Manafacturing and operation control

1. MANUFACTURING OPERATION AND
CONTROLS
PREPARED BY : SHIKHA BANKER
MPHARM (QA)
MQ009
GUIDED BY : MR. SHANTILAL PADHIYAR
[ ASSISTANT PROFESSOR ]
DEPARTMENT OF CHEMISTRY
FACULTY OF PHARMACY,
DHARMSINH DESAI UNIVERSITY

2. EXPIRY DATE
 The responsibility of the pharmaceutical manufacturer is that the drug
product should have the stated potency and therapeutic effectiveness till
the end of the shelf life of the product This shelf life should be based on
the stability studies data of the product concerned.
 For this purpose a detailed SOP on carrying out drug stability studies is
required. The data so obtained should be used to establish the shelf life
of each product; before it goes into the market.
 The expiration dates shall be related to any storage conditions stated on
the labelling as determined by stability studies carried out.

3. Shelf life of product - Determine -Stability studies.
Expiration date - Storage condition -Stated on label.
If drug is reconstituted product- Label should include
expiration-both reconstituted and un constituted
product
EXPIRY DATE

4. CALCULATION OF EXPIRY DATE:
• K= 2.303 Log C0
t C
• C0 = initial concentration
• C = concentration at any time
• t = time

5. FACTORS AFFECTING STABILITY OF DRUGS
 Moisture, hydrolysis and pH
 Oxygen and Oxidation
 Light
 Temperature
 Microbes

6. CALCULATION OF YIELD
 The actual yield and percentage of theoretical yield shall be determined
at the conclusion of each appropriate phase of manufacturing,
processing, packaging or holding of the drug product. Such
calculations shall be performed by one person and independently
verified by a second person".
 To meet these requirements each critical stage of the manufacturing
process should be identified and theoretical yield at the end of that
stage should be established. The actual yield at the end of the stages
should be calculated, recorded in B.P.C.R. and compared Any abnormal
deviation should be recorded and investigated to find out the reasons.

7.  What is yield: Yield is a measure of the percentage of items produced
that meet customer quality or specification requirements.
 Theoretical yield An amount of product calculated from the complete
reaction of the limiting reagent is called theoretical yield.
 Theoretical yield of product = quantity of product x MW of product
 MW of reactant Actual yield
 Actual yield The amount of product obtained when the reaction takes
place.
 Percent yield The ratio of actual yield to theoretical yield.
 percent yield = actual yield (g) x 100 theoretical yield (g)

8. PRODUCTION RECORD REVIEW
 The main principle of cG.M.P . is that "The quality of a product is built into it and
cannot be just tested in it".
 Quality control or testing can test only certain testable parameters only in the final
product, but it cannot assure the quality of the product. Testing has certain
limitations.
 Hence, the concept of Q.A. has come into existence. Q.A. not only believes in
testing, but it also tries to assure that the entire process of manufacturing has been
actually followed, the way it should have been followed. This activity is done with
the help of following:
 Carry out in process quality check and record them. ✓ Collect samples throughout
the manufacturing process on different times. ✓ Check all the documents related to
the batch production, along with quality control documents

9.  All drug product production and control records, including those for
packaging and labelling shall be reviewed and approved by the quality
control unit.
 Any unexplained discrepancy (including percentage of theoretical
yield exceeding the maximum or minimum percentage established in
M.P .C.R.) or the failure of a batch or any of its components to meet
any of its specifications shall be thoroughly investigated.
 The investigation of such batches shall extend to other batches of the
same drug product and other drug products that may have been
associated with the specific failure or discrepancy.
 A written record of such investigation shall be made and shall include
the conclusion and follow up.
PRODUCTION RECORD REVIEW

10. WHAT IS CHANGE?
 Amendment in the approved Process , Specifications , SOP’s, Vendor,
Batch Size etc. which effect the Product quality attributes (Safety,
Efficacy and Potency) or Regulatory, statutory or ISO requirements
whether minor or major will be considered as CHANGE
 CHANGE CONTROL: A Process that ensures that changes to
materials, methods, equipment, software etc. are properly documented
, reviewed , approved and traceable is known as Change control

11. SOP FOR CHANGE
 Control Program
 Purpose : To provide instruction for change control procedure.
 Objective : To provide a documented procedure for change control
procedure.
 Scope : This procedure is applicable for change control procedure.
 Responsibility : Primary: Officer / Supervisor of respective
department. Overall: Respective department Head.

12. REGULATORY REQUIREMENTS
 Any changes in the production and processes must be controlled-meaning
recorded, reviewed and approved by the QC unit.
 Manufacturers certified to ISO 9000:2000 and ISO 13485 standards are
required to ensure that any changes affecting QMS ( including product
requirements, deign and development changes) should be controlled.
 All changes should be made according to approved (approval implies
successful testing or thorough review/investigation) written company policies
and procedures.
 Change control procedures have to be written as a way of standardizing
instructions.
 In FDA and ISO environments, strict adherence to approved policies and
procedures is a key factor in keeping manufacturing operations in a state of
control and it is what makes change control crucial.

13. ELEMENTS OF CHANGE CONTROL
 INITIATOR: Change is typically introduced by a initiator or originator.
Initiating a changes involves filling out a change request form which them
moves through a process or system of review and approval.
 CHANGE CONTROL COMMITTE: May be a single entity for the whole
company or may be one for the company’s manufacturing site. It usually
includes representatives from different departments involved in production
such as quality, manufacturing, regulatory affairs and engineering. Depending
on the change, committee may include legal, sales and marketing
departments.
 CHANGE ADMINISTRATOR: In pharmaceutical companies, cGMP
requires that all changes must be reviewed and approved by quality unit. In
such companies, there must be a “Change Administrator”, a role usually
assumed by quality unit.

14. STEPS OF CHANGE CONTROL
 Record / Classify ( Initiator initiates a change by filling a change request form.
The change control team then records and categorize it).
 Assess (Assessors then make their risk analysis typically by answering a set of
questions concerning risk, both to the business and to the process, and follow this
by making a judgment on who should carry out the change, then it is sent for
planning ).
 Plan ( Planning team plans the change in detail as well as construct a regression
plan in case if the change is backed out).
 Build / Test ( team then make solutions, which will then be tested. They will then
seek approval and request a time and date to carry out the implementation phase) .
 Implement ( In this phase, finalized solutions or changes are implemented).
 Evaluation ( after change has been implemented, it should be evaluated)
 Close / Gain Acceptance ( when change is implemented correctly then it will be
closed).

15. STERILE PRODUCTION
 For keeping the premises clean and sanitised, one must use validated
cleaning and Sanitizing procedures.
 Certain locations in each area should be marked in each processing are for
collection of dust, debris, and waste or trash materials.
 SOP, of facility cleaning should clearly define the detergent and its
concentration to be used, the frequency of cleaning, the method of cleaning
and persons responsible for doing and supervising the job.
 Documents Required
 (I) SOP on housekeeping, covering, cleaning and disinfection of the
various areas.
 (II) Reports of cleaning and disinfection activities that have been actually
carried out.

16. PACKAGING OPERATIONS
 Similar to manufacturing operations, packaging operations should also
have to follow certain precautions to get a good quality product at the
end. Following are some of the critical points, which should be
remembered while carrying out the packaging Operations.

17.  Avoid risk of cross-contamination and mix-ups.
 a) "Line-clearance" SOP should be followed and records maintained.
 b) Normally, filling and sealing should be followed as quickly as possible
by labelling and final packing.
 c) Over printing on labels, cartons, coated tablet, etc. should be carefully
planned and activities clearly segregated to avoid mix-ups.
 d) Empty packet detections system in tab/cap. should be used.
 e) Printed and embossed information on packaging materials should be
distinct and and resistant to fading or erasing.
 f) Products which are involved in unusual event during packaging
operations, should be fully investigated recorded and packed.
 g) Upon completion of a packaging operation, any unused batch coded
packaging materials should be destroyed and the destruction recorded.

18. REPROCESSING
 Reprocessing is the treatment of a batch or sub-batch of materials of
unacceptable quality by repeating the same process steps from a
defined stage of production so that its quality may be made
acceptable.”
 “NOTE: The occasional repeating of one or more process steps during
manufacture after it was known that the pre-set limits had not been
met, or there was an unexpected process problem, is an acceptable part
of the process and a rational reaction to the results obtained.”

19. ACCORDING TO ICH Q7 GUIDELINE
 Introducing an intermediate or API, including one that does not conform to
standards or specifications, back into the process and reprocessing by repeating a
crystallization step or other appropriate chemical or physical manipulation steps
(e.g., distillation, filtration, chromatography, milling) that are part of the established
manufacturing process is generally considered acceptable. However, if such
reprocessing is used for a majority of batches, such reprocessing should be
included as part of the standard manufacturing process.
 Continuation of a process step after an in-process control test has shown that the
step is incomplete is considered to be part of the normal process. This is not
considered to be reprocessing.
 Introducing unreacted material back into a process and repeating a chemical
reaction is considered to be reprocessing unless it is part of the established process.
Such reprocessing should be preceded by careful evaluation to ensure that the
quality of the intermediate or API is not adversely impacted due to the potential
formation of by-products and over-reacted materials.

20. DRUG PRODUCT SALVAGING
 Drug products that have been subjected to improper storage conditions
including extremes in temperature, humidity, smoke, fumes, pressure,
age, or radiation due to natural disasters, fires, accidents, or equipment
failures shall not be salvaged and returned to the marketplace.

21.  Whenever there is a question whether drug products have been subjected
to such conditions, salvaging operations may be conducted only if there is
(a) evidence from laboratory tests and assays (including animal feeding
studies where applicable) that the drug products meet all applicable standards
of identity, strength, quality, and purity.
(b) evidence from inspection of the premises that the drug products and their
associated packaging were not subjected to improper storage conditions as a
result of the disaster or accident.
 Organoleptic examinations shall be acceptable only as supplemental
evidence that the drug products meet appropriate standards of identity,
strength, quality, and purity. Records including name, lot number, and
disposition shall be maintained for drug products subject to this section.
DRUG PRODUCT SALVAGING

22. HANDLING OF WASTE AND SCRAP
 Objective Handling of rejects from production assumes great
significance in the pharmaceutical industry, since the use of incorrect
destruction procedures have serious adverse consequences for the
manufacturing unit, particularly if such material finds its way into the
wrong hands, therefore, it is of utmost importance that the inherent
dangers of mishandling of rejects/scraps is understood by all the
persons concerned with production operations.
 Scope This part provides an overview regarding the generation of
rejects/scrap, its collection and accounting, and recommends
guidelines for dealing with rejects/scrap and their disposal.

23.  Responsibility the responsibility may depend on the following of the
peoples in the pharma industry.
 1. Employees in production unit
 2. Representative of qa
 3. Housekeeping staff
HANDLING OF WASTE AND SCRAP

24.  Materials like rejected foils, bottles, cans, and tins etc. which have a resale
value.
 The scraps are generated at various stages of manufacturing-
 During compression encapsulation coating & packing stages.
 In-process check.
 Rejected printing packing materials.
 From floor sweeping
 Expired or damaged goods.
 Excess sample in QC after test.
 Product sample from R&D at development stage
HANDLING OF WASTE AND SCRAP

25.  Pharmaceutical Waste: Pharmaceutical waste is potentially generated
thorough a wide variety of activities health care facility general
compounding partially used vials syringes, and IV preparation
discontinued & unused preparations unused unit dose repacks patients
personal medications
 Trash: This material is to be discarded or disposed by suitable means
and don’t have a resale value. E.g. dust, unsalable materials and
outdated pharmaceuticals.
HANDLING OF WASTE AND SCRAP

26. Regulatory bodies that oversee Pharmaceutical
Waste Management
 Environmental Protection Agency (EPA)
 Department of Transportation (DOT)
 Drug Enforcement Administration (DEA)
 Occupational Safety and Health Administration (OSHA)
 State Environmental Agencies
 State Pharmacy Board

27. THANK YOU