The European Commission Health and Consumers Directorate – General has published a draft “GUIDELINES ON THE PRINCIPLES OF GOOD DISTRIBUTION PRACTICES FOR ACTIVE SUBSTANCES FOR MEDICINAL PRODUCTS FOR HUMAN USE”.
The guideline addresses Quality systems, Personnel, Documentation, Order, Procedures, Records, Premises and Equipment, Receipts, Storage , Deliveries to Customers, Transfer of Information and Returns.
Following presentation is prepared by “ Drug Regulations” a non profit organization which provides free online resource to the Pharmaceutical Professional.
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Good distribution practices for API's
1. This presentation is prepared 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.
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2. This presentation is compiled from freely available
resources like the website of EU , EMA , specifically
“Guidelines on principles of Good Distribution
Practice of active substances for medicinal
products for human use”
“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.
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3. “GUIDELINES ON THE PRINCIPLES OF GOOD DISTRIBUTION
PRACTICES FOR ACTIVE SUBSTANCES FOR MEDICINAL
PRODUCTS FOR HUMAN USE”
Published in February 2012
Comments were open till February 2013.
Final guidance published on in March 2015.
This presentation gives a summary of this guidelines.
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4. Based on the fourth paragraph of Article 47 of
Directive 2001/83/EC
Follow principles of
◦ EudraLex Volume 4, Part II, Chapter 17, with regard to the
distribution of active substances and
◦ Guidelines of 5 November 2013 on Good Distribution Practice of
medicinal products for human use
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5. Provide stand-alone guidance on Good Distribution
Practice (GDP)
To be followed by
◦ Importers and distributors of active substances for medicinal
products for human use.
◦ Distributors of active substances manufactured by themselves.
Complement rules on distribution set out in the
guidelines of EudraLex Volume 4, Part II
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6. Commission Delegated Regulation (EU) No
1252/2014 (3) and EudraLex Volume 4, Part II are
applicable to
◦ Any manufacturing activities in relation to active substances
including
Re-packaging,
Re-labelling or
Dividing up
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7. Additional requirements apply to the importation of
active substances, as laid down in Article 46b of
Directive 2001/83/EC.
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8. These Guidelines are applicable as of
September 21 , 2015.
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9. Applicable to distribution of active substances,
◦ Defined in Article 1(3a) of Directive 2001/83/EC, for
medicinal products for human use.
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10. Active substances,
◦ An active substance is any substance or mixture of
substances intended to be used in the manufacture of a
medicinal product and that, when used in its production,
becomes an active ingredient of that product intended to
exert a pharmacological, immunological or metabolic
action with a view to restoring, correcting or modifying
physiological functions or to make a medical diagnosis.
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11. Distribution of active substances shall comprise all
activities consisting of
◦ Procuring
◦ Importing
◦ Supplying or exporting active substances
◦ Brokering
Guidelines do not apply to intermediates of active
substances.
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12. Develop and maintain a quality system
Set out responsibilities
Use process and risk management principles
Examples of quality risk management
◦ EudraLex Volume 4, Part III: GMP related documents
◦ ICH guideline on Quality Risk Management (ICH Q9).
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13. Should be adequately resourced
Competent personnel
Suitable and sufficient premises
Equipment and facilities
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14. Quality System should ensure that:
1. Active substances are procured, imported, held, supplied or
exported in a way that is compliant with the requirements of
GDP for active substances
2. Management responsibilities are clearly specified
3. Active substances are delivered to the right recipients within a
satisfactory time period
4. Records are made contemporaneously
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15. Quality System should ensure that:
4. Deviations from established procedures are documented
and investigated;
5. Appropriate corrective and preventive actions, commonly
known as ‘CAPA’, are taken to correct deviations and
prevent them in line with the principles of quality risk
management;
6. Changes that may affect the storage and distribution of
active substances are evaluated.
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16. Development & Modification of Quality
System
◦ Consider the size, structure and complexity of
the distributor’s activities
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17. Designated person
◦ Appoint at each location where distribution activities
are performed
◦ Should have defined authority and responsibility
◦ Should ensure that a quality system is implemented
and maintained
◦ Should fulfil his responsibilities personally
◦ Designated person can delegate duties but not
responsibilities
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18. Specify & document responsibilities of all
Should have the appropriate competence
and experience
Should ensure that active substances are
properly handled, stored and distributed.
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19. Training
◦ Initial
◦ Continuing / ongoing
◦ Relevant to their role
◦ Based on written procedures
◦ In accordance with a written training programme
◦ Cover requirements of GDP
◦ Keep record of all training
◦ Assess effectiveness of training
◦ Document effectiveness assessment
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20. Documentation
◦ Paper or in electronic data
◦ Written procedures
◦ Instructions
◦ Contracts
◦ Records
◦ Readily available
◦ Retrievable.
◦ Made available to competent authorities on request
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21. Documentation
◦ Sufficiently comprehensive w r t distributor’s
activities
◦ In a language understood by personnel
◦ Clear, unambiguous language
◦ Free from errors
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22. Documentation
◦ Any alteration should be signed and dated
◦ Any alteration should permit the reading of the
original information
◦ Reason for the alteration should be recorded
◦ Ready access to all responsible & accountable
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23. Written
Describe distribution activities which affect
the quality of the active substances
◦ Receipt and checking of deliveries
◦ Storage
◦ Cleaning
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24. Describe distribution activities which affect the
quality of the active substances
◦ Maintenance of the premises & Pest control
◦ Recording of the storage conditions
◦ Security of stocks on site & of consignments in transit
◦ Withdrawal from saleable stock
◦ Handling of returned product
◦ Recall plans
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25. Procedures
◦ Approved
◦ Signed
◦ Dated
By person responsible for the quality system
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26. Procedures
◦ Use only valid and approved procedures
◦ Review regularly
◦ Keep up to date
◦ Apply version control
◦ Implement document control system
◦ Prevent inadvertent use of the superseded version
◦ Remove superseded or obsolete procedures & archive
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27. Records
◦ Clear
◦ Be made at the time each operation is performed
◦ Significant activities or events are traceable
◦ Retained for at least 1 year after the expiry date
◦ For actives with retest dates for at least 3 years
after the batch is completely distributed
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28. Records that should be retained and be available include:
(i) Identity of supplier, original manufacturer, shipping agent and/or
consignee
(ii) Address of supplier, original manufacturer, shipping agent and/or
consignee
(iii) Purchase orders
(iv) Bills of lading, transportation and distribution records;
(v) Receipt documents
(vi) Name or designation of active substance
(vii) Manufacturer’s batch number
(viii) Certificates of analysis, including those of the original manufacturer;
(ix) Retest or expiry date
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29. Records
◦ Each purchase and sale
◦ Date of purchase or supply
◦ Name of the active substance
◦ Batch number
◦ Quantity received or supplied
◦ Name and address of the supplier
◦ Name & address of the original manufacturer, if not the same
◦ Name & address of the shipping agent and/or the consignee
◦ Ensure traceability of the origin and destination of products
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30. Records
Records that should be retained and be available include:
(i) Identity of supplier, original manufacturer, shipping agent and/or
consignee;
(ii) Address of supplier, original manufacturer, shipping agent and/or
consignee;
(iii) Purchase orders;
(iv) Bills of lading, transportation and distribution records;
(v) Receipt documents;
(vi) Name or designation of active substance;
(vii) Manufacturer’s batch number;
(viii) Certificates of analysis, including those of the original manufacturer;
(ix) Retest or expiry date.
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31. Premises & Equipment
◦ Suitable and adequate
◦ Ensure proper storage & protection from
contamination
Narcotics
Highly sensitising materials
Materials of high pharmacological activity or toxicity
Distribution of active substances.
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32. Premises & Equipment
◦ Suitably secure to prevent unauthorised
access
◦ Installed with monitoring devices to
guarantee the quality attributes
◦ Monitoring devices should be calibrated
◦ Approved & written schedule
◦ Use of certified & traceable standards
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33. Orders
◦ Manufacturer, importer or distributor of
API established in the EU should be
registered according to Article 52a of
Directive 2001/83/EC
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34. Receipt
Reception area
◦ Protect deliveries from prevailing weather
conditions during unloading
◦ Separate from the storage area.
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35. Receipt
Examine deliveries
(i) Containers are not damaged;
(ii) All security seals are present with no sign of tampering;
(iii) Correct labelling, including correlation between the name used
by the supplier and the in-house name, if these are different;
(iv) Necessary information, such as a certificate of analysis, is
available; and
(v) The active substance and the consignment correspond to the
order.
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36. Receipt
◦ Quarantine consignment
Physical
Equivalent Electronic system
◦ Broken seals
◦ Damaged packaging
◦ Suspected of possible contamination
◦ Investigate the cause of the issue
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37. Receipt
◦ Specific storage measures
Narcotics
Products requiring a specific storage
Temperature or humidity
◦ Identify immediately
◦ Store in accordance with written instructions
◦ Follow relevant legislative provisions
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38. Receipt
◦ Falsified A P I
◦ Segregate
Physically or
Using an equivalent electronic system
◦ Inform the national competent authority of
the country in which he is registered.
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39. Receipt
◦ Rejected materials
◦ Identify
◦ Control
◦ Quarantined
Prevent use in manufacturing
Prevent further distribution.
◦ Records of destruction activities should be readily
available.
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40. Storage
◦ Store under conditions specified by the manufacturer
◦ Controlled temperature and humidity when necessary
◦ In a manner to prevent contamination and/or mix up
◦ Monitor storage conditions
◦ Maintain records
◦ Quality responsible should review records
◦ Qualify storage area for specific storage conditions
◦ Operate area within specified limits
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41. Storage Facility / Area
◦ Clean
◦ Free from litter, dust and pests
◦ Implement precautions against
Spillage
Breakage,
Attack by micro-organisms
Cross-contamination.
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42. Storage
◦ Implement stock rotation,
‘first expiry (retest date), first out’,
◦ Check regularly that the system is operating correctly.
◦ Validate electronic warehouse management systems
◦ Separate Active substances beyond their expiry date
from approved stock
Physical separation or use an equivalent electronic
◦ Ensure that this material is not supplied
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43. Contracted Storage & Distribution
◦ Ensure that contractor
Knows his responsibilities
Follows the appropriate storage and transport conditions
◦ Have a written contract
Clearly establish duties of each party.
Do not permit further sub contracting without written
authorisation.
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44. Deliveries to customers
◦ Supplies within the EU
Only by distributors registered according to Article
52a of Directive 2001/83/EC
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45. Deliveries to customers
◦ Transport in accordance with conditions specified by
the manufacturer
◦ Transport should not adversely quality.
◦ Maintain product, batch and container identity at all
times.
◦ All original container labels should remain readable.
◦ Implement a system for identification & recall
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46. Transfer of Information
◦ Notification to customers
Any adverse information or event
Potential to cause an interruption to supply
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47. Transfer of Information
◦ Regulatory Information
◦ Product Quality Information
Distributor responsible for transfer
From an active substance manufacturer to the
customer
From the customer to the active substance
manufacturer
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48. Transfer of Information
◦ Distributor to provide information from the manufacturer to
the customer :
Name and address of the original active substance manufacturer
Batch number(s) supplied
Copy of the original certificate of analysis
Identity of manufacturer to competent authorities upon request
Original manufacturer can respond to the competent authority
directly or through its authorised agents
C OA
Refer section 11.4 of Part II of Eudralex Volume 4.
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50. Active substances should only be returned to saleable stock
if:
The active substance is in the original unopened container(s)
and in good condition
It is demonstrated that the active substance have been stored
and handled under proper conditions
The remaining shelf life period is acceptable
They have been examined and assessed by a person authorised
to do so
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51. Maintain records of returns.
Include following details in the records:
Name and address of the consignee
Active substance batch number and quantity
returned
Reason for return
Use or disposal of the returned active substance
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52. This assessment should take into account
The nature of the active substance
Any special storage conditions it requires
The time elapsed since it was supplied.
Give special attention to products requiring special
storage conditions.
Seek advice from the manufacturer of the active
substance.
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53. Release to active stock
◦ Only by appropriately trained and authorised
personnel
◦ Place such that the 'first expiry (re-test date)
first out' system operates effectively
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54. Complaints
◦ May be received orally or in writing
◦ Record all complaints
◦ Investigate according to a written procedure
◦ Review Quality Complaint with manufacturer
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55. Complaints
◦ Determine need for further action
With other customers
With the competent authority
Or both.
◦ Conduct Investigation
◦ Document investigation
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56. Complaint records should include:
◦ Name and address of complainant
◦ Name (and, where appropriate, title) and phone number of person submitting
the complaint
◦ Complaint nature (including name and batch number of the active substance)
◦ Date the complaint is received
◦ Action initially taken (including dates and identity of person taking the action)
◦ Any follow-up action taken
◦ Response provided to the originator of complaint (including date response sent)
◦ Final decision on active substance batch or lot
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57. Retain records of complaints
Take appropriate corrective action
Evaluate
◦ Trends
◦ Product related frequencies
◦ Severity
Make these records available to competent
authorities
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58. Responsibility of Original
Manufacturer
◦ Distributor may refer to Original Manufacture
◦ Distributor record should include Manufacturer
response
◦ Record the date and information provided by
original manufactuer
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59. Serious or Potentially life-threatening
situation
Inform
◦ Local authorities
◦ National authorities
◦ International authorities
◦ Obtain their advice
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60. Recall
◦ Designate a person to handle recalls
◦ Written procedure
◦ Define circumstances for recall
◦ Define
Person to evaluate information
How to initiate a recall
Whom to inform about recall
How to treat recalled material
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61. Conduct & Record Self Inspections
Self Inspections should monitor the
implementation of and compliance with this
guideline.
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62. This presentation was compiled from freely
available resources like the website of EU , EMA ,
specifically “Guidelines on principles of Good
Distribution Practice of active substances for
medicinal products for human use”
“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.
3/29/2015 62
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