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GMP for Warehouse

GMP Training – GMP for Warehouse by www.gmpsop.com

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Training Outcome of the Module:

The quality of a pharmaceutical product is defined as one that is pure, correctly

identified, effective and safe to use. Customers and patients have an ethical (and

legal) right to expect quality pharmaceutical products.

The warehouse plays a pivotal role in manufacturing quality products, as it is

responsible for all incoming goods (including labeling and packaging) and for

releasing finished products. Therefore, there are GMP rules in place to ensure

that materials are handled and stored properly, while appropriate

documentation is maintained.

By the end of this module, you will be able to:

Explain the role of the warehouse

List the GMP procedures needed in the warehouse to control incoming goods

Identify the GMP requirements for handling starting materials and finished

products in the warehouse

Recognize the GMP issues surrounding release of finished products to the

marketplace

Recognize issues around transport of goods to and from the public

Recognize how returns ore handled by the company

Identify the different documentation needed in the warehouse

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GOOD TO KNOW - GDP AND GWP

Good Distribution Practice (GDP) and Good Warehousing Practice (GWP)

are each special parts of GMP. GDP refers specifically to the transport

and distribution of the product. GWP refers to the practices specifically

within the company warehouse.

GDP and GWP each have their own legal definition end regulations.

These regulations recognize that product quality can be significantly

impacted offer manufacturing and packaging have taken place.

In this module, "GMP" for the warehouse incorporates practices, rules,

and regulations spanning GMP, GDP, and GWP.

GWP refers to the practices specifically within the

company warehouse.

GDP refers specifically to the transport and distribution of the product.

.



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Examples of government audit findings for warehouses

The top 10 GDP deficiencies listed in the table below. The results were taken

from the UK, but are indicative of the industry at large.

Description %

General storage - temperature control and monitoring 16.7

Unauthorized activity 9.6

Lack of or inadequate written procedures 8.8

Supplier status 7.9

Cold storage - temperature control and monitoring 7.9

Premises, equipment, and calibration 7.0

Cold chain transportation 7.0

Quality system and duties of the Responsible Person 5.3

Segregation of unsalable stock 3.5

Returns 3.5

Source: Orme-T (MHRA), "The Top 10 Deficiencies and Counterfeit Awareness",

22 Jan 2008

Once a finished product is received into the warehouse, it does not undergo any

further inspections or quality control tests. If the product is degraded or

damaged at this point, there is nothing that stops it from being given to the

patient. The warehouse must rely upon procedures and well-trained staff to

ensure that products arrive safely and with the same quality as when they left

manufacturing.

There have been many cases of product being affected by poor warehouse storage

conditions or rough handling on transport. Biopharmaceutical products often

have temperature-sensitive active ingredients that break down or degrade if

exposed to heat or light, thus becoming ineffective.




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What do the GMP rules say?

US FDA CFR 211:

Subpart H—Holding and Distribution

Sec. 211.142 Warehousing procedures

Written procedures describing the warehousing of drug products shall be

established and followed. They shall include:

(a) Quarantine of drug products before release by the quality control unit.

(b) Storage of drug products under appropriate conditions of temperature,

humidity, and light so that the identity, strength, quality, and purity of the drug

products are not affected.

Subpart H—Holding and Distribution

Sec. 211.150 Distribution procedures

Written procedures shall be established and followed, describing the distribution

of drug products. They shall include:

(a) A procedure whereby the oldest approved stock of a drug product is

distributed first. Deviation from this requirement is permitted if such deviation

is temporary and appropriate.

(b) A system by which the distribution of each lot of drug product can be readily

determined to facilitate its recall if necessary.

International GMPs:

Chapter 4 Documentation

Procedures and records

4.19. There should be written procedures and records for the receipt of each

delivery of each starting and primary and printed packaging material.



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Chapter 5

Production

5.5. Incoming materials and finished products should be physically or

administratively quarantined immediately after receipt or processing, until they

have been released for use or distribution.

Finished products

5.58. Finished products should be held in quarantine until their final release

under conditions established by the manufacturer.

Overview:

A pharmaceutical warehouse must be expertly managed and run in compliance

in order for the company to protect and distribute a quality product.

These compliant practices include control over receiving goods, quality control,

storing materials, components and products, fulfilling picking requests and

shipping the product to the marketplace. These practices must be completely

traceable in order to protect the integrity and stability of the product and its

packaging.

GMP rules for the warehouse enable manufacturers to:

protect medicines from damage during storage and transport

prevent degradation of the product by exposure to adverse temperature

conditions

avoid mix-ups and contamination by other materials

maintain product identity and traceability

prevent time-expired or damaged material or product from being used

What comes into the warehouse?



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The following goods generally do not appear on any production bill of materials,

and have a simplified check and release. Often, they do not have an in-house lot

number applied, but this varies from company to company.

non-production consumables (non-GMP material), e.g. toilet paper, stationery

production materials consumed in processing, e.g. filters, lubricants

laboratory reagents, e.g. buffers, chemicals

The last two items above will usually have their own QC approval processes.

The following goods will always appear on any production or packaging bill of

materials. They are each governed by GMP quality control and release

procedures. All these goods will be issued with unique lot numbers.

manufacturing starting materials and chemicals

packaging components, e.g. blister pack film, bottles, caps, vials, seals

printed matter, e.g. labels, cartons, inserts/leaflets, pre-printed tubes

GOOD TO KNOW - PROCEDURES FOR RECEIVING MATERIALS

When starting materials first arrive at the facility, they fall under the control

of the warehouse. Different types of materials can be treated in a number of

different ways. For example, materials consumed in production need to be

registered and checked for approved supplier and grade (pharmaceutical or

medical), but may or may not need a unique identifying number. Ensure that

you know your Standard Operating Procedures.

In the case of starting chemicals used in product formulation, they will always

need to be checked to see that they;

arrived from an approved supplier

are not damaged

are correctly labeled and identified with the supplier's lot number for

traceability purposes



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are given a unique in-house lot number

registered in inventory, and

quarantined, then sampled for release testing

Some of these chemicals may also deteriorate when exposed to heat, so they

may have to be stored under controlled temperatures, or even frozen.

Typical layout of a warehouse

Warehouses are typically classified by the types of material they contain, for

example, raw materials, packaging materials, intermediate or bulk product and

finished product. A typical warehouse will contain some or all of the areas in the

picture below.



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A quarantine area for storing goods that have not yet been inspected or tested.

Materials stored in Quarantine cannot be used or released until approved by

QC.

Some warehouses have a Dangerous Goods storage area to ensure the safety

of staff and the facility. For example, flammable goods such as ethanol would

be stored in this area. Special storage conditions, such as flame-proof

cabinets, are used here.

Some warehouses have a locked area for restricted goods, such as poisons

and drugs of addiction. This area is restricted to specifically authorized staff.

A separate area for isolating faulty or recalled goods, ensuring that they are

not issued or sold by mistake.

A "reject" area reserved for rejected batches.

The coolroom is usually operated at 2°C - 8°C so temperature-sensitive

materials (e.g. vitamins) do not deteriorate.

It is important to regularly check that the coolroom temperature is within

normal operating ranges. The coolroom usually has a quarantine and a

released area.

The sampling booth is the first place starting chemicals are opened. To protect

the material, the sampling room should have specific air controls to exclude

outside air from entering, and to contain any dust generated from sampling

to protect the environment. Sampling implements must also be clean before

use and cleaned after each use.

Pay particular attention to the air control systems, gowning and safe handling

of chemicals in this area.

A "released" area for batches that have been successfully tested and passed

for use.

A quarantine area for storing goods that hove not yet been inspected or tested.

Materials stored in Quarantine cannot be used or released until approved by

QC.



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Use of computer systems

Often, computer systems are used to control the inspection and test status of

materials and products. If computers are used, materials and products may not

need physical status labels, or even be stored in separate areas.

Inventory status control computer systems used in warehouses must be

validated for reliability and freedom from errors.

There will be strict procedures in place and security levels instituted to ensure

that information is accurately entered. You should be familiar with the security

and procedures associated with the use of these systems,

Repacking

Some raw material supply warehouses may decide to repack larger containers of

chemicals into smaller order quantities. While this may seem a simple process,

it must come under GMP controls and be accompanied by a processing record.

Repacking should be performed according to a written procedure and only by

trained staff.

What could go wrong with this repacking process?



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The labels on the smaller bags may not give exactly the same information

as the original larger pack.

The repacking may take place in a room which is contaminated with other

chemicals.

The smaller containers may not be compatible with the larger drum.

The re-packer may want to apply their company name and delete the

original manufacturer’s name.

The chemical may be hydroscopic (pick up moisture) during the repacking

process.

The chemical may be harmful to health if not handled correctly, or the

Material Safety Data Sheet (MSDS) may not be included.

Warehouse personnel and training

Warehouse personnel need to be skilled in a number of different functions,

including applying the GMP rules specific to the warehouse, just like

manufacturing personnel are trained in applying the GMP rules related to their

areas. All warehouse personnel need to be trained, even contract and casual staff

employed during peak times.

Warehouse personnel should also be trained in SOPs applicable to the

warehouse's operation.

Some examples of specific skills required relevant to warehouse personnel:

Pack and label stock so that it is protected during transport.

Interpret environmental monitoring displays such as temperature and

humidity gauges.

Be able to ensure materials and stocks are located under their correct storage

locations.



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Use safe handling procedures according to each chemical's Material Safely

Data Sheet (MSDS).

Conduct stock takes and maintain inventory records.

Accurately locate and select the right stock from pick lists and orders on a

first-fin, first-out basis.

Recognize situations where products or chemicals may be at risk, e.g.

spillage, broken pack, missing labels.

Safely operate picking machinery, such as a forklift or bay picker.

Accurately enter stock into the computer system inventory and maintain

accurate paper records.

Preventing contamination and deterioration

To prevent possible contamination or deterioration of materials during

warehousing, there are some important warehouse rules that must be followed:

No packs should be left unsealed. This prevents possible dirt contamination

from the environment or pest infestation.

All chemicals and products must be stored within their labeled temperature

zones, for example, products labeled:

- Store at 2°C-8°C.

- Do not freeze.

- Store below 25°C.

Use a first-in, first-out (FIFO) system. Chemicals and medicinal products

deteriorate over time, and generally have expiry dates. Not rotating stock

could result in partly degraded or aged materials being issued.

Follow the chemical spillage procedures to ensure that personnel and other

products are protected. Report all incidents to supervision.

Keep outer doors and exits closed whenever not in use. Outside dirt and pests

may contaminate the stock.



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Never use material or product that is either unlabelled or not correctly

labeled. If a label is missing, it generally means the stock should not be used.

Preventing mix-ups in the warehouse

In a busy warehouse, there is daily movement of starting materials into the

warehouse, daily pickups from production, regular storage of in-process bulk

goods, incoming finished products, and release of finished stock to distributors.

Space is often limited, and many warehouses can become overcrowded.

During all this movement of stock, staff have to maintain records, and sometimes

apply labels to indicate status.

As there are opportunities for mix-ups to occur on an almost daily basis, so too

are there GWP rules that help prevent these from happening:

Quarantine inward goods and finished goods until they are approved for

release.

Segregate material by their status labels (e.g., there should be only released

labeled stock in the released store).

Ensure that Unique Identifying Numbers and batch numbers are clearly

visible and legible.

Wherever possible, ensure that only one type of material is stored in one

location. (Note: Different companies may have different views on this.)

Why have material and product segregation?

One of the keys to ensuring that only the correct materials or products are

released is to practice good physical segregation and/or validated electronic

segregation. In the case of defective and recalled goods, it is essential to have

both physical and electronic segregation.



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PHYSICAL SEGREGATION

It is a GMP/GWP rule that goods with different

statuses be physically located in different and

designated areas if a validated computer system

is not used to control location. (Some companies

also use physical segregation even when they

employ validated computer systems.)

Physical segregation minimizes the chance of

someone accidentally selecting and using the

wrong material.

Always double-check the status of the item and

its location before selecting it. If the selected lot

is in a quarantine or reject location, refer the

error to your supervisor.

ELECTRONIC SEGREGATION

Many warehouses control their inventory by the

use of an MRP computer system. The computer

system must be validated (be 100% reliable) and

only allow access to authorized personnel.

Generally, warehouse computer systems are

used to:

register inward goods and their quantities, lot

numbers, expiry dates, suppliers, and assign

their status (e.g. Quarantine)

change the status of a lot or batch

depending on the status of the lot or batch,

allow or disallow planners and dispatchers

from selecting goods electronically

track inventory movement to specific

allocated locations in the warehouse so that



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only the right material or product can be

selected for use or release

provide an accurate history of stock

movement to allow for stock takes and

traceability

In summary, the warehouse computer system

serves a critical function, and staff required to

use it must be fully trained in its use. In

addition, staff should never share their

passwords with other staff, nor log on or off other

personnel.

GOOD TO KNOW - SEGREGATING SUSPECT OR DEFECTIVE MATERIALS

Warehouse personnel have to deal with materials and products that may have

different statuses, or may change status during storage. Some materials and

products may actually be damaged or defective, and staff need to isolate these

from good stock.

The following non-routine, suspect or defective goods may be encountered in

the warehouse:

damaged goods from stock

returned goods from customers

recalled goods

counterfeit products

"Not for Sale" samples



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A fundamental GMP control is to ensure that only approved starting materials

that meet specifications are used to formulate medicines. Patient safety depends

on it. Removing the protection of status controls will raise the risk of an error

occurring.

The government regulatory agencies and their auditors are very aware that lack

of control over material movement in the warehouse can, and has, led to defective

product. For this reason, they regularly conduct inspections of the warehouse

and the warehouse procedures to ensure that GMP rules are in place.


US FDA CFR 211

Subpart H~Holding and Distribution

Sec. 211.142 Warehousing procedures.

Written procedures describing the warehousing of drug products shall be

established and followed.

They shall include:

(a) Quarantine of drug products before release by the quality control unit.

(b) Storage of drug products under appropriate conditions of temperature,

humidity, and light so that the identity, strength, quality, and purity of the drug

products are not affected.

International GMPs

Chapter 5

Production

5.40. The purchase, handling and control of primary and printed packaging

materials shall be accorded attention similar to that given to starting materials.




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5.41. Particular attention should be paid to printed materials. They should be

stored in adequately secure conditions such as to exclude unauthorized access.

Cut labels and other loose printed materials should be stored and transported

in separate closed containers so as to avoid mix-ups. Packaging materials should

be issued for use only by authorized personnel following an approved and

documented procedure.

Chapter 3

Premises and equipment

3.18. Storage areas should be of sufficient capacity to allow orderly storage of

the various categories of materials and products: starting and packaging

materials, intermediate, bulk and finished products, products in quarantine,

released, rejected, returned or recalled.

Overview

Preventing contamination and mix-ups of materials and products are the main

focus of GMP in the warehouse.

Some general rules to prevent contamination and mix-ups are:

Materials must be purchased only from approved suppliers to written

specifications.

All incoming materials must be placed into quarantine.

Quarantined materials must be inspected and/or tested to verify their

suitability for use.

All materials must be labeled clearly to indicate their inspection and test

status.

Materials must be stored safely to protect from deterioration and damage.

Records must be maintained for all issued material in order to ensure

traceability.

GOOD TO KNOW - CONTAMINATION

Contamination refers to the presence of any foreign substance in a product.

It may be:



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physical, e.g. foreign objects, dirt, dust, pollens

chemical, e.g. cleaning agents, lubricants, impurities, degradation products

microbiological, e.g. bacteria, moulds, spores, yeasts

Housekeeping

A key to a successfully operated warehouse is good housekeeping. The

warehouse is generally a very busy place, with constant movement of inventory

in and out, as well as to different warehouse locations internally.

Good housekeeping, which essentially means "Everything in its place",

minimizes the opportunity for mix-up of goods, reduces the possibility of

dispatch or issue of incorrect goods, and improves warehouse safety.



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Pictured here is on area specifying a no-walk zone. Forklifts are constantly used

in this area, and are potentially dangerous. In addition to good housekeeping,

warehouse personnel should pay attention to safety rules, including what type

of safety clothing that should be worn.

Material identification information

Each separate material received should be labeled with a standard name and a

Unique Identifying Number (UIN). These are used throughout storage and

processing to identify that material. In order to prevent confusion with product

batches, the UIN is generally not called a batch number, and should not be the

same as the supplier's lot number.

Supplier's batch number

Within each delivery, containers bearing different manufacturers' batch or lot

numbers should be separate. This will help trace any contamination or other

problem back to a supplier's batch and make it easier to isolate the finished

product containing suspect material.



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Each group bearing the same batch, lot, or equivalent number in a single delivery

can be regarded as the same material. Subsequent deliveries of the same

manufacturer's batch or lot number should also be regarded as separate

materials, since the handling and transport may have affected their quality.

Standard name

The standard name refers to the unique approved name listed in the company's

standard names register. The standard name is the same one that is used in the

product formulation bill of materials. For example, sodium chloride can also be

generically called salt or sodium salt. Standardizing the name internally

eliminates any confusion.

The term "USP" refers to the grade or quality of the material. Generally, chemicals

will be labeled "USP", "BP", or "EP" grade to indicate that they ere pharmaceutical

grade.

Material item code

The material item code is linked to the Standard Name, and is used in the Master

Batch Record and formulation. This code also corresponds with the barcode, and

usually helps identify the approved supplier and grade of the material.

UIN (Unique Identifying Number)

The UIN (Unique Identifying Number) is alternately called the Goods Inward

Number (GIN), lot number, or batch number. The number is critical because it

uniquely identifies and allows traceability of that consignment of material. The

UIN is recorded in the laboratory, on the computer system, and in production

when a product is formulated.

Expiry date

The expiry date indicates the date after which the goods cannot be guaranteed

to be safe for use. Clearly, once goods have expired, they must be placed in reject

areas and not used.

Storage conditions

Materials and products can degrade if not stored under the approved storage

conditions. For finished products, storage conditions are registered with the

government, meeting it a legal requirement to store them in compliance.

Barcode



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Some companies apply a unique barcode, providing a second unique identifier

for the material a product. The barcode is used to electronically scan the identity

of the item before issue.

Status labels

In addition to the identification information, each lot requires a status label, so

that the status of any material is evident. Some examples of physical status

labels are below. Note the use of the different colors. (Note: Different companies

may have different colors for the types of status labels used.)

Status labels may be either:

physical labels on the container

electronic fields on a database

combination of physical and electronic

Be familiar with the system your company uses to ensure that only released

materials are used.

Before any lot may be used in manufacturing, it must be released for use QC.

Once a lot has passed inspection and testing, QC will change the status from

"Hold"/"Quarantine" to "Released"/"Approved".

STATUS LABELS

This label is used when the goods have not yet been

tested and released for use by the laboratory.

Materials labeled Quarantine should not be used.

The Hold label indicates the material may have a

problem and is under investigation. Do not use

under any circumstances.



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The Released label indicates the material is suitable

for use or released for supply. The batch has been

tested and cleared by the Quality Department.

The Approved label indicates the material is

suitable for use or released for supply. The batch

has been tested and cleared by the laboratory.

The Rejected label indicates that the batch has been

assessed as unacceptable or defective. Never use

these materials. They should be located in separate,

locked area.

Control of product labels

The control of product labels is a crucial port of GMP, since customers may be

adversely affected by mislabeled product. All product labels must therefore be

strictly controlled. Some of these controls include:

Each different type of label is clearly identified and segregated in the label

store to prevent mix-ups.

Access to the label store must be restricted to authorized personnel.

There should be no loose approved or released labels in the store.

Any unused or damaged labels should be returned to the Quality Department.

"Approved" or "Released" labels should only be issued by the Quality

Department.

Before the release of labels, they must be checked and double-checked

against the work order to verify the:

- product name and code

- label identity and version number



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- coded batch number and expiry date

Only when all the checks have been satisfactorily completed can labels be taken

into the packaging area.

GMP storage requirements

Staring materials and components must be stored in designated locations,

GOOD TO KNOW - SPECIAL STORAGE REQUIREMENTS

Some materials are required to have additional safety and security procedures.

For example, the following goods must be locked up or otherwise secured from

unauthorized access:

printed packaging materials

drugs of addiction, antibiotics, and highly potent drugs

poisons and flammable goods

rejected and recalled materials

returned goods

Keep powders, liquids, and corrosive and flammable materials separate.

Dangerous goods areas should be specially equipped to prevent contamination

and spills.

Keeping the warehouse Clean

GMP rules state that warehouses storing raw materials, components, printed

matter, and finished goods must be kept clean, dry, and orderly at all times.

This involves, but is not limited to:

protecting receiving areas from the weather

checking regularly to ensure that containers and packs are sealed properly

cleaning the facility regularly



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cleaning up spills immediately

The exterior of inward goods containers may also need to be cleaned before

storage.

Protecting goods from deterioration

To protect goods from deterioration:

Store goods at the temperatures specified on their labels.

Monitor and alarm freezers and refrigerators.

Monitor temperatures in other areas where goods requiring specific storage

conditions are being stored.

Review all records; analyse and file as appropriate.

Investigate all deviations and assess their impact on product suitability.

Protecting raw materials

Because raw materials may deteriorate on storage or become contaminated if

stored incorrectly, the storage conditions are critical to product purity. In order

to protect raw materials, there are some specific and important GMP rules

relating to this:

Separate quarantine and reject areas.

The storage environment should be temperature-controlled.

Store goods off the floor and away from walls.

Employ a system that identifies material about to expire, so that it can be

retested if necessary.

Periodically inspect stockrooms for past-expiry or expired stock, cleanliness,

housekeeping, and pest control.

Seal over all opened containers to protect from the environment.



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Ensure that there is a cleaning program for each separate area in the

warehouse, including for external areas, gangways, shelving, and racking.

Pest control

Some of the pests that are attracted to pharmaceutical warehouses include rats,

mice, birds, ants, and cockroaches. For example, stored goods can be

contaminated by bird or rodent droppings. Therefore, GMP rules require that a

manufacturing facility has:

a nominated pest control officer

specific instructions or agreements with pest control companies

maps showing bait locations

documentation of all pest control treatments

having frequent waste collections

WHAT AN EFFECTIVE PEST CONTROL PROGRAM INVOLVES

Environmental regulations and OH&S also require companies to protect

personnel and the surrounding environment from the chemicals used in pest

control programs.

An effective pest control program involves:

keeping track of any sightings of pests between visits by the pest control

companies

assigning someone to accompany the pest control agent when they are on

site

using only approved pesticides



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Air control in the warehouse

The warehouse links the outside environment to the inside production facility.

Therefore, the warehouse becomes a barrier to prevent dirt, dust, particles,

moisture and pests from entering the building.

In order to separate the inner production area from the outside, warehouses

generally have specific designs, and rely upon employees keeping doors shut

wherever possible.

Outside Air

The outside air is of course not controlled in any way. If the factory is left open,

wind will blow contamination into the factory, so it is important that the outer

door is kept shut when not in use. The outer door provides the first point of

protection for the warehouse and the production area.

Receipt Area

This is where goods are unloaded off the delivery truck and assessed before being

brought into the warehouse. Notice that this area has an outer roller door and

an inner curtain in order to prevent outside dirt or dust from entering the

warehouse. An important GMP rule is to not have both the outer roller door and

the inner barrier open at the same time. This area is sometimes referred to as a

"black" zone.



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This area is also the first point where outer bags and cartons are cleaned down,

so that minimal dirt is transferred to the warehouse itself. If goods are unclean

or damaged, they should not be sent into the warehouse.

Warehouse

The warehouse itself is not pressure-controlled, but is cleaner than the receipt

area. In the warehouse, goods should be stored off the floors and away from

walls, because moisture may be taken up through concrete walls and floors. This

area is sometimes referred to as a "grey" zone since it is cleaner than outside,

but still not clean enough to expose products to the environment.

Production Area

Some companies refer to the production area as a "white" or "clean" zone, where

only cleaned materials may be taken. Generally, goods transported to this area

are on plastic pallets, since wooden pallets cannot be cleaned and can harbor

fungus, mould, and bacterial contamination. The production zone is pressure-

controlled to provide an air barrier to dirt and particles entry. In order to

maintain positive pressure, it is critical to keep the doors between the production

and warehouse areas closed.

Before materials are taken into the production area, the outer cartons that had

arrived on the truck are generally removed, where possible, as an added

precaution. Most companies also have different dress codes when moving from

a grey zone to a white zone.

Importance of storage temperature controls

Temperature storage controls are important in the warehouse in order to ensure

product integrity throughout the product's shelf life. Medicinal products

damaged by exposure to extremes of temperature may escape detection,

resulting in physical damage and/or loss of therapeutic effect. Worst of all, it

may not be obvious at all.

For temperature-controlled warehouses, companies are expected to create a

temperature map of the facility. The map is used to identify the best places in

the warehouse to store goods. An initial study when creating this map will reveal



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where problems would most likely be encountered, e.g., storing goods against

north-facing walls, close to room heaters, close to windows or near the roof.

After initial mapping, temperatures are routinely monitored on a continuous or

daily basis. This monitoring may reveal seasonal patterns where temperatures

may rise or fall outside approved limits. It is important, then, to continue to

review temperature profiles in the warehouse over time, particularly during

summer and winter. Some companies monitor using an electronic building

management system.

AMBIENT TEMPERATURE STORAGE

The terms "room" or "ambient" temperature storage conditions have different

meanings to different companies and different regulators. It is now more

common the use the term "temperate" storage. Temperate storage has recently

been redefined as a storage temperature of between 15°C and 30°C, with

occasional excursions above that range.

Temperate storage controls vary from product to product, however, many

licensed products stipulate an upper limit of 25°C with no lower limit apart

from "protect from freezing". Inspectors have indicated that 8°C to 15°C is

acceptable temperate storage.

ADDITIONAL REQUIREMENTS FOR TEMPERATURE CONTROL

The conditions of storage for the goods should be compatible with the

storage conditions specified on their labels.

Controlled storage environments should be monitored, using suitable

temperature recording devices. All records should be reviewed and filed,

with their results tabulated and analyzed.

Refrigerated and freezing storage environments should be fitted with both

an alarm and a visual signal. This signal should permit resetting only by an

authorized person,

If any temperature is found to have deviated outside the relevant

recommended conditions for an extended time, the manufacturer of the



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goods should be contacted and the suitability of the product for use

resolved.

Equipment used for monitoring temperature should be calibrated on a

regular basis to ensure their accuracy.

How to create a temperature map

A simple temperature control example involves the physical location of material

storage in the warehouse. The higher up in the warehouse a material is stored,

the hotter the temperature the goods will be exposed to, so a physical space

nearer the ceiling without temperature controls will be inappropriate to store

goods that need to be kept cool.

Study the temperature profile of the premises, and identify potential "hot"

and "cold" areas.

Study the areas of greatest potential risk using calibrated temperature and

humidity monitoring instruments.

Develop a temperature mapping validation protocol.

Based on initial findings, commence monitoring on a regular basis.

Produce a temperature map of the premises.

Review the hot and cold areas when outside temperatures are extreme, for

example, in summer and winter.

Review the controls of heating and cooling systems.

Ensure an action plan exists in the event of temperatures becoming

compromised.

Cold storage

Cold storage refers to the storage of products requiring a storage temperature of

2°C-8°C, or when material is required to be stored frozen (e.g. below -20°C or

below -70°C).



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For a successful cold storage operation, the facility must select the right

temperature recording instrumentation, validate its processes, and maintain

documentation of records and procedures, including responding to alarm

conditions.

INSTRUMENTATIONS

The selection of recording instruments is vital. The

instruments must be easily read, and the data

must be retrievable. The instruments must be

calibrated to a national standard (the company

should retain a copy of the calibration certificate

for the equipment), and a high/low temperature

alarm should be incorporated. Max/min

thermometers are usually not acceptable.

Both air and product temperatures should be

recorded. Note that air temperature can fluctuate

considerably more than product (often called

"load") temperature.

VALIDATION

Validation efforts must:

Prove that temperature mapping checks for

areas of extreme temperatures.

Check on temperature variations during use.

Demonstrate performance in the event of a

power failure.

Demonstrate the function of alarms.



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DOCUMENTATION

Specific procedures that need to be incorporated

include:

checking temperature records at the start of the

waking day, and recording these checks in a log

what to do when certain staff are absent

responding to alarm conditions

When reviewing the cold storage controls, a

program should be set up to review cold store

temperature records both weekly and monthly as

part of a self-inspection program.

RESPONDING TO ALARM CONDITIONS

Out-of-hours alarm signals are often sent to

remote contractors or security offsite. It's therefore

very important to ensure the alarm system is

operating reliably, as repeated false signals may

result in a real signal being ignored. There are

many industry examples of degraded stock due to

late or no response to electrical failures in

warehouses. The alarm system should operate

independently of the main electrical system.

There must be a written procedure on how to respond and who to inform when

a temperature alarm monitor signals a problem. This procedure should cover

initial action (e.g. quarantining the cold store) and subsequent action. There

should be an available and current list of emergency numbers to call, and there

should be a backup plan to relocate any products are risk of deterioration (e.g.

frozen stock). Any response must be immediate, so the procedure should

ensure that weekends are addressed as well.



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Protecting sensitive materials

Many companies (particularly companies manufacturing biologicals and

vaccines) handle, store, and transport temperature-sensitive raw materials and

finished products. The protection of temperature-sensitive products is critical to

their effectiveness and safety.

Products can be degraded by excessive heat, moisture, light or repeated

freeze/thawing cycles.

STATUS LABELS

Freezers

Frozen materials are usually stable at -20°C and below,

though some materials require freezing at -80°C. If the

temperature rises, it will probably do so slowly over

several hours. Once the temperature rises above a

certain point, some to the frozen materials will start to

deteriorate or degrade. There must be a written action

plan that includes a contingency for relocation if the

temperature continues to rise.

Automatic defrost refrigerators

Some cold storage refrigerators have an automatic

nightly defrost cycle, these refrigerators may not be

suitable, as many frozen products can partially melt

then re-freeze, causing them to deteriorate and

degrade.

Heat and moisture

Almost all medicinal products are sensitive to heat and

will degrade at higher temperatures. Some products will

degrade at room temperature, while others can

withstand temperatures above 30°C for prolonged



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periods. It is practically impossible to know which

products are at risk or degrading at which

temperatures.

All products must undergo stability studies to prove

that they will not degrade under the approved storage

conditions.

GMP rules require that products be only stored within

approved temperature ranges. If the product is exposed

to excessive heat, a deviation notice should be raised.

Some products may absorb moisture from the

atmosphere it they are not properly sealed. One of the

main causes of moisture problems comes from

incorrect storage of products directly on concrete floors

and walls, as the product packaging can absorb

moisture from these surfaces.

Light

Some products are "photolytic", that is, they may

degrade it they are exposed to light for prolonged

periods. Be alert to packages that state "Protect from

light" and ensure that they are completely sealed.



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Many mis-formulation incidents commence with the wrong issue of starting

materials or other chemicals from the store.

The GMP rules clearly state that each issue of starting materials from the store

must be accompanied by requisition paperwork and that there is a cross-check

that issues match the documented request before being issued.

The reason for this requirement is that material issue is the first point of control

inside the factory. It is much better to prevent incorrect chemicals being issued

in the first place rather than finding them (or not) later on. Mis-formulation can

cause patient medication to be unsafe, which can result in serious injury or even

death of patients.


US FDA CFR211

Subpart B—Organization and Personnel

Sec. 211.22 Responsibilities of quality control unit. (extract)

(a) There shall be a quality control unit that shall have the responsibility and

authority to approve or reject all components, drug product containers, closures,

in-process materials, packaging material, labeling, and drug products, and the

authority to review production records to assure that no errors have occurred or,

if errors have occurred, that they have been fully investigated, The quality control

unit shall be responsible for approving or rejecting drug products manufactured,

processed, packed, or held under contract by another company.

International GMPs

Chapter 4 Documentation






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4.19. There should be written procedures and records for the receipt of each


Chapter 5 Production

5.5. Incoming materials and finished products should be physically or

administratively quarantined immediately after receipt or processing, until they

have been released for use or distribution.

Finished products

5.58. Finished products should be held in quarantine until their final release

under conditions established by the manufacturer.

Overview

One of the most important aspects of GMP is to ensure that the right raw

materials are received and that the correct raw material batch is issued to

production to commence manufacture.

Mistakes in this activity can have significant consequences for patient safety, or

cause batches to be rejected. Therefore, the utmost care must be taken when

receiving, logging in, storing, and issuing of raw materials.

STEPS INVOLVED BETWEEN RAW MATERIAL RECEIPT AND ISSUE

Receiving:

GMP commences on receipt of the raw materials

from the supplier. Raw materials must be checked

that they are intact, have been provided according

to the paperwork, and that labels identifying name,

batch number, and expiry date ere present.



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Sampling and testing:

Laboratory sampling and testing confirm that the

raw material received meets the company

specifications for quality. There are specific GMP

procedures for sampling of raw materials to protect

the sampler and to protect the batch from

environmental contamination.

Status labeling:

On initial receipt, raw materials should be labeled

"Hold" or "Quarantine", and once they have passed

QC testing, raw materials should be re-labeled

"Released" or "Rejected". It is important that the

storage location matches the status of the raw

material. GMP requires that only "Released" raw

materials may be used in production.

Storage:

When raw materials are stored, they may

deteriorate if they are exposed to elevated

temperatures, moisture, or are stored directly on

the floor, or are in contact with walls. GMP requires

that only authorized personnel are allowed to

remove raw materials from storage.

Issue:

Raw materials are issued against documentation or

requisitions provided by the company. GMP

requires that all issues of raw material are

accompanied by the correct paperwork, so that

there is no potential for mix-up. Incorrect selection

of a raw material may result in significant problems

in manufacture, or put the patient at risk.



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Receiving materials

Direct control over product quality begins when the starting materials first arrive

at the inward goods receiving bay.

There are a number of GMP controls that need to be put in place when goods

arrive into the receiving store, which include:

Separating receiving areas from storage areas.

Protecting receiving bays from the weather.

Checking that the identification is exactly the same on the container as it is

on the paperwork.

Examining each container and verifying that containers are sealed,

undamaged, and dean.

Raising a non-conformance notice before accepting the material if any

problems arise.

Rejecting raw materials when the contents are exposed.

Identifying products needing special storage (e.g. narcotics, temperature-

sensitive products) and dealing with them immediately.

APPROVING SUPPLIERS

Pharmaceutical companies are required to maintain an approved supplier list,

and starting materials may only be purchased from supplies on this list. When

the shipment and paperwork arrive off the delivery truck, the receiving person

should check that the supplier is on the approved list. Shipment from non-

approved suppliers must be set aside and notified to supervision immediately.

Some of the factors that contribute to a supplier being approved are:

completion of a supplier questionnaire



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successful purchasing and QA supplier audits

laboratory verification of quality by testing samples

provision of an authentic Certificate of Analysis (C of A) verified by the

laboratory.

on-time delivery

For a supplier to remain on the approved supplier list, they must have a good

history of acceptable deliveries (e.g. 3-5 consecutive approved consignments).

DURING RECEIVING MATERIALS

STEPS TO CHECK DURING RECEIVING MATERIALS

Chemical name:

Many raw materials have similar and sometimes

confusing names. For example, "Ergotamine" can be

confused with "Ergometrine", which are two very

different drugs. Similarly, the same item can be

called by different names by different suppliers, for

example, "sodium chloride" can be called "sodium

salt".

Pay particular attention to the names of the

material being delivered. Sometimes a supplier can

mix up a delivery and send the wrong raw material

with the right purchase order.

Always double-check the name of the product

needed against the paperwork of the supplier.

Standard Names Register:

GMP rules requires companies to have a Standard

Names Register matched to a unique standard

company item code. The purpose of this is to ensure

that everyone in production uses the same

terminology to avoid confusion. These names and

codes should match the Master Bill of Materials.



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When labeling starting materials, always use the

company standard name and matching code.

Approved supplier:

The purchasing department usually only purchases

from QA-approved suppliers, but occasionally there

may be a mix-up.

Always double-check the supplier origin to make

sure that the supplier is on the approved supplier

list before accepting the delivery.

Grade of material:

Purchasing department only purchases QA-

approved grades of chemicals, such as USP, BP or

EP graces. The grade should be printed on the

supplier label next to the name.

Double-check the grade against the purchase order

and supplier paperwork before accepting the lot.

Multiple lots on one delivery pallet:

Sometimes, different lots of the same material or

different materials arrive on the same suppliers

pallet. Often, the outer containers look alike as well.

This can be confusing.

Always double-check each container and physically

separate them from other lots, even of the same

material on receipt. Make sure that different lots are

not mixed up, because it is unlikely that this

problem will be picked up later in production.



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The Material Data Safety Sheet (MSDS)

An MSDS is provided by the supplier, and is designed to provide both workers

and emergency personnel with the proper procedures for handling or working

with a particular substance.

MSDSs include relevant information for the GMP warehouse on:

Health effects and first aid

Storage

Disposal

Spill/leak procedures

The MSDS is meant for:

Employees who may be exposed to hazards or who need to know the proper

methods of storage

Emergency responders (firefighters, hazardous material crews, emergency

medical technicians, emergency room personnel)

For safety responders, therefore, it is important for warehouse staff to be

cognizant of the materials coming into and going out of the warehouse.

Storing received materials

After receiving the material there are some essential GMP tasks that should be

undertaken before storage:

Remove the supplier's status labels.

Apply the company's identification and status labels.

Record the receipt of goods on company documentation.

Quarantine materials immediately after they have been accepted.

Check and process goods as soon as possible to help prevent material mix-

ups and damage.



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Only in rare circumstances should quarantined materials be used in production.

If this is to happen, there must be very strict controls in place in case of a recall.

Receiving printed matter

When dealing with starting materials, direct control over product quality begins

when the starting materials first arrive at the inward goods receiving boy.

The same principles apply when printed matter arrives at the manufacturer.

Inward goods must ensure that the right printed matter is received, so that the

correct printed matter is eventually released to the packaging area. When the

printed matter arrives from the printers, it must be given its own UIN, and then

be placed into quarantine.

Following receipt and quarantine, printed matter is examined and verified by QC

against standard specimens and specifications, in order to avoid any mix-ups or

errors. Since many labels, cartons, and leaflets look alike, it is important that

QC personnel take particular care in both sampling and testing. Packaging and

labeling samples should not be returned to inventory.

Only after printed materials have passed inspection should they be released for

use.

GOOD TO KNOW - SAMPLING PLANS FOR PRINTED MATERIAL

Sampling plans are used by QC in order to specify the number of samples of

printed matter to be taken. There are several types of sampling plans QC use,

e.g. statistical, targeted, and zero acceptance number Although QC use all of

them for printed matter in some respects, the reasons why each are chosen is

beyond the scope of this module.

Suffice it to say, sampling plans for printed matter account for at least the

following:

the quantity and quality of printed matter received

the quality of printed matter required



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the nature of the material (e.g. primary and/or printed materials)

the production methods

an audit of the printed matter supplier

RECEIVING PRINTED MATTER

Arrival:

Roll labels must be counted either on receipt or at

issue

Supplier counts are not acceptable unless the

supplier is specifically qualified and supplier

certifies the exact count for each roll.

Supplier numbering of labels is an acceptable

alternative.

Cut labels must be counted and effectively verified

by the manufacturer because of the risk of mix-up.

Quarantine

Printed matter must be quarantined from use until

it has been thoroughly quality-controlled.

Quarantining involves placing the received material

into a locked, separated store, secure from

unauthorized access.

All personnel, when they handle printed matter,

should double-check that the "Quarantine" label

has been replaced by an "Approved for use" label.

If it hasn't, do not use the printed matter.



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QC

Printed matter must undergo QC inspection in the

same way as starting materials.

Each company will have specific sampling plans for

different printed matter, e.g. labels, product

information leaflets, cartons.

Printed matter samples are compared directly to

official, company-approved sample standards.

During inspection, printed matter must be stored

in quarantine and not issued for use.

Printed matter must be released by the inspection

team, and status-labeled "Approved" before it can

be used.

Issue of materials

The issue of approved materials must be performed only by designated staff.

Other staff should never "help themselves". If an incorrect materiel is issued, a

disaster such as a mix-up or product failure may follow.

Here are some important GMP rules regarding issue:

Materials should only be issued from the store by authorised persons

following a written procedure.

Records of the quantities receipted into stock and the quantities issued to

manufacturing must be maintained.

Inventory records should be maintained in such a way that any discrepancy

between the quantity received and the quantity issued can be clearly seen.

Discrepancies are to be reported and investigated.



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It should also be noted that when transferring goods from the warehouse to

production, all goods must come off wooden pallets and onto plastic pallets.

GOOD TO KNOW - COMPUTER CONTROL OF RELEASE

GMP allows for a computer system to control status and allow release to

manufacturing. If computer systems are in use, they must be validated and

secure. Ensure that you know your computer system procedures and security

controls.

Only QA- or QC-nominated personnel can change the status of material to

"Released", but every company has specific GMP rules in this area.

Stock rotation

GMP rules require that starting materials, printed matter and primary packaging

be rotated, so that materials that may be time expiring or degrading are not left

in the store for use. Companies are required to practice a "FIFO" policy. FIFO

(first-in first-out) traditionally means the first stock that arrives is the first stock

picked for use. In practice, many companies actually use "FEFO" (first-expiry,

first-out), implying that the materials with the shortest expiry must be used first.

For finished product, the FIFO principles also apply. Customers often will reject

stock that has a short-dated expiry.

Warehouse staff should be aware of this policy and follow the company's written

procedures. When selecting stock, always check its expiry date to ensure FIFO

principles are adhered to. It in doubt, refer to management.



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GOOD TO KNOW - MONITORING STORED MATERIALS

Starting materials should be retested or re-examined after long storage or after

exposure to adverse conditions. Stored starting materials may not be used for

extended periods. If stored correctly, under controlled temperature conditions

they will be good through to expiry date.

Sometimes, the laboratory will want to retest materials before continuing use.

This is usually a precaution for materials that could, for example, pick up

moisture on storage.

Rejecting defective and expired materials

Starting materials and packaging materials may not meet qualify standards on

receipt, or may reach their use-by date ("time expire") during storage. GMP rules

require that there are written procedures for the handling and rejection of

materials that are defective or have time-expired.

GOOD TO KNOW - EXPIRING STARTING MATERIALS

It is not uncommon for starting materials and finished products to reach their

use-by date. Many companies have specific rules about only releasing finished

product that has, for example, over 50% of its shelf life remaining, because

customers may reject it as having too short a shelf life.

Companies also have rules regarding the receipt of "short-dated" starting

materials. Management should be alerted if incoming goods have, for example,

less than 75% of their expiry period left, Check your company procedures

regarding this policy. GMP rules then require that the expired stock be securely

disposed of, so that there is no chance it finds its way back into manufacturing

or onto the market. There should be specific secure disposal procedures in

place to control this activity.



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On rare occasions, subject to strict QA approvals, permission may be given to

extend the expiry of starting materials, provided they meet retesting by the

laboratory.

Overview

Customers of pharmaceutical products expect to receive a product that is not

only manufactured and packaged correctly but also one that arrives in good

condition. Warehousing, transport, and distribution procedures play a vital part

in protecting the product all the way to the customer.




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Release to Quarantine

After manufacturing, the Packaging Department checks that all the batch

documentation is complete and accurate, and the product has been correctly

packaged and labeled.

The batch is then assigned to the Quarantine area in the warehouse.

QA clearance

GMP rules require that Quality Assurance conduct a final audit or clearance of

the manufacturing and packaging records. This is to independently verify that

the product has been correctly manufactured, packaged and tested.

If there are any questions or unresolved issues with a batch, QA will hold up

release of the batch until these remaining issues are closed out.

Preparation for dispatch

The warehouse team will receive a picking or dispatch order for either the whole

batch or for smaller portions of the batch. At this time, it is critical to cross-

check the order against the batch details. If any batch still in the Quarantine

store is picked, supervision should be notified immediately.

Prior to shipment, the order must be protected from possible transport damage

or deterioration (e.g. addition of outer packaging, shrink wrap of pallets, labeling

of transport temperature conditions).

Preparation for transport

After QA has officially released the finished batch, it may be moved from the

Quarantine to Released store (and labeled as such), making it ready for dispatch

to other warehouses, hospitals, distributors, or retail outlets.

Transport

The quality of the product can be affected by incorrect transport. The product

may be damaged if it is not protected from rough handling or adverse

temperature conditions. Some product may also be sensitive to vibration,

changes in atmospheric pressure, or freezing or thawing.



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Release and distribution Process flow

Preparation for dispatch

Things can still go wrong in the warehouse even after the batch has been

successfully manufactured, packaged, and sent to the Finished Goods area for

release. For example, goods may inadvertently be released before they are

officially passed by QA, or they might be physically damaged in the warehouse,

they can pick up moisture or dirt, or they could be dispatched to the wrong

customer.

Worse still, goods that were returned from the marketplace because they were

defective may unintentionally be placed back into stock without quarantining

and checking by QA.

Some things to be aware of when preparing to dispatch product include:

When dispatching, goods must be checked and double-checked against the

paperwork. Check the authorization on the requisition, the released status,

the item name and code, and the integrity of the container.

Only the right quantity of the right products should ever leave the warehouse,

Manufactured correctly

Packaged correctly

Production release

Pass laboratory testing

Pass batch record audits

Quality release

Available in released

warehouse

Protected & packaged for distribution

Warehouse release



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Ensure that the oldest material is issued first (FIFO).

Maintain appropriate dispatch records to ensure that each lot of product can

be recalled if necessary.

GOOD TO KNOW - DISPATCH RECORDS

Invoices or packing slips should be issued for each delivery and should

accompany the goods.

Records should be maintained in such a way that they are clear and readily

available. Records should show the receipt and disposal of all products

purchased and sold.

Distribution records should be kept in a form which is accessible to the

regulatory authorities.

STEPS TO CHECK DURING RECEIVING MATERIALS

222



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Pick and pack

When picking and packing finished product, there are several checks of the

product against the paperwork that need to be made.

Verifying the correct customer

Verifying the product and strength

Cross-checking the dispatch order batch number

Verifying the product is within expiry

Verifying the dispatch order quantity

Ensuring that packing instructions are correct

Transportation

Things can go wrong during transportation and distribution. For example,

product may be counterfeited or substituted in the distribution chain, or it could

be damaged by the environment in which it was transported. These situations

may cause the product to degrade or otherwise lose quality.

GOOD TO KNOW - VALIDATION OF TRANSPORTATION CONDITIONS

Many companies validate their transport conditions to see if there is are

potential problems with long-distance transit. Once conditions are validated,

it is normal practice to include continuous temperature monitoring devices on

all consignments that are moved long distances, particularly if they have any

sensitivity to heat or cold. These monitoring records are then used to check

that there were indeed no transport issues, keeping the product safe



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Once a product leaves the control of the warehouse, it is subject to the possible

impact of transport mistakes and uncontrolled warehouse conditions. Many

medicines can degrade if heated or frozen even for short periods of time. These

issues particularly apply to biological products, vaccines and products that are

labeled: "Store 2°C - 8°C. Do not freeze."

For example, product that is required to be stored at 2°C - 8°C may degrade if it

was stored at more than 1 S°C for any period of time. If the product was frozen

and then thawed, it would be very hard to detect this physically, and it may make

the product unusable.

GMP rules require that returns be assessed formally before any decision is made

to return them to stock.


US FDA CFR211

Subpart K-Returned and Salvaged Drug Products

Sec. 211.204 Returned drug products.

Returned drug products shall be identified as such and held. If the conditions

under which returned drug products have been held, stored, or shipped before

or during their return, or if the condition of the drug product, its container,

carton, or labeling, as a result of storage or shipping, casts doubt on the safety,

identity, strength, quality or purity of the drug product, the returned drug

product shall be destroyed unless examination, testing, or other investigations

prove the drug product meets appropriate standards of safety, identity, strength,

quality, or purity. A drug product may be reprocessed provided the subsequent

drug product meets appropriate standards, specifications, and characteristics,

Records of returned drug products shall be maintained and shall include the

name and label potency of the drug product dosage form, lot number (or control

number or batch number), reason for the return, quantity returned, date of

disposition, and ultimate disposition of the returned drug product. If the reason




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for a drug product being returned implicates associated batches, an appropriate

investigation shall be conducted in accordance with the requirements of

211.192. Procedures for the holding, testing, and reprocessing of returned drug

products shall be in writing and shall be followed.

International GMPs

Chapter 3 Premises and Equipment

Storage Areas

3.18. Storage areas should be of sufficient capacity to allow orderly storage of

the various categories of materials and products: starting and packaging

materials, intermediate, bulk and finished products, products in quarantine,

released, rejected, returned or recalled.

Chapter 5 Production

5.65. Products returned from the market and which have left the control of the

manufacturer should be destroyed unless without doubt their quality is

satisfactory; they may be considered for re-sale, re-labeling or recovery with a

subsequent batch only after they have been critically assessed by the Quality

Control Department in accordance with a written procedure.

The nature of the product, any special storage conditions it requires, its

condition and history, and the time elapsed since it was issued should all be

taken into account in this assessment. Where any doubt arises over the quality

of the product, it should not be considered suitable for re-issue or re-use,

although basic chemical reprocessing to recover active ingredients may be

possible. Any action taken should be appropriately recorded.

Overview: Customer returns

Customers may return stock because it is oversupplied or incorrectly delivered.

However, it is not safe to assume that stock could be suitable for re-sale. There

is generally no way to tell whether the return has been tampered with, degraded

in transport or storage, or has been damaged in transit.



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GMP rules require that all returns be examined by the Quality Department and

if necessary re-tested, before they can be placed back into stock. In some cases,

if there is no way to tell if returned products have degraded, they must be

destroyed.

Products earmarked to be reissued must be kept separate from the rest of the

stock until they are investigated. They may be returned to stock, only if the

goods:

are in their original containers, unopened, and in good condition

are known to have been handled and stored correctly

have an acceptable shelf-life remaining

have been assessed by the appropriate, authorized personnel

Records must be kept of these returns, and if they are returned to stock, FIFO

must continue to be observed. Medicines that are unfit for sale must be stored

separately, and disposed of in a secure method (e.g. incineration).

GOOD TO KNOW - ASSESSING CUSTOMER RETURNS

The assessment of customer returns should take into account the nature of

the goods, and any special storage conditions they may require. If necessary,

advice should be sought from the person responsible for the quality assurance

of the manufactured product.

Considerations for handling the return of non-defective stock include:

Place a limit on the return period (e.g., 3-5 days from customer receipt).

No returns of "fridge lines".

Communicate the company's policy to customers,

Use a clear returns document that requires customers to include the

product's batch number and expiry date.

Have detailed procedures on how to handle, locate and identify returns.



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Ensure warehouse staff are trained to the returns procedure and how to

separate each return.

Ensure the returns procedure includes a detailed physical inspection, and

if necessary, a laboratory test to verify that the goods are "safe" to re-issue.

Maintain a product returns register showing dates, batch numbers,

amounts and condition of the return. This register is needed for later

investigation if there is a problem.

Managing recalls

It's almost inevitable that a company will experience a recall at some point. GMP

rules require that the warehouse (and the company) is prepared by having a

tested or validated recall procedure, which details how defective stock is

returned, registered, counted, securely separated, and securely destroyed.

GOOD TO KNOW – MANAGING RECALLS

Recalls must be very carefully managed by manufacturers in order to protect

patients and end-users. Risks surrounding recalls include:

the right people not being notified

the recalls not dealt with in a timely manner

recalled product re-entering the supply chain

The last point shows the pivotal role the warehouse plays during a recall

situation,

Warehouses should have a separate area for recalled stock where recalls from

customers are sent to the manufacturer.

Critical to a successful recall is complete and up-to-date documentation

showing where each and every part of the recalled product can be located,

either within the distribution chain or with customers.



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Step 1: Defective product in the market

In the event of a recall, QA will agree with the regulators on the scope of the

recall before the recall is triggered. The recall decision will usually happen very

quickly, so the warehouse must be recall-ready at all times. The company should

assess the quantity of stock in the marketplace at this time, with the aim of

recovering 100% of available stock.

Step 2: Recall notice Issued

The recall notice will state that the recall must occur at a particular level in the

marketplace. Class I recalls occur at the consumer level; Class II or III recalls

may occur at the retail or warehouse level. For consumer level recalls, there is

usually a company hotline to assist customers.

Step 3: Return to company locations

Defective product will be collected at nominated warehouses. It is progressively

checked, counted, and the returns recorded in a recall register. As the recall

progresses, the percentage of defective stock is monitored. The recall is

continued until 100% is returned, if possible.

Step 4: Move to dedicated Recall store

The detective product is eventually gathered in one central location in a separate,

secure Recall store or location. The recalled material must never end up in the

main warehouse.

Step 5: Destruction

Once the recalled product has been secured, it should be securely destroyed so

that there is no possibility it ends up back in the marketplace. Companies should

have secure destruction procedures, and the physical destruction should be

witnessed or otherwise verified.

Counterfeit products

Unfortunately, it has become prevalent for counterfeit medicines to make their

way into the distribution chain. Many of these products look almost identical to

the original products, both in drug appearance and packaging, These counterfeit

products contain no active ingredients (APIs), and can be dangerous to patient

health if consumed. They may even contain poisons.



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GOOD TO KNOW - BEING ALERT TO COUNTERFEIT PRODUCTS

Staff handling medicines in distribution or remote warehouse storage should

be very alert for any product that looks suspicious or different to the usual

product. If anything seems odd, it should be immediately reported to

supervision and placed in quarantine.

GOOD TO KNOW - RECALLS OF COUNTERFEITS IN THE UK

There have been 10 recalls between 2004 and 2007 where counterfeits had

reached patient level.

The MHRA counterfeiting strategy involves:

The operation of a targeted medicines surveillance scheme...to spot check

medicines on the UK market and then undertake laboratory analysis to test

for authentication.

Increased checks by MHRA inspectors for counterfeits when inspecting

pharmaceutical manufacturers and distributors.

Collaborative international enforcement action and a training and

education / awareness raising program amongst law enforcement agencies

and pharmaceutical stakeholders.



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A mix-up of sodium chloride and potassium chloride may be undetected by the

laboratory, but could have fatal consequences for patients injected with the

wrong salt.

GMP rules require that there is extensive record keeping on the receipt, testing,

storage, issue, and use of starting materials for this very reason. Without

accurate and detailed records in the warehouse, it may not be possible to

investigate a problem quickly or thoroughly. Any delay may cause additional

problems for patients. Certainly in the case of a recall the size of the recall will

be determined by the accuracy and completeness of the warehouse records.


US FDA CFR211

Subpart J-Records and Reports

Sec. 211.188 Batch production and control records.

Batch production and control records shall be prepared for each batch of drug

product produced and shall include complete information relating to the

production and control of each batch. These records shall include:

(a) An accurate reproduction of the appropriate master production or control

record, checked for accuracy, dated, and signed;

(b) Documentation that each significant step in the manufacture, processing,

packing, or holding of the batch was accomplished, including:

(1) Dates

(3) Specific identification of each batch of component or in-process material used.

Subpart J-Records and Reports

Sec. 211.196 Distribution records.

Distribution records shall contain the name and strength of the product and

description of the dosage form, name and address of the consignee, date and

quantity shipped, and lot or control number of the drug product.




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International GMPs


4.19, There should be written procedures and records for the receipt of each


4.20. The records of the receipts should include:

a) the name of the material on the delivery note and the containers;

b) the "in-house" name and/or code of material (if different from a);

c) date of receipt;

d) supplier's name and, if possible, manufacturer's name;

e) manufacturer's batch or reference number;

f) total quantity, and number of containers received;

g) the batch number assigned after receipt;

h) any relevant comment (e.g. state of the containers).

Chapter 8

Complaints and Product Recall

8.13, The distribution records should be readily available to the person(s)

responsible for recalls, and should contain sufficient information on wholesalers

and directly supplied customers (with addresses, phone and/or fax numbers

inside and outside working hours, batches and amounts delivered), including

those for exported products and medical samples.

Overview

GMP rules require that companies have starting materials and finished product

traceability all along the supply chain. This is achieved by accurate recording in

official records and registers, the movement of all materials and products at all

stages of the product cycle.



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"Forward" traceability is needed in case the supplier discovers a defective starting

material that may harm patients. "Backward" traceability is needed in case a

patient or healthcare professional reports an adverse event or defective product.

Only by having a complete chain of toward and backward traceability can

patients' health be protected.

Inward goods

Starting materials are purchased only from approved suppliers and to authorized

specifications.

Each separate material is given a Unique Identifying Number (UIN) from the

Goods Received Register.

The UIN and the standard name are used throughout manufacturing to identify

that material and to trace its history from supplier to customer.

Goods Received Register

Standard Names List



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Status labels

SOPs and Work Instructions

INWARDS GOODS

A register should be established showing the receipt

of starting materials. The register should include:

Date of receipt

The standard name of material

The supplier's and the manufacturer's name for

the material (if different)

Manufacturer's batch or reference number

Total quantity and number of containers

received

The UIN assigned after receipt

A Standard Names List, as a minimum, contains:

the approved supplier name for the chemical

the approved manufacturer name

the company item code

the company standard name that is used on the

Bill of Materials

the grade of the material e.g. USP, BP, EP

reference to any Material Safety Data Sheets

(MSDS) or safe-handling requirements



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A list showing the standard name for each starting

material should be established.

Standard names should be specific and be designed

to minimize mix-ups.

The standard names specified on this list should be

used to label and identify starting materials during

storage and manufacture.

The standards names should be consistent with the

master batch formula.

The status of any material should be evident from

the visual appearance of its status label.

Status labels are required for all materials and

products, including intermediates.

"Reject" labels should be used only for materials

that are unfit for use. Those of uncertain status or

destined for recovery, re-processing and the like

should be designated "Hold" or "Quarantine".

SOP for inventory can come from a few sources:

External customers, such as suppliers or

distributors, may submit a PO.

The warehouse management system may

generate a PO for materials when supply is low.

If this system is linked to an MRP or production

planning system, the warehouse management

system could create POs from suppliers.

Depending on the company setup, internal

company departments, such as the QC, the



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laboratory, a production, could "purchase" raw

materials from warehouse.

Warehouse staff routinely deal with POs when

receiving starting materials or dispatching finished

product. Matching the PO to the physical goods is

an important additional check to ensure that errors

are not made in receipt or dispatch.

Self-inspections

GMP self-inspections (or internal audits) are required by the regulators, are

managed by QA, and involve all manufacturing areas, including the warehouse.

During a QA audit of the warehouse, many things will be examined, including

housekeeping, location and labeling of stock, records, warehouse training, and

monitoring of environmental controls. In particular, receipt and dispatch

registers relating to stock movement are usually examined. QA will also often

check whether there is any expired stock remaining in the Released store, and

will compare this to the company computer records.



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Summary

This module highlighted the importance of the warehouse in the day-to-day

activities of the pharmaceutical manufacturer. The warehouse plays a crucial

role in the manufacture of quality products.

Warehouse staff must abide by GMP rues to prevent goods from being

contaminated, mixed up, or degraded, and issuing the right material:

Maintaining proper housekeeping, and storing the right goods in the right

locations.

Protecting goods from pests and maintaining appropriate air and temperature

controls for the goods.

Only issuing materials to manufacture that have been approved by QC.

Adhering to FIFO principles in issue to manufacture and dispatch to

customer.

Having procedures for managing recalls.

Maintaining accurate documentation.



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TEST NOW

Number of questions: 10

No time limit

Allow you save and finish at a later date

Allow you to go back and change your

answer

Attempting each question is mandatory

Pass mark at and above 70%

Print results and certificates

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