Development of Injectable Drugs

Technology Transfer and Process Validation

THESIS TO OBTAIN THE MASTER OF SCIENCE DEGREE IN PHARMACEUTICAL ENGINEERING

Chairperson: Professor Pedro Paulo Santos (IST)

Member of the Committee: Professora Helena Florindo (FFUL)
Supervisors: Professor José Cardoso de Menezes (IST)
Patrícia Antunes (Hikma Farmacêutica)

Anna Carolina Myers da Silva Luzia

1
Presentation

1. Introduction
2. Technology Transfer
3. Process Validation
4. Manufacturing Optimization
5. Developed Work: Production of Injectables for Submission
6. Conclusions and Future Work

2
1. Introduction
OBJECTIVES

 Contribute to the knowledge Process

about development of injectable Risk Assessment Validation
pharmaceutical products;
Scale-up
Production for
Submission
 Examine the possibility of
improving the control strategy and Technology
optimizing the processes. Transfer
R&D
PAT

3
2. Technology Transfer
DEFINITION AND CLASSIFICATION

Generation Values Site of

of Technology Skills Application
Knowledge

Movements of technology from:

 Drug discovery to product development;
Vertical Transfer
 Laboratory to industry;
 Between one manufacturing site to another. Horizontal Transfer

4
 2. Technology Transfer
ADVANTAGES AND OBSTACLES

- Lack of resources Leads to Creates - Economic growth

- Lack of marketing and Technology - University links to industry
Transfer
distribution channels - Quality products

Barriers:
Solutions:
 Low government funding;
 Political stability;
 High cost for pre-qualification;
 Flexibility.
 Restrictions on technology exportation.

5
3. Process Validation
DEFINITION AND STAGES

“Documented evidence with high degree of assurance that a process, operated within established
parameters, can perform effectively and reproducibly to produce a medicinal product meeting its
predetermined specifications and quality attributes” (World Health Organization)

Continued Process
Process Design Process Qualification Verification

6
 3. Process Validation
ADVANTAGES AND OBSTACLES

Allows - Less failure and higher productivity

Process - Increase in safety
Validation
- Cost reduction at a long term perspective

Barriers:
 High costs to complete all stages; Solutions:
 Extensive regulatory approvals;  21st century approach: wider
 Lack of flexibility for alterations. lifecycle knowledge and flexibility

7
4. Manufacturing Optimization
RISK ASSESSMENT

“Identification of hazards and evaluation of risks associated with exposure to those hazards.”
(ICH Q9)
Applicable to
Technology Transfer Scale-up between
between laboratory, pilot
manufacturing sites Manufacturing and production
processes

 Probability
Potential Effect
 Severity
Critical
Process Failure Cause  Criticality
Parameters  Detectability
Control
 Risk Priority Number

8
4. Manufacturing Optimization
PROCESS ANALYTICAL TECHNOLOGY (PAT)

Monitoring of Critical Process Parameters which affect the Critical Quality Attributes

Allows real-time adjustment

In-line On-line
Continuous
 Near-infrared spectroscopy
 Biosensors
Improvement
 Raman spectroscopy
 Fiber optics

Dynamic manufacturing processes compensate for variability

and guarantee consistent product quality

9
5. Developed Work
Production of Injectables for Submission
INDUSTRIAL FACILITY AND PRODUCTION LINES

Hikma 1 Hikma 2

Line 1 / 9 / 10 Line 2 / 5 Line 3 Line 4 / 7 Line 1 Line 2 Line 3

Lyophilized Vials Ampoules Bags Powders Powders Powders

Anti-infectives, cardiovascular and diabetes, controlled substances,

gastro-intestinal, nervous system, respiratory, antibiotics

10
5. Developed Work
Production of Injectables for Submission
PRODUCTION LINE 5

11
 5. Developed Work
Production of Injectables for Submission
STAGES

 Annual planning of new products to be validated; Technology

Transfer
 Transfer of product development information;
 Analytical method transfer to perform co-validation;
Process
 Process validation protocol release and production for submission; Validation
 Analytical testing;
 Process validation report release and submission to the authorities.
Authorities

12
5. Developed Work
Production of Injectables for Submission
PRODUCT A VALIDATION - DESCRIPTION
 Injectable for the treatment of heart complications

Presentation Concentration Batches Batch size Vial size

2 50 L (100 L tank)
1 mL/vial 2 mL vial
1 30 L (30 L tank)
0.2 mg/mL
2 50 L (100 L tank)
5 mL/vial 6 mL vial
1 30 L (30 L tank)

Highly sensitive to oxygen and light

13
 5. Developed Work
Production of Injectables for Submission
PRODUCT A VALIDATION – RISK ASSESSMENT
Failure Mode Effect Analysis (Process)

Process step Cause failure Potential effect Control

Calculations for API and excipients
Dissolution of API or excipients
Protection from light
Protection from oxygen
Filling
Incorrect added amount Low or high assay Calculations are double
verified
Incorrect visual evaluation Low or high assay Dissolution steps are
double verified
Human error Increase of impurities Filling room uses white
LED lights
Excessive ambient exposure Increase of impurities Nitrogen headspace
Machine mal function Product degradation In-process control

14
5. Developed Work
Production of Injectables for Submission
PRODUCT A VALIDATION – MANUFACTURING PROCESS

Sparge of Addition of
Addition of
WFI with Mixture excipient 1
initial WFI
nitrogen and mixture

Addition of Addition of Mixture and Mixture and

excipient 2 excipient 3 addition of addition of
and mixture and WFI API excipient 4

Solution is Mixture and Filling,

completed pH is Filtering stoppering and
with WFI adjusted capsulation

15
5. Developed Work
Production of Injectables for Submission
PRODUCT A VALIDATION – RESULTS

200-300 rpm (10 minutes) - 30 L batches

 Effects of mixing time and speed 300-400 rpm (10 minutes) - 50 L batches

 Effects of bulk holding time Stable for 48 hours

Initial dead volume of 300 mL

 Effects of initial set up and line stoppages
After 2 hours stoppage 200 mL rejected

 Effects of filtration and filling Oxygen out-of-specification results

16
5. Developed Work
Production of Injectables for Submission
PRODUCT A VALIDATION – PROCESS OPTIMIZATION

Oxygen Monitored by
headspace PAT tool

Critical Process Parameter

Out-of-specification Misaligned needle

results holder support Lighthouse oxygen headspace analyser

Performs non-destructive measurements

Solution: Regular and effective maintenance

17
5. Developed Work
Production of Injectables for Submission
PRODUCT B VALIDATION – DESCRIPTION
 Injectable used for heart surgery

Presentation Concentration Batches Batch size Vial size

5 mL/vial 1 50 L (100 L tank) 6 mL vial

10 mg/mL
25 mL/vial 1 200 L (200 L tank) 30 mL vial

Protein API. No special process precautions.

18
 5. Developed Work
Production of Injectables for Submission
PRODUCT B VALIDATION – RISK ASSESSMENT
(For Technology Transfer)

Item Current New Risk categorization

Batch size 80 L and 250 L 50L and 200 L Low. Compounding evaluated
Compounding Stainless steel tank with a propeller Stainless steel tank with a Low. Same material
tank 4 blade magnetic stirrer

Mixing speed 8-12 minutes (excipient) 178-182 minutes Challenging on each step Low. New mixing speeds/times
and time (API). Mixing speed: 550-600 rpm evaluated
Filling Platinum cured silicone tubing Teflon tubing Low. Teflon has lower extractables

Raw-materials API from Reliable. Bedford excipient suppliers Hikma excipient suppliers Low. Compounding evaluated

19
5. Developed Work
Production of Injectables for Submission
PRODUCT B VALIDATION – MANUFACTURING PROCESS

Addition of WFI.
Addition of excipient Addition of API.
Adjustment to
1. Mixture Mixture
temperature

Discontinue of
Filling of solution
Adjustment of pH. mixing, sealing of
into vials, stoppering
Mixture vessel and transfer to
and cappsulation
filtration area

20
5. Developed Work
Production of Injectables for Submission
PRODUCT B VALIDATION – RESULTS

400 rpm (5 mL/vial) 10 minutes excipients

 Effects of mixing time and speed
1200 rpm (25 mL/vial) 1 hour API

 Effects of bulk holding time Stable for 72 hours

 Effects of initial set up and line stoppages 2000 mL dead volume

2 hours line stoppage (300 mL purge)

 Effects of filtration and filling Conform results

21
5. Developed Work
Production of Injectables for Submission
PRODUCT B VALIDATION – PROCESS OPTIMIZATION

As per Technology Transfer Report:

API addition Homogenous solution after 1 hour - 3 hours mixture required
- Foaming observed

Transfer adaptations: Supplier improvements

Variability between materials causes

process alterations

Solution: NIR probe in the compounding tank can control dissolution and assure
a consistent quality product output.

22
 5. Developed Work
Production of Injectables for Submission
PRODUCT B VALIDATION – SCALE UP

Submission scale Commercial scale

Presentation 5 mL/vial 25 mL/vial Presentation 5 mL/vial 25 mL/vial

Batch size 50L (8928 units) 200L (7604 units) Maximum size 383 L 1821 L

Viable vials 6853 6925 Proposed size 380L 1800L

100% 100% Target fill volume 5.60 mL 26.30 mL

Filling speed
(≈ 466 vials/min) (≈ 216 vials/min) Number of vials 67857 vials 68441 vials

23
6. Conclusions & Future Work
CONCLUSIONS

 Technology transfers allow completeness of

development;

 Process validations prove effectiveness, however risk

assessment create alert on critical steps;

 PAT allows real-time monitoring of critical process

parameters and solves variability.

24
6. Conclusions & Future Work
FUTURE WORK

 Trend analysis of manufacturing results and deviations

at Hikma PT;

 Investigation about necessary PAT tools to implement in

accordance to the most regular problems detected.

25
 Development of Injectable Drugs
Technology Transfer and Process Validation
THESIS TO OBTAIN THE MASTER OF SCIENCE DEGREE IN PHARMACEUTICAL ENGINEERING

Chairperson: Professor Pedro Paulo Santos (IST)

Member of the Committee: Professora Helena Florindo (FFUL)
Supervisors: Professor José Cardoso de Menezes (IST)
Patrícia Antunes (Hikma Farmacêutica)

Anna Carolina Myers da Silva Luzia

26