GMP, GLP,TQM, QA-QC, FDA

By
Dr. Vikram Kr. Yadav
GMP & GLP
Good manufacturing practices (GMP)
Good manufacturing practices (GMP) refer to guidelines laid down by agencies
which control authorization and licensing for manufacture and sale of food,
drug products , and active pharmaceutical products. These guidelines are
laid down with the intention of providing minimum requirements that a
pharmaceutical or a food product manufacturer must meet while
manufacturing drugs or food products ,which then assures that the products
manufactured/produced are of high quality and do not pose any risk to the
consumer or public. Good manufacturing practice guidelines provides
guidance for manufacturing, testing, and quality assurance in order to ensure
that drug product is safe for human consumption.
Many countries have legislated that pharmaceutical and medical device
manufacturer must follow GMP procedures, and have created their own
GMP guidelines that correspond with their legislation. Basic concepts of all of
these guidelines remain more or less similar to the ultimate goals of
safeguarding the health of patient as well as producing good quality
medicine, medical devices or active pharmaceutical products.
In the U.S.A a drug may be deemed adulterated even though it has passed all of the
specifications tests and it is found to be manufactured in a facility or condition which
violates or do not comply with current good manufacturing guideline. Therefore
complying with GMP is a mandatory aspect in pharmaceutical manufacturing.
Although there are a number of them, all guidelines follow a few basic principles:
• Hygiene: Pharmaceutical manufacturing facility must maintain a clean and hygienic
manufacturing area.
• Controlled environmental conditions in order to prevent cross contamination of drug
product from other drug or extraneous particulate matter which may render the
drug product unsafe for human consumption.
• Manufacturing processes are clearly defined and controlled. All critical processes are
validated to ensure consistency and compliance with specifications.
• Manufacturing processes are controlled, and any changes to the process are
evaluated. Changes that have an impact on the quality of the drug are validated as
necessary.
• Instructions and procedures are written in clear and unambiguous language. (
Good Documentation Practices)
• Operators are trained to carry out and document procedures.
• Records are made, manually or by instruments, during manufacture that
demonstrate that all the steps required by the defined procedures and
instructions were in fact taken and that the quantity and quality of the drug
was as expected. Deviations are investigated and documented.
• Records of manufacture (including distribution) that enable the complete
history of a batch to be traced are retained in a comprehensible and accessible
form.
• The distribution of the drugs minimizes any risk to their quality.
• A system is available for recalling any batch of drug from sale or supply.
• Complaints about marketed drugs are examined, the causes of quality defects
are investigated, and appropriate measures are taken with respect to the
defective drugs and to prevent recurrence.
GMP guidelines are not prescriptive instructions on how to manufacture
products. They are a series of general principles that must be observed during
manufacturing. When a company is setting up its quality program and
manufacturing process, there may be many ways it can fulfill GMP
requirements. It is the company's responsibility to determine the most
effective and efficient quality process.
Enforcement
Within the European Union, GMP inspections are performed by National
Regulatory Agencies (e.g., GMP inspections are performed in the United
Kingdom by the Medicines and Healthcare products Regulatory Agency
(MHRA)); in the Republic of Korea (South Korea) by the Korea Food & Drug
Administration (KFDA); in Australia by the Therapeutical Goods
Administration (TGA); in Bangladesh by the Drug Administration (DGDA); in
South Africa by the Medicines Control Council (MCC); in Brazil by the Agência
Nacional de Vigilância Sanitária (National Health Surveillance Agency Brazil)
(ANVISA); in Iran in India gmp inspections are carried out by state FDA and
these FDA report to Central Drugs Standard Control
Organization and Pakistan by the Ministry of Health;, Nigeria has NAFDAC
and by similar national organisations worldwide. Each of
the inspectorates carry out routine GMP inspections to ensure that drug
products are produced safely and correctly; additionally, many countries
perform pre-approval inspections (PAI) for GMP compliance prior to the
approval of a new drug for marketing.
Guidelines
• Building and Facilities. Check whether
– Buildings used in the manufacture or storage of cosmetics are of suitable
size, design and construction to permit unobstructed placement of
equipment, orderly storage of materials, sanitary operation, and proper
cleaning and maintenance.
– Floors, walls and ceilings are constructed of smooth, easily cleanable
surfaces and are kept clean and in good repair.
– Fixtures, ducts and pipes are installed in such a manner that drip or
condensate does not contaminate cosmetic materials, utensils, cosmetic
contact surfaces of equipment, or finished products in bulk.
– Lighting and ventilation are sufficient for the intended operation and
comfort of personnel.
– Water supply, washing and toilet facilities, floor drainage and sewage
system are adequate for sanitary operation and cleaning of facilities,
equipment and utensils, as well as to satisfy employee needs and facilitate
personal cleanliness.
Equipment. Check whether:
– Equipment and utensils used in processing, holding, transferring and filling are
of appropriate design, material and workmanship to prevent corrosion, buildup
of material, or adulteration with lubricants, dirt or sanitizing agent.
– Utensils, transfer piping and cosmetic contact surfaces of equipment are well-
maintained and clean and are sanitized at appropriate intervals.
– Cleaned and sanitized portable equipment and utensils are stored and located,
and cosmetic contact surfaces of equipment are covered, in a manner that
protects them from splash, dust or other contamination.
• Personnel. Check whether:
– The personnel supervising or performing the manufacture or control of
cosmetics has the education, training and/or experience to perform the
assigned functions.
– Persons coming into direct contact with cosmetic materials, finished products
in bulk or cosmetic contact surfaces, to the extent necessary to prevent
adulteration of cosmetic products, wear appropriate outer garments, gloves,
hair restraints etc., and maintain adequate personal cleanliness.
– Consumption of food or drink, or use of tobacco is restricted to appropriately
designated areas.
•
Raw Materials. Check whether:
– Raw materials and primary packaging materials are stored and handled in a
manner which prevents their mix-up, contamination with microorganisms or
other chemicals, or decomposition from exposure to excessive heat, cold,
sunlight or moisture.
– Containers of materials are closed, and bagged or boxed materials are stored
off the floor.
– Containers of materials are labeled with respect to identity, lot identification
and control status.
– Materials are sampled and tested or examined in conformance with procedures
assuring the absence of contamination with filth, microorganisms or other
extraneous substances to the extent necessary to prevent adulteration of
finished products. Pay particular attention to materials of animal or vegetable
origin and those used in the manufacture of cosmetics by cold processing
methods with respect to contamination with filth or microorganisms.
– Materials not meeting acceptance specifications are properly identified and
controlled to prevent their use in cosmetics.
•
Production. Check whether manufacturing and control have been established and
written instructions, i.e., formulations, processing, transfer and filling instructions,
in-process control methods etc., are being maintained. Determine whether such
procedures require that:
– The equipment for processing, transfer and filling the utensils, and the containers for
holding raw and bulk materials are clean, in good repair and in sanitary condition.
– Only approved materials are used.
– Samples are taken, as appropriate, during and/or after processing, transfer or filling for
testing for adequacy of mixing or other forms of processing, absence of hazardous
microorganisms or chemical contaminants, and compliance with any other acceptance
specification.
– Weighing and measuring of raw materials is checked by a second person, and containers
holding the materials are properly identified.
– Major equipment, transfer lines, containers and tanks are used for processing, filling or
holding cosmetics are identified to indicate contents, batch designation, control status
and other pertinent information.
– Labels are examined for identity before labeling operations to avoid mix-up.
– The equipment for processing, holding, transferring and filling of batch is labeled
regarding identity, batch identification and control status.
Laboratory Controls. Check whether:
– Raw materials, in-process samples and finished products are tested or
examined to verify their identity and determine their compliance with
specifications for physical and chemical properties, microbial
contamination, and hazardous or other unwanted chemical
contaminants.
– Reserve samples of approved lots or batches of raw materials and
finished products are retained for the specified time period, are stored
under conditions that protect them from contamination or
deterioration, and are retested for continued compliance with
established acceptance specifications.
– The water supply, particularly the water used as a cosmetic ingredient, is
tested regularly for conformance with chemical-analytical and
microbiological specifications.
– Fresh as well as retained samples of finished products are tested for
adequacy of preservation against microbial contamination which may
occur user reasonably foreseeable condition of storage and consumer
use.
Records. Check whether control records are maintained of:
– Raw materials and primary packaging materials, documenting
disposition of rejected materials.
– Manufacturing of batches, documenting the:
• Kinds, lots and quantities of material used.
• Processing, handling, transferring, holding and filling.
• Sampling, controlling, adjusting and reworking.
• Code marks of batches and finished products.
– Finished products, documenting sampling, individual laboratory
controls, test results and control status.
– Distribution, documenting initial interstate shipment, code marks
and consignees.
Labeling. Check whether the labels of the immediate and outer
container bear:
– On the principal display panel:
• In addition to the name of the product, the statements of identity and net contents,
• The statement "Warning--The safety of this product has not been determined" if the
safety of the respective product has not adequately been substantiated. Determine
whether and what toxicological and/or other testing the firm has conducted to
substantiate the safety of its products.
– On the information panel:
• The name and address of the firm manufacturing the product or introducing it into
interstate commerce.
• the list of ingredients (only on outer container) if intended for sale or customarily
sold to consumers for consumption at home.
• The warning statement(s) required at 21 CFR 740.11, 740.12 and 740.17.
• Any other warning statement necessary or appropriate to prevent a health hazard.
Determine the health hazard or their basis for a warning statement.
• Any direction for safe use of product.
•
Complaints. Check whether the firm maintains a consumer complaint
file and determine:
– The kind and severity of each reported injury and the body part involved.
– The product associated with each injury, including the manufacturer and code
number.
– The medical treatment involved, if any, including the name of the attending
physician..
– The name(s) and location(s) of any poison control center, government agency,
physician's group etc., to whom formula information and/or toxicity data are
provided.
 GMP Key elements
1. Quality assurance
2. Good manufacturing practices for pharmaceutical
products
3. Sanitation and hygiene
4. Qualification and validation
5. Complaints
6. Product recalls
7. Contract production and analysis
– General
– The contract giver
– The contract accepter
– The contract
8. Self-inspection and quality audits
– Items for self-inspection
– Self-inspection team
– Frequency of self-inspection
– Self-inspection report
– Follow-up action
– Quality audit
– Suppliers’ audits and approval
9. Personnel
– General
– Key personnel
10. Training
11. Personal hygiene
12. Premises
– General
– Ancillary areas
– Storage areas
– Weighing areas
– Production areas
– Quality control area
13. Equipment
14. Materials
– General
– Starting materials
– Packaging materials
– Intermediate and bulk products
– Finished products
– Rejected, recovered, reprocessed and reworked materials
– Recalled products
– Returned goods
– Reagents and culture media
– Reference standards
– Waste materials
– Miscellaneous
15. Documentation
– General
– Documents required:
• Labels
• Testing procedures
• Specifications for starting and packaging materials, for
intermediate and bulk products and for finished products
• Master formulae and Batch Processing Records
• Packaging instructions and Batch Packaging Records
• Standard Operating procedures (SOP's) and records
• Logbooks
16. Good practices in production
– General
– Prevention of cross-contamination and bacterial
contamination during production
– Processing operations
– Packaging operations
17. Good practices in quality control
– Control of starting materials and intermediate, bulk and
finished products
– Test requirements
– Batch record review
– Stability studies
Quality Control (QC) in Pharmaceutical Industry
 Quality Control (QC) in Pharmaceutical Industry

• QC is the part of GMP concerned with sampling, specifications

and testing and with the organization, documentation and
release procedures which ensure that the necessary and
relevant tests are actually carried out and the materials are
neither released for use, nor products are used for sale & supply
until their quality has been satisfactory.
• The 4 Main responsibilities of quality control in pharmaceutical
industry include :
– Efficacy
– Safety
– Quality
– Compliance
 STEPS IN QUALITY CONTROL

1. DEVISING THE CONTROL OVER RAW MATERIALS: • The quality of the finished
products is determined mostly by the quality of raw materials.
2. FIXING STANDARDS AND SPECIFICATIONS: • In order to make any scheme of
quality control successful, it is necessary to predetermine standards and
specifications.
3. EXERCISING CONTROL OVER PRODUCTION OPERATIONS: • In order to execute
efficient practices, the technical expert of the Quality Control Department
must investigate the operating methods.
4. LOCATING INSPECTION POINTS: • When the points at which defects occur are
wrongly located or located with delay, it hinders quality control. Hence there
should first be inspection of raw material at vendors place, then at
company’s plant then at various stages during process.
5. MAINTAINING QUALITY OF EQUIPMENTS: • The final quality of the products is
conditioned by the quality of the equipment and other devices used.
6. MAINTAINING RECORDS: • The QC department is responsible for setting
records related to quality inspection and control and the number rejected 
ADVANTAGES OF QUALITY CONTROL
1) Improvement of the quality of production and reduction in the production
cost.
2) Uniformity in the production and supply of standard quality goods to
consumers.
3) Offering full return of the price paid by the consumers and giving
convenience and satisfaction to consumers .
4) Reduction in spoiled production and rejection from consumers and dealers.
5) Promotion of exports due to superior and standard quality production.
6) Reduction in inspection cost.
7) Making products popular in market.
TOTAL QUALITY MAANGEMENT (TQM)
 TOTAL QUALITY MAANGEMENT (TQM)
According to John Gilbert, Total Quality Management is "A process
designed to focus on customer expectations, preventing
problems, building commitment to quality in the workforce and
promoting open decision-making.“
PRINCIPLES OF TQM
– Stress on quality management
– Continuous process
– Stress on quality assurance system
– Linkage of quality and productivity
– TQM is a gradual process
– Focus on customers
– Employee involvement
– Formation of quality improvement teams
– Management's involvement 
ADVANTAGES OF TQM
– Customer satisfaction
– Quality improvement
– Absence of additional investment
– Raises competitiveness
– Facilitates expansion and diversification
– Provides trained and motivated employees
– Miscellaneous Advantages
• (a) Long-term consumer support,
• (b) Prestigious position in international marketing,
• (c) High standard of living to employees, and
• (d) Cost control.
Quality assurance
 Quality assurance
In the pharmaceutical industry, quality assurance (QA) is essential
for ensuring that pharmaceutical products are manufactured to
a safe and consistent standard.
QA is a very broad field that refers to any aspect that may affect a
drug’s quality during its research, development, manufacturing,
and sales phases.
It is the totality of the arrangements made with the object of
ensuring that pharmaceutical products are of the quality
required for their intended use.
QA is the heart and soul of quality control
QA = QC + GMP /Other Quality Systems
QA = GLP (QC) + GMP (Mfg)
CAPA-Corrective Action Preventive Action, APR-Annual Product Review, APQR-Annual
Product Quality Review, OOS-out of specification
Job Profile of QA Experts:
• Preparing and implementing quality assurance policies and
procedures.
• Performing routine inspections and quality tests.
• Identifying and resolving workflow and production issues.
• Ensuring that standards and safety regulations are observed.
• Addressing and discussing issues and proposed solutions with
superiors.
• Documenting quality assurance activities and creating audit
reports.
• Making recommendations for improvement.
• Creating training materials and operating manuals.
ROLE OF FDA IN DRUG DEVELOPMENT
• The Food and Drug Administration (FDA) is a regulatory agency
within the Department of Health and Human Services
• A key responsibility is to regulate the safety and effectiveness
of drugs
• FDA divides that responsibility into two phases: preapproval
(premarket) and postapproval (postmarket). It reviews
manufacturers’ applications to market drugs in the United States; a
drug may not be sold unless it has FDA approval.
• The FDA oversees the NDA process. It mainly focuses on the
disclosure of the ingredients and formulation ,assay methods
manufacuring processes and all animal and human testing
• Amendments were made in 1962 which focused on both saftey and
efficacy of new drug products prior to approval and requires
investigstor to file Investigational New Drug Application(INDs)
prior to testing new drugs in humans.
• The Food and Drug Administration (FDA) is a regulatory agency
within the Department of Health and Human Services
• A key responsibility is to regulate the safety and effectiveness of
drugs
• FDA divides that responsibility into two phases: preapproval
(premarket) and postapproval (postmarket). It reviews
manufacturers’ applications to market drugs in the United States; a
drug may not be sold unless it has FDA approval.
• The FDA oversees the NDA process. It mainly focuses on the
disclosure of the ingredients and formulation ,assay methods
manufacuring processes and all animal and human testing
• Amendments were made in 1962 which focused on both saftey and
efficacy of new drug products prior to approval and requires
investigstor to file Investigational New Drug Application(INDs)
prior to testing new drugs in humans.
 Why Are Drugs Evaluated By The FDA?
• Drugs intended for human use are evaluated by FDA’s Center
for Drug Evaluation and Research (CDER) to ensure that drugs
marketed in the United States are safe and effective. Biological
products are evaluated by FDA’s Center for Biologics Evaluation
and Research.

• To ensure drug safety and efficacy.

 Why Are Drugs Evaluated By The FDA?
• Drugs intended for human use are evaluated by FDA’s Center
for Drug Evaluation and Research (CDER) to ensure that drugs
marketed in the United States are safe and effective. Biological
products are evaluated by FDA’s Center for Biologics Evaluation
and Research.
Does FDA Test Drugs?
•  No. It is the responsibility of the company seeking approval
to market a drug to conduct laboratory and animal tests on
the safety and effectiveness of a proposed new drug and
then to submit that information to FDA for review by CDER
physicians, statisticians, chemists, pharmacologists, and
other scientist.
• Investigational New Drug Application (IND)--The
pharmaceutical industry sometimes seeks advice
from the FDA prior to submission of an IND.
• Sponsors--companies, research institutions, and
other organizations that take responsibility for
developing a drug. They must show the FDA
results of preclinical testing in laboratory animals
and what they propose to do for human testing.
At this stage, the FDA decides whether it is
reasonably safe for the company to move forward
with testing the drug in humans.
• Clinical Trials--Drug studies in humans can begin only
after an IND is reviewed by the FDA and a local
institutional review board (IRB). The board is a panel
of scientists and non-scientists in hospitals and
research institutions that oversees clinical research. 
• IRBs approve the clinical trial protocols, which
describe the type of people who may participate in
the clinical trial, the schedule of tests and
procedures, the medications and dosages to be
studied, the length of the study, the study's
objectives, and other details.
• IRBs make sure the study is acceptable, that
participants have given consent and are fully
informed of their risks, and that researchers take
appropriate steps to protect patients from harm.
• Phase 1 studies are usually conducted in healthy
volunteers. The goal here is to determine what
the drug's most frequent side effects are and,
often, how the drug is metabolized and excreted.
The number of subjects typically ranges from 20
to 80.
• Phase 2 studies begin if Phase 1 studies don't
reveal unacceptable toxicity. While the emphasis
in Phase 1 is on safety, the emphasis in Phase 2 is
on effectiveness. This phase aims to obtain
preliminary data on whether the drug works in
people who have a certain disease or condition.
• For controlled trials, patients receiving the drug
are compared with similar patients receiving a
different treatment--usually an inactive substance
(placebo), or a different drug. Safety continues to
be evaluated, and short-term side effects are
studied. Typically, the number of subjects in Phase
2 studies ranges from a few dozen to about 300.
• At the end of Phase 2, the FDA and sponsors try to
come to an agreement on how large-scale studies
in Phase 3 should be done. How often the FDA
meets with a sponsor varies, but this is one of two
most common meeting points prior to submission
of a new drug application.
• The other most common time is pre-NDA--right
before a new drug application is submitted.
• Phase 3 studies begin if evidence of effectiveness is
shown in Phase 2. These studies gather more
information about safety and effectiveness,
studying different populations and different
dosages and using the drug in combination with
other drugs.
• The number of subjects usually ranges from several
hundred to about 3,000 people.
• Postmarket requirement and commitment
studies are required of or agreed to by a sponsor,
and are conducted after the FDA has approved a
product for marketing.
• The FDA uses postmarket requirement and
commitment studies to gather additional
information about a product's safety, efficacy, or
optimal use.
• New Drug Application (NDA)--This is the formal step a drug
sponsor takes to ask that the FDA consider approving a new
drug for marketing in the United States.
• An NDA includes all animal and human data and analyses of
the data, as well as information about how the drug behaves
in the body and how it is manufactured.
• When an NDA comes in, the FDA has 60 days to
decide whether to file it so that it can be reviewed.
The FDA can refuse to file an application that is
incomplete. For example, some required studies
may be missing.
• In accordance with the Prescription Drug User Fee
Act (PDUFA), the FDA's Center for Drug Evaluation
and Research (CDER) expects to review and act on
at least 90 percent of NDAs for standard drugs no
later than 10 months after the applications are
received. The review goal is six months for priority
drugs.
 Drug Review Steps Simplified

• Preclinical (animal) testing.

• An investigational new drug application (IND) outlines what the sponsor of a new drug proposes
for human testing in clinical trials.
• Phase 1 studies (typically involve 20 to 80 people).
• Phase 2 studies (typically involve a few dozen to about 300 people).
• Phase 3 studies (typically involve several hundred to about 3,000 people).
• The pre-NDA period, just before a new drug application (NDA) is submitted. A common time for
the FDA and drug sponsors to meet.
• Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval.
• After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed.
• If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor's research on the
drug's safety and effectiveness.
• The FDA reviews information that goes on a drug's professional labeling (information on how to
use the drug).
• The FDA inspects the facilities where the drug will be manufactured as part of the approval
process.
• FDA reviewers will approve the application or issue a complete response letter.
 Quality Control in Pharmaceutical Industry

• Qc is the part of GMP concerned with sampling, specifications and testing and with
the organization, documentation and release procedures which ensure that the
necessary and relevant tests are actually carried out and the materials are neither
released for use, nor products are used for sale & supply until their quality has been
satisfactory.