Validation in 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.
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 re-occur 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.
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.
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 Sulfanilamide 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
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
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.
GMP 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.
1979 Good Laboratory practices GLPs (21 CFRFJ11
58) was established.
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
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 validation.
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
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.
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.
Validation 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.
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
There are 4 different
types of validation.
Prospective 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
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 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.
Revalidation 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)
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
It provides evidence that the URS requirements have been
met through FS/DS and any risks have been mitigated through FMEA
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
Installation 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..
Operational 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.
Test that may be completed at this stage include and
functional testing of the equipment
Performance 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 checks.
Benefits of Validation
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
in production and quality cost.
in lost time.
in the failure rate of product leading to lower rejection rate.
the manufacturing capability by reducing failures and rework.
less in-process and end-of-line testing.
be used to investigate invalids or deviation during production.
from batch to batch is minimized.
compliance with all regulatory agencies
of the process and equipment.
scheduling of all required Maintenance.
the training of production staff and gives them a better understanding of the
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
required if there are no down stream checks