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Integrating Good Distribution Practice Into The QMS

By Tim Sandle Sep 24, 2020 7:00 am EDT

Peer Reviewed

Editor’s Note - This topic is covered in a chapter of the recently

published, “Good Distribution Practice: A Handbook for
Healthcare Manufacturers and Suppliers, Volume 1,” as edited by Siegfried Schmitt. This article
will demonstrate the essential points for incorporation of GDP into the QMS based on the
strengths of the control mechanisms in place with the QMS to further ensure compliance with
GDP.

INTRODUCTION
Good Distribution Practice (GDP) concerns the distribution processes for pharmaceutical products
that results in medics and patients obtaining access to the medications required. For the
pharmaceutical organization, the distribution process occurs both upstream and downstream.
Upstream are the suppliers who create goods and services used in a manufacturer’s own
operations, such as raw components or materials. The downstream supply chain efficiently
distributes a company’s products or services to its customers. Each stage, both upstream and
downstream, needs to be proactively managed to minimize quality, as well as financial,
confidentiality, operational, reputational and legal risks.

These distribution processes concern supply chain, including cold supply chains (where required),
and the tracking and tracing of medicines. Traceability includes ensuring that the required
environmental controls are met, and that tampering or fraudulent activities are avoided, to the
level that each individual item can be traced from the completion of manufacture to its arrival with
the end-user (Marucheck et al., 2011). The distribution network for medicinal products is invariably
complex and it involves many different parties at different stages. In addition to the challenges
associated with this complexity and with protecting the product from being affected by
environmental conditions, damage, or loss, there is also a threat from criminal activities centered
on seeking to introduce falsified medicines into the supply chain (Bruinsma and Bernasco, 2004).

GDP requirements are designed to codify and to structure the processes. These requirements bear
close similarity to the requirements set out in Good Manufacturing Practice (GMP) regulations. The
primary difference is that GDP covers the wholesale distribution of medicines, whereas GMP covers
their manufacture. The overlap between the two rest with the need to maintain product quality
after a batch has been released from the manufacturing site, as well as the necessity to monitor
and control complaints, address problems, and have a system in place to enact a recall.

In assessing the requirements for GDP, there are different national and supranational standards. In
the US GMP is based on the Code of Federal Regulations 21 CFR 210/211, with additional guidance
contained within USP chapter 1079 “Good Storage and Distribution Practices for Drug Products.”
(USP, 2018a) There is an additional USP chapter of interest, chapter 1197 “Good Distribution
Practices for Pharmaceutical Excipients” (USP, 2018b). For Europe GDP is based on the Directive of
the Board of the European Community 92/25/EEC regarding the wholesale distribution of drugs for
human consumption, supported by guideline 2015/C 95/ 01 (European Commission, 2015), and the
Falsified Medicines Directive (European Commission, 2011), which requires a unique identifier and
an anti-tampering device to allow the verification of the authenticity of medicinal products. With the
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World Health Organization, the applicable text is Annex 5 of the WHO recommendations “good
distribution practices for pharmaceutical products.” (WHO, 2010a) One commonality through these
regulations and following on from items raised during pharmaceutical organization inspections, is
with a focus on serialization. This has required for new strategies, processes, and technologies that
allow for a business to, at any time, pinpoint the location and origin of any single drug.

A weak GDP system is one where there is a key disconnect between the manufacturer and the
process that occurs once the product leaves the facility (Rees, 2013). An overarching area of
regulatory concern is with the effectiveness of the incorporation of GDP into the Quality
Management System (QMS), a system that applies for both wholesaler and broker. This chapter
looks at Quality Risk Management in relation to GDP, covering areas like good distribution
principles, the necessity of having Quality Technical Agreements in place, and measures to take
appropriate corrective and preventative actions should deviations occur.

QUALITY MANAGEMENT SYSTEMS AND GDP

It is essential that the principles of Quality Management are understood and put into effect by
pharmaceutical distributors. Moreover, it is important that activities relating to the distribution of
pharmaceuticals are detailed within appropriate, approved procedures that set out clear
responsibilities for personnel and management. For this to happen, a robust quality system is
required. This system benefits both the customer and the supplier, allowing an organization to
ensure that it routinely delivers the expected service to the customer, reducing the time and
resource required to investigate and rectify errors and helping to maintain customer satisfaction
levels.

The Quality Management System (QMS) refers to a system that documents processes, procedures,
and responsibilities for achieving quality policies and objectives. In keeping with the ISO 9001
definition (ISO, 2015), a QMS is a formal system that helps coordinate and direct an organization’s
activities to meet both customer needs and regulatory requirements. Central to the QMS is the
philosophy of continuous improvement, in order to improve effectiveness and efficiency. To deliver
a successful QMS the correct management responsibilities need to be in place together with
appropriate leadership within the organization (Savin, 2016). For pharmaceuticals it is customary to
prefix the QMS with the nature of the industry – Pharmaceutical Quality System, sometimes
initialized to “PQMS”, as set out in ICH Q10 (ICH, 2008). ICH Q10 captures the range of activities
beginning with the acquisition and control of materials and stretching to the process of release,
storage, and distribution. ISO 9001 certification, for pharmaceutical and healthcare products, is not
sufficient to meet the GDP licensing requirements and the content of the main regulations,
described in the introduction, need to be taken account of.

Distributors of active substances need to develop and maintain a quality system setting out
responsibilities, processes and risk management principles. This quality system needs to be
appropriate and fitting to the individual organization. Sometimes generic quality systems are put in
place with only minor alterations made, such as a change of address. This approach fails to take
into account the size, structure and complexity of the organization’s distribution activities. This can
lead to losses and increase the risk of falsified medicines entering the supply chain.

A good QMS for GDP will operate in such a way so that:

Active substances are procured, imported, held, supplied or exported in a way that is
compliant with the requirements of national, regional or supranational GDP requirements for
active substances.
Active substances are delivered to the intended recipients within a satisfactory time period.
Management responsibilities are clearly outlined.
The GDP process has been risk assessed.
Records are made contemporaneously.
Any deviations from established procedures are documented and investigated.
Suitable corrective and preventive actions are implemented to correct deviations and to
prevent similar incidences from occurring.
Any changes that may affect the storage and distribution of active substances are evaluated
through change control.
There are various elements of an effective QMS for GDP that contribute to these expectations being
met. These include (PDA, 2013):

The use of risk management.

Good documentation practices (such as procedures, forms and registers).
Warehouse design and other suitable premises, equipment and facilities.
Quality Technical Agreements in place.
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Ensuring there is a responsible person in place.
Tracing and tracking product distribution (such as temperature mapping and journey
validation).
Having a system in place to deal with complaints.
Systems to deal with recalls.
These elements are discussed below. By way of example as to why the quality system is essential
for GDP, take the supply chain. When a supply chain goes wrong this leads to limited availability of
material, product sourcing issues, and contractors left with insufficient capacity. These issues can
arise due to weak compliance with quality technical agreements (or technical agreements poorly
written), such as where shipping conditions have not been defined (Rees, 2018).

An appropriate implementation of a QMS within a GDP operation will ensure that the principles of
GDP are consistently applied throughout the supply chain and it will maintain product integrity and
patient safety. An effective QMS not only ensures compliance, it also presents commercial
advantages such as reducing complaints and improving customer confidence; reducing wastage
and loss of product; and assisting with maintaining the reputation of the company. A strong QMS
for GDP can also help the pharmaceutical firm to exploit new market sectors and territories by
building on an already robust system. Such a system needs to be adequately resourced with
personnel who are trained and competent in their roles.

QMS ELEMENTS FOR EFFECTIVE GDP

The quality system needs to provide the appropriate infrastructure encompassing the
organizational structure, procedures, processes and resources, and systematic actions necessary to
ensure adequate confidence that a product, and the way the product is distributed, together with
the necessary and documentation, will satisfy given requirements for quality (WHO, 2010b). These
requirements include procurement, purchasing, storage distribution, transportation,
documentation and record keeping practices in the chain from the manufacturing plant to the
medical stores. This section of the chapter considers the main elements of a QMS for GDP,
including some of the things that can go awry to prevent the delivery of an effective GDP system.

An effective QMS can also help in the global battle against counterfeit medicines. Rates vary
worldwide, however a paper on drug quality and safety issues in India observed that approximately
20 percent of pharmaceutical products have serious issues originated during supply chain
operation such as spurious drugs, falsely labelled drugs and counterfeit drugs (Chokshi et al., 2015).

Good Documentation

As with any part of the quality system, GDP should have good documentation in place, with clearly
written and connected procedures. As a general point documentation comprises all written
procedures, instructions, contracts, records and data, in paper or in electronic form, with each
document subject to periodic review within a documentation control system (Nicholson, 2009). All
documentation should be readily available or retrievable. Where documentation is updated, version
control must be in place with controls in place to prevent the inadvertent use of the superseded
version. Superseded documents should be archived and held for at least one year after the active
substance has expired (or for three years where retesting of the active substance has taken place).

With paper records, any alterations made with documentation need to be signed and dated with
the alteration should permit the reading of the original information and the reason for the
alteration should be recorded. With electronic systems, any alternations must be clearly available in
the audit trail and a system in place to ensure that the audit trail is checked.

Specifically, to GDP, written procedures need to be produced which describe the distribution
activities which affect the quality of the active substances. This extends to the receipt and checking
of deliveries, storage, cleaning and maintenance of the premises, recording of the storage
conditions, security of stocks on site and of consignments in transit, withdrawal from saleable
stock, handling of returned products, recall plans, and so on. Records include each purchase and
sale, with data including the date of purchase or supply, name of the active substance, batch
number and quantity received or supplied, and name and address of the supplier and of the
original manufacture and of the shipping agent and the consignee.

It is important all documentation related to compliance of the distributor must be sufficiently

comprehensive, outlining the scope of the distributor’s activities and written in clear, unambiguous
language. All procedures pertaining to GDP must be approved, signed and dated by the person
responsible for the quality system (Hiob, 2009). As part of GDP, it is particularly important that
records are clear, made at the time each operation is performed and in such a way that all
significant activities or events are traceable.

Retained records, either paper or electronic, should include:

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The identity of supplier, original manufacturer, shipping agent and/or consignee.
The address of supplier, original manufacturer, shipping agent and/or consignee.
Purchase orders.
Bills of lading, transportation and distribution records.
Receipt documents.
Name or designation of active substance.
Manufacturer’s batch number.
Certificates of analysis, including those of the original manufacturer.
Retest or expiry date.
The use of blockchain provides a means to address some documentation challenges, since the use
of a digital ledger cannot be tampered with and therefore adds a layer of security and transparency
to the distribution operation.

Quality Technical Agreements

Quality technical agreements (QTA) need to be in place between the manufacturer and distributors,
and between the manufacturer and the suppliers. These are written contracts issued whenever a
company is outsourcing an activity covered by Good Manufacturing Practice or Good Distribution
Practice guidelines. The contract giver is responsible for the activities outsourced and a technical
agreement ensures the contract acceptor complies with GDP principles.

The QTA document should focus on quality aspects and not include legal terms or commercial
aspects (such as pricing), these aspects need to be covered in a separate commercial agreement
between the contract giver and contract acceptor. In terms of scope, according to Schmitt, a quality-
technical agreement needs to include all aspects that affect the identity, quality, safety, potency,
and purity of a product, and/or aspects that may affect compliance status of either the contract
giver or contract acceptor (Schmitt, 2014).

A typical technical agreement for GDP should have the following parts, as a minimum (Gnibl, 2018):

Purpose and scope

Definitions
Responsibilities
Contact list
List of products
Methods and specifications to test packaging materials
Inspection of packaging materials
Appropriate labelling methods, their review and approval
Packaging instructions, operations and documentation
Analysis of finished products and documents before release
Storage conditions, such as temperature, light and humidity
Shipping routes
Approval
Changes and revisions
List of any sub-contractors
Gathering of data for annual product reviews
Management of complaints
Specifications for product recalls and decision to initiate it
Management of the returned products
Many QTAs will included additional clauses, such as:

The contractor cannot make any changes in the process, raw materials or formulation
without prior written consent from the contract giver.
The contract giver and regulatory authorities should be allowed to perform audits and
inspections of the relevant processes, premises and documents.
The contractor must not sub-contract any of his responsibilities to a third party without
agreement of the contract giver.
All parties are to keep a record of deviations from pre-defined procedures or desired test
results.

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Taking a more specific example, a QTA between a distributor and a contract warehouse facility
might cover:

Scope and Purpose

Personnel (contract giver and contract acceptor)
Goods received
Storage conditions
Temperature monitoring
Stock control
Sales order procedure
Picking and packing
Batch control
Delivery of parcels and pallets
Product and distribution complaints
Returns and recalls
Product quarantine
Product disposal
GDP audit
Self-inspection
CAPA procedure
Documentation retention
Pest control
Security
Health and safety
Exceptional activities
Dispute resolution procedure
Contact details
Change control
Responsibilities matrix for both contract giver and contract acceptor
It is important that 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. Where each party has their own QTA
document, such as the manufacturer and a contract warehouse, it is important to ensure the two
agreements refer to each other and care should be taken to avoid any anomalies between the two
documents as this could be challenging in the event of a dispute.

Change Control

Changes to the GDP process must be captured via change control. Change control helps to
maintain the validated and established status. Validated processes and qualified facilities can be
influenced by changes and products that no longer comply with specifications. Hence, the change
control process provides assurance that changes made to the systems, facilities or equipment will
not result in negative effects that may result in the occurrence of costly mistakes or a loss of
process or product quality. Through this, details of the change, the rationale behind the change and
an assessment of the risks and potential impacts of the change will be documented. Change
controls are normally assessed by a review board, who will ensure that all changes are submitted
for approval of their appropriateness.

Change control will include all documents relating to the distribution process. Procedures must be
in place for both internally generated documents and those from external sources.

Deviations

The impact of a departure from a defined and approved process should be considered; this is done
through a deviation system. Deviations must be documented in real time and investigated
promptly. This investigation should include a root cause analysis, whether the problem has
occurred previously (recurrence analysis) and a risk assessment. Immediate actions should be
taken as appropriate to contain the impact of the problem; consideration should be given to
appropriate corrective and preventive actions (CAPA) (Gauseophol, 2018).

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An example of a deviation might be if inadequate temperature mapping had been carried out using
minimum and maximum thermometers. Other reason for temperature deviations are:

Unexpected delay in transportation due to which the temperature control cannot be

maintained effectively.
Mechanical failure of temperature control systems.
Product pallets are kept in hot zones of airport or shipping yards.
Reefer containers or refrigerated control vans are not deployed for transportation.
The transport agency fails to maintain the planned transport condition.
Power failure due to short lifespan of power bank during longer travel time.
Weak GDP understanding amongst supply chain personnel about the adverse impact on
product quality.
A second example is where an error has happened due to inadequate training between the
manufacturer and the distributor, leading to the use of an unauthorized third-party. Deviations can
also occur with storage, such as variances with temperature or anomalies with pest control or
failures to follow appropriate review procedures (Spencer, 2012).

Corrective and Preventive Actions (CAPA)

Where deviations occur in relation to GDP, part of the investigation will involve the setting of
corrective and preventive actions (CAPA), to correct the issue and to prevent is recurrence. In
relation to GDP, effective CAPA can help to minimize risk of counterfeit product entering the supply
chain and maintain product quality by ensuring the specified conditions for storage and
transportation of the product are respected (Anon., 2013).

CONSTITUENT PARTS OF THE GDP PROCESS

Procurement Function

Procurement is the process of finding, agreeing terms and acquiring goods, services or works from
an external source, often via a tendering or competitive bidding process. While pharmaceutical
companies will have a cost focus, it is important that goods purchased fall under sufficient quality
oversight and that the procurement process falls under the QMS. This includes having an approved
supplier list. Such a document should include the name of the manufacturer (at all of its locations);
the name of the supplier of the goods or services (if different); and a description of the product
type. Supplier assessment program need to cover every shipping and delivery company, as well as
any brokers used (brokers buy and sell products without physically handling them). Measures
should be in place to ensure that the shipping company selected is appropriate for the task and is
dedicated to the transfer of medicinal products – this extends to the transport vehicles or
containers being used for shipping not being used for any other purposes.

Ecommerce

It is increasingly common for commercial transactions to be conducted using digital technology.

Where electronic commerce (ecommerce) is used, i.e. electronic means are used for any of the
distribution steps, defined procedures and adequate systems should be in place to ensure
traceability and confidence in the quality of the pharmaceutical products concerned. Electronic
transactions (including those conducted via the Internet), relating to the distribution of
pharmaceutical products, should be performed only by authorized persons or entities.

Selection of Suppliers

As part of the approval process suppliers should be examined to make sure they are who they say
they are and that they are financially stable. Important checks include verifying that the supplier is
licensed to deal with the wholesaling of medicines, compliant with the GDP guidelines or in
possession of a marketing authorization, each of which must be supported by documented
evidence. There should also be periodic checks against lists of suspended or revoked licenses,
which are issued by most regulatory agencies. If it transpires that any customers or suppliers are
listed, it is best practice to cease trading with them immediately. Other due diligence checks include
obtaining reference checks from the company and assessing the risk of using the company.

The appropriateness of the supplier, depending on the services provided, will be subject to an
audit. At intervals, post-approval, suppliers should be checked at regular intervals to ensure they
continue to operate as intended. Typically, those products listed will be subject to a supplier audit.
Quality oversight will also extend to supplier review meetings where any quality issues relating to

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the supplier are discussed and reviewed, such as customer complaints, damage to goods, delivery
scheduling and audit findings.

As part of the QMS, the procurement and the management of material resources must satisfy the
following conditions:

Ensuring that all material resources are according to specified supply requirements.
To purchase the material resources in the necessary quantities and at the right time.
To achieve this, the process must (Popa, 2013).
Define the requirements related to the quality of material resources and issuing the technical
specifications.
Identify, evaluate and select suppliers based on their capability to supply material resources
in compliance with organizational requirements.
Establish, maintain, manage and develop relationships with the suppliers.
Monitor, measure and analyse the results in order to monitor the efficiency and efficacy of
the process.
While not part of pharmaceutical GDP, the Chartered Institute of Procurement and Supply (CIPS)
uses a model of five focal points for the procurement function which express the basic objectives of
procurement and the general criteria by which procurement performance is measured. These are:
that goods and services purchased should be of the right quality, in the right quantity, delivered to
the right place at the right time and obtained at the right price (CIPS, 2016).

The procurement function needs to work with the planning function within the pharmaceutical
firm, and this relationship also needs to be within the QMS (Hoyle, 2007). Quality planning can be
seen as both strategic and operational. With the strategic function, this is involves analysing all
external and internal sides of the business. From the operational side, this involves assessing
product goals linked to estimated demand and figures of productivity.

Commercial Function

Pharmaceutical firms have large commercial departments, responsible for seeking out businesses,
receiving orders, assessing local regulatory requirements, and for agreeing to shipments for
released products to be made. This process should also be part of the QMS, ensuring it is
connected with the person within the organization who has been appointed to have the defined
authority and responsibility for assuring that a quality management system is implemented and
maintained throughout the GDP process.

Shipments to and From the Site

The process of sending pharmaceutical products from the firm and receiving products onto site
represents a key part of the GDP process. In the world of modern pharmaceuticals, supply chains
are becoming increasingly complex and such complexity increases as supply chains cross multiple
countries and achieving control becomes hardest where there are multiple interfaces with third
parties. Other points of complexity that need to be considered include import and export
regulations, mutual agreements, and registration requirements.

Thus, there are several elements pertaining to supply that need to be covered by the QMS. These
include care of the product during transport, control of temperature, risk assessments of transport
routes and control over the vehicles used. The transport companies need to be assessed by the
pharmaceutical firm that employs them that they are following GDP principles, including the
suitability of the vehicles, the size of the vehicles (in terms of capacity, to avoid splitting up batches),
temperature control and the transport route. In considering the main elements:

Care of the product:

product: The product must be packaged appropriately using packaging designed to
protect the product from damage as well as from tampering (see below). Packaging should be
appropriately labeled (including artwork), with the contents, storage conditions, and source
(McIndae and Love, 2015). The quality of the packaging should be assessed at different stages of
the distribution process. Containers should also protect the product from external contamination.

If a pharmaceutical product cannot be held within a protective case, special measures need to be in
place in relation to the appropriateness of the design, use, cleaning and maintenance of the
equipment used for handling of pharmaceutical product.

As well as the above being important for distributors, incoming shipments also need to be
examined to verify the integrity of the containers, that tamper-evident packaging features are
intact, and that labelling is clear and has not been altered.

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Temperature: During transport the temperature needs to be monitored using validated
Temperature:
temperature measurement devices, and the temperature conditions assessed once the destination
is reached. The suitability of the vehicles used to distribute the product should be assessed.
Records of temperature need to be held for the shelf-life of the product, or longer if local
regulations require so.

Some drug products are at greater risk from temperature excursions than others. Drug product
sensitive to higher temperature excursions can be subject to oxidation, hydrolysis, decomposition,
polymerization. As longer as the time of exposure of product to unspecified temperature, higher
would be the impact on quality. Other products are affected by reductions in temperature. Adverse
effects include lattice positions dislocation due to extremely lower temperature or a change in the
property of some biological products (Porter, 2013).

Storage: The medication needs to be stored according to the directions from the manufacturer.
During storage, the temperature must be monitored constantly whether this be room temperature,
refrigerator or freezer. Storage conditions should extend to hubs (for short term storage, such as
when changing aircraft) to longer-term storage areas.

areas.
The importance of good shipment practices also extends to the delivery of active pharmaceutical
ingredients, which is over looked by some manufacturers (some may not be aware of who makes
the deliveries). Active substances should be transported in accordance with the conditions specified
by the manufacturer and in a manner that does not adversely affect their quality. Product, batch
and container identity should be maintained at all times. In addition, all original container labels
should remain readable.

Other factors that can serve to complicate the process and which need to be considered are part of
the quality overview include language barriers, especially those which could affect translation; the
use of abbreviations; problems of legibility; differences between what might be communicated
verbally and what is written; and cultural differences over what might constitute an error or a
deviation. These differences need to be ironed out through good, well-written protocols.

Traceability

An important aspect of the shipment and storage process is with ensuring traceability of the
pharmaceutical product. Items or containers should have unique identifiers and be sealed. The
identifiers should be numeric or alphanumeric and be issued in a tracked and sequential manner.

Throughout the process, the integrity of seals should be monitored, and identifiers verified during
transit and upon receipt. Written procedures need to be in place for the process. The procedures
should include measures for where pharmaceutical products are suspected of damaged, tampered
with or are suspected of being counterfeit (Metlan, 2009).

Storage, Warehousing and Premises

Warehouses are used for materials to dispatch from and receiving materials from suppliers. The
storage location for pharmaceutical products must be of a suitable design to protect the product
from damage, contamination, mix-up, or from being affected by adverse environmental conditions
or by pests. These areas should be clean and dry, with protocols in place designed to minimize the
risk of damage.

The required environment should be operating within the required range and will need to have
been qualified to demonstrate that the required range can be consistently achieved. Periodic
requalification needs to be conducted. In terms of on-going assessments, environmental
conditions, for light, temperature and humidity, need to be assessed through the use of monitoring
devices, calibrated to an appropriate standard and with a continuous monitoring system and
alarms in place (such devices can be connected to larger systems, as with the Internet of Things).
The records should be reviewed regularly by the person responsible for the quality system. For
certain classes of pharmaceuticals, like highly sensitizing materials, materials of high
pharmacological activity or toxicity, tighter controls will be required to prevent cross-contamination.

Released product needs to be held or demarcated separately from quarantined product, in areas
with restricted access (Schmitt, 2013). For this there should be appropriate demarcated areas or a
suitable electronic system in place. With electronic systems these need to be validated and risk
assessed to ensure that current requirements for data integrity are met (Bird, 2018). Warehouses
need to be of sufficient capacity and have in place measures to prevent unauthorized access. Any
variances to the storage conditions must be captured through deviation procedures. In terms of
access, premises should be secure as so to prevent unauthorized access.

Incoming materials should be assigned an expiry date following inspection and release. Materials
should be identified, and status labelled according to approved procedures. Full and secure records
are kept of all raw materials received and stored. These records contain the following minimum
information:
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Part number/item code.
Item description.
Lot number.
Quantity in stock.
Quality status.
Quantity available.
Storage location.
The areas used for receiving active substances should be designed to protect deliveries from
prevailing weather conditions during unloading.

Receipt

Reception areas should be located separate from the storage area. The receipt process needs to
ensure that each delivery is examined in order to assess that the containers are integral, not
damaged, dry and that all security seals are present with no sign of tampering. The receipt process
will also assess that the labelling is correct. If any labels are incorrect or if there are signs of
tampering or other evidence that the contents may be affected, such as broken seals, damaged
packaging, or potential contamination, all items of the lot need to be quarantined. If a material is to
be rejected or has gone past its expiry date, suitable control measures need to be in place to
prevent the containers from entering the manufacturing process and for avoiding any mix-ups with
materials designated for release. Where falsification is suspected, the appropriate national
regulator must be notified.

Reception staff will need to check there is correlation between the name used by the supplier and
the in-house name, and that all necessary information, such as a certificate of analysis, are
available. The process will also ascertain if the active substance and the consignment correspond to
the order. Each item will need to be logged, using a manual or electronic system with any required
temperature or humidity conditions noted and the items marked for the appropriate storage
conditions.

The receipt process may include returned items, which is an activity that will need to be performed
only by personnel who have received additional training. Such items need to be swiftly identified
and quarantined pending investigation. Items returned from a distributor should only be in
unopened containers, with full traceability including unopened security seals in place. Full records
must be available, detailing who has handled the items and the reason for the return. The history of
the material also needs to extent to inclusion of material handling, storage and maintenance of
environmental conditions. In terms of acceptability of returned materials, each organization will
have a stipulation in place for suitability of remaining shelf-life. If there are any doubts about
returned items, these should be placed in quarantine and considered for rejection.

Release of Materials

For the release of materials, checks should be in place to ensure that all appropriate in-house
checks have been made and that any testing required has been completed, reviewed against
specification and approved by the quality department. For the release of stock, it is best practice to
establish a system to ensure stock rotation, such as ‘first expiry (retest date), first out’, with regular
and frequent checks that the system is operating correctly.

Where either the storage or transportation of active substances is contracted out, the distributor
needs to be confident that the contract acceptor understands and is capable of following the
appropriate storage and transport conditions. In addition, there needs to be a contract in place
between the contract giver and contract acceptor, which describes the duties of each party,
including a proviso that the contract acceptor will not subcontract any of the work agreed under the
terms of the contract without prior authorization.

Complaints and Recalls

The distribution process, no matter how tightly controlled, will be subject to customer complaints
and there will be the periodic need to recall product, either in response to a breakdown in the
distribution process or in response to discovering something untoward with the manufacturing of
the material. When receiving complaints, the organization needs to have a system in place to deal
with them, with the process for handling complaints described in a pre-approved protocol. All
complaints, whether received orally or in writing, must be recorded and investigated and subject to
formal review. Where the distributor and manufacturer are separate entities, the two parties will
need to review the complaint together and assess whether any further action, either with other
customers who may have received this active substance or with the competent authority, or both, is
required.

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Examples of complaints include (Prinz, 2010):

Damage to packaging.
Expiry dates being too short.
Expiry date exceeded.
Unsatisfactory dispatch times.
Too much stock delivered.
Too little stock delivered.
Inconsistent delivery.
Poor communication.
Inadequate supporting information.
Product discoloured.
Product ineffective.
Product or packaging damaged.
Product not held under required environmental conditions.
Missing reports.
Poor or incorrect labelling.
Formal investigations in response to customer complaints need to be recorded as a quality record
and conducted according to a protocol, with each step documented and a deviation raised. As a
minimum, records need to include the name and address of complainant together with the name,
title, where appropriate, and phone number of people submitting the complaint, together with the
time and date that the complaint was received. The record must also include full details of the
complaint nature, including name and batch number of the active substance. The date and time of
any events needs to be captured, and if there has been any adverse drug reaction (and hence a
need to assess within the pharmacovigilance function), these details need to be captured.

The QMS needs to differentiate between those issues raised that are complaints and which are
grievances. Each needs to be acknowledged but the responses will be different. For legitimate
complaints, the complaint investigation record needs to detail the action initially taken, including
dates and identity of person taking the action, plus any follow-up action taken. The record should
also capture the response provided to the originator of complaint, including date response sent,
together with the final decision on active substance batch.

As part of the quality system, all records of complaints need to be retained in order to evaluate
trends, product related frequencies, and severity with a view to taking additional, and if
appropriate, immediate corrective action. A review of trends should form part of formal
management review. Each individual record must be stored and archived and be made available
during regulatory inspections.

As with other aspects of the quality system, complaints should be trended and examined as part of
management review.

Sometimes, especially in situations where there is a serious or potentially life-threatening situation,

the written procedure should cover the circumstances under which a recall of an active substance
should be considered. Given the complexity of recall, a periodic (such as annual) product recall
should be simulated. This enables the system to be assessed and for any weaknesses to be
addressed.

QUALITY ASSESSMENTS OF GDP

The distribution process should be subject to regular quality assessments, including a risk
assessment of the process and a system for management review and oversight.

Risk Assessment

Quality Risk Management should be an integral part of the system of control and governance. A
systematic and structured risk management process needs to be in place to pro-actively identify,
assess, remediate, mitigate, escalate, monitor, review and communicate potential quality risks
applicable to products and services, processes, systems and projects. This extends to GDP
practices, from storage to transportation.

The pharmaceutical distributor should develop process maps of their critical activities, define the
critical control points and describe the areas of responsibilities. Procedures should be developed
and verified by systematic reviews to ensure that they appropriately control processes to ensure
consistency and address potential risks. The implementation of the Quality Management System

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shall be led by the organization’s management and its importance to all personnel included in
training and regular reminders to ensure awareness leading to compliance and continual
improvement.

The risk assessments should be undertaken by appropriately trained individuals with an

appropriate level of knowledge and experience of products and processes (Savin, 2017). The
assessment process ensures that the assessment of risk is based on scientific knowledge, process
experience, GxP and regulatory compliance. As an example, when risk assessing transportation, it is
important to (Spiggelkotter, 2010; Wesch, 2012):

Understand which products are transported and to where.

Break the transportation chain into steps.
Assess each step from sender to recipient. Consider what will happen should delays arise at
any stage of the transport route.
Assess for how long the cargo remains at each step.
Assess effectiveness of anti-counterfeiting measures and how these can be assessed? Such as
by using anti-tamper proof locks or seals.
Consider environmental conditions at each step (this may need to extend to seasonality).
Understand the impact of temperature and humidity.
Understand the suitability of the container.
Understand the impact of shock and vibration on the goods and the packaging. For example,
how robust is the packaging? Have drop and rotation tests been performed?
Review the risks of exposure beyond specified temperature and the likely degradation of the
product.
The risk of a seal break causing microbial contamination.
The risks of mishandling leading to a defect related to product integrity.
Concerns with label scratching or ink smudging shall cause illegible product information.

information.
The risk where products are in transit in common cargo (for example, medicines in holds shared
with paint or cement).

The aim of the risk assessment is not simply to review the risks but to put in place additional
measures or controls, or to consider alternatives such as blockchain (a form of distributed ledger
technology). For example, with the risk of exposure beyond specified temperature that shall cause
degradation the following could be considered:

Endorsing environmental storage conditions in transport agreements.

Display of instructions on product packs.
Use of digital data loggers (temperature measuring devices).
Email or text alerts for temperature excursions.
Detailed investigation of cases reporting the environmental excursion during distribution and
transportation.
The output of such risk assessments is documented and retained. Quality risks assessments should
be consolidated, reported and followed through a risk register. The risk assessment concept can
also be applied to the level and frequency of audits designed to assess the effectiveness of the GDP
system (Holmes and Roenninger, 2010).

Management Review

As with other parts of the QMS, GDP should be subject to management review. Such reviews ensure
that senior management are given regular feedback as to the quality and risks associated with the
distribution of medicines. In relation to GDP, senior managers can assess the overall performance
of the Quality Management System and assess trends. The frequency of such a review will depend
on the size of the company – typically this will be monthly or three-monthly. For such reviews,
metrics are often set so that trends can be ascertained and reacted to. The types of GDP associated
topics that should be on the agenda for a review meeting include deviations in relation to storage
or distribution of medicines and associated corrective and preventative actions. In addition, senior
managers should assess customer complaints, self-inspection findings and external audit
inspection findings including regulatory authority inspections. Additionally, senior managers should
appraise themselves of change controls relating to distribution and any new or updated risk
assessments.

Where significant risks are apparent, senior managers will be able to identify these, review the
impact, and allocate adequate resources to ensure that future quality objectives can be achieved.
This process also ensures that the QMS remains aligned with both the business needs and the
regulatory expectations (Sandle and Lamba, 2012).
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Additionally, as part of the management oversight process it is good practice for the GDP system to
be audited internally to monitor the QMS. This should be supplemented by external audits of
suppliers and checks designed to assess the various stages in the medicine distribution process.

SUMMARY
An effective Quality Management System for Good Distribution Practice is one that ensures the
quality, integrity, safety and efficacy of materials and products during sourcing and distribution.
This will cover a range of key points, such as personnel, storage buildings, transportation vehicles,
the need for risk assessment, effective CAPA, technical agreements and so on. Several of these
components have been drawn out in this chapter. Given that some companies have yet to fully
integrate GDP into their quality management system, this chapter has provided a basis for doing so;
for those companies that have completed integration, the chapter provides a benchmark for
comparing systems against and establishing best practice.

Hence, as this chapter has set out to demonstrate, the essential points for the incorporation of GDP
into the QMS center on the strength of the control mechanisms in place within the QMS to assure
compliance with GDP. Each of the key stages associated with GDP, such as shipments to and from
the site, warehousing, traceability, documentation, and so on, need to be defined and evaluated.

This article is part of the Book “Good Distribution Practice: A Handbook for
Healthcare Manufacturers and Suppliers,” published in two volumes at DHI Books

DHI Books –

Volume 1 - http://dhibooks.com/books/17353.html
http://dhibooks.com/books/17353.html

Volume 2 - http://dhibooks.com/books/17354.html

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PRINTER-FRIENDLY VERSION

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