer. The CG will
solicit this agreement and pass it on to the CA for
information.

1 The responsibility for the release is established in

the supply contracts.
2 If the release of the batch is carried out by the
CG, the CA provides the duly signed
manufacturing and test report.

6 Complaints/recalls of the contract

manufactured products

1 CG and CA inform one another without delay

about any complaints about, and batch recalls of,
the contract manufactured products, and the
starting materials and packaging materials used
for them, that he becomes aware of. This applies
to external notices and also internal information
that arises, e.g. during processing or storage of
the contract manufactured products and starting
materials and packaging materials.
2 The CG and CA aid one another when reviewing
the complaints and determining the required
measures.

9 Final provisions

1 The contract enters into force upon signature by

both contract partners and is valid initially until
[enter date]. It is extended automatically by
[enter time limit] each time, if it is not cancelled
with a time limit of [enter time limit] by one of
the contract partners.
2 The cancellation must be notified in writing by
registered mail/with advice of receipt.
3 Changes and supplements to this contract and
its appendices are by mutual agreement and
should be in writing.
4 If one or more provisions of this contract is, or
becomes, ineffective, the validity of the other
provisions is not affected by this. The invalid
provision is replaced as soon as possible by
another provision, that comes closest to the
economic content of the ineffective provision.
The same applies for possible loopholes of this
contract.
5 Place of fulfilment is [enter location], Jurisdiction
is [enter location]
...................................... .....................................
Location, date Location, date
...................................... .....................................
Signature of the contract giver Signature of the
contract acceptor

7 Confidentiality

1 CG and CA undertake not to disclose the

mutually communicated experiences and
information about the manufacture and quality
control of the contract manufactured products.
They take all measures required to prevent a
third party discovering and utilising them. Staff
and employees should be sworn to secrecy,
insofar as this is not already required by their
work contract.
2 The contact partners will use the knowledge
gained through the contract only for the purpose
of the contract and on completion of the contract,
will no longer make use of it without the explicit
consent of the other party - not even in a
modified form.
3 The contract partners will return documents that
they each will have received from the other in
connection with the manufacture and quality
control of the contract manufactured products on
completion of the contractual relationship, to the
information provider without delay, if it has not
otherwise expressly been agreed contractually or
if strict legal reasons oppose delivery.
4 The confidentiality obligation does not apply to
the data that already counts as state-of-the-art,
public and therefore no longer protected.

gmp revew

Dr Gero Beckmann is a veterinarian specialising in

microbiology. He is an expert for DACH (German
accreditation body for chemistry) and on the board of
directors of the FAH (German Association of Research
Consortium of Drug Manufacturers).

This article, one of a series, is based on excerpts from the

GMP Manual, a comprehensive reference book published
by Maas & Peither AG Publishing: www.gmppublishing.com

vol 8 no 3 October 2009