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How to Apply DQ/IQ/OQ/PQ in New Framework

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How to Apply DQ/IQ/OQ/PQ in New Framework

This paper explains what European Annex 15 covers (excluding Cleaning Validation that is covered in other papers) and how it links to modern Process Validation (PV).

Note the regulatory authorities have said they expect to update Annex 15 -one assumes to align with the as yet unpublished final version of the EMA PV Guidance. (A draft was issued in Mar 2012 for comment by Oct 2012).

Annex 15

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Annex 15 is entitled ‘Qualification and Validation’ and is laid out as follows:

  1. Qualification and Validation (Principles)
  2. Planning for Validation
  3. Documentation
  4. Qualification
  5. Process Validation.
  6. Cleaning Validation
  7. Change Control
  8. Revalidation
  9. Glossary

Section 1 on Principles has one paragraph which in fact only mentions 3 Principles:

  • It is a requirement under GMP to identify what to validate
  • The use of a risk based approach, “A risk assessment approach should be used to determine the scope and extent of validation”
  • Making changes: “Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated.”

The remainder of Annex 15 covers the processes to be used i.e. VMP, DQ, IQ, OQ, PQ, see below.

It says that all validation activities should be planned. The key elements of a validation programme should be defined and documented in a validation master plan (VMP) or equivalent documents.

The VMP should be a summary document which is brief, concise and clear and contains data on at least the following:

  1. Validation policy
  2. Organisational structure of validation activities
  3. Summary of facilities, systems, equipment and processes to be validated
  4. Documentation format: the format to be used for protocols and reports
  5. Planning and scheduling
  6. Change control
  7. Reference to existing documents.

Annex 15 defines the terms DQ, IQ, OQ, PQ and Process Validation as follows:

  • Design qualification (DQ)

The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.

  • Installation Qualification (IQ)

The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations.

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  • Operational Qualification (OQ)

The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.

  • Performance Qualification (PQ)

The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.

  • Process Validation

The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes

Regarding Process Validation it says that, “It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the process.”

For documentation, Annex 15 says a protocol should be written specifying how validation and qualification will be carried out, specifying ‘critical steps’ and acceptance criteria.

It also covers the requirements of prospective, retrospective and concurrent validation (note these first two terms are not used in the FDA Guideline and the latter term is only referred to in regard to concurrent release).

Industry’s Historical Approach in Using Annex 15

Although Annex 15 doesn’t spell out the importance of product quality in Section 1, Principles, the topic is clearly there in the intent behind the processes that are to be used.

As a comment, maybe because this principle is not spelled out at the outset, plus the need to link to the patient requirements to process validation, historically the practice of validation has become bureaucratic and complex. Perhaps the explanation of this is:

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  • There has been rather too much emphasis placed on the administrative aspects of the validation process, i.e. start with DQ and then progress through to IQ, OQ etc
  • Interpreting (probably wrongly) that following a rather formal administrative approach to validation is what the regulators want.
  • A lack of realisation that it is demonstration of product quality that matters, rather than the administrative process of validation itself.

The outcome was that a bureaucracy of validation built up, often run in parallel to other project management processes, where the emphasis on product quality became subservient to the administrative process itself. However, there were still some good ideas in the traditional approach, for example the V-model, as shown in the second diagram.

The traditional validation process is shown in the diagram below:

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Industry used a ‘V model’ as shown below, starting with DQ and working through IQ, OQ, PQ etc and linked this to ‘specifications’ of various types. This normally meant, when a new plant was built, the first stage was to assess what was needed for Design Qualification (DQ), then IQ, OQ, PQ and finally when all the qualification was in place, process validation could start, i.e. the qualification steps followed the engineering procurement process.

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Indeed, Process Validation, although it is the last item in the exercise (and probably the most important), it didn’t appear in the V diagram.

One other matter, the term ‘critical’ is used about 6 times in Annex 15 but the context of it varies, so this may have also added to the historical confusion. For the future, the use of ICH definitions that define the context of the word ‘critical’ and link it to product quality (e.g. Critical Quality Attributes or Critical Process Parameter) will help clarify what is important to validate and where validation can confirm that plants and manufacturing processes do deliver what is critical for patient safety and efficacy.

Applying Annex 15 and the Principles of FDA 3 Stage Process

Say a company wishes to adopt the principles of the FDA PV Guideline 2011 including use of ASTM E2500 for equipment and utility verification, then Annex 15 requirements, as illustrated in the diagram below, can still be met in order to supply EU markets. Here the FDA 3 stage approach is shown with an adapted V model inserted for Stage 2.1 (equipment and facility verification) that enables the ASTM E2500 process (i.e. reference to terms Requirements, Specification and Design, Verification and Acceptance and Release) to be used. Note ASTM also supports the principles of Good Engineering Practice, use of Subject Matter Experts, a science-and risk-based approach, design review and change management.

Regarding documentation, the Annex 15 requirements for DQ/IQ/OQ/PQ/PV can be drawn out of the overall 3 stage process by referring to documents generated by that 3 stage process. This could include reference to, for example, plans (such as User Requirement Specifications (URS)), protocols, verification tests and vendor documents, (such as Factory Acceptance Tests (FAT), Site Acceptance Tests (SAT)), reports, etc.

These documents also would be used to demonstrate that the validation process had confirmed a control strategy (using the term from ICHQ10) was in place and that the manufacturing process was able to deliver quality product.

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So whereas historical validation under Annex 15 had proceeded along similar order of activities to engineering procurement for a new plant (i.e. Design, Install, Operate etc. viz DQ,OQ, IQ etc.) modern validation work shifts the sequence of activities for meeting Annex 15 requirements to the following, and so has an impact on how engineers will design plants to ensure product quality.

  • Put in place a validation strategy that includes a VMP and the regulatory (Process Validation) plan
  • Design the commercial manufacturing plant, starting from the patient requirements to the product quality requirements to the unit operations to the facility and its utilities.
  • Build the plant from facility to utility to process to unit operation to enable quality product to be manufactured to meet patient requirements (as well as of course meeting all other Good Engineering Practice (GEP) requirements).
  • Validate the elements that impact product quality, including verification of design and installation of equipment & utilities (= DQ, IQ and GEP), confirming the operation (=OQ and GEP)), and ensuring the plant as a whole produces quality product (=PQ and PV, supported by GEP). Note that Annex 15’s says this is demonstrated in 3 batches, but modern process validation would expect a statistical based approach.
  • Confirm regulatory requirements for VMP/DQ/IQ/OQ/PQ/PV have been met using documentary evidence from the above process e.g. protocols, reports, FATs, SATs, verification tests and batch records.

Conclusion

Compliance with Annex 15 can still be put in place using modern Process Validation principles but the administrative process shifts from a compliance-based approach, (using the terms DQ/IQ/OQ/PQ as the validation process and ‘proof’ of product quality being 3 batch validation) to a science- and risk-based approach to product quality, and it is this that drives the DQ/JQ/OQ/PQ/PV requirements, including necessary documentation.

 

Design of an Efficient Stability Programme -Bracketing and Matrixing

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Design of an Efficient Stability Programme -Bracketing and Matrixing

WHAT GUIDELINES EXIST?

Stability in Business as Motivation in Stone Wall

We will focus mostly on the following guideline:

Q1D Bracketing and Matrixing Designs for Stability Testing of 􀀉 Drug Substances and Products (2003.2.7)

FULL STUDY DESIGN

Key factors such as batch, strength, package size and fill can affect the specification attribute.
In addition to how the specification attribute may change with storage, these factors may have to be taken into consideration. For example if the % label claim is to considered in 3 batches and at 2 strengths then there is a total of 3 X 2 = 6 combinations. Each of these combinations may have to be monitored at each of 8 time points i.e. [0,3,6,9, 12, 18,24,36] months. Such a full study design would require at least 6 X 8 assays!

REDUCED STUDY DESIGNSAPI

Requirements are specified in ICH Q1D A design in which samples for every factor combination are not tested at all time points. Two types of reduced design; “bracketing and “matrixing”. Can be applied to most types of drug products. For drug substances (APIs), matrixing is of limited applicability and bracketing is not generally applicable.

REDUCED BRACKETING DESIGN

Bracketed designs are such that only samples at the extremes of certain design factors are tested at all times. This leads to economy on assay determinations but care must be taken as such reduced designs make assumptions that the assays either only increase or only decrease between the extremes. As an example lets look at the % label claim for three batches at 3 strengths and 3 container sizes. A full design would require 3 X 3 X 3 = 27 assays at any one time point.

A bracketed design using the extremes could reduce the design to only 12 assays:

Strength Low Medium High
Batch 1 2 3 1 2 3 1 2 3
Small Container T T T — — — T T T
Medium Container — — — — — — — — —
Large Container T T T — — — T T T

Where ‘T’ denotes assay test and ‘–‘ denotes no assay test. This is a big saving on the number of assays to be undertaken but we would need to be confident that nothing unusual happens at the medium levels!

Bracketed designs can be applied as follows:

  • To studies with multiple strengths of identical or closely related formulations
  • To studies of the same container closure system where either container size or fill varies while the other remains constant 􀀎
    • If both container size and fill vary; take care in selecting extremes (ICH 01 D 2.3.1.2)

REDUCED MATRIXING DESIGN

Matrixing designs are such that only a subset of all possible factor combinations may be collected at particular time points. At a subsequent time point a different subset of factor combinations are normally collected. Care must be taken in selecting the samples for testing to ensure the design is balanced and representative.

It is recommended that:

  • All factor combinations are collected at the start and end time points
  • All factor combinations be tested at 12 months, or the most recent time point when all full-term data are unavailable before review
  • Data should be available from at least three time points during the first 12 months

A matrix design with one half reduction on time points:

Time point (months) 0 3 6 9 12 18 24 36
Strength Low Half Data Collected Half Data Collected
Batch 1 T T T T T T
Batch 2 T T T T T T
Batch 3 T T T T T
Strength High All Data Collected All Data Collected All Data Collected
Batch 1 T T T T T
Batch 2 T T T T T T
Batch 3 T T T T T

Where ‘T’ denotes assay test and ‘–‘ denotes no assay test.

Matrixing designs are applicable if:

  • Previous data indicates predictable product stability
  • Previous data exhibit moderate variability
  • They are of appropriate statistical design

REDUCED DESIGNS – rules of thumbRule of thumb

At first you will find it easier to use a full design. Use a bracket design when you are confident that nothing unusual happens between extremes. Use the matrix design to cut down on numbers of assays at each time point. Read the ICH Guidelines. These are not easy because of the many different factors that can effect storage and shelf life but after repeated reading it should fall into place.

QP Declaration

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QP Declaration

Overview

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  • History
  • Behind the QP Declaration
  • The GMP Compliance Audit of the active substance Manufacturer
  • The Importance of the Technical Agreement (Contract)
  • QP Declaration – template
  • QP pedigree
  • Keeping manufacturers/suppliers “current”
  • Essential Messages

History behind the QP Declaration

The requirement for active substances to be manufactured in compliance with the principles of GMP has always been central to FDA practice. The FDA problem had been that GMP for active substances has never been enshrined in the 21 CFR, since Parts 210 and 211 apply specifically to drug products. Until the completion and signing of ICH Q7, inspectors had to rely on a number of guidance documents for Bulk Pharmaceutical Chemicals (BPCs) against which they based their observations and citations for “adulteration” and breaches of the requirements of the FDC Act. ICH Q7 became the formal basis of judgement of GMP compliance, being evidence that a facility or active substance was in compliance or breach of the requirements for manufacture to GMP, as required by the Act.

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Within the EU/EEC, at best it was implicit that manufacture of active substances should comply with GMP principles. There was no formal requirement that could be enforced and active substance manufacture was not inspected by regulators. Hence QPs had no formal involvement with or responsibility for the GMP compliance of the active substances used within the· products under their control. However, since the sterilisation stage to produce bulk sterile active substances was covered specifically within the Marketing Authorisation, it was considered to be the first stage of manufacture of the medicinal product and was subject to inspection against GMPs for products.

ICH Q7 was incorporated initially into the EU/EEC GMP guidelines as Annex 18. The opportunity was taken to amend Directive 2001/83/EC by Directive 2004/27/EC, which required the manufacture of Active Substances (active substances) to be GMP compliant. Annex 18 was converted to Part II with a re-written Introduction in EU terminology but the text of Q7a remained unchanged. Thus Part II became the EU definition of GMP Compliance for Active Substances.

Article 46f of Directive 2004/27 /EC requires MA holders “to comply with the principles and guidelines of good manufacturing practice for medicinal products and to use as starting materials only active substances, which have been manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials.”

Article 112 of Directive 2001/83/EC requires “Member States shall take all appropriate measures to ensure that the holder of the marketing authorization for a medicinal product and, where appropriate, the holder of the manufacturing authorization, furnish proof of the controls carried out on the medicinal product and/or the ingredients and of the controls carried out at an intermediate stage of the manufacturing process, … ”
Article 112 is effectively the origin of the requirement for a QP Declaration concerning GMP compliance of the manufacture of the active substance.

A secure basis of compliance is achieved by auditing the active substance manufacturer, in particular including their control of critical materials and by an extensive and well constructed Technical Agreement (Contract).

The Audit of the active substance Manufacturer

Why Audit active substance Manufacturers?

  • What are the requirements of the Directive?
  • The role of the regulators to enforce the requirements
  • The role of the Product Manufacturer (MAH)
  • What are the expectations from the active substance manufacturers?

Directive 2004/27 /EC introductory paragraph 19 states … “The quality of medicinal products for human use manufactured or available in the Community should be guaranteed by requiring that the active substances used in their composition comply with the principles of good manufacturing practice in relation to those medicinal products.”

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Insertion of Article 46a states … “Manufacture of active substances used as starting materials shall include both total and partial manufacture or import of an active substance used as a starting material as defined in Part I, point 3.2.1.1 (b) Annex I and the various processes of dividing up, packaging or presentation prior to its incorporation into a medicinal product, including repackaging or re-labelling, such as are carried out by a distributor of starting materials.”

Therefore the whole supply chain needs to be covered. The requirements of the amending directive came into force on October 30th 2005.

The EU Guide to GMP Part 1 (2.4a) states that for medicinal products manufactured within the European Community, a Qualified Person must ensure that each batch has been produced and tested/checked in accordance with the directives and the marketing authorisation. Therefore ultimate responsibility for ensuring that the active substances used in any licensed medicinal product have been manufactured in accordance with GMP lies with the QP certifying the product for release. The principal mechanism for ensuring GMP compliance is the GMP compliance audit of the active substance manufacturer.

The Role of the Regulatory Inspectors

From end October 2005, the competent authority of the Member State concerned shall ensure, by means of repeated inspections, and if necessary unannounced inspections, that the legal requirements governing medicinal products are complied with.

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The competent authority may also carry out unannounced inspections at the premises of manufacturers of active substances used as starting materials, whenever it considers that there are grounds for suspecting non-compliance with the principles and guidelines of good manufacturing practice referred to in Article 47.

When inspection reports or GMP certificates issued by EEA, MRA partners or other recognised authorities are available these can provide useful information to MA holders. These alone cannot fulfil the obligations of the MA holder nor the requirements of chapter 5 (sections 5.25 – 5.26) of the GMP Guidelines

The Role of the Manufacturing Authorisation Holder (MAH)

The amended legislation places the obligation on the MAH to use only active starting materials that have been manufactured in accordance with GMP.

The MAH must ensure that each active substance manufacturer listed in the MA for each medicinal product is audited on a regular basis, typically every two to three years. This applies to all active substances, whether manufactured in the EU, imported as active substances or imported as products.
The audit(s) must be conducted by properly qualified and trained staff, in accordance with approved procedures. The auditors should be qualified and/or experienced in active substance manufacture, not necessarily the QP himself/herself. If they are contracted/ consultants, there must be no Conflicts of Interest. Ensure that the auditors have detailed knowledge of active substance manufacture, as defined by Part II.

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The auditor’s report must be as thorough as possible and it is expected nowadays that it will be scrutinised by the regulatory inspector. It must include controls over suppliers of critical materials to the active substance manufacturer. Thus it is not to be treated as an internal GMP audit.

As a default structure for an audit report of an active substance manufacturer, it is good practice to follow roughly the style and audit headings of the EMA-standardised audit process (see Compilation of Community Procedures). It is also common practice to classify any deficiencies or observations according to the classification used by the EMA/regulatory inspectors (Critical/Major/Other (Minor).

What are the Expectations from the Active Substance Manufacturers? 
The audits performed should cover scope and requirements of Part II. The manufacturer’s quality system should be at least equivalent to all relevant requirements of Part II from the introduction of the registered active substance starting material through to the final packaging and delivery of the active substance.

The Importance of the Technical Agreement (Contract)

The purchase of starting materials (in this case active substance and certain excipients) is an important operation which should involve staff who have a particular and thorough knowledge of the suppliers.

EU GMP Guidelines, Part 1, 5.25-5.26 states:

“Starting materials should only be purchased from approved suppliers named in the relevant specification and, where possible, directly from the producer. It is recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is of benefit that all aspects of the production and control of the starting material in question, including handling, labelling and packaging requirements, as well as complaints and rejection procedures are discussed with the manufacturer and the supplier.

The purchase of active substance should be covered by a detailed Contract, often known as a Technical Agreement or Technical Supply Agreement. The minimum general contents of this agreement are set out in chapter 7 of the EU GMP Guidelines. The QP who will sign the declaration for GMP compliance of the active substance should be heavily involved in the detail of each contract relating to each manufacturer of active substance intended for the medicinal product.

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It is likely that many of the technical details of active substance manufacture will be contained in the closed part of the active substance MF (EDMF) and hence not available to the QP. Therefore it is important that the Contract includes procedures for planned and unplanned changes to the active substance MF, since the active substance MF forms part of the MA. Paragraph 7.2 of the product GMP guidelines states:

“All arrangements for contract manufacture and analysis including any proposed changes in technical or other arrangements should be in accordance with the marketing authorisation for the product concerned.”

Within the scope of this statement, it is forbidden to transfer any part of the contracted manufacture to a third party.
Thus the Contract is a key pillar of the QP Declaration.

QP Declaration Template

The EMA have developed a proposed template for the Qualified Person’s declaration concerning GMP compliance of the active substance used as starting material and verification of its supply chain, “The QP declaration template”.
Officially, there have been no new additions to the previous expectations of the QP declaration. However, formal inclusion of suppliers of critical materials in the supply chain is based on good audit practice.

The stated objective of the template is “to emphasise the importance of providing a comprehensive declaration, to harmonise the format for the declaration, to forestall questions during assessment, and to enhance the efficiency of the regulatory process”.

Since the MAH has the principal responsibility for ensuring GMP compliance during active substance manufacture (and for prevention of falsification of the active substance), the MAH should:

  1. i) Verify the GMP compliance of all parties in the supply chain and that all sources are in accordance with relevant marketing authorisations.
  2. ii) Fully understand and control the supply chain of active substances used by them (including brokers, re-labellers and re-packagers) and take steps to shorten the supply chain wherever possible.

iii) Clearly demonstrate that each batch of active substance accepted by them for use in the manufacture of medicinal products has been sourced through this supply chain.

From ii) above, it is implicit that active substance should be purchased directly from the manufacturer whenever possible.
QP Declarations are required from each EEA finished product manufacturing site and/or from each site of importation/batch certification. However, a single declaration from one QP from one of the registered finished product or batch release sites may be sufficient, if its basis is satisfactorily described and supported by technical agreements between these sites (see Part B and E).
The “QP Declaration” is a key part of the evidence of the MAH’s compliance with Article 46(f) of Directive 2001/83/EC (as amended). It is mandatory – not optional.
Confirmation of compliance is required for all applications for new marketing authorisations, for renewals and for variations concerning a change (addition or replacement) to the registered manufacturer(s) of the active substance, finished product or batch importation/certification sites.
Compliance for the above regulatory submissions is demonstrated by provision of the “QP declaration”.
The QP Declaration should be based upon the direct audit of the active substance manufacturers, by or on behalf of the MAH. GMP certificates from a relevant Competent Authority cannot replace direct audits, but the results of such inspections may be used, together with other supporting information, in a risk-based approach by the manufacturer in establishing priorities for its own audit programme of active substance suppliers.
The supply chain is considered to be a family tree for the active substance. In turn this allows traceability from the manufacturers of critical materials all the way through to the medicinal product. The supply chain should be established and documented, since verification is part of the QP Declaration (Part D). Changes to the list of critical suppliers need not be notified to the regulatory authority since they are before the registered starting material for the active substance but the Technical Agreement/Contract should require that they be notified to the MAH since verification of the supply chain is part of the QP Declaration. Thus active substance supply chain traceability, including critical raw materials, should be part of the quality system at the active substance manufacturer’s site.

The QP Declaration

A QP declaration is required in support of a submission for a new marketing authorisation (MA) application, renewal or variation, for a human or veterinary medicinal product. As such, the QP declaration will be accompanied by the relevant application form, which sets out the scope of the QP declaration and defines the applicable medicinal products.
The format of the QP declaration template is in five parts (Parts A to E) and each must be completed. In order for the QP declaration to be valid, all the relevant tick box(es) must be checked and the necessary information entered into the provided tables, as applicable.

Summary of Guidance Notes for the QP Declaration

A summary of the guidance notes for completion of the QP Declaration is set out below. Full guidance notes for completion of each section, as provided by European Medicines Agency.

The template has no new requirements but standardises what is necessary for current regulatory requirements by focusing on audit and verification of the active substance supply chain.

The objective of the QP Declaration Template is to emphasise the importance of providing a comprehensive declaration; to harmonise the format for the declaration; to forestall questions during assessment and to enhance the efficiency of the regulatory process.

The template has 5 Parts, A to E. All must be completed – it is NOT OPTIONAL.

Part A: ‘Concerned Manufacturing Sites’

This part requires the QP to list and attest the full name and address of all:

  • Active substance manufacturing site(s) and function(s)
  • Finished product site(s) and function(s)
  • Importation and/or batch certification site(s)

A Decision Tree for completion of Parts A & B is included in Annex 1 of the template document.

A QP Declaration is required for all applications.

For a new MA application:

All proposed active substance/finished product/importation/batch certification sites

For a Renewal:

All currently approved active substance/finished product/importation/batch certification sites

For a variation application to add a new finished product/importation/batch certification site:

The proposed site and all currently approved active substance/finished product/importation/batch certification sites

For a variation application to add a new active substance manufacturing site:

The proposed site and all currently approved/finished product/importation/batch certification sites.

According to the variation classification guideline, currently approved active substance manufacturing site(s) for which a valid QP declaration(s) is/are in place need not be listed in the table provided. Optionally, a MAH may include all currently registered active substance manufacturing sites to provide an updated QP declaration. No site may be exempted/omitted from the table provided. Redundant sites should be deleted from the MA. Manufacturing sites that are located outside the EEA should be listed for transparency. This puts the QP declaration and arrangements for auditing within the context of the regulatory submission.

Part B: ‘Declaration of GMP Compliance’

Requires the QP to declare that the API …

“is manufactured in accordance with the detailed guideline on GMP for active substances used as starting materials as required by Article 46( of Directive 2001/83/EC and Article 50) (of Directive 2001/82/EC, as amended).”

This declaration is underpinned by requirements as set out in PART E.

Part B: ‘Declaration of GMP Compliance’

A single declaration may suffice if one Manufacturing Authorisation covers several sites
(same company) or if more than one MA holder is involved but the QP signs on behalf of other QPs. This situation MUST be underpinned by Technical Agreements

Part C: ‘Basis of the Declaration’

The basis of the QP declaration is a statement that the active substance supplier has been audited by either the MA holder or a suitably qualified third party (on behalf of the MA holder). In both cases, the date of the last audit must be recorded. For third party auditor, the record must contain:

  • Name of the auditing body
  • Relationship to the MA holder
  • Justification if the last audit was more than 3 years ago

If the audit is conducted by a third party auditor (contractor) the OP must have evaluated each named audit body and ensured that audit(s) were conducted by properly qualified and trained staff, in accordance with approved procedures and that technical contractual arrangements were in place with the auditor(s).
“Evidence provided in lieu of audit” may be used exceptionally and if satisfactorily justified. (Justification must be attached.) There are only two possible grounds for this exceptional approach:

  1. Remote assessment based on (e.g.) question;1aires and/or review of documents and/or ISO 9000 certification and/or results of analytical testing and historical experience with the supplier
  2. Other situations (e.g.) non-traditional (or atypical) active substance

Part D: ‘Verification of the Active Substance supply chain traceability’

This section declares three key aspects of the defined supply chain for each of the active substance manufacturing sites listed in PART A i.e. that:

(i) the supply chain had been established and is documented

(ii) there exists a documented risk assessment for all sites in the supply chain

(iii) the above documents are available for inspection

The supply chain is a family tree for each active substance from manufacturers of critical materials (Part II, sections 7.11. & 7.13) to receipt of active substance.

It includes active substance manufacturers (each site) and brokers, traders, repackers, relabellers, micronisers and importers.

Part D requires the QP to declare that:

  • The supply chain of each AS at each manufacturing site been established and documented.
  • A documented risk assessment exists for all sites in the supply chain.
  • These documents are available for inspection.

PART E: ‘Attestation of the responsible QP’

Part E requires the signing QP to confirm that:

“I am a OP with responsibility for GMP compliance of the active substance and am authorised to make this declaration”

For multiple sites (PART B):

Declaration is made on behalf of all the involved QPs named on relevant Manufacturing Authorisation(s). A documented procedure defining GMP responsibilities is in place Agreements exist between the named companies concerning management of GMP responsibilities and the relevant technical agreements and procedures are available for inspection by the competent authorities.

General (from Q & A Document)

Use of the template is NOT optional. A QP declaration is required for all relevant submissions. This applies however the data requirements for the active substance are met:

  • EDOM (CEP) Certificate of Suitability
  • Active Substance Master File (ASMF)
  • Full details in the dossier

EUROPEAN MEDICINES AGENCY SCIENCE MEDICINES HEATH

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16 December 2010
EMA/CHMP/CVMP/QWP/696270/2010

Template for the Qualified Person’s declaration concerning GMP compliance of the active substance used as starting material and verification of its supply chain “The QP declaration template” Draft

Draft Agreed by QWP September 2010
Adoption by CVMP for release for consultation 9 December 2010
Adoption by CHMP for release for consultation 16 December 2010
End of consultation (deadline for comments) 30 April 2011
Comments should be provided using this template. The completed comments form should be sent to qwo@ema.eurooa.eu
Keywords Qualified Person; Active Substance; Starting Material; good Manufacturing Practise; Supply Chain

TEMPLATE FOR THE QUALIFIED PERSON’S DECLARATION CONCERNING GMP COMPLIANCE OF THE ACTIVE SUBSTANCE USED AS STARTING MATERIAL AND VERIFICATION OF ITS SUPPLY CHAIN “The QP Declaration Template”

  1. ISSUE/OBJECTIVE

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The objective of this Qualified Person (QP) Declaration Template is to emphasise the importance of providing a comprehensive declaration, to harmonise the format for the declaration, to forestall questions during assessment, and to enhance the efficiency of the regulatory process.

The quality of medicinal products depends to a large degree on the quality of the active substances used to formulate them. Medicinal product manufacturers have the prime responsibility for ensuring the quality of active substances in terms of GMP compliance and prevention of falsification and should therefore take appropriate measures to:

  1. i) Verify the GMP compliance of all parties in the supply chain and that all sources are in accordance with relevant marketing authorisations.
  2. ii) Fully understand and control the supply chain of active substances used by them (including brokers, re-labellers and re-packagers) and take steps to shorten the supply chain wherever possible.

iii) Clearly demonstrate that each batch of active substance accepted by them for use in the manufacture of medicinal products has been sourced through this supply chain.

In order to satisfy the above requirements, the manufacturer will submit a declaration that addresses GMP compliance and supply chain verification.

The attached QP declaration template provides, in a format considered suitable for submission, a basis for demonstrating compliance of the active substance manufacture with GMP requirements and that the manufacturer has relevant knowledge of the supply chain.

QP Declarations are required from each EEA finished product manufacturing site and/or from each site of importation/batch certification. However, a single declaration from one QP from one of the registered finished product or batch release sites may be sufficient, if its basis is satisfactorily described and supported by technical agreements between these sites (see Part B and E).

The QP Declaration should be provided in support of an application for a new marketing authorisation, variation or renewal of a medicinal product(s) authorised in the Community, using EU or national procedures within the scope of Directive 2001/83/EC1 (human medicinal products) and Directive 2001/82/EC2 (veterinary medicinal products). A declaration is not required for blood or blood components; they are subject to the requirements of Directive 2002/98/EC8.

  1. REGULATORY BASIS

2.1 GMP compliance

In accordance with Article 46(f) of Directive 2001/83/EC (human medicinal products) and Article SO(f) of Directive 2001/82/EC (veterinary medicinal products) as amended, Manufacturing Authorisation holders are required to use as starting materials only active substances which have been manufactured in accordance with the detailed guidelines on the Good Manufacturing Practice (GMP) for starting materials as adopted by the Community.

Confirmation of compliance is required for all applications for new marketing authorisations, renewals and for variations concerning a change (addition or replacement) to the registered manufacturer(s) of the active substance, finished product or batch importation/certification sites. For variations, the relevant legislative framework is provided by:- Commission Regulation (EC) No. 1234/2008 on variations3 and Communication from the Commission – Guideline on the details of the various categories of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products4.

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Compliance for the above regulatory submissions is demonstrated by provision of Qualified Person’s Declaration Concerning GMP Compliance of the Active Substance Used as Starting Material and Verification of its Supply Chain (i.e. the “QP declaration”).

The QP Declaration should be based upon the direct audit of the active substance manufacturers, by or on behalf of the MAH, by a suitably trained and experienced person, which may be a third party contractor 5-6.

GMP certificates from a relevant Competent Authority cannot replace direct audits, but the results of such inspections may be used, together with other supporting information, in a risk-based approach by the manufacturer in establishing priorities for its own audit programme of active substance suppliers7.

2.2 Verification of the Active Substance supply chain traceability

The supply chain is a family tree for the active substance tracing its history or supply chain from critical raw material(s) used in the manufacture of the active substance to the manufacturer of the dosage form. The sites will include manufacturers of critical raw materials (as defined in Part II of the EU GMP Guide 7.11, 7.13), active substance manufacturers, brokers, traders, repackers, relabellers, micronisers and importers.

This supply chain traceability should be established and documented. Verification of the availability of this forms part of the QP Declaration (Part D).

Supply chain traceability is considered a matter of GMP and it should be maintained by the Manufacturing Authorisation holder. This should be made available for inspection at the request of the competent authorities. Competent authorities need not be notified of amendments to the supply chain that are outside the scope of the Commission Regulation on variations4 • Therefore, variations will only be required for changes to active substance manufacturers involved in the synthesis of the active substance from the designated starting materials to the final active substance as described in the marketing authorisation dossier Module 3.2.S.

  1. FORMAT AND GUIDANCE NOTES FOR THE QP DECLARATION TEMPLATE

The QP declaration provides the necessary information required to demonstrate compliance with Article 46(f) of Directive 2001/83/EC and Article SO(f) of Directive 2001/82/EC that the Manufacturing Authorisation holder uses as starting materials only active substances which have been manufactured in accordance with the detailed guidelines on the Good Manufacturing Practice (GMP) for starting materials as adopted by the Community. Additionally, the QP declaration confirms the manufacturer has established a defined supply chain traceability for the active substance in compliance with Article 46a of Directive 2001/83/EC and Article 50a of Directive 2001/82/EC, as amended. Verification of this is a requirement of the QP Declaration (Part D).

A QP declaration is required in support of a submission for a new marketing authorisation (MA) application, renewal or variation, for a human or veterinary medicinal product. As such, the QP declaration will be accompanied by the relevant application form, which sets out the scope of the QP declaration and defines the applicable medicinal products.

The format of the QP declaration template is in five parts (Parts A to E) and each must be completed. In order for the QP declaration to be valid, all the relevant tick box(es) must be checked and the necessary information entered into the provided tables, as applicable. Guidance notes for completion of each section are provided below.

Part A: Concerned Manufacturing Sites

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This declares all the relevant sites that are subject to the QP declaration as applicable to the regulatory submission accompanying the QP declaration (i.e. a new MA, renewal or variation application). A decision tree for completion of Parts A and B of the QP declaration form is provided in Annex 1. The relevant sites and their respective functions are to be listed in the table provided according to the submission type, as shown below.

  • For a new MA application: all proposed active substance I finished product (EEA and non-EEA)/ importation/ batch certification sites;
  • For a Renewal: all currently approved active substance I finished product (EEA and non-EEA)/ importation I batch certification sites;
  • For a variation application to add a new finished product I importation/ batch certification site: the proposed site and all currently approved active substance I finished product (EEA and non­EEA) / importation I batch certification sites;
  • For a variation application to add a new active substance manufacturing site: the proposed site and all currently approved / finished product (EEA and non-EEA)/ importation/ batch certification sites.

Note: According to the variation classification guideline\ currently approved active substance manufacturing site(s) for which valid QP declaration(s) is/are in place need not be listed in the table provided.

Optionally, the applicant may take the opportunity to include all currently registered active substance manufacturing sites in order to provide an updated QP declaration.

The following are taken into consideration in respect of the relevant sites that are listed in the table and which are subject of this QP declaration:

  1. Batch certification can take place at the finished product manufacturer, at the importer (in the case of product manufactured in a third country) or at another EU site, if they hold an authorisation for batch certification.
  2. No site may be exempted i.e. omitted from the table provided. Sites that are considered redundant should be deleted from the MA. Manufacturing sites that are located outside the EEA should be listed for transparency as this puts the QP declaration and arrangements for auditing within the context of the regulatory submission.

Part B Declaration of GMP Compliance

In this section the QP declares GMP compliance of the active substance manufacturer(s) and indicates whether a single or multiple declarations are provided covering all relevant manufacturing sites listed in PART A. A decision tree for completion of Parts A and B of the QP declaration form and identification of those cases where single or multiple declarations are required is provided in Annex 1.

In principle, individual declarations are expected from:

  • The QP of each Manufacturing Authorisation holders (EEA) that use the active substance as a starting material

and

  • The QP of each Manufacturing Authorisation holder responsible for importation/ batch certification when the importation/ batch certification site is a different site from the above. This is because the QP responsible for importation/ batch certification takes overall responsibility for each batch.

Where more than one QP operates at a particular site, a declaration from one QP only is expected.

Thus in principle, multiple (individual) declarations are required covering all the relevant manufacturing (EEA) I importation I batch certification sites as listed in PART A that use the active substance as a starting material. However, a single declaration may be acceptable under certain circumstances.

In PART B, one of the following options must be completed as specified below by selecting the relevant tick-box. In each case, the QP signifies compliance with the requirements underpinning the declaration as set out in PART E.

(i). Single declaration encompassing all relevant sites listed in PART A

A single declaration signed by one QP may be acceptable in a situation where:-

  • only one Manufacturing Authorisation is involved i.e. the product manufacturing site (EEA) /importation / batch certification sites are the same site or group of companies,

or

  • more than one Manufacturing Authorisation holder is involved i.e. the product manufacturing site (EEA) / importation/ batch certification sites are NOT the same site or group of companies. In this situation, the QP makes the declaration on behalf of all concerned QPs and confirms that this is underpinned by a technical agreement as set out in PART E.

Note:- where a single declaration is provided, only one completed QP declaration form is to be submitted.

(ii). Multiple (individual) declarations covering all relevant sites listed in Part A

Where it is not feasible to provide a single declaration covering all applicable finished product (EEA) / importation/ batch certification sites where active substance is used as starting material, instead individual declarations may be submitted. In this case, the table provided should be completed to indicate those sites for which the QP is responsible for GMP compliance and is authorised to make the declaration.

Note:

  1. There may be instances where it is possible to provide a single QP declaration for some manufacturing sites but individual declarations are required for other sites.
  2. The Applicant is responsible for ensuring that that additional QP declaration forms have been provided to encompass all active substance I finished product (EEA ) I importation/ batch certification sites as listed in PART A.
    A covering note may be provided with the submission to confirm this.

Part C Basis of the Declaration

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According to Directives 2001/83/EC and 2001/82/EC, as amended, and GMP requirements, it is expected that Manufacturing Authorisation holders will normally gain assurance that the active substance(s) used are manufactured in accordance with GMP through direct audit of the active substance manufacturer(s)5.

The arrangements for auditing that are applicable to the present QP declaration are indicated by completing sections (i), (ii) or (iii) as show below. In case of multiple active substance manufacturing sites as listed in PART A, the required information should be stated for all sites referred to in the regulatory submission.

Section (iv) enables supplementary information to be optionally submitted in support of the QP declaration.

PART C includes tick boxes that should be completed as confirmation that audit reports and other documentation pertaining to the audit are available for inspection by the Competent Authorities.

Section (i) audit conducted by Manufacturing Authorisation holder(s)

Section (i) indicates that the Manufacturing Authorisation holder has conducted a direct audit of the active substance manufacturer(s). The table provided is completed to state those active substance manufacturing sites that have been audited by the Manufacturing Authorisation holder and the date of the last audit, which is expected to be within the last 3 years. Suitable justification should be provided in case the audit frequency exceeds 3 years.

Section (ii) audit conducted by third party

Section (ii) indicates that an audit of the active substance manufacturing sites listed in the table provided has been conducted on behalf of the Manufacturing Authorisation holder by a suitably qualified third party (contractor). In this case, information should be provided as to who has conducted any audit(s) as appropriate e.g. third party including their relationships to Manufacturing Authorisation holder.

Tick boxes are completed to certify that the contract acceptors are properly qualified and that appropriate technical agreements are in place between the contract giver and acceptor.

Section (iii) evidence provided in lieu of audit

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Section (iii) should be completed only in exceptional circumstances where direct audit of the active substance manufacturer is not possible. In these circumstances, other arrangements for verifying the GMP status of the active substance manufacturer may be deemed acceptable. The relevant tick box is completed to indicate one of two possible scenarios, as applicable:

  • remote assessment e.g. based on questionnaires and review of relevant documentation. This may be justified on grounds of current travel advice provided by the local authorities of the EEA member states;
  • other situations e.g. as applicable to non-traditional (or atypical) active substances. Appropriate elements of the EU GMP guide part II are nevertheless expected to be applied by the active substance and finished product manufacturers. As a principal, such controls must provide confidence that the ‘Atypical’ active substance is fit for purpose and will not negatively affect the safety and efficacy of the drug product. The QP is expected to justify the controls in place on a scientific basis and record a risk assessment on a product specific basis. Further guidance has been published 9 10

In each of the above exceptional cases, an appropriate justification for the lack of an on-site audit should be provided together with a list of supporting information on which the verification of GMP compliance is based. The suitability of the justification provided may also be subject to review by the competent authority inspectors.

Section (iv) supplementary supportive information (optional)

Section (iv) refers to supplementary information that may optionally be attached to the QP declaration to support a risk-based approach by the manufacturer in establishing priorities for its own audit programme. For example, results of inspection report(s) or GMP certificate(s) issued by EEA, Mutual Recognition Agreement (MRA) partners or other recognised authority together with other supporting information. The table provided should be completed to summarise the information that has been provided. It should be noted however that this supporting information alone cannot fulfill the statutory obligations of the Manufacturing Authorisation holder or the requirements of section 5.25 of the GMP Guide. Further guidance is available 7, 11.

Part D Verification of the active substance supply chain traceability

This section declares three key aspects of the defined supply chain for each of the active substance manufacturing sites listed in PART A i.e. that:-

  1. i) the supply chain had been established and is documented
  2. ii) there exists a documented risk assessment for all sites in the supply chain

iii) the above documents are available for inspection

Part E Attestation of the responsible QP

This declares that the signatory is the QP responsible for the relevant product manufacturer(s) (EEA) and importation and/or batch certification sites referenced in PART B.

Applicants are reminded that, according to Art. 41 of Directive 2001/83/EC and Article 45 of Directive 2001/82/EC, Manufacturing Authorisation holders shall have at their disposal at least one Qualified Person located in the EEA. Therefore declarations from persons employed by manufacturers in third countries, including those located within MRA partner countries, are not acceptable. The latter may, however be used to provide supportive information for the QP declaration – see PART C (iv).

This section also sets out the requirements in situations where a declaration covers multiple sites listed in PART A and the QP confirms that appropriate technical agreements are in place between
sites/companies concerning GMP compliance. It is expected that arrangements concerning GMP of the active substance between companies are underpinned by agreement/procedures irrespective of whether the companies are within the same group or not.

The declaration is signed and the relevant details of the QP are provided (name, status, and Manufacturing Authorisation holder name and number). The QP details should be consistent with those named within the relevant regulatory submission application form and/or the Manufacturing Authorisation.

QUALIFIED PERSON’S DECLARATION CONCERNING GMP COMPLIANCE OF THE ACTIVESUBSTANCE USED AS STARTING MATERIAL AND VERIFICATION OF ITS SUPPLY CHAIN “The QP Declaration Template”

PART A: Concerned Manufacturing Sites

I confirm that all sites concerned with manufacture of the active substance [insert name of active substance] , and finished product and importation and/or batch certification for product(s) defined in the accompanying application form for the MA application/renewal/variation [delete as applicable] , are stated below, as applicable.

MANUFACTURING SITES SUBJECT OF THIS DECLARATION
ACTIVE SUBSTANCE MANUFACTURING SITE 2, 3 AND FUNCTION ( S) FINISHED PRODUCT MANUFACTURING SITE(S) AND FUNCTION(S) IMPORTATION AND/OR BATCH CERTIFICATION SITE
  1. PART B: Declaration of GMP Compliance Where the Applicant has multiple sites for the manufacture of active substance, product or importation and/or batch certification, the QP declaration shall encompass all these sites, as applicable to the regulatory submission defined in the accompanying application form.
    No site may be exempted from this list.
    All sites concerned with part processing should be listed.
  2. State the site name and address in detail, including the building numbers and function. This information may additionally be provided in a flow chart for clarity.
  3. List each site involved in the synthesis of the active substance beginning with the introduction of the designated active substance starting material.

I declare that [insert name of active substance] used as starting material in the manufacture of
product as defined in the accompanying application form and in PART A of this QP declaration, is
manufactured in accordance with the detailed guideline on good manufacturing practice for active
substances used as starting materials as required by Article 46(f) of Directive 2001/83/EC and Article SO(f) of Directive 2001/82/EC, as amended. This declaration is underpinned by requirements as set out in PART E and is provided as follows:

Please tick and complete only one of the following options, either (i) or (ii), as applicable

(i). Single declaration encompassing all relevant sites listed in PART A

A single declaration signed by one QP is provided covering all applicable active substance / finished product (EEA)/ importation / batch certification sites as listed in PART A.

or

(ii). Multiple (individual) declarations covering all relevant sites listed in PART A

It is not feasible to provide a single declaration covering all applicable finished product (EEA) /
importation/ batch certification sites where active substance is used as starting material.

Instead, individual declarations are submitted from each of the manufacturing sites listed in PART A.

This QP declaration covers the manufacturing sites listed below that use active substance as starting material.


PART C: Basis of the Declaration

NAME OF ACTIVE SUBSTANCE MANUFACTURING SITE(S) NAME OF PRODUCT MANUFACTURING (EEA) /IMPORTATION/BATCH

CERTIFICATION SITE( S)

MANUFACTURING / IMPORTATION AUTHORISATION NUMBER (MIA)


I declare that:

GMP compliance of the manufacturer(s) of the active substance [insert name of active substance] listed in PART A has been verified on the basis of (i) or (ii) or (iii) – one of these sections should be completed. Additional supporting information may optionally be included in section (iv).

and

Audit report(s) and other documentation relating to the audit(s) of the active substance manufacturer(s) listed in PART A are in place and will be made available for inspection by the competent authorities if requested.

Please tick and complete each section, as applicable

  1. i) Audit of the active substance manufacturer(s) conducted by Manufacturing Authorisation holder(s):

Audit(s) of the active substance manufacturer(s) listed in PART A relative to the product stated in this declaration has/have been completed by the Manufacturing Authorisation holder as listed below and all critical concerns have been rectified:

Name of active substance manufacturer Name of Manufacturing Authorisation holder (or corporate representative, within the same group of companies} having conducted the audit Date of last audit

ii) Audit of the active substance manufacturer(s) conducted by third party. Justification should be provided below if the date of last inspection exceeds 3 years:

Audit(s) of the active substance manufacturer(s) listed in PART A relative to the product(s) stated in this declaration has/have been completed by the third party auditing body(ies) i.e. contract acceptor(s) on behalf of the Manufacturing Authorisation holder(s) i.e. contract giver(s) as listed below and all significant corrective actions have been completed:

Name of active substance manufacturer Auditing body (contract acceptor) Name of Manufacturing Authorisation holder

( contract giver)

Date of audit (completion)

 

Justification should be provided below if the date of last inspection exceeds 3 years:

and,

I declare that:

  1. i) I have evaluated each of the named contract acceptor(s) in respect of the above audit(s). The audit(s) was/were conducted by properly qualified and trained staff, in accordance with approved procedures.
  2. ii) Technical contractual arrangements are in place and that any measures taken by the contract giver(s) are documented e.g. signed undertakings by the auditor(s).

iii) Evidence provided in lieu of audit

Exceptionally, and if satisfactorily justified, other supporting evidence used in lieu of an on-site audit of the active substance manufacturer(s) by the manufacturer(s).

Please tick and complete the applicable section and provide appropriate supporting information:

Remote assessment based on, for example, questionnaires, review of documents, ISO 9000 certification, results of analytical testing and historical experience with the supplier.

The justification for this approach is attached.

Or

Other situations e.g. Non Traditional (or Atypical) Active Substance

The justification for this approach is attached (see guidance notes).

Supplementary supportive information (optional):

For the active substance manufacturing sites listed below results of inspection report(s) or GMP certificate(s) issued by EEA, MRA partners or other recognised authority together with other supporting information are attached.

Name of active substance manufacturer Summary of supporting information provided

I declare that:-PART D: Verification of the Active Substance supply chain traceability

  1. i) the active substance supply chain of each of the active substance manufacturing sites listed in Part A has been established and documented.

and

  1. ii) there exists a documented risk assessment for all sites in the supply chain of the active substance.

and

iii) the above documents are available for inspection.

PART E: Attestation of the responsible QP

This section declares that the signatory is the QP responsible for the relevant product manufacturer(s) (EEA) and importation and/or batch certification sites as referenced in PART B.

I confirm that:

  1. I am a QP with responsibility for GMP compliance of the active substance and am authorised to make this declaration;
  2. In the case of multiple sites as specified in PART B, this declaration is made on behalf of all the involved QPs named on the relevant Manufacturing Authorisation(s)
  3. the arrangements are underpinned by a technical agreement as described in Chapter 7 of the GMP Guide, as applicable;
  4. a documented procedure defining GMP responsibilities is in place and that
    arrangements/agreements exist between the named companies concerning management of GMP responsibilities;
  5. the relevant technical agreements and procedures are available for inspection by the
    competent authorities.

This declaration is submitted by:-

Signatory

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Status (job title)

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Print name

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Manufacturing Authorisation name:

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