New GMPs for Active Substances & Excipients

Presented by Eoin Hanley

4 July, 2016

Slide 2 © PharmOut 2015

What we will cover in this session

The changing landscape

EC Guideline on principles of GDP of active substances

Formalised RA for ascertaining the appropriate GMP for excipients

Proposed Optional Metrics

Slide 3 © PharmOut 2015

The changing GMP landscape

• EU: Falsified Medicines Directive (2011)

• US FDA Safety & Innovations Act-FDASIA (2012)

• EC Guideline on principles of GDP of active substances (March 2015)

• EU:Guidelines on the formalised risk assessment for ascertaining the appropriate GMP for excipients of medicinal products for human use (March 2015)

• NSF/IPEC/ANSI 363 – 2014 GMP for Pharmaceutical Excipients

Slide 4 © PharmOut 2015

EC Principles of GDP of active substances

• Issued by the European Commission on 19 March 2015

• Follow the same principles as EudraLex Vol. 4 Part II Chapter 17 and the Guideline on GDP of medical products (2013)

• Standalone guideline for importers and distributers of active substances

• They compliment EudraLex Vol. 4 Part II and also apply to distributors of active substances manufactured by themselves

• Guide is 9 pages and has 8 Chapters

Slide 5 © PharmOut 2015

Chapter 1 – Scope

• Very long definition!

• Distribution: procuring, importing, holding, supplying or exporting, apart from brokering.

• Does not apply to intermediates of active substances

“An active substance is any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis”

Slide 6 © PharmOut 2015

Chapter 2 – Quality System

Responsibilities, processes and risk management principles (ICH Q9)

Adequately resourced, competent personnel

Suitable Premises, equipment and facilities

Compliant with GDP for active substances

Clear management responsibilities

Active substances delivered to right excipients in a satisfactory time period

Records made contemporaneously

Deviations, Change Management and CAPA system

Slide 7 © PharmOut 2015

Chapter 3 - Personnel

• Distributor designate a person at each location where distribution activities are performed

• Must have authority/responsibility

• Can delegate duties-not responsibilities

• Clearly document responsibilities of all personnel

• Trained in GDP for active substances

• Competent/experience

• Initial & continuing training on written procedures with a written training program

• Training records should be kept

• Effectiveness of training periodically assessed/documented

Slide 8 © PharmOut 2015

Chapter 4 - Documentation

Documentation should be readily available/retrievableupon request of competent authorities

Sufficiently comprehensive in respect to scope of activities

In a language understood by personnel

Contains basic information on documentation practices

• From delivery to recall plans etc

• Reviewed regularly with version control

Section on Procedures:

Slide 9 © PharmOut 2015

Chapter 4 - Documentation

Section on Records:

• Retained for at least 1 year after expiry date of active substance batch or

• If has retest dates, retain for at least 3 years after batch is completely distributed

• Records for purchase/sale with records to show full traceability of the origin & destination of products

Slide 10 © PharmOut 2015

Chapter 5 – Premises & Equipment

• Suitable & adequate to ensure proper storage and protection from contamination e.g. from

• Narcotics

• Highly sensitising materials

• Materials of high pharmacological activity/toxicity

• Other active substances

• Secure to prevent unauthorised access

• Calibrated monitoring devices (traceable standards)

Slide 11 © PharmOut 2015

Chapter 6 - Operations

• Orders: If procured from a manufacturer, importer, distributer established in the EU, they must be registered according to Directive 2001/83/EC

• Receipt: Section covers protected areas for receipt, separate reception area, examination of deliveries at receipt, quarantine/rejection/destruction procedures, specific storage requirements, reporting falsified materials.

• Storage: Section covers specified conditions e.g. temperature & humidity, prevention of contamination/mix-up, qualified storage areas, cleaning, stock rotation, electronic warehouse management systems should be validated, written contract between contract giver and contract acceptor.

Slide 12 © PharmOut 2015

Chapter 6 - Operations

Deliveries to customers: Supplies in EU made only by registered distributors, transported under correct conditions, product/container/identity maintained at all times, system in place to permit a recall.

Transfer of information: if potential to cause an interruption to supply, relevant customers should be notified, copy of original COA should be provided along with all active substance manufacturer information

COA guidelines in Section 11.4 of Part II of Eudralex Vol 4

Slide 13 © PharmOut 2015

Chapter 7 – Returns, Complaints & Recalls

• Returns: should be identified and quarantined pending investigation. If the active substances have left the care of the distributor, they should only be returned to approved stock if all of the following conditions are met:

• Original unopened container (security seals present)

• Stored & handled under correct conditions

• Acceptable remaining shelf life

• Assessed by a trained/authorised person

• No loss of information/traceability

• If in any doubt, seek advice from manufacturer

• Only trained/authorised person release for return to stock

Slide 14 © PharmOut 2015

Chapter 7 – Returns, Complaints & Recalls

• Complaints and recalls: Recorded & investigated according to written procedure. If a complaint about quality, distributor should review with the original active substance manufacturer to determine action, also with other customers and/or the competent authority. Complaint records should capture all of the relevant information and be retained for trending and inspection.

• Written procedure that defines the circumstances under which a recall should be considered.

Slide 15 © PharmOut 2015

Chapter 8 – Self-Inspections

• The distributor should conduct and record self-inspections in order to monitor implementation of and compliance with these guidelines

• Regular self-inspections should be performed in accordance with an approved schedule.

The Guide also has an Annex that contains a glossary of terms applicable to the

document.

Slide 16 © PharmOut 2015

Formalised RA for ascertaining the appropriate GMP for excipients

• Also approved on 19 March 2015

• The appropriate GMP for excipients shall be ascertained on the basis of a formalised RA in accordance with these guidelines

• The RA shall take into account requirements under other appropriate quality systems as well as the source and intended use of the excipients and previous instances of quality defects. The manufacturing authorization (MnA) holder shall ensure that the appropriate GMP ascertained is applied. The MnA holder shall document the measures taken.

• The excipient RA management procedure should be incorporated in the PQS of the MnA holder.

Slide 17 © PharmOut 2015

Formalised RA for ascertaining the appropriate GMP for excipients

• MnA holders should have the RA/RA management documentation for appropriate GMP for excipients available on site for review by GMP inspectors.

• Consideration should be given to sharing relevant information from the RA with the excipient manufacturer to facilitate continuous improvement.

• A risk assessment as set out in these guidelines should be carried out for excipients by 21 March 2016.

• Document has 4 Chapters

• (next slides)

Slide 18 © PharmOut 2015

Chapter 1 - Scope

• These guidelines apply to the RA for ascertaining the appropriate GMP for excipients for medicinal products for human use.

• According to Article 1(3b) of Directive 2001/83/EC, an excipient is any constituent of a medicinal product other than the active substance and the packaging material.

These guidelines do not cover substances added to stabilise active substances that cannot exist on their own.

Slide 19 © PharmOut 2015

Chapter 2 – Determination of appropriate GMP

• QRM principles should be used to assess the risks presented to the quality, safety and functionof each excipient and to classify the excipient in question, e.g. as low risk, medium risk or high risk.

• Quality risk management tools such as those listed in ICH Q9 (e.g. hazard analysis and critical control points — HACCP) should be used for this purpose.

Slide 20 © PharmOut 2015

Chapter 2 – Determination of appropriate GMP

• For each excipient from each manufacturer used, the MnAholder should identify the risks presented to the quality, safety and function of each excipient from its source — be that animal, mineral, vegetable, synthetic, etc. — through to its incorporation in the finished pharmaceutical dose form.

• Areas for consideration should include, but are not limited to (see list in the document). Some examples on next page:

Slide 21 © PharmOut 2015

Chapter 2 – Determination of appropriate GMP

Examples:

• Transmissible spongiform encephalopathy (TSE)

• Potential for viral contamination,

• Potential for microbiological or endotoxin/pyrogencontamination

• Environmental control and storage/transportation conditions including cold chain management, if appropriate;

• Supply chain complexity

• Stability of excipient

• Packaging integrity evidence

Slide 22 © PharmOut 2015

Chapter 2 – Determination of appropriate GMP

• The pharmaceutical form, the function and the proportion of the excipient in the medicinal product

• Daily patient intake

• Any known quality defects/fraudulent adulterations,

• Whether the excipient is a composite

• Known or potential impact on the CQAs of the medicinal product;

• Other factors as identified or known to be relevant to assuring patient safety.

Additionally, with respect to the use and function of each excipient, the MnA holder should consider:

Slide 23 © PharmOut 2015

Chapter 2 – Determination of appropriate GMP

Having established and documented the risk profile of the excipient, the MnA holder should establish and documentthe elements of EudraLex Volume 4 that he believes are needed to be in place in order to control and maintain the quality of the excipient, e.g. Annex 1 or/and Annex 2; Part II: Basic Requirements for Active Substances used as Starting Materials.

These elements will vary depending on the source, the supply chain and the subsequent use of the excipient, but as a minimum the following high level GMP elements should be considered by the MnA holder: (see list in the document). Some examples on next page:

Slide 24 © PharmOut 2015

Chapter 2 – Determination of appropriate GMP

• Establishment and implementation of an effective PQS

• Systems for coding and identifying starting materials, intermediates and excipients to allow full traceability

• Qualification program of suppliers

• System for QC of the excipient

• Systems to ensure that any activity contracted out is subject to a written contract

• Complaints, recalls, change & deviation management systems

• Environmental control and storage conditions.

Slide 25 © PharmOut 2015

Chapter 3 – Determination of Excipient Manufacturers Risk Profile

• After determination of the appropriate GMP, a gap analysis of the required GMP against the activities and capabilities of the excipient manufacturer should be performed.

• Data/evidence to support the gap analysis should be obtained through audit or from information received from the excipient manufacturer.

• Certification of quality systems and/or GMP held by the excipient manufacturer and the standards against which these have been granted should be considered as such certification may fulfil the requirements.

Slide 26 © PharmOut 2015

Chapter 3 – Determination of Excipient Manufacturers Risk Profile

• Any gaps identified between the required GMP and the activities and capabilities of the excipient manufacturer should be documented. Furthermore, the MnA holder should perform a further risk assessment to determine the risk profile, e.g. low risk, medium risk or high risk, for that excipient manufacturer.

• The MnA holder should have a series of strategies ranging from acceptance through control to unacceptable for the different risk profiles and based on these a control strategy, e.g. audit, document retrieval and testing, should be established.

Slide 27 © PharmOut 2015

Chapter 4 – Confirmation of application of appropriate GMP

Once the appropriate GMP for the excipient and the risk profile of the excipient manufacturer have been defined, ongoing risk review should be performed:

• # of defects connected to batches of excipient received;

• type/severity of such defects;

• monitoring and trend analysis of excipient quality;

• loss of relevant quality system and/or GMP certification by excipient manufacturer;

Slide 28 © PharmOut 2015

Chapter 4 – Confirmation of application of appropriate GMP

• Observation of trends in drug product quality attributes; this will depend on the nature and role of excipient;

• Observed organisational, procedural or technical/process changes at the excipient manufacturer;

• Questionnaires

Based on the outcome of the risk review, the established control strategy should be reviewed and revised if needed.

Control Strategy

Slide 29 © PharmOut 2015

Section recap?

Based on FMD

Both guidelines issued in March 2015

RA for excipients by 21Mar16

Slide 30 © PharmOut 2015

Thank you for your time.Questions?

Eoin Hanley

eoin.hanley@pharmout.net

Technical Manager

www.pharmout.net