Quality assurance of pharmaceuticals
A compendium of guidelines and related materials Volume 2:
Good manufacturing practices and inspection
WHO good manufacturing practices: specific pharmaceutical products
Sterile pharmaceutical products
Investigational pharmaceutical products for clinical trials in humans
Herbal medicinal products
Investigational pharmaceutical products for clinical trials in humans
1. Introductory note
The legal status of investigational pharmaceutical products for human use varies from country to country; in some of them (e.g. Germany, the United States and others), these products are manufactured and inspected like "normal" licensed pharmaceutical products. In most other countries, however, they are not covered by legal and regulatory provisions in the areas of good manufacturing practice (GMP) inspection, etc.
However, the EC guide on GMP (1) recommends that the principles of GMP should be applied, as appropriate, to the preparation of these products, and the WHO guide on GMP, according to the statement in the general considerations, is applicable to "the preparation of clinical trials supplies" (2, page 18).
2. General considerations
The present guidelines supplement both the WHO guide on GMP and the guidelines on good clinical practice (GCP) for trials on pharmaceutical products (3). The application of the principles of GMP to the preparation of investigational products is necessary for several reasons:
• To assure consistency between and within batches of the investigational product and thus assure the reliability of clinical trials.
• To assure consistency between the investigational product and the future commercial product and therefore the relevance of the clinical trial to the efficacy and safety of the marketed product.
• To protect subjects of clinical trials from poor-quality products resulting from manufacturing errors (omission of critical steps such as sterilization, contamination and cross-contamination, mix-ups, wrong labelling, etc.), or from starting materials and components of inadequate quality.
• To document all changes in the manufacturing process.
In this context, the selection of an appropriate dosage for clinical trials is important. While it is accepted that in early trials the dosage form may be very different from the anticipated final formulation (e.g. a capsule instead of a tablet), in the pivotal Phase III studies it should be similar to the projected commercial presentation; otherwise these trials will not necessarily prove that the marketed product is both efficacious and safe.If there are significant differences between the clinical and commercial dosage forms, data should be submitted to the registration authorities to demonstrate that the final dosage form is equivalent, in terms of bioavailability and stability, to that used in the clinical trials. Final manufacturing methods must be revalidated following changes in processes, scaling-up, transfer to other manufacturing sites, etc.
This Annex specifically addresses those practices that may be different for investigational products, which are usually not manufactured in accordance with a set routine, and which may possibly be incompletely characterized during the initial stages of clinical development.
The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts.
Any systematic study on pharmaceutical products in human subjects, whether in patients or other volunteers, in order to discover or verify the effects of, and/or identify any adverse reaction to, investigational products, and/or to study the absorption, distribution, metabolism and excretion of the products with the object of ascertaining their efficacy and safety.
Clinical trials are generally divided into Phases I–IV. It is not possible to draw clear distinctions between these phases, and different opinions about details and methodology do exist. However, the individual phases, based on their purposes as related to the clinical development of pharmaceutical products, can be briefly defined as follows:
- Phase I. These are the first trials of a new active ingredient or new formulations in humans, often carried out in healthy volunteers. Their purpose
is to make a preliminary evaluation of safety, and an initial pharmacokinetic/pharmacodynamic profile of the active ingredient. Phase II. The purpose of these therapeutic pilot studies is to determine activity and to assess the short-term safety of the active ingredient in patients suffering from a disease or condition for which it is intended. The trials are performed in a limited number of subjects and are often, at a later stage, of a comparative (e.g. placebo-controlled) design. This phase is also concerned with the determination of appropriate dose ranges/regimens and (if possible) the clarification of dose-response relationships in order to provide an optimal background for the design of extensive therapeutic trials. Phase III: This phase involves trials in large (and possibly varied) patient groups for the purpose of determining the short- and long-term safety-efficacy balance of formulation(s) of the active ingredient, and assessing its overall and relative therapeutic value. The pattern and profile of any frequent adverse reactions must be investigated, and special features of the product must be explored (e.g. clinically relevant drug interactions, factors leading to differences in effect, such as age). The trials should preferably be randomized double-blind, but other designs may be acceptable, e.g. long-term safety studies. In general, the conditions under which the trials are conducted should be as close as possible to the normal conditions of use.
- Phase IV. In this phase studies are performed after the pharmaceutical product has been marketed. They are based on the product characteristics on which the marketing authorization was granted and normally take the form of post-marketing surveillance, and assessment of therapeutic value or treatment strategies. Although methods may differ, the same scientific and ethical standards should apply to Phase IV studies as are applied in premarketing studies. After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc., are normally regarded as trials of new pharmaceutical products.
Any pharmaceutical product (new product or reference product) or placebo being tested or used as a reference in a clinical trial.
The person responsible for the trial and for protecting the rights, health and welfare of the subjects in the trial. The investigator must be an appropriately qualified person legally allowed to practise medicine/dentistry.
A person appointed by, and responsible to, the sponsor for monitoring and reporting the progress of the trial and for the verification of data.
An instruction to process, package and/or ship a certain number of units of an investigational product.
For the purpose of this Annex, this term is defined in the same way as in the WHO guidelines on GCP (3), i.e. as any substance or combination of substances which has a therapeutic, prophylactic or diagnostic purpose, or is intended to modify physiological functions, and is presented in a dosage form suitable for administration to humans.
product specification file(s)
Reference file(s) containing all the information necessary to draft the detailed written instructions on processing, packaging, labelling, quality control testing, batch release, storage conditions and shipping.
A document which gives the background, rationale and objectives of the trial and describes its design, methodology and organization, including statistical considerations, and the conditions under which it is to be performed and managed. It should be dated and signed by the investigator/institution involved and the sponsor, and can, in addition, function as a contract.
The assembly, packing for shipment, and sending of ordered medicinal products for clinical trials.
An individual, company, institution or organization which takes responsibility for the initiation, management and/or financing of a clinical trial. When an investigator independently initiates and takes full responsibility for a trial, the investigator then also assumes the role of the sponsor.
4. Quality assurance
Quality assurance of pharmaceutical products has been defined and discussed in detail in the guide on GMP (2, pages 25–26).
The quality of dosage forms in Phase III clinical studies should be characterized and assured at the same level as for routinely manufactured products. The quality assurance system, designed, established and verified by the manufacturer, should be described in writing, taking into account the GMP principles to the extent that they are applicable to the operations in question. This system should also cover the interface between the manufacture and the trial site (e.g. shipment, storage, occasional additional labelling).
(For additional advice on validation, see Validation of manufacturing processes, pp. 53–71.)
Some of the production processes for investigational products that have not received marketing authorization may not be validated to the extent necessary for a routine production operation. The product specifications and manufacturing instructions may vary during development. This increased complexity in the manufacturing operations requires a highly effective quality assurance system.
For sterile products, there should be no reduction in the degree of validation of sterilizing equipment required. Validation of aseptic processes presents special problems when the batch size is small, since the number of units filled may be not adequate for a validation exercise. Filling and sealing, which is often done by hand, can compromise the maintenance of sterility. Greater attention should therefore be given to environmental monitoring.
The conclusions of any investigation carried out in response to a complaint should be discussed between the manufacturer and the sponsor (if different) or between the persons responsible for manufacture and those responsible for the relevant clinical trial in order to assess any potential impact on the trial and on the product development, to determine the cause, and to take any necessary corrective action.
Recall procedures should be understood by the sponsor, investigator and monitor in addition to the person(s) responsible for recalls, as described in the guide on GMP (2, pages 28–29).
Although it is likely that the number of staff involved will be small, people should be separately designated as responsible for production and quality control. All production operations should be carried out under the control of a clearly identified responsible person. Personnel concerned with development, involved in production and quality control, need to be instructed in the principles of GMP.
9. Premises and equipment
During the manufacture of investigational products, different products may be handled in the same premises and at the same time, and this reinforces the need to eliminate all risks of contamination, including cross-contamination. Special attention should be paid to line clearance in order to avoid mix-ups. Validated cleaning procedures should be followed to prevent cross-contamination.
For the production of the particular products referred to in section 11.20 of the guide on GMP (2, page 38), campaign working may be acceptable in place of dedicated and self-contained facilities. Because the toxicity of the materials may not be fully known, cleaning is of particular importance; account should be taken of the solubility of the product and excipients in various cleaning agents.
The consistency of production may be influenced by the quality of the starting materials. Their physical, chemical and, when appropriate, microbiological pro-perties should therefore be defined, documented in their specifications, and controlled. Existing compendial standards, when available, should be taken into consideration. Specifications for active ingredients should be as comprehensive as possible, given the current state of knowledge. Specifications for both active and non-active ingredients should be periodically reassessed.
Detailed information on the quality of active and non-active ingredients, as well as of packaging materials, should be available so as to make it possible to recognize and, as necessary, allow for any variation in production.
Chemical and biological reference standards for analytical purposes
Reference standards from reputable sources (WHO or national standards) should be used, if available; otherwise the reference substance(s) for the active ingredient(s) should be prepared, tested and released as reference material(s) by the producer of the investigational pharmaceutical product, or by the producer of the active ingredient(s) used in the manufacture of that product.
Principles applicable to reference products for clinical trials
In studies in which an investigational product is compared with a marketed product, steps should be taken to ensure the integrity and quality of the reference products (final dosage form, packaging materials, storage conditions, etc.). If significant changes are to be made in the product, data should be available (e.g. on stability, comparative dissolution) that demonstrate that these changes do not influence the original quality characteristics of the product.
Specifications (for starting materials, primary packaging materials, intermediate and bulk products and finished products), master formulae, and processing and packaging instructions may be changed frequently as a result of new experience in the development of an investigational product. Each new version should take into account the latest data and include a reference to the previous version so that traceability is ensured. Rationales for changes should be stated and recorded.
Batch processing and packaging records should be retained for at least 2 years after the termination or discontinuance of the clinical trial, or after the approval of the investigational product.
The order may request the processing and/or packaging of a certain number of units and/or their shipping. It may only be given by the sponsor to the manufacturer of an investigational product. It should be in writing (though it may be transmitted by electronic means), precise enough to avoid any ambiguity and formally authorized, and refer to the approved product specification file (see below).
Product specification file(s)
A product specification file (or files) should contain the information necessary to draft the detailed written instructions on processing, packaging, quality control testing, batch release, storage conditions and/or shipping. It should indicate who has been designated or trained as the authorized person responsible for the release of batches (see reference 2, page 18). It should be continuously updated while at the same time ensuring appropriate traceability to the previous versions.
In developing specifications, special attention should be paid to characteristics which affect the efficacy and safety of pharmaceutical products, namely:
• The accuracy of the therapeutic or unitary dose: homogeneity, content uniformity.
• The release of active ingredients from the dosage form: dissolution time, etc.
• The estimated stability, if necessary, under accelerated conditions, the preliminary storage conditions and the shelf-life of the product. (See Quality assurance of pharmaceuticals: a compendium of guidelines and related materials. Vol. 1. Geneva, World Health Organization, 1997:46–61.)
In addition, the package size should be suitable for the requirements of the trial.
Specifications may be subject to change as the development of the product progresses. Changes should, however, be made in accordance with a written procedure authorized by a responsible person and clearly recorded. Specifica-tions should be based on all available scientific data, current state-of-the-art technology, and the regulatory and pharmacopoeial requirements.
Master formulae and processing instructions
These may be changed in the light of experience, but allowance must be made for any possible repercussions on stability and, above all, on bioequivalence between batches of finished products. Changes should be made in accordance with a written procedure, authorized by a responsible person and clearly recorded.
It may sometimes not be necessary to produce master formulae and processing instructions, but for every manufacturing operation or supply there should be clear and adequate written instructions and written records. Records are particularly important for the preparation of the final version of the documents to be used in routine manufacture.
The number of units to be packaged should be specified before the start of the packaging operations. Account should be taken of the number of units necessary for carrying out quality controls and of the number of samples from each batch used in the clinical trial to be kept as a reference for further rechecking and control. A reconciliation should be carried out at the end of the packaging and labelling process.
The information presented on labels should include:• The name of the sponsor.• A statement: "for clinical research use only".
• A trial reference number.
• A batch number.
• The patient identification number.
(This is not necessarily inserted at the manufacturing facility but may be added at a later stage.)
• The storage conditions.
• The expiry date (month/year) or a retest date.
Additional information may be displayed in accordance with the order (e.g. dosing instructions, treatment period, standard warnings). When necessary for blinding purposes, the batch number may be provided separately (see also "Blinding operations" on p. 137). A copy of each type of label should be kept in the batch packaging record.
Processing and packaging batch records
Processing and packaging batch records should be kept in sufficient detail for the sequence of operations to be accurately traced. They should contain any relevant remarks which increase existing knowledge of the product, allow improvements in the manufacturing operations, and justify the procedures used.
Coding (or randomization) systems
Procedures should be established for the generation, distribution, handling and retention of any randomization code used in packaging investigational products.
A coding system should be introduced to permit the proper identification of "blinded" products. The code, together with the randomization list, must permit proper identification of the product, including any necessary traceability to the codes and batch number of the product before the blinding operation. The coding system must permit determination without delay in an emergency situation of the identity of the actual treatment product received by individual subjects.
Products intended for use in clinical trials (late Phase II and Phase III studies) should as far as possible be manufactured at a licensed facility, e.g.:
• A pilot plant, primarily designed and used for process development.
• A small-scale facility (sometimes called a "pharmacy") separate both from the company's pilot plant and from routine production.
(Note: Some manufacturers use the term "pharmacy" to designate other types of premises, e.g. areas where starting materials are dispensed and batches compounded.)
• A larger-scale production line assembled to manufacture materials in larger batches, e.g. for late Phase III trials and first commercial batches.
• The normal production line used for licensed commercial batches, and sometimes for the production of investigational pharmaceutical products if the number, e.g. of ordered ampoules, tablets or other dosage forms, is large enough.
The relation between the batch size for investigational pharmaceutical products manufactured in a pilot plant or small-scale facility to the planned full-size batches may vary widely depending on the pilot plant or "pharmacy" batch size demanded and the capacity available in full-size production.The present guidelines are applicable to licensed facilities of the first and second types. It is easier to assure compliance with GMP in facilities of the second type, since processes are kept constant in the course of production and are not normally changed for the purpose of process development. Facilities of the remaining types should be subject to all GMP rules for pharmaceutical products.
Administratively, the manufacturer has yet another possibility, namely to contract out the preparation of investigational products. Technically, however, the licensed facility will be of one of the above-mentioned types. The contract must then clearly state, inter alia, the use of the pharmaceutical product(s) in clinical trials. Close cooperation between the contracting parties is essential.
Validated procedures may not always be available during the development phase, which makes it difficult to know in advance what critical parameters and in-process controls would help to control these parameters. Provisional production parameters and in-process controls may then usually be deduced from experience with analogous products. Careful consideration by key personnel is called for in order to formulate the necessary instructions and to adapt them continuously to the experience gained in production.
For sterile investigational products, assurance of sterility should be no less than for licensed products. Cleaning procedures should be appropriately validated and designed in the light of the incomplete knowledge of the toxicity of the investigational product. Where processes such as mixing have not been validated, additional quality control testing may be necessary.
Packaging and labelling
The packaging and labelling of investigational products are likely to be more complex and more liable to errors (which are also harder to detect) when "blinded" labels are used than for licensed products. Supervisory procedures such as label reconciliation, line clearance, etc., and the independent checks by quality control staff should accordingly be intensified.
The packaging must ensure that the investigational product remains in good condition during transport and storage at intermediate destinations. Any opening of, or tampering with, the outer packaging during transport should be readily discernible.
In the preparation of "blinded" products, in-process control should include a check on the similarity in appearance and any other required characteristics of the different products being compared.
13. Quality control
As processes may not be standardized or fully validated, end-product testing is more important in ensuring that each batch meets its specification.
Product release is often carried out in two stages, before and after final packaging:
1. Bulk product assessment: this should cover all relevant factors, including production conditions, the results of in-process testing, a review of manu-facturing documentation and compliance with the product specification file and the order.
2. Finished product assessment: this should cover, in addition to the bulk product assessment, all relevant factors, including packaging conditions,
the results of in-process testing, a review of packaging documentation and compliance with the product specification file and the order.
(Note: This practice also exists at certain large companies with regard to licensed products.)When necessary, quality control should also be used to verify the similarity in appearance and other physical characteristics, odour, and taste of "blinded" investigational products.
Samples of each batch of product should be retained in the primary container used for the study or in a suitable bulk container for at least 2 years after the termination or completion of the relevant clinical trial. If the sample is not stored in the pack used for the study, stability data should be available to justify the shelf-life in the pack used.
14. Shipping, returns, and destruction
The shipping, return and destruction of unused products should be carried out in accordance with the written procedures laid down in the protocol. All unused products sent outside the manufacturing plant should, as far as possible, either be returned to the manufacturer or destroyed in accordance with clearly defined instructions.
Investigational products should be shipped in accordance with the orders given by the sponsor.A shipment is sent to an investigator only after the following two-step release procedure: (i) the release of the product after quality control ("technical green light"); and (ii) the authorization to use the product, given by the sponsor ("regulatory green light"). Both releases should be recorded.The sponsor should ensure that the shipment will be received and acknowledged by the correct addressee as stated in the protocol.
A detailed inventory of the shipments made by the manufacturer should
be maintained, and should make particular mention of the addressee's identification.
Investigational products should be returned under agreed conditions defined by the sponsor, specified in written procedures, and approved by authorized staff members.
Returned investigational products should be clearly identified and stored in a dedicated area. Inventory records of returned medicinal products should be kept. The responsibilities of the investigator and the sponsor are dealt with in greater detail in the WHO guidelines on GCP (3).
The sponsor is responsible for the destruction of unused investigational products, which should therefore not be destroyed by the manufacturer without prior authorization by the sponsor. Destruction operations should be carried out in accordance with environmental safety requirements.Destruction operations should be recorded in such a manner that all operations are documented. The records should be kept by the sponsor.
If requested to destroy products, the manufacturer should deliver a certificate of destruction or a receipt for destruction to the sponsor. These documents should permit the batches involved to be clearly identified.
1. Good manufacturing practice for medicinal products in the European Community. Brussels, Commission of the European Communities, 1992.
2. Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:14–79 (WHO Technical Report Series, No. 823).
3. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. In: The use of essential drugs. Model List of Essential Drugs (Eighth List). Sixth report of the WHO Expert Committee. Geneva, World Health Organization, 1995:97–137 (WHO Technical Report Series, No. 850).
1 Good manufacturing practices for pharmaceutical products, Part Three, section 17. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:59–72 (WHO Technical Report Series, No. 823). The original numbering has been retained.
2 Parts One and Two, Part Three, section 18, and the Introductory note, General considerations and Glossary of Good manufacturing practices for pharmaceutical products are reproduced elsewhere in this volume (see pp. 6–13, 13–45, 46–53, 75–83).
3 Good manufacturing practices for biological products. In: WHO Expert Committee on Biological Standardization. Forty-second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical Report Series, No. 822) and WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1993, Annex 3 (WHO Technical Report Series, No. 834).
4 Good manufacturing practices: supplementary guidelines for the manufacture of investigational pharmaceutical products for clinical trials in humans. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Health Organization, 1996, Annex 7 (WHO Technical Report Series, No. 863).
5 Guidelines for the assessment of herbal medicines are provided in Quality assurance of pharmaceuticals: a compendium of guidelines and related materials. Vol. 1. Geneva, World Health Organization, 1997:31–37.
6 Good manufacturing practices: supplementary guidelines for the manufacture of herbal medicinal products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Heath Organization, 1996, Annex 8 (WHO Technical Report Series, No. 863). p.134-139