api focussed mhra inspections at dosage form mfg

7/29/2019 API Focussed Mhra Inspections at Dosage Form Mfg

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API Focussed MHRA Inspections at Dosage Form Manufacturers

Background

The Medicines and Healthcare products Regulatory Agency (MHRA) are the UnitedKingdom (UK) Competent Authority responsible for implementation of European Union

(EU) medicines legislation in the UK. MHRA are also responsible for inspection againstand enforcement of the legislation in the UK and inspection of 3rd

country sites supplyingfinal dose form drug products to the UK.

In October 2005 new legislation was passed in the European Union requiring that Active

Pharmaceutical Ingredients (API) used as starting materials in dose form pharmaceuticalmanufacture must have been manufactured in compliance with Good Manufacturing

Practice (GMP). The relevant legislation is:

Amended EU medicines legislation Directive 2004/27/EC (2001/83/EC as amended).

This was transposed into law in each member state (in UK as Statutory Instrument S.I.2005/2789, October 2005).

Article 46(f) of 2004/27/EC introduced an obligation (by law via S.I. 2005/2789 in UK)

forManufacturing Authorisation holders (EU manufacturers or importers of the finaldose form) to use as starting materials only active substances, which have been

manufactured in accordance with the detailed guidelines on Good Manufacturing Practice

for active substances.

Such Manufacturing Authorisation holders may be European Economic Area (EU plusLichtenstein, Norway and Iceland) based manufacturers or EU based importers of

medicinal products from outside the European Economic Area (EEA).

In addition, from this date Marketing Authorisation Applications and variations to change

the source of the active substances used as starting materials have had to be supported by

a declaration of GMP Compliance of the active substance manufacturer by a QualifiedPerson (QP) of the dosage form manufacturer.

Inspections by EU Competent Authorities

Compliance with the above legislation is assessed during inspections of ManufacturingAuthorisation holders by EU Competent Authorities. As such MHRA are responsible for

such assessments in United Kingdom (UK) inspections.

In some cases the Manufacturing Authorisation holder may delegate agreedresponsibilities for demonstration of API GMP to 3rd Country (Non EEA) manufacturing

sites and in such circumstances MHRA would inspect the work carried out at 3 rd Country

sites. In such situations the Manufacturing Authorisation holder retains overallaccountability for compliance with the legislation.

The current inspection program for Manufacturing Authorisation Holders in the UK is

conducted on a two yearly cycle with 3rd

country sites inspected every 3 years.

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Manufacturing Authorisation holders are inspected for compliance with the requirementto use APIs, as starting materials, which are manufactured to GMP. However API

compliance forms only a portion of the inspection typically less than 5% of available

time (depending on type of site and nature of findings). As such this section of theinspection is focussed on the presence of specific quality systems to deliver the

requirements of the legislation and availability of supporting documented evidence.

Expectations of Manufacturing Authorisation Holders

MHRA will look for evidence of effective systems during inspections.

Manufacturing Authorisation holders must have a supplier evaluation and approvalprogram covering APIs (this must be in place irrespective of whether a QP declaration

has been required i.e. it applies to all existing drug products as well as new applications).

This program must accumulate a body of evidence which enables the GMP compliancestatus of each API supplier to be determined. The program must also include periodic re-

evaluation of each suppliers status.

A number of key pieces of evidence are typically required by MHRA:

Approved manufacturers andsupplier listings must be in place, be current, readily

available and be supported by documented evidence gained through the aboveevaluation program. Addresses of manufacturing sites should be requested to be

displayed on Certificate of Analysis and/or product containers to allow

comparison to the approved list; this is particularly important where APImanufacturers may have more than one API facility.

Procurement systems must only allow purchase and receipt of APIs that are

approved or undergoing controlled assessment (through change control).

Supply/quality agreements with API manufacturers/suppliers must unequivocallyidentify the approved site(s) of manufacture.

The entire supply chain for a supplied API must be defined and approved by theManufacturing Authorisation holder. This must include all steps from input of the

starting material to the API process through intermediate stages of manufacture

and any subsequent Agents, Brokers, Traders, Distributors, Repackers and

Relabellers i.e. all steps within the scope of the EU GMP Guide part II. Theprecise role and responsibilities of any Agents, Brokers, Traders, Distributors,

Repackers and Relabellers must be understood to ensure that the quality of API

leaving the manufacturing site is maintained. Additionally the temperatureconditions during transportation must be confirmed as appropriate to the needs of

the particular API or intermediate.

It is expected that in order to approve an API source an audit(s) will have been

conducted by or on behalf of the Manufacturing Authorisation holder.

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All steps in the supply chain of the active substances in use by a ManufacturingAuthorisation holder will have been audited, including those in third countries, by

or on behalf of the Manufacturing Authorisation holder.

Audits of API sites must be conducted against the requirements of the EU GMP

Guide part II (ICHQ7a) by auditors with suitable knowledge and experience inAPI manufacture.

Qualified auditors must have demonstrable evidence that they:

- Have been trained in the techniques of auditing

- Have sufficient training or experience in API manufacture to support a

capability to audit effectively in the environment. This is particularlyimportant as API plants and GMP issues are very different to a dose form

facility.

- Have specific knowledge and experience of the requirements of the EU

GMP Guide part II.

Any deficiencies identified through the audit(s) must be risk assessed, classifiedand appropriate action taken. Should high risk deficiencies be identified with

existing suppliers consideration must be given to immediate correction to prevent

impact on patient safety e.g. quarantining batches, recall of product.

Any deficiencies identified must be managed to conclusion via an effectiveCorrective and Preventive Action (CAPA) management system.

The audit report should be available for inspection by MHRA at theManufacturing Authorisation holder site. The report, and appropriate follow up

records, should be sufficiently detailed and confirm the following information:

- Date(s) performed

- Auditors (their qualifications should be available separately for inspection)

- The scope of the inspection

- The outcome i.e. number and category of deficiencies. Any deficienciesthat could threaten patient safety must be declared

- Current status of deficiencies/ CAPA

- Period of validity of the audit (depends on circumstances but nominally

three years is expected.)

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- Conclusion/recommendations for supplier approval.

A Technical Agreement (Supply/Quality Agreement) must be in place with the

API manufacturer/supplier(s).

Contents of the Technical Agreement (TA) should be compliant with Chapter 7 ofthe EU GMP Guide and specifically include:

- Arrangements for change control and agreement that the API site will

notify the Manufacturing Authorisation holder of any changes or

deviations that could impact the quality of the supplied API or alter thetypical profile.

- Requirement to notify the Marketing Authorisation holder of any changessubmitted to the Drug Master File.

-

Agreement to allow access to audit the API site

- Documentation of the agreed specification

- Agreement that sub contracting will not be allowed without theManufacturing Authorisation holders consent

An incoming goods inspection program must be in place that documents:

- Requirement for confirmation checks on source of API(manufacturer and supplier) and a visual inspection of goods.

- Sampling plans

- Testing arrangements/ Certificate of Analysis (C of A) requirements

- Non conforming goods process.

- Requirement to fully investigate any anomalies e.g. atypical test data,

unusual C of As, different packaging.

API audits by 3rd Party Auditors are regarded as suitable by MHRA on the

following basis:

- The scope of the audit must be clearly defined with the auditor and must

include appropriate/defined elements of the supply chain.

- A 3rd party auditor may provide audit reports to multiple manufacturing

authorisation holders. Manufacturing Authorisation holders may make

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use of such a report as far as the scope is fully pertinent to the APIs inquestion.

If auditing as a 3rd

party a Technical Agreement should be in place between theauditor and the contract giver complying with Chapter 7 of the EU GMP Guide

and auditors must have no vested interests in the outcome.

If using 3rd party auditors Manufacturing Authorisation holders should consider

the impact of absence of personal contact with and knowledge of the API

manufacturer. This can make discussions on any future quality problems or

changes more challenging and potentially less effective.

Where Competent Authority inspections reports or GMP certificates are available

these can provide useful information to Manufacturing Authorisation holders inthe assessment of API suppliers. However, these alone cannot fulfil the statutory

obligations of the manufacturing authorisation holder or the requirements of

section 5.25 of the GMP Guide. The results of inspections may be used togetherwith other supporting information in a risk-based approach by the manufacturer in

establishing priorities for its own audit programme of active substance suppliers.

Where used extreme caution should be taken that the scope of any Competent

Authority inspection covers the specific API and supply chain applicable tothe Manufacturing Authorisation holders product(s).

It should be noted that as inspection of an API manufacturer by a Competent

Authority is not compulsory the majority of APIs manufacturers will not havebeen inspected.

Should an API supplier be identified by audit or other means as not fully GMP

compliant appropriate action must be taken by the Manufacturing Authorisation

holder and dependent on specific circumstances may include:

A risk assessment of the deficiencies identified and effect on the supplied

APIs.

Consideration of suspension of approved status and discontinuation use of

applicable APIs.

Consideration of product recall and notification of same to local

Competent Authority.

Increased testing of API to focus on particular risks.

Repeat audit or coaching of API supplier to improve GMP compliance.

Consideration of notification to a Competent Authority of API site details

(to allow assessment against other licenses that may name the API sourceor as preventive information for new submissions). This may trigger an

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inspection of the API manufacturer by a Competent Authority as allowedfor in the new legislation.

Output of MHRA Inspections of Manufacturing Authorisation Holders

Any deficiencies identified by MHRA are addressed via the inspection reporting system.Required action will vary between member states but could in circumstances of seriousdeficiencies involve:

- Requirement to recall product.

Refusal to grant variation to a Marketing Authorisation

- Removal of the API site from a Marketing Authorisation

- Suspension or removal of a Manufacturing Authorisation

- Warning to a Qualified Person related to conduct/responsibilities or withdrawal of

QP from a Manufacturing Authorisation

- Inspection of the API site by the Competent Authority

In less significant deviations Manufacturing Authorisation holders would be required to

improve their quality system within an agreed timeframe.

Dosage Form Manufacturers Inspections - MHRA Inspection program findings

Deficiency category definitions used by MHRA are as per the EMEA

Compilation of Community Procedures.

Potential contributors to deficiency categories couldbe:

CRITICAL

- Findings of actual or potential threat to patient safety from the drug product

containing a particular API.

No supplier evaluation/ audit of API supplier and no receipt testing conducted

(API at most receipted on C of A with no supporting information)

Continued failure to demonstrate adequate compliance with the EU regulations on

use of GMP compliant APIs.

MAJOR

Significant deficiencies within the API compliance program but each batch of

API fully tested on receipt and no immediate threat to patient safety.

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API audit conducted with major deficiencies identified but current status ofdeficiencies and overall approval status unknown by Manufacturing Authorisation

holder.

OTHER

Minor deficiencies in API compliance program but general confidence that theAPI is GMP compliant.

Technical agreement does not include all requirements.

Experience to date of Compliance of Manufacturing Authorisation Holders with theLegislation

In General:

Dosage form manufacturers have or are working towardsfully compliant

programs to demonstrate APIs are manufactured to GMP.

The requirements are a particular challenge for generic manufacturers with a wide

API supply base taking additional resources and time to complete required

activities.

Many large pharmaceutical companies have had programs in place prior to the

introduction of the legislation and were already generally complaint.

Most companies are aware of their responsibilities and are at varying stages of

compliance.

Examples of specific findings in MHRA inspections:

No adequate system in place to verify the source of each delivery of API.

No (or inadequate) Technical Agreements in place with API suppliers.

No audits conducted of some or all API supplier sites.

Importers not taking responsibility themselves for GMP compliance of APIs usedin imported dose form. Importers assuming 3rd country dose form manufacturer

are conducting audits etc but importer not specifically aware of actual activities at

3rd

country site.

Importers delegate responsibility to 3rd country but do not retain accountability to

ensure that the work has been done in a compliant manner.

Brokers/Traders not included in supplier approval program.

Auditors not experienced/trained in API manufacture.

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GMP of Atypical APIs

The legislation referred to earlier applies to all registered Active PharmaceuticalIngredients. It is a requirement for all registered drug products that an active ingredient is

named on the Marketing Authorisation Application. In some cases materials named asthe active ingredient may not be pharmacologically active and may be commerciallymanufactured for uses other than in drug products. An Atypical API is one that falls

into this latter category.

Difficulties facing dose form manufacturers in assuring GMP of certain Atypical APIs

is understood by MHRA. It may be that the primary use of the material is not for drugproduct use and the primary use may not require standards fully equivalent to GMP. The

pharmaceutical user of the material may be a very small customer and does not have the

necessary influence to demand or guide the manufacturer toward full GMPmanufacturing standards. In worst cases suppliers may not provide access to audit

manufacturing facilities.

This situation has also been highlighted through a European Commission survey of

implementation of the new regulations that was conducted by the European Medicines

Agency (EMEA) via Competent Authorities in 2006/2007. The EMEA are to convene a

working party to develop proposals as to how to manage expectations for these AtypicalAPIs.

To date MHRA has taken a pragmatic approach to GMP compliance of these materialsand as such considered each case on its own merits.

Appropriate elements of the EU GMP guide part II are expected to be applied by the APIand dose form manufacturer.

As a principal such controls must provide confidence that the Atypical API is fit for

purpose and will not negatively impact on the safety and efficacy of the drug product.QPs should justify the controls in place on a scientific basis and record a risk assessment

on a product specific basis for use of such Atypical APIs for which GMP compliance

can not be demonstrated or is known to be incomplete

Summary

Inspections of dose form manufacturers by EU Competent Authorities are routinely

assessing the companys API GMP compliance programs.Expectations of programs are based on the requirements of Directive 2004/27/EC and

interpretation by EMEA http://www.emea.europa.eu/Inspections/GMPfaqAS.html

MHRA will expect to see evidence of specific elements of a supplier approval program, akey element of which is considered to be an audit(s) of all steps in the supply chain.

The Manufacturing Authorisation holder is responsible for taking appropriate action to

ensure API sources are GMP compliant.Adverse findings from inspections may result in various action steps taken by MHRA.

In general since the introduction of the new legislation dose form manufacturers are

taking steps to assure GMP compliance of the API supply chain.

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http://www.emea.europa.eu/Inspections/GMPfaqAS.htmlhttp://www.emea.europa.eu/Inspections/GMPfaqAS.html


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Written by:Graeme R McKilligan

GMP Inspector

MHRAYork, UK

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api focussed mhra inspections at dosage form mfg

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