Good distribution practices for API's

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.
3/29/2015 1

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.
3/29/2015 2
Drug Regulations : Online
Resource for Latest Information

 “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.
3/29/2015 3
Drug Regulations - Online
Resource latest information.

 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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 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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 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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Additional requirements apply to the importation of
active substances, as laid down in Article 46b of
Directive 2001/83/EC.
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These Guidelines are applicable as of
September 21 , 2015.
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 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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 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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 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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 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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 Should be adequately resourced
 Competent personnel
 Suitable and sufficient premises
 Equipment and facilities
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 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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 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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 Development & Modification of Quality
System
◦ Consider the size, structure and complexity of
the distributor’s activities
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 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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 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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 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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 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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 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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 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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 Written
 Describe distribution activities which affect
the quality of the active substances
◦ Receipt and checking of deliveries
◦ Storage
◦ Cleaning
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 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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 Procedures
◦ Approved
◦ Signed
◦ Dated
 By person responsible for the quality system
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 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
3/29/2015 26

 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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 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
3/29/2015 28

 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
3/29/2015 29

 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.
3/29/2015 30

 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.
3/29/2015 31

 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
3/29/2015 32

 Orders
◦ Manufacturer, importer or distributor of
API established in the EU should be
registered according to Article 52a of
Directive 2001/83/EC
3/29/2015 33

 Receipt
 Reception area
◦ Protect deliveries from prevailing weather
conditions during unloading
◦ Separate from the storage area.
3/29/2015 34

 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.
3/29/2015 35

 Receipt
◦ Quarantine consignment
 Physical
 Equivalent Electronic system
◦ Broken seals
◦ Damaged packaging
◦ Suspected of possible contamination
◦ Investigate the cause of the issue
3/29/2015 36

 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
3/29/2015 37

 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.
3/29/2015 38

 Receipt
◦ Rejected materials
◦ Identify
◦ Control
◦ Quarantined
 Prevent use in manufacturing
 Prevent further distribution.
◦ Records of destruction activities should be readily
available.
3/29/2015 39

 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
3/29/2015 40

 Storage Facility / Area
◦ Clean
◦ Free from litter, dust and pests
◦ Implement precautions against
 Spillage
 Breakage,
 Attack by micro-organisms
 Cross-contamination.
3/29/2015 41

 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
3/29/2015 42

 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.
3/29/2015 43

 Deliveries to customers
◦ Supplies within the EU
 Only by distributors registered according to Article
52a of Directive 2001/83/EC
3/29/2015 44

 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
3/29/2015 45

 Transfer of Information
◦ Notification to customers
 Any adverse information or event
 Potential to cause an interruption to supply
3/29/2015 46

◦ 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
3/29/2015 47

◦ 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.
3/29/2015 48

 Returns
 Identify
 Quarantine
 Conduct investigation
3/29/2015 49

 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
3/29/2015 50

 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
3/29/2015 51

 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.
3/29/2015 52

 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
3/29/2015 53

 Complaints
◦ May be received orally or in writing
◦ Record all complaints
◦ Investigate according to a written procedure
◦ Review Quality Complaint with manufacturer
3/29/2015 54

 Complaints
◦ Determine need for further action
 With other customers
 With the competent authority
 Or both.
◦ Conduct Investigation
◦ Document investigation
3/29/2015 55

 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
3/29/2015 56

 Retain records of complaints
 Take appropriate corrective action
 Evaluate
◦ Trends
◦ Product related frequencies
◦ Severity
 Make these records available to competent
authorities
3/29/2015 57

 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
3/29/2015 58

 Serious or Potentially life-threatening
situation
 Inform
◦ Local authorities
◦ National authorities
◦ International authorities
◦ Obtain their advice
3/29/2015 59

 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
3/29/2015 60

 Conduct & Record Self Inspections
 Self Inspections should monitor the
implementation of and compliance with this
guideline.
3/29/2015 61

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.
3/29/2015 62
Drug Regulations : Online
Resource for Latest Information

Good distribution practices for API's

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