Manufacturing Control Systems. J R Controls provides control systems for the manufacturing industry. A typical control system will monitor the progress of parts through the manufacturing and finishing process.
Malay PandyaStudent at K.B.Institute of Pharmaceutical Education & Research
1. To define the detergent and its concentration,
2. The frequency of cleaning,
3. The method of cleaning and
4. The person responsible for doing and supervising
• All such activities must be supervised by the
Sanitation of Manufacturing Premises
6. Mix-Up and Source of Contamination
• In pharmaceutical manufacturing, mix ups and contamination
poses a big danger and hence necessary precaution and
measure should be taken to avoid the same.
• Mix ups can be defined as presence of undesired materials
into desirable materials, which can generally be visibly seen,
1. Cartons of one product into another.
2. Tablets of one product with another product which have
similar size, shapes or color etc.
7. Causes that may give rise to a mix-up
The close proximity or location of similar items
Items having the same colour or combination of colours
Multiple products handled at the same time/packaging
Use of the same apparatus or equipment for multiple products
Improper storage of sterile and non-sterile products
Care not being taken during packaging and/or repackaging of
Mistakes made when dispensing
Unused labels or earlier production left in the production area
Improper documentation and labeling
No ID code on materials or products
8. Causes that may give rise to a mix-up
Inadequate training of personnel
Failure of the processing equipment
Manual packaging and repacking
Inadequate control or procedures
Improper affixing of labels
Vendor’s Location, for example the printer may be located
some distance from the PC or device that sends the output
to the printer. The wrong person may mistakenly use the
wrong printout e.g., for labels.
Improper or lack of proper communication
Same personnel handling two machines or equipment at
the same time
9. Mix-Up and Source of Contamination
• Contamination is also presence of some material where it is not desired.
However this may not always be visibly seen, e.g. fine dust of one product
into another product; fine black particles of dust into processing materials
• Cross Contamination: Contamination of a starting material, intermediate
product or finished product with another starting material or a product
• Contamination of products can be caused by:
Contaminated or faulty HVAC system
People, e.g., carrying harmful bacteria
10. Controlling of Contamination and
• Exhaust system with proper air filtration and dust collection
should be placed where heavy dust is generated. Collected dust
should be disposed off by suitable method.
• Separate air handling unit should be provided for each work
station activities so that a closed circuit air system along with
proper air filtration will be operating. This will avoid particulate
contamination from one possessing area to another.
• Depending upon the nature of the products being handled
different rooms should be maintained at different air pressure.
Generally more clean area should be maintained at high air
pressure, so that less clean air will not enter the cleaner area.
Doors of the rooms should open in the high air pressure area, so
that they always remain close. This is in addition to provision of
door closures. 10
11. Controlling of Contamination and
• Packaging lines in the central packaging areas should be
well segregated. A partition of at least 1.2 to 1.5 meters
is recommended in two adjacent packaging lines. This
avoids accidental mix-ups of materials from two adjacent
• Trained people : In Pharma processing the people should
be trained in their jobs and also in the principles of
• Following the correct and disciplined procedures and
good manufacturing practices help in avoiding cross-
contamination and mix-ups.
12. Controlling of Contamination and
Cross contamination should be avoided by appropriate technical or
organizational measures e.g.
Production in segregated areas (which may be required for products such as
penicillin, live vaccines, live bacterial preparations and certain other
biological), or by campaign (separation in time) followed by appropriate
Providing appropriate airlocks, pressure differentials and air extraction.
Minimizing the risk of contamination caused by recirculation or re-entry of
untreated or insufficiently treated air.
Wearing protective clothing in areas where products with special risk of cross-
contamination are processed.
Using cleaning and decontamination procedures of known effectiveness, as
ineffective cleaning of equipment is a common source of cross contamination.
Using a “closed system" for material handling and production
Testing of residues on equipments and areas.
Using cleanliness status on equipment. 12
13. Starting from the receipt of raw materials till these materials are
converted into bulk goods ready for packaging into their primary and then
ﬁnished packs, certain points are required to be kept in mind so that the
identity, strength, safety and purity of product is maintained.
Following are some of these paints:
Before starting any processing, the materials received from the stores
should be checked for the identity and quantity. This veriﬁcation can
be done against the labels on their containers and by actually weighing
or measuring the quantity of materials.
Process area and equipment must be clean and no traces of previous
product should be there.
Environmental conditions must meet the processing requirements
e.g. temperature, relative humidity, pressure gradient, class of air,
lighting etc, such observations should be recorded in BPCR and other
relevant registers etc.
Processing and intermediate and
14. Processing and intermediate and
All primary containers used for ﬁlling of ﬁnished products should be
clean to the acceptable level of cleanliness. Bulk containers used for
storage of in-process materials should also be thoroughly cleaned
Yield of materials at all critical stages of operations should be checked
e.g. granulation, compression, ﬁlling operations of capsules, liquid
bottles etc. and compared against theoretical yields expected, any
abnormal deviations must be investigated and corrective actions taken.
15. Processing and intermediate and
All measuring, weighing, recording and
controlling equipment and instrument should be
calibrated regularly so that they always remain in
a state of calibration. Records of such calibrations
should be maintained.
Repairs and maintenance operations should not
present any hazard to the quality of the products.
All IPQC checks should be carried out is to be
recorded and investigated.
Access to production areas should be restricted
only to authorized persons.
16. IPQC in Manufacturing and Packaging
• Standard operating procedures should be available and
followed for in-process quality control activity during
manufacturing and packaging activities.
• Critical steps should be identiﬁed in each formulation
process and speciﬁcations deﬁned for the parameters to
be tested at such stages.
18. IPQC test for various dosage form
A • Drug contents determination
B • Moisture contents of granules.
C • Assay of active ingredients.
D • Weight variation of uncoated tablets
E • Hardness test.
F • Disintegration test
19. IPQC test for various dosage form
Syrup and Suspension :
A • Drug contents determination
B • Assay of active ingredients
C • pH
D • Weight per mL
E • Particle size
20. IPQC test for various dosage form
• Drug contents determination
• Assay of active ingredients
• Uniformity and homogeneity test
• Viscosity and specific gravity test
21. IPQC test for various dosage form
A • Drug contents determination
B • Clarity Test
C • pH
D • Pyrogen Test
E • Leakage test
22. Packaging operation
Similar to manufacturing operations, packaging operations should
also have to follow certain precaution 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.
Avoid risk of cross-contamination and mix-ups.
All packaging equipment and lines must be cleaned before starting
a fresh packaging activity "Line-clearance" SOP should be followed
and records maintained.
Each Packaging equipment and line should be identiﬁed by a
conspicuously ﬁxed board, indicating minimum following
• Name of product
• Batch numbers
• Pack size
• Date of packing
23. Packaging operation
Printing on labels, cartons, coated tablet, etc. should be
carefully planned and activities clearly segregated to avoid
On line veriﬁcation of all labels by automated electronic beam
can be helpful in preventing mix-ups, provided that such
equipment are used correctly.
Empty packet detections system in tab/cap. should be used.
Printed and embossed information on packaging materials
should be distinct and resistant to fading or erasing.
Laminated cartons or labels should have non laminated
window space for over printing the batch details or suitable
fast drying inks should be used.
24. Packaging operation
On line packaging checks should be carried out at least
for the following things :
• General appearance of the package.
• Completeness of package e.g. if a carton has to
contain bottle, measuring cup, literature etc. then
all such components of the pack should be
• Correctness of pack and packaging materials.
• Correctness of over printed details.
• Correct version of printed packaging material is
• Weight check of carton and shipper may be useful.
25. Packaging operation
Products which are involved in an unusual event during
packaging operations, should be fully investigated, records
made and only when the authorized person is fully satisﬁed
about its inclusion, then only such products may be packed.
An additional vigilance by Q.A. department on such batch
will be advisable.
Any signiﬁcant or unusual discrepancy observed during
reconciliation of the quantity of bulk product and printed
packaging materials and the number of units produced
should be investigated and satisfactorily accounted for,
Upon completion of a packaging operation, any unused
batch coded packaging materials should be destroyed and
the destruction recorded. A documented procedure should
be followed if un-coded printed materials are returned to
26. Release of Finished Product
Releasing of ﬁnishing Product is the last activity in
the manufacturing and packaging operations at the
factory. Once the ﬁnished product is released then it
can move into the commerce freely. Hence, this is
very important activity and should be carried out
with most care.
27. Release of Finished Product
While doing these following points should be considered.
1. Finished products must be placed in quarantine in such a
way that these cannot be removed for use until such time
these are released.
2. Samples of the product taken at intervals during the
packaging process must be retained for examination by the
quality control laboratory and for retention purposes.
3. Documentation should be reconciled, completed/ and sent
for a complete documentation audit by quality assurance.
4. When all required parameters are satisﬁed, including the
document audit, Q. C. may recommend release of the
product from its quarantine status.
5. The ﬁnished product should be released for sale by the
authorized person from QA department. 27
28. SOP on Releasing of Finished Product
SOP on Releasing of Finished Product should address the following
Who is the authority to release the batch? He may be:
1. A authorized person as per regulatory requirement,
2. QA head
3. Any other person suitably authorized for this person.
Before releasing the finished product at least following point should
1. A completed BPCR
2. Test report of IPQC
3. Test report of Analysis
4. Deviation Reports if any
5. Sterility reports
29. Process deviation
Process deviations can be deﬁned as variation, in the
production or any other process, from the pre-deﬁned
Such deviations (drifting from the standard procedures)
may adversely affect the desired quality of the
pharmaceutical product and hence such deviations should
be generally avoided and if exceptionally required, then
such deviations must be justiﬁed and properly authorized
If a particular type of deviation is occurring frequently then
such deviation must be fully investigated and if required
this may be permanently changed through a change control
30. Process deviation
• The main purpose of written manufacturing
procedures is to built the desired quality into the
prod0uct, that means to assure that the drug products
have the identity, strength, safety and purity they
represent to have. So any deviation from these
procedure can be easily identiﬁed and recorded after
• The identiﬁed control process should be followed and
documented and any deviation from this will be
justiﬁed and corrected and steps taken to avoid change
the procedure to authorized change control procedure.
31. Types of Process deviation
1)Planned Deviation : Planned deviations, which are
described, and pre-approved deviation from the
current operational document/system, covering a
specified period of time or number of batches. Planned
deviation shall be approved before execution
2)Unplanned Deviation: Unplanned deviations also called
as incident. It is defined as unplanned or uncontrolled
event in the form of non-compliance from the
designed systems or procedures at any stage of
manufacturing, packaging, testing, holding and storage
of drug product due to system failure or equipment
breakdown or manual error.
32. WHY INVEISTIGATE DEVIATION?
To prevent reoccurrence
Failures are cost to company
Failures can have adverse health impact on the
consumers if go undetected
To identify the cause and take corrective actions
To identify other similar situations and take preventive
34. Drug Product Inspection
An activity of measuring, examining, testing one or
more characteristics of a product and comparing the
results with specified requirements in order to
establish conformity for each characteristic
1. To enforce Good Manufacturing practices in
pharmaceutical manufacturing facilities.
2. To authorize the manufacturing of specific
3. To monitor the quality of pharmaceutical products in
distribution channels from point of manufacturing to
delivery of recipient.
35. Drug Product Inspection
As described in 21 CFR PART 211
• Packaged and labeled products shall be examined
during finishing operations to provide assurance
that containers and packages in the lot have the
• A representative sample of units shall be
collected at the completion of finishing
operations and shall be visually examined for
• Results of these examinations shall be recorded
in the batch production or control records.
37. Frequency & duration of inspections
• For all companies inspection should be carried
• For large companies marketing wide range of
products inspection may be split into several
visits over a longer period.
• The length of inspection depends on size of
company & purpose of visit. It may also
depend on no of inspectors. It may extend
from days to weeks.
38. Expiration Dating
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.
40. Expiration Dating
If the drug product is to be reconstituted at the time of
dispensing, its labelling shall bear expiration information
for both the reconstituted and un-constituted drug
products e.g. in case of dry syrup preparations. Some eye
drops are also labelled as how long they can be used after
opening the bottle pack. This is in addition to the expiry
product of unopened containers.
Both the above or the ﬁnal expiry date whichever is
applicable, should be printed on the label and/or carton or
any appropriate primary packaging material.
41. 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
42. For the common formulations such
critical stages are as follows
43. Calculation of Yield
An amount of product calculated from the complete
reaction of the limiting reagent is called theoretical
The amount of product obtained when the reaction
The ratio of actual yield to theoretical yield.
percent yield = actual yield (g) x 100
theoretical yield (g)
44. Change Control
• Change Control is the process of handling proposed
alterations to items that have been previously designated
as fixed, and the procedure that controls change is called
• Changes refers to any modification in equipment,
manufacturing materials, facilities, utilities, design,
formulations, processes, packaging, labeling, computer
system and all associated documentation.
• According to WHO, "Change control is a formal system by
which qualified reprenstatives of appropriate disciplines
reviews proposed or actual changes that might effect a
validated status. The intent is to determine the need for
the action that would ensure that the system is maintained
in a validated state.
45. Change control is a procedure that ensures changes are
implemented in a controlled and coordinated manner.
The change control program evaluate all changes that
could affect the production and control of the drug
product, intermediate or API. It is the most critical
element in the overall quality management of
A change control system provides checks and balances
in the quality system by tracking, reviewing and
approving the changes. In adequate change control
procedures ends up in regulatory non compliance
46. Functional group involved in Change
47. Production : change in location , equipment , batch size, process
Engineering : changes in Any part of equipment, design &layout ,
Research & development : Change in specifications of raw
materials, Quantity of raw materials, Change in shelf life,
environmental conditions, stability protocols , stability conditions
Quality control : Change in Method of analysis, change in sampling
plan ,change in Hardware /software of computerized instruments.
Quality assurance : change in validation protocols, Sop‘s and
documents and sampling.
Cleaning procedures : change in cleaning aids, agents and
CHANGES IN PHARMACEUTICAL
50. SOP for Change Control Program
Purpose : To provide instruction for change
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
52. Returned drug products
Returned drug products shall be identified as such and held. If
the conditions under which returned drug products have been
held, stored, or shipped before or during their return, or if the
condition of the drug product, its container, carton, or
labeling, as a result of storage or shipping, casts doubt on the
safety, identity, strength, quality or purity of the drug product,
the returned drug product shall be destroyed unless
examination, testing, or other investigations prove the drug
product meets appropriate standards of safety, identity,
strength, quality, or purity.
53. Returned drug products
• A drug product may be reprocessed provided the
subsequent drug product meets appropriate standards,
specifications, and characteristics. Records of returned
drug products shall be maintained and shall include the
name and label potency of the drug product dosage
form, lot number (or control number or batch
number), reason for the return, quantity returned, date
of disposition, and ultimate disposition of the returned
• If the reason for a drug product being returned
implicates associated batches, an appropriate
investigation shall be conducted in accordance with the
requirements. Procedures for the holding, testing, and
reprocessing of returned drug products shall be in
writing and shall be followed.
“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.”
55. 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
• 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. 55
56. 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.
57. Drug product salvaging
• 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
• 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. 57
58. Handling of waste and scrap
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.
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.
59. Handling of waste and scrap
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
60. Handling of waste and scrap
Materials like rejected foils, bottles, cans, and tins etc. which have a
• 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
61. Handling of waste and scrap
• 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
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.
62. Regulatory bodies that oversee
Pharmaceutical Waste Management
• Environmental Protection Agency (EPA)
• Department of Transportation (DOT)
• Drug Enforcement Administration (DEA)
• Occupational Safety and Health Administration
• State Environmental Agencies
• State Pharmacy Board
63. Types of wastes:
On the bases of state
On the bases of effect
• Hazardous waste
• Bio hazardous waste
• Radioactive hazardous waste
64. Hazardous waste
A type of solid wastes that contain substantial or
potential threats to public health or the
Must meet any of the following criteria:
• Specifically listed as a hazardous waste by EPA
• Exhibits one or more of the characteristics of
hazardous wastes (ignitability, corrosiveness,
reactivity, and / or toxicity)
• Is generated by the treatment of hazardous
65. Storage requirements
1. Containers must be in good condition
2. Containers must be compatible with waste.
3. Containers must be handled in a manner to prevent
leaks and pills
4. Containers must be inspected
5. Containers must be labeled “Hazardous Waste” and
/ or list the contents of the container.
66. Characteristics of hazardous waste
Characteristics waste are regulated because they
exhibit certain hazardous properties:
67. Bio hazardous waste
• A solid waste that contains or may reasonably be expected to
contain pathogens of sufficient virulence and quantify that
exposure to the waste by a susceptible host could result in an
• This waste includes such materials as used shaps (needles,
syringes, blades, pipettes, broken glass, and blood vials), body
fluids or materials mixed with body fluids, bandages, or other
materials that have come in contact with body fluids.
68. Methods of product disposal
1. High temperature incineration
2. Waste immobilization: encapsulation
3. Waste immobilization: inertization
4. Discharge to sewer
5. Landfill deposit
6. Chemical decomposition
7. Medium temperature incineration
8. Open container incineration
69. Waste product disposal procedure
• Product disposal:
• Printed packaging disposal
• General trash and sewage
70. Scales of product disposal
• Large scale destruction
• Medium scale destruction
• Small scale destruction
71. Schedule M Guidelines
• All biomedical waste shall be destroyed as per
provisions of Biomedical Waste (Manufacturing and
Handling) Rules, 1996.
• Additional precautions shall be taken for storage and
disposal of rejected drugs.
• Hazardous toxic substance and flammable materials
shall be stored in suitably designed and segregated
enclosed areas in conformity with central and state
• Provision shall be made for proper and safe storage of
waste materials. Records shall be maintained for all
disposal of waste.
• Pharmaceutical Process Validation, Chapter 20 by Robert A Nash & Alfred H
• Pharmaceutical Quality Assurance, Manohar A Patidar, Nirali Prakashan.
• International Journal of Industrial Pharmacy and Bio Sciences 1(1): May-June 2014
• 21 Code of Federal Regulations Parts 210 and 211, 211.215
• Received: 09-05-2012; Revised; Accepted: 06-05-2014 IN PROCESS QUALITY
CONTROL: A REVIEW Pranshu Tangri*, Praveen Mamgain, Shaffi, Abhay ML Verma,
Lakshmayya GRD (PG) IMT, Dept. of Pharmacy, Dehrdaun, Uttarakhand, India