1. Basic Principles of GMP
Materials
In this module we shall be looking at the GMP guidelines for all aspects relating to the handling and processing and storage of materials. This includes guidance on the purchasing, receiving, storage and distribution of materials, finished product and waste materials.
We will be looking at the different types of materials, and materials at different stages in production processes.
The programme is as follows:
Presentation minutes
Group session 60 minutes
Plenary session 30 minutes
Test minutes
All timings are approximate
Part One Section 13

2. Materials
Objectives
To review specific requirements for each type of material:
Starting materials
Packaging materials
Intermediate and bulk products
Finished products
Rejected and recovered materials
Recalled products
Returned goods
Reagents and culture media
Reference standards
Waste materials
Miscellaneous materials.
To examine (in groups) the problems associated with materials, and how to overcome them.
Our main objective in this session is to review with you all the key issues relating to materials mentioned in the WHO GMP text, Part One. First of all, we will be discussing the general principles of GMP for materials. We will then review in turn different materials including:
Starting materials
Packaging materials
Intermediate and bulk products
Finished products
Rejected and recovered materials
Recalled products
Returned goods
Reagents and culture media
Reference standards
Waste materials
Miscellaneous materials.
We will then have a group discussion where we will be looking at specific issues and problems relating to materials, that you may encounter during your inspections.

3. Materials Principle Objective of the pharmaceutical manufacturer:
produce finished products
combination of materials
Materials combined:
active pharmaceutical ingredients
auxiliary materials(excipients)
packaging materials
Special attention
The main objective of a pharmaceutical factory is to produce finished products from a combination of materials. The way in which the factory is organised to look after all the materials is therefore of vital importance to the quality of the finished product. Special attention must be given to the requirements and guidelines regarding GMP for materials, all stages of production and quality control testing. It includes:
Specifying the materials (specifications)
Purchasing materials
Receiving materials
Storing materials
Dispensing
Using materials for production
Storing the finished product
Distributing the finished product
Dealing with all the reagents and standards used in testing
Dealing with the waste materials that arise from the processes.
Non-compliance with GMP guidelines could result in manufacturing products not containing the right materials, or the right quality of materials.
This is turn can result in products being rejected or recalled from the market.

4. General requirements for materials
All incoming materials and finished products:
quarantined after receipt,
until released for use
distribution
stored
under appropriate conditions
orderly fashion (batch segregation)
materials management
stock rotation (FIFO or EEFO))
In general, all incoming materials and finished products should be quarantined immediately after receipt for processing, until they are released for use or for distribution.
The manufacturer of starting materials normally specifies the storage conditions for raw materials. The manufacturer of the finished product must be aware of the storage conditions for the materials used in the factory, and must ensure that the materials are stored under appropriate conditions. Inspectors should check that the storage areas are maintained at the correct temperature and relative humidity specifications. The conditions should thus be controlled, monitored and recorded. Review the SOP and records for these parameters and ensure that the materials are stored in the correct environment by verifying the label information and environment control records
All containers of materials should be stored in an orderly way to prevent cross-contamination and mix-ups. Segregation between products is necessary to prevent possible cross-contamination. Segregation of different batches of the same product is also recommended to promote stock rotation.
Ensure that the manufacturer also has a system of controlling stock. Different systems exist for materials management, including a bin card system and bin locations, and computerized stock control. It is important to look at the process of issuing of material as well as the return of unused material back to the store.
During the inspection, also ensure that materials that have the shortest expiry date, are used first (First-in-first-out (FIFO) or EEFO (Earliest Expiry, First Out).
Part One 13.2–13.3

5. Materials Starting Materials – I Purchasing Suppliers Consignment:
integrity
seal
order
delivery note
supplier’s labels
Cleaned and labelled
The purchasing of starting or raw materials is an important activity of the manufacturer. It is not considered as merely an administrative activity. The inspector should ensure that the staff that are responsible for purchasing of materials, have sufficient knowledge of the materials, products and suppliers of the materials.
During your inspection, you should also verify that the materials are only bought from the specified suppliers. This is normally specified in the registration dossiers, or approved suppliers list, or specification of the material. To ensure that the correct materials are supplied, manufacturers are advised to rather purchase materials direct from the manufacturer of the material, and, where possible, not from an agent or broker.
It is advisable that the manufacturer discusses the specification for the raw materials with the manufacturer. This could ensure that the correct quality of material is supplied to the manufacturer of the finished products. All aspects relating to the production and control of the starting material, including the handling, labelling and packaging requirements can be agreed upon. Aspects relating to complaints and rejection procedures can also be discussed.
During your inspection, you will assess how the manufacturer receives materials from the suppliers. The procedure followed (check written SOP against actual procedure), should include checking the consignment for integrity of the containers or package, that the seals are intact, and that the information on the order, delivery note and label on the containers correspond with each other. All containers should be cleaned when necessary before these are taken into the premises, and should be properly labelled with relevant information (e.g. status, name of the material, reference code etc).
Part One 13.4–13.7

6. Starting Materials – II
Damaged containers
Different batches in one consignment
Starting material label:
name and internal code
batch number(s), (supplier and manufacturer on receipt)
status
expiry date or re-test date
Sampled containers identified
Make sure that the manufacturer checks the containers for any damage and possible contamination and cross-contamination.
Any damage to containers received (that could possibly have an adverse effect on the quality of the material), should be recorded on receipt and reported to the quality control section. It should also be investigated before a decision is made regarding the release or rejection of the material.
You should also assess how the manufacturer deals with a consignment of material, that is made up of different batches of the same material. It is required that the different batches be considered separate for sampling, testing and release. You should verify this by recording any materials with different batches that had been received in one consignment (by checking the shelf, or the goods received register), and comparing the sampling, testing and release results in the laboratory.
Starting materials in the storage area should be properly labelled. The label should bear at least:
- the name of the material and an internal reference code
- batch number given by the supplier, and manufacturer’s batch or receiving number
- the status of the material (e.g. quarantine, released, rejected)
- expiry date of the material, or a re-test date. (See also point of the WHO Text, GMP for Active Pharmaceutical Ingredients (bulk drug substances)).
Some manufacturers make use of computerized systems. In such cases, the above-mentioned information is not always on the label. However, in such cases, you have to inspect the computer system and ensure that the system has been validated.
As the materials normally have to be sampled and tested against the specification, a procedure has to be followed for sampling the material. The containers from which samples were taken, should be identified (e.g. a label).
Part One 13.8–13.11

7. Examples of Labelling of Starting Materials
This is an example of a status label

8. Starting Materials – III
Use only released material
Dispensing:
designated persons
written procedure
accurately weighed
clean, labelled containers
Independent checks
material and weight
Dispensed material:
kept together and labelled
The quality control department is responsible for sampling, testing, release and rejection of materials. It is important to verify that the manufacturer only uses materials in production that had been released by the quality control section. The materials must also be within their shelf-life.
The process of weighing or dispensing materials for production, should be done in accordance with an approved procedure. Only designated persons, who are qualified and trained, should dispense materials for production. Dispensing is a critical stage in the manufacturing process and should be properly controlled. It is important that the correct material, and the correct quantity of material is dispensed (accurately weighed) for the product to be manufactured.
As the materials are taken from labelled containers when dispensed, it should be weighed out into clean, labelled containers to ensure that the identification of the material isn’t lost. The label should reflect all the relevant information. There should be a second person who performs an independent check of the dispensing activity, to ensure that correct material and the correct weight (or volume) of the material had been dispensed. This check should be recorded e.g. on the batch manufacturing document or weighing ticket (label).
You can evaluate the SOP for dispensing, and assess whether the SOP is complete and will ensure that the dispensing activity complies with GMP requirements to prevent contamination, cross-contamination and mix-ups.
Materials dispensed for a particular batch of product, should be kept together (e.g. on a pallet) and properly labeled to identify the product and batch it was weighed out for.
Part One 13.12–13.15

9. Materials Packaging materials I Primary and printed materials:
as for starting materials
purchasing, handling and control
No unauthorized access
Storage and transport
avoid mix-ups
issue and return: SOP
Packaging materials should also be controlled by the manufacturer. Specific attention should be given, and controls exercised for primary packaging materials, and printed packaging materials. The product will come into direct contact with the primary packaging materials. Special care should be given to the quality of these materials such as ampoules, bottles and foil used in blister or strip packing. The prevention of mix-ups of printed packaging materials such as leaflets, labels and cartons is of great importance. The guidelines recommend that the purchase, handling and control of primary and printed packaging materials should be as for starting materials. (There should thus be approved suppliers and specifications for these materials. They should be quarantined on receipt, sampled and tested before release or rejection).
The access to printed packaging material should be controlled to prevent any unauthorized access. Cut labels and other loose printed packaging materials should be stored and transported in separate, closed (sealed) containers to prevent possible mix-ups. Only designated personnel should issue printed packaging materials to production. The issue (and return when allowed) of printed packaging materials should be done in accordance with written SOPs.
Part One 13.16–13.20

10. Packaging materials II
Specific reference number for batch or consignment
Packaging department checks:
quantity, identity and conformity
Outdated or obsolete material
It is recommended that manufacturers allocate reference numbers to materials. These reference numbers are unique for each batch or consignment of material and assist in the traceability of material.
Personnel in the packaging department should check materials delivered to the department to ensure that the correct quantity of the correct material, complying with the packaging instructions, had been issued.
All outdated or obsolete primary packaging material and printed packaging material should be destroyed in accordance with an SOP. The destruction should be recorded.
Part One 13.16–13.20

11. Intermediate and bulk products
Materials
Intermediate and bulk products
Appropriate conditions
Purchased:
as starting materials
Intermediate products are products that are in the process or being used in the process for the manufacture of a finished product. An example of an intermediate, is granules used in the production of tablets or capsules.
Bulk products such as tablets awaiting packing into final containers, or creams awaiting filling into final containers, should be handled in such a way that the product will not be adversely affected.
Intermediate and bulk products should be stored under appropriate conditions, such as correct temperature and relative humidity. The products should be stored only for periods as specified and that are suitable for these products.
It is also important to check the containers for appropriate labelling during the inspection. Any activities such as sampling, should not negatively affect the quality of the product (e.g. cross-contamination and contamination).
Some manufacturers buy intermediate and or bulk products from other manufacturers. In such cases, the intermediate and bulk products must be handled as if these were starting materials. (Specifications should exist, the products should be quarantined on receipt, sampled and tested before release or rejection).
Part One 13.21–13.22

12. Materials Finished products Quarantine until released
Storage conditions
Evaluation and documentation
product release
Finished products (product packed in their final containers) should be stored in quarantine until their final release. The manufacturer should have a formal procedure describing the release of final product.
Once the product is released, it should be stored under the specified conditions to ensure that the safety, quality and efficacy of the product is not adversely affected.
The release of the product includes evaluation of the manufacturing documentation and the relevant tests performed during manufacture and release of the product.
Part One 13.23–13.24

13. Rejected and recovered materials
Rejected materials
Clearly marked
Stored separately in restricted areas
Action
Reprocessing:
exceptional
procedure and records
batch number
additional testing
Rejected materials
When materials are rejected, they should be clearly marked as such. Rejected materials should be stored separately and access to the area should be controlled. This is to prevent the accidental use or distribution of rejected materials.
Manufacturers can return rejected materials to the suppliers, destroy the materials or reprocess the rejected materials. The action the manufacturer initiates, should however be described and defined in a procedure. The action to be taken should be approved by authorized personnel. The action and approval must be recorded.
Reprocessing
Reprocessing of rejected materials should only be done in exceptional cases. It should only be allowed if the quality of the product is not negatively affected. The product must still comply with the specifications. During your inspections, you should assess the SOP to ensure that it clearly describes the manufacturer’s policy and procedure for reprocessing, as well as who will be responsible for evaluating the risks that are involved in reprocessing rejected material. Remember, proper and complete records should be maintained for reprocessed materials. A reprocessed batch should be given a new batch number. The manufacturer should also consider additional testing of reprocessed materials, e.g. stability testing of the batch.
Part One 13.25–13.28

14. Rejected and recovered materials
Recovery:
prior authorization
additional testing
Recovery
Some manufacturers introduce part or all of a previous batch, into a batch of the same product. If this is company policy, establish whether this is done in accordance with a procedure, whether prior authorization is given within the company, and the risks considered, whether proper records are kept and whether any additional tests have been considered by the quality control department.
Part One 13.25–13.28

15. Recalled products and returned goods
Materials
Recalled products and returned goods
Recalled products:
identified
stored separately
access controlled
fate
Returned goods:
SOP: decision regarding the fate
nature of product, storage conditions
history, time lapse
records
Recalled products
There may be occasions when a manufacturer has to recall a product or a batch of a product from the market. There could be various reasons for the recall, such as a quality defect. Products that have been recalled from the market, should be identified (labelled). It is recommended that recalled products be stored separately in areas where access is controlled. This is to ensure that recalled products are not issued or sold again by accident. Recalled products should be kept in this controlled area, until a final decision is made by a designated or responsible person regarding the fate of the product. The decision regarding the fate of recalled products should be taken as soon as possible. The process of handling, and storage of recalled products should be in compliance with the company’s standard operating procedure. (See also the module on recalls).
Returned goods
Products that have left the premises of the manufacturer, can be returned to the manufacturer for various reasons. Products returned to the supplier must be handled in accordance with an SOP. Returned goods should preferably be destroyed.
The quality control department can critically assess the product to determine whether the quality of the product is still satisfactory, and recommend that the product be sold again, relabeled or reprocessed. In considering this, the nature of the product must be considered (e.g. dosage form), storage condition requirements (e.g. fridge storage), the condition and history of the product, as well as the time lapse since sale to return to the manufacturer. If the product was supposed to be stored between 2 and 8 degrees Celsius, and it had been in the distribution chain for a long time, the manufacturer could have difficulty in assessing whether the product had not been exposed to conditions that could have adversely affected the product.
Part One 13.29–13.30

16. Reagents and culture media
Materials
Reagents and culture media
Recorded upon receipt or preparation
Reagents:
preparation in accordance with SOP
label:
concentration, standardisation factor, shelf-life, date that re-standardisation is due, storage conditions
signed and dated
Culture media:
positive and negative controls
All reagents and culture media should be recorded upon receipt or preparation. Some manufacturers record the relevant information in registers, others record the information in computer systems.
Reagents
Written standard operating procedures should be followed for the preparation of reagents, when these are not purchased from suppliers. All reagents and volumetric solutions should be appropriately labelled. Ensure that the labels indicate at least the concentration, the standardization factor, the shelf-life, the due date for re-standardization and the storage conditions of the reagent. It is also necessary to check whether the analyst that prepared the reagent had signed and dated the label. You can use this information to verify who prepared the reagent, and whether the SOP was followed by verifying the calculations in the analyst log book.
Culture media
Manufacturers have to ensure that the culture media they will use is suitable for the intended use. However, false results indicating micro contamination, are also not desired. Verify whether the manufacturer applies both positive and negative controls on culture media.
The size of the inoculum used in positive controls should be appropriate to the sensitivity required.
Part One 13.31–13.33

17. Materials Reference standards Official reference standards
use only as per monograph
storage
Reference standards prepared by the producer:
tested, released
stored in same way as official reference standards
Secondary or working standards:
appropriate checks and tests
regular intervals
based on official reference standards
Manufacturers make use of reference standards to test products and materials.
An important part of the inspection in the laboratory, will be to assess hoe the laboratory handles, stores and uses reference standards.
Manufacturers should make use of reference standards, available as official reference standards. Official reference standards should be used only for the purpose described in the monograph (e.g. pharmacopoeia). Official reference standards should be stored under conditions as specified by the supplier to ensure that the conditions will not adversely affect their quality, resulting in inaccurate or unreliable results.
Reference standards prepared by the producer should be tested, released (or rejected) and stored in the same way as official standards. The standards should be stored in a secure area and a responsible person should be designated to control the reference standards.
The manufacturer may establish secondary or working standards by applying appropriate checks and tests on materials to be used as reference standards. These tests and checks must be performed on a regular basis to ensure standardization (and suitability of use of the secondary or working standard). All working standards should be based on official reference standards (when available).
(The trainer should refer the attendees to Annex 3 of the WHO Technical Report Series, No 885 (fifty-fifth report, published in 1999, regarding “General guidelines for the establishment, maintenance and distribution of chemical reference standards”).
Part One 13.34–13.37

18. Waste materials and miscellaneous materials
proper and safe storage
toxic and flammable materials
separate, enclosed, as per legislation
not allowed to accumulate
collected for safe disposal
regular intervals
Miscellaneous
rodenticides, insecticides, sanitizing material
contamination risks
Waste materials
In any manufacturing environment, there is a considerable amount of waste materials. This includes waste materials resulting from testing in laboratories.
Waste materials can not always be taken away from the premises, or destroyed immediately. The manufacturer should therefor make provision for proper and safe storage of waste material.
Some waste can contain toxic substances. Toxic substances and flammable materials should be stored in suitably designed, separate, enclosed cupboards. You should also assess whether these materials are stored in compliance with the legislation where you are inspecting.
It is important to make sure that waste materials are not allowed to accumulate. Waste materials should be removed at regular and frequent intervals. You can inspect the receptacles and assess the SOP for storage and disposal of waste to verify whether the manufacturer has policy regarding the removal and safe disposal of waste. Verify whether the manufacturer complies with its own policy and SOP. You should also make sure that the process of disposal is done safely and in a sanitary manner.
Miscellaneous
There are also several other miscellaneous materials used in the manufacturing site. These include rodenticides, insecticides, fumigating agents, and sanitizing materials. These materials are used for specific purposes and are often toxic or hazardous. Ensure that there is no possibility that these materials can contaminate equipment, starting materials, intermediate or bulk products when these materials are used or stored on the premises.
Part One 13.38–13.40