Among GMP other aspects, such as environmental controls, and safety, are necessary to be taken into account in order to be in compliance with regulations. Business efficiency and continuous improvement are needed to be competitive. Therefore GMP compliance should be incorporated into an overall Quality Management Systems (QMS) as it is recommended in the EU GMP philosophy.
The importance of an effective QMS on customer relations, continuous improvement, regulatory compliance and inspection readiness should be pointed out, which directly ensures benefit to the patient. A clearly defined QMS (e.g. ISO 9001: 2000) integrating API GMP requirements, should be designed, documented and implemented. To implement a QMS integrating GMP issues, please refer to chapter 1 Quality Management.
A regular report should be made available to senior management by the QU informing of key performance indicators. Senior management should review and agree any recommendations and ensure that appropriate resources are made available.
The responsibility for quality should be delegated by the Company Management to the appropriate organisational functions to apply the Quality policy and procedures. It is pointed out that this delegation goes far beyound the boarders of a quality department. Clear assignments for duties and decisions is the basic rule.
The responsibilities for quality duties (e.g. process and control review, validation, change control, equipment qualification, batch documentation review, batch release, regulatory compliance, auditing, process deviation, OOS treatments and complaint investigation) should be clearly assigned to one or more person(s) or function(s). The QU should be involved in many, if not all, of these issues.
Release of Materials
Release of raw materials and intermediates meeting the specifications (for internal use only) by Production is acceptable, provided QU has approved specifications and test methods. Production personnel should be adequately trained for these duties, the training recorded and all equipment used qualified and calibrated at regular intervals. The QU, as part of their responsibility for batch release, has the right to review all test results and data.
APIs and intermediates (for use outside of the control of the company) have to be released by a designated person of the QU. Deputy(s) for such designated person should be nominated.
For the release of APIs there is no need for a "Qualified Person" (pharmacist) as defined by the European GMP Guideline for Medicinal Products.
All activities should be directly recorded at the time they are performed in legible documents like note-books, electronic records, etc., which are retrievable and traceable. Recording in non-traceable documents like a blank sheet of paper (re-writing afterwards into traceable documents) is not acceptable. Electronic documents and recording requires appropriate validation of the systems used.
Documented explanations should be in place for every deviation. When deviations are considered critical, the QU should undertake a formal investigation, the findings should be recorded and, if defined , corrective actions should be implemented. See chapter 21.H Production and In-Process Controls for a more detailed explanation.
The release of an API or intermediate does not automatically require that all corrective measures or actions identified in deviation investigations have to be completed in advance (e.g. corrective actions related to ongoing training, maintenance, process investigations).
2 Responsibilities of the Quality Unit(s) - QU
QU duties may be delegated to other departments/functions provided there are systems in place to ensure that the QU has adequate control and/or supervision. Different levels of control depending on the nature of the activity are required by ICH: "make sure" (for example: put systems in place, verify by auditing, assigns responsibilities), "be involved" (means personal involvement of the QU responsible) or "establishing" (QU issues a system or procedure on its assigned duties).
Although it is stated "... should not be delegated" it is likely that company's will face problems during inspections if they come up with alternatives; this "should" has to be interpreted as "must"..
Figure 1 Main responsibilities of a quality unit in accordance with ICH Q7A
Main responsibilities of the quality unit(s)
- Release or rejection of all APIs
- Release or rejection of intermediates for use outside the control of the manufacturing company
- System for the release of raw materials and intermediates
- Reviewing the completed batch documentation of critical processing steps
- Making sure that critical deviations are investigated
- Approval of all master batch records and specifications
- Approval of all procedures/instructions that may potentially influence the quality of intermediates and APIs
- Making sure that internal audits (self-inspections) are performed
- Approval of contractor manufacturers of intermediates and APIs
- Approval of changes that potentially impact the quality of intermediates and APIs
- Reviewing and authorisation of validation protocols and reports
- Making sure that quality-related complaints are investigated and resolved
- Making sure that effective systems are used for the maintenance and calibration of critical equipment
- Making sure that the materials are sufficiently tested and the results are reported
- Making sure of the availability of stability data for intermediates and/or APIs to support the subsequent retest or expiration dates and the storage conditions
- Performing of product quality reviews (chapter 5 Product Quality Review)
Only the batch production records of critical steps (a step could be the entire unit operation, e.g. conversion of the final intermediate to the API or a single parameter such as temperature control at an earlier step) including laboratory records have to be reviewed by the QU, whilst the review of all other steps may be delegated.
There should be a system in place defining what changes are likely to "impact ... on API quality". This indicates that other changes can be initiated without involving the QU. Nevertheless any change has to be evaluated and communicated.
Stability data for intermediates are only required if they are intended to be sold, but there isn't the need to apply a full stability program as described in ICH Q1a and Q1b documents. In many instances, a retest of the material prior to use or shipment is sufficient to demonstrate that the product is still meeting its specifications. However it is recommended to derive some data during the development phase or during validation to support storage periods of intermediates during campaign production or storage of left-over between two campaigns. For details see alsochapter 8 Cleaning Validation.
Additional advice for quality related duties and its assignment to different functions/departments (Production, Quality Assurance, Quality Control/Analytical Lab) can be found in The rules Governing Medicinal Products in the European Community, Volume IV, Good Manufacturing Practice for Medicinal Products. Although these recommendations are only mandatory for drug products/medicines they also are applicable to the API manufacturers
3 Responsibility for Production Activities
An additional advice for the assignment of quality related duties to Production and other functions/ departments can be found in The rules Governing Medicinal Products in the European Community, Volume IV, Good Manufacturing Practice for Medicinal Products. Although these recommendations are only mandatory for drug products/medicines they also are applicable to the API manufacturers.
Figure 2 Responsibility for production activities in accordance with ICH Q7A
Main responsibilities of production activities
- Preparation, review, approval and distribution of instruction for the production of intermediates and APIs in accordance with written procedures
- Production of active pharmaceutical ingredients and if applicable, intermediates, in accordance with previously authorised instructions
- Review of all batch production records and assurance that these are complete and signed
- Make sure that all deviations are reported and evaluated, and that critical deviations are investigated and corresponding conclusions are recorded
- Making sure that the manufacturing facilities are clean and where necessary, disinfected
- Assurance that the necessary calibrations have been performed and records retained
- Making sure that premises and equipment are maintained and records kept
- Assurance that validation protocols (plans) and reports are reviewed and approved
- Evaluation of proposed changes to the product, process, or equipment
- Making sure that new and, if applicable, modified facilities and equipment are qualified
4 Internal Audits (Self-Inspections)
Internal Audits (Self Inspections) are a valuable management tool to evaluate if the company is in compliance with the principles of GMP and additional requirements of the company which are integrated in the QMS. The evaluation should be made by trained auditors, experienced in auditing skills and recruited from various departments of the company, if possible.
Quality Auditing Teams of normally 2 persons are recommended, however (depending on the focus of the audit) recruiting of additional experts (e.g. engineers, micro-biologists etc.) could increase audit efficiency. QU should always be represented in a team, but not always taking the lead for not being accused to be the "policeman".
The QU should be responsible for co-ordinating activities such as follows:
- pre-audit meetings for the audit team (brain storming)
- identifying major areas of concern and preparation of questions (questionnaire)
- collecting historic information such as deviations, changes, complaints, previous internal audit reports
- issuing the agenda and distribution to the auditee in due time
- co-ordinating the activities of the audit team
- starting the (internal) audit and summarising the findings in a close out meeting
- issuing the audit report, on the basis of the close out meeting
- propose corrective measures or improvements to management
- schedule (propose) a re-audit in case of major findings
- conduct follow-up activities.
Other members of the audit team could be involved in asking and taking extensive notes. The whole auditing process should be clearly defined and the following standard documents should be considered to be available in a generic layout form:
- Questionnaire Form
- Covering Letter
- Report Form
- Audit Team Evaluation Form
- Follow-up Report
- Training Programme
The frequency should be based on the compliance status of the area to be audited and may vary from half a year to three years. All participants in the audit should have the commitment from the management to use the specified time for preparing, performing and reporting the internal audit. Also un-announced audits or spot checks should be considered besides the "normal" audit programme.
If possible internal audits should not take more than to 3-4 hours. Remember to include at a minimum twice the time for preparing and writing the audit reports.
It is important to define deadlines for issuing (recommendation: 2 weeks) and finalising (recommendation: 4 weeks) the report and for the first follow-up meeting.
The internal Audit Report as well as the Follow-up Report should be kept confidential and should not be shown to external personnel, especially inspectors from authorities.
All Audit Reports should be made available for the management, and the findings discussed. Management is responsible to initiate necessary corrective actions and investments.
5 Product Quality Review
The major objective of the Product Quality Review is to evaluate the compliance status of the manufacture (process, packaging, labelling and tests) and to identify areas of improvement based on the evaluation of key data.
Product quality reviews should not be solely performed by QU personnel. It is important that other departments, like Production, Engineering, Maintenance, Purchase, etc. are also involved. QU is held responsible for the release and approval of the final report.
To ensure that key data is reviewed it may be helpful for each production process to identify the critical in process controls and critical API test results. These would normally be the critical raw material, intermediate and API test results which may be used to indicate the consistency of the process or to assess potential deviations in the quality of the API itself. In addition the critical reaction parameters should be evaluated. Ideally the critical parameters are identified in the development report prepared prior to process validation but may also be based on experience for well established processes.
In nearly all cases specification limits for the critical test results are in place. Therefore the first evaluation would consider the failure frequency to meet such limits. In addition any trends in data should be evaluated across the batches produced during the review period.
Appropriate statistical tools may be used to assess process capability when data from a large number of batches is being reviewed.
Where the data concludes that there is a drift in process capability, actions should be determined to evaluate the causes and improve performance in the forthcoming review period.
The review of all batches which fail to meet specification and the review of critical deviations should look specifically at recurring causes and identify appropriate actions to reduce the frequency and improve performance.
Figure 3 Contents of the PQR (product quality review) in accordance with ICH Q7A
Documentation throughout the report period (usually 1 year)
- Review (incl. trend development) of the
- analytical test results
- in-process control results
- critical production parameters
- for critical starting materials, critical intermediates and the API.
- Review of all OOS results
- Review of all critical deviations and non-conformances and the associated investigations
- Review of all changes to
- specifications and test methods
- processes/master batch records
- Review of the results of the stability monitoring program
- Review of all quality-related complaints, recalls and returns
- Review of the suitability of corrective actions
Common causes for batch failures and recurring deviations are (this list should not be regarded as complete):
- Equipment not functioning correctly or in need of maintenance or replacement.
- Inadequate batch instructions or training of operators.
- Process parameters so tightly defined that the equipment is not capable of routinely achieving the acceptance criteria.
- Inhomogeneous product or inadequate sampling procedures.
- Poor quality raw materials or lack of control of raw material suppliers.
The impact of changes (see chapter 19.C Change control) introduced to the processes or analytical methods should also be carefully evaluated to look for any direct affect on the critical test results.
In a similar way any trends in the stability monitoring program should be reviewed against changes introduced to the processes or analytical methods. Any trends indicating deterioration of product which could affect the retest period or expiry date of the API should be identified and an investigation into the causes should be performed.
The status of quality related returns, complaints or recalls should evaluate the adequacy of corrective actions and any trends which require further investigation.
Based on the Product Quality review a list of clearly defined corrective actions and recommendations should form the basis of the objectives for the product in the forthcoming period. This should include the possibility of process revalidation where significant changes or alterations in the trends of the key quality data indicate this is necessary.
Senior management should be involved in reviewing the recommendations and in providing the necessary resources and priorities to ensure the corrective actions and recommendations are implemented.