Transcript DRU STAKEHOLDERS’ WORKSHOP 17

DRU STAKEHOLDERS’ WORKSHOP
17-19 June 2009
Gaborone, Botswana
Phone a friend!!
Thanks in the main to….
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Dr. Sinah Selelo, Principal
Pharmacist and Head of Drug
Regulatory Unit
Seloi Mogatle, Principal
Pharmacist 1, Drug Regulatory
Unit
Mrs Olawami Oladiran, Principal
Pharmacist 1,
Pharmacovigilance/Post-Marketing
Surveillance (no longer head of
DRU)
Need Identified by DRU
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Large backlog necessitated revamping of DRU –
increased efficiency (evaluation = 3 years, currently)
Receipt of fully compliant, comprehensive dossiers –
FASTER APPROVALS
To provide guidance on DRU requirements
Prevent current situation where submissions lie
unresolved for months/years
To prevent perpetuating backlog situation
Proposed Guidelines

12 guidelines proposed for implementation in
use with MH2048 (retained)

DRU intends adopting some international guidelines
based on ICH, EMEA or FDA
DRU has developed some Botswana-specific
guidelines (generally based on SADC harmonised
guidelines)
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Proposed Guidelines (cont.)
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Stakeholders’ Workshop
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Proposed changes discussed by DRU
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Final guidelines presented to the Board, finalised for
November Parliamentary session
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Implementation – proposed
January 2010
ICH Guidelines for adoption in
Botswana
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Four ICH Guidelines to be adopted
unaltered
Minimal discussion was held on these
guidelines
1.
Validation of Analytical Procedures: Text and
Methodology. ICH Q2(R1), version 4, dated
November 1995
No points raised
ICH Guidelines for adoption in
Botswana (cont.)
2.
Impurities in New Drug Substances Q3A(R2),
current step 4 version, dated 25 October 2006
If we submit CEP for API, they MUST be updated as E.P. is
updated. Declaration that no changes have been made
since EMEA approved the CEP.
3.
Impurities in New Drug Substances Q3B(R2),
current step 4 version, dated 2 June 2006
Excludes biologicals, animal/plant extracts. No motivation
accepted for impurity limits outside provisions of guideline.
Generics to comply, different impurities limits will not be
accepted.*
ICH Guidelines for adoption in
Botswana (cont.)
4.
Pharmaceutical Development Q8, current Step 4
version, dated 10 November 2005

Include Pharmaceutical Development Report
in Page 2 of 7 of MH2048.
Required for generics.
Go to ICH website for Part II/Annexure to this
guideline, for further explanation.
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FDA Guideline for Implementation in
Botswana
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One FDA Guideline
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Bioanalytical Method Validation, Guidance for
Industry, CDER & CVM, dated May 2001
“A separate workshop will be arranged to discuss all
aspects of biologicals, to do the subject justice.”
Final Version of Annex 15 to the EU Guide to
Good Manufacturing Practice July 2001
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One EU Guideline
Qualification and Validation
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Adopted unchanged
Does not cover distribution of fridge-line products
Suggestion is DRU to adopt the distribution guideline of
WHO with locally-specific changes
Validation Protocol and Report to be submitted to DRU
(DRU wants to see all deviations from protocol, minor or
major)
Read with Guideline on Good Manufacturing Practices
You still with me???
Proposed Botswana-specific
Guidelines for discussion
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Six Botswana-specific guidelines
1.
2.
3.
4.
5.
6.
Drug Registration Applications
Variations
Stability Testing
Bioavailability & Bioequivalence
Good Manufacturing Practices
Clinical Trials using Medicines in Humans
1.
Guidelines on Drug Registration Applications
in Botswana, Third Revised Edition
Guideline 1st revision 2000, 2nd revision 2007,
3rd revision June 2009
In line with harmonised SADC guideline, but
local format MH2048
I.
II.
III.
IV.
Intro & definitions
Registration Guidelines
Application Pre-registration/Evaluation Report
Guidelines for Stability
1.
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Guidelines on Drug Registration Applications in
Botswana, Third Revised Edition (cont.)
Products addressing Botswana health
priorities automatically fast-tracked (antiHIV, anti-malarials, TB drugs)
Completed “Application PreRegistration/Evaluation Report” required
for all submissions
TOC to M2048 to be submitted
Dossiers bound in “dispot” clips; no lever
arch files
1.
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Guidelines on Drug Registration Applications in
Botswana, Third Revised Edition (cont.)
Follow format of existing MH2048, add extra
pages to include extra information mandated
by the guidelines
State ATC pharmacological classification, but
can motivate not to include in PI/PIL.
Motivation to use ZA PI/PIL.
Local agent currently not required but Act
being revised & MAY be required in future
1.
Guidelines on Drug Registration Applications in
Botswana, Third Revised Edition (cont.)
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Declaration (affidavit) to be completed &
signed by Applicant (not Agent) - SADC
Addresses compliance of dossier vs master
documents, GMP compliance, compliance
with national requirements (batch release,
adverse event reporting and batch recalls
In line with SADC guidelines
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1.
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Guidelines on Drug Registration Applications in
Botswana, Third Revised Edition (cont.)
Copy of current RM pharmacopoeial
monographs required, with statement to
comply with latest edition
Two COA’s for API’s, < two years old
One COA required per IPI (not in this
guideline) – DRU to revisit
Batch production records for samples
required – can arrange to view in DRU office
1.
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Guidelines on Drug Registration Applications in
Botswana, Third Revised Edition (cont.)
While biologicals are accepted, no “biosimilars” are
currently accepted
Extracts from standard references to be included as
well as BA/BE studies
Summaries only required for NCE’s
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Pharmacotoxicology
Clinical safety and efficacy, clinical pharmacology, etc.
Stability data requirements: see separate guideline
1.
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Guidelines on Drug Registration Applications in
Botswana, Third Revised Edition (cont.)
Registration in other countries:
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Include registration certificates from some ICH or
PICs countries, and South Africa (not essential)
DRU will accept submissions without CPP’s, with
commitment to submit when available
“Country of origin” = country of manufacture, not
research/development
1.
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Guidelines on Drug Registration Applications in
Botswana, Third Revised Edition (cont.)
Labeling:
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Annexure I on page 46 of guideline = Warnings to
be included on packages (problematic!!), different
from Act 101 (1965) requirements – suggest
applying for exemption
Date of manufacture & manufacturer name &
address required as per SADC
TPM – suggest “Manufactured by…for…”
Separate label for each manufacturer
1.
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Guidelines on Drug Registration Applications in
Botswana, Third Revised Edition (cont.)
Samples (cont.):
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Big increase in number of samples required to
facilitate analysis by Govt. laboratory
Samples to be in “actual distribution pack” (“can
do mock up of label provided it complies with
DRU guideline”)
1.
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Guidelines on Drug Registration Applications in
Botswana, Third Revised Edition (cont.)
Promotional/advertising
material
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Proposed materials to be
attached to submission if
available (otherwise apply
for exemption)
Guidelines to be discussed
at a separate forum (watch
this space!)
2. Guideline on Dossier Requirements
for Variations
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Based largely on WHO Pre-Qualification
Document 2007 & EU Document 2006
Adapted to suit local Botswana
requirements & conditions
Will determine the amount of “wiggle room” DRU will
permit from Industry
2. Guideline on Dossier Requirements
for Variations (cont.)
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Guideline significantly changed from that emailed to industry – new version provided at
Workshop
Future intention for 5 year renewal period
(cannot remove as in law, but the fact that
products remain in “Blue Book List of
Products Allowed into Botswana” means
registrations can be regarded as current)
2. Guideline on Dossier Requirements
for Variations (cont.)
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Requirements for Submission of Variations;
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Application Form for Variations
Table of Contents
Specific Supporting Documents (amended pages
of dossier always required)
Payment Fee (not yet specified)
Consult the Checklist for Variations
Applications for Medicines
2. Guideline on Dossier Requirements
for Variations (cont.)
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Generated LOTS of discussion !!
– Guideline provided before Workshop – no
resemblance to one provided at Workshop!
– Checklist does not tie up with guideline!
– Negotiated for maximum inclusion under “Minor
Variations”
– Practical issues eg. if prior approval required
regarding continuity of stock, unique labels etc.
– Discussion was not exhaustive – further feedback
to DRU from ZA industry
2. Guideline on Dossier Requirements
for Variations (cont.)
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Minor Variations (V1 – V37) (Annex I)
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Major Variations (Annex II)
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Notification only, can be implemented after
submission to DRU
New dossier & prior approval required
Proof required that quality of product unaffected
Changes that make necessitate a New
Application (Annex III)
2. Guideline on Dossier Requirements
for Variations (cont.)
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No fee currently for minor variations
Samples only required for packaging
changes (labeling, 1° & 2° containers)
Many changes requested to proposed
Guideline
2. Guideline on Dossier Requirements
for Variations (cont.)
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Minor Variations (V1 – V37) (Annex I)
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Description of variation
Conditions listed 1, 2, ….
Documentation
Changes exceeding the conditions of Minor
Variations default to Major Variations or changes
that require a new application – prior approval
required
2. Guideline on Dossier Requirements
for Variations (cont.)
V1 - Change of Name &/or Address Applicant
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“Formal document” = letterhead of new applicant
Points 2 & 3 deleted from “Documentation” required
as not applicable
V2 - Change of Name &/or Address or
Additional API Manufacturer
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“Conditions” Add – Method of API manufacture
unchanged
2. Guideline on Dossier Requirements
for Variations (cont.)
V4 – Change of name/address/site of
manufacturer, 1°, 2° packer & “all
manufacturing operations”
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Steriles excluded – requested reconsideration with
adequate validation
Stability data required, “or a commitment to carry out
stability studies” to be considered
2. Guideline on Dossier Requirements
for Variations (cont.)
V7 – Minor change in manufacturing process of
API
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Route of synthesis to stay “essentially” (to be added)
the same
V11 – Change in re-test period and/or storage
conditions of API
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No stability studies required if CEP submitted &
states storage container & re-test period
2. Guideline on Dossier Requirements
for Variations (cont.)
V13 – Change in specification of IPI (limits
tightened or additional parameter)
 Documentation required point 4 – COA of
minimum of two production batches “of
product manufactured with updated
excipient” (added) of concern to industry as
not available at time of submission
2. Guideline on Dossier Requirements
for Variations (cont.)
V16 – Change to comply with major
international pharmacopoeia, API/IPI
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DRU does not have access to all pharmacopoeias,
so copies of all pharmacopoeial specs (& methods?)
MUST BE submitted
Submit current monograph & state material will be
tested according to latest version
2. Guideline on Dossier Requirements
for Variations (cont.)
V17 – Change in specifications of 1° pack
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Condition 3, “Any change should be within the range
of approved limits, except for new parameters” (to be
added)
Documentation 4, COA’s of minimum of two batches
of finished product in packaging materials with the
new specifications (to be added)
2. Guideline on Dossier Requirements
for Variations (cont.)
V20 – Change in qualitative/quantitative
composition of 1° pack material
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Condition 1, sterile products excluded, to be
reconsidered
V23 – Change in batch size of the finished
product
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Condition 2, sterile liquid products excluded, to be
reconsidered
2. Guideline on Dossier Requirements
for Variations (cont.)
V24 – Change in colour/flavouring system of
finished product
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Documentation 2, “one sample of new product”
(added)
V25 – Minor change in manufacture of finished
product
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Documentation 3 & 4, to be expanded & read in
conjunction with Bioequivalence Guideline for
changes to finished product
2. Guideline on Dossier Requirements
for Variations (cont.)
V26 – change in shape/dimensions of container or
closure
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Documentation 3, DRU wanted “Samples of the new
container/closure” – to be changed to “One sample of product
in the new container”
V27 – Change in specifications of finished product
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Condition 3, “Any change should be within the range of
approved limits, except for new parameters” (to be added)
2. Guideline on Dossier Requirements
for Variations (cont.)
V28 – Change (replacement/addition) in the test
method of finished product
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Condition 1, “method of analysis should remain the same” (to
be reconsidered provided change adequately validated)
V30 – Change or inclusion of Score/Breakline of tablet
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Documentation 4, “official letter of commitment to inform users
of relevant changes, and that current stocks will be exhausted
before new product is marketed”. DRU required “Dear
Healthcare Professional” letters to be sent out – a database is
available from DRU
2. Guideline on Dossier Requirements
for Variations (cont.)
V31 – Change in dimensions…….tablets,
capsules, suppositories, pessaries
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Documentation 4, sample of finished product – DRU
increasing focus on counterfeits & moving towards
Ugandan model of current samples available for
importation approval by Customs officials
2. Guideline on Dossier Requirements
for Variations (cont.)
V33 – Change in pack size of finished product

Condition 3, volume of sterile injectables to remain unchanged (to be
added) – becomes a new product if volume changes
V35 – Addition/replacement/deletion of measuring or
administration device not being an integrated part of
primary packaging (spacer devices for metered dose
inhalers are excluded)
(clarification required regarding bracketed text - mouthpiece or true
secondary spacer device?)
2. Guideline on Dossier Requirements
for Variations (cont.)
V37 – Change in Package Inserts w.r.t.
indications, new dosage regimen, deletion of
CI’s, warnings, side-effects, precautions,
drug interactions etc.
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Documentation 3, requires legalised copy of
approval in country of origin (raised the problem of
Urgent Safety Restriction Notices as we won’t get
timeous response from MCC – submit stamped proof
of submission in ZA & Botswana, & do Dear
Healthcare Professional letter in Botswana)
2. Guideline on Dossier Requirements
for Variations (cont.)
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Major Variations (Annex II)
“ Includes changes like…..”
1.
∆ Manufacturing method of API ◄
2.
∆ Composition of Finished Product
3.
∆ Immediate packaging of Finished Product ◄
◄ DRU to reconsider
Guideline on Dossier Requirements for
Variations (cont.)
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Changes that make necessitate a New
Application (Annex III)
1.
Changes to API (change to different API, additional
API/ removal of API in multi-component product)
2.
Changes to Pharmaceutical Dosage Form
(immediate release → slow release; Liquid → powder for
reconstitution; Change in dose of one or more API’s)
3.
Change in Route of Administration
Still there…….are you sure?
3. Guideline on Stability Testing of
Pharmaceutical Products
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Adaptation & adoption of……..
1.
SADC Guidelines for Stability Studies
ICH Guidance on Bracketing and Matrixing Designs
for Stability Testing of Drug Substances and Drug
Products (Q1D)
WHO Classification of Climatic Zones
DRU local requirements
2.
3.
4.
3. Guideline on Stability Testing of
Pharmaceutical Products (cont.)
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WHO / ICH Climatic Zones:
Zone I: Temperate
 Zone II: Subtropical with possible high humidity
 Zone III: Hot and dry
 Zone IV: Hot and humid

Botswana is classified as Zone III – stability
studies to be appropriately designed
STORE BELOW 30°C
3. Guideline on Stability Testing of
Pharmaceutical Products (cont.)
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API:
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Stress testing SADC = 1 primary batch, DRU wants 2
primary batches
Accelerated and long term studies on 3 primary batches of
API
Long term stability studies at 30°C/35%RH (SADC allows
25°C/65RH)
12 months data at submission infers max. SL of
24 months; 24 months data at submission infers
max. SL of 36 months
3. Guideline on Stability Testing of
Pharmaceutical Products (cont.)
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Finished Product:
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Accelerated and long term studies on 3 batches
of product (min of 2 x pilot, 1 x production), using
different batches of API where possible
Long term stability studies at 30°C/65%RH
(SADC allows 25°C/65%RH)
12 months data at submission infers max. SL of
24 months; 24 months data at submission infers
max. SL of 36 months
3. Guideline on Stability Testing of
Pharmaceutical Products (cont.)
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Lively discussion regarding products already
registered with “Store below 25°C” storage
conditions – how should DRU proceed?
Possibility is to provide a proposal to DRU as
to how each applicant will commit to achieve
compliance with Climatic Zone III
requirements, with stated timelines per
product eg. Annual batches for GMP
compliance to be tested on stability at
30°C/65%RH. DRU to respond individually.
4. Guideline on Bioavailability &
Bioequivalence
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Based on SADC BE Guideline
Biowaver Application Form (supplied at the
Workshop) WHO Prequalification of
Medicines Programme
If innovator product not registered in
Botswana, DRU is not in favour of registering
a generic/generics (as they have no clinical
data on file for the drug product)
4. Guideline on Bioavailability &
Bioequivalence (cont.)
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BA/BE studies performed previously may not
comply with latest requirements – motivation
for acceptance will be looked at on individual
basis depending on:
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Therapeutic window of drug
Medical condition being treated
Lack of AE’s (must just be under-reported)
Lack of efficacy (may just be under-reported)
4. Guideline on Bioavailability &
Bioequivalence (cont.)
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Reference Product:
If the innovator product is not being used, the
market leader can be used as long as:
 It is authorised for marketing in SADC region
(PROOF TO BE SUBMITTED)
 PRIOR approval has been obtained from DRU
4. Guideline on Bioavailability &
Bioequivalence (cont.)
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Biowavers:

Applicant to provide justification and proof of safety,
efficacy & quality – submit copies of entries from
standard reference books showing linear kinetics
over dose range & that API is not a pro-drug (DRU
does not have access to these)
Biowaver Application Form to be used to PREAPPLY for a Biowaver for in-vitro testing. Applicant to
provide evidence of BCS class and that excipients
will not affect absorption of active.
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4. Guideline on Bioavailability &
Bioequivalence (cont.)
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Biowavers (cont.):
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Biopharmaceutics Classification System
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Class 1: High solubility – high permeability
Class 2: Low solubility – high permeability etc.
SADC & FDA accept ONLY BSC Class 1 drug substances
for biowavers
Developing countries need access to innovator products
whose API is not BCS Class 1 (in-vitro BE studies are much
cheaper than in-vivo BE studies; research is underway on
BSC Class II drug substances w.r.t. proof of BE)
4. Guideline on Bioavailability &
Bioequivalence (cont.)
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Bioequivalence Studies:
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If measurements of concentration of
active/inactive metabolites used instead of parent
compound, this must be stated in the protocol, not
after the study is complete.
Acceptance Criteria (AUCt, Cmax & Cmin (ss)): 0,8 –
1,25 (80 – 125%), based on FDA, EU, SADC &
Canadian criteria – wider limits may be accepted
if stated “a priori” & justified in protocol
4. Guideline on Bioavailability &
Bioequivalence (cont.)
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Bioequivalence Studies (cont.):
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Similarity factors F1 & F2:
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Submit F2 comparison as well as F1
Aerosols for inhalation require
bioequivalence/clinical testing, not in-vitro
testing
4. Guideline on Bioavailability &
Bioequivalence (cont.)
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Bioequivalence Studies (cont.):
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“Adequate wash-out periods” = 5-8 t½’s (as per
FDA)
Number of subjects to be calculated statistically to
provide at least 80% power of meeting
acceptance criteria – minimum is n=12 subjects
(immediate release oral dosage forms) & n=20
(modified release oral dosage forms)
(“South African companies tend to submit smaller
subject numbers & no account is taken of drop-outs”)
4. Guideline on Bioavailability &
Bioequivalence (cont.)
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Bioequivalence Reports
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Full studies to be submitted, not just summaries
Refer to FDA Guideline on Bioanalytical Method
Validation, for validation required for BA/BE
studies
Lower limit of quantitation, detection & recovery to
be stated in protocol
5. Guideline on Good Manufacturing
Practices

Developed & adapted from WHO GMP
Guideline and “other countries”

Inspections:
–
only on a prioritised basis (eg. If BMR’s show
problems, if products in the Public Health arena if
any concerns are raised)
5. Guideline on Good Manufacturing
Practices (cont.)

Complaints:
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–
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DRU wanted all complaints to be reported on all
products from all sites………
Discussion followed & DRU acknowledges they
lack resource to manage complaint reports and
even Annual Product Reviews, as well as SMF’s
(for further discussion within DRU)
DRU to be advised regarding all recalls &
incidents of counterfeiting
5. Guideline on Good Manufacturing
Practices (cont.)

Responsible Person:
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Currently law does not define a “Responsible
Person” within Botswana
Amendment to law in process to include local
“Responsible Person” (local competent person),
expected by end 2009
Implementation date to be specified
5. Guideline on Good Manufacturing
Practices (cont.)
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Batch Manufacturing Records (MBR):
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DRU will not waive requirement to see BMR’s
If parent companies do not want them submitted,
Applicant can arrange appointment to take them
to DRU offices for inspection
Packing Record to contain outer container label in
compliance with Botswana requirements (problem
for new products)
Almost time for lunch!
6. Draft Guideline – Clinical Trials
using Medicines in Human
Participants

Adapted from:
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1.
2.
3.
SADC guideline (approved 3-4 years ago)
ICH & RSA guidelines for Clinical Trials
TGA & FDA guidelines
Lays out requirements for regulatory evaluation of
CT applications by DRU (scientific & ethical review
done by HRU) – reviews the investigational drug
(SECTION 9 of guideline)
HRDC does scientific & ethical review of CTA –
must assist in capacity-building within the country
Submit 1 & 2 in parallel
6. Draft Guideline – Clinical Trials
using Medicines in Human
Participants (cont.)

Much more detail is required on the investigational
drug review by DRU than is found in Investigators’
Brochure → a slightly abbreviated pharmaceutical
dossier required:
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NCE’s, therefore DRU has no information on its chemical
nature or safety in humans
 eg. API: physico-chemical properties, method of
synthesis, impurities, specifications & test methods,
stability. Drug Product: formulation, method of
manufacture/packaging, specifications & test methods,
stability, labelling of investigational product is specified,
etc.
6. Draft Guideline – Clinical Trials
using Medicines in Human
Participants (cont.)

Clinical Trial Application:
–
–
Section 1 – Checklist of Required Information
Section 2 – Administrative and Supplementary
Details

Applicant details, Investigational Product control details,
Trialists’ & Trial Sites’ details, Trial subjects’ details,
Other details, Ethics, Applicants’ Report/Presentation
(summary of planned trial conduct)
6. Draft Guideline – Clinical Trials
using Medicines in Human
Participants (cont.)

Appendices 1 – 8:
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Clinical trial application form
Format for Investigators’ CV
Joint Financial Declaration – Sponsor & PI
Declaration by PI; Co-investigator; Regional
Monitor; Clinical Trial Protocol Amendment Form
Clinical Trial Protocol Amendment Form
Application Form for Additional Investigators &
Sites
6. Draft Guideline – Clinical Trials
using Medicines in Human
Participants (cont.)
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
Separate guidance for the application made
to HRDC (www.MOH.gov.bw)
HRDC gives final approval for CT when DRU
evaluation is complete
Secretary to HRDC:
Mary Kasule
[email protected]
Tel: 3632466 (office) +267 71862559 (cell)
General Q & A Session
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Pharmacovigilance: draft available, based on
TDA/SADC guidelines, due to be finalised by
end 2009
PSUR’S: no infrastructure to handle now at
DRU, may be required in the future
Renewals & retention fees: will be phased in
some time in the future (proposal: DRU to
include in guideline that currently renewal is
automatic unless DRU contacts Applicant)
General Q & A Session (cont.)

Safety Updates: DRU wants to approve
safety updates – sometimes disagree with
MCC’s requirements
–
For products coming from RSA, DRU will consider
proposal of i) Dear Healthcare Professional letter
for serious AE’s and ii) submit to MCC & then to
DRU (to be revisited)
General Q & A Session (cont.)

Section 21 Approvals:
–
–
–
require a prescription from a Doctor registered in
Botswana
Motivation for use (no effective alternatives)
DRU Application Form “Exemption from
Registration”
General Q & A Session (cont.)

Blue Book Updates?
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Currently have Blue Book plus Addenda
No update to Blue Book is planned
Must buy Blue Book & check with DRU as to
latest Addenda
Addenda listed by generic name instead of brand
names – Customs cannot use this, requested lists
to be stated by trade name
General Q & A Session (cont.)

Interaction between DRU & Customs
Control?
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–
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Currently very little communication
Increasing
Hope to follow Ugandan model in the future due
to increasing threat of counterfeits
Registration Certificates?
–
Due to be supplied by end 2009
DRU Structure (‘work in progress’)
Principal Pharmacist
Head of DRU
DR SINAH SELELO
Principal Pharmacist 1
Medicine Registration Unit
MS SELOI MOGATLE
Principal Pharmacist 1
Control Habit-Forming Drugs
Principal Pharmacist 1
Post-Marketing Surveillance
MRS OLAWAMI OLADIRAN
General

New Botswana banking details:
Government of Botswana Bank
Swift code is BBOTBWGX
Account No. 0101000016620000
Bank of Botswana
Credit Vote: 1108 23251 - Drug Registration and
licensing
Department of Clinical Services, Ministry of Health
Where to from here?
 Study the draft guidelines
 Provide feedback & comment on
areas of concern to:
–
SAPRAA or SAAPI or directly to Seloi Mogatle
at DRU
THANK YOU….
…..for your attention!