Interfaces to GLP and GCP

 

16.C.1 GLP - Good Laboratory Practice

Even some of the non-clinical phases of pharmaceutical development are strictly regulated. For example, experiments and tests relating to toxicological investigations must satisfy the requirements of Good Laboratory Practice (GLP). GLP regulations refer to all non-clinical safety tests relevant to health and/or the environment (figure 16.C-1).

The aim of GLP is to make safety data on new substances reliable and comparable, to enable trust in new substances, while also preventing duplicate studies, for example in different countries (for the purpose of animal welfare). GLP is an instrument to ensure the quality (reliability) and integrity (honesty) of data (information) about a new substance submitted to authorities for marketing application purposes. The implementation of GLP ensures that the test results are internationally comparable and mutually recognised (OECD).

The emphasis of GLP is on:

• Traceability of results through complete documentation
• Reduction of possible sources of error
• Assurance of consistent quality and reproducibility of experimental tests
• Establishment of (legally) responsible persons

GLP focuses on the quality of data - in contrast to GMP, which concentrates on the quality of the product (medicinal products or pharmaceutical active ingredients and excipients). GMP guidelines (and not GLP guidelines as the abbreviation may suggest), should therefore be applied in a control laboratory that performs analyses relating to the raw material controls, IPC, intermediate products, final inspection, stability tests, process or cleaning validation of medicinal products. Occasionally, the abbreviation GCLP (Good Control Laboratory Practices) is also used to summarise the GMP requirements in pharmaceutical control laboratories (see chapter 14 Laboratory and Analytical Controls). Important elements of GLP are shown in figure 16.C-2.

16.C.1.1 Comparison of GLP - GMP

Although many of these GLP elements appear to be the same, there are important differences between GLP and the requirements of GMP control laboratories:

• The aim of GLP is to guarantee the integrity of test data, while the aim of GMP is to protect patients and volunteers.
• The purpose of GLP tests is to analyse test objects, for example testing the properties of active pharmaceutical ingredients or determining blood or plasma concentrations. The purpose of tests in GMP control laboratories is the assurance of the quality of pharmaceutical raw materials and products.

GLP and GMP have similar requirements in terms of:

• Handling raw data (see chapter 14.I Raw data documentation), archiving documents (GLP 15 years, GMP at least five years, see chapter 15.B.2 Archiving)
• Analytical laboratory equipment: Suitable rooms, qualified personnel, qualified equipment, validated methods, approved test procedures (see chapter 14 Laboratory and Analytical Controls)
• Computer validation
• Description of all quality-relevant processes in SOPs
• Stability tests (GLP: for example on feed mixtures, GMP: for determination of the expiration period)

In contrast, important differences between the two are:

• Responsible persons
  In accordance with the EU-GMP-requirements the overall responsibility in a GMP-facility lies with the Qualified Person; while in the GLP area, a test facility manager must be named, along with a study director, an archivist, and a quality unit.
• Function of quality assurance
  Although it is standard practice to establish a quality unit (Q unit, quality assurance or QA) in the GMP area, this is not a legal requirement. The regulatory requirements merely refer to a "functioning quality assurance system". In the GLP area, a quality unit must be named that is required to fulfil precise legally prescribed functions (QA program statement, study audits, facility audits, etc.).
• The significance of self-inspections/audits
  In the GMP area, it is obligatory for the pharmaceutical manufacturer to perform and document regular internal audits (according to a schedule or SOP). The way in which the inspections are performed and the responsibilities for executing these self-inspections are up to the individual needs of each manufacturer.
  In the GLP area, the quality unit must regularly perform facility audits. Furthermore, each individual study (with a few exceptions, for example, short-term tests) must also be verified as part of a study audit.
• Significance of the study plan
  In the GLP area, the most important document is the study plan, which determines all test activities, responsibilities, detailed instructions, and required resources. The study plan must be checked for GLP conformity by the quality unit and approved by the study director and if necessary by the contract giver/sponsor, before the study begins. All changes to procedures must be recorded in a study plan amendment and approved by the study director.
  In the GMP control laboratory, the term "study plan" does not exist in this sense. Here, tests are performed according to previously approved control procedures, test procedures, or stability plans. If changes to these instructions or plans are required, these must be assessed by a change control committee before the changes are made (see chapter 19.C Change control).
• Master schedule
  This compilation gives an overview on the status of all current and completed tests in order to trace the workload and workflow within a test facility. There is no corresponding requirement in the GMP area.
• Standard procedures (SOPs) for batch release, change control, OOS, complaints, and recalls
  are legal requirements for GMP-facilities. Since GLP does not deal with the manufacturing of medicinal products, there are no such requirements.

Figure 16.C-3 shows an overview of the similarities and differences between GMP and GLP.

16.C.2 GCP - Good Clinical Practice

Another interface to a regulated area arises in the preparation of clinical supplies.

• The manufacture of investigational medicinal products, including packaging, labelling, storage, shipment, and if necessary withdrawal, destruction, investigational products accountability at site, and documentation, is subject to GMP requirements.
• For labelling, shipment, storage, destruction, investigational products accountability at site, and documentation, the requirements of GCP also apply (for a definition of GCP, see figure 16.C-4).

  Figure 16.C-4 Definition of GCP in accordance with the ICH "Note for Guidance on GCP"

  Definition: Good Clinical Practice (GCP)
  Good Clinical Practice is a standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials, that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected.

For the execution of clinical studies, certain quality standards exist that are summarised in the GCP Guidelines (ICH Topic E6 Note for Guidance on Good Clinical Practice) (see figure 16.C-5).

In addition to ICH Topic E6, in Europe, the GCP Directive (2001/20/EC from 4. 4. 2001) and in Germany, the regulations governing the application of Good Clinical Practice for the execution of clinical investigations with medicinal products for use on humans (German GCP regulation from 09. 08. 2004) are the authoritative regulations. This detailed and binding regulation controls tasks and responsibilities in relation to the planning and execution of clinical studies, and also includes detailed procedures for labelling clinical samples (see chapter 16.D.3 Packaging and labelling). Separate guidelines exist for the execution of clinical studies on animals (VICH Good Clinical Practice GL 9 June 2000).

Whoever wants to act as a sponsor of a clinical study requires the licence of the relevant local authorities. In order to be granted this approval, a comprehensive dossier must be submitted containing several documents, including the study protocol. This study protocol contains a detailed, written description of the objective of the study, the study design (for example, and open study or double-blinded study), the inclusion criteria for study participants, the test formulations, evaluation methods, the case report form, and many more details. The investigator responsible for running the clinical study at the study site not only has to be familiar with the study protocol and the clinical sample, but must also keep abreast of the latest clinical and non-clinical findings regarding the investigational medicinal product (investigator's brochure). Study participants must be accurately informed about the objective of the study, the process, and any possible risks, and subsequently have to provide their written consent (informed consent). Before the start of the study, an independent ethics committee, consisting of healthcare professionals and non-medical members, examines the suitability of the investigator, the study protocol, and further documents, and expresses an opinion within 60 days, in order to protect the rights, safety and welfare of study participants, and to establish trust among the general public. A clinical study can only be executed following a positive vote by the ethics committee.

All changes to the study protocol must be documented in an amendment to the study protocol and receive the written consent of the sponsor. If a change to the study protocol could potentially influence the health interests of the study subjects, the ethics committee must provide a revised vote and the patients are once again required to give their consent (IC), if they are still affected by the change.

Sponsors of clinical investigations who do not want to undertake the planning, management, and/or interpretation of the studies themselves, can also outsource these activities to external Contract Research Organisations (CRO). In this case, it is important that the competences and responsibilities are not only contractually defined in detail between the contract giver (sponsor) and the investigator, but also between the contract giver and the CRO, and between the CRO and the investigator.

The responsibility of the sponsor extents far beyond simply providing the clinical samples.

The German AMG and the ICH guideline Note for Guidance on Good Clinical Practice both define that the sponsor, who can be a natural person or a legal entity, is responsible for the initiation, management, and/or financing of clinical trials. The German GCP regulation also requires the sponsor to document all adverse events (any untoward medicinal occurence that occurs in the context of the study), serious adverse reactions and all suspicious cases and inform the responsible authorities. The EU-GMP Directive 2003/94/EC, which refers explicitly to the production of clinical samples, also defines additional responsibilities of the sponsor.

In detail, the sponsor is responsible for the aspects of study execution listed in figure 16.C-6.

Meanwhile, the investigator, is responsible for the points in figure 16.C-7. If a test is conducted by a team of individuals at a trial site, the responsible head of the group is known as the principal investigator (in accordance with the EEC-Directive 2001/20/EC).

If a CRO (Contract Research Organisation), which is contracted by the sponsor to execute one or more tasks and functions in relation to the clinical investigations, is also involved in the process, it is responsible for all duties and tasks related to the investigations taken over from the sponsor as defined in writing. Any duties that are not explicitly described in writing automatically remain the responsibility of the contract giver.

Monitors are responsible for monitoring that the study is executed correctly. Monitors are persons with adequate qualification nominated by the sponsor. They monitor the progress of a clinical investigation and ensure that this is executed in accordance with the study protocol, SOPs, GCP and any applicable legal requirements.

The monitor (whose qualification must be documented) must be familiar with the investigational medicinal product, the study protocol, SOPs, GCP and laws. The monitor's responsibilities are listed in figure 16.C-8.

In accordance with the ICH GCP guideline, the sponsor is obliged to have the whole clinical trial, including planning, inspected by an independent quality unit. This quality assurance is guaranteed by suitably qualified persons (auditors). The auditors are hierarchically independent from the clinical department of the sponsor. The aim of the audit is to verify that the clinical investigations and monitoring are being performed properly. Audits can be performed before, during, or after completion of the clinical investigation. In this independent inspection, the auditor compares, at least on the basis of random sampling, the conformance of the original data with entries in the case report form. Furthermore, the auditor also checks compliance with the study protocol and specifications to ensure that the clinical trial is performed in accordance with ICH-GCP. After the audit, a certificate is issued.

In addition to these sponsor audits clinical trials may be subject to monitoring by local authorities in order to check that the submitted documentation (application for authorisation for the clinical trial and application for marketing authorisation) conforms with reality. Particular attention is generally paid to changes, e.g. to study protocols that require approval.

16.C.3 Interfaces between the areas regulated by GMP
and those regulated by GCP

The preparation of investigational medicinal products involves employees both from the GMP and the GCP area. GMP and GCP each govern different subareas, and the responsibility for investigational medicinal products is handed over from one area to the other. At this transition point, problems, misunderstandings, delays and errors unfortunately often occur. It is therefore imperative that the processes, responsibilities, and the information flow are clearly defined - in the form of detailed SOPs, which must be enforced in both, the GMP area and the GCP area. The following typical problems occur:

Preparation of clinical supplies

Particularly in the early development phases (clinical phase I and II), the knowledge on stability of the test formulations is still limited. This means that clinical supplies cannot be manufactured at an unspecified time before the trial, to ensure that the expiration date has not already passed before the first volunteers or patients are treated.

On the other hand, from a clinical development perspective, it is not always possible to predict how long it will take until trial physicians are selected and suitable patients are recruited. Nevertheless clinical samples must be available in due time. To ensure this, pharmaceutical development (GMP area) needs certain pieces of information from clinical development (GCP area) at the right time (see figure 16.C-9).

Application and storage information

The information provided on clinical sample packaging regarding the storage and, if applicable, usage (for example "shake before use" or "spray only in an upright position" or "activate as follows before use") is based on development data and stability results. Since experience regarding the stability of the clinical samples is often still limited, strict compliance with the storage information and handling instructions is important for the significance of the study. These specifications are contained in the clinical study protocol and are hence binding for the test institute. It is the responsibility of the monitor to inform the trial physician of these instructions, and to monitor correct compliance during his or her visits.

The aspects named in figure 16.C-10 must be taken into account in the storage of clinical samples by the CRO or the trial physician.

Shipment under quarantine

Particularly in early phases of development, when no long-term stability data is yet available for the clinical samples, shipment under quarantine is sometimes required, in other words, shipment before all test results are available that are required for release for human use. This type of "Shipment under quarantine" is, however, quite questionable considering the requirements of Annex 13 of the EU-GMP Guideline (chapter C.6.13 Annex 13 - Revision 1 Manufacture of Investigational Medicinal Products), and must be agreed in individual cases with the authorities of the countries involved. Paragraph 44 of Annex 13 states quite clearly: "Investigational medicinal products should remain under the control of the sponsor until after completion of a two-step release procedure" (see chapter 16.D.4 Control and release of investigational medicinal products). This means that shipment cannot take place until it has been approved by the sponsor. If samples are to be shipped under quarantine, the sponsor (if necessary via the monitor) must ensure that the investigational medicinal products are not used in the CRO until formal release has been granted. However, if the products cannot be released in the end, it must be ensured that the test formulations are returned or destroyed on site (depending on the stipulations of the contract).

Extension of expiry date of clinical samples

During clinical phase II and phase III tests, it may occur that a clinical trial overruns its time. This may be due to delays in recruiting patients, or an unexpectedly high proportion of patients who withdraw participation in the trial for personal reasons (drop-outs), so that additional (replacement) patients have to be included in the trial. In these cases, the expiration date specified on the clinical samples may be exceeded. The clinical samples can then no longer be used.

In particular for very expensive clinical samples or samples with limited availability, it may be necessary to extend the shelf life, in order not to endanger continuation of the study as planned.

However, extension of the shelf life is a complex issue that is bound by strict safeguards. Ultimately, any mix-ups or other error occuring during relabelling would have fatal consequences for the result of the study.

• Subsequent analysis is performed using retention samples at the sponsor.
• The trial centre or monitors must inform the sponsor in good time before expiration of the use-by date.
• Proper storage at the trial site must be guaranteed (supervised by the monitor).
• Relabelling with new labels containing the extended expiry date is legally classified as a manufacturing step and may only be performed in a facility that is licensed to do so. Annex 13 of the EU-GMP Guideline (paragraph 42) formulates the following exception, that packaging or labelling may be carried out at the investigator site by, or under the supervision of a clinical trials pharmacist, or other health care professional as allowed in those regulations, in which case the qualified person is not required to certify the activity in question. At the same time, however, it is expressly indicated that the activity must be adequately documented and carried out in accordance with the principles of GMP, and the sponsor should seek the advice of the qualified person in this regard. It is most important to clarify individually whether a planned procedure complies with the law of the country in which the relabelling will take place.
• Relabelling should be adressed in the contract.
• The process of relabelling must be performed in accordance with a specific instruction (for example, the new label must not cover the original batch number/ID number in accordance with the EU-GMP guidelines, Annex 13 and the process must be controlled by a second person and documented in the trial documentation, as well as the batch protocol and batch packaging record.

Withdrawal and secondary release for clinical trials

In exception cases (for example for very expensive clinical samples), legislators permit clinical samples to be returned from the investigator site to the manufacturer, where they are re-analysed, repackaged, and released for a different clinical study. From a GMP perspective, this operation is particularly questionable, since the medicinal products have not been under control of the manufacturer in the meantime. During shipment and storage at the investigator site, any unrecorded damages (head, cold, humidity, vibrations, breakage, etc.) may occur in some or all of the clinical samples, which cannot be identified by the analysis of random samples.

Returns and destruction of unused clinical samples

After completion of a clinical study, unused test clinical samples or clinical samples whose expiration date has passed, must be returned to the manufacturer or destroyed on site - depending on the details of the contract with the sponsor. It is not permitted to use excess clinical samples for other purposes.

Both returns and destruction must be executed in accordance with written operating instructions as defined by the sponsor. Detailed records must be kept of the returns and destruction, from which the affected batches and/or patient identification numbers, as well as the actual amounts returned or destroyed, can be clearly identified (see chapter 16.D.6 Returns, recalls and destruction of clinical samples)