Unit-2 Equipment and Raw Materials Pharmaceutical Quality Assurance

 Introduction

Equipment may be defined as any piece of plant, machinery, instrument, etc which is used for  
carrying out a specific activity or operation e.g. mixer, granulator, dryer, HPLC, etc
Equipment can be single piece or it may consists of a set of integrated pieces to perform a  
common activity e.g. water demineralization plant.
Equipment is important because all the pharmaceutical manufacturing or control activities  
depends upon the good performance of the equipment. Hence the regulatory literature provides  
certain specific guidelines in this regard.

 
Design- the design of the equipment should met our requirements, for which we are selecting the  
equipment. For this purpose one should prepare a User Requirement Specification (URS); this  
spells out the requirements. It should vary from equipment to equipment but this should at least  
answer the following questions namely:
1. What operation you want to perform with this equipment?
2. What capacity we should have in terms of holding and in terms of output?
3. Which material we are going to use in this equipment and do they have any interaction  
with material of construction?
4. How this equipment will be cleaned?  
5. Do we have trained operators to operate this equipment? Or whether the manufacturer  
will help us in training our existing operators?
Based on such information the user requirement specification is made and sent to the suppliers  
who prepares the design qualification or design specification and sends back to user. 

Size- Size of the equipment is decided based on the volumes of materials, which are going to  
handle. Batch sizes are also directly related to the size of processing equipment. Following things  
should be considered in case of size of the equipment 

1. Physical dimension of the machinery (length X height X width), size of the room in  
which machine is going to be installed and the path of the plant through, which it will be  
transported, has to be taken into an account. If it is to be installed in a new facility which  
is under construction, then certain walls or partition can be constructed after the  
equipment is installed in place. This avoids lots of hassle of carrying the equipment to its  
point of installation.
2. Holding and output capacity is also directly related to the size of the equipment
3. What is the minimum and maximum volume of materials we are going to handle and  
whether the equipment can process those minimum and maximum volumes should be  
considered while deciding the size of the equipment.
Location- Decision of location of the equipment in the plant depends upon the logical process  
movement. In addition to this potential danger of contamination and mix-ups should be taken  into account. Other factors which influence the location of the equipment are:-
1. Utility service required
2. Material handling and movement
3. Movement of processing and cleaning
4. Men movement for repair and maintenance
5. If the equipment is discharging gases, fumes, powders, etc, then this factor is also  
important and should be considered while selection the location of the equipment in the  
plant.
Construction- Four main factors required to be considered. They are as follows
1. Ease of cleaning the equipment and surrounding area.
2. Ease of operation of the equipment
3. The material of construction (MOC), should not react with product, it should not leach  
any part of the MOC to the product being processed and MOC should not adsorbed any  
materials.
4. Ease of maintenance of the equipment.

Equipment Identification- Identity is one of the four major parameter of GMP (Identity,  
strength, safety and purity). It is very important to have Unique Identification Number (UIN)  
for each equipment and that must be recorded in Batch Production and Control Record.  
CFR-211.105 of USFDA gives very clear guidelines in this regard, it states that:
1. “All compounding and storage containers, processing lines and major equipment are used  
during production of a batch of a drug product shall be properly identified at all times to  
indicate their contents and when necessary, the phase of processing of the batch”
This label may have following details at the minimum
- Name of the product - Batch number
- Batch size
- Processing stage
- Date and sign of the production supervisor.
2. “Major equipment shall be identified by a distinctive identification number or code that  
shall be recorded in batch production record to show the specific equipment used in the  
manufacture of each batch of a drug product. In cases where only one of a particular type  
of equipment exist in manufacturing facility, the name of the equipment may be used in  
lieu of a distinctive identification number of code”
Equipment Log- Pharmaceutical manufacturers must maintain a register or log of the  
various operations carried out on the various equipment. This log should be for following  
these activities namely, operation, cleaning, and maintenance. Such logs should have  
following fields in it:- Sr. no, Name of the equipment and its distinctive identification code,  
product/batch numbers handled, date and time activities carried out like, operation, cleaning  
and maintenance. This record should in chronological order, name of the operator working  
on this equipment.
Purchase Specification for Equipments- While purchasing following parameters/  
specifications should be considered
1. Operating criteria are adequate for the process- size, speed and effectiveness.

2. Availability of spares and servicing 
3. Ease of maintenance and cleaning
4. Environmental issues (equipment disseminating dust may cause contamination to other  
products being manufactured and equipment producing noise)
5. Material of construction
6. Cost of equipment
7. Availability of SOP, design and maintenance manuals from supplier with equipments  
those are important for operating, handling, validation and qualification.  

Maintenance and Cleaning of Equipments

Purpose of cleaning equipment is to remove product residues of previous product or batch and to  
clean and sanitize the equipment for next batch.
Equipment should be cleaned regardless of their size. However, large equipment which are fixed  
or are too heavy to move should be cleaned on location. Detachable part or small equipment  
should be taken to cleaning area assigned for the purpose.
Written cleaning procedures or SOP should be prepared for all the equipments. This should be in  
the language that is understood by the workers and be available in the section. For guidance,  
some common steps for equipment cleaning are given below

For dry products

-Remove labels with the help of the, remove product residue from previous batch
- Disassemble and clean disassemble parts further with the help of brush.  
- Wash parts with soap and jet of water using a scrubber, then wash with sufficient clean water.
- Drain out water and dry in clean area
- Where necessary, sterilize with 70% isopropyl alcohol or other suitable disinfectant.
- After drying the parts, assemble the equipment.

For Liquid products- filling equipment

- Drain out holding tank or left over, if any fill the holding tank with water and start filling machine, collect water coming out of  filling machine and discard it 

 - now open drain valve of the holding tank - disassemble nozzles and washers - Remove tubing 

 - Clean all the parts with jet of water - Soak parts and flexible tubing in antiseptic solution for 30 min. (0.5% cetrimide  solution can be used for this purpose)

 - Wash these parts in running water - Soak in a hot water 

- If steam is available, use 70 % isopropyl alcohol and allow to dry 

 - Cover ends of the clean tubing with polyethylene sheets 

 - Clean holding tank with hot water, if steam is available treat with hypochlorite  solution 

 - Assemble the equipment 

Whenever there is product change over, final rinse of water should be tested for active  ingredients of the last product processed. Test of the active ingredient could be limit test  or UV spectrophotometer. 

Before use, equipment should be inspected for cleanliness and should be cleared by  person responsible for the job. Tags with words like ‘Equipment Cleaned’, ‘Cleaned’ or  ‘Ready to Use’ can be used for cleaned equipment. Cleaned equipment should be covered  to protect from extraneous contamination.  

Raw Materials 

Revised Schedule M has two separate elements, namely, “Raw materials (R.M)”, “Label and  other Printed Material (P.M.)”. The underlying principle of this element is that a finished  product is produced by using different type of materials (e.g. active material, excipient,  packaging material, etc) therefore; consideration should be given to various materials that may  be encountered in the pharmaceutical production and other activities.

There are two general guidelines.

 1) Any material which received should be quarantined; its quality should be assessed for its disposition. 

2) All materials should be stored in appropriate  conditions in a manner which will allow batch segregation and stock rotation.

Starting Material (Raw material)

“Raw material is defined as starting material used in manufacturing of finished product.”
Since a finished product is the result of processing of starting materials, purchasing of starting  
materials is an important operation. It should involve a person who has knowledge of materials  
and suppliers. There should be written procedures for receipt, identification, storage, handling,  
sampling, testing, and approval or rejection of starting material. The following guidelines will be  
useful to develop the system.
1. On receipt, each delivery of the starting material it should be visually examined for  
labels, damage to containers, spoilage and possible deterioration during transit.  
2. Particulars on the delivery challan/invoice should be tallied with labels on container of  
the materials. A goods-in inspection report may be prepared and filed along with delivery  
challan or invoice.
3. Starting materials then should be transferred to quarantine area and labels over printed  
with words ‘under test’ should be pasted on the containers of the materials.
4. Request should be made to in charge, Quality control for sampling
5. Quality control personnel, on receipt of request, should draw sample from raw materials.  
While sampling points that should be kept in mind are: - Samples for identification should be taken from each container of active ingredients  
as well as excipient. - Samples should be representative of batches of materials from which they are taken
- All sampling equipment which come in contact with the material must be clean
- Containers which have been sampled should be resealed after sampling
- Appropriate precaution should be taken during sampling of hazardous or toxic  
materials
- Sterile equipment or aseptic techniques should be used wherever necessary 

6. On the receipt of ‘approval’ or ‘rejection’ as the case may be, the starting material should  
be transferred to area marked for approved materials or rejected materials according to  
the status of the material.
7. Those materials which require special storage conditions (e.g. controlled temperature  
and/or humidity) should be stored in the special storage area provided for the purpose.
8. Staring materials in boxes and bags should be stored off the floor and be suitably spaced  
to permit cleaning and inspection.
9. Stocks of the starting materials should be inspected at intervals to ensure that containers  
are properly closed and labeled and are in good condition.
10. All materials should be stored under appropriate conditions in such a manner that will  
permit batch segregation and stock rotation by a “First In First Out” (FIFO) principle or  
“First Expiring First out” (FEFO) principle.
11. Segregated dispensing areas suitably equipped to avoid cross contamination should be  
provided, weighing and measuring equipment should have the capacity, accuracy  
appropriate to the material to be weighed and measured. These should be calibrated at  
regular intervals.
12. Materials issued against written demand (requisition) for each batch of finished product  
should be identified and be placed together.
13. Each dispensed material and its weight/volume should be checked by another person and  
such check should be recorded.
14. Inventory of all the starting material should be maintained according to Schedule U of  
Drug and Cosmetics Rule.
15. Raw materials in the storage area should be labeled with the following particulars
- Designated name and internal code, if any
- Analytical reference number
- Manufacturer’s name, address and batch number
- Status of the content (Quarantine, under test, approved, rejected)
- Manufacturing date. Expiring date and re test date.
Material Management include conversion of sales forecast into production forecast and then  
into raw materials, finishing supplies, intermediates, equipment loading and labor hours. A good  
material management requires that all these are available at the right time and place. To achieve this, there must be control over purchasing, receiving, warehousing, production planning and  
distribution. There are two most important activities that have been identified with materials  
management. 1. Production planning 2. Inventory control
One of the most important and simplest method which is used for inventory management is A, B,  
C classification of inventories. This classification is based on the principle outlined by famous  
mathematician and engineer, V. Pareto. In the simplest form, the principle states that in a large  
population in which many items are involved, relatively few items account for the major part of  
activity for example, 20 % of the highest value items in inventory (A) amounts to 75% or more  
of total inventory value. Another 20 % of medium value items (b) account for additional 15 % of  
the inventory value. Thus A and B combined values though only 40 % but represent a combined  
value of 90% of total inventory. The remaining 60 % (C) of items represent a small value. It  
means that when substantial number of items are to be controlled, emphasis should be given to A  
and B items. Inventory levels of C items may be given less attention than inventory level of A  
and B items.  
*Vendor Qualification for raw material purchase.