Good Manufacturing Practices, CFR, USFDA,

1. Definition:
• It is that part of Quality Assurance which ensures that Medicinal products are
consistently produced and controlled to the quality standards appropriate to their
intended use and as required by the marketing authorization or product
specification.
or
• Good Manufacturing Practice (GMP) is a set of regulations, codes, and
guidelines for the manufacture of drug substances and drug products, medical
devices, in vivo and in vitro diagnostic products, and foods.
• GMPs comprise a set of practices that ensure quality at every level of operation in
an industry.
• CDSCO: (Central Drugs Standard Control Organization) Comes in Schedule M
in Drug & Cosmetic Act 1940 & Rules 1945. Implemented in 1988.
• GMP are used by pharmaceuticals, medical devices and food manufacturers.

2. Chronological development of GMP
• 1962: The “Thalidomide Tragedy” leads the US Congress to add GMP to the Food,
Drugs and Cosmetic Act. The FDA publishes their first Regulation on Good
Manufacturing Practices” – A drug which is not made following GMP is adulterated
(Contaminated)
• 1969: The World Health Organization publishes the first universal guideline “Basic
Rules for the Manufacture of Pharmaceuticals and the Assurance of their Quality”
• 1978: cGMPs Final Rules for Drugs (21 CFR Parts 210–211)
• 1987: Guideline on General Principles of Process Validation
• 1989: FDA discovers mis-management and even fraud in the applications by US
generic drug manufacturers in trying to get approval for the sale of their products. This
leads to PRE-APPROVAL INSPECTIONS (PAIs)
• 1991: FDA publishes their “Guide to the Inspection of Bulk Pharmaceuticals” which
strongly influences the way in which Starting Materials for pharmaceuticals are
produced.
• 1998: “GMPs for Starting Materials” is added to the ICH work programme to be
decided by an Expert Working Group.
• 2001: ICH Q7A API Guidance ICH’s “Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients (APIs)”

3. Major GMP regulation agencies
S.No Country Agency Product Inspected
1 United States Food & Durg
Administration (Code of
Federal Regulations)
Bulk Pharmaceutical Chemicals,
Finished Pharmaceuticals
2 Canada Health Canada Finished Pharmaceuticals, Active
Pharmaceutical Ingredients
3 Brazil (National Agency for
Sanitary Surveillance,
ANVISA)
Finished Pharmaceuticals
4 Australia Therapeutic Goods
Administrations, TGA
Finished Pharmaceuticals, Active
Pharmaceutical Ingredients
5 United Kingdom Medicine and Healthcare
Products Regulatory
Agency, MHRA
Finished Pharmaceuticals
6 Germany Ministry of Health, Labour
and Welfare
Finished Pharmaceuticals, Active
Pharmaceutical Ingredients
7 South Africa Medicines Control Council Finished Pharmaceuticals

4. WHO guidelines
 WHO has published a handbook on the GMP in particular, entitled: Quality assurance of pharmaceuticals, a
compendium of guidelines and related materials, Volume 2: Good manufacturing practices and inspection
 It consists of 4 chapters:
Chapter 1: WHO GMP: main principles for pharmaceutical products
Chapter 2: Good manufacturing practices: starting materials
Chapter 3: Good manufacturing practices: specific pharmaceutical products
Chapter 4: Inspection
 And 7 annexes:
Annex 3: Radiopharmaceutical products
Annex 4: Good Manufacturing Practices for pharmaceutical products: main principles
Annex 5: Model Certificate of GMP
Annex 6: Sterile pharmaceutical products
Annex 7: Guidance on GMP inspection
Annex 8: Pre-approval inspection
Annex 9: Quality system requirements for national GMP inspectorates

5. FDA guidelines
 US FDA guideline for finished pharmaceutical product is given under 21 CFR
part 210 and 211.
 CFR: This is the code of federal regulations. Total : 50
21 CFR: Food and Drug.
 Parts: There are parts in every CFR.
210: Current good manufacturing practices for manufacture, processing,
packing, or holding of a drug
211: Current good manufacturing practices for Finished
Pharmaceuticals.
 The CGMP regulations for drugs contain minimum requirements for the
methods, facilities, and controls used in manufacturing, processing, controlling
and packing of a drug product. The cGMP is mainly covered in subparts A to K.

6. Sub-Parts in GMP
Subpart A: General Provisions
Subpart B: Organization & personnel
Subpart C: Buildings & facilities
Subpart D: Equipment
Subpart E: Control of components & drug product & closures.
Subpart F: Production & process control
Subpart G: Packaging & labelling control
Subpart H: Holding & distribution
Subpart I: Laboratory controls
Subpart J: Records & reports
Subpart K: Returned & salvaged drug products.

7. A. General provisions :
 The regulation in this part contain the minimum cGMP for preparation of drug
products for administration to humans or animals.
B. Organization & personnel:
 The establishment and maintenance of a satisfactory system of quality assurance
and the correct manufacture of quality products relies upon people.
 For this reason there must be sufficient qualified personnel to carry out all the tasks
which are the responsibility of the manufacturer.
Minimum requirements:
a). The manufacturer should have an adequate number of personnel with the necessary
qualifications and practical experience.

8. b). Key Personnel includes the head of Production, the head of Quality Control, the
head of engineering.
c). The manufacturer should provide training for all the personnel.
d). Personnel working in areas where contamination is a hazard, e.g. clean areas or
areas where highly active, toxic, infectious or sensitizing materials are handled,
should be given specific training.
e). Detailed hygiene programmes, should be established and adapted to the different
needs within the factory. They should include procedures relating to the health,
hygiene practices and clothing of personnel.
f). All personnel should receive medical examination upon recruitment.

9. C. Building & facilities:
a). Premises should be carefully maintained, ensuring that repair and maintenance
operations do not present any hazard to the quality of products.
b). Lighting, temperature, humidity and ventilation should be appropriate and such
that they do not adversely affect, directly or indirectly, either the medicinal
products during their manufacture and storage, or the accurate functioning of
equipment.
c). Premises should be designed and equipped so as to afford maximum protection
against the entry of insects or other animals.
d). Steps should be taken in order to prevent the entry of unauthorized people.
e). Interior surfaces (walls, floors and ceilings) should be smooth, free from cracks
and open joints, and should not shed particulate matter and should permit easy
and effective cleaning and, if necessary, disinfection.

10. f). Pipe work, light fittings, ventilation points and other services should be designed
and sited to avoid the creation of recesses which are difficult to clean.
g). Weighing of starting materials usually should be carried out in a separate weighing
room designed for that use.
h). Storage areas should be of sufficient capacity to allow orderly storage of the
various categories of materials and products: starting and packaging materials,
intermediate, bulk and finished products, products in quarantine, released, rejected,
returned or recalled.
i) Segregated areas should be provided for the storage of rejected, recalled or returned
materials or products.

11. I). Premises:
 Premises must be located, designed, constructed, adapted and maintained to suit
the operations to be carried out.
 Their layout and design must aim to minimize the risk of errors and permit
effective cleaning and maintenance in order to avoid cross-contamination, build
up of dust or dirt and, in general, any adverse effect on the quality of products.
II). Design & construction features:
 Building shall have adequate space for orderly placement of equipment &
materials to prevent mix-up.
 It should be designed in such a way to facilitate cleaning, maintenance &
proper operation.
 Floors, wall, ceiling surface should be easily cleanable. Temperature &
humidity control should be provided.

12. III). Lightning:
 Adequate lightning shall be provided in all areas.
IV). Ventilation, Air-filtration:
 Air ventilation shall be provided. Equipment for control over pressure,
microorganism, dust, humidity & temperature shall be provided.
V). Plumbing:
 Potable water shall be supplied. Drains shall be of adequate size and preventive
measures should be taken to prevent back- siphonage.
VI). Sewage & refuse:
 sewage trash & other refused material from building & intermediate premises
shall be disposed off in a safe & sanitary manner.

13. VII). Washing & toilet facilities:
 Adequate washing facilities shall be provided, including hot and cold
water, soap or detergent, air drier, towel and clean toilet facilities easily
accessible to working area.
VIII). Sanitation:
 Any building used in manufacturing, 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 & other vermin.
IX). Maintenance:
 Building shall be maintained in a good state of repair.

14. D. Equipment
• Equipment must be located, designed, constructed, adapted and maintained to suit
the operations to be carried out.
• Their layout and design must aim to minimize the risk of errors and permit
effective cleaning and maintenance in order to avoid cross-contamination, build
up of dust or dirt.
I). Equipment design, size & location:
Equipment used in manufacturing, processing, packing or holding of a drug product
shall be of appropriate design, adequate size and easily cleanable.

15. II). Equipment Construction:
• Equipment shall be constructed such that surface that contact components,
materials shall not be reactive.
III). Equipment Cleaning & maintenance:
• Equipment & utensils shall be cleaned, maintained & sanitized at appropriate
intervals to prevent contamination that would alter safety, identity, strength &
quality of drug product.

16. E. Control of components & drug product containers &
closure
• There shall be written procedures describing insufficient detail of receipt,
identification, storage, handling, sampling, testing and approval or rejection of
components and drug product containers & closures.
• It shall not be reactive, additive or absorptive so as to alter the safety, identity,
strength, quality or purity of drug.
• They shall provide adequate protection against environmental hazards.
• They shall be clean & sterilized.

17. F. Production & process control
Written procedure:
• There shall be written procedure for production & process control designed to
assure that the drug products have the identity, strength, quality and purity they
are represented to possess.
• To assure the batch uniformity & integrity of drug products, written procedures
have to be established to monitor the output & to validate the performance of
manufacturing process responsible for causing variability.

18. G. Packaging & labelling control
• Labelling and packaging materials shall be representatively sampled & examined
or tested upon receipt and before use in packaging or labeling of drug product.
• Records shall be maintained for each shipment.
• Packaged & labelled products have to be examined during finishing operations to
provide assurance that containers & packages in the lot have the correct label.
• Label should bear an expiry date determined by appropriate stability testing
method.

19. H. Holding & Distribution
Warehouse Procedure include: Storage of drug product under appropriate
conditions of temperature, humidity & light so that the identity, purity of drug
products are not affected.
I. Laboratory Control
• Laboratory control shall include appropriate specifications, standards, sampling
plans and test procedures designed to assure that components, drug product
containers, closures, in-process materials conform to appropriate standards of
identity, strength, quality & purity.

20. J. Records & Reports
Any production, control or distribution record that is required to be maintained
& shall be retained for at least 1 year after the expiration of the batch. (For OTC
drugs= 3 yrs)
K. Returned & Salvaged drug product
Returned drug products:
– Returned drug products shall be identified as such and held.
– Returned product shall be destroyed unless examination, testing or other
investigations prove the drug product meets appropriate standards of safety,
identity, strength, quality or purity.

21. Indian GMP
SCHEDULE M
PART 1
GOOD MANUFACTURING
PRACTICES FOR PREMISES
AND MATERIALS.
PART I-A
STERILE PRODUCTS,
PARENTERAL
PREPARATIONS
PART I-B
ORAL SOLID DOSAGE
FORMS
PART I-C
ORAL LIQUIDS
PART I-D
TOPICAL PRODUCTS i.e.
EXTERNAL PREPARATIONS
PART I-E
METERED-DOSE-
INHALERS
PART I-F
ACTIVE PHARMACEUTIAL
INGREDIENTS
(BULK DRUGS).
PART- II
REQUIREMENTS OF PLANT
AND EQUIPMENT
• SCHEDUE M-I: Requirements of factory premises for manufacture of Homoeopathic
preparations
• SCHEDULE M-II: Requirement of factory premises for manufacture of cosmetics
• SCHEDULE M-III: Requirements of factory premises for manufacture of medical
devices

22. General practices recently applied in the pharmaceutical
Industry
 Quality risk management
 Quality by design
 Corrective action and preventive actions
 Process capability analysis
 Six Sigma
 Process analytical technologies
 Lean manufacturing
 Total quality management
 ISO series
 HACCP

23. General practices recently applied in the pharmaceutical
Industry
 Quality risk management
• Quality Risk Management is defined as a method for the assessment, control,
communication and review of risks to the quality of the drug (medicinal) product
through the product lifecycle where decisions can occur at any point in the
process (ICH Q9 2003).
• In the guideline entitled Medical Device Use-Safety: Incorporating Human
Factors Engineering into Risk Management; it clarifies how hazards related to
medical device use should be directed during device development as part of the
risk management process.

24. General practices recently applied in the pharmaceutical
Industry
 Quality by design
• ICH Q8 defines design space from the concept that quality cannot be tested into
product but has to be built in by design (ICH Q8 2003).
• Design space is presented by the applicant and is subject to regulatory
assessment and approval.
• The design and conduct of pharmaceutical development research should be
consistent with their intended scientific purpose.

25. General practices recently applied in the pharmaceutical
Industry
 Corrective action and preventive actions
• The organization should focus on correcting and preventing problems.
Preventing problems is generally cheaper than fixing them after they occur.
• “Root cause analysis” is a process by which the manufacturer can identify
causes and preventive actions.
• In general, CAPA experts recommend that root-cause investigations follow a
four-step process
• Identify the problem.
• Evaluate its magnitude, which includes assessing risk.
• Investigate and assign responsibility.
• Analyze and document the root cause of the problem.

26. General practices recently applied in the pharmaceutical
Industry
 Process capability analysis
• Process capability is the comparison of the “Voice of the Customer” (VOC) with
the “Voice of the Process” (VOP).
• VOC, which is built on customer requirements, is defined by the specification
limits of the process, which are fixed, while VOP is defined by control limits,
which are based on performance data and vary over time.
• Metrics such as capability index namely Cp & Cpk were developed several years
ago to calculate this comparison between control and specification limits.

27. General practices recently applied in the pharmaceutical
Industry
 Six Sigma
• A business process that enables companies to increase profits dramatically by
streamlining operations, improving quality, and eliminating defects or mistakes
in everything a company does.
• The DMAIC model is the generic model of six sigma methodology. It is an
acronym that stands for; Define, Measure, Analyze, Improve and Control.
• An example of the pharmaceutical firms that adopted the methodology of Six
Sigma is AstraZeneca where the operations and quality staff were trained to
apply DMAIC principles every day, to measure and improve performance
through cross-functional “continuous improvement”.

28. General practices recently applied in the pharmaceutical
Industry
 Process analytical technologies
• plays a key role in enabling “quality by design” and scientific aspect of
manufacturing.
• PAT main aim is to understand and control the manufacturing process through
the application of integrated chemical, physical, microbiological, mathematical
and risk analysis methods.
• The benefits are lower production cycle times, improved manufacturing
efficiency, reduced rejects and increased production operating time.

29. General practices recently applied in the pharmaceutical
Industry
 Lean manufacturing
• Japanese manufacturers re-building after the Second World War were facing
declining human, material, and financial resources. These circumstances led to
the development of new, lower cost, manufacturing practices.
• Early Japanese leaders developed a disciplined, process-focused production
system now known as the "Toyota Production System", or "lean production.“
• The objective of this system was to minimize the consumption of resources that
added no value to a product.

30. General practices recently applied in the pharmaceutical
Industry
 Total quality management
• It is a philosophy that stresses a systematic, integrated, and consistent
perspective that would involve everyone and everything in the organization.
• It is a management philosophy that builds a customer driven, learning
organization that is devoted to total customer satisfaction through continuous
improvement in the effectiveness and efficiency of the organization and its
corresponding processes.
• It is widely known for improving quality and other performances such as
productivity, profit, market share, and competitive edge of organizations of
various types.

31. General practices recently applied in the pharmaceutical
Industry
 ISO series
• ISO 9000 is concerned with "quality management". This means what the
organization does to increase customer satisfaction through meeting customer
and regulatory requirements and continually improving its performance.
• ISO 14000 is an environmental management system, describes the requirements
for an organization's environmental management system and can be used for
certification/registration and/or self declaration of an organization's
environmental management system.
• ISO 17025 gives the general requirements for the competence of testing and
calibration laboratories.

32. General practices recently applied in the pharmaceutical
Industry
 HACCP
• The Hazard Analysis and Critical Control Point (HACCP) methodology is a safety
management system used in the food industry.
• Their main aim is to prevent known hazards and to reduce the risks that they will
cause at specific points in the food chain.
• The HACCP system is based on seven principles (Annex 7; WHO TRS no 908,
2003):
• Conduct a hazard analysis.
• Determine the critical control points (CCPs).
• Establish target levels and critical limit(s).
• Establish a system to monitor the CCPs.
• Establish the corrective action to be taken when monitoring indicates that a
particular CCP is not under control.
• Establish procedures to verify that the HACCP system is working effectively.
• Establish documentation concerning all procedures and keep records
appropriate to these principles and their application.

33. References:
1) United States- http://www.fda.gov/opacom/morechoices/industry/guidedc.htm
2) International Conference of Harmonization -http://www.ich.org
3) Indian GMP- https://isoindia.org/iso_GMP_Certification_in_India.php