ECONOMY    GOVERNMENT & POLICY

Food And Drug Administration (FDA)

REVIEWED BY WILL KENTON

 Updated May 17, 2018

DEFINITION of Food And Drug Administration (FDA)

The Food and Drug Administration (FDA) is a government agency established in
1906 with the passage of the Federal Food and Drugs Act. The agency is
separated into divisions that oversee a majority of the organization's obligations
involving food, drugs, cosmetics, animal food, dietary supplements, medical
devices, biological goods, and blood products.

BREAKING DOWN Food And Drug Administration (FDA)

The FDA is known for its work in regulating the development of new drugs. The
FDA has developed rules regarding the clinical trials that must be done on all
new medications. Pharmaceutical companies must test drugs through four
phases of clinical trials before they can be marketed to individuals.

According to the FDA, the agency holds responsibility for monitoring the safe
consumption of medical products, food and tobacco items worth more than $2.4
trillion. In fiscal 2016, the budget for the FDA was approximately $4.7 billion.

The FDA is relevant for investors specifically in regards to biotech and

pharmaceutical companies. FDA approval can be crucial to companies that are
heavily involved in developing new drugs. Without the agency’s
approval, regulated products under the FDA's purview cannot be released for
sale in the United States.

Ways Food and Drug Administration Approvals Influence Industry and the Market
Companies that are focused on the development and sale of new drugs can be
left without key products to drive their revenue if their products fail to receive
approvals. The influence the FDA wields regarding drug testing can affect the
stock market. The release of test data might be seen by investors as a measure
for future growth for companies that manufacture and market drugs.

The FDA is responsible for inspecting and reviewing production facilities that
make items that are regulated by the agency. This includes but is not limited
to vaccine and drug manufacturers, blood banks, food processing facilities, dairy
farms, animal feed processors, and compounding pharmacies.
The agency also inspects facilities where testing on animals and clinical trials are
conducted. Inspections may be regularly scheduled visits to facilities already in
use. The agency conducts preapproval inspections for companies that applied to
market new products. Inspections may be launched “for cause” if there is an
issue reported at a facility.

Imported regulated products must also be inspected by the FDA when they arrive
at the border of the country.

The agency publishes announcements of product recalls in collaboration with

companies and local partners. Such recalls can be the result of undeclared
ingredients in the contents, which can pose risks for consumers with allergies.
Contamination of products or the failure to handle the product according to safety
parameters can also be the cause for recalls. 

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What are the Differences between EU and FDA GMP?

While EU and FDA GMP Guidance is very similar, there are also some areas where there are
known differences. It is worthwhile being aware of these differences and how to prepare for
inspections and interaction with companies and authorities from the "other side".
Some examples:

The objective of the FDA "Annual Product Review" (APR) is to evaluate annually the quality
standards of each drug product but also to determine the need for changes in specifications or
manufacturing or control procedures. For this a representative number of batches is reviewed.
The objective of the EU ''Product Quality Review'' (PQR) is to concentrate more on the overall
manufacturing and quality system and to show that a company consistently produces products
with the appropriate quality. But the PQR should include all batches which have been
manufactured in the respective period. EU Inspectors are often requesting PQRs in advance of
inspections!

Tracking & Trending and Key Process Indicators (KPIs)

According to EU-GMP Chapter 1, "a Pharmaceutical Quality System appropriate for the
manufacture of medicinal products should ensure that (…) a state of control is established and
maintained by developing and using effective monitoring and control systems for process
performance and product quality." It is important to use KPIs to demonstrate a state of control
but also to initiate and control potential continuous improvement processes. This should be
periodically reviewed by senior management (1.6). Overall, all manufacturing processes should
be "clearly defined, systematically reviewed in the light of experience and shown to be capable
of consistently manufacturing medicinal products of the required quality and complying with
their specifications."

So the EU will have an eye on quality metrics data mainly in the course of GMP inspections
whereas the FDA has a different approach: The draft "Submission of Quality Metrics Data
Guidance for Industry" was issued in November 2016. The FDA wishes that, after it has come
into force, manufacturers will submit defined quality metrics to the FDA via an electronic portal.
The FDA will use these to calculate specific statistics which are supposed to allow for risk-based
inspection planning by the FDA.

Role of the QP

In the EU, a named Qualified Person (QP) must certify the GMP compliance for each batch of a
drug product, either commercial or investigational (IMPs). The responsibilities of the Qualified
Person are defined in Annex 16 to the EU-GMP Guidelines. If commercial products or IMPs are
manufactured or packaged in the US and then imported into the EU, additional analytical testing
in the EU is needed. Additionally a successful supplier qualification is needed including initial
and periodic compliance audits which are conducted according to the respective EU-GMP
Guidance. These audits are performed by the QP or on behalf of the QP. An inspection by a
competent authority does not replace the need for an audit. So US companies will still need to
face EU audits, even after full implementation of the MRA.

In the US, the Quality Control Unit is responsible for conducting a production record review
according to CFR Part 211.192 and for ensuring contractors meet GMPs (211.22 a). 
In the US, the Quality Control Unit is responsible for conducting a production record review
according to CFR Part 211.192 and for ensuring contractors meet GMPs (211.22 a).

Validation

There is growing conformity between the FDA Process Validation Guideline and the
revised Annex 15 ("Qualification and Validation"). A better match with the FDA Guideline was
also one of the reasons for the revision of EU-GMP Guide Annex 15.

As one difference the Annex 15 asks to also list non-critical attributes and parameters in the
validation protocol. The FDA Process Validation Guideline only requires the specification of
critical quality attributes and critical process parameters. The FDA sees another difference in the
number of validation batches. Annex 15 refers to the minimum number of three, whereas the
FDA Process Validation Guideline does not mention a number. For the FDA there is another
difference in terms of process validation approaches. In Annex 15 three approaches are
mentioned (traditional, continuous process verification, hybrid), while the FDA Process
Validation Guideline makes no distinction. Further, the requirements for statistics also differ in
the two documents. This topic is emphasized more in the FDA Process Validation Guideline.
The FDA even recommends that a statistician should create the data collection plans and should
also be consulted with regard to the use of statistical methods. The FDA also sees differences
regarding the subject of sampling in stage 3 of the process validation life cycle
(continued/ongoing process verification) and demands a higher number of samples - at least until
sufficient data exist to assess variability. There is no such demand for an increased number of
samples in the ongoing process verification in Annex 15.

EU Specifics

Contamination Control

The 2015 revision of EU-GMP Guide Chapter 3 and Chapter 5 put a lot of focus on
contamination control. The main changes in the new Chapter 3 "Premises and Equipment"
concern measures to prevent cross-contamination. The changes are closely associated with the
revision of Chapter 5 ("Production") and with the EMA-Guideline on setting health based
exposure limits for use in risk identification in the manufacture of different medicinal products in
shared facilities (EMA/CHMP/CVMP/SWP/169430/2012). The new text asks for a risk-based
assessment on the basis of toxicological data. This means that dedicated facilities are only
required if the identified risks can not be controlled using adequate technical or organisational
measures.

This is also supported by EMAs Toxicological Guideline, mentioned above. It has been valid
since 1 June 2015 and describes a risk assessment based on the toxicological evaluation of the
products manufactured in the shared facilities/production areas. The revised chapter 5
"Production" also has a high focus on the technical and organisational measures to prevent cross-
contamination.
 Overall, a documented Contamination Control Strategy is required and QRM principles should
be used to assess and control the risks of contamination & cross contamination.

Supply Chain Traceability

The qualification of (all) suppliers is a legal obligation of the marketing authorisation holder
(MAH). Already when applying for a marketing authorisation (MA), the respective API
suppliers need to be audited (and qualified) by the manufacturer. And this is the start of an
ongoing qualification.

Article 46 of EU-Directive 2001/83/EC requires that (to comply with the GMP guidelines) the
product manufacturer shall verify compliance of the API manufacturer it uses by conducting
audits at manufacturing and distribution premises. For excipient suppliers, a formalised risk
assessment is the minimum (see next paragraph).

Chapter 7 of the EU-GMP Guide ("Outsourced Activities") then requires that "the Contract
Giver is responsible for assessing the legality, suitability and the competence of the Contract
Acceptor to carry out successfully the outsourced activities" prior to outsourcing activities [7.5]
and that "the Contract Giver should monitor and review the performance of the Contract
Acceptor (…)" [7.7].

According to Annex 16 of the EU-GMP Guide, the QP has to ensure that "all audits of sites
involved in the manufacture and the testing of the medicinal products and in the  manufacture of
the active substance have been carried out and that the audit reports are available to the QP
performing the certification." [1.7.3]

GMP for Excipients

In the EU, there is GMP Guidance for pharmaceutical excipient suppliers: Guidelines of 19

March 2015 on the formalised risk assessment for ascertaining the appropriate good
manufacturing practice for excipients of medicinal products for human use. The expectation is
that Manufacturing Authorisation Holders perform a risk assessment to evaluate any risk
associated with the excipient manufacturer/ supplier to further define appropriate GMP controls
and a classification of the manufacturer's risk profile for the supplier qualification

Specific Differences in Technical GMP

Expectations
Whilst the EU and FDA GMP Guidelines are very similar, there are some areas where there have
been known differences in technical and GMP expectations:

 Reverse Osmosis is permitted in the USA as a means of producing Water for Injection. Only WFI by
distillation is permitted in the EU.
 Final capping of vials in the EU is expected to be performed in a classified environment, ideally under
Grade A laminar flow, whereas in the USA the FDA have accepted an unclassified environment for this

activity.

 Clean room classification for manufacturing sterile or low bioburden products. The EU uses Grade A
– D and the USA uses Class 100 – Class 100,000 to indicate the particulate levels required for the various
room classifications.

 The FDA accepts the use of active air sampling methods only for viable microbiological
environmental monitoring whereas the EU requires settle plate monitoring as well as active air sampling.

 The EU regulatory authorities are reluctant to approve any aseptic manufacture if the product can be
terminally sterilised. This is not the case in the USA.

 The approach in the USA to the validation and management of steam sterilisers for equipment and
porous loads has encountered severe criticism from EU inspectors. The importance of air removal in particular
has not been well understood and applied in the USA.

 The EU approach to basing sampling plans for raw materials on risk and knowledge of the supplier is
not a typical USA approach. Raw materials in the USA are often sampled on a –.ln + 1 approach regardless of
risk.

 The FDA focuses heavily on the blending operation and validation for solid dose products and has
issued quite specific guidance on this subject.

 The FDA has set many trends and this has been very evident with their very thorough and rigid
approach to the use of computers in the pharmaceutical industry, in particular to the use of electronic
signatures. CFR 21 Part 11 has encountered heavy criticism from the industry in its requirements for electronic
signatures which has been onerous.
 The FDA focuses heavily on the company procedures for dealing with Out Of Specification results
and their OOS Guidance finalised in 2006 has led the way in this issue and the EU Inspectors will apply the
same requirements.

 The manufacture of Over the Counter (OTC) products in the USA does not appear to be as important
as prescription medicines with respect to GMP compliance, in that these manufacturers are not inspected as
often as prescription only medicine manufacturers. In the EU the inspection frequency has been the same.

 In practice, GMPs applied throughout the world are all about ensuring that medicinal
products are made consistently to the quality specification required, by implementing controls
over all factors that could affect the product quality during manufacturing.
 There have been considerable differences in the past between the EU and USA in the
approach to inspections and in some specific areas of GMP.
 Hopefully the new FDA initiatives, the ICH process and the recent API inspection collaboration
project will promote a better internationally agreed approach to quality systems in the
pharmaceutical industry worldwide, and a more consistent interpretation of GMPs.

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