gdp and integrity of the supply chain -...

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


We are looking at the

Quality System for• Pharmaceutical distributors

• Wholesalers

• Importers

• Exporters

• Pharma companies

• [Pharmacies, hospitals, health care

providers]


What happened

• When and why did GDP become such a

major headache?

• Supply chain

• Temperature control of shipments

• Wooden pallets

• Track and trace


GDP development

Timelines based on PDA TRs


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?”


Map out the process for distribution

PCI Pharmaceutical Consulting Israel

Ltd10

What could go wrong

• Write down three risks and three

mitigations


Quality Agreements

• With whom

• A tool?

• Risk reduction?

• What is their role in the QS?


• Has a 20 page checklist of audit questions

for a pharmaceutical distribution

warehouse / service provider



Every Picture Tells a Story

http://www.airliners.net/photo/El-Al-Israel/Boeing-767-258-ER/1333967

http://www.airliners.net/photo/El-Al-Israel/Boeing-767-258-ER/1333967


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


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



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


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.


Organizational Structure

• Communication especially of RISKs

• Start with AWARENESS that each link in

the chain must be secured

• Management Responsibility

• (back to Cap 1)


Specifics

• Personnel responsibilities

• Oversight of outsourced operations

• Purchasing controls / supply chain

• Computerized systems – annex 11


Specifics

• Documentation

• Reporting requirements

• Process and product monitoring

• CAPA


Specifics

• Change control

• Deviations and non-conformances,

investigations

• Quality control

• Complaints, product quality defects and

recalls

• Self- inspection / internal audits



•C

ou

nte

rfeit M

ed

icin

es

To Protect the Public


How can Counterfeits enter the

legitimate supply chain


Too close for comfort?



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”


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)


Ltd31

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

PCI Pharmaceutical Consulting Israel Ltd 32/40

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)



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


34/40


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


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


– Safety and Efficacy (continuation of GMP)

• Storage and distribution temperatures and times



Topics Covered by GDP Regulations

• Quality Systems

• Personnel

• Documentation

• Premises and Equipment

• Deliveries to Customers

• Returns

• Self Inspections


The Legal Basis - EU


EU GDP Regulations: Principle

Quality Management

39/40

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


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



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 FDA USA


DSCSA – are you ready?

• https://www.fda.gov/Drug

s/DrugSafety/DrugIntegrit

yandSupplyChainSecurit

y/DrugSupplyChainSecur

ityAct/ucm427033.htm

https://www.fda.gov/Drugs/DrugSafety/DrugIntegrityandSupplyChainSecurity/DrugSupplyChainSecurityAct/ucm427033.htm



• 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



• 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



• 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



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



• 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

WHO GDP

• 30 page guidance from 2010

• Was basis for EU



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

Relabelling Controls


Temperature Control

• Risks and mitigation?


Goods Picking – track and trace

• FeFo / FiFo?

• documentation


Shipping / Vehicles / Fleet

• Qualification

• Dataloggers – how MANY???

• Contractors


Returns and Customer service

Recalls, Complaints


Audit

• By you

• Of you


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

Ltd63

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


Ltd66

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.


Ltd75

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


Ltd76

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.


Ltd81

Destruction of obsolete goods


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Picking


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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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Vehicles - Fleet

• Yours or theirs



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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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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


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)


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


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


Program in place, Audit,

Management Involvement


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)

gdp and integrity of the supply chain -...

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