BIO 221
REGULATORY COMPLIANCE IN
BIOMANUFACTURING
(3-3-4)
This course is an introduction to regulatory agencies and the role of cGMP compliance in
manufacturing of drugs, biologics and medical devices. The course initially explores the
role of governmental oversight and regulation, particularly by the FDA, during the
discovery, development and manufacturing of new products produced by the
pharmaceutical and biotechnological industries. Benchmark Congressional Acts (e.g. the
Food, Drug and Cosmetic Act) are studied while describing the evolution of the FDA to
its present state. Case studies are emphasized. Students are introduced to facilities and
processes used in the manufacture and packaging of pharmaceuticals (drugs and
biologics) and medical devices. Thus studied are facility design, monitoring systems,
cleaning and sterilization, clean room environments, and fill and packaging operations.
The course emphasizes how good documentation practices assure the quality and safety
of a product as the manufacturing process moves a product down the production pipeline.
Prerequisite: Program admission
Course objectives:
• Understand the history of the development of regulatory agencies
• Describe major legislative acts in the development of the regulatory process
• Describe the evolution and scope of the FDA
• Describe the process of drug development from preclinical trials to marketing of a new
drug
• Understand relevant requirements of the Code of Federal Regulations
• Understand process for formatting, assembling and submitting IND, NDA and other
relevant documents
• Describe the organization of the FDA including CDER and CBER
• Understand process for meeting with the FDA
• Understand documentation necessary to be in compliance with the FDA
• Describe aspects of good clinical practices
• Understand the role of cGMP requirements
• Understand post-marketing regulation
• Understand process of FDA inspection and warning letters
• Describe risk-based approach to FDA regulation
• Understand the role of patents in the drug discovery and marketing process
• Understand the practical application of cGMP
• Describe design of buildings and facilities
• Describe plant materials
• Perform receiving and quarantine operations
• Describe levels and operations of clean rooms and HEPA filters
• Describe design for air flow and filtration
• Describe operation of piping, pumps and valves
• Perform instrumentation and control bioprocesses
• Describe methods for cleaning, decontamination and sanitation
• Describe methods for sterilization of process equipment
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• Perform equipment validation
CHAPTER 1 - THE HISTORY OF THE DEVELOPMENT OF REGULATORY
AGENCIES
I. State versus Federal Powers and the Regulation of Commerce
In order to understand how 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 regulatory agencies came to be developed and how they
function, 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.
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),
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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 Key Regulatory Agencies and Legislation Underpinning Regulation
While there are many federal regulatory agencies the focus here will be on those most
relevant to the pharmaceutical, biotechnological, medical device and food industries, e.g.
the USDA, FDA and Environmental Protection Agency (EPA). Federal regulation is
usually dated from the creation in the late 19th century of the Interstate Commerce
Commission (ICC) which was charged with protecting the public against excessive and
exploitative railroad rates. The regulation was economic in nature, setting rates and
regulating the provision of railroad services. Subsequently formed were the Federal Trade
Commission (FTC) (1914), the Water Power Commission (1920) which later became the
Federal Power Commission, and the Federal Radio Commission (1927) which later
became the Federal Communications Commission. In addition, during the early 20th
century, Congress created several other agencies to regulate commercial and financial
systems, including the Federal Reserve Board (1913), the Tariff Commission (1916) and
the Commodities Exchange Authority (1922).
To ensure the purity of certain foods and drugs, the Food and Drug Administration
(FDA) was created in 1931. The background on how the FDA came to be formed and the
legislation which gave rise to the agency will be discussed in more detail in the next
chapter.
Federal regulation was spurred in the 1930s with the implementation of wide-ranging
New Deal programs. Some of the New Deal economic regulatory programs were
implemented by the Federal Deposit Insurance Corporation (FDIC) (1933), the
Commodity Credit Corporation (1933), the Securities and Exchange Commission (SEC)
(1934) and the National Labor Relations Board (1935). In addition, the jurisdiction of
both the Federal Communications Commission (FCC) and the Interstate Commerce
Commission were expanded to regulate other forms of communications (e.g. telephone
and telegraph) and other forms of transport (e.g. trucking).
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In 1938, the role of the FDA was expanded to include prevention of harm to consumers
in addition to corrective action. This will be discussed in more detail in the next chapter
when the FDA is examined specifically.
A second burst of regulation began in the late 1960s with the enactment of
comprehensive, detailed legislation intended to:
i.
Protect the consumer.
ii.
Improve environmental quality.
iii.
Enhance work place safety.
iv.
Ensure adequate energy supplies.
In contrast to the pattern of economic regulation adopted before and during the New
Deal, the new social regulatory programs tended to cross many sectors of the economy,
rather than individual industries. Moreover, they affected industrial processes, product
designs and by-products, rather than entry, investment, and pricing decisions. The
consumer protection movement of the late 1960s and early 1970s led to creation of,
among other agencies, the Consumer Product Safety Commission (1972).
In 1970, the Environmental Protection Agency (EPA) was created to consolidate and
expand environmental programs. Its regulatory authority was extended through the
following legislative acts:
i.
The Clean Air Act of 1970.
ii.
The Clean Water Act of 1972.
iii.
The Safe Drinking Water Act of 1974.
iv.
The Toxic Substances Control Act of 1976.
v.
The Resource Conservation and Recovery Act of 1976.
The efforts to improve environmental protection also led to the creation of the Materials
Transportation Board (1975) (now part of the Research and Special Programs
Administration in the DOT) and the Office of Surface Mining Reclamation and
Enforcement (1977) in the Department of the Interior (DOI).
The Occupational Safety and Health Administration (1970) was established in the
Department of Labor (DOL) to enhance work place safety. Major mine safety and health
legislation had been passed in 1969, following prior statutes reaching back to 1910.
Enforcement responsibility now lies with the Mine Safety and Health Administration,
also in the DOL.
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Another significant regulatory agency, the Department of Agriculture (USDA), was
formed in 1862. It has grown over time so that it now regulates:
a) The price, production, import and export of agricultural crops.
b) The safety of meat, poultry and certain other food products.
c) A wide variety of other agricultural and farm-related activities.
d) Expansive welfare programs.
Agriculture regulatory authorities, i.e. agencies which fall under the umbrella of the
USDA, have changed over time. These now include:
1. The U.S. Forest Service (1905).
2. The Natural Resources Conservation Service (1935).
3. The Farm Service Agency (1961).
4. The Food and Consumer Service (1969) which is now called the Food and
Nutrition Service.
5. The Agricultural Marketing Service (1972).
6. The Federal Grain Inspection Service (1976) which was combined in 1994 with
the Packers and Stockyards Administration (established in 1921 under the Packers
and Stockyards Act) to establish the Grain Inspection, Packers and Stockyards
Administration.
7. The Animal and Plant Health Inspection Service (1977).
8. The Foreign Agricultural Service (1974).
9. The Food Safety and Inspection Service (1981).
10. The Rural Development Administration (1990).
The consequence of the long history of regulatory activities is that Federal regulations
now affect virtually all individuals, businesses, State governments, local and tribal
governments, and other organizations in virtually every aspect of their lives or operations.
It bears emphasis that regulations themselves are authorized by and derived from law. No
regulation is valid unless the Department or agency is authorized by Congress to take the
action in question. In virtually all instances, regulations either interpret or implement
statutes enacted by Congress. Some regulations are based on old statutes; others on
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relatively new ones. Some regulations are critically important while some are relatively
trivial, but each has the force and effect of law and must be taken seriously.
CHAPTER 2 - EVOLUTION AND SCOPE OF THE FDA
I.
FDA History
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.
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.
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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. Horses can carry tetanus. 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
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.
5. 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.
6. 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
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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.
7. 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.
8. Its first Guidance to Industry was published by the FDA in 1949.
9. 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
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.
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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. Over-the-Counter (OTC) Drugs gained the attention of the FDA in 1972. This
time the shear number of drugs (300,000) to be reviewed led to the formation of
advisory panels of scientists, medical professionals and consumers. These were
charged with evaluating the active ingredients used in OTC products within 80
defined therapeutic categories. After examining both the scientific and medical
literature the advisory panels made decisions regarding active ingredients and
their labeling. The result was a monograph which described in detail acceptable
active ingredients and labeling for products within a therapeutic class. Those not
in compliance with monograph guidelines were deemed “not safe and effective or
misbranded” and removed from the marketplace or reformulated. This OTC Drug
Review took approximately 20 years to complete.
12. The Federal Controlled Substances Act, part of the Comprehensive Drug
Abuse and Prevention Act of 1970, focused on the practice of medical
professionals and the direct protection of consumers. It placed drugs with a
relatively high potential for abuse into five federal schedules along with a recordkeeping system designed to track federally controlled substances as they were
ordered, prescribed, dispensed and utilized throughout the healthcare system.
13. With the expansion of biotechnology in the 1980s and to encourage
biopharmaceutical companies to continue to develop their products, Congress
passed the Orphan Drug Act in 1983.
14. The Price Competition and Patent Restoration Act of 1984 was passed in
response to generic drugs entering the scene as patents expired on brand-named
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.
15. 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.
16. 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
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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.
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.
17. The Bioterrorism Act of 2002 charged the FDA with prevention of the willful
contamination of all regulated products and food by inspection of registered
manufacturing facilities. The Act provided for increased availability of means to
prevent, identify or treat injuries caused by biological agents such as toxins by
providing for accelerated approval, licensing or clearance for a drug, biologic
product, medical device, vaccine, vaccine adjuvant, antiviral or diagnostic test
intended to treat, identify or prevent infections or diagnose conditions caused by
these agents.
II. What the FDA Regulates
Some of the agency’s specific responsibilities include:
A. Food
1. Safety of all food products, except meat and poultry.
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.
C. Medical Devices
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1. Pre-market approval of new devices, e.g. pacemakers, contact lenses and hearing
aids.
2. Manufacturing 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.
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
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.
III. What the FDA Does Not Regulate
Homework Assignment: Access the following web page:
http://www.fda.gov/comments/noregs.html
From this page create a list of what the FDA does not regulate and the agency that is
responsible in each case.
IV. 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.
C. Tests products.
D. Evaluates claims and prescription drug advertising.
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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.
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.
CHAPTER 3 - ORGANIZATION OF THE FDA
I. 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 budget FDA has requested for
financial year 2008 is $2.1 billion. The FDA gets its authority through the laws passed as
Acts and amendments by Congress. It enforces its authority through:
i.
Regulations.
ii.
Guidelines on FDA-acceptable practices and current Good Manufacturing
Practice (cGMP).
II. 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
CHAPTER 4 - PROCESS OF DRUG DEVELOPMENT
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I. 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.
II. Requirements
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.
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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.
6. Comprehensive investigation protocols.
7. The compound’s chemistry.
8. Manufacturing and controls.
9. 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.
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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
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
15
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.
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.
III. 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
16
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.
6.
Vaccines.
Blood and blood products.
Human, animal or bacterial cells, tissues and cellular and tissue-based products.
Gene therapy products.
Antitoxins, antivenins and venoms.
Allergenic extracts used for the diagnosis and treatment of allergic diseases, and
allergen patch tests.
CHAPTER 5 - FORMAT, ASSEMBLY AND SUBMISSION OF IND
I. Introduction
The previous chapter mentioned the Investigational New Drug Application (IND) in the
process of drug development. It is a submission to the FDA that requests permission to
initiate a clinical study of a new drug in the United States. The IND provides the FDA
with the data necessary to decide whether the new drug and the proposed clinical trial
pose a reasonable risk to the human subjects participating in the study. The Federal Food,
Drug and Cosmetic Act directs the FDA to place investigations on clinical hold if the
drug involved presents unreasonable risk to the safety of the subjects. A clinical hold is
an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to
suspend an ongoing investigation.
This chapter will elaborate on the process of preparing and submitting an IND.
II. Requirement for an IND
An IND would be required to conduct clinical trials if the drug is:
1. A new chemical entity.
2. Not approved for the indication under investigation.
3. In a new dosage form.
4. To be administered at a new dosage level.
17
5. To have another route of administration.
6. In combination with another drug and the combination is not approved.
An IND is not required to conduct a study if the drug is:
1. Not intended for human subjects, but is intended for in vitro testing or laboratory
research animals, i.e. nonclinical studies.
2. The study is within the approved indication for use of an approved drug.
III. Pre-IND Meeting
A meeting between the sponsor and FDA is frequently useful in resolving questions and
issues raised during the preparation of an IND. It is a formal meeting requiring a written
request that includes a list of specific objectives and a list of specific questions. The
meeting may be face-to-face or FDA may prefer to have a telephone conference call to
serve as the meeting.
IV. Format of an IND
The content and format of an initial IND is given in 21CFR312 and in guidance
documents published by the FDA on its website.
1. Cover Sheet-21CFR 312.23(a)(1) FDA Form 1571-Investigational New
Drug Application (IND)
Form 1571 is a required part of the IND and every subsequent submission related
to the IND. Each IND Amendment, IND Safety Report, IND Annual Report or
general correspondence with regard to the IND submission must include a 1571.
This serves as a cover submission for IND submissions and provides FDA with
basic information about the submission:
a) Name of the sponsor.
b) IND number.
c) Name of the drug.
d) Type of submission.
e) Serial number.
f) Contents of the application.
Each submission to the IND must be consecutively numbered, starting with the
initial IND which is numbered 0000. The next submission (response to clinical
hold, correspondence, amendment, etc.) should be numbered 0001 with
subsequent submissions numbered consecutively in the order they are submitted.
Homework Assignment: Look up Form 1571 on the following page of the
FDA’s website: http://www.fda.gov/opacom/morechoices/fdaforms/1571es.pdf
List the commitments made on signing the form (page 2 of the form).
Definitions of IND Terms:
i.
IND Amendment-A submission to the IND file that adds new or revised
information to the file.
18
ii.
iii.
IND Safety Report-An expedited report to the FDA and all participating
investigators of a serious and unexpected adverse experience associated
with use of the drug or findings from nonclinical studies that suggest a
risk to human subjects.
IND Annual Report-A brief report to FDA of the progress of clinical
investigations. It is submitted each year within 60 days of the anniversary
date of the IND going into effect.
2. Table of Contents- 21CFR 313.23(a)(2)
This should accurately include all required sections, appendices, attachments,
reports and other reference material with page numbers.
3. Introductory Statement and General Investigational Plan-312.23(a)(3)
This should provide a brief overview of the investigational drug and the sponsor’s
investigational plan for the following year.
4. Investigator’s Brochure-21CFR 312.23(a)(5)
This document is provided to each clinical investigator and the institutional
review board at each of the clinical sites. It presents a summary of the essential
nonclinical, clinical and CMC (chemistry, manufacturing and control) data that
support the proposed clinical trials
5. Clinical Protocol-21CFR 312.23(a)(6)
This describes how particular clinical trials are to be conducted. It describes:
a) The objectives of the study.
b) Information about the investigators as provided on Form FDA 1572.
c) The design of the trials.
d) How subjects are selected
e) How the trials are to be carried out, e.g. drug doses, measurements and
observations.
The initial IND is required to have clinical protocols for each planned phase of
clinical trials. However, the IND regulations specifically allow Phase I protocols to
be less detailed and more flexible than protocols for Phase II or III studies.
6. Chemistry, Manufacturing and Controls Information-21CFR 312.23(a)(7)
This important section describes the composition, manufacturing process, and
controls of the drug substance and drug product. (The drug substance is the drug
in solution resulting from the production process and the drug product is the drug
in final formulation solution or buffer). The CMC section must provide sufficient
information to demonstrate the identity, quality, purity and potency of the drug
product. The amount of information needed to accomplish this is based on the
phase of the proposed study, the duration of the proposed study, the dosage form
of the investigational drug and the amount of additional information available. A
critical aspect in assuring the safety of the subjects participating in clinical trials is
adherence to current Good Manufacturing practices (cGMP). The FDA requires
that any drug product intended for administration to humans be manufactured in
19
accordance with cGMP. This provides a minimal level of control over the
manufacturing process and final drug product and helps to ensure the identity,
quality, purity and potency of the clinical trial material.
7. Pharmacology and Toxicology Information-21CFR 312.23 (a)(8)
This section of the IND includes the non-clinical safety data that the sponsor
generated to conclude that the new drug is reasonably safe for clinical study.
8. Previous Human Experience-21CFR 312.23(a)(9)
This section should contain a complete summary of all previous human studies
and experiences with the drug such as from previous trials and in other countries.
If the planned study will be the first administration to humans, this section should
be indicated as not applicable.
9. Additional Information-21CFR 312.23(a)(10)
This section is used to present information on relevant special topics:
a) Drug dependence and abuse potential.
b) Radioactive drugs
c) Pediatric studies.
d) Other information.
10. Relevant Information-21CFR 312.23(a)(11)
Any information specifically requested by FDA to review the IND.
V. Assembly and Submission of an IND
1. Copies
FDA requires sponsors to submit the original and two copies of all IND
submissions which include the initial IND and any amendments, correspondence
and reports.
2. Pagination
The initial IND and all subsequent submissions more than one page in length
should be fully paginated.
3. Printing
All IND submissions should be submitted on good quality 8½ x 11 inch paper
with a 1¼ inch left margin to allow for binding.
4. Binding
Individual volumes should be no more than approximately 2 inches thick and
bound in pressboard-type binders. FDA requires the following types of binders for
specific sections of IND submissions:
a) One copy of the submission will serve as an archive copy and should be
bound in a red polyethylene binder.
b) The CMC section should be bound in a green pressboard binder.
20
c) Microbiology information should be bound in an orange pressboard
binder.
5. Volume Labeling
Each volume should be labeled with permanent adhesive labels printed in
permanent black ink. The labels should contain the volume number of the
submission (vol. X of XX vols.), name of drug, the IND number and the sponsor’s
name.
6. Submission
For traceability and adequate documentation the initial IND and subsequent
submissions to the IND should be sent to FDA using an overnight delivery service
such as FedEx, UPS or DHL.
7. Electronic Submission
The IND may be submitted electronically if it is for the Center for Biologics
Evaluation and Research (CBER), but not if it is for the Center for Drug
Evaluation and Research (CDER). For an electronic submission to CBER the
basic format, with organization into appropriately-named files and folders, is
similar to that of a paper submission.
VI. Overview of Review Process
See Slide 1 of Regulatory Compliance Slides (for submission to CDER)
CHAPTER 6 - FORMATTING, ASSEMBLING AND SUBMITTING THE NEW
DRUG APPLICATION (NDA)
I. Introduction
FDA requires the drug sponsor to submit an NDA for review before a new
pharmaceutical can be approved for marketing and sale in the US. The NDA contains
clinical and non-clinical test data and analyses, drug chemistry information, and
descriptions of manufacturing procedures. FDA guidelines (www.FDA.gov) address the
format, assembly and submission of the NDA. For biologics a Biologics License
Application (BLA) would be submitted instead of an NDA, but it has the same purpose,
format and submission requirements as an NDA.
II. Format, Assembly and Submission of NDA
A. Copies
Three copies of the NDA have to be submitted to FDA.
1. Archival Copy
21
This contains all sections of the NDA including the cover letter, Form FDA-356h (this
is the Application to Market a New Drug, Biologic or an Antibiotic for Human
Use), the administrative sections, NDA index and all technical sections.
2. Review Copy
This contains the NDA’s technical sections, each packaged for reviewers in the
corresponding technical disciplines. In addition to the appropriate technical section,
each review copy also contains the cover letter, Form FDA-356h, the administrative
sections, the NDA index as well as an individual table of contents, the Labeling
section and the Application Summary.
3. Field Copy
This is for inspection of facilities for pre-approval. It includes the cover letter, Form
FDA-356h, the administrative sections, the NDA index as well as an individual table
of contents, the Labeling section, the Application Summary and the CMC and
Methods Validation Package. These terms will become clearer later.
B. Administrative Section
In addition to the cover letter and Form FDA-356h, other required documents include:
1.
2.
3.
4.
Patent Information.
Establishment Description.
FDA User Fee Cover Sheet.
Other/Pediatric Use.
C. NDA Contents
The components of the application must be organized in the manner required by FDA.
1. NDA Section 1: Index
A comprehensive table of contents should follow immediately after Form FDA356h and the administrative items. It must show the location of every section by
volume and page number.
Each separately bound technical section should also contain a copy of the overall
NDA index in addition to its own table of contents based on the index.
2. NDA Section 2: Labeling
The labeling section must include all draft labeling that is intended for use on the
product container, carton or package, including the proposed package insert.
The NDA must have four copies of the Labeling section. One copy should be
bound into the archival copy. Copies should also be placed in the review copies
for the clinical, chemistry and pharmacology technical sections of FDA.
22
3. NDA Section 3: Application Summary
The application summary is an overview of the entire application. All reviewers
receive this section and it should give them a clear idea of the drug and its
application. It usually comprises 50 to 200 pages. It must include the following:
a) Proposed annotated package insert. Per 21CFR 201.57 this must
provide comprehensive information about the drug.
b) Pharmacologic class, scientific rationale, intended use and potential
clinical benefits. One or two pages of text providing basic information
about the drug product.
c) Foreign marketing history. A list of any countries in which the drug or
a related form has ever been marketed together with the dates of
marketing.
d) Chemistry, manufacturing and controls summary. Summary of NDA
Section 4.
e) Non-clinical pharmacology and toxicology summary. Summary of
NDA Section 5.
f) Human pharmacokinetics and bioavailability summary. Summary of
NDA Section 6.
g) Microbiology summary. A section on microbiology is only required for
antibiotic drugs.
h) Clinical data summary and results of statistical analysis. Summary of
NDA Sections 8 and 10.
i) Discussion of benefit/risk relationship. A brief benefit/risk assessment
based on the results of the non-clinical and clinical studies. Any proposed
post-marketing studies should be described.
4. NDA Section 4: Chemistry, Manufacturing and Controls (CMC)
This section must include information on the composition, manufacture and
specifications of the drug substance and the drug product. The three main
elements are:
a) Chemistry, manufacturing and controls information. This will include
detailed information on the properties of the drug, the manufacturing
methods (including packaging) and analytical controls in the
manufacturing process.
b) Samples. The CMC section must include a commitment to submit
samples, on FDA request, for testing and validation of analytical
methods.
c) Methods validation package. This package must include detailed
information on specifications and validation of the test methods used in
the manufacturing process.
5. NDA Section 5: Non-Clinical Pharmacology and Toxicology
This second technical section of the NDA provides a description of all animal and
in vitro studies with the drug. This includes pharmacological, toxicological and
ADME (absorption, distribution, metabolism and excretion) studies.
23
6. NDA Section 6: Human Pharmacokinetics and Bioavailability
The first element in this technical section, which includes data from ADME
studies, is a tabulated summary of all in vivo biopharmaceutic studies performed.
A summary of data and overall conclusions should be included. The analytical
methods used in each in vivo biopharmaceutic study must be summarized.
Individual study reports of the biopharmaceutic studies must be included. These
studies are described below:
a) Pharmacokinetic studies are designed to define the drug’s time course
and, where appropriate, major metabolite concentrations in the urine,
blood and other body compartments.
b) Bioavailability studies define the rate and extent of absorption relative
to a reference dosage form such as IV (intravenous injection), solution
or suspension.
7. NDA Section 7: Microbiology
The microbiology technical section is only required for antimicrobial drug
products. These drugs differ from other classes of drugs in that they target
microbial physiology rather than patient physiology.
8. NDA Section 8: Clinical Data
This technical section is the largest and most complex section of the NDA and is
essential for FDA to understand the new drug’s safety and effectiveness. It
comprises 10 elements:
i.
List of investigators and list of INDs and NDAs. This must list all known
INDs under which the drug has been studied in any dosage form. Also
included must be any known relevant NDA.
ii. Background or overview of clinical investigations. This should describe
the rationale and general approach used in obtaining the clinical data.
iii. Clinical pharmacology. This should include ADME studies,
pharmacodynamic dose range, dose response studies and any other studies
of the drug’s action.
iv.
Controlled clinical trials. This provides a table of all studies and full
clinical trial reports of al controlled studies.
v.
Uncontrolled clinical trials. Generally does not contribute substantial
evidence for the effectiveness of a drug, but may be used to provide
support for controlled studies and critical safety information.
vi.
Other studies and information. Should include a description and analysis
of any additional information that the applicant has obtained from any
source, foreign or domestic, that is relevant to evaluation of the product’s
safety and effectiveness.
vii.
Integrated summary of effectiveness data. Serves to demonstrate
substantial evidence of effectiveness for each claimed indication. An
indication is a disease state or condition. A table of all studies should be
included. Data should be included from animal, pharmacokinetic,
pharmacodynamic, and controlled and uncontrolled studies.
24
viii.
ix.
x.
Integrated summary of safety information. Should include safety data from
all sources, including relevant animal data, clinical studies and any foreign
marketing experience.
Drug abuse and over dosage information. Required if the drug has the
potential for abuse.
Integrated summary of benefits and risks. This summarizes the evidence
for safety and effectiveness.
9. NDA Section 9: Safety Update Reports
A pending application must be updated when new safety data become available
that could affect any of the following:
a) Statements in draft labeling.
b) Contraindications.
c) Warnings.
d) Precautions.
e) Adverse events.
10. NDA Section 10: Statistics
This technical section includes descriptions and documentation of the statistical
analyses performed to evaluate the controlled clinical trials and other safety
information.
11. NDA Section 11: Case Report Form Tabulations
This section must include complete tabulations for each patient from each
adequately or well-controlled Phase II and Phase III efficacy study and from
every Phase I clinical pharmacology study. It must also include tabulations of
safety data from all clinical studies.
12. NDA Section 12: Case Report Forms (CRFs)
It is necessary to include the complete CRF for each patient who died during a
clinical study and for any patients who were dropped from the study due to an
adverse event, regardless of whether the adverse event is considered to be related
to the study drug.
D. Electronic Submission
The NDA may be submitted electronically. In this case the basic format, with
organization into appropriately-named files and folders, is similar to that of a paper
submission. The FDA website provides guidelines on how to accomplish this.
III. Overview of Review Process
See Slide 2 of Regulatory Compliance Slides (for submission to CDER)
CHAPTER 7 – MEDICAL DEVICES
25
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
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
26
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
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
27
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.
vi.
vii.
viii.
ix.
x.
manufacturers,
contract manufacturers that commercially distribute the device,
contract sterilizers that commercially distribute the device,
re-packagers and re-labelers,
specification developers,
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
28
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.
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.
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
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
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
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(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.

Medical Device Reporting
CHAPTER 8 - MEETING WITH FDA
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I. Introduction
A. Meetings with FDA are a critical component of the regulatory review and
approval process for new prescription drugs, biologics and medical devices.
B. Successful meetings depend on:
1. Good science and good medicine.
2. Regulatory knowledge.
3. Sound management of the meeting process.
C. Approval of a pharmaceutical product is ultimately determined by the strength
and adequacy of the scientific data, but the way a sponsor interacts with the FDA
throughout the lengthy drug development and drug review process can spell the
difference between a relatively smooth and timely approval and a costly delay or
rejection of the application. A product’s chances for approval can be substantially
increased if the sponsor manages the meeting process in a way that presents the
scientific data effectively and facilitates reaching consensus on major issues.
Well-handled meetings can actually reduce the approval time for a new product.
II. Types of FDA Meetings
The purpose of meeting with FDA and its Review Divisions is to:
i.
Present proposals.
ii. Provide answers.
iii. Resolve technical and scientific issues that arise concerning the development of a
pharmaceutical product.
iv.
To determine whether a product will be able to move forward to the next stage in
development.
Important FDA meetings follow.
A. Pre-IND Meetings
1. Sponsor presents characterization, manufacturing, non-clinical test data
and other information.
2. Sponsor discusses the initial plan and protocols for clinical trials.
3. Goal:
a) To receive FDA feedback on the proposed studies.
b) To reach agreement on what the sponsor needs to submit in the
IND so that it is likely to be placed on active status by FDA
rather than being placed on hold due to safety concerns.
B. End-of-Phase II Meetings
1. Efficacy data should be presented to demonstrate that the product is
performing its desired function.
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2. Discussion of Phase III trial designs, including the types of information on
indications, dosing, safety and manufacturing that the FDA would expect to
see in an NDA or BLA.
C. Special Protocol and Ad Hoc Technical Meetings
To discuss and resolve specific technical issues that arise during drug
development, including:
1. Detailed review of key clinical protocols.
2. Discussion of manufacturing issues.
D. Pre-NDA/BLA Meetings
For sponsor and FDA to discuss issues such as:
1. Organization of the application.
2. Presentation of the data.
E. Advisory Committee Meetings
Take place:
1. As a public forum.
2. With a panel of experts designated by the FDA.
3. After NDA/BLA submission.
4. For certain products when FDA wants to obtain the advice of academic,
medical and other external experts on whether an application can be approved.
F. Labeling Meetings
1. Consultations between FDA and sponsor on the specific language of the
product labeling. This is the prescribing information, i.e. it describes to
physicians what specific indications a product has been approved for, the
recommended doses, the side effects and other specific information that
physicians and patients need to know about a new prescription drug.
2. Held after an NDA/BLA is submitted.
III. Categories of FDA Meetings
Based on the priority and urgency of the meetings with the FDA, there are three different
types, Type A, B or C.
A. Type A Meetings
1. Immediately necessary to resolve an issue that is preventing a drug
development program from progressing, i.e. a high priority meeting.
2. Should occur within 30 calendar days of FDA receiving the request.
B. Type B Meetings
1. Normal priorities.
2. Should occur within 60 calendar days of FDA receiving the request.
C. Type C Meetings
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1. Lowest priorities.
2. Should occur within 75 days of FDA receiving the request.
IV. Preparing for FDA Meetings
A. Timing of Submission
The sponsor should submit an information package to FDA so that it is received in
accordance with the following time frames.
1. Type A Meetings
At least 2 weeks prior to the formal meeting.
2. Type B Meetings
At least 4 weeks prior to the formal meeting.
3. Type C Meetings
At least 2 weeks prior to the formal meeting.
B. Content of Information Packages
The sponsor or applicant should submit an information package to the appropriate
Division Director in CDER or CBER with product review responsibility. The
information package should provide summary information relevant to the product
and any supplementary information needed to develop responses to issues raised
by the sponsor or reviewing division. The content of the information package
should support the intended objectives of the formal meeting with FDA.
To facilitate FDA's review, the sponsor should organize, according to the
proposed agenda, the contents of the information package. A fully paginated
document with a table of contents, appropriate indices, appendices, cross
references, and tabs differentiating sections is recommended. Hard copies of the
information package should be provided for each FDA participant, with an extra 5
copies for consultation. The cover letter accompanying the information package
should clearly identify the date, time, and subject of the meeting. Although the
contents of the information package will vary depending on the product,
indication, phase of drug development, and issues to be discussed, information
packages generally should include the following:
1. Product name and application number (if applicable).
2. Chemical name and structure.
3. Proposed indication(s).
4. Dosage form, route of administration, and dosing regimen (frequency and
duration).
5. A brief statement of the purpose of the meeting. This statement could
include a discussion of the types of completed or planned studies or data that
the sponsor intends to discuss at the meeting, the general nature of the critical
questions to be asked, and where the meeting fits in overall development
plans.
6. A list of the specific objectives/outcomes expected from the meeting.
7. A proposed agenda, including estimated amounts of time needed for each
agenda item and designated speaker(s).
8. A list of specific questions grouped by discipline.
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9. Clinical data summary (as appropriate).
10. Preclinical data summary (as appropriate).
11. Chemistry, manufacturing, and controls information (as appropriate).
V. Conduct at FDA Meetings
A.
B.
C.
D.
E.
Listen carefully without interrupting.
No formal presentation.
Take extensive notes.
Focus on the agenda and objectives of the meeting.
Seek consensus and resolve all issues professionally and scientifically so that
pharmaceutical development can proceed.
CHAPTER 9 - GOOD CLINICAL PRACTICES
I. Introduction
A. Good Clinical Practices (GCPs)
1. Created to encompass a collection of regulations, guidelines, ethical
principles and industry standards.
2. To ensure that data derived from human clinical trials could be used to
support marketing applications made to regulatory agencies, i.e. FDA in
USA, for drugs, biologics or medical devices.
3. Not codified in a single regulation like Good Manufacturing Practices
(GMP) in 21CFR211: Current Good Manufacturing Practices for
Finished Pharmaceuticals.
4. To follow GCPs is to comply with a myriad of regulations, guidelines and
ethical standards.
5. To conduct a clinical trial in compliance with GCPs means:
i.
Study protects the safety and well-being of human subjects.
ii.
Study provides for quality scientific data to be derived.
II. Regulations and Guidance for GCPs
A. US Code of Federal Regulations (CFR)
1. Titles 21 and 45 of CFR are the US regulations that cover GCPs.
2. Title 21 of CFR applies to food, drugs and medical devices regulated by
FDA. Examples of parts pertaining to GCPs, equally well for clinical trials
conducted for drugs, biologics and medical devices, are:
a) 21CFR Subchapter A-General; Part 50 Protection of Human
Subjects
b) 21CFR Subchapter A-General; Part 56 Institutional Review
Boards (IRB)
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3. Drug-, biologic- and device-specific CFR sections include:
a) 21CFR Subchapter D-Drugs for Human Use; Part 312
Investigational New Drug Application.
b) 21CFR Subchapter D-Drugs for Human Use; part 314
Applications for FDA Approval to Market a New Drug.
c) 21CFR Subchapter F-Biologics; Part 601 Licensing.
d) 21CFR Subchapter H-Medical Devices; Part 812
Investigational Device Exemptions.
e) 21CFR Subchapter H-Medical Devices; Part 814 Premarket
Approval of Medical Devices.
4. Title 45 of CFR applies to Public Welfare and the applicable regulations
under this title apply to research conducted or funded in whole or in part
by any of the 18 government agencies that have adopted these standards.
These regulations are contained in 45CFR Subtitle A-Department of
Health and Human Services; Part 46 Protection of Human Subjects.
B. Guidance
1. International Conference on Harmonization (ICH) in 1996 and
subsequent publication by FDA in the Federal Register in 1997 created the
most comprehensive FDA guidance on GCPs. This guideline is intended
to provide a unified standard for GCPs and represents FDAs current
acceptance standard.
2. ICH established a list of principles which brought together the ethical and
regulatory requirements previously found in a variety of ethical documents
and statutory regulations. ICH principles are summarized below:
a) Clinical trials should be conducted ethically, consistent with the
Declaration of Helsinki and applicable regulations. The
Declaration of Helsinki is a document adopted, and subsequently
amended several times, by the World Medical Association at a
1964 meeting in Helsinki, Finland, which provided
recommendations to guide physicians in the conduct of biomedical
research involving human subjects.
b) Rights, safety and well-being of subjects are paramount.
c) Benefits of study must outweigh risks.
d) Study to adhere to protocol that has been reviewed and approved
by an ethics committee, i.e. IRB.
e) Study must be scientifically sound.
f) Investigator(s) must be qualified.
g) Informed consent must be obtained freely.
h) Records must be maintained to allow for accurate reporting,
interpretation and verification.
i) Confidentiality of records must be assured to respect the privacy
and confidentiality of study subjects.
j) Clinical trial supplies must comply with Good Manufacturing
Practices.
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k) Systems and procedures should be implemented to assure the
quality of the trial.
3. ICH GCP guideline:
a) Defines the responsibilities of:
i.
Institutional Review Boards (IRBs).
ii. Investigators.
iii. Sponsors (e.g. drug companies).
b) Defines the minimum information that should be included in:
i.
Clinical protocol.
ii. Investigator’s brochure (IB).
c) Lists:
i.
Essential documents describing each documents purpose.
ii. At what stage of the clinical trial the document should be
on file.
iii. Whether the document is required to be filed at the site of
the investigator, the sponsor or both.
CHAPTER 10 - THE ROLE 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 cGMP 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
37
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 cGMP 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, cGMP regulations are codified in 21CFR 820.
C. Current Good Manufacturing Practices
1. The basic premise for cGMP 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 cGMP regulations are the minimum requirements for the methods, facilities
and controls used to manufacture a product.
5. The cGMP 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.
Homework Assignment: Use the website of the FDA, www.fda.gov, to access the
Code of Federal Regulations Title 21 Part 211. List all the subparts of 21CFR 211
with the designation (A-K) and title. Choose two subparts and list all the sections,
with their numbers and titles, for each of those subparts. Remember to name the
particular subparts chosen.
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.
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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.
CHAPTER 11 - 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. Case Study: Nomifensine (Merital®), an antidepressant that had been
available in Germany since 1976, had been prescribed to an estimated ten
million patients prior to its marketing in the US in July, 1985. Initial
labeling for the product reflected a variety of long-recognized
hypersensitivity reactions, including fever, liver injury, hemolytic anemia
and eosinophilia, that were reportedly all readily reversible. At the time of
US approval, FDA was aware of reports of less than twenty hemolytic
anemia cases, all non-fatal; however, in 1985, when foreign adverse
reaction reports showed the hemolytic anemia might be fatal, labeling was
revised to reflect the potential seriousness of the reaction. Due to an
increase in serious hemolytic anemia cases seen in Europe, marketing of
nomifensine was reconsidered by the manufacturer, who announced a
worldwide withdrawal of the drug on January 21, 1986.
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The case of nomifensine illustrates that the safety profile of a drug evolves
over its lifetime on the market. Even after almost ten years experience, new
information that will impact the clinical use of a medical product can be
detected.
7. 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.
8. 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.
CHAPTER 12 - FDA INSPECTION AND WARNING LETTERS
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 (clinical studies) 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.
40
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.
See Slide 3: Shows an extract from an actual warning letter.
7. Other administrative enforcement powers of FDA are the following with
regard to product approvals:
a) Delay.
b) Suspension.
c) Withdrawal.
CHAPTER 13 - 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
41
4.
5.
6.
7.
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.
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.
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.
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.
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.
CHAPTER 14 - PATENTS AND THEIR ROLE IN DISCOVERY AND
MARKETING
I. The Patent
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1. A patent is an exclusive right granted by government to an inventor such that the
inventor may prevent others from exploiting the invention for a fixed term.
2. The patent term is 20 years in the United States for medical devices, biologics
and pharmaceutical products and processes.
3. In return for the exclusive legal right the inventor must make available a
detailed technical description of the invention so that when the term of the patent
has expired it may be exploited by others without the inventor’s permission.
Moreover, during the term of the patent, i.e. during the period of exclusive legal
right, others may use knowledge of the patent to “design around” it in the making
of new inventions.
4. A patent therefore encourages innovation by promoting research and
development since exclusive right to inventions, for a fixed period of time, could
be obtained. Furthermore, the knowledge disclosed in a patent may be used by
others as a basis for further inventions upon expiration of the patent term or
earlier if the new inventions are distinct from that of the patent.
5. A patent can also be regarded as a physical asset which can be sold or licensed
to third parties for a fee.
6. The technical description within a patent also constitutes a source of information
on the patented product.
II. How an Invention is Patentable
1. Patents in the United States are granted by the United States Patent and
Trademark Office.
2. The documentation which constitutes the patent application must firstly be
filed with the United States Patent and Trademark Office.
3. The patent application then undergoes a thorough review.
4. If the patent application is approved, i.e. the invention is patentable; a patent
may be issued or granted.
5. To be considered patentable an invention must be all of the following:
a) Novel.
b) Non-obvious.
c) Useful.
6. The criteria for patentability are applied during examination of the patent and
all must be satisfied to enable the patent to be granted.
III. The Role of Patents
1. The discovery and initial characterization of any substance of potential
pharmaceutical application are followed by its patenting.
2. The greater the provided details relevant to e.g. (i) a biologic’s or
pharmaceutical’s physicochemical characteristics, (ii) a method of synthesis
and/or purification, and (iii) its biological effects, the better the chances of
successfully securing a patent. Thus patenting may not take place until preclinical trials and Phase I clinical trials are completed.
43
3. The issue of a patent, once successfully achieved, does not in the case of medical
devices, biologics and pharmaceuticals grant the patent holder an automatic right
to prevent others from utilizing or selling the patented product. Firstly, it must be
proven safe and effective in subsequent clinical trials and then be approved for
general medical use by FDA.
4. The process of developing and bringing to market a new medical device,
biologic or pharmaceutical to treat an illness is long, costly and uncertain. In the
competitive medical device, biotechnology and pharmaceutical industries the
exclusive right granted by a patent to prevent others from making, using, offering
for sale and selling the medical device, biologic or pharmaceutical offers the
company an opportunity to recover the huge costs associated with development of
the medical device, biologic or pharmaceutical.
5. To be able to market the medical device, biologic or pharmaceutical with the
benefit of patent protection provides incentive to proceed with the discovery
process despite the risks and required investment in capital, technology and
human resources.
6. Patent protection, and the prospects it affords of good sales in an unrestricted
market, provides motivation for investors in the company who are hoping to
obtain profits from their investments.
7. Also, licensing of patents to other companies creates a revenue stream for the
patent-holder which may be directed to the discovery and marketing of other
medical devices, biologics and pharmaceuticals.
CHAPTER 15 - APPLICATION OF CURRENT GOOD MANUFACTURING
PRACTICES
I. Introduction
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.
2. CGMP is not a law, but it does have the force of law in court.
3. 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.
4. A company’s reputation and degree of profitability can be adversely impacted
by failures in cGMP.
5. Given the complexities of the manufacturing environment, rigorous attention
to detail is essential.
6. FDA publishes guidelines of procedures to be followed in order to satisfy the
minimum requirements of the cGMP regulations.
B. Fundamentals of cGMP
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1. Based on fundamental concepts of quality assurance.
2. Quality, safety and effectiveness must be designed and built into a product.
3. Each step of the manufacturing process must be controlled to maximize the
likelihood that the finished product will be acceptable.
II. 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.
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.
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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.
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)].
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vi.
vii.
viii.
ix.
x.
xi.
xii.
xiii.
xiv.
xv.
Approving all procedures affecting the quality of
intermediates or API [21CFR 211.22(c)].
Making sure that internal audits are performed [21CFR
211.22(a)].
Approving intermediate and API contract manufacturers
[21CFR 211.22(a)].
Approving changes that potentially affect intermediate or
API quality.
Reviewing and approving validation protocols and reports.
Making sure that quality-related complaints are
investigated and reported.
Making sure that effective systems are used for maintaining
and calibrating critical equipment.
Making sure that materials are appropriately tested and the
results are reported.
Making sure that there are stability data to support re-test or
expiry dates and storage conditions of API and/or
intermediates where appropriate.
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.
iv.
v.
vi.
vii.
viii.
ix.
x.
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.
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.
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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.
CHAPTER 16 - 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
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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].
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.
e) Prefabricated partitions may be used in packaging areas where flexibility
of layout is important. Prefabricated units have also been used in other
areas such as sterile suites where panel joints must be given particular
attention so that they do not become receptacles for dust and microbial
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growth. Where possible, walls should be flush and projections should be
avoided.
f) A typical finish for laboratory walls is 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. Ceramic and vinyl tiles usually are not recommended for
production areas. If used, the sealing between the tiles
should be flush and complete.
iii. 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.
iv.
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.
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)].
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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
computer control can additionally optimize energy utilization thereby reducing
costs.
IV. Plumbing
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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 backsiphonage [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
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].
52
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.
CHAPTER 17 - RECEIVING AND QUARANTINE OPERATIONS
I. Introduction
1. Requirements
a) Requirements for receiving and handling all materials, i.e. components,
drug product containers and closures, that will become part of the finished
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b)
c)
d)
e)
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.
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.
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.
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.
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.
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.
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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 must be documented for approval or rejection of each material
in view of its intended use.
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)].
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.
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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.
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
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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 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
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
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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
seals and other closures must be replaced as they were. Any holes cut
in bags must be closed with appropriate sealing materials.
d) The sampling process must not introduce contamination or cause
contamination of other items. Many firms are using sterile and
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disposable sampling instruments and containers for microbiological
sampling to avoid having to autoclave the sampling tools.
e) 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.
f) 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.
g) 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.
(4) When appropriate, components shall be microscopically examined.
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(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
pose less risk than others. There have been many recalls of non-sterile
drug products because they were found to contain pathogenic
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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
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].
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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.
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,
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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.
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)].
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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).
CHAPTER 18 - CLEAN ROOMS
I. Introduction
1. Clean rooms are environmentally controlled areas within the pharmaceutical
facility in which critical manufacturing steps for injectable and/or sterile
(bio)pharmaceuticals must be undertaken.
2. The rooms are specifically designed to protect the product from contamination.
3. Common potential contaminants include micro-organisms and particulate
matter. These contaminants can be airborne, or derived from process equipment,
personnel, etc. See Regulatory Compliance PowerPoint Slide 4: picture of a
clean room.
II. Design
1. Clean rooms are designed in a manner that allows tight control of entry of all
substances, e.g. equipment, personnel, in-process product, and even air. See the
two PowerPoint slides 2 and 5 on clean rooms. In this way, once a clean
environment is generated in the room, it can easily be maintained.
2. A basic feature of clean room design is the presence in their ceilings of high
efficiency particulate air (HEPA) filters. See Regulatory Compliance
PowerPoint Slide 5.
a) These depth filters, often several inches thick, are generally manufactured
from layers of high density glass fiber.
b) Air is pumped into the room via the filters, generating a constant
downward sweeping motion.
c) The air normally exits via exhaust units, generally located near ground
level.
d) This motion promotes continued flushing from the room of any
particulates generated during processing, i.e. it helps remove air-borne
particulate matter from the room. This is even though the air flow is nonunidirectional, i.e. not true laminar flow.
3. HEPA filters of different particulate-removing efficiency are available, allowing
the construction of clean rooms of various levels of cleanliness. Such rooms are
classified on the basis of the number of airborne particles present in the room. See
Regulatory Compliance PowerPoint slides 6 and 7.
a) HEPA filters in Classes 100 to 100,000 are normally spaced
evenly in the ceiling, occupying somewhere in the region of 2025% of total ceiling area.
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b) Generation of Class 10 clean room conditions generally requires
a modified design. The use of high-specification HEPA filters,
along with the generation of a unidirectional downward air
distribution pattern, i.e. laminar flow, is essential. This is only
achieved if filter occupancy of ceiling space is 100%.
4. Many additional elements, besides effective HEPA air-handling systems which
are essential in generating clean room conditions, are equally important in
maintaining such conditions.
a) All exposed surfaces in the clean room should have a smooth and
sealed impervious finish in order to minimize accumulation of
dirt and microbial particles and to facilitate effective cleaning
procedures. Floors, walls and ceilings can be coated with durable
and chemical-resistant materials such as epoxy resins, polyester
or PVC coatings. Alternatively, such surfaces may be completely
overlaid with smooth vinyl-based sheets, thermally welded to
ensure a smooth and unbroken surface.
b) Fixtures within the room, e.g. work benches, chairs, equipment,
etc., should be kept to a minimum. Ideally they should be
designed and fabricated from material that facilitates effective
cleaning, e.g. polished stainless steel. The positioning of such
fixtures should not hinder effective cleaning processes.
c) Pipe work should be installed in such a way as to allow effective
cleaning around them and the presence of uncleanable recesses
must be avoided.
d) All corners and joints between walls and ceiling must be rounded
and equipment with movable parts, e.g. motors and pumps,
should be encased.
5. The transfer of processing materials, or entry of personnel into clean areas,
carries with it the risk of reintroduction of microorganisms and particulate matter.
a) Such risks are minimized by stipulating that entry of all
substances and personnel into a clean room must occur via airlock systems. See Regulatory Compliance PowerPoint Slide 8.
Such air locks, with separate doors opening into the clean room
and the outside environment, act as a buffer zone.
b) All materials/process equipment entering the clean area are
cleaned and sanitized (or autoclaved if practicable) outside this
area and then passed directly into the transfer lock. In the transfer
lock the items are sanitized, where possible, by being rubbed
down with a disinfectant solution, for example. From the transfer
lock the items are transferred into the clean room proper by clean
room personnel.
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c) An interlocking system ensures that both doors of the transfer
lock are never simultaneously open, thus precluding formation of
a direct corridor between the uncontrolled area and the clean
area. Transfer locks are also positioned between adjacent clean
rooms of different grades of cleanliness. In practice, product may
be processed in a number of different, adjacent, clean rooms.
d) Processed product usually exits the clean room via an exit
transfer lock.
e) Personnel represent a major potential source of process
contaminants, e.g. microorganisms, particulates etc., hence they
are required to wear specialized protective clothing when
working in clean areas.
f) Operators enter the clean area via a separate air lock, which
serves as a changing area. They remove their outer clothing at
one end of the area and put on, usually pre-sterilized, gowns,
face masks and gloves at the other end of the changing area. See
Regulatory Compliance PowerPoint Slide 9 showing some
clean room clothing.
g) Clean room clothing is made from non-shedding material and
covers most of the operator’s body.
h) Personnel often exit the room via a changing room separate from
the one they entered. In some cases the same changing room is
used as an entry and exit route.
i) A high standard of operator personal hygiene is also of critical
importance and all personnel should receive appropriate training
in this regard.
j) Only the minimum number of personnel required should be
present in the clean area at any given time to reduce the risks of
contamination from personnel and the air turbulence that their
movements create.
CHAPTER 19 - EQUIPMENT PREPARATION AND ASSEMBLY
I. Introduction
1. Equipment preparation is the cleaning of equipment followed by sanitization or
sterilization.
2. Improper equipment preparation could result in:
a) Cross-contamination from product to product;
b) Cross-contamination from lot to lot of the same product;
c) Failed runs.
II. Equipment Cleaning
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1. Introduction
a) The purpose of equipment cleaning is to:
i.
Remove or obliterate previous batch components;
ii.
Prevent contamination that would alter the safety, identity,
strength, quality or purity of the drug product.
b) More specifically, cleaning:
i.
ii.
iii.
Reduces microbial contamination;
Reduces endotoxin level;
Removes cleaning agent residuals.
2. Methods for Cleaning Equipment
There are four ways to clean equipment:
a) Manual Cleaning. This involves hand scrubbing equipment with a
nylon brush and detergent and then rinsing with Water for Irrigation
(WFI) or purified water.
b) Glassware Washer. Using this method involves loading equipment
into a washer and subjecting the equipment to a cleaning cycle.
c) Clean-Out-Place (COP) Bath. Equipment is loaded into COP washer
and subjected to a cleaning cycle.
d) Clean-In-Place (CIP). A CIP skid is attached to the equipment
requiring cleaning and a cleaning cycle is executed by circulating
cleaning solution and rinse water through the equipment.
e) Note: A CIP skid is a system used to clean equipment in a consistent
and reliable manner and can be either portable or built-in. The CIP
skid is made up of:
i.
ii.
iii.
iv.
v.
vi.
A solution holding tank;
Pumps;
Automatic valves;
A heat exchanger;
A computer to control the flow and temperature of cleaning
solutions; and
Instrumentation to monitor and record operations.
3. Cleaning Validation
a) Cleaning validation studies are performed on all cleaning methods
and cycles to demonstrate that cleaning procedures are:
i. Effective;
ii. Reproducible;
iii. Under control.
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b) If soiled equipment were cleaned using a method that had not been
validated, one could not be sure the equipment was clean.
c) In general, manufacturing areas clean equipment using the methods
described under section 2 above.
d) However, some areas are moving toward validating WFI rinses as a
form of tank cleaning between same buffer batching steps.
III. Sanitary Versus Non-Sanitary Fittings
1. Sanitary Connection
a) A connection with a smooth inner bore that will not hold up residual
liquid that could act as a growth medium for bacteria.
b) Some examples of sanitary connections are tri-clamp connections on:
i.
Tanks;
ii.
Process lines;
iii. Clean steam utility drops.
See Bio 221 Regulatory Compliance Slide 10 for an example of a triclamp connection.
2. Non-Sanitary Connection
a) A connection with a rough bore such as threaded pipe or Swagelock
fitting that could potentially hold up liquids and provide a growth
medium for bacteria.
b) Examples of non-sanitary connections include standard pipe thread
such as:
i. Glycol supply lines; and
ii. Plant steam lines.
c) In order to prepare equipment properly, one needs to consider the
sanitary state of fittings used to transport required utilities.
IV. Notes on Selected Equipment
1. Material of Construction
a) Only parts made out of the following can be used if parts come in
contact with product:
i.
Stainless steel;
ii.
Viton;
iii. Teflon; or
iv.
Silicon.
b) These materials are inert and will not react with the product.
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c) Stainless steel parts should be inspected for roughing, corrosion,
scratches and visible debris prior to installation.
2. Tri-Clamp Connections
a) Select the gasket with the right Inner Diameter (ID). The gasket must
match the largest ID in the connection.
b) Ensure the gasket is centered and the two fittings are square.
c) Tri-clamp connections need only be hand-tightened to be effective.
3. Fittings with O-Rings
a) Ensure that the o-ring is not damaged and that it is the right size.
b) To facilitate installation, lubricate the o-ring with purified water,
WFI or ethanol.
4. Hose Barb Fittings
a) Select tubing so that it fits snuggly around the barb, ensuring that
tubing completely covers all the barb threads.
b) Use cable ties to secure the tubing on the barb.
5. Diaphragm Valve
a) See Slide 11 of BIO 221 Regulatory Compliance Slides for pictures
of diaphragm valves, including cut-away images.
b) Ensure the diaphragm is not worn or damaged.
c) Align the weir (saddle) mark with the valve, tighten screws
crosswise and ensure the valve is open when tightening.
6. Filters
a) Filters are used to remove particles from liquid or gaseous solutions.
b) They are used to filter product or in-process materials that come in
contact with product, i.e. buffers, media or gases.
c) Filters must be installed on equipment in the correct orientation to
be effective.
d) Hydrophobic filters will not allow water to pass through them and are
usually used as tank vents.
e) Hydrophilic filters are for solutions and will let liquids pass through
them.
7. Steam Traps
a) The purpose of a steam trap is to maintain steam pressure in the
vessel while evacuating all the steam condensate.
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b) Steam traps must be installed on equipment in the correct orientation
to be effective.
8. Check Valves
a) Check valves permit the flow of liquid in one direction only and must
be installed in the proper orientation t work correctly.
b) Check valves are typically used to prevent back flow.
9. Ball Valve
a) A ball valve, one type of quarter turn valve, is quite literally a ball
placed in a passageway through which fluid flows. The ball has a hole
through it, by which the valve opens and closes. When the ball is
positioned so that the hole runs the same direction as the passageway,
the fluid simply flows through the hole, and the valve is open.
However, when the ball is positioned so that the hole is perpendicular
to the passageway, the fluid cannot pass through, and the valve is
closed. The ball is controlled from outside the valve, often with a
handle that is turned 90 degrees, or a quarter turn, back and forth to
open and close the valve.
b) The basic ball valve, described above, is a two-way valve. This ball
valve has a single, straight passageway bored through the ball, making
two openings: one on each side, an inlet and an outlet. A ball valve can
also be a three-way valve if a third hole is bored partially through the
ball, until it meets the main hole, forming a T. A three-way ball valve
can shut off one or all of the three passageways it connects.
c) Because of the nature of the ball valve, it does not work well in
situations in which fine control of the valve is needed. However, a ball
valve works very well for situations in which a flow needs to be
completely shut off. Ball valves also do not tend to develop problems
if they are not used for long periods of time; they will still work
perfectly when needed again.
10. Butterfly Valve
a) The butterfly valve is also from the family of valves called quarter
turn valves. The "butterfly" is a metal disc mounted on a rod. When
the valve is closed, the disc is turned so that it completely blocks off
the passageway. When the valve is open, the disc is rotated a quarter
turn so that it allows unrestricted passage, although a pressure drop in
the fluid flow still occurs. The position of the disc is effected from
outside the valve.
b) There are different kinds of butterfly valves, each adapted for
different pressures and different usage.
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i. The resilient butterfly valve, which uses the flexibility of rubber,
has the lowest pressure rating.
ii. The high performance butterfly valve, used in slightly higherpressure systems, features a slight offset in the way the disc is
positioned, which increases the valve's sealing ability and
decreases its tendency to wear.
iii. The valve best suited for high-pressure systems is the tricentric
butterfly valve, which makes use of a metal seat, and is therefore
able to withstand a greater amount of pressure.
11. Piping
a) Stainless steel, Viton, Teflon or other inert polymers, are the
materials of construction of piping and pipe fittings, as with other
equipment parts that come in contact with product.
b) Piping is used both in-process, for transportation of materials,
including buffers and product ingredients, through different steps, and
for cleaning equipment.
c) See Slide 12 of PowerPoint BIO 221 Regulatory Compliance
Slides. This slide illustrates the central role of piping in
biomanufacturing facilities.
12. Peristaltic Pumps
a) A peristaltic pump is a type of positive displacement pump used for
pumping a variety of fluids. The fluid is contained within a flexible
tube fitted inside a circular pump casing. A rotor with a number of
“rollers”, “shoes” or “wipers” attached to the external circumference
compresses the flexible tube. As the rotor turns, the part of tube under
compression closes, or “occludes”, thus forcing the fluid to be pumped
to move through the tube. Additionally, as the tube opens to its natural
state after the passing of the cam (“restitution”) fluid flow is induced
to the pump. This process is called peristalsis. See PowerPoint Slide
13.
b) Peristaltic pumps are typically used to pump clean or sterile fluids
because the pump cannot contaminate the fluid.
c) Because the only part of the pump in contact with the fluid being
pumped is the interior of the tube, it is easy to sterilize and clean the
inside surfaces of the pump. Furthermore, since there are no moving
parts in contact with the fluid, peristaltic pumps are inexpensive to
manufacture. Their lack of valves, seals and glands makes them
comparatively inexpensive to maintain, and the use of a hose or tube
makes for a relatively low-cost maintenance item compared to other
pump types.
13. Centrifugal Pumps
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a) A centrifugal pump converts energy of a prime mover, i.e. an electric
motor or turbine, first into kinetic energy and then into pressure energy
of a fluid that is being pumped. The energy changes occur by virtue of
two main parts of the pump, the impeller and the volute or diffuser.
b) The impeller is the rotating part that converts driver energy into the
kinetic energy.
c) The volute or diffuser is the stationary part that converts the kinetic
energy into pressure energy.
d) The process liquid enters the suction nozzle and then into the eye
(center) of the revolving device known as the impeller. When the
impeller rotates, it spins the liquid sitting in the cavities between the
vanes outward and provides centrifugal acceleration. As liquid leaves
the eye of the impeller a low-pressure area is created causing more
liquid to flow toward the inlet. Because the impeller blades are curved,
the fluid is pushed in a tangential and radial direction by the
centrifugal force. This force acting inside the pump is the same one
that keeps water inside a bucket that is rotating at the end of a string.
e) Slide 14 depicts a side cross-section of a centrifugal pump indicating
the movement of the liquid.
f) Slide 15 indicates the general components of a centrifugal pump.
14. Positive Displacement Pumps
a) Positive displacement pumps are designed to move liquid by
pressurizing it.
b) The pumps come in many configurations, such as:
i. Rotary vane;
ii. Gear;
iii. Screw;
iv. Piston; and
v. Plunger.
c) The rotary vane pumps operate by filling and discharging variable
volume chambers formed by vanes, which slide in and out along
machined radial slots in the rotor.
d) The rotor and vane assembly fit into a jacket. The rotor and the jacket
are offset to create a particular geometry that is essential to pump
operation. See Slide 16.
e) When the rotor rotates, the particular geometry causes the vanes to
slide inward along their grooves, thereby shrinking the volume of each
chamber as it moves from the inlet to the outlet. Because the fluid
being pumped is not easily compressed, it is squeezed out of the
chamber when it reaches the pump outlet. Note that as the rotor turns
and chamber volume changes, the vanes "float" in their slot. A
combination of centrifugal force and hydraulic pressure forces the
vanes outward so that they remain in contact with the housing's inner
surface and, hence, provide an effective seal. A very thin layer of fluid
between the vane and the jacket keeps friction to a minimum.
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f) Unlike centrifugal pumps, the flow rate is steady regardless of the
system pressure drop.
CHAPTER 20 - CLEANING, DECONTAMINATION AND SANITATION (CDS)
I. Introduction
a) Essential to the production of a safe and effective product is the
application of and effective cleaning, decontamination and sanitation
(CDS) regime in the manufacturing facility.
b) Cleaning involves the removal of “dirt”, i.e. miscellaneous organic and
inorganic material which may accumulate in process areas or equipment
during production.
c) Decontamination refers to the inactivation and removal of undesirable
substances which generally exhibit some specific biological activity likely
to be detrimental to the health of patients receiving the drug. Examples
include:
i. Endotoxins;
ii. Viruses; or
iii. Prions.
d) Sanitation refers specifically to the destruction and removal of viable
microorganisms, i.e. bioburden.
e) Effective CDS procedures are routinely applied to:
i. Surfaces in the immediate manufacturing area which do not come
into direct contact with the product, e.g. clean room walls and
floors, work tops and ancillary equipment.
ii. Surfaces coming into direct contact with the product, e.g.
manufacturing vessels, chromatographic columns, product filters,
etc.
II. CDS of the General Manufacturing Area
a) Primary cleaning generally entails scrubbing/rinsing the target area
with water or a detergent solution.
b) Subsequent decontamination/sanitation procedures vary, often
involving application of disinfectants or other bactericidal agents.
c) Thorough cleaning prior to disinfectant application is essential as
dirt can inactivate many disinfectants or shield microorganisms from
disinfectant action.
d) A range of suitable disinfectants are commercially available,
containing active ingredients including:
i. Alcohols;
ii. Phenol;
iii. Chlorine and
iv. Iodine.
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e) Different disinfectants are often employed on a rotating basis to
minimize the possibility of the development of disinfectant-resistant
microbial strains.
f) CDS of clean room walls, floors and accessible surfaces of clean
room equipment is routinely undertaken between production runs.
g) The final CDS step often entails “fogging” the room.
i.
This is achieved by placing some of the disinfectant in an
aerosol-generating device (a “fogging machine”).
ii. This generates a fine disinfectant mist, or fog, within the
clean room which is capable of penetrating areas difficult
to reach in any other manner.
III. CDS of Process Equipment
a) CDS of surfaces/equipment coming into direct contact with the
product requires special consideration.
b) While CDS procedures of guaranteed efficiency must be applied, it
is imperative that no traces of the CDS agents subsequently remain on
such surfaces or equipment as these would result in automatic product
contamination.
c) The final stage of most CDS procedures, as applied to such process
equipment, involves exhaustive rinsing with highly pure water, i.e.
water for injections or irrigation, WFI. This is followed by autoclaving
if possible.
d) CDS of processing and holding vessels, as well as equipment that is
easily detachable or dismantled (e.g. homogenizers, centrifuge rotors,
etc.) is usually relatively straightforward.
e) However, CDS of large equipment/process fixtures can be more
challenging, due to the impracticality or undesirability of their
dismantling. Examples include the internal surfaces of fermentation
equipment, large processing or storage tanks, process-scale
chromatographic columns, fixed piping through which product is
piped, etc.
i.
Specific “cleaning in place” (CIP) procedures can
generally be used to accommodate such equipment.
ii. A detergent solution can be pumped through fixed pipework, followed by WFI and then the passage of
sterilizing “live” steam generated from WFI.
iii. Internal surfaces of fermentation or processing vessels
can be scrubbed down. Furthermore, such vessels are
generally jacketed (See PowerPoint Slide number 17:
diagram of a typical jacketed processing vessel), thus
allowing temperature control of their contents by
passage of cooling water or steam through the jacket, as
appropriate. Passage of steam through the jacket of the
empty vessel facilitates sterilization of its internal
surfaces by dry heat.
74
f) The cleaning of process-scale chromatography systems used in the
purification of biopharmaceuticals can also present challenges.
i.
Although such systems are disassembled periodically, this
is not routinely undertaken for each production run. CIP
protocols must thus be applied periodically to such
systems.
ii. The level and frequency of CIP undertaken will depend
largely on the level and type of contaminants in the
product-stream applied.
iii. Columns used during the earlier stages of purification may
require more frequent attention than systems used as a final
“clean-up” step of a nearly pure protein product.
iv.
While each column is flushed with buffer after each
production run, a full scale CIP procedure may be required
only after every 3-10 column runs; i.e. the lowest number
for columns used early in purification and the highest for
columns used later in the purification. Most of the
contaminants present in such columns are present from the
previous production runs.
v.
Processing of product derived from microbial sources can
result in contamination of chromatographic media with
lipid, endotoxins, nucleic acids and other biomolecules.
Application of plant-derived extracts can result in column
fouling with pigments and negatively-charged
polyphenolics, as well as various substances released from
plant cells vacuoles many of which are powerful protein
precipitants or denaturants.
vi.
Chromatography of extracts from animal/human tissue can
result in column contamination with infectious agents or
biomolecules such as lipids.
vii.
Furthermore, buffer components may sometimes precipitate
out of solution within the column.
viii. Fortunately, most types of modern chromatographic media
are resistant to a range of harsh physicochemical influences
that may be employed in CIP protocols (see PowerPoint
Slide 18; Table of range of CIP agents often used to
clean and sanitize chromatographic columns). CIP
protocols for chromatography columns are normally multistep, consisting of sequential flushing of the gel with a
series of two or more CDS agents.
g) Chromatographic systems are designed to facilitate effective CIP.
Internal surfaces of the column, its valves and piping, are smooth,
impervious and devoid of recesses which could harbor microorganisms
or other contaminants.
h) Periodic chromatographic system disassembly allows more
extensive CDS procedures to be undertaken.
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i.
Most columns are manufactured from tough plastic or
stainless steel and, less commonly, glass. After a thorough
cleaning of all disassembled components, sterilization by
autoclaving is usually undertaken prior to re-assembly.
ii. Most chromatographic media likewise can be autoclaved
before column re-pouring.
i) CIP of the ring main systems used to store and circulate WFI and
purified water around the pharmaceutical plant is also routinely
undertaken. Upon their in-house manufacture from incoming potable
water, WFI and purified water are separately fed into sealed storage
vessels, often made from stainless steel. The water in each case is
circulated via a series of pipe-work throughout the building and from
which a number of outlets are available. The pipe-work leads back to
the storage tank, allowing constant recirculation of the water
throughout the facility. Because of this it is known as a ring main or
loop system.
i.
CIP normally entails emptying the ring main systems,
including reservoirs, opening all the outlet valves and
subsequently pumping sterile stem through all the pipework.
ii. The foregoing is generally sufficient to dislodge physically
any traces of trapped particulate matter or biological agents
harbored in the system.
CHAPTER 21-STERILIZATION OF PROCESS EQUIPMENT
I. Introduction
a) Equipment surfaces that contact sterilized drug product or its sterilized
containers or closures must be sterile so as not to alter purity of the drug. Where
reasonable contamination potential exists, surfaces that are in the vicinity of the
sterile product should also be rendered free of viable organisms.
b) Sterilization is a process intended to kill all microorganisms including spores
and is the highest level of microbial kill that can be achieved.
c) The level of microbial contamination before sterilization is called the
Bioburden Load.
d) During sterilization the microbes die at a constant rate. They do not die all at
once. The kill rate depends on several variable factors:
i.
Chemical concentration. In general, for chemical sterilization and also
sanitization, the higher the concentration of the chemical the faster the
microbes die. Additionally, chemicals are more effective at higher
temperatures.
ii. Temperature. In steam sterilization the hotter the steam the faster the
microbes die.
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iii.
iv.
v.
vi.
vii.
Humidity. A certain level of moisture speeds up the sterilization process
in ethylene oxide gas sterilizers.
Resistance of the microbes. Some microbes are much more resistant than
others. The sterilization formulas are carefully worked out for the
microbes that are the most difficult to kill. In theory, if you can kill the
most resistant microbes than all the others should be killed as well/
Presence of biofilms. Microbes often grow in association with other
microbes on surfaces forming biofilms. The microbes at the deepest part
of the biofilm are the most protected from the sterilizing agent and will
require longer kill times than those microbes at the surface of the biofilm.
Growth phase of microbes. Microbes actively growing and metabolizing
are more susceptible to killing agents than microbes in metabolically
quiescent states.
Presence of organic macromolecules. The chemical environment of the
microbes influences killing efficiency. Generally, an environment higher
in organic macromolecules offers some protection for the microbes against
killing agents, especially killing agents.
II. Methods of Sterilization
a) Appropriate sterilization methods are:
i.
Steam under pressure as in autoclaving. Equipment is typically
autoclaved at 121°C for 15 to 20 minutes.
ii. Dry heat. The appropriate time for exposing equipment to dry heat, in an
oven for example, depends on the temperature reached as shown below:
Temperature
170 degrees C - 1 hour
160 degrees C - 2 hours
150 degrees C - 2.5 hours
140 degrees C - 3 hours
iii. Formaldehyde and hydrogen peroxide vapors.
iv.
Ethylene oxide gas.
b) The use of dry heat and autoclaving as described in Chapter 19 (Cleaning,
Decontamination and Sanitation) effectively sterilizes some process equipment. In
using dry heat care must be taken to ensure that a sufficiently high temperature is
reached and exposure of equipment to that heat is for the appropriate time
considering the temperature. Sterilization where practical achieves, to the highest
possible level, the process of sanitation. For moist heat (autoclaving) to be
effective, steam penetration must be assured and for this the sterilization chamber
must be evacuated prior to steam injection.
c) The type of sterilization used will depend on the material.
i.
Metallic items are best sterilized by dry heat.
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ii.
d)
e)
f)
g)
Silicone rubber, Teflon, polycarbonate and some other plastics should
be autoclaved for 20 minutes at 121°C, 100 kPa, with pre-evacuation and
post-evacuation steps.
iii. Many plastics cannot be exposed to the temperatures required for
autoclaving or dry heat sterilization. To sterilize such items, immerse in
70% alcohol for 30 minutes and dry off under UV light in a laminar flow
cabinet.
iv.
Ethylene oxide gas may be used to sterilize plastics, but 2 to 3 weeks
are required for the ethylene oxide to clear from the plastic surface.
v.
Gamma irradiation is the best method for plastics. Items should be
packaged and sealed.
For larger process equipment as encountered in commercial-scale
production, the sterilization of essential units by autoclaving becomes
impractical and some means of sterilizing the equipment in situ is needed.
Sterilization-in-Place (SIP) processes are then applied for such process
equipment as in (c).
i.
SIP modules are available as shown in Slide number 19.
ii. The SIP module is a fully automated Sterilization-in-Place system for
sterilization of processing vessels in sterile areas.
A typical SIP module has the following technical features:
i.
Completely automated sterilization process cycles.
ii. On line display of sterilization process parameters.
iii. Display of fault messages.
iv.
Automated valves for pure steam and sterile air.
v.
Vacuum pulsing cycles for validating vessel integrity.
The key benefits of an SIP module are:
i.
Enables sterilization of large and cumbersome process equipment which is
impractical to autoclave or expose to dry heat in an oven.
ii. The process for sterilization of process equipment can be validated.
iii. Lower facility operating costs.
iv.
Minimal dismantling of equipment and piping.
v.
Reduced turnaround time for sterilization.
III. Validation
a) Introduction
i.
ii.
iii.
It is as important in aseptic processing to validate the processes used to
sterilize critical process equipment as it is to validate processes used to
sterilize the drug product and its container and closure.
Moist heat and dry heat sterilization, the most widely used, are the primary
processes discussed here. However, many of the heat sterilization
principles discussed here are also applicable to other sterilization methods.
Sterility of aseptic processing equipment should normally be maintained
by sterilization between each batch.
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iv.
Following sterilization, transportation and assembly of equipment,
containers, and closures should be performed with strict adherence to
aseptic methods in a manner that protects and sustains the product's sterile
state.
b) Qualification and Validation
i.
Validation studies should be conducted to demonstrate the efficacy of the
sterilization cycle. Re-qualification studies should also be performed on a
periodic basis. The specific load configurations, as well as biological
indicator and temperature sensor locations, should be documented in
validation records. Batch production records should subsequently
document adherence to the validated load patterns.
ii. It is important to remove air from the autoclave chamber as part of a steam
sterilization cycle. The insulating properties of air interfere with the
ability of steam to transfer its energy to the load, achieving lower lethality
than associated with saturated steam. It also should be noted that the
resistance of microorganisms can vary widely depending on the material
to be sterilized. For this reason, careful consideration should be given
during sterilization validation to the nature or type of material chosen as
the carrier of the biological indicator to ensure an appropriately
representative study.
iii. Potentially difficult to reach locations within the sterilizer load or
equipment train (for SIP applications) should be evaluated. For example,
filter installations in piping can cause a substantial pressure differential
across the filter, resulting in a significant temperature drop on the
downstream side. It is recommended that biological indicators are placed
at appropriate downstream locations of the filter.
iv.
Empty chamber studies evaluate numerous locations throughout a
sterilizing unit (e.g., steam autoclave, dry heat oven) or equipment train
(e.g., large tanks, immobile piping) to confirm uniformity of conditions
(e.g., temperature, pressure). These uniformity or mapping studies should
be conducted with calibrated measurement devices.
v.
Heat penetration studies should be performed using the established
sterilizer loads. Validation of the sterilization process with a loaded
chamber demonstrates the effects of loading on thermal input to the items
being sterilized and may identify difficult to heat or penetrate items where
there could be insufficient lethality to attain sterility. The placement of
biological indicators at numerous positions in the load, including the most
difficult to sterilize places, is a direct means of confirming the efficacy of
any sterilization procedure. In general, the biological indicator should be
placed adjacent to the temperature sensor so as to assess the correlation
between microbial lethality and predicted lethality based on thermal input.
vi.
When determining which articles are difficult to sterilize, special attention
should be given to the sterilization of filters, filling manifolds, and
pumps. Some other examples include certain locations of tightly wrapped
79
vii.
viii.
or densely packed supplies, securely fastened load articles, lengthy tubing,
the sterile filter apparatus, hydrophobic filters, and stopper load.
Ultimately, cycle specifications for such sterilization methods should be
based on the delivery of adequate lethality to the slowest to heat locations.
The sterilizer validation program should continue to focus on the load
areas identified as most difficult to penetrate or heat. The suitability of the
sterilizer should be established by qualification, maintenance, change
control, and periodic verification of the cycle, including biological
challenges. Change control procedures should adequately address issues
such as a load configuration change or a modification of a sterilizer.
c) Equipment Controls and Instrument Calibration
i.
For both validation and routine process control, the reliability of the data
generated by sterilization cycle monitoring devices should be considered
to be of the utmost importance. Devices that measure cycle parameters
should be routinely calibrated. Written procedures should be established
to ensure that these devices are maintained in a calibrated state. For
example, it is recommended that procedures address the following:

Temperature and pressure monitoring devices for heat sterilization should be
calibrated at suitable intervals. The sensing devices used for validation
studies should be calibrated before and after validation runs.

Devices used to monitor dwell time in the sterilizer should be periodically
calibrated.

The microbial count of a biological indicator should be confirmed. Biological
indicators should be stored under appropriate conditions.

If the reliability of a vendor’s Certificate of Analysis is established through an
appropriate qualification program, the D-value of a biological indicator (e.g.,
spore strips, glass ampoules) can be accepted in lieu of confirmatory testing of
each lot. However, a determination of resistance (D-value) should be
performed for any biological indicator inoculated onto a substrate, or used in a
way that is other than described by the vendor. D-value determinations can be
conducted by an independent laboratory.

Where applicable, instruments used to determine the purity of steam should
be calibrated.

For dry heat depyrogenation tunnels, devices (e.g. sensors and transmitters)
used to measure belt speed should be routinely calibrated. Bacterial endotoxin
challenges should be appropriately prepared and measured by the laboratory.
80
ii.
iii.
iv.
To ensure robust process control, equipment should be properly designed
with attention to features such as accessibility to item being sterilized,
piping slope, and proper condensate removal (as applicable). Equipment
control should be ensured through placement of measuring devices at
those control points that are most likely to rapidly detect unexpected
process variability.
Where manual manipulations of valves are required for sterilizer or SIP
operations, these steps should be documented in manufacturing procedures
and batch records.
Sterilizing equipment should be properly maintained to allow for
consistent and satisfactory function. Routine evaluation of sterilizer
performance-indicating attributes, such as equilibrium (come up) time is
important in assuring that the unit continues to operate as per the validated
conditions.
CHAPTER 22 - PRODUCT FORMULATION AND FILLING OPERATIONS
I. Introduction
1. Protein Product
a) For proteins produced in a biotechnological process, this chapter will discuss the
formulation process and subsequent filling operations.
b) Critical process considerations in each unit operation will also be discussed.
2. Following Purification
a) After purification the protein has to be formulated into the recommended
formulation. This requires consideration of:
i.
Excipients. Excipients are substances other than the active ingredient(s)
which, for example, stabilize the final product or enhance the
characteristics of the product in some other way.
ii. Ionic strength.
iii. pH.
b) Figure of slide 17 shows sequence of formulation operations that typically
occur during protein commercial manufacturing.
c) If the formulation is a sustained-delivery formulation, or if a drug delivery
device, e.g. an insulin pen, is used for more convenient delivery of the drug, the
operations involved will vary from those described here.
II. Bulk Freeze-Thawing
1. Introduction
81
a) Purified protein is often frozen prior to formulation operations to facilitate
inventory buildup, transportation ease and to enable formulation in a campaign
mode for different products in a multi-product facility.
b) Under such conditions, thawing the frozen bulk often constitutes the first step in
formulation operations, as shown in the Figure of slide 17.
c) Since freezing and thawing are linked together, both steps will be discussed.
2. Detrimental Effects
a) Although one of the primary objectives of freezing the purified protein bulk is
to extend its stability, the freezing process itself can be detrimental to proteins in
several ways:
i.
All water-soluble species in the formulation can concentrate during
freezing, and the increased concentrations can lead to enhanced
degradation reaction rates.
ii. Buffer components can selectively crystallize causing solution pH shifts
that can potentially denature the protein.
iii. Protein-stabilizing excipients in the formulation can crystallize during
freezing, leaving the protein unprotected.
iv.
Protein adsorption on to the ice surface can lead to protein denaturation.
v.
Sometimes protein denaturation can be due to the low temperatures
achieved during the freezing process. This phenomenon, often termed cold
denaturation, is believed to be due to a decrease in the hydrophobic
interaction with reduced temperature.
vi.
Freezing can also lead to potential conformational changes, which can
subsequently lead to protein denaturation.
b) Possible sources for product degradation and denaturation during largescale thawing include the following:
i.
ii.
iii.
Excessive agitation can shear the protein, i.e. degradation.
Excessive agitation can cause foaming, which can lead to protein
denaturation at the air-water interface.
While thawing from the freeze-concentrated state, the protein may
precipitate, i.e. denature.
3. General Guidelines
a) Critical parameters
Based on the foregoing discussion, the following parameters are critical for a
large-scale freeze-thaw process.
i.
Freezing temperature. Freezing temperature influences product stability
in two ways. (1) It dictates the thermodynamic state of the protein.
Although in general colder temperatures impart better stability to proteins,
there are exceptions. It also controls the availability of formulation
82
excipients to the protein. If the product is frozen to a temperature below
the eutectic of a crystalline additive, such as salt, the additive crystallizes
and is no longer available to the protein.
ii. Freezing rate. Since freezing can be detrimental to protein stability, it
may be advisable to freeze as quickly as possible so that the time of
protein exposure to freezing-induced adverse conditions is minimized.
However, proteins can have an optimum freezing rate since very high
freezing rates can be detrimental to proteins because of the excessively
large ice-surface that results under fast freezing conditions.
iii. Freezing time. Ensures the completion of the freezing process.
iv.
Thawing temperature. Dictates thawing time and the rate of resolubilization of freeze-concentrated protein back into solution.
v.
Thawing rate and agitation. Similar to freezing rates, faster thawing
rates are, in general, better for stability up to an optimum. Although faster
thawing rates help reduce processing times, very high thawing rates may
cause foaming and lead to surface-mediated protein denaturation.
b) Guidelines for bulk freeze-thaw process development
i.
ii.
iii.
The development approach for a large scale protein freeze-thaw process
can vary with the batch size, production demand and the drug value.
Methods may vary from using readily available containers such as
freezing bags, carboys and the like in a variety of freezers to using
custom-designed vessels with stand-alone freeze-thaw capabilities.
In all cases, the success of a freeze-thaw process is determined by testing
the product before freezing and after thawing, and comparing the results.
III. Formulation Process
1. Introduction
a) The purified form of the protein is usually stored in a buffer. This may or may
not have all the ingredients specified in the formulation.
b) The protein concentration at the end of the final purification step can also be
different, usually higher, form what is required for dosing the patient. Therefore
after the frozen and purified material is thawed, its concentration is adjusted and
the recommended excipients are added to it.
c) Addition of the recommended excipients at the right concentrations, and the
adjustment of protein concentration, pH and ionic strength constitute the process
of formulation.
d) Excipients are usually prepared in the form of one or more buffer solutions. If
the formulation process involves only a protein concentration adjustment, then the
required buffer, which will be dilution buffer in this case, will be identical to the
recommended formulation buffer.
e) If there are additional ingredients that need to be added, they can be prepared
in a dilute buffer at the recommended concentration or at a higher concentration
which will be subsequently diluted.
83
2. General Considerations
a) Although the process of formulation in a manufacturing scenario may appear
to be the simple addition of different ingredients, careful consideration of this step
is warranted because of the following:
i.
The labile nature of proteins.
ii. The large scale of the operation.
iii. The very high purity of the product at this stage.
b) The formulation process should be carefully designed by taking into account
the following:
i.
ii.
iii.
All possible concentrations, present and future, of the purified bulk and
the formulated bulk.
Process consistency.
Ease of operation at multiple manufacturing sites based on the site
capabilities.
c) Constituent buffers should be carefully determined so that the operation is
manufacturing-friendly and logistically simple.
d) Buffers should also be characterized so that appropriate tolerances are in place
for their specifications.
e) Buffer tolerances are established such that the process is practically feasible,
while yielding a product that is within established specifications for purity, safety
and efficacy.
f) Purity of each of the ingredients is ensured by carefully choosing the excipient
supplier.
i.
ii.
iii.
Trace impurities such as peroxides in polysorbate can lead to protein
oxidation.
Bovine-derived polysorbate or other excipients with a mammalian tissue
source are currently under scrutiny by regulatory agencies because of the
potential concerns for Transmissible Spongiform Encephalopathy (TSE).
Therefore the choice of raw material supplier can be critical.
g) The order of addition of excipients can also impact product quality, as in some
cases interim interactions between excipients may occur at concentrations higher
than their equilibrium concentrations in the post-mixed and formulated bulk.
3. Buffer Filtration
a) Buffers that are used in formulation operations are typically filtered using
depyrogenation membranes, e.g. posidyne filters, so that the buffers are pyrogen
free.
b) It may be necessary to flush the depyrogenation membranes to minimize filter
extractables leaching into the filtered solutions.
84
c) The size of filter membranes and the flushing procedures, including the
allowable flow rate, are established up front.
d) Prior to their use in formulation, the buffers are tested for endotoxin levels to
ensure that the levels are below the preset specification limits.
4. Mixing
a) Mixing speeds and times are critical during the mixing of purified protein bulk
and the formulation buffers.
b) Inadequate mixing can leave the solution heterogeneous while excessive mixing
can shear the protein. Both scenarios could lead to product failing specifications.
c) Mixing studies are performed with solutions whose solution and flow properties
match those of the actual product. Full-scale experiments can be performed or
small-scale experimental results can be scaled-up using modeling or empirical
correlations with appropriate equipment.
5. Additional Parameters
a) Other parameters to be considered in formulation operations include:
i.
Acid/base volumes required for pH adjustment.
ii. Processing temperatures.
iii. The amount of time active product can be held at each stage.
iv.
Method of liquid transfer within the plant.
v.
Product compatibility with product-contacting equipment, pumps and
tubing.
IV. Sterile Filtration
1. Filtration
a) Following formulation and QC testing of the bulk final product to ensure its
compliance with bulk product specifications, the active product is sterile-filtered
(while implementation of GMP during manufacturing will ensure that the product
carries a low microbial load, it will not be sterile at this stage):
i.
Use of 0.22 μm pore size membrane to ensure a product that is free of
bioburden.
ii. PVDF membranes are commonly used for this purpose.
b) Product compatibility with the specific filter membrane material is tested by
validation studies, prior to using the filter at a commercial manufacturing site.
c) Filter size recommendation is critical and it can be product specific.
i.
ii.
Too small a filter could prolong the filtration times and also lead to filter
clogging.
Too large a filter could have a large holdup volume which in turn leads to
greater product loss during filtration.
85
d) Other critical parameters that require careful consideration include:
i.
ii.
iii.
iv.
Allowable pressure drop across the filter.
The duration over which filtered formulated product can be held.
Temperature of operation.
The mode of liquid transfer during filtration.
e) Sterile filtration in most cases is performed at point-of-use, i.e. in-line, just
before filling.
f) All filters are integrity-tested prior to and after use, per established procedures.
g) The sterile product is temporarily housed in a sterile product-holding tank from
where it is aseptically filled into pre-sterilized final product containers which are
usually glass vials.
V. Filling
1. Preparation
a) Prior to filling, the vials are washed, sterilized (which will include
depyrogenation) and then cooled to room temperature.
b) All items of equipment, pipe-work, etc. with which the sterilized product comes
into direct contact must obviously themselves be sterile. Most such equipment
may be sterilized by autoclaving and be aseptically assembled prior to the filling
operation which is undertaken under Grade A laminar flow conditions.
c) Stoppers are washed, siliconized and sterilized.
i.
Pre-washed and pre-siliconized stoppers that are ready for sterilization
are also commercially available.
ii. Sterilization of the vials and stoppers may be achieved by autoclaving or
passage through special equipment which subjects the vials and stoppers
to a hot WFI rinse, followed by sterilizing dry heat and UV treatment.
d) Some of the critical attributes of siliconized stoppers are:
i.
ii.
iii.
iv.
v.
The type of silicone used.
Extent of siliconization.
The stopper composition.
The residual moisture of the stoppers.
Moisture permissibility of the stoppers.
e) Use of a lower viscosity silicone can sometimes lead to more particulation
compared with the use of a higher viscosity silicone.
f) Adequate siliconization ensures proper machinability of the stoppers on the fill
equipment.
g) Based on some recent findings of allergic reactions there is an increased trend
to use latex-free stoppers for pharmaceutical purposes.
86
h) Knowledge of the residual moisture content and the moisture-vapor
transmissibility are critical for lyophilized formulations where moisture transfer
from and through the stopper to the product can be a concern.
i) Also, the possibility of any deleterious interactions between the product and
any leachables from the vials/stoppers must be investigated.
2. Filling Process
a) Filling of protein pharmaceuticals is performed in a clean room of
appropriate classification (Class 100).
b) Most manufacturing facilities use automatic fill machines with multiple
needles.
c) Studies are conducted with the product to determine the fill-accuracy
capabilities of the fill equipment, and the amount of unrecoverable product,
i.e. holdup volume, from vials and disposable syringes. Based on these values,
a target fill-weigh and tolerances around that target are established. Automatic
fill machines typically have the capabilities to test periodically fill-weighs online.
d) The filling devices materials of construction must be compatible with the
product.
e) While it is necessary to keep the filling speeds as high as practically
achievable to maintain high throughput, very high filling speeds can lead to
foaming, which can lead to protein denaturation.
f) The maximum time the product can be held at room temperature during
filling is specified based on product stability data and recorded for ensuring
product stability.
g) After filling, the product container (vial) is either sealed, by an automated
aseptic sealing system, or freeze-dried first to yield a powder form of the
product, followed by sealing.
h) For some liquid dose products, the vial headspace is overlaid with nitrogen
gas to prevent product oxidation by the headspace oxygen.
CHAPTER 23 - HOLDING AND DISTRIBUTION
I. Introduction
a) This chapter 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.
87
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.
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.
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i.
ii.
Optimum conditions will vary with the product, but they should always
be such that there are not extremes in temperature, humidity or light.
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
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.
h) It is recommended, however, that a well-conceived procedure be prepared that
will allow for quick and well-coordinated actions during a recall or emergency
situation. The regulation requires that the distribution of a lot of pharmaceutical
product “can be readily determined”. The decision-making process should be set
forth and understood by all managers with a role to play. Frequently, recall
procedures are managed by a standing recall board and include the naming of a
recall coordinator at the time a decision to recall is made. They include contact
points such as FDA, other regulatory officials, the media, etc.
i) It is a good idea to test a company’s recall procedure periodically, although
not required by the regulations. Recalls, it is hoped, do not occur too frequently
and as personnel turn over familiarity with the plan tends to be lost. It is fairly
simple to develop a scenario that would allow role playing to take place every
year or two. Usually it is best to choose the company’s best selling product to
perform the test.
j) If a well-known or therapeutically significant drug must be recalled, it is likely
the media will pick up the story and demand additional information about the
hazard involved, the amount of product remaining in the marketplace, its location,
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etc. If a company is not prepared both to exercise proper responsibility and be
responsive to the media, the company’s and the product’s image with the public
and the medical profession could be harmed.
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