Manufacture and control of clinical samples

 

16.D.1 Prerequisites for the approval of clinical investigations

Anyone wanting to perform clinical studies must have the approval of the authorities - granted by the responsible authorities in the individual country in which the study will be performed. In Germany for example, an application must be submitted to the responsible Higher Federal Authority. In accordance with the German GCP regulation § 7, this application must contain a dossier on the clinical sample which includes, among other things, documentation on the manufacturing and the manufacturing authorisation.

For studies that are to be performed in EU countries, a Clinical Trial Application (CTA) must be submitted. In addition to toxicology and pharmacology data, the application for authorisation must also be accompanied by an IMPD (Investigational Medicinal Products Dossier), which, similar to the later application file for marketing authorisation (CMC dossier, Chemistry, Manufacturing and Controls), provides relatively detailed specifications on the chemical and pharmaceutical quality of the investigational drug. Details on exactly which data must be provided in an IMPD are described in more detail in the EMEA document Guideline on the Requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (CHMP/QWP/185401/2004 - abbreviated in the following as the IMPD guideline). For studies that are to be carried out in the USA, an Investigation New Drug (IND) Application must be applied for from the FDA.

Among other details, these documents must contain a definition of the provisional formulation and a provisional manufacturing procedure. Analytical methods for the determination of content and purity must be defined and validated, even if these are preliminary methods. Stability data must also be presented that proves that the clinical sample is stable in the provisional packaging for the planned trial duration. This requires that the first GMP-relevant investigations must take place long in advance of the clinical phases, in order to obtain the necessary data for the dossiers to be submitted to the authorities.

16.D.2 Manufacturing of clinical samples and comparator drugs

When an application for approval of the clinical trial (IND or CTA) is submitted and the planning of clinical studies is underway, formulation development must have the environment ready for GMP-conformant manufacturing of the first clinical samples (see figure 16.D-1).

Master batch record and control procedures

Even if the manufacture of the first clinical samples follows most likely a provisional formulation and a temporary process, in accordance with Annex 13 of the EU-GMP Guideline, for each processing step or each delivery ... clear and appropriate written instructions and records must exist (chapter C.6.13 Annex 13 - Revision 1 Manufacture of Investigational Medicinal Products). This is important, because at this point usually, master records do not yet exist (in the terminology of the EU-GMP Guideline: "batch production record" or "processing instructions"), and traceability would otherwise not be guaranteed. The compilation of master records is not a legal requirement for development, but can be particularly useful in later phases, if the additional workload for the compilation of the master record is compensated for by the reduced workload in the creation of documentation for multiple batches that are the same.

Annex 13 of the EU-GMP Guideline does not explicitly require the "written instructions" to be approved by the responsible person before the start of manufacturing, but changes to instructions must be documented and evaluated by a responsible person in terms of their influence on stability and bioequivalence. The FDA Guideline on the preparation of investigational new drug products however, demands that an approval procedure is established from the beginning for all processing instructions and control procedures in the GMP area.

Specification of the theoretical yield is required as an important element in the processing instructions in all manufacturing steps where this is practical. The FDA Guideline on the preparation of investigational new drug products even demands that limits for actual yields are specified, and that any deviation from these limits is investigated in order to identify the cause, which might be, e.g. mix-ups, excess or low content, or contaminations. The EU-GMP Guideline only states the evaluation of significant deviations between the actual and the theoretical yield.

Similarly, specifications and validated, authorised test methods must be available before the start of the release analysis in the control laboratory. The test methods and specifications are also usually provisional, and will most likely change during the course of development. It is not an easy task to establish these specifications, but they should be based on data material from the research phase. It is also expected that all changes to specifications are recorded and justified ("product specification file", see chapter 16.E Documentation and recording of changes during development and chapter 16.F Development report), so that it can subsequently be identified whether specifications were changed at will. It would not be GMP-compliant to first perform tests and then use the results obtained to decide on an ad-hoc basis whether or not a result is acceptable.

Complete documentation

All processing steps relating to manufacturing, testing, packaging, and release of clinical samples must be carefully and completely documented. These documents must be archived for a minimum of five years following completion or termination of the clinical trial (see chapter 16.E Documentation and recording of changes during development).

Qualified, labelled equipment

Standard equipment in the manufacturing of clinical samples must be fully qualified (see chapter 6 Qualification). For newly acquired special equipment, a DQ and an IQ must exist. If applicable, the OQ can also be carried out concurrently with the manufacturing process, although the clinical samples then cannot be released for use in humans before the qualification report is approved. A PQ (feasibility and performance study over an extended period) is usually not possible in development, since statistically not enough data is available for the same product to enable conclusions to be drawn on the suitability of the machine, or to differentiate between the variability of the different processes.

Manufacturing equipment and containers must be labelled with the current product and if applicable, with the manufacturing step. This FDA requirement is particularly important because at the development site, several products or manufacturing steps are often performed in parallel and there is therefore a risk of confusion and mix-ups.

Hygiene concept and environmental monitoring

Clinical supplies must be manufactured in qualified premises that are classified according to a written hygiene concept. This concept describes the individual categories (zones) of the manufacturing premises in terms of room equipment, authorised access, air quality, microbiological environmental monitoring, gowning procedures, and cleaning measures (sanitation programme) (see chapter 3 Premises). If aseptic manufacturing steps are performed, increased environmental monitoring is required since filling and sealing is often performed manually, which is associated with a high contamination risk.

Control of raw materials, incl. packaging material

All components for the manufacturing of clinical samples, including raw materials, drug substances, excipients, process gases, and packaging materials must be controlled. This requirement can cause difficulties if new excipients or packaging materials are used. It is therefore important that any novel materials are characterised at an early stage concurrently with the development of the formulation or the packaging. For these materials, specifications must be created and suitable analysis methods developed. Release must be performed in good time before the first clinical samples are manufactured. Certificates from manufacturers or suppliers are unfortunately less helpful, unless these are qualified suppliers and at least five different batches of the relevant raw material are re-analysed by the manufacturer - whereby the results must match those on the supplier certificates. Since these requirements often cannot yet be fulfilled for new substances in development, enhanced analysis must be performed to prove the quality of the relevant excipient/packaging material batch to be used. The specifications for active pharmaceutical ingredients and excipients must be reviewed throughout the course of development and updated as required.

Release procedure

An established written release procedure is an important prerequisite for the supply with clinical samples. The detailed process flow of the release, including review of the manufacturing, packaging, and analysis documentation and the regulatory prerequisites (if release for use at a trial site abroad is intended) must be specified, together with responsibilities and deputisations (chapter 16.D.4 Control and release of investigational medicinal products).

Recording changes to the manufacturing process and product specifications

As soon as the first clinical samples are manufactured, any change to the formulation, process, packaging, or specifications must be recorded. The latest version must always be stored in the product specification file, (see chapter 16.E Documentation and recording of changes during development). Any effects that the changes may have on the quality of the clinical supplies or bioequivalence (and hence on the significance or comparability of the clinical trials) must be assessed, approved, and documented by responsible persons. For example, a distinctly improved dissolution caused by galenic skills may lead to a faster onset of action or cause inexplicably changed plasma level in clinical trials. On the other hand, changes to the manufacturing process can lead to unintentional changes in dissolution which, although still within the specifications, lead to unexpected effects in vivo.

Validation

The EU-GMP Directive 2903/94/EC requires that for clinical samples, "the manufacturing process shall be validated in its entirety ", with the limitation "in so far as is appropriate, taking into account the stage of product development. At least the critical process steps, such as sterilisation, shall be validated".

This last requirement is not new, and is obviously strictly necessary, because no other quality measure (with the exception of the 100 % test) can guarantee that each single dose is actually sterile following a sterilisation process.

However, the EU Directive does not explain in detail how a "manufacturing process in its entirety" should be validated. As long as "validation" is understood not only as a triple repetition of processes, but rather as a far broader concept in accordance with the definition in figure 16.B-20, even this requirement becomes practical and feasible (see also chapter 7.E Planning of process validation projects).

Manufacturing of clinical samples

Proper manufacturing of clinical samples is of the utmost importance for the safety of patients or volunteers who take part in the study. The quality of the clinical samples also plays an important role in the outcome of the study, since it is difficult to draw conclusions about efficacy, compatibility, unwanted side effects, therapeutic dose and range on the basis of clinical samples with, for example, variable content, inadequate stability, or non-reproducible dissolution.

Not only the verum must be manufactured in accordance with GMP. The same applies for any placebos and comparator drugs. An authorised batch production record must also exist for these formulations, product specifications must be created, and analysis methods developed, and the same release procedure must take place as for the verum. In the control of placebos, for example, the absence of drug substance must be tested. For the placebo and reference preparation, it must also be ensured that the general appearance, odour, and taste match the verum.

Comparator drugs

If a clinical sample is to be compared with a marketed product in a study, the integrity and quality of the comparator drug (finished product, packaging material, storage conditions, etc.) must be guaranteed. When the comparator drug is re-packed from its original packaging, for example, the expiration date specified on the original packaging cannot be used, since this was determined in this particular packaging and may no longer be applicable when the product is repacked into a different container. The new expiration date must be before the expiration date of the original packaging. If no stability data is available, this date must not exceed 25% of the remaining time between the date of repacking and the expiration date on the original packaging of the manufacturer (or a period of six months from the date of repacking of the drug substance, depending on which period ends first).

When comparator drugs have to be reprocessed (blinded) for double-blind studies, so that they cannot be distinguished from the verum, this reworking is classified as a major change. Data (for example on the stability, comparative dissolution, bioavailability) must therefore be obtained to prove that these changes do not have a major influence on the quality attributes of the original drug product. For example, it must be demonstrated that dissolution is not hindered if small tablets are filled in hard gelatine capsules for purposes of blinding, and then filled up to the filling weight of the capsule with excipient. Similarly, data must be obtained to prove the stability of a granulate that is emptied from coloured capsules and added into neutral capsules together with lactose. In particular for formulations with modified drug release profiles it may be extremely difficult to prove equivalence. Often, it is even necessary to perform a bioequivalence study between the comparator drug and the reworked form of comparator drug.

In the case of preparations that cannot be easily blinded, the double-dummy study design is a possible alternative: In this case, the reference medication remains unchanged and a matching placebo is manufactured. A matching placebo for the actual clinical sample is also manufactured. During the trial, each study participant is then always administered with two visually different preparations at the same time. Which preparation is the placebo, and which is the verum or reference, is not revealed until the statistical evaluation of the study.

16.D.3 Packaging and labelling

Along with manufacturing, the packaging of investigational medicinal products is also of the utmost importance for the safety of trial participants and for the results of the study. Errors in the packaging of clinical samples, if they are not detected during in-process controls or the final batch assessment, can later no longer be traced.

The revised Annex 13 of the EU-GMP Guideline (chapter C.6.13 Annex 13 - Revision 1 Manufacture of Investigational Medicinal Products) requires that any opening of the external packaging and any manipulation is easily detectable.

The packaging material is used to protect against damage, falsification, or deterioration during transport and storage. This includes the labels, which assign the investigational medicinal products to the individual patients at particular administration times in accordance with the randomisation list. The packaging of clinical samples is therefore considerably more complex and prone to errors than the packaging process for the commercial product - particularly the packaging of blinded medicinal products, where it is not possible to distinguish between the labels of the verum and the placebo. Aspects such as label reconciliation, line clearance and in-process controls by independent quality assurance staff, are therefore particularly important.

The points listed in figure 16.D-2 must be considered in the packaging of clinical samples.

Packing instructions

Packing instructions must precisely describe the packaging material to be used, the batch number(s) of the bulk material, the necessary equipment, and all packaging, labelling, control, and cleaning steps.

Bulk batches of clinical samples are often divided into numerous "sub-batches" and packed in different packaging operations over an extended period of time, for example for trial sites in different countries. The number of investigational products to be packed must therefore be precisely defined in each packing instruction. In doing so, the number of packages required for quality controls and retention samples must also be taken into account. At the end of each packaging and labelling process, the labels and completely packed clinical samples must be balanced, in order to detect any errors such as mix-ups.

Various specifications exist for the labelling of clinical samples. It is particularly important to comply with the current applicable country-specific requirements if clinical samples are packed for studies in different countries. For EU countries, the instructions are more or less uniform.

But still there are some country-specific detail requirements, which must be adhered to, if a clinical trial is planned abroad. For example, German law asks for specification of the EudraCT number on the label of investigational drugs. (This number identifies EU-trials and is assigned by an European database www. eudract.emea.eu.int.)

Figure 16.D-3 and figure 16.D-4 summarise the requirements of Annex 13 of the EU-GMP Guideline Manufacture of Investigational Medicinal Products.

All particulars must be displayed in the official language of the country in which the investigational drug will be used. If the informations are also repeated in another language, the content of both language versions must be identical.

For medicinal products with marketing authorisation that are being examined in phase-IV studies for long-term tolerability, the commercial name or the trade mark must not be given as the designation of the medicinal product. This is expressly forbidden e.g. under the German Pharmaceuticals Act (AMG). This has led to an increasing number of "application observational studies" in clinics or doctors' practices, which are not legally classified as clinical trials and can be performed with commercial products.

For blinded studies, the batch number of the verum, placebo or comparator drug used cannot be indicated on the label, since it would be possible for the study participants or trial physician to differentiate the test drugs based on this information. It is therefore common practice to assign a code number to the labels of double-blind studies (see chapter 16.D.3.1 Blinding and randomisation) that identifies the packaging operation.

The batch packaging records must include a sample of each type of label used.

Concerning the complex problems occuring when relabelling is necessary for extension of an expiry date, see chapter 16.C.3 Interfaces between the areas regulated by GMP and those regulated by GCP.

Reconciliation, returns and destruction of printed packaging material

The reconciliation of printed packaging material provides information on possible mix-ups. Returns to the warehouse of packaging materials that have already been dispensed once should be avoided, since this causes a risk of confusion and mix-ups.

Excess packaging materials with a printed batch number or expiration date must always be destroyed. All reconciliation, returns, and destruction should be documented (see chapter 13.B.11 Reconciliation).

16.D.3.1 Blinding and randomisation

Blinding

In order to avoid influencing the patient, the doctor, monitors or statisticians in a clinical trial, in comparative studies, the investigational medications are usually blinded, which means they cannot be distinguished from each other by appearance. In a single blind study, the patients/volunteers usually do not know which treatment they are receiving. In a double-blind study, the patient/volunteer, the investigator, and in some cases even those responsible for data evaluation do not know the assignment of different treatments to the patients/volunteers.

If, during manufacturing of clinical samples, placebos are produced with an identical appearance to the clinical sample, or a comparator drug is reworked so that it corresponds to the clinical sample in both appearance and taste, at the packaging and labelling stage, the last distinguishing feature - the batch number - gets "lost". It is therefore very important to implement a documented system for the identification of "blinded" preparations, which can be used to trace each individual clinical sample. The code number that is assigned in the packaging of double-blind studies is used to identify the packaging operation. In combination with the randomisation code and the randomisation list, it is possible to properly identify each product. In addition, retention samples of blinded preparations must also be held.

To guarantee the safety of study participants, each trial site in a double-blind study receives a sealed envelope for each individual patient, which is labelled with the study number and patient number, and which contains information on the relevant study medication. Alternatively, this information can also be attached to the clinical sample in a small pouch. The pouch or envelope may only be opened if it is necessary to identify the study medication in an emergency. In individual cases, the investigator must carefully decide whether it is actually an emergency and whether opening the emergency envelope is unavoidable in order to take appropriate actions. The monitor (see chapter 16.C.2 GCP - Good Clinical Practice) regularly inspects the integrity of all emergency envelopes and takes them back on his final visit.

Randomisation

In order to guarantee that the different investigational medicinal products (verum, placebo, comparator drug) in comparative studies are assigned purely at random to the different patients or patient groups, blinded studies are usually randomised, which means the assignment is performed according to the statistical rules of chance. A suitable randomisation list avoids that study participants are included in a non-representative way, thus increasing the statistical significance of the study. The creation, distribution, handling, and storage of randomisation codes used in the packaging of investigational medicinal products must be described in operating instructions. The randomisation list contains the following:

• Name and code of the clinical trial
• Test institute
• Number of the trial subject, if applicable medication number, treatment period number
• Assignment of verum (with dose), comparator drug or placebo

16.D.4 Control and release of investigational medicinal products

Clinical supplies must be analysed and released in accordance with GMP, which means:

• In accordance with approved test instructions
• According to previously established specifications
• Using validated test methods (in early development phases, only the methods for determination of content and degradation have to be validated)
• In accordance with an established release procedure

Specific requirements of the Qualified Person

The testing and release of clinical samples falls under the responsibility of a qualified person (in accordance with section 2.4 + Annexes 13 and 16 of the EU-GMP Guideline). This requires - in addition to the usual qualification of a qualified person, as defined in Annex 16 - that the QP has "a broad knowledge of pharmaceutical development and clinical trial processes." (quote from Annex 13 of the EU-GMP Guideline, paragraph 4).

Product release of investigational drugs is often performed in several stages:

Release of bulk material

In the assessment of the bulk material, all relevant factors must be taken into account, including manufacturing conditions, results of the in-process controls, review of the manufacturing documentation, and compliance with the product specification.

An important component in controlling the manufacturing process is the verification of the actual yield with the theoretical yield. This comparison should be performed in accordance with the FDA Guideline on the preparation of investigational new drug products in all manufacturing steps in which it is practical to do so. The calculations must be verified by a second person. For development products, material loss due to an increased number of in-process controls, division into several sub-batches, technical adjustments and machine startup attempts, etc., must be taken into account in the yield calculation. In cases of very large or inexplicable differences in yield, the clinical supplies cannot be released before a formal cause analysis has taken place.

In particular, compliance with specifications that affect the efficacy of the medicinal product, such as the uniformity of the content, the homogeneity, the release of the drug substance, and the estimation of stability must be taken into account. In the control of placebos, the absence of drug substance must be verified. For the placebo and reference preparations, it must also be ensured that the general appearance, odour, and taste match the verum.

Release of the product in its final packaging

To evaluate the final product for the batch certification - in addition to the evaluation of the bulk material - the qualified person must take all relevant factors into account, including

• Packaging conditions
• Results of the in-process controls during packaging operations
• Packaging documentation, including deviation reports
• Examination of the finished packages
• Conformance with product specifications (Product Specification File, see chapter 16.E Documentation and recording of changes during development),
• Compliance with the order, including randomisation
• Validation status of processing procedures and methods
• Stability reports
• Verification of the storage and transport conditions
• Audit reports referring to the manufacturer's quality assurance system
• If applicable, results of all tests performed after the import
• If applicable, inspection of the manufacturing authorisation (in particular for imported clinical samples)

Which of these points must be taken into account in each individual case depends on the country of origin of the investigational product (EU country or non-EU-country), on the authorisation status (whether or not the drug has already a marketing authorisation, in the EU or in a non-EU-country), and on the development phase of the product. (This release phase corresponds to the earlier designation of the technical green light.)

Similar to the procedure for commercial product, the qualified person must also enter each released batch consecutively into a register of released products "or equivalent document" (EU-GCP Guideline 2001/20/EC, Art 13, par. 4). This register of released products must be available to the authorities for a minimum of five years.

Before shipment to an investigator, release by the sponsor is also required (previously designated as the regulatory green light). This includes the approval of the sponsor for use of the investigational drugs, after it has been clarified that all regulatory requirements for the affected trial site are fulfilled (country-specific requirements, submission of the clinical study protocol to the relevant authority, etc.). Both releases must be recorded and the protocols stored (see Annex 13 of the EU-GMP Guideline, paragraphs 38-44).

Retention samples

In accordance with the EU-GMP Guideline from 08.10.2003, for investigational drugs, sufficient retention samples of each batch of a preparation in an unpacked form, and main components of the packaging for the individual final product batches, must be retained for a minimum of two years following completion or termination of the last clinical investigations in which the affected batch was used. Annex 13 of the EU-GMP Guideline regulates special features for retention samples of investigational drugs that partly deviate from the requirements of the new Annex 19 (Reference and Retention Samples). Annex 13 requires that retention samples of every packaging run or each section of the clinical investigation are retained until the test report is compiled, in order to enable the identity of the product to be confirmed in the case of an investigation of conflicting study results.

Samples must also be retained of the batches of active pharmaceutical ingredient that are processed in the investigational drugs. It is very important to ensure that sufficient retention samples are planned, for example, to allow for execution of analytical tests in case an extension of expiry dates might be necessary.

Expiration date of investigational drugs

The expiration date printed on the clinical samples must be supported by stability studies in the identical packaging material foreseen for the clinical studies. The expiration date, specified in month and year, must be calculated according to the CPMP Note for guidance on start of shelf life of the finished dosage form, starting from the release date. If the release process lasts longer than 30 days after the manufacturing date (the date on which the (first) drug substance is added to the other components of the formulation), the expiration date should be calculated starting from the manufacturing date. In blinded clinical samples, if the investigational drug and the reference samples have different expiration dates, this would endanger the blinding. Therefore, the shorter of the two expiration dates must be specified for both preparations. For determining the expiration dating period of comparator drugs, see chapter 16.D.2 Manufacturing of clinical samples and comparator drugs.

For more information on extending the expiry date of clinical samples and secondary release of returned clinical samples, see chapter 16.C.3 Interfaces between the areas regulated by GMP and those regulated by GCP.

16.D.5 Storage and shipment of investigational drugs

Packed investigational products must be stored under the supervision of the sponsor under quarantine, until the release procedure (chapter 16.D.4 Control and release of investigational medicinal products) is completed.

Investigational medicinal products may only be shipped by order of the sponsor and according to instructions in the shipment order. The packaging must guarantee that the medicinal products remain in a good condition during transport and interim storage. Any opening or tampering of the outer packaging during transport and storage at intermediate destinations should be readily discernible, in accordance with Annex 13. The sponsor should ensure that the delivery arrives at the correct recipient in the required state and this is acknowledged with a receipt. To ensure complete batch traceability (important, for example in the case of recalls), an exact inventory must be kept of all deliveries from the manufacturer, including information on the recipients (see figure 16.D-5).

Proper storage of clinical samples at the CRO, at the investigator, or in the hospital pharmacy, is very important and must be supervised by the monitor (see chapter 16.C.3 Interfaces between the areas regulated by GMP and those regulated by GCP).

Transfers of investigational medicinal products from one trial site to another should remain the exception and should only be permitted in the case of very expensive preparations, limited quantities of drug substances for clinical trials, or in emergencies (see Annex 13 of the EU-GMP Guideline, paragraph 47). Such transfers should be regulated in standard operating procedures. If the preparation to be transported was not stored in the pharmacy of the trial site, but instead with the trial physician, appropriate safety precautions and controls must be performed before use at a different trial site. This means that the preparation must first be returned to the sponsor for relabelling and for the execution of comprehensive retests, to ensure that it remains suitable for application and satisfies the prerequisites for secondary release.

16.D.6 Returns, recalls and destruction of clinical samples

Expired investigational products or unused clinical samples (after completion of a clinical investigation) must be returned to the manufacturer, unless it is contractually agreed that they are destroyed according to a documented process at the trial site (see chapter 16.C.3 Interfaces between the areas regulated by GMP and those regulated by GCP). The same applies for defective preparations that have been recalled by the manufacturer. The returns or recall process must be defined in writing and all involved persons (sponsor, investigator, monitor, and persons responsible for recalls) must be familiar with this SOP. All returns must be documented in detail, that is, with specification of the affected batches and/or patient numbers and the quantities actually returned.

Returned clinical samples must be unambiguously identified by the manufacturer and stored in a specifically designated area. An inventory must be kept of the returned medicinal products.

Unused clinical samples should not be destroyed by the manufacturer until after completion of the clinical investigations and completion of the final report, and not without the prior written approval of the sponsor. The destruction operations must be recorded in a way that enables all individual steps to be traced. Records must be retained by the sponsor. When destruction of investigational products takes place a dated certificate of destruction should be provided to the sponsor. This document should allow clear identification of the affected batches and/or patient numbers as well as the quantities actually destroyed.