The European Commission Health and Consumers Directorate – General has published draft “GUIDELINES ON THE FORMALISED RISK ASSESSMENT FOR ASCERTAINING THE APPROPRIATE GOOD MANUFACTURING PRACTICE FOR EXCIPIENTS OF MEDICINAL PRODUCTS FOR HUMAN USE” for public consultation. Following presentation has been prepared by " Drug regulations" a not for profit organization which provides free online resources for the Pharmaceutical Professional.

1. This presentation is compiled by “ Drug Regulations”
a non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
9/17/2015 1

2.  This presentation is compiled from freely
available resource like the website of EMA.
 “Drug Regulations” is a non profit
organization which provides free online
resource to the Pharmaceutical Professional.
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.
9/17/2015 2
Drug Regulations : Online
Resource for Latest Information

3.  Regulatory basis
 Directive 2011/83/EC provides, in Article 46(f)
 The holder of the manufacturing authorisation shall ensure that the
excipients are suitable for use in medicinal products by ascertaining what
the appropriate good manufacturing practice is.
 This shall be ascertained on the basis of a formalised risk assessment in
accordance with the applicable guidelines referred to in the fifth paragraph
of Article 47.
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4.  Regulatory basis
 Such risk assessment shall take into account requirements under other
appropriate quality systems as well as the source and intended use of the
excipients and previous instances of quality defects.
 The holder of the manufacturing authorisation shall ensure that the
appropriate good manufacturing practice so ascertained, is applied.
 The holder of the manufacturing authorisation shall document the measures
taken under this paragraph
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5.  Regulatory basis
 The fifth paragraph of Article 47 of Directive 2001/83/EC.
 The Commission shall adopt guidelines on the formalised risk
assessment for ascertaining the appropriate good
manufacturing practice for excipients referred to in the second
paragraph of point (f) of Article 46
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6.  EUROPEAN COMMISSION HEALTH AND CONSUMERS DIRECTORATE-
GENERAL has issued a draft “GUIDELINES ON THE FORMALISED RISK
ASSESSMENT FOR ASCERTAINING THE APPROPRIATE GOOD
MANUFACTURING PRACTICE FOR EXCIPIENTS OF MEDICINAL PRODUCTS
FOR HUMAN USE”
 Draft published on February 6th , 2013.
 Open for comments till April 30th , 2013.
 Final Guidance published in March 2015
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7.  Manufacturing Authorisation Holder should incorporate
excipient risk assessment/risk management procedure in the
Quality Management System.
 Risk assessment/management documentation for appropriate
GMP for excipients should be available on site.
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8.  Use tools listed in
◦ EudraLex Volume 4, Guidelines for G M P , Medicinal Products for Human
and Veterinary Use, Part III: GMP Documents
◦ Quality Risk Management guidelines (ICHQ9)
 Assess the risks presented to the quality, safety and function
 Classify the excipient as “low risk”, “medium risk” or “high risk.
 Use tools like Hazard analysis and Critical point analysis
 Refer following links for additional information
◦ Quality Risk Management
◦ Quality Risk Managment : Basic Concept
◦ Basic Risk Facilitaation Methods.
◦ FMEA
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9.  Identify the risks presented to the quality, safety and
function of each excipient from its source :
◦ Animal
◦ Mineral
◦ Vegetable
◦ Synthetic
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10.  Evaluate risk w r t
◦ Transmissible Spongiform Encephalopathy
◦ Potential for viral contamination
◦ Potential for microbiological or endotoxin/pyrogen contamination
◦ Potential, in general, for any impurity originating from the raw materials
 Aflatoxins,
 Pesticides
 Generated as part of the process and carried over (e.g. residual
solvents and catalysts
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11.  Evaluate risk w r t
◦ Sterility assurance (for excipients claimed to be sterile)
◦ Potential for impurities in the absence of use of dedicated equipment
and/or facilities
◦ Environmental controls
◦ Storage conditions / transportation conditions
◦ Cold storage management
◦ Supply chain complexity
◦ Stability of excipient
◦ Packaging integrity evidence
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12.  Evaluate risk with respect to function of the excipient
◦ The pharmaceutical form and use of the medicinal product containing
the excipient (e.g. ointment product, injection/infusion etc.)
◦ The function of the excipient in the formulation (e.g. lubricant in a tablet
product or preservative material in a liquid formulation etc.)
◦ Proportion of excipient in the medicinal product
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13.  Evaluate risk with respect to function of the excipient
◦ Any known quality defects/fraudulent adulterations, both globally and at
a local company level related to the excipient;
◦ Whether the excipient is a composite;
◦ Known or potential impact on the critical quality attributes of the
medicinal product;
◦ Other factors as identified or known to be relevant to assuring patient
safety.
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14.  Document the risk profile of the excipient
 Establish the elements of EU-GMP needed to be in place in
order to control and maintain the quality of the excipient.
◦ EU-GMP, Part I, Annex 1 and Annex 2, Part II etc
 GMP needed will vary depending on the source, the supply
chain and the subsequent use of the excipient
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15.  As a minimum the following high level GMP principles
should be considered:
◦ Establishment and implementation of an effective
Pharmaceutical Quality system
◦ Sufficiently competent and appropriately qualified personnel
◦ Defined job descriptions for managerial and supervisory
staff responsible for manufacturing and quality activities
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16.  As a minimum the following high level GMP principles
should be considered:
◦ Training programmes for all staff involved in manufacturing
and quality Activities
◦ Training programmes related to health, hygiene and clothing
◦ Provision and maintenance of premises and equipment
appropriate to the intended operations
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17.  As a minimum the following high level GMP principles should be
considered:
◦ Documentation system(s) covering all processes
◦ Specifications for the various manufacturing and quality operations
◦ Qualification programme for suppliers
◦ System for quality control of the excipient and a responsible person
independent from production to release the batches;
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18.  As a minimum the following high level GMP principles should be
considered:
◦ Retention of records for incoming materials and excipients and retention
of samples of excipients for the periods required by EudraLex Volume 4,
Part II;
◦ Systems to ensure that any activity contracted out is subject to a written
contract;
◦ Maintenance of an effective system whereby complaints are reviewed
and excipients may be recalled;
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19.  As a minimum the following high level GMP
principles should be considered:
◦ Change management and deviation management
system;
◦ Self-inspection program;
◦ Environmental control and storage conditions.
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20.  Preform a gap analysis of the required GMP against the
activities and capabilities of the excipient manufacturer
 Obtain data / evidence for above through audit or from
information received from the excipient manufacturer
 Consider Quality system certification or accreditation of the
excipient manufacturer
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21.  Document the identified gaps between the required GMP and the activities
and capabilities of the excipient manufacturer
 Perform a further risk assessment to determine the risk profile for that
excipient manufacturer as
◦ Low risk,
◦ Medium risk or
◦ High risk
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22.  Use the Quality Risk Management guidelines (ICHQ9) – EU GMP to
classify the risk profile of the excipient manufacturer.
 Quality risk management tools such as those listed in there (HACCP etc.)
should be used for this.
 Implement a series of risk mitigation strategies ranging for the different
risk profiles from acceptance through control to unacceptable
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23.  Establish a control strategy based on
◦ Audit
◦ Document retrieval
◦ Testing
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24.  Perform on-going risk review based on
◦ Number of defects on received batches of excipients
◦ Type/severity of defects on excipients
◦ Monitoring and trend analysis of excipient quality;
◦ Loss of relevant quality system accreditation by excipient
manufacturer
◦ Observation of trends in drug product quality attributes (this will
depend on the nature and role of excipient)
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25.  Perform on-going risk review based on
◦ Observed organisational, procedural or
technical/process changes at the excipient
manufacturer;
◦ Audit (re-audit) of excipient manufacturer
◦ Questioners.
◦
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26.  Perform on-going risk review based on
◦ Based on the outcome of the risk review, the established
control strategy should be reviewed and revised if needed.
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27.  This presentation is compiled from freely
available resource like the website of EMA.
 “Drug Regulations” is a non profit
organization which provides free online
resource to the Pharmaceutical Professional.
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.
9/17/2015 27
Drug Regulations : Online
Resource for Latest Information