DRU STAKEHOLDERS’ WORKSHOP 17-19 June 2009 Gaborone, Botswana

DRU STAKEHOLDERS’ WORKSHOP17-19 June 2009

Gaborone, Botswana

Phone a friend!!

Thanks in the main to….

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

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)

Proposed Guidelines (cont.)

Stakeholders’ Workshop

Proposed changes discussed by DRU

Final guidelines presented to the Board, finalised for November Parliamentary session

Implementation – proposed January 2010

ICH Guidelines for adoption in Botswana

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.

FDA Guideline for Implementation in Botswana

One FDA Guideline– 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

One EU Guideline Qualification and Validation

– 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

Six Botswana-specific guidelines1. Drug Registration Applications

2. Variations

3. Stability Testing

4. Bioavailability & Bioequivalence

5. Good Manufacturing Practices

6. 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. Intro & definitions

II. Registration Guidelines

III. Application Pre-registration/Evaluation Report

IV. Guidelines for Stability

1. Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont.)

Products addressing Botswana health priorities automatically fast-tracked (anti-HIV, anti-malarials, TB drugs)

Completed “Application Pre-Registration/Evaluation Report” required for all submissions

TOC to M2048 to be submitted Dossiers bound in “dispot” clips; no lever arch

files


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


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


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


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 – Pharmacotoxicology– Clinical safety and efficacy, clinical pharmacology, etc.

Stability data requirements: see separate guideline


Registration in other countries:– 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


Labeling:– 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


Samples (cont.):– 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”)


Promotional/advertising material– 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

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.)

Guideline significantly changed from that e-mailed 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)


Requirements for Submission of Variations;– 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


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


Minor Variations (V1 – V37) (Annex I)– Notification only, can be implemented after

submission to DRU

Major Variations (Annex II) – New dossier & prior approval required– Proof required that quality of product unaffected

Changes that make necessitate a New Application (Annex III)


No fee currently for minor variations Samples only required for packaging

changes (labeling, 1° & 2° containers) Many changes requested to proposed

Guideline


Minor Variations (V1 – V37) (Annex I)– 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


V1 - Change of Name &/or Address Applicant “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

“Conditions” Add – Method of API manufacture unchanged


V4 – Change of name/address/site of manufacturer, 1°, 2° packer & “all manufacturing operations”

Steriles excluded – requested reconsideration with adequate validation

Stability data required, “or a commitment to carry out stability studies” to be considered


V7 – Minor change in manufacturing process of API

Route of synthesis to stay “essentially” (to be added) the same

V11 – Change in re-test period and/or storage conditions of API

No stability studies required if CEP submitted & states storage container & re-test period


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


V16 – Change to comply with major international pharmacopoeia, API/IPI

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


V17 – Change in specifications of 1° pack 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)


V20 – Change in qualitative/quantitative composition of 1° pack material

Condition 1, sterile products excluded, to be reconsidered

V23 – Change in batch size of the finished product

Condition 2, sterile liquid products excluded, to be reconsidered


V24 – Change in colour/flavouring system of finished product

Documentation 2, “one sample of new product” (added)

V25 – Minor change in manufacture of finished product

Documentation 3 & 4, to be expanded & read in conjunction with Bioequivalence Guideline for changes to finished product


V26 – change in shape/dimensions of container or closure

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 Condition 3, “Any change should be within the range of

approved limits, except for new parameters” (to be added)


V28 – Change (replacement/addition) in the test method of finished product

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 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


V31 – Change in dimensions…….tablets, capsules, suppositories, pessaries

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


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?)


V37 – Change in Package Inserts w.r.t. indications, new dosage regimen, deletion of CI’s, warnings, side-effects, precautions, drug interactions etc.

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)


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.)

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

Adaptation & adoption of……..1. SADC Guidelines for Stability Studies

2. ICH Guidance on Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products (Q1D)

3. WHO Classification of Climatic Zones

4. DRU local requirements

3. Guideline on Stability Testing of Pharmaceutical Products (cont.)

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


API:– 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


Finished Product:– 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


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

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.)

BA/BE studies performed previously may not comply with latest requirements – motivation for acceptance will be looked at on individual basis depending on:– 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)


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


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 PRE-APPLY for a Biowaver for in-vitro testing. Applicant to provide evidence of BCS class and that excipients will not affect absorption of active.


Biowavers (cont.): Biopharmaceutics Classification System

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)


Bioequivalence Studies:– 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


Bioequivalence Studies (cont.): Similarity factors F1 & F2:

– Submit F2 comparison as well as F1

Aerosols for inhalation require bioequivalence/clinical testing, not in-vitro testing


Bioequivalence Studies (cont.):– “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”)


Bioequivalence Reports– 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:– 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


Responsible Person:– 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


Batch Manufacturing Records (MBR):– 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:– SADC guideline (approved 3-4 years ago)– ICH & RSA guidelines for Clinical Trials– TGA & FDA guidelines

1. 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)

2. HRDC does scientific & ethical review of CTA – must assist in capacity-building within the country

3. 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:

– 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.


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)


Appendices 1 – 8:– 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


Separate guidance for the application made to HRDC (www.MOH.gov.bw)

HRDC gives final approval for CT when DRU evaluation is completeSecretary to HRDC:

Mary Kasule

[email protected]

Tel: 3632466 (office) +267 71862559 (cell)

General Q & A Session

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)


Section 21 Approvals: – require a prescription from a Doctor registered in

Botswana– Motivation for use (no effective alternatives)– DRU Application Form “Exemption from

Registration”


Blue Book Updates?– 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


Interaction between DRU & Customs Control?– 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 PharmacistHead of DRU

DR SINAH SELELO

Principal Pharmacist 1Medicine Registration Unit

MS SELOI MOGATLE

Principal Pharmacist 1 Control Habit-Forming Drugs

Principal Pharmacist 1Post-Marketing SurveillanceMRS 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!