GMP regulations are always aimed at prevention. This means that for all GMP-relevant cases, written provisions must be in effect that describe what form aspects such as process workflows, operating conditions or product features must have. These theoretical precautions are mirrored in the logs and reports that record what actually took place in practice.
Thus, it is possible to distinguish between two basic types of document:
- Documents that describe requirements (such as specifications, procedural instructions, contracts). They must be examined and approved or released in accordance with internal company procedures. Moreover, these documents are to be checked at regular intervals for accuracy and plausibility and to determine if they are up to date. Requirement documents, particularly instructions, may not be handwritten.
- Records or reports that record practical activities or their results (such as batch processing records, quality certificates, inspection reports). They should present the essential procedures in an easy-to-follow manner and clearly relate to the instruction on which they are based. If handwritten entries are made, these must be ineradicable and permanent. Subsequent modifications must be made in a manner that leaves the previous entry legible. The reason for the change, the date and the signature of the person responsible must also be given.
Therefore, documentation that conforms with GMP often consists of a pair of documents: one document with instructive character (such as procedural instruction or SOP, qualification plan) and another document that confirms that in practice everything was done in accordance with the instructions (records, reports, for example). Instructions must be set up, reviewed and authorised in advance. Records and reports should always be written soon after the relevant event took place and on the basis of instructions that were authorised beforehand.
Specific documents are requested at various points in the pharmaceutical regulations:
- Job descriptions and organisational diagrams should be prepared in the area of personnel.
- Operating rooms shall be cleaned and/or disinfected according to a written sanitation program.
- Hygiene programs for the practice of good health habits during the production/analysis of medicinal products should be prepared.
- Production should be carried out on the basis of manufacturing instructions and documented in a batch record.
- The quality control should be carried out on the basis of a testing procedure and documented in a test report.
- Records must be kept on the husbandry of animals used for production/analysis.
- Regarding contract manufacture and/or analysis written contracts between contract giver and contract acceptor should be concluded.
- Records shall be kept on the acquisition, import, export, storage and marketing of medicinal products.
- Written instructions and descriptions of procedure must be created for the release for marketing.
- The Qualified Person for Pharmacovigilance is responsible for ensuring that all reports on pharmaceutical risks that become known are collected in accordance with a defined written procedure. All complaints must be systematically recorded.
- Records on self-inspection and the corrective actions subsequently taken must be kept and stored.
Chapter 4: Documentation of the EU GMP Guideline is entirely devoted to documentation: it reflects the great importance of this topic in pharmaceutical operations. It states that clearly written and unambiguous documents prevent verbal communication errors and make it possible to trace the history of a batch. The batch documentation represents therefore the most important records in terms of providing evidence of medicinal product quality. The EU GMP Guideline refers to “Manufacturing Formula” and “Processing Instructions”, “Packaging instructions”, “Batch Processing Records”, “Batch Packaging Records” as well as “procedures” for analysis and sampling.
Figure 1 Contents of batch documentation/manufacturing
||Batch Record Review
- Name of the medicinal product with reference code (item no.)
- Pharmaceutical form, strength, batch size
- Formulation (starting materials with amount of each)
- Expected final yield with acceptable limits,
- Relevant intermediate yields, where applicable
- Name and batch number of the product
- Manufacturing dates and times
- Persons involved
- Initial weighing
- Manufacturing carried out
- Results of in-process testing
- Equipment to be used
- Methods for preparing critical equipment (cleaning, assembling...)
- Checks of equipment and working place before start of production
- Detailed manufacturing procedure
- In-process controls including limits
- Requirements for storage and labelling
- Special precautions
To prevent misunderstandings, these terms should be applied uniformly. If the manufacturer decides to use different terms for the batch documentation, their meaning should be clarified by an index of synonyms.
The most important contents of the batch documentation are presented in Figure 1 and Figure 2.
Figure 2 Contents of batch documentation/testing
- Medicinal product (name/item no.)
- Dosage form, strength, batch size
- Sampling procedures
- Testing equipment
- Analytical procedures including standards and reagents to be used
- Medicinal product (name/batch no.)
- Test results
- Persons involved
- Raw data
- Evaluation of test results
- Special observations
Not only the batch documents, but also all records that provide evidence that GMP requirements have been and will be complied with are relevant to GMP (see Figure 3). Evidence is information that can be verified as being accurate and is based on facts obtained through observation, measurement, investigation or other methods of discovery (definition according to DIN EN ISO 9000).
Figure 3 GMP-relevant documentation contents
||GMP-relevant documentation contents
- QA instruction manual
- Organisation chart and job descriptions
- Instructions and records for self-inspection
- Validation master plan
- Change control program
- Release procedure
- Product quality review
- Contracts for manufacturing on a contract basis
- Qualification documents at external service providers and suppliers
- Management review
- Training methods
- Monitoring success and effectiveness
- Instructions on medical examination of personnel
- Hygiene programs: Work clothing and work hygiene
- Calibration/qualification of facilities and equipment
- Maintenance, repair and cleaning of equipment and facilities (log books)
- Operating instructions Process and cleaning validation
- Manufacturing formula/instruction
- Batch processing record
- Statistical Process Control/Quality Control
- Charts Measures in the event of manufacturing deviations
- Labelling and packaging of containers
- Sanitation program for rooms
- Hygiene programs for hygienic behaviour
- Records of environmental monitoring
- Documentation of storage including receipt
- Instructions on pest control
- Reports on audits at suppliers and contract manufacturers
- Control of starting materials
- Sampling procedures
- Testing procedure/test record
- Procedure for OOS results
- Calibration/qualification of laboratory equipment
- Analytical method validation
- Handling of standards and reagents
- Proof of sales
- Measures in the event of complaints
- Recall campaign schedules
Evaluations and conclusions in documents must be clear and understandable. A prerequisite for this is their traceability, for example back to raw data (primary data) that was directly gathered from measurements or observations. Raw data can be created in electronic or paper form, for instance as filled out worksheets, machine printouts, logs or notes. Raw data are needed to reconstruct results of calculations and evaluations. They should be stored with special care. The raw data can assume substantial proportions; they are often separated from the documentation and filed remotely as attachments or in separate archives, for example. In these cases care should be taken to ensure that all calculations and evaluations (secondary data) are linked to the raw data via cross-references or hyperlinks (indicating the current and correct filing location).
Dr. Michael Hiob
Ministry for Health of Land Schleswig-Holstein, Germany
This article is an extract from the GMP Subject Download "GMP Compliant Documentation - How to create, organize, review and archive GMP related documents in pharmaceutical industries" by Maas & Peither GMP Publishing.
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