Häufige Fragen im GMP-Umfeld

On this page we clarify the most frequently asked questions we receive on the subject of GMP.

The term GMP stands for Good Manufacturing Practice and stands for a comprehensive quality assurance system for the production of active ingredients and medicinal products. The quality assurance system covers all processes that can have an impact on the quality of the end product: From the purchase of raw materials, including checking the suitability of suppliers, to the actual production, storage and transportation of the manufactured products, there are guidelines that must be adhered to. The aim of GMP regulations is to ensure that high-quality, effective and safe active ingredients and medicinal products are produced.

In the USA, the abbreviation GMP is preceded by a “c”: cGMP. This “c” stands for “current” and is intended to express that the interpretation of the GMP rules by the companies and the corresponding design of their processes must be continuously adapted to the state of the art in science and technology. The US Food and Drug Administration (FDA) expressly points out that the cGMPs are minimum requirements and that many companies have therefore already implemented modern quality systems and risk management approaches to supplement them.

The GMP guidelines for the EU are described in the EU GMP guidelines, while in the USA the Code of Federal Regulations Title 21 (21 CFR for short) regulates the cGMP requirements.
There are also supplementary guidelines drawn up by the Pharmaceutical Inspection Co-Operation Scheme (PIC/S), the WHO or the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH).

Compliance with the GMP guidelines is a prerequisite for the granting of a manufacturing authorization and is also checked at regular intervals by the responsible supervisory authorities (e.g. DE: Regierungspräsidien; US: FDA, CH: Swissmedic) after the manufacturing authorization has been granted.

The Good Distribution Practice of medicinal products for human use (GDP) or “good distribution practice of medicinal products for human use” is a guideline published by the European Commission that describes binding regulations for the (wholesale) distribution of medicinal products. The term (wholesale) distribution covers the procurement, storage, supply or export of medicinal products, with the exception of the supply of medicinal products to the public.

These activities are carried out with pharmaceutical manufacturers or their commission agents, importers, other wholesalers or pharmacists and persons authorized to supply medicines to the public.

The main objectives of GDP regulations are to prevent falsified medicines from entering the legal supply chain and to ensure that the quality and integrity of medicines is maintained during distribution.

Good Laboratory Practice (GLP) is a quality assurance system for laboratories in which non-clinical health and environmental safety tests are planned, performed and monitored. The GLP guidelines include specifications on organizational procedures and framework conditions for carrying out the tests
The GLP guidelines are anchored in the German Chemicals Act. In the USA, the GLP guidelines can be found in 21 CFR Part 58.

Medical devices are products with a medical purpose that are intended by the manufacturer for use in humans.

Examples of medical devices are Implants, dialysis products, catheters, pacemakers, dental products, dressings, visual aids, medical instruments and laboratory diagnostics.

In contrast to medicinal products, which have a pharmacological, immunological or metabolic effect, the effect of medical devices is mainly physical.
Legal regulations on medical devices and their manufacture can be found for Germany in the Medical Devices Act and the associated Medical Devices Ordinance. In the USA, the requirements can be found in 21 CFR 820.

A Combination Product is a product that consists of two or more of the following components:

  • Conventional medicine
  • Biological drug
  • Medical device

These components can be physically, chemically or otherwise combined or mixed to form a single entity combination product (e.g. insulin injector pens).
It is also possible that the two or more separate components are packaged together in a single package or as a unit (“co-packaged combination product”, e.g. vaccine in a vial packaged together with a matching syringe).
Also referred to as a combination product are separately packaged conventional medicinal products, biological medicinal products or medical devices if they are only intended for use with one or more of the other components mentioned above and the intended effect is only achieved through the combination (“cross-labeled combination product”, e.g. insulin pump and separate insulin vial for filling the insulin pump).

The abbreviation CAPA stands for Corrective Action, Preventive Action and is the name of a quality assurance system. The CAPA system aims to counteract the development of non-compliant conditions and thus prevent a negative impact on product quality.

CAPA includes, on the one hand, the processing of deviations from defined processes that have already occurred (e.g. manufacturing processes, inspections, cleaning) = corrective action. On the other hand, the preventive, risk-based definition of measures = preventive action is intended to reduce the risk of undesirable deviations occurring (e.g. risk-based definition of the validation strategy or microbiological monitoring, regular staff training, self-inspections).

In practice, corrective and preventive action are often confused. The following definition, taken from the ICH Q10 (Pharmaceutical Quality Assurance System) glossary, clearly clarifies the difference between corrective and preventive action.

Corrective action Measure to eliminate the cause of a detected non-conformity or other undesirable situation. NOTE: A corrective action is taken to prevent recurrence, while the preventive action is taken to prevent the occurrence. (ISO 9000:2005)

Preventive measure Action to eliminate the cause of a potential mismatch or other undesirable potential situation. Note: A preventive measure is taken to prevent the occurrence, while the corrective measure is taken to prevent the recurrence. (ISO 9000:2005)

The Contamination Control Strategy is a comprehensive set of measures and controls designed to minimize the risk of contamination with microorganisms, pyrogens and particulate impurities in the manufacture of medicinal products.

The defined measures begin with the hygienic design of facilities and premises, continue with the monitoring of raw materials, intermediate products and consumables and also include specifications for facilities and premises (e.g. operation, cleaning, disinfection, maintenance), the zone concept, personnel hygiene, monitoring programs and much more.

In addition to the defined tests and measures, the CCS also includes the associated test methods and the frequency of the tests and monitoring.

Above all, it is important that the Contamination Control Strategy is developed on a risk-based basis against the background of the current understanding of systems, premises, processes and products. The individual measures, monitoring and control systems that are often already in place will also be evaluated together in future in order to gain a comprehensive understanding and overview of potential contamination. According to the results, the Contamination Control Strategy must be regularly reviewed with regard to its effectiveness and, if necessary, adjusted on a risk basis in order to achieve continuous improvement.

The control strategy is a set of controls derived from the current product and process understanding and is intended to ensure process performance and product quality. The controls may include the following: Parameters and properties related to active ingredients and starting materials and finished product ingredients, operating conditions of plant and equipment, in-process controls, finished product specifications and associated methods, and frequency of monitoring and controls.

Process parameters are operating conditions of machines, systems or devices that are used in the manufacturing process of medicinal products. The process parameters include, for example, stirring speeds, drying temperatures, differential pressures during filtration and much more.
A process parameter is a critical process parameter (CPP) if its fluctuations have an impact on one or more critical quality attributes (CQA) and thus on product quality. CPPs must therefore be monitored or controlled to ensure that the process yields a product of the desired quality.

A critical quality attribute is a physical, chemical, biological or microbiological property that should be within appropriate limits, ranges or distribution to ensure the desired product quality. CQAs are available for raw materials, intermediate and end products.

Examples of CQAs:

  • Starting material CQAS
    • Particle size distribution of the active ingredient (phys.)
    • Bioburden of the starting materials (microbiol.)
  • Intermediate product (IPCs):
    • Residual moisture of a granulate (phys.)
    • Tablet hardness (phys.)
    • Bioburden of a solution before sterile filtration (microbiol.)
  • End product (release specification):
    • pH value of a drug (chem./phys.)
    • Active ingredient content (chemical)
    • Sterility of the medicinal product (microbiological)

As part of the process validation, documented proof is provided that the commercial manufacturing process as described in the MBMR with the associated control strategy is suitable for reproducibly and reliably producing a high-quality end product that conforms to specifications. The process validation largely corresponds to the FDA’s Process Performance Qualification.

The “state of control” or “validated state” describes that a process is characterized by stability on the one hand and good process capability on the other.

Process stability means that the process delivers consistent and therefore predictable results from day to day and batch to batch. If these results are also reliably within the permissible specification, the process also has good process capability.

The APR (term used by the US FDA) or the PQR (term used by the EU) is a quality review of all approved medicinal products that is carried out regularly, at least once a year, but preferably continuously. The aim of the APR / PQR is to verify the consistency of the current process and the suitability of the current specifications for both the raw materials and the finished product. Furthermore, the APR/PQR enables trends to be visualized and thus opportunities for improving products and processes to be identified.
With regard to the required content and scope, there are some differences between APR and PQR, but the objective is identical for both systems.

The master manufacturing instruction or MBMR is the template for the batch-specific (i.e. with a batch designation) manufacturing instruction.
A manufacturing instruction is used to describe all processing procedures and work steps involved in the manufacture of the active substance or medicinal product, including the relevant process parameters and defined in-process controls.

As a rule, the PI sheet also contains documentation fields that make it possible to document the execution of the work steps. By documenting the execution, the batch-specific manufacturing instruction becomes a manufacturing record.

Continued Process Verification is the name for the third phase in the FDA’s process validation concept.
In this phase, which follows on from Process Performance Qualification (PPQ), parameters and quality features of the product that have been classified as critical and therefore relevant to product quality are continuously recorded and evaluated. The statistical evaluation of the recorded data is intended to provide scientifically sound proof that the process is capable of continuously producing a high-quality product. The CPV largely corresponds to the concept of the OPV in the EU GMP area.

The manufacturing record or BMR is used to document all processing procedures and work steps carried out as well as the associated in-process controls during the manufacture of the active substance or medicinal product.
The manufacturing record / BMR provides the basis for decisions on batch release on the one hand and enables all activities carried out to be traced if quality defects are identified at a later date (e.g. complaints, anomalies in stability tests) on the other. GMP-compliant documentation and the secure archiving of documents are therefore essential.

Batch record review is the review of the completed BMR/manufacturing record. The completeness of the entries and compliance with the defined specifications (e.g. compliance with specified process parameters or the acceptance criteria for in-process controls) are checked. The BRR is therefore a quality assurance system that contributes to the quality and safety of the manufactured active substance or medicinal product by systematically checking the manufacturing documents.

The QP (Qualified Person) is a function in accordance with European pharmaceutical legislation. The QP is responsible for ensuring compliance with the provisions of medicinal product legislation on the manufacture, testing and release of a medicinal product and the conformity of the medicinal product with the authorization dossier. The QP is also responsible for the complete documentation of compliance with legal regulations. Every pharmaceutical company requires at least one manufacturing authorization as a prerequisite for the granting of a manufacturing authorization. a QP.

Due to the increasing number of counterfeit medicines, strict EU-wide requirements for the labeling of prescription medicines with safety features were introduced in 2019. These ensure that counterfeit medicines do not enter the legal supply chain.

For this purpose, each medicine pack is given a randomized (randomly selected) unique serial number (serialized), which is encoded together with the batch number and expiry date in a two-dimensional barcode (data matrix code). This makes this pharmaceutical packaging clearly identifiable within Europe. Before a patient is given a medicine in a pharmacy, hospital or by a doctor running a family pharmacy, the serial number of the medicine is checked (verified), read from a database system and deactivated. This ensures the authenticity of the medicine. If discrepancies are found during the check, the medicine may no longer be dispensed.

The term compliance stands for adherence to legal provisions, regulatory standards and the fulfillment of other essential standards and requirements that are usually set by the company itself.

Extractables are chemical compounds that can be extracted from a material under extreme conditions (e.g. at elevated temperatures, using different solvents, at different pH values). They represent the worst case of those compounds that can theoretically get into the product from the system or machine (e.g. hoses or seals) during a manufacturing process and from the packaging material during storage. Whether these compounds actually get into the product under routine conditions is investigated in the so-called leachables studies.

Leachables are those chemical compounds that are released from parts of the production equipment (e.g. hoses or seals) under routine manufacturing conditions or from the packaging materials under routine storage conditions during the shelf life of a product and thus enter the product. In order to find out which potential leachables exist, compounds that can be extracted from plant components and packaging materials (so-called extractables) are first sought under extreme conditions (e.g. increased temperature, use of various solvents).

Technologie Transfer bezeichnet den Transfer von Produkten zu einer anderen Herstellungsstätte. Technologie Transfers können dabei zu einem anderen Unternehmen, z.B. einem CMO (Lohnhersteller) oder aber innerhalb eines Unternehmens z.B. von R & D in die Routineproduktion erfolgen.

Das Ziel des Technologie Transfers ist es, das vorhandene Produkt- und Prozesswissen zwischen Entwicklung und Herstellung oder zwischen zwei Herstellungsstandorten auszutauschen.
Dieses Wissen bildet die Basis für die erfolgreiche Implementierung des Herstellungsprozesses und die zugehörige Kontrollstrategie.
Der Technologie Transfer endet in der Regel mit dem erfolgreichen Abschluss der Prozessvalidierung.

Quality Risk Management (QRM) is a systematic process for the assessment, control, communication and monitoring of quality risks of medicinal products throughout the product life cycle. The QRM supports a scientific and practical approach to decision making based on a sound understanding of the products and processes under investigation and potential quality issues. As part of the risk assessment, potential risks are evaluated in terms of their probability of occurrence, impact and likelihood of detection.

The intended use of a product, system or process must be included in the assessment of potential risks and correctly weighted. In the case of medicinal products, patient safety and ensuring the availability of safe, medically necessary medicines is the top priority. Used correctly, QRM helps companies to increase the quality and safety of processes and products in a cost-effective manner. Through written documentation and structured procedures, the QRM also serves to make knowledge about products, processes and systems transparent.

Whenever possible, risk management activities should be carried out by interdisciplinary teams in order to bring different perspectives (e.g. process expert, technician, quality control, approval) into the process. Quality risk management is not a one-off action, but a process whose results should be regularly reviewed and reassessed throughout the life cycle of a plant, product or process in order to incorporate new findings and developments and adapt QRM measures accordingly.

The container closure system is the sum of all packaging materials that contain and protect the product. Accordingly, a container closure system always consists of at least the primary packaging materials that have direct product contact (e.g. blister, can, vial). If a secondary packaging material is used for additional protection of the product, this is also part of the Container Closure System (e.g. a folding box that protects the product from light).

FMEA (Failure Mode and Effect Analysis) is a methodical procedure for identifying potential risks in complex systems (e.g. processes, equipment, systems). The structured approach, in which individual process steps or parts of the systems or equipment under consideration are examined step by step for potential failure modes, allows even complex systems to be penetrated. As part of the FMEA, quantitative risk assessment is carried out after risk identification with regard to the probability of occurrence, significance of the effects and the probability of detection by assigning numerical values (e.g. scale from 1 to 5; 1 = low probability of occurrence, low significance, high probability of detection). The individual ratings are then multiplied to produce an overall rating. Previously defined limit values then make it possible to decide whether it is necessary to introduce risk-minimizing measures.

The qualification is written proof that the premises, systems or equipment are suitable for the intended purpose. The qualification of premises, systems or devices is divided into four different phases:
Design qualification (DQ = Design Qualification): As part of the DQ, the conformity of the design with the requirements defined in the user requirement specification (URS) and general GMP requirements is checked and documented.

Installation Qualification (IQ): IQ is used to check the correct installation of the system, machine, facility or room to be qualified on the basis of specified criteria (e.g. technical drawings and specifications). Construction materials used must be verified and integrated sensors and measuring instruments must be calibrated. Furthermore, operating and work instructions as well as maintenance requirements of the supplier are recorded and compiled.

Operational qualification (OQ): The OQ checks whether the system to be qualified functions as planned. The upper and lower operating limits must also be approached and their proper function confirmed.

The completion of a successful OQ should allow for the finalization of standard operating procedures and cleaning procedures, operator training and preventive maintenance requirements.
Performance qualification (PQ)
The performance qualification includes tests (with production materials or substitute materials if necessary) under routine conditions. The tests should cover the operating range of the desired process. If necessary, samples must be taken and analyzed to check the process.

The abbreviation OOS stands for Out of Specification and refers to an analysis result that is outside the defined specification limits. If such a result occurs during the analysis of an active substance, excipient, packaging material, intermediate product or medicinal product, a structured root cause analysis must be initiated. As part of this, investigations are carried out according to a defined procedure to clarify whether the OOS result can be attributed to a laboratory error (e.g. weighing error, dilution error, etc.) or an error during sample handling (e.g. segregation during sampling, samples stored under incorrect conditions, etc.) or whether there is actually a quality defect in the tested material.

If no laboratory error is found and repeat tests also lead to OOS results, this is referred to as a confirmed OOS.

Out-of-expectation results are the occurrence of implausible results or results outside the normally occurring scatter, whereby neither the specification limits nor the trend limits are violated. In an analytical measurement series, for example, this can be a single result that does not match the other results. To verify that the OOE result was not caused by a laboratory error or sample handling error, an examination analogous to the OOS must be performed.

An out-of-trend result exceeds internal limits that were determined based on statistical evaluations of historical data (e.g. μ± 3σ). To verify that the OOT result was not caused by a laboratory error or sample handling error, an examination analogous to the OOS must be performed.
The occurrence of a confirmed OOT result can be an indication of an out-of-control situation of the process. The cause of a confirmed OOT should therefore be investigated.

requires an examination analogous to an OOS result. As part of this review, in order to check whether a process

A trend is defined as a steady development of values over time without abrupt changes in direction. The values can rise or fall.

An active ingredient is not stored in a cool place, although this would be necessary. The lack of cold storage leads to increasing decomposition of the active ingredient over time. If batches are now produced with this active ingredient, the content of the batches produced continues to decrease over time, as the active ingredient continues to decompose with increasing storage time. An increase in the content is not possible as long as the incorrectly stored batch of active ingredient is used.

Bracketing is a risk-based approach to process and cleaning validation that makes it possible to reduce the scope of validation.
In bracketing, similar processes, products or systems to be cleaned are grouped together and representative representatives of the respective group are identified. The validation is then carried out on the identified representatives and the results are transferred to the other variants.

Bracketing is possible in process validation, for example, when validating different pack sizes and different batch sizes of one and the same product or different strengths of a medicinal product whose composition is very similar or. The revalidation of similar processes that have already undergone successful initial validation is also well suited to a bracketing approach.

As part of the cleaning validation, it is possible to combine identical or very similar systems on which the same products are manufactured into groups and carry out the cleaning validation on representative systems.

What is important in all cases of bracketing is the risk-based, written argumentation that explains why the selected representative(s) is/are suitable to enable a transfer of the validation results.

Medicinal products whose use requires sterility and which cannot be sterilized by terminal sterilization in an autoclave must be manufactured aseptically. For this purpose, the medicinal product, container and closure are first subjected to the necessary sterilization processes individually and then joined together as part of aseptic production.
Aseptic manufacturing must take place in a controlled environment where the air supply, materials and personnel are regulated to prevent microbial, pyrogenic and particulate contamination.
The risks associated with the aseptic process and the resulting requirements must be identified, evaluated and appropriately controlled (quality risk management).
The aseptic manufacturing process including all existing controls (e.g. with regard to cleanroom class, personnel, materials) must be regularly checked for suitability. This is carried out as part of an aseptic process simulation (APS; also known as media fill) using a sterile culture medium.

During filter validation, it is verified that the filter used for (sterilizing) filtration fulfils its intended purpose without having a negative impact on product quality. Various parameters are examined for this purpose, e.g. the ability to retain bacteria (load test), chemical compatibility with the product solution, maximum filter capacity, etc.

Media fill or APS (Aseptic Process Simulation) refers to the simulation of the aseptic manufacturing process using culture media filling. This must be carried out regularly twice a year for each system and packaging variant. This simulation is used to check all critical, aseptically performed production steps as well as routine interventions in the process that are known to occur during production (e.g. removal of broken glass or jammed stoppers from the filling line). Furthermore, worst-case situations, e.g. downtimes, should also be taken into account. Incubation of the filled units then makes it possible to prove their basic suitability or to identify weak points in the aseptic manufacturing process. As the process simulation is only a snapshot, it is supplemented in practice by further quality assurance systems to safeguard the aseptic manufacturing process against contamination. These systems include, for example, environmental monitoring, personnel monitoring, validation of sterilization procedures, bioburden determination and much more.

Bioburden is the microbial contamination of a starting material, intermediate product or end product. When determining the bioburden, a sample of the product to be tested is applied as evenly as possible to a culture medium (e.g. agar plate) and the culture medium is then incubated under suitable conditions. The microorganisms lying individually on the culture medium, which are alive and capable of reproduction, multiply to form separate colonies that can be counted. Accordingly, the bioburden is given as the number of CFU (= colony forming units) or CFU (= colony forming unit) per volume or per mass (e.g. 56 CFU/ml).

Since sterilization kills germs according to mathematical laws, by definition absolute sterility cannot be achieved during sterilization. By knowing the bioburden, i.e. the initial bacterial load and the key figures of the sterilization process, it can be ensured that the selected sterilization process is suitable for guaranteeing a sterile product with a high degree of probability.

The validation master plan is an overarching document that provides an overview of the general validation policy and strategy, the procedure and responsibilities and the current status of validation and qualification.
For this purpose, all facilities, systems and premises subject to qualification as well as processes subject to validation (analytical methods, manufacturing and cleaning processes) are listed. Furthermore, the required resources (financial, time and personnel) and the responsibilities for qualification and validation are specified.
In addition, statements should be included on the main acceptance criteria applied and the procedure for developing and defining acceptance criteria, on the documentation structure for validation documents and on the handling of changes (change control) and deviations.

The validation master plan should be short and concise and contain references to relevant, applicable documents instead of repeating their content.

The validation master plan is approved by the management. As explicitly required in Chapter 1 of the EU GMP guidelines, the company assumes responsibility for achieving the quality objectives.

Since sterilization kills germs according to mathematical laws, by definition absolute sterility cannot be achieved during sterilization. By knowing the bioburden, i.e. the initial bacterial load and the key figures of the sterilization process, it can be ensured that the selected sterilization process is suitable for guaranteeing a sterile product with a high degree of probability.

In the manufacture of sterile and other sensitive medicinal products (e.g. microbiologically sensitive products such as unpreserved creams), controlled environmental conditions are essential, e.g. with regard to airborne particles and microorganisms in the air and on surfaces. Rooms that are monitored in this way are referred to as cleanrooms. Annex 1 of the EU GMP guidelines “Manufacture of sterile products” defines various cleanroom classes (A to D), giving examples of processes for which the respective cleanroom class is required. Furthermore, limit values for the qualification and monitoring of the same are described with regard to particles and microorganisms in the air and on surfaces.

Deviations are unplanned and/or unforeseen events that do not comply with the approved specifications (e.g. process parameters, acceptance criteria, SOP specifications). Deviations can be caused, for example, by human error, machine defects, lack of training, incomprehensible specification documents and much more. In order to process a deviation that has occurred in accordance with GMP, it is essential to investigate the deviation and determine the cause. On the one hand, this makes it possible to better assess the deviation in terms of its impact and, on the other hand, to initiate suitable corrective measures that counteract a recurrence of the deviation (e.g. optimization of specification documents, adjustment of maintenance intervals, employee training).

An SOP (standard operating procedure) is an approved and therefore binding written description of a procedure or process. SOPs are used to standardize quality-relevant, usually non-product-specific processes so that different employees all carry out the described process in the same way (e.g. cleaning a system, receiving goods, evaluating suppliers, carrying out and documenting maintenance).
For SOPs to be well accepted and practiced, it is necessary to present the described processes clearly and unambiguously in simple, easily understandable language. SOPs must be trained before they become valid and must be checked regularly (e.g. every 2 – 3 years) to ensure that they are up to date.


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