Risk Management in Drug Product Manufacturing with Emphasis on Batch Documentation/Execution

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Brittany Randall
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1 Risk Management in Drug Product Manufacturing with Emphasis on Batch Documentation/Execution Manufacturing Breakout Session I Jack Pellett (Genentech) and Eleni Dokou (Vertex)

2 What are typical lead-times before start of Phase 1/2a manufacturing campaign? Varies, from several weeks to several months Company A: variable a few weeks to months Company B: Extemporaneous Preparations are very often used, making notification times a non-issue Company C: variable, but typically 3 months 2

3 What is the role of Quality in Approving Batch Records? No one in the breakout session indicated that their Quality Unit does not pre-approve batch records (with the exception of packaging) Company A: Considering removing the requirement for Quality preapproval of batch records. Concurrent (daily) line review of batch records is performed during each campaign. Company B: CMOs have been qualified to perform quality compliance activities. Quality is still pre-approving batch records. However, there is a business risk, as quality does not approve the executed batch record before release of the batch. Company D: Quality Unit does not pre-approve batch records for packaging operations. 3

4 Process Parameters in Batch Records- Most companies only provide process parameter ranges in cases where sufficient process knowledge has been accumulated. Values set/obtained during processing are recorded Ranges are specified in cases where process knowledge is limited. Health authorities would likely want to see some targets/ranges. However, they are mainly concerned that the manufacturer knows what needs to be done to assure high quality product for the clinic. Most companies do not start applying QBD principles in early development (prior to market-image selection). One exception (Company F) felt it was useful to start early to build QBD into culture. 4

5 Change control in Early Development Change control approaches vary between companies, but there was agreement that systems in early development must be able to quickly address deviations/changes Company A: Has a Quality group dedicated to early development. A simple system (not TrackWise) is used to track changes. However, if they are using a Manufacturing site that also supplies Phase III material, they will use systems already in place at the site. Changes and deviations are prescreened by the Quality group to ensure that they are not tracked together with changes/deviations associated with Phase III manufacturing operations. Company G: Woks exclusively with CMOs and relies on partner s Quality Systems. Comment was made that direct and timely quality involvement at Early Development stage is a positive step that appropriately captures or dismisses potential Mfg concerns. Two companies indicated that their Phase I batch records are relatively simple (30 to 40 page. 5

6 Control Systems for Inventory (Excipients, Drug Product) Most companies have a common inventory system for early/late development excipients. If a unique material is needed by Company B for a early development campaign, they have an exception process to bring in the material. Others companies often work with a late development group to use same vendors and leverage vendor qualification. One company prefers to stay with Vendors that are already qualified when sourcing new excipients. Use of questionaire is sufficient in early development. On-site audits more appropriate for later development programs. A couple of companies have separate inventory systems for material in early and late phase development. One company indicated that drug product manufactured for Phase I could potentially be used for Phase II studies after a formal review by Quality. 6

7 ADME studies and new dosage form (e.g., controlled release) evaluations are commonly performed. Most companies treat these as Phase I studies, but may tailor the testing and control strategy to be appropriate for study objective. These Early Development studies can be used to obtain information, e.g. impact of particle size, that help to inform next steps in product development. Scintigraphy studies are another good Phase I example. In addition, most radiolabeled PK studies and absolute bioavailability (IV) studies are conducted in PhIII and prepared through extemporaneous preparation (on-site formulation) in which the Phase 1 Guidance is implicitly leveraged. Industry and Health Authorities Embrace Innovation! 7

8 Extemporaneous Preparations Breakout Session II William Marinaro (Merck) and John Skoug (Abbvie)

9 Per Survey: 80 % of companies have capability to do OSF, but are only using this approach about 20% of the time Opportunity to utilize OSF approach more frequently in order to quickly answer key product questions (and get drug to patient faster)! Three short presentations Key Points: Patient Safety is the Top Priority Sponsors are ultimately responsible What is the Inhibitor to use EP Complexity level (e.g., PIB less challenging than Matrix tablets) Access to good quality or compounding capability/clinical sites Access to in house sites (Only one company indicated that they have in house capability) Interpretation of Regulations / Health Authority Expectations 9

10 What is done to Qualify a Compounding Prep Site Quality group audits site Perform a practice preparation at site to confirm individual preparations Develop a Preferred Vendor list, limit the number of sites Is Release testing done Some companies use development studies and mock runs at site to verify performance and thus do not perform end release test More complex EPs may be end release tested In process testing at EP site adds assurance in addition to pre EP development assessments. Materials for compounding are released. 10

11 Release Testing Cont. Internal data in development should show very good robustness Provide stability data for further assurance Strategies for Equipment Cleaning Use disposable or dedicated equipment/vessels, even disposing of low cost blenders to avoid cleaning concerns. Less expensive than cleaning validation. Minimize contamination and support site EP from central sponsor Regulatory Strategy Do Phase I amendment for studies New IND if first time 11

12 Osmotic Capsules One company uses osmotic capsules to study PK as a function of release rate Capsule components are described in IND and the components are released prior to shipping to Site for assembly and dosing. Europe All compounding pharmacies are GMP QP site is registered, and EP products are QP released Singapore No CMC documentation submission required for EP, but some submit and Singapore HA will actually inspect the EP Site. USP chapter versus PDA paper PDA was first and higher level and non region specific. Includes business rationale and practices USP addresses US compounding for Clinical Trials, focuses on pharmacy activities 12

13 Stability Micro evaluation for over 72hours (non sterile) of storage and if ok then apply 14 day refrigerated storage Tablets usually given 2 weeks shelf-life (based on prototype stability) but may give longer (1 to 2 months) for longer clinical programs. Stability studies often done just at long term condition, as accelerated studies are not practical for extending shelf-life. Some companies use USP 14 day refrigerated guidance and successful with FDA Others include a very limited BUD (24 hours for oral liquids) API in Bottle Any post preparation testing? As a single dose unit, no testing possible. Containers are rinsed and rinse also delivered to patient. Development studies would provide the in use stability. 13

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Industry Perspective on Manufacturing in Early Development

Industry Perspective on Manufacturing in Early Development IQ Workshop, Feb 4-5, 2014, Washington, D.C. Eric Schmitt AbbVie IQ Drug Product Manufacturing Working Group August 2012 issue of Pharmaceutical