BASIC PRINCIPLES OF GMP

 

Basic principles of GMP

Pharmaceutical industry or industry drugs formulation 

Basic principles of GMP

 Every fabricator, packager/labeller, distributor and importer of a drug shall have written procedures prepared by qualified personnel in respect of the drug to ensure that the drug meets the specifications for that drug.

Every person required to have written procedures referred to in subsection

 (1) shall ensure that each lot or batch of the drug is fabricated, packaged/labelled and tested in compliance with those procedures.

• Rationale:

This Regulation requires that measures be taken to maintain the integrity of an API from the moment the various raw materials enter the plant to the time the API is released for sale or for further fabrication. These measures ensure that all manufacturing processes are clearly defined, systematically reviewed in light of experience, and demonstrated to be capable of consistently manufacturing APIs of the required quality that comply with their established specifications.

Interpretation:

1) Access to production areas is restricted to designated personnel.

  2) All handling of raw materials, products, and packaging materials such as receipt,identification, quarantine, storage, sampling, testing, approval or rejection of materials, tracking, labeling, packaging, dispensing, processing, and distribution should be done in accordance with written procedures or instructions and recorded.

 3 . Validation should extend to those operations determined to be critical to the quality and purity of the API.

3.1). The potential impact of the proposed change on the quality of the API should be evaluated. A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g., as minor or major)

 depending on the nature and extent of the changes, and the effects these changes may impart on the process. Scientific judgement should determine what additional testing and validation studies are appropriate to justify a change in a validated process. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.

4. A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units. For more information on this matter, refer to Section 12 Validation of the ICH Q7 Guidelines.

4.1. The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g. retrospective, prospective, concurrent) and the number of process runs.

A validation report that cross-references the validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.

Any variations from the validation protocol should be documented with appropriate justification.

Before starting process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed.

 Any deviation should be documented and explained. Any critical deviation (i.e. one which could affect the quality and/or purity of the API) should be investigated.

 Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data. Deviations in yield associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches.

 Residual materials can be carried over into successive batches of the same API as long as there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. 

Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.

 Provided that validated changeover procedures are implemented, non-medicinal products may be fabricated or packaged/labelled in areas or with equipment that is also used for the production of APIs.

 Facilities where APIs are fabricated, packaged and labelled should be inspected immediately before use to ensure that all materials not needed for the next operation have been removed. This examination should be documented in the batch production records, the facility log, or other documentation system.

 Production operations should be conducted in a manner that will prevent contamination of APIs by other materials.

 In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material and other APIs. Procedures should be established to ensure the integrity of samples after collection.

 Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the development stage or historical data.

 The acceptance criteria and type and extent of testing can depend on the nature of the API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product's quality. Less stringent in-process controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., isolation and purification steps).

Critical in-process controls (and critical process monitoring), including the control points and methods, should be stated in writing and approved by the quality unit(s).

In-process controls can be performed by qualified production department personnel and the process adjusted without prior quality unit(s) approval if the adjustments are made within pre-established limits approved by the quality unit(s). All tests and results should be fully documented as part of the batch record.

Written procedures should describe the sampling methods for in-process materials, intermediates, and APIs. Sampling plans and procedures should be based on scientifically sound sampling practices.

Precautions to avoid contamination should be taken when APIs are handled after purification.

Production operations on different products may be carried out in the same area provided that appropriate measures and controls are in place to prevent mix-up or cross-contamination.

Appropriate measures should be established and implemented to prevent cross-contamination from personnel, materials, etc. moving from one dedicated area to another.

Where applicable, checks should be carried out to ensure that removable and interchangeable transfer lines and other pieces of equipment used for the transfer of materials from one area to another are correctly connected.

Equipment or segregated process areas should be identified as to its contents, including name of product and batch number,and its cleanliness status by appropriate means.

The processing status of major units of equipment should be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.

Rejected materials should be identified and controlled under a quarantine system designed to prevent their unauthorized use in manufacturing.

 Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use.

 Upon receipt and before acceptance, each container or grouping of containers of materials should be examined visually for correct labelling (including correlation between the name used by the supplier and the in-house name, if these are different), container damage, broken seals and evidence of tampering or contamination. All containers are verified to ensure that the information on the order, the delivery note and the vendor's labels is in agreement.

Materials should be held under quarantine until they have been sampled, examined or tested as appropriate, and released for use.

Before incoming materials are mixed with existing stocks (e.g., solvents or stocks in silos), they should be identified as correct, tested, if appropriate, and released. Procedures should be available to prevent discharging incoming materials wrongly into the existing stock.

If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-contamination from the tanker. Means of providing this assurance could include one or more of the following:

• certificate of cleaning,
• testing for trace impurities, and
• audit of the supplier.

Intermediates held for further processing should be stored under appropriate conditions to ensure their suitability for use.

Critical materials should be transported in a manner that does not adversely affect their quality.

 Special transport or storage conditions for an API should be stated on the label.

 Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials.

 Containers from which samples are withdrawn should be opened carefully and subsequently reclosed. They should be marked to indicate that a sample has been taken.

 Large storage containers, and their attendant manifolds, filling and discharge lines should be appropriately identified.

 Each container or grouping of containers (batches) of materials should be assigned and identified with a distinctive code, batch, or receipt number. The identification number should be used in recording the disposition of each batch. A system should be in place to identify the status of each batch.

 Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-contamination.

Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection.

 Materials should be stored under conditions and for a period that have no adverse effect on their quality, and should normally be controlled so that the oldest stock is used first.

 Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.

 Raw materials for API manufacturing should be weighed or measured under appropriate conditions that do not affect their suitability for use.

 Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control. Prior to use, production personnel should verify that the materials are those specified in the batch record for the intended API.

 Other critical activities should be witnessed or subjected to an equivalent control.

 All quality related activities should be recorded at the time they are performed.

 When entries are made in records, these should be made indelibly in spaces provided for such entries, directly after performing the activities, and should identify the person making the entry. Correct

ions to entries should be dated and signed and leave the original entry still readable.

All documents related to the manufacture of APIs should be prepared, reviewed, approved and distributed according to written procedures.

43.1 To ensure uniformity from batch to batch, master production instructions for each API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit(s).