תהליך הערכת ביצועים משוב לעובדים על fy2007

Q11 Development and manufacture of Presented by Alex Weisman, Ph D Vice President R&D,

Q11 Development and manufacture of Drug product: Chemagis overview • Founded in 1987, Chemagis is a subsidiary
, Israel's second largest pharmaceutical conglomerate and
part of the Perrigo Group.

• Chemagis develops, produces and markets an extensive line of
high-quality nly for
generic pharmaceutical industries.

• Its products comply with the exacting regulatory requirements
of leading health authorities.

• This guideline describes approaches to developing process and drug substance understanding and also provides guidance on what information should be provided in CTD sections 3.2.S.2.2 – 3.2.S.2.6. It provides further clarification on the principles and concepts described in ICH guidelines on Pharmaceutical Development (Q8), Quality Risk Management (Q9) and Pharmaceutical Quality Systems (Q10) as they pertain to the development and manufacture of drug substance.

• A company can choose to follow different approaches in developing a drug substance. For the purpose of this guideline, the terms "traditional" and "enhanced" are used to differentiate two possible approaches. In a traditional approach, set points and operating ranges for process parameters are defined and the drug substance control strategy is typically based on demonstration of process reproducibility and testing to meet established acceptance criteria. In an enhanced approach, risk management and more extensive scientific knowledge are used to select process parameters and unit operations that impact critical quality attributes (CQAs) for evaluation in further studies to establish any design space(s) and control strategies applicable over the lifecycle of the drug substance. As discussed in ICH Q8 for drug product, a greater understanding of the drug substance and its manufacturing process can create the basis for more flexible regulatory approaches. The degree of regulatory flexibility is generally predicated on the level of relevant scientific knowledge provided in the application for marketing authorisation

• DS = Drug substance • DS = Design space

3.1 General principles 3.1.1 DS Quality link to Drug product 3.1.2 Process development tools: Quality risk management Knowledge management

Q11: Approaches to development • ICH Q8 recognizes that "Strategies for product development vary from company to company and from product to product. The approach to, and extent of, development can also vary and should be outlined in the submission." These concepts apply equally to the development of the drug substance manufacturing process. An applicant can choose either a traditional approach or an enhanced approach to drug substance development, or a combination of both.

Q11 Development and manufacture of Drug • The guideline describes approaches… • Which approach is preferable? Traditional or enhanced? The answer: implement whatever is good
for your company!!!
What is good? What are the criteria to make a decision? - No compromises in Quality; - Shorter time to approval (=cost). If the cost for development and implementation for the "enhanced" approach is higher than for the "traditional one" –
use the traditional one!
Q11 Development and manufacture of Drug Considerations should be taken into account before choosing one of the approaches: • 1) RM availability and suppliers stability; • 2) "Scale up"? • 3) Future changes in Engineering design; etc. Traditional approach • Typical CQA's: DS quality = safety, potency, strength, purity; - Genotoxic impurities directly effect safety; - Crystalline form and PSD can effect potency (bioavailability can be sufficiently different for the different forms of PSD of the same DS ); - Related substances, residual solvents etc. directly effects the purity; CQA's are important not only with the
reference to quality, but to with the reference
to the DS markets.
CQA's with the reference to specific markets Desired DS quality may sufficiently varies within territory: Example 1 : EP/USP description of DS: white to off white is acceptable; Japan – off white will not pass!!!! Example 2: Related substances level: for same DS approved in EC with ICH limits, FDA requested 0.05% /0.10% as exceeding 2g/day – obesity problem in Q11: Manufacturing process development
should include, at a minimum….
• Identifying potential CQAs associated with the drug substance so that those characteristics having an impact on product quality can be studied and controlled; • Defining an appropriate manufacturing process; • Defining a control strategy to ensure process performance and drug substance quality; Q11: Manufacturing process development
should include, at a minimum….
An enhanced approach to manufacturing process development would additionally include the following elements: A systematic evaluation, understanding and refining of the manufacturing process, including; » Identifying, through e.g. prior knowledge, experimentation and risk assessment, the material attributes and process parameters that can have an effect on drug substance CQAs; » Determining the functional relationships that link material attributes and process parameters to drug substance CQAs; • Using the enhanced approach in combination with QRM to establish an appropriate control strategy which can, for example, include a proposal for a design space(s) and/or real-time release testing (RTRT). Q11: Linking MA and Process parameters to DS CQAs • The manufacturing process development program should identify which material attributes (e.g., of raw materials, starting materials, reagents, solvents, process aids, intermediates) and process parameters should be controlled. Risk assessment can help identify the material attributes and process parameters with the potential for having an effect on drug substance CQAs. Those material attributes and process parameters that are found to be important to drug substance quality should be addressed by the control strategy Material attributes and process parameters • Raw materials, reagents, solvents, catalysts used for DS production; Traditional approach – works not bad for the generic industry: Example 1: Process related impurity – N-Alkyl Example 2: Reagent related impurity – S-methyl Example 3: RM/process related impurity - D- Cetirizine Material attributes and process parameters vs. CAQ's of DS • Quality by Design: A systematic approach to development that begins with predefined objectives and emphasizes product and
process understanding and process control, based on sound
science and quality risk management. (ICH Q8)
• The process designed in a way that being within the Critical Process Parameters (CPP) results in producing a material, meeting "Critical Quality Attribute" (CQA) • Every process at its development time should be investigated
• Kinetics of desired product and impurities formation performed
in variable conditions;
• Solid state research and crystallization parameterization;
• Identification of impurities;
• Control of process parameters and MA's.

Q11: design space • For chemical entity design space development, a major focus is knowledge of formation, fate, and purge of impurities through every step of a manufacturing process. It is important to understand the formation, fate (whether the impurity reacts and changes its chemical structure), and purge (whether the impurity is removed via crystallisation, extraction, etc.) as well as their relationship to the resulting impurities that end up in the drug substance as CQAs. All steps (or unit operations) should be evaluated to establish appropriate acceptance criteria for impurities as they progress through multiple process operations Design space for purification and crystalline form control DS a proprietary purification method was developed. The API character- Hardly soluble in any "conventional" organic solvents
Easily decomposes in water and in protic solvents (as MeOH).
To get the pure material, very polar and high boiling point solvents
had to be chosen (e.g. DMF, DMAA), DMF found to be the best choice for
purification.
However… residual DMF (CQA), found to be difficult to remove

We have found during defining of the design space of crystallization parameters, by DOE, that crystallization at lower temperatures and volumes enable to remove the DMF later on, by drying, to get in spec material. Contour Plot of DMF vs Volume, Temp
200 – 300300 – 400400 – 500 500 – 600600 – 700700 – 800 Design space for purity control by manufacturing process • Tramadol – one of ours largest product, at EOR
• we get 80% desired trans and 20% cis,
• Performing a step of isomeriztion- converting 20% of the
• undesired cis- "by product",
• to the desired trans-product
• Minimize the level of "by-product" from 20 to 13%.
• The process performed today at:
• 80C , 5 hr, acid of concentration of 25%.
• Performing DOE experiments and defining reaction surface,
• we get clearer picture of the interaction between the parameters of
the reaction and conclude that: • Simultaneous changes of the parameters may give better yields
up to 92%.

Isomerization Stage - Reaction Surface
Isomerization stage with different temperature and acid concentration
After 1 hr
After 2 hr
After 3 hr
After 4 hr
After 5 hr
% T.trans
Design space for manufacturing Design space for manufacturing • % of water in the system strongly effects the level of Imp Y. Finally, process design includes: - Control of water in RM's, solvents and - Control of manufacturing equipment; Q11; Submission of Manufacturing s development information • 3.2.1 Overall Process Development summary • 3.2.2 List of DS CQAs; • 3.2.3 Manufacturing process history; • 3.2.4 Manufacturing process Studies; Q1: Description of Manufacturing Process and Process controls • The description of the manufacturing process should be provided in the form of a flow diagram and sequential procedural narrative. The in-process controls for each step or stage of the process should be indicated in the description. Scaling factors should be included for manufacturing steps intended to span multiple operational scales when the process step is scale dependent. Any design spaces in the manufacturing process should be included as part of the manufacturing process description. Example 3 gives an example of the presentation of a design space for a biotechnological product. Q11: Selection of SM and Source • Regulatory authorities assess whether the controls on the drug substance and drug substance manufacturing process can be considered adequate, including whether there are appropriate controls for impurities. To conduct this assessment, enough of the drug substance manufacturing process should be described in the application for regulatory authorities to understand how impurities are formed in the process, how changes in the process could affect the formation, fate, and purge of impurities, and why the proposed control strategy is suitable for the drug substance manufacturing process. This will typically include a description of multiple chemical transformation steps; Selection of Starting Materials for Semi
Erythromycin as RM for Azithromycin & Clarithromycin
Q11:Justification of Information for Starting Material or Source Material Q11: Control Strategy Q11: Controls strategy • 6.1.1 Approaches to Developing Control strategy • 6.1.2 Consideration in Developing a Control Strategy Process Validation / Evaluation • PV is the documented evidence that process, operated within established parameters can perform effectively and reproducibly a drug substance… • To be performed before commercialization. • When should be repeated? - When manufacturing process changes have a place: scale up, changes in RM, equipment etc. • Continuous process verification vs. traditional process validation (ICH Q8)

Source: http://pdaisrael.co.il/ICH%20Q11%20Presentation%20by%20Alex%20Weisman.pdf