The document discusses equipment design, construction, cleaning, maintenance and repair for use in manufacturing pharmaceutical products. It emphasizes that equipment must be of appropriate design for its intended use and constructed of materials that will not react with or contaminate products. Cleaning and maintenance procedures must be established and validated to prevent contamination and ensure equipment functions properly. Equipment must undergo qualification testing before use and be cleaned and maintained regularly to guarantee product quality is not compromised.

1. Equipment
• Design of equipment for
intended purpose
• Repair and maintenance
operation
• Washing and cleaning

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

3. Equipment Design
• The effectiveness of equipment, like the quality of a product,
starts at the design stage.
• Most pharmaceutical companies are not directly involved
with the designs and construction of equipment but they can
contribute indirectly. They can, and do, provide information
on requirements and feedback on existing equipment. When
evaluating alternate types or makes of equipment, several
parameters need to be considered:
1. Operating criteria are adequate for the process—size, speed,
effectiveness (of, say, a mixer).
2. Availability of spares and servicing. This can result in using
different makes of equipment in different parts of the world.

4. Equipment Design
3. Maintenance. The frequency and ease of maintenance will significantly
impact on productivity and even quality. Equipment breakdown during
processing could adversely affect quality. Included in the maintenance
evaluation should be the cleanability of the equipment. This will involve
accessability to the parts needing to be cleaned and the relative ease of
disassembly and reassembly.
4. Environmental issues. Does the equipment disseminate dust, with the
potential for contaminating other products or making it necessary for
operators to wear additional protective clothing and facilities to be
cleaned more frequently? The possible impact of noise and energy use
and dissipation should be considered.
5. Construction materials and design.

5. Equipment Design
6. Availability of process controls such as automatic weight
adjustment on tablet presses and temperature recorders on
ovens. Although initially more expensive they could prove to
be very economic overall by providing more consistent
product quality and better records.
7. Cost. A comprehensive cost should, if possible, be compiled
which will include the base price plus any additional costs.
8. Availability of design and maintenance manuals from the
supplier that are important for validation/qualification and
maintenance programs
New equipment should not be used for commercial production until it
has been qualified and the process in which it is to be used has been
validated; this applies equally to laboratory and other test equipment

6. Equipment Construction
a) Equipment shall be constructed so that surfaces that contact components, in-process materials, or
drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or other established
requirements.
(Compliance with this subsection requires the manufacturer to determine which drug products and
materials are to be processed in the equipment and where contact between materials and machinery
occurs. Since many of the surfaces of processing equipment are either stainless steel or glass this is
not too great a task. However, stainless steel is not totally inert and care should be exercised in
choosing the grade—note that distilled water is very corrosive and requires 316 grade, which should
then be passivated, usually with 15–30% nitric acid. Evaluation of potential interactions will include
introduction of unacceptable extractives from the equipment into the product, alteration of the
physical or chemical properties of the product, and introduction of particulates from abrasion of
surfaces).

7. Equipment Construction
(b) Any substances required for operation, such as lubricants or coolants, shall not come into contact
with components, drug product containers, closures, in-process materials, or drug products so as to
alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other
established requirements.
(This requirement affects the design, construction, and placement of manufacturing equipment.
Motors, drive belts, gears, and other potential sources of lubricant contamination should be located
away from vessel or package openings that could result in product contamination. For equipment
where this is not possible, such as some mixers and tablet and encapsulating machines, lubrication
needs to be controlled and monitored; buildup of lubricant and powdered product should be regularly
removed and lubricants should be of food grade. Gaskets and other connecting surfaces should be
monitored to ensure they don’t break down, thereby allowing environmental contamination or gasket
particles into the product).

8. Equipment Cleaning And Maintenance
It is of interest to note that (a) identifies two reasons for cleaning, maintenance and
sanitation.
• First, to prevent contamination from materials previously utilizing the equipment.
• The second reason is an acknowledgment that inadequate cleaning or maintenance
may cause equipment to malfunction or break down and that this could have an
adverse effect on the process or product. For example, if a process required stirring
for 30 minutes at 60°C and the stirrer broke down, it is likely that the exposure to
heat could exceed 30 minutes by the time the stirrer was repaired or replaced.
The importance of the plant maintenance program is often underestimated with respect
to its potential impact on product quality. The main emphasis for maintenance programs
is to minimize the potential for breakdowns and to optimize production cycle times.
This emphasis is important. However, poor maintenance can also result in equipment
not functioning as intended, with consequent impact on processing and quality.
Inadequate maintenance can also enhance the potential for lubricant leakage, wear on
bearings and other equipment components, which could disgorge metal into the
product, and difficult-to-remove buildup of residues, which could later dislodge.

9. Repair and maintenance operation
• Balances and measuring equipment of an appropriate range and
precision should be available for production and control
operation.
• Weighing and testing equipment used in manufacture and quality
control should be calibrated, checked and properly recorded at
regular intervals and maintained properly to enable them to
perform their proper functions.
• Written procedures should be established and followed for
cleaning and maintenance of equipment, including utensils used
in the manufacture, processing, packing or holding of medicines
• Equipment should be checked for cleanliness prior to each use.
• Equipment used for the preparation of internal products should
be separated from that of external products.

10. Repair and maintenance operation
• Defective equipment should, if possible, be removed from production and quality control areas, or
at least be clearly labelled as defective.
• Repair and maintenance operations should not present hazard to the quality of the products.
• Production equipment should not present any hazard to the products. The parts of the production
equipment that come into contact with the product must not be reactive, additive or absorptive to
such an extent that it will affect the quality of the product and thus present any hazard.
• The equipment, filtering materials etc. used in the manufacturing processes must be compatible
with the extraction solvent, in order to prevent any release or undesirable absorption of substance
that could affect the product.
• Pipework and hoses for treated water and products should be cleaned and sanitised according to
written procedures.

11. Cleaning and sanitisation of equipment
• Equipment and utensils shall be cleaned, maintained, and sanitized at
appropriate intervals to prevent malfunctions or contamination that would
alter the safety, identity, strength, quality, or purity of the drug product
beyond the official or other established requirements
• Any missing components such as nuts, springs, clips, etc. should be
reported and investigated immediately.
• Vacuum or wet cleaning methods are preferred. Compressed air, fibrous
material and brushes should be used with care and avoided if possible, as
they increase the risk of product contamination.
• Adequate space, preferably separated from processing areas, should be
provided for cleaning and storing mobile equipment and the storage of
cleaning materials.
• Written procedures should be established and followed for cleaning and
sanitising equipments, utensils and containers used in the manufacture of
traditional medicines and health supplemen

12. Cleaning and sanitisation of equipment
• These procedures should be designed to prevent equipment contamination by cleaning or sanitising
agents and should at least include the following:
responsibility for cleaning.
cleaning schedule.
cleaning methods.
equipment and materials used in cleaning operations.
methods of disassembling and reassembling equipment.
removal of previous batch identification.
protection of clean equipment and utensils from contamination prior to use.
• Records of cleaning, where appropriate sanitising and inspection prior to use should be
maintained.

13. Cleaning Validation Program
• Equipment cleaning validation may be performed concurrently with actual production
steps during process development and manufacturing.
• Validation program should be continued through full scale commercial production.
• The concept “Test Until-Clean” should be applied. This concept involves cleaning,
sampling and testing with repetition of this sequence until an acceptable residue limit is
attained.
• A validation program generally encompasses at least three consecutive successful
replicate to establish that the procedure is reproducibly effective.
• If the equipment of the similar size, design and construction is cleaned by the same
procedure, studies need not be conducted on each unit as long as a total of three
successful replicates are done on similar piece of equipment; this concept is known as
equipment grouping.

14. Cleaning
Validation
Program
• Selection of cleaning Level (Type)
• Selection of cleaning method
• Selection of sampling method
• Selection of Scientific basis for the
contamination limit (acceptance criteria)
• Selection of Worst case related to the equipment
• Selection of Worst case related to the product
• Establishing the storage period after cleaning
(hold time study)
• Selection of analytical method
• Documentation

15. Selection Of Cleaning
Level (Type)
• TYPE A (MINOR)
This type of cleaning take place between two
batches of same product or between different
strengths of the same product. For minor cleaning,
cleaning validation is not required, since cross
contamination is not an issue.
• TYPE B (MAJOR)
This type of cleaning take place between two
products. In this case, validation of the
effectiveness of the cleaning procedure in
removing residues to the required level is
mandatory.

16. Selection of
Cleaning Method
• Manual cleaning
 Difficult to validate.
 Most extensive and elaborate cleaning procedures are required.
 A high quality and extensive training program is required).
• Semi automatic or fully automatic cleaning systems
• Cleaning in place (CIP)
 Cleaning of the equipment is performed in place without disassembling
 Cleaning process may be controlled manually or by an automated program.
 Very consistent and reproducible cleaning method.
 Can be validated readily.
 Being a closed system visual inspection of all components is difficult.
• Cleaning out of place (COP)
 Cleaning of disassembled equipment is performed in a central washing
machine.
 The washing machine also requires validation such as the temperature,
ultrasonic activity, cycle time, cleaning operation sequence, detergent
quantity dispensed etc.

17. Selection of sampling method
Generally there are two types of sampling that are accepted. The
most desirable is the direct method of sampling the surface of the
equipment, another method being the use of rinse sampling.
• Swab sampling (direct method)
It is also know as direct surface sampling method. This method is
based on the physical removal of residue left over on a piece of
equipment after it has been cleaned and dried. A swab wetted with a
solvent is rubbed over a previously determined sample surface area
to remove any potential residue, and thereafter extracted into a
known volume of solvent in which the contaminant active
ingredient residue is soluble. The amount of contaminant per swab
is then determined by an analytical method of adequate sensitivity.
• Rinse samples (indirect method)
This method is based on the analytical determination of a sample of
the last rinsing solvent (generally water) used in the cleaning
procedure. The volume of solvent used for the last rinse must be
known to allow for the quantitative determination of the
contamination.

18. Direct surface sampling (swab method)
Advantages
• Direct evaluation of surface contamination.
• Insoluble or poorly soluble substances may
be physically removed from the equipment
surfaces.
• Hard-to-clean but accessible areas are easily
incorporated into the final evaluation.
Disadvantages
• Difficult to implement in large-scale
manufacturing equipment.
• Extrapolation of results obtained for a small
sample surface area to the whole product
contact surface area.
Rinse samples (Indirect method)
Advantages
• Ease of sampling.
• Evaluation of entire product contact surface.
• Accessibility of all equipment parts to the
rinsing solvent.
• Best fitted to sealed or large scale equipment
and equipment which is not easily or
routinely disassembled.
Disadvantages
• No physical removal of the contaminant.
• The rinsing solvent may not reach
inaccessible or occluded part of equipment.
• Use of organic solvents for water insoluble
materials.

19. Selection of Scientific basis for the
contamination limit (acceptance criteria)
The rationale for selecting
limits for product residues
should be logically based on
a consideration of the
materials involved and their
therapeutic dose. The limit
should be practical,
achievable and verifiable.

20. Selection of Worst
Case Related to:
• The Equipment
Bracketing by equipment should be done only when it is
similar equipment, or the same equipment in different sizes
(e.g. 300-L, 500-L and 1000-L tanks). An alternative
approach may be to validate the smallest and the largest sizes
separately.
The worst case for a group of equipment is represented by the
equipment with the larger product contact surface and the
hardest-to-clean locations.
• The Product
Only one product out of a group of product processed in a
piece of equipment is selected for the cleaning validation
study, based on the lowest solubility of the active ingredient
and its therapeutic dose.

21. Establishing the Storage Period After
Cleaning (Hold Time Study)
• The objective for establishing time limit between
equipment cleaning and reuse is to ensure that the
equipment remains clean till the next use. This needs
demonstration that there is no microbial proliferation
in cleaned equipment's during storage.
• For establishing the time limit, the equipment should
be dried. Initial swab samples for surface should be
taken. Thereafter, the equipment should be protected
and stored in its designated area.
• Periodic samples of product contact surface for
microbiological contamination should be taken. (1st
day, 2nd day, 3rd day etc.)
• Based on the data generated establish the acceptable
time limit.

22. Selection of Analytical Method
There are many analytical techniques available that can be used in cleaning validation including:
• Specific Methods
 Chromatographic methods such as GC, HPLC etc.
 Thin layer chromatography.
 Specific ion meter.
Of the above methods, chromatography methods are the methods of choice, as they separate analytes, are highly
specific, highly sensitive, and quantitative. But the methods are costly and time consuming.
• Non-specific Methods.
 Spectrophotometric methods in the visible, infrared, or UV ranges
 Total organic carbon (TOC)
 Other Methods
For monitoring cleaning procedure TOC method is used. It offers at a moderate cost and in addition to its rapidity, a
detection capability down to the ppb range.

23. Documentation
• A Cleaning Validation Protocol is required to define how the cleaning process will be validated.
• Depending upon the complexity of the system and cleaning processes, the amount of documentation
necessary for executing various cleaning steps or procedures may vary.
• When more complex cleaning procedures are required, it is important to document the critical cleaning
steps.
• Other factors such as history of cleaning, residue levels found after cleaning, and variability of test
results may also dictate the amount of documentation required.
• A Final Validation Report should be prepared. The conclusions of this report should state if the
cleaning process has been validated successfully. Limitations that apply to the use of the validated
method should be defined

24. References
• Guidelines On Good Manufacturing Practice For Traditional Medicines And
Health Supplements.
• Good Manufacturing Practices for Pharmaceutical A Plan far Total Quality Control
from Manufacturer to Consomer Fifth Edition, Revised and Expended (Book).
• Goyal, D., Maurya, S., & Verma, C. (2016). Cleaning validation in pharmaceutical
industry-an overview. PharmaTutor, 4(9), 14-20.
• Raj, A. (2014). CLEANING VALIDATION IN PHARMACEUTICAL
INDUSTRIES. Journal of Atoms and Molecules, 4(4), 779.