Safeguarding public health
The 2001 Review and its Impact
upon Excipient Suppliers
Richard Andrews
Operations Manager GMP
© Crown copyright 2005
Agenda
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Current Guidance and Standards
The 2001 Review and Directive 2004/27/EC
Potential Risks with Excipients
Development of a New Directive
A List of 'Certain Excipients'
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 1
7th February 2006
© Crown copyright 2005
Current Guidance and Standards
• No legislative basis in the UK for the inspection of
manufacturers and suppliers of pharmaceutical excipients
• Medicinal product manufacturers are responsible for the
quality of their starting materials
• Certificates of Suitability (TSE and EP materials)
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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7th February 2006
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2001 Review
Review of existing legislation relating to the manufacture of
medicinal products, with the view to clarifying the definitions
and scope in order to achieve high standards for the quality,
safety and efficacy of these products.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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Directive 2004/27/EC
Directive 2004/27/EC amends Directive 2001/83/EC on the
Community code relating to medicinal products for human use
The requirements of the amending directive came into force
on October 31st 2005.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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Directive 2001/83/EC as Amended
Amendments to Title IV: Manufacture and Importation
• Article 46(f)
• to comply with the principles and guidelines of good manufacturing
practice for medicinal products and to use as starting materials only
active substances, which have been manufactured in accordance with
the detailed guidelines on good manufacturing practice for starting
materials.
• This point shall also be applicable to certain excipients, the list of
which as well as the specific conditions of application shall be
established by a Directive adopted by the Commission in
accordance with the procedure referred to in Article 121(2).
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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7th February 2006
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What has changed?
• Article 46f of Directive 2001/83/EC as amended obliges manufacturing
authorisation (MA) holders to use as starting materials only active
substances that have been manufactured in accordance with GMP.
• In addition MA holders are also obliged to only use 'certain excipients'
that have been manufactured in accordance with GMP. The article calls
for a new Directive to be developed and adopted on GMP for excipients.
• The directive shall include a list of the excipients which when used by
an MA holder must have been manufactured in accordance with GMP
and will specify the GMP principles that should be applied.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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7th February 2006
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Potential Risks with Excipients
Excipients are used in the formulation of medicinal products for a
variety of reasons:
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to facilitate bioavailability of product
to aid the manufacturing process
for aesthetic reasons e.g. taste, colour
to stabilise the product e.g. buffers, preservatives
to make the product a practical dose size e.g. bulking agent
• Excipients are an intrinsic part of nearly all medicinal products and
therefore they have an impact upon the quality, safety and efficacy of
these products.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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7th February 2006
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Potential Risks with Excipients
When appropriate controls are not applied the following may occur:
• presence of extraneous matter e.g. metal, paper, particles
• cross-contamination with other chemicals (either excipients or APIs or
breakdown products)
• contamination with TSE risk materials not permitted by legislation
• inconsistent manufacture such that the quality of the final products
cannot be assured
• mis-labelling of containers leading to product mix-up
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 8
7th February 2006
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What is the Purpose of Applying GMP to
'Certain Excipients'?
• To protect (assure) public health.
• To ensure consistent standards of manufacture and control
are applied.
• To meet the legal requirement within Directive 2001/83/EC
as amended.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 9
7th February 2006
© Crown copyright 2005
Development of a New Directive
• Article 46(f)
• This point shall also be applicable to certain excipients, the list of which
as well as the specific conditions of application shall be established by a
Directive adopted by the Commission in accordance with the procedure
referred to in Article 121(2).
• Outputs required:
- List of 'Certain Excipients'
- Good Manufacturing Practice principles to be applied
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 10
7th February 2006
© Crown copyright 2005
Development of a New Directive
• Excipients Team formed
- Members drawn from European regulatory agencies, EMEA and
European Commission
• Role of the Team
- To derive and agree a list of excipients that should appear on the list
of ‘certain excipients’
- To determine the GMP principles that should be applied to the
materials listed.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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7th February 2006
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List of 'Certain Excipients' - Process
• In developing a list of ‘certain excipients’ the Excipients team wanted to
involve key stakeholders from the beginning
• Input was therefore requested from both regulators and industry
• Three Questionnaires were prepared and distributed targeting:
- Excipient manufacturers
- Medicinal Product manufacturers
- Member states
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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List of 'Certain Excipients' - Questionnaires
Topics covered by the Questionnaires:
• Examples of cases where an excipient has or potentially had caused a
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risk to patient health.
Suggestions for materials that should be included on a list of 'certain
excipients' and why.
Whether the list should name individual materials, material groups or be
based on the materials use.
Views on whether the respondents felt that a list of 'certain excipients'
would add value in terms of patient safety.
What audit approaches were being employed
What standards were audits being performed against
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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7th February 2006
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List of 'Certain Excipients' – Questionnaires
Review of Responses
• There was no clear consensus of views relating to whether or not a
Commission Directive should be prepared. Many respondees welcomed a
document outlining the GMP requirements for excipient manufacturers.
• Regarding the key question about whether a list of 'certain excipients' would
add benefit 18 respondees stated “yes”, 15 “no” and 7 gave no opinion.
• As to how the list of 'certain excipients' should be defined - 3 respondees
suggested listing individual names, 7 material groups, 4 based upon usage,
1 name and group and 3 gave no response.
• It was clear that most pharmaceutical companies perform audits of
excipient manufacturers using a wide variety of standards, including:
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IPEC GMPs
ISO 9000:2000
21 CFR 210 and 211
PQG PS 9100:2002
WHO-GMP
ICH Q7A
21 CFR 820
EU GMP
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
HACCP
Company internal standards
National Food Code Requirements
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7th February 2006
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List of 'Certain Excipients' – Questionnaires
Review of Responses
• Many respondents outlined the difficulties in having a specific list of
excipients as the same material could be used in many different
products, some of the uses could be defined as high risk whereas
others could be defined as low risk.
• Other key difficulties were that excipient manufacturers’ main customers
are food or cosmetics industries with pharmaceutical supply accounting
for only a small proportion of the output. Requiring such companies to
meet stringent GMP requirements may lead them to withdraw from the
pharmaceutical market and thus lead to product shortages.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
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7th February 2006
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List of 'Certain Excipients' - Options
• Potential Approaches for defining the list of 'certain excipients':
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Individually named excipients
Grouped by material type
Based upon material usage
Define the minimum standard for all excipients and then identify the
additional requirements for the listed 'certain excipients'.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 16
7th February 2006
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List of 'Certain Excipients' - Process
• Excipients Team agreed to adopt a risk assessment approach to define
which excipients should appear on the list.
• Benefits of using this approach are:
- Fits with current regulatory thinking – ICH Q9
- The specific use of an excipient can help define the risk category.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 17
7th February 2006
© Crown copyright 2005
List of 'Certain Excipients' - Process
• A list of Risk Criteria was developed
• Based on the responses from industry and regulatory agencies to the
2004 questionnaire a list of possible excipients was established.
• The items on this list were then subject to a risk based analysis using
FMEA (Failure Mode Effect Analysis) techniques and each material was
assigned a Risk Priority Number (RPN). A cut off value of < 25 was set.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 18
7th February 2006
© Crown copyright 2005
List of 'Certain Excipients' - Output
The result of this analysis was a draft list containing the following
excipients:
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Animal derived excipients with a known TSE risk
Human derived excipients, in particular albumin
Sodium chloride used for injections
Propylene glycol
Glycerine
Pyrogen-free excipients, e.g. glucose, mannitol, sorbitol, xylitol
Sterile excipients, e.g. aluminium phosphate, sodium carbonate,
lactose, media for fermentation
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 19
7th February 2006
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List of 'Certain Excipients' - Consultation
• Draft list and risk assessment tools provided to industry
• Industry associations performed their own risk assessments and the
results were fed back to Excipients Team.
• In general industries view on which excipients should be included on
the list was similar to that of the Excipients Team.
• Other comments included:
- The objective of introducing GMP for excipients is not clear
- Glycerine and propylene glycol should be removed from the list as
problems in the past were caused by criminal activity.
- Detectability of risk was not considered by the risk assessment tool.
- Application of good practice should also cover the supply chain.
- The IPEC PQG GMP guide should be used for excipient manufacture
and the WHO guide for distribution.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 20
7th February 2006
© Crown copyright 2005
List of 'Certain Excipients' - Consultation
• Industry association representatives were invited to meet with the
Excipients Team to discuss the different views, to establish the basis for
an impact assessment, decide which products should be contained in
the list and what GMP principles should be applied.
• The main concerns presented by Industry at the meeting were:
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The problem to be resolved and the aim of the Directive are unclear
Detectability should be part of the risk management process
GMP will not resolve the problem of fraud and adulteration
The application of GMP for excipients to the distribution chain
The inclusion of non-sterile excipients used in parenteral preparations
and substances with a known history of fraud, such as propylene
glycol and glycerol.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 21
7th February 2006
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List of 'Certain Excipients' - Consultation
• A template to be used for the evaluation of GMP requirements for
'certain excipients' was also presented.
• The template had been designed to collect information on the current
situation for the 'certain excipients' / excipient categories under
discussion in preparation for an impact assessment with respect to:
- the detailed requirements available in other sectors (e.g. food,
cosmetics: HACCP, ISO Standards)
- the extent of current application of GMPs for excipients on a voluntary
or mandatory basis both by excipient and by pharmaceutical
manufacturers
- the justification of additional requirements compared to those
currently used or required by legislation
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 22
7th February 2006
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List of 'Certain Excipients' – Next Steps
The list of categories / substances currently under discussion to be further
reviewed.
Discrepant views between industry and the regulators regarding the
categories of excipients to be incorporated into sterile products as well as
regarding glycerine and propylene glycol to be resolved.
Concerning the development of GMP principles the current requirements
and the status of application of different standards utilised by
pharmaceutical and excipient manufacturers are to be analysed and the
need for possible additional elements compared to current practice
identified.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 23
7th February 2006
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List of 'Certain Excipients' – Progress to date
• The European Commission held a further meeting with representatives
from different industry organisations including EFPIA, EGA, APIC,
FECC, Eyecare industry, AESGP which resulted in the following:
• Two questionnaires will be published on the European Commission
Website covering the following categories:
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animal derived excipients with potential TSE risk
human/ animal derived excipients with a potential viral contamination risk
excipients claimed to be sterile and used without further sterilisation
excipients claimed to be pyrogen / endotoxin controlled
propylene glycol, glycerine
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 24
7th February 2006
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List of 'Certain Excipients' – Progress to date
One questionnaire will be for excipient manufacturers and the other for
excipient users, with the aim of gathering data on:
- The different quality standards currently applied to excipients that fall into
the agreed categories.
• These questionnaires are expected to be available mid February and
responses should be made where possible via trade organisations.
• In addition the Industry proposed high level GMP principles for a
directive are to be sent to the Excipient Team for review.
• Finally it was noted that Industry would like a GMP Part III for excipients
to be developed, based on the IPEC guide.
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 25
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Thank You
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 26
7th February 2006
© Crown copyright 2005
Contact Details
Richard Andrews - Operations Manager GMP
e-mail:
tel:
[email protected]
+44 (0)1904 610556
MHRA
Hunter House
57 Goodramgate
York
YO1 7FX
The 2001 Review and its Impact upon Excipient Suppliers
Richard Andrews
Slide 27
7th February 2006
© Crown copyright 2005