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cGMP Quality Management of Western Contract Manufacturers for Korean Virtual Pharma Companies
| 작성자 | 임이슬 | 카테고리 | 전문가 인사이트 |
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| 작성일 | 2017-11-21 | 조회수 | 4,047 |
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cGMP Quality Management of Western Contract Manufacturers for Korean Virtual Pharma Companies
Kay Olmstead President, TKO Pharma Solutions
- 글 Kay Olmstead
- GPKOL위원
컨설팅 분야
- GMP, 인허가
컨설팅 내용
- GMP：GMP/GLP compliance audits of API and Drug Product CMO, Quality Risk Assessment,General QA Activities and GMP/GLP Training and Education
- Regulatory Affairs(RA)：Dossier preparation for IND, IMPD, NDA, MMA for both DS and DP modules, CMC Regulatory strategies and ICH Guideline compliance
- CMC Project Management：Global CDMO selection and management, project management for both chemical and Pharmaceutical Development
Introduction
According to the report by Medspace (Presentation at Baird Global Healthcare Conference, September 2016), the total outsourced development market size in 2016 ($26 billion USD) was approximately 20% of worldwide R&D spending by bio/pharmaceutical development ($127 billion USD). In another report by Catalant Pharma Solutions (Presentation at JP Morgan Conference, Jan 2016), the market for outsourced CMC (Chemistry, Manufacturing and Control) development spending was approximately $7 billion USD, which was approximately 1/3 of the total CMC spending worldwide in 2014 ($22 billion USD). An increasing number of innovative Korean biopharm and pharmaceutical companies are developing therapies for Western markets like the US and/or EU countries, which necessitates CMC outsourcing to Western CDMOs (Contract Development and Manufacturing Organizations). The current outsourcing market upshot is that most large and leading CDMOs of the Western world highly value big pharma contracts and cater to their whims and requirements as big pharma hands out large accounts, and their development projects often lead to commercial contracts down the road. In this competitive environment, how can a small and medium sized Korean Bio/Pharma (a combination name for biopharm/pharma companies) demand Western CDMOs for client-centric and quality-focused work? This article will list five key points directed at Korean virtual Bio/Pharma for managing the quality of work performed by western CDMOs, especially for compliance with cGMP requirements.
Five Golden Rules for Managing Western CDMOs
Listed below are five rules I use in managing outsourced work in North America, Europe, China, Indian or other outsourcing markets. Most CDMOs in these regions who are Western-GMP-compliant follow basically the same business practices and project management principals. Before I present them, I will include one universal fact: the business language is English, regardless of region. The local language may differ depending on the specific location, but all written and verbal communication-including the GMP documentation (SOP, Batch Records, Notebooks, etc.)-should be English or, if necessary, bilingual (i.e., both English and the local language). Therefore, English proficiency is paramount for Korean contract givers. If the company does not have a project lead proficient in both written and verbal English (e.g., an SME-chemist, formulator, etc.), then it is almost mandatory for the company to retain an English-speaking SME as a consultant. Due to the time difference and geographical distance, it is desirable to hire the said SME within the same continent of the Western CDMO so s/he can communicate with the CDMO even outside the Korean workday. Aside from this important fact, the other five rules are included below.
1. Know the GMP requirements of the Regulatory Authorities.
Minimum requirements for a drug company who contract out GXP (GMP, GLP, or GCP) works are to know the drug’s target market’s regulations—whether the target market is the US, a European Nation, Japan, or elsewhere. Each of these major markets has slightly different interpretations of cGMP, but if one relies on various ICH (International Conference on Harmonization) principals, you will be speaking the common language of GMP with your Western CDMOs. If the sponsor company gives the impression of not being versed in cGMP regulations, the CDMO counterpart will not work as hard to meet the client’s cGMP standard which is apparently missing.
Some staffs at Korean biopharm companies have past experience with generic drug development via the aNDA (amended new drug application) route, but generic regulations are different from the NDA route, which concerns NCE (New Chemical Entities), and/or the 505B2 NDA, which concerns new indications of approved drugs. If the company does not have internal experts on CMC/GMP regulations, then it is recommended that the company retain CMC/GMP consultant(s) who will guide the outsourced programs from the RFP (Request for Proposal) to batch manufacturing. It is true that the ICH Guidelines and the US Federal Drug Administration’s (FDA) Guidance for Industry documents are for approved drugs, but the current worldwide practice is that these harmonized GMP guidelines are used for most of Phase 2 and definitely for Phase 3 programs.
2. RFP: Know the scope and expected duration of outsourced work.
The RFP (Request for Proposal) is a document that a sponsor provides to outsourcing firms for quoting purposes. It contains a brief introduction on the project, including the structure of API or formulation tables if available, existing technical knowledge that will be transferred to the firm to assist the work outsourced, and the scope of the work that is being quoted to name a few (Table 1). The more detailed the RFP, the more accurate the quote will be, and conversely an RFP lacking in necessary information will result in either an incomplete quote that will be amended many times at the expense of both parties’ time and resources, or the outsourcing firm(s) will include the missing information as “to do” items for them and will unnecessarily inflate the quote accordingly. Since the RFP discloses technical information to the vendor, it is important to establish a solid non-disclosure agreement (NDA) between the two parties before the RFP is shared. Often a sponsor company thinks they are the one disclosing technology; therefore a one-way NDA is adequate for the quoting. However, the pricing information is proprietary to the vendor and should be protected by a two-way NDA.
Often the RFP is the first formal document the contractor will see. As such, RFPs can and do form a first impression of the sponsor company from the contents included in the RFP. It is not simply good ambassadorship to present a solid RFP: it saves time and money. The key components of an example RFP are shown in Table 1.
| Item | Average Length | Contents |
|---|---|---|
| Introduction | 1-2 page | Company background Project background (development phase) Any known risk (high potency, toxicity, solubility, etc.) |
| Technical Background | 2-5 page | For DS:
|
| Scope of Work | 1-2 page | -Accurate description of work and sub-tasks -Whether each sub-task is GXP or non-GXP (cost difference) -Expected Duration of each sub-task - |
| Request for Timeline | <1 page | Request a Gantt chart for each sub-tasks |
| Request for T&C | <1 page | Request a general terms and cost of estimated pass-through or consumable items such as HPLC column, analytical standards, shipping coordination, etc. Some CDMOs have sur-charge on the items they order for clients project, so it is good to know it up front. |
| Quote due date and contact information | <1 page | Average quote takes 2-3 weeks. |
A word of advice on the quoting process: it is always good to have a short teleconference shortly after the RFP is sent to answer any questions that the vendor may have. In addition, it is good practice to request to review the draft quote if possible. In my experience, almost half of vendors either do not quote for the explicitly requested tasks or, they proactively add additional work with an assumption that the information is missing (see the abovementioned need for a thorough RFP). The approval of any quote by the upper management of CDMOs take 2-5 days, so having a quick check to makes sure the quote accurately represents the RFP saves time on both sides.
I normally send out the same RFP to three different contractors who have the capability to perform the tasks listed in the RFP. This way, you form meaningful contacts with as many CDMOs as possible, whom you may use at later time. This also allows you to get price comparisons from each of the leading vendors and acquaint yourselves with the current cost of contracts. If you obtain multiple quotes for the same RFP, it is important to compare the line items by tabulating each vendor’s cost and duration for the sub-tasks. Some CDMOs will not provide detailed line items but rather list an aggregated cost, while others will list each step with unit cost (e.g., one price for a batch production vs. collection of costs for batch record, raw material testing, manufacturing, packaging, release testing, reports, etc.). You can always ask the former to detail the unit item cost included in one aggregate pricing, and often this exercise can reveal hidden costs that can be identified and discussed.
3. GMP compliance audit and Quality Agreement (QA) before GXP Activities.
Once a sponsor company identifies one or two potential candidate CDMOs which will manufacture/test the next drug candidate for Western regulatory markets, then there should be a face-to-face meeting. Travel by Korean company staff members to Western CDMOs may sound like an unnecessary burden and cost. However, I cannot emphasize state this strongly enough: The success of project is dependent on forming a good team relationship from the start. These are the project teams with which a sponsor will work for several months, sometimes years together. Forming a good relationship is the most important factor in the success of project. Get to know the team, project manager, and also allow them to get familiar with you and your company. Below are three important activities in the pre- or early-contract stage of working with CDMO.
a. Quality Audit of CDMO for GMP work and Audit Report:
a. Currently, Western regulatory authorities are requiring the sponsor to audit the contract manufacturing/testing facilities of pharmaceuticals that are being outsourced. The pertinent regulatory guidance on the compliance audit and risk assessment is listed in the bibliography section. In recent years, data integrity is becoming a number-one non-compliance item in outsourcing firms. To avoid data integrity issues, it is important to make sure there are no loose ends with the contractor (see Guidance on Data Integrity). I recommend that you perform the compliance audit before signing a major contract—especially if there is more than one CDMO candidate for the project. The ideal audit-team composition is one internal or external QA (Quality Assurance) auditor and the project PM. Considering the distance traveled and time spent visiting the potential CMDO, it is recommended to combine the audit trip and the kick-off meeting.
b. Kick-off Meeting:
a. This is the meeting to introduce the project teams on both sides and to initiate the project. Often the project timeline discussion negotiation is done in this meeting. As I mentioned earlier, the kick-off meeting can take place during the QA compliance audit, even before the project is officially granted to the CMDO. A few large, conglomerate CDMOs with rigid procedure sometimes say that they cannot assign a PM (project manager) or a lead scientist(s) before the project is granted, but this does not happen often. Most CMDOs understand the benefits of a face-to-face meeting and early interaction of counterpart PMs and scientists, and they usually go the distance to accommodate the wishes of sponsor companies to have the kick-off meetings as if they receive the project, if the compliance audit is satisfactory. This is a winning attitude of the potential contractor. Sometimes the contractor wishes to invite the compliance audit/kick-off team members to a nice dinner. Although it is always desirable to form good teamwork by sharing a meal as often as you can, I recommend declining pre-audit meals to avoid the appearance of impropriety and instead share meals after the audit is completed.
c. Quality Agreement with Responsibilities of Each Party:
a. engaging in GXP activities at the contractor firm, it is important to outline who is responsible for which decision/documentation of GXP provisions. It is especially important to have a well understood quality agreement in place between the contract giver (sponsor) and the contract receiver (outsourcing firm) to resolve any disputes that may arise from the project. If a sponsor company feels strongly about receiving a call when there are unexpected results in analytical testing or other minor variations (or deviations) in the manufacturing process, then the company must explicate this, and it must be mutually agreed upon, to avoid any surprised on both sides. Contractor management is basically people management, so establishing firm boundaries and ground-rules governing GXP activities is crucial in avoiding unpleasant exchanges when problems arise—and thy always do in the GXP world. It is recommended to review the existing Quality Agreement every few years to align the document to the development cycle of the project. For example, the quality agreement of the Phase 1 CTM (Clinical Trial Material) manufacturing should be reviewed before the registration batches are manufactured at the same CMO.
4. Project Management: GMP Document Review and Sponsor’s Quality Systems SOPs
In my working with Korean biopharma companies, several of them do not perform thorough reviews of their contractors’ GXP documents, such as analytical method validation/transfer protocols and reports, batch manufacturing record templates (BMRs), development reports, etc. This may occur because of lack of experience or English proficiency. Some clients have told me that they trust the contractors to “do the right thing.” It is good to trust, but systematic verification is both important and expected by regulatory authorities (see QUA). Contractor firms list the sponsor company’s approval signature line on GXP documents which is legal expression of a shared responsibility of the work performed, therefore blindly signing on the approval section is not only bad business, but a dereliction of GMP duty as a sponsor company. Undoubtedly, approval of the GXP document is a responsibility of the sponsor listed in the Quality Agreement with the Contractor (see Quality Agreement); therefore, a sponsor who does not read and understood a contractor’s GXP document has no recourse if a compliance issue arises due to missing items or misconduct in action or documentation.
5. Cultural and Geographical Sensitivities
Successful western CDMOs have well trained project managers who are experienced in working with sponsors from various continents, and in my experience most of them are professional and take pride in serving clients regardless of the cultural backgrounds. The culture difference I am alluding here is not national culture, but corporate cultures. If a CDMO is very rigid and buttoned-down with focus on process and your company is more casual and open, it may not be possible for the companies to thrive together. It is important to identify and align with a partner’s culture as this drives both the operational and communicational aspects of the relationship. It is not easy to “glean” company’s culture by asking a few questions to business development representatives. The best way to get this information is from the CDMO’s past and existing customers. Ask for at least 3 references and talk to ALL of them. Ask them to describe their own culture and the respective CDMO’s culture. Also ask them to give examples of the situation that CDMO had to overcome its own culture/procedural rigidity to accomplish goals for the sponsor. Also, it is good to know your own corporate culture-are you rigid or do you expect things to happen creatively and innovatively at the cost of procedures and vertical approvals.
The time differences between the two locations can pose some challenges in scheduling periodical teleconference between Korean site and US contractors, and both parties give consideration to this. However, it is good to discuss this upfront if your company insists on having the call only during your business hours as this can pose some challenges to some contractors. Frequent and cordial communication is the key in overcoming any of these “soft issues” working as a team. When there seems to be strain or serious issues while working as a team, it is always good idea to have a face to face meeting-it pays more than the cost of traveling by resolving issues before it can become a bigger obstacle that can negatively impact the on-going project.
Conclusions
Outsourcing GXP works to the western CDMO is becoming a requirement for Korean Biopharma companies to develop drugs for Western markets. Well managed outsourcing program can leverage the company’s resources without increasing the personnel resources or hard assets. Managing the outsourced projects which are done thousand miles away in a foreign country can be daunting, but if you have project leads who have strong English language skills and GXP regulatory knowledges, the most important work boils down to 3C’s: Communication, Capability of CMDO, and Cultural Alignment. But before insisting on the CDMOs to provide these 3C’s, each sponsor company needs to take self-assessment of own 3C’s to select a good partner to bring the project to the successful outcome.
Bibliography :
- Data Integrity and Compliance With CGMP Guidance for Industry (Draft); US FDA April 2016
- Quality Compliance Audit: Quality Systems Approach to Pharmaceutical CGMP Regulations; US FDA September 2006.
- ICH Q8 Pharmaceutical Development (R2), August 2009
- ICH Q9 Quality Risk Management, June 2006
- ICH Q10 Pharmaceutical Quality System, June 2008
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