Chapter 9: Quality Unit (Site) Management

Regulations define the quality unit (QU) as the concept that is consistent with modern quality systems in ensuring that the various operations associated with all systems are appropriately planned, approved, conducted, and monitored. Assigned responsibilities for the QU include ensuring that controls are implemented and completed satisfactorily during manufacturing operations and that developed procedures and specifications are appropriate and followed; approving and rejecting incoming materials, in-process materials, and drug products; and reviewing production records and investigating any unexplained discrepancies.

Responsibilities are divided between quality control (QC) and quality assurance (QA) functions. QC typically assesses suitability of components and products, evaluates the performance of the manufacturing process with respect to specifications and limits, and determines the acceptability of each batch for release. QA typically reviews and approves procedures, reviews records, and performs audits and trend analyses.

The United States Food and Drug Administration (FDA) has not moved away from the term quality control unit (QCU), which is defined in 21 CFR 210.3(b)(15) and described in 211.22. According to 21 CFR 210.3, the QCU is responsible for the duties relating to QC, whereas according to 211.22, the QCU is an independent group with unique responsibilities and authority to manage product excellence, consumer safety, compliance, and company liability. The QU encompasses nearly all manufacturing processes, including setting ingredient standards to ensure they are met, qualifying third-party testing laboratories, packaging components and labeling, calculating practical cost considerations, and ensuring finished product quality.

Qualified Person

The legal basis for the qualified person (QP) is defined in the European Directives. These Directives specify that European Union (EU) member states take all appropriate measures to ensure that the holder of the manufacturing authorization has permanently and continuously at its disposal the services of at least one QP. Additionally, member states must ensure that the QP fulfills the minimum conditions of qualification.

Qualifications for the role of QP include possession of a diploma, certificate, or other evidence of formal qualifications awarded on completion of a university course of study or a course recognized as equivalent by the member state concerned, obtained over a period of at least four years of theoretical and practical study in one of six scientific disciplines (pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology, or biology). Alternatively, the minimum duration of the university course may be 3.5 years where the course is followed by a period of theoretical and practical training for a minimum of one year, and must include a training period of at least six months in a pharmacy open to the public, corroborated by an examination at university level. The course of studies includes both theoretical and practical usage in a number of subjects, including applied physics, general and inorganic chemistry, organic chemistry, analytical chemistry, pharmaceutical chemistry, including analysis of medicinal products, general and applied biochemistry (medical), physiology, microbiology, pharmacology, pharmaceutical technology, toxicology, and pharmacognosy (study of the composition and effects of natural active substances of plant and animal origin).

In addition to the formal training, a QP must have acquired practical experience over at least two years, in one or more facilities that are authorized to manufacture medicinal products, in the activities of qualitative analysis of medicinal products, of quantitative analysis of active substances, and of the testing and checking necessary to ensure the quality of medicinal products. The duration of practical experience may be reduced by one year when a university course lasts for at least five years and by 1.5 years when the course lasts for at least six years.

Responsibilities of the Qualified Person

The QP has several important responsibilities. In the case of medicinal products, the QP must ensure that each batch of medicinal products has been manufactured and checked in compliance with the laws in force in the member state and in accordance with the requirements of the marketing authorization; and in the case of medicinal products coming from third countries, the QP must ensure that each production batch has undergone in the importing member state a full qualitative analysis, a quantitative analysis of at least all the active constituents, and all the other tests or checks necessary to ensure the quality of medicinal products in accordance with the requirements of the marketing authorization. The batches of medicinal products that have undergone such controls in a member state are exempt from the controls if they are marketed in another member state and are accompanied by the control reports signed by the QP. In the case of medicinal products imported from a third country, where appropriate arrangements have been made by the European Community (EC) with the exporting country, the QP must ensure that the manufacturer of the medicinal product applied standards of good manufacturing practices (GMP) at least equivalent to those of the EC, and must ensure that the controls have been carried out in the exporting country. The QP may be relieved of responsibility for carrying out those controls. In all cases, and particularly where the medicinal products are released for sale, the QP must certify in a register or equivalent document provided for that purpose that each production batch satisfies the provisions of the regulations, and that the register or equivalent document is kept current as operations are completed and remains at the disposal of the agents of the competent authority for the period specified in the provisions of the member state concerned, and in any event for at least five years.

Specific Requirements for the Qualified Person

Qualification of Suppliers of Active Pharmaceutical Ingredients. EU Directives require that active pharmaceutical ingredients (APIs) used for the manufacture of medicinal products have been manufactured according to the GMP for starting materials. The ICH Q7A Guide Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients has been transferred to Part II of the EU Guide to GMP. It is expected that these standards are implemented in API manufacturing.

The QP responsible for the final production batch must be satisfied that the provisions of the Directive(s) are met and that a systematic system of supplier qualification is in place to give the assurance that only GMP-compliant API will be used for the manufacture of medicinal products.

Contract Manufacture and Analysis. Chapter 7, “Contract Manufacture and Analysis,” of Part 1 of the EU Guide to GMP states that the contract manufacture and analysis must be correctly defined, agreed on, and controlled to avoid misunderstandings that could result in a product or work of unsatisfactory quality. To realize this objective, the QP needs to have the assurance that a written contract is in place that clearly defines the duties of each party, and that the contract contains the requirements. Any proposed changes in technical or other arrangements should be in accordance with the marketing authorization for the product concerned. The QP must ensure that a system to assess the competence of the contract acceptor to fulfill the principles of GMP is in place, and the contract acceptor must be aware of any problems associated with the product or the work that might pose a hazard to the premises, equipment, personnel, other materials, or other products. All processed products and materials delivered by the contract acceptor comply with their specification or have been released by the responsible quality unit.

Manufacture of Investigational Medicinal Products. Annex 13 of the GMP guide Manufacture of Investigational Products defines in detail the requirements in the manufacture and testing of investigational medical products (IMP), as well as ordering, shipping, and returning clinical supplies. In the case of IMPs, the QP is specifically responsible for ensuring that systems are in place that meet the requirements of Annex 13. The QP must, therefore, have a broad knowledge of pharmaceutical development and clinical trial processes. The QP is charged with making sure that release of IMPs does not occur until after the QP has certified that relevant requirements have been met.

Shipping. Investigational medicinal products should remain under the control of the sponsor until completion of a two-step release procedure: certification by the QP and release after fulfillment of the requirements of Article 9 (“Commencement of a Clinical Trial”) of Directive 2001/20/EC. The sponsor should ensure that these are consistent with the details actually considered by the QP. Both releases should be recorded and retained in the relevant trial files held by or on behalf of the sponsor. Transfers of IMPs from one trial site to another should be an exception to the process. Such transfers should be covered by standard operating procedures (SOPs). The product history while outside of the control of the manufacturer, through trial monitoring reports and records of storage conditions at the original trial site, should be reviewed as part of the assessment of the product’s suitability for transfer, and the advice of the QP should be sought. The product should be returned to the manufacturer or another authorized manufacturer for relabeling, if necessary, and certification by a QP. Records should be retained and full traceability ensured.

Complaints. The conclusions of any investigation carried out in relation to a complaint that could arise from the quality of the product should be discussed between the manufacturer or importer and the sponsor (if different). This discussion should involve the QP and those personnel responsible for the relevant clinical trial to assess any potential impact on the trial, product development, or subjects.

Certification of Batch Release

The certification of batch release is defined in Annex 16 of the EU Guide to GMP. In addition, European Medicines Agency (EMA) published a paper on a proposed solution for dealing with minor deviations from the detail described in Marketing Authorization for Human and Veterinary Medicinal Products (including biological products).

Maintenance of a Quality Management System

Chapter 1 of the EU Guide to GMP requires that a comprehensively designed and correctly implemented system of QA incorporating GMP, and thus QC, is in place. It should be fully documented and its effectiveness monitored. The key requirement for the QP (specific to Chapter 1) is to ensure that medicinal products are not sold or supplied before a QP has certified that the batch has been produced and tested in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control, and release of medicinal products. To realize this objective, a QP should be involved in the implementation and maintenance of the quality management system (QMS).

The Qualified Person and the Product Quality Review

The requirement of a product quality review (PQR) was introduced with the addition of article 1.5 in Chapter 1 (“Quality Management”) of the EU Guide to GMP. The aim of this requirement is to verify the consistency and appropriateness of the existing process, the adequacy of current specifications for starting material and finished product, and the presence of product and process improvements.

The PQR should be conducted and documented annually and should cover all aspects of the supply chain: starting materials, the process, process environment, and the final product. The manufacturer and marketing authorization holder, where different, should evaluate the results of this review, and an assessment should be made as to whether corrective and preventive action or any revalidation should be undertaken.

The QP responsible for final batch certification, together with the marketing authorization holder, should ensure that the quality review is performed in a timely manner and is accurate. It is necessary to understand the aim and basic principles of the PQR to assume responsibility. The generation of the PQR can be done by any of the functions, but QA, in association with the QP, should lead the way to interpret data and define and follow up any consequences.

The Qualified Person and Reference and Retention Samples

The requirements on the taking and holding of reference samples of starting materials, packaging materials, or finished products, and retention samples of finished products, are defined and included in the EU GMP as Annex 19 to the EU Guide to GMP Part 1. Reference samples are samples of starting materials or finished products intended to be reanalyzed in case of any complaint, dispute, or discrepancy; retention samples are samples of a fully packaged unit from a batch of finished product stored for identification purposes.

According to the different purposes, the amounts to be stored are different: reference samples are usually in a sample size sufficient to allow at least two full analytical controls on the batch (with some dispute still ongoing whether this would include sterility testing if appropriate), and retention samples are usually only one package per packaging presentation.

Reference and retention samples from finished products must be retained for at least one year after the expiry date. If no longer period is required under national law, samples of starting materials (other than solvents, gases, or water used in the manufacturing process) must be retained for at least two years after the release of the product. Storage conditions must be in accordance with the conditions submitted in the marketing authorization. In case a product has been manufactured (partially) outside the EU, reference samples must be stored in the EU, unless there is an operational mutual recognition agreement (MRA) in place.

External Qualified Persons

Some companies may use an external QP who provides an independent service. The duties and responsibilities do not differ from the ones that are applicable to QPs that are full-time employees of a company. To fulfill the tasks, it is required to have a detailed contract to ensure that all duties and responsibilities are met.

Delegation of Tasks/Absence of a Qualified Person

In general, the task of a QP, especially the process of batch certification and release, can only be delegated to another QP who is registered with the responsible authority for supervision of the marketing authorization and/or supervision.

Organizational Duties to Be Established by the Company of the Qualified Person

To perform their duties and responsibilities, a QP needs support from the company and its senior management. Three organizational tasks should be implemented:

• Senior management should be actively involved in the imple-mentation, maintenance, and further development of the QMS.

• A clear job description should be in place to define the responsibilities of the QP and their relationship to other departments, responsible managers, and especially to the head of production and the head of QC, and, if appropriate, the head of QA.

• The QP should at all times have access to the marketing authorization dossier and should be informed about all changes related to the dossier.

Annex 16 to the EU Guide to GMP Certification and Batch Release

Annex 16 covers those cases where a batch has had different stages of production or testing conducted at different locations or by different manufacturers, and where an intermediate or bulk production batch is divided into more than one finished product batch. It also covers the release of batches that have been imported both when there is and is not an MRA between the EC and the third country.

Principle

Each batch of finished product must be certified by a QP before being released for sale or supply or for export. The purpose of controlling batch release in this way is to ensure that the batch has been manufactured and checked in accordance with the requirements of its marketing authorization, the principles and guidelines of EC GMP or the GMP of a third country recognized as equivalent under an MRA, and any other relevant legal requirement before it is placed on the market. In the event that a defect needs to be investigated or a batch recalled, this process ensures that the QP who certified the batch and the relevant records are readily identifiable.

Introduction

Manufacture, including QC testing, of a batch of medicinal products takes place in stages that may be conducted at different sites and by different manufacturers. Each stage should be conducted in accordance with the relevant marketing authorization, GMP, and the laws of the member state concerned, which should be taken into account by the QP who certifies the finished product batch before release to the market.

In an industrial situation, however, it is usually not possible for a single QP to be closely involved with every stage of manufacture. The QP who certifies a finished product batch may need therefore to rely in part on the advice and decisions of others. Before doing so, the QP should ensure that this reliance is well founded, either from personal knowledge or from the confirmation by other QPs within a quality system.

When some stages of manufacture occur in a third country, it is still a requirement that production and testing are in accordance with the marketing authorization, that the manufacturer is authorized according to the laws of the country concerned, and that manufacture follows GMP of the EC.

General

One batch of finished product may have different stages of manufacture, importation, testing, and storage before release conducted at different sites. Each site should be approved under one or more manufacturing authorizations and should have at its disposal the services of at least one QP. The correct manufacture of a particular batch of product, regardless of how many sites are involved, should be the overall concern of the QP who certifies that finished product batch before release.

Different batches of a product may be manufactured or imported and released at different sites in the EC/European Economic Area (EEA). For example, an EC marketing authorization may name batch release sites in more than one member state, and a national authorization may also name more than one release site. In this situation, the holder of the marketing authorization and each site authorized to release batches of the product should be able to identify the site at which any particular batch has been released and the QP who was responsible for certifying that batch.

The QP who certifies a finished product batch before release may do so based on personal knowledge of all the facilities and procedures employed, the expertise of the persons concerned, and of the quality system within which they operate. Alternatively, the QP may rely on the confirmation by one or more other QPs of the compliance of intermediate stages of manufacture within a quality system. This confirmation by other QPs should be documented and should identify clearly the matters that have been confirmed. The systematic arrangements to achieve this should be defined in a written agreement.

This agreement is required whenever a QP wishes to rely on a confirmation by another QP. The agreement should be in general accordance with Chapter 7. The QP who certifies the finished product batch should ensure that the arrangements in the agreement are verified. The form of such an agreement should be appropriate to the relationship between the parties, for example, an SOP within a company or a formal contract between different companies, even if within the same group.

The agreement should include an obligation on the part of the provider of a bulk or intermediate product to notify the recipient(s) of any deviations, out-of-specification (OOS) results, noncompliance with GMP, investigations, complaints, or other matters that should be taken into account by the QP who is responsible for certifying the finished product batch.

When a computerized system is used for recording certification and batch release, particular note should be taken of the guidance in Annex 11. Certification of a finished product batch against a relevant marketing authorization by a QP in the EC/EEA need not be repeated on the same batch provided the batch has remained within the EC/EEA.

Whatever particular arrangements are made for certification and release of batches, it should always be possible to identify and recall without delay all products that could be rendered hazardous by a quality defect in a batch.

Batch Testing and Release of Products Manufactured in the EC/EEA

All Manufacture Occurs at a Single Authorized Site. When all production and control stages are carried out at a single site, the conduct of certain checks and controls may be delegated to others, but the QP at this site who certifies the finished product batch normally retains personal responsibility for these within a defined quality system. However, he or she may, alternatively, take account of the confirmation of the intermediate stages by other QPs on the site that is responsible for those stages.

Different Stages of Manufacture Are Conducted at Different Sites within the Same Company. When different stages of the manufacture of a batch are done at different sites within the same company (which may or may not be covered by the same manufacturing authorization), a QP should be responsible for each stage. Certification of the finished product batch should be performed by a QP of the manufacturing authorization holder responsible for releasing the batch to the market, who may take personal responsibility for all stages or may take account of the confirmation of the earlier stages by the relevant QP responsible for those stages.

Some Intermediate Stages of Manufacture Are Contracted to a Different Company. One or more intermediate production and control stages may be contracted to a holder of a manufacturing authorization in another company. A QP of the contract giver may take account of the confirmation of the relevant stage by a QP of the contract acceptor but is responsible for ensuring that this work is conducted within the terms of a written agreement. The finished product batch should be certified by the QP of the manufacturing authorization holder responsible for releasing the batch to the market.

Bulk Production Batch Is Assembled at Different Sites into Several Finished Batches Released under Single Marketing Authorization. This situation could occur, for example, under a national marketing authorization when the assembly sites are all within one member state, or under an EC marketing authorization when the sites are in more than one member state. One alternative is for a QP of the manufacturing authorization holder making the bulk production batch to certify all the finished product batches before release to the market. In doing so, he or she may either take personal responsibility for all manufacturing stages or take account of the confirmation of assembly by the QPs of the assembly sites. Another alternative is for the certification of each finished product batch before release to the market to be performed by a QP of the manufacturer who has conducted the final assembly operation. In doing so, he or she may either take personal responsibility for all manufacturing stages or take account of the confirmation of the bulk production batch by a QP of the manufacturer of the bulk batch.

In all cases of assembly at different sites under a single marketing authorization, one person, normally a QP of the manufacturer of the bulk production batch, should have overall responsibility for all released finished product batches that are derived from one bulk production batch. The duty of this person is to be aware of any quality problems reported on any of the finished product batches and to coordinate any necessary action arising from a problem with the bulk batch. While the batch numbers of the bulk and finished product batches are not necessarily the same, there should be a documented link between the two numbers so that an audit trail can be established.

Bulk Production Batch Is Assembled at Different Sites into Several Finished Batches Released under Different Marketing Authorizations. This situation could occur, for example, when a multinational organization holds national marketing authorizations for a product in several member states or when a generic manufacturer purchases bulk products and assembles and releases them for sale under its own marketing authorization. A QP of the manufacturer doing the assembly who certifies the finished product batch may either take personal responsibility for all manufacturing stages or may take account of the confirmation of the bulk production batch by a QP of the bulk product manufacturer. Any problem identified in any of the finished product batches that may have arisen in the bulk production batch should be communicated to the QP responsible for confirming the bulk production batch, who should then take any necessary action with respect to all finished product batches produced from the suspected bulk production batch. This arrangement should be defined in a written agreement.

A finished product batch may be purchased and released to the market by a manufacturing authorization holder, which could occur, for example, when a company supplying generic products holds a marketing authorization for products made by another company, purchases finished products that have not been certified against its marketing authorization, and releases them under its own manufacturing authorization in accordance with its own marketing authorization. In this situation, a QP of the purchaser should certify the finished product batch before release. In doing so he or she may either take personal responsibility for all manufacturing stages or may take account of the confirmation of the batch by a QP of the vendor manufacturer.

Quality Control Laboratory and Production Site Are Authorized under Different Manufacturing Authorizations. A QP certifying a finished product batch may either take personal responsibility for the laboratory testing or may take account of the confirmation by another QP of the testing and results. The other laboratory and QP need not be in the same member state as the manufacturing authorization holder releasing the batch. In the absence of such confirmation, the QP should have personal knowledge of the laboratory and its procedures relevant to the finished product to be certified.

Batch Testing and Release of Products Imported from a Third Country

General

Importation of finished products should be conducted by an importer. Each batch of imported finished product should be certified by a QP of the importer before release for sale in the EC/EEA. Unless an MRA is in operation between the EC and the third country, samples from each batch should be tested in the EC/EEA before certification of the finished product batch by a QP. Importation and testing need not necessarily be performed in the same member state. The guidance in this section should be applied as appropriate to the importation of partially manufactured products:

• A complete batch or the first part of a batch of a medicinal product is imported. The batch or part batch should be certified by a QP of the importer before release. This QP may take account of the confirmation of the checking, sampling, or testing of the imported batch by a QP of another manufacturing authorization holder (that is, within EC/EEA).

• Part of a finished product batch is imported after another part of the same batch has previously been imported to the same or a different site. A QP of the importer receiving a subsequent part of the batch may take account of the testing and certification by a QP of the first part of the batch. If this is done, the QP should ensure, based on evidence, that the two parts do come from the same batch, that the subsequent part has been transported under the same conditions as the first part, and that the samples that were tested are representative of the whole batch. The conditions are most likely to be met when the manufacturer in the third country and the importer(s) in the EC/EEA belong to the same organization operating under a corporate system of quality assurance. If the QP can not ensure that the conditions are met, each part of the batch should be treated as a separate batch. When different parts of the batch are released under the same marketing authorization, one person, normally a QP of the importer of the first part of a batch, should take overall responsibility for ensuring that records are kept of the importation of all parts of the batch and that the distribution of all parts of the batch is traceable within the EC/EEA. The QP should be made aware of any quality problems reported on any part of the batch and should coordinate any necessary action concerning these problems and their resolution. This should be ensured by a written agreement between all the importers concerned.

Location of Sampling for Testing in EC/EEA

Samples should be representative of the batch and be tested in the EC/EEA. To represent the batch, it may be preferable to take some samples during processing in the third country. For example, samples for sterility testing may best be taken throughout the filling operation; however, to represent the batch after storage and transportation, some samples should be taken after receipt of the batch in the EC/EEA.

When any samples are taken in a third country, they should either be shipped with and under the same conditions as the batch that they represent, or if sent separately, it should be demonstrated that the samples are still representative of the batch, for example, by defining and monitoring the conditions of storage and shipment. When the QP wishes to rely on testing of samples taken in a third country, this should be justified on technical grounds.

Batch Testing and Release of Products Imported from a Third Country with EC MRA

Unless otherwise specified in the agreement, an MRA does not remove the requirement for a QP within the EC/EEA to certify a batch before it is released for sale or supply within the EC/EEA. However, subject to details of the particular agreement, the QP of the importer may rely on the manufacturer’s confirmation that the batch has been made and tested in accordance with its marketing authorization and the GMP of the third country and need not repeat the full testing. The QP may certify the batch for release when he or she is satisfied with this confirmation and that the batch has been transported under the required conditions and has been received and stored in the EC/EEA by an importer under defined conditions.

Routine Duties of a Qualified Person

Before certifying a batch for release, the QP doing so should ensure that at least the following requirements have been met:

• The batch and its manufacture comply with the provisions of the marketing authorization (including the authorization required for importation, where relevant).

• Manufacture has been done in accordance with GMP or, in the case of a batch imported from a third country, in accordance with GMP standards at least equivalent to EC GMP.

• The principal manufacturing and testing processes have been validated, and account has been taken of the actual production conditions and manufacturing records.

• Any deviations or planned changes in production or QC have been authorized by the persons responsible in accordance with a defined system. Any changes requiring variation to the marketing or manufacturing authorization have been reported to and authorized by the relevant authority.

• All the necessary checks and tests have been performed, including any additional sampling, inspection, tests, or checks initiated because of deviations or planned changes.

• All necessary production and QC documentation has been completed and endorsed by the staff authorized to do so.

• All audits have been carried out as required by the QA system.

• The QP should in addition take into account any other factors of which he or she is aware that are relevant to the quality of the batch.

A QP may have additional duties in accordance with national legislation or administrative procedures. A QP who confirms the compliance of an intermediate stage of manufacture has the same obligations in relation to that stage as there would be with final release. A QP should maintain his or her knowledge and experience up to date in the light of technical and scientific progress and changes in quality management relevant to the products that he or she is required to certify.

If a QP is called on to certify a batch of a product type with which they are unfamiliar, for example, because the manufacturer for whom they work introduces a new product range or because they start to work for a different manufacturer, they should first ensure that they have gained the relevant knowledge and experience necessary to fulfill this duty. In accordance with national requirements, the QP may be required to notify the authorities of such a change and may be subject to renewed authorization.