Validation is one of the most regulated sectors of

in the Pharmaceutical Industry


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The Manufacture of pharmaceutical
products is a highly complex procedure and is one of the most regulated sectors
of any manufacturing industry. The original method of pestle and mortar
of yester year have given way to highly advance and complex manufacturing
procedures of pharmaceutical products. What was once the preserve of a chemist
or pharmacist are now controlled by computerized system. Due to the growth of
the pharmaceutical sector fuelled by the demand for existing and new products,
the methods of ensuring that all products that are released to the markets are
safe ,pure and effective for use by the general public have also developed The
regulatory requirement on the sector by such agencies as the FDA (USA), EMA
(EU),MHRA (UK) and the HPRA (Ireland) have helped to ensure the high standards
of quality and met and so preventing the mistakes of the past.


The history of Regulatory
Requirement in the Pharmaceutical Industry is a history of tragedy. At the
beginning of the nineteenth century there was very little if any Regulatory
requirement for the manufacture of medical products. Company would advertise
their latest products some of which would contain substances such as cocaine,
heroin, arsenic and oxalic acid. These products were hailed as a cure-all`s for
all aliments and some were regularly given to children as in the case of opium
based produces to help with teething. As a result of the tragedieFJ1 s it became clear that a
path forward required to control the manufacture of Pharmaceutical products
through GMP  using  strong regulations and procedures. After each
tragedy stronger regulation was introduced to ensure FJ2 such mistakes may not
againFJ3 .

The FJ4 pure Food and Drug Act
and the Meat Inspection Act which were both signed into law on June 30th
1906. This is widely accepted as the founding date of what is now the FDA.

The Elixir
Sulfanilamide Disaster in the USA in 1937.
Between the months of September and October 1937 Elixir Sulfanilamide was responsible for more than 75 deaths in 15 different
states. It was as a result of poor understanding of the chemicals used
and poor regulatory requirement for the testing of products before been released
on to the market.

The company Massergill and Co discovered
a method to dissolve Elixir Sulfanilamide which was
very difficult to dissolve using a formula containing diethylene glycol
(antifreeze) and raspberry flavoured water this give it a nice appearance and a
sweet taste which would make it appealing to children. The new formula was sent
to production and a week later released on to the market. Within week there
were reported cases of deaths due to the product.

As a consequence of the
Disaster the federal government realised that greater regulation were required,
this lead to the Food, Drug and Cosmetic act of 1938. Up to this point a companyFJ5  could not be prosecuted
as was the case of Massergill and Co who were only charged with mislabelling of
the product.

With the introduction the Food,
Drug and Cosmetic act (FDCA) companies were required to carry out safety
testing on their products and would be held accountable for any deaths or
injury caused by their products. The goal of the Food, Drug and Cosmetic act
was to verify that the food, drugs and cosmetics were pure, safe and effective
before been released for general sale. The FDCA also ensure the correct
labelling and packaging of products 

The Sulfathiazole tragedy occurred
as a result of the Winthrop Chemical Company of New
York released sulfathiazole tablets which were contaminated with phenobarbital
to the marketFJ6 , the result
was hundreds of deaths and injuries. The FDA`s investigation revealed serious
plant control deficiencies and irregularities in the firm’s recall processes.
As a result of the Sulfathiazole
tragedy the FDA drastically revise their current rules on manufacturing and
quality controls. The 1941 sulfathiazole disaster was
hailed as the birth of good manufacturing practices (GMP).

Future amendments to
the FDC 1938 act were due to the Thalidomide Tragedy between 1953-1962  Thalidomide was  developed as a sleeping aid and given freely
to workers by Chemie Grunenthal , one worked give it to his pregnant wife
resulting in their child been born without ears. The drug was sold in over 40
different countries. In the USA FDA officer Frances Kelsey prevented the drug
from been approved and resulted in prevent the same tragedy happening in the
USA. She
was awarded President’s
Award for Distinguished Federal Civilian Service from
President John F. Kennedy. 

Good Manufacturing Practices

to FJ7 1970 the quality and
sterility of products was only completeFJ8  at final product
testing. The Septicaemia outbreak of the early 1970`s in hospitals which was
caused Enterobacter cloacae of E.
agglomerans due to improper sterilising of large volume parenteral
resulting in 54 deaths. As a consequence of the FDA investigation which
resulted in total product recall and closure of the plant the FDA proposed
changes to the GMP`s which resulted in the introduction of GMP`s procedures

 In 1976 the Medical Device Amendments was
signed in to law. This
give FJ9 the FDA greater powers
over medical devices. The FDA also Proposed changes to the GMP`s with a strong FJ10 emphasis
on the Sterilisation procedures used to sterilize manufactured products. It was
at this time that terms validation and Qualification began to be used within
the pharmaceutical sector. In 1978 the cGMP`s rules final established the
minimum current good manufacturing practices for the manufacturing process ,
packing ,storage and transportation of medical products and devices.

In 1979 Good Laboratory practices
GLPs (21 CFRFJ11 
58) was established.

In 1980 the Infant formula Act was
passed into law due to the serious illness of dozens of children due to the
lack of chloride in soy based formula. The Act give greater power to the FDA to
enforce a minimum nutritional quality standard. 

In 1983 the Anti-Tampering act was
introduced making it a crime to tamper with medical packing, this was a result of
tampering with Acetaminophen capsules containers and the lacing of the capsules
with cyanide. Also in 1983 better documentation was published to inspect
computerised systems in drug manufacturing which was the beginning in computer

The Therac Tragedy was
another step along the road of GMP which was a result of software errors. Many valuable
lessons were learned and better quality practice ware implemented to improve
the quality and testing of the software used in medical devices.

In 2001 the European
Union (EU) published a set regulation called Eudralex. Eudralex are a set of
regulations that govern the manufacture of medical products for both human and
veterinary use. Eudralex consist of 10 volumes, volume 4 deals with GMP`s has
19 Annex. Annex 15 deals with Qualification and Validation. Annex described the
method of qualification and validation of the facilities, utilities, equipment
(FUE) and the process used to manufacture the medical product. It also requires
that the manufactures control all the critical aspects of the life cycle of the
product and process through qualification and validation. Any changes in the
product, process or FUE should be documented and assessed for its impact on the
validated process. In 2015 an updated revision of Annex was published to take
into account the changes in other sectors of the EUDRALEX.

Along the long and
tragic road that has led to the current point where the Pharmaceutical Industry
is now one of the most regulated industries where GMP is something that is
built into every stage of the planning and manufacturing and where
qualification and validation are a critical part of every stage of the full
life cycle of every product. GMP regulatory is now a legal requirement for
every company wishing to manufacture medical products.


Quality is very important in the
manufacture of any produce sold today. But when that productFJ12 
is a lifesaving products like Pharmaceutical products quality becomes even more
important. Quality is now a mandatory requirement by both Governments and
Regulatory bodies. CGMP requires that quality be built in to the product at
every stage of its life-cycle.

is a documented procedure to provide assurance that a process reaches a
specified level of quality attributes consistently and be able to reproduce
that consistently during all the different stages of the life of the product.  

Process Validation is process to
collect data throughout the life-cycle of a product which provides scientific
evidence that the process is capable of producing consistent high quality
product to ensure that it meets the regulation guideline requirements of such
regulatory agencies like the FDA and EMA. In the case of equipment validation
it is referred to a Qualification.  In
short you validate a process but you qualify equipment.

There are 4
different types of validation.

Prospective Validation

Validation is validation done before distribution of a new process or an
existing process that may have had some changes made to it. The requirements
for Prospective Validation is to provide documentary evidence that the process
works in accordance with the pre-prepared protocol and is normally completed
before the product is released for sale and all the validation protocols are
executed before the process is ready for commercial use. At the product
development stage the process is broken down into its own individual stepFJ13 s and each step is checked for its criticality to
the quality of the product. All the facilities, utilities, equipment (FUE) as well
as the test methods must be fully validated. The Master batch documents can
only be prepared after all of the critical parts of the process have been
determined. This method of validation is the preferred approach and is the most
widely used method of validation


Concurrent validation is validation
that used documentary evidence to show that a process or FUE preformed the way
it is expected to, based on information gathered during the actual production
process. This method measured all the critical steps within the process and end
testing and compared them to existing data to ensure the process is preforming
as expected within the existing control parameters. An example of where
Concurrent Validation was used is during the Ebola disease outbreak where
validation is being done while the product is being manufactured. It is not
usually allowed except in one off cases or as in the Ebola example where it is
urgently required.


Retrospective Validation


Validation is a validation carried out on a well-established process using
historical documentary evidence to show that the process dose what it is meant
to do and to the level expected of it. Retrospective Validation is only used on
well-established process where there has been no change to the raw material,
FUE or the production process which are critical to the quality of the product.
Retrospective Validation should only be used where there is enough historical
data to show that the process has being consistently producing produce that
meet pre-established quality parameters. During the retrospective
validation samples, should be taken from all batches made during the validation
period including
batches FJ14 that have failed, the number of
batches should be a large enough to show consistency of the process.





is used when there has been a change to any part of the process and FUE, it is
used to determine the effect of the change on the process and FUE and decide if
revalidation is required. An example of revalidation is if a piece of equipment moving FJ15 for one location to another, revalidation
would be carried out to ensure that the equipment’s  acceptance criteria is met. Another example
would be where maintenance work carried out and key components were changed, Revalidation
would be required before the equipment is returned to production.

stages of Validation

User requirement specification (URS)


The URS is
a document that described the requirements specification of a new process as
required by the owner or end user. User Requirements Specifications are written by the
system owner or end user typically before the validation process starts. The User
Requirements Specifications document is not intended to be a technical document
but more a general description of the requirements of the intended process and
should be used as a reference throughout the validation life cycle.


can be broken down to several different stages which are called Qualifications

Design Qualification (DQ)

Installation Qualification

Operational Qualification (OQ)

Performance Qualification (PQ)



Design Qualification


It provides evidence that the URS requirements
have been met through FS/DS and any risks have been mitigated through FMEA

DQ is the design of the instrument it is not evidence of the URS being
met, it is used to state the URS and the FS/DS and will show how the user
requirements will be tested .Included in the DQ also ensures that any failure
modes are identified and will also be controlled in either the IQ/OQ of in an



Qualification (IQ)


Installation Qualification (IQ) provides documentary proof that the
equipment or system has been delivered and installed in accordance with the
installation specification documents and that the respective DS has been tested
to ensure URS are met..




Qualification (OQ)


Operational Qualification provides documentary evidence that the Facilities
Utilities, Equipment (FUE) and processed can consistency perform to the standard stated in the
operational specifications.


that may be completed at this stage include and functional testing of the


Qualification (PQ)FJ16 


Qualification provides verification that the process can constantly produce a
quality product over a certain period. PQ is preformed when there are no down-stream







Benefits of Validation


In the previous section, we have looked at the
evolution of regulatory requirements leading to GMP for the production of
medical products and how validation became a very important tool in this
process. We have also looked at the different types of validation and the
different qualification stages within validation

is a regulatory requirement but that is not the only reason that company
preform validation. There are a lot of benefits of validation some of them are
listed below.


in production and quality cost. Increased
in lost time.  Reduction
in the failure rate of product leading to lower rejection rate.                                                                                           
the manufacturing capability by reducing failures and rework.Required
less in-process and end-of-line testing.Can be used
to investigate invalids or deviation during production. Variation
from batch to batch is minimized.Better
compliance with all regulatory agenciesOptimisation
of the process and equipment.Better
scheduling of all required Maintenance.Improves
the training of production staff and gives them a better understanding of the


The Pharmaceutical
sector is now one of the most regulated industries and safest. People have
confidence that product`s or device are safe to use and will not have any major
side effects. Regulatory guidelines provides a clear
pathway for the manufacture of medical products. Validation is a key tool in
providing the quality assurance that is required to manufacture medical