QA

UNIT-1
CONCEPTS OF QUALITY ASSURANCE:

The ever-increasing technical complexity of present-day surface ships and submarines
has spawned the need for special administrative and technical procedures known collectively
as the QA Program. The programs concept is fundamentally the prevention of defects. This
encompasses all events from the start of maintenance operations until their completion and is the
responsibility of all maintenance personnel. Achievement of QA depends on preventing
maintenance problems through your knowledge and special skills. As a supervisor, you must
consider QA requirements whenever you plan maintenance. The fundamental rule for you to
follow for all maintenance is that TECHNICAL SPECIFICATIONS MUST BE MET AT ALL
TIMES. Prevention is concerned with regulating events rather than being regulated by
them. It relies on eliminating maintenance failures before the y happen. This extends to
safety of personnel, maintenance of equipment, and virtually every aspect of the total
maintenance effort. Knowledge is obtained from factual information. Quality assurance
knowledge is acquired through the proper use of data collection and analysis programs. The
maintenance data collection system provides maintenance managers with unlimited
quantities of factual information. Their correct use of this information provides them with
the knowledge required to achieve maximum readiness of aircraft and weapon systems.
Special skills, normally not possessed by production personnel, are required by a staff of
trained personnel who analyze data and supervise QA programs. The QA program provides
an efficient method for gathering and maintaining information on the quality characteristics
of products and on the source and nature of defects and their impact on the current operation. It
permits decisions to be based on facts rather than on intuition or memory. It provides
comparative data that will be useful long after the details of particular times or events have been
forgotten. Quality assurance requires that certain individuals have both the authority and the
responsibility for overseeing QA related actions. A properly functioning QA program
points out problem areas to maintenance managers so they can take appropriate action to
accomplish the following: 1. 2. 3. 4. 5. 6. 7. To Improve the quality, uniformity, and reliability
of the total maintenance effort Improve the work environment, tools, and equipment used
in the performance of maintenance Eliminate unnecessary man-hour and dollar expenses
Improve the training, work habits, and procedures of maintenance personnel Increase
the excellence and value of reports and correspondence originated by the maintenance
activity Distribute required technical information more effectively Establish realistic material
and equipment requirements in support of the maintenance effort obtain full benefits
from a QA program, teamwork must be achieved first. Blend QA functions with the
interest of the total organization and you produce a more effective program. Allow each
worker and supervisor to use an optimum degree of judgment in the course of assigned
daily work; a persons judgment plays an important part in the quality of his or her work
Quality assurance techniques supply each person involved with a job with information
concerning actual product quality. This information provides a challenge to the person to
improve the quality of the work. The resulting knowledge encourages the best efforts of all your
maintenance personnel. Quality assurance is designed to serve both management and
production equally. Management is served when QA monitors the complete maintenance effort
of the department, furnishes factual feedback of discrepancies and deficiencies, and
provides the action necessary to improve the quality, reliability, and safety of maintenance.
Production is served by having the benefit of collateral duty inspectors formally trained in
inspection procedures; it is also served in receiving technical assistance in resolving
production problems. Production personnel are not relieved of their basic responsibility y for
quality work when you introduce QA to the maintenance function. Instead, you increase their
responsibility by adding accountability. This accountability is the essence of QA.
TOTAL QUALITY MANAGEMENT

It would be fair to say that the idea of TQM is a bit like idea of God, depending on
which sect one belongs to. Different experts have attempted various definitions from
time to time. It may be defined as- It is continuously meeting agreed customer
requirements at the lowest cost by realizing the potential of all employees.
It may also be defined as performance superiority in delighting customers. The means
used are people, committed to employing organizational resources to provide value to
customers, by doing the right things right the first time, every time
.
Therefore, total quality management (TQM) means:
1. Satisfying customers first time, every time;
2. Enabling the employees to solve problems and eliminate wastage;
3. A style of working, a culture more than a management technique;
4. Philosophy of continuous improvement, never ending, only achievable by/or through
people. British Quality Association offers three alternative
definitions of TQM:
1.
The first focuses on soft quality characteristics
and may be defined as integrative
management concept for continuously
improving the quality of good/services
delivered through the participation of all levels
and functions.
2.
The second focus on hard
production/operation management type of
view involving less discretion for employees.
It may be defined as a set of techniques and
procedures used to reduce or eliminate
variation from a production/process or service
delivery system in order to improve efficiency,
reliability and quality.
3.
The third definition is a mixture of hard and
soft comprising 3 features and obsession with
quality, need for a scientific approach and the
view that all employees are involved in this

process.
The key elements of the TQM approach are:
1.
Focus on the customer: It is important to
identify the organizations customers. External
customers consume the organizations product
or service. Internal customers are employees
who receive the output of other employees.
2.
Employee Involvement: Since the quality is
considered the job of all employees,
employees should be involved in quality
initiatives. Front line employees are likely to
have the closest contact with external
customers and thus can make the most
valuable contribution to quality. Therefore,
employees must have the authority to innovate
and improve quality.
3.
Continuous improvement: The quest for
quality is a never-ending process in which
people are continuously working to improve
the perfor mance, speed and number of features
of the product or service. Continuous
improvement means that small, incremental
improvement that occurs on a regular basis
will eventually add up to vast improvement in
quality.
Preparation of audit:
An audit can and should be as painless as possible. Most people become anxious about audits
because they fear the unknown, however, the internal audit process is not designed to be a
surprise attack. The audit team works with the audit client during every step of the process to
help improve operations and add value to the organization. Employing the following easy steps
can pave the way to a pleasant and productive audit experience:
Pre-Audit Planning
As a general rule, departments should always ensure they are doing the following:
o Reviewing and approving transactions before they are processed
o Reconciling accounts
o Preparing documents on a timely basis within the prescribed deadlines/timeframes

o Filing and retaining documents in an organized fashion consistent with the
departments or the organizations record retention policies
o Segregating duties within a function such that no one person performs all of the
procedures from beginning to end within that business process
If a unit is doing the above, the audit should run smoothly.
Upon receipt of the Notification of Audit, review it, determine a convenient time, and
respond to the auditor as soon as possible.
Once an agreed upon timing is reached, commit to it. Ensure resources are available to
assist the auditors with answering questions, obtaining documentation, etc. The longer it
takes to complete the audit, the longer the auditors will be on site.
Identify space within your unit for the audit team to work. If space is unavailable, please
let the auditor in charge know up front so other arrangements can be made.
Entrance Meeting
TOP
Bring only key personnel to the Entrance Meeting who will have significant direct
involvement in the audit (e.g., supervisors, managers, directors, etc.).
Ask questions to ensure you understand the audit process, the scope, timing, and any
other requirements.
Inform the auditor of any potential issues (e.g., operational, timing, resources, etc.).
Issues are best handled proactively rather than reactively.
Make specific audit requests to review or pay closer attention to areas that may not have
been included in the auditors original scope. This is your opportunity to help design the
audit or voice particular concerns of interest to management.
Inform the auditor of any blocks of vacation or illness time that may occur during the
proposed audit time. If absolutely necessary, the timing of the audit may be adjusted to
accommodate the absence of key personnel due to vacation or illness time.
Establish a standard status meeting date that is mutually convenient for all parties and
commit to a day and time. No one likes surprises. An inform audit client is a cooperative
client.
Inform your staff of the impending audit and request their full cooperation. Explain the
audit process and timing to them so they understand the scope and overall objectives.
Designate key contact personnel to interact with the audit team. These individuals should
be someone who is knowledgeable about the process and can authorize access to
documents and other staff members for inquiries.
Information Request List
Review the Information Request List and determine if the items requested are available
and in what form (e.g., electronic, microfilm, reports, etc.).
Inform the auditor if any of the items requested are not available and be proactive at
providing viable information alternatives. Again, not providing information is not going
to shorten the duration of the audit. The audit objectives must be achieved so working
together to find alternatives will make the audit more efficient.
Make personnel available to answer questions, provide explanations and documentation.
During Fieldwork
Attend the status meetings and discuss progress and issues.
Issue Management and Resolution
TOP
Address and resolve issues proactively. This is a very critical aspect of any audit. If issues
can be resolved, they will not be identified as findings and documented in preliminary
audit report comments (PARCs). Avoid reportable findings by doing the following:
o Ensure the facts are correct
o Discuss the issue with the auditor and provide any information that may be
critical to understanding the full scope of the issue
o Obtain supporting documentation to clear or resolve a potential finding
If it is decided that the issue is a reportable finding, request draft copies of any
preliminary audit report comments (PARCs)
Keep your senior management apprised of the audit and any issues that arise. Again, no
one likes surprises.
Discuss the planned corrective action plan with your senior management prior to writing
your formal response to ensure they agree with your course of action
Prepare a written response. See How To Respond to Audit Findings for more details.
Ensure you have all findings before the completion of the audit.
Quality Assurance
Internal Audit management reviews all audit work papers, findings, and a draft of the audit report
prior to the issuance of the final report. During this phase, IA management may identify
additional questions or issues that will require some follow up by the audit team. While the audit
team may have left your department, the audit is not complete until the final audit report is
issued. So please be patient, IA must ensure that every audit is a quality audit that met all of its
goals and objectives. The majority of the audit is over once this stage is reached.
During Reporting
TOP
Review the draft of the final audit report.
Review each section thoroughly
Ensure each section is accurate and complete. The findings section should mirror the
PARCs you reviewed and discussed during fieldwork with the exception of minor
wording changes youve agreed upon with the auditor.
Make revisions, if needed, to convey the appropriate wording and tone and give the
report Executive Presence. Remember, the reports audience is senior management and
the Board of Governors.
Discuss the draft report with your senior management so they are apprised of the issues
before they see the draft report. Again, no one likes surprises.
Ensure the auditor makes all proposed revisions the report draft.
A final report draft is issued to all levels of management.
Ensure the auditor makes all proposed revisions the report draft.
If no further revisions are required, a final audit report is issued.
Share the final audit report with your staff so they are informed about the results of the
audit. This also serves as an excellent training and motivation tool for staff to see how
their daily work activities impacts the department and the university as a whole.
GMP Audit
Introduction:
The independent third-party GMP audit is to evaluate GMP compliance
status of the manufacturer in accordance with the current GMP requirements
set forth in 21 CFR Part 210 & 211 ICH Q 7 and EU GMP with its
interpretations.
The compliance status will be evaluated in terms of Quality Compliance
with respect to all the six GMP systems And hardware, software,and
personnel.
All deficiencies identified during the cGMP audits will be noted in the audit
report with gap analysis and proposed corrective actions.
GMP Audit Definition
GMP inspection:
on-site assessment of the compliance with the GMP principles performed by
officials of competent authorities or authorities found equivalent (Qualified
inspectors) .
A systematic, independent and documented process for obtaining
evidence and evaluating
It objectively to determine the extent to which criteria are fulfilled.
GMP Audit Benefits:

-The following benefits to the Pharmaceutical industry:
Effective assessment of GMP Compliance
Reduced costs
Improved performance
Facilitating harmonised guidelines for auditing
Increased external confidence
Inspection readiness Trouble free operation.
GMP Audit process:
Following this document will provide the current state of the art in
pharmaceutical auditing.
Before the Audit:

-Audit communication to understand the know how about the firm to be
audited
Pre-Audit Questionnaire Document requesting general information for the
preparation of the auditors.
Audit plan: Gives a general overview of the audit units, the frequency in
which the audit units ought to be audited and provides a summary of the
audit units to be conducted
Audit schedule: Fixed dates at which the audit will take place for a predefined timeframe (usually a year). If not too complex, the Audit Plan and
Audit Schedule can be combined to one document
Letter announcing/requesting the audit:The
Auditee must be given the chance to organise himself. For this reason the
auditor(s) should seek for an invitation well in advance of the
planned/scheduled audit. This may be in form of a letter (mostly external) or
memo (mostly internal) or even by e-mail.
Conduct of GMP audit:
The compliance status will be evaluated in terms of Quality compliance
with respect to all the six systemsand hardware, software, and personnel.
All deficiencies identified during the cGMP audits will be noted in the audit
report with gap analysis and proposed corrective actions. A pharmaceutical
auditing process may include review of the following
Documentation and Record Control
Verification of data integrity and its control measures
Manufacturing Process and Equipment
Training Validation and Qualification
Audit report:A detail report of audit report shall be prepared and sent to
the Firm for
CAPA
Response to audit report:
A detail response letter from firm to the auditing agency with actions taken,
CAPA details with covering letter sent to the regulatory agency.
GMP Certificate/compliance:
Statement: certificate with validity period and a statement of GMP
compliancewill be issued to the firm after satisfactory audit response letter.
Monitoring: The firm internally monitoring the
Compliance statusin their Quality meetings
UNIT 2
Organization and personnel:
CONTENTS:
CONTENTS Introduction Qualification, Experience & Training Responsibilities Key Personnel
Personal Hygiene & Clothing Documents & Formats 5/9/2012 2
Introduction :
Introduction Managements basic job is the effective utilization of the people, which they have, to
achieve from organizational objectives Without human efforts, no organization can achieve their
objectives. 5/9/2012 3
Organogram at overall organizational level:

Organogram at overall organizational level 5/9/2012 4 chairman Managing director president / V.
President (Technical Operations) Head manufacturing Quality management Engineering
Personnel Finance & Administration
Qualification, Experience & Training :

Qualification, Experience & Training Why organization fail in regulatory inspection?
Organizers feel that good buildings, costly equipments & few cleverly designed formats is the
key to success in inspection but they forgot the most important factor in a success story that is
people 5/9/2012 5
Qualification, Experience & Training:

Qualification, Experience & Training Technical / Professional Qualification Training of
Employees Number of People Ability To Perform Task Managerial Skills 5/9/2012 6
Technical / Professional Qualification :

Technical / Professional Qualification Qualification for relevant areas Pharma production Q.A. or
Q.C. Managerial Other areas 5/9/2012 7
Training of Employees:
Training of Employees A person is called trained person when he has appropriate knowledge,
skill & attitude Knowledge theoretical background excepted Skill ability to use theoretical
knowledge Attitude behavioral trait of a person 5/9/2012 8
Number of People :
Number of People There should be sufficient number of qualified personnel to carry out all the
task Manufacturing plant should have sufficient number of people such that they are able to
perform all the work assign to them so that no risk of quality because of overload of work to any
person 5/9/2012 9
Ability To Perform Task :

Ability To Perform Task Organizations must identify the different level task & sets of
knowledge, skills & attitudes required to make a person able to perform his task Machine
operator Shopfloor supervisors Junior/ Senior managers Top managers & directors. 5/9/2012 10
Managerial Skills:
Managerial Skills managers carry out the functions of planning, organizing, staffing, leading &
controlling Productivity implies effectiveness & efficiency. 5/9/2012 11
Responsibilities & Job Description:

Responsibilities & Job Description A job description is an organized, factual statement of the
duties & responsibilities of a specific job, in brief, it should tell, what is to be done, how it is
done, & why it is done Ideally a job description must contain knowledge about :- Reporting
relationship Individual assignments Job summary Working conditions, hazards of the job
5/9/2012 12
Key Personnel:
Key Personnel Key personnel can be defined as those positions in the organization, which have
a direct impact on the working of the organization & quality of the product produced There are
six different key personnel :- Head of production Head of Q.C. Head of Q.A. Head of sales &
distribution Authorized person Managing director 5/9/2012 13
Responsibilities of head of quality control:
Responsibilities of head of quality control To approve or reject starting & packaging material,
intermediate, bulk & finished product. To evaluate batch records. To approve & monitor analysis
carried out under contract. To approve sampling instructions, specifications test methods & other
quality control procedure. To check validation of analytical procedures & calibration of
equipment. To establish, verify & implement all quality control procedure. 5/9/2012 14
Responsibilities of head of production:

Responsibilities of head of production Appropriate documentation To approve instruction
relating to production operation, including in process control & their strict implantations. To
ensure that production records evaluated & signed by designated person. To check the
maintenance of the department, premises & equipment. 5/9/2012 15
Personal hygiene & clothing:

Personal hygiene & clothing persons engaged in manufacturing of the pharmaceuticals must be
healthy & not only healthy, but they themselves have good hygienic & sanitational habits
Regulatory guidelines to manufacturer High standards of personal cleanliness should be
observed by all those with production process Habit of hand washing. Hygiene programmes for
employees. cont.. 5/9/2012 16
PowerPoint Presentation:
Eating, drinking, chewing & smoking or storage of food, drink, smoking materials should not be
permitted. Direct contact should be avoided. There should be pre-employment medical check.
Annual eye examination. Report skin infection & skin lesion . cont.. 5/9/2012 17
Detailed dress code procedure should be implemented. Hygiene programmes should be
promoted. Requirements regarding personal hygiene & protective clothing apply to all persons
entering production. 5/9/2012 18
Documents & Formats:

Documents & Formats Documents for training :- Each organization should have a training
manual specifying the policy & procedures. Types of training :- a) GMP/GLP related training b)
Job specific training c) Behavioral training 5/9/2012 19
Training manual records contains :-:
Training manual records contains :- Attendance record Training evaluation record 5/9/2012 20
Format : Personnel training records Date :- Topic :- Trainer:- Method :- Time :- Venue :- Sr. no.
Name of participants department signature
Sr. no. Name of participants Department Evaluation 5/9/2012 21 Format :- personnel training
evaluation records Sr.no . Name JoiningDate Desig -nation Qualifi-cation Exper-iance FDA
approval Format :- Technical staff with qualification, experience & F.D.A. approval
Forma t :- certificates of Medical Check-up 5/9/2012 22 Name & address of the person examined
:- Sex :- Age :- Marital status :- Blood group :- He / she examined for the following :- Height
,Weight, Pulse Eye sight, respiratory , Git & Cardiac diseases Leprosy & communicable diseases
He / She needs following treatment/ investigation. 1. 2. Declaration :- He / She is medically fit /
unfit for any type of job Signature of Examining Doctor
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premises:
Content :
Content Pharmaceutical industry Location Design & Construction Plan and layout Maintenance
Sanitation Environmental Control Sterile Areas
Pharmaceutical industry :
Pharmaceutical industry Pharmaceutical industry can be classified arbitrarily on the following :
Crude and processed botanical drugs Fine chemical and pharmaceuticals Proprietary drugs
Location :
Location The selection of a location for the construction of a pharmaceutical or chemical plant is
a vital decision to be taken, because it determines the balancing of investment and profit. The
factory building (s) for manufacture of drugs shall be so situated and shall have such measures as
to avoid risk of contamination from external environment including open sewage, drain, public
lavatory or any factory which produces disagreeable or obnoxious, odour, fumes, excessive soot,
dust, smoke, chemical or biological emissions.
Factors for location :

Factors for location Fundamental (primary) factors Derived (secondary) factors
Fundamental (primary) Factors :

Fundamental (primary) Factors Raw materials Market Energy availability Transportation facility
Labour supply
Derived (secondary) factors :

Derived (secondary) factors Climate and soil Government concession Water supply Waste
disposal Site Characteristics Flood and Fire Protection Community Factors
Design & Construction :

Design & Construction The building(s), used for the factory shall be designed, constructed,
adapted and maintained to suit the manufacturing operations so as to permit production of drugs
under hygienic conditions. They shall conform to the conditions laid down in the Factories Act,
1948 (63 of 1948).
Construction (contn) :
Construction (contn) The premises used for manufacturing, processing, warehousing,
packaging labeling and testing purposes shall be :- compatible with other drug manufacturing
operations Proper Space for Working should be there. Proper logically placement of equipment
and material Avoid the risk of mix-up between different categories of drugs or with raw
materials, intermediates and in-process material.
Contn. :
Contn. 5. Control the cross contamination by other drugs or substances. 6. Deign should such
that it prevent the entry insect and rodents. Interior surface (walls, floors and ceilings) shall be
smooth and free from cracks, and permit easy cleaning, painting and disinfection. Provide with
adequate lighting and ventilation, if necessary air conditioning to maintain a satisfactory
temperature.
Contn. :
Contn. 9. The interior surfaces shall not shed particles. 10. A periodical record of cleaning and
painting of the premises shall be maintained. 11. It should be proper underground drainage
system in the processing area as far as possible. 12. Sanitary fitting and electrical should be
concealed.
Contn :
Contn Water supply: The water used in manufacture shall be pure and drinkable quality, free
from Pathogenic microorganism. Disposal of waste: Waste water and other residues from
laboratory which might be prejudicial to worker or the public health shall be disposed of after
suitable treatment as per requirement of water pollution control authorities.
Plan and layout :

Plan layout is a coordinated effort to achieve the final objective to integrate machines, material
and personal for economic production. Plan and layout
Advantages of plan layout :

Advantages of plan layout A proper lay out has the advantages from point of Workers Labour
cost Other production cost Production controls Super- vision Capital investment.
Type of plan layout :

Type of plan layout Plant layouts are of two types: Process layout or functional layout Product or
straight line layout
Process layout or Functional layout :

Process layout or Functional layout DEFINATION : It the arrangement of machines of a
particular class doing a particular type of work or process as a separate department. Eg. All
cutting machines may be placed in one department. i.e cutting department.
Process layout (contn.) :

Process layout (contn.) Advantages of process layout : More effective supervision can be
achieved Division of Labour can be provided Less disruption occur in production High scope for
expansion Disadvantages This is not possible in chemical &Pharmaceutical industry
Product or straight line layout :

Product or straight line layout DEFINATION: The arrangement of machines doing various
operation in a line as one department. Eg. In manufacture of tablet; Dispensing, powder
blending, granulation, drying , compression and coating. All of the above look as different
operation but logically arranged in a series.
Product layout (contn.) :

Product layout (contn.) Advantages: Process of work will be quick and smooth Cost of
material handling will reduced Production time is reduce and manufacturing cycle can be
speeded up. Space of floor can be properly used
Factor Influencing Plant layout :

Factor Influencing Plant layout New site development or additional to developed site. Type of
Process and product control. Space available and space required. Operational convenience.
Economic distribution of utilities and services. Health and safety considerations. Waste disposal
problem. Possible future Expansion.
Method of Plant and Factory Layout :

Method of Plant and Factory Layout A proper layout in each case includes arrangement of
processing areas, storage area and handling area in efficient co-ordination The lay out processing
units in a plant, the equipment within these units must be planed. Then detail piping, structural
and electrical design. Plan layout play important in determining construction and manufacture
cost.

Method of Plant and Factory Layout

Method of Plant and Factory Layout
Method of Plant and Factory Layout Different type of information are needed design an
appropriate layout Dimensions of work places. Sequence of operations. Flow pattern of
materials. Storage space for raw materials, in process inventory and finished goods. Space for
offices, aisles, toilets etc
Special Provision of Pharmaceutical plant layout. :

Special Provision of Pharmaceutical plant layout. They shall conform to the condition laid down
in Factories Act 1948 The wall of room in which manufacturing operation are carried out shall:
Have a height of six feet from floor. Have smooth and waterproof. Be capable of cleaning.
Slide 26:
Flooring shall : Be smooth, even washable. Have no creak and crevices Be in such a way as not
to permit any retation or accumulation of dust.
Different Type of Layout :

Different Type of Layout
Raw Material Ware House :

Raw Material Ware House
Center storage and Perimeter Production :

Center storage and Perimeter Production
Storage And Production Side by Side :

Storage And Production Side by Side
Straight Line Type :

Straight Line Type
Office layout :
Office layout
Warehouse layout :
Warehouse layout
Maintenance :
Maintenance Many problem involved in maintenance due to the faculty design and layout of
plant and equipment. Sufficient space and facilities for maintenance work must be provided in
plant layout. It is essential to consider maintenance regulations while making decisions on
equipment.
Maintenance (contn.) :
Maintenance (contn.) Schedule and procedures must be established for the preventive
maintenance of equipment. Written procedures must be established for the cleaning and its
subsequent release for use in manufacturing. Equipments and utensils must be cleaned, stored
and wherever appropriate sanitized or sterilized to prevent contamination or carry over.
Maintenance (contn.) :
Maintenance (contn.) Non dedicated equipment must be cleaned between productions of
different materials to prevent cross contamination.
Sanitation :
Sanitation It consist of three thing: Sanitary condition Maintenance Disposal of sewage and
refuse
Sanitation :
Sanitation Manufacturing area should not be used for any other purpose. It should be maintain
clean, orderly manner and free from accumulated waste, dust, debris etc. Eating, chewing
smoking or any unhygienic particle should not permitted in manufacturing area. Production areas
shall be well lit, particularly where visual on-line controls are carried out.
Contn :
Contn A routine sanitation program shall be drawn up and observed, which shall be properly
recorded and which shall indicate-- (a) specific areas to be cleaned and cleaning intervals; (b)
cleaning procedure to be followed, including equipment and materials to be used for cleaning;
and (c) personnel assigned to and responsible for the cleaning operation.
Environment control :
Environment control Thermal pollution and control Water pollution and control Air pollution
control
Thermal pollution and control :

Thermal pollution and control Various off stream cooling system are required to handle thermal
discharge from process. There different ways for controlling thermal pollution Wet cooling
towers Dry cooling towers
Water pollution :
Water pollution There is a great problem to handling a liquid waste effluent is more complex
then gas effluent. The treatment could be done by Physical treatment Chemical treatment
Biological treatment
Air control :
Air control There are two major categories Those suitable for removing particulate matter Those
associated with removing gaseous pollutant Removed by chemical And Physical way
Sterile Area :
Sterile Area For Sterile drugs separate enclosed area specially designed for the purpose shall be
provided. Area shall be provided with air locks for entry and shall be essentially dust free and
ventilate with air supply. For all areas where aseptic manufacture has to be carried out air supply
shall be filtered through HEPA filters and shall be at a pressure higher than in the adjacent area.
Sterile Area (contn.) :

Sterile Area (contn.) Routine microbial counts of all sterile area shall be carried out during
manufacturing operation. Area where Manufacturing progress is going on that area must not be
occupied by access people. Special procedure should be followed for entering and leaving the
manufacturing area
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OVER VIEW FOR EQUIPMENT:

OVER VIEW FOR EQUIPMENT Introduction Equipment selection Equipment design, size and
location Equipment construction Equipment identification Cleaning and maintenance
Automated, mechanical and electronic equipment Filter Weighing balance Purchase specification
SOP 2
Introduction:
Introduction Equipment may be defined as a physical entity which is used to carry out a general
or specific activity in the plant. Equipment is the major inputs in the manufacture of the
pharmaceutical products, in the regulatory literature on GMP in various countries gives the
importance & hence provide guidelines on the management of equipment in pharmaceutical
plants. Equipment may be : Single system or piece, Integrated system. 3
Equipment Selection:
Equipment Selection Selection of equipment has both strategic and financial impact on the
companies . It is an essential for any company because it has direct influence on the success of
the product facilities by optimum cost ,improving quality , safety and reducing environmental
hazards . Factor that affect selection of equipment Operating criteria, Availability of spares and
servicing Maintenance, Environmental issues, Availability of design & maintenance manuals,
Cost. 4
Equipment design, size and location:

Equipment design, size and location 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. Availability of design and maintenance manuals from
the supplier that are important for validation/qualification and maintenance programs. Equipment
suitably located & designed for easy cleaning and maintenance. 5
Equipment construction:
Equipment construction Equipment shall be constructed so that surfaces that contact components
& drug products shall not be reactive or absorptive as it alter the safety, identity, strength, quality
or purity of the drug product. The construction material used for parts which are direct contact
with products & manufacturing vessels may be stainless steel 316 or Borosilicate glass & tubing
should be capable of being washed and autoclaved. Any substances required for operation such
as lubricants or coolants shall not come into contact with components, drug product containers
closures or drug products. 6
Equipment Identification:
Equipment Identification All compounding and storage containers, processing lines and major
equipment used during production of a batch of drug product shall be properly identified at all
times to indicate their content. Major equipment shall be identified by a distinctive identification
no. or code that shall be recorded in the batch production record to show the specific equipment
used in the manufacture of each batch of drug product. 7
Cleaning And Maintenance :

Cleaning And Maintenance Equipment and utensils shall be cleaned, maintained, and sanitized at
appropriate intervals to prevent contamination. Written 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. A cleaning procedure desired at
end of working shift only for equipment in which a wet processing stage has been carried out.
Cleaning and washing may be : Manual Automated -CIP , -SIP 8
cleaning validation:-:
cleaning validation:- why it is important? Essential to establish adequate cleaning procedures.
Cleaning validation should be performed in order to confirm the effectiveness of a cleaning
procedure. The data should support a conclusion that residues have been reduced to an
acceptable level. sampling methods: Swab sampling, Rinse fluid, Placebo flush, Visual
Examination. Analytical method: HPLC, GC, HPTLC, pH , Conductivity, UV, ELISA. 9
Slide 10:
Every equipment must have SOPs for operation, cleaning and maintenance. There may be
system to distinguish equipment in three categories: Operational equipment ( with green card ),
Equipment under maintenance ( yellow card ), Defective equipment (red card ). The operator
doing cleaning and maintenance must be so trained that their activities of cleaning and
maintenance will not affect or contaminate product. Records of all activities on equipment must
be chronologically recorded in the equipment log book. 10
Types of Maintenance:
Types of Maintenance 11 Equipment Maintenance : defined as facilities maintain to some desired

level of efficiency to keep assets in a satisfactory condition.
Slide 12:
12 Breakdown maintenance:- It means that people waits until equipment fails and repair it. Such
a thing could be used when the equipment failure does not significantly affect the operation or
production or generate any significant loss other than repair cost. Corrective maintenance
( 1957 ):- It improves equipment and its components so that preventive maintenance can be
carried out reliably. Equipment with design weakness must be redesigned to improve reliability
or improving maintainability . Maintenance prevention ( 1960 ):- It indicates the design of a new
equipment. Weakness of current machines are sufficiently studied and are incorporated before
commissioning a new equipment.
Slide 13:
13 Preventive maintenance ( 1951 ) :- It is a daily maintenance ( cleaning, inspection, oiling and
re-tightening ), design to retain the healthy condition of equipment and prevent failure through
the prevention of deterioration, periodic inspection or equipment condition diagnosis, to measure
deterioration. It is further divided into periodic maintenance and predictive maintenance.
Periodic maintenance ( Time based maintenance - TBM) : Time based maintenance consists of
periodically inspecting, servicing and cleaning equipment and replacing parts to prevent sudden
failure and process problems. Predictive maintenance :- This is a method in which the service life
of important part is predicted based on inspection or diagnosis, in order to use the parts to the
limit of their service life. Compared to periodic maintenance, predictive maintenance is condition
based maintenance.
SOP on cleaning, operation and maintenance:

SOP on cleaning, operation and maintenance Name of equipment and its unique identification
no. Responsible person to carry out and supervise operation schedule maintenance and cleaning.
Material use for cleaning and its complete removal after cleaning. Removal of previous batch
identification. Protection of cleaned equipment. Inspection of cleaned equipment. Detailed step
by step operation of equipment. Detailed step by step prcedure to carry out prevententive
maintenance. Record of cleanig, maintenance and operation. 14
Equipment cleaning & maintenance record:

Department : Month: Equipment: Make: Equipment identification No.: Working Capacity:
Cleaning sop no. : Maintenance sop no.: Cleaning Maintenance Date Sign Remark Date Sign
Remark Equipment cleaning & maintenance record 15
Slide 16:
INDIAN PHARMACEUTICAL LTD. Daily maintenance record sheet Sr. no. Department Work
performed Time Part replaced Starting completion Date:________ Work left for next
day:______________________________________
________________________________________________________
Remark:_________________________________________________ Work performed by
Inspected by Deptt. Head ________________________________________________________
________________________________________________________ 16
INDIAN PHARMACEUTICAL LTD. Machine breakdown card:

INDIAN PHARMACEUTICAL LTD. Machine breakdown card Name Of Machine: Room No.:
Identification No.: Department: 17 Sr. No. Date Time Type of breakdown Maintenance work
performed Time Sign Part Name/Part No. Replace From To
USP divides the equipment into three groups based on respective complexity :
USP divides the equipment into three groups based on respective complexity Group A Group B
Group C E.g. stirrer E.g. pH meter, balance E.g. HPLC,GC They are simplest. Only visual
observation is needed to confirm that it is qualified. Little complex. Written procedure must be
followed. Though testing of their qualification is generally straightforward and identifiable.
Highest complex. Deep n complete literature must be provided. 18
Slide 19:
AIQ (ANALYTICAL INSTRUMENT QUALIFICATION) DQ (DESIGN QUALIFICATION)
IQ (INSTALLATION QUALIFICATION) OQ (OPERATIONAL QUALIFICATION) PQ
(PERFORMANCE QUALIFICATION) There are four qualification phases are also described by
the WHO's Good Manufacturing Practices Guide for Quality Assurance of Pharmaceuticals. 19
Slide 20:
These types of equipment includes computers or related systems that will perform a function
satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug
product. It should 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. 20 AUTOMATIC, MECHANICALAND ELECTRONIC
EQUIPMENT
Slide 21:
Appropriate controls shall be exercised over computer or related system 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 or
data shall be checked for accuracy. The degree and frequency of input/output verification shall be
based on the complexity and reliability of the computer or related system A backup file of data
entered into the computer or related system shall be maintained except where certain data, such
as calculations performed in connection with laboratory analysis, are eliminated by
computerization or other automated processes. In such instances a written record of the program
shall be maintained along with appropriate validation data. 21
Filters:
Filters Filter used as a part of equipment & Filtration is one of the processes use in
pharmaceutical operation and air systems. Filter for liquid filtration used in the manufacture,
processing or packing of injectable drug products intended for human use shall not release fiber
into products. As a part of GMP, filters should be considered from following: Type of filter and
filration process, Compatibility of filter media with processing material, Cleaning of reusable
filter and their sanitization, validation of filter, Disposal of filter. 22
Slide 23:
INDIAN PHARMACEUTICAL LTD. Pre-air filter record Sr. no. location Cleaning date Clean
by Manometer reading before Manometer reading after washing Remark water Air 1 2 3 4 5
Name of filter: Size: Pore size: 23
Weighing balance:
Weighing balance Balance and other measuring equipment of appropriate range and precision
should be available for production and control operation. Measuring, weighing, recording and
control equipment should be calibrated & checked at defined interval by appropriate method.
Adequate record of such tests should be maintained. All weighing balance should be in a state of
calibration. The name, signature and date of person weighing and supervising weighing
operations must be recorded. A list of various weighing balance should be made with following:
Description of balance , Model number, Weighing range, location, Frequency of calibration. 24
Purchase specification of equipment:

Purchase specification of equipment Definition:- Detailed description of the measurable
characteristics desired in an equipment to be purchased such as quality, size, weight ,
performance parameters, safety requirements etc. The documents used for the procurement of
equipment should consist: User Requirement Specification Relevant Standard Demand
Specifications, and Purchase Agreement. 25
Purchase specification of UV-VIS Spectrophotometer, double beam:

Purchase specification of UV-VIS Spectrophotometer, double beam Wavelength : 190-900 nm or
more Optical System : Double beam with double monochromator Light Source : D2 and
Tungsten Wavelength accuracy : +/- 0.1 nm Spectral Bandwidth : at least, 0.5, 1, 2, 5 (variable)
Photometric Range : at least -0.3~3 Abs Photometric Modes : Abs,%T Stray Light minimum
Wavelength Scan Speed : 800-10 nm/min Baseline Stability : +/-0.0008Abs/Hour or less
Detector : Photomultiplier R928 Control : By Computer Quartz Cuvette Branded Computer
monitor with latest specification Laser Printer D2 Lamp, tungsten Lamp 5 years maintenance of
the system 26
Purchase specification of water bath :

Purchase specification of water bath 10 L to 15 L water tank volume Water circulation to
maintain uniform temperature Working temperature : ambient +5C to 100C or more Stability :
0.1C or less Increment : 1C or less Microprocessor control for precise temperature Overtemperature cut-off Audible and visible alarms LED display with 0.1C resolution for
temperature Operable at 220 volts 5 year equipment maintenance 27
SOP for Equipment:

SOP for Equipment Definition : A written authorized procedure which gives instructions for
performing operations necessarily specific to a given equipment. What are SOPs ? They are the
tools to ensure that GMP is being followed wherever applicable. It contains relevant information
about any activity or process carried out (like calibration validation , maintenances , cleaning ,
production , packing or even for receipt or movement of raw material ). Why SOPs are needed?
Due to demand of safe and efficacious drug product in the market. In addition to clinical factors
storage , handling of raw material and final product , cross contamination and batch to batch
deviation affects the quality of product. We dont want any loss or refusal. 28
Slide 29:
29 Precautions for preparing SOPs:- Information & procedures in clear and unambiguous
language and specifications for the facilities should be provided. By following SOPs the quality
product should be expected. Significant deviations are recorded and investigated. Documents
must not be changed or added or reviewed or amended without any authorization. Easy to
retrieve from master SOP and check also critical steps should be highlighted. Must not allow any
error. Regularly updated and previous suspended SOPs are preserved for at least 1 year after the
last batch made on it has been expired. Original copy is kept in locker and one copy is displayed
in all the concern areas and retained with each member who has signed in it.
Steam in Place
Sterilization in place or Steam in place (SIP) is a method used to clean or disinfect process equipment and
piping without disassembly. The SIP process can be done manually or automated through the control
system. The thermal validation of this process is accomplished by using thermocouples or wireless
dataloggers. Typically, the temperature sensors are inserted into the process piping through flanges using
Smart gaskets.
During the initial qualification of the SIP process, thermocouple based systems can be advantageous. The
ability to see live data allows for optimum adjustments and to establish control parameters of
sterilization time and exposure. Multiple datalogger systems and very long thermocouples (50-75 ft) are
usually required. Setup and installation is quite time intensive using the thermocouple approach.
Thermocouples can get entangled or damaged if not carefully secured around traffic areas.
Lives XpertLog wireless dataloggers are the best solution for SIP re-qualifications or periodic
verifications. The dataloggers can be installed in a small fraction of the time compared to thermocouple
based systems (see chart). Also, disruption to normal operations is minimal.
v
http://www.authorstream.com/Presentation/nayan_jagani10-1200693-equipment/
raw materials:
Contents:: Contents: Definition. Purchase specifications. Selection of Vendors Control on raw
materials and finished dosage forms. Sampling of raw materials Raw materials testing
Maintenance of Stores. 2 2
RAW MATERIALS It is basically the chemical ingredients of a process. Basic raw materials are
starting material ,which is used in production of final product. Good raw material specifications
must be written in precise terminology , must be complete , must provide specific details of test
methods, type of instruments, and manner of sampling, and must be properly identified. 3 3
CRITERIA FOR RAW MATERIALS PURCHASE SPECIFICATION:

CRITERIA FOR RAW MATERIALS PURCHASE SPECIFICATION It must be noted that
pharmacopoeial standards are minimum. Where no such stds. are applicable to raw material, the
specifications should include at least requirements for identification, limits for purity and
potency and limits for impurities. Where such standard exist for raw material, alternative test
methods may be used but there should be written evidence to show that such method are at least
as precise and specific as the official methods. 4
5 RAW MATERIAL PURCHASE SPECIFICATIONS 1. Active or Therapeutic Materials 2 .

Active material other than antibiotics 3. Modified specification for tablets 4. Modified
specification for parenteral system 5. Raw material quality assurance monograph 5
6 1. Active or Therapeutic Materials Testing of antibiotics is usually performed either chemically,
microbiologically, biologically or by all three methods Sampling procedure must be done in
special condition . Assay for potency of antibiotic raw materials must be carefully achieved. 2.
Active material other than antibiotics Specifications normally include solubility, identification,
melting range, loss on drying, residue on ignition, special metal testing. Raw materials can
evaluated and controlled with special instrumentation In general, a typical raw material currently
found in a compendium has a purity requirement of at least 97%. 6
7 3. Modified specification for tablet In the development of raw material specifications, the
analytical research and development chemists should strive for the following: Ascertain which
chemical, physical and biological characteristics are critical for assuring reproducibility from lotto-lot of raw material to be used for evaluating each lot of raw material produced or purchased.
Specification: - Nonvolatile residue - Particle size - Ash - Polymorphic forms - Acid-insoluble
ash - Crystallinity characteristic - Loss on drying - Water content 7
8 4. Modified specification for parenteral system Great number of potential sources of
contamination, strict sanitation of plant warehouse is an absolute necessity. Microbial flora is
usually associated with raw materials from natural sources where as synthetic raw materials are
normally free or low in microbial contamination. A sterilization procedure may include heat
treatment, radiation or recrystallization from a bactericidal solvent, such as alcohol.
Specifications: -Color -Powder fineness or density -Solvent -Microbial count -Sterility -Pyrogen
8
9 5. Raw material quality assurance monograph A. Name of Raw Material: 1. Structural formula,
molecular weight 2. Chemical name(s) 3. Item number 4. Date of issue 5. Signature of writer 6.
Signature of approval B. Samples: 1. Safety requirement 2. Sample plan and procedure 3.
Sample size and sample container to be used 4. Preservation sample required C. Retest Program:
1. Retesting schedule 2. Reanalysis to be performed to assure identity, strength, quality and
purity. 9
10 D. Specifications (wherever applicable ) 1. Description 2. Solubility 3 . Identity a Thin-layer,
paper, liquid, or gas chromatography b. Infrared absorption c. Ultraviolet absorption d. Melting
range e. Boiling point or range 4 . Purity and quality a. pH, specific rotation, nonvolatile residue,
ash, acid-insoluble ash, residue on ignition, loss on drying, water content, heavy metals, sulfate,
chloride, carbonates, acid value, saponification value. b. Special quality tests - particle size,
crystallinity characteristics, and polymorphic forms 5. Assay, calculated either on anhydrous or
hydrous basis 6. Microbial limits, especially for raw materials from natural sources 10
SPECIFICATIONS (For Ascorbic acid USP):
Structural formula: C 6 H 8 O 6 Molecular formula: 176.13 Chemical name: L-Ascorbic acid

Specifications: Description - white or slightly yellow crystal or powder Solubility freely
soluble in water; sparingly soluble in alcohol, Specification rotation between +20.5 and 21.5
SPECIFICATIONS (For Ascorbic acid USP) 11
Identification test Infrared the infrared absorption spectrum of a potassium bromide dispersion
of it exhibits maxima only at the same wavelength as that of a similar preparation of USP
Ascorbic cid RS. Alkaline cupric tartrate color slowly reduces at room temperature but more
readily upon heating. Residue on ignition NMT 0.15 Heavy metal NMT 0.002 Assay
99.0-100.5 on anhydrous basis Identification test Infrared the infrared absorption spectrum of
a potassium bromide dispersion of it exhibits maxima only at the same wavelength as that of a
similar preparation of USP Ascorbic cid RS. Alkaline cupric tartrate color slowly reduces at
room temperature but more readily upon heating. Residue on ignition NMT 0.15 Heavy
metal NMT 0.002 Assay 99.0-100.5 on anhydrous basis 12
As per GMP and WHO guidelines for handling of raw materials.:

As per GMP and WHO guidelines for handling of raw materials. On receipt, each delivery
of raw materials should be visually examined for labels,damage to containers .. Raw materials
,then should be transferred to quarantine area and labels over printed with words Under test .
Request should be made to incharge, quality control for sampling . Quality control persons
should withdraw the sample from quarantine. while sampling, the point should be kept in mind:
-sample should be representative of the batches. -all sampling equipment must be clean.
-Containers should be resealed after sampling. 13
-Precaution should be taken during sampling. -Sterile equipment should be used when necessary
On receipt of approval or rejection of the raw material, it should be transferred to area
marked for approved materials or rejected materials. Raw material should be stored at optimum
temperature and humidity. Raw materials should be stored in clean container. Rawmaterials
should be inspected at some intervals . It should be retested if it has been lying in store for too
long periods. It should be store in such a manner that material received first is issued first. The
clean equipment should be used for dispensing. Raw materials are used only when are approved
by quality control department. 14
Raw materials in the storage area shall be appropriately labelled. Labels shall be clearly marked
with the following information: designated name of the product and the internal code reference,
where applicable, and analytical reference number Manufacturer's name, address and batch
number The status of the contents (e.g. quarantine, under test, released, approved, rejected) The
manufacturing date, expiry date and re-test date. 15
Preparing a Prospective Supplier List:

Preparing a Prospective Supplier List You can search for the potential vendors by looking at
several information sources: Past experiences Interviewing with the salesperson of the supplier
Catalogs published by the vendors Trade Directories Classifies suppliers according to the
products they make Includes names of company personnel, financial status, and location of sales
offices 16
Types of Suppliers:
Types of Suppliers In the search for suppliers, all available types (that is , distributors,
manufacturers, and foreign sources) should be considered. The number of suppliers to be used
should also be considered. Trade-offs between price, delivery, and service and community
relations and goodwill must be weighed when selecting various types of vendors. 17
Local vs. National Suppliers:

Local vs. National Suppliers There are inherent natural advantages to buying from local suppliers
whenever possible. Among the most significant are the following: 1. Saving of money when the
distance between firms is relatively short. 2. Close proximity permits for communication and
service; shorter lead times , and exchanges. There are also considerations that favor national
suppliers: 1.Low price 2.Large inventory 18
Distributor vs. Direct:

Distributor vs. Direct The buyer will often have to choose between buying through a distributor
or direct from a manufacturer. Both options have their advantages and disadvantages. The
manufacturer often offers lower prices than the distributor; this difference usually depends on the
volume of business. Manufacturers generally prefer large-quantity orders. But in case of
purchase of lower Quantity a distributor may offer lower prices than manufacturer. Since
distributors are generally local firms, they are often able to provide better service than
manufacturers. 19
Foreign Sources:
Foreign Sources The increasing industrialization of third-world countries, coupled with lower
labor costs, has made foreign purchasing increasingly attractive in recent years. However, the
drawbacks of foreign sources sometimes negate the cost savings. The first problem is long lead
times . In addition to the actual travel time of the goods, time is spent in customs . Another
problem is currency fluctuation .With such long lead times, the price agreed upon may rise or fall
between purchase and payment simply because the foreign currency exchange rate fluctuates
against the buyer countrys currency 20
Supplier Evaluation Factors:

Supplier Evaluation Factors After potential suppliers have been determined and located, a
qualitative evaluation and elimination process is used. This process compares suppliers in terms
of their ability to provide the desired quality, quantity, price, and service. Thus, a supplier who
might be able to supply the desired quantity during the specified period , but could not supply
this quantity on specified dates, would not be a satisfactory supplier. A price is good only if the
item supplied has the desired quality and quantity and is accompanied by sufficient useful
services. 21
Location:
Location The geographical location of the supplier is an important consideration in evaluating
service.. Companies may overcome some of their geographical disadvantages by providing pool
car shipments, branch warehouses, and make-and-hold services. Providing supply in regular
production schedule. In sudden increase in demand local suppliers easily supply the API. 22
RESERVE CAPACITY:
RESERVE CAPACITY The reserve facilities of a supplier are another consideration in
evaluating service. A supplier with an adequate reserve of productive facilities can respond to
increased customer requirements. WARRANTIES Service also includes the kind and form of
warranties that accompany a supplier's products. The supplier should assure the buyer that the
product delivered will be maintained throughout its normal life. 23
Inspection:
Inspection The inspection methods and quality control procedures used by the prospective
supplier are also considered. A supplier who is careless about inspecting finished goods will ship
items that must eventually be rejected and returned as unsatisfactory for their purpose. If such a
supplier is also careless in controlling production quality, the problem is aggravated, because
some imperfections may not be discovered until the item has been incorporated into the finished
product. 24
Labor Relations:
Labor Relations Another source of interference with the continuity of production in a supplier's
plant may be the workers themselves. If relations of the supplier with its workers are poor, there
may be strikes or slowdowns in production. QUALITY MANAGEMENT Quality is the most
important, factor on the evaluation list. Without good quality, the lowest-cost supplier in the
world will not be acceptable. The ISO series ( ISO 9001, 9002, 9003 ) of quality standards is
becoming more and more a requirement worldwide. 25
Financial Status of Supplier:

Financial Status of Supplier The financial status of the supplier directly affects its ability to serve
and should be carefully evaluated. Credit reports contain information about suppliers' financial
standings. These reports also provide information on the experience, management, and facilities
of the potential vendor. SUPPLIER GOODWILL Developing supplier goodwill is a vital part of
purchasing personnel's strategic planning. Goodwill benefits the organization in emergencies and
helps ensure adequate levels of supply during periods of shortages. 26
RAW MATERIAL CONTROL:

RAW MATERIAL CONTROL There is sufficient management systems in place to control the
handling and use of all raw materials on site. The staff is sufficiently informed, instructed,
trained and supervised to minimize a potential human failing during raw material delivery, test
and storage. The procedures in place to vet the suppliers of raw materials ( Audits, supplier
history, reputation). 27
CONT.:
CONT. The amount of information with each raw material delivery (Trem Cards, Certificate of
Analysis, Safety Data Sheets, representative samples). The suitability of validated quality control
test methods and equipment in place to identify any potentially hazardous contaminants present
within a raw material delivery. 28
Sampling of raw materials:

Sampling of raw materials After sanitising instrument under laminar flow . They are to be rested
on sterile cloths throughout sampling process to prevent contamination . Prior to containers being
opened, they need to be marked in numerical order on the outer container. This identified the
container number from which the will be taken. Sterile jar are marked with marker with the
following information relating to their type of sample. 29
Lab sample(LS) Micro status sample Outside testing Print out the sampling labels which has the
following information. Laboratory batch number Product description Sample type Number of
samples Examine all material containers for damage before sampling. Report any damage to
laboratory manager. Dont touch any material with your hand. Always use appropriate sampling
tools. 30
Any raw material requiring a microbiologically check (micro. status sample) is to be sampled
with sterile tools . And into sterile jars. the analyst should wear gloves for sampling of raw
materials. Samplers are to clean room with respect to absence of watches, rings, nail polish
etc. Before sampling any raw material, read carefully the given instruction on raw material
specification. The air conditioning setting and timer are not to be alter in any way. 31
Raw materials testing:

Raw materials testing Raw materials testing ensures that the raw materials used in
pharmaceutical products are suitable for their intended use. Conducting raw materials analysis
using appropriate test methods and successfully meeting the challenges of such testing can
prevent costly production problems and delays. before finished pharmaceutical dosage forms are
produced, the identity, purity, and quality of raw materials must be established with the use of
suitable test methods. Some qualify a raw materials supplier by performing an initial detailed
vendor audit followed by an annual qualification consisting of full pharmacopeial monograph
testing on three lots of material. 32
To perform even basic monograph testing, laboratories must contain a wide spectrum of
instrumentation. The most commonly specified instruments include Analytical Chemistry &
Testing - pH meters - balances - gas chromatographs - HPLC - infrared spectrophotometers - UV
spectrophotometers - Karl Fischer moisture titrators - general titration apparatus - vacuum ovens
- melting-point apparatus 33
- TLC - polarimeters - refractometers - viscometers - muffle furnaces. To expand the number and
variety of excipients that can be tested, additional instrumentation is required. These include flame atomic absorption spectrophotometers - graphite furnace atomic - absorption
spectrophotometers - elemental analyzers - differential scanning calorimeters thermogravimetric analyzers. 34
Quality control of packed raw materials in pharmaceutical industry:

Quality control of packed raw materials in pharmaceutical industry The possibility of routine
testing of pharmaceutical substances directly in warehouses is of great importance for
manufactures, especially taking into account the demands of PAT. The application of NIR
instruments with remote fiber optic probe makes these measurements simple and rapid. On the
other hand carrying out measurements through closed polyethylene bags is a real challenge. 35
Continue.:
Continue. As a result, testing can be performed not only in the lab but also directly in a
warehouse. Raw materials are quickly tested for identity and quality conformance. Once a model
for a substance is developed, routine testing takes place in a few seconds , making it possible to
test every unit of incoming ingredient to verify the identity. At the same time the application of
fiber probe diffuse reflectance NIR spectroscopy is an especially challenging problem when
measurements are carried out through closed polyethylene (PE) bags. This could produce
spectral artifacts that are comparable with the substance physical or chemical fingerprints. 36
Continue:
Continue The spectra were measured through closed polyethylene bags in the 4000
10,000cm1 region with a 2cm1 spectral resolution. Prior it is known that all samples present
the substance of satisfactory quality. All spectra were pre-treated by the SNV procedure. For
detailed data processing, model analysis, and general approach elaboration various spectra were
measured: those of the substance in closed bags, substance without packaging, and empty
polyethylene bags. 37
Spectrum S1 obtained from sample 1 without PE bag. - substance P is a spectrum of PE bag A1 is a spectrum of sample 1 in PE bag. - A2 is a spectrum of sample 2 in PE bag. 38
if a sample belongs to Class 1, this is a sample of a satisfactory quality (decision accepted); if a
sample belongs to Class 2, measurement should be repeated (no decision); if a sample does not
belong to Class 2, such a sample is an alien (decision rejected). 39
Maintenance of Stores. :
Maintenance of Stores. FDA Inspection and audits begins at receiving documents and follows
the flow of material. Creates the starting impression on auditors mind about the entire firm.
SOPS are reviewed. ABOUT THE STORES CLEANLINESS: FLOORS LIGHTING SOPS
APPROVED SOURCES 40
STATUS IDENTIFICATION Yellow, Green or Red sticker on each material. Palletized bags are
film wrapped should identified with a single label. Computer controlled system SAMPLING
LOCATION STOCK ROTATION STORAGE CONDITION CLEANLINESS OF MATERIAL
CONTAINER SEGREGATION OF REJECTED MATERIALS KEEP ALL THE RECORDS OF
RAW MATERIALS 41
Outdoor Storage of Raw Materials:

Outdoor Storage of Raw Materials Raw materials, by-products, finished products, containers,
and material storage areas exposed to rain and/or runoff can pollute stormwater . Stormwater can
become contaminated when materials wash off or dissolve into water or are added to runoff by
spills and leaks. Improper storage of these materials can result in accidental spills and the release
of materials. To prevent or reduce the discharge of pollutants to storm water from material
delivery and storage: pollution prevention source control measures 42
minimizing the storage of hazardous materials on-site enclosing or covering materials storing
materials in a designated area conducting regular inspections preventing storm water run-on and
runoff training employees and subcontractors must be implemented. Pollution Prevention:
Minimize inventory of raw materials. Keep an accurate, up-to-date inventory of the materials
delivered and stored on-site. Try to keep chemicals in their original containers, and keep them
well labeled . 43
Inspection: Conduct regular inspections of storage areas so that leaks from bottle are detected as
soon as possible. Conduct routine inspections and check for external corrosion of material
containers. Maintenance Accurate and up-to-date inventories should be kept of all stored
materials. Sweep the storage areas regularly for collection and disposal of loose solid materials,
Keep outdoor storage areas in good condition (e.g. repair roofs, floors, etc. to limit releases to
runoff). 44
VENDORS AUDIT:
VENDORS AUDIT cGMP observation NDN D N/A COMMENTS DOCUMENTATION SOP

MANUAL QA/QC PROGRAME PERSONAL TRAINING MASTER RECORDS REWORK
FAILURE INSPECTION 45
http://www.authorstream.com/Presentation/hemshah09-1447816-raw-material/
UNIT-3
Concept of validation:
GMP-definition is the validation of "establishing documented evidence that establishes a high
degree of certainty that a particular process will consistently a product that provides the
previously established specifications and quality attributes are available."
Appropriate and complete documentation is recognized as crucial for the validation. Standard
Operating Procedures (SOPs), production formulas, detailed documentation batch
changeControl, experimental reporting systems, analytical documents, reports development,
validation protocols and reports are an integral part of validation philosophy. The validation of
the documentation provides a source of information for the ongoing operation of the plant and is
a resource that is used in the subsequent process of development or modification activities.
All test activities will take a level of impact assessment to ensure that systems, services
andProducts were determined directly affected by the test.
A revalidation program should be implemented on a permanent equipment on the revalidation
requirements and change control.
Types of Validation
Prospective validation
Establishing documented evidence that a device / process or system to do what they do, on a preplanned series of scientific investigations within the meaning of validation sets basedPlan.
Concurrent validation
Is used when an existing process can be shown to be in a state of control by use of tests on
samples taken at strategic points in a process, and at the end of the process. All data are collected
simultaneously with the implementation of the process, to demonstrate sufficient information to
process reproducibility.
Retrospective Validation
Establishing documented evidence that a process does notwhat it purports to do, based on review
and analysis of historical data.
Design Qualification (DQ)
The intent of the DQ is in the planning and commissioning process met with a number of
mechanisms, including:
- Generation of User Requirement Specifications
- Verification of this type corresponding user requirement specifications.
- Supplier Evaluation / Audit
- Check the Challenge of the design by GMP audits
- Product Quality ImpactAssessment
- Specifying Validation documentation requirements of suppliers
- Agreements with the suppliers about the performance targets
- Factory Acceptance Test (FAT), Site Acceptance Test (SAT) and commissioning procedures
- Definition of construction and installation documentation) to assist with Installation
Qualification (IQ.
Installation Qualification (IQ)
IQ is a proof that the equipment or system has been documented in developeddelivered and
installed in accordance with design drawings, vendor recommendations and in-house
requirements. Moreover, IQ, that a record of the main features of the equipment or system is
installed, how available and ensure that they are supported by sufficient and appropriate
documentation to implement satisfactory operation, maintenance and control of changes.
Operational Qualification (OQ)
OQ is documented proof that operates the facilityas provided in the above design, operation or
approved acceptance range of equipment, as applicable. In cases where process steps are
considered an appropriate placebo batch is used to demonstrate device functionality.
All new devices should be fully taken into service before the start of OQ to ensure that at least be
sure to use the device, complete with all mechanical assembly and pre-qualification checks are
that the device is fully functional and thatDocumentation is complete.
Performance Qualification (PQ)
The goal of PQ is documented proof that the equipment can always be achieved while producing
the specifications for a longer period at a defined operating point, a product of the specified
quality. The specification will make reference to process parameters, in-process and product
specifications. PQ requires three product batches available for all acceptanceCriteria for inprocess and product testing. For supply PQ requires the benefits of medium to fulfill all the data
over a longer period of sampling.
The PQ documentation should be on standard manufacturing procedures and batch records and
describe the methodology of sampling and testing to be.
Master plan:
A Validation Master Plan, also referred to as "VMP", outlines the principles involved in the
qualification of a facility, defining the areas and systems to be validated, and provides a written
program for achieving and maintaining a qualified facility. A VMP is the foundation for the
validation program and should include process validation, facility and utility qualification and
validation, equipment qualification, cleaning and computer validation. It is a key document in the
GMP (Good manufacturing practice) regulated pharmaceutical industry as it drives a structured
approach to validation projects.
Food and Drug Administration inspectors often look at VMPs during audits to see whether or not
a facility's validation strategy is well thought-out and organized. A VMP should have logical
reasoning for including or excluding every system associated with a validation project based on a
risk assessment.
Common topics to be covered in a Validation Master Plan: Introduction, scope, responsibilities,
description of facility and design, building and plant Layout, cleanrooms and associated
controlled environments, storage areas, personnel, personnel and material Flow, water and solid
waste handling, infrastructure and utilities, water system, ventilation and air-conditioning
system, clean steam, compressed air, gases and vacuum system, list manufacturing equipment,
building management systems, products that are planned to be validated, qualification/validation
approach, process validation and cleaning validation approach, microbiological monitoring,
computer Validation, calibration, maintenance, related SOPs.
Process validation
contents:
contents INTRODUCTION VALIDATION AND QUALIFICATION STAGES OF PROCESS
VALIDATION TYPES OF PROCESS VALIDATION PROCESS VALIDATION OF SOME
PHARMACEUTICAL PROCESSES REFERENCES 2
introduction:
introduction 3
VALIDATION: VALIDATION Validation means confirmation by examination and provision

of evidence that the particular requirements for a specific intended use can be consistently
fulfilled. 4 PROCESS VALIDATION Process validation means establishing by objective that a
process consistently produces a result or product meeting its predetermined specifications.
Process validation is Established documented evidence Which give high degree of assurance
That a specific process will Consistently produce a product meeting its quality characteristics
and Pre-determined Specifications 5
systematic approach : :
systematic approach : identifying , measuring , evaluating , Documenting re-evaluating a series
of steps in the manufacturing process that require control to ensure reproducible final product 6
factors::
factors: For assurance of product quality (according to FDA) Selection of quality components
and materials adequate product and process design control (statistical) of the process through, inprocess testing.. end-product testing 7
quality control procedures 3 basic steps : finished product testing :

quality control procedures 3 basic steps : finished product testing 1.Establishment of
specifications and performance characteristics 2. Selection of methodology , Equipment
instrumentation Ensures testing of product meets specification 3 final product testing using
validated analytical method and testing methods 8
new addition:
new addition 4 Qualification processing facility and its equipment 5 Qualification and validation
manufacturing process 6 Auditing, monitoring, sampling, or challenging the key steps for
conformation of specification 7 Revalidation if significant change in mfg process or product 9
Reasons for validation programming:

Reasons for validation programming law to conform to CGMP regulations good business
(rejected or recalled batches) ensuring product uniformity, reproducibility, quality 10
When to validate:
When to validate After finalizing formula, process, and specifications Either before or after new
drug (NDA) Approval Prefer to start during process development phase More frequently being
done before NDA approval/filing 11
12
Process validation: order of priority:

Process validation: order of priority A companys most profitable products should be given a
higher priority. The following order of importance or priority with respect to validation is
suggested: 13 A. Sterile Products and Their Processes 1. Large-volume parenterals (LVPs) 2.
Small-volume parenterals (SVPs) 3. Ophthalmics , other sterile products, and medical devices B.
Nonsterile Products and Their Processes 1. Low-dose/high-potency tablets and capsules/
transdermal delivery systems (TDDs) 2. Drugs with stability problems 3. Other tablets and
capsules 4. Oral liquids, topicals , and diagnostic aids
General view of process validation:

General view of process validation 14
Validation and qualification:

Validation and qualification 15
Validation vs. qualification:

Validation vs. qualification VALIDATION : Refers to the total life cycle of a product from
development through use and maintenance. Customers(Owners ) are responsible for Validating
Their Processes (personnel , equipment, methods, SOPs) to ensure compliance to CGMP/GLP
regulations. QUALIFICATION : (Inspection, functional testing and documentation review) Is a
part of the validation process which verifies module and system functional performance prior to
being placed on-line and thereafter according to a standard operating procedure. 16
Process validation timeline:
Process validation timeline 17

19 3 stages of process validation
Stage 1 Process design : The commercial manufacturing process is defined during this stage
based on knowledge gained through development and scale-up activities Stage 2 Process
Performance Qualification (PPQ): During this stage, the process design is evaluated to determine
if the process is capable of reproducible commercial manufacturing Stage 3 Continued Process
Verification/Continuous quality Verification (CQV) : On-going assurance 20
Types of process validation:

22 Types of process validation
1. Prospective validation:
1. Prospective validation Also called as premarket validation Carried out prior to distribution of
new product or existing product made under a revised manufacturing processes where such
revision may affect product specification or quality characteristic In prospective process
validation, an experimental plan called the validation protocol is executed before the process is
put into commercial use. This particular type of process validation is normally carried out in
connection with the introduction of new drug products and their manufacturing processes. 24
The formalized process validation program should never be undertaken unless and until the
following operations and procedures have been completed satisfactorily: Facilities & equipmt
meet CGMP requirements (IQ understanding of thecmpltn ) operators and supervising
personnel process and its requirements design, selection, and optimization of the formula have
been completed qualification trials using (10 size) pilot-laboratory batches have been
completed. Detailed technical information on the product and the manufacturing process have
been provided. Finally, at least one qualification trial of a pilot-production (100 size) batch has
been made and shows that there were no significant deviations from the expected performance of
the process. 25
2. Concurrent validation:
2. Concurrent validation Study is carried out under a protocol during a course of normal
production. It gives assurance of present batch being studied and offer limited assurance
regarding consistency of quality from batch to batch. This may be practical approach under
certain circumstances. When previously validated process is being transferred to a third party
contract manufacturer or to another manufacturing site. Where the product is a different strength
of a previously validated product with the same ratio of active / inactive ingredients. 26
3. Retrospective validation:
3. Retrospective validation Conducted for a product already being marketed , and is based on
extensive Historical data accumulated over several lots and over time. Some essential elements
of retrospective validation:- Batches manufactured for a defined period Batch size/ strength/
manufacturer/ year Master manufacturing/ packaging documents Current specifications for
active materials/ finished pdts List of process deviations, corrective actions and change to mfg
documents Data for stability testing for several batches Trend analysis including those for quality
related complaints 27
4. revalidation:
4. revalidation All or a portion of validation that is required to be repeated when changes that
affect original validation are made. Examples of changes requiring revalidation Changes to
product specifications Process parameters Equipment (type, function, location, control system,
major repairs) Raw materials Manufacturing materials Packaging material 28
Change control:
Change control Written procedures should be in place to describe actions to be taken if a change
is proposed to a product component, process equipment, process environment, processing site,
method of production or testing or any other change that may affect product quality or support
system operations. All changes must be formally requested, documented and accepted by the
validation team. The likely impact / risk of the change on the product must be assessed and the
need for the extent of re-validation should be determined. Commitment of the company to
control all changes to premises, supporting utilities, systems, materials, equipment and processes
used in the fabrication/ packaging of pharmaceutical dosage forms is essential to ensure a
continued validation status of the systems concerned. 29
Process validation of some pharmaceutical processes:

Process validation of some pharmaceutical processes 30
Mixing or blending:
Mixing or blending M ay occur once or several times during the tablet manufacture P hysical
properties of the drug and excipients taken into consideration are: Bulk density Particle shape
Particle size distribution Surface area 31
Items to consider : Mixing or blending technique Mixing or blending speed Mixing or blending
time Drug uniformity Excipient uniformity Lubricant Color Equipment capacity/load 32
Wet granulation:
Wet granulation Wet granulation parameters to be considered during development and validation
are: Binder addition Binder concentration Amount of binder solution/granulating solvent Binder
solution/granulating solvent addition rate Mixing time Granulation end point 33
Cleaning validation:
http://www.authorstream.com/Presentation/bharatrbh-436837-cleaning-validation/
Air handling validation:

Contents:
Introduction Types of clean room Component of HVAC System HVAC Qualification Validation
Parameter Contents 2
Introduction:
HVAC H eating Ventilation and Air Conditioning The need and reason for pharmaceutical air
handling system The technical requirements for air handling system Different types of air
handling system Qualification and Validation requirements Introduction 3
What is clean room ?:

What is clean room ? A room in which the concentration airborne is controlled and which is
constructed and use in a manner to minimize the introduction , generation and retention of
particle inside the room and in which other relevant parameter. e.g., temperature, humidity and
pressure are controlled as necessary 4
Why clean room necessary ?:

It controls 3 types of contamination transfer Air borne contamination Direct contamination by
personnel, equipment etc. Contamination from fluids like cleaning fluids, solution etc. As air
borne particulate are reduced , chances of particles entry in the process reduced. Protect product ,
personnel and environment Why clean room necessary ? 5
Types of clean room ?:

Horizontal clean room Horizontal laminar flow (HEPA filter in wall force clean air from one
side of room to other.) Vertical clean room Vertical laminar flow (HEPA filter on the ceiling
push clean air down to the floor.) Types of clean room ? 6
The manufacturing environment is critical for product quality:

Environment consist of, Light Temperature Humidity Air movement Microbial contamination
Particulate contamination Uncontrolled environment can be leads to product degradation Product
contamination Loss of product and profit The manufacturing environment is critical for product
quality 7
HVAC consist of following parts:

Air conditioner AHU s Dehumidifier/Heater Filter Dust extractors Ducting Supply fans Smoke
detector Dumpers humidity/ temperature/ pressure sensor Bag filters Heating/ cooling coil
HVAC consist of following parts 8
HVAC Specification:
HVAC Specification 9 Temperature 18-23 c Relative Humidity 45% 5% Dry powder- 30%
5% Moisture sensitive drug- 5% 5% Air Velocity 80-120 ft/min Air flow Laminar Airflow
Pressure Gradient 15 Pascal Particulate Count NMT 100 Particle of 0.5 mm/ Temperature 18-23
c Relative Humidity 45% 5% Dry powder- 30% 5% Moisture sensitive drug- 5% 5% Air
Velocity 80-120 ft/min Air flow Laminar Airflow Pressure Gradient 15 Pascal Particulate Count
USFDA:
21 CFR part 211 (requirement for building and facilities) Under 211 .42 (C) Operation shall be
perform within the specifically defined area and such other control necessary to prevent
contamination. Temperature and humidity controlled. A system of monitoring environmental
condition. Under 211.46 (C) Air filtration system including pre-filter and particulate matter air
filtration shall be used when appropriate on air supply to production areas. USFDA 10
Air flow pattern:

Air flow pattern 12
HVAC Qualification:
Validation master plan User requirement specification Design qualification Installation

qualification Operation qualification Performance qualification Re-qualification HVAC
Qualification 13
User requirement specification:

Room dimension Machine horse power and lighting load Temperature R.H Pressure gradient
Class of air Air changes per hour User requirement specification 14
Design qualification:
Technical data: General Make and model no. Noise level Overall dimension in mm. Weight in
kg. Design qualification 15 C asing Outer skin Inner skin Material of frame structure Insulation
material and thickness Fan Type and make Fan speed in RPM Fan BHP Recommended motor
Operating voltage and frequency 16
Design qualification:
Chilled water and hot water coils Make Air quantity through coil Face area sq. feet Selected
water velocity across coil Material of cooling coil Tube diameter Design qualification 17
Installation qualification:
System Description Equipment Delivery Utilities / Facility / Environment Assembly &
Installation Installation qualification 18
IQ Should include, Instrumentation checked against current engineering drawings and
specifications Verification of materials of construction Installation of equipment and with piping
Calibration of measuring instruments requirements Collection and collation of supplier operating
and working instructions and maintenance requirements Installation qualification 19
Practical aspect of IQ (Cont.) Calibration of measuring instruments. Calibration of
additionally used instruments. Initial cleaning records. Basic commissioning checks.
Maintenance requirements. IQ process checks that the correct components are installed in the
correct location. Materials of construction Spare parts Change controls Installation qualification
20
IQ Document should contain, Instrument name, model, I.D. No., Personnel responsible for
activities and Date. A fully verified installation that complies with the documented design. (all
deviations will have been recorded and assessed.) All equipment documentation and maintenance
requirements would be documented. Completed calibration of measuring instruments.
Verification of Materials of construction. Installation qualification 21
Operation qualification:
Operation Qualification Checks , Ability to provide air of sufficient quality and quantity to
ensure achievement of specified clean room conditions. Ability to maintain temperature, relative
humidity and pressure set points. Ability to maintain any critical parameters stated in the DQ
consistently. Operation qualification 22
Includes the tests that have been developed from knowledge of processes, systems and
equipment. Tests to include a condition or a set of conditions encompassing upper and lower
operating limits, sometimes referred to as worst case conditions. Operation qualification 23
IQ reports must be completed and signed off. OQ protocols to be written and approved prior to
completion. Measurement reports are required to demonstrate achievement of critical parameters
as detailed in DQ. E.G : * All relevant SOPs should be in place * Temperature measurement
report * Humidity measurement report * Differential pressure measurement report * Air flow
direction measurement report * Room particle count measurement report * All drawings etc.
done in as-built status * All maintenance/ cleaning instructions available * All O & M staff to
be trained to use and maintain the system. * Sign off. (Compliance Certificate by Engineering
Dept. & QA) Operation qualification 24
Performance qualification:
The purpose of PQ is to verify and document that an HVAC system provides acceptable control
under Full Operational conditions. PQ should follow successful completion of IQ and OQ. PQ
verifies that over time, the critical parameters, as defined in the DQ are being achieved.
Performance qualification 25
Performance qualification:
PQ Should include, Tests, using production materials, qualified substitutes or simulated product,
that have been developed from knowledge of the process and facilities, systems or equipment.
Test to include a condition or set of conditions encompassing upper and lower operating limits.
PQ is used to demonstrate consistent achievement of critical parameters over time .( under
manufacturing conditions) PQ is ongoing. Performance qualification 26
Qualification Complete \Documentation:

Verification of design documentation, including Description of installation and functions
Specification of the requirements Instructions for performance control Operating procedures
Maintenance instructions Maintenance records Training of personnel (program and records)
Environmental records Discussion on actions if OOS values Walking around the plant Finally
certification (Sign Off) by Engineering, User (Production) and QA Heads . Qualification
Complete \Documentation 27
Validation :
Document act of proving that any procedure, process, system / equipment ACTUALLY leads to
expected results . To ensure that system provides continuously required environmental
conditions. Validation 28
Validation Parameter:
HEPA filter leak test. Temperature control test. Humidity control test. Test for air flow pattern.
Pressure control test. Particle count test. Airborne microbial sampling. Air flow velocity test.
Validation Parameter 29
HEPA filter leak test:

Purpose : To ensure against filter damage. Method : Installation of DOP aerosol (0.3mm)
upstream of the filter through a test port and search for leak downstream with an aerosol
photometer. Acceptance criteria : An unacceptable leak is defined as 0.01% of the reference
calibration curve. HEPA filter leak test 30
Temperature control test:

Purpose : To demonstrate the ability to control temp. at 72F 10% all year round. Equipment :
Calibrated dry-bulb thermometer, thermocouple and recorder. Method : Air conditioning system
and all light to be in continuous operation at least 24hr prior to test. Measure and record temp at
15 min internal for 2hr . Repeat the test for at rest and dynamic condition. Acceptance criteria : It
should be capable of maintaining a dry-bulb temp. of 72F 10% . Temperature control test 31
Humidity control test:

Purpose : To demonstrate the capability to control humidity at specified level for each room.
Equipment : Calibrated dry-bulb and wet bulb thermometer and recorder . Method : Measure and
record humidities at rest and dynamic condition. Operate the system at least 6hr prior to test.
Record the wet/dry temp. at the beginning and at end. Acceptance criteria : RH should be within
tolerance limit. Humidity control test 32
Air flow pattern test:

Purpose : To demonstrate minimum turbulence and determine air flow pattern. Equipment :
white visible or yellow smoke generator, anemometer, 35mm camera. Method : Generate white
smoke. Film the smoke as it travel. Measure and maintain temp. at 15min interval for 2hr. Repeat
the test for as rest and dynamic condition. Acceptance criteria : It should be capable of
maintaining a dry bulb temp. of 72F 10 %. Air flow pattern test 33
Pressure control test:

Purpose : To demonstrate the capability of system to control pressure level within the specified
levels. Equipment : Pressure gauge. Method : All HVAC and laminar units to be used in
continuous operation during the test. All doors and sterile facility must be closed. Pressure
reading are taken with high and low pressure tubings at selected location. Acceptance criteria :
Pressure differentials should be above 0.02 at the primary environments. Pressure control test 34
Particle count test:

Purpose : To establish that within clean room, a count of less than 100 particle per cubic foot,
0.5mm is maintained. Equipment : Light scattering particle counter. Method : Using particle
analyzer, count particle grater than or equal to 0.5 microns at height of 40 inches in the center of
each grid. Acceptance criteria : The particulate count shall not be exceed 100 particle of 0.5
microns per cubic foot of air. Particle count test 35
Air borne microbial sampling:

Purpose : To determine air borne microbial contamination level. Equipment : Andersons air
sampler (1 cubic foot/min). Method : Sampling time 20mins at every location. Plates are placed
in an incubator, maintained inverted to prevent condensation drop for a periods of 18-24 hrs. at
35 c. After incubation the number of colonies on each plates is counted using a standard bacterial
colony counter. Acceptance criteria : No of colonies per cubic meter of air, limit established is
3.5 colonies in class 100. Air borne microbial sampling 36
Air flow velocity test:

Purpose : To demonstrate that air system is balanced and capable of delivering sufficient air
volume. Equipment : Hot wire anemometer. Method : Measurement take at 15min intervals.
Record the pressure readings (in inches) Acceptance criteria : Average measure clean air velocity
shall be higher than 90 foot/min and not exceeding 150 foot/min at 6 inches downstream from
the filter face. Air flow velocity test 37
Validation of equipment:
Validation of Equipments: The basic component of pharma industry are the Equipments.
Therefore before validating a process that is carried out in a pharma industry, the issue of
equipment validation becomes a prime importance. Equipment validation is covered in several
steps: 7 User requirement specifications/ customer requirements(USR) Design Qualification(DQ)
Installation Qualification(IQ) 4. Operational Qualification(OQ) 5. Performance
Qualification(PQ)
Principle Equipment must be located designed constructed adapted maintained to suit the
operations to be carried out. 8
9 Equipment layout and design must aim: to minimize risks of error. to permit effective cleaning
and maintenance. To avoid: cross-contamination, dust and dirt build-up. any adverse effect on the
quality of products. Equipment must be installed to: minimize risks of error. minimize risks of
contamination.
Control laboratory equipment- Equipment and instruments- suitable for the tests to be performed.
Defective equipment- Removed. Labelled. Washing, cleaning and drying- Equipment used for
washing and drying not the source of contamination. Equipment design should promote easy
cleaning. Cleaning on scheduled basis, procedures and records. 10
Qualification policy for systems and equipment- To include instruments used in production and
quality control. New systems and equipment: All stages of qualification applicable (DQ, IQ, OQ
and PQ). Qualification should be done in accordance with predetermined and approved
qualification protocols. The results of the qualification should be recorded and reflected in
qualification reports. 11
13 A) User requirement specifications: What are the expectations of the customer? General
requirements may be stated as follows: size of the equipment Speed of the equipment
Effectiveness of the equipment Availability of the spares, change parts, prompt services at
reasonable cost. Ease of operation, cleaning & maintenance. Low dust & sound generation.
Lesser breakdowns. Overall good construction & workmanship.
2. Preparation of Design qualification- User requirements should be considered when deciding
on the specific design of a system or equipment. A suitable supplier should be selected for the
appropriate system or equipment (approved vendor). For purchasing a standard equipment, it is

not essential to prepare a D.Q. document. If the user asks for a specialized type of instrument,
then he must submit his Requirements in the form of a detailed design qualification document to
the supplier. 14
15 3. Installation qualification- Verifies that the correct equipment has been received and
installed as per plan and protocol. Also that it is complete and undamaged (parts, services,
controls, gauges and other components). Verifies that equipment has been properly installed and
calibrated including connections to utilities. Documented records for the installation Installation
qualification report. Include details, e.g. The supplier and manufacturer. System or equipment
name, model and serial number. Date of installation. Spare parts, relevant procedures and
certificates.
4. Operational qualification: Systems and equipment should operate correctly operation
verified as in the qualification protocol. Verifies that the equipment operates consistently within
established limits and tolerances over the defined operating ranges. Challenges equipment
functionally to verify compliance with manufacturers specifications and end user defined
requirements. 16
17 Documented records - (Operational qualification report) Finalize and approve SOP
(operation) Training of operators provided training records. Systems and equipment released
for routine use after completion of operational qualification, provided that: All calibration,
cleaning, maintenance, training and related tests and results were found to be acceptable.
Performance qualification: Verifies that the equipment performs according to design
specifications and user defined requirements in a reliable and reproducible manner under normal
production conditions. Verified in accordance with a performance qualification protocol.
Documented records performance qualification report Show satisfactory performance over a
period of time, i.e. carried out long enough to prove that the equipment is under control and turns
out product of specified quality consistently. 18
19 Assembling of a validation protocol: Documented formats or protocols. Helps in
systematizing the study of equipment validation. Different formats have been specified for
designing protocols & carrying out IQ, OQ & PQ.
20 Purpose : This procedure details the assembly & contents of the validation protocol for use
in validation testing. Principle: This protocol is generated by a validation specialist/engineer.
Protocol section contains required forms & procedures. Procedure describes how the system is
to be validated while Forms document these procedures & provide a written record of the
executed qualification & validation processes.
21 Testing procedures: Protocol packages are divided as OQ PQ IQ SECTIONS OF A
STANDARDISED PROTOCOL: Table of contents List of standard sections. Unique testing
procedures. Approval page Pre-approval section. Final approval section. Description Statement
of purpose. Standard operating procedures. (correct, complete & most current versions)
Calibration. Utilities.
22 Purpose : This procedure describes the testing sections of an installation qualifications for a
piece of an equipment. Principle : It includes the sections of the standardized protocol. A general
description of the approaches & rationale to be used when writing the Inspection & Installation
sections of this protocol. Procedure: Inspection checklist. Installation checklist. Installation
qualification- Equipment:
23 I. Inspection checklist: Instruction explains how this section is physically executed. Table of
Contents lists the major components of an equipment. Specified Explains manufacturers
specifications. Actual The things that are actually observed they are listed here. Two approaches
are commonly employed: Like components Order of sequence Like components of the system
may be grouped in the Table of contents, but their individual characteristics will be listed out
separately. Order of sequences starts with the component which begins the process & then
proceeds through the system.
24 II. Installation checklist: This section of protocol determines whether or not a piece of the
equipment or system as a whole meets the manufacturers design specifications. It is recorded as
yes or no. Any no's are then recorded as deviations or deficiencies. Environmental
requirements: Specifically considers humidity, temperature, of a particular piece of the
equipment.
25 Operational qualification: Purpose: It defines the procedure for the operational qualification
of a piece of equipment. Principle: After installation, the verification of equipment capability is
performed. Includes: Alarm testing, control system testing, operation & maintenance procedures.
Test equipments: List the necessary test instruments, before starting the test, first the instrument
is to be Calibrated & maintained as such till the completion of the test. Test procedure: e.g. alarm
testing, Operation testing.
26 C. Performance qualification: Purpose : To define testing requirements in a product/ process/
performance qualification/ validation protocol. Principle: This gives a general outline of the
issues related to the process or plan. Includes: Background & reason for the plan. Testing method
used. Predetermined general /specific acceptance criteria.
27 Test equipment: List any test instrument necessary & must be calibrated prior to use & till the
process completes. Procedure: This is the final phase of the validation process. Before PQ
validation testing is implemented for all processes Product specifications are established &
judged acceptable. Testing procedures: Design of the expt. These procedures are tailored to
challenge the exact process or product to be validated using normal operating parameters in a
SOP Validation will demonstrate that by using these parameters the quality product intended can
be produced consistently.
28 Worst case conditions: A worst case challenge will encompass upper & lower process limits &
circumstances & will pose greatest chance of process or product failure when compared to actual
production conditions. Microbiological challenges: Controlled environment is necessary for the
production of many pharmaceutical products & sterile environments is essential for the
manufacture of parenterals. For a predetermined period of time test for microbial growth is
performed under certain challenge condition.
29 Conclusion : User requirement specifications play an important role in the design of an
equipment. In order to design a specialized instrument a design qualification document is to be
submitted by the customer to the supplier. When an equipment passes all the norms that are
specified in an I.Q., O.Q. & P.Q. test, the equipment is said to be validated.
Facilities for sterile and non-sterile areas:

Environmental Conditions
All environmental conditions for clean areas must be classified and maintained in
accordance with requirements in EU GMP Annex 1 and FDA 21 CFR, Guidance for
Industry Sterile Drug Products By Aseptic Processing, September 2004, ISO
146441and IPSE Pharmaceutical Engineering Guides for New and Renovated
Facilities, Volume 2, Oral Dosage Forms and Volume 3 Sterile Manufacturing
Facilities as appropriate. Comparison tables for particles and microbiological
organisms see Appendix A - B. Sites manufacturing for global markets should adhere
to the strictest requirements described in Appendix A B in order to meet all market
requirements.
5.2.1 Environmental Conditions for Sterile Manufacturing

Sterile manufacturing must take place in clean areas. The areas should be classified in
accordance with the requirements in Appendix A - B. All areas must be built and
validated to meet these requirements. The particulate conditions for Grade A should be
maintained in the zone immediately surrounding the product whenever the product or
open container is exposed to the environment. It is accepted that it may not always be
possible to demonstrate conformity with particulate standards at the point of fill when
filling is in progress, for example due to the generation of particles and droplets from
the product itself. There should be written justifications for any situation or process
steps where this could apply.
The particulate conditions for the at rest state should normally be achieved in the
unmanned state after a short clean up period of 15 - 20 minutes after completion of
operations. This cleanup period should be validated and periodically monitored.
In some cases, the processing room and the adjacent clean rooms have the same
classification. Maintaining a pressure differential between the processing rooms
and the adjacent rooms can provide beneficial separation.
In order to reach Grade A, B and C the number of air changes should be related to the
activity of the room. Re-circulation of air within clean areas should not be practiced
where the activities are creating dust. Re-circulation should preferably not be used to
re- circulate air from areas where different products are handled. In cases where recirculation is practiced the air should pass a filter system of an appropriate filter also
minimized and protection is provided against contamination during filling and closing
of units.
5.2.2 Environmental Conditions for Non-sterile Manufacturing

Non-sterile manufacturing should take place in general manufacturing areas.
There are no cGMP requirements to classify these areas with the exemption of
manufacturing of inhalation products, which must take place in Grade D.
Good engineering practice (GEP) should dictate the basic requirements for these
areas. The ISPE Pharmaceutical Engineering Guide for New and Renovated
Facilities, Volume 2, Oral Solid Dosage Forms should be consulted. Re-circulation of
air within general manufacturing areas should be justified and it should be taken into
account process activities that create dust. In cases where recirculation is practiced
the air should pass a filter system of an appropriate filter efficiency to avoid crosscontamination and to prevent recirculation of dust from production. In areas where air
contamination occurs during production, consideration should be given to provide
localized exhaust systems or other means to minimize potential for cross
contamination.
5.3 Production Areas
5.3.1 Layout
The layout of areas must minimize the possibility of product mix-ups.
The adequacy of the working and in-process storage space must permit the orderly
and logical positioning and separation of equipment and materials so as to minimize
the risk of confusion between different medicinal products or their components, to
avoid cross-contamination and to minimize the risk of omission or wrong
applicationof any of the manufacturing or control steps.
5.3.2 Air Treatment (HVAC)
5.3.2.1 General
Production areas should be effectively ventilated, by air handling units (including
filtration control and when necessary temperature and humidity control) appropriate to
the products handled, to the operating personnel, to the operations undertaken within
them and to external environment.Temperature and humidity controls should be

considered in terms of potential adverse effect on the medicinal products during their
manufacture and storage, or the accurate functioning of equipment. Areas were aseptic
processing takes
5.3.7 Sinks and Drains

Separate process and sanitary drainage must be provided. Drains must be of adequate
size and, were connected directly to a sewer, must be provided with an air break or
other mechanical device to prevent back-siphonage. They must be easy to clean. The
floor must slope locally towards the drain. Overflow outlets should normally not be
used. Floor drains with minimal usage should be filled with vegetable oil or contain a
trap primer in order to prevent the trap from drying out.
5.3.7.1 Special Requirements in Sterile Manufacturing
Sinks and drains should be prohibited in Grade A and B areas used for aseptic
manufacture.
5.3.8 Installations
All permanent pipe work, light fittings, ventilation ducts and other services in
classified areas should be designed and installed to avoid uncleanable recesses.
Services should run outside the processing areas and should be sealed into walls
and partitions through which they pass. The sealed pass through should be
designed to withstand vibrations. Fixed equipment should be installed without any
recesses where dirt can accumulate.
5.3.9 Airlocks
The use of airlocks should be considered as part of any manufacturing facility
design. Airlocks are one means to control containment necessary due to process or
product requirements. Personnel airlocks may be necessary for connection
of areas where dust- generating processes are performed or certain active substances
are handled. Such airlocks should be provided with cleaning facilities as needed.
The airlocks must have a system in place to prevent the opening of entry and
exit doors at the same time. This could be achieved by means of an interlocking
system and the doors should be self-closing.
Phases of the Prevalidation or activities

The prevalidation process would involve collaboration between established and
competent laboratories registered with the RVA, and would include three main phases:
1.Protocol refinement
2.Protocol transfer
3.Protocol performance
Protocol refinement
It involving interaction between Laboratory 1 and the laboratory 2.
A laboratory with sufficient experience in the relevant area would be contracted to act
as Laboratory 2
1. Creation of a workable, GLP-compliant protocol for the procedure.
2. Production of accompanying SOPs.
3. Determination of the intralaboratory reproducibility of the method.
4. Evaluation of its suitability for progression to Phase II
PROTOCOL TRANSFER
It involving collaboration between Laboratory 1, Laboratory 2 and the protocol
transfer laboratory
1. Transfer of the method to Laboratory 3 using the protocol and SOPs defined by
Laboratory 2.
2. Determination of interlaboratory transfer-ability (using the materials tested in
PhaseI).
3. Further refinement of the protocol, as necessary.
4. Evaluation of the suitability of the method for progression to Phase III.
5. Submission of an optimised protocol to INVITTOX (if a toxicity test method).
PROTOCOL PERFORMANCE
It comprising a blind study involving two or more laboratories, including Laboratory
2 and Laboratory 3.
Planning of phase-3;
management team reports to steering committee
discussion with RVA and/or other sponsors on specific aims of Phase III
detailed planning of Phase III, including selection of appropriate test chemicals
testing of coded materials in at least three laboratories
preparation of report on performance of the method
confirmation or redefinition of the prediction model
PROTOCOL-DEFINITION
A protocol is a predefined written procedural method in the design and

implementation of experiments.
Protocols are written whenever it is desirable to standardize a laboratory method to
ensure successful replication of results by others in the same laboratory or by other
laboratories.
Contents in protocol
Purpose and scope of study
Responsibilities and functioning of persons /organisational units involved in
study
Type of study conducted
Number of process validation runs
Quality of materials used in the process
Description of process
All major equipment used in the process
Critical process parameters and operating ranges
Sampling plans( i.e. sampling points,frequencies, quantities,procedures for
collecting samples)
Specifications and test data to be collected Acceptance critieria to conclude
that test study is successful Measures to betaken in the event of test method
failure
In addition to detailed procedures and lists of required equipment and
instruments,protocols often include information on safety precautions, the
calculation of results and reporting standards, including statistical analysis
and rules for predefining and documenting excluded data to avoid bias.
Written protocols are also employed in manufacturing to ensure consistent
quality SafteySafety precautions range from requiring goggles to provisions
for containment of microbes, environmental hazards, toxic substances.
Procedures
It may include not only safety procedures but also procedures for avoiding
contamination,calibration of equipment,equipment testing, documentation.
Calculations,statistics
Protocols for methods that produce numerical results generally include
detailed formulae for calculation of results
Reports
A protocol may specify reporting requirements. Reporting requirements
would include all elements of the experiments design and protocols and any
environmental factors.
PROTOCOL EXECUTION
It should contains
Test specifications
Fault and Observation Forms
Test report
Test documentation
Attachment list
Result of test specifications
Test specifications
It contains the test instructions, test acceptance criteria and results for the
items under test. It is very important to read the test specification carefully
before entering into any test execution. An entire dry run (time permitting)
should always be performed on any test script before official execution.
Fault and Observation Forms This will record the details and resolutions
for any incidents noted during testing One form is completed for each
incident noted and this is referenced in the test specification Any reference
to a fault or observation form should clear, and they are included in the
attachment listing section.
Test report This is the summary document that reports the findings of the
Test Phase The test report is an important document in the sense that an
auditor should be able to see quite clearly from the report how successful
the test phase was for the particular module/equipment/application.
Test documentation If its not written down then it didnt happen In this
the following are included Signature log Before commencing test, all testers,
witnesses and reviewers are required to sign the Signature Log which is
included in the test protocol, usually located at the back of the document
Test results The tester & witness must sign and date at the bottom of each
page. Completing pass/fail column If the results match the expected result
then mark as pass. If the results do not match the expected result then mark
as fail and reference the corresponding observation/ deviation number If the
test section does not apply to the test step then mark this section as N/A & a
brief explanation to all these should mention
Attachment list
Test Reference
Test Section
Attachment Number
Page No _ of _
Initial and Date
Complete the table in the attachment list section of the test
specification to list all Test Attachments.
Result of test specification If all tests were passed without incident,then

mark clearly on the protocol passed. If any test failed and faults or
observations were raised, state whether the faults or observations are closed
or resolved, if resolved mark as pass. Mark the overall test protocol as
passed if all the faults and observations have been closed out, if not indicate
that observations or deviations are still open
Deviation and change control:

What is the deviation? A deviation is an activity performed or occurred either
planned or unplanned in a different or modified form from specified manner.
3. How many part of deviation? Deviation Divided into two parts Planned &
Unplanned deviation : Planned Deviation: Any deviation from documented
procedure opted deliberately for temporary period to manage unavoidable situation
without affecting the quality and safety of drug substances or drug product shall be
termed as planned deviation. Unplanned Deviation: Any deviation occurred in
unplanned manner due to system failure or equipment breakdown or manual error
shall be termed as unplanned deviation.
4. Documents covered under the scope of this standard operating procedure
include the following, but are not limited to: Standard Operating Procedures
Manufacturing Procedures Packing Procedures Cleaning Procedures
Environmental Monitoring Batch analysis (In-Process Control) Quality control
testing Utility Operations Calibration Procedures Analytical Procedures
Stability Procedures
5. Rules and Regulations No process deviation should be permitted under normal

operating conditions however in case the deviation is unavoidable; the same should
be immediately brought to the notice of QA In-charge. No deviation shall be
permitted from Pharmacopoeia and other Regulatory specifications. Before
initiating the deviation format, an evaluation shall be done to assess whether the
deviation has any quality impact or quality non-impact
6. Rules and Regulations Quality Impact occurs during execution of an activity

which will affect the quality, purity or strength of the drug product. Quality Nonimpacting occurs during execution of an activity which will have no impact on the
quality, purity or strength of the drug product Only the deviation which is quality
nonimpacting in nature can be allowed with corrective actions. Planned
continuous deviation may be incorporated as Documentation change through
appropriate change control
7. Rules and Regulations The initiator shall indicate the deviation and mention the
stage of operation in the deviation report as per format along with the immediate
proposed corrective action in consultation with department head and the deviation
report shall be forwarded to QAD. QA designated representative shall evaluate the
deviation with respect to the impact on quality and propose a suitable corrective
action based on the nature of deviation. QA designated representative shall
approve the deviation and assign the number. QA designated representative shall
forward the report to Head Quality Assurance for authorization. The Head of Quality
Assurance shall review the report with their own recommendation if required, in the
remarks column. Head QA shall give the final approval for remedial action

8. Rules and Regulations In case of deviation related to the products of contract
giver, the deviation shall be immediately brought in to the notice of Qualified Person
of contract giver through e-mail or fax. The deviation shall be approved or rejected
based on the recommendation of qualified person of contract giver. The report
shall then be forwarded to concerned department as applicable based upon the
nature of deviation. The department head shall ensure that the authorized
remedial actions are implemented. Quality assurance shall retain the original for
records irrespective of the approved / reject status of the deviation report, and a
photocopy of the same shall be filed with the subjected batch processing / packing
record or analytical reports.
9. Wherever a deviation could affect multiple batches, e.g. due to equipment or
facility failure or material or process deviation report, a photocopy of the same shall
be filed with the subjected batch processing / packing record or analytical report.
QA designated representative shall maintain summary of Deviations, Department
wise, every year in a logbook. Deviation log fill as per format. Deviation control
numbering system as per SOP. Rules and Regulations
10. Originating Department When deviation occurs prepare the report QA

Designated Representative Assess type of deviation Allot the Deviation Control
Number and forward to concerned department head Concerned Department Head
Comments after evaluation / reason for deviation Other Department Head
Other department heads for corrective action to avoid their justification Quality
Assurance Forwarded to Head QA for Comments / conclusions Quality
Assurance After approval one copy to deviation log and one copy along with
respective report / record End of Deviation Reporting SOP Repeat deviations to
be investigated Yes Remedial action to avoid reoccurrences Raise change
control to make it part of process / procedure if accepted Procedure/ Function of
Deviation Process
Procedure of change control:

Process of change control [13]
Commitment of the company to control change to premises,
supporting utilities, materials, equipment and processes used in
the manufacture of medicinal products is essential to ensure a
continued validation status of the systems concerned. This
commitment should be stated in the relevant company
documentation. For example, the Quality Manual, Quality Policy

Documents or the Validation Master Plan; as part of its Quality
Management System the company should have a defined and
formalized Change Control Procedure.
Procedure for change control process at Company and/or Sponsor
Level Following procedure is applies for both GMP [14]
The procedure should always begin with a request for a change.
This request should be formalized in some way, for example as a
form, and be signed.
The request triggers the question of the impact of the change on
the product quality/safety of the population. It can be necessary
to define several levels of impact on product quality but there
should be at least two categories; major and minor impact. The
treatment of these two options should be clearly different.
There should be clear rules for the decision, whether the impact
of the change on the product quality and/or on study is major or
minor: who decides and why the decision is taken.
For the management of changes, an early decision is required of
who should be involved. The decision should be taken by the
process owner, who normally has the best knowledge of the
impact of changes on the product or study (or at least can
estimate it with a high degree of certainty). The principle of
double checking should be implemented at this point of the
procedure. A signature by the technical department is first
required. Depending on the companys or sponsors procedure,
the quality unit can be involved as an approver to check
periodically by self-inspection audits.
If the owner has decided that the change is minor and there is
nolikely to impact on the quality of the product, it can be
implemented. The change should be adequately documented.
The implementation of the changes with minor impact can be
achieved in a very rapid and efficient manner using checklists of
standard changes. The list of these changes should have been
approved by the quality unit.
If the decision has been taken that the change can or will have
an impact on the quality of the product and/or safety of the
population, the quality unit has to be involved. An adequate
rationale and an appropriate action plan should accompany such

request. This builds the basis for the approval by the quality unit.
After the Quality Unit approval
, the change can be implemented. If other aspects are affected by
the change
, for example safety aspects, additional release activities can be
needed. Where such activities have been define , these should be
fulfilled before the refuse of the equipment. Release of the
equipment itself can be one of these activities.
The start of a change control system for technical equipment
should be established after the completion of qualification. This
will ensure that the qualified status is maintained.
Change control before completing qualification need not possess
the same degree of formality as it can be easier regulated and
can proceed without the formal and immediate involvement of the
quality unit. The required activities in this case are adequate
documentation of the changes and a periodical adaption of the
documentation.
The change requests for emergency changes can be formalized
after the replacement. Emergency cases should be defined by
each company in an appropriate way.
validation:
validation Validation is the process of establishing a documented evidence which provides a high
degree of assurance that a specific process will consistently produce a product meeting it predetermined specifications and quality characteristics. Validation is the act of proving that any
procedure, process, equipment actually leads to the expected results and produce the quality
result.
revalidation:
revalidation Revalidation means repeating the original validation or any part of it and includes
investigative review of existing performance data. It is done annually in form of reviewing and
analyzing annual records in the form existing data such as those from manufacturing batch
records, etc.. It reconfirms that the control parameter ranges are appropriate.
Need for revalidation:

Need for revalidation Whenever there is the major change in the process or in the equipment
used or due to changes in environment conditions , then there should be revalidation of the
validated process. When change in critical components(Raw materials) When there is change in
location or site Significant increase in batch size Change or replacement in equipment To reduce
batch to batch variations , revalidation must be done.
Scale up and post approval changes:

Scale up and post approval changes SCALE UP Post approval changes When we go for higher
production(i.e. from pilot to manufacturing scale) Make changes in already approved or
validated
UNIT-4
Packaging labeling control
Materials examination andusage criteria.
(a) There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing
of labeling and packaging materials; such written procedures shall be
followed. Labeling and packaging materials shall be representatively
sampled, and examined or tested upon receipt and before use in packaging
or labeling of a drug product.
(b) Any labeling or packaging materials meeting appropriate written
specifications may be approved and released for use. Any labeling or
packaging materials that do not meet such specifications shall be rejected to
prevent their use in operations for which they are unsuitable.
(c) Records shall be maintained for each shipment received of each different
labeling and packaging material indicating receipt, examination or testing,
and whether accepted or rejected.
(d) Labels and other labeling materials for each different drug product,
strength, dosage form, or quantity of contents shall be stored separately with
suitable identification. Access to the storage area shall be limited to
authorized personnel.
(e) Obsolete and outdated labels, labeling, and other packaging materials
shall be destroyed.
(f) Use of gang-printed labeling for different drug products, or different
strengths or net contents of the same drug product, is prohibited unless the
labeling from gang-printed sheets is adequately differentiated by size, shape,
or color.
(g) If cut labeling is used, packaging and labeling operations shall include
one of the following special control procedures
(1) Dedication of labeling and packaging lines to each different strength of
each different drug product;
(2) Use of appropriate electronic or electromechanical equipment to conduct
a 100-percent examination for correct labeling during or after completion of
finishing operations; correct labeling during or after completion of finishing
operations for hand applied labeling. Such examination shall be performed
by one person and independently verified by a second person. (h) Printing
devices on, or associate with, manufacturing lines used to imprint labeling
upon the drug product unit label or case shall be monitored to assure that all
imprinting conforms to the print specified in the batch production record.
Labeling issuance.
(a) Strict control shall be exercised over labeling issued for use in drug
product labeling operations.
(b) Labeling materials issued for a batch shall be carefully examined for
identity and conformity to the labeling specified in the master or batch production records.
(c) Procedures shall be used to reconcile the quantities of labeling issued,
used, and returned, and shall require evaluation of discrepancies found
between the quantity of drug product finished and the quantity of labeling
issued when such discrepancies are outside narrow preset limits based on
historical operating data. Such discrepancies shall be investigated in
accordance with 211.192. Labeling reconciliation is waived for cut or roll
labeling if a 100-percent examination for correct labeling is performed in
accordance with 211.122(g)(2).
(d) All excess labeling bearing lot or control numbers shall be destroyed.
(e) Returned labeling shall be maintained and stored in a manner to prevent

mixups and provide proper identification.
(f) Procedures shall be written describing in sufficient detail the control
procedures employed for the issuance of labeling; such written procedures
shall be followed.
Line clearance:
Overview
Packaging Instructions should normally include, or have reference to the
following:
* (f) Special precautions to be observed, including a careful examination of
the area and equipment in order to ascertain the line clearance before
operations begin."
Packaging lines represent a large investment. How best to maximise the
Return-On-Investment (ROI) is the most important factor!
Remember - Good GMP never conflicts with line efficiency, so minimising
line clearance time and overall changeover time must go hand-in-hand with
minimising risk!
Correct machine design means easy to change over, easy to clear and
therefore easier to return to production status.
Correct selection of the auxiliary components like the security and printing
equipment will also maximise the ROI for the same reasons and optimise line
clearance and overall changeover time.
Considering the application in terms of long or short production runs, this
will help select the correct type of equipment for the application and can
optimise line clearance time.
Example: clinical trials and small blister machines
Falling batch sizes are increasingly presenting the pharmaceutical
packaging industry with a challenge. The ratio of set-up time to running time
is constantly worsening, with the result that in many cases line efficiency is
below 30%.
Ideas to Improve Line Clearance

Consider the flow of materials and personnel with time, avoiding the risk of
re-contamination after clearance. Cleaning and clearance are separate
processes.
Segregate materials from the old batch. Have clear identification of the
next product to be packed and all other packaging components to be used
aids clearance.
Consider methods of reconciliation of components on the line. The largest
source of contamination is leftovers from a previous batch - John Sharp 2000.
Ideas to Improve Line Clearance
Have physical separation between adjacent lines aids clearance.
Good housekeeping aids clearance, we cannot clean where there is mess!
Advertise the status of the line clearly both pre and post clearance and into
production line mounted information sheets help everyone understand the
line status.
Primary Packaging
Improving the visibility within the machine additional lighting and clear
guards, add mirrors for difficult to see spaces where small components like a
tablets can lodge.
Make difficult to clean parts of the machine dedicated to a product.
Dedicated de-duster
Dedicated settling brush
Primary and Secondary Packaging

Methodology of line clearance for efficiency, identify hot-spots on the
machine and give consideration to improving them.
Designated areas of machine receiving different cleaning protocols.
Having to clear, clean and change-over only from the operator side speeds
up the line clearance.
Avoiding flat surfaces where packaging components can collect, this

philosophy can extend across the entire packaging area, not just the
machine and aids line clearance.
Secondary Packaging
Balcony construction machine improves line clearance efficiency by
removing traps
Example:
A leaflet on the bottom of the machine could not get into the finished
product and
therefore can be considered to be low risk
Human Machine Interfaces (HMIs)

Mechanical Requirements
Touch screen
Easy to clean
No traps like keyboards, mice or heatsinks with small fins
No exposed components smooth external surfaces
Operational Requirements
Easy to visualise and program
Ergonomic for speed and efficiency
Product oriented download Security and Printers
Single point data entry for bar codes, variable text cameras and
programmable printers
Moving away from embossing except for Braille Human Machine Interfaces
Security and Printers
Some customers already require that they be able to load zero data sets
in between
batches the electronic equivalent of line clearance prior to new product

data being
brought to the line
Final integration step - Production security data can be integrated directly
with the
manufacturing systems ERP, MES for direct download of product specific
security information
MES = Manufacturing Enterprise System
ERP = Enterprise Resource Planning Security and Printers
On-demand in line printing for foils bring less product specific material to
and from the line lowers the risk and aids clearance
Ultimate goal The white lines packaging concept packaging materials
printed in line, on
demand and just in time
This can be just a data change when full digital printing is done
Printing and Late Stage Customisation (LSC)
LSC allows suppliers to produce a standard, generic, core pack (Blister,
Carton) in bulk volumes, with only a single bar code identification on it.
Then have this blister or pack customised with local language either
in-house, or at an outsourcing facility.
This is a genuine new development in the industry and brings with it new
considerations for line clearance activities.
Pack Rationalisation & Brand Imaging
Standardised Pack and blister formats imaging reduces machine
changeover
Time
Brand imaging seek to make all packs identical
But these factors can have negative effect on line clearance, as visible
differentiation
becomes more difficult for the operators
Of course the security devices will detect incorrect packaging elements
Quality control laboratories:

Quality control::
Quality control: Quality control deals with the system which accepts or rejects any activities or
parameter which affects the quality of product and thus prevent quality deficiency. Quality
assurance: It is a system which assure that the overall activities in the laboratory are being
performed as designed by particular standards. 2
Responsibilities::
Responsibilities: Study Directors Responsibilities 1. The Study Director has the responsibility
for the overall conduct of the study and for its final report. 2. These responsibilities should
include, but not be limited to, the following functions. 11
The Study Director should: a) Approve the study plan and any amendments to the study plan
by dated signature.
b) Ensure that the Quality Assurance personnel have a copy of the study plan and any
amendments in a timely manner and communicate effectively with the Quality Assurance
personnel as required during the conduct of the study.
c) Ensure that study plans and amendments and Standard Operating Procedures(SOP s) are
available to study personnel. 12
d) Ensure that the procedures specified in the study plan are followed, and asscess and document
the impact of any deviations from the study plan on the quality and integrity of the study, and
take appropriate corrective action if necessary.
e) Ensure that all raw data generated are fully documented and recorded.
f) Ensure that computerised systems used in the study have been validated. 13
g) Sign and date the final report to indicate acceptance of responsibility for the validity of the
data and to indicate the extent to which the study complies with these Principles of Good
Laboratory Practice.
h) Ensure that after completion (including termination) of the study, the study plan,the final
report, raw data and supporting material are archived. 14
Principle Investigators responsibilities: The principle investigator will ensure that the
delegated phases of the study are conducted in accordance with the applicable principles of Good
Laboratory Practice(GLP). 15
Study personnels responsibilities 1. All personnel involved in the conduct of the study must be
knowledgeable in those parts of the principles of Good Laboratory Practice which are applicable
to their involvement in the study.
2. Study personnel will have access to the study plan and appropriate Standard Operating
Procedures applicable to their involvement in the study. It is their responsibility to comply with
the instructions given in these documents. Any deviation from these instructions should be
documented and communicated directly to the Study Director, and/or if appropriate, the Principal
Investigator(s). 16
3.All study personnel are responsible for recording raw data promptly and accurately and in
compliance with these Principles of Good Laboratory Practice, and are responsible for the
quality of their data.
4.Study personnel should exercise health precautions to minimise risk to themselves and to
ensure the integrity of the study. They should communicate to the appropriate person any
relevant known health or medical condition in order that they can be excluded from operations
that may affect the study. 17
Good laboratory practices:

Definition:Good Laboratory Practice is defined as a quality system
concerned with the organisational process and the conditions under which
non-clinical health and environmental safety studies are planned, performed,
monitored, recorded, archived and reported. 1
SCOPE: These principles of good laboratory practice should be applied to the nonclinical safety testing of test items contained in pharmaceutical products,
pesticide products, cosmetic products, veterinary drugs as well as food
additives, feed additives, and industrial chemicals. These test items are
frequently synthetic chemicals, but may be of natural or biological origin
and, in some circumstances, may be living organisms.
The purpose of testing these test items is to obtain data on their properties
and/or their safety with respect to human health and/or the environment.
Non-clinical health and environmental safety studies covered by the
principles of good laboratory practice include work conducted in the
laboratory, in greenhouses, and in the field.
The purpose of the Principles of Good Laboratory Practice is to promote the
development of quality test data and provide a tool to ensure a sound
approach to the management of laboratory studies, including conduct,
reporting and archiving.
The Principles may be considered as a set of standards for ensuring the

quality, reliability and integrity of studies, the reporting of verifiable
conclusions and the traceability of data
However, adherence to GLP will remove many sources of error and
uncertainty, adding to the overall credibility of the study.
Respecting the GLP Principles will thus indirectly optimise the scientific
yield of studies. Fulfil the legal requirements of some FDA and EPA research
studies. GLP principles can be followed to increase the quality of basic
research. 1
Depending on national legal situations, the GLP requirements for nonclinical laboratory studies conducted to evaluate drug safety cover the
following classes of studies :
Single dose toxicity
Repeated dose toxicity (sub-acute and chronic)
Reproductive toxicity (fertility, embryo-foetal toxicity and teratogenicity,
peri-/postail in study plans or natal toxicity)
Mutagenic potential
Carcinogenic potential
Toxicokinetics (pharmacokinetic studies which provide systemic exposure
data for the above studies)
Pharmacodynamic studies designed to test the potential for adverse
effects (Safety pharmacology)
Local tolerance studies, including phototoxicity, irritation and sensitisation
studies,or testing for suspected addictive and/or withdrawal effects of drugs.
Organization:
In large laboratories, the sample may be sub-divided between several
specialized subunits. each of which carries out the part of the analysis that
class for a particular skills.
In every case , however lead unit or a focal point must be made

responsible for the distributing and testing the sample and collating and
interpreting the results.
The division of the laboratory into subunits may be based on :
The main techniques used: (chemical unit, instrumental unit,
microbiological unit, unit for biological safety testing).
Or on the type of product tested (antibiotic unit, crude drug unit,
radiopharmaceuticals unit)
Whichever plan is chosen care must be taken to ensure even distribution of
the workload between units and precise allocation of responsibilities.
Division of laboratory unit into subunits should never be allowed to inhibit
communications between the staff involved in testing the same sample.
Inter communication helps the lead unit to piece together all the
information on which the quality of the sample is ultimately judged.
Large laboratory need various supporting and coordinating sections,
including a central registry and specification repertory
The head of the central registry must be a person with wide experience in
analysis and will be responsible for
receiving the all incoming samples and accompanying documents,
Supervising their delivery to the lead units and keeping a constant check
on the progress of analyses and dispatch of completed reports.
The specification repertory maintains an up to date collection of all quality
specifications and related documents
STAFFING:
The head of the laboratory, and the heads of the various subunits in larger
establishments, should be of high professional standing and have had
extensive previous experience in drug analysis and laboratory management
in QC laboratory in the regulatory sector or in industry
Non-supervisory analyst should be a graduate in pharmacy, analytical
chemistry, microbiology or other relevant subjects.
Technical staff should preferably hold diplomas in their subjects from

technical or vocational schools. The head of the laboratory must be satisfied
that all the key members of the laboratory staff requisite competence and
are given grades matching their responsibilities 2
To reduce the possibility of human error, supervisors should periodically
arrange for standard samples to be analyzed and, where called for, review of
adequacy of existing staffing, management and training procedures.
Regular in-service training programmers should be arranged to update
and extend the skills of both professional and technicians.
In large laboratories the staffing of various units should be based not only
on their workload but also on the technical demands of the work involved.
Technician : analyst :: 1:3 in a chemical or physicochemical unit
Technician: analyst ::2:5 in biological or microbiological unit
ROUTINE CONTROLS:
Contamination Checks: On a routine basis and/or when a problem is
suspected, materials and supplies used in sample testing are tested for
contamination, using known controls
The shipping/transport container holding the samples is externally
decontaminated prior to opening. Upon opening of container, the inside of
the container is inspected for sample spillage. All shipping containers should
be disinfected properly following use.
Tubes, bags or other items containing tissue samples are removed,
externally disinfected, and placed in clean laboratory racks, bags or
containers bearing the appropriate CHR number.
Data on each tissue sample is recorded and entered onto the CHR data
sheet as described in section II.F. Any written material and sample
descriptions received with the samples are attached to the CHR.
Wear lab coats within laboratory (coats are laundered regularly).
Wash hands with antibacterial soap before and after lab.
Clean countertops with an appropriate disinfectant preceding and following

any lab work
Decontaminate container surfaces with alcohol spray before and after use.
Clean countertops, floors and waste cans routinely or when needed with an
appropriate solution of disinfectant.
Clean inside surfaces of refrigerators when spills occur.
Decontaminate waste materials from sample processing/ necropsies in an
appropriate disinfectant solution prior to disposal, freeze excess material in
plastic bags, or autoclave prior to proper disposal. If autoclaved, use
autoclave tape for assurance of proper sterilization.
Thoroughly decontaminate tube racks, slide boxes and other items with
possible contamination prior to reuse.
Do not eat, drink or smoke in the lab.
Immediately clean and disinfect any biological agent or media spills.
In general, avoid clutter and maintain lab equipment in an orderly and
functional manner.
Laboratory Data Log All incoming samples must be logged into a Lab data
logging system designed to record the number and type of samples, and
field sampling date. The log must contain designated spaces for logging each
case out as they are completed, to include the date and initials of the
employee completing the lab work.
Data Entry Forms a form must be completed for all assays and must
include the CHR number, type of procedure used for analysis, and results.
All testing records must be initialed and dated by the employee performing
the lab work.
INSTRUMENTS;The requirements for instruments will depend on the type of samples that
are to be tested in a testing laboratory. Approved drug testing laboratories
carry out testing of a approved of a variety of samples major equipments
that a testing laboratory may require are, Analytical balances including
monopan balance, IR Spectrophotometer, UV Visible Spectrophotometer, Gas

Chromatograph, Polarimeter , PH meters, Disintegration test apparatus,
potentiometer, IR hydraulic pellet press with dies, agate mortar with pestle,
Karlfischer titrator, Oxygen flask combustion apparatus, HPLC, Flame
photometer, HPTLC.
Equipments for microbiological laboratory are also given below;Autoclaves, Microscopes.[bacteriological],Incubators, Centrifuge with
refrigeration, Membrane filter assembly for sterility tests, Colony counter
with mangnifying glass, Laninar flow
bench,Hotairsterilizer,Spectrophotometer(visiblerange),Nephelometer,Refrig
erators,Deepfreezer;,Large plate microbiological assay equipment including
zone reader and recorder,pH meter Cleansing machines for glassware
especially for cleaning pipettes.
Thermostatically controlled water baths. These lists should not be taken as
exclusive. Before major items of instruments are purchased, It should be
ensured that facilities are available for their proper maintenance and repair
preferably by proper maintenance and repair preferably by representatives
or their agents. Electrical equipments should be compatible with available
frequency and line voltage. Standard sets of replacement parts required for
routine repairs containing such items as gaskets and spare bulbs should
always be available in stock. Certain sophisticated equipments like gas-liquid
and high-pressure liquid chromatography and atomic absorption
spectrophotometers require regular supply of special solvents, reagents and
compressed gases of high purity, Availability of these should also be
ascertained before their purchase. Laboratory equipments and instruments
should be maintained and calibrated periodically. For maintenance, service
contract with the manufacturer or supplier can be made.
An important consideration when procuring equipment/instruments is design
specifications. Design specifications of important glass wares have been
mentioned above, for balances and weights the following Indian standards
may be referred.
-IS 9440; 1979-Specifications for laboratory Balances,
- IS 9865-1981- Specifications for laboratory weights.
Different pharmacopoeias describe apparatuses in the appendices, Although
apparatus manufacturers take into account the design specifications while
fabricating apparatuses, but it will be worthwhile to carry out design
qualification of the apparatus when it is received in the laboratory. Although

qualification of equipment is a part of validation. But it is relevant here
therefore, qualification of equipment will be satisfy design qualification,
installation qualification, operational qualification, performance qualification.
PROTOCOL:
Means a document established in each study which is to ensure that the
study methods and operating procedures required to attain the intended
purpose of the study will be authentically adopted. For each study, a plan
should exist in a written form prior to initiation of the study. The study plan
should be retained as raw data. All changes, modifications, or revisions of the
study plan, as agreed to by the study director including justification (s)
should be documented, signed and dated by the study director, and
maintained with the study plan. That support and regulate the conduct of the
scientific studies.
The purpose of these documents is to:
describe general policies, decisions and principles governing the way in
which the research centre operates
define the experimental design for particular studies;
instruct staff about how to carry out routine operations;
Provide support retrospectively when investigating what was actually done.
The protocol is the central document through which the study director
communicates the objectives and conduct of the study to the study staff and
to third parties (such as the quality assurance unit [QAU] or the study
sponsor). In the case of a study performed by a contract research
organization (CRO), the protocol may also be contractual. The protocol
contains the overall experiment plan with timeframe, a description of the
study design with methods and materials and the responsibilities of the
scientific staff concerned. Since the protocol is the principal means of
communication with study staff it should be designed and written with clarity
so that it can be readily understood by everyone. 6
Content of the protocol
Identification:
The study identification number, or the number attributed to the protocol,
must provide a means of uniquely identifying the study in the records of the
laboratory and of confirming the identity of all data generated during the
study.
Title and Statement of Purpose:
It is important to state why a study is being performed. A study must be
planned and designed in advance. This can be done adequately only if the
designer has a clear understanding of the purpose of the work.
Identification of Test (and Control) Items
This includes not only the chemical name and/or code number of the test
item but also its specifications or characterizations or details about how
these will be determined if they are not yet available. The protocol must also
detail any control materials to be used in addition to the vehicle.
Name of Sponsor and Address of Test Facility:
The sponsor and the test facility may or may not be the same company. The
protocol should indicate where the test is to be carried out and also include
the address of any consultants involved. The name of the sponsor should
also be included.
Name of Study Director and Other Responsible personnel:
The name of the study director must be included in the protocol. It is good
practice to identify any other responsible scientists who are going to
contribute significantly to the study. Most laboratories include the names of
scientists who will be responsible for the interpretation of the data generated
under their responsibility (e.g. pathologists, clinical pathologists).
Proposed Dates:
The proposed dates for the study are the start and finish dates
(corresponding to the date when the protocol is signed and the date when
the report is signed by the study director) and the experimental dates. These
correspond to the dates when the first and last experimental data are
collected. To help study personnel perform their work.
Justification for Selection of the Test System:
When animals are the test system being used in an experiment, the species
and possibly the strain may be defined in scientific test guidelines. However,
even if working to test guidelines, it is still important to state in the protocol
why the test system has been chosen. Often the choice is based on the
background (historical) data available at the test facility (or site).
Description of the Test System:
For animal experiments, this will include the proposed species, strain, age,
weight and source of animals and how they are to be identified. It will also
contain details of the animal husbandry including environmental conditions,
diet and its source.
Experimental Design:
Dosing details: Dose levels
Frequency of dosing
Vehicles used
Method of preparation
Quality control.
Method of assigning animals to their experimental groups.
Parameters to be measured and examined:
This section identifies the measurements to be made and the frequency of
measurement.If certain procedures are not routine and not covered by SOPs,
complete details of the non-standard procedures, or references to them,
would be require,
Records: A list of records to be retained.
NON-CLINICAL TESTING:
Nonclinical or Preclinical studies are research studies that are conducted,
typically on animals, before a permit for clinical trial humans can be
obtained. Preclinical studies serve a vital role in the drug discovery and
development processes. These studies can be used to identify lead
compounds likely to possess favorable biopharmaceutical and
pharmacokinetic properties in humans. In addition, they can facilitate
transition of discovery to development, as well as decrease the need for

expensive and time-consuming clinical studies.
The main goals of pre-clinical studies (also named preclinical studies and
nonclinical studies) are to determine a product's ultimate safety profile.
Products may include new or iterated or like-kind medical devices, drugs,
gene therapy solutions, etc.
Types of preclinical research:
Each class of product may undergo different types of preclinical research. For
instance, drugs may undergo pharmacodynamics (PD), pharmacokinetics
(PK), ADME, and toxicity testing through animal testing. This data allows
researchers to allometrically estimate a safe starting dose of the drug for
clinical trials in humans. Medical devices that do not have drug attached will
not undergo these additional tests and may go directly to GLP testing for
safety of the device and its components. Some medical devices swill also
undergo biocompatibility testing which helps to show whether a component
of the device or all components are sustainable in a living model. Most preclinical studies must adhere to Good Laboratory Practices (GLP) in ICH
Guidelines to be acceptable for submission to regulatory agencies such as
the Food & Drug Administration in the United States.
Typically, both in vitro and in vivo tests will be performed. Studies of a
drug's toxicity include which organs are targeted by that drug, as well
as if there are any long-term carcinogenic effects or toxic effects on
mammalian reproduction.
Choice of species:
The choice of species is based on which will give the best correlation to
human trials. Differences in the gut, enzyme activity, circulatory system, or
other considerations make certain models more appropriate based on the
dosage form, site of activity, or noxious metabolites. For example, canines
may not be good models for solid oral dosage forms because the
characteristic carnivore intestine is underdeveloped compared to the
omnivore's, and gastric emptying rates are increased. Also, rodents
can not act as models for antibiotic drugs because the resulting alteration to
their intestinal flora causes significant adverse effects. Depending on a drugs
functional groups, it may be metabolized in similar or different ways between
species, which will affect both efficacy and toxicology. Medical device studies
also use this basic premise. Most studies are performed in larger species
such as dogs, pigs and sheep which allow for testing in a similar sized model
as that of a human. In addition, some species are used for similarity in
specific organs or organ system physiology (swine for dermatological and
coronary stent studies; goats for mammary implant studies; dogs for gastric
studies; etc.).
CONTROL ON ANIMAL HOUSE:

Good animal husbandry and human comfort and health protection require
separation of animal facilities from personnel areas such as offices,
conference rooms, and most laboratories.
Laboratory animals are very sensitive to their living conditions. It is
important that they shall be housed in an isolated building located as far
away from human habitations as possible and not exposed to dust, smoke,
noise, wild rodents, insects and birds.
The building, cages and environment of animal rooms are the major
factors, which affect the quality of animals.
This separation can be accomplished by having the animal quarters in a
separate building, wing, floor, or room. Careful planning should make it
possible to place animal housing areas adjacent to or near laboratories, but
separated from them by barriers such as entry locks, corridors, or floors.
In planning an animal facility the space should be well divided for various
activities.
The animal rooms should occupy about 50-60% of the total constructed
area and the remaining area should be utilized for services such as stores,
washing, office and staff, machine rooms, quarantine and corridors.
The environment of animal room (microenvironment) and animal cage
(microenvironment) are factors on which the production and experimental
efficiency of the animal depends. Since animals are very sensitive to
environmental changes, sharp fluctuations in temperature, humidity, light,
sound and ventilation should be avoided.
Data generation and storage:
A data should contain description of the conduct of the technique, including

the results of the observation or measurement, and demonstrating that the
actions required by the protocol were carried out. The data should indicate
that they were collected and recorded in accordance with the methods set
out in the SOPs and Protocol, or indicate where there were deviations from
these instructions. This is done by recording the date and, if necessary, the
time that the procedure was conducted. For certain procedures (for example
sampling in a toxicokinetic study) very exact timing is necessary. The data
should clearly identify who was responsible for carrying out the procedure
and recording the data. If more than one person is involved in a procedure
this should be recorded in the data, along with an identification of the
responsibilities of each. All data generated during the conduct of a study
should be identified and recorded directly, promptly, accurately, legibly and
indelibly by the person entering the data, and be signed or initialled, and
dated. Any changes should me made so as not to obscure the previous entry,
and should indicate the reason for such change.
The person making the change must sign and date it. 11
Identified: The study number, animal number, etc. must be recorded with
the data in order to ensure that data mix-ups do not occur. The parameter
evaluated must be identified.
Directly: Since the first written records are considered to constitute the raw
data and must be retained, records should not be made on scraps of paper
and then transcribed into a final form. When data are acquired directly by
computer the raw data are considered to be the electronic medium. For data
derived from equipment, the raw data may be a direct print out (or trace) or
in an electronic form.
Promptly: Data must be recorded as the operation is done. It is not
acceptable to make the record some time after the task has been completed.
Accurately: This is most important as the accuracy underpins the scientific
interpretation and integrity of the study.
Legibly: Data that cannot be read are useless and records that are difficult
to decipher raise doubts as to their credibility.
Indelibly: One of the original problems that gave rise to GLP was that data
had been recorded in pencil and were subject to subsequent changes without
this being evident. Use indelible and waterproof ink; ballpoint pens are well
suited for the purpose. Check the robustness of machine-print outs. Some
print disappears quickly (or become totally black) as is the case with lightsensitive print-outs from thermo-printers. In this case, take an authorised
(signed and dated) photocopy for storage.
Signed: Accountability is one of the basic tenets of GLP, hence the need for
a record of who did every job on a study.
Dated: The date of each signature demonstrates that the procedure was
conducted and recorded at the correct point in the study. Reasons for
corrections: Records may require alteration from time to time, but a clear
audit trail is needed showing why a change was carried out, when and by
whom. Data should be recorded and organised in a way that facilitates both
the making of the record and the performance of subsequent processes (e.g.
data entry, reporting, audit, archiving). Data should be recorded in a logical
way, and duplication should be avoided wherever possible. Pro-forma
documents assist in this by encouraging staff to record all the data required,
without forgetting any. A clear structure for the study file, defined upfront,
helps you to organize and archive the documents as they are produced in
real-time, preventing loss and facilitating reference between records.
The Use of Computerised Systems:

Computers are used not only for the collection of data but also for planning
and other organizational purposes. The use of computerised systems has
undoubtedly increased the efficiency of study performance and the reliability
of data.
Term of storage:
The retention period is stated in national GLP regulations. Often, however,
because reports are submitted to several authorities at different times or
may be needed for other purposes, the period of retention may exceed
these. Each event of archive destruction must, therefore, be treated on a
case by case basis. 11
HOW are holdings stored? Securely:
Only authorised personnel permitted.
Fire, pest and vandalism protection. Under conditions which minimise
deterioration:
Air conditioned general environment.
Copies of heat sensitive papers made.

Refrigeration used where necessary.
General warehousing procedures defined.
Blocks sealed, tissues wrapped in preservative soaked gauze on heat
sealed bags, slides cover slipped, etc.
Computer backups maintained in security cabinet.
Indexing
As rapid retrieval may be necessary, it is good practice to impose a rigorous
system of indexing archived material. This is often computerised and
provides complete and quick retrieval starting from any one of the indexed
parameters. For example, all study or lot specific materials are given a
unique holding number which corresponds to a specific location. Facility
specific material is filed using common-sense (i.e.chronologically,
alphabetically). 12
Decision to Retain Records Electronically
The decision to retain records in electronic form has important implications.
The long-term retention of electronic records may influence the choice of
storage medium since deterioration of storage media can lead to permanent
loss of records. Computer technology is developing rapidly and devices
capable of reading storage media in common use today may not be available
in the future. Electronic records should be stored in a format that is readable
for the duration of the applicable record retention period.
Storage Media
Records may be migrated from a computerised system onto a storage
medium, e.g. magnetic tape, diskette, CD or optical disk that can be placed
in a physical archive. Archive procedures should include the consideration of
additional controls for the migration of electronic records from old to new
media of these records. Consideration should be given to future access to the
data or records stored on these media. There may be a need for special
storage conditions, e.g. protection from magnetic fields.
UNIT-5
Manufacturing and controls on dosage form

Manufacturing documents:
DEFINITION: As per ISO, documentation can be defined as: Information
created, received and maintained as evidence and information by an
organization or person, in pursuance of legal obligation or transaction of
business.
IMPORTANCE OF DOCUMENTATION:
9. D- Design, development, deviations, dossiers, drug master files for

regulation purposes O- Operational procedures/methods/techniques, out
of specifications(OOS), out of trends(OOS) C- Cleaning, calibration, control,
complaints, closures, containers and contamination U- User requirement
specifications, utilities like water systems, HVAC, AHU, etc. 9
10. M- Man, materials, methods, maintenance, manufacturing operations

and control, monitoring, master formula, manuals E- Engineering control and
practices, environmental control, equipment qualification documents NNon-routine activities, new products and substances T- Technology,
transfer, training, testing, trend analysis, technical dossiers 10
11. S- SOPs, safety practices, sanitation, self inspection, storage,

standardization, standard test procedures, site master file 11
ADVANTAGES OF MANUFACTURING DOCUMENTS:
1) REDUCE COSTS Labour expense Improve productivity Decrease storage
costs Decrease time and cost with managing compliance program
2) REDUCE CYCLE TIME Shorten time to market Improve order fulfilment
Supply chain collaboration Support manufacturing
3) INCREASE SERVICE LEVELS Improve issue resolution methods Share
knowledge assets Strengthen customer relations Increases sales proficiency
4) Compliance-Regulatory, Corporate Policies, And Certification Assistance ISO

Compliance FDA Compliance OSHA Compliance Corrective and Preventive
Action (CAPA) Compliance Sarbanes-Oxley (SOX) Compliance Disaster
Recovery practices
5) Mainatainence of management
6) Information about equipment
7) Gives information about product, premises, personnel,etc
APPLICATIONS:
ACCOUNTING- Account receivables/payables processing
CUSTOMER SERVICE- Order processing, complete customer profiling, resolution
handling
ENGINEERING- Change process management
HUMAN RESOURCES-Sensitive employee management, hiring processing
OPERATIONS- Continuous improvement planning initiatives, project management
QUALITY ASSURANCE- Issue resolution, documented standard processes, safety
compliances
REGULATORY COMPLIANCE- Complete document security and audit trial
capabilities
RISK AVERSION-Complete disaster recovery, design
WHICH ARE CONSIDERED AS MANUFACTURING DOCUMENTS?

Specification and standards Raw Material Records Labels and printed packaging
material records Master Formula Records Batch Production Records Quality
Control Records Calibration & Validation Records Distribution Records Batch
Packaging Records 20
MASTER FORMULA RECORD AND BATCH

MANUFACTURING RECORD
Master production and control record: This document also known in

various regulatory literatures as:
Master formula record (sch. M of DandC act, India )
Master formulae and packaging instruction (WHO)
Manufacturing formulae and processing instructions (TGA Australia)
Master manufacturing instructions and packaging instructional (MCC South
Africa)
Def: Manufacturing formula is an approved master document that describes

the full process of manufacturing for the batch of product with at least a
cross reference to the support operations for a batch of a specific product.
It is prepared for a particular product, describing all technical details,
required to do error less manufacturing of a particular product upon which all
validations are done.Master production and control records for each drug
product describe all aspects of its manufacture, packaging and control. To
assure uniformity from batch to batch, master production and control records
for each drug product, should be prepared, dated, and signed, by one person
and independently checked, dated and signed by at least a second person.
Master production record is a product specific document complied, checked,
authorized and approved by competent technical personnel from product
development, production, packaging,quality control etc.
For manufacturing and packaging operations it is important to have master

production and control records for each batch size in order to eliminate the
need for recalculation of quantities of components, packaging materials, and
in process samples.
Master production record shall include:[3]
The name and strength of the product and description of the dosage form.
The product name is usually the manufactures patent or proprietary name.
Dosage form refers to tablet, capsules, injection, etc. Since many
pharmaceutical products are manufactured with more than one strength this
should be obvious in the master documentation.
The name and weight or measure of each active ingredient for dosage unit
or per unit weight of the drug product, and a statement of the total weight or
measure of a dosage unit.
A complete list of components designated by names or codes sufficiently
specific to indicate any special quality characteristics. Every ingredient
should be covered irrespective of whether, or not, the material is an active
drug substance in the formulation or not, is used as a pharmaceutical aid or
is detected in the final product or not.
This double identification, although frequently used primarily for
accounting purposes, helps to reduce the potential for usage of incorrect
components particularly if the chemical name is complex or similar to other
materials.
An accurate statement of the weight or measure of each component, using
the same weight system for each component. Ideally only one unit,
preferably kilos, should be throughout with a consistent policy with respect
to zeros and decimal points. However there are significant variations, such as
kilos and milligrams, the consistent use of one unit may be confusing to
operator, in these instances, it may be better to use both designations e.g.:
0.0001g or 100mg. there is a advantage in using the same weight
throughout a production facility to reduce the potential for misunderstanding
when operators transfer between processes.
A statement of theoretical and practical yields at different stages of
manufacture with minimum and maximum limits, beyond which investigation
is required should be included.
Complete manufacturing and control instruction, sampling and testing
procedures, specifications, special notations and precautions to be
followed. The master manufacturing and control records should provide
sufficient details to ensure that different, but properly trained, people will
perform the process similarly.
The master manufacturing records should clearly identify:
Equipment to be utilized designated by name and, where appropriate, by
number
Step-wise manufacturing process with details of conditions such as time,
temperature, speed and sequence of adding ingredients
Critical in process checks and controls, including limits thereof

Special precautions and hazardous conditions that may exist and the
necessary safety equipment to be used.
Theoretical yields and actual yields
Space for signature and date of operator performing or checking each
significant step
A description of the drug product containers, closures, and packaging
material, including a specimen or copy of each label and all other labeling,
including inserts, signed and dated by the person responsible for approval of
such labeling.
Batch manufacturing record:

Batch manufacturing record is a product and batch specific document
designed to give a complete and reliable picture of the manufacturing history
of each batch of every product.
It should be compiled, checked, approved and authorized by competent
technical persons responsible for production and quality control.
It provides a detailed description of all the processing operations and
controls, when they are performed, by whom, and where.
The batch records which accompany material through processing provide
information for information for operations and also serve as means for
documenting which ingredients were added, which control measures were
exercised in process and final assay of the drug product, huge amount of
information produced during the manufacturing cycle.
Batch manufacturing record should include:
Dates
Identity of individual major equipment and lines used
Specific identification and quantities of materials used whether or not the
material appears, or tested, in the finished product for each batch of
component or in process material used.
This may also include quantity and source of recovered materials used,
provided, it is in accordance with relevant master production record.
In processing and laboratory control results

A statement of the actual yield and as percentage of theoretical yield at
appropriate phases of processing
Signed authorization if there is any deviation from the master formula
record or batch manufacturing records
Complete labeling control record, including specimens or copies of all
labeling used
Description of drug product containers and closures
Any sampling performed
Identification of the persons performing and directly supervising or
checking each significant step in the operations
Reconciliation of materials received, used, rejected, or destroyed and
returned to warehouse, or any pre-designated location.
The batch manufacturing record shall be retained for a period
not less than the shelf life of the product for which the record has been
compiled. It is however, a common practice to keep all the records for a
period of 5 years or 2 years after the expiry date of the product, whichever is
later. In exceptional cases, such as pending disputes in the court of law, the
relevant records may have to be retained till the dispute is finally settled.
STANDARD OPERATING PROCEDURES:

What is SOP:
In the face of a challenging regulatory environment, some leading
Pharmaceutical companies have found ways to improve quality and costs
significantly. To drive this kind of beneficial change, companies must first
create a culture where quality objectives are transparent, well understood,
and undoubtedly these goals can be achieved by following certain sets of
procedures called as Standard Operating Procedures (SOP). Procedures are
essential for any plants effectiveness and efficiency, and they are regulatory
requirement in the Pharmaceutical Industry
A Standard Operating Procedure (SOP) is a set of written instructions

that document a routine or repetitive activity which is followed by employees
in an organization. The development and use of SOPs are an integral part of
a successful quality system. It provides information to perform a job properly,
and consistently in order to achieve pre-determined
specification and
quality end-result
Need Of SOP:
SOPs detail the regularly recurring work processes that are to be conducted
or followed within an organization. They document the way activities are to
be performed to facilitate consistent conformance to technical and quality
system requirements and to support data quality. They may describe, for
example, fundamental programmatic actions and technical actions such as
analytical processes, and processes for maintaining, calibrating, and using
equipment. Sops are intended to be specific to the organization or facility
whose activities are described and assist that organization to maintain their
quality control and quality assurance processes and ensure compliance with
governmental regulations.
SOP must contain step by step instructions that employ must refer in
daily work to complete various tasks more reliably and consistently. SOP
makes clear about followings What is the objective of SOP (Purpose)
What are applicability and use of SOP (Scope)?
Who will perform tasks (Responsibility)
Who will ensure implementation of procedure (Accountability)
How tasks will be performed (Procedure)
Procedures are not an end in themselvesthey do not guarantee good
performance or results.
More important are well-designed systems and processes, qualified
employees, and a motivating company culture. Procedures support process
peopleenvironment but do not create processes, qualified people, or a good
working environment
Benefits Of SOP:
1.To provide people with all the safety, health, environmental and operational
information necessary to perform a job properly. Placing value only on
production while ignoring safety, health and environment is costly in the long
run. It is better to train employees in all aspects of doing a job than to face
accidents, fines and litigation later.
2.To ensure that production operations are performed consistently to
maintain quality control of processes and products. Consumers, from
individuals to companies, want products of consistent quality and
specifications. SOPs specify job steps that help standardize products and
therefore quality.
3.To ensure that processes continue uninterrupted and are completed on a
prescribed schedule. By following SOPs, you help ensure against process
shut-downs caused by equipment failure or other facility damage.
4.To ensure that no failures occur in manufacturing and other processes that
would harm anyone in the surrounding community. Following health and
environmental steps in SOPs ensures against spills and emissions that
threaten plant neighbors and create community outrage.
5.To ensure that approved procedures are followed in compliance with
company and government regulations. Well-written SOPs help ensure that
government regulations are satisfied. They also demonstrate a
company's good-faith intention to operate properly. Failure to write and
use good SOPs only signals government regulators that your company is not
serious about compliance.
6.To serve as a training document for teaching users about the process for
which the SOP was written. Thorough SOPs can be used as the basis for
providing standardized training for employees who are new to a particular
job and for those who need re-training.
7.To serve as a checklist for co-workers who observe job performance to
reinforce proper performance. The process of actively caring about fellow
workers involves one worker coaching another in all aspects of proper job
performance. When the proper procedures are outlined in a good SOP, any
co-worker can coach another to help improve work skills.
8.To serve as a checklist for auditors. Auditing job performance is a process
similar to observation mentioned in the previous item only it usually involves
record keeping. SOPs should serve as a strong basis when detailed audit
checklists are developed.
9.To serve as an historical record of the how, why and when of steps in an
existing process so there is a factual basis for revising those steps when a
process or equipment are changed. As people move from job to job within
and between companies, unwritten knowledge and skills disappear from the
workplace. Properly maintained written SOPs can chronicle the best
knowledge that can serve new workers when older ones move on.
10.To serve as an explanation of steps in a process so they can be reviewed
in accident investigations. Although accidents are unfortunate, view them as
opportunities to learn how to improve conditions.
IPQC TESTS FOR sterile products:

i) Clarity test
ii) Leakage test
iii) Uniformity of content
iv) Pyrogen test
1. CLARITY TEST (TEST FOR PARTICULATE MATTER) :
Particulate matter is defined as presence of unintentional & undesirable
extraneous, mobile & undissolved substances(other than gas bubbles)
within the parenteral preparations. Presence of particulate matter could
make the user to conclude that it is of inferior quality. It has been suggested
that as erythrocytes have a diameter of approximately 4.5m,particles of
more than 5 should be the basis of evaluation. If the particle size more than
RBC, then it cause obstruction of blood vessels leading to severe
consequences like emboli in the vital organs of humans and animals.
Permissible limits (maximum limits) for particulate matter according to I.P:
Particulate matter can be detected by following tests:

Visual method
Microscopic count method/membrane filtration method
Light obscuration method

Coulter counter method
i) VISUAL METHOD:
The field containers are examined by holding the neck of the containers
against strong illuminated screen. The containers are slowly inverted and
rotated and the contents are examined for the presence of any foreign
particles. Black surface is used for the detection of light coloured particles
and white surface for dark coloured particles. If any foreign particle is visible,
then that container is discarded.
ii) MICROSCOPIC COUNT METHOD (OR) MEMBRANE FILTRATION

METHOD:
A measured sample solution is filtered through a membrane filter. The
collected particles on the surface of the filter are then counted with the help
of a microscope at 100X magnification. The whole method is carried out
under aspectic conditions. However, it is a time consuming process.
iii) LIGHT OBSCURATION METHOD:

This method uses an electronic instrument that produces a light beam of
high intensity. The solution is allowed to pass under this bright light. If the
particle present in the solution passes through, a shadow cast is produced
due to the obstruction of light by the particle. The particles are measured
and counted automatically by the device means of the shadow castings.
Limits for Sub visible Particulate Matter in Injectable Preparations as

prescribed in I.P.
iv) COULTER COUNTER METHOD:

This electronic method is used to detect the particles and also determine the
particle size. The sample solution is added to an electrolyte solution. This
solution is drawn through a small orifice of the device. Positive and negative
electrodes are present one on either side of an orifice. As the particle passes
through the orifice, it displaces its own volume of electrolyte and at the same
moment, an increase in electrical resistance is observed between the two
electrodes. The resulting voltage pulses which are proportional to the particle
size, are amplified and are measured and counted. Particles below 0.2 m can
also detected by this method.
2. LEAKAGE TEST:
Ampoules are subjected to leakage test because ampoules are sealed by
fusion. Therefore, there is a chance for a incomplete sealing or for
micropores to exist, allowing the contents to leak or microorganisms and
other contaminants to enter the ampoules.
METHOD:
(a) This test is performed by immersing the ampoules in a vaccum chamber
consisting of a dye such as 1% methylene blue solution.
(b) A vacuum (negative pressure) of about 27 inch Hg or more is created for
about 15 to 30 minutes.
(c) This negative pressure causes the methylene blue solution to enter the
ampoules with defective sealing.
(d) The vacuum is released, ampoules are washed externally and observed
for the presence of dye in the ampoules
(e) The coloured solution because of the dye in the ampoules confirms the
leakage and hence those ampoules are discarded.
3. UNIFORMITY OF CONTENT:
Unless otherwise stated in the individual monograph, suspensions for

injection that are presented in single dose containers and that contain less
than 10 mg or less than 10 per cent of active ingredient comply with the
following test. For suspensions for injection containing more than one active
ingredient carry out the test for each active ingredient that corresponds to
the above conditions.
METHOD:
Determine the content of active ingredient(s) of each of 10 containers
taken at random, using the method given in the monograph or by any other
suitable analytical method of equivalent accuracy and precision.
The preparation under examination complies with the test if the individual
values thus obtained are all between 85-115% of the average value.
The preparation under examination fails to comply with the test if more
than one individual value is outside the limits 85-115% of the average value
or if any one individual value is outside the limits 75-125 % of the average
value.
If one individual value is outside the limits 85-115 % but within the limits
75-125% of the average value, repeat the determination using another 20
containers taken at random. The preparation under examination complies
with the test if in the total sample of 30 contains not more than one
individual value is outside the limits 85 -115 % and none is outside the limits
75 -125 % of the average value.
4. PYROGEN TEST:
Pyrogens are fever inducing substances. These are metabolic products of
gram ve micro organisms and when injected into body can cause fever,
chills, pain in the back and legs. This test can be conducted by:
A) USING RABBITS AS TEST ANIMALS:
Rabbits are used as test animals as they show a physiological response to
pyrogenic substances similar to that of man
.Sterile solution of parenteral preparation being examined is injected into

ear vein of each of 3 rabbits and rise in body temperature of rabbits is
recorded at an interval of half an hour for 1 to 3 hrs subsequent to the
injection.
RESULTS:
o If no rabbit shows an individual rise in temperature of 0-5 or more,the
product meets the requirements for the absence of pyrogens.
o If any rabbit shows an individual temperature rise of 0.5c,continue the
test using 5 other
rabbits.
o If not more than 3 of the 8 rabbits show individual rise in temperature of
0.5c or more,& if the sum of the 8 individual max temperature rises
does not exceed 3.3,th material under examination meets the requirements
for the absence of pyrogens.
B) LIMULUS AMOEBOCYTE LYSATE (LAL) TEST:
In this method, test soln is combined with a cell lysate from the
amoebocyte(blood cells)of a horse shoe crab.
Any pyrogenic endotoxin that might be present will be coagulated with
protein fraction of amoebocytes & results in the formation of a gel.
IPQC tests for biological products:

IPQC tests for biological products Sterility test Pyrogen test Staining test Freedom from
abnormal toxicity
Staining test: Approximately 10 mL of the test sample is centrifuged in a pointed centrifuge

tube for 30 minutes. The sediment or the bottom portion is spread on a slide glass, dried and
heat-fixed over a flame. The smear is then stained by the Grams method and, unless otherwise
specified, examined microscopically at an approximately 1,000-fold magnification. Criterion for
judgment No bacterial shall be observed other than those defined in the individual monographs.
21 Staining test
Freedom from abnormal toxicity: Freedom from abnormal toxicity Test in mice Test in
guinea pigs Take 5 healthy mice weighing 17-22g. Inject one human dose NMT 1 ml Intraperitoneally Observe the mice for 7 days If more than one animal dies preparation fails the test If
one animal dies repeat the test Preparation passes the test if no animal dies in the second group
Take 2 healthy guinea pigs (250-350 g) Inject one human dose NMT 5 ml Intra- peritoneally
Observe guinea pigs for 7 days If more than one animal dies/shows ill health preparation fails the
test If one animal dies/ shows ill health repeat the test Preparation passes the test if no animal
dies/ shows ill health in the second group 22
SOF FOR CLEANING:

Cleaning involves testing for acceptable residues on pharmaceutical manufacturing or medical
device surfaces. Efficient and safe cleaning is a crucial prerequisite for the manufacture of drug
products or medical devices. The appropriate selection and control of cleaning agents (solvents,
detergents and sanitizers) is an essential part of the entire cleaning process.
How to Improve Cleaning Processes
Some key methods for a more efficient cleaning process
Pharmaceutical manufacturing equipment must be properly cleaned to ensure the removal of
product residue, cleaning chemical residue, and microbes prior to manufacturing. Because
cleaning methods are developed and to prevent the risk of producing contaminated products by
confirming that the cleaning process is sufficient, its important to establish method limits and
select the proper cleaning techniques and detection methods. (4)
Procedure
1.Walls and Windows : Wipe the entire halls and glass windows with soap solution followed by
dry lint free cloth.
2. Floor : Morning : Clean the entire floor using soap water, subsequently spray the floor with
diluted phenyl and wipe it once again.
3. Evening: Clean the entire floor using soap water, subsequently spray the floor with diluted
phenyl and wipe it once again.
Types of different manufacturing sections in cleaning:
1.oral solids manufacturing section
It includes:
Cleaning of double cone blender
Cleaning of dry syrup powder filling machine
Cleaning of fluid bed dryer

Oral liquids manufacturing section
It includes:
Cleaning of filling machine
Cleaning of bottle labelling machine
Cleaning of tanks
Semi solids manufacturing section
It includes:
Cleaning of bulk storage drum
Cleaning of compounding kettle
Cleaning of utensils
Sterile liquids manufacturing section
Cleaning of the stirrer
Cleaning of vial sealing machine
Cleaning of holding vessels
Cleaning of double cone blender
Caution:
1. Disconnect the equipment from electrical main supply
2. Set the position of the blender vertical-butterfly valve facing the floor
A. Procedure for product to product changeover

1. Dismantling-a) remove the safety guard of the blender b) remove thecircular lid and gasket by
unclamping wing nuts
2. cleaning external surfaces- clean the body of the blender with dry duster first and then with
moist duster and again wipe with a clean dry duster

3. position of the blender a) set the position of the blender vertically so that the butterfly valve
outlet is facing the floor. b) keep the butterfly valve close and keep an ss container below it.
4. cleaning of blender: a) initially wash the inside surface of the blender with tap water b) drain
out the water through butterfly valve c) clean inside surface of the blender with warm water (40
to 50 0 c). clean inside surface of the blender with 0.1%teepol solution. d) wash inside of the
blender with sufficient warm water to remove the traces of teepol e) finally rinse with 5 micron
filtered water
5. cleaning of gasket, rectangular lid and butterfly valve lid- clean the parts with 0.1% teepol
solution. Wash thoroughly with warm water(40-50 0 c) followed by 5 micron filtered water.
6. confirming effectiveness of cleaning- the final 5 micron filtered water rinse of blender is to be
sent to quality control department, confirm the absence of previous product.
7. drying- wipe dry, the different parts of blender using a clean lint free duster
8. assembling- fix the cleaned gasket circular lid and butterfly valve and lid to the blender.
B. procedure for batch to batch changeover

1. Dry clean to blender and lids with clean lint free duster.
2. Dedust external surfaces with clean lint free duster
3. Cleaning of bottle labelling machine
Objective:The cleaning of the labelling machine is equally important as the labeling operation
itself. Split content of the product due to breakage as well as gum is prone to bacterial and fungi
contamination which is hazardous to the product.
Procedure
Dismantle and cleaning
1. Switch off the main power first.
2. Remove the gum from the gum pot
3. Remove the labels from the label holder
4. Wash the gum pot, the gum roller and associated area throughlywith water.
5. Soak the gum roller in water and remove the adhering gum with the help of a nylon brush.
6. Remove any soiled labels. Count and give them to the supervisor for destruction.
7. Clean the parts of the machine, which are liable to get soiled with water.
8. Finally clean the adjoining areas thoroughly
9. Get the floor cleaned by the janitor with the disinfectant of benzyl septol(1 part in 40 parts of
water)
Assembly
1. When the complete cleaning is over, follow the assembly prodedure as follows
2. Set the gum pot on its position
3. Set label holder in its position
4. Cover the machine with clean over
5. Put status label with supervisors signature
Record
Line clearance checklist is filled and attached to the respective packing record of the batch
Responsible person-packaging supervisor
Standard Operating Procedure for FILLING

Make sure that the filling area has been cleaned properly. Switch on the Laminar flow and make
sure that, it has been wiped with 70% IPA. Feed the Ampoules to an inclined charging hopper.
The Ampoules are passed continuously through rotating feeding wheel to the conveyor. The
Ampoule conveyor carries the Ampoules vertically at an angle of 300. Pass the nitrogen (Inert
Gas) into the empty Ampoules. SOP for FILLING
7. The volume to be filled passes through the pumps into the Ampoules. 8. Again pass the
nitrogen (Inert Gas) into the filled Ampoules. 9. The filled Ampoules are moved to sealing
station for sealing. 10. Make sure that the sealing has been done before the Inert gas can diffuse
to the outside. 11. Collect the sealed Ampoules through the collection hopper and sent for
labelling .
Standard Operating Procedure for DRYERS:

5.1 PROCEDURE: (FLUIDISED BED DRYER)
5.2 PRE STARTUP
5.1.1 Visually check the cleanliness of the Room/Equipment and ensure that
the area/equipment is free from remnants of previous product/Batch.
5.1.2 Remove the Cleaned Room/Equipment Label from the machine
& Room duly signed by the IPQA personal.
5.1.3 Fix Room/Equipment Status Label on the Machine and room.
5.1.4 Check the Room temperature and Relative humidity and record the
observation as Per SOP, if Environmental conditions are not in the limit,
inform the maintenance department for rectification and dont proceed
further, till it gets rectified.
5.2 STARTUP
5.2.1 Check the integrity of the finger Bag made up of canvas for any type of
damage or hole, by looking at it.
5.2.2 Check the tare weight of the IPC with a double polybag inside and
record the same on the semi-finished label on the IPC.
5.2.3 Fix the finger sleeve of the bag to the respective hook on the holding
ring.
5.2.4 Insert the bag support frame and clip the filter bag unit to the retaining
strap.
5.2.5 Check the wire mesh sieve of product bowl for any damage and label
the bowl i.e, Product Name, Batch No, Batch Size , Mfg date, Exp date and
container no.
5.2.6 Switch ON the main power supply by pushing the Black colour handle.
5.2.7 Bring the material to be process near the machine.
5.3 SHUTDOWN:
5.3.1 Switch off the machine by pressing Red colour Button.

5.3.2 Switch off the main power supply .
OPERATING PROCEDURE FOR TRAY DRYER:

5.1 Load the material that has to be dried in the trays
5.2 Load the loaded trays in dryer.
5.3 Switch on the mains for supply of power to the Tray Dryer.
5.4 Set the drying temperature and time as per BMR
5.5 Open the exhaust valve of the tray dryer
5.6 Once activity is complete then switch of the mains.
Standard Operating Procedure for Compression:

PROCEDURE:
5.1 PRE STARTUP:
5.1.3 Fix Room/Equipment Status Label on the Machine and room.
observation as Per SOP, if Enviornmental conditions are not found in the
limit, inform the maintenance department for rectification and dont proceed
further, till it gets rectified.
5.2 STARTUP:
5.2.1 Check the integrity of the Punches and Dies hole for any type of
damage, by looking at it.
5.2.2 Ensure that the punches, dies, feeder frame and Hopper is fitted
properly.
5.2.3 Place empty cleaned pre labeled with Semi-finished HDPE container
below the discharge chute load with double poly bags.
5.2.4 Bring the approved (granules)in the compression room.
5.2.5 Switch ON the main power supply by pushing the handle.
5.3 OPERATION
5.3.1 Charge the granules (blend) with the help of scoops and full the each
hopper.
5.3.2 Switch on the machine by press Inching Yellow colour Button, collect
the tablets of first 2-3 round and treat them as non recoverable reject.
5.3.3 Adjust the weight of the tablet with in specified limits with the help of
die fill
assembly as specified in BMR.
5.3.4 After tablet weight achieved, check the thickness.
5.3.5 Adjust the thickness of tablet with in specified limits by
increasing/decreasing the compression pressure with the help of hydraulic
pressure adjusting knob.
5.3.6 Check the hardness of the tablets and adjust if required.
5.3.7 Collect few tablet from both chutes and perform in-process checks i.e,
Weight, Hardness, Thickness, DT and Friability etc.
5.3.8 Take initially 40 tablets from each chute and perform weight variation
separately.
it should fall with in specified limits.
5.3.9 Ensure good appearance of the tablets.
5.3.10 Switch on the machine by pressing Green colour Button and run
continuously till
the batch is over .Perform in-process checks and record in the in-process
chart as given in BMR at following specified intervals
1 Avg. wt (20 tablet) every 30 minutes

2 Hardness every 60 minutes
3 Thickness every 60 minutes
4 DT every 60 minutes
5 Friability every 60 minutes
6 Weight variation every 60 minutes
5.3.11 Ensure that the above parameters shall be with in specified limits. If
observed out of limits ,stop operation and take corrective action. After
rectification operation shall be started.
5.3.12 After the batch is over , collect left over powder from feeder frame
and turret and keep in the same polybag labeled as Non-Recoverable
residue. Check the weight of Non-recoverable residue and record in BMR as
Non-recoverable residue.
5.3.13 Check the weight of compressed tablets and record the gross weight,
Tare weight, Net weight on the label.
5.3.14 Record the operation in the Equipment log book.
5.4 SHUTDOWN:
5.4.1 Switch off the machine by pressing Red colour Button.
5.4.2 Switch off the main power supply.
SOP FOR COATING:

5.0 PROCEDURE
6.0 PRE STARTUP
6.1.3 Fix Room/Equipment Status Label on the Machine and room..
observation as Per SOP if Environmental conditions are not found in the limit,
inform the maintenance department for rectification and dont proceed
further, till it gets rectified
6.2 STARTUP
6.2.1 Bring and check the material dispensed for the preparation of coating
solution . prepare the coating solution as per the procedure mentioned in the
BMR.
6.2.2 Open the steam valve of the hot air unit .put ON the main switch of the
panel board and open the compressed air line valve.
6.2.3 Bring the compressed tablets to be coated in the room.
6.3 OPERATION
6.3.1 Load the uncoated and dedusted tablets n the coating pan.
6.3.2 Place the spray gun at the height of 30cm from the tablet bed.
6.3.3 Switch ON the Exhaust system.
6.3.4 After loading the uncoated tablets to the pan for at least 15 min to
achieve uniformity in bed temperature as per requirement given in the BMR
for a particular product .
6.3.5 Switch ON the main power supply to spray assembly .
6.3.6 Check the flow criteria in peristaltic pump and adjust the flow rate.
6.3.7 Switch ON the blower to the tablet bed .
6.3.8 Start revolving the coating pan and simultaneously start the spray.
6.3.9 Coat the tablet at desired parameters as mention in BMR for particular
product .
6.3.10 Set the following parameters as per the process requirement in the
BMR.
Pan RPM
Bed Temperature
Hot air Temperature
Exhaust Temperature
Drying Time
6.3.11 During coating check the tablets for uniformity of coating and weight
build-up.
6.3.12 Repeat the step till the solution finished and desired weight build-up is
obtained.
6.3.13 Once all the above parameters are set then only start continuous
spraying. Observe visually every 10 minutes for uniformity of the coating .
6.3.14 Once coating is complete , unload the tablets and record the tablets
weight.
6.3.15 Discard the left-over coating material .(if any)
6.3.16 Record the coating details in BMR and Equipment log book. and sign
it.
7.0 SHUTDOWN
7.1 Switch OFF the spray assembly and blower .
7.2 Switch OFF the coating pan revolution.
7.3 Switch OFF the exhaust and close the steam and air line valves .
7.4 Switch off the main power supply .
SOP FOR STERILIZATION:

OPERATION OF AUTOCLAVE:
1. Open the main line steam inlet valve.
2. Open bypass the valve of the moisture separator installed before PRV for 5
minutes to remove all the condenser from the line, then close it.
3. Open the bypass valve of the 20 microns SS steam filter housing to
remove the condenser for 3 mints then close it.
4. Open the bypass valve of the 10 microns SS steam filter housing installed
after the PRV for 3 mints to remove condenser close it.
5. Open the bypass valve of the moisture separator before autoclave for 3
mints and close it.
6. Before opening autoclave pressure locks door from non-sterile side ,
confirm with the filling room operators that the sterilised charge is unloaded
and pressure lock door is tightly closed.
7. Open the pressure lock door by turning the handle anti-clockwise , till the
quick throw handle could be easily pushed down.
8. Load the chamber with sterilized load as per the validation load pattern.
9. Close the pressure lock door by pulling up quick throw handles , after
which the handle is to be turned clockwise till it is reasonably tight.
10. Check the thermograph for recording chart and ink and then put it on
11. Put the operation valve in SLOW EXHAUST position. Open the steam
valve , pressure will be gradually build up in the jacket.
12. Open the bypass valve of the jacket for 5 mints to remove all the
condensate from the jacket and close it.
13. Put the operation valve in STER position when jacket pressure guage
indicates 20 psi.
14. Open the bypass valve of the chamber slightly to remove the condenser
for a few minutes and close it.
15. The slightly thermometer will show gradual rise in temperature when it
reads steady 123 0 c.Timing for the exposure period should begin.
16. Exposure period should be as per the validated time for various loads.
17. After exposure period, close down the steam inlet valve . put the
operation valve in SLOW EXHAUST position.
18. DO NOT FAST EXHAUST the charge containing membrane holders with
membrane disc
19. Allow steam to exhaust till both the pressure gauge indicates zero psi.
20. If the sterilization indication, inform the supervisor before using the
sterilization load.
21. During unloading of charge in sterile side, confirm the working of warning
buzzer sound.
22. DO NOT try to open the door from non-sterile side when buzzer sounds
23. Clean the chamber of autoclave after sterilization of every load by fresh
distilledwater from non-sterile side
DRY HEAT STERILIZATION
Equipment: Double door heat sterilization with mounted HEPA filter module
Temperature required for sterilization : 220 0 c
Time of cycle : 90mints. At 220 0 c
Set temperature : 260 0 c
Time : validated time depending on load.
PROCEDURE:
1. Remove the lock and open the pressure lock door by turning the handle
anti-clockwise
2. Unload carriage on the trolley provide.
3. Cheking working of alaram system when the door is opened . if not report
the supervisor.
4. Wipe and clean the carriage and the chamber of the dry heat sterilization
with distilled water.
5. Place systemically the load to be sterilization as per the loading pattern on
the carriage.
6. Close the pressure door and display DO NOT OPEN board on the door
7. Fill the sterillization card provide stating date, items sterilized , time , no of
units and operators.
8. Put NO the mains and checking working of the booster fan and the HEPA
module
9. Put ON the panel switch on AUTO

10. Set the temperature to 260 0 c on the temperature controller unit.
11. Set the timer on the temperature controller unit the validated set time
depending upon the load to be sterilised.
12. Start the heater switch and simultaneously start the timer switch.the
heater timer display and the heap timer display should start with ZERO
readings.
13. Check the current in all the three phases of the heater with the aid if the
built in ammeter switch. (ammeter reading should be between 3538amperes for each phase. )
14. Check the thermograph,thermograph recorder and the ink flow through
the thermograoh recorder.
15. The temperature will gradually rise and will be indicated by the
temperature indicator and the thermograph.
16. After the sterilisation cycle is completed, the heater will stop and the
heap module will start to cool the load.
17. Prior to unload the charge on the sterile side check the following
a)thermograph as recorded the desired time and temperature relation ship
b) above module is operating
c)load is sufficiently cool to be unloaded on the sterile side.
18 Intial the sterilisation card and release the load for unloading on the
sterile area for filling of sterile products.
19 indicate on the load,date of sterilisation and the day before which should
be used.
SOP FOR MEMBRANE FILTERS:

The acceptability and quality of any solution that is rendered sterile by
aseptic filtration is dependent upon the cleanliness of the membrane filters
holders and proper functioning of the membrane filters. Prevent the cross
contamination of the product.
PROCEDURE:
1. Disassemble the membrane filters holders immediately after use.
2. Rinse all the parts with hot pyrogens free distilled water twice and keep in
a clean plastic buckets after draining of the rinse water.
3. Take the membrane filter holder near to the distillation still.
4. Start the distillation still and dump off the initial distillate
5. Check the conductivity of the water and use the water only if the
conductivity is within required limits.
6. Wash all the components i.e the top plate , gasket , support screen ,
nozzles and its holder twice with hot pyrogen free water directly from the
distillation still.
7. Use a clean sponges to scrubs all the hard to clean area.
8. Check the all parts carefully for cleanliness , product residue and stains
and rinse all the parts three times with hot pyrogen free distilled water.
9. Finally , rinse all parts once with hot pyrogen free distilled water and give
the final rinse water if required for QC tests.
10. Air-dry all the components and do not wipe with cloth or tissue. If
required use filtered compressed air to remove traces of moisture from
screen and recesses.
11. Take all the items and accessories required for assembling the filter
holder after washing and drying under a laminar flow hood.
12. If the membrane is not required for immediate use, then completely dry
all the parts and affix a clean tag indication date of cleaning , product name
for which last used and To be clean before use
DIS INFECTION OF THE STERILE AREA:

Dis-infection of the sterile area is of utmost importance to maintaine the
integrity of the are and it is also a primary requirements of goods
manufacturing practices. The cleaning and dis-infection of the sterile area
should be performed daily at end of the days operation using sterile disinfection solution.this is important, as both the viable and non-viable
particulate level tends to be very high at this time due to continous shedding
by the operatiora and materials during the course of the days operation. It is
necessary to change the sterile dis-infection solution on a fortnightly basis in
order to prevent development of mutant strains of common contaminating
micro-organism.
1. At the end of days operation , promptly removed all unneeded material
from the sterile area including reject vials , stoppers etc. via the UV pass box.
2. Use only lint free sterile sponges and mops for cleaning and dis-infection
in the sterile area.
3. Prepare approximately 15 liters of sterile of sterile dis-infection solution
using sterile distiiled water.
4. Wipe the entire sterile area using sponges and mops wet with the required
concentration off the sterile dis-inffection solution, the area include walls ,
floor and doors.
5. Spary and wipe the exposed surface off all equipemets and glass panel
using sterile 70% isopropanol prepared in sterile distilled watwr.
6. Mops up any liquid or materile spilled using sponges wet with sterile disinffection solution.
7. Wipe the plastic buckets using sterile 70% iso-propanol.
8. Wipe the interior of the filling hood using the sterile 70% isopropanol.
9. Wipe all the UV lamps in sterile area with 70% isopropanol.
10. Once every week , wipe the ceiling of the sterile area using sterile 70%
isopropanol.
11. Collect all the wash in the SS pit in the sterile area and drain out using a
pupm a pump with sterilized tubing to direct the wash outside.
12. Dis-infections used.
CLEANING & DIS-INFECTION OF THE STERILE AREA CLASS 10000 AFTER

MEDIA FILLING:Cleaning and dis-infection of the sterile area media filling ,
becomes an important factor to ensure sterility and integrity of the area
during subsequent product runs.
PROCEDURE
1. At the of the media run . promptly remove all unneeded material from the
sterile from the sterile area including flasks and filling assemblies used for
media filling.
2. Prepare approx. 15 liters of 2% Bacilloid or cidex solution for dis-infection
of the area.
3. Dismantle the filling line conveyors and remove it outside the sterile area
for through cleaning with the help of a brush , soap and running water.
4. Wipe the all machine parts and area is sterile by the media of 2%
bacilliocid or cidex solution.
5. Dis-infection solution should be sprayed with the help of a spray gun and
ensured that all inaccessible parts are thoroughly wetted by the dis-infection
solution.
6. Walls and floor should be sprayed with dis-infection solution.
7. Wipe exposed surface os all equipment and glass panels using 70%
isopropanol.
8. Wipe plastics buckets, stools, pass box, switches, spanels, handles ,
doors , light housing , spray gun with 70% isopropanol.
9. Collect all the wash in SS pit in the sterile area using floor squeezers and
drain out the wash using with sterile tubes.
10. Wipe the floor squeezer with 70% isopropanol.
11. Wipe the SS pit with 70% isopropanol.
12. After washing the conveyor belts of the vials filling line are removed and
washed thoroughly with distilled water and 0.05% Benzalkonium chloride
solution.
Guidelines for quality assurance of human

blood products:
INTRODUCTION:
INTRODUCTION Human blood is the source of a wide range of medicinal products used for the
prevention and treatment of a variety of often life-threatening injuries and diseases. Despite
measures such as donor selection, testing of donations and of plasma pools, the transmission of
blood-borne viruses by plasma and purified plasma products is still considered to constitute a
risk to patients. Several procedures for virus inactivation and removal have proven to be robust
and to contribute substantially to blood product safety.
The transmission of blood-borne viruses by plasma and puried plasma products is considered to
constitute a risk to patients. The chances of transmission viral e.g. hepatitis B virus (HBV),
hepatitis C virus (HCV) and human immunodeciency virus (HIV) is still a serious problem in
many areas of the world. The overall goal of the National Regulatory Authorities is to ensure that
only blood products of demonstrated quality, safety and efficacy should be used.
Challenges and Issues: :

Challenges and Issues: To strengthen National Regulatory Authorities on quality assurance
systems for the control of quality and safety of blood products. Need to assure quality and safety
of blood and plasma globally to prevent transmission of blood-borne viral diseases via blood
products. To facilitate access to and appropriate use of WHO International Reference Materials
by national control laboratories or designated laboratories and manufacturers in developing
countries. To promote support for the implementation of new manufacturing technologies to
avoid viral contamination and other infectious agents via blood products .
Categories of Human Blood products Concentrated red blood corpuscles. Platelets concentrates
Granulocytes concentrates Fresh frozen plasma Cryoprecipitate ( concentrate of anti hemophiliac
factor)
Process of blood product Collection of blood for fractionation Inactivation of virus
Pasteurization of albumin Heating of dry (lyophilized) products Heating of lyophilized products
under humidied conditions (vapour heating) Solvent/detergent treatment 3 . Method of virus
removal By precipitation By Nanofiltration
Collection of blood for fractionation Plasma shall be collected form license Blood Banks and
store in frozen condition at -20 C Individual plasma shall remain in quarantine till it is tested for
Hepatitis B, Hepatitis C, HIV I, HIV II Individual plasma unit shall be tested and if sample is
found negative, then shall be taken up for fractionation.
Method of Virus Inactivation Pasteurization of albumin Albumin solutions are heated as a liquid
at 60 0.5 C for 1011 hours. Sterile ltration and dispensing into nal containers (glass vials).
To prevent denaturation of albumin, low concentrations of sodium caprylate alone or with n
acetyl tryptophan are added. Infectious virus can no longer be detected after 10 minutes of
treatment.
Heating of dry (lyophilized) products Heating at 80 C has produced favourable results with
respect to transmission of HBV, HCV, HIV and HAV. But it leads to inactivation of coagulation
factor. To prevent it, manufacturer has been treating coagulation factor with solvent/detergent.
Also heats nal product for 30 minutes at 100 C.
Heating of lyophilized products under humidied conditions (vapour heating):

Heating of lyophilized products under humidied conditions (vapour heating) A higher level of
virus inactivation can be achieved by the addition of water vapour before initiating the heat
cycle. The freeze-dried product is transferred into a stainless steel tank where an amount of water
vapours is slowly added to adjust the water content to 78% (w/w). The tank is ushed with dry
nitrogen to remove oxygen, and a pressure test is performed to ensure that the cylinder is airtight.
This cylinder is then transferred to a heating cabinet equipped with an electric heater and heated
according to the temperature regimen specied for the particular product. After vapour heating,
the heating cabinet is opened from the other side, and the product is further processed . Cont
Solvent/detergent treatment:
Solvent/detergent treatment The conditions typically used are 0.3% tri(n-butyl) phosphate
(TNBP) and 1% nonionic detergent, either Tween 80 or Triton X-100. At 24 C Organic
solvent/detergent mixtures disrupt the lipid membrane of enveloped viruses. Once disrupted, the
virus can no longer bind to and infect cells. For a minimum of 4 hours with Triton X-100, or 6
hours with Tween 80.
Method of virus removal 1. By precipitation:

Method of virus removal 1. By precipitation Precipitation with ethanol is the single most widely
used plasma fractionation tool worldwide. Viruses, as large structures, tend to precipitate at the
beginning of the fractionation process when the ethanol concentration is still relatively low.
Many manufacturers separate the precipitated proteins by centrifugation whereas others have
introduced ltration as an alternative. To prevent clogging of the lters, ltration is carried out
using lter aids. Because these substances (diatomaceous earth or similar products) also adsorb
virus.
2. By Nanofiltration Nanoltration removes viruses according to their size- particularly those
that tend to form aggregates. Effective removal requires that the pore size of the lter be smaller
than the effective diameter of the virus. Filters with a pore size that exceeds the virus diameter
may still remove some virus if it is aggregated such as by inclusion in antibody/ antigen or lipid
complexes.
Careful monitoring of the performance of the nanolters in every run is mandatory. Filter
integrity should be ascertained before and after use, and every lter manufacturer offers test
methods that have been developed specically for this purpose. E.g.- Membranes with 15 and 35
nm pore size were reported to removal of murine xenotropic retrovirus, SV40 and pseudorabies
virus from IgG and IgM solutions.
Process design:
Process design The benet of viral inactivation and removal will be negated if the plasma
fractions from preceding steps are permitted to recontamination the intermediates or products
that follow; thus, the manufacturer must describe how the operating procedures reduce the
likelihood of cross-contamination. Usually, decisions are made after a multidisciplinary team
consisting of responsible staff from manufacturing, engineering, quality assurance and
microbiology has made its recommendations. The following points illustrate how some
manufacturers have addressed these cross-contamination issues.
Cont In-process/bulk virus inactivation (e.g. solvent/detergent, low pH, pasteurization) If
bacterial growth during virus inactivation is a consideration, the solution is sterile- ltered (pore
size 0.45mm or less) before treatment. On completion of the rst stage of inactivation, the
product is aseptically transferred (sterile coupling) into the second vessel, which is located in a
safety zone, for completion of the second stage of viral inactivation.
All processing after virus inactivation and prior to sterile ltration and dispensing (e.g. removal
of solvent/detergent or stabilizers and further purication steps) are carried out in the safety area.
All the equipment used in the safety area that is in contact with the product must be GMP
certified which will not recontaminate the product.
Review of newer viral inactivation methods under development:

Review of newer viral inactivation methods under development Psoralen treated fresh frozen
plasma Irradiation with ultraviolet light- Typically at a wavelength of 254nm targets nucleic acid,
thus a wide variety of viruses are inactivated irrespective of the nature of their envelope. Viruses
containing single stranded nucleic acids are more sensitive, because they are unable to repair
damage in the absence of a complementary strand.
3. Gamma-irradiation- The principal challenge in using gamma irradiation is the inactivation of
the desired quantity of virus while maintaining the structural and functional integrity of blood
protein. 4. Iodine - Iodine is a strong oxidizing agent and, as a result, is a powerful microbicidal
agent. However, in its free form iodine is not sufficiently selective. When bound to polymers,
such as polyvinylpyrrolidone, cross-linked starch the virucidal action of iodine is more
controlled.
GUIDELINES LARGE VOLUME PARENTERALS

GUIDELINES . DURG AND COSMETIC ACT 1948..
QUALITY AND STABILITY: The quality of the starting materials and solutes is critical to the
finished LVPs product. Presence of contaminants or degradates that effect finished product are
considered. Heat ,light, moisture and air can adversely effect many of these materials. The
containers for these drug substances can also be imp factors in stability considerations.
PRODUCTION
RECEIVING: A specific, isolated area is usually dedicated as a delivery point for the receipt of
raw materials. All raw materials must be inspected, identified, documented and sampled in
accordance with written procedures. Materials should be received covered or in closed
containers. STORAGE AREAS: All materials associated with the final drug products must be
sampled, distributed to laboratory functions. Labels on materials.
BATCH MIXING: The majority of LVPs are simple aqueous solns. The process for
manufacturing simple LVPs is straight forward, since the solutes are readily soluble in water .
The solution mix tanks are made of stainless steel and are fitted with agitators to provide a
uniform concentration throughout the contents.
Some solutions may require heat to effect dissolution of the solutes for example: Solutions That
Are Very Concentrated Or Solutions Where Solutes Have Low Solubility. Jacketed mixing tanks
are used. These tanks also have temperature monitoring devices to mointor the temperature of the
solution.
IN-PROCESS ASSAYS: In-process assays may be performed for one or more ions or other
substances and adjustments in solute concentrations made as required before dilution to final
prescribed volume Analytical methods performed as in-process assays must be precise and
accurate.
FILTRATION: Filtration may be defined as the separaton of undissolved particles from a liquid
by passing a solution through a septum or porous medium that allows the liquid to pass but
retains the particles.
The filtration of liquids is one of the most important operations in pharmaceutical technology.
Originally, liquid products were filtered to improve their clarity and pharmaceutical elegance.
The rate of filtration can be measured as the volume (mass) of fluid passing through the filter in a
unit of time. Membrane filters, screen filters, cake filters, depth filters are used for this filtration
process.
CLEANING PROCESS EQUIPMENT Water systems: Study of microbiology of
water is imp, because water is used for cleansing the equipment before and
after manufacture of parenterals . Mostly gram-negative orgs like Coliform
bacteria, pseudomonas, xanthomonas , flavobacterium are water born and
these are killed by autoclaving. All the parts of the equipment should be
disassembled, sanitized, cleaned, thoroughly rinsed with water, dried ,and
inspected for leaks before reassembly.

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UNIT-1

CONCEPTS OF QUALITY ASSURANCE:

TOTAL QUALITY MANAGEMENT

view that all employees are involved in this

o Preparing documents on a timely basis within the prescribed deadlines/timeframes

Information Request List

Make personnel available to answer questions, provide explanations and documentation.

Attend the status meetings and discuss progress and issues.

Issue Management and Resolution

Review the draft of the final audit report.

Review each section thoroughly

A final report draft is issued to all levels of management.

If no further revisions are required, a final audit report is issued.

GMP Audit Benefits:

Before the Audit:

Organization and personnel:

Organogram at overall organizational level:

Qualification, Experience & Training :

Qualification, Experience & Training:

Technical / Professional Qualification :

Ability To Perform Task :

Responsibilities & Job Description:

Responsibilities of head of quality control:

Responsibilities of head of production:

Personal hygiene & clothing:

Documents & Formats:

Training manual records contains :-:

Factors for location :

Fundamental (primary) Factors :

Derived (secondary) factors :

Design & Construction :

Plan and layout :

Advantages of plan layout :

Type of plan layout :

Process layout or Functional layout :

Process layout (contn.) :

Product or straight line layout :

Product layout (contn.) :

Factor Influencing Plant layout :

Method of Plant and Factory Layout :

Method of Plant and Factory Layout :

Method of Plant and Factory Layout :

Method of Plant and Factory Layout :

Special Provision of Pharmaceutical plant layout. :

Different Type of Layout :

Raw Material Ware House :

Center storage and Perimeter Production :

Storage And Production Side by Side :

Straight Line Type :

Thermal pollution and control :

Sterile Area (contn.) :

OVER VIEW FOR EQUIPMENT:

Equipment design, size and location:

Cleaning And Maintenance :

Types of Maintenance 11 Equipment Maintenance : defined as facilities maintain to some desired

SOP on cleaning, operation and maintenance:

Equipment cleaning & maintenance record:

INDIAN PHARMACEUTICAL LTD. Machine breakdown card:

Purchase specification of equipment:

Purchase specification of UV-VIS Spectrophotometer, double beam:

Purchase specification of water bath :

SOP for Equipment:

CRITERIA FOR RAW MATERIALS PURCHASE SPECIFICATION: