COURSE ON GOOD MANUFACTURING PRACTICES IN
THE PHARMACEUTICAL, BIOTECHNOLOGY AND
MEDICAL DEVICE INDUSTRIES
MODULE 1- THE HISTORY OF THE DEVELOPMENT OF GOOD
MANUFACTURING PRACTICES (GMP)
I. State versus Federal Powers and the Regulation of Commerce
In the United States, Good Manufacturing Practices (GMP) is regulated by the federal
agency known as the Food and Drug Administration (FDA). In order to understand how
the FDA and other regulatory agencies came to be formed in the United States, the
system of government in the country needs to be considered. The United States is a
federal system of government with powers divided between the states and the federal
government. In some areas the federal government has imposed a uniform standard that
all states must follow. E.g. a new drug must only be approved by the Food and Drug
Administration (FDA) to be sold in the 50 states. In other areas, such as compensation for
persons injured by prescription drugs, a state may have a liability standard that differs
greatly from that of other states.
The United States Constitution grants to the federal government the power to regulate
international and interstate commerce. Hence food and drug laws require that the product,
or at least one of its ingredients, travel in interstate commerce. Thus a pharmaceutical
company that wants to market a new drug throughout the country must have FDA
approval before it can be advertised or shipped in interstate commerce. The FDA does
not, however, have the authority to regulate the practice of medicine because that is
regulated by the state. Most states require FDA approval for drugs sold within the state,
but there have been occasions when states have permitted prescription of non-FDA
approved drugs. As long as these are made wholly in the state and are prescribed only by
physicians in the same state, the FDA has no authority to ban the use of the drug.
II. Separation of Powers
As further background on how FDA came to be developed, the separation of powers in
the Federal Government needs to be considered. The Constitution divides the Federal
Government into three branches which are intended to act as checks and balances to each
other to prevent any branch from dominating the government. The states have basically
the same organizational structure. Only the Federal system is to be discussed here in light
of the federal regulatory agencies.
1. The Legislative Branch: This is constituted by Congress which has two Houses:
Senate (100 members; two from each state) and House of Representatives (several
hundred members, each representing a particular voting district). Each proposed
law (bill) must be passed by both houses of Congress. Congress passes laws and
the Constitution gives the power to enforce the laws to the Executive Branch.
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2. The Executive Branch: The President is head of the Executive Branch and is
charged with enforcing laws passed by Congress. Enforcement is carried out
through various agencies, including the US Department of Agriculture (USDA),
the FDA and the Environmental Protection Agency (EPA). Congress creates
agencies and gives them power through laws called enabling legislation. This
specifies what the agency is to do, how it is structured and its budget. Once an
agency is established, Congress can modify or expand its duties with subsequent
legislation. E.g. FDA was given the authority to regulate medical devices by
amendments that were made in 1976 to its enabling legislation. Congress also
controls agency action through setting the agency’s budget, which can include
specific limits on funding for each agency activity. Congress may not directly
interfere with agency management. The heads and top administrators of most
agencies, such as the FDA’s Commissioner of Food and Drugs, are political
appointees chosen by the President and approved by the Senate. This allows the
President to set agency policy, within the limits of the legislation governing the
agency.
3. The Judicial Branch: This consists of the Supreme Court, the courts of appeal
and the district (local) federal courts.
III. History of FDA
A. Basic Timeline
In the United States all food, drugs, cosmetics and medical devices for both humans and
animals are regulated under the authority of the Food and Drug Administration (FDA).
The FDA and its regulations were created by the federal government in response to tragic
events which resulted in the sickness or death of Americans.
1. Origins. The origins of the FDA can be traced back to the establishment in 1848
of the Agricultural Division of the Patent Office.
2. USDA Association. More than half of FDA’s existence was spent in the USDA,
beginning with the transfer of the Agriculture Division to the USDA upon this
Department’s creation in 1862. The Division’s chemical laboratory became
known as the USDA Chemical Division.
3. Division of Chemistry became the title of the agency in 1890.
4. Bureau of Chemistry became the title of the agency in 1901.
5. Law Enforcement Function. As will be discussed later, until 1906 the agency
had no law enforcement duties, but primarily provided information and advice to
other USDA offices and other agencies such as the Treasury Department.
6. Food, Drug and Insecticide Administration. In 1927 the agricultural research
and the enforcement functions of the Bureau of Chemistry were separated, with
the latter becoming the Food, Drug and Insecticide Administration (FDIA). The
Drug Control Laboratory, which was responsible for the surveillance of
proprietary drugs, was included in the FDIA.
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7. FDA. In 1931 the FDIA became the Food and Drug Administration (FDA).
However, the agency did not officially exist by statute until the Food and Drug
Administration Act of 1988.
8. Drug Marketing. In 1938 the agency was given responsibility for approving the
marketing of new drugs and this function has been broadened by subsequent
legislation.
9. Federal Security Agency. The FDA remained a part of the USDA until 1940
when it was transferred to the Federal Security Agency, which also included such
agencies as the Public Health Service, the Office of Education and the Social
Security Administration. At the same time the head of the FDA became known as
the Commissioner of Food and Drugs, the present title of the post.
10. Department of Health, Education and Welfare became the new name of the
Federal Security Agency in 1953. Subsequently this became the Department of
Health and Human Services in 1979 when a separate Department of Education
was created.
11. FDA became part of the Public Health Service in 1968.
B. Events and Legislation Underlying the Evolution and Scope of the FDA
1. Federal Control over the US drug supply began in 1848 with the Drug
Importation Act which required US Customs to stop the importation of
adulterated drugs. This was in response to the discovery that US soldiers serving
in Mexico were given adulterated quinine, an anti-malarial drug. This law allowed
for the inspection of laboratories and the detention and destruction of drugs that
did not meet acceptable standards.
2. Chemist Charles M Wetherill was appointed in 1862 by President Abraham
Lincoln to head the Chemical Division of the newly formed USDA. Numerous
food studies were performed in the division.
3. The Biologics Control Act was passed in 1902 to ensure the purity and safety of
therapeutic sera, vaccines and similar products used to prevent or treat diseases in
humans. Vaccines had long been widely accepted in the United States, but
regulation of their safety and purity had been left to the states. This Act was
passed in response to tetanus-infected diphtheria antitoxin which led to the death
of 13 children in 1901. The tetanus came from the horse “Jim” that was used to
produce the diphtheria serum. This Act for the first time required federal
government pre-market approval of a product.
4. The Hygienic Table was established by the chief chemist, from 1883, of the
USDA, Dr Harvey W Wiley. This used a group of young men who volunteered to
serve as human guinea pigs. They allowed Dr Wiley to feed them a controlled diet
laced with a variety of preservatives and artificial colors. This “Poison Squad”
helped Dr Wiley gather enough data to show that many of the United States’
foods and drugs were adulterated, many product strengths or purities were
misrepresented and many products were labeled inaccurately. At the same time
Upton Sinclair’s book The Jungle described the shockingly unsanitary conditions
and food adulteration in meat packing plants. Both of these events led Congress to
pass the Pure Food and Drug Act, also known as the Wiley Act, and the Meat
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5.
6.
7.
8.
9.
Inspection Act in 1906. The former was enforced by the predecessor, Bureau of
Chemistry within the USDA, of the FDA. The latter was, and remains, the
jurisdiction of the USDA itself. This federal law prohibited the interstate
commerce of misbranded and adulterated food, drinks and drugs based on their
labeling. It did not affect unsafe drugs in that its legal authority would come to
bear only when a product’s ingredients were falsely labeled or were adulterated.
The government was not authorized to establish industry-wide standards or rules
to protect the public health or to approve any product before it could be marketed.
Even intentionally false therapeutic claims were not prohibited. This began to
change with the Sherley Amendment.
The Sherley Amendment (1912) prohibited the labeling of medications with
false therapeutic claims that were intended to defraud the purchaser. However the
government was required to find proof of intentional labeling fraud.
In 1937 another major event further strengthened the government’s regulatory
role. To make the bitter sulfa drugs on the market pleasant tasting, a company
used diethylene glycol to solubilize the sulfa for a raspberry-flavored product.
This resulted in the deaths of 180 people, mostly children. This event resulted in a
complete revision of the Food and Drug Act. Congress passed the Federal, Food,
Drug and Cosmetic Act (FD&C Act) in 1938. This Act repealed the Sherley
Amendment and:
a. Increased the FDA’s control to cosmetics and therapeutic devices.
b. Required new drugs to be proven safe before marketed. Manufacturers
of drugs had to test their products and send the results to the government
for marketing approval via the New Drug Application.
c. Mandated that drugs be labeled with adequate directions if they were
shown to have had harmful effects.
d. Authorized factory inspection which could be announced.
e. Authorized standards of identity and quality of containers for food.
f. Increased legal tools available to enforce provisions of the Act.
After the FD&C Act passage, during the mid 1900s numerous amendments and
laws were passed which covered:
a. Food sanitation.
b. Prosecution for violations.
c. Drug safety, labeling and effectiveness.
d. Pesticide residue.
e. Biologics.
f. Food additives.
g. Packaging and labeling.
h. Low-acid canned food.
i. Medical devices.
j. Infant formula.
k. Nutrition labeling
l. Dietary supplements.
Its first Guidance to Industry was published by the FDA in 1949.
During the late 1950s physicians in Europe and Canada began to encounter birth
defects due to the use of thalidomide, a drug that relieved morning sickness. The
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manufacturer of this drug applied for US marketing approval of the drug as a
sleep aid. The FDA’s Chief Medical Officer Dr Francis O Kelsey argued that the
drug was not safe and should not be released into the US marketplace. Dr
Kelsey’s efforts along with the US Congress resulted in the passage of the
Kefauver-Harris Act in 1962. This increased controls over manufacturing and
testing for effectiveness was added. Manufacturers were now required to:
a. Prove a drug’s safety and efficacy.
b. Register with the FDA.
c. Be inspected every two years.
d. Have their prescription drug advertising approved by the FDA.
e. Obtain documented “informed consent” from research subjects prior to
human trials.
10. To address the new provisions of the FD&C Act the FDA, with the help of the
National Academy of Sciences and the National Research Council, tested for
efficacy all drugs (3,400) approved between 1938 and 1962 based on safety alone.
Those drugs that did not pass were made to carry warning labels or removed from
the shelves. This was referred to as the Drug Efficacy Study Implementation
Review of 1966.
11. The Price Competition and Patent Restoration Act of 1984 was passed in
response to generic drugs entering the scene as patents expired on brand-name
products. This Act was adopted to make generics maintain the same absorption,
action and dosage forms as their non-generic counterparts. The Act was also
designed to aid and encourage research for new and useful medicinal compounds
by innovating pharmaceutical companies by extending the patent terms of new
drug products while undergoing FDA review. However, use of the patent term
extension benefit has decreased due to an overall reduction in FDA review time as
a result of prescription drug user fees.
12. The Prescription Drug User Fee Act was passed by Congress in 1992. It was
intended to help the FDA generate additional funds to hire more reviewers and
streamline its operations to accelerate drug approval. It authorized FDA to charge
pharmaceutical manufacturers a “user fee”. Consequently the approval time of
new pharmaceutical products has been reduced from more than 30 months to
about 13 to 15 months currently.
13. The Food and Drug Administration Modernization Act (FDAMA) was passed
in 1997. It covered the widest set of reforms since 1938.
a. The Act improved FDA’s public accountability.
b. Required an FDA mission statement to define the scope of the agency’s
responsibilities.
c. FDA must consult and cooperate with the appropriate scientific and academic
experts, consumer and patient advocacy groups, regulated industry, health
care professionals and FDA counterparts abroad, to publish a compliance
plan. This was intended to ensure the timely review of applications.
d. As part of the agency’s new mission statement. FDA must promptly and
efficiently review clinical research and take appropriate action on the
marketing of regulated products so that innovation and product availability are
not impeded.
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e. The FDAMA also created a statutory fast track approval process, based on
existing FDA regulations, for serious or life-threatening diseases and
conditions. It established a data bank of information on clinical trials for such
conditions with the help of the National Institutes of Health.
f. Authorized the use of expert scientific panels to review clinical investigations
of drugs.
g. Expanded the rights of drug and device manufacturers to disseminate
treatment information.
h. Provided streamlined procedures and greater flexibility in FDA regulations
regarding nutrient and health claims for foods. Such claims may be permitted
on food labels, without the need for FDA to issue a regulation, if a scientific
body of the US Government, e.g. the National Institutes of Health or USDA
has published an authoritative statement endorsing the claim.
IV. What the FDA Regulates
Some of the agency’s specific responsibilities include:
A. Food
1. Safety of all food products, except meat and poultry which are the responsibility
of the USDA.
2. Nutrition.
3. Dietary Supplements.
4. Labeling.
5. Bottled water.
B. Drugs
1. Product approvals.
2. Prescription and over-the-counter (OTC) drug labeling.
3. Drug manufacturing standards (GMP).
C. Medical Devices
1. Pre-market approval of new devices, e.g. pacemakers, contact lenses and hearing
aids.
2. Manufacturing (GMP) and performance standards.
3. Tracking reports of device malfunctioning and serious adverse reactions.
D. Biologics
1. Product, e.g. vaccines and blood products, and manufacturing establishment
licensing (GMP).
2. Safety of the nation’s blood supply
3. Research to establish product standards and improved testing methods.
E. Veterinary Products
1. Livestock feeds.
2. Pet food
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3. Veterinary drugs and devices.
F. Cosmetics
1. Safety.
2. Labeling.
G. Radiation-Emitting Products
1. Cell Phones.
2. Lasers.
3. Microwave ovens
4. X-ray equipment.
V. Summary of the Mission and Fundamental Activities of the FDA
A. The mission of the FDA is to protect the public health by assuring the safety,
efficacy, and security of human and veterinary drugs, biological products, medical
devices, our nation’s food supply, cosmetics, and products that emit radiation. The
FDA is also responsible for advancing the public health by helping to speed
innovations that make medicines and foods more effective, safer, and more
affordable; and helping the public get the accurate, science-based information they
need to use medicines and foods to improve their health.
B. It licenses and inspects manufacturing facilities. Adherence to GMP is central to
these activities.
C. Tests products.
D. Evaluates claims and prescription drug advertising.
E. Through MedWatch (see the FDA website) FDA provides safety information on
drugs and other FDA-related products, and allows for adverse event reporting.
F. Monitors research.
G. Creates regulations, guidelines, standards and policies. Some of these are related
to GMP.
H. Recalls. FDA posts significant product actions of the last 60 days.
I. Advisory Committees. FDA convenes public meetings with outside experts for
advice on making key public health decisions.
MODULE 2 - THE FDA AND PHARMACEUTICAL DEVELOPMENT
I. FDA Background
The FDA is a federal science-based law enforcement agency mandated to protect public
health and safety by ensuring safe foods and cosmetics, and safe and effective drugs and
medical devices in the US marketplace. It is one of several agencies within the US
Department of Health and Human Services (HHS) which also includes the Center for
Disease Control and Prevention (CDC), National Institutes of Health (NIH) and
Healthcare Financing Administration (HCFA). The FDA gets its authority through the
laws passed as Acts and amendments by Congress. It enforces its authority through:
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i.
ii.
Regulations.
Guidelines on FDA-acceptable practices and current Good Manufacturing
Practice (cGMP).
II. FDA Organization
A. The FDA is headed by a Commissioner who is appointed by the President with
the consent of the Senate.
B. FDA consists of six centers and several offices through which it conducts its
activities:
1.
2.
3.
4.
5.
6.
7.
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Center for Drug Evaluation and Research (CDER)
Center for Food Safety and Applied Nutrition (CFSAN)
Center for Veterinary Medicine (CVM)
National Center for Toxicological Research (NCTR)
Office of the Commissioner (OC)
8. Office of Regulatory Affairs (ORA)
9. Several other offices
III. Process of Drug Development
A. Introduction
A drug is a substance that exerts an action on the structure or function of the body by
chemical action or metabolism and is intended for use in the diagnosis, cure, mitigation,
treatment or prevention of disease. A new drug is defined as one that is not generally
recognized as safe and effective for the indications proposed. This definition extends
further than simply a new chemical entity. The term new drug also refers to:
i.
A drug product already in existence though never approved by the FDA for
marketing in the US.
ii. New therapeutic indications.
iii. A new dosage form.
iv.
A new route of administration.
v. A new dosing schedule.
Therefore any chemical substance intended for use in humans or animals for medicinal or
veterinary purposes, or any existing chemical or biological substance that has some
significant change associated with it, is considered not safe and effective and a “new
drug” until proper testing and FDA approval is met.
B. Requirements
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The process of approval for a drug is a very costly and time consuming process.
Pharmaceutical manufacturers must follow a closely regulated step-wise process, as
follows, before their drugs are allowed to be marketed in the US:
a. Preclinical Investigation.
b. Investigational New Drug Application (IND).
c. Phase I clinical trials.
d. Phase II clinical trials.
e. Phase III clinical trials.
f. New Drug Application (NDA).
Each of these will be considered in turn.
a. Preclinical Investigation
During this phase of drug approval the company must provide solid evidence that a drug
product can be used with reasonable safety in humans. Therapeutic effects of the drug on
living organisms and safety data are collected, usually via in vitro laboratory, such as in
the use of cell cultures, and in vivo animal testing. A company does not need prior
approval for this phase, but it is required to follow Good Laboratory Practices (GLP)
regulations. These are specified in Title 21 of the Code of Federal Regulations (CFR),
part 58. GLP regulations govern laboratory facilities, personnel, equipment and
operations. They have a different standard to current Good Manufacturing Practices
(cGMP) which are required for producing drugs for humans. Compliance with GLP
requires written procedures and documentation of:
i.
Personnel training.
ii. Study schedules.
iii. Processes.
Status reports must be submitted to facility management. It may take 1-3 years to
complete the preclinical investigation after which the sponsor may proceed with the
Investigational New Drug Application, if at this time enough data has been gathered to
attain the goal of potential therapeutic effect and reasonable safety.
b. Investigational New Drug Application (IND)
Unlike the preclinical phase, the FDA has more active oversight during this stage in
which data are collected on efficacy and safety in human subjects. Clinical trials are
carefully scrutinized by the FDA to protect the health of the human subjects and to ensure
the integrity and usefulness of the clinical study data. The clinical investigation stage may
take several years to complete. Only one in ten compounds tested may actually
demonstrate sufficient clinical effectiveness and safety to enter the US marketplace. The
IND is submitted to the FDA. It must contain information on the compound itself as well
as the study. The IND must contain the following basic elements:
1. Cover sheet.
2. Table of contents.
3. Introductory statement.
4. Basic investigative plan.
5. Investigator’s brochure.
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6.
7.
8.
9.
Comprehensive investigation protocols.
The compound’s chemistry.
Manufacturing and controls.
Pharmacology or toxicology information, using data from the preclinical
investigation.
10. Any previous human experience with the compound.
11. Any other information the FDA may require.
Thus the IND covers (i) information on the study itself and (ii) information on the
proposed clinical investigation. As to the study drug, the sponsor must provide the
pharmacological and toxicological data upon which the sponsor concluded it was
reasonably safe to propose human clinical trials. The IND must also include information
describing the manufacturing and controls of the study drug, as well as information on
the drug’s chemical composition, structural formula, proposed dosage form and proposed
route of administration. Information on any prior human experience with the drug is also
required, including any relevant foreign experience, as well as any history of the drug’s
withdrawal from investigation or marketing. For information on the proposed
investigation, the application must include (i) proposed study protocols which identify the
objectives and purpose of the study, (ii) names and qualifications of investigators, (iii)
patient selection criteria, (iii) study design and methodologies, and (iv) the study’s
measurement criteria, including clinical or laboratory monitoring. The IND must also
identify the person(s) with overall responsibility for monitoring the study, as well as
outside contract research organizations. In addition, the application must include an
“investigative plan” addressing the rationale behind the proposed clinical research, an
outline of the proposed approach, the types of clinical trials to be conducted, an estimate
of the number of patients involved, and a discussion of any significant patient risks based
on toxicological data.
After submission, the sponsor must wait 30 days before beginning the clinical trials. If
there are no objections, the trials may begin.
Prior to the beginning of the clinical trials the sponsor must also develop a clinical study
protocol which is reviewed by an Institutional Review Board (IRB). The required IRB is
made up of medical and ethical experts set up at the institution, such as a university
medical center, where the trial will take place. The IRB oversees the research, ensures
that the rights of human test subjects are protected and that rigorous scientific and
medical standards are maintained. IRBs must approve the proposed clinical study which
entails review and approval of documents for informed consent prior to commencement
of the proposed clinical study. The Code of Federal Regulations (21CFR part 50) requires
that potential participants are informed adequately about the risks, benefits and treatment
alternatives before participating in experimental research. All of the IRB’s activities must
be well-documented and open to FDA inspection at any time. Once the IRB is satisfied
that the proposed trials are ethical and proper they will begin. The process of clinical
trials has three phases. Each has a purpose and can take longer than a year to complete.
c. Phase I Clinical Trials
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These are usually short in duration and involve a relatively small, usually greater than 20
and less than 100, group of subjects. The main objective is to determine toxicology,
metabolism, pharmacologic actions and any evidence of effectiveness. The results from
these studies are used to design the Phase II trials.
d. Phase II Clinical Trials
These are the first controlled studies. They usually involve several hundred subjects who
are actually affected with the disease or condition being studied. The purpose of Phase II
is to determine effectiveness of the drug against the targeted disease, to explore further
risks and side effect issues, and to confirm preliminary data regarding optimal dosage
ranges. At the end of Phase II trials, the sponsor and FDA will usually meet to discuss
specific scientific or regulatory concerns the sponsor must address in designing and
conducting its Phase II studies.
e. Phase III Clinical Trials
These are the final and most important studies. They are considered “pivotal” trials that
are designed to collect all of the necessary data to meet the safety and efficacy standards
FDA requires to approve the compound for the US marketplace. Usually they are very
large and can consist of thousands of patients in many different study centers with a large
number of investigators who conduct long term trials over several months or years. Also,
Phase III studies establish final formulation, marketing claims, stability, packaging and
storage conditions. On completion of Phase III and analysis of all the safety and efficacy
data the sponsor is ready to submit the compound to FDA for market approval. This
process begins with submission of a New Drug Application (NDA).
f. New Drug Application (NDA)
An NDA is a regulatory mechanism that is designed to give the FDA sufficient
information to make a meaningful evaluation of a new drug (21CFR 314). Specific NDA
data requirements cover seven broad categories:
1. Preclinical data, such as animal and laboratory studies, evaluating the drug’s
pharmacology and toxicology.
2. Human pharmacokinetic and bioavailability data.
3. Clinical data, i.e. data obtained from administering the drug to humans which
must include adequate tests to demonstrate that the drug is safe under the
proposed conditions of use, as well as “substantial evidence” that the drug is
effective under those conditions.
4. A description of methods by which the drug will be manufactured, processed and
packed.
5. A description of the drug product and drug substance.
6. A list of patents claiming the drug or method of use, or a statement that there are
no relevant patents.
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7. The drug’s proposed labeling. This includes statements on the product’s package
label, package insert, media advertising and professional literature.
The NDA must also provide a summary of the application’s contents concluding with a
presentation of the risks and benefits of the new drug. In addition, the NDA must contain
various regulatory certifications covering such matters as financial ties between the
sponsor and clinical investigators. Sponsors are allowed to submit the NDA electronically
in a standardized format.
FDA is required to review an application within 180 days of filing. If the requirements
for approval are met, FDA will approve the application and send the applicant an
approval letter. The approval becomes effective on the date the approval letter is issued.
The sponsor company can then begin marketing the drug.
IV. Notes
The use of the term “drug” above may include, in addition to a chemically synthesized
pharmaceutical compound, a biologic. Biologics are defined as substances derived from
or made with the aid of living organisms that include:
i.
Vaccines, antitoxins, sera, blood and blood products.
ii. Therapeutic protein drugs derived from natural sources, e.g. anti-thrombin III, or
biotechnology, e.g. proteins derived using recombinant DNA technology.
iii. Gene or somatic cell therapies.
The same regulatory and clinical testing requirements, with regard to safety and efficacy,
for approval of more traditionally derived drug products also apply to biologics. A
Biologics License Application (BLA) is used rather than a New Drug Application (NDA)
though the official forms are identical. The sponsor merely indicates in a check box if the
application is for a drug or a biologic. The biologics, or biological products, are reviewed
either by CDER or CBER depending on their category.
A. Categories of Biologics Reviewed by CDER
1. Proteins intended for therapeutic use, including cytokines (e.g. interferons),
enzymes (e.g. thrombolytics), growth factors and other proteins except for those
that are specifically assigned to CBER (e.g. vaccines and blood products). This
category includes therapeutic proteins derived from plants, animals or
microorganisms without or with the use of recombinant DNA technology.
2. Monoclonal antibodies for in vivo use.
B. Categories of Biologics Reviewed by CBER
1.
2.
3.
4.
5.
Vaccines.
Blood and blood products.
Human, animal or bacterial cells, tissues and cellular and tissue-based products.
Gene therapy products.
Antitoxins, antivenins and venoms.
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6. Allergenic extracts used for the diagnosis and treatment of allergic diseases, and
allergen patch tests.
MODULE 3 – THE FDA AND MEDICAL DEVICES
I. Introduction
FDA`s Center for Devices and Radiological Health (CDRH) is responsible for regulating
firms who manufacture, repackage, re-label, and/or import medical devices sold in the
United States. In addition, CDRH regulates radiation-emitting electronic products
(medical and non-medical) such as:
i.
ii.
iii.
iv.
v.
Lasers;
X-ray systems;
Ultrasound equipment;
Microwave ovens; and
Color televisions.
Medical devices are classified into Class I, II, and III. Regulatory control increases from
Class I to Class III. The device classification regulation defines the regulatory
requirements for a general device type. Most Class I devices are exempt from Premarket
Notification 510(k); most Class II devices require Premarket Notification 510(k); and
most Class III devices require Premarket Approval. Explanations of Premarket
Notification 510(k) and Premarket Approval will be given below. A description of device
classification follows.
II. Classification of a Medical Device
(a) Introduction
The Food and Drug Administration (FDA) has established classifications for
approximately 1,700 different generic types of devices and grouped them into 16 medical
specialties referred to as panels. Each of these generic types of devices is assigned to one
of three regulatory classes based on the level of control necessary to assure the safety and
effectiveness of the device. The three classes and the requirements which apply to them
are:
Device Class and Regulatory Controls
1. Class I General Controls
o With Exemptions
o Without Exemptions
2. Class II General Controls and Special Controls
o With Exemptions
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o
Without Exemptions
3. Class III General Controls and Premarket Approval
The class to which a device is assigned determines, among other things, the type of
premarketing submission/application required for FDA clearance to market. If a device is
classified as Class I or II, and if it is not exempt, a 510k will be required for marketing.
All devices classified as exempt are subject to the limitations on exemptions. Limitations
of device exemptions are covered under 21 CFR xxx.9, where xxx refers to Parts 862892. For Class III devices, a premarket approval application (PMA) will be required.
Device classification depends on the intended use of the device and also upon indications
for use. For example, a scalpel's intended use is to cut tissue. A subset of intended use
arises when a more specialized indication is added in the device's labeling such as, "for
making incisions in the cornea". Indications for use can be found in the device's labeling,
but may also be conveyed orally during sale of the product. In addition, classification is
risk based, that is, the risk the device poses to the patient and/or the user is a major factor
in the class it is assigned. Class I includes devices with the lowest risk and Class III
includes those with the greatest risk.
As indicated above all classes of devices are subject to General Controls. General
Controls are the baseline requirements of the Food, Drug and Cosmetic (FD&C) Act that
apply to all medical devices, Classes I, II, and III.
(b) How to Determine Classification
To find the classification of a device, as well as whether any exemptions may exist, one
needs to find the regulation number that is the classification regulation for the device.
There are two methods for accomplishing this: go directly to the classification database
on the FDA’s website and search for a part of the device name, or, if the device panel
(medical specialty) is known to which the device belongs, go directly to the listing for
that panel and identify the device and the corresponding regulation. A choice may be
made now, or one may continue with the background information below to provide other
ways to obtain the classification.
If the appropriate panel is already known one can go directly to the CFR (Code of Federal
Regulations; available on the FDA’s website) and find the classification for the device by
reading through the list of classified devices. Alternatively, one can use the panel
keyword directory in the classification database. In most cases this database will help
identify the classification regulation in the CFR.
Each classification panel in the CFR begins with a list of devices classified in that panel.
Each classified device has a 7-digit number associated with it, e.g., 21 CFR 880.2920 Clinical Mercury Thermometer. Once the device is found in the panel's beginning list, go
to the section indicated: in this example, 21 CFR 880.2920. It describes the device and
says it is Class II. Similarly, in the Classification Database under "thermometer", there
are several entries for various types of thermometers. The three letter product code, FLK
14
in the database for Clinical Mercury Thermometer, is also the classification number
which is used on the Medical Device Listing form.
Once the correct classification regulation has been identified one may return to What are
the Classification Panels and click on the correct classification regulation or go to the
CFR Search page. Exemptions from premarket notification and parts of the good
manufacturing practices (GMP) regulations are listed in the classification regulations of
21 CFR and also have been collected together in the Medical Device Exemptions
document. Most Class I devices are exempt from the premarket notification and some are
exempted from parts of the GMP regulations. Some Class II devices are exempt from
premarket notification, but none are exempt from the GMP regulations.
III. Regulatory Requirements for Medical Devices
The basic regulatory requirements that manufacturers of medical devices distributed in
the U.S. must comply with are:
i.
ii.
iii.
iv.
v.
vi.
vii.
Establishment registration,
Medical Device Listing,
Premarket Notification 510(k), unless exempt, or Premarket Approval (PMA),
Investigational Device Exemption (IDE) for clinical studies
Quality System (QS)/GMP regulation,
Labeling requirements, and
Medical Device Reporting (MDR)
a) Establishment Registration - 21 CFR Part 807
Manufacturers (both domestic and foreign) and initial distributors (importers) of medical
devices must register their establishments with the FDA. All establishment registrations
must be submitted electronically unless a waiver has been granted by FDA. All
registration information must be verified annually between October 1st and December
31st of each year. In addition to registration, foreign manufacturers must also designate a
U.S. Agent for facilitating interactions between FDA and the foreign establishment.
Beginning October 1, 2007, most establishments are required to pay an establishment
registration fee.
b) Medical Device Listing - 21CFR Part 807
Different manufacturers must list their devices with the FDA. Establishments required to
list their devices include:
i.
ii.
iii.
iv.
v.
manufacturers,
contract manufacturers that commercially distribute the device,
contract sterilizers that commercially distribute the device,
re-packagers and re-labelers,
specification developers,
15
vi.
vii.
viii.
ix.
x.
re-processors single-use devices,
remanufacturer
manufacturers of accessories and components sold directly to the end user
U.S. manufacturers of "export only" devices
foreign manufacturers and processors of devices exported to the United States
Medical device listing and updated information must be submitted electronically unless
FDA grants a waiver.
c) Premarket Notification 510(k) - 21 CFR Part 807 Subpart E
Each domestic or foreign manufacturer, developer, and re-packer or re-labeler who wants
to market in the U.S. a Class I, II, and III device intended for human use, for which a
Premarket Approval (PMA) is not required, must submit a 510(k) to FDA unless the
device is exempt from 510(k) requirements of the Federal Food, Drug, and Cosmetic Act
(the Act) and does not exceed the limitations of exemptions in .9 of the device
classification regulation chapters (e.g., 21 CFR 862.9, 21 CFR 864.9). There is no 510(k)
form; however, 21 CFR 807 Subpart E describes requirements for a 510(k) submission.
Before marketing a device, each submitter must receive an order, in the form of a letter,
from FDA which finds the device to be substantially equivalent (SE) and states that the
device can be marketed in the U.S. This order "clears" the device for commercial
distribution.
A 510(k) is a premarket submission made to FDA to demonstrate that the device to be
marketed is at least as safe and effective, that is, substantially equivalent, to a legally
marketed device (21 CFR 807.92(a)(3)) that is not subject to PMA. Submitters must
compare their device to one or more similar legally marketed devices and make and
support their substantial equivalency claims. A legally marketed device, as described in
21 CFR 807.92(a)(3), is a device that was legally marketed prior to May 28, 1976
(preamendments device), for which a PMA is not required, or a device which has been
reclassified from Class III to Class II or I, or a device which has been found SE through
the 510(k) process. The legally marketed device(s) to which equivalence is drawn is
commonly known as the "predicate." Although devices recently cleared under 510(k)
are often selected as the predicate to which equivalence is claimed, any legally marketed
device may be used as a predicate. Legally marketed also means that the predicate
cannot be one that is in violation of the Act.
Until the submitter receives an order declaring a device SE, the submitter may not
proceed to market the device. Once the device is determined to be SE, it can then be
marketed in the U.S. The SE determination is usually made within 90 days and is made
based on the information submitted by the submitter.
FDA does not perform 510(k) pre-clearance facility inspections. The submitter may
market the device immediately after 510(k) clearance is granted. The manufacturer
should be prepared for an FDA quality system (21 CFR 820) inspection at any time after
510(k) clearance.
16
On October 26, 2002 the Medical Device User Fee and Modernization Act of 2002
became law. It authorizes FDA to charge a fee for medical device Premarket Notification
510(k) reviews. A small business may pay a reduced fee. The application fee applies to
Traditional, Abbreviated, and Special 510(k)s. The payment of a premarket review fee is
not related in any way to FDA's final decision on a submission.

510(k) Review Fees
Most Class I devices and some Class II devices are exempt from the Premarket
Notification 510(k) submission. A list of exempt devices is located at:

510(k) Exempt Devices
If you plan to send a 510(k) application to FDA for a Class I or Class II device, you may
find 510(k) review by an Accredited Persons beneficial. FDA accredited 12 organizations
to conduct a primary review of 670 types of devices. By law, FDA must issue a final
determination within 30 days after receiving a recommendation from an Accredited
Person. Please note that 510(k) review by an Accredited Person is exempt from any FDA
fee; however, the third-party may charge a fee for its review.

Third Party Review
(c) Premarket Approval (PMA) - 21 CFR Part 814
Product requiring PMAs are Class III devices are high risk devices that pose a significant
risk of illness or injury, or devices found not substantially equivalent to Class I and II
predicate through the 510(k) process. The PMA process is more involved and includes
the submission of clinical data to support claims made for the device.

Premarket Approval
Beginning fiscal year 2003 (October 1, 2002 through September 30, 2003), medical
device user fees apply to original PMAs and certain types of PMA supplements. Small
businesses are eligible for reduced or waived fees.

PMA Review Fees
(d) Investigational Device Exemption (IDE) - 21CFR Part 812
An investigational device exemption (IDE) allows the investigational device to be used in
a clinical study in order to collect safety and effectiveness data required to support a
Premarket Approval (PMA) application or a Premarket Notification 510(k) submission to
17
FDA. Clinical studies with devices of significant risk must be approved by FDA and by
an Institutional Review Board (IRB) before the study can begin. Studies with devices of
nonsignificant risk must be approved by the IRB only before the study can begin.

Investigational Device Exemption
(e) Quality System Regulation (QS)/Good Manufacturing Practices (GMP) - 21
CFR Part 820
The quality system regulation includes requirements related to the methods used in and
the facilities and controls used for: designing, purchasing, manufacturing, packaging,
labeling, storing, installing and servicing of medical devices. Manufacturing facilities
undergo FDA inspections to assure compliance with the QS requirements.

Quality System
The quality system regulation includes design controls (21 CFR 820.30) which must be
complied with during the design and development of the device. Information on design
controls can be found in the following guidance documents:



Design Control Guidance for Medical Device Manufacturers
Do It By Design - An Introduction to Human Factors in Medical Devices
Medical Device Quality Systems Manual: A Small Entity Compliance Guide
(f) Labeling - 21 CFR Part 801
Labeling includes labels on the device as well as descriptive and informational literature
that accompanies the device.

Labeling
(g) Medical Device Reporting - 21 CFR Part 803
Incidents in which a device may have caused or contributed to a death or serious injury
must to be reported to FDA under the Medical Device Reporting program. In addition,
certain malfunctions must also be reported. The MDR regulation is a mechanism for FDA
and manufacturers to identify and monitor significant adverse events involving medical
devices. The goals of the regulation are to detect and correct problems in a timely
manner.
18

Medical Device Reporting
MODULE 4 – ESSENTIALS OF GOOD MANUFACTURING PRACTICES
I. Introduction
A. Regulations for Good Manufacturing Practices (GMP)
1. Developed to ensure that producers of drugs, biologics and medical devices
maintain a level of quality, safety and consistency during manufacturing.
2. Upheld and enforced by the FDA and apply to any product intended for
interstate commerce in the US.
B. Current Good Manufacturing Practices (cGMP)
The use of “current” is to remind manufacturers that they must use up-to-date systems,
equipment and technologies for the manufacture of drugs, biologics and medical devices
in order to comply with the regulations. Systems, equipment and technologies which
were in use 20 years ago to prevent contamination, mix-ups and errors, may be less than
adequate for today’s standards.
II. Regulations
A. Basis
The law providing the basis for GMP is the Food, Drug and Cosmetic Act. The Act states
that a drug or device is deemed adulterated if “….the methods used in, or the facilities or
controls used for, its manufacture, processing, packaging or holding do not conform to or
are not operated or administered in conformity with current good manufacturing practice
to assure that such drug meets the requirements of this Act as to safety and has the
identity and strength, and meets the quality and purity characteristics which it purports
or is represented to possess.”
B. Code of Federal Regulations (CFR)
The GMP regulations are published in the Code of Federal Regulations (CFR) Title 21
Part 210 and Part 211 (21CFR 210 and 211). The regulations apply to drugs and
biologics. In addition, biologic products are regulated by 21CFR Part 600. For medical
devices, GMP regulations are codified in 21CFR 820.
C. Background on Good Manufacturing Practices
19
1. The basic premise for GMP is that quality cannot be tested into a product.
2. The product must be manufactured under controlled conditions where quality is
built into the process.
3. Quality control testing of the final product is not sufficient to ensure the quality,
purity, safety, identity and strength of the product.
4. The GMP regulations are the minimum requirements for the methods, facilities
and controls used to manufacture a product.
5. The GMP regulations, as is demonstrated by their organization, tend to focus on
systems.
6. The parts are divided into subparts that cover the major systems.
7. Each subpart is then further divided into sections that address specific topics.
8. Information contained in each section describes what information, actions and
documentation are required to comply with the regulations.
9. The regulations for drugs, biologics and medical devices basically state that:
a) Facilities used to manufacture the product should be clean and wellcontrolled.
b) Personnel should have the appropriate training and experience to perform
their required tasks.
c) Equipment should be qualified for use in the particular process
d) The receipt and release of all components, drug product containers and
closures, should be documented and controlled.
e) The method of production should be validated and in a controlled,
reproducible state with in-process controls.
f) Analytical methods should be validated.
g) Materials should be traceable.
h) Procedures should be covered by controlled standard operating procedures
and activities documented at the time of performance.
i) There are procedures in place for making changes, i.e. change control,
investigating deviations, product complaints and adverse events.
j) Records are retained for at least the minimum required time period.
III. Risk-Based Approach to FDA Regulation of GMP
1. GMP regulations do not provide detailed instructions to manufacturers of
pharmaceuticals and medical devices on how to achieve compliance with the
regulations, i.e. the regulations are broad and open to some interpretation.
2. An ongoing debate as to what constitutes “current” good manufacturing
practice. Both FDA and industry may have their own interpretation and often
industry standards are the more current interpretation. This situation has the
potential to lead to problems when the company’s interpretation of cGMP
does not meet that of the FDA.
3. To counter these potential problems and modernize the regulation of drug
manufacturing and product quality, in August 2002 FDA launched a major
Agency-wide 2-year initiative called Pharmaceutical cGMPs for the 21st
Century: A Risk-Based Approach. This applied to human drug and biological
drug (biologic) products and veterinary drugs.
20
4. The overall goal of the initiative was to evaluate and improve the FDA’s
approach to reviews and inspections related to the manufacturing of regulated
products.
5. The initiative had several objectives:
a) To encourage the early adoption of new technological advances by the
pharmaceutical industry.
b) To facilitate industry application of modern quality management
techniques, including implementation of quality systems approaches,
to all aspects of pharmaceutical production and quality assurance.
c) To encourage implementation of risk-based approaches that focus both
industry and Agency attention on critical areas. A risk-based
approach is the adoption of a strategy whereby in the interest of
patient safety special focus is placed on those processes of high risk
for the patient. For example, in the manufacture of a drug more
emphasis would be placed on aseptic processing rather than on solid
dosage forms.
6. The initiative is ongoing, but a final report was issued in September 2004. In
this report FDA completed its assessment of the existing cGMP programs. It
was stated that:
a) A risk-based orientation remained a guiding principle of FDA.
b) The primary focus remained the same: to minimize the risks to
public health associated with pharmaceutical product
manufacturing.
c) The risk-based approach is to be applied to the review, compliance
and inspectional components of FDA regulation.
7. The initiative has come to be called: Pharmaceutical Quality for the 21st
Century: A Risk-Based Approach. A progress report was issued in May 2007.
In this report it is stated that the risk management group of FDA was initially
formed to explore opportunities for applying risk-based approaches to
prioritize and focus the various activities performed by FDA concerning the
oversight of GMP requirements. The group then concentrated its efforts on
developing and implementing a quantitative model to prioritize inspections of
drug manufacturing facilities. The work group developed and implemented
the expert elicitation survey, which gathered data from agency experts to
identify and weigh factors associated with (1) maintaining manufacturing
process control and (2) vulnerability to cross-product or environmental
contamination.
IV. Further Background on Current Good Manufacturing Practices
A. What are Current Good Manufacturing Practices?
1. Current Good Manufacturing Practices (cGMP) are a series of controls with
traceability to ensure that medical device, biologic and drug products meet the
requirements of safety, quality and efficacy.
21
2. The most up-to-date systems, equipment and technologies must be used as
mentioned under section I above. The use of “current” is to remind manufacturers
of this requirement.
3. CGMP is not a law, but it does have the force of law in court.
4. Rigid adherence to cGMP is required even considering that businesses are under
pressure to develop and deliver their products to market ahead of the competition.
5. A company’s reputation and degree of profitability can be adversely impacted
by failures in cGMP.
6. Given the complexities of the manufacturing environment, rigorous attention
to detail is essential.
7. FDA publishes guidelines of procedures to be followed in order to satisfy the
minimum requirements of the cGMP regulations.
B. Fundamentals of cGMP
I. Based on fundamental concepts of quality assurance.
II. Quality, safety and effectiveness must be designed and built into a product.
III. Each step of the manufacturing process must be controlled to maximize the
likelihood that the finished product will be acceptable.
V. CGMP Procedures
A. Personnel
1. Qualifications
a) An adequate number of persons required [21CFR 211.25(c)].
b) Appropriate education, training and experience is required to perform the
duties necessitated [21CFR 211.25(a)].
c) Responsibilities should be in writing, i.e. written procedures are required
[21 CFR 211.25(a)
d) Training is required which should:
i.
Be regularly conducted by qualified individuals.
ii.
Cover operations related to employees’ functions [21CFR
211.25(a)].
iii. Be recorded and the records maintained.
iv.
Be periodically assessed to ensure that employees remain
familiar with cGMP applicable to them.
2. Responsibilities
a) Good sanitation and health habits should be practiced [21CFR 211.28(b)],
for example:
i. Regular washing of hands.
ii. Yearly physicals.
iii. Smoking, eating, drinking, chewing and the storage of food should be
restricted to certain designated areas separate from the manufacturing
areas.
22
iv. Direct contact with the active pharmaceutical ingredient (API) should
be avoided.
b) Clean clothing should be worn which is appropriate for the duties
performed. “Protective apparel, such as head, face, hand and arm
coverings, shall be worn as necessary to protect drug products from
contamination.” [21CFR 211.28(a)].
c) Personnel suffering from infectious diseases or having open lesions or
exposed body surfaces should not engage in activities that could result in
compromising the quality of the API [21CFR 211.28(d)].
3. Consultants [21CFR 211.34]
a) Consultants advising on the manufacture, processing, packing or holding
of drug products should have sufficient education, experience and training
to provide advice on the subjects for which they are retained.
b) Records should be maintained stating the name, address, qualifications
and type of service provided by consultants.
B. Quality Control Functions
1. Principle
a) Quality should be the responsibility of all persons involved in
manufacturing.
b) All quality-related activities should be defined and documented.
c) The system for managing quality should cover the whole company to
ensure confidence that the API will meet its intended specifications for
quality and purity.
d) There should be a quality unit(s) that is independent of production that
fulfils quality assurance (QA) and quality control (QC) responsibilities.
e) The quality unit can be a single individual or a group depending on the
size of the organization.
f) The person(s) authorized to release intermediates and APIs should be
specified.
g) All quality-related activities should be recorded at the time they are
performed.
h) No materials should be released or used before the satisfactory completion
of evaluation by the QC/QA unit(s).
i) Procedures should exist for notifying responsible management in a timely
manner of regulatory inspections, serious cGMP deficiencies, product
defects and related actions.
2. Responsibilities of the Quality Control Unit
a) These are derived from 21 CFR and FDA guidelines.
b) The quality unit(s) (QC/QA) should be involved in all quality-related
matters [21CFR 211.22(c)].
c) The quality unit(s) should review and approve all appropriate qualityrelated documents.
23
d) The main responsibilities of the independent quality unit(s) should not be
delegated. These responsibilities should be described in writing and the
written procedures followed [21CFR 211.22(d)]. They are not limited to,
but should include the following:
i.
Releasing or rejecting all APIs [21CFR 211.22(a)].
ii. Releasing or rejecting all intermediates for use outside the
control of the manufacturing company
iii. Establishing a system to release or reject raw materials,
intermediates, packaging and labeling materials [21CFR
211.22(a)].
iv.
Making sure that critical deviations are investigated and
resolved [21CFR 211.22(a)].
v.
Approving all specifications and master production
instructions [21CFR 211.22(c)].
vi.
Approving all procedures affecting the quality of
intermediates or API [21CFR 211.22(c)].
vii.
Making sure that internal audits are performed [21CFR
211.22(a)].
viii. Approving intermediate and API contract manufacturers
[21CFR 211.22(a)].
ix. Approving changes that potentially affect intermediate or
API quality.
x. Reviewing and approving validation protocols and reports.
xi. Making sure that quality-related complaints are
investigated and reported.
xii. Making sure that effective systems are used for maintaining
and calibrating critical equipment.
xiii. Making sure that materials are appropriately tested and the
results are reported.
xiv. Making sure that there are stability data to support re-test or
expiry dates and storage conditions of API and/or
intermediates where appropriate.
xv. Performing product quality reviews.
3. Responsibilities of Quality Unit for Production Activities
Responsibilities for production activities should be described in writing
and should be as follows:
i.
ii.
iii.
Preparing, reviewing, approving and distributing the
instructions for the production of intermediates or APIs
according to written procedures.
That APIs and intermediates are produced according to preapproved instructions.
Reviewing all production batch records and ensuring that
these are completed and signed.
24
iv.
v.
vi.
vii.
viii.
ix.
x.
Making sure that all production deviations are reported and
evaluated and that critical deviations are investigated and
the conclusions are reported.
Making sure that production facilities are clean and, when
appropriate, disinfected.
Making sure that the necessary calibrations are performed
and the records kept.
Making sure that premises and equipment are maintained
and records kept.
To ensure that validation protocols and reports are
reviewed and approved.
To evaluate proposed changes in product, process or
equipment.
Making sure that new and, when appropriate, modified
facilities and equipment are qualified.
4. Internal Audits
a) To verify compliance with the principles of GMP for APIs, regular
internal audits should be performed in accordance with an approved
schedule.
b) Audit findings and corrective actions should be documented and
brought to the attention of responsible management of the firm.
c) Agreed corrective actions should be completed in a timely and
effective manner.
5. Product Quality Review
a) Regular quality reviews of APIs should be conducted with the
objective of verifying the consistency of the process.
b) Such reviews should normally be conducted and documented annually
and should include at least:
i.
A review of critical in-process controls and critical API test
records.
ii.
A review of all batches that failed to meet established
specifications.
iii. A review of all critical deviations or nonconformities and related
investigations.
iv.
A review of any changes carried out to the process or analytical
methods.
v.
A review of results of the stability monitoring program.
vi.
A review of all quality-related returns, complaints and recalls.
vii.
A review of adequacy of corrective actions.
VI. FDA Inspection, Warning Letters and Post-Marketing Regulation
A. FDA Inspection and Warning Letters
25
1. FDA enforcement actions begin with an inspection in which investigators look
for evidence of non-compliance with cGMP
2. Building a case against the product manufacturer is essentially what the Agency
looks for.
3. There are various types of inspections such as:
a) GMP (biennial).
b) Pre-Approval (PAI).
c) Bioresearch monitoring.
4. Documentation of inspections includes:
a) Form FDA 482-Notice of Inspection. This officially notifies the
manufacturer that FDA inspection has begun.
b) Form FDA 483-Inspectional Observations, i.e. list of items deemed to
be non-compliant with cGMP presented to the manufacturer on
completion of the inspection.
c) Form FDA 484-Receipt of Samples. This allows the FDA to take
samples, e.g. adulterated product, as evidence of non-compliance.
d) Establishment Inspection Report (EIR)-official document written by
the FDA investigation team that clearly describes issues identified on
Form 483 with supporting evidence.
5. The EIR is evaluated by FDA officials for further regulatory actions including:
a) No action indicated (NAI).
b) Voluntary action indicated (VAI). This means objectionable conditions
were found, but the FDA is not prepared to take or recommend any
action.
c) Official action indicated (OAI). This means sanctions will be
recommended and may include voluntary recalls of product.
6. Subsequent to an OAI ranking the FDA may issue a Warning Letter.
a) This is an informal advisory to a firm communicating the Agency’s
position on a matter.
b) Does not commit FDA to taking enforcement action.
c) Warning letters will contain direct citations to GMP regulations. For
biologics, citations would be to both 21CFR 211 and 21CFR 600.
d) The policy of the FDA is that warning letters should be issued for
violations which are of regulatory significance in that failure to
promptly and adequately make corrections, so that the violations
continue, may be expected to result in enforcement action.
e) The pharmaceutical or biotechnology company must respond to the
warning letter within 15 working days.
f) FDA will conduct a follow-up inspection to ensure that all of the items
in the warning letter have been appropriately addressed.
7. Other administrative enforcement powers of FDA are the following with
regard to product approvals:
a) Delay.
b) Suspension.
c) Withdrawal.
26
B. Post-Marketing Regulation
1. Pharmaceutical or biotechnology companies that successfully gain
marketing approval for their products are subject to further regulatory
requirements.
2. Many products are approved for market on the basis of a continued
submission of clinical research data to FDA. These data may require:
a) Further validation of efficacy and/or safety.
b) Detection of new uses or abuses for the product.
c) Determination of its effectiveness per labeled
indications under conditions of widespread usage.
3. FDA may also require a Phase IV study for pharmaceuticals approved
under the fast track provisions of the Food and Drug Administration
Modernization Act.
4. Any changes to the approved product’s indications, active ingredients,
manufacturing and labeling require the manufacturer to submit a
supplemental NDA (SNDA) for agency approval.
5. Adverse drug reports are required to be reported to FDA. All such reports
must be reviewed promptly by the manufacturer. If found to be serious,
life-threatening or unexpected, i.e. not listed in the product’s labeling, the
manufacturer is required to submit an alert report within 15 working days
of receiving the information. All adverse reactions thought not to be
serious or unexpected must be reported quarterly for three years after the
application is approved and annually thereafter.
6. Post-Marketing Surveillance is an ongoing process by FDA for
monitoring the safety of medical products. It is accomplished through the
collection of data about drugs, or any other medical product, once they are
marketed and thus available to the general population. This process
includes adverse event reports evaluation.
7. MedWatch, the FDA Medical Products Reporting Program, was
established to facilitate post-marketing surveillance. While FDA's longstanding post-marketing surveillance program predates MedWatch, this
educational/promotional initiative was designed to emphasize the
responsibility of healthcare providers to identify and report adverse events
related to the use of medical products. Through the MedWatch program
health professionals can report serious adverse events and product
problems that occur with such medical products as drugs, biologics,
medical and radiation-emitting devices, and special nutritional products,
e.g. medical foods, dietary supplements and infant formulas.
27
MODULE 5 - BUILDINGS AND FACILITIES FOR GMP
I. Design and Construction
1. Buildings and facilities should be designed to facilitate cleaning, maintenance
and operations as appropriate to the type and stage of manufacture [21CFR
211.42(a)].
2. The design of the building and facility should minimize potential contamination
by objectionable microorganisms [21CFR 211.42(b)].
3. There should be adequate space for the orderly placement of equipment and
materials to prevent mix-ups and contamination [21CFR 211.42(b)].
4. The flow of materials through the building or facility should be designed in
such a way to prevent mix-ups or contamination [21CFR 211.42(b)].
5. To prevent contamination or mix-ups there should be designated areas [21CFR
211.42(c)] for the following:
a) Receipt, identification, storage and quarantine of incoming materials and
labeling, pending the appropriate sampling, testing or examination by the
quality control unit before release, for manufacturing or packaging, or
rejection.
b) Holding rejected materials before further disposition, i.e. return,
reprocessing or destruction.
c) Storage of released materials
d) Production operations.
e) Quarantine before release or rejection of intermediates and APIs (drug
products).
f) Storage of APIs (drug products) after release.
g) Packaging and labeling operations.
h) Laboratory operations, e.g. for control.
i) Aseptic processing, which includes as appropriate:
i.
Floors, walls, and ceilings of smooth, hard surfaces that are
easily cleanable;
ii.
Temperature and humidity controls;
iii. An air supply filtered through high-efficiency particulate air
filters under positive pressure, regardless of whether flow is
laminar or non-laminar;
iv.
A system for monitoring environmental conditions;
v.
A system for cleaning and disinfecting the room and equipment
to produce aseptic conditions;
vi.
A system for maintaining any equipment used to control the
aseptic conditions.
6. There should be adequate areas for showering and changing clothes when
appropriate.
7. The washing and toilet areas should be adequately supplied and separate from,
but easily accessible to, manufacturing areas [21CFR 211.52].
28
II. Plant Materials
1. Walls
a) The position of walls should provide an orderly movement of materials
and personnel.
b) The position of walls should take into account noise levels to provide
acceptable working conditions.
c) Sectioning and arrangement of different operations should minimize the
potential for cross-contamination and for component mix-up during
storage and interdepartmental shipping.
d) Walls in manufacturing areas, corridors and packaging areas should be of
plaster finish on high-quality concrete blocks or gypsum board. The finish
should be smooth, usually with enamel or epoxy paint.
2. Floors
a) Floor covering should be selected for:
i. Durability;
ii. Cleanability;
iii. Resistance to the chemicals with which it is likely to come in
contact with.
b) Types of floor coverings:
i.
Terrazzo provides a hard-wearing finish. Both tiles and
poured-in-place finishes are available. The latter is
preferable for manufacturing areas. If tiles are used, care
must be taken to ensure effective sealing between the tiles
which otherwise could become a harboring area of dirt and
microorganisms.
ii. Welded vinyl sheeting provides an even and easy to clean
surface. This is not practical for heavy traffic areas, but can
be of value in production areas, especially for injectables.
Here the lack of joints improves the ease of cleaning and
sanitation.
iii. Epoxy flooring provides a durable and readily cleanable
surface. However, the subsurface finish is extremely
important and therefore must be considered.
3. Ceilings
a) Suspended ceilings may be provided in office areas, laboratories,
toilets and cafeterias. They usually consist of lay-in acoustical panels
of non-brittle, non-friable, non-asbestos and non-combustible material.
b) Manufacturing areas require a smooth finish, often of seamless plaster
or gypsum board with epoxy paint. All ceiling fixtures such as light
fittings, air outlets and returns, PA system and sprinkler heads should
be designed to assure ease of cleaning and to minimize the potential
for accumulation of dust.
4. Services
a) In the building design, provisions must be made for drains, water,
steam, electricity and other services to allow for ease of maintenance.
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b) Maintenance access to rooms provided with the services should,
ideally, be possible without disruption of activity therein.
III. Ventilation, Air Filtration; Air Heating and Cooling
1. Adequate ventilation should be provided [21CFR 211.46(a)].
2. Equipment for controlling air pressure, micro-organisms, dust, humidity and
temperature should be provided when appropriate for the manufacture,
processing, packing or holding of a drug product [21CFR 211.46(b)].
3. Air filtration systems, including pre-filters and particulate matter air filters,
should be used when appropriate on air supplies to production areas [21CFR
211.46(c)].
4. If air is re-circulated to production areas, appropriate measures should be taken
to control recirculation of dust from production [21CFR 211.46(c)].
5. In areas where air contamination occurs during production, there should be
adequate exhaust systems or other systems adequate to control contaminants
[21CFR 211.46(c)].
6. Air-handling systems for the manufacture, processing and packing of
penicillin should be completely separate from those for other products for human
use [21CFR 211.46(d)].
7. Air for aseptic processing areas should be filtered through high-efficiency
particulate air filters under positive pressure [21CFR 211.42(c)(10)(iii)].
8. Air-handling systems should consider the following factors:
a) Placement of air inlet and outlet ports. These should be sited to minimize
the entry of airborne particulates or odors from the surrounding areas.
Outlets should not be sited near inlets.
b) Where recirculation of air is acceptable, adequate precautions must be
taken to ensure that particulates from a processing area are removed. Dust
extraction systems should be provided, where appropriate, to minimize
further this potential problem.
c) The degree of filtration and the air volumes should be matched to the
operations involved.
d) Temperature and humidity conditions should provide personnel comfort
which will enhance employee performance.
e) Where differential pressures are required between adjacent areas, suitable
monitoring equipment should be provided. For example, manufacturing
areas using solids are usually maintained at a negative pressure in relation
to adjacent rooms and corridors in order to minimize the possibility of dust
migration to these other areas.
f) The location of final air filters close to each room being serviced
eliminates concerns regarding the possibility of small leaks in the air duct
system. Air usually enters rooms near the ceiling and leaves from the
opposite side near the floor.
9. Computer control of HVAC (heating, ventilation and air conditioning) systems is
more likely to allow the delicate balancing of the various air pressures, air flows,
temperature and humidity. When this is expanded to the entire plant systems, the
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computer control can additionally optimize energy utilization thereby reducing
costs.
IV. Plumbing
1. Potable water should be supplied under continuous positive pressure in a
plumbing system free of defects that could contribute contamination to any drug
product. Potable water should meet the standards prescribed in the Environmental
Protection Agency’s Primary Drinking Water Regulations. Water not meeting
such standards shall not be permitted in the potable water system [21CFR
211.48(a)].
2. Drains should be of adequate size and, where connected directly to a sewer,
should be provided with an air break or other mechanical device to prevent backsiphoning [21CFR 211.48(b)]. Drains should also be regularly disinfected.
V. Lighting
1. Adequate lighting should be provided in all areas [21CFR 211.44].
2. Lighting should be defined as adequate at levels that ensure worker comfort and
ability to perform efficiently and effectively.
VI. Sewage and Refuse
1. Sewage, trash, and other refuse in and from the building and immediate
premises shall be disposed of in a safe and sanitary manner [21CFR 211.50].
2. Sanitary and storm sewers in and around pharmaceutical manufacturing sites
should be in good repair and not overloaded.
3. Trash and refuse provides good harborage for pests such as rodents and insects
so it should be removed promptly far enough from the plant so that it does not
present a problem.
VII.
Sanitation
1. Any building used in the manufacture, processing, packing, or holding of a
drug product shall be maintained in a clean and sanitary condition. Any such
building shall be free of infestation by rodents, birds, insects and other vermin
(other than laboratory animals). Trash and organic waste matter shall be held
and disposed of in a timely and sanitary manner [21CFR 211.56(a)].
2. There shall be written procedures assigning responsibility for sanitation and
describing in sufficient detail the cleaning schedules, methods, equipment, and
materials to be used in cleaning the buildings and facilities; such written
procedures shall be followed [21CFR 211.56(b].
3. There shall be written procedures for use of suitable rodenticides, insecticides,
fungicides, fumigating agents, and cleaning and sanitizing agents. Such written
procedures shall be designed to prevent the contamination of equipment,
components, drug product containers, closures, packaging, labeling materials, or
31
drug products and shall be followed. Rodenticides, insecticides, and fungicides
shall not be used unless registered and used in accordance with the Federal
Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135) [21CFR 211.56(c].
4. Sanitation procedures shall apply to work performed by contractors or
temporary employees as well as work performed by full-time employees during
the ordinary course of operations [21CFR 211.56(a)].
5. In addition to the cleaning of floors, walls and ceilings, there should be
attention to dust extraction and air input systems.
6. The use of rodenticides, insecticides, fungicides, fumigating agents and other
techniques should be combined with good hygienic practices. Spilled materials,
such as sugar, that might attract creatures should immediately be eliminated.
Holes in buildings that could provide additional means of access should be
blocked. Where creatures succumb to lethal techniques there should be frequent
examination and removal of their dead remains which could in time become a
source of further contamination. If these lethal techniques consistently yield
results, attempts should be made to identify and eliminate the source of the
problem.
VIII.
Maintenance
1. Any building used in the manufacture, processing, packing, or holding of a drug
product shall be maintained in a good state of repair [21CFR 211.58].
2. Deterioration of buildings not only presents a poor image of the facility, it can
also impact on product quality. Cracks and holes in walls, floors or ceilings can
provide access for insects, rodents, birds, dirt or microorganisms. They can also
hinder cleaning and sanitation, thereby increasing the potential for crosscontamination or microbial multiplication. Floor cracks can also become a safety
hazard for people or can even result in the dislodging of material from carriers
being moved across the floor.
3. The entry of water from roof leaks can cause significant damage to materials
and equipment, give rise to electrical failures and fires and result in damage to the
basic structure of the building. In addition, holes in the roof or near the tops of
buildings provide ready access to birds, which may then be encouraged to nest
within the building.
4. Damage to insulation of pipes and duct work will detract from the basic
purpose of such insulation. It may also result in freezing and eventual leakage of
pipes and in the shedding of insulation material into product and equipment.
5. Light fittings need regular cleaning to remove any accumulated dust which can
act as both a potential source of contamination and reduce light intensity.
MODULE 6 - RECEIVING AND QUARANTINE OPERATIONS
I. Introduction
1. Requirements
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a) Requirements for receiving and handling all materials, i.e. components,
drug product containers and closures, that will become part of the finished
drug product are set forth in subpart E of Title 21 of the Code of Federal
Regulations (21CFR 211.80-211.94). They include, among other things,
measures for status identification, testing and release for storage. These
operations are critical in ensuring materials will consistently meet
specifications for the production of quality drug products.
b) If components of inferior or unknown quality are used, finished drug
products may be produced that do not meet the desired and required
standards. Similarly, containers and closures play a critical role in
ensuring that patients ultimately receive a drug product of essentially the
same strength, quality and purity as when it was produced by the
manufacturer. Failure to control properly these factors could contribute to
contamination with foreign material, stability failures and bioavailability
problems.
c) While the potential problems are numerous, they seldom have an impact
on the finished product because there are many opportunities to exercise
control as processing proceeds.
d) Many of the controls for receiving and quarantine operations have to do
with tasks that are carried out in warehouse areas. This serves to illustrate
the importance of warehousing functions and component control.
e) Many receiving and storage operations provide much room for
improvement as shown below.
i.
They are often poorly lit and cluttered with outdated material or
waste.
ii.
Materials are placed on incorrect pallets or in incorrect storage
bays.
iii. Entries in paper receiving records sometimes do not agree with
entries in automated receiving systems.
iv.
Sampling is sometimes not representative of the lots.
2. Case Study
a) A breakdown in control of receiving and release together with another
breakdown could have the drastic consequence of a defective product
escaping into distribution.
b) For instance a number of years ago a lot of thyroid tablets had to be
recalled because they were of 114% potency.
c) The investigation revealed that during dispensing of the active
ingredient, operators weighed out what was left of the working stock
and then went to the warehouse to withdraw another container. The
back-up supplies had been sampled, but not assayed and released by
quality control. Contrary to the regulations the decision was made to
go ahead and use the material that had not been released, i.e.
production then continued.
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d) A sample of the finished product for release testing was taken early in
the tablet-forming run so that there would be little delay in releasing
the product for packaging and then distribution.
e) The results of the finished product assay were within limits and the
product was released.
f) An examination of the batch record indicated that there had been a
problem during mixing of this batch and the mixer had to be restarted.
In retrospect, it appeared likely that mixing had been inadequate.
However, no samples had been taken to demonstrate uniformity of the
mixture. The finished product assay itself may have therefore been
correct.
g) The lot was already in customer warehouses when the assay of the
second lot of thyroid powder revealed it was significantly more potent
than the first lot that was used to calculate the amount to be dispensed
for tablet production.
h) An equipment problem probably contributed to this problem.
However, had the component been checked and released, inordinately
high potency active ingredient would not have been used and the recall
may have been prevented.
II. General Requirements
1. 21CFR 211.80(a)
a) There shall be written procedures describing in sufficient detail the
receipt, identification, storage, handling, sampling, testing, and approval
or rejection of components and drug product containers and closures;
such written procedures shall be followed [21CFR 211.80(a)].
b) The written procedures required here may be documented entirely in a
firm’s SOPs or in a combination of documents that may include materials
specifications sheets, etc. Frequently, receipt and handling is covered by a
warehouse procedure whereas sampling and testing is covered by a
laboratory procedure.
c) The qualifier “sufficient detail” is intended to mean a description of each
significant step with concise instructions that would be meaningful to a
trained worker.
d) The criteria for approval or rejection of each material in view of its
intended use must be documented.
2. 21CFR 211.80(b) and (c)
a) Components and drug product containers and closures shall at all
times be handled and stored in a manner to prevent contamination
[21CFR 211.80(b)].
b) Bagged or boxed components of drug product containers, or closures
shall be stored off the floor and suitably spaced to permit cleaning and
inspection [21CFR 211.80(c)].
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c) Good warehousing practices require materials to be stored on pallets or
shelving with sufficient clearance around the loads to allow for
inspection and cleaning.
d) Products normally can be stored in the original bags or drums in which
they were received. They must be stored such that contamination with
dust, dirt or other materials is avoided and there is no contact with
floors. If they have special temperature or humidity requirements,
provisions must be made for appropriate storage. They must be kept
free of adulteration by vermin (insects, rodents, etc.).
3. 21CFR 211.80(d)
a) Each container or grouping of containers for components or drug
product containers, or closures shall be identified with a distinctive
code for each lot in each shipment received. This code shall be used in
recording the disposition of each lot. Each lot shall be appropriately
identified as to its status (i.e., quarantined, approved, or rejected)
[21CFR 211.80(d)].
b) Most firms use a system for assigning unique receiving codes to each
lot received. This code is used for tracking all acceptance/rejection
testing or evaluation information, and is used throughout to account
for all use and disposition of the lot of component.
c) Containers and components are not required to be placed in a physical
quarantine area, although many firms find this to be a useful
procedure. They are required, however, to be identified as to status of
quarantined, released or rejected. Although many firms use separate
storage areas for products of different status this is not required if there
is an adequate “paper quarantine/release” system to prevent use of
unapproved components and containers. What is required is that the
status of the material can be easily determined by physical location,
identification on the product, records, or a combination of these.
III. Receipt and Storage of Untested Components, Drug Product Containers and
Closures
1. 21CFR 211.82(a) and (b)
a) Upon receipt and before acceptance, each container or grouping of
containers of components, drug product containers, and closures shall be
examined visually for appropriate labeling as to contents, container
damage or broken seals, and contamination [21CFR 211.82(a)].
b) Components, drug product containers, and closures shall be stored under
quarantine until they have been tested or examined, as appropriate, and
released. Storage within the area shall conform to the requirements of
211.80 [21CFR 211.82(b)].
c) Most firms incorporate the requirements of 21CFR 211.82(a) and (b) into
their receiving procedures.
35
d) These rules require that all materials be held under quarantine until
release.
e) If damaged or otherwise suspect containers are accepted, they should
remain in quarantine until the contents of each container can be examined
and a decision is made whether additional special handling is necessary.
The results of these examinations should be recorded in the receiving
records, and in any special records maintained for recording deviations or
unusual events.
f) As discussed in section B3c above, quarantine may be a system of records
and/or physical quarantine to prevent the use of unapproved materials.
IV. Testing and Approval or Rejection of Components, Drug Product Containers
and Closures
1. Each lot of components, drug product containers, and closures shall be withheld
from use until the lot has been sampled, tested, or examined, as appropriate, and
released for use by the quality control unit [21CFR 211.84(a)].
a) FDA has made it very clear that materials must not be used until released.
b) There is too great a risk that a finished product containing a nonconforming material may be released into the marketplace.
2. Representative samples of each shipment of each lot shall be collected for testing
or examination. The number of containers to be sampled, and the amount of
material to be taken from each container, shall be based upon appropriate
criteria such as statistical criteria for component variability, confidence levels,
and degree of precision desired, the past quality history of the supplier, and the
quantity needed for analysis and reserve where required by 211.170 [21CFR
211.84(b)].
a) Examination of each lot of each shipment received is necessary is
necessary even when a portion of the same lot previously has been
received, tested or approved. This is necessary because subsequent
shipments may have been subjected to different conditions, which may
have caused changes in materials. One shipment of a particular lot may
meet specifications, another may not.
b) When samples are taken they must represent the lot from both a
practical and statistical perspective. Certainly if the receiving
inspection showed that the containers appeared different or if a
material could separate during shipment, a lot could not be assumed to
be homogeneous. Each container, or possibly different layers of
material within a container, may have to be sampled.
c) When there is no reason to apply special sampling plans based on
experience, there should be a statistical basis for sampling.
d) The past quality history of suppliers can be used to determine
sampling plans for articles received. If few problems have been
encountered with a particular supplier, a less extensive sampling plan
may be needed. Conversely, the more problems encountered with
36
articles from a particular supplier, the more extensive the sampling
plan will need to be.
e) While not required by cGMP, many firms use a vendor certification
program to give them confidence that quality materials are being
received or that lots can be expected to be homogeneous. Such
programs often decrease the amount of sampling required.
3. Samples shall be collected in accordance with the following procedures:
(1) The containers of components selected shall be cleaned where necessary, by
appropriate means.
(2) The containers shall be opened, sampled, and resealed in a manner designed
to prevent contamination of their contents and contamination of other
components, drug product containers, or closures.
(3) Sterile equipment and aseptic sampling techniques shall be used when
necessary.
(4) If it is necessary to sample a component from the top, middle, and bottom of
its container, such sample subdivisions shall not be composited for testing.
(5) Sample containers shall be identified so that the following information can
be determined: name of the material sampled, the lot number, the container
from which the sample was taken, the date on which the sample was taken, and
the name of the person who collected the sample.
(6) Containers from which samples have been taken shall be marked to show
that samples have been removed from them [21 CFR 211.84(c)].
a) The extent to which sampling areas should be contained will vary
depending on the product line. However, it is desirable to have a
separate area for collecting samples. Sampling out in the warehouse
storage area presents the possibility of contamination. Some
components are dusty and could contaminate nearby materials. Other
components may have special sensitivity to humidity, light or other
environmental impacts when opened for sampling.
b) Separate sampling areas should be equipped with dust control and
whatever other special provisions particular products require.
c) Containers to be sampled do not always need to be cleaned, but they
should be inspected prior to sampling to determine whether cleaning is
necessary. Cleaning sometimes will consist only of wiping or
vacuuming. What is necessary is that they be clean or cleaned to the
extent that product contamination does not occur. After sampling, all
37
d)
e)
f)
g)
seals and other closures must be replaced as they were. Any holes cut
in bags must be closed with appropriate sealing materials.
The sampling process must not introduce contamination or cause
contamination of other items. Many firms are using sterile and
disposable sampling instruments and containers for microbiological
sampling to avoid having to autoclave the sampling tools.
The intent of section (4) is to prohibit the compositing of samples
taken from different portions of a container when there is a possibility
that the composition of the material being sampled varies within the
container. The sampling plan for a material should be clear as to
whether samples should be kept separate. There is no prohibition on
compositing samples taken from different containers when a material
is known to be homogeneous and the sampling instructions call for a
composite.
It is critical that all required information is recorded and both the
samples and the containers from which they were removed are
properly identified at the time of sampling. In the event of a problem
with the analysis it may be necessary to resample the same material. If
variability with a lot is suspected, the investigator should include the
identification of all sampling points.
The containers from which samples are drawn can be identified simply
by marking on each container sampled or placing some type of label
on them. The marking should provide the date the sample was taken
and the initials of the individual who did the sampling.
4. Samples shall be examined and tested as follows:
(1) At least one test shall be conducted to verify the identity of each component of
a drug product. Specific identity tests, if they exist, shall be used.
(2) Each component shall be tested for conformity with all appropriate written
specifications for purity, strength, and quality. In lieu of such testing by the
manufacturer, a report of analysis may be accepted from the supplier of a
component, provided that at least one specific identity test is conducted on such
component by the manufacturer, and provided that the manufacturer establishes
the reliability of the supplier's analyses through appropriate validation of the
supplier's test results at appropriate intervals.
(3) Containers and closures shall be tested for conformance with all appropriate
written procedures. In lieu of such testing by the manufacturer, a certificate of
testing may be accepted from the supplier, provided that at least a visual
identification is conducted on such containers/closures by the manufacturer and
provided that the manufacturer establishes the reliability of the supplier's test
results through appropriate validation of the supplier's test results at appropriate
intervals.
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(4) When appropriate, components shall be microscopically examined.
(5) Each lot of a component, drug product container, or closure that is liable to
contamination with filth, insect infestation, or other extraneous adulterant shall
be examined against established specifications for such contamination.
(6) Each lot of a component, drug product container, or closure that is liable to
microbiological contamination that is objectionable in view of its intended use
shall be subjected to microbiological tests before use [21CFR 211.84(d)].
a) Even when a company has confidence that a supplier provides valid
certificates of analysis, it is expected that each component shall be
positively identified to ensure it is the component that was ordered and
is needed for production (paragraph (1)). Mix-ups can occur at the
supplier or in-transit. Where two or more tests are necessary to identify
a component they should be performed. This requirement also includes
inactive components.
b) The basic thrust of paragraphs (2) and (3) is the same. There must be
written specifications for each component, container and closure.
These must detail the sampling and testing that will be done before
they are released for use. Manufacturers may rely on a supplier’s
report of analysis for components, or a certificate of testing for
containers and closures, if complete testing is not done provided the
incoming material is identified and the supplier’s test results are
periodically shown to be valid.
c) The requirements articulated in paragraphs (4)-(6) require some
judgment as to whether the particular type of testing is necessary.
Particulate contamination is of concern for certain classes of drugs.
Identification and classification of particulate matter may require
microscopic examination of the components prior to use to ensure the
levels of particulates are acceptable. It is the manufacturer’s
responsibility to determine what materials are liable to contamination
with filth or extraneous material and then to establish appropriate
specifications for their acceptance and use.
d) The general requirement for microbial testing (paragraph (6)) is
applicable to all materials and should not be viewed as simply
pertaining to sterility testing of components, containers and closures
used in aseptic filling operations. To determine properly the extent of
testing needed the susceptibility to microbial contamination and
growth must be considered for the material itself and the formulation
containing the material. Indeed, the intended treatment use of the drug
product must also be considered. A material to be used in a topical
preparation applied to mucous membranes or near the eyes would have
more microbiological concern than a dry powder for use in a solid
dose form. Not that solid dose forms should be considered immune
from microbiological problems; they are simply less susceptible and
39
pose less risk than others. There have been many recalls of non-sterile
drug products because they were found to contain pathogenic
organisms such as various pseudomonas strains. Some such
contamination problems were found after human illnesses were traced
through epidemiological evidence to the drug product.
e) Case Study: In December 1993 and January 1994 a major
manufacturer, Copley Pharmaceuticals, of an inhalation product,
Albuterol Sulphate Inhalation Solution 0.5%, experienced a problem.
Several lots of the product were unfortunately contaminated with a
pseudomonas species. The source of the organism was traced to the
water supply. The problem would not have occurred, however, if
personnel were following the proper procedures and written SOPs
(standard operating procedures). The problem occurred because filling
lines were not completely dried or re-sanitized prior to being reused.
Concentrated pockets of micro-organisms were able to contaminate
new production once the lines were set up. The contamination of this
product resulted in a major recall and significant lawsuits by patients
tasking this product who alleged injury due to the microbiological
contamination.
5. Any lot of components, drug product containers, or closures that meets the
appropriate written specifications of identity, strength, quality, and purity and
related tests under paragraph (d) of this section may be approved and released
for use. Any lot of such material that does not meet such specifications shall be
rejected [21CFR 211.84(e)].
a) This paragraph is very straightforward in terms of its requirement that
materials must meet their specifications and pass any related tests
described in section 211.84(d) before they are used in producing a
finished drug product. Materials that fail must be rejected.
b) Rejected materials could possibly be assigned a different material
stock number, then tested and determined to meet specifications for
some other use. This would be acceptable handling if an investigation
disclosed that a vendor had supplied a material designed to meet
specifications for a material the manufacturer, in the normal course of
business, used in other products.
V. Use of Approved Components, Drug Product Containers, and Closures
40
Components, drug product containers, and closures approved for use shall be rotated
so that the oldest approved stock is used first. Deviation from this requirement is
permitted if such deviation is temporary and appropriate [21CFR 211.86].
a) The concept of using the oldest approved stock is fundamentally
sound.
b) There may be legitimate reasons for varying from this requirement. If
temporary and appropriate deviations occur, they should be
documented and justified. It would be acceptable to write a procedure
that would allow variations from first in-first out as long as the general
principle is observed. For example, in certain operations it may be
advantageous to work with full pallets of materials. Part pallets might
be set aside for some limited period of time pending re-palleting of
those materials so that they can be brought to the work area in full
pallets.
VI. Retesting of Approved Components, Drug Product Containers, and Closures
Components, drug product containers, and closures shall be retested or reexamined, as
appropriate, for identity, strength, quality, and purity and approved or rejected by the
quality control unit in accordance with 211.84 as necessary, e.g., after storage for long
periods or after exposure to air, heat or other conditions that might adversely affect the
component, drug product container, or closure [21CFR 211.87].
a) Deterioration of containers and closures is of considerably less
concern than for components and certain components are much more
stable than others. This allows for different treatment of various items.
b) Based on knowledge of items, manufacturers can set re-test dates “as
necessary.” However, usually a set yearly schedule of re-sampling and
re-testing is used even for the most stable items because of the
possibility a storage problem may have affected the materials.
VII.
Rejected Components, Drug Product Containers, and Closures
Rejected components, drug product containers, and closures shall be identified and
controlled under a quarantine system designed to prevent their use in manufacturing or
processing operations for which they are unsuitable [21CFR 211.89].
a) This control is to ensure that all rejected materials, whether they are
incoming, in-process, or finished goods, are not inadvertently used in a
product, passed along to the next step in the process, or released for
sale.
41
b) Disposition of these items is within the manufacturer’s discretion as
long as all regulatory commitments and cGMP requirements are met.
Depending on the investigation of the cause of the rejection,
disposition may include destruction, return to the supplier or use in
other products where specifications are met.
VIII.
Drug Product Containers and Closures
1. Drug product containers and closures shall not be reactive, additive, or
absorptive so as to alter the safety, identity, strength, quality, or purity of the drug
beyond the official or established requirements [21CFR 211.94(a)].
a) Manufacturers are responsible for establishing the suitability of the
container-closure system for a drug product during development and then
ensuring that the appropriate specifications are maintained thereafter.
2. Container closure systems shall provide adequate protection against foreseeable
external factors in storage and use that can cause deterioration or contamination
of the drug product [21CFR 211.94(b)].
a) Manufacturers need to consider conditions that can be expected to
occur occasionally. For example, extreme temperature and humidity
variations that may be encountered during winter and summer months
for drug products that are in transit should be taken into account when
considering the suitability of container-closure systems.
b) Controls must ensure that the design characteristics of the containerclosure system are met. For example, the component parts of
container-closure systems must mate properly to exclude moisture or
other possible contaminants.
3. Drug product containers and closures shall be clean and, where indicated by the
nature of the drug, sterilized and processed to remove pyrogenic properties to
assure that they are suitable for their intended use [21CFR 211.94(c)].
a) Suitable specifications for such possible contaminants as cleaning
agents, solvents and micro-organisms should be agreed to by the
manufacturer and the supplier if the containers and closures will be
used as received.
b) If washing is performed after receipt, the manufacturer must develop
specifications for the validation of the cleaning procedure and the
monitoring of the cleaning operation. For some drug product
containers cleaning is a simple operation such as passing the empty
containers over an air jet whereas for others the manufacturer will
have to perform extensive cleaning cycles.
42
4. Standards or specifications, methods of testing, and, where indicated, methods of
cleaning, sterilizing, and processing to remove pyrogenic properties shall be
written and followed for drug product containers and closures [21CFR
211.94(d)].
a) The requirement is to have appropriate written SOPs or specifications,
or both, to cover all of the operations discussed above under section
211.94 (a) to (c).
MODULE 7 - HOLDING AND DISTRIBUTION
I. Introduction
a) This module sets forth the requirements for the holding and distribution and
finished drug products. In concept the FDA regulations separate these
warehousing requirements from those for the receiving of components. In
practice, however, many pharmaceutical companies are using large central
warehouses for the storage of components, in-process materials and finished
drugs.
i.
Such warehouse systems have been designed to meet fully the
requirements of all cGMP sections.
ii. Because such warehouses serve the front end of the process as well as the
back, traffic patterns for materials in and out of the space must be
carefully thought out.
b) Large central warehouses are nearly always served by an inventory control
system based on customized software.
c) Computerized inventory control systems also are being used to:
i.
ii.
iii.
iv.
v.
Print material identification labels;
Assign storage space;
Quarantine stocks;
Ensure stock rotation; and
A variety of other activities.
d) It is necessary to perform periodically a physical inventory to verify accuracy
of the data in the inventory control system.
e) When all materials and finished products are identified properly when they
enter warehouse areas, the primary concern becomes general sanitation and
ensuring the environmental conditions are appropriate. Care must be used to
ensure proper storage conditions are maintained, e.g. refrigeration or freezing of
heat-sensitive products. Consideration of storage conditions also must be given to
any company conveyances, such as trucks and freight cars, used for transfers
between plants or deliveries to customers.
43
II. Warehousing Procedures
a) 21CFR 211.142: 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.
b) The physical separation of products that have been released by quality control
from those not yet released is not necessary if a system of controls has been
validated to ensure that a product may not be shipped until released. The system
of controls may include either a paper or computer quarantine.
c) If a company’s drug products are all stable when stored at ordinary room
temperatures and there are no special storage requirements in labeling, only the
usual HVAC systems are necessary. It is general industry practice to monitor
warehouse conditions and maintain those conditions, especially in cases of
weather changes.
d) To maintain conditions consistent with those necessary to ensure the stability of
certain products, special storage conditions may be necessary.
i.
Optimum conditions will vary with the product, but they should always
be such that there are not extremes in temperature, humidity or light.
ii. When special storage conditions are necessary they should always be
monitored to ensure they do not vary outside of acceptable ranges. It is
good practice to equip monitoring devices or controllers with alarms.
III. Distribution Procedures
a) 21CFR 211.150(a): 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) First-in first-out is practiced throughout the pharmaceutical industry.
c) With expiration-dated products it is particularly important.
d) Note that deviations from strict observance of these procedures are allowed if
they are temporary and appropriate. This simply means that some temporary
adjustments, if in order, can be made in pulling orders as long as consideration is
given to maintaining stock rotation. For example, a company may wish to ship a
large order consisting of a single batch to a customer and to do so it may be
necessary to skip over a slightly older partial lot.
e) First-in first-out also helps with stock rotation and facilitates keeping the
warehouse clean and orderly.
f) 21CFR 211.150(b): Written procedures shall be established, and followed,
describing the distribution of drug products. They shall include: (b) A system by
44
which the distribution of each lot of drug product can be readily determined to
facilitate its recall if necessary.
g) To meet this requirement in f), the system a company maintains may be a
simple paper or computer-assisted method of determining where each shipment of
a lot was distributed.
MODULE 8 - QUALITY ASSURANCE AND VALIDATION
I.
FUNDAMENTALS
1. Introduction
a)
Quality Assurance
There are three basic principles of Quality Assurance:
i.
Quality, safety and effectiveness;
ii. Cannot inspect quality into a product. Quality must be designed and built
into the production process; See Slide 1 of GMP Course Slides.
iii. Processes must be under control.
b)
Validation
See slides 2-4 of GMP Course Slides.
i.
ii.
iii.
iv.
v.
vi.
The term Validation describes the inspection and qualification, together
with the associated documentation, of Good Manufacturing Practices
(GMP) equipment and systems to verify that predetermined fabrication,
installation and operational specifications are met. See Slide 5 of GMP
Course Slides.
Validation can be succinctly defined as “the documented act of proving
that any procedure, process, equipment, material, activity or system leads
to the expected results”. See Slide 6 of GMP Course Slides.
Routine and adequate validation studies form a core principle of GMP, as
applied to the manufacture of (bio)pharmaceuticals and medical devices,
as such studies help ensure the overall safety and quality of the finished
product. See Slides 7 and 8 of GMP Course Slides.
The FDA demanded that these activities be part of all GMP manufacturing
installations in response to identified failures with the post-manufacturing
inspection methods that were previously in practice.
Validation applies to all equipment and support systems involved in the
manufacturing of (bio)pharmaceutical products, as well as to any
associated automation and computer systems. For medical devices, this
also applies to the device itself.
Validation is required by law and is described in Title 21 of the Code of
Federal Regulations under those sections dedicated to drug and medical
45
vii.
device manufacturing. Many other regulatory agencies in other countries
and regions of the world also require validation for the manufacturing of
drugs and devices.
Since validation is often a complex operation, the appropriate planning
and strategic implementation can help ensure that the validation activities
are performed in a timely and cost-effective manner. This course will
describe some strategies for the effective deployment of validation.
2. History of Validation
Prior to 1978, drug product quality and sterility were based solely on finished product
testing. This approach became seriously questioned in the 1960s and 1970s as a result of
serious incidents that demonstrated that product testing by itself was not reliable as an
indication of product safety. Examples of this are the Thalidomide scandal in 1962 and
the Septicemia outbreaks in the United States in the 1970s. See slide 9 of GMP Course
Slides.
The Septicemia outbreaks in the early 1970s had the largest impact on the development
of the validation concept. They were caused by sterility problems with large volume
parenterals (LVP). Large volume parenterals (sometimes called large volume injections)
are aqueous solutions usually supplied in volumes of at least 100 ml with sizes of 250 ml,
500 ml, and 1000 ml most common. Directions usually recommend that large quantities
be administered. The usual route of administration is intravenous (IV) but other routes,
such as intraperitoneal (IP) or subcutaneous (SQ or SC), are sometimes recommended.
These Septicemia outbreaks resulted in 54 deaths and 410 injuries. This prompted the
FDA to inspect all LVP manufacturing facilities. This resulted in 600 LVP product
recalls and temporary closure of several plants.
The FDA inspections of facilities found severe problems, including inadequate
specifications, procedures and test data for production or control systems. There was a
lack of environmental monitoring procedures, specifications and test data for water, air
and surfaces.
In 1976 the FDA proposed changes to GMP detailing how equipment and processes were
to be designed, constructed and tested. These changes were primarily aimed at
sterilization procedures including:
a) Steam and Dry Heat Sterilization;
b) Ethylene Oxide (ETO) Sterilization;
c) Depyrogenation;
d) Steam in Place (SIP); and
e) Filtration.
Terms such as Validation, Protocol and Qualification began to be used.
The FDA then expanded the need for validation of processes and systems outside of
sterilization. While these systems were not intended to sterilize they were critical
elements in the preparation of parenteral products. The areas affected included:
46
a)
b)
c)
d)
e)
Aseptic processing;
Media Fills;
Environmental Controls;
Sanitization; and
Water Systems.
The FDA used frequent inspections and the issuance of FDA 483s to convince industry of
the seriousness of its intentions. Form FDA 483 is the official form used to inform a
company of the observations identified during an inspection. The desire and necessity to
comply with the FDA ensured a quick response and implementation of FDA demands.
3. What Must Be Validated?
a)
General Approach
See Slides 10-15 of GMP Course Slides.
The Current Good Manufacturing Practices (cGMP) state that any facilities or systems
used in the manufacturing, processing, packing or holding of a drug or medical device
shall conform to Current Good Manufacturing Practice Guidelines to assure the product
meets its predetermined quality characteristics. In furtherance of this statement a quality
assurance function shall exist. Examples of the types of systems and utilities that are
included in the statement are given below.
b)
General Examples
The following list provides examples of what must be validated:
i.
Environmental systems, e.g. in clean rooms
ii. HVAC (Heating, ventilation and air conditioning)
iii. Sanitary water systems, e.g. for WFI, i.e. pure water for irrigation
iv.
Sanitary utilities
v.
Sterilization systems
vi.
Sanitization processes
vii.
Solution preparation systems
viii. Filtration processes
ix. Aseptic filling
x. Labeling systems
xi. Packaging systems
c)
Examples of Sterilization and Thermal Processes
Examples of sterilization, or aseptic, and thermal processes that must be validated are
given below:
i.
Steam autoclaves
ii. Dry heat ovens
47
iii.
iv.
v.
vi.
vii.
viii.
ix.
x.
xi.
xii.
xiii.
Depyrogenation tunnels
ETO (ethylene oxide) sterilizers
Freeze dryers
Form, fill and seal
Filling lines (SIP)
Cold rooms
Stability chambers
Incubators
Warehouses (those that are environmentally controlled)
Refrigerators
WFI/Clean steam systems
See Slide 16 of GMP Course Slides.
4. Why Validate?
a)
Reasons for Validation
Some of the key reasons for validation are the following:
1st)
i.
ii.
Regulatory Requirement
21CFR 211.68(b): Appropriate controls shall be exercised over computer
or related systems to assure that changes in master production and control
records or other records are instituted only by authorized personnel. Input
to and output from the computer or related system of formulas or other
records or data shall be checked for accuracy. The degree and frequency
of input/output verification shall be based on the complexity and reliability
of the computer or related system. A backup file of data entered into the
computer or related system shall be maintained except where certain data,
such as calculations performed in connection with laboratory analysis, are
eliminated by computerization or other automated processes. In such
instances a written record of the program shall be maintained along with
appropriate validation data. Hard copy or alternative systems, such as
duplicates, tapes, or microfilm, designed to assure that backup data are
exact and complete and that it is secure from alteration, inadvertent
erasures, or loss shall be maintained.
21CFR 211.84(d) (2) & (3): Samples shall be examined and tested as
follows:
(2) Each component shall be tested for conformity with all appropriate written
specifications for purity, strength, and quality. In lieu of such testing by the
manufacturer, a report of analysis may be accepted from the supplier of a component,
provided that at least one specific identity test is conducted on such component by the
manufacturer, and provided that the manufacturer establishes the reliability of the
supplier's analyses through appropriate validation of the supplier's test results at
appropriate intervals.
48
(3) Containers and closures shall be tested for conformance with all appropriate written
procedures. In lieu of such testing by the manufacturer, a certificate of testing may be
accepted from the supplier, provided that at least a visual identification is conducted on
such containers/closures by the manufacturer and provided that the manufacturer
establishes the reliability of the supplier's test results through appropriate validation of
the supplier's test results at appropriate intervals.
iii.
iv.
v.
2nd)
i.
ii.
iii.
3rd)
i.
4th)
i.
ii.
iii.
See Slides 17 and 18 of GMP Course Slides.
Section 501 (a) (2) (B) of the Federal Food, Drug and Cosmetic Act: A
drug or device shall be deemed to be adulterated—...(B) if it is a drug and
the methods used in, or the facilities or controls used for, its manufacture,
processing, packing, or holding do not conform to or are not operated or
administered in conformity with current good manufacturing practice to
assure that such drug meets the requirements of this Act as to safety and
has the identity and strength, and meets the quality and purity
characteristics, which it purports or is represented to possess;…
FDA Guidelines on General Principles of Process Validation.
More Economic Process
Increase yields
Improve efficiency of operations
More reliable process
Builds Team Confidence
Increases confidence of production staff, laboratory personnel and
customers
Fewer Rejected or Deviant Lots
Reduces cost of production
Less reworks
Reduces risks, such as recalls and FDA action, etc.
5. Qualification or Validation?
a)
b)
c)
d)
A system, material or equipment must be qualified to operate in a validated
process.
You qualify a system and/or equipment.
You validate a process.
Qualification versus validation, e.g. you qualify an autoclave, whereas you
validate a sterilization process.
II.
IMPLEMENTATION OF VALIDATION
1.
Introduction
49
a) The validation of a GMP manufacturing facility is a complex and multifaceted operation.
b) There are many associated documents that need pre- and post-validation
approval.
c) Qualified staff must perform the inspections and performance tests in the
facility.
d) Required for the successful deployment of validation activities and the
timely completion of reports are:
i.
Good planning;
ii. Good resource allocation; and
iii. Good test design.
e) See Slide 19 of GMP Course Slides.
2.
3.
Validation Life Cycle
See Slide 20 of GMP Course Slides.
a) Once the initial validation is concluded, the equipment or system must be
monitored to ensure that it remains in a validated state throughout its use. This is
described as the validation life cycle.
b) This indicates that any changes or modifications to a system must be evaluated
for their impact on the validated state. Revalidation must be conducted as
appropriate.
c) Equipment must be periodically tested to ensure that it is still operating within
its pre-determined specifications. Revalidation must be done after modifications
to ensure the same.
Steps of Validation
1. System Documentation
2. SOPs (operation, calibration, maintenance, sampling, testing)
3. Write Documentation (IQ/OQ/PQ, these are the Validation Protocols as defined
below) with input from:
a) Engineering
b) Facilities
c) Manufacturing
d) QA
e) Regulatory Affairs (RA); often as policies
4. Execution of IQ/OQ/PQ in Facility
5. Review and Approvals (by same functions that approved the Protocols)
III.
HOW VALIDATION GETS DONE
A.
Introduction
1. A Validation Protocol needs to be developed.
50
2. The validation procedures as defined by the Validation Protocols (IQ, OQ, PQ)
need to be performed and documented.
3. The Validation Technical Report needs to be signed and issued.
B.
Validation Protocols
1. Definition: A Validation Protocol is an experimental plan intended to produce
documented evidence that a system has been validated. See Slides 21, 22 and 23.
2. Types of Validation Protocols:
See Slide 24 of GMP Course Slides.
C.
i.
Installation Qualification (IQ)
An IQ is documented verification that all key aspects of the installation
adhere to appropriate codes and approved designs, and conform to the
manufacturer’s and production department’s specifications.
ii.
Operational Qualification (OQ)
An OQ is documented verification that the system or sub-system performs
as intended throughout all anticipated operating ranges.
iii.
Process Qualification (PQ)
A PQ is documented evidence which provides a high degree of assurance
that a specific process will consistently produce a product that meets its
predetermined specifications and quality attributes.
Executing the Validation Protocols
a)
b)
c)
D.
The procedures described in the respective SOP need to be followed
carefully and documented fully.
The validation work continues until the acceptance criteria are met.
If acceptance criteria cannot be met, the suitability of the following
needs to be discussed:
i.
The facility;
ii.
Equipment,
iii. Process; or
iv.
The specified criteria.
Technical Report
a)
b)
c)
The technical report should summarize the validation study’s goals and
approach.
The results should be summarized.
Deviations from the original acceptance criteria should be explained and
justified.
51
d)
E.
Approval signatures are required.
Review of IQ Requirements
1. Importance
It is important to understand the rationale for the IQ and OQ in order to
comprehend why certain information is required for them to be satisfactory.
2. IQ Requirements
The rationale for the Installation Qualification is to document that the equipment
installed not only meets the design criteria and specifications, but that the
equipment is installed properly and connected to the correct services. See Slide
25 of GMP Course Slides.
Some of the typical information required (see Slide 26 of GMP Course Slides):
a) Original specification documentation.
b) Purchase Orders and Shipping Invoices.
c) Vendor submittals.
d) Drawings. To include:
i.
PI&Ds (piping and instrumentation diagrams).
ii.
Mechanical.
iii. Electrical.
iv.
Orthometrics (physical dimensions and angles).
e) Materials documentation. To include:
i.
ASTM (information from American Society for Testing and Materials).
ii.
Passivation Reports, i.e. reports on how materials were treated to
increase resistance to other materials or to prevent corrosion.
iii. Biocompatibility, i.e. the quality of the materials being not toxic or
injurious to biological systems.
f) Weld log with borescope, i.e. visual, report and welder certifications.
g) Slope verifications for self-draining piping.
h) Industrial code documentation. This could include:
i. UL; certification of the equipment by Underwriters Laboratories Inc.
ii. ASME; certification by the American Society of Mechanical
Engineers.
iii. NEMA; compliance with standards of the Association of Electrical
and Medical Imaging Equipment Manufacturers.
iv.
ASTM; the equipment fulfils the standards set by the American
Society for Testing and Materials.
v.
NEC; compliance with the National Electric Code (NEC), or NFPA
70, for the safe installation of electrical equipment and wiring.
vi.
NFPA; compliance with codes and standards of the National Fire
Protection Association. One such specific code is the NEC or NFPA
70 above.
52
i)
j)
k)
l)
F.
Vendor manuals received in-house.
Spare parts list.
Computer hardware documentation and installation.
Copies of software documentation and software.
Review of OQ Requirements
The rationale for the Operational Qualification is to document that the equipment or
system operates according to its predetermined specifications. See Slides 27, 28 and 29
of GMP Course Slides. Some of the typical information required:
a)
b)
c)
d)
e)
f)
g)
h)
i)
j)
G.
SOP.
Personnel training verification.
Operator’s manual.
Start-up and shut-down details.
Instrumentation calibration.
Alarms test.
Instrumentation operation.
Controls test. To include:
i.
Manual override.
ii. Local control.
iii. Safety interlocks.
Integrity of filters, vessels and seals, e.g. by leakage or pressure testing.
Emergency recovery; after loss of power or services.
Examples of Typical OQ Testing
Some of the equipment requiring OQ testing includes:
a)
b)
Pumps
i.
Direction of rotation.
ii. RPM (revolutions per minute).
iii. Amperage draw (a measure of the electrical power being used).
iv.
Deadhead pressure (maximum output pressure of the pump).
HEPA filters
Particulate reduction. This is done using the DOP (Di-Octyl Phthalate) test.
DOP is condensed into a mist with a high concentration of particles of 0.3
micron diameter. Filtration efficiency is determined by measuring and
comparing the concentration of DOP in the inlet and outlet air streams.
ii.
Uniformity of air flow across filter.
iii. Measurement of the air flow rate in m/s. Compliance with ISO (The
International Organization for Standardization) 14644.
i.
c)
Chromatography
i.
Meets flow and pressure specifications.
53
ii.
iii.
iv.
v.
d)
H.
Valve sequences.
Gradients.
Sample injecting.
Peak detection.
Fermentors
i.
Pressure test.
ii. Sanitization cycle.
iii. Sterility hold (quarantine to ensure sterility).
iv.
Valve and pump operation.
v.
Temperature maintenance.
vi.
Control and monitoring systems.
Review of PQ Requirements
1.
Rationale of PQ
PQ is performed after successful completion of the Installation Qualification (IQ) and
Operational Qualification (OQ) execution. The testing carried out is targeted at verifying
that the performance specified in the User Requirements Specification (URS) is being
delivered. Verification is also required to confirm the requirements specified in cGMP,
health and safety rules and other guidance documents. Test objectives, acceptance criteria
and methodologies must all be specified and pre-approved.
2.
Scope of PQ
The normal expectations for Performance qualification (PQ) are given as requiring
documented verification that facilities, systems and equipment, as connected together,
can perform effectively and reproducibly, based on the approved process method and
product specification. On to that now should be grafted the verification that the all the
requirements specified in the User Requirements Specification (URS) have been fully
complied with.
The PQ represents the final qualification of the equipment or system. This incorporates a
range of testing to simulate the production process options and provide assurance that the
systems and the operating documentation are capable of subsequent process validation
activities. It is used to establish and or confirm;
i.
ii.
iii.
iv.
Definition of performance criteria and test procedures.
Selection of critical parameters, with predefined specifications.
Determination of the test intervals, e.g.,
(a) - Everyday.
(b) - Every time the system is used.
(c) - Before, between and after a series of runs.
Define corrective actions on what to do if the system does not meet the
established criteria.
54
I.
Scope of the Validation Project
a)
It is critical to identify correctly the scope of the validation project.
b)
A pre-project audit of the following can be helpful in the accurate
determination of the scope of the validation work:
i.
Existing documentation.
ii. Equipment and systems.
iii. Available resources.
c)
A clear and concise presentation needs to be made to management to:
Show the true scope of the work.
Underline the fact that allowing sufficient funds in the future will save funds
in the future.
iii. Prevent the common “change of scope” request once execution of the
validation project has commenced.
i.
ii.
IV.
PLANNING THE VALIDATION PROJECT
a)
Types of Validation
See Slide 30 of GMP Course Slides.
b)
Prospective Validation
See Slide 31 of GMP Course Slides.
c)
Concurrent/Retrospective Validation
d)
See Slide 32 of GMP Course Slides.
The V-Model
See Slide 33 of GMP Course Slides.
e)
Project Plan
See Slide 34 of GMP Course Slides.
f)
The Compliance Pyramid
See Slide 35 of GMP Course Slides.
V.
PROCESS VALIDATION
A. Introduction
55
1.
2.
3.
4.
5.
i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
Process validation of a biotechnology, pharmaceutical or medical device process
is a set of activities that documents a process is in control and consistently
performs to predefined in-process acceptance criteria and final product (purified
bulk for biotechnology and pharmaceutical processes) specifications. It differs
from equipment and utilities validation in that it focuses on aspects of the
process itself, which would be the microbiology and biochemistry for a
biotechnology process.
Process validation is a requirement of the Current Good Manufacturing Practices
Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211, and of the
Good Manufacturing Practice Regulations for Medical Devices, 21 CFR Part
820, and therefore, is applicable to the manufacture of pharmaceuticals and
medical devices.
Process validation involves sampling, testing and monitoring of initial largescale runs to show consistency.
Following validation, the sampling is reduced to a few key points that are
tracked continually to demonstrate the process remains in a state of statistical
process control.
Definitions: (Some of these definitions have been given previously and some
can be inferred from those given before)
Installation qualification – Establishing confidence that process equipment and
ancillary systems are capable of consistently operating within established limits
and tolerances.
Process performance qualification - Establishing confidence that the process is
effective and reproducible.
Product performance qualification - Establishing confidence through appropriate
testing that the finished product produced by a specified process meets all release
requirements for functionality and safety.
Prospective validation - Validation conducted prior to the distribution of either a
new product, or product made under a revised manufacturing process, where the
revisions may affect the product's characteristics.
Retrospective validation - Validation of a process for a product already in
distribution based upon accumulated production, testing and control data.
Validation - Establishing documented evidence which provides a high degree of
assurance that a specific process will consistently produce a product meeting its
pre-determined specifications and quality attributes.
Validation protocol - A written plan stating how validation will be conducted,
including test parameters, product characteristics, production equipment, and
decision points on what constitutes acceptable test results.
Worst case - A set of conditions encompassing upper and lower processing limits
and circumstances, including those within standard operating procedures, which
pose the greatest chance of process or product failure when compared to ideal
conditions. Such conditions do not necessarily induce product or process failure.
B. General Concepts
56
1.
Assurance of product quality is derived from careful attention to a number of
factors including:
i.
ii.
iii.
iv.
2.
3.
Due to the complexity of today's medical products, routine end-product testing
alone often is not sufficient to assure product quality for several reasons:
i.
Some end-product tests have limited sensitivity.
ii. In some cases, destructive testing would be required to show that the
manufacturing process was adequate.
iii. In other situations end-product testing does not reveal all variations that
may occur in the product that may impact on safety and effectiveness.
The basic principles of quality assurance have as their goal the production of
articles that are fit for their intended use. These principles, mentioned before,
may be stated as follows:
i.
ii.
iii.
4.
5.
6.
7.
Selection of quality parts and materials;
Adequate product and process design;
Control of the process; and
In-process and end-product testing.
Quality, safety, and effectiveness must be designed and built into the
product;
Quality cannot be inspected or tested into the finished product; and
Each step of the manufacturing process must be controlled to maximize
the probability that the finished product meets all quality and design
specifications.
Process validation is a key element in assuring that these quality assurance goals
are met
It is through careful design and validation of both the process and process
controls that a manufacturer can establish a high degree of confidence that all
manufactured units from successive lots will be acceptable.
Successfully validating a process may reduce the dependence upon intensive inprocess and finished product testing. It should be noted that in most cases endproduct testing plays a major role in assuring that quality assurance goals are
met; i.e., validation and end-product testing are not mutually exclusive.
The FDA defines process validation as follows:
Process validation is establishing documented evidence which provides a high degree of
assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.
8.
It is important that the manufacturer prepare a written validation protocol which
specifies the procedures (and tests) to be conducted and the data to be collected.
The purpose for which data are collected must be clear; the data must reflect
facts and be collected carefully and accurately. The protocol should specify a
sufficient number of replicate process runs to demonstrate reproducibility and
57
provide an accurate measure of variability among successive runs. The test
conditions for these runs should encompass upper and lower processing limits
and circumstances, including those within standard operating procedures, which
pose the greatest chance of process or product failure compared to ideal
conditions; such conditions have become widely known as "worst case"
conditions. (They are sometimes called "most appropriate challenge"
conditions.) Validation documentation should include evidence of the suitability
of materials and the performance and reliability of equipment and systems.
9. Key process variables should be monitored and documented. Analysis of the
data collected from monitoring will establish the variability of process
parameters for individual runs and will establish whether or not the equipment
and process controls are adequate to assure that product specifications are met.
10. Finished product and in-process test data can be of value in process validation,
particularly in those situations where quality attributes and variability can be
readily measured. Where finished (or in-process) testing cannot adequately
measure certain attributes, process validation should be derived primarily from
qualification of each system used in production and from consideration of the
interaction of the various systems.
C. Preliminary Considerations
1.
2.
3.
4.
5.
A manufacturer should evaluate all factors that affect product quality when
designing and undertaking a process validation study. These factors may vary
considerably among different products and manufacturing technologies and
could include, for example:
i.
Component specifications;
ii. Air and water handling systems;
iii. Environmental controls;
iv.
Equipment functions, and
v.
Process control operations.
No single approach to process validation will be appropriate and complete in all
cases; however, the following quality activities should be undertaken in most
situations.
During the research and development (R& D) phase, the desired product should
be carefully defined in terms of its characteristics, such as physical, chemical,
electrical and performance characteristics. It is important to translate the product
characteristics into specifications as a basis for description and control of the
product.
Documentation of changes made during development provides traceability
which can later be used to pinpoint solutions to future problems.
The product's end use should be a determining factor in the development of
product (and component) characteristics and specifications. All pertinent aspects
of the product which impact on safety and effectiveness should be considered.
These aspects include performance, reliability and stability. Acceptable ranges
or limits should be established for each characteristic to set up allowable
variations. These ranges should be expressed in readily measurable terms.
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6.
7.
The validity of acceptance specifications should be verified through testing and
challenge of the product on a sound scientific basis during the initial
development and production phase.
Once a specification is demonstrated as acceptable it is important that any
changes to the specification be made in accordance with documented change
control procedures.
D. Elements of Process Validation
1. Prospective Process Validation
Prospective validation includes those considerations that should be made before an
entirely new product is introduced by a firm or when there is a change in the
manufacturing process which may affect the product's characteristics, such as uniformity
and identity. The following are considered as key elements of prospective validation.
a) Equipment and Process
The equipment and process(es) should be designed and/or selected so that product
specifications are consistently achieved. This should be done with the participation of all
appropriate groups that are concerned with assuring a quality product, e.g.:
i.
Engineering design;
ii. Production operations: and
iii. Quality assurance personnel.
a. Equipment: Installation Qualification
Installation qualification studies establish confidence that the process equipment and
ancillary systems are capable of consistently operating within established limits and
tolerances. After process equipment is designed or selected, it should be evaluated and
tested to verify that it is capable of operating satisfactorily within the operating limits
required by the process. This phase of validation includes:
i.
Examination of equipment design;
ii. Determination of calibration, maintenance, and adjustment requirements;
and
iii. Identifying critical equipment features that could affect the process and
product.
Information obtained from these studies should be used to establish written procedures
covering:
i.
Equipment calibration;
ii. Maintenance;
iii. Monitoring; and
iv.
Control.
In assessing the suitability of a given piece of equipment, it is usually insufficient to rely
solely upon the representations of the equipment supplier, or upon experience in
59
producing some other product. Sound theoretical and practical engineering principles and
considerations are a first step in the assessment.
It is important that equipment qualification simulate actual production conditions,
including those which are "worst case" situations.
Tests and challenges should be repeated a sufficient number of times to assure reliable
and meaningful results. All acceptance criteria must be met during the test or challenge.
If any test or challenge shows that the equipment does not perform within its
specifications, an evaluation should be performed to identify the cause of the failure.
Corrections should be made and additional test runs performed, as needed, to verify that
the equipment performs within specifications. The observed variability of the equipment
between and within runs can be used as a basis for determining the total number of trials
selected for the subsequent performance qualification studies of the process. Once the
equipment configuration and performance characteristics are established and qualified,
they should be documented. The installation qualification should include a review of
pertinent maintenance procedures, repair parts lists, and calibration methods for each
piece of equipment. The objective is to assure that all repairs can be performed in such a
way that will not affect the characteristics of material processed after the repair. In
addition, special post-repair cleaning and calibration requirements should be developed to
prevent inadvertent manufacture of a non-conforming product. Planning during the
qualification phase can prevent confusion during emergency repairs which could lead to
use of the wrong replacement part.
b. Process: Performance Qualification
The purpose of performance qualification is to provide rigorous testing to demonstrate
the effectiveness and reproducibility of the process. In entering the performance
qualification phase of validation, it is understood that the process specifications have
been established and essentially proven acceptable through laboratory or other trial
methods and that the equipment has been judged acceptable on the basis of suitable
installation studies.
Each process should be defined and described with sufficient specificity so that
employees understand what is required. Parts of the process which may vary so as to
affect important product quality should be challenged. In challenging a process to assess
its adequacy, it is important that challenge conditions simulate those that will be
encountered during actual production, including "worst case" conditions. The challenges
should be repeated enough times to assure that the results are meaningful and consistent.
Each specific manufacturing process should be appropriately qualified and validated.
There is an inherent danger in relying on what are perceived to be similarities between
products, processes, and equipment without appropriate challenge.
c. Product: Performance Qualification
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For purposes of this discussion, product performance qualification activities apply only to
medical devices. These steps should be viewed as pre-production quality assurance
activities.
Before reaching the conclusion that a process has been successfully validated, it is
necessary to demonstrate that the specified process has not adversely affected the finished
product. Where possible, product performance qualification testing should include
performance testing under conditions that simulate actual use. Product performance
qualification testing should be conducted using product manufactured from the same type
of production equipment, methods and procedures that will be used for routine
production. Otherwise, the qualified product may not be representative of production
units and cannot be used as evidence that the manufacturing process will produce a
product that meets the pre-determined specifications and quality attributes.
After actual production units have successfully passed product performance qualification,
a formal technical review should be conducted and should include:
i.
ii.
iii.
Comparison of the approved product specifications and the actual
qualified product.
Determination of the validity of test methods used to determine
compliance with the approved specifications.
Determination of the adequacy of the specification change control
program.
b) System to Assure Timely Revalidation
There should be a quality assurance system in place which requires revalidation
whenever there are changes in packaging, formulation, equipment, or processes which
could impact on product effectiveness or product characteristics, and whenever there are
actual changes in product characteristics. Furthermore, when a change is made in raw
material supplier, the manufacturer should consider subtle, potentially adverse
differences in the raw material characteristics. A determination of adverse differences in
raw material indicates a need to revalidate the process.
One way of detecting the kind of changes that should initiate revalidation is the use of
tests and methods of analysis which are capable of measuring characteristics which may
vary. Such tests and methods usually yield specific results which go beyond the mere
pass/fail basis, thereby detecting variations within product and process specifications and
allowing determination of whether a process is slipping out of control.
The quality assurance procedures should establish the circumstances under which
revalidation is required. These may be based upon equipment, process, and product
performance observed during the initial validation challenge studies. It is desirable to
designate individuals who have the responsibility to review product, process, equipment,
and personnel changes to determine if and when revalidation is warranted.
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The extent of revalidation will depend upon the nature of the changes and how they
impact upon different aspects of production that had previously been validated. It may
not be necessary to revalidate a process from scratch merely because a given
circumstance has changed.
c) Documentation
It is essential that the validation program is documented and that the documentation is
properly maintained. Approval and release of the process for use in routine
manufacturing should be based upon a review of all the validation documentation,
including data from the equipment qualification, process performance qualification, and
product/package testing to ensure compatibility with the process.
For routine production, it is important to record adequately process details (e.g., time,
temperature, equipment used) and to record any changes which have occurred. A
maintenance log can be useful in performing failure investigations concerning a specific
manufacturing lot. Validation data (along with specific test data) may also determine
expected variance in product or equipment characteristics.
2. Retrospective Process Validation
In some cases a product may have been on the market without sufficient premarket
process validation. In these cases, it may be possible to validate, in some measure, the
adequacy of the process by examination of accumulated test data on the product and
records of the manufacturing procedures used.
Retrospective validation can also be useful to augment initial premarket prospective
validation for new products or changed processes. In such cases, preliminary prospective
validation should have been sufficient to warrant product marketing. As additional data is
gathered on production lots, such data can be used to build confidence in the adequacy of
the process. Conversely, such data may indicate a declining confidence in the process and
a commensurate need for corrective changes.
Test data may be useful only if the methods and results are adequately specific. As with
prospective validation, it may be insufficient to assess the process solely on the basis of
lot by lot conformance to specifications if test results are merely expressed in terms of
pass/fail. Specific results, on the other hand, can be statistically analyzed and a
determination can be made of what variance in data can be expected. It is important to
maintain records which describe the operating characteristics of the process, e.g., time,
temperature, humidity, and equipment settings. Whenever test data are used to
demonstrate conformance to specifications, it is important that the test methodology be
qualified to assure that test results are objective and accurate.
E. Acceptability of Product Testing
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1. Introduction
In some cases, a drug product or medical device may be manufactured individually or on
a one-time basis. The concept of prospective or retrospective validation as it relates to
those situations may have limited applicability, and data obtained during the
manufacturing and assembly process may be used in conjunction with product testing to
demonstrate that the instant run yielded a finished product meeting all of its
specifications and quality characteristics. Such evaluation of data and product testing
would be expected to be much more extensive than the usual situation where more
reliance would be placed on prospective validation.
2. Consideration of Examples of Applicability
a)
b)
c)
USP XXI states, for example: "No sampling plan for applying sterility tests to a
specified proportion of discrete units selected from a sterilization load is capable
of demonstrating with complete assurance that all of the untested units are in
fact sterile."
In one instance, by way of example, a visual inspection failed to detect a
defective structural weld which resulted in the failure of an infant warmer. The
defect could only have been detected by using destructive testing or expensive
test equipment.
In another example, a manufacturer recalled insulin syringes because of
complaints that the needles were clogged. Investigation revealed that the needles
were clogged by silicone oil which was employed as a lubricant during
manufacturing. Investigation further revealed that the method used to extract the
silicone oil was only partially effective. Although visual inspection of the
syringes seemed to support that the cleaning method was effective, actual use
proved otherwise.
MODULE 9 – AUDITS
I. Introduction
To verify compliance with the principles of GMP for pharmaceuticals, biologics and
medical devices, regular audits should be performed in accordance with an approved
schedule. These audits are designed with two important goals:
1. Goal 1
Audits are intended to verify that manufacturing and control systems are operating under
a state of control.
2. Goal 2
Audits can detect potential problems and allow for timely correction, for example, they
can prevent release of adulterated products into the marketplace.
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Audits can be used by management to establish, with a high degree of confidence, that
systems can be expected to remain under an adequate level of control. Each firm must
design and implement an audit program that will meet its own needs and goals. Audit
findings and corrective actions should be documented and brought to the attention of
responsible management of the firm. Agreed corrective actions should be completed in a
timely and effective manner.
Audit procedures will vary in complexity depending on the size of the establishment and
the specific processes under review. Individuals conducting audits should possess
sufficient knowledge, training, and experience to identify problems in the specific
processes under review. The auditor or audit team should not be responsible for
performing the procedures being audited.
There should be a written report documenting audit procedures and results. Procedures
should include a plan for the Responsible Head or designated qualified person and other
appropriate responsible officials to review and evaluate the results of the audit. The
purpose of the review and evaluation is to ensure that responsible individuals are aware
of problems, and corrective action is implemented. Audit reports should be retained for a
period consistent with product record retention requirements.
II. What is an Audit?
An audit, sometimes called a quality audit, can be defined as an independent review
conducted to compare some aspect of quality performance with a standard for that
performance. The GMP-related FDA regulations for finished pharmaceuticals (21CFR
211) contain neither a definition nor a requirement for audits, but it is common industry
practice to conduct such audits. There is a requirement in the regulations pertaining to
pharmaceuticals for annual product review as shown below:
21CFR 211.180 (e) Written records required by this part shall be maintained so that
data therein can be used for evaluating, at least annually, the quality standards of each
drug product to determine the need for changes in drug product specifications or
manufacturing or control procedures. Written procedures shall be established and
followed for such evaluations and shall include provisions for:
(1) A review of a representative number of batches, whether approved or rejected, and,
where applicable, records associated with the batch.
(2) A review of complaints, recalls, returned or salvaged drug products, and
investigations conducted under 211.192 for each drug product.
(f) Procedures shall be established to assure that the responsible officials of the firm, if
they are not personally involved in or immediately aware of such actions, are notified in
writing of any investigations conducted under 211.198, 211.204, or 211.208 of these
regulations, any recalls, reports of inspectional observations issued by the Food and
64
Drug Administration, or any regulatory actions relating to good manufacturing practices
brought by the Food and Drug Administration.
The FDA regulations require medical device manufacturing to be audited:
820.3(t) Quality audit means a systematic, independent examination of a manufacturer's
quality system that is performed at defined intervals and at sufficient frequency to
determine whether both quality system activities and the results of such activities comply
with quality system procedures, that these procedures are implemented effectively, and
that these procedures are suitable to achieve quality system objectives.
820.20(b)(2) Resources. Each manufacturer shall provide adequate resources, including
the assignment of trained personnel, for management, performance of work, and
assessment activities, including internal quality audits, to meet the requirements of this
part.
21CFR 820.22 Quality audit. Each manufacturer shall establish procedures for quality
audits and conduct such audits to assure that the quality system is in compliance with the
established quality system requirements and to determine the effectiveness of the quality
system. Quality audits shall be conducted by individuals who do not have direct
responsibility for the matters being audited. Corrective action(s), including a reaudit of
deficient matters, shall be taken when necessary. A report of the results of each quality
audit, and reaudit(s) where taken, shall be made and such reports shall be reviewed by
management having responsibility for the matters audited. The dates and results of
quality audits and reaudits shall be documented.
820.100 Corrective and preventive action. (a) Each manufacturer shall establish and
maintain procedures for implementing corrective and preventive action. The procedures
shall include requirements for:
(1) Analyzing processes, work operations, concessions, quality audit reports, quality
records, service records, complaints, returned product, and other sources of quality data
to identify existing and potential causes of nonconforming product, or other quality
problems. Appropriate statistical methodology shall be employed where necessary to
detect recurring quality problems;
820.180(c) … Upon request of a designated employee of FDA, an employee in
management with executive responsibility shall certify in writing that the management
reviews and quality audits required under this part, and supplier audits where
applicable, have been performed and documented, the dates on which they were
performed, and that any required corrective action has been undertaken.
An acceptable definition of the elements of audit procedures is found in medical device
GMP regulations as indicated, in part, above. 21CFR 820.20(b) requires audit procedures
to be planned with periodic audits of the quality assurance program to verify compliance.
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While these regulations do not apply to finished (bio)pharmaceuticals, they describe the
key elements of audit programs for quality assurance programs including the following:
1.
2.
3.
Audits are performed in accordance with written procedures by specially trained
individuals who do not have direct responsibility for the systems under review;
Written reports describing the results are reviewed by responsible management;
Appropriate documented follow-up action must be taken to correct deficiencies.
Thus, quality audits must be conducted by individuals who do not have direct
responsibility for the areas being audited. They are used to assure compliance with
established quality system requirements. They do not define requirements; rather they
confirm that the requirements are functional. Audits assess whether the existing quality
system is effective. Audit findings which continually repeat a problem will indicate a
systemic problem which management must address. For such occasions, corrective
actions are indicated, with reaudits of deficient areas to assess whether corrective actions
were effective
III. What is an Internal Audit?
An internal audit describes audits conducted at a firm’s own facility by its employees or
representatives such as consultants. For example, personnel from within the facility may
conduct the audit, or corporate personnel may conduct on-site audits at the various
facilities that are under the direct control of the company. Internal audits are planned
activities that are usually conducted at regular scheduled intervals. Major or
comprehensive audits are often performed on an annual, bi-annual or quarterly basis.
Alternatively, some firms choose to conduct audits at variable time intervals throughout
the year, as needed. It is common to schedule audits in advance and to notify key
personnel about the intended nature, scope and objectives. However, in some cases audits
may involve unannounced visits. Planning audits is the responsibility of the QA unit.
IV. What is an External Audit?
External audits are those made at facilities that are not under the direct control of the
personnel conducting the audit. Examples of external audits include on-site visits to firms
that supply products or services. A firm may send auditors to visit suppliers, to observe
conditions and practices in their facilities, of:
1.
2.
3.
Raw materials;
Packaging components; and
Labeling.
Equipment vendors or contract manufacturers are frequently inspected to verify that
actual practices conform to contract specifications. Auditors may also be sent by the
manufacturer to observe the performance of other outside contractors such as
laboratories, engineering or design consultants.
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External audits have the same basic goals as internal audits, but there are important
differences:
1.
A relatively limited access to records, reports and data since these are under the
control of the company hosting the audit;
2.
They are usually scheduled in advance by mutual consent;
3.
The company being audited may deny access to confidential records or restrict
access to certain manufacturing processes.
4.
If auditors are denied access to records or facilities their conclusions may be
severely limited.
External audits are, like internal audits, the responsibility of the firm’s QA unit.
V. The Quality Systems Approach
1. A quality systems approach calls for audits to be conducted at planned intervals to
evaluate effective implementation and maintenance of the quality system and to
determine if processes and products meet established parameters and specifications.
2. Audit procedures should be developed and documented to ensure that the planned
audit schedule takes into account:
a) The relative risks of the various quality system activities;
b) The results of previous audits and corrective actions; and
c) The need to audit the complete system.
3. Procedures should describe how auditors are trained in objective evidence
gathering, their responsibilities, and auditing procedures.
4. Procedures should also define auditing activities such as the scope and
methodology of the audit, selection of auditors, and audit conduct (audit plans,
opening meetings, interviews, closing meeting and reports).
5. It is critical to maintain records of audit findings and assign responsibility for
follow-up to prevent problems from recurring.
6. The quality systems model calls for managers who are responsible for the areas
audited to take timely action to resolve audit findings and ensure that follow-up
actions are completed, verified, and recorded.
VI. Example of a Quality Audit
Consider an aseptic environmental monitoring program in a pharmaceutical company.
1. A quality audit of the program would be performed by independent QA auditors.
2. The QA personnel would not have direct responsibility for the environmental
monitoring program.
3. QA auditors may review the various microbiological testing records and observe
employee practices. Some issues that might be addressed include the following:
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a)
b)
c)
d)
e)
f)
g)
Sampling practices may be compared against SOP instructions to determine if
each site was tested at the appropriate intervals. Audits of SOPs determine
whether or not the sampling plan is representative of the environment.
Auditors may watch personnel in the aseptic filling area to observe behavior
and determine if employee practices are proper and consistent with the
applicable SOPs.
Laboratory facilities and record keeping practices are examined for
conditions that may affect reliability or integrity of data.
Data audits compare original entries in laboratory notebooks or logs against
analytical reports to confirm accuracy.
Documentation covering preparation and use of media might be compared
against established SOPs.
Auditors may verify existence of incubator temperature records, or
determine if appropriate actions were taken if temperatures deviated from
established limits.
Records of test failures could be reviewed to verify whether or not appropriate
follow-up and corrective actions were taken.
VII.
Medical Device Regulations
1. Unlike 21CFR for pharmaceuticals, which do not mention quality assurance audits,
the medical device regulations (21CFR 820) contain explicit language requiring
audits.
2. The medical device regulations specifically state that planned and periodic audits of
the quality assurance program shall be implemented.
3. The objective of such audits is to verify compliance with the quality assurance
program.
4. The auditors must have special training and not have direct responsibilities for
matters they review.
5. Responsible management is required to review written audit reports and
document corrective actions taken.
6. The regulations authorize FDA access to the written SOPs that describe audit
procedures for medical devices.
7. FDA may request from management a written certification that audits have been
conducted and that appropriate corrective action was taken. FDA has the general
policy not to access or review audit reports.
VIII.
Detecting Potential Problems
1. Audits frequently find objectionable conditions that were unknown to responsible
production, QC, QA or management personnel.
2. A major benefit from audits is to obtain objective views of conditions and practices.
Auditors may readily detect problems that are not apparent to the personnel involved
with the day-to-day operations. For example, an auditor may observe an operator at
the aseptic filling machine reaching over exposed vials. The employee may not have
68
realized his or her actions were a source of potential contamination and supervisory
personnel may not have noticed the practice.
3. A trained auditor may be able to use observed behavior to signal other potential
problems. For example, improper employee actions may result from:
a) SOPs not containing clear instructions;
b) Inadequate employee training; or
c) Lack of adequate supervision.
IX. The Audit Program
1. Background
a)
b)
c)
There are diverse technologies involved in (bio)pharmaceutical and medical
device manufacturing and control. No single audit method can be advocated for
all firms.
Audit programs provide a practical way to improve the assurances that dayto-day manufacturing and control procedures remain under a suitable state of
control.
Audits permit detection of potential problems that were not properly dealt
with by the normal day-to-day QC or QA procedures.
2. Elements of a Systematic Audit Program
a)
Introduction
i.
A systematic audit program includes development of formal written
documents that have been reviewed and approved by responsible
management.
Each firm must establish its own means for assuring that the appropriate
procedures, records and reports have been properly reviewed during
audits.
ii.
b)
Key Elements
The following identifies some of the key elements involved with developing and
administering a formal and systematic audit program.
i.
ii.
iii.
iv.
v.
Management must clearly define its philosophies and expectations for
audit programs to operate at maximum efficiency and effectiveness.
Audit approaches or formats need to be determined.
Written criteria and SOPs need to spell out complete details of the
audit practices and procedures.
Audits need to be performed on a planned periodic basis.
Audits should be conducted by specially trained personnel with
responsibilities independent of the areas being audited.
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vi.
vii.
c)
Philosophies and Expectations
i.
ii.
iii.
d)
Senior management may use various ways to establish and communicate
the fundamental expectations of an audit program.
One practical approach involves the use of a formal written master plan
that is prepared and approved, i.e. documented, by responsible
management.
The master plan defines in an organized and systematic manner the overall
scope, objectives and responsibilities for the audit program.
Audit Approaches or Formats
i.
ii.
iii.
e)
Written audit reports must completely and accurately describe
findings.
Regular assessments are needed to assure the adequacy of the audit
program performance.
Audit approaches or formats may differ between companies.
Each auditor, after many years of experience, may develop preferences for
certain personal techniques or styles in the approach used. But being
systematic is central to every approach.
Audit methods can be divided into three categories based on the approach
or format used to evaluate GMP compliance. The categories are the
checklist format, the GMP regulation approach, and the systems (or
problem) analysis method. These arbitrary groupings are not intended to
be mutually exclusive. Firms may employ alternative approaches that
combine desirable features from each of the categories.
Checklist Format
i.
ii.
iii.
iv.
v.
Medical device and (bio)pharmaceutical manufacturers commonly
use checklists as audit guides and for reporting findings. These are printed
documents that have a series of questions or instructions that are grouped
in logical order.
Blocks may be used to record answers or spaces may be provided to
record observations or comments as needed.
There are various styles and formats used including questionnaires,
outlines and narrative-type documents. Checklists are often in
questionnaire format with a series of specific questions followed by
spaces, or blocks, to record answers.
Some questionnaires are designed to allow answers to be conveniently
checked off. Examples of answers include: Yes, No, Not Applicable, or
Not Observed. Space may also be provided to record brief comments or
explanations as necessary.
Other formats include outlines or narrative-style summary sheets
which spell out important elements which should be verified during an
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


f)
GMP Regulation Format
i.
ii.
iii.
iv.
v.
g)
audit. They can help to ensure that audit findings are reported in a logical
and complete manner. As an example, a sterilizer validation checklist in
outline format may include a listing of the:
Critical process parameters;
Specific validation criteria, such as number of runs, loading
configurations, acceptance criteria;
Required documentation.
An auditor may follow the outline as a guide during an audit and use it as
the framework for the final report.
Some firms may choose to audit their manufacturing and control systems
by using the pharmaceutical (Part 211) and medical device (Part 820)
GMP regulations as a guide.
With this approach, auditors compare elements contained in the GMPs
against actual practices.
Proponents of this approach find benefit from being able to determine
the degree of compliance for particular GMP elements.
Audit programs that do not use this approach may find that the
language contained in the GMPs is not specific enough to serve as the
foundation of an audit program. The regulations contain broad statements
of what is expected to be accomplished, but the language does not usually
describe how it is to be done. The GMP regulations are general statements
of conditions and practices that are considered to be minimum
requirements. Considerable freedom is permitted to choose alternative
ways to satisfy the requirements. Manufacturers are given great latitude in
design of systems and control procedures, but this may pose problems for
auditors using the GMP regulations as a guide. Auditors may find the
nonspecific terms like adequate, appropriate, as appropriate, as
necessary, to assure, etc., to be of little value when determining what
specific elements need to be audited and in what manner. For example
Part 211.113(b) contains the following requirement: “Appropriate written
procedures designed to prevent microbiological contamination of drug
products purporting to be sterile, shall be followed”. An auditor will not
find any clues in this language concerning what practices and procedures
are necessary to prevent microbiological contamination or the essential
elements of sterilizer validation.
Since GMP language is so general, the auditor must use other sources of
information, such as supplemental instructions, annotated guides or other
documents, to determine if conditions and practices satisfy the GMPs.
Systematic Potential Problem Analysis
i.
This approach involves systematic evaluation of the factors that are
likely to affect product quality.
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ii.
Formal assessments are made to determine whether or not conditions or
practices exist that may adversely affect assurances of product quality
This format includes several variations depending upon the basic
approach used to evaluate the systems. One program identifies points in
the manufacturing process where loss of control would result in defective
or unacceptable product. Auditors carefully examine equipment, facilities
and procedures to determine if critical control points are being controlled
adequately. Another approach emphasizes the importance of establishing a
basis set of criteria to evaluate the cause and effect relationship of
production and QC operations to final product quality.
iii.
h)
Written SOPs
i.
Formal written standard operating procedures (SOPs) should fully
describe the details for carrying out the various audit functions. The
number of SOPs should be sufficient to represent each of the major audit
operations.
SOPs should contain enough details to define completely and clearly
what is expected to be done and by whom. The personnel (job positions)
who are responsible for conducting audits need to be specified. In
addition, SOPs should establish the responsibility for audit data reviews
and which personnel are expected to make recommendations and
decisions concerning corrective actions.
Audit SOPs should be documented and controlled in the same manner
as is customary for GMP systems. This includes formal double checking
and approvals that are documented by responsible personnel.
ii.
iii.
i)
Written Criteria
i.
ii.
j)
Formal written criteria need to be established defining which audit
data or elements are to be considered in the assessment of program
performance.
How well audit data reflect a firm’s true state of control is
dependent upon many variables including the reliability of vendors
who supply raw materials, components or services. These variables
need to be identified and formal criteria established for audit data
review.
Planned Periodic Frequency
i.
ii.
A planned audit frequency is an important element of a systematic audit
program. A written plan ensures that audits are done after regular
intervals, with allowances for flexibility.
There is not a generally recognized audit frequency. Each firm must
establish the best time interval between audits based on several important
factors including:
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




iii.
iv.
v.



vi.
Intended purpose;
Objectives;
Scope;
Depth; and
Prior history of audit findings.
Audits vary in their intended scope from limited coverage of a single
matter to comprehensive evaluations of many systems. Audits can range in
depth of coverage from superficial to exhaustive.
The significance of audit findings can range from minor technical
violations to serious health hazards.
The following are factors to be considered when deciding how often
audits should be performed:
Major or comprehensive audits may be scheduled in advance at fixed
intervals, e.g. annual, bi-annual or quarterly frequencies.
Other audits may be made without advanced notification as surprise visits,
such as limited examinations or spot checks of selected issues.
Most audit programs use a combination of scheduled and unannounced
visits as needed.
The decision of whether or not to provide advanced notice, and to what
degree, should be based on the likelihood that affected personnel may
modify conditions or practices in a manner that will affect the audit. Prior
notice may not be appropriate if employees are likely to alter their normal
behavior.
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