EQUIPMENTS AND RAW MATERIALS || QUALITY ASSURANCE

 

EQUIPMENTS AND RAW MATERIALS

EQUIPMENTS

• The pharmaceutical industry makes use of different equipment at each stage of the manufacturing of drug products. 
• Equipment used may be a single piece - such as a weighing machine, or a granulator or a group of equipment working in a process to deliver a single outcome such as a purified water system.
• The ingredients of a formulation come into intimate contact with the equipment at every step. 
• Naturally, the quality of this equipment plays a major role in determining the quality of the final products. 
• Equipment must be designed and constructed in a manner that prevents contamination or any other adverse impact on the drug material.

Design and Construction

• Equipment must be designed and constructed to suit the purpose of its use. 
• The material of construction must be adequate to the nature of processing to be undertaken. 
• Equipment surfaces that come into contact with drug product must not be additive, reactive or absorptive. 
• If the surface of equipment adds chemicals from its surface into the drug material, or reacts with it or absorbs the formulation ingredients, there can be a serious impact on the identity, safety, strength, purity and quality of the final product.
• Equipment must be designed for closed operation as far as possible to reduce the risk of contamination of material it holds. 
• If open equipment is unavoidable, it must be designed and handled in a way that minimizes contamination. 
• Diagrams of critical equipment must be maintained. Lubricants used in equipment maintenance should be of non-toxic or edible grade. 
• Such lubricants or coolants used on the equipment must not come into contact with the drug product, its containers or closures, Failure to ensure this will contaminate the drug and render it unsafe for use.

Location

• Equipment must be located in a clean, hygienic area that is suitable for the operation being performed. 
• When several equipment's are to be used as part of a process, they must be located in such a way as to allow the linear and sequential flow of the production process. 
• The equipment must be situated in a way that it allows ease of cleaning and maintenance.

Installation

• Equipment must be installed in keeping with the manufacturer's specifications. 
• All necessary utilities must be provided and there must be arrangements to access the equipment for maintenance work without having to enter the production areas. 
• Pipework leading to and from any equipment must be labeled with contents and direction of flow. 
• Any equipment that is defective must be removed to a separate area outside the production or quality control area. 
• In case this is not possible, the equipment must bear a conspicuous label that states its defective status.

Cleaning and Maintenance

• Written procedures must exist for the cleaning of equipment and their regular maintenance. 
• Cleaning must be done at regular intervals to avoid the entry of contaminants: equipment must also be cleaned thoroughly between different batches of product to avoid risk of cross-contamination. 
• For equipment used in manufacturing sterile products, additional steps need to be taken to sanitize and sterilize the equipment to maintain it in sterile condition. 
• Regular maintenance must be performed for all critical equipment to ensure there are no malfunctions during a processing run. 
• Cleaning validation studies must be performed to ensure equipment cleaning leads to the desired levels of cleanliness.

Qualification and Calibration

• Qualification of equipment begins right at the design state when it is designed to be constructed in a particular manner suitable to its intended purpose. 
• Steps of design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ) must be carried out to ensure the equipment is designed installed, operated and performed as expected to give a quality product.
• Once equipment has become operational, with wear and tear over time, there is a chance of a drift in its performance from expected profiles. 
• So, it is vital to have a regular calibration program in which the equipment and any associated instruments are checked to obtain a measure of how accurately it is performing. 
• These calibration results can help to identify defects in the equipment, which can then be dealt with in the appropriate manner.
• Records of calibration and qualification must be maintained for all equipment.
• When computer or related systems are used, there must be sufficient control to ensure that any changes in records take place only after due authorization by higher management. 
• Backup files of data must be maintained and stored in a way that it is protected from alteration or loss, Hard copies of backup data must be maintained, too.

Documentation

• All the major equipment's should have a unique identification code or number, and this must be recorded in the batch manufacturing record (BMR). 
• Separate cleaning and maintenance logs must be maintained for each of the major equipment, and any cleaning or maintenance activity must be recorded in these. 
• Standard operating procedures must exist for operating all equipment, and they must be placed close to the equipment for use by the personnel handling them.
• The major equipment being used in manufacturing a given batch must be labeled with details of product name and batch number at all times to indicate the contents within.

Purchase Specifications for Equipment

• Pharmaceutical industry equipment is quite expensive and therefore, selecting the right equipment is a critical process. 
• Some of the most important factors to be considered in making this decision are as follows:

1.     Desired output capacity: Equipment purchased must be capable of processing desired quantity of product at the desired speed of operation. Understanding one's production scale in terms of batch size requirements and comparing this with the load capacity of the equipment being considered is an important first step when choosing equipment.
2.   Product characteristics: The nature of the product, its reactivity, any special conditions necessary to ensure retention of its safety, efficacy and quality are all important while choosing equipment.
3. Ease of operation: Equipment operation must be simple, and not involve complex maneuvers or require special skills. The equipment must be easy for the operator to operate after receiving proper training. It is important to strike a balance between efficiency of performing the given operation and ease of operating the equipment Digitally enabled equipment can help to manage manufacturing process better, it will however require special skills for operation and the capacity of one's workforce to learn those skills must be considered.
4.  Ease of cleaning and maintenance: Equipment will require regular cleaning and special, more thorough cleaning between batches of different products. The time used for cleaning is time lost from the production run. So equipment must be easy to clean (either in-place, or by disconnecting and taking to a special cleaning area). It must also be easy to maintain and not require frequent maintenance activities which again are a time-consuming process.
5. Equipment supplier: When buying equipment, price is often considered an important criterion, but it is more important to focus on the quality parameters on offer and the industry reputation of the supplier and how reliable their product is, their customer service, and their capability to provide equipment troubleshooting service when necessary.

RAW MATERIAL

• Between 1995 and 1996, Haiti saw incidents of around 80 children dying after ingesting a cold-and-cough syrup. 
• An investigation fixed the responsibility on glycerol in the product being contaminated with diethylene glycol. 
• This and other such incidents highlight the need for drug product manufacturers to pay attention to the quality of starting materials they use.
• While active pharmaceutical ingredients (APIs) may be manufactured under cGMP (current Good Manufacturing Practices), excipients may not be so produced, especially the ones commonly used in other industries like cosmetics or food. 
• This makes it even more important to ensure these excipients are of a grade suitable for pharmaceutical use Containers and closures must also be evaluated because they play a vital role in ensuring product stays stable and safe throughout the shelf life.

Purchase of Materials

• Purchasing must be done by staff with a thorough knowledge of those materials and their suppliers. 
• Materials must be procured only from approved suppliers who have consented to provide materials in keeping with quality specifications of the drug product manufacturer. 
• It is advisable for pharmaceutical manufacturers to enter into contracts with specific vendors after performing a vendor audit that provides an assurance of raw materials and packaging materials of the desired level of safety and meeting quality standards.

Receiving, handling and storage of materials

• Specific written procedures must be prepared to describe how materials (both drug components and drug containers and closures) will be received, identified, stored, handled, sampled, tested and accordingly approved or rejected, and these procedures must be followed as written.
• When receiving materials, the consignment must be visually examined and the labels checked to confirm the content, quantity, integrity of seals and to verify that there is no damage or contamination. 
• Any damaged containers found must be separated, and details recorded and informed to the supplier.
• The materials must be stored under quarantine until samples have been drawn and tests have been performed. 
• They must not be issued for use before approval. 
• Handling and storage of all materials in the storage area must be in such a way that there is no contamination. 
• Boxes or bags holding containers and closures must be stored off the floor. 
• The storage must be done in a way that suitable space is left for proper cleaning and inspection of the materials.

Sampling

• Representative samples must be drawn from each shipment of each lot. 
• If different batches are present in a single shipment, samples must be drawn from each of those. 
• The quantity must be sufficient to perform all required tests and reserve when specified Statistical criteria must also be used to determine quantity of samples drawn. 
• Containers must be cleaned before sampling to avoid introducing contamination, and resealed after sampling to prevent contamination of the contents, and appropriately labeled to show sample has been taken. 
• Samples must be drawn from the bottom, middle and top of the containers, and marked accordingly. 
• Sample-holding containers shall be labeled with details of name of material, lot number, container number, date of sampling, and name of person collecting the sample.

Testing of Samples

• At least one specific test must be performed to verify the material's identity. 
• Tests must be carried out to determine conformity with predetermined specifications for quality, strength and purity. 
• In case materials are supplied along with a certificate of analysis by the supplier, the materials may be used without sampling and testing, provided the supplier is a reliable, validated vendor and at least one specific identity test has been performed and mentioned in the certificate.
• Materials that are liable to contamination with adulterants or insect infestations or filth must be examined for such contaminants. 
• If materials are prone to microbial contamination, microbiological tests must be performed to test for it.

Approval/Rejection of Materials

• All materials that meet the manufacturer's quality requirements of identity, quality, purity and strength and other tests are to be approved for use. 
• Materials not meeting these requirements must be rejected.

Labeling

• Labels must carry the name of the product, the company's unique reference code, manufacturer's name and address, and their assigned batch number. It must also state the status of the contents (For example - "Sampled", "Quarantined", "Approved" and "Rejected"), manufacturing and expiry dates and re-test date. 
• When attaching such labels, care must be taken that original information on the supplier's label is not lost.
• Approved materials must be so marked while rejected materials must be conspicuously labeled and stored in a separate area to avoid chances of mix-ups or misuse.

Using Approved Materials

• Approved materials must be stored properly and issued for use in a way such that earliest approved stock is used first before more recently approved stock. 
• Many companies use a FEFO (First Expire First Out) system for stock rotation. 
• Another deciding factor is that the drug product's shelf life must not exceed the shelf life of the APIs.
• If materials have been stored for very long period without usage, or if they have been exposed to any condition that may have an adverse effect on their quality or safety, they must be re-tested for the same parameters as the initial test. 
• Results of the re-test must be used to determine if the materials are approved or rejected.

Handling Rejected Materials

• Rejected materials must be identified with appropriate labels and kept in quarantine until safely disposed. 
• Care must be taken to prevent use of such materials in manufacturing operations.

Containers and Closures

• Containers and closures are used for packing of drug products must not be additive reactive or absorptive. 
• This is important to ensure they do not cause a change in the identity safety, quality, strength, or purity of the drugs beyond specifications.
• Closures and containers must be capable of protecting the drug product from external conditions that may cause its contamination or deterioration. 
• Containers and closures must be clean and if required, sterilized to remove contamination by microorganisms and pyrogens.