1. REGULATORY COMPLEXITIES
IN HIGH POTENT DRUGS:
REQUIREMENTS FOR GLOBAL
REGULATORY COMPLIANCE
Presented at the CPhI UBM High Potent Drugs 2013
Mumbai, January 23, 2013
1
Dr. Bhaswat S. Chakraborty
Sr. VP & Chair, R&D Core Committee
Cadila Pharmaceuticals Ltd., Ahmedabad

2. CONTENTS
 Understanding the complex regulatory requirements with
respect to manufacturing & research & development
 Establishing an overview of OSHA and European
classification to stay updated with global regulatory
standards
 Determination of ADEs which forms a key component of the
Risk-maPP approach to manage the risk of cross product
contamination in multi-product facilities.
 Clarifying the regulatory concerns on multiple High Potent
Drugs being manufactured in the same facility to ensure
compliance
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3. DEFINITION OF HIGH
POTENT (HP) DRUGS
 Potency is a measure of drug activity expressed in terms of the
amount required to produce an effect of given intensity
 A highly potent (HP) drug evokes a larger response at low
concentrations,
 Lower potency drug evokes a smaller response at similar concentrations
 A HP drug has
 occupational exposure levels (OELs) of less than 10 μg/m 3 of
air after applying appropriate uncertainty factors or
 A daily therapeutic dose of 10 mg/day, or
 A dose of 1 mg/kg/day in laboratory animals producing serious
toxicity
 All HP drugs are, therefore, potentially hazardous drugs and
along with drug handling and manufacturing standards, 3
occupational safety and environmental issues are paramount

4. DEFINITION OF A
HAZARDOUS DRUG
 Exhibits one or more of the characteristics in humans
or animals:
 Carcinogenicity
 Teratogenicity
 Reproductive toxicity
 Organ toxicity at low doses
 Genotoxicity
 Environmental damage or pollution
 National Institute for Occupational Safety and Health
(NIOSH) provides a list of hazardous drugs, e.g.,
 Antineoplasitc (Methotrexate, topotecan, irinotecan, vinorelbine)
 Antiviral (Ganciclovir)
 Hormone (Progesterone)
4
 Misc. (Cyclosporin)

5. The performance-based
exposure control limits
(PBECL) are very popular
in Pharma industries
 Category 1: compounds are low
potency with higher dosage levels
 Category 2 compounds: moderate
acute or chronic toxicity, but their
effects are reversible
 Category 3 compounds: have elevated potency, with high acute or
chronic toxicity; these effects may be irreversible
 Category 4 compounds: have high potency and extreme acute and
chronic toxicity, cause irreversible effects and are likely to be
strong sensitizers, with poor or no warning properties and a rapid
absorption rate
 All HP products are category 3 or 4, based on their cumulative
risk factors; regulatory requirements for containment and 5
protection vary among the categories

6. HISTORY OF CONTROL BANDING
OF DRUGS & PHARMACEUTICALS
 The concept of using categorization schemes for managing chemical
handling was developed in late 80’s
 The system of severity of hazard, and the controls required to
reduce exposures to acceptable levels by US Pharma companies in
early 90’s
 Hazard categorization scheme by British Pharmaceutical Industry
in mid-90’s
 COSHH Essentials by Health and Safety Executive (HSE), UK: late
90’s
 The International Labor Organization toolkit for less-developed
countries, early 2000’s
 Other recent guidances by ACGIH, AIHA, ILO, IOHA, NIOSH,
OSHA and WHO for control banding 6

7. REGULATORY
REQUIREMENTS OF HP
DRUGS?
 As a novel drug (pre-IND or IND stage), one does not what
kind of impact this drug will have on human body
 At occupational exposure levels of <10 μg/m3, these drugs are
(or potentially) toxic or highly toxic to the operator/handler
 Could be cytotoxic, teratogenic or genotoxic
 A lot of uncertainty about safety of the processing
environment (common sense is not enough)
 In hazardous situations, the paradigm is “highly potent until
proven otherwise”
 Facilty & equipment design, writing SOPs, BMRs, reports
 Product control, dust control, yield control…
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8. REGULATORY
REQUIREMENTS
 They are complex as several different laws, acts and
regulations cover same and different aspects
 A reductionist approach may not work for a thorough
insight but cGMP product protection & personnel safety
are two main focal points
 Handling, Equipment, Containment, Engineering,
Administrative, Safety & Environmental are the main
regulatory issues
 Covered by 21 CFR part 210 (211), 29 CFR 1910, ICH Q7A,
OSHA (& NIOSH), Controlled Compound Act and many
other overlapping regulations and guidances
 No single document tells you exactly what to document
 However, especially for manufacturing, the approach and 8
milestones are cGMP appropriate for HP drugs

9. BASICS OF CGMP
 SOPs are clearly and instructionally written and
practiced in letter & spirit
 Facilities are well designed to contain cross-
contamination and mix ups
 Build validated quality at every step of manufacturing
 Well trained personnel
 Manufacturing processes are well defined and
controlled
 Documentation of all steps, tests and deviations
 Practice, learn, update, practice, learn, update…
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10. THE GLOBALLY HARMONIZED
SYSTEM OF CLASSIFICATION AND
LABELING OF CHEMICALS (GHS)
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Source: Health and Safety Executive (HSE), UK

11. EXPOSURE
 Exposure can occur by:
 Aerosolization, contact with contaminated surface,
volatility
 Inhalation, skin contact, skin absorption, ingestion, and
injection.
 Inhalation, skin contact, and skin absorption are the most
likely to occur
 Evidence of exposure
 Mutagenicity
 Developmental and Reproductive Effects
 Cancer
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12. RISK-MAPP
 Risk-based Manufacture of Pharmaceutical Products, A Guide to
Managing Risks Associated with Cross Contamination (Risk-
MaPP), 2010
 Volume 7 of Baseline Guide series by International Society of
Pharmaceutical Engineers (ISPE)
 Provides a scientific, risk-based approach to managing the risk of
cross product contamination in multi-product facilities
 Allows determination of Acceptable Daily Exposure Limits (ADEs)
 ADEs are based on the toxicological and pharmacological
properties of the specific API
 Risk-MaPP defines the ADE of an API to be the estimated
dose that is unlikely to cause an adverse effect if an
individual is exposed to the API by any route, at or below
this dose every day for a lifetime
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13. CALCULATION OF ACCEPTABLE
DAILY EXPOSURE (ADE)
 ADE = (NOAEL x BW) / (UFC x MF x PK)
 where:
 BW = Body Weight (kg) [default for an adult is 50 kg];
 UFC = Composite Uncertainty Factor;
 MF = Modifying Factor; and
 PK = Pharmacokinetic Adjustment(s)
 In cases where a NOAEL is not available, a LOAEL may be used.
 In the event that a human dose is used in a derivation, the NOAEL (or
LOAEL or Lowest Therapeutic Dose) may be expressed as mg/day and
the BW factor becomes unnecessary
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 Usually ADE< 10 OEL

14. ADE DEVELOPMENT PROCESS
 Identification of the hazard
 Comprehensive review of readily available animal and human
(clinical and tox) data to determine the critical effect for ADE
 Assessment of the dose-response relationship
 Once the critical endpoint(s) are determined, LOAEL &
NOAEL are for threshold effects; for non-threshold effects,
such as cancer, level of acceptable risk is defined
 Calculation of the ADE
 After selecting a critical effect, uncertainty factors are applied
to calculate an ADE
 Usually range from 1 to 10
 More than one endpoint may be chosen as a critical effect and
leading to multiple calculations
 Limit with the fewest sources of uncertainty is often
considered appropriate
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 Documentation

15. MANUFACTURING MULTIPLE
HP DRUGS IN THE SAME
FACILITY
1. Robust site policy and system for administrative and engineering
standards, controls and practices for HP compounds
2. Process isolation through area separation, isolators, laminar flow
hoods, single pass filtered exhausts, -ve pressure differential in
compound handling areas… (focus on the entire facility while
preventing cross contamination)
3. Determination of OEL in order to effectively and efficiently
establish proper engineering controls, administrative controls,
policies, procedures and cleaning verifications
4. Verifying the effectiveness of the containment control strategy by
an Industrial Hygiene monitoring of employees
5. Other containment and operational measures that are adequate
for preventing cross contamination
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6. One set of specifications may not stop all cross contaminations
Source: Calkins (2010)Bioprocess Int, Sept. 2010;Doherty P (2012). CROs/CMOs, Chemistry Today, 30, July/Aug

16. ENGINEERING CONTROLS
 Closed inline sampling systems, continuous bag systems,
isolator/glove box technology, split butterfly valves, and
rapid transfer ports to ensure a properly contained system
 Engg. control approaches begin with the ventilation, ensuring
that an engineered local exhaust system is effective to 100
μg/m3
 Laminar flow hoods may be effective between 50 to 100 μg/m3
and directionalized laminar flow booths may be effective to 50
μg/m3
 The greatest risk is the solid dry powder form; therefore a lot
of attention is paid to the charging system and drying
 See possibility of something like soft gel
 The most commonly overlooked area for exposure risk is associated
with degowning practices 16
Source: Doherty P (2012). CROs/CMOs, Chemistry Today, 30, July/Aug

17. THE SYSTEM FOR
CONTAMINATION
PREVENTION
 Establish an OEL or an exposure control banding
system
 For novel compound, estimate a potency to assign an
OEL
 Can be developed from comparison of NOEL or LOEL data
of similar compounds
 (at clinical stage one can get a better estimate of true
potency)
 For given potency category, document the site policy re:
 Engineering controls, administrative controls and personal
protective equipment for handling that potent compound
 Its handling and quality control 17
Source: Doherty P (2012). CROs/CMOs, Chemistry Today, 30, July/Aug

18. SAFETY MANAGEMENT
CONTROLS
 Safety in handling HP drugs apply to
 Personnel in Research & Development, Manufacturing, Pharmacy and
nursing, Physicians, Environmental services, Shipping and receiving,
Veterinary, Waste management …
 Carefully considered site policy or procedure that establishes the
containment strategy associated with each potency category
 Identify required personal protective equipment, gowning and
degowning requirements, cleaning requirements and procedures,
and so on.
 The point of this practice is to have a well-established practice on
how to handle a potent compound and avoid having to make
decisions on a case by case basis.
 eg, for a decision on how a lab handles a 100 ml sample of a 0.1
percent solution of a HP drug, category 4 will have more
precautions than a category 2 drug 18

19. CROSS-CONTAMINATION
PREVENTION: SHARED
FACILITIES
 Remember, the first principle of containment is: physical separation and
isolation of unit operations
 Cross contamination from the processing environment must be prevented
 By protecting employees from spreading cross contamination into other drugs/ products
 Through equipment designs, engineering and administrative controls
 Strict SOP for handling HP compounds
 e.g., no open handling of dry powders with a potency of category III or higher
 Specialized containment equipment
 e.g., isolators will have advertised containment levels <1 μg/m 3
 Monitoring containment with a drug is more rigorous
 e.g., naproxen Na gives a more stringent test of containment than does lactose
 Containment levels are highly dependent on operational practices
 e.g., low exposures inside a booth but higher exposures during removal of gloves and/or
degowning
 Usually containment level demonstrated for one HP compound in a
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equipment may not apply to another compound in the same equipment

20. CROSS-CONTAMINATION
PREVENTION: SHARED
EQUIPMENTS
 For R&D or early small scale work, use stringent disposable or
low cost dedicated equipment to avoid extensive and costly
cleaning
 With scale up, cleaning SOPs have to be developed
 HP compounds must be neutralized and reduced to a negligible
amount (very expensive)
 Calculate actual Maximum Allowable Carry Over (MACO) for each HP
 For many HP compounds to be manufactured in a shared
equipment, cleaning analytical test methods and SOPs must be
developed.
 Review 3 successive trials of sampling and analysis of residues on the wetted
surfaces of the manufacturing equipment
 cleaning validation trials will include: visual inspection assessment, rinse
residue assessment, residual swab assessment, microbial assessment, dirty 20
equipment hold time, calibration & analytical method validation, and trainingveri
record verification ficat
ion
Source: Doherty P (2012). CROs/CMOs, Chemistry Today, 30, July/Aug

21. TYPES OF MAXIMUM ALLOWABLE
CARRY OVER (MACO)
1. Dosage MACO - based on a normal therapeutic dose of Product
A (previous), the maximum daily dose of Product B (next) and
the minimum batch size of Product B (next)
2. Toxicology MACO - based on toxicological information (LD50 or
OEL) of product A (previous), normal daily dose of Product B
(next), safety factors based on if Product B is administered
topically, orally or parenterally, and minimum batch size of
Product B (next)
3. General Limit MACO – typically based on an assumed 10 ppm
limit. Use of the general limit MACO should only be used when
no data yet exists and such use should be justified or explained
 The MACO limits established above are used to calculate
Acceptable Swab Residue and Acceptable Rinse Residue limits.
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22. ISOLATORS
 Often more stringent than Biological Safety Cabinets
Class III
 Cabinet with a ventilated controlled environment with
fixed walls, floor, and ceiling.
 Operator access through fixed glove ports
 Supplies entry through an air lock
 Must be able to be sanitized and decontaminated
 Ventilated glove box.
 Compounding Aseptic Containment Isolator (CACI)
 Designed to meet the requirements of both an aseptic
isolator and an containment isolator
 Used for aseptic hazardous drug preparation
 Exhaust air removed from cabinet by properly designed
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building ventilation.

23. Weighing isolator Cytotoxic solids handling zone
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High potency pilot plants

24. MATERIAL SAFETY DATA SHEETS
(MSDSS)
1. IDENTIFICATION OF THE SUBSTANCE
8. EXPOSURE CONTROL / PERSONAL
/ PREPARATION AND COMPANY
PROTECTION
UNDERTAKING 9. PHYSICAL AND CHEMICAL
2. COMPOSITION / INFORMATION ON
PROPERTIES
INGREDIENTS
10. STABILITY AND REACTIVITY
3. HAZARDS IDENTIFICATION
11. TOXICOLOGY INFORMATION
4. FIRST – AID MEASURES
12. ECOLOGICAL INFORMATION
5. FIRE FIGHTING MEASURES 13. DISPOSAL CONSIDERATIONS
6. ACCIDENTAL RELEASE MEASURES
14. TRANSPORT INFORMATION
7. HANDLING AND STORAGE
15. REGULATORY INFORMATION
16. OTHER INFORMATION
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25. CONCLUDING REMARKS
 There are no unique regulations in major jurisdictions which
specifically address the manufacture of highly potent
pharmaceuticals
 R&D level may require higher containment program as unknowns
are more
 Figure out Acceptable Daily Exposure Limits for all HPs
 Handling, Equipment, Containment, Engineering,
Administrative, Safety & Environmental are the main areas to be
competent in and document
 Consider outsourcing when you don’t have a “beyond doubt”
facility & capability
 For manufacturing of HP drugs, have a cGMP mindset, practice,
learn, update, practice further….
 For manufacturing Multiple HP Drugs in the Same Facility, map
& design the entire facility, not just the production area
 Use appropriate engineering and administrative controls 25
 Document extensively

26. THANK YOU VERY
MUCH
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