Rephine Symposium 2018: Total Pharma Services

5th Rephine
Symposium
Royal College of Physicians
London
29 January 2018
Rephine Symposium 2018
1

• Update on Rephine – Dr. Rino Coladangelo
• GDP Regulatory Framework of Medicinal Products, API and Excipients - Damiano
Papini
• Regulatory GCP inspections - Brexit on MHRA/EMA GCP inspections - Ian Oulsnam
• Afternoon Refreshments
• Auditing of Intermediates – Requirements for Drug Manufacturers - Mehul Patel
• Open Discussion - Audit Case Studies
Agenda
2

• 2018 – 20year anniversary!
• 1998 – Pharmaceutical Operational Consultancy
• 2005 – GMP consultancy and auditing
• 2008 – Library GMP audit reports
• 2015 – Regulatory affairs
• 2016 – GCP consultancy and auditing
• 2017 – Rephine Sourcing
A brief history of Rephine
3

• Setting up facilities to comply
• Gap analysis
• Mock inspection
• Remedial actions
• Audit
• Rephine Library -180 reports
Good Manufacturing Practice
4

• Marketing Authorisation applications
• MA maintenance
• API dossiers
• Pharmacovigilance
Regulatory affairs
5

• Consultancy
• Training
• Gap analysis
• Mock inspection
• Audit
• CRO Qualification Audit programme: 2 reports +7
imminent
Good Clinical Practice
6

• Focus on APIs
• Vendors
• Marketing Channel
• Efficient method of providing product information
• Buyers
• Fast access to manufacturers
• Rapid indication of quality of product
• Immediate access to QA documentation
• Website launched January 2018
RephineSourcing.com
7

Rephine: Total Pharma Services
9

Rephine = Quality compliance
10

Papini
Agenda
11

Good Distribution Practices (GDP) Regulatory
Framework
Pharmaceutical Products and
Starting Materials
D. Papini
29 January 2018

Outline
✓ Overview of GDP regulations and Industrial Guidelines
✓ Commonalities and differences regarding the application of
GDP to Finished Products, API and Excipients
✓ Criticalities of GDP

CSafe IncheonWorkshop, Excelsius Consul.017
The key issue of GDP

GDP: definition
Article 1(17) of Directive 2001/83/EC
« wholesale distribution is "all activities consisting of procuring, holding, supplying or
exporting medicinal products, a part from supplying medicinal products to the
public” »
EU GDP Guideline 2013/C 343/01 Medicinal Products
“GDP is that part of quality assurance which ensures that the quality of medicinal
products is maintained throughout all stages of the supply chain from the site of
manufacturer to the pharmacy or person authorized or entitled to supply medicinal
products to the public.”
EU GDP Guideline 2015/C 95/01 API
“ the distribution of active substances for medicinal products for human use (hereafter
'active substances') is the procuring, import, holding, supplying or exporting active
substances.”

Guidelines GDP
 Rationale of Guidelines to take into account:
✓ Increased complexity of operations
✓ Technological development advancement
✓ Risk assessment approaches
✓ Supply Chains are more complex, longer
✓ Globalisation
✓ Potential issues with counterfacting and illegal commerce
✓ Seasonal temperature variations

GDP – EU Guideline 94/C 63/03
01/03/1994 Medicinal Products
First EU guideline on GDP

Directive
2001/83/EC
2001 ► 2013 …

… Data from the accelerated storage condition … can be used to evaluate the
effect of short term excursions outside the label storage conditions (such as
might occur during shipping)…
… There should be a direct link between the label storage statement and the
demonstrated stability of the drug product…
Q1A 1992
Q1A(R1) 2000
Q1A(R2) 2003
adoption of ICH Q1F
“Stability Data Package for
Registration Applications in
Climatic Zones III and IV”

Annex II: Potential Applications for Quality Risk Management
…
Storage, logistics and distribution conditions
▪ To assess the adequacy of arrangements to ensure maintenance of appropriate storage and
transport conditions (e.g., temperature, humidity, container design);
▪ To determine the effect on product quality of discrepancies in storage or transport conditions (e.g.,
cold chain management)
▪ To maintain infrastructure (e.g., capacity to ensure proper shipping conditions, interim storage,
handling of hazardous materials and controlled substances, customs clearance);
▪ To provide information for ensuring the availability of pharmaceuticals (e.g., ranking risks to the
supply chain).
2005

Directive 2011/62/EU
(EU Falsified Medicines Directive)
✓ … today’s distribution network for medicinal products is increasingly complex and involves
many players who are not necessarily wholesale distributors as referred to in that
Directive.
✓ In order to ensure the reliability of the supply chain, legislation in relation to medicinal
products should address all actors in the supply chain. This includes not only wholesale
distributors, whether or not they physically handle the medicinal products, but also brokers
who are involved in the sale or purchase of medicinal products without selling or
purchasing those products themselves, and without owning and physically handling the
medicinal products.

GDP – EU Guideline 2013/C 343/01
Medicinal Products

1992 ► 1994: Guideline (94/C63/03)
7 Paragraphs, 4 pages
1. Personnel
2. Documentation
3. Premises and equipment
4. Deliveries to customers
5. Returns
6. Self inspections
7. Provision of information to Member
States in relation to wholesale activities
2001 ► 2013: Guideline (2013/C 343/01)
10 Chapters, 34 pages
1. Quality management (including QRM in line
with ICHQ9 - Ed.)
2. Personnel
3. Premises and equipment
4. Documentation
5. Operations
6. Complaints, returns, suspected falsified
medicinal products and medicinal product
recalls
7. Outsourced activities
8. Self inspections
9. Transportation
10. Specific provisions for brokers
Evolution of EU GDP
Guidelines 94/C63/03 vs 2013/C 343/01

Quality Risk Management (QRM)
9.1 … Risk assessment of delivery routes should be used to determine where
temperature controls are required
…
10.2 … The quality system of a broker should be defined in writing, approved and
kept up-to-date. It should set out responsibilities, processes and risk management
in relation to their activities.
Responsible Person
2.2 … The wholesale distributor must designate a person as responsible person…
A degree in pharmacy is desirable. The responsible person should be continuously
contactable and he may delegate some duties but not his responsibilities” .
GDP – EU Guideline 2013/C 343/01 Medicinal Products

Segregation of Goods
Falsified medicinal products
6.4. … Any falsified medicinal products found in the supply chain should
immediately be physically segregated …
… Wholesale distributors must immediately inform the competent authority and
the marketing authorisation holder of any medicinal products they identify as
falsified or suspect to be falsified . A procedure should be in place to this effect.
Products requiring special conditions
9.4. … There should be adequate physical segregation between frozen and chilled
ice packs.

Temperature control during transport
9.2. …
Where the transportation route includes unloading and reloading or transit storage at
a transportation hub, particular attention should be paid to temperature monitoring,
cleanliness and the security of any intermediate storage facilities.
Provision should be made to minimise the duration of temporary storage while
awaiting the next stage of the transportation route.
9.4. …
For temperature-sensitive products, qualified equipment (e.g. thermal packaging,
temperature-controlled containers or temperature-controlled vehicles) should be used
to ensure correct transport conditions are maintained between the manufacturer,
wholesale distributor and customer.
If temperature-controlled vehicles are used, the temperature monitoring equipment
used during transport should be maintained and calibrated at regular intervals.
Temperature mapping under representative conditions should be carried out and
should take into account seasonal variations.

PIC/S Guide To Good Distribution Practice
For Medicinal Products, PE 011-1 1 June 2014
✓ This Guide is based on the EU Guidelines on Good
Distribution Practice (GDP) of Medicinal Products for
Human Use (2013/C 343/01)
✓ It is up to each PIC/S Participating Authority to
decide whether it should become a legally-binding
standard

United Kingdom - GDP Regulations
 GDP inspections of wholesalers in UK are carried out by MHRA GDP
Inspectorate against:
▪ Human Medicines Regulations 2012 (as amended)
✓ Conditions for holding a wholesale dealer’s licence and obligations of licence
holder to comply with the guidelines on good distribution practice published by
the European Commission
▪ GDP – EU Guideline 2013/C 343/01 for Medicinal Products
 MHRA GDP Deficiency Data published annually on the MHRA website (last
report for 2016 issued in November 2017, based on a sample of approx.
10% of inspections
https://mhrainspectorate.blog.gov.uk/2017/12/13/gdp-inspection-deficiency-data-for-
2016/

MHRA GDP Deficiency Data Report 2016

Code of Practice
The Responsible Person for GDP

WHO GDP - Medicinal Products
 1999 WHO Technical Report Series, No. 885, 1999, Annex 6, Guidelines for
inspection of drug distribution channels
 2003 WHO Technical Report Series, No. 908, 2003, Annex 9, Guide to good
storage practices for pharmaceuticals
 2010 WHO Technical Report Series, No. 957, 2010, Annex 5, WHO good
distribution practices for pharmaceutical products
 2011 WHO Technical Report Series, No.961, 2011, Annex 9 Model guidance for
the storage and transport of time- and temperature–sensitive pharmaceutical
products
✓ WHO Technical supplements to Model guidance (The technical supplement
series): 16 chapters on specific topics

WHO Technical Report Series, No.961, 2011, Annex 9
technical supplement series
Technical guidance on each topics

WHO GDP - Medicinal Products –
Technical supplements example

International Air Transport Association (IATA)

 2000 - GDP generic principles laid down in EudraLex - Volume 4 GMP Guidelines – Part
II - ICHQ7 Chapt. 10.2 Distribution Procedures and Chapt.17 Agents, Brokers, Traders,
Distributors etc.
 2003 - WHO Guides Technical Report Series, No. 917, 2003 Annex 2 - Good trade and
distribution practices for pharmaceutical starting materials was a reference document
with broad acceptance in industry on a voluntary basis and not specific for APIs
 2011 - PIC/S Questions & Answers document regarding Distribution Activities for APIs,
PS/INF 20/2011 24 March 2011, guidance to inspectors when inspecting areas relating
to Supply Chain & Distribution
 2011 - the first time binding GDP requirements for APIs were defined and enforced
with the EU Falsified Medicines Directive 2011/62/EU
 2014 - APIC Guideline GDP for APIs How to Do doc, May 2014. Bridging document
between the WHO GTDP Guidelines for Starting Materials (2003) and the draft
(2013) of the EU APIs GDP Guidelines (eventually 2015/C 95/01)
APIs GDP prior to EU Guidelines 2015/C 95/01

Guidelines GDP of APIs (2015/C 95/01)
 8 Chapters, 9 pages:
✓ Scope
✓ Quality System
✓ Personnel
✓ Documentation (Procedures, Records)
✓ Premises and equipment
✓ Operations (Order, Receipt, Storage,
Delivery to customers, Transfer of
information
✓ Returns, complaints and recalls
✓ Self-inspections
✓ Annex: Glossary
… Distributors of active substances should develop and
maintain a quality system setting out responsibilities,
processes and risk management principles
… The distributor should designate a person at each
location where distribution activities are performed who
should have defined authority and responsibility for
ensuring that a quality system is implemented and
maintained.
… Where the distributor suspects that an active substance
procured or imported by him is falsified, he should
segregate it .. and inform the national competent authority
of the country in which he is registered.
… Where storage or transportation of active substances is
contracted out, the distributor should ensure that the
contract acceptor knows and follows the appropriate
storage and transport conditions.
First EU regulatory binding document specifically for distribution activities of APIs

WHO - APIs
 GTDP for Pharmaceutical Starting Materials, WHO Technical Report Series, No. 996,
2016, Annex 6
✓ As in previous Annex 2, WHO technical report series 917, 2003, APIs, Excipients and
“any others used in the manufacture of a medicinal product” are within the scope
 But:
✓ Added procurement activities and purchase control
✓ Actions to be taken to minimize the risk of falsified or non-conforming materials
entering the supply chain.
✓ Quality Management including appropriate quality risk management (QRM) system
to enable a systematic process for the assessment, control, communication and
review of risks to the quality of the product.
✓ More prescriptions to ensure stock inventory control and segregation of expired
materials
2016

Good Distribution Practices
Excipients
 The IPEC Good Distributions Practices Guide For Pharmaceutical Excipients,
2017 (supercedes 2006 version)
✓ contains views of The International Pharmaceutical Excipients Council (IPEC)
✓ provides additional explanatory notes to GTDP for pharmaceutical starting
materials, WHO Technical Report Series, No. 996, 2016, however, alternative
approaches may be acceptable
 The IPEC Good Distributions Practices Audit Guideline For Pharmaceutical
Excipients, 2011 (supercedes 2008 version)
✓ provides a tool for those auditing companies involved in the supply chain of
pharmaceutical excipients.
✓ should be used in conjunction with the IPEC Good Distribution Practices Guide.
 EXCiPAC TTM GMP/GDP Certification Standard for
Pharmaceutical Excipient Supplier

FDA has the authority to regulate transportation of products:
 21 CFR 211.150 of the GMPs addressing Distribution Procedures
United States
USP chapters to address GDP:
 Chapter <659> Packaging and storage requirements
 Chapter <1079> Good Storage and Shipping Practices –
Finished Products
 Chapter <1197> Good Distribution Practices - Excipients
 Chapter <1083> Good Distribution Practices
✓ Revision of Chapter <1079>, superceding Chapter <1197>
plus subchapters 1083.1 to 1083.9

Basics in <1079>
and <1197>
Replacing <1197>
Mary G. Foster, USP Chair,
AAPS Mini Symposium Frozen State Storage and Cold Chain Transportation, June 9, 2015, San Francisco

 Technical Report No. 39, Guidance for Temperature-Controlled Medicinal Products:
Maintaining the Quality of Temperature-Sensitive Medicinal Products through the
Transportation Environment, 2007.
 Technical Report No. 46, Last Mile: Guidance for Good Distribution Practices for
Pharmaceutical Products to the End User, 2009.
 Technical Report No. 52, Guidance for Good Distribution Practices (GDPs) for the
Pharmaceutical Supply Chain, 2011.
 Technical Report No. 53, Guidance for Industry: Stability Testing to Support Distribution
of New Drug Products, 2011.
 Technical Report No. 58, Risk Management for Temperature Controlled Distribution,
2012.
Parenteral Drug Association (PDA)

ISPE - International Society for
Pharmaceutical Engineering
ISPE Cold Chain
Management Guideline - 2011

Thanks for your attention

Acknowledgment
Materials used for this presentation are taken from:
 Public documents and official websites (ICH, MHRA, FDA, WHO, EMA, IATA, ECA
etc.)
 Presentations and articles freely available from websources
• Steve Todd, Pharmaceutical Journal; Volume 281
• Cold Chain Shipping:Protecting Temperature Sensitive Products January 8, 2009 Diane McLean
Pfizer Global Manufacturing
• A Compliant Cold Chain Management for the Integrity of Biological Products” by Cyril Chaput,
Ph.D. Alternatives Technologie Pharma Inc., Canada
• A Global Review of Good Distribution Practices Brought to you, by Cold Chain IQ
• Temperature Risk Management for the Pharma Supply Chain Erik van Asselt, PhD MSD, PCCIG
EU Branch Leader
• CSafe Incheon Workshop, Good Distribution Practice and Supply Chain Risk Evaluation,
Excelsius consultancy

Papini
Agenda
49

Facts
• Referendum 23 June 2016
• 17.4M (51.9%) LEAVE
• 16.1M (48.1%) REMAIN
• 11pm GMT 29 March 2019 Britain will leave EU
• 3M EU citizens live in UK
• 1.2M British Citizens live in EU
Brexit
50

Brexit, Clinical Trials and
GCP inspections
…..How it looks to an experienced observer……

Contents
•
• Introduction
Government and MHRA positions
Brexit options
Brexit and UK clinical trials
Brexit and GCP inspections in UK
52

Introduction – Ian Oulsnam
• 38 years in pharma industry and regulation
• 33 years GXP auditing / inspecting
• 23 years GCP / PV auditing and inspecting
• 12 years MHRA: Designed, developed and led the MHRA statutory
GCP inspection programme
Actively participated in EMA IWG meetings and led 4 EMA inspections,
assisting with a fifth.
Freelance consultant since 2012
53

Brexit options
• There is a great deal of uncertainty regarding the next 2-10 years
• Several Brexit models possible:
• The European Economic Area (EEA) model?
• EFTA – The ‘Swiss’ model?
• Exit Single Market and Customs Union?
• Trade Agreements; sector specific?
• Free trade?
• WTO rules?
54

• If UK joins the European Economic Area (EEA), impact
on pharmaceuticals should be minimal
• Full access to single market
• For most practical purposes the same as being in the EU
• HOWEVER……….
• Politically unlikely as still have free movement of people
and pay levy to EU
• 83% of what we currently pay
Brexit options - The EEA Model

• If we do not join EEA then potential for a much
• more profound impact
• UK would become a ‘third country’
Brexit options – outside the EEA

• Failure to secure a deal by 29 March 2019 could risk:
• Increased costs
• Some EU specific roles moving out of UK to EU
• Potential for divergence of UK and EU laws for pharma.
Brexit options – outside the EEA

• Paper, Continuity in the availability of goods for the EU
and the UK
• Published in late August 2017
• Desire to maintain the “deeply integrated trade and
economic relationship”
• Compliance activity post-Brexit should continue as
before
UK Government Position

MHRA Position – 16 Jan 2018 1/5

• While negotiations continue, the UK remains a
full and active member of the EU, with all the
rights and obligations of EU membership firmly in
place.
MHRA Position 16 Jan 2018 – 2/5

• Playing a full, active role in European regulatory procedures for medicines
remains a priority.
• We contribute significantly in both the centralised and decentralised
regulatory procedures…. including new rapporteur and reference member
state (RMS) appointments
• maintain our programmes for implementing EU legislation as required by
our obligations as a Member State.
• BUT WHAT ABOUT AFTER BREXIT???

• Should however there be no implementation period, MHRA’s approach would be in
line with the following principles:
• the European Union (Withdrawal) Bill will convert the existing EU legislative
framework into UK law at the moment of exit, so there would be no sudden
changes to the UK regulatory framework.
• we would be pragmatic in establishing UK regulatory requirements. We would
give adequate notice and ensure that companies had sufficient time to implement
any changed requirements.
• I THINK THIS MEANS THAT UK LAW FOR CTs COULD DIVERGE from
EU OVER TIME??

• Nothing specific found from MHRA on -
• Brexit planning for clinical trials
• or
• GCP inspections

• Some thoughts about
• Brexit affects on clinical trials

• Even before Brexit has happened…….
• - EMA is being relocated from London to Amsterdam
• Will the MHRA budget allow regular attendance at GCP IWG meetings
• Especially if UK only has observer status ??
• - Implementation of the EU Clinical Trials regulation has been
• further delayed/postponed – until after the Brexit date!
• So, if UK adopts EU laws in force by 29 March 2019, will the regulation
• be adopted by UK when it is eventually implemented after that date??
Pre-Brexit effects

• Warning
• The following slides contain the best
• guesses of an experienced observer…..
Some ‘Hard’ Brexit Implications for CTs
and GCP inspections

• If UK has no agreement with EU everything is
uncertain…..
• UK unlikely to retain the roles of the QPs and
QPPV?
• Will UK GCP law diverge from that of EU GCP?
• Will companies file MAAs in UK after the EU?
• Will EU recognise UK GCP inspections and vice
versa?
• Answers will not be known on the day we leave the
EU
- Uncertainty could persist for a decade or more
Some ‘Hard’ Brexit Implications for CTs

• UK Sponsors to set up legal entity in EU
• Marketing authorisations where UK is RMS
– transfer of RMS to EU country?
• Trials involving UK and EU sites likely to require
• UK approvals, in addition to EU approvals
Section 2 ‘Hard Brexit’ and Clinical Trials

UK QP certification not accepted by EU?
• QP Release of IMP from 3rd countries, for use in EU
• will have to be based in EU?
• Import of IMPs into EU no longer via UK
• EU QPs required to inspect UK IMP manufacturing facilities?
• Transfer of analytical methods for testing IMPs inside EU?

• Transfer of personal data outside EU :-
Will Data Management facilities in UK need a
• A ‘Safe Harbour’ accreditation, In order to
• process patient data from investigator sites in EU?

SOME THOUGHTS ABOUT
• POSSIBLE IMPLICATIONS OF BREXIT
• FOR GCP INSPECTIONS

Section 3 ‘Hard Brexit’ and GCP inspections 1/4
• MHRA divergence from EU standards:
• EMA GCP IWG attend only as observers
• Attend less often – after EMA moves to Amsterdam
Consequences :
• Loss of influence on EMA procedures
• Less exchange of inspection findings with EMA/MS
•
72

Section 3 Hard Brexit and GCP inspections 2/4
More GCP inspections in UK?
• EMA will continue to inspect in UK,
but such inspections may not be led by MHRA
• MHRA likely to have their own UK GCP and
Foreign GCP Inspection Programmes
• in relation to UK licensing applications
73

• Collaboration programmes are possible as has happened
• between EMA and US FDA.
Could inspection collaboration between MHRA and FDA
(or other major nations) become more likely??
74

• Availability of GCP inspection reports under FoI:-
• Currently the GCP Directives (2001/20 and 2005/28) prevent this.
• However, this could change if….
• UK no longer bound by EU Directives. Presumably MHRA will want consistency
with other GXP inspection programmes
• Note – the draft EU regulation for clinical trials does not appear to prevent FoI
requests.
• So, FoI availability of GCP inspection reports may happen in EU anyway.
75

•Warning
• The preceding ideas given in this presentation, relating to ’Hard
Brexit’ are mostly the best guesses of an experienced observer.
• Until we all have definite information on the final nature of Brexit,
• All we can do is………
76

In conclusion …..
• Hope for a ‘Soft Brexit’
• But
• Plan for a ‘Hard Brexit’
77

Papini
Agenda
78

Auditing
Intermediates
Manufacturing site

Definition
• Chemical intermediate, any chemical substance produced
during the conversion of reactants to a product.
• Intermediates can be in
1. Powder form
2. Liquid form
3. Gas form

Key points
• It is not a Finished product API.
• API manufacturing process may involve processing one intermediate stage
or multiple intermediates.
• Sometime intermediates are manufactured at CMO or purchased from
suppliers.
• Sometime Intermediates are stored in containers for long term use.
• Intermediates can be sold to other customers.

Risks
• Process consistency
• Level of GMP implemented
• Contamination, cross contamination
• Supplier Quality Assurance
• CMO Oversight
• Stability
• Building and facility controls
• Training of operators
• Etc, etc, etc

Manufacturing Facilities
API Intermediates

Key Message- Auditing
• Stay ready for surprises.
• Risk assessment is a key word, Assess the risks as you are auditing.
• Don’t be critic, Be curious to learn the process.
• Ask open questions and closed ones when required.
• Ask question to the manager first and repeat same question to operators.
• Don’t jump to conclusion, take time to investigate deficiencies.
• If you see one production block and not satisfied , check others too.
• Gather evidences if you think something is critical or major. Try to link deficiencies.

Key Message- Pre Audit
• Review pre audit questionnaires
• Read about the product and Intermediates.
• Company overview
• Manufacturing site overview
• Read about regulatory actions

Key Message- Heath and Safety
• Make sure you are hydrated, It can be dry and hot
• Take break if required, wear suitable clothes
• Follow Health and Safety . Request safety hat and steel toe shoes if not given.
• Don’t touch dripping liquids from pipe.
• Be carful of height , don’t venture climbing in congested space.
• Follow notices
• Observe the Health and Safety followed by operators.

Key Message- Legal
• Check local license documents, As Chemical production in majority of countries
required license
• Check local inspection certificates
• Observe senior management of the site. As hands on management and quality
focussed attitude shall be easily visible.
• Always ensure that temporary workers are trained
• I prefer to take copy of opening presentation after the presentation is completed.

Guidance Documents
ICH Q7
Part 2 of Eu GMP guide

Quality unit
• The persons authorised to release intermediates and APIs should be specified
• No materials should be released or used before the satisfactory completion of
evaluation by the quality unit
• Only Quality Unit can release or reject intermediates for use outside the control of the
manufacturing company
• Approving Intermediates supplier
• Approving Intermediates Quality
• Stability data gathered for long term storage of intermediates

Quality unit
• Appropriate laboratory tests should be conducted to determine conformance to specifications
• Appropriate microbiological tests should be conducted where microbial quality is specified
• All specifications, sampling plans, and test procedures should be scientifically sound
• Expiry dates shall be provided for Intermediates stored for longer duration
• When an intermediate is intended to be transferred outside the control of the manufacturer’s
material management system and an expiry or retest date is assigned, supporting stability

Production unit
• Production operations should be conducted in a manner that will prevent
contamination of intermediates.
• Cleaning validation
• Process validation
• Trained workforce

Personnel
• The responsibilities of all personnel engaged in the manufacture of intermediates and
APIs should be specified in writing.
• Personnel should wear clean clothing suitable for the manufacturing activity with which
they are involved and this clothing should be changed when appropriate.
• Additional protective apparel, such as head, face, hand, and arm coverings, should be
worn when necessary, to protect intermediates and APIs from contamination.

Building and Facility
• Buildings and facilities shall be designed to allow easy maintenance.
• Defined area for storage of quarantine intermediates.
• Defined area for sampling the intermediates.
• Permanently installed pipework should be appropriately identified.
• Buildings used in the manufacture of intermediates and APIs should be properly
maintained and repaired and kept in a clean condition.

Equipment
• Suitably located for its intended use, cleaning, sanitization.
• Equipment surfaces shall not alter quality of intermediates.
• Any substances associated with the operation of equipment, such as lubricants, heating
fluids or coolants, should not contact intermediates.
• Written procedures should be established for cleaning of equipment and its
subsequent release for use in the manufacture of intermediates.

Documents
• Batch production records should be prepared for each intermediate.
• Written procedures should be established and followed for investigating critical
deviations or the failure of a batch of intermediate.
• Written procedures should be established and followed for the review and approval
of batch production and laboratory control records.
• The quality unit(s) can delegate to the production unit the responsibility and
authority for release of intermediates, except for those shipped outside the control of
the manufacturing company.

Packaging
• Containers should provide adequate protection against deterioration or contamination
of the intermediate.
• Containers should be clean and, where indicated by the nature of the intermediate or
API, sanitised to ensure that they are suitable for their intended use.
• Labels used on containers of intermediates or APIs should indicate the name or
identifying code, the batch number of the product, and storage conditions.
• Intermediate or API containers that are transported outside of the manufacturer's
control should be sealed.

Storage and Distribution
• APIs and intermediates should be transported in a manner that does not adversely
affect their quality.
• Special transport or storage conditions for an API or intermediate should be stated
on the label.
• The manufacturer should ensure that the contract acceptor (contractor) for
transportation of the API or intermediate knows and follows the appropriate
transport and storage conditions.

Quality is Everyone's Responsibility
W. Edward Deming

Papini
Agenda
99

Case Study 1
Request to change level of observation

Case Study 1 - Summary
• Dedicated Metformin production site
• Investigation for a major customer complaint was found to be weak
and this was deemed a critical observation.
• Aggregation found with the product.
• Auditor not satisfied that investigation was sufficiently thorough.
• CEO of Auditee informed but no response received.
• Auditee disagreed and wanted to change the observation from critical
to major.
• Auditor refused to allow the observation to be downgraded
102

Discussion Questions
• What should be done in the situation where an auditee disagrees
with level of severity?
• What should be done if CEO does not respond to official letter?
• When is it acceptable to change the severity of an observation?
103

Final Auditee Response
• Aggregates are easily breakable and material come back to its original state
after sifting without leading any quality impact to product.
• Gone through various literature data, as well as taken information from
various manufacturers of the Metformin Hydrochloride. No data is
available with respect to aggregations of Metformin Hydrochloride.
• Aggregations of Metformin Hydrochloride is a concern for the industry due
to material property. The aggregations formed during storage do not have
any impact on the product quality. The lumps are breakable without
affecting quality of the product.
• Various experiments have been done with respect to packing and storage
condition; however a measurable benefit has not been observed.
• We do not have firm solution to assure that material will remain in powder
form for 5 years.
104

Auditor Response
• As per response it appears that agglomeration is a common issue
within the industry .Therefore I recommend that the label of the
powder shall be amended to mention that ,agglomeration of the
powder is possible due to Hygroscopic nature. If the agglomeration is
not impacting the quality and specification of the product then only
issue here is a label claim.
• We also need to think about specifications listed on the
pharmacopoeia , as if Pharmacopoeias are acknowledging the above
claim i.e. hygroscopic nature can cause agglomerations then there is
no issue of changing label.
• This was agreed by Auditee and Auditor issued Closure Statement.
105

Case Study 2
Good Clinical Practice

• Caribou Pharma has developed has developed a promising new growth factor enema
preparation for the treatment of ulcerative colitis. They embark on a clinical trial
comparing the growth factor to a placebo enema preparation. The physician in charge of
the trial at Deer University noted that when the enemas were mixed, one set of study
medication was slightly tinted. The physician thought that the tinted enemas were most
likely the active medication. As patients were randomised into the study, he worked with
a pharmacist to make sure that the tinted enemas went to the patients with the highest
disease activity index thinking that they needed the active medication more than the
patients who had the less active disease.
• Deer University enrolled the largest number of patients into this clinical trial from among
the study sites.
• The overall study results showed that the enema therapy was ineffective
• At Deer University there was a 20% response to active therapy and a 30% response to
placebo
• At the other sites combined, there was a 70% response to active drug and a 30%
response to placebo
GCP; Case Study 2
107

• What happened in this case?
• How does it deviate from GCP?
• How can randomisation blind be ensured in a study – to comply with
GCP?
• How can study sites ensure that this type of event will not occur?
• Is there a problem with trial design?
GCP Case History 2
108

Case Study 3
Response to auditing a site issued with an FDA Warning Letter

FDA inspects manufacturing facility, makes certain observations
Rephine audits same facility, findings different to FDA findings
CEO’s Nightmare
110

Discussion
• What should Rephine do in this situation?
• How does one reconcile the difference between the FDA findings
and the Rephine findings?
• Does the lack of deficiencies identified by the auditor at the time
of the Rephine audit offer proof that the manufacturer was
rectifying / had rectified the deficiencies uncovered in time for
their re-audit by the FDA (conducted in July 2017)?
• If you were the client of this manufacturer, would you be happy
to continue using the supplier?
111

• As a QP, I would have concerns with the type of observations made by the
FDA, as they are serious quality breaches.
• The company still holds EU GMP certification and can supply US with
existing products so from a regulatory perspective they are currently GMP
compliant.
• It would be advisable to send a communication update to the companies
that have purchased this report. This is good due diligence on behalf of
Rephine as this is new information that has come to light.
• It is also advisable for Rephine to bring forward the next re-audit date and
include these observations on the next agenda. A 'for cause' audit may
also be required in order to assess proposed actions for the observations
made.
Auditor’s Response:
112

Timeline of response to Warning Letter
02 February 2017:
- Rephine is made aware that a Warning Letter was issued by the FDA in
January 2017 and actions its response strategy based on the internal
Quality Management System.
03 February 2017:
- The Auditor’s response is received. Rephine begins to implement the
remedial action strategy by sending a communication update to all
applicable clients informing them of the situation and asking them to
confirm if they will require a “for-cause” audit.
06 February 2017:
- Rephine liaises with the manufacturer in light of this development.
02 April 2017:
- Rephine is satisfied that the applicable clients have been given
adequate time to respond and decides not to proceed with the for-cause
audit. Rephine instead makes plans to bring forward the re-audit to 2018
and begins the process of requesting dates.
113

Thank you
114

Case Study Timeline:
February 2016:
- FDA inspects an Indian manufacturer.
October 2016:
- Rephine conducts an audit of the same facility. At the time of audit,
Rephine was made aware of the FDA’s inspection but the deficiencies
identified during that audit were not disclosed.
January 2017:
- A Warning Letter was issued by the FDA.
February 2017:
- Rephine learns of the Warning Letter’s existence and actions its
response strategy based on the internal Quality Management System.
June 2017:
- Rephine’s auditor is satisfied with the Auditee’s response to the CAPA
and issues the closure statement.
116

Specific deviations identified by the FDA included the following:
1) Failure to have adequate cleaning procedures to prevent
contamination or carry-over material that would alter the API.
2) Failure of the quality unity to exercise its responsibility to ensure
the API manufactured at their facility was done so in compliance
with CGMP and met specifications for quality and purity.
3) Failure to ensure all production deviations are reported and
evaluated, and that critical deviations are investigated and
conclusions are recorded.
4) Failure to ensure that test procedures are scientifically sound
and appropriate to ensure that APIs conform to established
standard of quality and/or purity.
FDA Observation:
117

Rephine’s audit of the facility identified 9 minor observations. No critical
or major observations were identified during the audit. The following
observations were identified:
1) Record for water system sanitation, filter changes etc. seen in Block B
for October 2016 was deficient in that entry for 18 Oct had not been
completed though activity had been done. In some cases there were
blank boxes whereas elsewhere in the record these were correctly
marked as ‘N/A’.
2) Clocks in the Production blocks are individual and unlikely to be in
synchronisation hence time recordings maybe incorrect.
3) Management review is not being conducted and this is required.
4) The recall procedure and recall example seen was deficient in that
classification was not identified and record not sufficiently thorough.
Rephine Observations:
118

5) Data integrity responsibility is not assigned to any Senior
Manager/Director at present.
6) Root cause analysis was not done correctly for the deviation record
seen e.g. cause not identified.
7) Data integrity training is not in place and this should be done. There is
no general Data Integrity procedure though many of these aspects are
covered in the various procedures seen.
8) Quality risk management is not used as extensively as it should be e.g.
for major change controls such as SAP implementation or building Block
E, risk assessments should have been conducted. A useful risk
assessment would be for checking their compliance to DI practice.
9) APIs sold by this manufacturer require PDE values to be calculated as
these are needed by their customers to meet Eudralex vol 4, Part 1, Ch3
& Ch5 requirements.
Rephine Observations:
119

Supply Chain Risk Evaluation
 Thermal protection of temperature-sensitive medicines is essential
throughout the distribution process
 Manufacturers and suppliers must pre-evaluate their transportation routes
and audit their supply chain partners before use
 Contracted supply chain activities require a quality/service level agreement to
be in place
 Quality Management Systems and preventive measures are to protect product
quality in the total supply chain

 Knowing Key Risk Points means knowing where to act
 Entire route and intermediate points needs to be qualified
 Preserve the adequate Storage & Handling Conditions (temperature) throughout the Supply
Chain.
 Document the Storage Conditions (temperature) throughout the Supply Chain.
 Maintain the Product Safety throughout the Supply Chain (temperature, counterfeiting).

Contributing factors: Temperature
Excursions During Transport
 Product transfers many times during
transportation
 Extreme temperatures
✓ Tarmac time
✓ Containers in extreme temperatures
 Mishandling
✓ Lack of instructions
✓ Human error
 Delays
✓ Customs
✓ Transportation changes
✓ Weather
How Can We Minimize Risk to the
Product During Transportation?
 Communication with carriers and
forwarders
 Knowledge of product stability
 Appropriate product protection
✓ Active containers
✓ Passive containers

Outsourced Activities are a key area of Risk
 Contract giver is responsible for activities contracted out through:
✓ Audits
✓ GDP risk assessments
 Contract acceptor accountable for activities in and must have adequate premises, expertise,
procedures etc. to carry out the work
 Extends to any third party supplier/vendor. Quality Agreements between:
– Manufacturer-Wholesaler
– Manufacturer-Transporter
– Manufacturer-Contractor
– Wholesaler-Transporter
 Must have pre-assessed a supplier before any activity
124

Qualification of the Logistics Service Provider
 Pre-audit:
✓ SOP Lists
✓ Handouts
✓ Organisational Charts
✓ Questionnaires
✓ Certifications - Standards GXP, GDP, HACCP, ISO9001, ISO14001 etc.
 Audit:
✓ How long at a location Storage / No storage
✓ Controlled drugs
✓ Inventory
✓ Packaging / Labelling / Segregation
✓ Equipment validation
✓ Recall procedures
✓ Pharmacopeial requirements
✓ TSE certificates / batch releases / CofA
✓ OOS / Deviation / Non conformity procedures

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