Overview of HPRA Sampling

and Analysis (S&A) Programme

Kevin O’Donnell, Maria Filancia and Patrick Saunders

GMP Conference

12th November 2014

Relevance for Manufacturers

Structure of the S&A

Programme

Objective & Scope

• This is a risk-based surveillance programme focussed on patient and

animal health protection

– Objective: To independently monitor the quality of medicinal

products in the Irish marketplace and those manufactured in Ireland

for export

– To give effect to national and EU legislation for the independent

surveillance of H&V medicines (including investigational medicinal

products for human use) and their active constituents

• Scope:

– All MA types – National, MRP/DCP, Centrally Authorised Products

– Active Substances & Excipients

– Unauthorised & Borderline products (e.g. Enforcement samples)

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Key Features of the Programme

• Approx. 400 samples per year are tested or examined

• Products are prioritised for surveillance work using a formal risk ranking tool

developed at the HPRA

• Wide ranging types of analysis and checks are performed

• Physico-chemical testing (e.g. identity, assay, related subs, dissolution)

• Microbiological testing (e.g. TAMC as per Ph. Eur.)

• Biological tests (e.g. Bio-assays, PCR, etc)

• Product usability tests & checks (e.g. eye drop products)

• Packaging & Labelling checks

– Presence of correct safety information in Package Leaflets

– Presence of correct and legible Braille

– Indications of falsification

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Key Features of the Programme

• An annual S&A plan is developed with input across HPRA (Quality Defect staff,

PhV staff, Inspectors, Assessors, etc.)

• Most samples are tested using company test methods

– the methods should already have been validated

– the adequacy of the test methods can be formally assessed in-use

• Product compliance is assessed against:

– Registered specifications & other MA requirements

– Compendial monograph requirements

– Braille declarations, etc.

• Follow-up actions are taken when OOSs and method issues are identified

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Testing Laboratories

• HPRA uses labs in Ireland and in other EEA countries for testing work

• Public Analyst’s Laboratory, Galway (HPRA’s OMCL) – physico-

chemical testing

• State Laboratory, Co. Kildare – physico-chemical testing

(Enforcement samples)

• Various other OMCLs in other countries, e.g.

– UK - Physico-chemical testing (e.g. NIR)

– Czech Republic & Finland – Microbiological testing

– Sweden & Denmark – Biological Testing & some Physico-

chemical testing (e.g. NMR)

• The labs work to ISO 17025 and a set of GMP-related guidelines

• The labs are either externally accredited or assessed (by the OMCL

Network’s own Mutual Joint Audit (MJA) programme)

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European Dimensions…

• Strongly aligned with EU surveillance programmes – esp. for

MRP/DCP and Centrally Authorised Products

– Significant use is made of the OMCL Network

• For test capability not available to HPRA in Ireland (e.g.

biological assays, NMR)

• For lab capacity considerations

• Mutual Recognition of test results is important - extensive

Proficiency Testing Scheme (PTS) in operation annually

– Cost effective and helps avoid duplication of effort

– Co-ordinated workplans, sample exchange and sharing of results

occur

– Best practices and problem issues shared

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European Dimensions cont’d…

• HPRA is active in the OMCL Network at a European & Global level

– Member of the Network’s General Advisory Committee 2006-2010

– Member of the Network’s Advisory Committee for Centrally

Authorised Products 2010-2014

– Current member of several Working Groups (Counterfeit Medicines

WG, API WG, Unlicensed Products WG)

– Rapporteur for several projects

• e.g. Project identifying Key Learnings from the Heparin

Contamination Case – triggered three large scale heparin

surveillance projects 2011- 2015

• e.g. Ongoing development of better approaches to risk-based

surveillance work – new risk assessment tool under

development 2014-2015

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The Annual S&A Plan

Test types

Packaging &

Labelling

Checks

Lab Analysis

Product

Usability

Checks

Dealing with

Sample-only

Requests

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• Safety warnings

• Braille checks

• Parallel

imported/distributed

products checks

• General Packaging

& Leaflet checks, e.g.

presence of PLs in

packs

• Physico-chemical

• Microbiology

• Biological Tests

• From other HPRA

staff• e.g. Can product be

used as per leaflet

instructions?

EXTENT OF THE 2014 PROGRAMME:

• 410 Samples, spanning ~ 800 TESTS

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TYPE OF ANALYSIS PLANNED NO. OF SAMPLES

PHYSICO-CHEMICAL 241

MICROBIOLOGICAL 25

BIOLOGICAL 16

PACKAGING AND

LABELLING

123

PRODUCT USABILITY 5

Actual Physico-Chemical testing 2014

• Approx. 250 samples in 2014

• Generic medicines (atorvastatin, esomeprazole, acetylsalicylic acid...):

– To support HPRA interchangeability assessments

– 6 molecules, 88 products analysed for assay and dissolution

• Authenticity checks: e.g. PDE5 inhibitors, alprazolam, capecitabine, …

– NIR spectroscopy & packaging examinations

• APIs and API Starting Materials (mainly FT-IR spectroscopy)

• Nicotine content by HPLC in vials for e-Cigarettes

• Milk Thistle products (Silymarin content by HPLC)

• Subdivision of Tablets on human and veterinary products

– EP monograph requirements

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Actual Biological Testing 2014

28 samples to date

• Panitumumab (monoclonal antibody) product – various assay and

other biological tests

• Heparin APIs: Species id (PCR), %Mn (ICP-MS)

• Heparin FP: %Mn (ICP-MS), Impurities (NMR & SAX-LC)

• Enoxaparin API: Species id (PCR), %Mn (ICP-MS)

• Enoxaparin FP: Impurities (NMR & SAX-LC)

• Tinzaparin API: %Mn (ICP-MS)

• Tinzaparin FP: %Mn (ICP-MS), Impurities (NMR & SAX-LC)

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Actual Microbiological testing 2014

30 samples to date

• Total Yeast and Mould Count (TYMC) as per Ph. Eur.

• Total Aerobic Microbial Count (TAMC) as per Ph. Eur.

• Specified Micro-organisms (e.g. E. Coli) as per Ph. Eur.

– Several OOSs identified and follow-up actions are in progress

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Packaging & Labelling Examinations

121 samples in 2014 to date

• Safety Information in Product Info (checks done at HPRA office)

– New restrictions: e.g. ”not to be used by patients with

Parkinsons and severe renal impairment”

– Cough & Cold meds: e.g. restriction for children under six years

of age

– Presence of the Black triangle

• Braille compliance (NCBI)

– Against the Braille Declaration registered for the product

• Parallel Imports (PPAs, DPRs and PD CAPs)

– Note: some of these samples were examined also for safety

info and Braille compliance

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Product Usability Checks

4 samples to date in 2014

– e.g. Container closure system checked as a consequence

of a complaint received on a veterinary product.

• No issue identified

– However, the same sample was found to be non-

compliant as regard difficulties in opening the peel back

PL label.

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2015 S&A planning has started!

• Generic / Interchangeable medicines (assay/dissolution)

• Generic Levothyroxine testing – assay and dissolution

• Heparin Testing: NMR by Swedish OMCL

• Vet Cephalosporins:

– Safety variation implementation checks: e.g. contraindication re

use in poultry (including treatment of eggs)

• Domperidone products:

– Safety variation implementation checks: e.g. New posology info

and restricted indications

• Fentanyl Patches:

– Safety variation implementation checks re patch visibility to

minimise the risk of exposure to non-patients

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Sampling and Analysis Work

Processes – key interactions

with Manufacturers and

MAHs

The Lifecycle of a Sample

S&A

Request

Log-in and

Validation

Risk

Assessment

and

Planning

Sample

Collection

Sample

Dispatch to

Lab

Receipt of

COA and

Follow-up

actions

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Risk Assessment and Planning

HPRA requires certain items from manufacturers to facilitate the

surveillance work (Supporting Items Request Form):

1. Copies of Analytical Methods and Specifications

2. Chromatography Columns (not always)

3. Reference Standards and Placebos

4. Relevant Certificates of Analysis

5. Current Chromatograms from QC testing

HPRA will either request these items from the Manufacturer or MAH

When might we contact you…

Supporting Items Request Form

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Sample collection

• For Marketing Status information on the product

• For information on which Wholesalers may have the product

• To arrange a date for sampling at your premises (if relevant –

uncommon- e.g. mainly for sampling APIs and Excipients)

When might we contact you…

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Receipt of COA and Follow-up Actions

• To inform you or the MAH of the results

• To follow-up on any OOSs or Test Method deficiencies

identified

• To follow-up on any other issues identified (e.g. problems

with Ref. Standards)

When might we contact you…

‘Actioning’ the surveillance results

NO ISSUES IDENTIFIED

• Inform MAH/Manufacturer of the GOOD news

• Close the Case

OOS IDENTIFIED

• Contact MAH or Manufacturer to start investigating

the issue

• Comment on the OOS, review manufacturing

records for deviations, change controls, similar

OOSs, OOTs etc. Review QC records.

• Test a reference sample – may be done in parallel

with retesting at the HPRA lab

• Possibly test a marketplace sample

• Review stability data for OOSs and significant OOTs

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CASE STUDY:

Analytical Method Issues

XX Hard Capsules – Related Substances method

1 Stability problem identified with a test solution. (No specific maximum time

for the injection of the solution was given.)

2 The required elution order of three related substances could not be

obtained. (The MAH acknowledged that the correct order and separation

were not always obtained by their QC lab either.)

3 The company method used multiple naming conventions for the same

peaks . Method was very unclear and difficult to follow.

4 The analysis identified a peak that was stated to be rarely present. It was

discovered that the peak was misidentified due to a method error in

naming the peaks in the reference standard chromatogram provided by the

MAH.

5 Other calculation errors / issues in the method.

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Case Study: Method Issues

12th November 2014

Case Study: Actions Taken

Multiple rounds of correspondence with the MAH – no clear resolution of the issues

1. The MAH was requested to submit an assessment of the surveillance findings by the QP responsible for batch certification to the Irish market.

2. The QP was to provide a justification for the continued certification and release of the product to Ireland.

3. The QP was to provide a statement on the compliance status of batches already on the Irish market, given the various problems identified with the test method.

4. The methods were to be corrected and re-validated.

5. The revised methods and validation data were to be assessed as part of a Type IB variation.

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Key S&A Findings in 2013

Key Findings in 2013 – Lab OOSs

• 275 samples tested, the majority complied with their specifications

• Several OOS results were obtained, e.g.:

– 11 products OOS for assay (of active substance)

– 8 products failed the Ph. Eur. subdivision of tablets test

– 3 products OOS with the Ph. Eur. uniformity of mass of delivered

dosages test

– 1 product OOS for alcohol content –excipient in paediatric product

– 1 product OOS for related substances

– 1 unauthorised product OOS for dissolution

– 2 intermediates used to produce a biological active substance were

OOS by PCR

• Appropriate follow-up actions were taken in each case 12th November 2014 29

Dealing with OOS Results

Discrepancies between OMCL results and company release results

do occur

• Analytical method issues need to be resolved before taking any action

• Sometimes additional sampling and testing is performed

• If the sample was not tested with the company method, the

company method is obtained and applied

• The manufacturer will be requested to open an investigation

• When OOSs are confirmed as valid, the case triggers a Quality Defect

investigation which applies risk-based principles to determining

whether market action is needed

• Most cases do not result in market action, but some recalls do occur

– e.g. Recall of a vet product with OOS Ph. Eur. microbiological

results for mesophilic bacteria, yeast and mould content

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Key Findings in 2013 – Method Issues

• 21 deficiencies identified in analytical methods and specification

documents used by manufacturers, e.g.

– Non-robust Related Substances methods – could not adequately

separate the impurities (poor resolution, wrong elution order)

– Insufficient procedures for identifying impurities, esp with RRTs

– Presence of incorrect calculations in test methods (e.g. a

correction factor applied twice in an assay test)

– General lack of detail in methods (e.g. the need to prepare

duplicate samples when running the test, how to handle certain test

solutions to ensure a valid test result is obtained, temperature

details, etc.)

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Method Issues cont’d

• Problems in Sample & Mobile Phase preparation details:

• Shaking Times, Filtration Steps, Heating Times and pH Adjustments

are often missing or not detailed in the methods used in QC labs

• Problems with Reference Materials

• Incorrectly labeled storage conditions

• Incorrect instructions for use (assay vs. identification)

• Reagents used as Ref. Standards

• Appropriate follow-up actions were taken in each case

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Key Findings in 2013 – Packaging &

Labelling Issues

• 162 samples checked, the majority complied

• 19 non-compliances identified

– 3 products had incorrect safety and other information in

package leaflets

– 3 unauthorised products carried medicinal claims on their

packaging.

– 13 products had Braille non-compliances

• the Braille on 5 products did not match what was registered

• the Braille on 7 products were of poor quality or were

comprised of the wrong dots

• 1 product had no Braille

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Key Messages…

Key Messages for Manufacturers

• Ensure QC test methods contain sufficient and clear instructions for standard and sample preparation, System Suitability, etc.

• If there are ancillary documents that support the use of a particular test method, ensure those are referenced in the main method document and that they are controlled documents

• Ensure that calculations in test methods are correct

• Ensure that related substances methods are capable of unambiguously identifying peaks

– Critique methods based on RRT identification only

• Ensure robustness experiments are built into method validation exercises – not a formal requirement of ICH Q2R1

• When we request your test methods, ensure you provide the methods actually used in your QC lab

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Key Messages for Manufacturers

• Ensure the arrangements with your MAHs give assurance that

your site is provided with the correct version of the Module 3

information and with correct versions of labels and leaflets, etc.

– How is this assurance obtained?

– Is your QC lab using the currently registered test methods and

specs?

– Are you using the correct version of package leaflets?

• Ensure that you know and understand the implementation

requirements for MA variations (Type IA, IAin, IB, II)

• Ensure you obtain a copy of the Braille Declaration your MAH

sent HPRA – do you know what is in it?

– Ensure your arrangements for complying with it are robust

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Questions / Discussion