Lecture

2 - Current
Good Manufacturing Prac5ces

cGMP Basic Requirements

Quality System
Deni5ons
Regula5ons
Requirements

Quality Management System

QMS
Management Responsibility,
Resource Management,
Product Realiza5on,
Measurement,
Analysis and Improvement

Input
Raw Materials
Energy
Costomer Requirement

PROCESS

Output

Plan-Do-Check-Act
PLAN
-Dene the systems
-- Assess current situa5on
- Analyze causes
ACT
- Standardize improvements
-Plan con5nuous
improvement

DO
-- Try out system or
improve theory

CHECK
- Study the system or
results

QMS and cGMP in Biopharmaceu5cal Co.

Senior Management Responsibility
- Quality

- Safety

- Ecacy

To archive the quality objec5ves, a well-establish and

documented system of Quality assurance (QA)
incorpora5ng Good Manufacturing Prac5ce (GMP) should
be followed)

Quality Assurance and Quality Control

QA

Is dened as the sum total of organized

arrangements made with the objec5ve of
ensuring that the products are of quality
required for their intended use.

QC

It is the part of GMP which is concerned

with sampling, specica5ons, tes5ng,
documenta5on and release which ensures
that necessary and relevant tests are
carried out and that materials/products
are released For use/ sale only aZer their
quality is judged to be sa5sfactory.

What QA systems should includes?

1.

GMP and GLP are taken into account during designing and developing
products.
2. All produc5on and control opera5ons are clearly specied and
documented.
3. Key personnel responsibili5es are clearly dened.
4. All arrangements for procurement and use of correct star5ng materials
and packaging materials are made.
5. In process checks and valida5ons are carried out in a dened manner.
6. The nal product is manufactured, packed and checked as per dened
procedures.
7. Regulatory aspects and internal requirements for the nal product are
fullled.
8. Storage, handling and distribu5on procedures for the nal product are
followed to ensure maintenance of quality throughout shelf life.
9. Self-inspec5on procedures are dened to regularly monitor the
eec5veness of the quality assurance system.
10. Correc5ve ac5ons
11. Sta5s5cal process control

What QC systems should includes?

1.

Appropriate procedures, training personnel and adequate facili5es for sampling,

inspec5on and tes5ng of star5ng materials, intermediate, bulk and nished
products.

2.

Validated test methods

3.

Maintenance of records to demonstrate that all procedures have been carried

out.

4.

Cer5ca5on of star5ng materials to be of specied quality and purity, and their

storage and adequate labeling before use in nal product.

5.

Release of batch of product ONLY aZer cer5ca5on by qualied person that it

meet required criteria or specica5ons.

6.

Maintain sucient samples of star5ng materials and nal product for future
examina5on, if necessary.

7.

Recording and inves5ga5on of out of specica5on results, changes, incidents

and devia5ons.

cGMP Guidelines for Biopharmaceu5cals

1. All manufacturing process are clearly dened, systema5cally
reviewed in the light of experience, and shown to be capable of
consistently manufacturing biopharmaceu5cal products of the
required quality and specica5ons.
2. All steps of manufacturing processes and any signicant changes
made to the process are validated.
3. All necessary facili5es are provided, including:

Appropriate qualied and trained personnel

Adequate premises and space
Suitable equipment and services
Correct materials, containers and labels
Approved procedures and instruc5ons
Suitable storage and transport
Adequate personnel, laboratories and equipment for in-process
control under the responsibility of the produc5on management.

cGMP Guidelines for Biopharmaceu5cals (cont)

4.

Instruc5ons and procedures are wrijen in clear language, specically applicable to

the facili5es provided.

5.

Operators are trained to carry out procedures correctly

6.

Records are made (Manually, with signature or recording instruments) during

manufacturing to show that all steps required by the dened procedures have been
taken and the expected quan5ty and quality were reached. Any signicant devia5ons
are fully recorded and inves5gated.

7.

Records covering manufacturing and distribu5on, which enable the complete history
of a batch to be traced, are retained in a comprehensible form.

8.

Proper storage and distribu5on of the products minimized any risk to their quality

9.

A system is available to recall any batch or product from sale or supply

10. Complains about marketed products are examined, the causes of quality defects
inves5gated, and appropriate measurements taken in respect of the defec5ve
product(s) and to prevent recurrence.

Informa(on and material ow in pharmaceu(cal/ biopharmaceu(cal

produc(on process

The cGMP Regula5ons

cGMP for nised Pharmaceu5cals
21 CFR 210, 211
First issued: June 1963
Current = Dynamic roles (standarsd evolve over 5me)
www.fda.gov/cder/dmpq

Examples of cGMP codes (FDA)

Building, Facili5es, Equipments (21 CFR 211.42-72)

Equipment Iden5ca5on (21 CFR 211.105)

Equipment cleaning and use (21 CFR 211.182)

Electronic records, electronic signature (21 CFR Part 11)

Process valida5on (General code of FDA process
valida5on)

Rubber ar5cles for repeated use (21 CFR 177.2600)

Buildings and Facili5es

211.42 Design and Construc5on features

a) Any building or buildings used in the manufacture,

processing, packing or holding of drug product shall
be of suitable size, construc5on and loca5on to
facili5es cleaning, maintenance, and proper
opera5on

External Environment and Internal Environment

Site prepara5on and Plant design

v Site arrangement and over-all layout design (green spaces parking, trac,
recrea5on area, tanks, site u5li5es, etc..)
v Water supply and waste management area (waste contractor!!)
v Site security and access (fences, guard, cameras, etc..)
v U5li5es design, layout, backup (cri5cal u5li5es backup)
v Equipment-design, layout, spares, capacity
v Safety (personnel and equipment), emergency services access.
v External architecture should take in account the local environment
(temperature, humidity, wind, etc..)
v Ease of maintenance (service ducts, cat oor, etc..)
v Project management (managers, consultants, etc..)
v Valida5on Plans and an eec5ve change control procedures. Provision of
design and (as builds) drawing.
v Contractor (Experienced contractor)

 211.42 Design and Construc(on features

b) Any such building shall have adequate space for the

orderly placement of equipment, drug product
containers, closures, labeling, in-process materials,
or drug products, and to prevent contamina5on. The
ow of components, drug product containers,
closures, labeling, in-process materials, and drug
products through the buildings shall be designed to
prevent contamina5on.

211.42 Design and Construc(on features

c) Opera5ons shall be performed within specically dened areas
of adequate size. There shall be separate or dened areas or
other such control systems for the rms opera5ons as are
necessary to prevent contamina5on or mix-ups during the
course of the following procedures:
1.

2.
3.
4.
5.
6.
7.
8.
9.

Receipt, iden5ca5on, storage and with folding from use of components, drug
product containers, closures and labeling, pending the appropriate sampling,
tes5ng, or examina5on by quality control unit before release for manufacturing
or packaging.
Holding rejected components, drug product containers, closures and labeling
before dispersion.
Storage of released components, drug product containers, closures and labeling
Storage of in-process materials
Manufacturing and processing opera5ons
Packaging and labeling opera5ons
Quaran5ne storage before release of drug products
Storage of drug products aZer release
Control and laboratory opera5on

211.42 Design and Construc(on features

Part (c) cont
10.Asep5c processing, which include as appropriate:
i.
ii.
iii.
iv.
v.
vi.

Floors, walls, and ceilings of smooth, hard surfaces the

easily cleanable
Temperature and humidity controls
An air supply ltered through high-eciency par5cular air
lters under posi5ve pressure, regardless of whether ow
is laminar or non-laminar
A system for monitoring environmental condi5ons
A system for cleaning and disinfec5ng the room and
equipment to produce asep5c condi5ons
A system for maintaining any equipment used to control
the asep5c condi5ons.

Construc5on Materials
walls
Floors
Ceilings

Provide ordinary movement of materials and personnel

Provide acceptable noise level during opera5on
Smooth surface, cleanable, non-porous
Flush without any projec5ons
Usually made of epoxy, enamel or prefabricated smooth materials
(rounded oor to wall junc5on)
Durable, cleanable, acid/base resistance, non-porous, smooth
Usually made of epoxy materials. Subsurface nish!!
Ceramic and vinyl 5les are not recommended

Smooth nish surface

All ceiling xtures (light, qng, air outlets and returns, etc..) should designed to
ensure ease cleaning and to minimize dust accumula5on
Cat-oor in the produc5on area is essen5al for maintenance during opera5on.

Typical nishing materials in

Biopharmaceu5cal facili5es
Walls

Floors

Ceiling

Warehouse

Sanitary pain5ng Hard, sealed

(pref. epoxy)

Clean, painted

Dispensary

Epoxy
Coved

Epoxy or in situ terrazzo

Coved

Epoxy
Coved

Manufacturing Epoxy
Coved

Epoxy or in situ terrazzo

Coved

Epoxy
Coved

Packaging

Epoxy or in situ terrazzo

Coved

Epoxy
Coved

Epoxy
Coved

211.42 Design and Construc(on Features

d) Opera5ons rela5ng to the manufacture, processing

and packing of PENICILIN shall be performed in
facili5es separate from those used for other drug
products for human use

211.44 Ligh(ng
Adequate ligh5ng shall be provided in all area

The amount of light reaching the working surface of each area involved in the
production chain should be defined (lux or foot-candles)
Normally, for public standard, a range of 30-50 candles is necessary to ensure
worker comfort and ability to perform efficiently and effectively
One hundred (100) foot-candles is required in some area such as inspection and
filling area
Lighting should measured periodically and the results recorded.
Routine replacement of light sources on some schedule to ensure that light levels
do not drop below the established minimum.

211.46 Ven(la(on, air ltra(on, air hea(ng and

cooling
a)

Adequate ventilation should be provided.

b)

Equipment for adequate control over air pressure, micro-organisms, dust,

humidity, and temperature shall be provided when appropriate for the
manufacture, processing, packing, or holding of a drug product

c)

Air filtration system, including pre-filters and particulate matter air filters,
shall be used when appropriate on air supplies to production areas,
measures shall be taken to control recirculation of dust from production. In
areas where air contamination occurs during production, there shall be
adequate exhaust systems adequate to control contaminants.

d)

Air-handling systems for the manufacture, processing and packing of

PENICILIN shall be completely separate from those for other drug,
products for human use.

Considera5on of Air-Handling System

Placement of air inlet and outlet ports. These should be sited to minimize the entry of airbone
particles or odors from the surrounding areas. Outlets should not be sited near inlet.
Where recirculation of air acceptable, adequate precautions must be taken to ensure that
particulates from a processing area are removed. This will usually require an alarm system or
an automatic cutoff in the event that a filter develops a hole. Dust extraction systems should
be provided, where appropriate, to further minimize this potential problem.
The degree of filtration and air volumes should be matched to the operations involved.
Temperature and humidity conditions should provide personnel comfort- to enhance performance
Temperature and humidity conditions should be within the optimal condition of equipment
operation
Where differential pressures are required between adjacent areas, suitable monitoring equipment
must be provided.
The siting 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.

211.48 Plumbing
a) Potable water shall be supplied under con5nuous posi5ve
pressure in a plumbing system free of defects that could
contribute contamina5on to any drug product. Potable water
shall meet the standard prescribed in the Environmental
Protec5on Agencys Primary Drinking Water Regula5on set in
40 CFR Part 141. water not mee5ng such standards shall not
be permijed in the potable water systems.
b) Drains shall be of adequate size and, where connected directly
to a sewer, shall be provided with air break or other
mechanical device to prevent back-siphonage

FDA usually not inquire documents that the potable water is

meeting the standard if the manufacturer connects the
potable waterline to a public supply that meet the standard
The water can lose quality in transmission through the public
piping system and through the manufacturers system
If potable water is obtained from wells under the control of
manufacturer, periodic testing is mandatory.
In case of providing potable water storage system, an
automatic chlorination system should be installed, usually at
2-3ppm

211.50 Sewage and refuse

Sewage, trash, and other refuse in and from the building
and immediate premises shall be disposed of in a safe
and sanitary manner
Product disposal: any product requiring disposal should initially be separated from
packaging. Disposal procedures should involve agents with a proven record of dealing
with such sensitive material from plant to disposal.
Printed packaging disposal: labels, inserts and cartons poses usually no health risk.
For public. However, this may rise the public concern that product may be associated
with the packaging. Incineration of such materials is preferred.
General trash and sewage: an internal procedures should be established to ensure
that product and packaging waste does not get intermixed. Containers used wiyhin the
plant to accumulate waste materials should be clearly marked to denote their
designated use.

Facility Requirements Review

(Building)
NON-GMP area

GMP facility ( Produc(on area)

Wall pain5ng

PVA paints

Epoxy or enamel

Flooring

Normal oor (non-porous) Homogenous sealed oor; Epoxy nish or

welded vinyl

Windows

Windows s5ll (openable)

Flush gluzed windows (preferably double

glass, not opened)

Floor drain

Open oor drain

Hygienic drains

Ceiling

With joints

Smooth sealed ceiling

Ligh5ng

Exposed open light qng

Flush light qngs

Furniture

Wooden is allowed

Must be of non-porous materials

(stainless steel or Melamine)

211.52 Washing and toilet facili(es

Adequate washing facilities shall be provided, including hot and
cold water, soap or detergent, air driers or single-service towels, and
clean toilet facilities easily accessible to working areas.
Separates toilet facility for each sex except where individual locked toilet rooms are
available (the number is based on the number users)

Suggested addi5onal emphasis.

Ea5ng facility: Ea5ng, drinking are permijed in separate area and well segregated from all
produc5on areas. Prominent sign indica5ng this role at the entrance of produc5on areas.
Enforcement procedures against viola5on are taken by management

In produc5on area: Tissues and loosed disposal containers are readily available.

Lavoratories and lockers: Adequate number for personnel employed, hot shower facility,
disinfectant soaps, adequate ash and waste receptacles are provided, periodic cleaning of
area during each shiZ, complete daily cleaning using disinfectant, specic rest area for
female employees should provided, areas separated from all asep5c spaces by an air lock.

211.56 Sani(za(on
a) Any building used in the manufacture, processing, packing, or holding of a drug product shall
be maintained in a clean and sanitary condi5on. Any such building shall be free of infesta5on
by rodents, birds, insects, and other vermin (other than laboratory animals). Trash and
organic waste majer shall be held and disposed of in a 5mely and sanitary manner.
b) There shall be wrijen procedures assigning responsibility for sani5za5on and describing in
sucient detail the cleaning schedules, methods, equipment and materials to be used in
cleaning the building and facili5es; such wrijen procedures should be followed.
c) There shall be wrijen procedure for use of suitable roden5cides, insec5cides, fungicides,
fumigita5on agents, and cleaning and sani5za5on agents. Such wrijen, procedures shall be
designed procedures should be designed to prevent the contamina5on of equipment,
components, drug product containers, closures, packaging, labeling materials, or drug
product and shall be followed. Roden5cides, insec5cides, fungicides shall not be used unless
registered and used in accordance with the Federal Insec5cide, Fungicide, and Roden5cide
Act (7 U.S.C. 135).
d) Sanita5on procedures shall apply to work performed by contractors or temporary
employees as well as work performed by full-5me employees during the ordinary course of
opera5ons.

211.58 Maintenance
Any building used in the manufacture, processing,
packing or holding of a drug product shall be maintained
in a good state of repair
Deterioration of buildings not only presents poor image of the facility, but also can
influence product quality. Cracks in ceiling, hole in wall or floor crack is potential
source of insects, microbial contaminations.
Water leakage can cause significant damage for materials and equipment, give rise
to electrical failure and fires and result in damage to the basic structure of the
building.
Holes in the roof or near the tops of building proved ready access to birds, which
may then be encourages to nest within the building.

Equipment

 211.62 Equipment design, size and loca(on

Equipment used in the manufacture, processing, packing,
or holding of a drug product shall be of appropriate
design, adequate size, and suitably located to
facilitate operations for its intended use and for its
cleaning and maintenance.

211.65 Equipment construc(on

Equipment shall be constructed so that surfaces that contact
components, in-process materials, or drug products shall not be
reactive, additive, or absorptive so as to alter the safety,
identify, strength, quality, or purity of the drug product beyond
that official or other established requirements.
Any substance required for operation, such as lubricants or
coolants, shall not come into contact with components, drug
product containers, closures, in-process materials, or drug
products so as to alter the safety, identity strength, quality, or
purity of the drug product beyond the official or other
established requirements.

211.67 Equipment cleaning and maintenance

a) Equipment and utensils shall be cleaned, maintained and sani5zed at appropriate
intervals to prevent malfunc5ons or contamina5on that would alter the safety, iden5ty,
strength, quality, or purity of the drug product beyond the ocial or other established
requirements.
b) Wrijen procedures shall be established and followed for cleaning and maintenance of
equipment, including utensils, used in the manufacture, processing, packing, or holding
of a drug product. These Procedure shall include, but not necessarily limited to the
following:
1) Assignment of responsibility for cleaning and maintaining equipment.
2) Maintenance and cleaning schedule, including, where appropriate, sani5zing schedule.
3) A descrip5on in sucient detail of the methods, equipment and materials used in
cleaning and maintenance opera5ons, and the methods of dissembling equipment as
necessary to assure proper cleaning and maintenance.
4) Removal of oblitera5on of previous batch iden5ca5on
5) Protec5on of clean equipment from contamina5on prior to use
6) inspec5on of equipment for cleanliness immediately before use.
c) Records shall be kept of maintenance, cleaning, sani5zing and inspec5on as specied in
211.180 and 211.182

211.68 Automa(c, mechanical, and electronic

equipment
a) Automatic, mechanical or electrical equipment or other types of
equipment, including computers, or related systems that will
perform a function satisfactorily, may be used in manufacture,
processing, packing, and holding of a drug product. If such
equipment is so used, it shall be routinely calibrated, inspected,
or checked according to a written program designed to assure
proper performance. Written records of those calibration checks
and inspections shall be maintained.

211.68 Automa(c, mechanical, and electronic

equipment
b) Appropriate controls shall be exercised over a computer or related
systems to assure that changes in master production and control
records or other records are instituted only by authorized
personnel. Input and output from the computer or related system
of formulas or other records data shall be checked for accuracy.
The degree and frequency of input/output verification shall be
maintained except where certain data, such as calculations
performed in connection with laboratory analysis, are eliminated
by computerization or other automated processes. In such
instances a written record of the program shall be maintained
along with appropriate validation data. Hard copy or alternative
systems, such as duplicate, stapes, or microfilm, designed to
assure that backup data are exact and complete and that it is secure
from alteration, inadvertent erasures, or loss shall be maintained

211.70 Filters
Filters for liquid ltra5on used in manufacture, processing, or
packing of injec5ble drug products intended for human use shall
not release bers into such products. Fiber-releasing lters may not
be used in the manufacture, processing, or packing of these
injectable drug products without the use of such lters. If use of a
ber-releasing lter in necessary, an addi5onal non-ber releasing
lter of 0.22 micron maximum mean porosity (0.45 micron if the
manufacturing condi5ons so dictate) shall subsequently be used to
reduce the content of par5cles in the injectable drug product.

Use of an asbestos-containing lter, with or without subsequent
use of a specic non-ber releasing lter, is permissible only upon
submission of proof to the appropriate bureau of the Food and
Drug Administra5on that use of a non-ber-releasing lter will, or is
likely to, compromise the safety or eec5veness of the injec5ble
drug product

Filters in Biopharmaceu5cals Factory

Air filters

- pre-lters/lter
HEPA / ULPA lters
- Microbiological Filters
(Filter defect cause contamina2on)

-Air lter for opera5on (pneuma5c valves)
(Filter defect is destruc2ve for the valve system)

- Air lter for process (aera5on and transfer)
(Filter defect cause contamina2on)

Filters in Biopharmaceu5cals Factory (cont.)

Liquid filters

A- For Cooling line

I.
Prefilter
II. Filter
(Filter defect is destructive for heat exchanger and valve on the
cooling line)
B- For Process water
I.
Water filtration before distillation
II. Medium filtration (sterilization)
III. WFI for buffer and product formulation (Pyrogen free)
(Filter defect directly affecting process and product Quality,
depending on the filter position)
C- For media preparation
I.
Microbiological filter
(Filter defect cause direct contamination)
41

Filters in Biopharmaceu5cals Factory (cont.)

Steam filters

(Filtering steam from solid par5cles)

- Process steam:
(heating, sterilization of double jacketed vessels
(Filter defect make damage in heat exchangers and also
for steam valves)
- Sterilization steam (direct steam injection):
(for sterilization of empty vessels such as for media
transfer tanks and holding tanks), or SIP equipments
(Filter defect make damage for filter and direct
contamination of products by foreign particle!)
42

Filters in Biopharmaceu5cals Factory (cont.)

Steam filters

(Filtering steam from solid particles)

- Process steam:
(heating, sterilization of double jacketed vesels)
(Filter defect make damage in heat exchangers and steam
valves)
- Sterilization steam (direct steam injection)
(for sterilization of empty vessels such as for media transfer
tanks and holding tanks), or SIP equipments.
(Filters defect make valve damage and direct contamination
of products by foreign particle!)

43

Filters in Biopharmaceu5cals Factory (cont.)

Ultra ltra5on system (protein concentrator)

Used for protein separa5on based on membrane

molecular weight cut-o. Dierent lter systems are
usually applied. The common used are
1000/10000/50000/100000 Daltons
(Filters defect cause improper protein separa5on and
leakage and loss of total protein produc5on)

44

 Assignment
1. Design stages in drug approval process.
2. Post-marke5ng evalua5on.
3. Compare and contrast QA and QC.

Stages in a new product launch (simplied)