Managing Contract Manufacturers and Testing Labs

Managing Contract Manufacturers and Testing Labs

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Table of ContentsIntroduction

The Selection Process ............................................................................................................................3

Relations Between Drugmaker and Contractor .....................................................................................7

Duties of the Contractor .........................................................................................................................9

Contract Manufacturer Agreement ......................................................................................................13

Audits of Contract Manufacturers .......................................................................................................16

SOP for Assigning Manufacturing Contracts ......................................................................................24

Framework Contract for Contract Manufacture and Quality Control .................................................29

Outsourcing Analysis and Testing .......................................................................................................40

Appendices ...........................................................................................................................................55

A. Eudralex Chapter 7 — Outsourced Activities

B. EU GMP Guide, Annex 16 – Certification by a Qualified Person and Batch Release

IntroductionToday, many drugmakers simply cannot escape the external assignment of manufacturing and testing

activities, despite the problems doing so may entail.

One of the problems they face lies in knowing when and to whom to “shop out” jobs. Unfortunately, in such an increasingly complex and diverse industry, no single entity can do it all. And even when drugmakers find a partner, how can they control those activities that will now occur beyond their gates, much less ensure a contractor will abide by the same standards they have set?

Regulatory bodies in both the U.S. and the European Union acknowledge the growing use of con-tractors. Annex 16 of the EU’s GMP guideline states: “Manufacture, including quality control testing, of a batch of medicinal products takes place in stages which may be conducted at different sites and by different manufacturers.”

EU regulations set forth a clear description of the various activities that may be contracted to another facility. Meanwhile, the FDA provides less specific contracting guidance for drugmakers. Even so, FDA regulations make it clear that, no matter what the contracting arrangement, the manufacturer that con-tracts out work still retains responsibility for the final product.

In both the U.S. and the EU, manufacturers must ensure their contractors follow the same good manufacturing practices (GMP) they themselves must use.

Despite the regulatory burden, drugmakers know there are many good reasons to outsource. They may not have the time, resources or expertise to perform a particular task. They may be constrained by legal requirements. Or the cost of producing small numbers of necessary ingredients may be prohibitive.


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The Selection ProcessOnce a drugmaker decides to go out of house, it must consider several issues before settling on the

best contractor for the job.

Initial Decisions

The drugmaker should start by selecting a pool of candidates that specialize in the task at hand. A contract client might use two ways to identify potential contractors: reliance on a history of collaborative efforts and on recommendations from other firms.

Next, the drugmaker must consider whether to select only one contractor or pick a second candi-date to hold in reserve in case problems arise with its first choice. For example, a long-term equipment malfunction could hold up production at the original contractor longer than the drugmaker can afford to wait, forcing it to move to a back-up contractor. Another potential problem could arise if a first choice contractor cannot handle an unanticipated market or supply problem; a reserve contractor could help make up the difference and keep the work moving forward. Furthermore, contractors sometimes encoun-ter regulatory problems with the FDA, EMA and other agencies that can halt their operations. In such cases, it’s good to have a “Plan B” already in place.

Handover of confidential documents

Drugmakers must hand over the relevant documents to a contract manufacturer before reaching a conclusion on the feasibility of manufacturing and calculating a quote. These documents might include extracts from the application file (NDA, ANDA, dossier for marketing authorization), as well as extracts from the manufacturing and analysis documents relating to the preparation. At this stage in the collaboration, the drugmaker should require a potential contractor to sign a confiden-tiality agreement that bars it from passing on extracts of confidential documents to a third party without permission.

Feasibility check

After allowing candidate contractors to examine the mandatory documents, the drugmaker then must assess the ability of each candidate to perform the work described. Questions to ask include:

• Can the contractor complete the work by the desired delivery date?

• Can the contractor provide the required technology on the premises?

• Does the contractor have sufficient experience in performing the work?

• Should the contractor manufacture a development batch (smallest scale, in the range of three to five kilograms) or a pilot batch (scale of the future production batch)?

• Does the contractor have all the required product-specific material and capabilities (e.g., raw materials, packaging, manufacturing and testing equipment)?

Once the drugmaker has answered these questions, it then can decide which candidates to ask for a job quote and schedule.


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Audits

Before a drugmaker makes its final selection, it should audit the contract manufacturer’s prem-ises. This will ensure that the responsible persons, from the sides of both the client and the contrac-tor, become acquainted at an early stage. It allows the client to form an impression of the contractor’s GMP-compliant processes and systems, as well as of its quality-assurance activities. Auditors should document all observations in an audit report. The results of the audit, along with contractor approval, if applicable, form the conclusion to the report.

The report, beyond general information about the company’s structure, should also contain notes about any observed deficiencies.

Approval of the contract manufacturer

The audit generally forms the basis for the drugmaker’s candidate selection. The drugmaker should compile a formal approval document for presentation to its in-house quality assurance department and, if necessary, to the relevant regulatory authorities.

In the U.S., it’s important to note that the FDA generally will not ask to see actual audit reports. The agency usually will accept documentation that shows audits occurred and follow-up actions performed. However, under certain circumstances, the FDA may ask for copies of audit reports, especially when significant legal concerns exist. In such cases, the drugmaker should consult its legal counsel to deter-mine its response to the request.

Scope of the contract assigned

Once a drugmaker has selected and formally approved a contractor, a significant step remains before it may draft a contract. First, it must define in detail all activities and responsibilities that each party must carry out. Issues to address include:

• Manufacture of development or pilot batches;

• Procurement of primary and secondary packaging materials;

• Procurement of raw materials, excipients and active pharmaceutical ingredients;

• Approval of the starting materials;

• Transfer of analytical methods;

• Manufacturing of validation batches;

• Determination of the manufacturing technology;

• Determination of the packaging technology;

• Determination of sampling during validation and routine manufacture;

• Physical and analytical testing scope;

• Release of intermediate products and final products; and

• Storage and delivery of the finished product.


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Both parties must understand that defining these issues does not simply entail a two-party agreement; the law requires it. Regulatory or other responsible supervisory authorities routinely check on it during the course of GMP inspections.

Development and pilot batches

A fundamental component of the drugmaker-contractor agreement involves determining whether, as part of the product transfer, provision should be made for the manufacture of development batches.

This discussion should address the following issues:

• Does product transfer require any changes in manufacturing technology? If the feasibility study already assessed and determined the need for changes, the contractor should communicate this to the drugmaker. If the contractor deems that the manufacture of the medicinal product or API does not comply with the manufacturing steps and technologies described in the drugmaker’s marketing authorization application, the drugmaker may end up spending more money and time to correct the situation. Is it necessary to change the batch size?

• Does the drugmaker already have experience in setting parameters for the facilities/machines?

• What are the critical processing steps (after risk analysis)?

• Are stability data and follow-up results already available?

• Do investigations for cleaning validation need to be carried out?

As a result of this risk analysis, both drugmaker and contractor must define whether the manufacture of one or more development or pilot batches is necessary. If, in a product transfer, they dispense with the manufacturing of development or pilot batches, there remains a sizeable risk that the first manufacture of the preparation will not occur in an optimum manner. Since officials normally treat the first three batches as validation batches, therein lurks a risk that the validation will not comply with legal requirements.

It is understandable that smaller companies in particular may prefer to dispense with the devel-opment and pilot batches. Rather than represent a lack of understanding of GMP, it likely reflects a financial problem. It may be that, for test purposes, a contractor requires starting materials for a com-plete batch. Those materials cannot then be turned into products for sale, as they do not correspond to requirements. In such a case, it would behoove the contractor, given its experience with numerous ac-tive pharmaceutical ingredients and excipients, to advise its client about this specific issue and deliver a realistic evaluation.

Validation

Carrying out the validation work lays the foundation for meaningful product transfer. For a pro-spective or concurrent validation, three batches generally must be planned, manufactured, packaged, analyzed and evaluated. The contractor evaluates the results and then communicates any facility- or machine-setting changes, or otherwise makes suggestions for further optimization of manufacture and analysis, all in accordance with the client’s specifications. Only the holder of the marketing authoriza-tion or the pharmaceutical entrepreneur can make the decision whether to actually release the recom-mendation for implementation. If the scope of the validation work was inadequately defined during the design phase, then considerable delays can result.


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Implementation of the validation results

The contractor usually evaluates the validation results. Since the contractor does not hold the mar-keting authorization, it cannot be responsible for the implementation of the validation results. Rather, it should share its findings and recommendations with the drugmaker. The drugmaker then must check its marketing authorization to determine whether, from a regulatory point of view, the contractor may implement those recommendations without further ado (e.g., notification of changes to the regulatory authorities). The contractor can only adopt the recommendations into its change-control program once it receives the client’s written authorization.

Approval of the manufacturing instructions

The contractor must then include any drugmaker-approved changes in a new manufacturing instruc-tion. A version number or new edition date should make it apparent which version applies to both parties at all times. The contractor also should insist that the responsible persons, both in-house and on the drug-maker’s side, sign and date as approved the valid master copy of the manufacturing instructions. These signed documents generally appears as an appendix to the contract.

Change control

If the results of the validation go on to form part of the manufacturing instructions, and both parties approve those instructions, then the contractor must next put in place a working change-control system. This involves communicating changes and deviations from the approved manufacturing and packaging instructions, as well as from the testing procedure, to the drugmaker immediately. The contractor must ensure that no changes can be made without the verifiable written agreement of the holder of the market-ing authorization, as the contract manufacturer cannot usually assess whether the changes require har-monization with the marketing authorization application file.


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Relation between Drugmaker and ContractorIt is in the nature of things that when a drugmaker assigns a contract, a portion of the information

about the manufacture of the preparation in question moves beyond its immediate reach. Therefore, drugmaker and contractor alike must enjoy a considerable level of trust. To help build this trust, one effective approach involves establishing at an early stage close and permanent contact with the contract manufacturer. To build trust, both parties should share know-how and a general culture of communica-tion, along with a readiness to provide information, an understanding of audits and absolute transparency regarding errors. Practice and day-to-day business eventually should reveal how the collaboration actu-ally works.

Many drugmakers hold marketing authorizations for several preparations with differing dosage forms. This often means selecting a number of different contract manufacturers with different core busi-nesses (e.g., specialization in particular APIs, dosage forms and manufacturing technologies).

Factors such as delivery date and quotation price still play a large part in the selection of a contract manufacturer. Drugmakers should also consider how the two parties work together during day-to-day busi-ness, particularly if problems arise during manufacture. How does the contractor handle problems? How quickly does it provide information? What solutions does it suggest? Drugmakers should get to know the relevant responsible person at an early stage to gain a first impression about the contract company’s level of understanding of basic pharmaceutical matters and a rough view of the production processes.

Responsibilities of the client

Drugmakers often share the opinion that collaborating with one contract manufacturer suffices. In contrast, other drugmakers favor assigning a particular preparation to several contract manufacturers. In that manner, should any problems with delivery reliability or quality arise, the drugmaker can switch production quickly to an alternative contractor. In principle, of course, a client likely would find it easier to communicate with a smaller stable of contractors. Drugmakers also should bear in mind the consider-able investment required in qualifying additional or alternative contractors. They must both select and audit the best candidate. Even then, if the drugmaker commissions the alternative contractor to carry out production, in addition to defining all responsibilities in a contract, the contractor also must manufacture three validation batches.

A well-functioning business relationship generally does not require the appointment of an alterna-tive contractor. Experience shows that a good partner contractor generally communicates only what is absolutely necessary. That means the drugmaker places an order for a defined quantity and by a defined deadline, and that the contractors delivers the goods in qualitatively faultless condition on the agreed delivery date and at the agreed price.

Definition of the requirements of the task

The drugmaker’s individual in-house departments set different priorities. So, a commercial- and planning-oriented department, responsible for purchasing and the assignment of contracts and com-pliance with delivery dates, would make its assessments based primarily on price and delivery reli-ability. In contrast, a department dealing with the assessment of contractors, specifically with audits and approval, would make an assessment based on GMP principles and according to an appreciation


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of quality-management issues. Thus, the drugmaker must define the requirements of the task. The contractor agreement has shown itself to be a beneficial tool for this type of definition. Therefore, the drugmaker and contractor together should agree, in the form of a contract, to all requirements and ar-rangements before the start of production.

Handover of the necessary documents to the contractor

The drugmaker must hand over to the contractor all documents relevant to the transfer of a drug product. On the one hand, the drugmaker in doing so hands over a large part of its know-how about a preparation. On the other hand, the contractor absolutely must receive this information, along with results from the documents, in order to assess its in-house manufacture, packaging and analysis. The documents include primarily the following:

• Sections of the application file for marketing authorization The contractor needs in partic-ular the sections defining the details of the manufacturing, packaging and analytical procedure, with accompanying instructions and specifications. The drugmaker often sees these as the only documents that enable the contractor to compile manufacturing instructions.

• Manufacturing instructions and batch production records If the drugmaker has already manufactured a preparation in-house, it should hand over the relevant manufacturing instruc-tions to the contractor. These manufacturing instructions contain both a detailed description of the manufacturing procedure and the setting parameters for the facilities and machines used. It is certainly helpful if the drugmaker hands over the batch production records or at least allows them to be accessed. All deviations from specifications and manufacturing-area staff notes should be apparent.

• Test procedures and test protocols As with the manufacturing instructions and records, the documents available to the drugmaker that address analysis remain in need, all in order to ap-propriately transfer the analysis of a preparation to a contractor.

• Validation documents If the drugmaker already has validation documents in-house, it is es-sential that it hand them over to the contractor. From these, the contractor can see, for example, an assessment of the limits and setting specifications as determined previously for the facilities and machines. In addition, the drugmaker will have already determined and defined the critical processing steps. Using the previously determined results, the contractor therefore can compile the risk analysis and the validation protocol much more quickly.

Approval of manufacturing instructions

A working change management system starts with the drugmaker’s approval of the manufacturing instructions. This ensures that the drugmaker receives notification of all changes and deviations at an early stage. In addition, it guarantees that the contractor always carries out production in accordance with valid manufacturing instructions approved by the drugmaker. The contractor must communicate all changes to the client; the changes then must be documented in a new version of the manufacturing instructions.


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Duties of the ContractorThe primary duty of the contractor involves supplying the quality and quantity desired by the client

as cheaply as possible and by the agreed deadline. To satisfy these requirements, the parties must take specific measures and strike certain agreements.

Basically, a contractor’s core competency will cover a particular market segment in contract manu-facturing. A contract manufacturer may have specialized in API, manufacturing particular dosage forms or in offering several dosage forms in parallel. The market remains very diverse regarding service scope. Hence, full-service contract manufacturers vary a great deal, especially with regard to development, spe-cific technologies or even competencies in the laboratory and microbiology areas. Still, certain obliga-tions apply to all contractors.

Flexibility

A contractor must maintain an adequate supply of resources, including personnel and rooms, beyond capacity, equipment and machines. A contractor with available capacity has the advantage of being able to offer more flexibility and shorter delivery times. In contrast, a contractor with a high degree of capac-ity utilization finds itself in a more problematic position. On the one hand, a contractor’s planning and business goal remains having high capacity utilization of its personnel and facilities. On the other hand, the contractor faces the risk of leaving its customers unsatisfied due to the potential of long delivery times. There remains a risk that a client could reject such a contract manufacturer when at the transfer stage of a preparation. Developments in the market, however, mean that the contract manufacturer must act differently. Contracts that used to be awarded in good time and with long delivery times for a large number of items, preferably as campaigns, no longer crop up frequently in this form. To satisfy market demand, flexibility joins quality and price as another key requirement.

Full-service

Full-service consists of a form of service that includes procurement of the starting materials (ex-cipients and APIs) and packaging material (primary and secondary packaging material); analysis of the procured materials upon receipt; and provision of the finished product, as well as storage and delivery of that product to the customer. The drugmaker and contractor should contractually define and agree to the detailed scope of a contract assigned.

These days, when a contractor provides comprehensive and full service, the process begins with qualified consultation by drugmaker relating to its product or preparation and/or special problems.

Procurement and testing of starting materials

When a drugmaker assigns preparations to the contractor, it must clarify the basic responsibility for the procurement part. Two scenarios are possible:

Option 1

One option would require the drugmaker to purchase the starting materials directly. The drugmaker investigates the starting materials on its premises and issues the approval by means of a label and certifi-cate of analysis. In this case, the drug marketer retains responsibility for supplier qualification, sampling


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and analysis. The only duty the contractor retains usually involves the examination on receipt, which is intended as an identity test. The contract manufacturer must ensure that the sampling for the identity test takes place in a GMP-compliant environment. The contract manufacturer agreement should specify the scope of the identity test.

Option 2

If the contractor retains responsibility for the procurement of the starting materials, it should check whether the application file for marketing authorization already specifies the suppliers of ex-cipients, APIs or packaging materials. The file often specifies a supplier at least for the API. Some application files name a second supplier, in addition to the first. If the application file does specify a supplier, the contractor must use the starting materials from this supplier; use of a different supplier is not permissible. The drugmaker must hand over this extract from the application file as part of the transfer to the contract manufacturer. If the contractor has already audited and approved the supplier, then the certificate of analysis can be recognized and an identity test suffices. In contrast, if a contract manufacturer has yet to audit a supplier specified in the application file, then as a rule, a complete analysis, independent of the certificate of analysis, must be carried out on at least the first three re-ceipts. Open discussion between client and contractor at an early stage about the responsibility for and apportioning of costs remains advisable.

In practice, this means that the drugmaker audits the contractor. Then again, drugmakers must audit and approve their own suppliers too. Since the costs of doing so remain high in terms of personnel, the issue of distributing that cost also arises.

In addition, the parties should define the scope of the contractor’s sampling on its premises. Sampling must be implemented in line with the requirements in the EU GMP Guide or the FDA’s relevant regula-tions or other guidances. An identity test pursuant to a limited inspection of a few containers according to a set formula would conform to the state-of-the-art only under certain conditions. The exact rules following play will depend upon where the contract specifies the product is to be delivered and/or used.

Analysis of products manufactured under contract

As part of a drugmaker’s transfer of a preparation to a contractor, beyond the duties and responsi-bilities related to procurement and manufacturing, it must also establish the scope of the analysis. The analysis can occur either on the premises of the drugmaker or of the contractor. The contract analysis can also be confined to certain parts of the test scope.

If analysis occurs on the contractor’s premises, or if the contractor subcontracts part of the analy-sis to other laboratories, a contract must contain a written provision. The contractor agreement usually already defines such arrangements. Indeed, contractors often cannot carry out the complete analysis of a preparation in-house. Moreover, that is always the case when specific control tests, such as atomic absorption spectroscopy (AAS), enzymology or vitamin determination, are required, over and above the normal pharmacopeial analysis. Many contractors do not have their own microbiology capability in-house and thus outsource this function to an external laboratory. However, contractors may not out-source an unlimited number of control tests. In the U.S., the analyses that they may contract usually are identified within the submitted NDA, ANDA, DMF or dossier. If such information is not filed with the FDA, it would be expected that the owner of the product should use its personnel to perform all labora-tory work within its facilities. Indeed, the majority of the control tests must take place on the premises of


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the manufacturer. It should be pointed out that the relevant laboratory must be audited and approved and the competent authorities notified.

In line with the drugmaker-contractor agreement, a separate contract with the laboratory must be drawn up to specify all duties and responsibilities. The contractor must notify in advance the drugmaker when it subcontracts analysis to a third-party laboratory.

If a drugmaker assigns a control test to a contractor, it must first define the exact scope of the ana-lytical work for any development or validation batches and for later production batches. The contrac-tor must know at which point in the manufacture samples should be taken for analysis—for example, whether from the blended formulation prior to compression or from the formed tablets.

The drugmaker must hand over to the contractor, in order to carry out the analysis commissioned, all required documents and information. This ensures that the contractor can carry out the analysis in con-formity with the marketing authorization or application as well as all additional legal regulations.

One issue often neglected during the handover of information and documentation is safety. The con-tractor must be able to correctly assess the hazards posed by substances and materials.

Any contract that binds a drugmaker and a contractor must make abundantly clear who bears respon-sibility for the release. The responsibility of the drugmaker usually relates to the release for the market. The contractor, in contrast, can only use its release to confirm that it has manufactured a preparation or a medicinal product in accordance with the manufacturing instructions and inspected in accordance with the testing procedure. Therefore, the contractor must inform the drugmaker immediately if out-of-speci-fication results occur.

Implementation of the client’s requirements

From the drugmaker’s perspective, it has the right to expect a qualitatively higher standard of the contractor—sometimes even higher than it could achieve in-house. This means that the contractor may find itself in the situation of implementing as many requirements from the audit and observations by the contractor in the operation as possible. As a contract manufacturer usually faces audits several times a month by drugmakers, this inevitably results in having numerous different observations and activi-ties linked to it. Since each audit takes place separately, and remains highly unpredictable, contrac-tors should at least be prepared to face the standard topics. Certain questions crop up again and again. Therefore, contractor should implement observations on these topics, according to a list of priorities. It would be advantageous for contractors to regularly inform the drugmaker of the status of those activities already implemented.

Manufacture and analysis in accordance with the relevant instructions from the drugmaker

The contractor usually bases its compilation of manufacturing and packaging instructions and of testing procedures on the marketing application or authorization. Less frequently, it does so on specific manufacturing instructions or directions received from the drugmaker. This transfer documentation is transposed into a manufacturing and packaging instruction, along with a testing procedure, all of which remain typical of the contractor.

The contractor must ensure, in the course of daily business, that it communicates to the drugmaker all deviations from the manufacturing and packaging instruction. The contractor may not make any


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changes without the drugmaker’s written authorization. This procedure forms part of a system of change control and should be specified in the contract manufacturer agreement. Since the contractor does not hold or own the marketing authorization, only the drugmaker may make decisions regarding a deviation from a specification. To ensure transparent documentation, as indicated above, the drugmaker should provide a brief written acceptance. This remains absolutely necessary, since at any later date it would be impossible to clarify who specifically authorized a change or deviation.

If, due to technical adjustments to the facilities and machines, the contractor finds itself in no posi-tion to receive a preparation or material conforming to specification, the drugmaker again must provide written authorization before the contractor may continue manufacturing the preparation or product.

Quality assurance activities

The contractor must have a suitable in-house quality assurance system. This includes the following quality assurance measures:

• Training programs and personnel;

• Validation;

• Qualification;

• Cleaning validation;

• Standard operating procedures (SOP);

• Production hygiene (clothing, cleaning, etc.);

• Change management (change control, internal and external complaints); and

• Quality assurance instruction manual.

The contractor must produce corresponding SOPs for all topics mentioned and provide evidence that it has integrated these topics into daily operations.


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Contract Manufacturer AgreementIn a contract manufacturer agreement, those sections with legal content always represent a critical

issue. These often cause substantial delays until the drugmaker and contract can draw up a final version of the contract. However, if they already possess model contracts that must be merged into one common contract, that can represent a further hurdle. Each contract must contain certain succinct titles. These represent primarily the arrangements that define the detail of the manufacture and analysis. It is particu-larly important for drugmaker and contractor to note the responsibility each bears with respect to the procurement, manufacture and analysis or release of the medicinal product to the market.

In addition, the parties should make other arrangements relating to the purchase of starting materials (APIs and excipients, primary and secondary packaging material) and their approval. The transfer of a preparation from one contractor to a subcontractor creates an exception in the formulation of the con-tract.

Legal background

In the EU, a contract manufacturing agreement is a requirement from the EU GMP Guide:

“Contract manufacture and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings which could result in a product or work of unsatisfactory quality. There must be a written contract between the [client] and the Contractor which clearly establishes the du-ties of each party. The contract must clearly state the way in which the Qualified Person releasing each batch of product for sale exercises his full responsibility.”

In the U.S., regulators expect contracts to adhere to the requirements outlined in applicable drug regulations and guidance. Both the drugmaker and contractor retain responsibility for conforming to drug GMPs. The FDA expects to see an executed Quality Agreement that specifically addresses all qual-ity responsibilities between the drugmaker and the contractor. While the FDA does not discuss contract requirements in the same detail as found within the EU GMP Guide, such requirements still exist and reflect the GMP principles expected under U.S. law. Typically, local regulatory authorities discuss and review these topics when conducting supplier audits and GMP inspections.

Minimum requirements for contents

The contract manufacturer agreement at minimum should include:

• Definition of responsibilities, including manufacturing and packaging, quality control, problems of a pharmaceutical-technical nature, and release for dispatch/shipment and for sale. It should list the responsible persons by name and respective function with specimen signatures, if pos-sible in an appendix to the contract.

• Scope of the contractor’s duties. This involves the agreement of the responsibilities for produc-tion, packaging, quality control and procurement. Since this section can sometimes turn out to run for many pages, it is advisable to define the duties and activities in an appendix, along the lines of the list of signatures. The advantage here occurs should there be any changes, since only the appendices would require updating, rather than the entire contract. That saves both parties considerable administrative effort.


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• Documentation. This section should specify which documents and records the contractor must hand over to the drugmaker after concluding manufacturing. The retention of documentation (including the operating procedures) should also be agreed.

• Determination of the production site. Specifying a location prevents production of a preparation being changed to a subcontractor without the client’s being informed.

• List of preparations. Listing the preparations under contract in an appendix can prove profitable here too, as only one appendix will require adaption in case of additions.

• Conformity of the manufacturing instructions. The drugmaker must check and sign the contrac-tor’s manufacturing instructions.

• Development batches. In particular, this section must describe the risk of a defective batch in the development and improvement phase.

• Liability. Finding a mutually acceptable solution to this issue often requires a lot of time.

• Audits. The timing, frequency and scope of the audits should be established here. From a U.S. perspective, the drugmaker should clearly have the authority to perform audits on an as-needed basis. The contractor would be expected to facilitate such requests should they reflect a regula-tory need.

• Retention samples. The responsibility for the storage of the retention samples of manufactured goods, starting materials and packaging material should be established. The scope of the sam-pling for retention samples during routine production should also be established.

• Transport. The responsibilities during transport (potentially involving starting materials dis-patched from the drugmaker to the contractor and finished products from the contractor to the drugmaker) should be clearly defined.

• Release of artwork. Since the contractor does not bear responsibility for the content on the printed packaging material, the client must approve all artwork.

• Deviations. The contractor must inform the client in the event of deviations from specifications and arrangements.

• Complaints. An action plan for handling of complaints should be established

• Change control. The contractor must be informed if there is a change of supplier of starting materials or packaging material provided by the drugmaker. This is important in that the con-tractor often includes the permitted supplier or manufacturer in the manufacturing instructions or formulation.

Regular review of the contract. The interval between reviews of the contract should not exceed two years. The agreement also should include prices and delivery dates, compliance with the legal provisions and agreements relating to additional analysis of starting materials

(See page 29 for a model contract.)


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Compilation of a confidentiality agreement

The contractor normally receives from the drugmaker a confidentiality agreement for signature as part of a request for a transfer of a preparation or other contracted manufacturing related activity. With this signature, the contractor assures the drugmaker that it will treat all information as confidential. This means that the contractor may not hand over the documents, or share any provided information or knowledge, to a third party without the consent of the drugmaker.

In addition, the confidentiality agreement determines what would happen to the drugmaker’s docu-ments if it does not award the manufacturing order.

Time needed

At this point, it bears reemphasizing that no drugmaker should underestimate the amount of time needed to compile a contract manufacturer agreement. The amount of time can vary, from several weeks to several months, depending on whether the drugmaker and contractor may rely on a model contract or if the parties need to forge a new agreement. Experience shows that the section on liability and warranty requires much time to negotiate. That is because the two parties should clearly establish a policy that addresses the event of consequential loss with a preparation on the market. More and more drugmakers also demand special payments when a contractor delays preset delivery dates.

Representatives from the supervisory/regulatory authorities place great value on a contract’s being signed, thereby regulating all responsibilities, before manufacture starts. This applies in the same way to the manufacture of any validation batches, since they may be offered for eventual sale in some cases.

Contract manufacturer agreements for audits

The experience with numerous supplier audits and official inspections of contractor premises clearly shows a change in contract topics and basic conditions that they had previously agreed upon with their drugmaker clients. The review and discussion of changes, if necessary, of contract manufacturer agree-ments forms a fixed part of the program for supplier audits. As part of an inspection, the authorities pay attention in particular to all agreements regarding the responsibilities of the drugmaker and the contrac-tor and the sequence of the deadline agreements. The drugmaker and the contractor must also ensure that the responsible persons named in the contract remain employed by the respective company. Many contract manufacturer agreements often reveal weaknesses at precisely this point, since the parties fail to regularly update their contracts. It is, therefore, strongly recommended, that they review their contracts on a regular basis. In the U.S., the FDA expects regular audits of contract manufacturers; these should always include a clearly defined requirement of the contract or Quality Agreement.


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Audits of Contract ManufacturersThe EU GMP Guide requires a drugmaker to audit a contractor. This same expectation exists for the

United States. According to the EU Guide, the drugmaker must inspect the contractor’s facility. Were the drugmaker not to do so, it would be impossible to evaluate the competency of the contractor. These audits often entail two to three auditors and usually last one to three days. U.S. regulators expect the drugmaker to regularly conduct audits for the purpose of evaluating the GMP compliance level of the contractor, including its quality systems, staffing and facility conformance. The FDA neither specifies the number of auditors nor the length of the audit.

Frequency of audits

Regular audits ensure in the first place that the contact persons in each company can cultivate regular contact and, in the second, that they can discuss personnel technological changes as well as all problems the contractor may have on its premises with a preparation. However, experience reveals that not all drugmakers fulfill this routine obligation.

With regard to the time intervals, drugmakers fall into any one of roughly four groups, based on how they treat the auditing responsibility:

• Group 1: annually

• Group 2: every 2 years

• Group 3: every 3–5 years

• Group 4: sporadically

The drugmakers belonging to the fourth group are those who carry out an audit only when faced by an inspection by regional regulatory authorities. The philosophy of these companies consists of their believing that day-to-day business activities hold more importance than the suspension of one day’s production as part of an audit. It should be pointed out that this contravenes current pharmaceutical law. Therefore, in such cases, the contractor must take on the role of the consultant and indicate this defi-ciency to its drugmaker client.

Several limiting factors should be mentioned here, which in practice have shown to make regular auditing of a contractor difficult:

• Many drugmakers work with numerous contractors. This can be due to company philosophy or the need to utilize different contractors to manufacture different dosage forms. Regardless, all must be regularly audited.

• The capacity of auditors often remains limited, since staff from the manufacture, purchasing, laboratory and quality assurance departments carry out the audits. The day-to-day business goes left virtually undone during the audit.

• A drugmaker must immediately deal with a rapidly rising level of complaints about one or more preparations with a contractor. On the other hand, if daily business reveals no problems with product quality or deviations, it seems unnecessary to carry out an audit at short notice.


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Types of audits

As part of the preparation of an audit, officials should define the focus of the audit. Generally, there are three audit types.

System audit

A system audit primarily involves the verification of the contractor’s whole QM/QA system. The audit focuses on compliance with legal requirements. A classic system audit includes the whole pro-cess method of a medicinal or drug product, from the delivery of the starting materials to the storage of the final product. Depending on the size of the operation, these audits can last one to three days. Depending on the drugmaker, one to three auditors carry out the audit.

Procedure or process audit

In a procedure or process audit, operational concerns hold primary importance. Here, one tries to follow the production flow for a previously defined preparation. This type of audit focuses on the review of all documentation, including the logbooks, records of environmental conditions, batch production records, testing results and cleaning records, as well as the qualification and validation documentation.

Product audit

A product audit involves reviewing whether the contractor adheres to the arrangements forming the basis for the contract manufacturer agreement. This audit usually treats a particular preparation as its subject matter.

Audit priorities

Many drugmakers send out special questionnaires as part of its preparations for a contract manu-facturer or supplier audit, often using these to define priorities. It then remains up to the contractor to prepare these topics accordingly. If a drugmaker does not send out a questionnaire, it has proven to be advantageous to ask for a consultation about the content of the audit. Various chapters from the EU GMP Guide, the U.S. regulations at 21 CFR parts 210 and 211 or audit checklists used by organizations and consultants can usually form the basis for an audit.

The following audit checklist refers to those typical topics and questions broached as part of an au-dit. However, no one provides any guarantee of completeness, since some drugmakers like to review and test particular product-specific topics that they have found more important for evaluating compliance levels of a contract manufacturer.

Audit Checklist

Personnel training and assessment

• How are personnel from the production, laboratory and engineering areas trained?

• How often does training take place?

• How is the training documented?


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• Is there a management system for training and participants?

• Is there an approved training program?

• How is it ensured that the participants have understood the topic?

• How are the instructors trained?

• Is an assessment carried out?

State of repair of the premises

This depends primarily on the condition of the ceilings, windows and floors.

• Is the ceiling sealed?

• Are the floor tiles damaged?

• Is there a wall guard? Is it sealed?

• Is a dust-tight ceiling fitted?

Cleaning and sanitation programs for personnel and facilities

• Are there cleaning schedules for production rooms?

• Are they adhered to and documented?

• Are there cleaning procedures for all machines?

• Are there approved cleaning agents and disinfectants?

• Are the ceilings cleaned regularly?

• How is cleaning documented?

• Are regular checks made of the cleaning?

• How often is protective apparel changed?

• Are there specific regulations for particular areas?

• Does regular training of the cleaning staff take place?

Calibration of balances

• How often are the balances calibrated?

• Is there a calibration instruction?

• Is the function of the balances tested daily?

Maintenance and repair measures

• Is there an SOP for maintenance?


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• Who monitors the maintenance due dates?

• How is the maintenance documented?

• Is there a maintenance schedule?

• Are the calibration weights certified regularly?

Quality management system/safety measures

• Is there an SOP system?

• How often are SOPs updated?

• Who is responsible for SOP training?

• How are deviations handled?

• How are changes controlled?

• Is there a change-control system?

• Is there a process for out-of-specification results?

Approval systems

• Who is authorized to release a product?

• Is there a user draft for the release in the computer?

• Who approves raw materials?

• Who assigns the expiration date?

• Is the computer system validated for the release part?

• Who can release in the event of absence?

Storage: Where are the samples taken from?

• Who is responsible for sampling?

• Who trains the staff who carry out the sampling?

• How are receipts checked?

• Who creates the labels?

• Who controls the products supplied?

• Are all partially filled containers sealed?

• How is the temperature and humidity monitored in the warehouse?

• Are samples taken from all containers? If not, what is the basis of the sampling plan?


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• How is container labeling carried out?

• How is reprinting of labels carried out?

Complaints

• Are internal and external complaints analyzed?

• Are there any statistics on complaint trends?

• Who is responsible for processing complaints?

• Are the topics of the complaint incorporated in the training program?

Documentation systems

• Who is responsible for compiling the manufacturing instructions?

• Who compiles the test procedures?

• Is there a packaging instruction?

• Is there a variant of the manufacturing instructions?

• Are there logbooks for all machines and media equipment?

• Who completes the cleaning documentation?

• Who can change bills of materials?

Job descriptions for key personnel

• Are there current job descriptions for staff in charge? In the U.S., job descriptions for all per-sonnel performing GMP-related activities should exist.

• How often are the job descriptions updated?

• Is responsibility for the release clearly worded?

Building installation

• How are temperature and humidity monitored?

• What is the air exchange rate?

• Are the measuring instruments calibrated?

• Where can the temperatures and pressures be read?

• Is there an alarm signal in the event of deviations?

• What happens in the event of deviations?

• Is the building control system qualified?


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Risk of contamination

• How is contamination between machines and areas prevented?

• How is contamination by staff prevented?

• Is there specific clothing or are there air locks?

• What ventilation systems are installed?

• What are the pressure differentials in the rooms?

Zonal concept

• What is the company zonal concept?

• Is there an SOP for it?

• Are room plans with personnel and material flow available?

• How often is monitoring carried out (particle, organism)?

Utilities and supply

• Are all measuring instruments calibrated?

• Are there maintenance schedules for utilities?

• Are there any current drawings?

• Is there a qualification of the water treatment system?

• Where appropriate, is validation performed?

Validation of process and analytical procedures

• How are validations carried out?

• Who is responsible for the validation?

• When must revalidation be carried out?

• Is a risk analysis carried out?

• Are all analytical procedures validated?

• Is there a validation master plan?

• Are regular checks made that the manufacture still conforms to the validation data?

Qualification of facilities and machines

• Are all existing facilities qualified?

• Are new facilities qualified?


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• How is a performance qualification carried out?

• How is the qualification of old facilities carried out?

• Who compiles the user specifications?

• Who carries out monitoring of activities?

Cleaning validation

• Is a cleaning validation carried out?

• Which product groups are defined?

• Is there a cleaning procedure?

• Do the cleaning procedures contain the detergent and the concentration?

• How is the cleaning result defined?

• What is the basis for classification into product groups?

• How are new products handled?

Specifications and test procedures

• Are inspections always carried out in accordance with prevailing instructions?

• How are raw data documented?

• Who transfers the raw data to the certificate of analysis?

• Is there a separate material number for each material?

• Are complete analyses always carried out?

• Are laboratory reagents correctly labeled?

Labeling of containers and premises

• Are there cleaning labels?

• How are containers identified?

• Does staff sign these labels?

• How long is cleaning valid?

• Are all rooms labeled and assigned a floor plan?

Self-inspection

• Are self-inspections carried out on a regular basis?

• How are the results of the self-inspection implemented?

• Who carries out the self-inspection?

• Who takes over monitoring of activities?


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Result of an audit

The drugmaker usually compiles an audit report. This audit report often consists of a completed questionnaire or a checklist. Some drugmakers, however, write out the audit report in full. The report then contains the observations made about the contractor. These observations can be classified into dif-ferent categories, including high, medium and low risk. In each case, the drugmaker should add com-ments to the observations that help explain any observed deficiency. Depending on the company, the contractor is given four to eight weeks to respond to the observations cited and report on actions taken to correct the observed deficiencies.

This audit report also includes the drugmaker’s final assessment of the contractor, which can be at any one of three levels:

• Not approved: The audit of a contractor revealed that the contractor cannot be approved.

• Qualified: The audit of a contractor revealed rectifiable deficiencies.

• Certified: The audit of a contractor revealed no deficiencies.

How does a contractor prepare for an audit?

The correct preparation for an audit includes examining the observations from previous audits. It is not possible for all contractors to implement all observations at short notice. Many observations will be out of step with the philosophy of a company; however, other topics may be implemented with little ef-fort or resistance. The contractor should compile a list of priorities, culled from those audits carried out over a certain time, and in a structured manner start with implementing the most important observations. It is certainly advantageous if the contractor provides the drugmaker with a regular written status report after receiving the audit report. This should continue until it has addressed completely the audit report.

Carrying out follow-up audits

Today, it is common practice for a drugmaker to allow a contractor a certain amount of time to implement and comment on any observations. Some companies, particularly the larger ones, carry out a follow-up audit of the contractor when this time has expired. This audit considers only the corrections implemented for observations cited during the first audit.

Positive spin offs of audits

Audits are time-consuming and costly for the drugmaker and contractor alike. They are nevertheless worthwhile. Both parties can agree on certain topics more quickly and simply through shorter official means. Moreover, a drugmaker may only compare the contractor to other contract manufacturers once it has completed an audit of the contractor. In addition, drugmakers may always use any suggestions for its own operations, enabling it consider an audit as a form of cost-saving consulting. For a contractor, the large number of audits carried out on its premises puts it in a more secure position, both when dealing with the drugmaker and in the site specification regarding its own competitiveness.


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SOP for Assigning Manufacturing ContractsLogo Company name

Operating procedure (part 1 of 6)

SOP no. Assignment of manufacturing contracts

TitleAssignment of manufac-turing contracts

Valid from

Appendices

Replaces SOP no.

Scope • Production• Quality control• Quality assurance• Purchasing• Legal department

For information to

created name/function date

checked name/function date

approved name/function date

Change index• New compilation

1. Introduction

1.1 Objectives

The pharmaceutical manufacturer assigns the manufacture and analysis to a third party on contract. The principles of GMP apply to the contract manufacture and analysis of medicinal products. The SOP describes the procedure for issuing manufacturing contracts and the requirements for the compilation of contract agreements.

1.2 Regulatory background

Commission Directive 2003/94/EC, Article 12;

EU GMP Guide, Part I, chapter 7;

EU GMP Guide, Part II, chapter 16;

U.S. Code of Federal Regulations, Title 21, Part 211.

1.3 Definitions

Manufacturing contract: contractual instruction on the manufacture and/or analysis of a specific quan-tity of a product or medicinal product agreed between manufacturer and contractor.


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Logo Company name



1.4 Scope and responsibilities

The SOP is valid in the pharmaceutical company for the contract manufacture and analysis by a third party.

The pharmaceutical company is the specialist function responsible for the product to be manufactured and/or tested.

Responsible head(s) of the following departments participate in decision-making:

• Legal • Production• Quality assurance• Quality control• Purchasing• Development (optional)• Engineering (optional)• Marketing (optional)

Quality assurance

• Coordinates the activities for decision-making, contract formulation, negotiation, implementa-tion and monitoring.

• Is the contact person for the contractor.

The Legal department is responsible for formulating the contract and legal analysis and the archiving of the contracts.

2. Carrying out

2.1 First contacts, pre-selection

Once the basic decision has been made as to whether and which product or dosage form should be contract manufactured and/or analyzed, a pre-selection of the suitable contract manufacturers is under-taken.

Prior to decision-making, feasibility, risks, cost and benefit, and regulatory requirements should be checked. Technological, pharmacological and toxicological risks must be reviewed and evaluated.

The following specialists and responsible persons participate in the decision-making:

• Legal department• Production• Quality assurance• Quality control• Purchasing


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Logo Company name



• Development (optional)• Engineering (optional)• Marketing (optional)

At the start of the information exchange between manufacturer and contractor, a confidentiality agree-ment is drawn up—irrespective of whether a contract is subsequently concluded or not. Subsequently, a quote is issued by the potential contract manufacturer(s).

2.2 Evaluation and selection

Before a contract is concluded, an audit of the future contract manufacturer should be carried out in order to obtain the following information, among other things:

2.2.1 General Aspects

• General impression• Manufacturing authorization (possession, expiry, renewal)• Inspections planned and carried out, complaints and their processing

2.2.2 GMP aspects

• Key personnel• Quality assurance system• Batch Record Review• Premises• Technical equipment• Starting materials (reception inspection, documents)• Finished products (final inspection; documentation)• Personnel and production hygiene• Documentation (batch records, instructions, SOPs)• Labeling and packaging• Qualification of the facilities and validation of processes and systems• Quality control• Handling of grievances and complaints

2.2.3 Product/problem-specific aspects

• Is the contract manufacturer suitable to manufacture/test the specific product?• Are duties and pharmaceutical responsibility well defined?• Who provides what (active pharmaceutical ingredient, reference product, etc.)?• Does the company have the relevant qualified personnel?• Is the existing technical equipment adequate?• Is there a guarantee that deadlines will be adhered to?


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Logo Company name



2.3 Formulation and conclusion of a contract

After re-examination and decision-making by the specialist function providing the contract, the order is placed and a framework contract concluded by the competent legal department. The contract is signed by the contract partners and archived by the legal department.

The framework contract between the pharmaceutical manufacturer and the contractor contains written agreements on:

• Manufacturing authorization• Subject of contract• Term of the contract• Capacities in:

• Manufacturing• Testing• Sampling and storage of retention samples

• Validation and revalidation• Documentation and archiving• Quality assurance

• Authority to carry out inspections• Audit by the contract manufacturer, frequencies• Official inspections

• Logistics• Determination of the procurement of starting materials and packaging material, property

rights• Deadlines• Transport methods

• Guarantee • Information flow and agreements required in the event of deviations, changes, defective

batches• Change Control

• Assignment of responsibility• Approvals

• Liability• Pricing• Legal aspects

• Regulations on rights matters, patent protection, etc.• Jurisdiction

• Verbal agreements• Principles for assigning contracts to a third party


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Logo Company name



• Confidentiality obligations• Competition

• Reference contracts

From the framework contract, reference should be made to:

• List of all work to be carried out in detail and the party responsible for it• List of the contact persons in both companies

2.4 Contract implementation

Regularly recurring audits monitor that the contract is implemented according to the regulations.

After fulfillment of the contract, all documents are handed over to the pharmaceutical company. The handover should be documented.

3. Process flow


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Framework Contract for Contract Manufacture and Quality Control

The following framework contract is concluded between:

Contract giver [Company, exact address] – hereafter referred to as CG –

and

Contract acceptor [Company, address of the plant] – hereafter referred to as CA –

§ 1 Principles

1. CA is the holder of a manufacturing authorization and is insofar liable for supervision by the competent authority. He observes the legal drug product provisions, the recognized pharmaceu-tical regulations and ensures compliance with the principles of good manufacturing practice in accordance with the EU GMP Guide (for the USA: 21 CFR Part 210 and 211) over the whole term of the contract. The observation of further instructions going beyond these should be estab-lished between CG and CA separately in writing.

2. CA is not permitted to transfer the execution of his contractual obligations to a third party with-out the written agreement of the CG.

3. CA communicates to the CG any subsequent, fundamental changes to the rooms and facilities relevant to the subject of the contract immediately. The CA indicates to the CG without delay the suspension, the withdrawal or the retraction of the manufacturing authorization and the vol-untary surrender of the same during the term of the contract.

4. CA grants the CG access to the rooms and facilities relevant to the subject of the contract and makes documentation relevant to the subject of the contract available for him to inspect.

5. The relevant contact persons for the subject of the contract from the CG and the CA are listed in Appendix 1. The contract partners should indicate subsequent changes without delay.

§ 2 Subject of the contract

The subject of this contract is the manufacture and quality control of the medicinal products (Drug Products) and dosage forms listed in Appendix 2, hereafter referred to as contract manufac-tured products.

1. The batch size and labeling, the processing of the order and all commercial agreements, such as prices, delivery conditions/transfer of perils are established in separate, batch-related supply contracts according to the model in Appendix 3.

2. A supply contract results from the written placing of an order by the CG with the specifications of the contract manufactured products according to paragraph (1) and the specifications accord-ing to paragraph (2) and the written order confirmation from the CA.


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§ 3 Starting materials and packaging materials

The specifications and permissible manufacturers/suppliers of the starting materials and packaging material to be processed by the CA are established in Appendix 4. Subsequent changes require the writ-ten agreement of both parties.

1. Responsibility for the procurement, quality control and release of starting materials and packag-ing materials is established in the supply contracts in accordance with § 2 (2).

2. In the event that the CG provides to the CA the starting materials or packaging materials to be processed, the CG also provides the corresponding batch-related certificate of quality. The CA must always carry out a container identity and labeling inspection and an external integrity check. Additional quality controls to be carried out by the CA should be agreed in the respec-tive supply contract. The CG absorbs the costs of transportation from the CG to the CA and of the transport insurance linked to the provision of the starting materials and packaging materials. The CG takes over the responsibility for guaranteeing the quality of the starting materials and packaging materials during transportation to the CA. The starting materials and packaging ma-terials provided by the CG can only be used to manufacture the contract-manufactured products as part of the contract.

3. If the CA provides starting materials or packaging materials himself, he is responsible for the proper verification of their quality on the basis of the specifications in Appendix 3 and 4. He en-sures that the starting materials or packaging materials are only being purchased from qualified manufacturers or suppliers and meet required specifications as provided by the CG. The costs of the qualification are borne by the CG. If the CA conducts the quality control on the basis of his own specifications, he is liable for ensuring that the methods correspond to the state of the scientific and technical knowledge and are validated. If the CG provides testing standards, the responsibility for their suitability lies with the CG.

4. The print release of printed materials is always on the basis of the artwork approved by the CG.

5. The CA is responsible for carrying out sampling and storage of retention samples of the starting materials.

§ 4 Manufacture and quality control of the contract manufactured products/retention samples

Manufacture and quality control of the contract-manufactured products is carried out on the basis of manufacturing instructions and test procedures to be compiled by the CA. To this end, the CG sur-renders to the CA the required submittals, if applicable the extracts from the application file for market-ing authorization, in the form of manufacturing formula and testing standard. Each newly compiled or changed manufacturing or testing procedure should be approved by CG and CA jointly.

1. The CA guarantees that the applied manufacturing and analytical procedures are validated and the facilities used are qualified. The costs for the necessary validation work are borne by the CG.

2. The CA draws up a manufacturing and test report for each batch on the basis of the directions in accordance with §1. The CG is authorized to see the originals of the manufacturing and test protocols and to have copies made of them.


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3. All deviations from the manufacturing or testing procedure should be documented in the manufac-turing and test protocol. The CA informs the CG promptly of any deviation which could possibly affect product quality or process reliability. Possible measures are established in mutual agreements.

4. The CA is responsible for ensuring that manufacturing/test procedures and records are retained at least six years.

5. The CA is responsible for ensuring that retention samples from every batch manufactured are retained at least six years.

§ 5 Release of the contract manufactured products

The responsibility for the release is established in the supply contracts.

1. If the release of the batch is carried out by the CG, the CA provides the duly signed manufactur-ing and test reports with all required records included with the signed reports.

§ 6 Complaints and recalls of the contract manufactured products

CG and CA inform one another without delay about any complaints about, and batch recalls of, the contract manufactured products, and the starting materials and packaging materials used for them, that he becomes aware of. This applies to external notices and also internal information that arises, e.g. during processing or storage of the contract manufactured products and starting materials and packaging materials.

1. The CG and CA aid one another when reviewing the complaints and determining the required measures.

§ 7 Confidentiality

CG and CA undertake not to disclose the mutually communicated experiences and information about the manufacture and quality control of the contract manufactured products. They take all measures re-quired to prevent a third party from discovering them. Staff and employees should be sworn to secrecy, insofar as this is not already required by their work contract.

1. The contract partners will use the knowledge gained through the contract only for the purpose of the contract. On completion of the contract, they will no longer make use of it without the explicit consent of the other party—not even in a modified form.

2. The contract partners will return information they each will have received from the other in connection with the manufacture and quality control of the contract manufactured products on completion of the contractual relationship, to the information provider without delay, if it has not otherwise expressly been agreed contractually or if strict legal reasons oppose delivery.

3. The confidentiality obligation does not apply to data that already count as state-of-the-art or public and therefore are no longer protected.

§ 9 Waiver of recourse

(Since this is a significant legal liability issue, the wording used in this section should always be ex-amined and approved by the legal representatives of the CG and CA. This is especially important in the U.S., where liability laws may differ from the EU.)


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If, after processing, the CG launches the subject of the contract for sale as a finished medicinal product and loss or damage under the pharmaceutical liability insurance occurs, that can be traced to a deficiency in the area of responsibility of the CA, the CG asserts waiver of recourse.

1. The CG is aware that this waiver of recourse requires the agreement of its insurer. The CG will solicit this agreement and pass it on to the CA for information.

§ 10 Final provisions

1. The contract enters into force upon signature by both contract partners and is valid initially until [enter date]. It is extended automatically by [enter time limit] each time, if it is not cancelled with a time limit of [enter time limit] by one of the contract partners.

2. The cancellation must be notified in writing by registered mail/with advice of receipt.

3. Changes and supplements to this contract and its appendices are by mutual agreement and should be in writing.

4. If one or more provisions of this contract is, or becomes, ineffective, the validity of the other provisions is not affected. The invalid provision is replaced as soon as possible by another pro-vision that comes closest to the economic content of the ineffective provision. The same applies for possible loopholes of this contract.

5. Place of fulfillment is [enter location], Jurisdiction is [enter location]

...................................... ..................................... Location, date Location, date

...................................... ..................................... Signature of the contract giver Signature of the contract acceptor

Appendices Appendix 1 Contact persons from the CG and the CA Appendix 2 Contract manufactured products Appendix 3 Model for a supply contract Appendix 4 Specifications for starting materials and packaging materials


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Appendix 1 On the framework contract for contract manufacture and quality control

Between CG [name, location] and CA [name, location)] on [date of basic agreement]

Version: valid from page [no.] of [number of pages]

Contact persons from the contract giver and contract acceptor

Department Contract giver Contract acceptor

Purchasing

Name

Address

Telephone No.

Specimen signature

Sales

Name

Address

Telephone No.

Specimen signature

Head of Production or mandated person

Name

Address

Telephone No.

Specimen signature

Head of control or mandated person

Name

Address

Telephone No.

Specimen signature

Complaints

Name

Address

Telephone No.


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Department Contract giver Contract acceptor

Specimen signature

Quality assurance

Name

Address

Telephone No.

Specimen signature




35



Version: valid from: page [no.] of [number of pages]

Contract manufactured products

Product A B C D E F G

Material No. of the CG

Designation

Strength

Dosage form

Package size

Packages/shipping containers

Type of package

Package height/pallet

Shipping packaging




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Version: valid from: page [no.] of [number of pages]

Model for a supply contract Supply contract based on the framework contract between CG [name, location] and CA [name, loca-tion)] on [date of basic agreement]

Material No. of the CG

Designation

Strength

Dosage form

Package size

Batch size

Batch No.

Delivery conditions

Delivery date

Contract price incl. VAT

Procurement, quality control and release of the active pharmaceutical ingredients

m by contract giver

m by contract acceptor

Procurement, quality control and release of the excipients

m by contract giver


Procurement, quality control and release of the primary packaging material

m by contract giver


Procurement, quality control and release of the printed materials

m by contract giver


Procurement, quality control and release of other packaging material

m by contract giver


Release of the finished medicinal product m by contract giver


Other agreements. Insert any other expected actions not cov-ered in other sections of this agreement and note the responsible party


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Specifications

Active pharmaceutical ingredients

Designation Specification (e.g. pharmacopeia monograph, cross-reference to docu-ments if necessary)

Source(s) (suppliers/manufacturers)

Excipients



Primary packaging material



Printed materials (e.g. package inserts, labels, outer cartons)

Designation Specification (e.g. print design edition)

Source(s) (print shop)


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Other packaging material

Designation Specification Source(s) (suppliers/manufacturers)




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Outsourcing Analysis and TestingThere is no doubt that it lies in the interests of quality assurance and progress to outsource specific

tests to specialized facilities equipped with (for example) complex and modern devices and staffed by the necessary qualified and experienced personnel.

When deciding whether external testing of medicinal products is permissible, the potential for im-provement of medicinal product safety through high-quality testing at facilities developed to carry out specific control tests should be considered. Such facilities are, from the point of view of personnel and equipment, often superior to average pharmaceutical businesses.

Both in the EU and the U.S., all contract analysis remains subject to supervision and inspection by regulatory or other competent authorities. But the responsibility of the Qualified Person or the head of quality control of the drugmaker for externally implemented analyses nonetheless remains unaffected.

Therefore, the drugmaker and contractor must agree to a contract that clearly defines the tasks of and responsibilities for both parties if one company analyzes a medicinal product on behalf of another. The EU GMP Guide states in chapter 7.2 that all arrangements for contract analysis, including any proposed changes in technical or other arrangements, should be in accordance with the marketing authorization of the medicinal product. The drug manufacturer is in charge of assessing the competence of the contrac-tor, as well as ensuring that the contractor follows the GMP rules. The drugmaker has to provide any information necessary for the contractor to test the medicinal products in compliance with the marketing authorization and then has to assess the results of the tests, OOS results or deviations from the provided test instructions. The drugmaker must make sure (e.g., by carrying out audits) that the contractor under-takes proper analysis of the medicinal product in accordance with the registered testing procedure.

The contractor has to run an adequate QA-system, meaning it remains in compliance with the GMP rules and follows the provided test procedures. The contractor also must ensure that the client stays informed about any critical deviation or occurrence that might influence the quality of the medicinal product.

According to the agreement, the contractor may not pass on any work awarded under the terms of the contract to third parties without first obtaining the written consent of the client.

Examples of pharmaceutical quality control analysis/testing that could be outsourced are:

• Microbiological quality testing of sterile products (sterility testing)

• Microbiological quality testing of non-sterile products

• Microbiological and biological assays (vitamins, heparins, antibiotics, antimycotics)

• Preservation efficacy testing

• Testing for bacterial endotoxins

• Testing for pyrogens

• Abnormal toxicity tests


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• Determination of particular impurities (e.g., heavy metals, aflatoxins, pesticides)

• Investigations using radioactive substances

• Special instrumental analysis (e.g., GC-MS, LC-MS, NMR analysis, AAS, Electrophoresis)

• Different stability studies (e.g., ongoing stability studies, in-use stability studies, long-term stability studies)

• Container closure integrity tests

• Analytical procedures for cleaning validation purposes

• Analytical procedures for qualification and process validation purposes

• Analytical tests for batch release

Selection of an external testing laboratory

When selecting an external testing laboratory, the drugmaker can assess the competence of its can-didates by reviewing third-party certification of the contract lab (e.g., manufacturing license, GMP-cer-tification and accreditation), inspection reports of other pharmaceutical companies or its level of active participation in committees and organizations, as well as scientific contributions made and involvement in projects where an expert opinion was given.

The drugmaker also can ask a variety of questions, as shown in the table below:

Criteria for the selection of an external laboratory

Mandatory suitability criteria Desirable suitability criteria

• Has the laboratory notified the national au-thorities for testing of medicinal products?

• Is the laboratory inspected regularly by a competent authority and found acceptable, e.g., by local authorities or by the FDA?

• Has a manufacturing license or a GMP-cer-tificate issued by a competent authority?

• Has the laboratory been accredited in accor-dance with ISO/IEC 17025?

• Are suitable rooms and facilities available for contract analysis?

• Are GMP standards observed during work at the laboratory?

• Does the external laboratory have a suffi-cient number of experienced and qualified academic personnel (e.g., pharmacists, vets, chemists, food chemists, biologists)?

• Do FDA approvals exist or have other positive experiences with the FDA been noted?

• Does the external laboratory regularly and successfully take part in suitable inter-laboratory tests?

• Is there an authorized counter-checking expert?


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Sequence of external contracting

1. Request to external laboratory for basic information, including:

• Range of services

• Availability of manufacturing license

• GMP status

• Certifications/accreditations

• Availability of Site Master File

• Internet presence

• Other available information

2. Request for specific services information, including:

• Type of service provided by laboratory

• Harmonization of methods (must generally be carried out before a specific offer can be made)

• Delivery dates and quantities

• Pricing

3. If required, preliminary audit or written preliminary qualification (e.g. based on written accessible audit reports)

4. Modality of lab-to-lab transfers/determination of analytical methodology

5. Liability limitation contract

• Standardized contract from external laboratory; or

• Standardized contract from pharmaceutical manufacturer

Typical errors

Typical errors that occur when working with a contract laboratory include the following:

Drugmaker errors:

• Application file for marketing authorization not updated

• Contract analysis not included in the change-control procedure

• No validation or transfer of test method ordered

• No plausibility checks

• Incomplete documentation of development and validation of test procedures

• No clear and precise specifications


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• No adjustment of OOS instructions with the contract laboratory

• No integration in the QA system

• No precise orders

Contractor errors:

• Application file for marketing authorization or excerpts of it unknown

• No change-control procedure

• Missing validation or method transfer

• No assessment of test instructions and specifications

• No SOP for OOS, no adjustment of OOS instructions with the client

• Unclear orders

• No compatible QA system

Liability limitation contract

To reduce the risks of liability and noncompliance, the drugmaker should consider the following issues:

• No combination of commercial contracts with liability limitation contracts, in accordance with medicinal product legislation.

• All specifications subject to regular amendments, such as the list of preparations and methods for checking, as well as responsible persons and contact persons, should form separate and freely interchangeable appendices to the contract. The benefit lies in the ability to dispense with the need for both sides to regularly carry out time-consuming signing for formal legal reasons. A simple, regular notification of the accumulated changes suffices. If required, acknowledge-ment of receipt notes can be exchanged.

• Clearly define the obligations of each party, for example, by creating separate paragraphs in each case.

The following points relating to the liability limitation contract must be taken into consideration:

1. General duty of disclosure of external laboratory to the relevant authorities.

2. Confirmation that suitable rooms and equipment remain available to carry out the contract analyses.

3. Designation of supervising authorities according to applicable regulations.

• Responsible authorities

• Authorities responsible for the monitoring of narcotic substances

• Authorities responsible for enforcement of infection-protection legislation


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• Authorities responsible for monitoring compliance with animal-protection legislation

• Authorities responsible for the monitoring of GLP basic principles, as required

• Accreditation organization

4. Confirmation that medicinal products are checked for the necessary quality in accordance with recognized pharmaceutical regulations, e.g. by referring to the EU GMP Guideline and/ or the USA GMP regulations (21CFR Parts 210 and 211) as the basis for testing and documentation.

5. Confirmation that the contractor will inform the client of any change in its certification or accreditation.

6. The final responsibility rests with the head of quality control (Qualified Person in the EU) of the drugmaker and cannot be changed under the terms of the contract under any circumstances.

7. Statements on questions of liability

8. Assurance that work awarded to the contractor under the terms of the contract will not be subcontracted to third parties without the written consent of the drugmaker.

9. Information on documentation of the contract analyses (the analysis of starting materials and each medicinal product batch is to be fully documented). Sample documentation is to be provided in an appendix as required (optional).

10. List of persons responsible for all technical questions, provided in the appendix.

11. Information on the storage (periods) of documents and test samples

12. Audit rights for the drugmaker (normally following advance notification and during normal hours of business) and relevant supervisory authorities (see chapter 7.14 of EU GMP Guideline). As an option, contract manufacturers acting on behalf of drugmakers may also be granted indirect rights to carry out audits for their clients.

13. Handling of test procedures

14. Additional duties of contractor to provide information, e.g. in the event of deviations from the specifications (OOS procedure) or the provided test instructions (deviation procedure)

15. Duty of the contractor to inform the client about any change which might influence the provided test instructions (change management)

16. Duty of drugmaker to provide information on approval-compliant data for test implementation purposes as well as special safety instructions for hazardous materials, e.g., zytostatics (safety data sheets, waste disposal information).

17. Storage of raw data and documents (e.g., timelines)


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Sample agreement for contract analysis

Contract for testing of finished medicinal products by contract analysis

(If applicable, can be extended to include raw materials, intermediate products, etc.)

between … company N.N. – hereafter referred to as contract giver –

and the

… contract laboratory … – hereafter referred to as contract acceptor

Preamble

The contract giver is a company dealing with the manufacturing and sale of medicinal products. The contract acceptor operates a laboratory and performs tests and analysis for the contract giver based on individual orders.

The contract acceptor performs tests and analysis used by the contract giver for the release of me-dicinal products. The contractual parties agree on the above-mentioned individual orders being executed in accordance with the stipulations below.

Section 1

The contract acceptor has registered his activities with the relevant national authorities and is au-thorized to carry out external testing of medicinal products by proxy (see Appendix N.N.). The contract acceptor is subject to inspections by … relevant medicinal product supervisory authorities … (medicinal product testing), by the health authorities (handling of pathogens in accordance with infection protec-tion legislation) and veterinary authorities (livestock farming) for district … N.N …), and accreditation according to ISO/IEC 17025; other accreditors, if required. The contract acceptor is performing a QA-system which meets the requirements of GMP rules (e.g., EU GMP Guideline and/or 21 CFR 211, see copy of GMP certificate in appendix N.N., … if available and/or issued by the relevant authorities …).

The contract acceptor possesses a manufacturing license issued by the relevant national authority (if relevant, Appendix N.N.).

Any change that restrains the above mentioned registrations, permissions and accreditations must be communicated immediately to the contract giver in writing.

The contract acceptor appoints the persons named in Appendix N.N. as contact persons for all tech-nical questions.

The contract giver appoints the persons named in Appendix N.N. as contact persons for all technical and organizational questions.

Section 2

The contract giver hereby awards the testing of the quality of the finished medicinal products, inter-mediates, pharmaceutical packaging materials and pharmaceutical raw materials listed in Appendix N.N. according to the specifications and test instructions in this appendix to the contract acceptor. The con-tract sets out the responsibilities of contract giver and contract acceptor pursuant to article 7 of the EU GMP Guideline.


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Section 3

The contract acceptor guarantees that he has adequate specialized know-how and experience as well as sufficiently competent staff to carry out properly the tests and studies assigned to him by the contract giver.

The contract acceptor accepts to execute the orders with due care and as speedily as possible depend-ing on the technical requirements. Delivery periods have to be agreed on separately in writing. In case of doubt, the delivery period is the date of receipt of the order or of the test sample if the latter is received by the laboratory only after the order has been placed.

The tests are to be performed in accordance with the information, test instructions and test speci-fications or test instructions supplied by the contract giver. If the contract giver submits no test speci-fications, the tests are to be performed in accordance with the stipulations of the applicable version of the European Pharmacopeia or U.S. Pharmacopeia (USP). Amendments of test instructions have to be approved by the contract giver.

The contract acceptor bears the responsibility for the consignments as from receipt at the laboratory. He will assure that samples and reference standards made available are properly handled.

If required, the contract acceptor will (re)validate—normally subject to charge – the methods laid down by the contract giver to the necessary extent, for example in the case of relevant equipment modi-fications following the contract giver’s approval and instructions regarding the extent of validation.

The contract acceptor ensures that his equipment is qualified, maintained and calibrated on a regular basis.

The contract acceptor has set up procedures for the analysis, processing and documentation of out-of-specification test results (OOS results), as well as for deviations and change control procedures. The contract acceptor will inform the contract giver of OOS results, as well as of relevant deviations and planned changes affecting the tests ordered on the basis of the standard operating procedures (SOPs) in place at the contract acceptor’s laboratory.

The contract acceptor is not authorized to assign the tasks entrusted to him by the contract giver to third parties without the contract giver’s consent in writing.

The contract acceptor is not compelled to preserve the test samples or any reference samples. The documentation has to be preserved for at least ten years.

Section 4

The contract giver, represented by the Qualified Person and/or the head of Quality Control, bears the ultimate responsibility to ensure that the specifications and test procedures of the products tested by order are appropriate in every respect, particularly that they are validated and in accordance with the marketing authorization.

The contract giver is responsible—if applicable following consultation with the contract acceptor—for sending in appropriate test samples. The contract giver is responsible for sampling, packaging, and transport of samples. He informs the contract acceptor of the storage conditions of samples and refer-ence material in writing.

The head of the contract giver’s Quality Control Department is responsible for approving or reject-ing starting materials, intermediate products and packaging materials pursuant to applicable legal regula-


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tion. Responsibility for release for marketing pursuant to applicable legal regulation lies with the con-tract giver’s Qualified Person/head of QC.

The contract giver has to ensure that the contract acceptor is in a position to conform to the statu-tory obligations incumbent on him in connection with the acceptance, delivery, storage and testing of the contract giver’s samples (particularly for controlled drugs or substances pursuant to the Commodi-ties Control Act and the European directive concerning the appropriation of certain substances for the unlawful production of addictive and psychotropic substances).

The contract giver is responsible for the fact that the specified control methods are in accordance with the state of the art, and that they are validated and suitable to assess the quality. All specifications and test instructions have to be provided to the contract acceptor in writing.

Section 5

The contract acceptor makes the test results available to the contract giver in the form of a test report (certificate of analysis), which is signed by an authorized person.

The contract acceptor provides the contract giver with additional relevant documents in case of OOS investigations and deviations.

The contract acceptor informs the contract giver immediately of any possible closing of the labora-tory, thus the contract giver carries over the documentation to fulfill his duty of documentation.

The contract acceptor provides the contract giver with additional documents, information and as-sessments which are used by the contract giver to compile relevant product quality reviews (PQR) as described in Appendix N.N.

Section 6

In order to fulfill his responsibilities to an appropriate extent, the contract giver is entitled to visit the labo-ratory of the contract acceptor—also on a regular basis, if required—during the analysis of his product. It must be possible to arrange these kinds of visits by prior arrangement with the contract acceptor at any other time.

Section 7

The contract acceptor and the contract giver undertake to keep mutually strict secrecy of both par-ties’ know-how, particularly of the test specifications in as much as they are not generally accessible. The necessary inspections by the supervisory authorities are exempted from these restrictions.

Without consent, neither of the contracting parties is authorized to continue using the expert knowl-edge disclosed to him by the other party following termination of the agreement. The contract giver is exempt from this obligation with regard to the method developments ordered by himself.

The obligation regarding secrecy and non-use of the information does not apply provided:

a) it was already known to the other contractual party before disclosure by a contractual party and the party concerned notifies this immediately, or

b) it is in or will enter the public domain as a result of publication or in some other manner, or

c) it becomes known to one of the contractual parties without originating, directly or indirectly, from the other contractual party.


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Section 8

This contract comes into force when signed by the contractual parties. It shall remain in force for an unlimited period and its termination is subject to a 3-month period of notice.

Changes and additions to this contract must be agreed by both parties and must be made in writing.

The contract acceptor’s general terms and conditions of business shall otherwise apply.

If individual provisions of this contract become ineffective, the remaining provisions shall remain valid; suitable effective ones must replace ineffective provisions.

...................................... .................................... Location, date Location, date

...................................... .................................... Signature contract giver Signature contract acceptor

Appendices

Appendix (responsible persons)

Executive member of staff at contract acceptor responsible for technical-organizational questions: (Name, first name, function, phone, fax, e-mail, specimen signature, paragraphs if necessary)

Executive member of staff at contract giver responsible for technical-organizational questions: (Name, first name, function, phone, fax, e-mail, specimen signature, paragraphs if necessary)

Appendix (list of products for external analysis and required test methods)

Products: Listing + supplement “as well as additional raw materials, intermediate and final products, as required”

Appendix (test method: listing) Appendix (manufacturing license, if available) Appendix (GMP certificate, if available) Appendix (comparison of responsibilities, if required) Appendix (sample documents, if required) Appendix (information for product quality report provided by the contract acceptor)


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Test procedure—Who is responsible for what?

In practice, meaningful test procedures are not always available or do not always correspond to the pharmacopeias.

Test procedures must generally be compiled in writing prior to the analysis. They also must also provide information on sampling. These must correspond with the application or registration documents. The pharmaceutical manufacturer either owns the marketing authorization itself or is acting as the contract manufacturer on behalf of the owner of a marketing authorization. From a legal point of view, therefore, the drugmaker clearly has that greater proximity to, and sphere of influence over, approval or registration. During the contract-award process, the test procedures coordinated with the application file for marketing authorization must be handed over by the drugmaker.

Review of the literature suggests that in formal legal terms the reference to a pharmacopeia mono-graph can be recognized as an adequate test procedure. This of course does not relieve the drug-maker of the obligation of regulatory conformity and (re)validation. Contractually, the problem can be solved by arranging for the tests to be carried out according to the specific requirements of the drugmaker. If additional information beyond the pharmacopeia test methods remains necessary, an individual product-specific test method must be used. If these do not exist, the contractor may suggest a method. If no other arrangement has been made, then the analysis should be carried out according to the relevant current version of the appropriate pharmacopeia, such as the European Pharmacopeia or the USP, if relevant. Legal specialists even recommend specifying a deadline in such a case. If the drugmaker does not object to this time limit, a “fictional agreement” can be assumed by implication. Strictly speaking, this procedure only applies for a limited number of procedures that do not indicate a product specific validation.

Questions of liability

Apart from legal liability, the following options have proven suitable to the requirements of the pharmaceutical industry. These take into account the special situation of the contract laboratory, as they cannot be connected to the pool of pharmaceutical insurers’ liability limitation.

• Liability limitation according to amount (partial waiver of recourse): In this case, the extent of liability in the event of damages arising from pharmaceutical liability (see federal state law) resulting from defects in the service rendered by the contract laboratory is limited to the total sum insured under the terms of the company liability insurance. This partial waiver of recourse requires the consent of the drugmaker’s pharmaceutical insurer in every case.

• Liability limitation based on fault: It can be arranged that the drugmaker is only liable if the de-ficient service rendered is due to deliberate and/or grossly negligent acts. For simple negligence, no recourse can be requested. In every case, liability exclusion for deliberate and/or grossly neg-ligent acts is not legally permissible. The drugmaker’s pharmaceutical insurer must also accept this where it is a consequence of a partial waiver of recourse.

• Full waiver of recourse: In the event of damages, the drugmaker fully waives any assertion of claims against the contract laboratory. In the liability limitation contract, the drugmaker expressly declares a waiver of recourse. The pharmaceutical insurer must agree to such an arrangement.


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• Limitation of liability to direct deficiencies: The contractor can limit its liability to the repetition of analyses free of charge where a claim for damages is made due to deficient services rendered. With this option, the consent of the pharmaceutical insurer is also required.

The listed liability options can be partially combined. Due to ongoing changes in liability law, legal experts should formulate and regularly review the relevant provisions in a liability limitation contract. This section primarily applies within the EU. In the U.S., liability laws differ and generally are not the subject of FDA regulation. FDA liability only concerns the proper application of GMP; the financial risks associated with GMP remain independent of the FDA’s consideration. Therefore, legal experts should always be consulted relative to financial and insurance liability questions and answers as they pertain to the U.S.

Certificate of Analysis

Once testing is established at the contract laboratory, the drugmaker, as a matter of routine operation, receives a certificate of analysis concerning the performed tests. This certificate should contain the re-sults and the applied methods, as well as permit identification of the samples. The contracting laboratory archives the raw data. Since the drugmaker must prove during inspections that the contracting laboratory carried out the tests according to validated methods that comply with the accreditation, it may be helpful if the documentation for at least one complete batch test remains available there.

The Certificate of Analysis should contain the following information:

• Identification of sample

• Name of client, customer number (if applicable)

• Batch identification of the customer

• Identification number of the customer at the contracting laboratory

• Results and specifications

• Agreed and applied methods

• Signature of the person responsible for the testing

• If applicable, indication whether an OOS result has been detected and reference to OOS processing

• If applicable, reference to deviations during testing

The analysis results can be made available to the client in the form of reports on paper or electroni-cally. The person responsible for testing should sign the certificate, either with a pen or electronic signature. Personnel authorized to sign at the contracting laboratory should, if required, be listed with signature samples in an enclosure to the contract and be subject to a change procedure.

Deviations to the specified test procedure or OOS results are generally disclosed to the client, along with the certificate of analysis, through the QA procedures established at the contracting laboratory. The client retains responsibility for entering this information into its system and making it available to the person responsible for the release of the batch.


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Furthermore, the marketing authorization holder and the QP responsible for product release must evaluate the tests carried out by order for the preparation of a Product Quality Review (PQR). The client can agree with the contracting laboratory that, for example, the laboratory should make available ten-dency evaluations for the tests, evaluations of OOS processing or deviations.

It is in the interest of the drugmaker that it receives usable testing data as well as required evaluations.

It is imperative that the contract laboratory receives clear specifications and additional information necessary for the certification of test results.

Reportable values

The test instructions must clearly define the reportable value. This is necessary given the unequal approaches among companies concerning the evaluation of OOS results. Some companies examine each result of single injections (e.g., in HPLC or GC analysis) as a reportable value, which they must prove against the specification. Other companies calculate the mean of a number of injections as the report-able value, which here must be proven against a specification. The contract laboratory must be aware of this, especially in the case of OOS investigations. Therefore, it must be clarified which result—single or mean—must be proven against the specification and which result garners a mention on the certificate of analysis. The test instruction must include the calculation and a clear description.

Evaluation of microbiological enumeration tests

The evaluation of microbiological enumeration tests involves greater complexity. The European Pharmacopeia and USP specify limits for germ counts within different medicinal products. Addition-ally, the type of germs should be assessed even when a germ count remains under the limit of the speci-fication. The harmonized monograph of acceptance criteria for microbiological quality of non-sterile dosage forms states that the significance of other micro-organisms recovered in the test and not listed in the monograph should be evaluated in terms of use of the product, nature of the product, method of application, intended recipient, use of immunosuppressive agents and presence of disease. Therefore, the contract laboratory and the drugmaker must define in which case additional investigation (e.g., further identification of germs or risk assessments) would be necessary.

Other microbiological or biological pharmacopeia tests are easily evaluated. Examples include steril-ity or pyrogen testing. In the case of pyrogen testing, the networking of data can ensure whether permis-sible retesting in suspected cases can be taken into account when calculating the final values.

Transfer of the test to the contract laboratory

The party responsible for the test must guarantee the application of validated, authorization-compli-ant analytical methods. The methods must be transferred in a way that the tests remain valid when an external laboratory receives an assignment to perform the task.

No official guideline defines the transfer of analytical procedures. Parameters, including devices, equipment and process flow that involve personnel, are indirectly analyzed in scope of the transfer as far as materials such as culture media, reference substances and so on are concerned.

Therefore, the transfer of methods could be considered a revalidation, which must be carried out if parameters change within the test procedures, or as an “interlaboratory test” between two or more parties.


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Transfer plan

Before routine testing at an external laboratory can begin, all parties subject to the contract must agree on a transfer plan that guarantees testing will proceed as the manufacturer original envisioned. The party with the most experience with the specific testing method should develop the plan, whether that is the drugmaker or the contractor.

The laboratory taking over must review regulations and available documents, including analytical procedures, validation methods, results of System Suitability Tests (SST) and, if applicable, any previ-ously conducted revalidations and transfers.

The laboratory taking over must verify whether it can carry out the procedure exactly as described in the test instructions included in the transfer plan. Should an assessment of the available documentation suggest that the contracting laboratory needs to make serious changes to the validated and authorized method in order to implement a revalidation of certain parameters, that would require a completely new validation of the procedure according to ICH-Guideline Q2(R1).

The transfer plan also should consider the volume of the transfer tasks and suitable acceptance crite-ria as well as:

• Goal-setting for the analytical transfer;

• Definition of the test procedures to be transferred and specifications of the products to be applied;

• Test regulations to be applied, with reference to the available validation reports;

• Description of the samples, equipment, reagents, media, reference substances, strain organisms and other working materials;

• Determination who provides standards, samples and, where applicable, placebos;

• Description of the tasks and tests to be carried out (amount of preparations and injections, SSTs to be applied, staff to be involved, evaluation and calculation of the results, etc.);

• Form of report for the results; and

• Procedure for statistical evaluations.

Once transfer is complete, one of the parties should prepare a report that includes a description of the results, a list of the tasks carried out, specific observations and any deviations from the transfer plan. Each party should sign the report confirming the correctness of the data.

Transfer of analytical procedures

To ensure successful transfer of analytical methods, it is helpful to have both the laboratory holding the original contract and the subcontracted laboratory split a sample for individual testing. If both laboratories get the same result, the subcontractor’s ability to conduct the testing according to plan is validated. The robustness of the procedure in general usually does not undergo testing during the transfer of test methods.

During chromatographical testing, additional information, such as linearity and specificity, must be available. In some cases, information concerning the limit of quantification and the limit of detection should be evaluated.


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If development and validation of the procedure in which the separation capacity of the system is tested generated a significant System Suitability Test (SST) during development and validation of the procedure in which the separation capacity of the system is tested, then the laboratory taking over may omit a revalidation of the specificity of the method may be omitted in the laboratory taking over. The SST can be amended for the transfer of methods in a way that, for example, the linearity of the proce-dure is may be determined with a multipoint calibration in the determination area to be able to keep on working with a single-point calibration.

In the event of a change in a laboratory that precludes the possibility of involving the previous labo-ratory, the basis of the available validation documents must be weighed in deciding whether a new vali-dation is necessary or a revalidation of individual parameters would suffice. In case of chromatographic procedures values for the evaluation of specificity, linearity, accuracy and precision of the range, beyond the detection and determination, limits should be generated for contamination during the test. These data must then be compared with the initial validation of the procedure in order to evaluate whether the procedure remains valid within the laboratory taking over.

Since the tasks to be carried out depend on the quality of already existing documents, the method itself and any previous experiences, the transfer should be planned and carried out on the basis of a suit-able risk evaluation.

Transfer of microbiological methods

The pharmacopeias describe the validation of microbiological methods. Testing reveals whether the products inhibit microbial growth. In addition, the detection of key bacteria tests the selective character-istics of the method.

It is not feasible to prepare a sample with microbial contamination that may be later distributed to the laboratories for testing. Microbiological methods are generally newly validated in the test facility tak-ing over. This makes sense, as high variance has been observed in microbiological methods. The Euro-pean Pharmacopeia demands, for example, in chapter 2.6.1, Test for Sterility, that the method should be newly validated, among other things, in case of any change to experimental conditions.

The extent of the validation for the transfer of methods must also be scrutinized during microbiologi-cal methods—for example, in form of a risk evaluation. In general, a one-time evaluation of a sample suffices for materials and preparations known to have no inhibiting influence on microbial growth.

A suitable preliminary preparation of the samples, such as dilution, filtration and rinsing or addition of substances that can neutralize the growth-inhibiting characteristics, may be necessary for materials and preparations that have inhibiting influences on the microbial growth, such as antibiotic preparations.

In these cases, the transfer of the method to another laboratory could possibly comprise several validation runs, since it must be guaranteed that the procedure for the elimination of growth-inhibiting characteristics proves robust enough to function under usual laboratory fluctuations. According to the USP, three validation runs are required if procedures contain the elimination of growth inhibitors.

Handling of samples

The producer or the company marketing the product usually carries out sampling. The samples are taken according to already existing sampling instructions and then sent to the contracting laboratory.


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Sampling by the tasked laboratory generally plays a more important role only in case of tests concern-ing plant hygiene. That is because in such a case, special equipment and techniques unavailable to the contractor prove partly necessary. Should such activities for sampling be handed over to external labora-tories, first of all, suitable sampling instructions must be made available to the laboratory.

It is appropriate to subject the sample transport to a risk evaluation and then document the critical steps. The validation of the transport may also be necessary where sensitive samples are concerned.

The contracting laboratory must be informed in advance about special sample storage requirements. It in turn must then declare whether it can comply with these specifications. An SOP usually describes the storage of samples, with adjustments to be made where applicable. The compliance with special stor-age specifications, for example cold storage or storage under –20°C, should be documented.

In case a third party, such as a postal or courier service, subjects temperature-sensitive samples to storage or transport over a longer period of time, then monitoring, per data loggers or testing of the temperature, must occur upon receipt of the samples. Furthermore, the process requires discerning which sample container can be used so that the sample is not compromised during transport. For example, attention has to be paid to suitable light protection as well as the gas and water vapor tightness of the sample containers.

In special cases where TOC or bacterial endotoxins testing in water for pharmaceutical purposes requires sterile or especially cleaned containers, the laboratory may provide them, since it already has established the necessary sterilization, depyrogenisation and cleaning procedures.

For samples subject to influence during transport that may cause changes, suitable transport condi-tions and, if necessary, maximum transport periods shall be defined and procedures established defin-ing how they can be monitored and documented. Furthermore, the procedures should spell out how to proceed in case of deviations.

Microbiological samples that cannot tolerate microbial growth or the death of the organisms (e.g., wa-ter samples or aqueous solutions) should be shipped at 2–8°C. Refrigerated boxes or thermal packs often suffice. Such samples should be processed preferably within 24 hours. Therefore, it must be determined beforehand whether the contracting laboratory can accept and process samples on weekends and holidays.

In contrast, culture media, such as agar plates or strips from air samplers, can be transported at room temperature, since secondary microbial growth only leads to enlargement of the colony forming units (cfu) and does not increase the amount of cfu on the plate.

Samples that require superficial disinfection, as the test occurs in clean rooms or isolators, should be packed and transported in clean plastic containers that can be easily disinfected—and not in boxes with Styrofoam pellets.


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AppendicesA. Eudralex Chapter 7 — Outsourced Activities

B. EU GMP Guide, Annex 16 – Certification by a Qualified Person and Batch Release

Appendix A: Eudralex Chapter 7 — Outsourced Activities

EUROPEAN COMMISSION HEALTH AND CONSUMERS DIRECTORATE-GENERAL

Health Systems and Products Medicinal Products - Quality, safety and efficacy

Brussels, SANCO/AM/sl/ddg1.d.6(2012)860362

EudraLex

The Rules Governing Medicinal Products in the European Union Volume 4

EU Guidelines forGood Manufacturing Practice for

Medicinal Products for Human and Veterinary Use

Chapter 7Outsourced Activities

Legal basis for publishing the detailed guidelines: Article 47 of Directive 2001/83/EC on the Community code relating to medicinal products for human use and Article 51 of Directive 2001/82/EC on the Community code relating to veterinary medicinal products. This document provides guidance for the interpretation of the principles and guidelines of good manufacturing practice (GMP) for medicinal products as laid down in Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use.

Status of the document: revision 1

Reasons for changes: In view of the ICH Q10 guideline on the Pharmaceutical Quality System, Chapter 7 of the GMP Guide has been revised in order to provide updated guidance on outsourced GMP regulated activities beyond the current scope of contract manufacture and analysis operations. The title of the Chapter has been changed to reflect this.

Deadline for coming into operation: 31 January 2013

Ref. Ares(2012)778531 - 28/06/2012

Commission Européenne, B-1049 Bruxelles / Europese Commissie, B-1049 Brussel – Belgium. Telephone: (32-2) 299 11 11 Principle

Any activity covered by the GMP Guide that is outsourced should be appropriately defined, agreed and controlled in order to avoid misunderstandings which could result in a product or operation of unsatisfactory quality. There must be a written Contract between the Contract Giver and the Contract Acceptor which clearly establishes the duties of each party. The Quality Management System of the Contract Giver must clearly state the way that the Qualified Person certifying each batch of product for release exercises his full responsibility.

Note: This Chapter deals with the responsibilities of manufacturers towards the Competent Authorities of the Member States with respect to the granting of marketing and manufacturing authorizations. It is not intended in any way to affect the respective liability of Contract Acceptors and Contract Givers to consumers; this is governed by other provisions of Community and national law.

General

7.1 There should be a written Contract covering the outsourced activities, the products or operations to which they are related, and any technical arrangements made in connection with it.

7.2 All arrangements for the outsourced activities including any proposed changes in technical or other arrangements should be in accordance with regulations in force, and the Marketing Authorisation for the product concerned, where applicable.

7.3 Where the marketing authorization holder and the manufacturer are not the same, appropriate arrangements should be in place, taking into account the principles described in this chapter.

The Contract Giver

7.4 The pharmaceutical quality system of the Contract Giver should include the control and review of any outsourced activities. The Contract Giver is ultimately responsible to ensure processes are in place to assure the control of outsourced activities. These processes should incorporate quality risk management principles and notably include:

7.5 Prior to outsourcing activities, the Contract Giver is responsible for assessing the legality, suitability and the competence of the Contract Acceptor to carry out successfully the outsourced activities. The Contract Giver is also responsible for ensuring by means of the Contract that the principles and guidelines of GMP as interpreted in this Guide are followed.

7.6 The Contract Giver should provide the Contract Acceptor with all the information and knowledge necessary to carry out the contracted operations correctly in accordance with regulations in force, and the Marketing Authorisation for the product concerned. The Contract Giver should ensure that the Contract Acceptor is

fully aware of any problems associated with the product or the work which might pose a hazard to his premises, equipment, personnel, other materials or other products.

7.7 The Contract Giver should monitor and review the performance of the Contract Acceptor and the identification and implementation of any needed improvement.

7.8 The Contract Giver should be responsible for reviewing and assessing the records and the results related to the outsourced activities. He should also ensure, either by himself, or based on the confirmation of the Contract Acceptor’s Qualified Person, that all products and materials delivered to him by the Contract Acceptor have been processed in accordance with GMP and the marketing authorisation.

The Contract Acceptor

7.9 The Contract Acceptor must be able to carry out satisfactorily the work ordered by the Contract Giver such as having adequate premises, equipment, knowledge, experience, and competent personnel.

7.10 The Contract Acceptor should ensure that all products, materials and knowledge delivered to him are suitable for their intended purpose.

7.11 The Contract Acceptor should not subcontract to a third party any of the work entrusted to him under the Contract without the Contract Giver’s prior evaluation and approval of the arrangements. Arrangements made between the Contract Acceptor and any third party should ensure that information and knowledge, including those from assessments of the suitability of the third party, are made available in the same way as between the original Contract Giver and Contract Acceptor.

7.12 The Contract Acceptor should not make unauthorized changes, outside the terms of the Contract, which may adversely affect the quality of the outsourced activities for the Contract Giver.

7.13 The Contract Acceptor should understand that outsourced activities, including contract analysis, may be subject to inspection by the competent authorities.

The Contract

7.14 A Contract should be drawn up between the Contract Giver and the Contract Acceptor which specifies their respective responsibilities and communication processes relating to the outsourced activities. Technical aspects of the Contract should be drawn up by competent persons suitably knowledgeable in related outsourced activities and Good Manufacturing Practice. All arrangements for outsourced activities must be in accordance with regulations in force and the Marketing Authorisation for the product concerned and agreed by both parties.

7.15 The Contract should describe clearly who undertakes each step of the outsourced activity, e.g. knowledge management, technology transfer, supply chain, subcontracting, quality and purchasing of materials, testing and releasing materials,

undertaking production and quality controls (including in-process controls, sampling and analysis).

7.16 All records related to the outsourced activities, e.g. manufacturing, analytical and distribution records, and reference samples, should be kept by, or be available to, the Contract Giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect or to investigating in the case of a suspected falsified product must be accessible and specified in the relevant procedures of the Contract Giver.

7.17 The Contract should permit the Contract Giver to audit outsourced activities, performed by the Contract Acceptor or his mutually agreed subcontractors

Appendix B: EU GMP Guide, Annex 16 – Certification by a Qualified Person and Batch Release

Version 8 (final)

EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL

Single market, regulatory environment, industries under vertical legislationPharmaceuticals and cosmetics

Brussels, July 2001

S\common\legal-legislation\75-319nd81-851\91-356\eudralexvol4\Annex 15

Working Party on Control of Medicines and Inspections

Final Version of Annex 16 to the EU Guide to Good Manufacturing Practice

Title: Certification by a Qualified Person and Batch Release

.

Discussion in Working group June to November 1999

Transmission of Draft 3 to the Pharmaceutical Committee September 1999 Transmission of Draft 4 to Interested Parties December 1999

Deadline for comments on Draft 4 May 2000 Consideration by drafting group and working party July to October 2000

Consideration of Draft 5 by Working Party November 2000 Transmission of Draft 6 to Interested Parties January 2001

Draft 7 showing comments received by 15 March April 2001 Pharmaceutical Committee (for information) April 2001

Date for coming into operation January 2002

European Commission Enterprise Directorate General

Annex to the Guide to Good Manufacturing Practice for Medicinal Products: Certification by a Qualified Person and Batch Release 2

1. Scope

1.1 This annex to the Guide to Good Manufacturing Practice for Medicinal Products ("the Guide") gives guidance on the certification by a Qualified Person (Q.P.) and batch release within the European Community (EC) or European Economic Area (EEA) of medicinal products holding a marketing authorisation or made for export. The relevant legislative requirements are contained in Article 51 of Directive 2001/83/EC or Article 55 of Directive 2001/82/EC.

1.2 The annex covers in particular 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 which have been imported to the EC/EEA both when there is and is not a mutual recognition agreement between the Community and the third country. The guidance may also be applied to investigational medicinal products, subject to any difference in the legal provisions and more specific guidance in Annex 13 to the Guide.

1.3 This annex does not, of course, describe all possible arrangements which are legally acceptable. Neither does it address the official control authority batch release which may be specified for certain blood and immunological products in accordance with Article 11 point 5.4 and Articles 1091 and 110 of Directive 2001/83/EC.

1.4 The basic arrangements for batch release for a product are defined by its Marketing Authorisation. Nothing in this annex should be taken as overriding those arrangements.

2. Principle

2.1 Each batch of finished product must be certified by a Q.P. within the EC/EEA before being released for sale or supply in the EC/EEA or for export.

2.2 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 authorisation, the principles and guidelines of EC Good Manufacturing Practice or the good manufacturing practice of a third country recognised as equivalent under a mutual recognition agreement and any other relevant legal requirement before it is placed on the market, and

• in the event that a defect needs to be investigated or a batch recalled, to ensure that the Q.P. who certified the batch and the relevant records are readily identifiable.

3. Introduction

1 As amended by Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC (OJ L 33, 8.2.2003, p.30)



3.1 Manufacture, including quality control testing, of a batch of medicinal productstakes place in stages which may be conducted at different sites and by different manufacturers. Each stage should be conducted in accordance with the relevant marketing authorisation, Good Manufacturing Practice and the laws of the Member

State concerned and should be taken into account by the Q.P. who certifies the finished product batch before release to the market.

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

3.3 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 authorisation, that the manufacturer is authorised according to the laws of the country concerned and that manufacture follows good manufacturing practices at least equivalent to those of the EC.

3.4 Certain words used in this annex have particular meanings attributed to them, as defined in the glossary.

4. General

4.1 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 authorisations and should have at its disposal the services of at least one Q.P. However the correct manufacture of a particular batch of product, regardless of how many sites are involved, should be the overall concern of the Q.P. who certifies that finished product batch before release.

4.2 Different batches of a product may be manufactured or imported and released at different sites in the EC/EEA. For example a Community marketing authorisation may name batch release sites in more than one member state, and a national authorisation may also name more than one release site. In this situation the holder of the marketing authorisation and each site authorised to release batches of the product should be able to identify the site at which any particular batch has been released and the Q.P. who was responsible for certifying that batch.

4.3 The Q.P. who certifies a finished product batch before release may do so based on his 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 he may rely on the confirmation by one or more other Q.P.s of the compliance of intermediate stages of manufacture within a quality system which he has accepted.

This confirmation by other Q.P.s should be documented and should identify clearly the matters which have been confirmed. The systematic arrangements to achieve this should be defined in a written agreement.



4.4 The agreement mentioned above is required whenever a Q.P. wishes to rely on the confirmation by another Q.P. The agreement should be in general accordance with Chapter 7 of the Guide. The Q.P. who certifies the finished product batch should ensure the arrangements in the agreement are verified. The form of such an agreement should be appropriate to the relationship between the parties; for example a standard operating procedure within a company or a formal contract between different companies even if within the same group.

4.5 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 results, non-compliance with GMP, investigations, complaints or other matters which should be taken into account by the Q.P. who is responsible for certifying the finished product batch.

4.6 When a computerised system is used for recording certification and batch release, particular note should be taken of the guidance in Annex 11 to this Guide.

4.7 Certification of a finished product batch against a relevant marketing authorisation by a Q.P. in the EC/EEA need not be repeated on the same batch provided the batch has remained within the EC/EEA.

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

5. Batch testing and release of products manufactured in EC/EEA

5.1 When all manufacture occurs at a single authorised 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 Q.P. at this site who certifies the finished product batch normally retains personal responsibility for these within a defined quality system. However he may, alternatively, take account of the confirmation of the intermediate stages by other Q.Ps on the site who are responsible for those stages.

5.2 Different stages of manufacture are conducted at different sites within the same company

When different stages of the manufacture of a batch are carried out at different sites within the same company (which may or may not be covered by the same manufacturing authorisation) a Q.P. should be responsible for each stage. Certification of the finished product batch should be performed by a Q.P. of the manufacturing authorisation 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 Q.P.s responsible for those stages.



5.3 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 authorisation in another company. A Q.P. of the contract giver may take account of the confirmation of the relevant stage by a Q.P. 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 a Q.P. of the manufacturing authorisation holder responsible for releasing the batch to the market.

5.4 A bulk production batch is assembled at different sites into several finished product batches which are released under a single marketing authorisation. This could occur, for example, under a national marketing authorisation when the assembly sites are all within one member state or under a Community marketing authorisation when the sites are in more than one member state.

5.4.1 One alternative is for a Q.P. of the manufacturing authorisation holder making the bulk production batch to certify all the finished product batches before release to the market. In doing so he may either take personal responsibility for all manufacturing stages or take account of

the confirmation of assembly by the Q.P.s of the assembly sites.

5.4.2 Another alternative is for the certification of each finished product batch before release to the market to be performed by a Q.P of the manufacturer who has conducted the final assembly operation. In doing so he may either take personal responsibility for all manufacturing stages or take account of the confirmation of the bulk production batch by a Q.P. of the manufacturer of the bulk batch

5.4.3 In all cases of assembly at different sites under a single marketing authorisation, there should be one person, normally a Q.P. of the manufacturer of the bulk production batch, who has an overall responsibility for all released finished product batches which 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 co-ordinate 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.

5.5 A bulk production batch is assembled at different sites into several finished product batches which are released under different marketing authorisations. This could occur, for example, when a multi-national organisation holds national marketing authorisations for a product in several member states or when a generic manufacturer purchases bulk products and assembles and releases them for sale under his own marketing authorisation.

5.5.1 A Q.P. 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 Q.P. of the bulk product manufacturer.

5.5.2 Any problem identified in any of the finished product batches which may have arisen in the bulk production batch should be communicated to the Q.P. responsible for confirming the bulk production batch, who should then take any necessary action in respect of all finished product batches produced from the suspected bulk production batch. This arrangement should be defined in a written agreement.

5.6 A finished product batch is purchased and released to the market by a manufacturing authorisation holder in accordance with his own marketing authorisation. This could occur, for example, when a company supplying generic products holds a marketing authorisation for products made by another company, purchases finished products which have not been certified against his marketing authorisation and releases them under his own manufacturing authorisation in accordance with his own marketing authorisation.

In this situation a Q.P. of the purchaser should certify the finished product batch before release. In doing so he may either take personal responsibility for all manufacturing stages or may take account of the confirmation of the batch by a Q.P. of the vendor manufacturer.

5.7 The quality control laboratory and the production site are authorised under different manufacturing authorisations.

A Q.P. certifying a finished product batch may either take personal responsibility for the laboratory testing or may take account of the confirmation by another Q.P. of the testing and results. The other laboratory and Q.P. need not be in the same member state as the manufacturing authorisation holder releasing the batch. In the absence of such confirmation the Q.P. should himself have personal knowledge of the laboratory and its procedures relevant to the finished product to be certified.

6. Batch testing and release of products imported from a third country.

6.1 General:

6.1.1 Importation of finished products should be conducted by an importer as defined in the glossary to this annex.

6.1.2 Each batch of imported finished product should be certified by a Q.P. of the importer before release for sale in the EC/EEA.

6.1.3 Unless a mutual recognition agreement is in operation between the Community and the third country (see Section 7), samples from each batch should be tested in the EC/EEA before certification of the finished product batch by a Q.P. Importation and testing need not necessarily be performed in the same member state.

6.1.4 The guidance in this section should also be applied as appropriate to the importation of partially manufactured products.



6.2 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 Q.P of the importer before release. This Q.P. may take account of the confirmation of the checking, sampling or testing of the imported batch by a Q.P. of another manufacturing authorisation holder (i.e. within EC/EEA).

6.3 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.

6.3.1 A Q.P. of the importer receiving a subsequent part of the batch may take account of the testing and certification by a Q.P. of the first part of the batch. If this is done, the Q.P. should ensure, based on evidence, that the two parts do indeed 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.

6.3.2 The conditions in paragraph 6.3.1 is most likely to be met when the manufacturer in the third country and the importer(s) in the EC/EEA belong to the same organisation operating under a corporate system of quality assurance. If the Q.P. cannot ensure that the conditions in paragraph 6.3.1 are met, each part of the batch should be treated as a separate batch.

6.3.3 When different parts of the batch are released under the same marketing authorisation, one person, normally a Q.P. 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. He should be made aware of any quality problems reported on any part of the batch and should co-ordinate any necessary action concerning these problems and their resolution.

This should be ensured by a written agreement between all the importers concerned.

6.4 Location of sampling for testing in EC/EEA

6.4.1 Samples should be representative of the batch and be tested in the EC/EEA. In order 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 in order to represent the batch after storage and transportation some samples should also be taken after receipt of the batch in the EC/EEA.

6.4.2 When any samples are taken in a third country, they should either be shipped with and under the same conditions as the batch which 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 Q.P. wishes to rely on testing of samples taken in a third country, this should be justified on technical grounds.



7. Batch testing and release of products imported from a third country with which the EC has a mutual recognition agreement (MRA).

7.1 Unless otherwise specified in the agreement, an MRA does not remove the requirement for a Q.P. 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 Q.P. of the importer may rely on the manufacturer’s confirmation that the batch has been made and tested in accordance with its marketing authorisation and the GMP of the third country. and need not repeat the full testing. The Q.P. may certify the batch for release when he 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 as defined in section 8.

7.2 Other procedures, including those for receipt and certification of part batches at different times and/or at different sites, should be the same as in Section 6.

8. Routine duties of a Qualified Person

8.1 Before certifying a batch prior to release the Q.P. doing so should ensure, with reference to the guidance above, that at least the following requirements have been met:

a) the batch and its manufacture comply with the provisions of the marketing authorisation (including the authorisation required for importation where relevant);

b) manufacture has been carried out in accordance with Good Manufacturing Practice or, in the case of a batch imported from a third country, in accordance with good manufacturing practice standards at least equivalent to EC GMP;

c) the principal manufacturing and testing processes have been validated; account has been taken of the actual production conditions and manufacturing records;

d) any deviations or planned changes in production or quality control have been authorised by the persons responsible in accordance with a defined system. Any changes requiring variation to the marketing or manufacturing authorisation have been notified to and authorised by the relevant authority;

e) all the necessary checks and tests have been performed, including any additional sampling, inspection, tests or checks initiated because of deviations or planned changes;

f) all necessary production and quality control documentation has been completed and endorsed by the staff authorised to do so;

g) all audits have been carried out as required by the quality assurance system;

h) the QP should in addition take into account any other factors of which he is aware which are relevant to the quality of the batch



A Q.P. may have additional duties in accordance with national legislation or administrative procedures.

8.2 A Q.P. who confirms the compliance of an intermediate stage of manufacture, as described in paragraph 4.3, has the same obligations as above in relation to that stage unless specified otherwise in the agreement between the Q.P.s.

8.3 A Q.P. should maintain his knowledge and experience up to date in the light of technical and scientific progress and changes in quality management relevant to the products which he is required to certify.

8.4 If a Q.P. is called upon to certify a batch of a product type with which he is unfamiliar, for example because the manufacturer for whom he works introduces a new product range or because he starts to work for a different manufacturer, he should first ensure that he has gained the relevant knowledge and experience necessary to fulfil this duty. In accordance with national requirements the Q.P. may be required to notify the authorities of such a change and may be subject to renewed authorisation.



9 Glossary

Certain words and phrases in this annex are used with the particular meanings defined below. Reference should also be made to the Glossary in the main part of the Guide.

Bulk production batch: a batch of product, of a size described in the application for a marketing authorisation, either ready for assembly into final containers or in individual containers ready for assembly to final packs. (A bulk production batch may, for example, consist of a bulk quantity of liquid product, of solid dosage forms such as tablets or capsules, or of filled ampoules).

Certification of the finished product batch: the certification in a register or equivalent document by a Q.P., as defined in Article 51 of Directive 2001/83/EC and Article 55 of Directive 2001/82/EC, before a batch is released for sale or distribution.

Confirmation: a signed statement that a process or test has been conducted in accordance with GMP and the relevant marketing authorisation, as agreed in writing with the Q.P. responsible for certifying the finished product batch before release. Confirm and confirmedhave equivalent meanings.

Finished product batch: with reference to the control of the finished product, a finished product batch is defined in Part 1 Module 3 point 3.2.2.5 of Directive 2001/83/EC2 and in Part 2 section F 1 of Directive 2001/82/EC. In the context of this annex the term in particular denotes the batch of product in its final pack for release to the market.

Importer: the holder of the authorisation required by Article 40.3 of Directive 2001/83/EC and Article 44.3 of Directive 2001/82/EC for importing medicinal products from third countries.

Mutual Recognition Agreement (MRA): the ‘appropriate arrangement’ between the Community and an exporting third country mentioned in Article 51(2) of Directive 2001/83/EC and Article 55(2) of Directive 2001/82/EC.

Qualified Person (Q.P.): the person defined in Article 48 of Directive 2001/83/EC and Article 52 of Directive 2001/82/EC.

2 Amended by Commission Directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (OJ L 159, 27.06.2003, p.46)

About the AuthorsFrank Boettcher, head of quality management at Labor L+S AG, is also a consultant and author on

quality assurance and pharmaceutical analysis topics. His career has included positions as the head of laboratories for Solvay Pharmaceuticals GmbH, and head of quality control for Wülfing Pharma GmbH.

Michael Hiob is head of the medicinal products, pharmacies and narcotics section and in charge of the supervision of the GMP-inspection services at the German Ministry for Health of Land Schleswig-Holstein. He is an expert in numerous committees, e.g. of EMEA and ICH. He is a member of the expert group on “Qualification/Validation” (1998-2008 head of the group) and associate lecturer at the University of Kiel.

Max Lazar, following a 40-year career in the pharmaceutical industry, established a consulting busi-ness specializing in API GMP issues and the training of personnel covering the ICH Q7A guidance.

Thomas Peither has been a GMP consultant for more than 18 years and an expert in the Euro-pean GMPs. He co-founded the GMP publishing company Maas & Peither (Germany, USA) and the midsize pharma consulting company Halfmann Goetsch Peither (Switzerland, Germany, Singapore), which advises numerous pharmaceutical companies.

Cornelia Wawretschek is a pharmaceutical quality consultant whose work with the pharmaceuti-cal industry dates back to 1979. Her experience includes work with Dr. Mann Pharma Berlin and Schering AG Berlin, where she was responsible for GMP optimization, SOP systems, manufacturing documentation, preparation and execution of audits and inspections by authorities, training programs, qualification and validation.

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