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QbD and CMC Explained | Cell Culture Technology

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TECHNOLOGY EXPLAINER

QbD and CMC
— why swapping one medium component becomes a regulatory filing

If GMP is the standard for making a product as specified, QbD and CMC sit on the other side: deciding what is specified. What is learned in development goes into the application, and once approved it becomes a binding commitment (the approved particulars). And that commitment includes the control of raw materials.

Built from primary sources: the ICH quality guidelines (Q8 to Q14, M4Q, Q5E), Japan's PMD Act and GMP Ordinance, the US Code of Federal Regulations (21 CFR 601.12) and FDA guidance / Last updated September 2026

Conceptual image of a row of plain clear bottles, with just one placed slightly in front of the others
AI-generated concept. An impression of changing just one of a row of raw materials. It does not represent any real product, medium or container.
What this article covers
  1. What QbD and CMC are (the short version)
  2. Where they sit within the GMP framework
  3. The key points of ICH Q8 to Q14 — six guidelines built up over 20 years
  4. The vocabulary of QbD — CQA, CPP, design space, control strategy
  5. A materials engineer's view (1): material attributes are input variables of the design space
  6. CMC — the quality part of the application (CTD Module 3)
  7. Why changing a raw material is a big deal — how post-approval changes work
  8. Our calculation: how many lots it takes to show comparability for a cell product
  9. A materials engineer's view (2): don't change, and if you must, agree the plan first
  10. Open problems and what is still undecided
  11. Glossary / References / Claim-to-source audit
How claims are labelled in this article

Sourced = stated in a law, guideline or published document (link given)
Our calculation = a figure this article derived, with the assumptions spelled out
Not yet confirmed = a draft, a plan or anything else not yet settled
Our own structuring of the rules and readings from the materials-supplier side are marked separately as Commentary. Quotations from Japanese laws and ordinances are our own translations; quotations from ICH, US and EU texts are in the original English. This article explains the regulatory system; it says nothing about the efficacy of any individual product or about treatment choices.

1. What QbD and CMC are (the short version)

  • QbD (Quality by Design): ICH Q8(R2) defines it as “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”Sourced. The idea is not to make it and then test it, but to understand how quality arises and design for it (commentary)
  • CMC (Chemistry, Manufacturing, and Controls): the quality part of a marketing application, describing the manufacturing process, raw materials, specifications, analytical methods, stability and so on. In the internationally shared application format (the CTD) it is Module 3 (Quality)Sourced
  • How the two fit together: the understanding gained through QbD is written into the CMC section. Once approved, it becomes the approved particulars, which are then kept under GMP — one continuous chain (commentary)
The single most important line in this article

On the established conditions (ECs) written into an application, ICH Q12 says: “ECs are legally binding information considered necessary to assure product quality. As a consequence, any change to ECs necessitates a submission to the regulatory authority.”Sourced

And the Q12 appendix lists, among the places where ECs typically sit, the drug substance section on control of materials, including “source of materials (e.g., cell and seed source, raw materials) and control of critical materials of biological origin”Sourced. Culture media and reagents can become part of the commitment written into an application. That is where this article starts (commentary).

2. Where they sit within the GMP framework

In legal form they are separate things: GMP is the standard for control at the manufacturing site, CMC is the content of the marketing application, and QbD is a development approach set out in ICH guidelines. Even so, this article treats QbD and CMC as part of GMP in the broad sense of the pharmaceutical quality assurance framework (commentary). The reason is that Japan's GMP Ordinance itself ties them together.

  • Following the approved particulars: Article 3-2 of the GMP Ordinance requires manufacturers to “manufacture in accordance with the approved particulars”Sourced. What is written in the CMC section becomes something GMP requires you to follow
  • Pharmaceutical quality system: Article 3-3 requires manufacturers to “establish an effective pharmaceutical quality system”Sourced. This is the concept set out in ICH Q10 (commentary)
  • Quality risk management: Article 3-4 requires the quality system to be built using quality risk managementSourced. This is the territory of ICH Q9 (commentary)
  • Change control: Article 14 requires that, when specifications of raw or packaging materials or manufacturing procedures change, the manufacturer “assess the impact on product quality and on the approved particulars”Sourced
QbD, CMC and GMP within the pharmaceutical quality system (our summary) Pharmaceutical quality system (ICH Q10 / GMP Ordinance Art. 3-3) Development: QbD Understand how quality arises; design for it Q8, Q11, Q14 Application: CMC Write it into the dossier as approved particulars M4Q (Module 3) Manufacture: GMP Make it as approved, every time, with records GMP Ordinance Art. 3-2 Post-approval change Assess and file when a commitment changes Q12, GMP Ordinance Art. 14 Quality risk management (ICH Q9 / GMP Ordinance Art. 3-4) runs through every stage Note: document names for each stage follow the ICH guidelines [Refs 1-7] and the GMP Ordinance [Ref. 9]. Note: the four stages inside a quality-system frame are our own layout. In practice the stages overlap and loop back.
Fig. 1 Conceptual diagram (vector drawing). Provisions of ICH Q8 to Q14 and M4Q [Refs 1-7] and of the GMP Ordinance [Ref. 9], arranged by this article along the product lifecycle. Treating QbD and CMC as part of the GMP framework is this article's own framing (commentary). See also the companion explainer on GMP.

3. The key points of ICH Q8 to Q14 — six guidelines built up over 20 years

Of the quality guidelines of the ICH (the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), six bear directly on QbD and CMC. All are documents recommended for adoption to the regulatory bodies of Japan, the US and the EUSourced.

ICH guidelines relevant to QbD and CMC (when the current version was agreed) Placement above or below the line is only for legibility and carries no meaning 2005 2010 2015 2020 2025 Q9 November 2005 Risk management Q8(R2) August 2009 Development, QbD Q12 November 2019 Post-approval changes Q14 November 2023 Analytical methods Q10 June 2008 Quality system Q11 May 2012 Drug substances Q9(R1) January 2023 Revision of Q9 Note: dates are Step 4 or adoption dates from each document history [Refs 1-6]; the original Q8 and M4Q (2002) are omitted. Note: horizontal positions are approximate and not strictly proportional to the dates.
Fig. 2 Conceptual diagram (vector drawing). Dates follow the document-history sections of each ICH guideline [Refs 1-6]. The one-phrase labels for each guideline's role (such as “Risk management”) are this article's own summaries. The full list of ICH quality guidelines is available at [Ref. 15].
GuidelineTitleKey points confirmed for this articleWhere raw materials come in (commentary)
Q8(R2)Pharmaceutical DevelopmentSets out the content of CTD section 3.2.P.2 (Pharmaceutical Development). Defines QbD, CQA, CPP, design space, control strategy, RTRT and moreMaterial attributes are among the inputs to a design space
Q9(R1)Quality Risk ManagementDescribes quality risk management as “a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle”Used to judge how critical a raw material is
Q10Pharmaceutical Quality SystemThe quality system extends to control of outsourced activities and quality of purchased materials, and the pharmaceutical company is ultimately responsibleThe basis for supplier management
Q11Development and Manufacture of Drug SubstancesLinks material attributes of raw materials, starting materials, reagents, solvents and so on, and process parameters, to drug substance CQAs. For biotechnological/biological products, most drug product CQAs are associated with the drug substanceMedia and reagents are “inputs” to the drug substance process
Q12Pharmaceutical Product Lifecycle ManagementIntroduces established conditions (ECs), the post-approval change management protocol (PACMP) and the product lifecycle management (PLCM) documentCritical controls on raw materials can be ECs
Q14Analytical Procedure DevelopmentApplies to analytical procedures for release and stability testing of commercial drug substances and products; can also be applied to other procedures that are part of the control strategyMethods for incoming-material testing may fall within scope

“Key points confirmed for this article” are Sourced (ICH Q8(R2) [Ref. 1], Q9(R1) [Ref. 2], Q10 [Ref. 3], Q11 [Ref. 4], Q12 [Ref. 5], Q14 [Ref. 6]). The right-hand column is this article's commentary.

Do they apply to cell products as they stand?

Q8(R2) says it “might also be appropriate for other types of products” and asks applicants to consult the regulatory authorities about applicabilitySourced. Q11 likewise covers drug substances within the scope of Q6A and Q6B, but might also be appropriate for other types of productsSourced. Q5E, on the other hand, which deals with comparisons before and after manufacturing changes, is scoped to proteins and polypeptidesSourced. So for cell products, the thinking is shared, but how each document applies is worked out product by product with the regulators (commentary).

4. The vocabulary of QbD — CQA, CPP, design space, control strategy

Linking up the terms defined in ICH Q8(R2), the QbD flow can be laid out like this (our structuring).

The QbD flow — linking the terms of ICH Q8(R2) (our summary) 1 Set the target Quality target product profile (QTPP) What quality to aim for 2 Define the CQAs Critical quality attributes: properties that must stay within appropriate limits 3 Assess risk Work out which inputs affect the CQAs (Q9) 4 Identify inputs Raw material properties (material attributes) Critical process parameters (CPPs) 5 Design space Multidimensional combination of inputs shown to assure quality Moving within it is not a change 6 Control strategy Raw materials, equipment, in-process controls, specs: a planned set of controls 7 Lifecycle Keep updating knowledge after approval; manage change Q10, Q12 Note: definitions from the Q8(R2) glossary [Ref. 1]; risk assessment from Q9(R1) [Ref. 2]; lifecycle from Q10 [Ref. 3], Q12 [Ref. 5]. Note: the seven-step, one-way flow is our own layout. Whether to establish a design space is the applicant's choice.
Fig. 3 Conceptual diagram (vector drawing). Term definitions follow ICH Q8(R2) [Ref. 1]. Laying them out as a seven-step flow is this article's own structuring, not a procedure set out by ICH. Box 4 is highlighted to show where materials enter the picture.
TermICH Q8(R2) definition
CQA (critical quality attribute)A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
CPP (critical process parameter)A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled
Design spaceThe multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. “Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process.” It is proposed by the applicant and subject to regulatory assessment and approval
Control strategyA planned set of controls, derived from current product and process understanding, that ensures process performance and product quality. It can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls and finished product specifications
RTRT (real time release testing)The ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls (see our explainer on process analytical technology)

All Sourced (ICH Q8(R2) glossary [Ref. 1]). Definitions are quoted or closely paraphrased from the original English.

5. A materials engineer's view (1): material attributes are input variables of the design space

Why this matters for materials engineers: the definition says “material” in so many words

Read the design-space definition again: “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters”Sourced. The control-strategy definition includes “materials and components” tooSourced. And Q11 asks for the material attributes of raw materials, starting materials, reagents, solvents, process aids and so on, and process parameters, to be linked to drug substance CQAsSourced.

From that, a materials supplier can read the following (commentary).

  • What the customer “understands” is only the range of material attributes it has tried. Its development data were gathered only across the lot-to-lot variation of the material it was supplied
  • Changes outside that range are “unknown” to the customer. Material that is within specification but has a different distribution from before may fall outside the design space
  • So information about variability is valuable in itself. If the supplier can show what varies between lots, by how much, and which attributes could affect the process, the customer can verify a wider range from the start

Put another way, QbD writes into regulatory language the idea of treating material attributes as process inputs. The distributions of composition, impurities and physical properties that materials engineers deal with every day become variables in the customer's quality design (commentary).

6. CMC — the quality part of the application (CTD Module 3)

The CTD (Common Technical Document) is the common format for marketing applications set by ICH. Quality is covered by M4Q, which sets out the structure of Module 3Sourced. The current version of M4Q is dated September 2002 and was recommended for adoption to the regulatory bodies of the EU, Japan and the USSourced.

Where raw materials and components appear in CTD Module 3 (excerpt) Brown boxes = sections where information on the materials or components themselves is written Module 3 Quality (CMC) 3.2.S Drug substance 3.2.P Drug product 3.2.A Appendices 3.2.S.2.3 Control of materials (media, enzymes, antibodies) 3.2.S.2.4 Controls of critical steps and intermediates 3.2.S.4 Control of drug substance (specs, methods) 3.2.P.2 Pharmaceutical development (QbD knowledge) 3.2.P.7 Container closure system (materials, specs) 3.2.A.1 Facilities and equipment 3.2.A.2 Adventitious agents safety evaluation Note: section numbers and headings follow ICH M4Q(R1) [Ref. 7]; the notes in brackets are our own summaries. Note: not every section of Module 3 is shown; the excerpt centres on sections relevant to raw materials and components.
Fig. 4 Conceptual diagram (vector drawing). Section numbers and content follow ICH M4Q(R1) [Ref. 7]. The choice of sections and the brown highlighting are this article's own; this is not the full structure of Module 3.

M4Q contains passages a materials supplier cannot afford to skipSourced.

  • 3.2.S.2.3 Control of Materials: materials used to make the drug substance (raw materials, starting materials, solvents, reagents, catalysts and so on) should be listed, identifying where each is used in the process, with information on their quality and control. Information showing that materials, “including biologically-sourced materials, e.g., media components, monoclonal antibodies, enzymes”, meet standards appropriate for their intended use should be provided as appropriate. For biologically sourced materials this can include information on source, manufacture and characterisation
  • 3.2.P.7 Container Closure System: includes “the identity of materials of construction of each primary packaging component and its specification”
  • 3.2.A.1 Facilities and Equipment: for biotech products, a diagram illustrating the manufacturing flow, including movement of raw materials, personnel, waste and intermediates, should be provided

All Sourced (ICH M4Q(R1) [Ref. 7]).

7. Why changing a raw material is a big deal — how post-approval changes work

How much procedure it takes to change what was approved depends on how much the change could affect quality. Both Japanese and US law set up tiersSourced.

RegionHeaviest procedureIntermediateLightest procedure
Japan (PMD Act)To change part of the approved particulars, approval of the Minister of Health, Labour and Welfare must be obtained for that change (partial change approval)—Minor changes specified by MHLW ordinance require only a notification (minor change notification)
United States (21 CFR 601.12, biologics)Changes with a “substantial potential” to have an adverse effect on quality as it relates to safety or effectiveness need FDA approval before distribution (prior approval supplement)Changes with a “moderate potential” need a supplement submitted at least 30 days before distributionChanges with a “minimal potential” are documented in an annual report

All Sourced (PMD Act Articles 14 and 23-25 [Ref. 10], 21 CFR 601.12(b), (c), (d) [Ref. 11]). Which tier a given change falls into is decided by the product and the nature of the change.

The US regulation gives as examples of changes in the heaviest tier “changes in the source material or cell line”, “changes in the virus or adventitious agent removal or inactivation method(s)” and “changes which may affect product sterility assurance, such as changes in product or component sterilization method(s)”Sourced.

How a supplier's change becomes a post-approval change procedure (our summary) 1 Materials maker Wants to change the formula, process or site Notifies in advance under the agreement GMP Ordinance Art. 11-4 2 Manufacturer Assesses impact on product quality and approved particulars Notifies the MAH GMP Ordinance Art. 14 3 Comparability Pre- and post-change quality highly similar; differences do not harm safety or efficacy ICH Q5E (proteins) 4 Regulatory filing Japan: partial change approval or minor notice US: prior approval / 30 days / annual report PMD Act, 21 CFR 601.12 5 Switch over Start making with the changed material Revise documents and train staff GMP Ordinance Art. 14 One change on the materials side becomes testing, filing and waiting for approval at the customer Note: 1, 2 and 5 follow the GMP Ordinance [Ref. 9]; 3, ICH Q5E [Ref. 8]; 4, the PMD Act [Ref. 10] and 21 CFR 601.12 [Ref. 11]. Note: Q5E is scoped to proteins and polypeptides. For cell products, FDA's draft (July 2023) sets out an approach to comparison [Ref. 12]. Note: the five-step layout is our own and does not show real procedures, order or timelines.
Fig. 5 Conceptual diagram (vector drawing). The provisions behind each step follow the GMP Ordinance [Ref. 9], ICH Q5E [Ref. 8], the PMD Act [Ref. 10] and 21 CFR 601.12 [Ref. 11]. The five-step flow and the band at the bottom are this article's own structuring and commentary, and do not show actual procedures or timelines.

ICH Q12 — what is a commitment and what is supporting information

ICH Q12 divides an application's content into established conditions (ECs) and supportive information, and says any change to ECs needs a submission to the regulatory authoritySourced. Appendix 1 of Q12 lists the CTD sections where ECs are generally located. Under drug substance 3.2.S.2.3 (Control of Materials) it gives “raw material/reagent/solvent critical controls” and “source of materials (e.g., cell and seed source, raw materials) and control of critical materials of biological origin”; under drug product 3.2.P.7 (Container Closure System) it gives “material of construction and specification” and “where applicable, supplier/manufacturer of primary container closure system”Sourced. The appendix does state, however, that the table “does not contain a complete list of ECs”; what counts as an EC is decided product by productSourced.

Q12 also introduces the post-approval change management protocol (PACMP), a tool for agreeing with the regulator in advance what data a future change will need and what type of submission it will takeSourced. And because supply chains involve multiple stakeholders — marketing authorisation holders, R&D organisations, manufacturers, contract manufacturing organisations and suppliers — Q12 says robust change management across multiple sites, outsourced or not, is necessarySourced.

For cell products, the comparison itself is hard

On comparisons before and after a manufacturing change, FDA's draft guidance (July 2023) says that cell-based products where each lot is derived from a different donor often have product characteristics with very wide ranges, and that the number of lots needed for a statistically valid comparison “could be quite large, or even unfeasible”Sourced. As a countermeasure, FDA recommends using, whenever possible, a “split-source” design, in which each cellular source material is split into two portions, one made under pre-change conditions and the other under post-change conditionsSourced. The same document includes changes to “materials” among the manufacturing changes that can present riskSourced. It is, however, a draft, not final guidanceNot yet confirmed.

8. Our calculation: how many lots it takes to show comparability for a cell product

How large is FDA's “quite large” number of lots? We check the order of magnitude with a standard statistical formulaOur calculation.

Our calculation: the lot count is set by the ratio of variability to the difference you want to detect
  • Assumption: we want to detect a difference in the mean of one quality attribute at a 5% significance level (two-sided) with 80% power, using a normal approximation
  • Assumption: σ = lot-to-lot variability (standard deviation), δ = the difference to be detected. The z-values are 1.96 (5%, two-sided) and 0.84 (80%)
  • Two independent groups: per group, n = 2 × (1.96 + 0.84)² × (σ/δ)² ≈ 15.7 × (σ/δ)²

Working

  • σ/δ = 1: 15.7 × 1 → 16 lots per group (32 for both groups)
  • σ/δ = 2: 15.7 × 4 = 62.8 → 63 lots per group (126 for both)
  • σ/δ = 3: 15.7 × 9 = 141.3 → 142 lots per group (284 for both)

Split-source design (paired comparison): splitting the same cellular source material in two subtracts out donor-to-donor variability. For the variability of the differences, σd, n = (1.96 + 0.84)² × (σd/δ)² ≈ 7.85 × (σd/δ)². With σd/δ = 1 that is 8 donors (16 manufacturing runs).

Assumptions and limits: the values of σ/δ are assumptions this article set for illustration, not values from any real product. Real comparability assessments combine many quality attributes, in-process data, stability and more, rather than a single test of a difference in means, and may use other statistical designs such as equivalence testing. This calculation exists only to show, in orders of magnitude, that the lots needed grow with the square of the variability.

Lots needed to compare before and after a change (per group, our calculation) 5% significance (two-sided), 80% power, normal approximation. σ = lot-to-lot variability, δ = difference to detect 0 50 100 150 16 63 142 8 σ/δ = 1 σ/δ = 2 σ/δ = 3 Split-source σd/δ = 1 Two independent groups (blue) Paired (green, donors) Note: all values are our calculation. The σ/δ values are illustrative assumptions, not values from any real product. Note: the split-source design is the approach recommended in FDA's draft guidance (July 2023) [Ref. 12].
Fig. 6 Drawn from our calculation (vector drawing). Every number was calculated by this article with a standard sample-size formula; none is a published value. σ/δ is an assumption set for illustration. The split-source design follows FDA's draft guidance [Ref. 12].

9. A materials engineer's view (2): don't change, and if you must, agree the plan first

Why this matters for materials engineers: the cost of a material change is incurred outside the materials company

Reading all of this again from the supplier's side, the reasons a raw material change is so heavy fall into three groups (commentary).

  • It is written into the application: critical controls on raw materials and the source of biological materials sit in sections where ECs can be locatedSourced. For container closure systems, the supplier's name itself can be an ECSourced
  • Comparison costs time and starting material: for cell products, the lots needed for a comparison grow with the square of the variabilityOur calculation. In autologous products the starting material of each lot is a patient's cells, so lots for comparison cannot simply be added at will (commentary)
  • No switching while the procedure runs: for changes in the heaviest tier, the post-change product cannot be distributed until approval is obtainedSourced

In other words, this is a market where “we've improved it, so please use the new one” is a hard sell. That carries several implications for how materials are designed and how the business is set up (commentary).

  • Lock down formulation and process early: a material adopted early in development may go straight into the approved particulars
  • Share change plans with customers in advance: frameworks such as Q12's PACMP exist to agree the evaluation of a change beforehandSourced. Data from the materials side can underpin such a plan
  • Design for multiple sites and continuity of supply from the outset: adding or moving a manufacturing site can also be a “change”. Starting up in a way that can show equivalence from day one is less of a burden on customers than bolting on a second site later
  • Hand over variability data: as Section 5 showed, information on lot-to-lot variation widens the range a customer can verify from the start

The EU's GMP for ATMPs asks manufacturers to understand, for research-grade raw materials, “the risks to the continuity of supply”Sourced, which can be read as the flip side of the same structure. A material that cannot be changed is also a material that must never stop (commentary).

10. Open problems and what is still undecided

(1) The scope and operation of ECs are left to regional legal systems

Q12 says regional legal frameworks may define ECs and their reporting categoriesSourced. How far Q12's approach is actually applied in each region was not checked down to individual regional notices within the scope of this article's research.

(2) US guidance on comparability for cell products is still a draft

FDA's document on manufacturing changes and comparability for cell and gene therapy products is a July 2023 draftNot yet confirmed. In its May 2026 guidance FDA sets out a flexible position that, for investigational products, it may accept limited comparability data for changes it considers minor and with a low risk to product qualitySourced, but this concerns the development stage leading up to a licence application and does not change the tiers for post-approval changes (commentary).

(3) Applying ICH guidelines to cell products is decided case by case

Q8(R2) and Q11 say they may be appropriate for other products, and Q5E covers proteinsSourced. As of this article's research (September 2026), we found no international document that applies these guidelines uniformly to cell products.

The article in summary
  • QbD is a development approach built on understanding how quality arises; CMC is the quality part of the application where that understanding is written downSourced
  • Japan's GMP Ordinance sets out adherence to approved particulars, a quality system, risk management and change control, tying QbD and CMC to the GMP frameworkSourced
  • The input variables of a design space include “material attributes”Sourced
  • Critical controls on raw materials and the source of biological materials can be ECs, and any change to ECs requires a submission to the regulatorSourced
  • The larger the variability, the more lots a comparison needs, growing with the squareOur calculation
  • For a materials supplier, a material that cannot be changed is also a material that must never stop (commentary)

11. Glossary

QbD
Quality by Design. A systematic development approach that starts from predefined objectives and emphasises product and process understanding and control (ICH Q8(R2)).
CMC
Chemistry, Manufacturing, and Controls. The quality part of an application: manufacturing process, raw materials, specifications, analytical methods and so on.
CTD
Common Technical Document. The common format for marketing applications set by ICH. Quality is Module 3.
QTPP
Quality target product profile. A prospective summary of the quality characteristics the product should achieve.
CQA
Critical quality attribute. A property that must be within an appropriate range for the desired quality.
CPP
Critical process parameter. A process parameter whose variability affects a CQA.
Material attributes
Properties of raw materials such as composition, impurities and physical properties. They can be input variables of a design space.
Design space
The multidimensional range of inputs and process parameters shown to assure quality. Moving within it is not considered a change.
Control strategy
A planned set of controls that ensures process performance and product quality.
EC
Established conditions. Legally binding information considered necessary to assure product quality (ICH Q12).
PACMP
Post-approval change management protocol. A mechanism for agreeing in advance how a future change will be evaluated and which submission type it needs.
Partial change approval / minor change notification
The Japanese procedures for changing approved particulars, tiered by the size of the potential impact.
Comparability
Showing that products before and after a manufacturing change are highly similar and that any differences have no adverse impact on safety or efficacy.
Split-source design
A design in which the same cellular source material is split in two and manufactured in parallel under pre- and post-change conditions for comparison.

12. References

  1. ICH “Q8(R2) Pharmaceutical Development”, August 2009 https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf
  2. ICH “Q9(R1) Quality Risk Management”, adopted 18 January 2023 https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2022_1219.pdf
  3. ICH “Q10 Pharmaceutical Quality System”, June 2008 https://database.ich.org/sites/default/files/Q10%20Guideline.pdf
  4. ICH “Q11 Development and Manufacture of Drug Substances”, May 2012 https://database.ich.org/sites/default/files/Q11%20Guideline.pdf
  5. ICH “Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management”, November 2019 https://database.ich.org/sites/default/files/Q12_Guideline_Step4_2019_1119.pdf
  6. ICH “Q14 Analytical Procedure Development”, November 2023 https://database.ich.org/sites/default/files/ICH_Q14_Guideline_2023_1116.pdf
  7. ICH “M4Q(R1) The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality”, September 2002 https://database.ich.org/sites/default/files/M4Q_R1_Guideline.pdf
  8. ICH “Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process”, November 2004 https://database.ich.org/sites/default/files/Q5E%20Guideline.pdf
  9. Ministry of Health, Labour and Welfare (e-Gov Law Search) “Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Drugs and Quasi-drugs”, MHLW Ordinance No. 179 of 2004 (in Japanese) https://laws.e-gov.go.jp/law/416M60000100179
  10. e-Gov Law Search “Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices” (the PMD Act), Act No. 145 of 1960 (in Japanese) https://laws.e-gov.go.jp/law/335AC0000000145
  11. U.S. Government Publishing Office “21 CFR Part 601 — Licensing” (2025 edition, including §601.12 Changes to an approved application) https://www.govinfo.gov/content/pkg/CFR-2025-title21-vol7/pdf/CFR-2025-title21-vol7-part601.pdf
  12. U.S. FDA (CBER) “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products” (Draft Guidance for Industry), July 2023 https://www.fda.gov/media/170198/download
  13. U.S. FDA (CBER) “Chemistry, Manufacturing, and Controls Flexibilities for Developing Human Cellular and Gene Therapy Products for a Biologics License Application” (Guidance for Industry), May 2026 https://www.fda.gov/media/192321/download
  14. European Commission “Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products”, 22 November 2017 https://health.ec.europa.eu/system/files/2017-11/2017_11_22_guidelines_gmp_for_atmps_0.pdf
  15. ICH “Quality Guidelines” (list page) https://www.ich.org/page/quality-guidelines

13. Claim-to-source audit

Claim in the textBasisLabel
Definitions of QbD, QTPP, CQA, CPP, design space (that its input variables include material attributes; that working within it is not a change and movement out of it would normally initiate a post-approval change process; that it is proposed by the applicant and subject to regulatory assessment and approval), control strategy (including materials and components) and RTRT. That Q8(R2) sets out the content of 3.2.P.2, might also be appropriate for other types of products, and that applicants can consult regulators on applicability. That the current version is dated August 2009. Recommendation for adoption to the regulatory bodies of Japan, the US and the EUICH Q8(R2), Reference 1 https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdfSourced
The definition of quality risk management. That Q9 was adopted in November 2005 and Q9(R1) on 18 January 2023ICH Q9(R1), Reference 2 https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2022_1219.pdfSourced
That the quality system extends to control of outsourced activities and quality of purchased materials, with the pharmaceutical company ultimately responsible. That the current version is dated June 2008ICH Q10, Reference 3 https://database.ich.org/sites/default/files/Q10%20Guideline.pdfSourced
Linking material attributes of raw materials, starting materials, reagents, solvents, process aids and so on, and process parameters, to drug substance CQAs. That for biotechnological/biological products most drug product CQAs are associated with the drug substance. Scope (drug substances under Q6A and Q6B; might also be appropriate for other products). That the current version is dated May 2012ICH Q11, Reference 4 https://database.ich.org/sites/default/files/Q11%20Guideline.pdfSourced
That ECs are legally binding information and changes to them need a submission. The distinction between ECs and supportive information. PACMPs and the PLCM document. That Appendix 1 lists, under 3.2.S.2.3, “raw material/reagent/solvent critical controls” and “source of materials and control of critical materials of biological origin”, and under 3.2.P.7 “material of construction and specification” and “where applicable, supplier/manufacturer of primary container closure system”, and states it is not a complete list. That change management is needed across the multiple stakeholders of a supply chain (including contract manufacturing organisations and suppliers). That regional legal frameworks may define ECs and reporting categories. That it is dated November 2019ICH Q12, Reference 5 https://database.ich.org/sites/default/files/Q12_Guideline_Step4_2019_1119.pdfSourced
The scope of Q14 (analytical procedures for release and stability testing of commercial drug substances and products; other procedures that are part of the control strategy) and Step 4 on 1 November 2023ICH Q14, Reference 6 https://database.ich.org/sites/default/files/ICH_Q14_Guideline_2023_1116.pdfSourced
The structure of CTD Module 3. That 3.2.S.2.3 lists materials with where each is used and shows the suitability of biologically sourced materials such as media components, monoclonal antibodies and enzymes, with information on source, manufacture and characterisation. That 3.2.P.7 gives the identity of materials of construction of primary packaging components and their specifications. That 3.2.A.1 gives a manufacturing-flow diagram for biotech products. The heading of 3.2.A.2. That the current version is dated September 2002 and was recommended for adoption to the regulatory bodies of the EU, Japan and the USICH M4Q(R1), Reference 7 https://database.ich.org/sites/default/files/M4Q_R1_Guideline.pdfSourced
That comparability means not that quality attributes are identical but that they are highly similar and differences have no adverse impact on safety or efficacy. That the scope is proteins and polypeptidesICH Q5E, Reference 8 https://database.ich.org/sites/default/files/Q5E%20Guideline.pdfSourced
Following the approved particulars (Article 3-2), pharmaceutical quality system (Article 3-3), quality risk management (Article 3-4), control of and arrangements with suppliers of raw materials, etc. (Article 11-4), change control (Article 14: assessment of impact on quality and approved particulars, notification of the MAH, document revision and training)GMP Ordinance, Reference 9 https://laws.e-gov.go.jp/law/416M60000100179Sourced
That partial changes to approved particulars need the Minister's approval, and minor changes specified by MHLW ordinance need only a notification (drugs and regenerative medical products)PMD Act Articles 14 and 23-25, Reference 10 https://laws.e-gov.go.jp/law/335AC0000000145Sourced
The three tiers of post-approval changes for biologics (substantial potential = prior approval; moderate = supplement at least 30 days before distribution; minimal = annual report). Examples in the heaviest tier: changes in source material or cell line, in virus or adventitious agent removal or inactivation methods, and changes that may affect sterility assurance. That product cannot be distributed until approval is obtained21 CFR 601.12, Reference 11 https://www.govinfo.gov/content/pkg/CFR-2025-title21-vol7/pdf/CFR-2025-title21-vol7-part601.pdfSourced
That cell-based products where each lot comes from a different donor have wide ranges of characteristics, so the lots needed for comparison could be quite large or even unfeasible. The recommendation of a split-source design. That changes to materials are among the changes that can present riskFDA draft guidance (July 2023), Reference 12 https://www.fda.gov/media/170198/downloadSourced
That the same draft guidance is not finalIt is dated July 2023 and marked “Draft – Not for Implementation”. No final version could be found as of this article's research (September 2026), Reference 12 https://www.fda.gov/media/170198/downloadNot yet confirmed
The position that limited comparability data may be accepted for investigational-stage changes considered minor and low-riskFDA guidance (May 2026), Reference 13 https://www.fda.gov/media/192321/downloadSourced
That the risks to continuity of supply of research-grade raw materials should be understoodEU GMP Part IV (ATMPs) 7.13, Reference 14 https://health.ec.europa.eu/system/files/2017-11/2017_11_22_guidelines_gmp_for_atmps_0.pdfSourced
The list of ICH quality guidelinesICH, Reference 15 https://www.ich.org/page/quality-guidelinesSourced
Per group for two independent groups, n = 15.7 × (σ/δ)², giving 16, 63 and 142 lots for σ/δ = 1, 2 and 3; for a split-source design, n = 7.85 × (σd/δ)², giving 8 donors for σd/δ = 1Our calculation. 5% significance (two-sided), 80% power and a normal approximation; all σ/δ values are assumptions set by this article, not values from any real productOur calculation
Treating QbD and CMC as part of the GMP framework. Restating QbD as understanding how quality arises and designing for it. Mapping Q9 and Q10 onto articles of the GMP Ordinance. The reading, from the definition of material attributes, that customers understand only the range they have tried and that variability information is valuable. The three reasons a raw material change is heavy, and the implications for materials suppliers (lock down early, share change plans, multiple sites, variability data). The point that development-stage flexibility does not change post-approval tiers. The framing that a material that cannot be changed must never stop. The right-hand column of the table, and the layouts and flows of Figs. 1 to 5This article's own structuring and commentary based on the published material. Not views expressed by regulators or companiesCommentary
Details of how Q12 operates in each region; uniform application of ICH guidelines to cell productsIndividual regional notices were not checked within the scope of this article's research, and no uniform international document could be found, so neither is describedCommentary
That Figs. 1 to 5 are explanatory drawings and Fig. 6 is drawn from our calculation. That the hero image is AI-generatedOur noteCommentary

Last updated 23 September 2026. Sources are limited to primary material (ICH guidelines, Japanese laws and ordinances, the US Code of Federal Regulations, FDA guidance and European Commission guidelines). Because the article includes our own structuring of the rules and readings from the materials-supplier side, those are marked as Commentary and kept separate from sourced fact. The lot counts in Section 8 are this article's calculation under stated assumptions, not values for any real product or requirements set by any regulator. FDA's document on manufacturing changes for cell and gene therapy products is a July 2023 draft. This article says nothing about the efficacy or safety of individual products or about treatment choices. Figs. 1 to 5 are vector drawings, Fig. 6 is a vector drawing based on our calculation, and the hero image is AI-generated; none of them shows a real product, application or measured value.

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