gdp and integrity of the supply chain -...
TRANSCRIPT
PCI Pharmaceutical Consulting Israel Ltd
QS, GDP (+GMP?)
Maintaining the Integrity of
The Supply Chain
Presented by: Karen Ginsbury
For IFF 01 March, 2017
Pharma Supply Chain
Standards of Good Distribution Practice (GDP) are applied to ensure that the high level of product quality achieved by observing Good Manufacturing Practice is maintained throughout the supply chain.
2
Raw
Material
Supply
Production Transport Warehouse DistributionEnd
user
Manufacturer Wholesaler
GMP GDP
Who / What are you / your company?
• Importer ?
• Wholesaler ?
• Agent ?
• Broker ?
• MAH ?
• Responsible and accountable
PCI Pharmaceutical Consulting Israel Ltd
We are looking at the
Quality System for• Pharmaceutical distributors
• Wholesalers
• Importers
• Exporters
• Pharma companies
• [Pharmacies, hospitals, health care
providers]
PCI Pharmaceutical Consulting Israel Ltd
What happened
• When and why did GDP become such a
major headache?
• Supply chain
• Temperature control of shipments
• Wooden pallets
• Track and trace
PCI Pharmaceutical Consulting Israel Ltd
Functional Requirements Document –
critical product paramaters:• Transportation: duration, mode(s) route(s)
• Product stability (established temp range)
• Packaging
• Min / Max expected shipping volumes
• Min / max thermal mass
• Expected ambient profiles
• Materials requirements
• Marketing requirements / restrictions
• User requirements
And so on….can purchase it for US$100PCI Pharmaceutical Consulting Israel Ltd
• GDP but from the end of the line
perspective
• E.g. can RT materials be shipped “cold?”
PCI Pharmaceutical Consulting Israel Ltd
What could go wrong
• Write down three risks and three
mitigations
PCI Pharmaceutical Consulting Israel Ltd
Quality Agreements
• With whom
• A tool?
• Risk reduction?
• What is their role in the QS?
PCI Pharmaceutical Consulting Israel Ltd
• Has a 20 page checklist of audit questions
for a pharmaceutical distribution
warehouse / service provider
PCI Pharmaceutical Consulting Israel Ltd
PCI Pharmaceutical Consulting Israel Ltd
Every Picture Tells a Story
PCI Pharmaceutical Consulting Israel Ltd
ONE CALL STARTS THE PROCESS
CONTAINER RENTAL (DRY ICE & BATTERIES)
PICKUP AT AIRLINE
CUSTOMS CLEARANCE IN EUROPE, CLEAR THE CARGO WHILE STILL IN-
FLIGHT
ENVIROTAINER LOADED, TEMPERATURE SET,
CONTAINER SEALED AND IMMEDIATELY TAKEN TO
AIRPORT
CUSTOMER CALL
PROCESS INITIATION
NON-STOP FLIGHT
ENROUTE TO CONSIGNEE
ARRIVAL AT CONSIGNEE LOCATION
ENROUTE
Quality is…
• Meeting all the requirements all the time
• We have to define the requirements
PCI Pharmaceutical Consulting Israel Ltd
What is a Quality System
• A process
• The sum total of the organized
arrangements made with the intention to
ensure that the processes support /
maintain a product meeting all its defined
requirements all the time
PCI Pharmaceutical Consulting Israel Ltd
PCI Pharmaceutical Consulting Israel Ltd
GDP (and GMP) Regulations
• LEGISLATION
• REGULATION
• GOOD MANUFACTURING PRACTICE
• GOOD DISTRIBUTION PRACTICE
• CURRENT
Good Manufacturing Practice
1. Pharmaceutical Quality System
2. Personnel
3. Premises and Equipment
4. Documentation
5. Production
6. Quality Control
7. Outsourced Operations
8. Complaints, Quality Defects and Product Recalls
9. Self-Inspection
PCI Pharmaceutical Consulting Israel Ltd
Size and Complexity of PQS
• 1.3 The size and complexity of the company’s activities should be taken into consideration when developing a new Pharmaceutical Quality System or modifying an existing one
• While some aspects of the system can be company-wide and others site-specific, the effectiveness of the system is normally demonstrated at the site level.
PCI Pharmaceutical Consulting Israel Ltd
Organizational Structure
• Communication especially of RISKs
• Start with AWARENESS that each link in
the chain must be secured
• Management Responsibility
• (back to Cap 1)
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Specifics
• Personnel responsibilities
• Oversight of outsourced operations
• Purchasing controls / supply chain
• Computerized systems – annex 11
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Specifics
• Documentation
• Reporting requirements
• Process and product monitoring
• CAPA
PCI Pharmaceutical Consulting Israel Ltd
Specifics
• Change control
• Deviations and non-conformances,
investigations
• Quality control
• Complaints, product quality defects and
recalls
• Self- inspection / internal audits
PCI Pharmaceutical Consulting Israel Ltd
PCI Pharmaceutical Consulting Israel Ltd
The size of the problem
• WHO estimates >12% of global medicines are counterfeit, costing the industry up to US$ billions a year
• Annual growth of counterfeit medicines outstrips that of legitimate medicines worldwide
• “The untrained eye wouldn’t distinguish the difference. Some of them contain active ingredients; some contain no ingredients; some lighter ingredients; and some toxic ingredients”
PCI Pharmaceutical Consulting Israel Ltd
GDP Definition
Good Distribution Practice (GDP) is that
part of quality assurance which ensures
that products are consistently stored,
transported and handled under suitable
condition as required by the marketing
authorisation (MA) or product specification
Consider
• EU: Directive and regulations
• WHO
• The role of the pharmacist (responsible
person)
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What Has Changed
• Maintenance of a quality system setting out responsibilities, processes and risk management principles in relation to wholesale activities
• Suitable documentation which prevents errors from spoken communication;
• Sufficient competent personnel to carry out all the tasks for which the wholesale distributor is responsible
• Adequate premises, installations and equipment to ensure proper storage and distribution of products
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What Has Changed
• Appropriate management of complaints, returns, suspected falsified medicinal products and recalls;
• Outsourced activities correctly defined to avoid misunderstandings;
• Rules for transport in particular to protect products against breakage, adulteration and theft, and to ensure that temperature conditions are maintained within acceptable limits during transport
• Specific rules for brokers (person involved in activities in relation to the sale or purchase of medicinal products)
PCI Pharmaceutical Consulting Israel Ltd 33/40
PCI Pharmaceutical Consulting Israel Ltd
GDP – The Aim
• Integrity meaning two things:
– Lack of tampering / prevent counterfeiting opportunities
• Reconciliation of quantities
• Tamper evident seals on individual units and on boxes
• Visual inspection
• Relabeling activities
– Safety and Efficacy (continuation of GMP)
• Storage and distribution temperatures and times
• Relabeling activities
34/40
PCI Pharmaceutical Consulting Israel Ltd
GDP – The Aim
• To get the product, manufactured under GMP to
the pharmacists and thereby to the end user in a
manner that ensures the integrity of the product
• Parties to GDP:
– The manufacturer
– The transporters
– The wholesale distributor
(and their transporters)
– The pharmacies
PCI Pharmaceutical Consulting Israel Ltd
GDP – The Aim
• Integrity meaning two things:
– Lack of tampering / prevent counterfeiting
opportunities
• Reconciliation of quantities
• Tamper evident seals on individual units and on boxes
• Visual inspection
• Relabeling activities
– Safety and Efficacy (continuation of GMP)
• Storage and distribution temperatures and times
• Relabeling activities
PCI Pharmaceutical Consulting Israel Ltd
Topics Covered by GDP Regulations
• Quality Systems
• Personnel
• Documentation
• Premises and Equipment
• Deliveries to Customers
• Returns
• Self Inspections
Quality System
• The system for managing quality should
encompass the organisational structure,
procedures, processes and resources, as
well as activities necessary to ensure
confidence that the product delivered
maintains its quality and integrity and
remains within the legal supply chain
during storage and/or transportation
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EU Directive November 2013
• Wholesale distribution of medicinal products is ‘all
activities consisting of procuring, holding, supplying or
exporting medicinal products, apart from supplying
medicinal products to the public
• Such activities are carried out with manufacturers or their
depositories, importers, other wholesale distributors or
with pharmacists and persons authorized or entitled to
supply medicinal products to the public
PCI Pharmaceutical Consulting Israel Ltd
PCI Pharmaceutical Consulting Israel Ltd
The legal basis - USA
• No specific GDP regulations
• Is apparently covered by state and
interstate laws rather than FDA regulated
• USP has chapter <1079>
Good Storage and Shipping Practices
in the general information chapters
• BUT do have the Drug Quality and
Security Act of 2013 and DSCSA
DSCSA – are you ready?
• https://www.fda.gov/Drug
s/DrugSafety/DrugIntegrit
yandSupplyChainSecurit
y/DrugSupplyChainSecur
ityAct/ucm427033.htm
PCI Pharmaceutical Consulting Israel Ltd
EU GDP Regulations: Principle
• The Community pharmaceutical industry
operates at a high level of quality assurance,
achieving its pharmaceutical quality objectives
by observing Good Manufacturing Practice to
manufacture medicinal products which must
then be authorised for marketing
• This policy ensures that products released for
distribution are of the appropriate quality
PCI Pharmaceutical Consulting Israel Ltd
EU GDP Regulations: Principle
• This level of quality should be maintained
throughout the distribution network so that
authorised medicinal products are
distributed to retail pharmacists and other
persons entitled to sell medicinal products
to the general public without any alteration
of their properties
PCI Pharmaceutical Consulting Israel Ltd
EU GDP Regulations: Principle
• The concept of Quality Management in the
pharmaceutical industry is described in Chapter
I of the Community Guide to Good
Manufacturing Practice for medicinal products
and should be considered when relevant for the
distribution of medicinal products
• The general concepts of quality management
and quality systems are described in the CEN
standards (series 29 000) = ISO 9000
PCI Pharmaceutical Consulting Israel Ltd
EU GDP Regulations: Principle
The quality system operated by distributors (wholesalers) of medicinal products should ensure that:
• medicinal products are authorised in accordance with Community legislation
• storage conditions are observed at all times, including during transportation
• contamination from or of other products is avoided
• an adequate turnover of the stored medicinal products takes place
• products are stored in appropriately safe and secure areas
PCI Pharmaceutical Consulting Israel Ltd
EU GDP Regulations: Principle
• The quality system should ensure that the
right products are delivered to the right
addressee within a satisfactory time period
• A tracing system should enable any faulty
product to be found
• There should be an effective recall
procedure
PCI Pharmaceutical Consulting Israel Ltd
What are the Risks in GDP?
• For a formal assessment need to use one
of the tools in ICH Q9 / Annex 20:
– HACCP
– FMEA
– Ishikawa (Fishbone) diagram + one of the
other methods
• Will take you to a lot of the points already
mentioned
Goods Picking – track and trace
• FeFo / FiFo?
• documentation
PCI Pharmaceutical Consulting Israel Ltd
Shipping / Vehicles / Fleet
• Qualification
• Dataloggers – how MANY???
• Contractors
PCI Pharmaceutical Consulting Israel Ltd
CHAPTER 2 – PERSONNEL
PRINCIPLE
• The correct distribution of medicinal products relies upon people. There must be sufficient competent personnel to carry out all the tasks for which the wholesale distributor is responsible. Individual responsibilities should be clearly understood by the staff and be recorded.
• Responsible Person: Quality Manager?
– Fulfill duties personally and be continuously contactable…
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Hygiene
• Appropriate procedures relating to
personnel hygiene, relevant to the
activities being carried out, should be
established and observed. Such
procedures should cover health, hygiene
and clothing.
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Chapter 3 – Premises and Equipment
Principle
• Wholesale distributors must have suitable
and adequate premises, installations and
equipment to ensure proper storage and
distribution of medicinal products
• In particular, the premises should be
clean, dry and maintained within
acceptable temperature limits
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Premises
• Premises should be designed or adapted to ensure that the required storage conditions are maintained. They should be suitably secure, structurally sound and of sufficient capacity to allow safe storage and handling of the medicinal products. Storage areas should be provided with adequate lighting to enable all operations to be carried out accurately and safely.
• Where premises are not directly operated by the wholesale distributor, a contract should be in place. The contracted premises should be covered by a separate wholesale distribution authorisation.
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Premises
• Medicinal products should be stored in
segregated areas which are clearly
marked and have access restricted to
authorised personnel. Any system
replacing physical segregation, such as
electronic segregation based on a
computerised system, should provide
equivalent security and should be
validated. PCI Pharmaceutical Consulting Israel
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Premises
• Reception areas where deliveries are
examined following receipt should be
designated
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Premises
• Premises should be designed and equipped so as to afford protection against the entry of insects, rodents or other animals. A preventive pest control programme should be in place.
• Rest, wash and refreshment rooms for employees should be adequately separated from the storage areas.
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Temperature and environment
control
• Suitable equipment and procedures
should be in place to check the
environment where medicinal products are
stored. Environmental factors to be
considered include temperature, light,
humidity and cleanliness of the premises
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Temperature mapping
• An initial temperature mapping exercise
should be carried out on the storage area
before use, under representative
conditions. Temperature monitoring
equipment should be located according to
the results of the mapping exercise,
ensuring that monitoring devices are
positioned in the areas that experience the
extremes of fluctuations. PCI Pharmaceutical Consulting Israel
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EQUIPMENT
• Adequate records of repair, maintenance and calibration activities for key equipment should be made and the results should be retained. Key equipment would include for example cold stores, monitored intruder alarm and access control systems, refrigerators, temperature and humidity recording devices, air handling units and any equipment used in conjunction with the onward supply chain.
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Chapter 4- Documentation
Principle
• Good documentation constitutes an
essential part of the quality system.
Written documentation should prevent
errors from spoken communication and
permits the tracking of relevant operations
during the distribution of medicinal
products.
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Documentation
• Documentation should be sufficiently
comprehensive with respect to the scope
of the wholesale distributor’s activities and
in a language understood by personnel. It
should be written in clear, unambiguous
language and be free from errors.
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Documentation
• Version control should be applied to
procedures. After revision of a document a
system should exist to prevent inadvertent
use of the superseded version.
Superseded or obsolete procedures
should be removed from workstations and
archived.
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Chapter 5 – Operations
Principle
• Actions taken by distributors should ensure that the identity of the medicinal product is not lost and that the distribution is performed according to the information on the outer packaging
• The distributor should use all means available to minimise the risk of falsified medicinal products entering the legal supply chain.
• All medicinal products distributed in the EU by a wholesale distributor must be covered by a marketing authorisation granted by the EU or by a Member State
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Chapter 5 – Operations
Principle• Any distributor, other than the marketing
authorisation holder, who imports a medicinal product from another Member State must notify the marketing authorisation holder and the competent authority in the Member State to which the medicinal product will be imported of their intention to import that product
• All key operations described below should be fully described in the quality system in appropriate documentation
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Receipt of Medicinal Products
• The purpose of the receiving function is to
ensure that the arriving consignment is
correct, that the medicinal products
originate from approved suppliers and that
they have not been visibly damaged
during transport.
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Damage during transport
• Can have pallets dropped or other
accident (water damage) that is not visible
on receipt
• Signs of opening…
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Qualification of Suppliers
• Only purchase products through an
approved, documented supply chain with
appropriate authorisations
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Qualification of customers
• Wholesale distributors must ensure they
supply medicinal products only to persons
who are themselves in possession of a
wholesale distribution authorisation or who
are authorised or entitled to supply
medicinal products to the public.
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Cap 6 – Complaints, Returns,
Suspect Falsified and Recalls –
Principle• All complaints, returns, suspected falsified
medicinal products and recalls must be recorded and handled carefully according to written procedures
• Records should be made available to the competent authorities
• An assessment of returned medicinal products should be performed before any approval for resale
• A consistent approach by all partners in the supply chain is required in order to be successful in the fight against falsified products
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Complaints
• Refer to Revisions to Chapter 8 in GMPs –
just revised and address QUALITY
DEFECTS
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Returns – Case Studies
• Time limitations
• Conditions
• Separation
• Return to stock?
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Chapter 7 – Outsourced Activities
Principle
• Any activity covered by the GDP Guide that is outsourced should be correctly defined, agreed and controlled in order to avoid misunderstandings which could affect the integrity of the product
• There must be a written Contract between the Contract Giver and the Contract Acceptor which clearly establishes the duties of each party.
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Quality Agreement
• Shippers, forwarders, airlines
• Storage and distribution (distributors)
• Brokers and agents
• Importers
• Manufacturers if you import
• Other…calibration, maintenance, pest
control…
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Chapter 8 – Self Inspections
Principle
• Self-inspections should be conducted in
order to monitor implementation and
compliance with GDP principles and to
propose necessary corrective measures
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Chapter 9 – Transportation
Principle
• It is the responsibility of the supplying wholesale distributor to protect medicinal products against breakage, adulteration and theft, and to ensure that temperature conditions are maintained within acceptable limits during transport
• Regardless of the mode of transport, it should be possible to demonstrate that the medicines have not been exposed to conditions that may compromise their quality and integrity. A risk-based approach should be utilised when planning transportation
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Transportation
• Packaging for transportation
– Type of boxes
– Sealing and other anti-counterfeit measures
– Method of loading within containers
– Insulating measures
– validation
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Transportation
• Definition for temperature range during
transport
– 150-250C (for Room Temperature)
– 20-80C (for Cold chain products)
APPROPRIATE CONDITIONS AS PROVED
BY STABILITY STUDIES
COOLER IS NOT NECESSARILY BETTER
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Transportation
• Temperature data loggers
– Type
– Number
– Location
– Calibration
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Transportation
• Type of shipping container:
– Environtainer
– Insulated boxes/pallets
– Uncontrolled container
• For cold chain products in insulated boxes
– Note : insulated boxes with cooling packs may
not be stored under refrigerated conditions
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Transportation
• Transportation route
– Location of starting point
– Land shipper (train, trucks)
– In transit hubs
– Air/Sea shipper
– Customs
– Land shipping to warehouse
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Transportation
• Transportation route– Is the route fixed?
– Duration?
– Unexpected events?
• Forwarders– Do they have the knowledge and expertise in
handling of pharmaceuticals?
– How many are involved?
– How do they communicate?
– What is the exact point of delivery of charge?
– Where is it defined
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Transportation
• Forwarders:
• Does the forwarder have a quality system in place?
• How many subcontractors are involved?
• How are subcontractors qualified?
• Does the forwarder have to inform where deviations during transport occur?
• Does the forwarder notify on major changes prior to implementation?
• How long are records kept?
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Chapter 10 – Brokers
Principle
• A ‘broker’ is a person involved in activities
related to sale or purchase of products,
except for wholesale distribution, that do
not include physical handling and that
consist of negotiating independently and
on behalf of another legal or natural
person
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Chapter 10 – Brokers
Principle• Brokers are subject to a registration
requirement. They must have a permanent address and contact details in the Member State where they are registered. They must notify the competent authority of any changes to those details without unnecessary delay.
• Requirements for premises, installations and equipment do not apply
• However, all other rules in Directive 2001/83/EC that apply to wholesale distributors also apply to brokers
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PCI Pharmaceutical Consulting Israel Ltd
Quality Reviews
• CAPA system is an integral part of any
functional quality system
(Corrective and Preventive Actions)
• Periodic quality reviews at the
management level (means General
Manager or President) engages their
attention and allows for resources to be
diverted as needed
PCI Pharmaceutical Consulting Israel Ltd
Quality Reviews
• Formal reviews should be performed
• Don’t focus on positive!!
• Highlight UNRESOLVED problems so that
management can provide the solutions
– We need 4 new refrigerated vans
– The warehouse cannot maintain the required
temperature profile in summer and summer is
approaching
– We need additional quarantine storage space
(provide figures)
PCI Pharmaceutical Consulting Israel Ltd
Measures of Improvement
• Complaints (logistics AND quality):
– Reduction in number
– Reduction in severity
– Decreased response time
• Deviations (as above)
• Self-inspection / vendor audits
– Reduction in severity of findings
– Improved quality of responses
– Improved response time
PCI Pharmaceutical Consulting Israel Ltd
CAPA Program
1. ID existing problems CA
– ID quality data sources
– analyze data
2. ID potential problems PA
– as above (but trends, SPC)
3. Challenge Data– complete, accurate, timely
4. Identify extent of problems
5. Failure investigation– Follow SOP; depth relative to
risk, root cause if possible, stop distribution
6. Appropriate Action Taken
7. Actions:– appropriate; verified /
validated, do notadversely affect product
8. Actions:– implemented
– documented
9. Information Transfer tothose responsible for– assuring product quality
– preventing quality problems
PCI Pharmaceutical Consulting Israel Ltd
In conclusion
• GMP / GDP regulations: EU and WHO, USP
• FDA appear to be lagging behind but ISO is certainly a good place to start
• Quality System MUST be in place
• Would expect a Quality Manager who is familiar with GDP requirements
• Need quality contracts in place and need to audit:– Manufacturing sites
– Your distributor
– Their distributor
– Their print houses (or rely on their audits)